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Thank you HEALTH CANADA!! Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids

Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids

(PDF Version – 2,236 K)

Dried or fresh plant and oil for administration by ingestion or other means
Psychoactive agent

This document has been prepared by the Cannabis Legalization and Regulation Branch at Health Canada to provide information on the use of cannabis (marihuana) and cannabinoids for medical purposes. This document is a summary of peer-reviewed literature and international reviews concerning potential therapeutic uses and harmful effects of cannabis and cannabinoids. It is not meant to be comprehensive and should be used as a complement to other reliable sources of information. This document is not a systematic review or meta-analysis of the literature and has not rigorously evaluated the quality and weight of the available evidence nor has it graded the level of evidence. Despite the similarity of format, it is not a Drug Product Monograph, which is a document which would be required if the product were to receive a Notice of Compliance authorizing its sale in Canada.

This document should not be construed as expressing conclusions or opinions from Health Canada about the appropriate use of cannabis (marihuana) or cannabinoids for medical purposes.

Cannabis is not an approved therapeutic product, unless a specific cannabis product has been issued a drug identification number (DIN) and a notice of compliance (NOC). The provision of this information should not be interpreted as an endorsement of the use of this product, or cannabis and cannabinoids generally, by Health Canada.

Prepared by Health Canada

Date of latest version: Spring 2018

Reporting Adverse Reactions to Cannabis (marihuana, marijuana) Products

Reporting adverse reactions associated with the use of cannabis and cannabis products is important in gathering much needed information about the potential harms of cannabis and cannabis products for medical purposes. When reporting adverse reactions, please provide as much complete information as possible including the name of the licensed producer, the product brand name, the strain name, and the lot number of the product used in addition to all other information available for input in the adverse reaction reporting form. Providing Health Canada with as much complete information as possible about the adverse reaction will help Health Canada with any follow-ups or actions that may be required.

Any suspected adverse reactions associated with the use of cannabis and cannabis products (dried, oils, fresh) for medical purposes should be reported to the Canada Vigilance Program by one of the following three ways:

  1. Report online
  2. Call toll-free at 1-866-234-2345
  3. Complete a Canada Vigilance Reporting Form and:
    • Fax toll-free to 1-866-678-6789, or
    • Mail to:
      Canada Vigilance Program
      Health Canada
      Postal Locator 0701D
      Ottawa, Ontario K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site.

Table of contents

List of figures and tables

Figures

  • Figure 1.
    The Endocannabinoid System in the Nervous System
  • Figure 2.
    Pharmacokinetics of THC
  • Figure 3.
    A Proposed Clinical Algorithm for Physicians Considering Supporting Therapeutic Use of Cannabis for a Patient with Chronic, Intractable Neuropathic Pain

Tables

  • Table 1.
    Selected Pharmacologic Actions of Cannabis/Psychoactive Cannabinoids
  • Table 2.
    Recommendations for the Evaluation and Management of Patients
  • Table 3.
    Relationship between THC Percent in Plant Material and the Available Dose (in mg THC) in an Average Joint
  • Table 4.
    Comparison between Cannabis and Prescription Cannabinoid Medications
  • Table 5.
    Published Positive, Randomized, Double-Blind, Placebo-Controlled, Clinical Trials on Smoked/Vapourized Cannabis and Associated Therapeutic Benefits

List of abbreviations

2-AG:
2-arachidonoylglycerol
5-ASA:
5-aminosalicylic acid
5-HT:
5-hydroxytryptamine
2-OG:
2-oleoylglycerol
AA:
arachidonic acid
AB:
Alberta
ACCESS:
AIDS Care Cohort to evaluate Exposure to Survival Services
ACE:
angiotensin-converting enzyme
ACMPR:
Access to Cannabis for Medical Purposes Regulations
ACTH:
adrenocorticotropic hormone
AD:
Alzheimer’s disease
AED:
anandamide
AIDS:
acquired immune deficiency syndrome
AKT1:
AKT Serine/Threonine Kinase 1
ALS:
amyotrophic lateral sclerosis
ALSPAC:
Avon Longitudinal Study of Parents and Children
ALT:
alanine transaminase
AMP:
adenosine monophosphate
AOR:
adjusted odds ratio
ApoE:
apolipoprotein E
APP:
amyloid precursor protein
APRI:
AST-to-platelet ratio index
ART:
anti-retroviral therapy
AST:
aspartate transaminase
AUC:
area-under-the-curve
AUC12:
12-hour AUC
Aβ:
amyloid-beta
b.i.d.:
bis in die (i.e. twice per day)
BAC:
blood alcohol concentration
BC:
British Columbia
BCOS:
Bipolar Comprehensive Outcomes Study
BDNF:
brain-derived neurotrophic factor
BDS:
botanical drug substance
BHO:
butane hash oil
BMI:
body mass index
BPI:
Brief Pain Inventory
Ca2+:
calcium
CADUMS:
Canadian Alcohol and Drug Use Monitoring Survey
CAMPS:
Cannabis Access for Medical Purposes Survey
CAMS:
Cannabis in Multiple Sclerosis
CAPS:
Clinician-Administered PTSD Scale
CARDIA:
Coronary Artery Risk Development In young Adults
CB:
cannabinoid
CBC:
cannabichromene
CBD:
cannabidiol
CBDA:
cannabidiolic acid
CBDV:
cannabidivarin
CBG:
cannabigerol
CBN:
cannabinol
CCL:
chemokine (C-C motif) ligand
CDAI:
Crohn’s disease activity index
CDKL5:
cyclin-dependent kinase-like 5 gene
CHS:
cannabis hyperemesis syndrome
CI:
confidence interval
CINV:
chemotherapy-induced nausea and vomiting
CGI-I:
clinical global impression improvement
CGI-S:
clinical global impression scale
cMAS:
combined modified Ashworth score
Cmax:
Maximal concentration of a drug in the blood
CNR1:
cannabinoid receptor 1
CNR2:
cannabinoid receptor 2
CNS:
central nervous system
COMT:
catechol-O-methyltransferase
COX:
cyclo-oxygenase
CRP:
C-reactive protein
CRPS:
complex regional pain syndrome
CSF:
cerebrospinal fluid
CUD:
cannabis use disorder
CUPID:
Cannabinoid Use in Progressive Inflammatory Brain Disease
CYP:
cytochrome P450
D:
duration of action
DAG:
diacylglycerol
DAGL:
diacylglycerol lipase
DAT1:
dopamine active transporter 1
DIO:
diet-induced obesity
DNA:
deoxyribonucleic acid
DNBS:
dinitrobenzene sulfonic acid
DSM-5:
diagnostic and statistical manual of mental disorders (fifth edition)
DSM-IV:
diagnostic and statistical manual of mental disorders (fourth edition)
DUIA:
driving under the influence of alcohol
DUIC:
driving under the influence of cannabis
ECS:
endocannabinoid system
ED50:
median effective dose
EDSP:
Early Developmental Stages of Psychopathology
EDSS:
expanded disability status scale
EEG:
electroencephalogram
e.g.:
for example
EMBLEM:
European Mania in Bipolar Longitudinal Evaluation of Medication
EORTC QLQ-C30:
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core Module
EQ-5D:
EuroQoL five dimensions questionnaire
ESM:
experience sampling methodology
ETA:
ethanolamine
FAACT:
Functional Assessment of Anorexia-Cachexia Therapy
FAAH:
fatty acid amide hydrolase
FEV1:
forced expiratory volume in one second
fMRI:
functional magnetic resonance imaging
FSH:
follicle stimulating hormone
FVC:
forced vital capacity
g:
gram
GABA:
gamma-aminobutyric acid
GAD:
generalized anxiety disorder
GI:
gastrointestinal
GnRH:
gonadotropin-releasing hormone
GPR55:
G protein-coupled receptor 55
GRADE:
Grading of Recommendations, Assessment, Development and Evaluation
GVHD:
graft-versus-host disease
h:
hour
H1-MRS:
proton magnetic resonance spectroscopy
HD:
Huntington’s disease
HDL:
high density lipoprotein
HIV:
human immunodeficiency virus
HMG-CoA:
3-hydroxy-3-methyl-glutaryl-coenzyme A
HMO:
health maintenance organization
HOMA-IR:
homeostatic model assessment of insulin resistance
HPA:
hypothalamic-pituitary-adrenal
HPO:
hypothalamic-pituitary-ovarian
HRQoL:
health-related quality of life
I.M.:
intramuscular
I.P.:
intraperitoneal
I.V.:
intravenous
IBD:
inflammatory bowel disease
IBS:
irritable bowel syndrome
IBS-A:
alternating pattern (alternation constipation/diarrhea) IBS
IBS-C:
constipation-predominant IBS
IBS-D:
diarrhea-predominant IBS
IC50:
median inhibitory concentration
ICAM-1:
intercellular adhesion molecule-1
ICD:
International Classification of Diseases
ICM:
inner cell mass
IFN:
interferon
IL:
interleukin
IND:
investigational new drug
iNOS:
inducible nitric oxide synthase
IOP:
intraocular pressure
IQ:
intelligence quotient
IQR:
interquartile range
IRR:
incident rate ratio
K+:
potassium
kg:
kilogram
L:
liter
LCT:
lipid long-chain triglyceride
LD50:
median lethal dose
LDL:
low density lipoprotein
LH:
luteinizing hormone
LOX:
lipo-oxygenase
MAGL:
monoacylglycerol lipase
MB:
Manitoba
Met:
methionine
mg:
milligram
min:
minute
miRNA:
micro ribonucleic acid
mL:
milliliter
MMP:
matrix metalloproteinase
MOVE 2:
Mobility Improvement in MS-Induced Spasticity Study
mRNA:
messenger ribonucleic acid
MS:
multiple sclerosis
MSIS-29:
MS Impact Scale 29
MUSEC:
Multiple Sclerosis and Extract of Cannabis trial
N/A:
not applicable
Na+:
sodium
NAFLD:
non-alcoholic fatty liver disease
NAPE:
N-arachidonoylphosphatidylethanolamine
NASEM:
National Academy of Sciences, Engineering and Medicine
NB:
New Brunswick
NCS:
National Comorbidity Survey
NCS-R:
National Comorbidity Survey-Replication
NEMESIS:
Netherlands Mental Health Survey and Incidence Study
NESARC:
National Epidemiological Survey on Alcohol and Related Conditions
ng:
nanogram
NHANES:
National Health and Nutrition Examination Survey
NK:
natural killer
NK-1:
neurokinin 1
NL:
Newfoundland and Labrador
nM:
nanomolar
NMDA:
N-methyl-D-aspartic acid
nmol:
nanomole
NNT:
number needed to treat
NRG1:
neuregulin 1
NRS:
numerical rating scale
NRS-PI:
numerical rating scale for pain intensity
NS:
Nova Scotia
NSAIDs:
nonsteroidal anti-inflammatory drugs
NSDUH:
National Survey on Drug Use and Health
NT:
Northwest Territories
NU:
Nunavut
O:
onset of effects
OA:
osteoarthritis
OEA:
oleoylethanolamide
ON:
Ontario
OR:
odds ratio
P:
peak effects
PE:
Prince Edward Island
P.O.:
oral administration
PD:
Parkinson’s disease
PDQ-39:
39-Item Parkinson Disease Questionnaire
PEA:
palmitoylethanolamide
PLD:
phospholipase-D
pNRS:
pain numerical rating score
PPAR:
peroxisome proliferator-activated receptor
PRISMA:
Preferred Reporting Items for Sytematic Reviews and Meta-Analyses
PTSD:
post-traumatic stress disorder
PWID:
people who inject drugs
QC:
Quebec
q.i.d.:
quater in die (i.e. four times per day)
QoL:
quality of life
RA:
rheumatoid arthritis
RCT:
randomized controlled trial
REM:
rapid eye movement
RNA:
ribonucleic acid
Rx:
prescription
s:
second
SAFTEE:
Systematic Assessment of Treatment Emergent Events
s.c.:
subcutaneous
SCI:
spinal cord injury
SD:
standard deviation
SDLP:
standard deviation of lateral position
SF-36:
36-Item Short Form Health Survey
SIBDQ:
short IBD questionnaire
SIV:
simian immunodeficiency virus
SK:
Saskatchewan
SNP:
single nucleotide polymorphism
sNRS:
subjective numerical rating spasticity scale
S-TOPS:
Short-Form Treatment Outcomes in Pain Survey
SYS:
Saguenay Youth Study
t.i.d.:
ter in die (i.e. three times per day)
TGCT:
testicular germ cell tumours
THC:
delta-9-tetrahydrocannabinol
THCA:
tetrahydrocannabinolic acid
THCV:
tetrahydrocannabivarin
TIA:
transient ischemic attack
Tmax:
Time to maximal blood concentration of a drug
TNBS:
trinitrobenzene sulfonic acid
TNF:
tumor necrosis factor
TRH:
thyrotropin-releasing hormone
TRP:
transient receptor potential
TRPV1:
transient receptor potential vanilloid channel 1
TS:
Tourette’s syndrome
TWSTRS:
Toronto Western Spasmodic Torticollis Rating Scale
U.K.:
United Kingdom
UPDRS:
Unified Parkinson’s Disease Rating Scale
Val:
valine
VAS:
visual analogue scale
VCAM-1:
vascular cellular adhesion molecule-1
w/w:
weight/weight
WHO:
World Health Organization
YT:
Yukon
Δ9-THC:
delta-9-tetrahydrocannabinol
µg:
microgram
μM:
micromolar

Authorship and acknowledgements

Author: Hanan Abramovici Ph.D.
Co-authors: Sophie-Anne Lamour, Ph.D.: and George Mammen, Ph.D.

Affiliations:
Cannabis Legalization and Regulation Branch, Health Canada, Ottawa, ON, Canada K1A 0K9
Email: hanan.abramovici@canada.ca

Acknowledgements:
Health Canada would like to acknowledge and thank the following individuals for their comments and suggestions with regard to the content in this information document:

Donald I. Abrams, M.D.
Chief, Hematology-Oncology
San Francisco General Hospital
Integrative Oncology
UCSF Osher Center for Integrative Medicine
Professor of Clinical Medicine
University of California San Francisco
San Francisco, CA 94143-0874
USA

Pierre Beaulieu, M.D., Ph.D., F.R.C.A.
Full professor
Department of Pharmacology and Anesthesiology
Faculty of Medicine
University of Montreal
Office R-408, Roger-Gaudry Wing
P.O. Box 6128 – Downtown Branch
Montréal, Québec
H3C 3J7
Canada

Bruna Brands, Ph.D.
Full Professor
Department of Pharmacology and Toxicology
Program Director, Collaborative Program in Addiction Studies
University of Toronto
33 Russell Street
Toronto, ON
M5S 2S1
Canada

Ziva Cooper, Ph.D.
Assistant Professor of Clinical Neurobiology
Division on Substance Abuse
New York State Psychiatric Institute and Department of Psychiatry
College of Physicians and Surgeons Columbia University
1051 Riverside Drive
New York, NY 10032
USA

Paul J. Daeninck, M.D., M.Sc., F.R.C.P.C.
Chair, Symptom Management and Palliative Care Disease Site Group
CancerCare Manitoba
Assistant Professor,
College of Medicine, University of Manitoba
St. Boniface Hospital
409 Taché Ave
Winnipeg, MB
R2H 2A6
Canada

Mahmoud A. ElSohly, Ph.D.
Research Professor and Professor of Pharmaceutics
National Center for Natural Products Research and Department of Pharmaceutics
School of Pharmacy
University of Mississippi
University, MS 38677
USA

Javier Fernandez-Ruiz, Ph.D.
Full Professor of Biochemistry and Molecular Biology
Department of Biochemistry and Molecular Biology
Faculty of Medicine
Complutense University
Madrid, 28040
Spain

Tony P. George, M.D., F.R.C.P.C.
Professor and Co-Director, Division of Brain and Therapeutics
Department of Psychiatry, University of Toronto
Chief, Schizophrenia Division
Centre for Addiction and Mental Health
1001 Queen Street West, Unit 2, Room 118A
Toronto, ON
M6J 1H4
Canada

Manuel Guzman, Ph.D.
Full Professor
Department of Biochemistry and Molecular Biology
Faculty of Chemistry
Complutense University
Madrid, 28040
Spain

Matthew N. Hill, Ph.D.
Assistant Professor
Departments of Cell Biology and Anatomy & Psychiatry
The Hotchkiss Brain Institute
University of Calgary
Calgary, AB
T2N 4N1
Canada

Cecilia J. Hillard, Ph.D.
Professor
Department of Pharmacology and Toxicology
Director of the Neuroscience Research Center
Medical College of Wisconsin
8701 Watertown Plank Road
Milwaukee, Wisconsin 53226
USA

Mary Lynch, M.D., F.R.C.P.C.
Professor of Anaesthesia, Psychiatry and Pharmacology
Dalhousie University
Director, Pain Management Unit-Capital Health
Queen Elizabeth II Health Sciences Centre
4th Floor Dickson Building
5820 University Avenue
Halifax, NS
B3H 1V7
Canada

Jason J. McDougall, Ph.D.
Professor
Departments of Pharmacology and Anaesthesia, Pain Management & Perioperative Medicine
Dalhousie University
5850 College Street
Halifax, NS
B3H 4R2
Canada

Raphael Mechoulam, Ph.D.
Professor
Institute for Drug Research, Medical Faculty
Hebrew University
Jerusalem
91120
Israel

Linda Parker, Ph.D.
Professor and Canada Research Chair
Department of Psychology
University of Guelph
Guelph, Ontario
N1G 2W1
Canada

Roger G. Pertwee, MA, D.Phil. D.Sc.
Professor of Neuropharmacology
Institute of Medical Sciences
University of Aberdeen
Aberdeen
AB25 2ZD
Scotland, United Kingdom

Keith Sharkey, Ph.D.
Professor
Department of Physiology and Biophysics and Medicine
University of Calgary
HSC 1745
3330 Hospital Drive NW
Calgary, AB
T2N 4N1
Canada

Mark Ware, M.D., M.R.C.P., M.Sc.
Associate professor
Departments of Anesthesia and Family Medicine
McGill University
Director of Clinical Research
Alan Edwards Pain Management Unit
A5.140 Montreal General Hospital
1650 Cedar Avenue
Montréal, Québec
H3G 1A4
Canada

Overview of Summary Statements

The following bullet-point statements are meant to summarize the content found within sections 4.0 (Potential Therapeutic Uses) and 7.0 (Adverse Effects) and their respective subsections. The bullet-point statements can also be found in their respective sections and sub-sections in the body of the document itself. Note: most, but not all, clinical studies of cannabis (experimental or therapeutic) have been conducted with dried cannabis containing more THC than CBD and typically, but not always, with lower-potency THC (< 9% THC). Furthermore, the majority of the clinical studies of cannabis (experimental or therapeutic) have administered dried cannabis by smoking. Lastly, the findings from clinical studies of cannabis for therapeutic purposes may not be applicable to other chemotypes of cannabis or other cannabis products with different THC and CBD amounts and ratios.

4.0 Potential Therapeutic Uses

4.1 Palliative care

  • The evidence thus far from some observational studies and clinical studies suggests that cannabis (limited evidence) and prescription cannabinoids (e.g. dronabinol, nabilone, or nabiximols) may be useful in alleviating a wide variety of single or co-occurring symptoms often encountered in the palliative care setting.
  • These symptoms may include, but are not limited to, intractable nausea and vomiting associated with chemotherapy or radiotherapy, anorexia/cachexia, severe intractable pain, severe depressed mood and anxiety, and insomnia.
  • A limited number of observational studies suggest that the use of cannabinoids for palliative care may also potentially be associated with a decrease in the number of some medications used by this patient population.

4.2 Quality of life

  • The available clinical studies report mixed effects of cannabis and prescription cannabinoids on measures of quality of life (QoL) for a variety of different disorders.

4.3 Chemotherapy-induced nausea and vomiting

  • Pre-clinical studies show that certain cannabinoids (THC, CBD, THCV, CBDV) and cannabinoid acids (THCA and CBDA) suppress acute nausea and vomiting as well as anticipatory nausea.
  • Clinical studies suggest that certain cannabinoids and cannabis (limited evidence) use may provide relief from chemotherapy-induced nausea and vomiting (CINV).

4.4 Wasting syndrome (cachexia, e.g., from tissue injury by infection or tumour) and loss of appetite (anorexia) in AIDS and cancer patients, and anorexia nervosa

  • The available evidence from human clinical studies suggests that cannabis (limited evidence) and dronabinol may increase appetite and caloric intake, and promote weight gain in patients with HIV/AIDS.
  • However the evidence for dronabinol is mixed and effects modest for patients with cancer and weak for patients with anorexia nervosa.

4.5 Multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury and disease

  • Evidence from pre-clinical studies suggests THC, CBD and nabiximols improve multiple sclerosis (MS) associated symptoms of tremor, spasticity and inflammation.
  • The available evidence from clinical studies suggest cannabis (limited evidence) and certain cannabinoids (dronabinol, nabiximols, THC/CBD) are associated with some measure of improvement in symptoms encountered in MS and spinal cord injury (SCI) including spasticity, spasms, pain, sleep and symptoms of bladder dysfunction.
  • Very limited evidence from pre-clinical studies suggest that certain cannabinoids modestly delay disease progression and prolong survival in animal models of amyotrophic lateral sclerosis (ALS), while the results from a very limited number of clinical studies are mixed.

4.6 Epilepsy

  • Anecdotal evidence suggests an anti-epileptic effect of cannabis (THC- and CBD-predominant strains).
  • The available evidence from pre-clinical studies suggests certain cannabinoids (CBD) may have anti-epileptiform and anti-convulsive properties, whereas CB1R agonists (THC) may have either pro- or anti-epileptic properties.
  • However, the clinical evidence for an anti-epileptic effect of cannabis is weaker, but emerging, and requires further study.
  • Evidence from clinical studies with Epidiolex® (oral CBD) suggest efficacy and tolerability of Epidiolex® for drug-resistant seizures in treatment-resistant Dravet syndrome or Lennox-Gastaut syndrome.
  • Evidence from observational studies suggest an association between CBD (in herbal and oil preparations) and a reduction in seizure frequency as well as an increase in quality of life among adolescents with rare and serious forms of drug-resistant epilepsy.
  • Epidiolex® has received FDA approval (in June 2018) for use in patients 2 years of age and older to treat treatment-resistant seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

4.7 Pain

4.7.1 Acute pain

  • Pre-clinical studies suggest that certain cannabinoids can block the response to experimentally-induced acute pain in animal models.
  • The results from clinical studies with smoked cannabis, oral THC, cannabis extract, and nabilone in experimentally-induced acute pain in healthy human volunteers are limited and mixed and suggest a dose-dependent effect in some cases, with lower doses of THC having an analgesic effect and higher doses having a hyperalgesic effect.
  • Clinical studies of certain cannabinoids (nabilone, oral THC, levonontradol, AZD1940, GW842166) for post-operative pain suggest a lack of efficacy.

4.7.2 Chronic pain

4.7.2.1 Experimentally-induced inflammatory and chronic neuropathic pain

  • Endocannabinoids, THC, CBD, nabilone and certain synthetic cannabinoids have all been identified as having an anti-nociceptive effect in animal models of chronic pain (inflammatory and neuropathic).

4.7.2.2. Neuropathic pain and chronic non-cancer pain in humans

  • A few studies that have used experimental methods having predictive validity for pharmacotherapies used to alleviate chronic pain, have reported an analgesic effect of smoked cannabis.
  • Furthermore, there is more consistent evidence of the efficacy of cannabinoids (smoked/vapourized cannabis, nabiximols, dronabinol) in treating chronic pain of various etiologies, especially in cases where conventional treatments have been tried and have failed.

4.7.2.3 Cancer pain

  • The limited available clinical evidence with certain cannabinoids (dronabinol, nabiximols) suggests a modest analgesic effect of dronabinol and a modest and mixed analgesic effect of nabiximols on cancer pain.

4.7.2.4 “Opioid-sparing” effects and cannabinoid-opioid synergy

  • While pre-clinical and case studies suggest an “opioid-sparing” effect of certain cannabinoids, epidemiological and clinical studies with oral THC and nabiximols are mixed.
  • Observational studies suggest an association between U.S. states with laws permitting access to cannabis (for medical and non-medical purposes) and lowered rates of prescribed opioids and opioid-associated mortality.

4.7.2.5 Headache and migraine

  • The evidence supporting using cannabis/certain cannabinoids to treat headache and migraine is very limited and mixed.

4.8. Arthritides and musculoskeletal disorders

  • The evidence from pre-clinical studies suggests stimulation of CB1 and CB2 receptors alleviates symptoms of osteoarthritis (OA), and THC and CBD alleviate symptoms of rheumatoid arthritis (RA).
  • The evidence from clinical studies is very limited, with a modest effect of nabiximols for RA.
  • There are no clinical studies of cannabis for fibromyalgia, and the limited clinical evidence with dronabinol and nabilone suggest a modest effect on decreasing pain and anxiety, and improving sleep.
  • The role of cannabinoids in osteoporosis has only been investigated pre-clinically and is complex and conflicting.

4.9 Other diseases and symptoms

4.9.1 Movement disorders

4.9.1.1 Dystonia

  • Evidence from limited pre-clinical studies suggests that a synthetic CBand CB2 receptor agonist may alleviate dystonia-like symptoms, and CBD delays dystonia progression.
  • Evidence from a limited number of case studies and small placebo-controlled or open-label clinical trials suggests improvement in symptoms of dystonia with inhaled cannabis, mixed effects of oral THC, improvement in symptoms of dystonia with oral CBD, and lack of effect of nabilone on symptoms of dystonia.

4.9.1.2 Huntington’s disease

  • Evidence from pre-clinical studies reports mixed results with THC on Huntington’s disease (HD)-like symptoms.
  • Limited evidence from case studies and small clinical trials is mixed and suggests a lack of effect with CBD, nabilone and nabiximols, and a limited improvement in HD symptoms with smoked cannabis.

4.9.1.3 Parkinson’s disease

  • The evidence from a limited number of pre-clinical, case, clinical and observational studies of certain cannabinoids for symptoms of Parkinson’s disease (PD) is mixed.
  • One case study of smoked cannabis suggests no effect while an observational study of smoked cannabis suggests improvement in symptoms.
  • One small clinical study of nabilone suggests improvement in symptoms, while another clinical study of an oral cannabis extract (THC/CBD) and a clinical study with CBD suggest no improvement in symptoms.

4.9.1.4 Tourette’s syndrome

  • The limited evidence from small clinical studies suggests that oral THC improves certain symptoms of Tourette’s syndrome (TS) (tics).

4.9.2 Glaucoma

  • The limited evidence from small clinical studies suggests oral administration of THC reduces intra-ocular pressure (IOP) while oral administration of CBD may, in contrast, cause an increase in IOP.

4.9.3 Asthma

  • The limited evidence from pre-clinical and clinical studies on the effect of aerosolized THC on asthmatic symptoms is mixed.
  • Inhalation of lung irritants generated from smoking/vapourizing cannabis may worsen asthmatic symptoms.

4.9.5 Stress and psychiatric disorders

4.9.5.1 Anxiety and depression

  • Evidence from pre-clinical and clinical studies suggests that THC exhibits biphasic effects on mood, with low doses of THC having anxiolytic and mood-elevating effects and high doses of THC having anxiogenic and mood-lowering effects.
  • Limited evidence from a small number of clinical studies of THC-containing cannabis/certain prescription cannabinoids suggests that these drugs could improve symptoms of anxiety and depression in patients suffering from anxiety and/or depression secondary to certain chronic diseases (e.g. patients with HIV/AIDS, MS, and chronic neuropathic pain).
  • Evidence from pre-clinical studies suggests that CBD exhibits anxiolytic effects in various animal models of anxiety, while limited evidence from clinical studies suggest CBD may have anxiolytic effects in an experimental model of social anxiety.
  • Limited evidence from some observational studies also suggests that cannabis containing equal proportions of CBD and THC is associated with an attenuation of some perturbations in mood (anxiety/dejection) seen with THC-predominant cannabis in patients using cannabis for medical purposes.

4.9.5.2 Sleep disorders

  • Human experimental data suggests cannabis and THC have a dose-dependent effect on sleep-low doses appear to decrease sleep onset latency and increase slow-wave sleep and total sleep time, while high doses appear to cause sleep disturbances.
  • Limited evidence from clinical studies also suggest that certain cannabinoids (cannabis, nabilone, dronabinol, nabiximols) may improve sleep in patients with disturbances in sleep associated with certain chronic disease states.

4.9.5.3 Post-traumatic stress disorder

  • Pre-clinical and human experimental studies suggest a role for certain cannabinoids in alleviating post-traumatic stress disorder (PTSD)-like symptoms.
  • However, while limited evidence from short-term clinical studies suggests a potential for oral THC and nabilone to decrease certain symptoms of PTSD, there are no long-term clinical studies for these preparations or any clinical studies of smoked/vapourized cannabis for PTSD.
  • Limited evidence from observational studies suggests an association between herbal cannabis use and persistent/high levels of PTSD symptom severity over time.
  • There is limited evidence to suggest an association between PTSD and CUD.

4.9.5.4 Alcohol and opioid withdrawal symptoms (drug withdrawal symptoms/drug substitution)

  • Pre-clinical studies suggest CB1 receptor agonism (e.g. THC) may help increase the reinforcing properties of alcohol, increase alcohol consumption, and increase risk of relapse of alcohol use, as well as exacerbate alcohol withdrawal symptom severity.
  • Pre-clinical studies suggest certain cannabinoids (e.g. THC) may alleviate opioid withdrawal symptoms.
  • Evidence from observational studies suggests that cannabis use could help alleviate opioid withdrawal symptoms, but there is insufficient clinical evidence from which to draw any reliable conclusions.

4.9.5.5 Schizophrenia and psychosis

  • Significant evidence from pre-clinical, clinical and epidemiological studies supports an association between cannabis (especially THC-predominant cannabis) and THC, and an increased risk of psychosis and schizophrenia.
  • Emerging evidence from pre-clinical, clinical and epidemiological studies suggests CBD may attenuate THC-induced psychosis.

4.9.6 Alzheimer’s disease and dementia

  • Pre-clinical studies suggest that THC and CBD may protect against excitotoxicity, oxidative stress and inflammation in animal models of Alzheimer’s disease (AD).
  • Limited case, clinical and observational studies suggest that oral THC and nabilone are associated with improvement in a number of symptoms associated with AD (e.g. nocturnal motor activity, disturbed behaviour, sleep, agitation, resistiveness).

4.9.7 Inflammation

4.9.7.1 Inflammatory skin diseases (dermatitis, psoriasis, pruritus)

  • The results from pre-clinical, clinical and case studies on the role of certain cannabinoids in the modulation of inflammatory skin diseases are mixed.
  • Some clinical and prospective case series studies suggest a protective role for certain cannabinoids (THC, CBD, HU-210), while others suggest a harmful role (cannabis, THC, CBN).

4.9.8 Gastrointestinal system disorders (irritable bowel syndrome, inflammatory bowel disease, hepatitis, pancreatitis, metabolic syndrome/obesity)

4.9.8.1 Irritable bowel syndrome

  • Pre-clinical studies in animal models of irritable bowel syndrome (IBS) suggest that certain synthetic cannabinoid receptor agonists inhibit colorectal distension-induced pain responses and slow GI transit.
  • Experimental clinical studies with healthy volunteers reported dose- and sex-dependent effects on various measures of GI motility.
  • Limited evidence from one small clinical study with dronabinol for symptoms of IBS suggests dronabinol may increase colonic compliance and decrease colonic motility index in female patients with diarrhea-predominant IBS (IBS-D) or with alternating pattern (alternating constipation/diarrhea) IBS (IBS-A), while another small clinical study with dronabinol suggests a lack of effect on gastric, small bowel or colonic transit.

4.9.8.2 Inflammatory bowel diseases (Crohn’s disease, ulcerative colitis)

  • Pre-clinical studies in animal models of inflammatory bowel disease (IBD) suggest that certain cannabinoids (synthetic CB1 and CB2 receptor agonists, THC, CBD, CBG, CBC, whole plant cannabis extract) may limit intestinal inflammation and disease severity to varying degrees.
  • Evidence from observational studies suggests that patients use cannabis to alleviate symptoms of IBD.
  • A very limited number of small clinical studies with patients having IBD and having failed conventional treatments reported improvement in a number of IBD-associated symptoms with smoked cannabis.

4.9.8.3 Diseases of the liver (hepatitis, fibrosis, steatosis, ischemia-reperfusion injury, hepatic encephalopathy)

  • Pre-clinical studies suggest CB1 receptor activation is detrimental in liver diseases (e.g. promotes steatosis, fibrosis); while CB2 receptor activation appears to have some beneficial effects.
  • Furthermore, pre-clinical studies also suggest that CBD, THCV and ultra-low doses of THC may have some protective effects in hepatic ischemia-reperfusion injury and hepatic encephalopathy.

4.9.8.4 Metabolic syndrome, obesity, diabetes

  • Pre-clinical studies suggest acute CB1 receptor activation results in increased fat synthesis and storage while chronic CB1 receptor activation (or CB1receptor antagonism) results in weight loss and improvement in a variety of metabolic indicators.
  • Observational studies suggest an association between chronic cannabis use and an improved metabolic profile, while pre-clinical and very limited clinical evidence suggests a potential beneficial effect of THCV on glycemic control (in patients with type II diabetes).

4.9.8.5 Diseases of the pancreas (diabetes, pancreatitis)

  • Pre-clinical studies in experimental animal models of certain cannabinoids in the treatment of acute or chronic pancreatitis are limited and conflicting.
  • Limited evidence from case studies suggests an association between acute episodes of heavy cannabis use and acute pancreatitis.
  • Limited observational studies suggest an association between chronic cannabis use and lower incidence of diabetes mellitus.
  • One small clinical study reported that orally administered THC did not alleviate abdominal pain associated with chronic pancreatitis.

4.9.9 Anti-neoplastic properties

  • Pre-clinical studies suggest that certain cannabinoids (THC, CBD, CBG, CBC, CBDA) often, but not always block growth of cancer cells in vitro and display a variety of anti-neoplastic effects in vivo, though typically at very high doses that would not be seen clinically.
  • While limited evidence from one observational study suggests cancer patients use cannabis to alleviate symptoms associated with cancer (e.g. chemosensory alterations, weight loss, depression, pain), there has only been one limited clinical study in patients with glioblastoma multiforme, which reported that intra-tumoural injection of high doses of THC did not improve patient survival beyond that seen with conventional chemotherapeutic agents.

7.0 Adverse effects

7.1 Carcinogenesis and mutagenesis

  • Evidence from pre-clinical studies suggests cannabis smoke contains many of the same carcinogens and mutagens as tobacco smoke and that cannabis smoke is as mutagenic and cytotoxic, if not more so, than tobacco smoke.
  • However, limited and conflicting evidence from epidemiological studies has thus far been unable to find a robust and consistent association between cannabis use and various types of cancer, with the possible exception of a link between cannabis use and testicular cancer (i.e. testicular germ cell tumours).

7.2 Respiratory tract

  • Evidence from pre-clinical studies suggests that cannabis smoke contains many of the same respiratory irritants and toxins as tobacco smoke, and even greater quantities of some such substances.
  • Case studies suggest that cannabis smoking is associated with a variety of histopathological changes in respiratory tissues, a variety of respiratory symptoms similar to those seen in tobacco smokers, and changes in certain lung functions with frequent, long-term use.
  • The association between chronic heavy cannabis smoking (without tobacco) and chronic obstructive pulmonary disease, is unclear, but if there is one, is possibly small.

7.3 Immune system

  • Pre-clinical studies suggest certain cannabinoids have a variety of complex effects on immune system function (pro-/anti-inflammatory, stimulatory/inhibitory).
  • The limited clinical and observational studies of the effects of cannabis on immune cell counts and effect on HIV viral load are mixed, as is the evidence around frequent cannabis use (i.e. daily/CUD) and adherence to ART.
  • Limited but increasing evidence from case studies also suggests cannabis use is associated with allergic/hypersensitivity-type reactions.

7.4 Reproductive and endocrine systems

  • Pre-clinical evidence suggests certain cannabinoids can have negative effects on a variety of measures of reproductive health. Furthermore, limited evidence from human observational studies with cannabis appears to support evidence from some pre-clinical studies.
  • Evidence from human observational studies also suggests a dose- and age-dependent association between cannabis use and testicular germ cell tumours.
  • Pre-clinical evidence clearly suggests in utero exposure to certain cannabinoids is associated with a number of short and long-term harms to the developing offspring.
  • However, evidence from human observational studies is complex and suggests that while confounding factors may account for associations between heavy cannabis use during pregnancy and adverse neonatal or perinatal effects, heavy cannabis use during pregnancy is associated with reduced neonatal birth weight.

7.5 Cardiovascular system

  • Pre-clinical studies suggest that ultra-low doses of THC may be cardioprotective on experimentally-induced myocardial infarction.
  • Evidence from case and observational studies suggests that acute and chronic smoking of cannabis is associated with harmful effects on vascular, cardiovascular and cerebrovascular health (e.g. myocardial infarction, strokes, arteritis) especially in middle-aged (and older) users.
  • However, a recent systematic review suggests that evidence examining the effects of cannabis on cardiovascular health is inconsistent and insufficient.

7.6 Gastrointestinal system and liver

  • Evidence from case reports suggests chronic, heavy (THC-predominant) cannabis use is associated with an increased risk of cannabis hyperemesis syndrome (CHS).
  • Limited evidence from observational studies suggests mixed findings between (THC-predominant) cannabis use and risk of liver fibrosis progression associated with hepatitis C infection.

7.7 Central nervous system

7.7.1 Cognition

  • Evidence from clinical studies suggests acute (THC-predominant) cannabis use is associated with a number of acute cognitive effects.
  • Evidence from observational studies suggests chronic cannabis use is associated with some cognitive and behavioural effects that may persist for varying lengths of time beyond the period of acute intoxication depending on a number of factors.
  • Limited evidence from human clinical imaging studies suggests THC and CBD may exert opposing effects on neuropsychological/neurophysiological functioning.
  • Evidence from mainly cross-sectional human clinical imaging studies suggests heavy, chronic cannabis use is associated with a number of structural changes in grey and white matter in different brain regions.
  • Furthermore, early-onset use and use of high-potency, THC-predominant cannabis, has been associated with an increased risk of some brain structural changes and cognitive impairment.

7.7.2 Psychomotor performance and driving

  • Evidence from experimental clinical studies suggests acute use of (THC-predominant) cannabis impairs a number of psychomotor and other cognitive skills needed to drive a motor vehicle.
  • While chronic/frequent cannabis use may be associated with a degree of tolerance to some of the effects of cannabis in some individuals, chronic cannabis use can still pose risks to safe driving due, in part, to significant body burden of THC leading to a chronic level of psychomotor impairment.
  • Evidence from clinical and epidemiological studies suggests a dose-response effect, with increasing doses of THC increasing the risk of motor vehicle crashes that can lead to injuries and death.
  • Combining alcohol with cannabis (THC) is associated with an increased degree of impairment and increased risk of harm.

7.7.3 Psychiatric effects

7.7.3.1 Anxiety, PTSD, depression and bipolar disorder

  • Evidence from clinical studies suggests a dose-dependent, bi-phasic effect of THC on anxiety and mood, where low doses of THC appear to have an anti-anxiety and mood-elevating effect whereas high doses of THC can produce anxiety and lower mood.
  • Epidemiological studies suggest an association between (THC-predominant) cannabis use, especially chronic, heavy use and the onset of anxiety, depressive and bipolar disorders, and the persistence of symptoms related to PTSD, panic disorder, depressive disorder, and bipolar disorder.
  • Preliminary evidence from surveys suggests an association between use of ultra-high-potency cannabis concentrate products (e.g. butane hash oil, BHO) and higher rates of self-reported anxiety and depression and other illicit drug use as well as higher levels of physical dependence than with high-potency herbal cannabis.

7.7.3.2 Schizophrenia and psychosis

  • Evidence from clinical studies suggests that acute exposure to (THC-predominant) cannabis or THC is associated with dose-dependent, acute and transient behavioural and cognitive effects mimicking acute psychosis.
  • Epidemiological studies suggest an association between (THC-predominant) cannabis use, especially early, chronic, and heavy use and psychosis and schizophrenia.
  • The risk of schizophrenia associated with cannabis use is especially high in individuals who have a personal or family history of schizophrenia.
  • Cannabis use is also associated with earlier onset of schizophrenia in vulnerable individuals and exacerbation of existing schizophrenic symptoms and worse clinical outcomes.

7.7.3.3 Suicidal ideation, attempts and mortality

  • Evidence from epidemiological studies also suggests a dose-dependent association between cannabis use and suicidality, especially in men.

7.7.3.4 Amotivational syndrome

  • The available limited evidence for an association between cannabis use and an “amotivational syndrome” is mixed.

Important Note: For the sake of completeness and for contextual purposes, the content in the following document includes information on dried cannabis and other cannabis-based products as well as selected cannabinoids. However, cannabis products and cannabinoids should not be considered equivalent even though the information on such products is presented together within the text. Cannabis and cannabis products are highly complex materials with hundreds of chemical constituents whereas cannabinoids are typically single molecules. Drawing direct comparisons between cannabis products and cannabinoids must necessarily take into account differences in the route of administration, dosage, individual pharmacological components and their potential interactions, and the different pharmacokinetic and pharmacodynamic properties of these different substances.

1.0 The Endocannabinoid System

The endocannabinoid system (ECS) (Figure 1) is an ancient, evolutionarily conserved, and ubiquitous lipid signaling system found in all vertebrates, and which appears to have important regulatory functions throughout the human bodyReference1. The ECS has been implicated in a very broad number of physiological as well as pathophysiological processes including nervous system development, immune function, inflammation, appetite, metabolism and energy, homeostasis, cardiovascular function, digestion, bone development and bone density, synaptic plasticity and learning, pain, reproduction, psychiatric disease, psychomotor behaviour, memory, wake/sleep cycles, and the regulation of stress and emotional state/moodReference2Reference4. Furthermore, there is strong evidence that dysregulation of the ECS contributes to many human diseases including pain, inflammation, psychiatric disorders and neurodegenerative diseasesReference5.

Components of the endocannabinoid system

The ECS consists mainly of: the cannabinoid 1 and 2 (CB1 and CB2) receptors; the cannabinoid receptor ligands N-arachidonoylethanolamine (“anandamide”) and 2-arachidonoylglycerol (2-AG); the endocannabinoid-synthesizing enzymes N-acyltransferase, phospholipase D, phospholipase C-β and diacylglycerol-lipase (DAGL); and the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) (Figure 1)Reference2. Anandamide and 2-AG are considered the primary endogenous activators of cannabinoid signaling, but other endogenous molecules, which exert “cannabinoid-like” effects, have also been described. These other molecules include 2-arachidonoylglycerol ether (noladin ether), N -arachidonoyl-dopamine, virodhamine, N -homo-γ-linolenoylethanolamine and N-docosatetraenoylethanolamineReference2Reference6Reference9. Other molecules such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) do not appear to bind to cannabinoid receptors but rather to a specific isozyme belonging to a class of nuclear receptors/transcription factors known as peroxisome proliferator-activated receptors (PPARs)Reference9. These fatty acyl ethanolamides may, however, potentiate the effect of anandamide by competitive inhibition of FAAH, and/or through direct allosteric effects on other receptors such as the transient receptor potential vanilloid (TRPV1) channelReference10. This type of effect has been generally referred to as the so-called “entourage effect”Reference10Reference11. The term “entourage effect” is also used in the context of the interactions between phytocannabinoids and terpenes in a physiological system (see Section 1.1.2).

Endocannabinoid synthesis

Endocannabinoids are arachidonic acid derivatives which are synthesized “on demand” (e.g. in response to an action potential in neurons or in response to another type of biological stimulus) from membrane phospholipid precursors in response to cellular requirementsReference2Reference12Reference14. Synthesis of endocannabinoids “on demand” ensures that endocannabinoid signaling is tightly controlled both spatially and temporally. Anandamide is principally, but not exclusively, produced by the transfer of arachidonic acid from phosphatidylcholine to phosphatidylethanolamine by N-acyltransferase to yield N-arachidonoylphosphatidylethanolamine (NAPE). NAPE is then hydrolyzed to form anandamide by a NAPE-specific phospholipase DReference2Reference15. Other synthetic routes include acyl-chain removal from NAPE by α/β-hydrolase 4 to yield glycerophospho-N-arachidonoylethanolamine followed by phosphodiester bond hydrolysis of glycerophospho-N-arachidonoylethanolamine by phosphodiesterase 1 to yield anandamideReference16. In contrast, 2-AG is principally synthesized through phospholipase C-β-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate, with arachidonic acid on the sn-2 position, to yield diacylglycerol (DAG). DAG is then hydrolyzed to 2-AG by a DAGLReference2Reference15. While anandamide and 2-AG are both derivatives of arachidonic acid, they are synthesized by pathways distinct from those used to synthesize eicosanoidsReference17. Nevertheless, it appears that there may be a certain amount of cross talk between the eicosanoid and endocannabinoid pathwaysReference17.

Genetics and signaling through the cannabinoid receptors

Endocannabinoids such as anandamide and 2-AG, as well as the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-THC, cannabinol (CBN) and others, bind to and activate (with differing affinities and efficacies) the CB1 and CB2 receptors which are G-protein coupled receptors that activate Gi/Go-dependent signaling cascadesReference18Reference19. The receptors are encoded by separate genes located on separate chromosomes; in humans, the CB1 receptor gene (CNR1) locus is found on chromosome 5q15 whereas the CB2 receptor gene (CNR2) locus is located on chromosome 1p36Reference20. The CNR1 coding sequence consists of one exon encoding a protein of 472 amino acidsReference21. The CB1 receptor protein shares 97 – 99% amino acid sequence identity across species (human, rat, mouse)Reference21. As with the CNR1 coding sequence, the CNR2 coding sequence consists of only one exon, but it encodes a shorter protein 360 amino acids in lengthReference21. The human CB2 receptor shares 48% amino acid identity with the human CB1 receptor; the mouse CB2 receptor shares 82% amino acid sequence identity with the human CB2 receptorReference21.

Activation of the CB1 or CB2 Gi/o-protein coupled receptors results in inhibition of adenylyl cyclase activity, decreased formation of cyclic AMP with a corresponding decrease in protein kinase A activity, and inhibition of Ca2+ influx through various Ca2+ channels; it also results in stimulation of inwardly rectifying potassium (K+) channels and the mitogen-activated protein kinase signaling cascadesReference3Reference13. Anandamide is a partial agonist at cannabinoid receptors, and binds with slightly higher affinity at CB1 compared to CB2 receptorsReference2Reference22. 2-AG appears to bind equally well to both cannabinoid receptors (with slightly higher affinity to CB1), but has greater potency and efficacy than anandamide at cannabinoid receptorsReference2Reference22.

In the central nervous system (CNS), the overall effect of CB1 receptor activation is suppression of neurotransmitter release (5-hydroxytryptamine (5-HT), glutamate, acetylcholine, GABA, noradrenaline, dopamine, D-aspartate, cholecystokinin) at both excitatory and inhibitory synapses with both short and long-term effectsReference2Reference18Reference23. Inhibition of neurotransmitter release occurs through a retrograde signaling mechanism whereby endocannabinoids synthesized and released from the cell membrane of post-synaptic neurons diffuse backwards across the synaptic cleft and bind to CB1 receptors located on the pre-synaptic terminals (Figure 1)Reference3. This retrograde signaling mechanism permits the regulation of neurotransmission in a precise spatio-temporal mannerReference3. In immune cells, activation of CB2 receptors inhibits cytokine/chemokine release and neutrophil and macrophage migration, giving rise to complex modulatory effects on immune system functionReference19.

Cannabinoid receptor expression and receptor distribution

Most tissues contain a functional ECS with the CB1 and CB2 receptors having distinct patterns of tissue expression. The CB1 receptor is one of the most abundant G-protein coupled receptors in the central and peripheral nervous systemsReference19. It has been detected in the cerebral cortex, hippocampus, amygdala, basal ganglia, substantia nigra pars reticulata, internal and external segments of the globus pallidus and cerebellum (molecular layer), and at central and peripheral levels of the pain pathways including the periaqueductal gray matter, the rostral ventrolateral medulla, the dorsal primary afferent spinal cord regions including peripheral nociceptors, and spinal interneuronsReference4Reference23Reference24. CB1 receptor density is highest in the cingulate gyrus, the frontal cortex, the hippocampus, the cerebellum, and the basal gangliaReference5. Moderate levels of CB1 receptor expression are found in the basal forebrain, amygdala, nucleus accumbens, periaqueductal grey, and hypothalamus and much lower expression levels of the receptor are found in the midbrain, the pons, and the medulla/brainstemReference5. Relatively little CB1 receptor expression is found in the thalamus and the primary motor cortexReference5. The CB1 receptor is also expressed in many other organs and tissues including adipocytes, leukocytes, spleen, heart, lung, the gastrointestinal (GI) tract (liver, pancreas, stomach, and the small and large intestine), kidney, bladder, reproductive organs, skeletal muscle, bone, joints, and skinReference25Reference43. CB2 receptors are most highly concentrated in the tissues and cells of the immune system such as the leukocytes and the spleen, but can also be found in bone and to a lesser degree in liver and in nerve cells including astrocytes, oligodendrocytes and microglia, and even some neuronal sub-populationsReference44Reference45.

Other molecular targets for cannabinoids

Besides the well-known CB1 and CB2 receptors, a number of different cannabinoids are believed to bind to a number of other molecular targets. Such targets include the third putative cannabinoid receptor GPR55 (G protein-coupled receptor 55), the transient receptor potential (TRP) cation channel family, and a class of nuclear receptors/transcription factors known as the PPARs, as well as 5-HT1A receptors, the α2 adrenoceptors, adenosine and glycine receptors. For additional details on this subject please see Section 2.1 and consult the following resourcesReference8Reference9Reference22Reference46Reference49. Modulation of these other cannabinoid targets adds additional layers of complexity to the known myriad effects of cannabinoids.

Signal termination

Endocannabinoid signaling is rapidly terminated by the action of two hydrolytic enzymes: FAAH and MAGLReference3. FAAH is primarily localized post-synapticallyReference50Reference51 and preferentially degrades anandamideReference14; MAGL is primarily localized pre-synapticallyReference50Reference51 and favors the catabolism of 2-AG (Figure 1)Reference14. Signal termination is important in ensuring that biological activities are properly regulated and prolonged signaling activity, such as by the use of cannabis, can have potentially deleterious effectsReference52Reference53.

Dysregulation of the endocannabinoid system and general therapeutic challenges of using cannabinoids

Dysregulation of the ECS appears to be connected to a number of pathological conditions, with the changes in the functioning of the system being either protective or harmfulReference54. Modulation of the ECS either through the targeted inhibition of specific metabolic pathways, and/or directed agonism or antagonism of its receptors may hold therapeutic promiseReference13. However, a major and consistent therapeutic challenge confronting the routine use of (THC-predominant) cannabis and psychoactive cannabinoids (e.g. THC) in the clinic has remained that of achieving selective targeting of the site of disease or symptoms and the sparing of other bodily regions such as the mood and cognitive centres of the brainReference23Reference54Reference57. Despite this significant challenge, emerging evidence from clinical studies of smoked or vapourized (THC-predominant) cannabis for chronic non-cancer pain (mainly neuropathic pain) suggests that use of very low doses of THC (< 3 mg/dose) may confer therapeutic benefits with minimal psychoactive side effectsReference58Reference59 (and also see Section 3.0 and 4.7.2.2 for additional details).

Role of the endocannabinoid system in nervous system development

The CB1 receptor is highly expressed in the developing brainReference60. For example, CB1 receptors are highly expressed from early fetal stages, beginning as early as E12.5 (in mice) and into late fetal stages (E21) with high expression in white matter within a number of different structures including the hippocampus, cerebellum, caudate-putamen and cerebral cortex that continues to increase after birth and into adulthood; in contrast, after birth there is tapering of CB1receptor expression in other structures such as the corpus callosum, fornix, stria terminalis and the fasciculus retroflexusReference60. Furthermore, in the adult brain, the CB1 receptor appears to be localized on the axonal plasma membrane and in somatodendritic endosomes, whereas in fetal brain the CB1 receptor is mostly localized to endosomes both in axons and in the somatodendritic regionReference60. The available evidence suggests a neurodevelopmental role for the ECS including in functions such as survival, proliferation, migration and differentiation of neuronal progenitorsReference60. CB1 receptor activation, in response to stimulation by endocannabinoids, such as 2-AG and anandamide, promotes these functions but delays the transition from multipotent, proliferating, and migration-competent progenitor phenotype towards a more settled, well-differentiated, post-mitotic neuronal phenotypeReference60Reference61. In vitro studies examining the effects of CB1receptor activation in primary neuronal cultures suggest that the CB1 receptor is mainly a negative regulator of neurite growth since activation of the receptor results in growth cone arrest, repulsion or collapse and thereby influences the ability of axons to reach their targetsReference60. However, these CB1 receptor-mediated responses may be surmountable by the effects of local growth-promoting effectors at the growth cone and the balance between the effects of endocannabinoids and growth factors would determine the overall outcome of neuronal development. The CB1 receptor appears also to act as a negative regulator of synaptogenesis and in doing so can also affect the fate of neuronal communicationReference60. Exposure to cannabinoids that activate the CB1 receptor (such as THC) during developmental periods of nervous system development such as during embryonic development in pregnancy could alter the course of normal neuronal development in offspring and negatively affect normal brain function potentially causing long-lasting impairment of a number of cognitive functions and behavioursReference61 (and also see Sections 2.5 and 7.4 for additional information). For example, a study conducted in pregnant mice using a low dose of THC has been shown to alter the expression level of 35 proteins in the fetal cerebrumReference62. Furthermore this study concretely identified a specific molecular target for THC in the developing CNS whose modifications can directly and permanently impair the wiring of neuronal networks during corticogenesis by enabling formation of ectopic neuronal filopodia and altering axonal morphologyReference62. Another in vitro study with retinal ganglion cell explants showed that CBD decreased neuronal growth cone size and filopodia number as well as total projection length and induced growth cone collapse and neurite retraction (i.e. chemo-repulsion) through the GPR55 receptorReference63.

Figure 1. The Endocannabinoid System in the Nervous System

Figure 1. Text version below.

(1) Endocannabinoids are manufactured “on-demand” (e.g. in response to an action potential in neurons) in the post-synaptic terminals: anandamide (AEA) is generated from phospholipase-D (PLD)-mediated hydrolysis of the membrane lipid N-arachidonoylphosphatidylethanolamine (NAPE); 2-AG from the diacylglycerol lipase (DAGL)-mediated hydrolysis of the membrane lipid diacylglycerol (DAG); (2) These endocannabinoids (anandamide (AEA) and 2-AG) diffuse retrogradely towards the pre-synaptic terminals and like exogenous cannabinoids such as THC (from cannabis), dronabinol, and nabilone, they bind to and activate the pre-synaptic G-protein-coupled CB1 receptors; (3) Binding of phytocannabinoid and endocannabinoid agonists to the CB1 receptors triggers Gi/Go protein signalling that, for example, inhibits adenylyl cyclase, thus decreasing the formation of cyclic AMP and the activity of protein kinase A; (4) Activation of the CB1 receptor also results in Gi/Go protein-dependent opening of inwardly-rectifying K+ channels (depicted with a “+”) causing a hyperpolarization of the pre-synaptic terminals, and the closing of Ca2+ channels (depicted with a “-“), arresting the release of stored excitatory and inhibitory neurotransmitters (e.g. glutamate, GABA, 5-HT, acetylcholine, noradrenaline, dopamine, D-aspartate and cholecystokinin) which (5) once released, diffuse and bind to post-synaptic receptors; (6) Anandamide and 2-AG re-enter the post- or pre-synaptic nerve terminals (possibly through the actions of a specialized transporter depicted by a “dashed” line) where they are respectively catabolized by fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) to yield either arachidonic acid (AA) and ethanolamine (ETA), or arachidonic acid (AA) and glycerol. See text for additional details. Figure adapted fromReference64Reference66.

1.1 Cannabis

1.1.1 Chemistry and composition

Cannabis sativa (i.e. cannabis, marihuana, marijuana) is a hemp plant that grows throughout temperate and tropical climatesReference67. The leaves and flowering tops of Cannabis contain over 500 distinct compounds distributed among 18 different chemical classes, and harbor over 100 different phytocannabinoidsReference68Reference71 The principal phytocannabinoids appear to be delta-9-tetrahydrocannabinol (i.e. Δ9-THC, THC), CBN, and cannabidiol (CBD)Reference72Reference74, although the relative abundance of these and other phytocannabinoids can vary depending on a number of factors such as the Cannabis strain, the soil and climate conditions, and the cultivation techniquesReference75Reference76. Other phytocannabinoids found in cannabis include cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV) and many othersReference70. In the living plant, these phytocannabinoids exist as both inactive monocarboxylic acids (e.g. tetrahydrocannabinolic acid, THCA) and as active decarboxylated forms (e.g. THC); however, heating (at temperatures above 120 °C) promotes decarboxylation (e.g. THCA to THC)Reference77Reference79. Furthermore, pyrolysis (such as by smoking) transforms each of the hundreds of compounds in cannabis into a number of other compounds, many of which remain to be characterized both chemically and pharmacologically. Therefore, cannabis can be considered a very crude drug containing a very large number of chemical and pharmacological constituents, the properties of which are only slowly being understood.

Among all the chemical constituents of cannabis, and particularly among the cannabinoids, Δ9-THC is by far the best studied and is responsible for many, if not most, of the physical and psychotropic effects of
cannabisReference80. Other phytocannabinoids (e.g. CBD, CBC, CBG) are present in lesser amounts in the plant and have little, if any, psychotropic propertiesReference80. However, Canadian licensed producers of cannabis for medical purposes have now made available a large variety of cannabis strains containing varying levels of THC and CBD, including THC-predominant, CBD-predominant or balanced strains for patients who have received authorization from their healthcare practitioner to access cannabis for medical purposes. For more information, please consult the Health Canada authorized licensed producers of cannabis for medical purposes website.

1.1.2 Other constituents

The large number of compounds found in cannabis spans many chemical classes including phytocannabinoids, nitrogenous compounds, amino acids, proteins, enzymes, glycoproteins, hydrocarbons, simple alcohols, aldehydes, ketones and acids, fatty acids, simple esters and lactones, steroids, terpenes, non-cannabinoid phenols, flavonoids, vitamins, and pigmentsReference70. Furthermore, differences in the presence and the relative abundance of some of these various components have been investigated, and differences in various components have been noted between cannabis extract, vapour, and smoke, and also between cannabis varietiesReference81. Of note, cannabis smoke contains many compounds not observed in either extracts or vapour, including a number which are known or suspected carcinogens or mutagensReference81Reference83. Moreover, comparisons between cannabis smoke and tobacco smoke have shown that the former contains many of the same carcinogenic chemicals found in the latterReference82Reference84 (see Section 7.1 for more information).

Relatively little is known about the pharmacological actions of the various other compounds found within cannabis (e.g. terpenes, flavonoids). However, it is believed that some of these compounds (e.g. terpenes) may have a broad spectrum of action (e.g. anti-oxidant, anti-anxiety, anti-inflammatory, anti-bacterial, anti-neoplastic, anti-malarial), but this information comes from a few in vitro and in vivo studies and no clinical trials exist to support these claims. Terpenes vary widely among cannabis varieties and are thought to be primarily responsible for differences in fragrance among the different Cannabis strainsReference75. Furthermore, it is thought that terpenes may contribute to the distinctive smoking qualities and possibly to the character of the “high” associated with smoking cannabisReference75, but again, this has not been studied in any detail. The concept that terpenes may somehow modify or enhance the physiological effects of the cannabinoidsReference85Reference86,i.e. the “entourage effect”, is, for the moment, hypothetical as there is little, if any, pre-clinical evidence to support this hypothesis and no clinical trials on this subject have been carried out to date.

1.1.3 Stability and storage

Most of the information on the stability of cannabis does not distinguish between Δ9-THC and its carboxylic acid (Δ9-THCA). The latter is transformed to Δ9-THC by heating during vapourization or cooking, or by pyrolysis during smoking or in the inlet of gas chromatographs used in forensic analysisReference87. Complete decarboxylation of Δ9-THCA to Δ9-THC has been shown to occur starting at 98 °C and up to a temperature of 200 °C. As the temperature increases, the rate of decarboxylation increases: it takes 4 hours for complete decarboxylation at 98 °C, but only seconds at 200 °CReference88Reference90. Heat, light, humidity, acidity and oxidation all affect the stability of cannabis and phytocannabinoidsReference91Reference92. The National Institute on Drug Abuse reports that retention samples of their carefully prepared and standardized cigarettes are stable for months, particularly when stored below 0 oC (-18 °C) in the dark, in tightly-closed containersReference93. Even when stored at +18 °C, only a third of the Δ9-THC content is lost over a five-year period with some increase in the concentration of CBN. Cannabis cigarettes with lower Δ9-THC content (1.15% THC) appear to lose more Δ9-THC compared to cigarettes with higher Δ9-THC content (2.87% THC)Reference93. Turner et al. found that the THC content of cannabis decayed at a rate of 3.83, 5.38, and 6.92% per year for cannabis stored at -18 °C, 4 °C and 22 °C respectivelyReference94. Sevigny has provided the following formula for calculating decay of THC: THC0 = THCa / e-(k)(t) where THC0 is the unknown initial concentration of THC, THCa is the assayed concentration of THC, k is the decay rate constant which can vary according to two conditions: k = 0.0263 (the lower-bound average decay rate for samples stored in darkness at 3 ºC) and k = 0.0342 (the upper-bound average decay rate for samples stored in natural light of a laboratory at 22 °C), and t is the seizure-to-assay analysis lag (in months)Reference95. For specific stability and storage conditions for cannabis provided by licensed commercial producers in Canada, please consult information provided by the licensed commercial producers.

2.0 Clinical Pharmacology

2.1 Pharmacodynamics

Much of the pharmacodynamic information on cannabis refers to the effects of the major constituent, Δ9-THC, which acts as a partial agonist at both CB receptorsReference46Reference48Reference96, has activity at non-CB receptors and other targetsReference46Reference48Reference97, and is responsible for the psychoactive and potential therapeutic effects of cannabis through its actions at the CB1 receptorReference46Reference48Reference98. Δ8 -THC (an isomer of Δ9-THC) is found in smaller amounts in the plant, but like Δ9-THC, it is a partial agonist at both CB receptors and shares relatively similar efficacy and potency with Δ9-THC in in vitro assaysReference96. An in vivo animal study and one clinical study suggest Δ8 -THC to be a more potent anti-emetic than Δ9-THCReference99Reference100.

CBN is a product of Δ9-THC oxidation and has 10% of the activity of Δ9-THC at the CB1 receptorReference101. Its effects are not well studied but it appears to have some possible immunosuppressive properties in a small number of in vitro studiesReference102.

CBG is a partial CB1/2 receptor agonist and a small number of in vitro studies suggest it may have some anti-inflammatory and analgesic propertiesReference49Reference101Reference103Reference104. For example, in vitro assays have shown that CBG, at a concentration of 100 µg/ml (approximately equivalent to a concentration of 300 µM and above the typical physiological range, and therefore not truly representative of human in vivo conditions), is associated with a greater than 30% inhibition of cyclooxygenase (COX) 1 and 2 enzymes, but only produced weak inhibition (<10%) of prostaglandin production in vivo at concentrations that did not cause cytotoxicityReference104. Cannabigerolic acid has a similar profile. CBG has also been shown to block 5-HT1A receptors and act as an α2-adrenoceptor agonistReference105. There is some emerging evidence that suggests CBG can produce signs of analgesia by activation of α2-adrenoceptorsReference46.

CBD lacks detectable psychoactivity and does not appear to bind to either CB1 or CB2 receptors at physiologically meaningful concentrations, but there is some emerging evidence suggesting it may act as a non-competitive, negative, allosteric modulator of CB1 receptorsReference106. There is also a considerable body of evidence suggesting CBD also affects the activity of a significant number of other targets including ion channels, receptors, and enzymesReference18Reference101Reference107. For example, CBD has been shown to block the activity of FAAH resulting in an increase in anandamide levels, act as an agonist of the TRPV1 channel, inhibit adenosine uptake by acting as an indirect agonist at adenosine receptors, act as an agonist of 5-HT1A receptors, act as a positive allosteric modulator of glycine receptors, and act as an anti-oxidant and reactive oxygen species scavenger as well as regulating calcium homeostasis via the mitochondrial sodium/calcium (Na+/Ca2+)-exchangerReference108. The effects of CBD at these and other molecular targets are associated with anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform effectsReference101Reference108Reference109.

THCV acts as a CB1 receptor antagonist and CB2 receptor partial agonist in vitro and in vivoReference110Reference111, as well as a 5-HT1A receptor agonistReference47 and pre-clinical studies suggest it may have anti-epileptiform/anti-convulsant, anti-nociceptive and potential anti-psychotic propertiesReference47Reference108Reference112.

Much of what is known about the beneficial properties of the non-psychotropic cannabinoids (e.g. CBD, THCV) is derived from in vitro and in vivo studies and few well-conducted, rigorous clinical studies of these substances exist. However, the results from these pre-clinical studies point to potential therapeutic indications such as psychosis, epilepsy, anxiety, sleep disturbances, neurodegeneration, cerebral and myocardial ischemia, inflammation, pain and immune responses, emesis, food intake, type-1 diabetes, liver disease, osteogenesis, and cancerReference18Reference101Reference113. For more in-depth information on the pharmacology of cannabinoids, the reader is invited to consult the following resourcesReference22Reference46Reference48Reference101Reference114.

Phytocannabinoid-phytocannabinoid interactions and phytocannabinoid differences among cannabis strains

Despite anecdotal claims, there is limited reliable information regarding actual or potential interactions, of biological or physiological significance, among phytocannabinoids, especially Δ9-THC and CBD. The limited information that exists is complex and requires further clarification through additional investigation. The following paragraphs summarize the available information on this subject.

Factors affecting the nature of the potential phytocannabinoid-phytocannabinoid interactions

Various studies have reported either potentiating, opposing, or neutral interactions between Δ9-THC and CBDReference46Reference48Reference106Reference115Reference136. The discrepancies in the nature of the interactions between Δ9-THC and CBD reported in the literature may be explained by differences in the doses and ratios of THC and CBD used in the different studies, differences in the routes of administration, dose ordering effects (CBD pre-treatment vs. simultaneous co-administration with Δ9-THC), differences in the duration or chronicity of treatment (acute vs. chronic), differences in the animal species used, as well as the particular biological or physiological end-points being measuredReference123.

Pharmacokinetic vs. pharmacodynamic interactions

In general, there appear to be two types of mechanisms which could govern possible interactions between CBD and Δ9-THC: those of apharmacokinetic originReference123Reference129, and those of a pharmacodynamic originReference133Reference135. Despite the limited and complex nature of the available information, it generally appears that pre-administration of CBD may potentiate some of the effects of THC (through a pharmacokinetic mechanism). Potentiation of THC effects by CBD may be caused by inhibition of THC metabolism in the liver, resulting in higher plasma levels of THCReference123Reference129.Simultaneous co-administration of CBD and THC may result in the attenuation of some of the effects of THC (through a pharmacodynamic mechanism). Furthermore, the ratio between the two phytocannabinoids also appears to play a role in determining whether the overall effect will be of a potentiating or antagonistic nature. CBD-mediated attenuation of THC-induced effects may be observed when the ratio of CBD to THC is at least 8: 1Reference120Reference134, whereas CBD appears to potentiate some of the effects associated with THC when the CBD to THC ratio is around 2: 1Reference120. Some emerging pre-clinical evidence suggests combined anti-emetic sub-threshold doses of THC and CBD or cannabidiolic acid (CBDA) may be effective in animal models of acute nausea and/or anticipatory nausea (see Section 4.3 for additional details).

Psychological and physiological effects associated with varying phytocannabinoid concentrations

A number of studies have examined the neurophysiological, cognitive, subjective, or behavioural effects of varying the concentrations of Δ9-THC, CBD, or other cannabinoids such as CBC in smoked cannabisReference128Reference137. In one study, 24 healthy men and women who had reported using cannabis at least 10 times in their lifetime were subjected to a double-blind, placebo-controlled, mixed between- and within-subject clinical trial that showed that deliberate systematic variations in the levels of either CBD or CBC in smoked cannabis were not associated with any significant differences in any of the measured subjective, physiological, or performance testsReference128. In another study, the subjective effects associated with the smoked or oral administration of cannabis plant material were directly compared to those associated with smoked or oral administration of Δ9-THC (using matched doses of Δ9-THC) to normal, healthy subjectsReference137. This double-blind, placebo-controlled, within-subject, crossover clinical study reported few reliable differences between the THC-only and whole-plant cannabis conditionsReference137. The authors further concluded that other cannabinoids present in the cannabis plant material did not alter the subjective effects of cannabis, but they speculated that cannabis samples with higher levels of cannabinoids or different ratios of the individual cannabinoids could conceivably produce different results, although no evidence to support this claim was provided in the study. They also hypothesized that whole-plant cannabis and THC alone could differ on other outcome measures more relevant to clinical entities (e.g. spasticity or neuropathic pain). With the possible exception of one studyReference138, (see Section 4.7.2.3. Cancer Pain), which suggested differences between a whole-plant cannabis extract (i.e. nabiximols, marketed as Sativex®) and THC alone on cancer pain analgesia, no other clinical studies have examined this possibility. One study compared the subjective and physiological effects of oral THC to those of nabiximols in normal, healthy subjectsReference122. The authors reported the absence of any modulatory effect of CBD (or other components of cannabis) at low therapeutic cannabinoid doses, with the potential exception of the subjective “high”Reference122.

An internet-based, cross-sectional study of 1 877 individuals with a consistent history of cannabis use reported that those individuals who had indicated using cannabis with a higher CBD to THC ratio had also reported experiencing fewer psychotic symptoms (an effect typically associated with exposure to higher doses of THC)Reference139. However, the authors noted that the effects were subtle. The study was also hampered by a number of important methodological issues suggesting that the conclusions should be interpreted with caution.

Brunt et al. (2014) conducted a study examining the self-reported therapeutic satisfaction and subjective effects of different strains of pharmaceutical-grade cannabis sold in the NetherlandsReference118. The authors reported that among the study population of about 100 patients using medical cannabis for conditions such as multiple sclerosis (MS), chronic pain, nausea, cancer and psychological problems, those who used cannabis with cannabinoid concentrations of 6% THC and 7.5% CBD (i.e. “low THC” cannabis) reported significantly less anxiety and dejection (i.e. feeling down, sad, depressed), but also reported less appetite stimulation. Importantly, those patients using the “low THC” condition reported equivalent levels of therapeutic satisfaction as those patients who reported using “high THC” (19% THC, < 1% CBD) and “medium THC” (12% THC, < 1% CBD) cannabis. There was also surprisingly little difference in terms of daily gram amount used between the different THC/CBD varieties with all categories reporting, on average, use of less than one gram of dried cannabis per day. The study findings are also consistent with the rest of the literature in terms of the average daily gram dose of dried cannabis used by patients (i.e. up to 3 g at most, but generally around one gram or less of variable THC content). Taken together, the study suggests that the use of cannabis containing approximately equivalent “lower” levels of THC and “higher” levels of CBD is associated with self-reported therapeutic efficacy and satisfaction across a number of different medical conditions for which dried cannabis is typically used, and also associated with attenuated levels of mood perturbation. The evidence also suggests that cannabis containing higher levels of THC and little CBD is not necessarily more effective than lower dose strains, except for stimulation of appetite. However, the study findings suggest that the use of higher-THC strains is associated with greater mood perturbation than the lower-THC strains. The study carried a number of caveats being that it only looked at a small number of patients, had a limited number of medical conditions and consisted of a self-reported survey.

Two in vivo studies conducted in non-human primates (i.e. rhesus monkeys) showed that CBD attenuated some of the effects of THC including cognitive-impairing effects and disruption of motor inhibitory behaviourReference115Reference119.

An in vivo study conducted in non-human primates (i.e. rhesus monkeys) showed that CBD, administered in a 1: 1 ratio with THC, attenuated some of the cognitive-impairing effects of THC, especially effects on spatial memory, but not on THC-induced performance deficits (i.e. non-specific motor and motivational effects)Reference119. Another in vivo study conducted in non-human primates (i.e. rhesus monkeys) examining the acute and chronic effects of CBD on THC-induced disruption of motor inhibitory behaviour showed that CBD, at ratios of 3: 1 but not 1: 1 relative to THC, attenuated some of the acute and chronic behavioural effects of higher-dose THC on disruption of motor inhibitory behaviourReference115.

In summary, although it appears that CBD may modulate some of the behavioural effects of THC, further careful study is required to elucidate the influence of CBD, and other phytocannabinoids or terpenoids, on the physiological or psychological effects associated with the use of Δ9-THC, as well as on any medical disorders.

Overview of pharmacological actions of cannabis

Most of the available information regarding the acute and long-term effects of cannabis use comes from studies conducted on non-medical users, with much less information available from clinical studies of patients using cannabis for medical purposes.

The acute effects of smoking or eating cannabis include euphoria (the marijuana “high”) as well as cardiovascular, bronchopulmonary, ocular, psychological and psychomotor effects. Euphoria typically occurs shortly after smoking and generally takes longer with oral administrationReference80. However, some people can experience dysphoria and anxietyReference140. Tachycardia is the most consistent of the acute physiological effects associated with the consumption of cannabisReference141Reference144.

The short-term psychoactive effects associated with cannabis smoking in non-medical users include the above-mentioned euphoria but also relaxation, time-distortion, intensification of ordinary sensory experiences (such as eating, watching films, and listening to music), and loss of inhibitions that may result in laughterReference145. This is followed by a depressant periodReference146. Most reviews note that cannabis use is associated with impaired function in a variety of cognitive and short-term memory tasksReference102Reference146Reference151 and the levels of Δ9-THC in the plasma after smoking appear to have a dose, time, and concentration-dependent effect on cognitive functionReference152Reference154. Driving and operation of intricate machinery, including aircraft, may be significantly impairedReference155Reference158.

Table 1 (below), adapted from a reviewReference159, notes some of the pharmacological effects of cannabis in the therapeutic dosage range. Many of the effects are biphasic, with increased activity with acute or smaller doses, and decreased activity with larger doses or chronic useReference141Reference160Reference161. Effects differ greatly among individuals and may be greater in those who are young, severely ill, elderly, or in those taking other drugs.

Table 1: Selected Pharmacologic Actions of Cannabis/Psychoactive Cannabinoids (mainly in reference to THC-predominant cannabis) (*selected, non-exhaustive list of sources)
For additional information please see the text.
Body System/Effect Detail of Effects
Central Nervous System (CNS)
Psychological(Sections 4.9.5and 7.7) Euphoria (“high”), dysphoria, anxiety, depersonalization, precipitation or aggravation of psychosis, schizophrenia or bipolar disorder (esp. in vulnerable individuals) and suicidal ideation/attempts (esp. among men), limited and mixed evidence in PTSD, mixed evidence for amotivational syndromeReference80Reference162Reference203.
Perception(Section 7.7.1) Heightened sensory perception, distortion of space and time sense, hallucinations, misperceptionsReference175Reference179Reference190Reference204Reference211.
Sedative(Sections 6.2and 7.7) Generalized CNS depression, drowsiness, somnolence (dose-dependent effect on sleep); additive with other CNS depressants (opioids/alcohol)Reference59Reference141Reference162Reference172Reference176Reference179Reference184Reference185Reference195Reference212Reference227.
Cognition, psychomotor performance(Sections 7.7.1and 7.7.2) Fragmentation of thoughts, mental clouding (attention and concentration), memory impairment/amnesia, global impairment of performance especially in complex and demanding tasks and additive effect with other CNS depressants (e.g. alcohol)Reference128Reference149Reference151Reference155Reference158Reference185Reference205Reference206Reference227Reference235.
Motor function(Sections 4.9.1and 7.7.2) Incoordination, ataxia, falls, dysarthria, weaknessReference141Reference172Reference174Reference176Reference180Reference206Reference207Reference222Reference227Reference236Reference240. Limited and mixed evidence in dystonia, Huntington’s disease, Tourette’s syndrome and Parkinson’s diseaseReference179Reference241Reference261.
Epilepsy(Section 4.6) Anti-epileptiform and anti-convulsive properties with CBD (and possibly also with CBDV and THCV)Reference215Reference217Reference262Reference264. Mixed pro- and anti-epileptiform and pro- and anti-convulsive effects with THCReference263Reference265Reference266.
Analgesic(Section 4.7) Limited evidence of mixed effects for acute painReference267Reference274. Modest effect for chronic non-cancer pain (mainly neuropathic)Reference58Reference59Reference108Reference176Reference179Reference184Reference185Reference195Reference218Reference222Reference225Reference226Reference268Reference273Reference275Reference281 Modest/mixed effect for cancer painReference138Reference282Reference285. Mixed “opioid-sparing” effectReference138Reference280Reference284Reference286Reference288. Very limited evidence for mixed effects for headache and migraineReference289Reference293.
Anti-nausea/anti-emetic;
hyper-emetic
(Sections 4.3and 7.6.1)
Observed with acute dosesReference109Reference286Reference294Reference297. Tolerance may occur with chronic useReference298. Conversely, nausea and/or vomiting may also be observed with use for medical purposesReference227. Hyperemesis has also been observed with larger doses or chronic use in non-medical contextsReference299Reference309.
Appetite(Sections 4.4and 4.9.8.4) Increased in normal, healthy subjects, but also in patients suffering from HIV/AIDS-associated anorexia/cachexiaReference118Reference179Reference223Reference224Reference227Reference310Reference313. Evidence mixed and modest for loss of appetite in cancerReference314Reference321. Evidence weak for anorexia nervosaReference322Reference323.
Tolerance(Section 2.4) To most behavioural and somatic effects, including the “high” (with chronic use)Reference181Reference229Reference324Reference333.
Dependence, withdrawal syndrome(Section 2.4) Dependence has been produced experimentally, and observed clinically, following prolonged intoxicationReference145Reference162Reference190Reference329Reference334Reference337. Abstinence leads to withdrawal symptoms which can include anger, anxiety, restlessness, irritability, depressed mood, disturbed sleep, strange dreams, decreased appetite, and weight lossReference190Reference329Reference338Reference342.
Cardiovascular and Cerebrovascular System
Heart rate/rhythm(Section 7.5) Tachycardia with acute dosing; tolerance developing with chronic exposureReference141Reference144Reference184Reference185Reference343Reference346. Premature ventricular contractions, palpitations, atrial fibrillation, ventricular arrhythmia also seen with acute dosesReference144Reference227Reference347Reference351.
Peripheral circulation(Section 7.5) Vasodilatation, conjunctival redness, supine hypertension, postural hypotensionReference219Reference227Reference345Reference347Reference352Reference354.
Cardiac output(Section 7.5) Increased cardiac outputReference347 and myocardial oxygen demandReference352.
Cerebral blood flow(Section 7.5) Increased with acute dose, decreased with chronic use, region-dependent variationsReference345Reference355.
Myocardial infarction(Section 7.5) Increased risk of acute myocardial infarction within one hour after smoking cannabis especially in individuals with existing cardiovascular diseaseReference144Reference352.
Stroke(Section 7.5) Increased risk of experiencing stroke after an acute episode of smoking cannabisReference347Reference356Reference357.
Carcinogenesis/mutagenesis
(Section 7.1) Cannabis smoke contains many of the same chemicals as tobacco smoke, and cannabis smoke condensates are more cytotoxic and mutagenic than condensates from tobacco smokeReference82Reference84. Conflicting evidence linking cannabis smoking and cancerReference358Reference361. Possible link between cannabis smoking and testicular cancerReference362.
Respiratory System
Histopathological changes/ inflammation(Section 7.2) Chronic cannabis smoking associated with histopathological changes in the lung (basal cell hyperplasia, stratification, goblet cell hyperplasia, cell disorganization, inflammation, basement membrane thickening, and squamous cell metaplasia)Reference363. Long-term smoking associated with cough, increased production of phlegm, and wheezeReference364.
Bronchodilatation(Sections 4.9.3and 7.2) Acute THC exposure causes dilatation; possibly reversed with chronic exposure (by smoking)Reference364. Smoked/vapourized cannabis may worsen asthmatic symptomsReference365Reference366.
Pulmonary function (FEV1; FVC)(Section 7.2) Acute, low-level exposure possibly stimulatory; long-term, heavy smoking possibly associated with decreased lung functionReference364Reference367Reference371.
Gastrointestinal System
(Sections 4.9.8and 7.6) Decreased gastrointestinal motility, decreased secretion, decreased gastric/colonic emptying, anti-inflammatory actions, limited and mixed evidence of benefit in irritable bowel syndrome and inflammatory bowel diseaseReference33Reference185Reference279Reference372. Abdominal pain, nausea, vomiting, diarrheaReference227.
Liver(Sections 4.9.8.3 and 7.6.2) Increased risk of hepatic steatosis/fibrosis, especially in patients with Hepatitis CReference35Reference373Reference375. Increased Hepatitis C treatment adherence resulting in a potential sustained absence of detectable levels of Hepatitis C virusReference376.
Pancreas(Section 4.9.8.5) Risk of acute pancreatitis with chronic, daily, heavy useReference377Reference381.
Musculoskeletal system
(Sections 4.5.14.5.3 and 4.8) Possible positive effect in chronic pain associated with rheumatoid arthritisReference382Reference384 and fibromyalgiaReference184Reference385Reference386. May attenuate spasticity from MS and spinal cord injuryReference225Reference226Reference278Reference387. May negatively affect bone healingReference388.
Eye
(Section 4.9.2) Limited evidence for decreased intraocular pressureReference389Reference391.
Immune System
(Section 7.3) Complex immunomodulatory effects with suppressive and/or stimulatory effects (acute and chronic dosing)Reference26Reference392. Hypersensitivity/allergic reactionsReference365Reference366Reference393Reference394.
Reproductive System
Males(Sections 2.5and 7.4) Follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels either unaffected or decreased with chronic cannabis smokingReference395 (but seeReference396 which reports increased testosterone levels). Decreased sperm concentration and sperm count and altered morphology with chronic cannabis smoking in menReference395Reference396. Decreased sperm motility, capacitation and acrosome reaction with in vitro THC exposureReference395. Dose-dependent stimulatory (low-dose) or inhibitory (high-dose) effects on sexual behaviour in menReference395Reference397 (but seeReference398 which suggests increased coital frequency with increased frequency of use in men and women).
Females(Sections 2.5and 7.4) Acute administration of THC suppresses release of gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) with decreased release of prolactin and gonadotropins (FSH and LH) in animal and human studiesReference399. Association between cannabis use and menstrual cycle disruptions in women including: slightly elevated rate of menstrual cycles lacking ovulation (i.e. anovulatory cycles), higher risk of decreased fertility, prolonged follicular phase/delayed ovulation, though evidence is mixedReference399. Chronic/sub-chronic administration of THC in animals: altered hypothalamic-pituitary-ovarian (HPO) axis function, disruption of follicular development, decreased estrogen and progesterone production, blocking of LH surge, anovulationReference399. Cannabis can alter HPO axis functionality and ovarian hormones produced by the HPO axisReference399. Dose-dependent stimulatory (low-dose) or inhibitory (high-dose) effects on sexual behaviour in womenReference397 (but seeReference398 which suggests increased coital frequency with increased frequency of use in men and women).

2.2 Pharmacokinetics

This section covers human pharmacokinetics of smoked and vapourized cannabis, oral preparations including prescription cannabinoid medicines such as dronabinol (Marinol®) and nabiximols (Sativex®), and other routes of administration (e.g. rectal, topical). See Figure 2 (below) for a graphical representation of the pharmacokinetics of THC.

Figure 2. Pharmacokinetics of THC (and other cannabinoids). Figure adapted fromReference400.

Figure 2. Text version below.

THC (and other cannabinoids) can be administered by inhalation (e.g. smoking/vapourizing), orally (e.g. edibles, capsules, sprays), rectally (e.g. suppositories) or dermally (e.g. topicals) resulting in absorption through the lung, intestine, colon or skin. The concentration of THC (and other cannabinoids) in the extracellular water varies depending on serum protein binding (lipoproteins, albumin), tissue storage (fat, protein), metabolism (hepatic microsomal, non-microsomal, extrahepatic), biliary excretion (enterohepatic recirculation) and renal excretion (glomerular filtration, tubular secretion, passive reabsorption). The metabolism of THC (and other cannabinoids) produces metabolites which can also be found in the extracellular water. The concentration of THC in the extracellular water affects the THC (and other cannabinoids) concentration at the site of action. The effects of THC (and other cannabinoids) are observed when THC (and other cannabinoids) interacts with cannabinoid receptors or other targets of action. THC (and other cannabinoids) can also be detected in hair, saliva and sweat.

2.2.1 Absorption

2.2.1.1 Smoked cannabis

Smoking cannabis results in more rapid onset of action (within minutes), higher blood levels of cannabinoids, and a shorter duration of acute pharmacodynamic effects compared to oral administrationReference78. The amount of Δ9-THC (and other cannabinoids) delivered from cannabis cigarettes is not uniform and is a major variable in the assessment of absorptionReference78. Uncontrolled factors include the source of the plant material and the composition of the cigarette/joint, together with the efficiency and method of smoking used by the subjectReference78Reference401. While it has been reported that smokers can titrate their Δ9-THC intake, to a certain extent, by adapting their smoking behaviour to obtain desired levels of Δ9-THCReference402, other reasons may also explain the observed variation in smoking topographyReference403. As mentioned, Δ9-THC absorption by inhalation is extremely rapid but quite variable, with a bioavailability of 2 to 56% through the smoking route depending on depth of inhalation, puff duration, and breathholdReference400Reference404. In practice, a maximum of 25 to 27% of the THC content in a cannabis cigarette is absorbed or delivered to the systemic circulation from the total available amountReference141Reference405. It has been estimated that between 2 and 44 µg of THC penetrates the brain following smoking of a cannabis cigarette containing 2 to 22 mg of THC (e.g. 1 g joint containing 0.2 – 2.2% THC, delivering between 0.2 and 5.5 mg of THC based on a smoked bioavailability of 10 to 25%)Reference406.

The relationships between cannabis Δ9-THC content, dose administered, and resultant plasma levels have been investigated. Mean plasma Δ9-THC concentrations were 7.0 ng/mL and 18.1 ng/mL upon a single inhalation of either a 1.75% “low-dose” Δ9-THC cannabis cigarette (total available dose ~16 mg Δ9-THC), or a 3.55% Δ9-THC “high-dose” cannabis cigarette (total available dose ~34 mg Δ9-THC)Reference78. Smoking cannabis containing 1.64% Δ9-THC (mean available dose 13.0 mg Δ9-THC) resulted in mean peak THC plasma levels of 77 ng/mLReference407. Similarly, smoking cannabis joints containing 1.8% Δ9-THC (total available dose ~14 mg Δ9-THC) resulted in mean peak plasma THC levels of approximately 75 ng/mL, whereas with 3.6% Δ9-THC (total available dose ~28.8 mg Δ9-THC), mean peak plasma Δ9-THC levels of 100 ng/mL were attainedReference408. Smoking a 25 mg dose of cannabis in a pipe containing 2.5, 6, or 9.4% Δ9-THC (total available doses of ~0.6, 1.5, or 2.4 mg Δ9-THC) was associated with mean peak plasma Δ9-THC concentrations of 10, 25, or 45 ng/mL Δ9-THC, respectivelyReference59. Smoking one cannabis cigarette (800 mg) containing 6.8% THC, (w/w) yielding a total THC content of 54 mg per cigarette was associated with a median whole blood peak THC concentration of approximately 60 ng/mL Δ9-THC (occurring 15 min after starting smoking)Reference409. Compared to the data available for absorption with smoked THC, there is far less such information available for smoked CBD. In one early clinical study, smoking one cannabis cigarette containing 19 mg CBD (~2.4% CBD) was associated with a mean peak blood plasma level of CBD of 110 ng/mL (range: 42 – 191 ng/mL) at 3 min post-doseReference410. The estimated systemic bioavailability of CBD by smoking was 31 % (range: 11 – 45%), generally similar to that seen with Δ9-THC.

2.2.1.2 Vapourized cannabis

Vapourization of cannabis has been explored as an alternative to smoking. The potential advantages of vapourization include the formation of a smaller quantity of toxic by-products such as carbon monoxide, polycyclic aromatic hydrocarbons, and tar, as well as a more efficient extraction of Δ9-THC (and CBD) from the cannabis materialReference402Reference411Reference414. The subjective effects and plasma concentrations of Δ9-THC obtained by vapourization of cannabis are comparable to those obtained by smoking cannabisReference402. In addition, the study reported that vapourization was well tolerated with no reported adverse effects, and was preferred over smoking by the test subjectsReference402. While vapourization has been reported to be amenable to self-titration (as has been claimed for smoking)Reference402Reference413, the proper use of the vapourizer for optimal administration of cannabis for therapeutic purposes needs to be established in more detailReference414. The amount and type of cannabis placed in the vapourizer, the vapourizing temperature and duration of vapourization, and, in the case of balloon-type vapourizers, the balloon volume are some of the parameters that can affect the delivery of Δ9-THC and other phytocannabinoidsReference413. Bioequivalence of vapourization compared to smoking has not been thoroughly established. Inhalation of vapourized cannabis (900 mg of 3.56% Δ9-THC; total available dose of 32 mg of Δ9-THC) in a group of patients taking stable doses of sustained-release morphine or oxycodone resulted in mean plasma Δ9-THC levels of 126.1 ng/mL within 3 min after starting cannabis inhalation, rapidly declining to 33.7 ng/mL Δ9-THC at 10 min, and reaching 6.4 ng/mL Δ9-THC at 60 minReference280. Peak Δ9-THC concentration (Cmax) was achieved at 3 min in all study participantsReference280. No statistically significant changes were reported for the AUC12 (12-hour area-under-the-curve) for either morphine or oxycodone, but there appeared to be a statistically significant decrease in the Cmax of morphine sulfate, and a delay in the time needed to reach Cmax for morphine during cannabis exposureReference280. One clinical study reported that vapourizing 500 mg cannabis containing low-dose (2.9%) THC (~14.5 mg THC), or high-dose (6.7%) THC (~33.5 mg THC) was associated with median whole-blood Cmax values of 32.7 (low-dose) and 42.2 ng/mL (high-dose) THC, and median plasma Cmax values of 46.5 (low-dose) and 62.1 ng/mL (high-dose) THC at 10 min post-inhalation respectivelyReference206. Median whole-blood Cmax values for 11-hydroxy-THC were 2.8 (low-dose) and 5.0 ng/mL (high-dose) and median plasma Cmax values were 4.1 (low-dose) and 7 ng/mL (high-dose) at 10 – 11 min post-inhalation respectively. Another clinical study reported that vapourizing cannabis with 11 – 12% THC content (administered dose of 300 µg/kg) was associated with mean plasma concentrations of 73.8 ng/mL THC and 6.9 ng/mL 11-hydroxy-THC 5 min post-vapourizationReference415. A different clinical study showed that inhalation of 8 to 12 puffs of vapourized cannabis containing either 2.9% or 6.7% THC (400 mg each) was associated with a blood plasma Cmax of 68.5 ng/mL and 177.3 ng/mL respectively and median blood plasma concentration of 23 and 47 ng/mL respectivelyReference416. Plasma Cmax of 11-hydroxy-THC was 5.6 and 12.8 ng/mL for the 2.9 and 6.7% doses, respectively.

2.2.1.3 Oral

Whereas the acute effects on the CNS and physiological effects occur within minutes by the smoking route or by vapourizationReference149Reference417, the acute effects proceed on a time scale of hours in the case of oral ingestionReference417Reference418. Acute oral administration results in a slower onset of action, lower peak blood levels of cannabinoids, and a longer duration of pharmacodynamic effects compared to smokingReference78. The psychotropic effect or “high” occurs much more quickly by the smoking than by the oral route, which is the reason why smoking appears to be the preferred route of administration by many, especially among non-medical usersReference419.

For orally administered prescription cannabinoid medicines such as synthetic Δ9-THC (dronabinol, formerly marketed as Marinol®), only 10 to 20% of the administered dose enters the systemic circulation indicating extensive hepatic first-pass metabolismReference227. Administration of a single 2.5 mg dose of dronabinol in healthy volunteers was associated with a mean plasma Δ9-THC Cmax of 0.7 ng/mL (range: 0.3 – 1 ng/mL), and a mean time to peak plasma Δ9-THC concentration of 2 h (range: 30 min – 4 h)Reference227. A single 5 mg dose of dronabinol gave a reported mean plasma Δ9-THC Cmax of 1.8 ng/mL (range: 0.4 – 3.3 ng/mL), whereas a single 10 mg dose yielded a mean plasma Δ9-THC Cmax of 6.2 ng/mL (range: 3.5 – 9 ng/mL)Reference227. Again, the mean time to peak plasma Δ9-THC concentration ranged from 30 min to 3 h. Twice daily dosing of dronabinol (individual doses of 2.5 mg, 5 mg, 10 mg, b.i.d.) in healthy volunteers yielded plasma Δ9-THC Cmax values of 1.3 ng/mL (range: 0.7 – 1.9 ng/mL), 2.9 ng/mL (range: 1.2 – 4.7 ng/mL), and 7.9 ng/mL (range: 3.3 – 12.4 ng/mL), respectively, with a time to peak plasma Δ9-THC concentration ranging between 30 min and 4 h after oral administrationReference227. Continuous dosing for seven days with 20 mg doses of dronabinol (total daily doses of 40 – 120 mg dronabinol) gave mean plasma Δ9-THC concentrations of ~20 ng/mLReference420.

A phase I study evaluating the pharmacokinetics of three oral doses of THC (3 mg, 5 mg and 6.5 mg) in 12 healthy older subjects (mean age 72, range: 65 – 80 years) showed wide inter-individual variation in plasma concentrations of THC and 11-hydroxy-THCReference180. For those subjects who reached Cmax within 2 hours, the mean THC concentration was 1.42 ng/mL (range: 0.53 – 3.48 ng/mL) for the 3 mg dose, 3.15 ng/mL (range: 1.54 – 6.95 ng/mL) for the 5 mg dose, and 4.57 ng/mL (range: 2.11 – 8.65 ng/mL) for the 6.5 mg dose.

A randomized, double-blind, placebo-controlled, cross-over trial that evaluated the pharmacokinetics of oral THC in 10 older patients with dementia (mean age 77 years) over a 12-week period reported that median time to reach Cmax (Tmax) was between one and two hours with THC pharmacokinetics increasing linearly with increasing dose, but again with wide inter-individual variationReference421. Patients received 0.75 mg THC orally twice daily over the first six weeks and 1.5 mg THC twice daily over the second six-week period. The mean Cmax after the first 0.75 mg THC dose was 0.41 ng/mL and after the first 1.5 mg THC dose was 1.01 ng/mL. After the second dose of 0.75 mg THC or 1.5 mg THC, the Cmax was 0.50 and 0.98 ng/mL respectively.

Δ9-THC can also be absorbed orally by ingestion of foods containing cannabis (e.g. butters, oils, brownies, cookies), and teas prepared from leaves and flowering tops. Absorption from an oral dose of 20 mg Δ9-THC in a chocolate cookie was described as slow and unreliableReference401, with a systemic availability of only 4 to 12%Reference407. While most subjects displayed peak plasma Δ9-THC concentrations (6 ng/mL) between one and two hours after ingestion, some of the 11 subjects in the study only peaked at 6 h, and many had more than one peakReference78. Consumption of cannabis-laced brownies containing 2.8% Δ9-THC (44.8 mg total Δ9-THC) was associated with changes in behaviour, although the effects were slow to appear and variableReference418. Peak effects occurred 2.5 to 3.5 h after dosing. Modest changes in pulse and blood pressure were also noted. Plasma concentrations of Δ9-THC were not measured in this study. In another study, ingestion of brownies containing a low dose of Δ9-THC (9 mg THC/brownie) was associated with mean peak plasma Δ9-THC levels of 5 ng/mLReference137. Ingestion of brownies containing a higher dose of Δ9-THC (~13 mg Δ9-THC/brownie) was associated with mean peak plasma Δ9-THC levels of 6 or 9 ng/mL depending on whether the THC in the brownie came from plant material or was added as pure THCReference137. Using equivalent amounts of Δ9-THC, inhalation by smoking cannabis yielded peak plasma levels of Δ9-THC several-fold (five to six times or more) higher than when Δ9-THC was absorbed through the oral routeReference137. Tea made from dried cannabis flowering tops (19.1% Δ9-THCA, 0.6% Δ9-THC) has been documented, but the bioavailability of Δ9-THC from such teas is likely to be smaller than that achieved by smoking because of the poor water solubility of Δ9-THC and the extensive hepatic first-pass effectReference422.

After oral administration of chocolate cookies containing 40 mg CBD in healthy human subjects, mean plasma CBD levels ranged between 1.1 and 11 ng/mL (mean: 5.5 ng/mL) after one hour and the course of CBD in the plasma over six hours was in the same range as the course after 20 mg THCReference423. Daily oral doses of 10 mg/kg CBD for six weeks resulted in a mean weekly plasma concentration of 5.9 – 11.2 ng/mLReference424. Oral intake of 5.4 mg CBD resulted in plasma CBD concentrations ranging between 0.2 and 2.6 ng/mL (mean: 0.95 ng/mL) after one hourReference425. Bioavailability through the oral route was estimated at 6%Reference423Reference426.

While cannabinoids are lipophilic and anecdotal evidence suggests that cannabinoids dissolve better in fats and oils, the influence of various fats on cannabinoid absorption in vivo has been poorly studied. A pre-clinical study examined the effect of dietary fats on THC and CBD absorption in in ratsReference427. A dose of 12 mg/kg of THC or CBD in either lipid-free formulation or lipid long-chain triglycerides (LCT)-based formulation (sesame oil) was administered to rats by oral gavage. The absolute bioavailability of THC was 2.5 times higher in the lipid-based (Cmax = 172 ng/mL; AUC = 1050 h.ng/mL) versus lipid-free formulation (Cmax= 65 ng/mL; AUC = 414 h.ng/mL). The absolute bioavailability of CBD was three times higher in the lipid-based (Cmax = 308 ng/mL; AUC = 932 h.ng/mL) versus lipid-free formulation (Cmax = 87 ng/mL; AUC = 327 h.ng/mL). Furthermore, an in vitro lipolysis model was used to assess the mechanism by which lipids could enhance the bioavailability of THC and CBD. Results showed that 30% of THC and CBD was solubilized in the micellar layer and therefore was readily available. Incubation studies suggested that cannabinoids have a 70 to 80% association range with natural chylomicrons from rat and human. Chylomicrons act as carriers in the intestine and potentially transfer THC and CBD to the systemic circulation via the intestinal lymphatic system and therefore avoid hepatic first-pass metabolism, which would explain the increased bioavailability with the lipid-based formulation. The authors concluded that administration of cannabinoids with a fatty meal or in the form of a lipid-rich cannabis-containing cookie may increase systemic exposure and therefore change the efficacy of the drug by turning a barely effective dose into a highly effective one, or even, a therapeutic dose into a toxic one.

In vitro and in vivo studies suggest that exposure of CBD to (simulated) gastric fluid results in the conversion of CBD to THC and hexahydrocannabinolsReference428Reference429. In mice, it was shown that hexahydrocannabinols could, as is typically observed with THC, produce cataleptogenic effectsReference429. The clinical implications of this conversion of CBD to THC and hexahydrocannabinols are the subject of heated debate and currently unclear.

Comparing smoked, vapourized and oral administration

A randomized, double-blind, placebo-controlled, double-dummy, cross-over clinical study examined the pharmacokinetics of THC and its phase I and II metabolites between frequent and occasional cannabis smokers after smoked, vapourized and oral cannabis administrationReference430. Cannabis plant material (800 mg) containing 6.9% THC and 0.20% CBD was used, delivering a maximal THC dose of 51 mg and a maximal CBD dose of 1.5 mg. Vapourization was carried out using the Volcano® vapourizer (210 °C). Cannabis was administered orally by ingestion of cannabis-containing brownies. In frequent cannabis smokers (≥ five times per week over previous three months), the mean baseline-adjusted THC Cmax after smoking was 151 ng/mL, after vapourization it was 85 ng/mL, and after oral consumption it was 15 ng/mL. Mean Tmax was 7 min (smoking), 5 min (vapourization), and 2.5 h (oral). The mean AUC0-72 h (ug ∙ h/L) was 200 (smoking), 174 (vapourization), and 167 (oral). In occasional cannabis smokers (> two times per month but ≤ three times per week), the mean baseline-adjusted THC Cmax after smoking was 52 ng/mL, after vapourization it was 48 ng/mL, and after oral consumption it was 10 ng/mL. Mean Tmax was 7 min (smoking), 7 min (vapourization), and 2.3 h (oral). The mean AUC0-72 h (ug ∙ h/L) was 20 (smoking), 12 (vapourization), and 43 (oral). In frequent cannabis smokers, the mean baseline-adjusted 11-hydroxy-THC Cmax after smoking was 9 ng/mL, after vapourization it was 5 ng/mL, and after oral consumption it was 7 ng/mL. Mean Tmaxwas 13 min (smoking), 11 min (vapourization), and 2.3 h (oral). The mean AUC0-72 h (ug ∙ h/L) was 31 (smoking), 27 (vapourization), and 52 (oral). In occasional cannabis smokers, mean baseline-adjusted Cmax after smoking was 3 ng/mL, after vapourization it was 2 ng/mL, and after oral consumption, it was 5 ng/mL. Mean Tmax was 13 min (smoking), 6 min (vapourization), and 2.4 h (oral). The mean AUC0-72 h (ug ∙ h/L) was 3 (smoking), 2 (vapourization), and 33 (oral). These findings suggest, among other things, that peak blood THC concentration (THC Cmax) was significantly lower after oral consumption compared to either route of inhalation and time to peak blood THC concentration (Tmax) occurred significantly later for oral consumption compared to inhalation for both frequent and occasional cannabis smokers. In addition, Cmax was significantly higher for the smoking route compared to vapourization, but only among frequent cannabis smokers. In addition, THC Cmax values were significantly greater among frequent smokers compared to occasional smokers after smoking and vapourization only, and 11-hydroxy-THC Cmax values were significantly greater among frequent smokers regardless of route of administration.

2.2.1.4 Oro-mucosal and intranasal

Following a single oro-mucosal administration of nabiximols (Sativex®) (four sprays totalling 10.8 mg Δ9-THC and 10 mg CBD), mean peak plasma concentrations of both THC (~5.5 ng/mL) and CBD (~3 ng/mL) typically occur within 2 to 4 h, although there is wide inter-individual variation in the peak cannabinoid plasma concentrations and in the time to onset and peak of effectsReference431. When administered oro-mucosally, blood levels of Δ9-THC and other cannabinoids are lower than those achieved by inhalation of the same dose of smoked cannabis, but Δ9-THC blood levels are comparable to those seen with oral administration of dronabinolReference121Reference431. Oro-mucosal administration of nabiximols is also amenable to self-titrationReference122Reference383Reference432Reference433.

A small number of pre-clinical studies have explored intranasal administration of both THC and CBD. In one study in rabbits, intranasal administration of a 1 mg/kg dose of THC in a liquid solution or in a chitosan-based gel formulation produced a Cmax of 20 ng/mL and 31 ng/mL, with Tmax of 20 and 45 min respectively, compared to intravenous administration where the Cmax and Tmax were 1475 ng/mL and 0 min respectivelyReference434. In rats, intranasal administration of 200 µg/kg CBD in various formulations yielded Cmax values ranging from 20 – 35 ng/mL with Tmax values ranging between 20 and 30 min; by comparison, intravenous administration yielded a Cmax of 3 596 ng/mLReference435.

2.2.1.5 Rectal

While Δ9-THC itself is not absorbed through the rectal route, the pro-drug Δ9-THC-hemisuccinate is absorbed; this fact, combined with decreased first-pass metabolism through the rectal route, results in a higher bioavailability of Δ9-THC by the rectal route (52 – 61%) than by the oral routeReference436Reference440. Plasma concentrations of Δ9-THC are dose and vehicle-dependent, and also vary according to the chemical structure of the THC esterReference439. In humans, rectal doses of 2.5 to 5.0 mg of the hemisuccinate ester of Δ9-THC were associated with peak plasma levels of Δ9-THC ranging between 1.1 and 4.1 ng/mL within 2 to 8 h, and peak plasma levels of carboxy-Δ9-THC ranging between 6.1 and 42.0 ng/mL within 1 to 8 h after administrationReference436.

2.2.1.6 Topical

Cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion processReference78. No clinical studies have been published regarding the percutaneous absorption of cannabis-containing ointments, creams, or lotions. However, some pre-clinical research has been carried out on transdermal delivery of synthetic and natural cannabinoids using a dermal patchReference441Reference442. A patch containing 8 mg of Δ8-THC yielded a mean steady-state plasma concentration of 4.4 ng/mL Δ8 -THC within 1.4 h in a guinea pig model, and this concentration was maintained for at least 48 hReference441. Permeation of CBD and CBN was found to be 10-fold higher than for Δ8-THCReference443. Transdermal application of a gel containing CBD with or without permeation enhancers in hairless guinea pigs showed that Cmax without the enhancer was 9 ng/mL, and 36 ng/mL with the enhancer, and that maximal concentrations (Tmax) were reached by 38 and 31 h post-application, respectivelyReference435. Furthermore, steady-state concentrations were 6 and 24 ng/mL without and with the permeation enhancer, respectively. Another pre-clinical study of a transdermal CBD gel formulation (1% or 10%) applied with increasing daily dose of 0.6, 3.1, 6.2 and 62 mg/day yielded plasma concentrations of 4 ng/mL, 18 ng/mL, 33 ng/mL, and 1 630 ng/mL respectivelyReference444. Lastly, a pre-clinical study conducted with a 1% CBD cream reported a Cmax of 8 ng/mL, a Tmax of 38 h, and a steady-state plasma concentration of 6 ng/mLReference445.

2.2.2 Distribution

Distribution of Δ9-THC is time-dependent and begins immediately after absorption. Due to its lipophilicity, it is taken up primarily by fatty tissues and highly perfused organs such as the brain, heart, lung, and liverReference78. Δ9-THC has a large apparent volume of distribution, approximately 10 L/kg, because of its high lipid solubilityReference446. The apparent average volume of distribution of CBD is 32.7 L/kg (higher than THC) owing also to its very high lipid solubilityReference410. CBN has an even higher volume of distribution, 50 L/kgReference447. The plasma protein binding of Δ9-THC and its metabolites is approximately 97%Reference448Reference449. Δ9-THC is mainly bound to low-density lipoproteins (LDL), with up to 10% present in red blood cellsReference450, while the metabolite, 11-hydroxy-THC is strongly bound to albumin with only 1% found in the free-fractionReference451.

The highest concentrations of Δ9-THC are found in the heart and in adipose tissue, with levels reaching 10 and 1 000 times that of plasma, respectivelyReference452. Despite the high perfusion level of the brain, the blood-brain barrier appears to limit the access and accumulation of Δ9-THC in this organReference78Reference453Reference454, and the delay in correlating peak plasma concentration to psychoactive effects may be attributed, in part, to the time required for Δ9-THC to traverse this barrierReference401. Pre-clinical studies in mice suggest a more rapid penetration of 11-hydroxy-THC into the brain compared to the parent compound, on the order of 6: 1 for 11-hydroxy-THC to THCReference400Reference455Reference456.

As mentioned, Δ9-THC accumulates and is retained in fatty tissue, and its release from this storage site into the blood is slowReference453. It is also not entirely certain if Δ9-THC persists in the brain (a highly fatty tissue) in the long-term; however, the presence of residual cognitive deficits in abstinent heavy cannabis users suggests this may be the case, at least in the short-termReference457Reference458. A study that characterized cannabinoid elimination in blood from 30 male daily cannabis smokers during monitored sustained abstinence for up to 33 days on a closed residential unit found that both THC and its inactive metabolite 11-nor-9-carboxy Δ9-THC were detected in blood up to one month after last smoking, which was reported by the authors as being four times longer than previously describedReference459. This finding lends further support to the evidence on the distribution, accumulation, and storage of THC (and metabolites) in the adipose tissue and the slow release of THC (and metabolites) from adipose tissue stores back into the bloodstreamReference229. Residual THC in plasma (likely coming from bodily adipose stores) detected weeks after last smoking episode may be associated with persisting psychomotor impairment in frequent chronic cannabis smokers according to the study authorsReference229. Lastly, one animal study suggested food deprivation or adrenocorticotropic hormone (ACTH) administration in rats accelerates lipolysis and the release of Δ9-THC from fat stores, however further research is needed to determine if these effects are associated with subsequent intoxication or behavioural/cognitive changesReference460.

2.2.3 Metabolism

Most cannabinoid metabolism occurs in the liver, and different metabolites predominate depending on the route of administrationReference78Reference401. The complex metabolism of Δ9-THC involves allylic oxidation, epoxidation, decarboxylation, and conjugationReference401. Δ9-THC is oxidized by the xenobiotic-metabolizing cytochrome P450 (CYP) mixed-function oxidases 2C9, 2C19, and 3A4Reference78. The major initial metabolites of Δ9-THC are the active 11-hydroxy Δ9-THC, and the non-active 11-nor-9-carboxy Δ9-THCReference78. The psychoactive 11-hydroxy Δ9-THC is rapidly formed by the action of the above-mentioned hepatic microsomal oxidases, and plasma levels of this metabolite parallel the duration of observable drug actionReference461Reference462.

CBD undergoes extensive Phase I metabolism, with a reported 30 different metabolites in the urine, and the most abundant metabolites are hydroxylated 7 (or 11)-carboxy derivatives of CBD, with 7 (or 11)-hydroxy CBD as a minor metaboliteReference78Reference463Reference464.

CYP isozyme polymorphisms may also affect the pharmacokinetics of THC (and 11-nor-9-carboxy Δ9-THC). For example, subjects homozygous for the CYP2C9*3 allelic variant displayed significantly higher maximum plasma concentrations of Δ9-THC, significantly higher AUC, and significantly decreased clearance among other measures compared to the CYP2C9*1 homozygote or the *1/*3 heterozygoteReference465.

Xenobiotics are not only metabolized by CYPs but they also modulate the expression level and activity of these enzymes; CYPs are therefore a focal point in drug-drug interactions and adverse drug reactionsReference466. Polyaromatic hydrocarbons found in tobacco and cannabis smoke induce the expression of CYP1A2Reference467, while Δ9-THC, CBD, and CBN inhibit the activity of the CYP1A1, 1A2, 1B1 and 2A6 enzymesReference74Reference468. CBD has also been shown to inhibit the formation of Δ9-THC metabolites catalyzed by CYP3A4, with less effect on CYP2C9Reference446, albeit sufficiently to decrease the formation of 11-hydroxy-THCReference129Reference469. Please see Section 6.2 for more detailed information.

Results from in vitro experiments also suggest that Δ9-THC inhibits CYP3A4, CYP3A5, CYP2C9, and CYP2C19, while CBD inhibits CYP2C19, CYP3A4, and CYP3A5; however, higher concentrations than those seen clinically appear to be required for inhibitionReference74Reference431. While few clinical studies have specifically sought to evaluate cannabis-drug interactions per se, many, if not most, studies investigating the therapeutic effects of cannabis (e.g. smoked, vapourized, or orally ingested) and cannabinoid-based medicines (e.g. dronabinol, nabilone, nabiximols) have used patients that were concomitantly taking other medications (e.g. nonsteroidal anti-inflammatory agents (NSAIDs), opioids, anti-depressants, anti-convulsants, protease inhibitors) and, in general, did not report significantly increased incidences of severe adverse effects associated with the combination of cannabis or cannabinoids and these other medications. Nevertheless, careful monitoring of patients who are concomitantly consuming cannabis/cannabinoids and other medications that are metabolized by the above-mentioned enzymes may be warranted. Please see Section 6.2 for more detailed information.

The Sativex® product monograph cautions against combining Sativex® with amitriptyline or fentanyl (or related opioids) which are metabolized by CYP3A4 and 2C19Reference431. One clinical study that investigated the effects of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC and CBD delivered from Sativex® reported that co-administration of rifampicin with Sativex® is associated with slight decreases in the plasma levels of THC, CBD and 11-hydroxy-THC, while co-administration of ketoconazole with Sativex® is associated with slight increases in plasma levels of THC, CBD, and 11-hydroxy-THCReference470. No significant effects on plasma levels of THC, CBD or 11-hydroxy-THC were noted with omeprazole.

Cannabis smoking, as well as orally administered dronabinol may also affect the pharmacokinetics of anti-retroviral medications, although no clinically significant short-term impacts on anti-retroviral effects were notedReference471. Concomitant administration of cannabis as a herbal tea (200 mL, 1 g per liter; 18% THC, 0.8% CBD) with 600 mg i.v. irinotecan or 180 mg i.v. docetaxel for 15 consecutive days did not significantly affect the plasma pharmacokinetics of irinotecan or docetaxelReference472.

In addition, and as seen with tobacco smoke, cannabis smoke has the potential to induce CYP1A2 thereby increasing the metabolism of xenobiotics biotransformed by this isozyme such as theophyllineReference473 or the anti-psychotic medications clozapine or olanzapineReference474. Further detailed information on drug-drug interactions can be found in Section 6.2.

2.2.3.1 Inhalation

Plasma values of 11-hydroxy-THC appear rapidly and peak shortly after Δ9-THC, at about 15 min after the start of smokingReference475. Peak plasma concentrations of 11-hydroxy-THC are approximately 5% to 10% of parent THC, and the AUC profile of this metabolite averages 10 to 20% of the parent THCReference462. Similar results were obtained with intravenous THC administrationReference476. Following oxidation, the phase II metabolites of the free drug or hydroxylated-THC appear to be glucuronide conjugatesReference401.

Peak plasma values of the psycho-inactive metabolite, 11-nor-9-carboxy THC, occur 1.5 to 2.5 h after smoking, and are about one third the concentration of parent THCReference475.

2.2.3.2 Oral

In contrast to the limited metabolism of Δ9-THC to the 11-hydroxy metabolite through pulmonary administration, oral administration of Δ9-THC results in a significantly greater metabolism of Δ9-THC to the 11-hydroxy metabolite resulting in similar plasma concentrations of Δ9-THC and 11-hydroxy Δ9-THC through the oral routeReference404Reference418Reference477. The plasma levels of active 11-hydroxy metabolite, achieved through oral administration, are about three times higher than those seen with smokingReference462. Furthermore, 11-hydroxy- Δ9-THC has been reported to be as psychoactive or even more psychoactive than the parent THCReference400Reference406Reference478Reference480. Concentrations of both parent drug and metabolite peak between approximately 2 to 4 h after oral dosing, and decline over several daysReference481.

Information from the dronabinol (Marinol®) product monograph suggests that single doses of 2.5 mg, 5 mg, and 10 mg of Δ9-THC in healthy volunteers result in mean plasma Cmax values of 11-hydroxy Δ9-THC of 1.19 ng/mL (range: 0.4 – 1.9 ng/mL), 2.23 ng/mL (range: 0.7 – 3.7 ng/mL), and 7.51 ng/mL (range: 2.25 – 12.8 ng/mL), respectivelyReference227. Twice daily dosing of dronabinol (individual doses of 2.5 mg, 5 mg, 10 mg, b.i.d.) in healthy volunteers resulted in mean plasma Cmaxvalues of 1.65 ng/mL (range: 0.9 – 2.4 ng/mL), 3.84 ng/mL (range: 1.5 – 6.1 ng/mL), and 7.95 ng/mL (range: 4.8 – 11.1 ng/mL) of 11-hydroxy Δ9-THC, respectivelyReference227. Time to reach Cmax for 11-hydroxy Δ9-THC ranged from 30 min to 4 h, with a mean of approximately 2.5 hReference227. As stated above, 11-hydroxy Δ9-THC has psychotomimetic properties equal to or greater than those of Δ9-THCReference404Reference406Reference478Reference480Reference482Reference483.

2.2.4 Excretion

Δ9-THC and CBD levels in plasma decrease rapidly after cessation of smoking. Mean THC plasma concentrations are approximately 60% and 20% of peak plasma THC concentrations 15 and 30 min post-smokingReference484, respectively, and are below 5 ng/mL THC 2 h after smoking, although mean serum THC concentrations may be slightly higher when smoking higher THC potency cigarettesReference404. One study showed that CBD levels fall to below 5 ng/mL in the plasma about 2.5 h after smoking a 19 mg CBD cigaretteReference410.

Following smoking, elimination of THC and its metabolites occurs via the feces (65%) and the urine (20%)Reference78. Whole-body clearance of Δ9-THC and its hydroxy metabolite averages about 0.2 L/kg-h, but is highly variable due to the complexity of cannabinoid distributionReference227. The psycho-inactive 11-nor-9-carboxy Δ9-THC is the primary acid metabolite of Δ9-THC excreted in urine and itReference485 is the cannabinoid often screened for in forensic analysis of body fluidsReference486Reference487. A study that characterized cannabinoid elimination in blood from 30 male daily cannabis smokers during monitored sustained abstinence for up to 33 days on a closed residential unit found that low levels (approx. < 1 ng/mL) of both THC and its inactive metabolite 11-nor-9-carboxy THC were detected in blood up to one month after last smoking, which was reported by the authors as being four times longer than previously describedReference459.

Following oral administration, THC and its metabolites are also excreted in both the feces and the urineReference78Reference462. Biliary excretion is the major route of elimination, with about half of a radiolabelled THC oral dose being recovered from the feces within 72 h in contrast to the 10 to 15% recovered from urineReference462. Plasma clearance of CBD is similar to that of THC, ranging from 58 to 94 L/h (i.e. 960 – 1560 ml/min)Reference400Reference410. A large portion of administered CBD is excreted intact or as its glucuronideReference463Reference488Reference489. Sixteen percent of an administered dose of CBD was recovered in the urine as intact or conjugated CBD within 72 h, while 33% of an administered dose of CBD was recovered mostly unchanged (accompanied by several mono-, di-hydroxylated and mono-carboxylic metabolites) in the feces within 72 hReference410Reference463.

The decline of Δ9-THC levels in plasma is multi-phasic, and the estimates of the terminal half-life of Δ9-THC in humans have progressively increased as analytical methods have become more sensitiveReference446. While figures for the terminal elimination half-life of Δ9-THC appear to vary, it is probably safe to say that it averages at least four days and could be considerably longerReference78. The variability in terminal half-life measurements are related to the dependence of this measure on assay sensitivity, as well as on the duration and timing of blood measurementsReference490. Low levels of THC metabolites have been detected for more than five weeks in the urine and feces of cannabis usersReference446. The degree of Δ9-THC consumption does not appear to influence the plasma half-life of Δ9-THCReference401Reference491.

Like THC, the decline of CBD levels is also multi-phasic, and the half-life of CBD in humans after smoking has been estimated at 27 – 35 h, and 2 – 5 days after oral administrationReference401Reference426Reference464.

2.3 Pharmacokinetic-pharmacodynamic relationships

Much of the information on cannabinoid pharmacokinetic-pharmacodynamic relationships (mostly on Δ9-THC) is derived from studies of non-medical cannabis use rather than from studies looking at therapeutic use, but in either case, this relationship depends to some extent on the point in time at which observations are made following the administration of the cannabinoid. Furthermore, the temporal relationship between plasma concentrations of Δ9-THC and the associated clinical/therapeutic, psychotropic, cognitive and motor effects is not well established. But it is known that these effects often lag behind the plasma concentrations of Δ9-THC, and tolerance is known to develop to some of the effects but not to othersReference128Reference211Reference490 (See Section 2.4 Tolerance and Dependence).

As mentioned above, the relationship between dose (and plasma concentration) versus response for possible therapeutic applications is ill-defined, except for some information obtained for oral dosing with dronabinol (synthetic Δ9-THC, marketed as Marinol® but no longer available in Canada), nabiximols (a botanical cannabis extract containing approximately equal concentrations of Δ9-THC and CBD as well as other cannabinoids, terpenoids and flavonoids, marketed as Sativex®), or nabilone (synthetic Δ9-THC analog marketed as Cesamet®) for their limited indicationsReference227Reference431Reference492. More limited information is available for inhaled cannabisReference58Reference59. Interpretations of the pharmacokinetics of Δ9-THC are also complicated by the presence of active metabolites, particularly the potent psychoactive 11-hydroxy THC metabolite, which is found in higher concentration after oral administration than after inhalationReference418Reference477.

Target Δ9-THC plasma concentrations have been derived based on the subjective “high” response that may or may not be related to the potential therapeutic applications. Various pharmacodynamic models provide blood plasma concentration estimates in the range of 7 to 29 ng/mL Δ9-THC necessary for the production of a 50% maximal subjective “high” effectReference490. Other studies suggest that Δ9-THC plasma concentrations associated with 50% of the maximum “high” effect range between 2 and 250 ng/mL Δ9-THC (median of 19 ng/mL; mean of 43 ng/mL Δ9-THC) for the smoked or intravenous routes, while for the oral route the values range between 1 and 8 ng/mL Δ9-THC (median and mean of 5 ng/mL Δ9-THC)Reference137Reference493. Notably, impairment of driving performance is seen with plasma concentrations between 7 and 10 ng/mL (whole blood, approximately 3 – 5 ng/mL) and this blood THC concentration has been compared to a blood-alcohol concentration (BAC) of 0.05% which itself is associated with driver impairmentReference154.

Smoked cannabis

Simulation of multiple dosing with a 1% THC cigarette containing 9 mg Δ9-THC yielded a maximal “high” lasting approximately 45 min after initial dosing, declining to 50% of peak at about 100 min following smokingReference211. A dosing interval of 1 h with this dose would give a “continuous high”, and the recovery time after the last dose would be 150 min (i.e. 2.5 h). The peak Δ9-THC plasma concentration during this dosage is estimated at about 70 ng/mL.

One clinical study reported a peak increase in heart rate and perceived “good drug effect” within 7 min after test subjects smoked a 1 g cannabis cigarette containing either 1.8% or 3.9% THC (mean doses of Δ9-THC being 18 mg or 39 mg in the cigarette, respectively)Reference149. Compared to the placebo, both doses yielded statistically significant differences in subjective and physiological measures; the higher dose was also significantly different from the lower dose for subjective effects, but not physiological effects such as an effect on heart rate. Pharmacokinetic-pharmacodynamic modelling of the concentration-effect relationship of Δ9-THC on CNS parameters and heart rate suggests that THC-evoked effects typically lag behind THC plasma concentration, with the effects lasting significantly longer than Δ9-THC plasma concentrationsReference494. The equilibration half-life estimate for heart rate was approximately 7 min, but varied between 39 and 85 min for various CNS parametersReference494. According to this model, the effects on the CNS developed more slowly and lasted longer than the effect on heart rate.

The psychomotor performance, subjective, and physiological effects associated with whole-blood Δ9-THC concentrations in heavy, chronic, cannabis smokers following an acute episode of cannabis smoking have been studiedReference409. Subjects reported smoking a mean of one joint per day in the previous 14 days prior to the initiation of the study (range: 0.7 – 12 joints per day). During the study, subjects smoked one cannabis cigarette (mean weight 0.79 g) containing 6.8% THC, 0.25% CBD, and 0.21% CBN (w/w) yielding a total THC, CBD, and CBN content of 54, 2.0, and 1.7 mg of these cannabinoids per cigarette. Mean peak THC blood concentrations and peak Visual Analogue Scale (VAS) scores for different subjective measures occurred 15 min after starting smoking. According to the authors of the study, the pharmacodynamic-pharmacokinetic relationship displayed a counter-clockwise hysteresis (i.e. where for the same plasma concentration of a drug (e.g. THC), the pharmacological effect is greater at a later time point than at an earlier one) for all measured subjective effects (e.g. “good drug effect”, “high”, “stoned”, “stimulated”, “sedated”, “anxious”, and “restless”). This particular kind of relationship demonstrates a lack of correlation between blood concentrations of THC and observed effects, beginning immediately after the end of smoking and continuing during the initial distribution and elimination phases. All participants reported a peak subjective “high” between 66 and 85 on the VAS, with peak whole blood THC concentrations at the time of these responses ranging from 13 to 63 ng/mL. Following the start of cannabis smoking, heart rate increased significantly at the 30 min time point, diastolic blood pressure decreased significantly only from the 30 min to 1 h time point, and systolic blood pressure and respiratory rate were unaffected at any time.

A study that examined the acute subjective effects associated with smoked cannabis at three different doses (i.e. 29.3, 49.1 and 69.4 mg THC) reported that THC significantly increased feelings of “high”, “dizziness”, “impaired memory and concentration” as well as “down”, “sedated” and “anxious” feelingsReference495. In addition, the study also showed that higher doses of THC were associated with longer duration of subjective effects. Findings from the study showed that the time required to reach a maximal “high” rating was slightly delayed (11 – 16 min) compared to the time required to reach the peak THC serum concentration. The “high” rating declined after reaching the peak within the first 3.5 h post-dose. Scores on the VAS for “dizziness”, “dry mouth”, “palpitations”, “impaired memory and concentration”, “down”, “sedated”, and “anxious feelings” reached a maximum within the first 2 h post-dose and these effects were dose-dependent. With a dose of 29.3 mg THC in the cigarette (equivalent to, for example, a 300 mg joint containing 10% THC or 150 mg of a 20% THC joint), the maximal serum THC concentration was ~120 ng/mL and was associated with a 50% maximal “high”. A dose of 49.1 mg THC in the cigarette (equivalent to, for example, a 500 mg joint containing 10% THC or a 250 mg joint containing 20% THC) was associated with a maximal serum THC concentration of 170 ng/mL and a 60% maximal “high”. Finally, a THC dose of 69.4 mg of THC (equivalent to, for example, 700 mg of a 10% THC joint or 350 mg of a 20% THC joint) was associated with a serum THC concentration of 200 ng/mL and an 80% maximal “high”. The THC-induced decrease in stimulation (i.e. sedation) and increase in anxiety lasted up to 8 h post-smoking. In fact, sedation was increased by almost six-fold compared to placebo. The low THC dose was associated with the highest ratings of “like the effects of the drug” and “want more of this drug”.

Vapourized cannabis

Inhalation of vapourized cannabis (900 mg of 3.56% Δ9-THC; total available dose of 32 mg of Δ9-THC) resulted in mean plasma Δ9-THC levels of 126.1 ng/mL within 3 min after starting cannabis inhalation, rapidly declining to 33.7 ng/mL Δ9-THC at 10 min, and reaching 6.4 ng/mL Δ9-THC at 60 minReference280. Peak Δ9-THC concentration (Cmax) was achieved at 3 min in all study participants. Maximal subjective “high” ratings occurred at 60 min following beginning of inhalation.

One clinical study reported that ad libitum vapourization of 500 mg cannabis containing a low-dose (2.9%) of THC (~14.5 mg THC), or high-dose (6.7%) of THC (~33.5 mg THC) was associated with median whole-blood Cmax values of 32.7 (low-dose) and 42.2 ng/mL (high-dose) THC, and median plasma Cmax values of 46.5 (low-dose) and 62.1 ng/mL (high-dose) THC at 10 min post-inhalationReference206. Median whole-blood Cmax values for 11-hydroxy-THC were 2.8 (low-dose) and 5.0 ng/mL (high-dose) and median plasma Cmax values were 4.1 (low-dose) and 7 ng/mL (high-dose) at 10 – 11 min post-inhalation. Subjective effects were then measured at several time points and effects were correlated with concentrations of cannabinoids in oral fluid and blood. Blood THC was positively associated with “high”, “good drug effect”, “stimulated”, “stoned”, “anxious”, and “restless” and with feelings of altered time, “slowed/slurred speech”, “dizziness”, and “dry mouth/throat”. There were no significant differences between the effects seen with the low (2.9%) and the high (6.7%) dose of cannabis. Vapourized cannabis significantly increased measures of “stoned” and “sedated” immediately post-dose and lasted 3.3 h (or 4.3 h with the addition of alcohol). Feelings of “anxious” showed significant cannabis-dose effects through 1.4 h. Undesirable effects, including “feeling thirsty” and “dry mouth/throat”, increased for the first 3.3 h post-dose. “Difficulty concentrating” and “altered sense of time” produced mixed effects over 2.3 h. Effects and time course of effects were similar between vapourized and smoked cannabis.

Another study measured 17 different psychoactive effects as a function of THC dose and time in vapourized cannabisReference276. In this randomized, double-blind, placebo-controlled clinical study, patients inhaled a total of 8 to 12 puffs of vapourized cannabis containing either 0%, 2.9% or 6.7% THC (400 mg each). The 2.9% dose was associated with a Cmax of 68.5 ng/mL and the 6.7% dose was associated with a Cmax of 177.3 ng/mL. Plasma 11-hydroxy-THC Cmax for the 2.9% dose was 5.6 ng/mL and for the 6.7% dose was 12.8 ng/mL. The lower dose produced effects lower than that for the high dose and placebo effects were lower than both active doses for “any drug effect”, “good drug effect”, “high”, “impaired”, “stoned”, “sedated” and “changes perceiving space”. For “bad drug effect”, “like the drug”, “nauseous”, “changes perceiving time”, ratings with placebo were significantly lower than both active doses. The higher dose (6.7%) was associated with significantly higher ratings of “desires more”, “hungry”, “difficulty remembering things”, “drunk”, “confused”, and “difficulty paying attention” compared with placebo, with only “drunk”, “confused” and “difficulty paying attention” significantly different between the high and low dose. There was a clear dose-response effect for the majority of psychoactive effects.

Oral and oro-mucosal cannabinoids

The subjective and physiological effects after controlled administration of oro-mucosal nabiximols (Sativex®) or oral Δ9-THC have also been comparedReference122. Increases in systolic blood pressure occurred with low (5 mg) and high (15 mg) oral doses of THC, as well as low (5.4 mg Δ9-THC and 5 mg CBD) and high (16.2 mg Δ9-THC and 15 mg CBD) oro-mucosal doses of nabiximols, with the effect peaking at around 3 h after administration. In contrast, diastolic blood pressure decreased between 4 and 8 h after dosing. Heart rate increased after all active treatments. A statistically significant increase in heart rate relative to placebo was observed after high-dose oral THC (15 mg Δ9-THC) and high-dose oro-mucosal nabiximols (16.2 mg Δ9-THC and 15 mg CBD), but the authors indicated that the increases appeared to be less clinically significant than those typically seen with smoked cannabis. High-dose oral THC (15 mg Δ9-THC) and high-dose oro-mucosal nabiximols (16.2 mg Δ9-THC and 15 mg CBD) were associated with significantly greater “good drug effects” compared to placebo, whereas low-dose oro-mucosal nabiximols (5.4 mg Δ9-THC and 5 mg CBD) was associated with significantly higher “good drug effects” compared to 5 mg THC. A subjective feeling of a “high” was reported to be significantly greater after 15 mg oral THC compared to placebo and to 5 mg oral THC. In contrast, neither the high nor the low doses of oro-mucosal nabiximols were reported to produce a statistically significant subjective “high” feeling. Study subjects reported being most “anxious” approximately 4 h after administration of 5 mg oral THC, 3 h after 15 mg oral THC, 5.5 h after low-dose nabiximols, and 4.5 h after high-dose oro-mucosal nabiximols. All active drug treatments induced significantly more anxiety compared to placebo. After 15 mg oral THC, the concentration of THC in plasma was observed to have a weak, but statistically significant, positive correlation with systolic and diastolic blood pressure, “good drug effect”, and “high”. After high-dose oro-mucosal nabiximols, positive correlations were also observed between plasma THC concentrations and “anxious”, “good drug effect”, “high”, “stimulated”, and M-scale (marijuana-scale) scores. Consistent with other studies, the authors of this study reported that linear correlations between plasma THC concentrations and physiological or subjective effects were weak. Lastly, although CBD did not appear to significantly modulate the effects of THC, the authors suggested it might have attenuated the degree of the subjective “high”.

A dose run-up clinical study looking at the pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of THC (i.e. 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg) in seven cannabis users reported that Cmax generally increased as a function of dose but varied considerably across subjects, especially at higher dosesReference496. There was also substantial variability for Tmax both within and between subjects with an overall median of 3.3 h for both THC and 11-hydroxy-THC. THC dose-dependently elevated heart rate, and systolic blood pressure dropped at the lower dose (i.e. 30 mg) but increased at higher doses (i.e. 75 mg and 90 mg). No changes were noted for diastolic blood pressure. With regard to subjective responses, “any drug effect” and “thirsty”‘ ratings increased as a function of dose, however for effects such as “good drug effects”, “high”, “tired/sedated”, “stoned”, “forgetful” and “confused/difficulty concentrating” doses larger than 30 mg were not consistently associated with higher ratings.

2.4 Tolerance, dependence, and withdrawal symptoms

Tolerance

Tolerance, as defined by the Liaison Committee on Pain and Addiction (a joint committee with representatives from the American Pain Society, the American Academy of Pain Medicine, and the American Society of Addiction Medicine) is a state of adaptation in which exposure to the drug causes changes that result in a diminution of one or more of the drug’s effects over timeReference497.

Tolerance to the effects of cannabis or cannabinoids appears to result mostly from pharmacodynamic rather than pharmacokinetic mechanismsReference328. Pre-clinical studies indicate that pharmacodynamic tolerance is mainly linked to changes in the availability of the cannabinoid receptors, principally the CB1 receptor, to signal. There are two independent but interrelated molecular mechanisms producing these changes: receptor desensitization (or uncoupling of the receptor from intracellular downstream signal transduction events), and receptor downregulation (resulting from the internalization and/or degradation of the receptor)Reference498. Furthermore, within the brain, these adaptations appear to vary across different regions suggesting cellular- and tissue-specific mechanisms regulating desensitization/downregulationReference328. Studies have reported that CB1 receptors in the caudate-putamen and its projection areas (e.g. globus pallidus and substantia nigra) show the least magnitude of CB1 receptor desensitization and downregulation, whereas CB1 receptors in the hippocampus exhibit the greatest magnitude of desensitization and downregulation in response to chronic THC exposureReference499. CBreceptors located in the striatum are also less susceptible to desensitization and downregulation relative to the hippocampusReference499.

One clinical study showed that chronic cannabis use was associated with a global decrease in CB1 receptor availability in the brain with significant decreases in CB1 receptor availability in the temporal lobe, anterior and posterior cingulate cortices, and the nucleus accumbensReference500. Study subjects were mostly male, had a mean age at onset of cannabis use of 16 years of age, a mean duration of cannabis use of 10 years, a mean amount of cannabis use of three joints per day, and 60% of the study subjects were considered heavy users (several times per day), 30% were moderate users (once per day to 3 – 4 times per week), and 10% used infrequently (two to three times per month or less). Furthermore, a couple of clinical studies have examined the time course of changes in the availability of CB1 receptors following chronic THC administration and abstinenceReference334Reference501. In the first study, heavy chronic daily cannabis smoking (average 10 joints/day for average of 12 years) was associated with reversible and regionally selective downregulation (20% decrease) of brain cortical (but not subcortical) cannabinoid CB1 receptorsReference501. In the second study, cannabis dependence (with chronic, moderate daily cannabis smoking) was associated with CB1 receptor downregulation (i.e. ~15% decrease at baseline, not under intoxication or withdrawal) compared to healthy controlsReference334. CB1 receptor downregulation began to reverse rapidly upon termination of cannabis use (within two days), and after 28 days of continuous monitored abstinence CB1 receptor availability was not statistically significantly different from that of healthy controls (although CB1 receptor availability never reached the levels seen with healthy controls). CB1receptor availability was also negatively correlated with cannabis dependence and withdrawal symptoms.

The observed regional variations in cellular adaptations to THC in the brain may also generalize to other tissues or organs, explaining why tolerance develops to some of the effects of cannabis and cannabinoids but not to other effects. In animal models, the magnitude and time-course of tolerance appear to depend on the species, the cannabinoid ligand, the dose and duration of the treatment, and the measures employed to determine tolerance to cannabinoid treatmentReference328.

Tolerance to most of the effects of cannabis and cannabinoids can develop after a few doses, and it also disappears rapidly following cessation of administrationReference140. Tolerance has been reported to develop to the effects of cannabis on perception, psychoactivity, euphoria, cognitive impairment, anxiety, cortisol increase, mood, intraocular pressure (IOP), electroencephalogram (EEG), psychomotor performance, and nausea; some have shown tolerance to cardiovascular effects while others have notReference324Reference332Reference333. There is also some evidence to suggest that tolerance can develop to the effects of cannabis on sleep (reviewed inReference209). As mentioned above, the dynamics of tolerance vary with respect to the effect studied; tolerance to some effects develops more readily and rapidly than to othersReference330Reference331. However, tolerance to some cannabinoid-mediated therapeutic effects (i.e. spasticity, analgesia) does not appear to develop, at least in some patientsReference216Reference325Reference327. According to one paper, in the clinical setting, tolerance to the effects of cannabis or cannabinoids can potentially be minimized by combining lower doses of cannabis or cannabinoids along with one or more additional therapeutic drugsReference502.

One study reported that tolerance to some of the effects of cannabis, including tolerance to the “high”, developed both when THC was administered orally (30 mg; q.i.d. for four days; total daily dose 120 mg)Reference503 and when a roughly equivalent dose was given by smoking (3.1% THC cigarette; q.i.d. for four days)Reference504. There was no diminution of the appetite-stimulating effect from either route of administration. In another study, the intensity of THC-induced acute subjective effect was reportedly decreased by up to 80% after 10 days of oral THC administration (10 – 30 mg THC every 3 – 4 h)Reference505.

A clinical study that evaluated the effects of smoked cannabis on psychomotor function, working memory, risk-taking, subjective and physiological effects in occasional and frequent cannabis smokers following a controlled smoking regimen reported that when compared to frequent smokers, occasional smokers showed significantly more psychomotor impairment, more significant impairment of spatial working memory, significantly increased risk-taking and impulsivity, significantly higher scores for “high” ratings, for “stimulated” ratings, and more anxietyReference181. Significantly higher scores were reported by occasional than frequent smokers for “difficulty concentrating”, “altered sense of time”, “feeling hungry”, “feeling thirsty”, “shakiness/tremulousness”, and “dry mouth or throat”. Compared with frequent smokers, occasional smokers had significantly increased heart rates relative to baseline and higher systolic and diastolic blood pressure just after dosing. These findings suggest that frequent cannabis users can develop some tolerance to some psychomotor impairments despite higher blood concentrations of THC. Occasional smokers also reported significantly longer and more intense subjective effects compared with frequent smokers who had higher THC concentrations suggesting tolerance can develop to the subjective effects.

A clinical study evaluated the development of tolerance to the effects of around-the-clock oral administration of THC (20 mg every 3.5 – 6 h) over six days, in 13 healthy male daily cannabis smokersReference324. The morning THC dose increased intoxication ratings on day 2 but had less effects on days 4 (after administration of a cumulative 260 mg dose of THC) and 6, while THC lowered blood pressure and increased heart rate over the six-day period suggesting the development of tolerance to the subjective intoxicating effects of THC and the absence of tolerance to its cardiovascular effects. Tolerance to the subjective intoxicating effects of THC administered orally was manifested after a total exposure of 260 mg of THC over the course of four daysReference324.

Another clinical study reported that while heavy chronic cannabis smokers demonstrated tolerance to some of the behaviourally-impairing effects of THC, these subjects did not exhibit cross-tolerance to the impairing effects of alcohol, and alcohol potentiated the impairing effects of THC on measures such as divided attentionReference506.

An uncontrolled, open-label extension study of an initial five-week randomized trial of nabiximols in patients with MS and central neuropathic pain reported the absence of pharmacological tolerance (measured by a change in the mean daily dosage of nabiximols) to cannabinoid-induced analgesia, even after an almost two-year treatment period in a group of select patientsReference327. Another long-term, open-label extension study of nabiximols in patients with spasticity caused by MS echoed these findings, also reporting the absence of pharmacological tolerance to the anti-spastic effects (measured by a change in the mean daily dosage of nabiximols) after almost one year of treatmentReference325. A multi-centre, prospective, cohort, long-term safety study of patients using cannabis as part of their pain management regimen for chronic non-cancer pain reported small and non-significant increases in daily dose over a one-year study periodReference216.

More recently, a double-blind, placebo-controlled, three-way cross-over clinical study with regular cannabis users suggested that tolerance may not develop towards some of the acute effects on neurocognitive functions despite regular cannabis useReference415. One hundred and twenty-two subjects who regularly used cannabis (average duration of use: 7 years; range: 1 – 23 years), with an average rate of use of 44 use occasions (range: 2 – 100) over the course of the previous three months, participated in the study. Treatments consisted of vapourized placebo or 300 µg/kg THC (cannabis containing 11 – 12% THC). Acute administration of vapourized cannabis impaired performance across a wide range of neurocognitive domains: executive function, impulse control, attention and psychomotor function were significantly worse after cannabis compared to placebo. Frequency of cannabis use correlated significantly with change in subjective intoxication following cannabis administration and also correlated and interacted with changes in psychomotor performance meaning that subjective intoxication and psychomotor impairment following cannabis exposure decreased with increasing frequency of use, however the baseline for subjective intoxication and psychomotor impairment was already higher for frequent users compared to less frequent users (likely owing to already elevated THC body burden which can cause sufficient levels of intoxication and mild psychomotor impairment). The authors suggest that the neurocognitive functions of daily or near daily cannabis users can be substantially impaired from repeated cannabis use, during and beyond the initial phase of intoxication.

Pharmacokinetic tolerance (including changes in absorption, distribution, biotransformation and excretion) has also been documented to occur with repeated cannabinoid administration, but apparently occurs to a lesser degree than pharmacodynamic toleranceReference507.

Dependence and withdrawal

Dependence can be divided into two independent, but in certain situations interrelated concepts: physical dependence and psychological dependence (i.e. addiction)Reference497. Physical dependence, as defined by the Liaison Committee on Pain and Addiction, is a state of adaptation manifested by a drug-class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonistReference497. Psychological dependence (i.e. addiction) is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations, and is characterized by behaviours that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and cravingReference497. The ECS has been implicated in the acquisition and maintenance of drug taking behaviour, and in various physiological and behavioural processes associated with psychological dependence or addictionReference2. In the former DSM-IV (diagnostic and statistical manual of mental disorders (fourth edition), the term ‘dependence’ was closely related to the concept of addiction which may or may not include physical dependence, and is characterized by use despite harm, and loss of control over useReference508. There is evidence that cannabis dependence (physical and psychological) occurs, especially with chronic, heavy useReference145Reference190Reference329. In the new DSM-5, the term “cannabis dependence” has been replaced with the concept of a “cannabis use disorder” (CUD) which can range in intensity from mild to moderate to severe with severity based on the number of symptom criteria endorsedReference509. The DSM-5 defines a CUD as having the following diagnostic criteria: a problematic pattern of cannabis use leading to clinical significant impairment or distress, as manifested by at least two symptoms, occurring within a 12-month period. For a list of symptoms, please refer to the DSM-5 Reference509.

Psychological dependence

Risk factors for transition from use to dependence have been identified and include being young, male, poor, having a low level of educational attainment, urban residence, early substance use onset, use of another psychoactive substance, and co-occurrence of a psychiatric disorderReference510. Notably, the transition to cannabis dependence occurs considerably more quickly than the transition to nicotine or alcohol dependenceReference510. It has been reported that after the first year of cannabis use onset, the probability of transition to dependence is almost 2%, while the lifetime prevalence of cannabis dependence among those who ever used cannabis is approximately 9%Reference510. The prevalence of developing a CUD increases to between 33 and 50% among daily usersReference511. More recent U.S. epidemiological data suggest that 12-month and lifetime prevalence of DSM-5 CUD was 2.5% and 6.3% respectively, and the corresponding DSM-IV 12-month and lifetime rates showed a substantial increase between 2001 – 2002 and 2012 – 2013 increasing from 12-month and lifetime rates of 1.5% and 8.5% respectively to 2.9% and 11.7% respectivelyReference338. These increases in both 12-month and lifetime prevalence are thought to be driven by increases in the prevalence of cannabis users.

The National Epidemiological Survey on Alcohol and R elated Conditions (NESARC), a large U.S. national prospective study conducted among 34 653 respondents examining the association between cannabis use and risk of mental health and substance use disorders in the U.S. general adult population, reported that cannabis use (at Wave 1, 2001 – 2002) was associated with later development (at Wave 2, 2004 – 2005) of substance use disorders (i.e. any substance use disorder: OR = 6.2, 95% CI = 4.1 – 9.4; any alcohol use disorder: OR = 2.7, 95% CI = 1.9 – 3.8; any CUD: OR = 9.5, 95% CI = 6.4 – 14.1; any other drug use disorder: OR = 2.6, 95% CI = 1.6 – 4.4; and nicotine dependence: OR = 1.7; 95% CI = 1.2 – 2.4), but not any mood disorder or anxiety disorderReference512. Higher frequency of cannabis use was associated with greater risk of disorder incidence and prevalence, supporting a dose-response association between cannabis use and risk of substance use disorders.

Another study using the U.S. NESARC data (2012 – 2013) found that the odds of 12-month and lifetime CUD were higher for men, Native Americans, unmarried individuals, those with low incomes, and young adults (e.g. among those 18 – 24 years of age compared to those over 45, OR = 7.2, 95% CI = 5.5 – 9.5)Reference338. Furthermore, 12-month CUD was associated with other substance use disorders (OR = 6.0 – 9.3), affective/mood disorders (OR = 2.7 – 5.0), anxiety disorders (OR = 1.7 – 3.7), and personality disorders (OR = 3.8 – 5.0). Survey respondents with 12-month CUD differed significantly from others on all disability components of the survey, with disability increasing significantly, as cannabis disorder severity increased. Among participants with 12-month DSM-5 CUD, 61% had craving for cannabis, 32% had cannabis withdrawal symptoms, and 23% had both.

Comparing data between the NESARC 2001 – 2002 (Wave 1) and 2012 – 2013 (Wave 2), one study reported that the prevalence of cannabis use more than doubled between the two waves of the surveyReference513. Furthermore, there was a large increase in CUD during this intervening time, with nearly 3 out of 10 cannabis users reporting a CUD in 2012 – 2013. Young adults were at highest risk of CUD in both survey waves (OR = 7.2 for ages 18 – 29; OR = 3.6 for ages 30 – 44) however, the relative increases in prevalence of CUD among adults aged 45 to 64 years and 65 years and older were much greater than the increases in young adults.

A retrospective study among a nationally representative sample of 6 935 Australian adults examining the initiation of cannabis use and transition to CUD found that the mean time from first use to the onset of CUD was 3.3 years (median time = 2 years), with 90% of cases manifesting within eight yearsReference514. Younger age of initiation and other substance use were strong predictors of the transition from use to CUD. In fact, younger age of first cannabis use was associated with increased risk of transition to CUD, with each year older at first use associated with 11% lower odds of onset of CUD. Social phobia and panic disorder were also associated with transition from cannabis use to CUD. Male cannabis users had greater risk of CUD than female users, but among women, those with depression were more likely to develop a CUD. Early-onset of alcohol and daily cigarette smoking were each associated with marked increased risk of early initiation of cannabis use.

A handful of clinical studies have examined the differences between men and women with respect to development of dependence, withdrawal symptoms and relapseReference515. See Section 2.5, Sex-dependent effects for additional information.

Physical dependence

Physical dependence is most often manifested in the appearance of withdrawal symptoms when use is abruptly halted or discontinued. Withdrawal symptoms associated with cessation of cannabis use (oral or smoked) appear within the first one to two days following discontinuation; peak effects typically occur between days 2 and 6 and most symptoms resolve within one to two weeksReference516Reference518. The most common symptoms include craving, anger or aggression, irritability, anxiety, nightmares/strange dreams, insomnia/sleep difficulties, headache, restlessness, and decreased appetite or weight lossReference190Reference329Reference342Reference516Reference517. Other symptoms appear to include depressed mood, chills, stomach pain, shakiness and sweatingReference190Reference329Reference342Reference517. Withdrawal symptoms are reported by up to one-third of regular users in the general population and by 50 – 95% in heavy users in treatment or in research studiesReference519. Cannabis withdrawal symptoms appear to be moderately inheritable with both genetic and environmental factors at playReference519. There are also emerging reports of increased physical dependence with highly potent cannabis extracts (e.g. concentrates such as butane hash oil and dabs) (OR = 1.2, p = 0.014)Reference520Reference521.

There are no approved pharmacotherapies for managing cannabis withdrawal symptomsReference522. A range of medications have been explored including antidepressants (e.g. buproprion, nefadozone)Reference523Reference524, mood stabilizers (e.g. divalproex, lithium, lofexidine)Reference525Reference527, and quetiapineReference528 but only limited benefits have been observedReference522. Zolpidem has also been explored as a potential pharmacotherapy to specifically target abstinence-induced disruptions in sleepReference529Reference530. However, agonist substitution therapy (e.g. dronabinol, nabilone, nabiximols) may be a more promising approachReference522.

A pilot clinical study that measured the feasibility/effects of fixed and self-titrated dosages of nabiximols on craving and withdrawal among cannabis-dependent subjects found that high fixed dosages of nabiximols (i.e. up to 40 sprays per day or 108 mg THC and 100 mg CBD) were well tolerated and significantly reduced cannabis withdrawal symptoms during abstinence, but not craving, compared to placeboReference339. Self-titrated doses were lower and showed limited efficacy compared to high fixed doses and subjects typically reported significantly lower ratings of “high” and shorter duration of “high” with nabiximols and placebo compared to smoking cannabis.

A randomized, double-blind, placebo-controlled, six-day, inpatient clinical study of nabiximols as an agonist replacement therapy for cannabis withdrawal symptoms reported that nabiximols treatment attenuated cannabis withdrawal symptoms and improved patient retention in treatmentReference522. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use at follow-up. Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal symptoms relative to placebo including effects on irritability, depression and craving as well as a more limited effect on sleep disturbance, anxiety, appetite loss, physical symptoms and restlessness.

A placebo-controlled, within-subject, clinical study demonstrated that nabilone (6 – 8 mg daily) decreased cannabis withdrawal symptoms including abstinence-related irritability and disruptions in sleep and food intake in daily, non-treatment seeking cannabis smokersReference531. It also decreased cannabis self-administration during abstinence in a laboratory model of relapse. While nabilone did not engender subjective ratings associated with abuse liability (i.e. drug liking, desire to take again), the high dose (8 mg) modestly decreased psychomotor task performance. A follow-up study found that nabilone (3 mg, b.i.d.) co-administered with zolpidem (12.5 mg) also ameliorated abstinence-induced disruptions in mood, sleep, and appetite, decreased cannabis smoking in the laboratory model of relapse, and did not affect cognitive performanceReference529.

A double-blind, placebo-controlled, 11-week clinical trial testing lofexidine and dronabinol for the treatment of CUD reported no significant beneficial effect compared to placebo for promoting abstinence, reducing withdrawal symptoms, or retaining individuals in treatmentReference532 in contrast to a previous study that showed efficacy of 40 mg dronabinol daily vs. placebo in alleviating withdrawal symptoms and improving treatment retention but not abstinenceReference533.

Cannabidiol for cannabis and other drug dependence

A recent systematic review of the evidence of CBD as an intervention for addictive behaviours reported that to date, only 14 studies have been conducted, the majority in animals with only a handful in humansReference341. The limited number of pre-clinical studies carried out to date suggest that CBD may have therapeutic potential for the treatment of opioid, cocaine and psychostimulant addiction, and some preliminary data suggest CBD may also be beneficial in cannabis and tobacco addiction in humansReference341. The limited number of pre-clinical studies published thus far suggest CBD may have an impact on the intoxication and relapse phase of opioid addiction, while CBD does not appear to have an impact on the rewarding effects of stimulants (e.g. cocaine, amphetamine) but may affect relapseReference341.

With respect to cannabis dependence, pre-clinical studies show that CBD is not reinforcing on its own, but its impact on cannabis-related dependence behaviour remains unclearReference341. In one clinical study, a 19 year-old female with cannabis dependence exhibiting cannabis withdrawal symptoms upon cannabis cessation was administered up to 600 mg of CBD (range: 300 – 600 mg) over the course of an 11-day treatment period and CBD treatment was associated with a rapid decrease in withdrawal symptomsReference341Reference534. In another human study, cannabis with a higher CBD to THC ratio was associated with lower ratings of pleasantness for drug stimuli (explicit “liking”), but no group difference in “craving” or “stoned” ratings was notedReference341Reference535. However, a multi-site, double-blind, placebo-controlled study demonstrated that CBD (200 – 800 mg) had no effect on subjective ratings associated with cannabis abuse liabilityReference536.

A randomized, double-blind, placebo-controlled clinical study of 24 tobacco smokers seeking treatment for tobacco dependence investigated the impact of CBD on nicotine addiction and found that inhalation of CBD (400 µg/inhalation), as needed, was associated with a significant reduction in the number of cigarettes smokedReference341Reference537.

A randomized, double-blind, crossover clinical study in 10 healthy volunteers examining the effects of CBD on the intoxication phase of alcohol addiction reported no differences in feelings of “drunk”, “drugged”, or “bad” between the alcohol only and the alcohol and CBD groupsReference341Reference538.

No pre-clinical studies exist on the use of CBD for hallucinogen-, sedative-, tobacco-, or alcohol-addictive behaviours and no human studies exist on the use of CBD for opioid-, psychostimulant-, hallucinogen-, or sedative-addictive behavioursReference341.

2.5 Special populations

Pediatric/Adolescent

The ECS is present in early development, is critical for neurodevelopment and maintains expression in the brain throughout lifeReference539. Furthermore, the ECS undergoes dynamic changes during adolescence with significant fluctuations in both the levels and locations of the CB1 receptor in the brain as well as changes in the levels of the endocannabinoids 2-AG and anandamideReference539. The dynamic changes occurring in the ECS during adolescence also overlap with a significant period of neuronal plasticity that includes neuronal proliferation, rewiring and synaptogenesis, and dendritic pruning and myelination that occurs at the same timeReference540. This period of significant neuroplasticity does not appear to be complete until at least the age of 25Reference540. Thus, this neurodevelopmental time window is critical for ensuring proper neurobehavioural and cognitive development and is also influenced by external stimuli, both positive and negative (e.g. neurotoxic insults, trauma, chronic stress, drug abuse)Reference540. Based on the available scientific evidence, youths are more susceptible to the adverse effects associated with cannabis use, especially chronic useReference182Reference541. Studies examining non-medical use of cannabis strongly suggest early onset (i.e. in adolescence and especially before age 15), regular and persistent cannabis use (of THC-predominant cannabis) is associated with a number of adverse effects on brain and behavioural development including CUD and addiction, other illicit drug use, compromised cognitive functioning and decreased IQ, deficits in attention, poorer educational attainment, suicidal ideation, suicide attempt, and increased risk of schizophrenia as well as an earlier onset of the latter diseaseReference151Reference542Reference552. Based on the current available evidence, it is unclear for how long some or all of the neurocognitive effects persist following cessation of use. Some investigators have found certain cognitive deficits to persist for up to one year or longer after cannabis cessation, while others have demonstrated a far shorter period of recovery (i.e. 28 days) for at least some of the evidenced deficitsReference150Reference151Reference552Reference554. A recent literature review of observational and pre-clinical studies revealed consistent evidence of an association between adolescent cannabis use (frequent/heavy use) and persistent adverse neuropsychiatric outcomes in adulthood. Though the data from human studies do not establish causality solely from cannabis use, the pre-clinical studies in animals do indicate that adolescent exposure to cannabinoids can catalyze molecular processes leading to functional deficits in adulthood – deficits that are not found following adult exposure to cannabis. The authors note that definitive conclusions cannot be made yet as to whether cannabis use – on its own – negatively impacts the adolescent brain, and future research can help elucidate this relationship by integrating assessments of molecular, structural, and behavioral outcomesReference555. Factors that may influence persistence of cognitive deficits can include age at onset of use, frequency and duration of use, co-morbidities, and use of other drugs (tobacco, alcohol, and other psychoactive drugs).

While adverse effects associated with THC-predominant cannabis use in youth have been well documented, far less is known about the adverse effects associated with CBD-predominant cannabis use. Nevertheless, as mentioned above, the ECS plays important roles in nervous system development in utero as well as during youth (see Section 7.4) and exposure to exogenous cannabinoids, especially at higher doses, on a daily basis and over a protracted period of time may alter the course of neurodevelopment (see Section 1.0 for additional information on the role of the ECS in the development of the nervous system).

Geriatric

There is evidence to suggest that like the changes seen with the ECS during development and adolescence, there are changes in the ECS associated with ageing. In rodents, there is a marked decline in the levels of CB1 mRNA and/or specific binding of CB1 agonists in the cerebellum, cortex, hippocampus and hypothalamus of older animalsReference556. In addition, the coupling of CB1 receptors to G proteins is also reduced in specific brain areas in older animalsReference556. Age-related changes in the expression of components of the ECS appear similar in rodents and humansReference556. Disruption of CB receptors appears to enhance age-related decline of a number of tissues suggesting an important role for the ECS in the control of the ageing processReference556.

In general, the elderly may be more sensitive to the effects of drugs acting on the CNSReference557. A number of physiological factors may lie at the root of this increased sensitivity such as: (1) age-related changes in brain volume and number of neurons as well as alterations in neurotransmitter sensitivity which can all increase the pharmacological effects of a drug; (2) age-related changes in the pre- and post-synaptic levels of certain neurotransmitter receptors; (3) age-related changes in the sensitivity of receptors to neurotransmitters; and (4) changes in drug disposition in the elderly being generally associated with higher concentrations of psychotropic drugs in the CNS. There is very little information available on the effects of cannabis and cannabinoids in geriatric populations and based on current levels of evidence, no firm conclusions can be made with regard to the safety or efficacy of cannabinoid-based drugs in elderly patients (but see below for one of the few clinical studies of safety carried out specifically in geriatric populations)Reference421Reference557Reference558. Furthermore, as cannabinoids are lipophilic, they may tend to accumulate to a greater extent in elderly individuals since such individuals are more likely to have an increase in adipose tissue, a decrease in lean body mass and total body water, and an increase in the volume of distribution of lipophilic drugsReference557. Lastly, age-related changes in hepatic function such as a decrease in hepatic blood flow and slower hepatic metabolism can slow the elimination of lipophilic drugs and increase the likelihood of adverse effectsReference557.

Clinical Studies

A randomized, double-blind, placebo-controlled, cross-over clinical trial that evaluated the pharmacokinetics of THC in 10 older patients with dementia (mean age 77 years) over a 12-week period reported that the median time to reach maximal concentration in the blood (Tmax) was between 1 and 2 h with THC pharmacokinetics increasing linearly with increasing dose but with wide inter-individual variationReference421. Patients received 0.75 mg THC twice daily over the first six weeks and 1.5 mg THC twice daily over the second six-week period. The mean Cmax after the first 0.75 mg THC dose was 0.41 ng/mL and after the first 1.5 mg THC dose was 1.01 ng/mL. After the second dose of 0.75 mg THC or 1.5 mg THC, the Cmax was 0.50 and 0.98 ng/mL respectively.

Only one clinical study has thus far been carried out looking specifically at the safety of THC in an elderly population. This phase I, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial of three single oral doses of Namisol®, a novel tablet form of THC (i.e. 3 mg, 5 mg, 6.5 mg THC)Reference180reported that, overall, the pharmacodynamic effects of THC in healthy older individuals were smaller than effects previously reported in young adults and that THC, at the doses tested, appeared to be well-tolerated by healthy older individualsReference180. In this study, 12 adults aged 65 and older who were deemed to be healthy were included, and exclusion criteria included high falls risk, regular cannabis use, history of sensitivity to cannabis, drug and alcohol abuse, compromised cardiopulmonary function, and psychiatric comorbidities. The most commonly reported health problems were hypertension and hypercholesterolemia and subjects reported using an average of 2 medications (e.g. lipid-lowering drugs, aspirin, and beta-blockers). The most frequently reported adverse effects associated with THC were drowsiness (27%), dry mouth (11%), coordination disturbance (9%), headache (9%), difficulties concentrating (7%), blurred vision (5%), relaxation, euphoria and dizziness (5% each); nausea, dry eyes, malaise and visual hallucinations were all reported at a frequency of 2% in this trial. Adverse events first occurred within 20 min of dosing, with all adverse events occurring between 55 and 120 min after dosing and resolving completely within 3.5 h after dosing. There appeared to be a dose-dependent increase in the number of individuals reporting an increased number of adverse events with increasing doses of Namisol®. No moderate or serious adverse events were reported in this trial. While this clinical study adds important information regarding the safety and tolerability of THC in a healthy elderly population, additional studies are needed to evaluate the safety and tolerability of cannabis and cannabinoids in elderly populations having various co-morbidities.

Sex-dependent effects

In humans, sex-dependent differences have been often observed in the biological and behavioural effects of substances of abuse, including cannabisReference559. In male animals, higher densities of CB1 receptors have been observed in almost all cerebral regions analyzed whereas in females a more efficient coupling of the CB1 receptor to downstream G-protein signaling has been observedReference560. In humans, sex differences in CB1 receptor density have also been reported, with men having higher receptor density compared to womenReference561. Sex-dependent differences have also been noted with respect to cannabinoid metabolism. Pre-clinical studies in females report increased metabolism of THC to 11-hydroxy-THC compared to males where THC was also biotransformed to at least three different, less active metabolitesReference562. There is also evidence to suggest that effects of cannabinoids vary as a function of fluctuations in reproductive hormonesReference515Reference563. Together, these findings suggest that the neurobiological mechanism underlying the sex-dependent effects of cannabinoids may arise from sexual dimorphism in the ECS and THC metabolism, but also from the effects of fluctuations in hormone levels on the ECSReference515Reference563.

There is also evidence to suggest sex-dependent differences in subjective effects and development of dependence, withdrawal symptoms, relapse and incidence of mood disorders. Data combined from four double-blind, within-subject studies measuring the effects of smoked “active” cannabis (3.27 – 5.50% THC) against smoked “inactive” cannabis (0.0 % THC) showed that, when matched for cannabis use (i.e. near-daily), women reported higher ratings of abuse-related effects relative to men under “active” cannabis conditions but did not differ in ratings of intoxicationReference515. These findings suggest that, at least among near-daily cannabis users, women may be more sensitive to the subjective effects of cannabis, especially effects related to cannabis abuse liability compared to men. Another study demonstrated dose-dependent sex differences in subjective responses to orally administered THCReference564. In this study, women showed greater subjective effects at the lowest dose (5 mg), whereas men showed greater subjective responses at the highest (15 mg) dose. Together, these studies suggest that while women may be more sensitive to the subjective effects of THC at lower doses, they may develop tolerance to these effects at higher doses, which could, for example, have implications for the development of dependence. For example, while cannabis use among men is more prevalent and men appear to be more likely than women to become dependent on cannabis, women tend to have shorter intervals between the onset of use and regular use or development of dependence (commonly referred to as the “telescoping effect”)Reference565. In addition, women abstaining from cannabis use reported more withdrawal symptoms, with some being more severe, than those seen in men and which have been linked to relapseReference566Reference567. Women with CUD also present with higher rates of certain comorbid health problems such as mood and anxiety disordersReference170Reference568Reference569.

3.0 Dosing

The College of Family Physicians of Canada, along with other provincial medical regulatory colleges, has issued a guidance document (in 2018) for authorizing the use of cannabis for medical purposes. Please consult these and any other official guidance documents, as applicable, for additional information regarding dosing and other matters associated with authorizing cannabis for medical purposes.

Cannabis has many variables that do not fit well with the typical medical model for drug prescribingReference405. The complex pharmacology of cannabinoids, inter-individual (genetic) differences in cannabinoid receptor structure and function, inter-individual (genetic) differences in cannabinoid metabolism affecting cannabinoid bioavailability, prior exposure to and experience with cannabis/cannabinoids, pharmacological tolerance to cannabinoids, changes to cannabinoid receptor distribution/density and/or function as a consequence of a medical disorder, the variable potency of the cannabis plant material and varying amounts and ratios of different cannabinoids, and the different dosing regimens and routes of administration used in different research studies all contribute to the difficulty in reporting precise doses or establishing uniform dosing schedules for cannabis (and/or cannabinoids)Reference405Reference484.

While precise dosages have not been established, some “rough” dosing guidelines for smoked or vapourized cannabis have been published (see below). Besides smoking and vapourization, cannabis is known to be consumed in baked goods such as cookies or brownies, or drunk as teas or infusions. However, absorption of these products by the oral route is slow and erratic, varies with the ingested matrix (e.g. fat content), and the onset of effects is delayed with the effects lasting much longer compared to smoking (see Section 2.2); furthermore, dosages for orally administered products are even less well established than for smoking/vapourization, however, some preliminary data has emerged for dosing with cannabis oilsReference137Reference418Reference422Reference570Reference571. Other forms of preparation reported in the lay literature include cannabis-based butters, candies, edibles, oils, compresses, creams, ointments, and tincturesReference80Reference572Reference575but again, limited dosing information exists here with much of the information being anecdotal in nature.

Dosing remains highly individualized and relies largely on titrationReference405. Patients with no prior experience with cannabis and initiating cannabis therapy for the first time are cautioned to begin at the very lowest dose and to stop therapy if unacceptable or undesirable side effects occur. Consumption of smoked/inhaled or oral cannabis should proceed slowly, waiting a minimum of 10 – 20 minutes between puffs or inhalations and waiting a very minimum of 30 minutes, but preferably 3 h, between bites of cannabis-based oral products (e.g. cookies, baked goods) to gauge for strength of effects or for possible overdosing. Subsequent dose escalation should be done slowly, once experience with the subjective effects is fully appreciated, to effect or tolerability. If intolerable adverse effects appear without significant benefit, dosing should be tapered and stopped. Tapering guidelines have not been published, but the existence of a withdrawal syndrome (see Section 2.4) suggests that tapering should be done slowly (i.e. over several days or weeks).

Minimal therapeutic dose and dosing ranges

Clinical studies of cannabis and cannabis-based products for therapeutic purposes are limited to studies carried out with dried cannabis that was smoked or vapourized and with synthetic or natural cannabis-based products that have received market authorization (i.e. dronabinol, nabilone, and nabiximols). With the possible exception of trials conducted with Epidiolex® (CBD-enriched oil) for epilepsyReference576Reference577 and one open-label pilot clinical trial of oral THC oil for symptoms associated with post-traumatic stress disorder (PTSD)Reference571 there are no other clinical studies of fresh cannabis or cannabis oils for therapeutic purposes. As such, providing precise dosing guidelines for such products is not possible although existing sources of information can be used as a reference point (see below).

Prescription cannabinoids

Information obtained from the monograph for Marinol® (dronabinol; no longer available in Canada) indicates that a daily oral dose as low as 2.5 mg Δ9-THC is associated with a therapeutic effect (e.g. treatment of AIDS-related anorexia/cachexia). Naturally, dosing will vary according to the underlying disorder and the many other variables mentioned above. Dosing ranges for Marinol® (dronabinol) vary from 2.5 mg to 40 mg Δ9-THC/day (maximal tolerated daily human dose = 210 mg Δ9-THC/day)Reference227. Average daily dose of dronabinol is 20 mg and maximal recommended daily dose is 40 mgReference227. Doses less than 1 mg of THC per dosing session may further avoid incidence and risks of adverse effects. Dosing ranges for Cesamet® (nabilone) vary from 0.2 mg to 6 mg/dayReference492Reference578. Dosing ranges for Sativex® (nabiximols) vary from one spray (2.7 mg Δ9-THC and 2.5 mg CBD) to 16 sprays (43.2 mg Δ9-THC and 40 mg CBD) per dayReference284Reference431. Information from clinical studies with Epidiolex®, an oil-based extract of cannabis containing 98% CBD, suggests a daily dosing range between 5 and 20 mg/kg/dayReference263Reference576. For additional information on dosing, please see the Access to Cannabis for Medical Purposes Regulations – Daily Amount Fact Sheet (Dosage).

Survey and clinical data

Various surveys published in the peer-reviewed literature have suggested that the majority of people using smoked or orally ingested cannabis for medical purposes reported using between 10 and 20 g of cannabis per week or approximately 1 to 3 g of cannabis per dayReference225Reference405Reference579.

An international, web-based, cross-sectional survey examining patients’ experiences with different methods of cannabis intake reported that from among a group of 953 self-selected participants, from 31 countries, the vast majority preferred inhalation over other means of administration (e.g. teas, foods, prescription cannabinoid medications) for symptoms such as chronic pain, anxiety, loss of appetite, depression, and insomnia or sleeping disorder. Mean daily doses with smoked or vapourized cannabis were 3.0 g (median for smoked cannabis was 2 g per day; for vapourized cannabis it was 1.5 g per day)Reference580. With foods/tinctures, mean daily dose was 3.4 g (median was 1.5 g per day), and with teas the mean daily dose was 2.4 g (median 1.5 g). Information regarding cannabinoid potencies of cannabis products (i.e. THC/CBD levels) was not available. Daily frequency of use for smoking was six times per day, whereas with vapourizing it was five times per day. Teas and food/tinctures were used on average twice per day. First onset of effects for smoking were noted on average around 7 min after start of smoking, 6.5 min after start of vapourizing, 29 min after ingestion of tea, and 46 min after ingestion of foods/tinctures. Other data suggests that those patients who use cannabis for medical purposes use up to one gram or less per day. For example, data from the Netherlands suggests the average daily dose of dried cannabis for medical purposes stood at 0.68 g per day (range: 0.65 – 0.82 g per day), whereas information obtained from the Israel medical cannabis program in 2016 suggests the average daily amount used by patients was slightly under 1.5 g (Health Canada personal communication). Canadian market data collected from licensed producers under the Access to Cannabis for Medical Purposes Regulations (ACMPRs) showed that, from April 2017 to March 2018, clients had been authorized by their healthcare practitioners to use, monthly, an average of 2.1-2.5 g/day of dried cannabis. However, since this data is collected per licensed producer, it does not include cases where clients split their authorization into two or more authorizations in order to register with more than one licensed producer at a time or personal production registrations with Health CanadaReference581. There is no specific data on the average amount of oil authorized by healthcare practitioners since authorized amounts are always in g/day. To fulfill orders for oils, licensed producers equate oil to dried cannabis based on the formulation of their oil products. On average, licensed producers equate 1 g of dried cannabis to 6.6 g of oil. Using this average conversion factor, healthcare practitioners have authorized an equivalent average of 13.9-16.5 g/day of oil.

Satisfaction ratings for criteria such as onset of effects and ease of dose finding were reported to be higher for smoking and vapourizing (i.e. smoking/vapourizing favoured) over other means of administrationReference580. However, prescription cannabinoid medications (e.g. dronabinol, nabilone, nabiximols) scored similarly to foods/tinctures and teas on satisfaction ratings related to daily dose needed, and ease of dose finding. Satisfaction ratings in terms of side-effects were higher for non-prescription unregulated cannabis products, with the inhaled route rated best, although the survey did not ask specific questions about the types of side effects. Satisfaction ratings were only slightly higher for orally ingested cannabis products for criteria such as duration of effects. Satisfaction ratings in terms of costs were slightly higher for smoking/vapourizing, teas, and foods/tinctures compared to prescription cannabinoid medications. Satisfaction ratings in terms of ease of preparation and intake were lowest for teas and foods/tinctures. The majority of survey participants had indicated having used cannabis products prior to onset of their medical condition.

A prospective, open-label, longitudinal study of patients with treatment resistant chronic pain reported that patients titrate their cannabis dose starting with one puff or one drop of cannabis oil per day, increasing in increments of one puff or one drop of oil per dose, three times per day until satisfactory pain relief was achieved or side effects appearedReference582. THC concentrations in the smoked product ranged between 6 – 14 % THC and between 11 – 19 % in the oral oil formulations, with CBD concentrations between 0.2 – 3.8 % in the smoked product and 0.5 – 5.5 % in the oral oil formulation. Mean monthly prescribed amount of cannabis was 43 g or 1.4 g/day.

Data from randomized, double-blind, placebo-controlled clinical studies of smoked or vapourized cannabis used a daily dose of up to 3.2 grams of dried cannabis of varying potencies (range: 1 – 23 % THC; see Table 5).

Data from a pilot clinical trial with the Syqe Inhaler™ has shown that an inhaled (vapourized) dose of 3 mg THC (delivered from an amount as low as 15 mg of dried cannabis plant material at a potency of 20% THC; actual dose absorbed 1.5 mg THC) was associated with analgesic efficacy with minimal adverse effectsReference58. In contrast to the gram amounts of cannabis used with smoked, vapourized, and oral routes of administration, the mean daily amounts for prescription cannabinoids such as dronabinol were 30 mg, for nabilone 4.4 mg, and for nabiximols 46 mg THC and 43 mg CBD (i.e. 17 sprays).

Taken together, data from patient surveys and clinical studies suggests that most patients use up to 3 g of dried cannabis per day for medical purposes, although much less (< 1 g/day) can be used with apparent efficacy and decreased incidence of side-effects.

Dosing and threshold of psychotropic effects

With respect to the relationship between dosing and psychotropic effects, it has been estimated that an inhaled dose of 0.045 – 0.1 mg/kg of THC (i.e. an individual inhaled dose of 3 – 6 mg THC) would be sufficient to reach the threshold for psychotropic effects, with an inhaled dose of 0.15 – 0.3 mg/kg THC (i.e. an individual inhaled dose of 10 – 20 mg THC) being sufficient to produce marked intoxicationReference415Reference583. Furthermore, it has been estimated that between one and three puffs of higher potency cannabis would be sufficient to produce significant psychoactive effectsReference495. One study has shown that while cannabis smokers titrate their dose of THC by inhaling lower volumes of smoke when smoking “strong” joints (i.e. “skunk”, > 15% THC), this did not fully compensate for the higher THC doses per joint when using “strong” cannabis and therefore users of more potent cannabis are exposed to greater quantities of THCReference584. For oral administration, a dose of 0.15 – 0.3 mg/kg of THC (i.e. an individual oral dose of 10 – 20 mg THC) would be sufficient to reach the threshold for psychotropic effects and a dose of 0.45 – 0.6 mg/kg of THC (i.e. an individual oral dose of 30 – 40 mg of THC) would be sufficient to produce marked intoxicationReference415Reference583Reference585.

Monitoring and clinical practice guidelines

The College of Family Physicians of Canada has published a guidance document describing a patient monitoring strategy/approach for physicians considering authorizing the use of marijuana for medical purposesReference586. Other provincial bodies may also provide guidelines on monitoringReference275. The College of Family Physicians of Canada has recently published a simplified guideline for prescribing medical cannabinoids in primary careReference587.

Beaulieu et al. have elaborated recommendations for physicians with respect to the evaluation and management of patients that could be candidates for cannabis/cannabinoidsReference275. The recommendations are as follows:

Table 2. Recommendations for the Evaluation and Management of Patients

  1. Take a medical history and perform a physical examination
  2. Assess symptoms to be treated, identify any active diagnoses, and ensure patients are under optimal management
  3. Assess psychological contributors and risk of addiction or substance abuse
  4. Document any history or current use of illicit or non-prescribed drugs, including cannabis and synthetic cannabinoids
  5. Determine the effect of previous use of cannabinoids for medical purposes
  6. Consider a urinary drug screening to assess current use of prescribed and non-prescribed medications
  7. Set goals for treatment with cannabis – e.g., pain reduction, increased functional abilities, improved sleep quality, increased quality of life, reduced use of other medications
  8. Develop a treatment plan incorporating these goals
  9. Discuss likely and possible side effects that might be experienced with cannabis/cannabinoid use
  10. Discuss the risks of addiction
  11. Develop a follow-up schedule to monitor the patient
  12. Determine whether the goals of treatment are being achieved and the appropriateness of the response
  13. Monitor for potential misuse or abuse (being aware of clinical features of cannabis dependence)
  14. Develop a treatment strategy, particularly for patients at risk
  15. Maintain an ongoing relationship with the patient

3.1 Smoking

According to the World Health Organization (WHO)Reference588, a typical joint contains between 500 mg and 1.0 g of cannabis plant matter (average weight = 750 mg) which may vary in Δ9-THC content between 7.5 and 225 mg (i.e. typically between 1 and 30%; see Table 3), and in CBD content between 0 and 180 mg (i.e. between 0 and 24%). The majority of clinical trials with smoked cannabis for medical purposes have used joints of dried cannabis weighing between 800 and 900 mg. Estimates that are more recent suggest the mean weight of cannabis in a joint is 320 mgReference589. The gram amount of cannabis plant material combusted in a “typical” puff has been estimated to range between 25 and 50 mg/puff, although amounts as high as 160 mg/puff have been notedReference59Reference143Reference403Reference583Reference590.

The actual amount of Δ9-THC delivered in the smoke varies widely and has been estimated at 20 to 70%, the remainder being lost through combustion or side-stream smokeReference405. Furthermore, the bioavailability of Δ9-THC (the fraction of Δ9-THC in the cigarette which reaches the bloodstream) from the smoking route is highly variable (2 – 56%) and influenced by the smoking topography (i.e. the number, duration, and spacing of puffs, hold time and inhalation volume)Reference404. In addition, expectation of drug reward can also influence smoking dynamicsReference591. Thus, the actual dose of Δ9-THC absorbed systemically when smoked is not easily quantified, but has been approximated to be around 25% of the total available amount of Δ9-THC in a cigaretteReference141Reference405Reference592.

Relationship between a smoked/vapourized dose and an oral dose

Little reliable information exists regarding conversion of a “smoked dose” of THC to an equivalent oral dose. However, based solely on measures of bioavailability, multiplication of a “smoked dose” of Δ9-THC by a conversion factor of 2.5 (to correct for differences between the bioavailability of Δ9-THC through the smoked route (~25%) vs. the oral route (~10%), ~ three-fold difference between inhaled and oral routes) can yield an approximately equivalent oral dose of Δ9-THCReference141Reference583Reference592. However, it is important to point out that these studies did not accurately measure the exact smoked dose of Δ9-THC that was delivered, and as such remains a very rough approximation. It is also important to emphasize that this “conversion factor” appears to relate mostly to psychoactive effects (e.g. euphoria, feeling mellow, feeling a good drug effect, feeling sedated, feeling stimulated, Addiction Research Center Inventory marijuana scale), psychomotor performance, and food intake and is based on a very small number of comparative pharmacology studiesReference137Reference592Reference593. Further rigorous comparative pharmacology studies are required. In addition, no comparative studies have been done with vaping. In addition, this theoretical conversion factor may or may not apply for therapeutic effects. Indeed, it is important to highlight that two studies reported that individuals using cannabis for therapeutic purposes indicated they used approximately similar gram amounts of cannabis regardless of route of administrationReference216Reference580.

Plasma concentrations of Δ9-THC following smoking/vapourization and therapeutic efficacy

There are a small number of efficacy studies on the amounts of smoked/vapourized cannabis and plasma concentrations of Δ9-THC required for therapeutic effects (see Table 5 for a quick overview, and information throughout this document for more detailed information).

A Canadian dose-ranging study showed that a single inhalation of a 25 mg dose of smoked cannabis (Δ9-THC content 9.4%; total available dose of Δ9-THC = 2.35 mg) yielded a mean plasma Δ9-THC concentration of 45 ng/mL within 2 min after initiating smokingReference59. The study reported improvements in sleep and pain relief in patients suffering from chronic neuropathic pain with minimal/mild psychoactive effects.

A single-dose, open-label, clinical trial of patients with neuropathic pain and using very low doses of inhaled THC reported a statistically significant improvement in neuropathic pain with minimal adverse effectsReference58. In this clinical study, 10 patients suffering from neuropathic pain of any type were administered a vapourized dose of 3 mg of THC (available in the device; ~ 1.5 mg THC actually absorbed) resulting from vapourization of 15 mg of dried cannabis containing 20% THC. THC administration was associated with a statistically significant reduction in baseline VAS for pain intensity of 3.4 points (i.e. a 45% reduction in pain) within 20 min of inhalation, which returned to baseline within 90 min. THC was detected in blood within 1 min following inhalation and reached a maximum within 3 min at a mean THC concentration of 38 ng/ml and there were minimal/mild psychoactive effects.

A randomized controlled clinical trial of vapourized cannabis for the alleviation of pain and spasticity associated with spinal cord injury (SCI) and disease reported that median blood plasma concentrations of THC of 23 ng/mL (from vapourization of 46 mg of 2.9% low THC strength cannabis; estimated 1.3 mg THC inhaled) and 47 ng/mL (from vapourization of 56 mg of 6.7% higher strength cannabis; estimated 3.8 mg THC inhaled) were associated with an analgesic and anti-spastic responseReference276 Many of the psychoactive effects showed a dose-dependency, with the low dose (2.9%) condition associated with lower intensity of psychoactive effects.

These above-mentioned studies suggest that, at least in the case of chronic neuropathic pain, psychoactive effects can be separated from therapeutic effects and that very low doses of THC may actually be sufficient to produce analgesia while keeping psychoactive effects to a minimum.

A review of U.S. state clinical trials on the use of smoked cannabis for the treatment of chemotherapy-induced nausea and vomiting (CINV) reported that plasma THC levels > 10 ng/mL were associated with the greatest suppression of nausea and vomiting but plasma levels between 5 and 10 ng/mL were also effectiveReference296.

Table 3: Relationship between THC Percent in Plant Material and the Available Dose (in mg THC) in an Average Joint
% THC mg THC per 750 mg dried plant materialTable 3 Footnote*
(“average joint”)
1 7.5
2.5 18.75
5 37.5
10Table 3 Footnote † 75Table 3 Footnote †
15 112.5
20 150
30 225

Table 3 Footnotes

Table 3 Footnote 1
WHO average weight

Return to Table 3 footnote*referrer

Table 3 Footnote 2
see text in Section 3.1 for additional details

Return to Table 3 footnotereferrer

Table 4: Comparison between Cannabis and Prescription Cannabinoid Medications
Cannabinoid
(Generic name)
Brand/Registered name Principal constituents/Source Official status in Canada Approved indications Onset of effects (O) / Peak effects (P)/ Duration of action (D) Route of administration Availability on provincial/ territorial formulary
Rx cannabinoids DronabinolTable 4 Footnote Marinol®Table 4 FootnoteReference227 SyntheticΔ9-THC Approved (but no longer available in Canada-see note)Table 4 Footnote AIDS-related anorexia associated with weight loss;Severe nausea and vomiting associated with cancer chemotherapy O: 30 – 60 minP: 2 – 4 h

D: Psychoactive effect: 4 – 6h

Appetite stimulant effect: up to 24 h or longer

Oral MBTable 4 Footnote; NBTable 4 Footnote; NSTable 4 Footnote; ONTable 4 Footnote; PETable 4 Footnote; QCTable 4 Footnote; YTTable 4 Footnote
Nabilone Cesamet®Reference492RAN-Nabilone

TEVA-Nabilone

CO-Nabilone

PMS-Nabilone

ACT-Nabilone

SyntheticΔ9-THC analogue Marketed Severe nausea and vomiting associated with cancer chemotherapy O: 60 – 90 minP: 3 – 4 h

D: 8 – 12 h

Oral AB; BC; MB;NB; NL; NS;

NT; NU; ON;

PE; QC; SK;

YT.

Nabiximols(THC+CBD and

other minor

cannabinoids,

terpenoids, and

flavonoids)

Sativex®Reference431 Botanicalextract from established

and well-characterized

C. sativa strains

MarketedTable 4 Footnote* Table 4 Footnote* O: 5 – 30 minP: 1.5 – 4 h

D: 12 – 24 h

Oro-mucosal spray NS
Cannabidiol (CBD) Epidiolex® Botanical extract from established and well-characterized C. sativa strains Being studied in clinical trials -Not an approved product (as of March 2018) N/A N/A Oral N/A
Plant product Cannabis(smoked or vapourized) N/A C. sativa (various) Not an approved product N/A O: 5 minP: 20 – 30 min

D: 2 – 3 hReference495Reference594

Smoking or inhalation N/A
Cannabis (oil for sublingual administration) N/A C. sativa (various) Not an approved product N/A O: 5 – 30 minP: 1.5 – 4 h

D: 12 – 24 h [based on Sativex®Reference431]

Oral N/A
Cannabis(oral edible) N/A C. sativa(various) Not an approved product N/A O: 30 – 90 minP: 2 – 3 h

D: 4 – 12 hReference400

Oral N/A
Cannabis(topical) N/A C. sativa(various) Not an approved product N/A N/A Topical N/A

Table 4 Footnotes

Table 4 Footnote 1
Product has been discontinued by the manufacturer (post-market; as of February 2012; not for safety reasons)

Return to Table 4 footnotereferrer

Table 4 Footnote 2
For Sativex®, the following marketing authorizations apply:

Return to Table 4 footnote*referrer

  • Standard marketing authorization: Adjunctive treatment for symptomatic relief of spasticity in adult patients with multiple sclerosis who have not responded adequately to other therapy and who demonstrate meaningful improvement during an initial trial of therapy.
  • Marketing authorization with conditions: Adjunctive treatment for symptomatic relief of neuropathic pain in adult patients with multiple sclerosis; and adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain.

AB: Alberta; BC: British Columbia; MB: Manitoba; N/A: not applicable; NB: New Brunswick; NL: Newfoundland and Labrador; NS: Nova Scotia; NU: Nunavut; NT: Northwest Territories; ON: Ontario; PE: Prince Edward Island; QC: Quebec; Rx: prescription; SK: Saskatchewan; YT: Yukon

3.2 Oral

The pharmacokinetic information described in Section 2.2.1.3 reports the erratic and slow absorption of Δ9-THC from the oral route, and oral doses of THC are estimated from the information in the monograph for Marinol® (dronabinol, no longer available in Canada). A 10 mg b.i.d. dose of Marinol® (20 mg total Δ9-THC per day) yielded a mean peak plasma Δ9-THC concentration of 7.88 ng/mL (range: 3.33 – 12.42 ng/mL), with a bioavailability ranging between 10 and 20%Reference227. By comparison, consumption of a chocolate cookie containing 20 mg Δ9-THC resulted in a mean peak plasma Δ9-THC concentration of 7.5 ng/mL (range: 4.4 – 11 ng/mL), with a bioavailability of 6%Reference407. An 8 mg orally-administered THC tablet (Namisol®) yielded a mean plasma THC Cmax of 4 ng/mL and a similar mean plasma 11-hydroxy-THC Cmax Reference595. Tea prepared from Cannabis flowering tops and leaves has been documented, but no data are available regarding efficacyReference422.

Marinol

Although Marinol® (dronabinol) is no longer available for sale in Canada, the Marinol® product monograph suggests a mean of 5 mg Δ9-THC/day (range: 2.5 – 20 mg Δ9-THC/day) for AIDS-related anorexia associated with weight lossReference227. A 2.5 mg dose may be administered before lunch, followed by a second 2.5 mg dose before supper. On the other hand, to reduce or prevent CINV, a dosage of 5 mg t.i.d. or q.i.d. is suggested. In either case, the dose should be carefully titrated to avoid the manifestation of adverse effects. Please consult the Marinol® drug product monograph for more detailed instructions.

Cesamet

The Cesamet® (nabilone) product monograph suggests administration of 1 to 2 mg of the drug, twice a day, with the first dose given the night before administration of the chemotherapeutic medicationReference492. A 2 mg dose of nabilone gave a mean plasma concentration of 10 ng/mL nabilone, 1 to 2 h after administration. The second dose is usually administered 1 to 3 h before chemotherapy. If required, the administration of nabilone can be continued up to 24 h after the chemotherapeutic agent is given. The maximum recommended daily dose is 6 mg in divided doses. Dose adjustment (titration) may be required in order to attain the desired response, or to improve tolerability. More recent clinical trials report starting doses of nabilone of 0.5 mg at night for pain or insomnia in fibromyalgia, and for insomnia in PTSDReference578Reference596Reference597. Please consult the Cesamet® drug product monograph for more detailed instructions.

Epidiolex

Data from an open-label clinical study of Epidiolex® for treatment-resistant childhood-onset epilepsy suggest that dosing with Epidiolex® (98 – 99% pure CBD oil) begin at a starting dose of 2 to 5 mg/kg per day divided in twice-daily dosing in addition to baseline antiepileptic drug regimen, then up-titrated by 2 to 5 mg/kg once a week until intolerance or a maximum dose of 25 mg/kg per day is reachedReference262. In some specific situations, the study authors mention that an increase to a maximum dose of 50 mg/kg per day could be considered. In patients with drug- resistant seizures in the Dravet syndromeReference576 or treatment-resistant Lennox-Gastaut syndromeReference577, a dose of 20 mg/kg per day is efficacious and generally well tolerated.

Cannabis oil

Data from an open-label longitudinal study of cannabis oil for patients with treatment-resistant chronic non-cancer pain reported that patients titrated their cannabis oil dose starting with one drop of cannabis oil per day, increasing in increments of one drop of oil per dose, three times per day, until satisfactory analgesia was achieved or until side effects appearedReference582. THC concentrations ranged from 11 – 19% and 0.5 – 5.5% CBD in cannabis oil in this study.

An open-label, pilot study of add-on oral THC (25 mg/ml in olive oil) for the treatment of symptoms associated with PTSD suggested dosing begin by placing 2.5 mg THC b.i.d. beneath the tongue (i.e. 0.1 mL of the oil solution) 1 h after waking up and 2 h before going to bedReference571. Maximum daily dose was 5 mg b.i.d. (i.e. 0.2 mL b.i.d.), or a total 10 mg daily dose (i.e. 0.4 mL).

3.3 Oro-mucosal

Dosing with nabiximols (Sativex®) is described in the product monograph along with a titration method for proper treatment initiationReference431. Briefly, dosing indications in the drug product monograph suggest that on the first day of treatment patients take one spray during the morning (anytime between waking and noon), and another in the afternoon/evening (anytime between 4 p.m. and bedtime). On subsequent days, the number of sprays can be increased by one spray per day, as needed and tolerated. A fifteen-minute time gap should be allowed between sprays. During the initial titration, sprays should be evenly spread out over the day. If at any time unacceptable adverse reactions such as dizziness or other CNS-type reactions develop, dosing should be suspended or reduced or the dosing schedule changed to increase the time intervals between doses. According to the drug product monograph, the average dose of nabiximols is five sprays per day (i.e. 13 mg Δ9-THC and 12.5 mg CBD) for patients with MS, whereas those patients with cancer pain tend to use an average of eight sprays per day (i.e. 21.6 mg Δ9-THC and 20 mg CBD). The majority of patients appear to require 12 sprays or less; dosage should be adjusted as needed and tolerated. Administration of four sprays to healthy volunteers (total 10.8 mg Δ9-THC and 10 mg CBD) was associated with a mean maximum plasma concentration varying between 4.90 and 6.14 ng/mL Δ9-THC and 2.50 to 3.02 ng/mL CBD depending whether the drug was administered under the tongue or inside the cheek. Please consult the Savitex® drug product monograph for more detailed information.

3.4 Vapourization

The Dutch Office of Medicinal Cannabis has published “rough” guidelines on the use of vapourizersReference422. Although the amount of cannabis used per day needs to be determined on an individual basis, the initial dosage should be low and may be increased slowly as symptoms indicate. The amount of cannabis to be placed in the vapourizer may vary depending on the type of vapourizer used.

Studies using the Volcano® vapourizer have reported using up to 1 g of dried cannabis in the chamber, but 50 to 500 mg of plant material is typically usedReference414; Δ9-THC concentrations up to 6.8% have been tested with the Volcano® vapourizerReference402Reference414. Subjects appeared to self-titrate their intake in accordance with the Δ9-THC content of the cannabisReference402. Peak plasma Δ9-THC levels varied between 70 and 190 ng/mL depending on the strength of Δ9-THC. The levels of cannabinoids released into the vapour phase increased with the temperature of vapourizationReference414. Vapourization temperature has typically been reported to be between 180 – 195 °CReference422; higher temperatures (e.g. 230 °C) greatly increase the amounts of cannabinoids released, but also increase the amounts of by-productsReference414.

One study reported the use of a uniform “cued” puffing procedure for vapourization with the Volcano® vapourizer: inhalation for five seconds, holding the breath for 10 seconds, and a 45-second pause before a repeat inhalationReference280. Participants inhaled as much of the 900 mg dose of dried cannabis (3.56% THC; 32 mg THC) as they could tolerate. Vapourization temperature was set to 190 °C.

In another study, patients followed a similar “cued-puff” procedure and inhaled 4 puffs, followed by an additional round of between 4 and 8 puffs 2 h later for a total of between 8 and 12 puffs over a 2 h periodReference598.

Another vapourization study also with the Volcano®, using the same cued-puff procedure, used 400 mg of dried cannabis of three variable strengths (1%, 4% and 7% THC or 4, 16 and 28 mg THC per dosing session)Reference599. Vapourization temperature was 200 °C.

Lastly, a more recent set of studies again using the Volcano® vapourizer and the same “cued-puff” procedure, reported using 400 mg of dried cannabis with either 2.9% (12 mg THC) or 6.7% THC (27 mg THC), with a vapourizing temperature of 185 °CReference276. Subjects inhaled 4 puffs at the beginning of the testing session, followed by an additional round of between 4 and 8 puffs 3 h later for a total of between 8 and 12 puffs over a 3 h period.

Data from a pilot clinical trial with the Syqe Inhaler™ has shown that an inhaled dose of as little as 3 mg THC (~1.5 mg THC absorbed, delivered from an amount as low as 15 mg of dried cannabis plant material at a potency of 20% THC) was associated with analgesic efficacy with minimal adverse effectsReference58. THC was detected in the plasma within 1 min following inhalation and reached a maximum within 3 min at a mean THC concentration of 38 ng/ml.

4.0 Potential Therapeutic Uses

While there are countless anecdotal reports concerning the therapeutic uses of cannabis, clinical studies supporting the safety and efficacy of cannabis for therapeutic purposes in a variety of disorders are limited, but slowly increasing in number. Furthermore, the current level of evidence for the safety and efficacy of cannabis for medical purposes does not meet the requirements of the Food and Drugs Act and its Regulations except for those products that have received a notice of compliance and market authorization from Health Canada. With the exception of one small open-label, pilot clinical study of orally-administered THC in an olive oil solution for symptoms associated with PTSD and clinical trials of orally-administered CBD in an oil solution (Epidiolex®) for symptoms associated with childhood epilepsy (see section 4.6 Epilepsy), there are no well-controlled clinical studies on the use of other orally-administered cannabis products such as cannabis edibles (e.g. cookies, baked goods) or topicals for therapeutic purposes.

It has been repeatedly noted that the psychotropic side effects associated with the use of (psychoactive) cannabinoids have been found to limit their therapeutic utilityReference23Reference55Reference57Reference268Reference600Table 5 (“Published Positive, Randomized, Double-Blind, Placebo-Controlled, Clinical Trials on Smoked/Vapourized Cannabis and Associated Therapeutic Benefits”) summarizes the information on published clinical trials that have been carried out thus far using smoked/vapourized cannabis and oil-based products.

A comprehensive review of 72 controlled clinical studies evaluating the therapeutic effects of cannabinoids (mainly orally administered THC, nabilone, nabiximols, or an oral extract of cannabis) up to the year 2005 reported that cannabinoids present an interesting therapeutic potential as anti-emetics, appetite stimulants in debilitating diseases (cancer and AIDS), analgesics, and in the treatment of MS, SCIs, Tourette’s syndrome (TS), epilepsy, and glaucomaReference601.

However, a more recent systematic review and meta-analysis of randomized clinical trials of cannabinoids (i.e. smoked cannabis, nabiximols, nabilone, dronabinol, CBD, THC, levonontradol, ajulemic acid) reported that most trials showed improvement in symptoms associated with cannabinoid use but the associations did not reach statistical significance in all trialsReference179. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete improvement in nausea and vomiting, reduction in pain, a greater average reduction in numerical rating scale pain assessment, and average reduction in the Ashworth spasticity scaleReference179. There was also an increased risk of short-term adverse events with cannabinoids. Commonly reported adverse events included dizziness, dry mouth, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance and hallucinationsReference179. Overall, the review and meta-analysis conducted using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach suggested that there was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic neuropathic or cancer pain as well as MS-associated spasticity, but low-quality evidence to support use for CINV, weight gain in HIV infection, sleep disorders, and TSReference179. The review and meta-analysis only included only one study with smoked cannabis and all other included clinical studies were with oral or oro-mucosal administration of cannabinoid-based medicines (e.g. nabiximols, nabilone, dronabinol).

The National Academy of Sciences, Engineering and Medicine (NASEM) has published a report on the health effects of cannabis and cannabinoidsReference602. This comprehensive report includes information on the therapeutic effects of cannabis and the cannabinoids but also other health effects such as cancer, cardiometabolic risks, respiratory disease, immunity, injury and death, prenatal, perinatal and neonatal effects, psychosocial and mental health effects. It also discusses challenges and barriers in conducting cannabis research as well as recommendations to support and improve cannabis research. Much of the evidence included in the report came from systematic reviews and meta-analyses and selected high quality primary research. Evidence gathered from in vitro or in vivo animal studies was not included.

Dronabinol is the generic name for the oral form of synthetic Δ9-THC and is marketed in the U.S. as Marinol®. It was available for sale in Canada in capsules containing 2.5, 5, or 10 mg of the drug dissolved in sesame oil. It is indicated for the treatment of severe CINV in cancer patients, and for AIDS-related anorexia associated with weight lossReference227. The drug is no longer sold in Canada (post-market discontinuation of the drug product as of February 2012; not for safety reasons). Please consult the Marinol® drug product monograph for more detailed information.

Nabilone is the generic name for an orally administered synthetic structural analogue of Δ9-THC, which is marketed in Canada as Cesamet® but also now available in generic forms (e.g. RAN-nabilone, PMS-nabilone, TEVA-nabilone, CO-nabilone, ACT-nabilone). It is available as capsules (0.25, 0.5, 1 mg) and is indicated for severe CINV in cancer patientsReference492. Please consult the Cesamet® drug product monograph for more detailed instructions.

Nabiximols is the generic name for a whole-plant extract of two different, but standardized, strains of Cannabis sativa giving an oro-mucosal spray product containing approximately equivalent amounts of Δ9-THC (27 mg/mL) and CBD (25 mg/mL), and other cannabinoids, terpenoids, and flavonoids per 100 μl of dispensed spray. Nabiximols is marketed as Sativex® in Canada and has received a notice of compliance for use as an adjunctive treatment for the symptomatic relief of spasticity in adult patients with MS who have not responded adequately to other therapy, and who demonstrate meaningful improvement during an initial trial of therapy. It is also marketed (with conditions) as an adjunctive treatment for the symptomatic relief of neuropathic pain in adults with MS and (with conditions) as an adjunctive analgesic in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background painReference431. Please consult the Sativex® drug product monograph for more detailed instructions.

Epidiolex® is the brand name for a whole-plant cannabis extract of a high CBD strain of Cannabis sativa and is an oral oil-based solution product containing > 98% CBD at a concentration of 100 mg/ml. Epidiolex® has received Orphan Drug Designation in the U.S. for the treatment of Lennox-Gastaut Syndrome, Dravet Syndrome and Tuberous Sclerosis Complex. At the time of writing this document Epidiolex® has not received a Notice of Compliance from Health Canada and is not marketed in Canada.

The existing scientific and clinical evidence for cannabis and certain cannabinoids in treating various symptoms associated with various medical conditions is summarized in the following sections beginning on the next page.

Table 5: Published Positive, Randomized, Double-Blind, Placebo-Controlled, Clinical Trials on Smoked/Vapourized Cannabis and Associated Therapeutic Benefits
Primary medical conditions and associated secondary end-points (if any) for which benefits were observed Percent and dose of Δ9-THC (if known) Trial duration; and number of patients/participants Reference
HIV/AIDS-associated weight loss One cannabis cigarette (~800 mg) containing 1.8% or 3.9% THC by weight, smoked once daily (i.e. one dose per day)
(~14 – 31 mg Δ9-THC /day)
8 sessions total
(3 sessions per week);
30 participants
Reference224
HIV/AIDS-associated weight loss; disease-associated mood and insomnia One cannabis cigarette (~800 mg) containing 2.0% or 3.9% THC by weight, smoked four times per day (i.e. four doses per day) (~64 – 125 mg of Δ9-THC /day) 4 days total;
10 participants
Reference223
Multiple sclerosis-associated pain and spasticity One cannabis cigarette (~800 mg) containing 4% THC by weight, smoked once per day (i.e. one dose per day) (~32 mg Δ9-THC /day) 3 days total;
30 patients
Reference278
Central and peripheral chronic neuropathic pain (various etiologies) One cannabis cigarette (~800 mg) containing either 3.5% or 7% THC by weight, smoked in bouts over a 3 h period (i.e. one dose per day) (daily dose of THC unavailable) 1 day total;
38 patients
Reference222
Chronic neuropathic pain from HIV-associated sensory neuropathy One cannabis cigarette (~900 mg) containing 3.56% THC by weight, smoked three times daily (i.e. three doses per day) (~96 mg Δ9-THC /day) 5 days total;
25 patients
Reference195
HIV-associated chronic neuropathic pain refractory to other medications One cannabis cigarette (~800 mg) containing between 1 and 8% THC by weight, smoked four times daily (i.e. four doses per day) (daily dose of THC unavailable) 5 days total;
28 patients
Reference281
Chronic post-traumatic or post-surgical neuropathic pain refractory to other medications and associated insomnia One 25 mg dose of cannabis containing 9.4% THC by weight, smoked three times daily (i.e. three doses per day) (~7 mg Δ9-THC /day) 5 days total; 21 patients Reference59
Chronic pain of various etiologies (musculoskeletal, post-traumatic, arthritic, peripheral neuropathy, cancer, fibromyalgia, migraine, multiple sclerosis, sickle cell disease, thoracic outlet syndrome) One 900 mg dose of vapourized cannabis containing 3.56% THC by weight administered three times per day (one dose the first day, three doses per day for next three days, one dose the last day) (~96 mg Δ9-THC /day) 5 days total;
21 patients
Reference280
Neuropathic pain of various etiologies (spinal cord injury, complex regional pain syndrome (CRPS) type I, causalgia-CRPS type II, diabetic neuropathy, multiple sclerosis, post-herpetic neuralgia, idiopathic peripheral neuropathy, brachial plexopathy, lumbosacral radiculopathy, and post-stroke neuropathy) Inhalation of vapourized cannabis (800 mg) containing either a low (1.29% or 10.3 mg Δ9-THC) or a medium-dose of Δ9-THC (3.53% Δ9-THC or 28.2 mg Δ9-THC) 3 sessions total;
39 patients
Reference598
Crohn’s disease One cannabis cigarette (500 mg) containing 23% THC by weight, smoked twice daily (i.e. two doses per day) (23 mg Δ9-THC /day) 8 weeks;
21 patients
Reference603
Neuropathic pain of various etiologies Inhalation of a single vapourized dose of 15 mg dried containing 20% Δ9-THC by weight (~3 mg Δ9-THC) One session only;
10 patients
Reference58
Diabetic peripheral neuropathy (i.e. diabetes mellitus type I and II) Inhalation of single vapourized doses of dried cannabis (400 mg/dose) containing either low (1% Δ9-THC or 4 mg Δ9-THC), medium (4% Δ9-THC or 16 mg Δ9-THC) or high (7% Δ9-THC or 28 mg Δ9-THC) doses of Δ9-THC (four single dosing sessions; each separated by two weeks) 4 sessions total;
16 patients
Reference599
Neuropathic pain from spinal cord injury or disease Inhalation of between 8 and 12 puffs from 400 mg of dried cannabis (2.9% and 6.7% THC) 3 sessions total;
42 patients
Reference276

4.1 Palliative care

  • The evidence thus far from some observational studies and clinical studies suggests that cannabis (limited evidence) and prescription cannabinoids (e.g. dronabinol, nabilone, or nabiximols) may be useful in alleviating a wide variety of single or co-occurring symptoms often encountered in the palliative care setting.
  • These symptoms may include, but are not limited to, intractable nausea and vomiting associated with chemotherapy or radiotherapy, anorexia/cachexia, severe intractable pain, severe depressed mood and anxiety, and insomnia.
  • A limited number of observational studies suggest that the use of cannabinoids for palliative care may also potentially be associated with a decrease in the number of some medications used by this patient population.

Among the goals of palliative care described by the WHO are relief from pain and other distressing symptoms, and the enhancement of quality of life (QoL)Reference604. While integration of cannabis into mainstream medical use can be characterized as extremely cautious, its use appears to be gaining some ground in palliative care settings where the focus is on individual choice, patient autonomy, empowerment, comfort and especially QoLReference605. Nevertheless, establishing the effectiveness of cannabis as a viable treatment option in a palliative care context requires a careful assessment of its effects in a wide range of conditions; such evidence is not yet abundant and further research is neededReference606. Certain patient populations (e.g. the elderly or those suffering from pre-existing psychiatric disease) may also be more sensitive or susceptible to experiencing adverse psychotropic, cognitive, psychiatric or other effectsReference607Reference608.

Data from observational studies

A prospective, non-randomized, and unblinded observational case-series study assessing the effectiveness of adjuvant nabilone therapy in managing pain and symptoms experienced by 112 advanced cancer patients in a palliative care setting reported that those patients using nabilone had a lower rate of starting NSAIDs, tricyclic anti-depressants, gabapentin, dexamethasone, metoclopramide, and ondansetron and a greater tendency to discontinue these drugsReference288. Patients were prescribed nabilone for pain relief (51%), for nausea (26%), and for anorexia (23%). Treated patients were started on 0.5 or 1 mg nabilone at bedtime during the first week and titrated upwards in increments of 0.5 or 1 mg thereafter. At follow-up, the majority of patients were on a 2 mg daily nabilone dose with a mean daily dose of 1.79 mg. The two primary outcomes of the study, pain and opioid use in the form of total morphine sulfate equivalents were reduced significantly in treated patients compared to untreated patients. Side effects from nabilone consisted mainly of dizziness, confusion, drowsiness, and dry mouth. Patients also demonstrated less tendency to initiate additional new medications and could reduce or discontinue baseline medications.

One observational study that examined over 100 self-reported cannabis-using patients in a cancer palliative care setting reported significant improvement in a variety of cancer and anti-cancer treatment-related symptoms including nausea, vomiting, mood disorders, fatigue, weight loss, anorexia, constipation, sexual function, sleep disorders, itching, and painReference609. While the daily dose of cannabis remained constant throughout the study period, 43% of patients using pain medications reported a dose reduction and 1.7% reported a dose increase. In addition, 33% of cannabis-using patients reduced the dose of their anti-depression/anti-anxiety medications. No significant adverse effects were noted in those using cannabis, with the exception of a reported reduction in memory in about 20% to 40% of the study sample. The reported decrease in memory among a proportion of the study sample could be a function of cannabis use along with the use of other medications such as opioids, anti-depressants, or even vary with age. Improvements in symptom and distress scores were also noted. Limitations of the study included its observational nature, the lack of an appropriate control group, and the reliance on self-report.

Another observational study looking at the patterns of cannabis use among adult Israeli advanced cancer patients reported that of approximately 17,000 cancer patients monitored at a single Israeli healthcare institution, 279 patients were authorized to use cannabis for medical purposes; among these, the median age of patients was 60 years (range: 19 – 93 years) and the most common cancer diagnoses were lung (18%), ovarian (12%), breast (10%), colon (9%), and pancreatic (7.5%), and the majority (84%) of the patients had metastatic diseaseReference237. The majority of patients (71%) were designated as active palliative, supportive (13%), and curative (6%). In most patients, cannabis was requested for multiple indications. The most common indication for which cannabis was prescribed was pain (76%), with anorexia (56%), generalized weakness (52%), and nausea (41%) also being common indications. Furthermore, 70% of patients reported improvement in pain control and general well-being, 60% reported improvement in appetite, 50% reported reduced nausea and vomiting, and 44% reported reduced anxiety with cannabis. Eighty-three percent of patients rated the overall efficacy of cannabis as being high. The most common route of administration (more than 90%) was smoking. While the majority of responders (62%) reported no adverse effects associated with the use of cannabis, the most commonly reported adverse effects were fatigue (20.3%) and dizziness (18.8%), while a minority of patients reported delusions (6%) and mood change (4.4%).

For information on the use of cannabis/cannabinoids for the control of nausea and vomiting please consult Section 4.3 of this document. For additional information on the use of cannabis/cannabinoids for anorexia/cachexia associated with HIV/AIDS infection or cancer, please consult Sections 4.4.1 and 4.4.2, respectively. For further information on the use of cannabis/cannabinoids for chronic pain syndromes (including cancer pain), please consult Sections 4.7.2.2 and 4.7.2.3. For further information on the use of cannabis/cannabinoids in the treatment of sleep disorders associated with chronic diseases please see Section 4.9.5.2, and please consult Section 4.9.9 for information on the use of cannabis/cannabinoids in oncology.

4.2 Quality of life

  • The available clinical studies report mixed effects of cannabis and prescription cannabinoids on measures of quality of life (QoL) for a variety of different disorders.

A handful of clinical studies have used standardized QoL instruments to measure whether the use of cannabis or prescription cannabinoids (e.g. nabilone, dronabinol, or nabiximols) is associated with improvements in QoL. The evidence from these studies is summarized below.

Clinical studies with dronabinol

A randomized, double-blind, placebo-controlled, crossover trial of dronabinol (maximum dose of 10 mg Δ9-THC per day, for a total of three weeks) for the treatment of central neuropathic pain in patients suffering from MS reported statistically significant improvements in measures of QoL (36-Item Short Form Health Survey, SF-36; measures for bodily pain and mental health)Reference610.

A two-centre, phase II, randomized, double-blind, placebo-controlled 22-day pilot study carried out in adult patients suffering from chemosensory alterations (i.e. changes in olfaction and gustation) and poor appetite associated with advanced cancer of various etiologies reported improved and enhanced chemosensory perception among patients treated with dronabinol (2.5 mg b.i.d.) compared to those receiving placeboReference611. The majority (73%) of dronabinol-treated patients self-reported an increased overall appreciation of food compared to those receiving placebo (30%). While global scores on the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) QoL instrument improved to a similar extent for dronabinol and placebo-treated groups, the FAACT sub-domain for anorexia-cachexia-related nutritional well-being improved with dronabinol compared to placebo. Statistically significant improvements were also noted for quality of sleep and relaxation with dronabinol treatment compared to placebo. According to the study authors, negative psychoactive effects were minimized by starting patients at a low dose (2.5 mg once a day for three days) followed by gradual dose escalation (up to a maximum of 7.5 mg dronabinol per day).

Clinical studies with cannabis extract

A multi-centre, phase III, randomized, double-blind, placebo-controlled, three-arm, parallel study in adult patients with advanced incurable cancer and suffering from cancer-related anorexia-cachexia syndrome concluded that neither cannabis extract (2.5 mg Δ9-THC, 1 mg CBD, for six weeks) nor THC (2.5 mg Δ9-THC b.i.d., for six weeks) provided any statistically significant benefit compared to placebo on measures of QoL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core Module – EORTC QLQ-C30)Reference315.

Clinical studies with nabilone

A randomized, double-blind, placebo-controlled trial of nabilone in patients suffering from fibromyalgia reported that adjuvant nabilone therapy (four weeks; maximum dose in the final week of treatment: 1 mg b.i.d.) was associated with a significant improvement in measures of QoL (VAS for pain, and the Fibromyalgia Impact Questionnaire)Reference596.

An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel-assignment efficacy study of nabilone as an adjuvant in the treatment of long-standing diabetic peripheral neuropathic pain reported statistically significant improvements in measures of QoL (Composite EuroQoL five dimensions questionnaire, EQ-5D, Index Score) and overall patient status compared to placeboReference612. Doses of nabilone ranged from 1 to 4 mg/day; treatment duration was five weeks.

A seven-week, randomized, placebo-controlled study comparing the effects of nabilone to placebo on QoL and side effects during radiotherapy for head and neck carcinomas reported that at the dosage used (0.5 – 2.0 mg/day titrated upwards over study duration), nabilone did not lengthen the time necessary for a 15% deterioration of QoL (measured on the EORTC QLQ-C30 and the EORTC QLQ-Head and Neck Module, H&N35, scales), and it was not better than placebo for relieving pain and nausea, or improving loss of appetite and weight, mood and sleepReference613. There was also no statistically significant difference in the occurrence of adverse effects between the nabilone and placebo groups.

Clinical studies with nabiximols

A ten-week, prospective, randomized, double-blind, placebo-controlled trial assessing the safety and efficacy of nabiximols (Sativex®) as an adjunctive medication in the treatment of intractable diabetic peripheral neuropathy concluded that nabiximols failed to show statistically significant improvements in measures of QoL (EuroQOL, SF-36, and the McGill Pain and QoL Questionnaire)Reference614.

A twelve-week, double-blind, randomized, placebo-controlled, parallel-group, enriched enrolment study of nabiximols as add-on therapy for patients with refractory spasticity concluded that there was no significant difference between active treatment and placebo on measures of QoL (EQ-5D Health State Index, EQ-5D Health Status VAS, SF-36)Reference615.

A five-week, multi-centre, randomized, double-blind, placebo-controlled, parallel-group, graded-dose study evaluated the analgesic efficacy and safety of nabiximols in three dose ranges in opioid-treated cancer patients with poorly-controlled chronic painReference284. The study reported the lack of any positive treatment effects on overall QoL in this study population even at the highest doses of nabiximols (11 – 16 sprays per day).

Clinical and observational studies with smoked cannabis

A randomized, double-blind, placebo-controlled, four-period, cross-over trial of smoked cannabis in the treatment of chronic neuropathic pain (chronic post-traumatic or post-surgical etiology) concluded that inhalation of smoked cannabis (25 mg of cannabis containing 2.5, 6.0, or 9.4% Δ9-THC, t.i.d. for five days) was not associated with a statistically significant difference compared to placebo on measures of QoL (EQ-5D Health Outcomes QoL instrument)Reference59.

In contrast, a cross-sectional survey examining the benefits associated with cannabis use in patients with fibromyalgia reported a statistically significant benefit in the mental health component summary score of the SF-36 QoL questionnaire in patients who used cannabis compared to non-usersReference184. However, no significant differences between cannabis and non-cannabis users were found in the other SF-36 domains, in the Fibromyalgia Impact Questionnaire, or the Pittsburgh Sleep Quality Index.

A preliminary observational, open-label, prospective, single-arm trial in a group of 13 patients suffering from Crohn’s disease or ulcerative colitis reported that treatment with inhaled cannabis over a three-month period improved subjects’ QoL, caused a statistically significant increase in subjects’ weight, and improved the clinical disease activity index in patients with Crohn’s diseaseReference279. Patients reported a statistically significant improvement in their perception of their general health status, their ability to perform daily activities, and their ability to maintain a social life. Patients also reported a statistically significant reduction in physical pain as well as improvement in mental distress.

A recent systematic review and meta-analysis of 20 studies [11 randomized controlled trials (RCTs); 9 cohort/cross-sectional designs) examining the impact of a variety of cannabinoid-based products (herbal cannabis, nabiximols, nabilone, dronabinol, dexanabinol] on health-related quality of life (HRQoL) across multiple conditions reported no overall significant associations. The authors attributed the null findings to the heterogeneity of study characteristics, and the limitation in which HRQoL were secondary and not primary outcomes in most studies. However, the studies showing a positive relationship between cannabinoids and HRQoL were more likely to be from pain-related symptoms (neuropathic pain, multiple sclerosis, headaches, inflammatory bowel disease), while negative relationships were observed mostly in HIV patients who reported significant reductions in physical and mental HRQoLReference616.

4.3 Chemotherapy-induced nausea and vomiting

  • Pre-clinical studies show that certain cannabinoids (THC, CBD, THCV, CBDV) and cannabinoid acids (THCA and CBDA) suppress acute nausea and vomiting as well as anticipatory nausea.
  • Clinical studies suggest that certain cannabinoids and cannabis (limited evidence) use may provide relief from chemotherapy-induced nausea and vomiting (CINV).

CINV is one of the most distressing and common adverse events associated with cancer treatmentReference617. In the absence of effective anti-emetics, chemotherapy-associated nausea can be so severe that as many as 20% of patients opt to discontinue chemotherapeutic treatmentReference618. Once a patient experiences nausea, it tends to persist throughout treatment and make subsequent episodes of nausea more severeReference619. Post-treatment nausea is also associated with impaired patient functioning, increased anxiety, depression, and reduced QoL which can all negatively impact treatment adherence or even cause discontinuation of treatment entirelyReference620.

While nausea typically occurs before vomiting, the two have distinct neural circuitries and can be separated behaviourallyReference295. Furthermore, while the central mechanisms of vomiting are well-known, those responsible for nausea remain less well understoodReference295. Nevertheless, scientific studies point to the insular cortex as the seat of sensations such as nausea and disgust, with other central regions (e.g. area postrema, parabrachial nucleus) as well as GI input also contributing to the generation of nauseaReference295Reference621.

Whereas chemotherapy-induced vomiting generally appears to be well-controlled with current first-line therapies/triple-combination therapies (e.g. 5-HT3antagonists, neurokinin-1 antagonists, and corticosteroids), the associated acute, delayed, and especially anticipatory nausea remain more poorly controlled and the use of cannabis/cannabinoids may provide some measure of benefit in such casesReference109Reference297Reference620. A significant proportion (25 – 59%) of patients undergoing chemotherapy experience anticipatory nausea during treatment and once it develops, it is refractory to standard treatment with 5-HT3 antagonistsReference620. Non-specific anti-anxiety treatments (e.g. benzodiazepines) are used to treat anticipatory nausea but drawbacks include significant sedationReference620.

It is important to note that excessive use of cannabis has been reported to paradoxically trigger a chronic cyclic vomiting syndrome (i.e. hyperemesis) (see Section 7.6.1 for further details on this syndrome).

Pre-clinical studies

Patient claims that smoked cannabis relieves CINV are widely recognized, and increasing evidence suggests a role for the ECS in the regulation of nausea and vomitingReference109Reference295Reference620Reference622Reference628. CB1 and CB2 receptors have been found in areas of the brainstem associated with emetogenic controlReference629Reference630, and results from animal studies suggest the anti-nausea and anti-emetic properties of certain cannabinoids (e.g. Δ9-THC, dronabinol, nabilone) are most likely related to their agonistic actions at centrally-located CB1 receptorsReference99Reference109Reference631. Levels of 2-AG are increased in the visceral insular cortex during an acute episode of nausea in rats and localized blockade of 2-AG through targeted MAGL inhibition in the insular cortex reduces acute nauseaReference294. Similarly, infusion of 2-AG into the insular cortex dose-dependently blocks anticipatory nausea, while infusion of anandamide was without effectReference632. These findings suggest that 2-AG, but not anandamide, drives acute and anticipatory nausea. Elsewhere, elevation of endocannabinoids such as anandamide and 2-AG by inhibition of the endocannabinoid degradative enzymes FAAH and MAGL, has been shown to suppress acute and anticipatory nausea in animal modelsReference295Reference633 and localized infusion of a peripherally-restricted CB1 receptor agonist into the visceral insular cortex suppressed nausea-like behaviour in rats, whereas systemic administration had no effectReference621.

An in vivo animal study and one small clinical study have also suggested Δ8-THC to be a more potent anti-emetic than Δ9-THCReference99Reference100. In addition to its actions at CB1 receptors, an in vitro study has also shown that Δ9-THC antagonizes the 5-HT3 receptorReference634, a target of current standard anti-emetic drugs, raising the possibility that cannabinoids may exert their anti-emetic action through more than one mechanism. Other studies carried out in animal models of nausea and vomiting have shown that CBD (5 mg/kg, subcutaneous (s.c.)) suppressed chemical-induced vomiting (and nausea) through potential activation of somatodendritic 5-HT1A autoreceptors located in the dorsal raphe nucleusReference627, while another study showed that the anti-nausea/vomiting effects of CBD could be reversed by pre-treatment with CBG (5 mg/kg, i.p.)Reference628.

Cannabinoid acids and other cannabinoids

Additional work has revealed novel and important roles for cannabinoid acids (i.e. THCA, CBDA) in suppressing nausea and vomiting in animal modelsReference116Reference117Reference622Reference623Reference625. In one study, when administered alone, a very low dose (0.5 µg/kg i.p.) of CBDA suppressed behaviour modelling acute nausea, and a subthreshold dose of CBDA (0.1 µg/kg i.p.), when administered along with ondansetron at a dose of 1 µg/kg produced an enhancement of the acute anti-nausea effectReference625. In addition, the effective dose of CBDA that attenuated acute nausea was approximately 1 000 times lower than the effective dose for CBDReference625. THCA at doses of 0.5 and 0.05 mg/kg (i.p.) reduced behaviours modelling acute nausea and vomiting, and at a dose of 0.05 mg/kg (i.p.) reduced behaviours modelling anticipatory nausea in animal models of acute and anticipatory nausea, and vomitingReference623.

THCA has been shown to lack CB1 receptor activityReference635 and administration of THCA was not associated with some of the classical animal behavioural signs of CB1 receptor agonists (i.e. hypothermia, catalepsy)Reference623, supporting previous findings of lack of THCA-associated psychoactivity in animalsReference636. THCA was also found to be at least 10 times more potent than THC in reducing acute and anticipatory nausea modelsReference623.

Other work has shown that THC, CBDA, and the benzodiazepine chlordiazepoxide reduced behaviour modelling anticipatory nauseaReference622. In this study, CBDA (0.001, 0.01, and 0.1 mg/kg i.p.) was shown to be between 5 and 500 times more potent than THC (0.5 mg/kg) in reducing anticipatory nausea and 20 times more potent than chlordiazepoxide (10 mg/kg). Treatment with CBDA was not associated with any effects on locomotor activity at any tested dose whereas chlordiazepoxide significantly reduced locomotor activity. Co-administration of subthreshold doses of CBDA (0.1 µg/kg i.p.) and THCA (5 µg/kg i.p.) reduced behaviour modelling anticipatory nausea, and pharmacological studies suggest the involvement of CB1 (for THCA) and 5-HT1A (for CBDA) receptors in the mechanism of suppression of anticipatory nausea. Further research is needed to resolve the conflicting evidence around the mechanism of action, if any, of THCA at the CB1 receptor. As for CBDA, a dose as low as 1 µg/kg (i.p.) potently suppressed anticipatory nausea in an animal model and compared to the doses of CBD needed for the same degree of effect (1 – 5 mg/kg i.p.), CBDA could be said to be between 1 000 and 5 000 times more potent than CBD in suppressing anticipatory nausea.

Additional animal studies have shown that administration of subthreshold doses of THC (0.01 and 0.1 mg/kg i.p.) and CBDA (0.01 and 0.1 µg/kg i.p.) reduced acute nausea, and higher doses of THC (1.0 and 10 mg/kg i.p.) or CBDA (1.0 and 10 µg/kg i.p.) alone also reduced acute nauseaReference116. In contrast to the effect seen for acute nausea, combined subthreshold doses of THC and CBDA did not suppress anticipatory nausea in animalsReference116. Higher doses of either THC (1.0 and 10 mg/kg i.p.) and/or CBDA (1.0 and 10 µg/kg i.p.) were effective in reducing anticipatory nausea. The higher dose of THC (10 mg/kg) was associated with hypoactivity, and this was not attenuated by CBDA.

A subsequent study examined the effects of combining CBD and THC, and CBDA and THC on acute nausea and vomitingReference117. The study showed that 2.5 mg/kg CBD (i.p.), when combined with 1 mg/kg THC (i.p.), resulted in significant suppression of acute nausea and vomiting in an animal model and similarly, when 0.05 mg/kg (i.p.) CBDA was combined with 1 mg/kg THC, acute nausea and vomiting were significantly suppressed. Singular administration of either 2.5 mg/kg CBD, 1 mg/kg THC, or 0.05 mg/kg (i.p.) CBDA was not associated with any suppression of acute nausea and vomiting.

In addition to THC, CBD, THCA and CBDA, two other phytocannabinoids THCV and cannabidivarin (CBDV) have been studied, though to a far lesser extent, for their potential to alleviate nausea in animal modelsReference620. THCV at a dose of 10 mg/kg (i.p.) and CBDV at a dose of 200 mg/kg (i.p.) have been shown to reduce acute nausea in rats, potentially through a CB1 receptor-independent mechanism, but nothing is known about their ability to suppress anticipatory nauseaReference626.

Taken together, the findings from the above pre-clinical studies suggest that Δ9-THC, CBD, CBDA, and THCA can all suppress acute nausea and vomiting as well as anticipatory nausea to varying degrees, and with varying potencies and efficacies, whereas THCV and CBDV suppress acute nausea. Furthermore, certain subthreshold combinations of some of these cannabinoids can produce synergistic anti-nausea and vomiting effects compared to when used alone.

Clinical studies

The evidence for smoked cannabis and prescription cannabinoids such as nabilone (Cesamet®), dronabinol (Marinol®), (and levonantradol) in treating CINV has been reviewedReference179Reference210Reference601Reference637. One systematic review and meta-analysis of 28 randomized controlled trials (RCTs) (N = 2 454 participants) of cannabinoids using the GRADE approach reported a greater benefit of cannabinoids compared with both active comparators and placebo, but statistical significance was not reached in all of the studiesReference179. The average number of patients showing a complete anti-nausea and vomiting response was greater with prescription cannabinoids (dronabinol or nabiximols) than placebo (OR = 3.82 [95% CI 1.55 – 9.42]).

While prescription cannabinoids present clear advantages over placebo in the control of CINV, the evidence from randomized clinical trials shows cannabinoids to be clinically only slightly better than conventional dopamine D2-receptor antagonist anti-emeticsReference210Reference637. In some cases, patients appeared to prefer the cannabinoids to these conventional therapies despite the increased incidence of adverse effects such as drowsiness, dizziness, dysphoria, depression, hallucinations, paranoia, and arterial hypotension. This may be explained in part by the notion that for certain patients a degree of sedation and euphoria may be perceived as beneficial during chemotherapy.

While no peer-reviewed clinical trials of smoked cannabis for the treatment of CINV exist, Musty and Rossi have published a review of U.S. state clinical trials on the subjectReference296. Patients who smoked cannabis showed a 70 to 100% relief from nausea and vomiting, while those who used a Δ9-THC capsule experienced 76 to 88% relief. Plasma levels of > 10 ng/mL Δ9-THC were associated with the greatest suppression of nausea and vomiting, although levels ranging between 5 and 10 ng/mL were also effective. In all cases, patients were admitted only after they failed treatment with standard phenothiazine anti-emetics.

In one small open label trial with eight children with various blood cancers were administered Δ8-THC (18 mg/m2) two hours before the initiation of chemotherapy as well as every six hours for the next 24 hours showed that Δ8-THC successfully prevented vomiting and no delayed nausea or vomiting episodes were observed in the next two days following antineoplastic treatmentReference100. Δ8-THC could also be administered at doses considerably higher than the doses of Δ9-THC generally administered to adult patients, with a lack of major side effects.

Few, if any, clinical trials directly comparing cannabinoids to newer anti-emetics such as 5-HT3 (Ondansetron, Granisetron) or NK-1 receptor antagonists have been reported to dateReference617Reference637. A small clinical trial comparing smoked cannabis (2.11% Δ9-THC, in doses of 8.4 mg or 16.9 mg Δ9-THC; 0.30% CBN; 0.05% CBD) to ondansetron (8 mg) in ipecac-induced nausea and vomiting in healthy volunteers showed that both doses of Δ9-THC reduced subjective ratings of queasiness and objective measures of vomiting; however, the effects were very modest compared to ondansetronReference297. Furthermore, only cannabis produced changes in mood and subjective state. In another clinical study with a small sample size, ondansetron and dronabinol (2.5 mg Δ9-THC first day, 10 mg second day, 10 – 20 mg thereafter) provided equal relief of delayed CINV, and the combination of dronabinol and ondansetron did not provide added benefit beyond that observed with either agent aloneReference638. However, two animal studies showed that low doses of Δ9-THC, when combined with low doses of the 5-HT3 receptor antagonists ondansetron or tropisetron, were more efficacious in reducing nausea and emesis frequency than when administered individuallyReference639Reference640. More research is required to determine if combination therapy provides added benefits above those observed with newer standard treatments.

A retrospective chart review of dronabinol use for CINV in an adolescent oncology population (i.e. leukemia, lymphoma, sarcoma, brain tumour) in a tertiary pediatric hospital reported that the majority of patients who received moderate or highly emetogenic chemotherapy and standard anti-emetogenic therapy (i.e. 5-HT3 receptor antagonist and corticosteroids) also received dronabinolReference641. The most commonly prescribed dose of dronabinol in this study was 2.5 mg/m2 oral solution every 6 h (as needed), and the median number of dronabinol doses received per hospitalization was 3.5. Sixty percent of the pediatric patients in this study were reported to have had a “good” response to dronabinol. Limitations of this study include retrospective design, lack of a comparison group, lack of chemotherapy standardization, and lack of standardized anti-emetic regimens.

The use of cannabinoids (whether administered orally or by smoking cannabis) is currently considered a fourth-line adjunctive therapy in CINV when conventional anti-emetic therapies have failedReference417Reference642Reference646. Nabilone (Cesamet®) and dronabinol (Marinol®) are indicated for the management of severe nausea and vomiting associated with cancer chemotherapyReference227Reference492, however dronabinol is no longer available for sale on the Canadian market. Nabilone may be administered orally every 12 h at dosages ranging from 1 – 2 mg, whereas dronabinol may be administered every 6 – 8 h orally, rectally, or sub-lingually at doses ranging from 5 – 10 mgReference311Reference647.

4.4 Wasting syndrome (cachexia, e.g., from tissue injury by infection or tumour) and loss of appetite (anorexia) in AIDS and cancer patients, and anorexia nervosa

  • The available evidence from human clinical studies suggests that cannabis (limited evidence) and dronabinol may increase appetite and caloric intake, and promote weight gain in patients with HIV/AIDS.
  • However the evidence for dronabinol is mixed and effects modest for patients with cancer and weak for patients with anorexia nervosa.

The ability of acute cannabis exposure to increase appetite has been recognized anecdotally for many yearsReference312. In addition, results from epidemiological studies suggest that people actively using cannabis have higher intakes of energy and nutrients than non-usersReference648. Controlled laboratory studies with healthy subjects suggest acute exposure to cannabis, whether by inhalation or oral ingestion of Δ9-THC-containing capsules, correlates positively with an increase in food consumption, caloric intake, and body weightReference312Reference313. Studies showing a high concentration of CB1 receptors in brain areas associated with control of food intake and satiety lend further support to the link between cannabis consumption and appetite regulationReference649Reference651. Furthermore, increasing evidence suggests a role for the ECS not only in modulating appetite, food palatability, and intake, but also in energy metabolism and the modulation of both lipid and glucose metabolism (reviewed inReference19Reference650Reference652).

4.4.1 To stimulate appetite and produce weight gain in AIDS patients

The ability of cannabis to stimulate appetite and food intake has been applied to clinical situations where weight gain is deemed beneficial such as in HIV-associated muscle wasting and weight loss.

A randomized, open-label, multi-center study to assess the safety and pharmacokinetics of dronabinol and megestrol acetate (an orexigenic), alone or in combination, found that only the high-dose megestrol acetate treatment alone (750 mg/day), but not dronabinol (2.5 mg b.i.d, 5 mg total Δ9-THC/day) alone or the combination of low-dose megestrol acetate (250 mg/day) and dronabinol (2.5 mg b.i.d, 5 mg total Δ9-THC/day), produced a significant increase in mean weight over 12 weeks of treatment in patients diagnosed with HIV-associated wasting syndromeReference653. The lack of an observed clinical effect in this study could have been caused by too low a dose of dronabinol.

Despite the findings of the above-noted study, AIDS-related anorexia associated with weight loss was an approved indication in Canada for dronabinol (Marinol®) (no longer available in Canada). The Marinol® product monograph summarizes a six-week, randomized, double-blind, placebo controlled-trial in 139 patients, with the 72 patients in the treatment group initially receiving 2.5 mg dronabinol twice a day, then reducing the dose to 2.5 mg at bedtime due to side effects (feeling high, dizziness, confusion and somnolence)Reference654. Over the treatment period, dronabinol significantly increased appetite, with a trend towards improved body-weight and mood and a decrease in nausea. At the end of the six-week period, patients were allowed to continue receiving dronabinol, during which appetite continued to improve. This secondary, open-label, 12 month follow-up study suggested that dronabinol was safe and effective for long-term use for the treatment of anorexia associated with weight loss in patients with AIDS. The use of higher doses of dronabinol (20 mg – 40 mg per day) has been reported both in the Marinol® product monographReference227 as well as in the literatureReference223Reference224. However, caution should be exercised in escalating dosage because of the increased frequency of dose-related adverse effects.

A clinical study that used higher doses of dronabinol or smoked cannabis showed that acute administration of high doses of dronabinol (four to eight times the standard 2.5 mg Δ9-THC b.i.d. dose, or 10 – 20 mg Δ9-THC daily, three times per week for a total of eight sessions) and smoked cannabis (three puffs at 40 sec intervals; ~800 mg cigarettes containing 1.8 – 3.9% THC giving an estimated total daily amount of 14.4 mg – 31.2 mg THC in the cigarette, three times per week, over a total of eight study sessions) increased caloric intake in experienced HIV-positive cannabis smokers with clinically significant muscle mass lossReference224. Another subsequent inpatient study employed even higher doses of dronabinol (20 – 40 mg total Δ9-THC daily, for four days) and smoked cannabis (~800 mg cannabis cigarettes containing 2.0 and 3.0% THC, administered four times per day, with an estimated 64 – 125 mg total Δ9-THC daily in the cigarette, over a total study period of four days)Reference223. Both drugs produced substantial and comparable increases in food intake and body weight, as well as improvements in mood and sleepReference223Reference224. Others have shown that the cannabis-associated increase in body weight in this patient population appears to result from an increase in body fat rather than lean muscle massReference655Reference656.

A double-blind, cross-over, placebo-controlled pilot sub-study examining the effects of cannabis use on appetite hormones in HIV-infected adult men with HIV sensory neuropathy on combination anti-retroviral therapy (ART) found that compared to placebo, smoked cannabis (1 – 8% THC) was associated with significant increases in plasma levels of ghrelin (increase of 42% vs. decrease of 12% with placebo) and leptin (increase of 67% vs. 11.7% with placebo), and decreases in plasma levels of peptide YY (decrease of 14.2% vs. 23% increase with placebo)Reference657. Higher THC levels were associated with greater increases in ghrelin showing a dose-response relationship, whereas higher THC levels were associated with smaller increases in leptin; no dose-response was observed for peptide YY.

A systematic review and meta-analysis of 28 RCTs (N = 2 454 participants) of cannabinoids (i.e. smoked cannabis, nabiximols, nabilone, dronabinol, CBD, THC, levonontradol, ajulemic acid) using the GRADE approach reported that there was some evidence that dronabinol was associated with an increase in weight when compared with placebo and that it may also be associated with increased appetite, greater percentage of body fat, reduced nausea, and improved functional status in patients with HIV/AIDSReference179.

4.4.2 To stimulate appetite and produce weight gain in cancer patients

Anorexia is ranked as one of the more troublesome symptoms associated with cancer, with more than half of patients with advanced cancer experiencing a lack of appetite and/or weight lossReference658Reference659. While it is anecdotally known that smoking cannabis can stimulate appetite, the effects of smoking cannabis on appetite and weight gain in patients with cancer cachexia have not been studied. The results from clinical trials with oral Δ9-THC (dronabinol) or oral cannabis extract are mixed and the effects, if any, appear to be modest (reviewed inReference314.

In two early studies, oral THC (dronabinol) improved appetite and food intake in some patients undergoing cancer chemotherapyReference319Reference320. An open-label study of dronabinol (2.5 mg Δ9-THC, two to three times daily, four to six weeks) in patients with unresectable or advanced cancer reported increases in appetite and food intake, but weight gain was only achieved in a few patientsReference317Reference318. Modest weight gain was obtained with a larger dosing regimen of dronabinol (5 mg t.i.d.), but the CNS side effects including dizziness and somnolence were limiting factorsReference321. In contrast, a randomized, double-blind, placebo-controlled study involving cancer patients with related anorexia-cachexia syndrome failed to demonstrate any differences in patients’ appetite across treatment categories (oral cannabis extract, Δ9-THC, or placebo)Reference315. Furthermore, when compared to megestrol acetate, an orexigenic medication, dronabinol was significantly less efficacious in reported appetite improvement and weight gainReference316.

A two-centre, phase II, randomized, double-blind, placebo-controlled, 22-day pilot study carried out in adult patients suffering from advanced cancer reported improved and enhanced chemosensory perception among patients treated with dronabinol (2.5 mg Δ9-THC b.i.d.) compared to those receiving placeboReference611. The majority (73%) of dronabinol-treated patients self-reported an increased overall appreciation of food compared to those receiving placebo (30%). Similarly, the majority of dronabinol-treated patients (64%) reported increased appetite, whereas the majority of patients receiving placebo reported either decreased appetite (50%) or no change (20%). Total caloric intake per kilogram body weight did not differ significantly between treatment groups but did increase in both groups compared to baseline. Furthermore, compared to placebo, dronabinol-treated patients reported an increase in their protein intake as a proportion of total energy. According to the study authors, negative psychoactive effects were minimized by starting patients at a low dose (2.5 mg Δ9-THC once a day, for three days) followed by gradual dose escalation (up to a maximum of 7.5 mg dronabinol per day).

According to a review of the medical management of cancer cachexia, the current level of evidence for cannabinoids (e.g. dronabinol) in the treatment of this condition is lowReference660. Cancer cachexia is not an approved indication for dronabinol in either Canada or the U.S.

4.4.3 Anorexia nervosa

The ECS has been implicated in appetite regulation and is suspected to play a role in eating disorders such as anorexia nervosaReference650Reference661. Increased peripheral ECS activity (i.e. increased plasma anandamide and increased CB1 mRNA expression in blood) has been found in patients with eating disordersReference662. In spite of epidemiological and familial studies, which suggest a genetic basis for anorexia nervosa, genetic studies have thus far failed to agree on an association between genes coding for ECS proteins and the manifestation of anorexia nervosaReference663Reference664.

No studies have examined the effects of smoking cannabis on anorexia nervosa and limited information exists on the use of cannabinoids to treat anorexia nervosa. Furthermore, inter- and intra-species differences in animals with respect to anorexia nervosa-like behaviour have to some extent hampered pre-clinical research on the effects of Δ9-THC in this disorder.

One study in a mouse model of anorexia nervosa reported conflicting resultsReference665, while another study in a rat model reported a significant attenuation in weight loss only at high doses of Δ9-THC (2.0 mg/kg/day Δ9-THC i.p.)Reference666.

A small, randomized, crossover trial of oral Δ9-THC in female anorexic patients suggested that THC produced a weight gain equivalent to the active placebo (diazepam)Reference323. Δ9-THC was administered in daily doses increasing from 7.5 mg (2.5 mg, t.i.d.) to a maximum of 30 mg (10 mg, t.i.d.), 90 min before meals, for a period of two weeks. Three of the eleven patients administered Δ9-THC also reported severe dysphoric reactions, withdrawing from the study.

Lastly, a four-week, prospective, double-blind, randomized, cross-over clinical study of 5 mg daily doses of dronabinol in 24 adult women with severe, chronic anorexia nervosa reported a small, yet significant increase in body mass index (BMI) compared to placeboReference322.

4.5 Multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury and disease

  • Evidence from pre-clinical studies suggests THC, CBD and nabiximols improve multiple sclerosis (MS) associated symptoms of tremor, spasticity and inflammation.
  • The available evidence from clinical studies suggests cannabis (limited evidence) and certain cannabinoids (dronabinol, nabiximols, THC/CBD) are associated with some measure of improvement in symptoms encountered in MS and spinal cord injury (SCI) including spasticity, spasms, pain, sleep and symptoms of bladder dysfunction.
  • Very limited evidence from pre-clinical studies suggests that certain cannabinoids modestly delay disease progression and prolong survival in animal models of amyotrophic lateral sclerosis (ALS), while the results from a very limited number of clinical studies are mixed.

MS is an (auto)immune-mediated, demyelinating and neurodegenerative chronic disease of the CNS that affects between 2 and 3 million people worldwide and is characterized by periods of relapsing and remitting neurological attacks and accumulating disability over many yearsReference667Reference668. Demyelination and axonal and neuronal loss within different neural pathways of the CNS lead to a variety of different cognitive, sensory and motor problems (e.g. pain and spasticity) that accumulate as the disease progressesReference667. ALS is a progressive neurodegenerative disease caused by the selective damage of motor neurons in the spinal cord, brainstem, and motor cortexReference669. Although most cases are sporadic, familial cases can occur in an autosomal recessive or dominant or dominant X-linked inheritance patternReference670. The pathogenesis of ALS includes excitotoxic damage, chronic inflammation, oxidative stress, and protein aggregationReference669.

One systematic review of the efficacy and safety of cannabinoids for the treatment of selected neurological disorders, including symptoms such as spasticity, central pain and painful spasms, urinary dysfunction, and tremor associated with, for example, MS suggested that, based on existing clinical trial data, cannabinoids were probably effective for reducing patient-reported and objective measures of spasticity, effective or probably effective for reducing central pain or painful spasms, probably effective for reducing the number of bladder voids/day, but probably ineffective for reducing bladder complaints and probably or possibly ineffective for reducing tremorReference671.

In contrast to the findings of the above systematic review, a more recent systematic review and meta-analysis of 28 RCTs (N = 2 454 participants) of cannabinoids (i.e. smoked cannabis, nabiximols, nabilone, dronabinol, CBD, THC, levonontradol, ajulemic acid) using the GRADE approach reported that cannabinoids were associated with improvements in spasticity but that this failed to reach statistical significanceReference179. Cannabinoids (nabiximols, dronabinol, and THC/CBD) were associated with a greater average improvement on the Ashworth scale for spasticity compared with placebo, although this did not reach statistical significance. Cannabinoids (nabilone and nabiximols) were also associated with a greater average improvement in spasticity assessed using numerical rating scales. The average number of patients who reported an improvement on a global impression of change score was also greater with nabiximols than placebo.

Differences between the findings from these two systematic reviews of cannabinoids for selected neurological disorders include differences in methodology, approach, and inclusion/exclusion criteria. Nevertheless, both systematic reviews suggest that cannabis/cannabinoids are associated with some measure of improvement in spasticity, spasms and pain in selected neurological disorders (e.g. MS, SCI/disease).

Below is a summary of the peer-reviewed evidence on the use of cannabis and cannabinoids in MS, ALS and SCI and disease.

4.5.1 Multiple sclerosis

A number of studies, both in patients suffering from MS and in animal models of the disease, suggest the disorder is associated with changes in endocannabinoid levels, although the findings are conflictingReference667Reference668Reference672Reference675.

Pre-clinical studies

Pre-clinical studies across different animal species suggest cannabinoids improve the signs of motor dysfunction in experimental models of MS (reviewed inReference667Reference668Reference676). Lyman was one of the first to report the effects of Δ9-THC in one such modelReference677. In that study, affected animals treated with Δ9-THC either had no clinical signs of the disorder or showed mild clinical signs with delayed onset. The treated animals also typically had a marked reduction in CNS tissue inflammation compared to untreated animals. Subsequent studies in murine models of MS have supported and extended these findings demonstrating that Δ9-THC, but not CBD, ameliorated both tremor and spasticity and reduced the overall clinical severity of the diseaseReference672Reference678. Further work highlighted the importance of the CB1 receptor in controlling tremor, spasticity, and the neuro-inflammatory response. In contrast to findings with the CB1 receptor, the exact function of the CB2 receptor in MS remains somewhat unclear, although it is believed to play a role in regulating the neuro-inflammatory responseReference678Reference680.

Two studies examined the potential therapeutic effects of three kinds of botanical-derived cannabis extracts on different mouse models of MS (i.e. Theiler’s murine encephalomyelitis virus-induced demyelinating disease and the experimental autoimmune encephalitis)Reference681Reference682. Extracts used were a nabiximols-like extract, containing a 1:1 ratio of THC: CBD at 10 mg/kg for each phytocannabinoid, a THC-rich extract (5 mg/kg or 20 mg/kg) containing 67.1% THC, 0.3% CBD, 0.9% CBG, 0.9% CBC, and 1.9% other phytocannabinoids, or a CBD-rich extract (5 mg/kg or 20 mg/kg) containing 64.8% CBD, 2.3% THC, 1.1% CBG, 3.0% CBC, and 1.5% other phytocannabinoids. One of the studies reported that a 10-day treatment regimen with the nabiximols-like extract improved motor activity, reduced CNS infiltrates, microglial activity, axonal damage and restored myelin morphology and that the CBD-rich extract (5 mg/kg) alone appeared to alleviate the motor degeneration to a similar extent as the nabiximols-like extract, whereas the THC-rich extract (5 mg/kg) appeared to produce weaker effectsReference681. The other study reported that treatment with the nabiximols-like extract (10 mg/kg) as well as the THC-rich extract (20 mg/kg), but not the CBD-rich extract (20 mg/kg), improved the neurological deficits typically observed with experimental autoimmune encephalitis in mice, as well as reduced the number and extent of cell aggregates present in the spinal cord; by contrast the CBD-rich extract appeared to only delay the onset of the disease without improving disease progression and reduced the cell infiltrates in the spinal cordReference682. Taken together, the studies suggest that optimal therapeutic effects in these animal models of MS depend on a combination of THC, CBD and potentially other phytocannabinoids. Another study reported that daily topical treatment with a 1% CBD cream exerted neuroprotective effects against the experimental autoimmune encephalomyelitis model of MSReference445. Treatment was associated with a diminished clinical disease score, attenuated paralysis of hind limbs, and improvements in histological scores (i.e. reduced demyelination, axonal loss, reduced inflammatory cell infiltration) and expression of pro-inflammatory cytokines.

Historical and survey data

In humans, published reports spanning 100 years suggest that people with spasticity (one of the symptoms associated with MS) may experience relief with cannabisReference683. In the UK, 43% of patients with MS reported having experimented with cannabis at some point, and 68% of this population used it to alleviate the symptoms of MSReference684. In Canada, the prevalence of medicinal use of cannabis among patients seeking treatment for MS, in the year 2000, was reported to be 16% in Alberta, with 43% of study respondents stating they had used cannabis at some point in their livesReference226. Fourteen percent of people with MS surveyed in the year 2002 in Nova Scotia reported using cannabis for medical purposes, with 36% reporting ever having used cannabis for any purposeReference225. MS patients reported using cannabis to manage symptoms such as spasticity and chronic pain as well as anxiety and/or depressionReference225Reference226. MS patients taking cannabis also reported improvements in sleep. Reputed dosages of smoked cannabis by these patients varied from a few puffs to 1 g or more at a timeReference225.

Clinical studies with orally administered cannabinoid medications (cannabis extract, oral THC, nabiximols)

The results of randomized, placebo-controlled trials with orally administered cannabinoids for the treatment of muscle spasticity in MS are encouraging, but modest.

The large, multi-centre, randomized, placebo-controlled CAnnabis in Multiple Sclerosis (CAMS) study researching the effect of cannabinoids for the treatment of spasticity and other symptoms related to MS enrolled over 600 patientsReference387. The primary outcome was change in overall spasticity scores measured using the Ashworth scale. The study did not show any statistically significant improvement in the (objective) Ashworth score in patients taking either an oral cannabis extract ((Cannador®) containing 2.5 mg Δ9-THC, 1.25 mg CBD, and < 5% other cannabinoids), or oral Δ9-THC, for 15 weeks. However, there was evidence of a significant treatment effect on subjective, patient-reported spasticity and pain, with improvement in spasticity using either orally administered cannabis extract (61%) (dosing: 5 – 25 mg Δ9-THC; 5 – 15 mg CBD/day; and < 5% other cannabinoids, adjusted to body weight and titrated according to side effects) or oral Δ9-THC (60%) (dosing: 10 – 25 mg Δ9-THC/day, adjusted to body weight and titrated according to side effects) compared to placebo (46%). Patients were concomitantly taking other medications to manage MS-associated symptoms. In contrast, a long-term (12 months), double-blind, follow-up to the CAMS study showed evidence of a small treatment effect of oral Δ9-THC (dosing: 5 – 25 mg Δ9-THC/day, adjusted to body weight and titrated according to side effects) on muscle spasticity measured by objective methods, whereas a subjective treatment effect on muscle spasticity was observed for both oral Δ9-THC and oral cannabis extract (Cannador®)Reference685. Cannador® is not available in Canada at this time.

Other randomized clinical trials using standardized cannabis extract capsules (containing 2.5 mg Δ9-THC and 0.9 mg CBD per capsule)Reference686 or nabiximols (Sativex®)Reference432Reference687Reference688 reported similar results, in that improvements were only seen in patient self-reports of symptoms but not with objective measures (e.g. Ashworth scale). The reasons behind the apparent discrepancies between subjective and objective measures are not clear; however, a number of possible explanations may be found to account for the differences. For example, it is known that spasticity is a complex phenomenonReference689 and is affected by patient symptoms, physical functioning, and psychological dispositionReference685. Spasticity is also inherently difficult to measure, and has no single defining featureReference688. In addition, the reliability and sensitivity of the Ashworth scale (for objectively measuring spasticity) has been called into questionReference387Reference688.

The efficacy, safety, and tolerability of a whole-plant cannabis extract administered in capsules (2.5 mg THC and 0.9 mg CBD/capsule) were studied in a fourteen-day, prospective, randomized, double-blind, placebo-controlled crossover clinical trial in patients with clinically stable MS-associated spasticity and an Ashworth score greater than 2Reference686. Slightly more than half of the study subjects had a maintenance dose of 20 mg/day of THC or more (maximum of 30 mg THC/day). Patients were concomitantly taking anti-spasticity medications. Many study subjects had had previous experience with cannabis; a significant number of those who withdrew from the study upon starting treatment with the cannabis extract did not have previous experience with cannabis. While there were no statistically significant differences between active treatment with the cannabis extract and placebo, trends in favour of active treatment were observed for mobility, self-reported spasm frequency, and ability in getting to sleep. The cannabis extract was generally well tolerated with no serious adverse events during the study period. However, adverse events were slightly more frequent and more severe during the active treatment period.

Nabiximols

A six-week, multi-centre, randomized, double-blind, placebo-controlled, parallel-group clinical study of nabiximols (Sativex®) for the treatment of five primary symptoms associated with MS (spasticity, spasm frequency, bladder problems, tremor, and pain) reported mixed resultsReference432. Patients had clinically confirmed, stable MS of any type, and were on a stable medication regimen. Approximately half of the study subjects in either the active or placebo groups had previous experience with cannabis, either non-medically or for medical purposes. While the global primary symptom score, which combined the scores for all five symptoms, was not significantly different between the active treatment group and the placebo group, patients taking cannabis extract showed statistically significant differences compared to placebo in subjective, but not objective measures of spasticity (i.e. Ashworth Score), in Guy’s Neurological Disability Score, and in quality of sleep, but not in spasm frequency, pain, tremor, or bladder problems among other outcome measures. Patients self-titrated to an average daily maintenance dose of nabiximols of 40.5 mg THC and 37.5 mg CBD (i.e. ~15 sprays/day). Adverse effects associated with active treatment included dizziness, disturbance in attention, fatigue, disorientation, feeling drunk, and vertigo.

A long-term, open-label, follow-up clinical study of nabiximols (Sativex®) concluded that the beneficial effect observed in the study by Wade et al. 2004Reference432was maintained in patients who had initially benefited from the drugReference687. The mean duration of study participation in subjects who entered the follow-up study was 434 days (range: 21 – 814 days). The average number of daily doses taken by the subjects remained constant or was slightly reduced over time. The average number of daily doses of nabiximols was 11, corresponding to a dose of 30 mg THC and 28 mg CBD/day. Long-term use of nabiximols in this patient population was associated with reductions in subjective measures of spasticity, spasm frequency, pain, and bladder problems. Dizziness, diarrhea, nausea, fatigue, headache, and somnolence were among the most frequently reported adverse effects associated with chronic nabiximols use in this study. A two-week withdrawal study, incorporated into the long-term follow-up study, suggested that cessation of nabiximols use was not associated with a consistent withdrawal syndrome but it was associated with withdrawal-type symptoms (e.g. interrupted sleep, hot/cold flushes, fatigue, low mood, decreased appetite, emotional lability, vivid dreams, intoxication) as well as re-emergence/worsening of some MS symptoms.

The efficacy, safety and tolerability of nabiximols in MS were investigated in a six-week, multi-centre, phase III, double-blind, randomized, parallel-group clinical study in patients with stable MS who had failed to gain adequate relief using standard therapeutic approachesReference688. Patients had to have significant spasticity in at least two muscle groups, and an Ashworth score of 2 or more to be included in the study. A significant number of patients had previous experience with cannabis. Forty percent of subjects assigned treatment with nabiximols showed a ≥ 30% reduction in self-reported spasticity using an 11-point subjective numerical rating spasticity scale (sNRS) compared to subjects assigned to placebo (21.9%) (difference in favour of nabiximols = 18%; 95% CI = 4.73, 31.52; p = 0.014). Mean number of sprays per day was 9.4 (~25 mg THC and ~24 mg CBD). Subjects on placebo or nabiximols exhibited similar incidences of adverse effects, but adverse CNS effects were more common with the nabiximols group. The majority of adverse events were of mild or moderate severity (e.g. dizziness, fatigue, depressed mood, disorientation, dysgeusia, disturbance in attention, blurred vision).

An observational, prospective, multicenter, non-interventional, clinical practice study examined the safety and effectiveness of nabiximols in the treatment of symptoms associated with MS (i.e. the MObility improVEment in MS-induced spasticity study, MOVE 2)Reference690. MS patients were followed over a three- to four-month period on outcomes, tolerability, QoL and treatment satisfaction. Prior to initiation on nabiximols, other anti-spastic medications were tried in 90% of study patients and the majority of the patients in the study (73%) were put on nabiximols. The mean number of nabiximols sprays/day was 6.9 (range: 1 – 12) reported at follow-up period 1, and 6.7 (range: 1 – 16) reported at follow-up period 2. Physician-based assessment of patients suggested a one-month course of treatment with nabiximols provided relief of resistant MS spasticity in the majority of patients who were administered the drug. After a one-month period, there was an initial response for spasticity detected in 42% of patients and a clinically relevant response for spasticity detected in 25% of these patients. At three-months’ time, an initial response for spasticity was detected in 59% of patients and a clinically relevant response for spasticity detected in 40% of these patients. Scores in mean sleep disturbance decreased by 33% over a one-month treatment period in patients with an initial response, and by 40% in patients with a clinically relevant response. Scores on the combined modified Ashworth score (cMAS) decreased by 12% after one-month treatment in patients with an initial response and by 15% in patients with a clinically relevant response. Scores on the MSQoL-54 physical health composite scale and the mental health composite score showed statistically significant improvements over the three-month period in patients with an initial response and a clinically relevant response. After three-months’ treatment with nabiximols, the mean EQ-5D-3L index value remained stable and a statistically significant reduction was observed in the percentages of patients considering muscle stiffness, restricted mobility, pain, and bladder disorders as most disturbing symptoms. Overall, at three-months’ treatment time, almost 80% of the entire study population of patients on nabiximols was either “completely satisfied” or “satisfied” with the effectiveness of nabiximols. Most commonly observed adverse events with nabiximols were dizziness (4%), fatigue (2.5%), drowsiness (1.9%), nausea (1.9%), and dry mouth (1.2%).

A 12-month prolongation study of the MOVE 2 clinical trial to determine long-term effectiveness and safety of nabiximols in clinical practice reported that from among 52 patients enrolled in the study that were included in the effectiveness analysis, the mean spasticity numerical rating scale score decreased significantly from 6.0 points at baseline to 4.8 points after one month and remained at this level after the 12-month period, including in patients who were classified as “initial responders”Reference691. At baseline, the mean sleep disturbance numerical rating scale (NRS) score was 5.1 points in the subsample of participants and after 12 months it decreased to 3.2 points; in patients with an initial response, scores dropped from 5.4 to 2.4, and in patients with a clinically relevant response mean sleep disturbance NRS scores decreased from 5.3 to 1.9 points. Furthermore, the mean values of the MSQoL-54 physical health composite score and the mean mental health composite score both showed improvements, but were not statistically significant. The EQ-5D-3L index value showed improvement over the 12-month period for those patients who showed an initial and clinically relevant response. Furthermore, at study end, fewer patients who showed an initial and clinically-relevant response considered the MS spasticity-related symptoms of muscle stiffness, pain, restricted mobility, fatigue, and bladder disorders as the most disturbing symptoms compared to baseline. From the patient’s perspective, impairment of daily activities was significantly improved after 12-month treatment with nabiximols compared to baseline and fewer patients complained about daily impairment of activities and notably, the improvement was more prominent in responders than in the entire study group. The majority of patients did not report adverse events. Most commonly reported adverse events included GI disorders, psychiatric disorders, and nervous system disorders. Mean daily number of nabiximols sprays was 6.2 (range: 2 – 12) and at least one other anti-spastic drug was still prescribed in 28 patients (e.g. baclofen, tizanidine, tolperisone, or gabapentin).

A pilot, prospective, multicentre, non-interventional post-marketing surveillance study conducted to collect data on driving ability, tolerability and safety from 33 patients with MS starting nabiximols treatment reported that a four to six-week treatment period with nabiximols (average 5.1 sprays per day, or 13.7 mg THC and 12.8 mg CBD/day) was associated with a statistically significant improvement in self-rated spasticity and was also not associated with a statistically significant deterioration in patients’ ability to drive, as measured in the laboratory using a battery of cognitive and psychomotor testsReference692. However, less than half of the patients met the “fit to drive” criteria. In addition, 4 out of the 33 patients experienced a non-serious, mild or moderate adverse event associated with nabiximols treatment (e.g. dizziness and vertigo).

A non-randomized, non-placebo-controlled study quantitatively assessed the functional effects of nabiximols treatment on gait patterns in 20 patients with MSReference693. Enrolled MS patients had an expanded disability status scale (EDSS) score of 5.3 at study start, were unresponsive to spasticity treatments, and were able to walk unaided for 6 min. Patients were treated with nabiximols for one month (average number of sprays per day = 5.6 or a daily dose of 15 mg THC and 14 mg CBD) and the study reported that nabiximols treatment was associated with statistically significant improvements in Gait Profile Score, speed, cadence and stride length.

A four-week, prospective, randomized, double-blind, placebo-controlled, crossover clinical study of 44 patients with progressive primary or secondary MS, with moderate to severe spasticity and inadequate response to anti-spasticity agents investigated nabiximols-induced changes in neurophysiological measures of spasticity in patients with lower limb MS-associated spasticity, as well as changes in spasticity and related functional parametersReference694. At baseline, patients were concomitantly using glatiramer acetate, cyclophosphamide, azathioprine, fingolimod, natalizumab, interferon beta-1b, interferon beta-1a and methotrexate. Other medications included baclofen, eperisone, tizanidine, and benzodiazepines. Average daily dose of nabiximols was seven sprays per day or 18.9 mg THC and 17.5 mg CBD. The study reported no significant difference in the change from baseline to week 4 in the neurophysiological measure of spasticity (H/M ratio) with either nabiximols or placebo. Furthermore, no significant effect was found for all secondary neurophysiological measures. However, there was a statistically significant improvement in mean lower limb modified Ashworth scale score with nabiximols compared to placebo. There were no statistically significant differences for functional outcomes (timed 10 meter walk, 9-Hole Peg Test scores, pain NRS scores, sleep NRS scores, and Fatigue Severity Scale scores) between nabiximols and placebo. Most patients experienced an adverse event; the most commonly reported one was mild to moderate dizziness (21%), followed by lower limb weakness, vertigo, hypotension, hypertension, somnolence, and pharyngodynia. Most side effects were transient and appeared mostly during the titration phase or during increases in the number of sprays and resolved after reduction in the number of sprays. Limitations of the study included small sample size, short treatment period and relatively large number of study dropouts (14%) which limited the statistical power of the study.

A one-year, prospective, cohort study of 144 patients with moderate-to-severe MS spasticity and with evidence of inadequate response to traditional anti-spastic medications explored the efficacy, safety and tolerability of nabiximols at 4, 14, and 48 weeks and also assessed whether baseline demographic and clinical features could predict treatment responseReference695. Patients were initially enrolled in a four-week “titration phase” to identify responders showing at least a 20% reduction in sNRS from baseline. Responders were then subsequently enrolled in the study. sNRS score dropped significantly in responders from 7.6 (baseline) to 5.2 at four weeks, with the mean number of daily sprays being 6.5 in responders vs. 7.7 in non-responders. sNRS score further improved in the responder group to a score of 5.0 (or a 30% clinically significant reduction in sNRS score) between 4 and 14 weeks’ treatment. The cMAS was 4.0 at baseline in responders and significantly improved at four weeks’ time and was persistently lower at 14 weeks’ time compared to baseline. Nabiximols treatment was also associated with a significant improvement in the 10 min walking test after four weeks’ treatment and improvement was maintained at 14 weeks compared to baseline. The ambulation index also showed a significant improvement in responders at 4 weeks and was maintained at 14 weeks despite an EDSS score that remained unchanged throughout the study period. Pain numerical rating score (pNRS) in responders showed a statistically significant decrease from 4.2 at baseline to 3.3 after 4 weeks’ treatment and decreased further to 2.9 at 14 weeks. In responders who remained in the study at the 48-week follow-up, nabiximols efficacy was maintained with a spasticity score that remained statistically and clinically significantly lower than at baseline (i.e. 33% reduction) and the mean number of sprays taken daily was 6.2. Improvement in median cMAS was still evident, with a score of 3.0 at 48 weeks compared to 4.0 at baseline. The score on the pNRS was consistently lower at 48 weeks compared to baseline. No further improvement was noted for either the 10 min walking test or ambulation index. Eighty percent of patients in the study reported side effects, which appeared at a mean daily dose of 7.2 sprays (19.44 mg THC and 18 mg CBD). The most commonly reported side effects were confusion/ideomotor slowing (35%), dizziness (24%) and fatigue (20%). The majority of the reported side effects developed during the titration phase, were mild in intensity, and decreased with dosage adjustment. Nine percent of all patients enrolled in the study (responders and non-responders) discontinued treatment within 4 weeks of starting nabiximols because of side effects, while 9% of responders discontinued treatment for the same reason within 14 weeks of initiating treatment. One subject reported depersonalization two months after starting nabiximols while another subject developed depression. Lastly, demographic analysis suggested that patients with shorter disease duration and younger age tended to respond more favourably to nabiximols (i.e. “responders”). Study limitations included observational design, limited sample size, and lack of assessment of QoL and impairment in daily living.

CUPID and MUSEC clinical studies

The Cannabinoid Use in Progressive Inflammatory Brain Disease (CUPID) study was a randomized, double-blind, clinical investigation designed to measure whether orally administered Δ9-THC was able to slow the progression of MS. This three-year publicly-funded trial took place at the Peninsula Medical School in the U.K. and followed the earlier, one-year long, CAMS study. A total of 493 subjects with primary or secondary progressive, but not relapse-remitting, MS had been recruited from across the U.K. in 2006. The CUPID trial found no evidence to support an effect of Δ9-THC on MS progression, as measured by using either the EDSS or the MS Impact Scale 29 (MSIS-29). However, the authors concluded that there was some evidence to suggest a beneficial effect in participants who were at the lower end of the disability scale at the time of patient enrolment. Since the observed benefit only occurred in a small sub-group of patients, further studies would be required to more closely examine the reasons for this selective effectReference696.

A double-blind, placebo-controlled, phase III clinical study (the MUltiple Sclerosis and Extract of Cannabis trial, MUSEC) published by the same group of researchers that conducted the CUPID trial, reported that a twelve-week treatment with an oral cannabis extract (Cannador®) (2.5 mg Δ9-THC and 0.9 mg CBD/capsule) was associated with a statistically significant relief in patient-reported muscle stiffness, muscle spasms, and body pain as well as a statistically significant improvement in sleep compared to placebo, in patients with stable MSReference697. There were no statistically significant differences between cannabis extract and placebo on functional measures such as those examining the effect of spasticity on activities of daily living, ability to walk, or on social functioning. The majority of the patients using cannabis extract used total daily doses of 10, 15, or 25 mg of Δ9-THC with corresponding doses of 3.6, 5.4, and 9 mg of CBD. The majority of the study subjects were concomitantly using analgesics and anti-spasticity medications, but were excluded if they were using immunomodulatory medications (e.g. interferons). Active treatment with the extract was associated with an increase in the number of adverse events, but the majority of these were considered mild to moderate and did not persist beyond the study period. The highest number of adverse events were observed during the initial two-week titration period and appeared to decrease progressively over the course of the remaining treatment sessions. The most commonly observed adverse events were those associated with disturbances in CNS function (e.g. dizziness, disturbance in attention, balance disorder, somnolence, feeling abnormal, disorientation, confusion, and falls). Disturbances in GI function were the second most commonly occurring adverse events (e.g. nausea, dry mouth).

Clinical studies with smoked cannabis

There has only been one clinical study so far using smoked cannabis for symptoms associated with MSReference278. The study, a double-blind, placebo-controlled, crossover clinical trial reported a statistically significant reduction in patient scores on the modified Ashworth scale for measuring spasticity after patients smoked cannabis once daily for three days (each cigarette contained 800 mg of 4% Δ9-THC; total available Δ9-THC dose of 32 mg per cigarette). Smoking cannabis was also associated with a statistically significant reduction in patient scores on the VAS for pain, although patients reportedly had low levels of pain to begin with. No differences between placebo and cannabis were observed in the timed-walk task, a measure of physical performance. Cognitive function, as assessed by the Paced Auditory Serial Addition Test, appeared to be significantly decreased immediately following administration of cannabis; however, the long-term clinical significance of this finding was not examined in this study. The majority of patients (70%) were on disease-modifying therapy (e.g. interferon β-1a, interferon β-1b, or glatiramer), and 60% were taking anti-spasticity agents (e.g. baclofen or tizanidine). Cannabis treatment was associated with a number of different, but commonly observed adverse effects including dizziness, headache, fatigue, nausea, feeling “too high”, and throat irritation. Study limitations included the fact that the majority of patients had prior experience with cannabis, and that the study was unblinded since most of the patients were able to tell apart the placebo from the active treatment with cannabis.

Cannabis/cannabinoid tolerability in multiple sclerosis

Generally speaking, cannabis and orally administered prescription cannabinoids (e.g. dronabinol, nabilone, nabiximols, Cannador®) are reported to be well tolerated in patients with MSReference686Reference690Reference692Reference694Reference695Reference698Reference699. Clinical trials to date do not indicate serious adverse effects associated with the use of these prescription cannabinoid medications (or cannabis). However, there appears to be an increase in the number of non-serious adverse effects associated with the short-term use of cannabinoidsReference4. The most commonly reported short-term physical adverse effects are dizziness, drowsiness, and dry mouthReference387Reference699.

Prolonged use of ingested or inhaled cannabis was associated with poorer performance on various cognitive domains (information processing speed, working memory, executive function, and visuospatial perception) in patients with MS according to one cross-sectional studyReference233. Another cross-sectional study reported that while patients with MS who smoked cannabis daily are more cognitively impaired than non-users especially with respect to working memory, attention and information processing speed, no structural differences (lesion volume, global atrophy, diffusion tensor imaging [DTI] metrics) were discernible between users and non-usersReference700. However, a follow-up study suggested that in the same cannabis-smoking patients, but not in the non-users, volume reductions in gray matter and white matter (in medial and lateral temporal regions, thalamus, basal ganglia, prefrontal cortex) were associated with the observed widespread cognitive deficitsReference701.

In contrast, another study concluded that nabiximols treatment, in cannabis-naïve MS patients, was not associated with cognitive impairmentReference699. However, the study did raise the possibility that higher dosages could precipitate changes in psychological disposition, especially in those patients with a prior history of psychosis. In any case, important information is generally lacking regarding the long-term adverse effects of chronic cannabinoid use in MS patients, and more generally in patients using for therapeutic purposes.

Bladder dysfunction associated with multiple sclerosis or spinal cord injury

Bladder dysfunction occurs in most patients suffering from MS or SCIReference702. The most common complaints are increased urinary frequency, urgency, urge, and reflex incontinenceReference703. cannabinoid receptors are expressed in human bladder detrusor and urotheliumReference37Reference38, and may help regulate detrusor tone and bladder contraction as well as affecting bladder nociceptive response pathways (reviewed inReference38).

An early survey of MS patients regularly using cannabis for symptomatic relief of urinary problems reported that over half of these patients claimed improvement in urinary urgencyReference538. A sixteen-week, open-label, pilot study of cannabis-based extracts (a course of nabiximols treatment followed by maintenance with 2.5 mg Δ9-THC only) for bladder dysfunction, in 15 patients with advanced MS, reported significant decreases in urinary urgency, number and volume of incontinence episodes, frequency, and nocturiaReference704. Improvements were also noted in patient self-assessments of pain and quality of sleep. A subsequent RCT of 250 MS patients suggested a clinical effect of orally administered cannabinoids (2.5 mg Δ9-THC or 1.25 mg CBD with < 5% other cannabinoids per capsule, up to a maximum 25 mg/day) on incontinence episodesReference702.

4.5.2 Amyotrophic lateral sclerosis

There is some pre-clinical evidence implicating the ECS in the progression of an ALS-like disease in mouse models of the disorder; under certain conditions, cannabinoids, or elevation of endocannabinoid levels through pharmacological inhibition or genetic ablation, have been reported to modestly delay disease progression and prolong survival in these animal models (reviewed inReference705.

Anecdotal reports suggest decreased muscle cramps and fasciculations in ALS patients who smoked herbal cannabis or drank cannabis tea, with up to 10% of these patients using cannabis for symptom controlReference706Reference707.

Only two clinical trials of cannabis for the treatment of symptoms associated with ALS exist, and the results of the studies are mixed. In one four-week, randomized, double-blind, crossover pilot study of 19 ALS patients, doses of 2.5 to 10 mg per day of dronabinol (Δ9-THC) were associated with improvements in sleep and appetite, but not cramps or fasciculationsReference708. In contrast, a shorter two-week study reported no improvement in these measures in ALS patients taking 10 mg of dronabinol per dayReference707. In either case, dronabinol was well-tolerated with few reported side effects in this patient population at the tested dosages.

4.5.3 Spinal cord injury (or spinal cord disease)

Pre-clinical animal studies have shown the existence of an ECS in the spinal cord and a basal endocannabinoid tone in non-injured spinal cordsReference709. While the role of the ECS in the intact spinal cord is only partially known, endocannabinoids modulate spinal cord analgesia as well as excitability, participating in the physiological control of reflexesReference709. Pre-clinical animal studies suggest that SCI triggers changes in the activity of the ECS, with an acute spike in production of anandamide and 2-AG in the epicenter of the damaged areaReference709. The spike in endocannabinoid levels, reflecting an active protective process induced by injury, returns to basal levels within a few days’ post-injury; however 2-AG levels go through a subsequent secondary and more protracted rise in levels over a subsequent 28-day periodReference709. Blocking both CB1 and CB2 receptors worsens SCI-associated damage, whereas stimulation of these two cannabinoid receptors appears to be protective and may also alleviate neuropathic pain associated with SCIReference710Reference712. One pre-clinical study also reported a beneficial effect of CBD in restoring motor function and reducing extent of injury following SCI in a mouse modelReference713. Subjective improvements have been anecdotally reported by SCI patients smoking cannabisReference642Reference714

However, despite the evidence from animal studies and anecdotal claims, limited clinical information exists regarding the use of cannabis and cannabinoids to treat symptoms associated with SCI such as pain, spasticity, muscle spasms, urinary incontinence, and difficulties sleeping. Double-blind, crossover, placebo-controlled studies of oral Δ9-THC and/or nabiximols suggested modest improvements in pain, spasticity, muscle spasms, and sleep quality in patients with SCIReference642Reference715Reference716. More recently, a randomized, double-blind, placebo-controlled parallel study using a minimum of 15 to 20 mg Δ9-THC/day (mean daily doses of 31 mg Δ9-THC orally, or 43 mg Δ9-THC-hemisuccinate rectally) showed a statistically significant improvement in spasticity scores in patients with SCIReference717 and a double-blind, placebo-controlled, crossover study using nabilone (0.5 mg b.i.d.) also showed an improvement in spasticity compared to placebo in patients with SCIReference718.

A recent randomized, double-blind, placebo-controlled, cross-over clinical trial of vapourized cannabis showed analgesic and anti-spastic benefit for patients with SCI and diseaseReference276. In this clinical trial, 42 patients (the majority of whom were currently using or had used cannabis) with neuropathic pain from SCI and disease were administered between 8 and 12 inhalations of cannabis placebo, or cannabis containing either low (2.9%) strength THC or high (6.7%) strength THC over an 8 h treatment session (400 mg dried cannabis material; vapourization temperature 185 ºC). While 400 mg of dried cannabis was placed in the vapourizer, only 45.9 mg (range: 29.9 – 83.8 mg) of the lower strength and 56.3 mg (range: 15.7 – 172.9 mg) of the higher strength cannabis was vapourized. These amounts and strengths suggest that on average between 1.3 and 3.8 mg of THC may have been inhaled (range: 0.86 – 11.6 mg THC). Median blood plasma concentrations of THC were 23 ng/mL (peak: 68.5 ng/mL) for the 2.9% strength and 47 ng/mL (peak: 177 ng/mL) for the 6.7% strength 3 h after an initial round of four inhalations and immediately after a second round of between four and eight additional inhalations. Pain intensity (primary outcome) decreased with increasing THC strength and was statistically significantly different from placebo for both strengths of THC after the first hour of exposure (round 1: 4 inhalations) and improved further compared to placebo after a second-round of inhalations (an additional 4 to 8 inhalations for a total of 8 to 12 inhalations overall). Pain relief showed a statistically significant difference between low and high strengths compared with placebo. The number of patients needed to treat (NNT) to achieve a 30% reduction in pain during the 8 h treatment session was 4 for the lower (2.9%) strength and 3 for the higher (6.7%) strength compared to placebo, whereas the NNT was 6 when comparing between the lower and higher strengths (but CIs were wide). By comparison, for neuropathic pain the NNT for pregabalin is 3.9 and for gabapentin, 3.8. Both strengths of cannabis provided statistically significant improvements on a variety of pain descriptors (i.e. sharpness, burning, aching, cold, sensitivity, unpleasantness, deep pain and superficial pain) but only the higher strength provided short-term relief of itching. No general effect was noted on allodynia. Only the lower strength (2.9%) was associated with a statistically significant decrease in spasticity and only 3 h after treatment initiation. Generally, there were no statistically significant differences between study medications on various measures of neuropsychological performance. Many of the psychoactive effects (“high”, “good drug effect”, “any drug effect”, “impaired”, “stoned”, and “sedated”) showed a dose dependency with greater effects with the higher dose compared to the lower dose and with both doses compared to placebo. The authors suggest that patients with SCI or disease who wish to avoid the psychomimetic effects while benefiting from the therapeutic effects consider using the lower dose (2.9%).

4.6 Epilepsy

  • Anecdotal evidence suggests an anti-epileptic effect of cannabis (THC- and CBD-predominant strains).
  • The available evidence from pre-clinical and limited clinical studies suggests certain cannabinoids (CBD) may have anti-epileptiform and anti-convulsive properties, whereas CB1R agonists (THC) may have either pro- or anti-epileptic properties.
  • However, the clinical evidence for an anti-epileptic effect of cannabis is weaker, but emerging, and requires further study.
  • Evidence from clinical studies with Epidiolex® (oral CBD) suggests efficacy and tolerability of Epidiolex® for drug-resistant seizures in treatment-resistant Dravet syndrome or Lennox-Gastaut syndrome.
  • Evidence from observational studies suggests an association between CBD (in herbal and oil preparations) and a reduction in seizure frequency as well as an increase in quality of life among adolescents with rare and serious forms of drug-resistant epilepsy.
  • Epidiolex® has received FDA approval (June 2018) for use in patients 2 years of age and older to treat treatment-resistant seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

Epilepsy is one of the most common neurological disorders with a worldwide prevalence of approximately 1%Reference217Reference719. It is not a singular disease entity, but a variety of disorders reflecting underlying brain dysfunction arising from many different causesReference720. Epilepsy is characterized by recurrent, unprovoked seizures, which are transient occurrences of signs and symptoms caused by abnormal excessive or synchronous neuronal activity in the brainReference720. Seizures can be of various types including genetic and occurring in childhood (e.g. Dravet Syndrome, Lennox-Gastaut), or acquired and occurring in adulthood (e.g. after severe head injury, stroke, or from a tumour)Reference265. Co-morbidities associated with epilepsy include cognitive decline, depressive disorders, and schizophreniaReference721.

Despite the availability of many anti-epileptic medications, close to 30% of patients with epilepsy remain refractory to conventional treatments leading them to search for other therapeutic modalities, such as cannabis (e.g. CBD-enriched cannabis oils)Reference722.

The endocannabinoid system and epilepsy

The ECS is known to regulate cortical excitability, and endocannabinoids have been suggested to produce a stabilizing effect on the balance between excitatory and inhibitory neurotransmitters in the CNSReference723.

Temporal lobe epilepsy, one of the most common kinds of epilepsy seen in adults, is associated with changes in the hippocampus where CB1 receptor expression is downregulated during the acute phase, shortly after the precipitating insult, but then upregulated in the chronic phase of the disorderReference217Reference265Reference724Reference725. Furthermore, it appears that the expression of the CB1 receptor on excitatory glutamatergic axon terminals, as well as the expression of DAGL, which is responsible for yielding the endocannabinoid 2-AG, are both downregulatedReference265. In contrast, CB1 receptor expression on inhibitory GABAergic axon terminals appears to be upregulated. In addition, reduced levels of the endocannabinoid anandamide have been detected in the cerebrospinal fluid (CSF) of patients with untreated, newly diagnosed, temporal lobe epilepsyReference726, whereas normally, anandamide is found in high concentrations in the hippocampus, a brain region known to be involved in epileptogenesis and seizure disordersReference263. Taken together, these and other studies demonstrating changes in CB1receptor and DAGL expression in the hippocampus and changes in anandamide levelsReference727Reference729 suggest important and widespread changes in the functioning of the ECS in epilepsy. Since the ECS is generally thought to act as a neurotransmitter braking system, the reported dysregulation of the ECS in epilepsy may play a role in the generation and maintenance of epileptic seizuresReference265. There is also some evidence to suggest that endocannabinoids promote the maintenance, but not the initiation, of epileptiform activity by activating CB1 receptors located on astrocytesReference730.

Pre-clinical studies

In vitro and in vivo studies suggest certain phytocannabinoids (and endocannabinoids) can have anti-convulsive but also, in some cases, pro-convulsive rolesReference263Reference265Reference266Reference719Reference721Reference731Reference739.

CB1 receptors are located mainly pre-synaptically where they typically inhibit the release of classical neurotransmittersReference740.The purported anti-epileptic effect of certain cannabinoids (e.g. THC) is thought to be mediated by CB1-receptor dependent pre-synaptic inhibition of glutamate releaseReference265Reference728Reference741; on the other hand, epileptogenic effects may be triggered by pre-synaptic inhibition of GABA releaseReference265Reference736Reference739Reference742Reference744. CB1 receptor agonists (e.g. THC) therefore have the potential to trigger or suppress epileptiform activity depending upon which cannabinoid-sensitive pre-synaptic terminals are preferentially affected (i.e. glutamatergic or GABAergic)Reference112Reference266Reference741. Because of the ability of CB1 receptor agonists such as THC to yield either pro- or anti-convulsant activities and because of the reported development of tolerance to their anti-convulsant effects, CB1 receptor agonists are thought to be unlikely to yield therapeutic benefit for patients with epilepsyReference263Reference266.

In contrast to the ambiguous situation with CB1 receptor agonists such as THC, phytocannabinoids such as CBD, CBDV, THCV, and CBN appear to mainly have anti-convulsant roles and may have more potential therapeutic value for the treatment of epilepsyReference263Reference266. A number of in vivo studies have demonstrated the anti-epileptic effects of CBD across different animal models of epilepsy (reviewed inReference263). Early studies using various rat and mouse models of epilepsy reported that CBD was an effective anti-convulsant and its potency was significantly increased when combined with anti-epileptic drugs such as phenytoin and phenobarbital used to treat major seizuresReference263Reference745. In contrast, CBD reduced the anti-convulsant potencies of chlordiazepoxide, clonazepam, trimethadione, and ethosuximide used for minor seizuresReference263Reference745. ED50 doses for CBD in rats ranged from as low as 12 mg/kg (p.o.) to as high as 380 mg/kg (i.p.) in miceReference263Reference745Reference746. Another study reported that CBD attenuated epileptiform activity in vitro in hippocampal slices and displayed anti-convulsant activity in vivo (100 mg/kg) in one rat model of epilepsy, attenuating seizure severity, tonic-clonic seizures and mortalityReference735. A follow-up study by this same group examined the anti-convulsive effects of CBD in two other rat models of temporal lobe and partial epilepsyReference733. CBD at doses of 1, 10, and 100 mg/kg significantly attenuated the percentage of animals displaying seizure events (temporal lobe epilepsy); however, there was no significant effect upon the mean number of seizure occurrences per animal or on seizure severity. In the model of partial seizure, CBD (1, 10, 100 mg/kg) decreased the percentage of animals that developed tonic-clonic seizures and was associated with decreased mortality rate (at 10 and 100 mg/kg), but had no effect on overall seizure severity. CBD was also reported to have some minor negative effects on motor function at a dose of 100 mg/kg, which was paradoxically attenuated when the dose was doubled (200 mg/kg)Reference733.

The anti-convulsant effects of pure CBDV as well as botanical extracts containing CBDV (and significant amounts of CBD), with and without THC and THCV, have been investigated in a number of animal models of epilepsyReference263Reference719Reference721Reference747. CBDV (> 10 µM) was found to significantly attenuate epileptiform activity in vitro as well as having significant anti-convulsant effects in vivo (min. > 50 mg/kg i.p.) in different mouse models of epilepsyReference747. A dose of 200 mg/kg (i.p.) of CBDV was associated with complete cessation of tonic convulsions in two models of epilepsy and attenuated seizure severity and mortality at a 200 mg/kg i.p. dose as well as significantly delaying seizure onset in a third epilepsy modelReference747. Furthermore, co-administration of CBDV and the anti-epilepsy drugs valproate, ethosuximide, or phenobarbital was associated with significant anti-convulsant effectsReference747. For example, co-administration of CBDV (200 mg/kg) with valproate (50 – 250 mg/kg) or ethosuximide (60 – 175 mg/kg) was associated with significant anti-convulsant effectsReference747. Co-administration of 200 mg/kg CBDV and phenobarbital (10 – 40 mg/kg) was also associated with significant anti-convulsant effectsReference747. CBDV did not appear to have any significant effects on motor performance at the tested doses and also appeared to be well-tolerated when co-administered with these anti-epileptic drugsReference747. In mice and rats, CBDV showed significant anti-convulsive effects with doses ranging from 50 mg/kg to 400 mg/kg or moreReference263Reference719Reference721. Furthermore, in vivo animal studies with two types of botanical extracts enriched in CBDV (47.4 – 57.8 %) and CBD (13.7 – 13.9%) with and without THC (1%) and THCV (2.5%) were studied for their anti-convulsive effects as well as their toxicitiesReference721. The study found that both botanical extracts showed similar significant anti-convulsive actions in three different animal models of epilepsy and that the presence of THC/THCV at the doses administered in the extracts did not contribute to the anti-convulsive actionsReference721. On the other hand, the presence of THC/THCV in the extract contributed to some observed adverse motor effectsReference721. Lastly, CBDV was found to bind only weakly to the CB1 receptor, suggesting the anti-convulsant mechanism of action of CBDV is CB1-receptor independentReference721.

In contrast with CBD and CBDV, the anti-convulsant effects of CBN have not been as well studied. In one study, CBN produced anti-convulsant effects with an ED50 of 18 mg/kgReference263Reference745.

Although in vitro studies show that THCV binds with relatively high affinity at CB1 receptorsReference112Reference748, THCV does not appear to be a potent CB1 receptor agonistReference112Reference263Reference748. Instead, experimental studies suggest THCV acts more like a CB1 receptor antagonist and a potent CB2 receptor partial agonistReference18Reference112Reference263Reference748Reference749. At higher doses however, THCV appears to have some agonist activity at the CB1 receptorReference18. Furthermore, in vitro studies suggest THCV has some anti-epileptiform effects at micromolar concentrationsReference112 and in vivo studies suggest THCV (0.25 mg/kg) has some limited anti-convulsant effects in one mouse model of epilepsyReference112Reference266.

There is little experimental evidence thus far for the anti-convulsant effects of CBG. While one in vitro study suggests anti-epileptiform activity for CBG, an in vivo study in rats suggests that in one model of epilepsy, CBG (at doses ranging from 50 – 200 mg/kg) does not have anti-convulsant effectsReference263Reference750.

Data from observational studies and patient surveys

According to some studies, about 20% of epilepsy patients are actively using cannabisReference722Reference731Reference751Reference752. A telephone survey of 136 patients of a Canadian tertiary care epilepsy centre revealed that 48% had used cannabis in their lifetime, 21% were active users, 13% were frequent users (one day per week or more), and 8.1% were heavy users (every other day or more)Reference752. Three percent of subjects met the criteria for cannabis dependence. When asked about their personal experiences with cannabis use, 68% of respondents said their seizure severity improved, while 32% said there was no effect. With regard to seizure frequency, 54% claimed improvement, while 46% stated no effect. Eleven percent noted fewer side effects from medications when using cannabis, while 85% did not notice an effect. Forty-three percent of respondents stated medical reasons for cannabis use. The survey authors noted that cannabis use was associated with increased seizure frequency and longer duration of disease. While the reasons for these associations is not clear, it is possible that patients with more severe epilepsy are more prone to trying or using cannabis or that cannabis use is associated with worsening epilepsy.

Another study interviewed epilepsy outpatients at a tertiary epilepsy clinic in Germany. Out of 310 epilepsy patients that were interviewed, 28% said they had used cannabis in their lifetime while 63% had consumed cannabis after their epilepsy diagnosisReference751. Almost 70% of epilepsy patients had partial epilepsy, a little over 20% had idiopathic generalized epilepsy, and approximately 10% were undetermined. Common reasons for cannabis use included curiosity, enjoyment and relaxation. The majority of patients (84%) who had started using cannabis after their epilepsy diagnosis did not observe any effect on their epilepsy, 5% had reported improvement in their seizures or symptoms associated with cannabis use, and 11% reported worsening of seizures associated with cannabis use.

A retrospective clinical chart review of 18 Canadian patients with epilepsy who were authorized to possess cannabis for medical purposes reported that 61% had focal epilepsy, with 39% having generalized epilepsyReference753. Twenty-two percent had mesial temporal sclerosis, 17% had idiopathic epilepsy, 17% had epilepsy associated with a tumour, 11% had been diagnosed with Lennox-Gastaut, 11% had epilepsy associated with a congenital malformation, and 11% were classified as unknown. Psychiatric comorbidity was common (61%) with depression being the most frequent entity. Most patients had used an average of five anti-epileptic medications in the past. Eighty-nine percent of patients had a long history of cannabis use before obtaining an authorization to possess. Mode of administration was mainly by smoking (83%). Mean number of daily puffs was 4 and the estimated amount of cannabis consumed per day was 2 g. All patients that stopped cannabis use reported exacerbation of seizures associated with drug withdrawal. None reported status epilepticus as a complication. One hundred percent of patients reported improvement in seizure severity and seizure frequency. Eighty-nine percent of the patients reported no side effects, while all reported an improvement in mood disorders, and general well-being. Eighty-nine percent reported an improvement in sleep quality and appetite. Limitations of this study included its retrospective nature and bias associated with self-reporting, as well as the lack of a control group and its small sample size.

Treatment-resistant, childhood-onset epilepsy

The results from two parent surveys of children with treatment-resistant childhood epilepsy and who tried cannabis oils have been published and are summarized hereReference215Reference264. In one survey of 19 children, 13 had Dravet syndrome, 4 had Doose syndrome, 1 had Lennox-Gastaut and 1 had idiopathic early-onset epilepsyReference264. Children ranged in age from 2 to 16 years. The parents reported that the children had a variety of different seizure types including focal, tonic-clonic, myoclonic, atonic, and infantile spasms. In virtually all cases, the study reported that the children had treatment-resistant epilepsy for more than three years before trying CBD-enriched cannabis. The children had tried an average of 12 other anti-epileptic medications before beginning CBD-enriched cannabis treatment. Dosages of CBD reported ranged from less than 0.5 mg/kg/day to 28.6 mg/kg/day, while dosages of THC were reported to range from 0 to 0.8 mg/kg/day. Duration of CBD-enriched cannabis use was reported to range from two weeks to over one year. Eighty-four percent of the parents that responded to the survey reported a reduction in their child’s seizure frequency. Two parents reported a complete halt of seizures in their children after more than four months of treatment. Forty-two percent of the surveyed parents reported a greater than 80% reduction in seizure frequency, 16% reported a greater than 50% reduction in seizure frequency and the same proportion of parents reported a greater than 25% reduction as well as no reduction. Sixty-percent of parents reported weaning their child from another anti-epileptic medication after starting CBD-enriched cannabis treatment. Parent-reported beneficial effects included better mood (79%), increased alertness (74%), better sleep (68%), and decreased self-stimulation (32%), while adverse effects included drowsiness (37%), and fatigue (16%). Limitations of such a survey include the self-selection bias, lack of a control group, the inability to independently verify any of the parents’ claims including information about dosing, as well as the small sample size and the under-representation of epilepsy types other than Dravet syndrome.

The results of a second parent surveyReference215 have also been published. In this survey, 117 parents of children with treatment-resistant epilepsy responded. Forty-five percent of parents reported a child with infantile spasms and/or Lennox-Gastaut syndrome, while 13% reported severe myoclonic epilepsy of infancy (Dravet syndrome). Four percent reported myoclonic-astatic epilepsy (Doose syndrome) and 38% reported other types of epilepsy. Age range of children was 3 to 10 years and the median number of anti-epileptic medications tried and failed prior to trial of CBD-enriched cannabis preparations was eight. Median duration of CBD treatment was 6.8 months (range: 3.8 to 9.8 months). Median dosage of CBD in the preparations was 4.3 mg/kg/day (range: 2.9 to 7.5 mg/kg/day). The vast majority of respondents reported using CBD-enriched oil-based extracts, typically administered two to three times per day. The reported CBD to THC ratio in the oil preparations was at least 15:1. Eighty-five percent of respondents reported a reduction in seizure frequency, including 14% reporting complete seizure freedom while 9% reported no change and 4% reported an increase in seizure frequency. Eighty-six percent of respondents reported either an improvement or worsening within 14 days of starting treatment. Adverse effects associated with treatment included increased appetite (29.9%) and weight gain (29.1%). Interestingly, the median number of side effects reported during treatment was much lower than that reported before treatment. The reported decrease in the number of side effects during treatment was attributed to the claimed discontinuation of at least one anti-seizure medication during treatment. While overall, the prevalence of adverse effects was decreased during treatment with the cannabis preparations, the most often encountered adverse effects were drowsiness (12.8%), fatigue (9.4%), irritability (9.4%), and nausea (6.8%). Respondents reported improvement in sleep (53%), alertness (71%), and mood (63%). Again, as with the survey carried out by Porter et al., the survey by Hussain et al. 2015 carries the same limitations and the data must be interpreted with caution.

A retrospective chart review of 75 children and adolescents in Colorado who were given oral cannabis extracts for the treatment of refractory epilepsy reported that 57% of patients showed improvement in seizure control and 33% reported a > 50% reduction in seizuresReference754. Average age was 7.3 years (range: 6 months to 18 years) when starting oral cannabis extract treatment. Four percent of the patients had Doose syndrome, 17% had Dravet syndrome, and 12% were diagnosed with Lennox-Gastaut syndrome. Among children with a specified syndrome, those with Lennox-Gastaut represented the greatest proportion of responders to oral cannabis extracts (89%), followed by those with Dravet syndrome (23%) and those with Doose syndrome appeared to respond the least (0%). When classified by seizure type, those with atonic seizures appeared to have the greatest response rate (44%), followed by those with focal (38%) and epileptic spasms (36%), generalized tonic-clonic (30%), absence (28%), myoclonic (20%), and tonic (17%)Reference215. Reported improvements included an increase in alertness/behavior (33%), language (11%), motor skills (11%), and sleep (7%). Adverse events were reported in 44% of patients treated with an oral cannabis extract. Adverse effects associated with oral cannabis extract administration included worsening of seizures (13%), somnolence (12%), GI symptoms (11%), and irritability (5%). Surprisingly, there were no reported differences in response based on the strain or type of oral cannabis extract the patients were treated with (i.e. high CBD, CBD plus other oral cannabis extracts, THCA, and other oral cannabis extract types). The majority of patients used an oral cannabis extract with high CBD content with or without other oral cannabis extracts. Study limitations included small sample size, heterogeneity of products used, uncertain dosages of cannabinoids, inability to determine dose-response, and discrepancy in ratings of treatment benefit between families that had moved to Colorado for treatment vs. those that were state residents.

A retrospective, multicenter study examined the effect of CBD treatment for severe intractable epilepsy (i.e. acquired epilepsy, early epileptic encephalopathy with known genetic etiology, epileptic encephalopathy with unknown genetic etiology, congenital brain malformation, hypoxic ischemic encephalopathy, and other, with resistance to five to seven anti-epileptic medications, ketogenic diet and vagal nerve stimulation)Reference213. The study examined the clinical records of clinic and phone call visits of children and adolescents (age range: 1 – 18) with refractory epilepsy being treated in four pediatric epilepsy centres in Israel. Seventy-four children and adolescents were included in the study and the reported daily dose of CBD (1 – 20 mg/kg/day) was administered over an average period of six months (minimum three months). Highest daily CBD dose was 270 mg/day. Eighty percent of the children included in the study used less than 10 mg/kg/day CBD with the remainder (20%) using more than 10 mg/kg/day CBD. The ratio of CBD to THC was 20: 1 and cannabinoids were dissolved in canola oil. Parents or older children reported any changes in seizure number. CBD treatment was associated with a reduction in seizure frequency as well as improved behaviour and alertness, improved language, improved communication and motor skills and improved sleep. Approximately half of the patients reported side effects with 18% reporting seizure aggravation, 22% reporting somnolence or fatigue and 7% reporting GI problems or irritability. Side effects led to withdrawal of cannabis oil extract in five patients. Limitations of the study include retrospective design, lack of a control group, no consistent rate of dosage elevation, reliance on parental report of effect on seizure frequency, short duration of the study and lack of long-term outcome, lack of EEG results, and no measurement of other drug levels.

Clinical studies

Note: Epidiolex® is the brand name for a whole-plant cannabis extract of a high CBD strain of Cannabis sativa and is an oral oil solution product containing > 98% CBD at a concentration of 100 mg/ml. Epidiolex® has received FDA approval (June 2018) for use in patients 2 and older to treat Dravet syndrome and Lennox-Gastaut syndrome. It has also received Orphan Drug Designation in the U.S. for the treatment of Lennox-Gastaut Syndrome, Dravet Syndrome and Tuberous Sclerosis Complex. At the time of writing of this publication, Epidiolex® has not received a Notice of Compliance from Health Canada, and is not marketed in Canada.

While there are many anecdotal accounts of dramatic improvements with cannabis-based products with high CBD to THC (e.g. 20 > 1) ratios, the available clinical evidence supporting the safety and efficacy of cannabis for epilepsy is relatively sparseReference217Reference266Reference671. The available evidence from clinical studies is discussed below and summarized in a Cochrane reviewReference217.

One randomized, placebo-controlled clinical study of nine individuals with uncontrolled temporal lobe epilepsy who had failed treatment with multiple anti-epileptic medications reported that two of the individuals that received daily doses of 200 mg of CBD for three months were seizure-free, one showed partial improvement and one did not show any improvementReference217Reference755. None of the placebo-treated patients showed any signs of improvement. No adverse effects were noted. Limitations of this study included lack of comparison between the CBD-treated group and the placebo-group for baseline seizure characteristics, small sample size, unclear methodology, possible lack of blinding, and lack of statistical analysis.

Another randomized, placebo-controlled clinical study of 15 epileptic patients suffering from uncontrolled temporal lobe epilepsy reported that daily treatment with doses of 200 to 300 mg of CBD (in combination with a variety of conventional anti-epileptic drugs) lasting 3 to 18 weeks was associated with seizure cessation in four (out of eight) patients treated with CBDReference217Reference756. One placebo-treated patient (out of seven) became seizure-free. Adverse reactions included somnolence. Limitations of this study included lack of comparison between the CBD-treated group and the placebo-group for baseline seizure characteristics, small sample size, unclear methodology, possible lack of blinding, and lack of statistical analysis.

One placebo-controlled clinical trial of 12 patients with frequent seizures who were not taking any anti-epileptic medications reported no statistically significant difference in seizure frequency between patients given daily doses of 200 to 300 mg of CBD for four weeks compared to placeboReference217Reference757. Reported adverse effects included drowsiness. Limitations of the study included small sample size, possible unblinding, lack of comparison between the CBD-treated group and the placebo-group for baseline seizure characteristics, and unclear methodology.

A randomized, double-blind, placebo-controlled, cross-over clinical study of 12 patients with incompletely controlled epilepsy reported that treatment with 100 mg of CBD, three times daily, for six months, appeared to be associated with a decrease in seizure frequency although seizure frequency was not well measured and no statistical analysis was performedReference217Reference758. CBD treatment also did not appear to be associated with any adverse behavioural changes. Limitations of this study included small sample size, lack of statistical analysis and lack of objective measurement of seizure frequency.

A Cochrane review of the clinical evidence for cannabinoid treatment for epilepsy reviewed the four clinical studies discussed aboveReference755Reference758 and concluded that, based on their evaluation criteria, all of these reports were of low quality and no reliable conclusions could be drawn based on these studies regarding the efficacy of cannabinoids (CBD) as a treatment for epilepsy. However, a dose of 200 to 300 mg of CBD daily could be safely administered to small numbers of patients for short periods of time but the safety of long-term CBD treatment could not be reliably assessed in these studiesReference217.

Treatment-resistant, childhood-onset epilepsy

A clinical study investigating differences in ECS components and in molecular targets associated with CBD action found an increase in expression levels of the voltage-dependent calcium channel α-1h subunit, in CB2 receptor gene expression, and a decrease in the expression of the serotonin transporter gene in lymphocytes isolated from Dravet Syndrome patientsReference759.

A report from an expanded access investigational new drug (IND) trial of Epidiolex®, an oil-based cannabis extract containing 98% v/v CBD, examined the interaction between clobazam and Epidiolex® (CBD) during the treatment of refractory pediatric epilepsyReference236. Thirteen subjects with refractory epilepsy were included in the study. Diagnoses included Dravet syndrome, Doose syndrome, cortical dysgenesis, isodicentric duplication chromosome 15q13, CDKL5 (Cyclin-Dependent Kinase-Like 5) mutation, Tuberous sclerosis complex, and lissencephaly. Seventy percent of the included patients had a > 50% decrease in seizures. Daily doses of Epidiolex® ranged from 5 mg/kg/day to a maximum of 25 mg/kg/day. The average daily dose of clobazam was 1 mg/kg/day with a range of 0.18 to 2.24 mg/kg/day. Co-administration of CBD and clobazam was associated with higher plasma levels of clobazam and its active metabolite n-desmethylclobazam and close monitoring of plasma levels of clobazam and n-desmethylclobazam is recommended as is dose adjustment of clobazam, as needed, to prevent overdose. Side effects were reported in 77% of the 13 study subjects and included drowsiness, ataxia, irritability, restless sleep, urinary retention, tremor and loss of appetite.

An expanded-access, prospective, open-label, 12-week clinical trial of Epidiolex® (98 – 99% CBD oil oral preparation, 100 mg/mL) in patients aged 1 to 30 years with severe, intractable, childhood-onset, treatment-resistant epilepsy (mainly Dravet and Lennox-Gastaut syndromes) examined whether addition of CBD to existing anti-epileptic treatment regimens would be safe, tolerated and efficaciousReference262. Patients were started at a dose of CBD between 2 and 5 mg/kg/day divided into twice-daily dosing added to existing anti-epileptic treatments (i.e. ketogenic diet, clobazam, valproate), and slowly titrated upwards by 2 to 5 mg/kg once per week until intolerance or up to a maximum dose of 25 mg/kg per day (or up to a maximum of 50 mg/kg/day, depending on the study site). The maximum dose at the 12-week clinic visit was 41 mg/kg/day, and the mean CBD dose at 12 weeks was 23 mg/kg in the safety analysis group and in the efficacy analysis group. The median monthly frequency of motor seizures was 30 at baseline and 16 over the 12-week treatment period, and the median reduction in monthly motor seizures was 37%. The greatest reduction in seizures occurred in those patients with focal seizures (-55%) or atonic seizures (-54%), followed by tonic seizures (-37%), or tonic-clonic seizures (-16%). Combination therapy (CBD with clobazam or valproate) was associated with a greater reduction in seizures compared to patients not using clobazam or valproate. Adverse events were reported in 79% of the patients within the safety group. Adverse events in more than 5% of patients were somnolence (25%), decreased appetite (19%), diarrhea (19%), fatigue (13%), convulsions (11%), appetite changes (9%), status epilepticus (8%), lethargy (7%), changes in blood concentrations of concomitant anti-epileptic drugs (6%), gait disturbance and sedation. Most adverse events were mild or moderate and transient. Serious adverse events deemed possibly related to CBD use (10%) included status epilepticus (6%), diarrhea (2%), pneumonia (<1%), and weight loss (1%). Patients taking more than 15 mg/kg/day CBD were more likely to report diarrhea or related side-effects (e.g. weight loss). Three percent of the enrolled patients withdrew from the study, and reasons for study withdrawal included allergy to the sesame oil vehicle, hepatotoxicity, excessive somnolence and poor efficacy, GI intolerance, worsening seizures, and hyperammonemia. Major limitations of this study included open-label design and lack of an appropriate control group. In addition, the issue of a significant placebo response was noted by the authors to be of special significance in pediatric trials of cannabis-based treatments. The authors note that the placebo response in RCTs of add-on treatments in patients with epilepsy appears to be more significant in the pediatric population compared to adults (19% vs. 9.9 – 15%).

A randomized, double-blind, placebo-controlled trial was conducted to determine the efficacy and safety of Epidiolex® in treating drug-resistant seizures in the Dravet syndromeReference576. After a 4-week baseline period, a total of 120 affected children and young adults (2.3 to 18.4 years old) were randomized (1:1) to receive either 20 mg/kg/day CBD oral solution or placebo, in addition to standard antiepileptic treatment, for 14 weeks (2 weeks of dose escalation and 12 weeks of dose maintenance). At the end of the treatment period there was a 10-day taper period (10% in dose reduction per day) followed by a 4-week follow-up period. The most common type of convulsive seizure was generalized tonic-clonic (78%) followed by secondarily generalized tonic-clonic seizures (21%). Nonconvulsive seizures were reported by 61% of the patients in the CBD group and 69% in the placebo group. Treatment with CBD decreased the median frequency of convulsive seizures per month (primary endpoint) from 12.4 (range: 3.9 to 1,717) to 5.9 (range: 0.0 to 2,159), while placebo had no effects (from 14.9 to 14.1). The adjusted median difference between the CBD and placebo groups in change in seizure frequency was -22.8 percentage points (95% CI = -41.1 to -5.4; p = 0.01). The effects of CBD on convulsive seizures were seen in the first month of the maintenance period. In the CBD group, 43% of the patients had at least a 50% reduction in the frequency of convulsive seizures compared to 27% in the placebo group (OR, 2.00; 95% CI = 0.93 to 4.30; p = 0.08). During the treatment period, 3 patients (5%) in the CBD group and no patients in the placebo group became seizure-free (p = 0.08). CBD decreased from 24.0 to 13.7 the median frequency of seizures per month (adjusted reduction 28.6%), while placebo decreased it from 41.5 to 31.1 (adjusted reduction 9.0%), for a significant adjusted median difference between groups of -19.2 percentage points (p = 0.03). There was no significant difference between groups for reduction in nonconvulsive seizures (p = 0.88). Common adverse events (>10% frequency) in the CBD group were somnolence (36%), diarrhea (31%), decreased appetite (28%), fatigue (20%), vomiting (15%), pyrexia (15%), lethargy (13%), upper respiratory tract infection (11%), and convulsion (11%). Most of them were mild or moderate in severity (84% in the CBD group) and considered related to the trial agent (75%). In the CBD group, 8 patients withdrew from the trial because of adverse events, compared with 1 in the placebo group. A total of 12 patients in the CBD group and 1 in the placebo group had elevated aminotransferase levels; they were all also taking valproate. Of the 9 patients who continued taking CBD (3 patients withdrew from the trial), enzyme levels returned to normal during the trial, suggesting transient metabolic stress on the liver. Differences in unpalability between the active treatment and placebo could have affected blinding in a small number of patients. The length of the trial did not allow for the assessment of the potential development of tolerance so additional data are needed to determine the long-term efficacy and safety of CBD for the Dravet syndromeReference576.

A randomized, double-blind, placebo-controlled clinical trial was conducted to investigate the efficacy of Epidiolex® as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndromeReference577. After a 4-week baseline period, 171 eligible patients (aged 2-55 years) were randomized (1:1) to either receive 20 mg/kg CBD daily (n = 86) or placebo (n = 85) as 2 equivalent doses (morning and evening) for 14 weeks (2 weeks of dose escalation and 12 weeks of dose maintenance). The median percentage reduction in monthly drop seizure frequency from baseline (primary endpoint) was 43.9% [interquartile range (IQR) -69.6 to -1.9] in the CBD group and 21.8% (IQR -45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was -17.21 (95% CI -30.32 to -4.09; p = 0.0135) during the 14-week treatment period. The treatment effect of CBD on the primary endpoint was established during the first 4 weeks of the maintenance period and was maintained during the full treatment period. In the CBD group, 38 patients (44%) had a reduction in drop seizure frequency of ≥50% from baseline during the treatment period compared with 20 patients (24%) in the placebo group (OR 2.57, 95% CI 1.33-4.97; p = 0.0043). There were 3 patients in the CBD group who were free of drop seizures throughout the 12-week maintenance period; their monthly frequency of drop seizures at baseline was in the lower range of 15.6 to 99.2. During the treatment period, CBD also significantly decreased the estimated median difference in the monthly frequency of total seizures [-21.1 (95% CI -33.3 to -9.4; p = 0.0005)] and non-drop seizures [-26.1 (95% CI -46.1 to -8.3; p = 0.0044)] compared to placebo. This suggested that add-on CBD may have broad spectrum effects on seizure reduction. Common adverse events (occurring in ≥10% of patients) in the CBD group were diarrhea (19%), somnolence (15%), pyrexia (13%), decreased appetite (13%) and vomiting (10%). Most of the adverse events were mild or moderate in severity (78% in the CBD group) and resolved by the end of the trial (61%). Adverse events led to study withdrawal in 12 patients (14%) in the CBD group and 1 (1%) patient in the placebo group. Of the 20 patients in the CBD group who had elevations in ALT or AST (>3 times upper limit of normal), irrespective of whether they were reported as adverse events, 16 were also taking valproate. The most common serious treatment-related adverse events (occurring in >3% of patients) were collectively reported in 4 patients in the CBD group and comprised increased ALT (n = 4), AST (n = 4) and γ-glutamyltransferase (n = 3) concentrations. No patients met standard criteria for drug-induced severe liver injury (Hy’s law). Overall, this trial demonstrated that add-on CBD was efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and was generally well tolerated. However, only a single dose of CBD was tested in this trial; dose-response effects will be assessed further in another study (GWPCARE3; ClinicalTrials.gov,number NCT02224560). Further assessment of the long-term efficacy and safety of CBD is being carried out in the ongoing open-label extension of this trial and will also be done using real-world data, once availableReference577.

A double-blind, placebo-controlled clinical trial was conducted to determine the efficacy and safety of Epidiolex® (CBD) as an adjunct to conventional antiepileptic drugs to treat drop seizures in patients with Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathyReference760. A total of 225 patients (aged 2-55) with Lennox-Gastaut syndrome and ≥2 drop seizures per week during a 28-day baseline period were randomly assigned to receive 20 mg/kg CBD (n = 76), 10 mg/kg CBD (n = 73) or placebo (n = 76) as 2 equally divided doses daily for 14 weeks (2 weeks dose escalation followed by 12 weeks of maintenance). The median percent reduction from baseline in the frequency of drop seizures per 28 days during the treatment period (primary outcome) was 41.9% (p = 0.005), 37.2% (p = 0.002) and 17.2% in the 20 mg/kg CBD, 10 mg/kg CBD and placebo groups, respectively. During the treatment period, a total of 30 patients (39%) in the 20 mg/kg CBD group (OR 3.8; 95% CI 1.75-8.47; p < 0.001), 26 patients (36%) in the 10 mg/kg CBD group (OR 3.27; 95% CI 1.46-7.26; p = 0.003) and 11 patients (14%) in the placebo group had ≥50% reduction from their baseline in drop-seizure frequency. The percentage of patients who had ≥75% reduction from baseline in drop-seizure frequency was higher in the 20 mg/kg CBD group (25%) and the 10 mg/kg CBD group (11%) than in the placebo group (3%). No patients were free from drop seizures during the entire treatment period (day 1 onward); however, 5 patients (7%), 3 patients (4%) and 1 patient (1%) in the 20 mg/kg CBD, 10 mg/kg CBD and placebo groups, respectively, were free from drop seizures during the entire maintenance phase (day 15 onward). The median percent reduction from baseline in the frequency of all seizures per 28 days during the treatment period was 38.4% (p = 0.009), 36.4% (p = 0.002) and 18.5% in the 20 mg/kg CBD, 10 mg/kg CBD and placebo groups, respectively. Adverse events were reported in 72-94% of patients, the majority of which (89%) were considered mild or moderate in severity. The most common adverse events with CBD were somnolence (n = 14-25), decreased appetite (n = 11-21), and diarrhea (n = 7-12); these events occurred more frequently in the 20 mg/kg CBD group. Serious adverse events (n = 26 vs. n = 7) and trial withdrawal (n = 7 vs. n = 1) were more common in the CBD groups than in the placebo group. Serious adverse events considered related to CBD occurred in 7 patients (1 patient had multiple events) and included elevated aspartate aminotransferase concentration (n = 2), elevated alanine aminotransferase concentration (n = 1), elevatedγ-glutamyltransferase concentration (n = 1), somnolence (n = 1), increased seizures during weaning (n = 1), non-convulsive status epilepticus (n = 1), lethargy (n = 1), constipation (n = 1) and worsening chronic cholecystitis (n = 1). Maximum elevations in aspartate aminotransferase or alanine aminotransferase concentrations 3.2-12.2 times the upper limit of normal were the most common adverse events leading to trial withdrawal in the CBD groups (n = 5). Elevations in aminotransferase concentrations >3 times the upper limit of normal occurred more frequently in patients receiving 20 mg/kg CBD (n = 11) than in those receiving 10 mg/kg CBD (n = 3). In most of these cases (n = 11, 79%), patients were receiving valproate concomitantly. No patient met the criteria for severe drug-induced liver injury (DILI). The majority of these cases (n = 9) resolved after the dose of CBD was tapered, discontinued or the dose of another antiepileptic drug was reducedReference760.

A recent systematic review of 36 studies (30 observational; 6 RCTs) regarding cannabinoids’ impact as an adjunctive treatment in epileptic patients (mean age 16 years) suggested that pharmaceutical-grade CBD was more effective than placebo at reducing seizure frequency by 50%, achieving complete seizure freedom (RR 6.17, 95% CI 1.50 – 25.32), and improving quality of life (RR 1.73, 95% CI 1.33 – 2.26) compared to placebo. Adverse effects from pharmaceutical-grade CBD included drowsiness, fatigue, diarrhea, changes in appetite, and ataxia. These findings were specific to individuals with rare and serious forms of drug-resistant epilepsy; hence, the results cannot be generalized to adult/older population or to those with less severe epilepsy syndromesReference761.

4.7 Pain

It is now well established that the ECS plays an important role in the modulation of nociceptive and pain states. Key in these roles is the specific positioning of the endocannabinoid signaling machinery at neuronal synapses in pain processing pathways at supraspinal, spinal, and peripheral levelsReference24Reference762Reference764.

Role of CB1 and CB2 receptors

The CB1 and CB2 receptors play important roles in nociception and pain. Structures involved in transmission and processing of nociceptive signals such as the nociceptors, the dorsal horn of the spinal cord, the thalamus, the periaqueductal grey matter, the amygdala and the rostroventromedial medulla show a moderate to high level of CB1 receptor expressionReference765. In various animal models of chronic pain, both CB1 and CB2 receptor mRNA and protein levels in the CNS are upregulatedReference765. Selective deletion of the CB1 receptor in mice appears to greatly attenuate the anti-nociceptive efficacy of cannabinoids in animal models of acute and chronic pain, suggesting an essential role for this receptor in modulating nociception and painReference762Reference766. At peripheral and central terminals of nociceptive sensory nerves, CB1 receptors gate the transduction of peripheral noxious stimuli into central neuronal pain signalsReference762Reference767, while in the spinal cord, CB1 receptors act to reduce or enhance propagation of pain signals to the brainReference762Reference768Reference770. At the neuronal circuit level, the end result of CB1receptor activity can be either excitatory or inhibitory depending on the identity of the presynaptic cell and its location within the neural networkReference762. In higher brain regions tasked with processing of nociceptive input such as the periaqueductal grey matter and the rostroventromedial medulla, the CB1 receptors can initiate descending inhibition or block descending facilitation to the spinal cord nociceptive circuitryReference762Reference771Reference776. Most importantly to the subject of pain, CB1 receptors are highly expressed in frontal-limbic pathways in the brain, which play a key role in the affective/emotional aspects of pain in humansReference762Reference772Reference777. CB2 receptors appear to also play an important role in pain signaling, especially in the development of chronic pain states, by inhibiting the release of pro-inflammatory and pro-nociceptive mediators thereby attenuating the inflammatory and hyperalgesic responsesReference762Reference778. In this respect, the strategic localization of CB2 receptors on a variety of immune cells (macrophages, lymphocytes, and mast cells in the periphery), astrocytes and microglia in the CNS (i.e. the spinal cord) is essential to the roles of the CB2 receptors in modulating pain states.

Role of endocannabinoids, anandamide and 2-AG

Endocannabinoids such as anandamide and 2-AG have been shown to have analgesic or anti-nociceptive effects at peripheral, spinal, and central levels, mainly by virtue of their ability to stimulate the activity of the cannabinoid receptors, although other receptors (i.e. TRPV1) are also likely involvedReference779. Peripheral inhibition of FAAH and MAGL enzymes (which hydrolyze anandamide and 2-AG respectively) and the resulting increase in the respective synaptic levels of anandamide and 2-AG has been shown to reduce nociception in animal models of acute and chronic painReference762Reference767Reference780Reference791. Meanwhile, the arachidonoyl moiety of anandamide and 2-AG makes these endocannabinoids susceptible to metabolism by eicosanoid biosynthetic enzymes such as COXs, lipo-oxygenases (LOXs), and CYPs with the subsequent generation of known or potential pro -nociceptive prostamide endocannabinoid metabolitesReference762Reference792Reference793. Therefore, the upregulation of COX-2 expression in chronic pain states may promote the additional production of these pro-nociceptive metabolites both peripherally and centrally thus contributing to nociception and painReference765.

Considerations and caveats

Animal vs. human studies

Pre-clinical studies in animals predict that cannabinoids should relieve both acute and chronic pain in humans. However, results from both experimental models of pain in human volunteers and from clinical trials of patients suffering from pain instead suggest cannabinoids may be more effective for chronic rather than acute pain in humansReference794Reference796. A number of possible explanations can exist to account for discrepancies in findings between animal studies and human clinical trials. Such explanations include interspecies differences, differences in experimental stimuli and protocols used in the studies, and differences in the outcomes measured in the studies. Data from animal pain models are mostly based on observations of behavioural changes, and cannabinoid doses sufficient to produce relevant anti-nociception in rodents are similar to those which cause other behavioural effects such as hypomotility and catatoniaReference23Reference797. This pharmacological overlap can make it difficult to distinguish between cannabinoid-associated anti-nociceptive effects and behavioural effectsReference23Reference797.

Experimental models of acute pain vs. chronic pain

Translation of research findings from human experimental models of pain (i.e. acute pain) to clinical (chronic) pain is also complex and not straightforwardReference268. In contrast to acute pain, chronic pain is a complex condition that involves interaction between sensory, affective, and cognitive componentsReference268. Furthermore, unlike acute pain, chronic pain is considered a disease and generally originates from prolonged acute pain that is not managed in a timely or effective mannerReference798. Chronic pain also appears to involve distinct spatiotemporal neuronal mechanisms which differ from those recruited during acute, experimental painReference799; chronic pain involves altered neural transmission and long-term plasticity changes in the peripheral and CNS which generate and maintain the chronic pain stateReference798Reference799. As such, it is difficult to compare studies of interventions for chronic pain with studies of experimentally-induced pain because of fundamental differences in the physiological state of the subjects, differences in the stimulus conditions and experimental protocols employed in the studies, and differences in the outcomes which are measuredReference268.

Placebo effect

The placebo effect is another consideration to keep in mind when considering studies of cannabis/cannabinoids for the treatment of pain. The placebo effect, a psychobiological phenomenon, is perhaps more salient in disorders which have a more significant subjective or psychological component (e.g. pain, anxiety/depression), and may be somewhat less salient in diseases which have a more objective pathophysiological component (e.g. infectious diseases, cancer)Reference800Reference801. Of note, in one randomized, placebo-controlled clinical study of vapourized cannabis for painful diabetic neuropathy, the placebo effect was as high as 56% for euphoria and as high as 37.5% for somnolence out of a maximum 100% euphoria and 73.3% somnolence responses (observed with the highest THC dose condition at 7% THC)Reference599. Emerging evidence also suggests an important role for the ECS in mediating placebo analgesiaReference802Reference804. These findings highlight the complexities of studying the true analgesic potential of cannabinoids and underscore the importance of including a properly designed placebo control when studying the analgesic potential of cannabinoids.

Patient/study subject population

Many, if not most, of the clinical trials of cannabinoids for the treatment of pain (and even other disorders such as MS) have recruited patients or volunteers who have had prior exposure or experience with cannabis or cannabinoids. This has raised the issue of “unblinding” because any study subjects having prior experience with cannabis or cannabinoids would be more likely to be able to distinguish active treatment with these drugs from the placebo controlReference612. Furthermore, a number of clinical trials of cannabis/cannabinoids for the treatment of pain (or other disorders) have also used an “open-phase” period which enriched for patients that responded favourably to the treatment and conversely, eliminated subjects who would have either responded poorly to cannabinoids or who would have had greater chances of experiencing adverse effectsReference55. Therefore, the use of individuals with prior experience with cannabis or cannabinoids or the use of an “open-phase” period would increase the proportion of patients yielding results tending to overestimate some of the potential therapeutic benefits of cannabis/cannabinoids, while also tending to underestimate the extent or degree of adverse effects among the general patient populationReference55Reference612. There is also some evidence from pre-clinical and clinical studies that suggests sex-dependent effects on cannabinoid and cannabis-induced analgesia (see Section 2.5,Sex-dependent effects, for more information)Reference563Reference805Reference807.

Other considerations

It is also perhaps worth mentioning that a number of clinical studies suggest the presence of a relatively narrow therapeutic window for cannabis and prescription cannabinoids for the treatment of painReference23Reference55Reference57Reference797. The well-known psychotropic and somatic side-effects associated with the use of THC-enriched cannabis and cannabinoids (e.g. dronabinol, nabilone, nabiximols) are known to limit the general therapeutic utility of these drugs; it has therefore been suggested that it may be preferable to pursue therapies which focus on manipulation of the ECS (e.g. by inhibiting the endocannabinoid-degrading enzymes FAAH or MAGL), or to combine low doses of cannabinoids with low doses of other analgesics in order to achieve the desired therapeutic effects while minimizing the incidence, frequency, and severity of the adverse effectsReference23Reference57.

With the above considerations and caveats in mind, the sections below summarize the results of studies examining the analgesic potential of cannabis or cannabinoids in pre-clinical and clinical models of experimentally-induced acute pain, as well as in clinical studies of chronic pain.

4.7.1 Acute pain

  • Pre-clinical studies suggest that certain cannabinoids can block the response to experimentally-induced acute pain in animal models.
  • The results from clinical studies with smoked cannabis, oral THC, cannabis extract, and nabilone in experimentally-induced acute pain in healthy human volunteers are limited and mixed and suggest a dose-dependent effect in some cases, with lower doses of THC having an analgesic effect and higher doses having a hyperalgesic effect.
  • Clinical studies of certain cannabinoids (nabilone, oral THC, levonontradol, AZD1940, GW842166) for post-operative pain suggest a lack of efficacy.
4.7.1.1 Experimentally-induced acute pain

Pre-clinical studies

Cannabinergic modulation of neuronal circuits in the brain and spinal cord can inhibit nociceptive processingReference808Reference811 and a number of pre-clinical studies suggest that anandamide, THC, and certain synthetic cannabinoids block pain responses in different animal models of acute pain (reviewed inReference23Reference797).

Clinical studies with smoked cannabis

An early study by Hill of 26 healthy male cannabis smokers failed to demonstrate an analgesic effect of smoked cannabis (1.4% Δ9-THC, 12 mg Δ9-THC available in the cigarette) in response to transcutaneous electrical stimulationReference812. The study did, however, report an increase in sensory and pain sensitivity to the applied stimulus. In contrast, Milstein showed that smoked cannabis (1.3% Δ9-THC, 7.5 mg Δ9-THC available in the cigarette) increased pain tolerance to a pressure stimulus in both healthy cannabis-naïve and cannabis-experienced subjects compared to placeboReference813. Another study employing healthy cannabis smokers reported that smoking cannabis cigarettes (containing 3.55% Δ9-THC, or approximately 62 mg Δ9-THC available in the cigarette) was associated with a mild, dose-dependent, anti-nociceptive effect to a thermal heat stimulusReference273. A more recent randomized, double-blind, placebo-controlled, crossover trial examined the effects of three different doses of smoked cannabis on intra-dermal capsaicin-induced pain and hyperalgesia in 15 healthy volunteersReference268. Capsaicin was administered either 5 min or 45 min after smoking cannabis. Effects appeared to be dose- and time-dependent. No effect was observed 5 min after smoking, but analgesia was observed 45 min after smoking, and only with the medium dose of smoked cannabis (4% Δ9-THC); the low dose (2% Δ9-THC) had no effect whereas a high dose (8% Δ9-THC) was associated with significant hyperalgesia. This study identified a so-called “narrow therapeutic window”; a medium dose provided analgesic benefit, a high dose worsened the pain and was associated with additional adverse effects, and a low dose had no effect.

Clinical studies with oral THC and cannabis extract

A randomized, placebo-controlled, double-blind, crossover study of 12 healthy cannabis-naïve volunteers administered a single oral dose of 20 mg Δ9-THC reported a lack of a significant analgesic effect following exposure to a multi-model pain test battery (pressure, heat, cold, and transcutaneous electrical stimulation)Reference272. In addition, significant hyperalgesia was observed in the heat pain test. Psychotropic and somatic side effects were common and included anxiety, perceptual changes, hallucinations, strange thoughts, ideas and mood, confusion and disorientation, euphoria, nausea, headache, and dizziness.

Another randomized, double-blind, active placebo-controlled, crossover study in 18 healthy female volunteers reported a lack of analgesia or anti-hyperalgesia with an oral cannabis extract containing 20 mg THC and 10 mg CBD (other plant cannabinoids were less than 5%) in two different experimental pain models (intra-dermal capsaicin or sunburn)Reference267. Side effects (sedation, nausea, and dizziness) were frequently observed. Hyperalgesia was also observed at the highest dose as in the study conducted by Wallace (above)Reference268.

Clinical studies with nabilone

A randomized, double-blind, placebo-controlled, crossover study of single oral doses of nabilone (0.5 mg or 1 mg) failed to show any analgesic effects during a tonic heat pain stimulusReference814. However, an anti-hyperalgesic effect was observed at the highest administered dose, but only in female subjects. The authors noted a significant placebo effect and also suggested that the lack of analgesia could have been attributed to the single-dose administration of the cannabinoid; a gradual dose escalation could have potentially revealed an effect.

Similarly, a randomized, double-blind, placebo-controlled, crossover study in subjects receiving single oral doses of nabilone (1, 2, or 3 mg) failed to show any analgesic, or primary or secondary anti-hyperalgesic effects in response to capsaicin-induced pain in healthy male volunteersReference600. Adverse effects of mild to moderate intensity were noted in the majority of subjects. Severe adverse reactions (e.g. dizziness, sedation, anxiety, agitation, euphoria, and perceptual and cognitive disturbances) were reported only at the highest administered dose (3 mg) in four subjects leading to their withdrawal from the study. Dose-dependent CNS effects were observed 1.5 to 6 h after dosing, reaching a maximum between 4 and 6 h after administration.

4.7.1.2 Post-operative pain

Despite the introduction of new standards, guidelines, and educational efforts, data indicate that post-operative pain continues to be under or poorly managed and many of the drugs commonly used in this setting either lack sufficient efficacy or cause unacceptable side effectsReference270Reference815. To date, there are eight published reports and a systematic review on the use of cannabinoids in post-operative painReference269Reference271Reference274Reference816Reference269Reference271Reference274Reference796Reference816Reference819. The conclusions from the systematic review was that the studied cannabinoids (THC, nabilone, or an oral cannabis extract containing a 2: 1 ratio of THC to CBD, levonontradol, AZD1940, GW842166) were not ideally suited for the management of acute post-operative pain because they were either only moderately effectiveReference270Reference274, less effective than placeboReference817, not different from placeboReference271Reference796Reference816Reference818Reference271Reference796, or even anti-analgesic at high dosesReference269.

4.7.2 Chronic pain

Acute pain that is poorly managed can lead to chronic painReference820Reference821. In contrast to acute pain, chronic pain is typically considered a far more complex condition which involves physical, psychological, and psychosocial factors, and which contributes to a reduced QoLReference822. The International Association for the Study of Pain defines pain as chronic if it persists beyond the normal tissue healing time of three to six monthsReference823. Furthermore, chronic pain is associated with an abnormal state of responsiveness or increased gain of the nociceptive pathways in the CNS (referred to as “central sensitization”), as well as with alterations in cognitive functioningReference823. The information below summarizes pre-clinical studies carried out in animal models of chronic pain, and clinical studies in human subjects administered an experimental stimulus mimicking chronic pain or in patients suffering from chronic pain of various etiologies.

4.7.2.1 Experimentally-induced inflammatory and chronic neuropathic pain
  • Endocannabinoids, THC, CBD, nabilone and certain synthetic cannabinoids have all been identified as having an anti-nociceptive effect in animal models of chronic pain (inflammatory and neuropathic).

The anti-nociceptive efficacy of cannabinoids has been unequivocally demonstrated in several different animal models of inflammatory and neuropathic pain (reviewed inReference765Reference779Reference824Reference825}}). In addition, the findings from these studies suggest that modulation of the ECS through administration of specific cannabinoid receptor agonists, or by elevation of endocannabinoid levels, suppresses hyperalgesia and allodynia induced by diverse neuropathic states (reviewed inReference765Reference779Reference825). As such, similar to the situation with acute pain, pre-clinical studies of chronic pain in animal models suggest that endocannabinoids (anandamide and 2-AG), THC, and several synthetic cannabinoids have beneficial effects in this pain state (reviewed inReference23Reference797Reference825).

With respect to CBD, chronic oral administration of CBD effectively decreased hyperalgesia in a rat model of inflammatory painReference826. One study suggested that a medium or a high dose of CBD attenuated tactile allodynia and thermal hypersensitivity in a mouse model of diabetic neuropathy, when administered early in the course of the disease; on the other hand, there was little, if any, restorative effect if CBD was administered at a later time pointReference827. In contrast, the same study showed that nabilone was not as efficacious as CBD if administered early on, but appeared to have a small beneficial effect when administered later in the course of the disease. CBD also appeared to attenuate microgliosis in the ventral lumbar spinal cord, but only if administered early in the course of the disease, whereas nabilone had no effect. Xiong et al. (2012) reported that systemic and intrathecal administration of CBD potentiated glycine currents, through α3 glycine receptors, in dorsal horn neurons in rat spinal cord slices and also attenuated chronic inflammatory and neuropathic pain in vivoReference828.

4.7.2.2 Neuropathic pain and chronic non-cancer pain in humans
  • A few studies that have used experimental methods having predictive validity for pharmacotherapies used to alleviate chronic pain, have reported an analgesic effect of smoked cannabis.
  • Furthermore, there is more consistent evidence of the efficacy of cannabinoids (smoked/vapourized cannabis, nabiximols, dronabinol) in treating chronic pain of various etiologies, especially in cases where conventional treatments have been tried and have failed.

Clinical studies with cannabinoids

A systematic review and meta-analysis of 28 RCTs (N = 2 454 participants) for chronic pain (including smoked cannabis, nabiximols, dronabinol) reported that there was moderate quality evidence of efficacy to support the use of cannabinoids to treat chronic pain of various etiologies mostly reducing central or peripheral neuropathic pain in individuals already receiving analgesic drugsReference179. The working definition of chronic pain included neuropathic (central/peripheral), cancer pain, diabetic peripheral neuropathy, fibromyalgia, HIV-associated sensory neuropathy, refractory pain due to MS or other neurological condition, rheumatoid arthritis (RA), non-cancer pain (nociceptive/neuropathic), central pain, musculoskeletal pain and chemotherapy-induced pain. The average number of patients who reported a reduction in pain of at least 30% was greater with cannabinoids vs. placebo (OR = 1.41), although for smoked cannabis the effect was greater (OR = 3.43). Side effects appeared to be comparable to existing treatments and included dizziness/lightheadedness, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, hallucinations, sedation, ataxia, a feeling of intoxication, xerostomia, dysgeusia, and hungerReference172Reference176Reference829Reference830. However, these adverse effects may be minimized by employing low doses of cannabinoids that are gradually escalated, as required.

The following summarizes the existing clinical information on the use of smoked/vapourized cannabis and cannabinoids (THC, nabilone, dronabinol and nabiximols) to treat neuropathic and chronic non-cancer pain.

Clinical studies with smoked or vapourized cannabis

A within-subject, randomized, placebo-controlled, double-dummy, double-blind clinical study compared the acute therapeutic analgesic potential of two potencies of smoked cannabis (1.98% and 3.56% THC, 800 mg cigarettes with 16 mg and 28 mg THC respectively) to two doses of dronabinol (10 and 20 mg) in response to an experimental pain stimulus (i.e. cold pressor test) that has predictive validity for pharmacotherapies used to treat chronic painReference831. The study found that both cannabis and dronabinol produced analgesic effects in this model and there were also no significant differences between dronabinol and smoked cannabis in measures of pain sensitivity (i.e. latency to first feel pain). However, in terms of pain tolerance, low potency smoked cannabis (1.98% THC) and both low and high dronabinol doses increased the latency to report pain relative to placebo. Both strengths of cannabis and the high dronabinol dose (20 mg) decreased subjective ratings of pain intensity and bothersomeness of the cold-pressor test compared to placebo although these decreases were greater after cannabis relative to dronabinol. Both cannabis strengths and the high dronabinol dose increased subjective ratings of “high” and “good drug effect” relative to placebo, and both cannabis strengths (but not the low dronabinol dose) increased ratings of “stimulated” relative to placebo. Lastly, both strengths of cannabis and the high dronabinol dose increased ratings of “marijuana strength”, “liking”, and “willingness to take again”. There did not appear to be any sex-dependent differences in terms of baseline pain measures, analgesic, subjective, or physiological effects across all cannabis or dronabinol conditions. Overall, dronabinol decreased pain sensitivity and increased pain tolerance and these effects peaked later and lasted longer compared to smoked cannabis, while smoked cannabis produced a greater attenuation of subjective ratings of pain intensity compared to dronabinol. Peak subjective ratings of dronabinol’s drug effects occurred significantly earlier than decreases in pain sensitivity and increases in pain tolerance (60 min vs. 4 h). Limitations of this study include a potentially biased study population that consisted of daily cannabis users as well as the experimental nature of the pain stimulus in subjects not normally experiencing pain.

A retrospective analysis that compared the analgesic, subjective, and physiological effects of smoked cannabis (3.56 or 5.60% THC, 800 mg cigarettes with 28 mg and 45 mg THC respectively) in 21 men and 21 women under double-blind, placebo-controlled conditions showed that among men, cannabis significantly decreased pain sensitivity in the cold pressor test compared to placebo, while in women active cannabis failed to decrease pain sensitivity relative to placeboReference807. Active cannabis increased pain tolerance in both men and women immediately after smoking as well as increased subjective ratings associated with abuse liability (“take again”, “liking”, “good drug effect”), drug strength, and “high” relative to placebo. Ratings of “high” varied as a function of sex, with men exhibiting elevated ratings throughout the session relative to women. Men also exhibited greater increases in heart rate after smoking cannabis compared to women. Study subjects smoked cannabis daily or near-daily, and smoked on average 7 to 10 cannabis cigarettes/day.

In a randomized, placebo-controlled study, a greater than 30% decrease in HIV-associated sensory neuropathic pain was reported in 52% of cannabis-experienced patients smoking cannabis cigarettes containing 3.56% Δ9-THC (32 mg total available Δ9-THC per cigarette), three times per day (96 mg total daily amount of Δ9-THC) for five days, compared to a 24% decrease in pain in the placebo groupReference195. The NNT to observe a 30% reduction in pain compared to controls was 3.6 and was comparable to that reported for other analgesics in the treatment of chronic neuropathic pain. In the “experimentally-induced pain” portion of the study, smoked cannabis was not associated with a statistically significant difference in acute heat pain threshold compared to placebo. However, it did appear to reduce the area of heat and capsaicin-induced acute secondary hyperalgesia. Patients were taking other pain control medications during the trial such as opioids, gabapentin or other drugs. Adverse effects of smoked cannabis in this study included sedation, dizziness, confusion, anxiety, and disorientation.

In another randomized, double-blind, placebo-controlled, cross-over study of cannabis-experienced patients suffering from chronic neuropathic pain of various etiologies (complex regional pain syndrome (CRPS), central neuropathic pain from SCI or MS, or peripheral neuropathic pain from diabetes or nerve injury) reported that administration of either a low dose or a high dose of smoked cannabis (3.5% Δ9-THC, 19 mg total available Δ9-THC; or 7% Δ9-THC, 34 mg total available Δ9-THC) was associated with significant equianalgesic decreases in central and peripheral neuropathic painReference222. No analgesic effect was observed in tests of experimentally-induced pain (tactile or heat stimuli) in these participants. Patients were taking other pain control medications during the trial such as opioids, anti-depressants, NSAIDs, or anti-convulsants. Adverse effects associated with the use of cannabis appeared to be dose-dependent and included feeling “high”, sedation, confusion, and neurocognitive impairment. Cognitive changes appeared to be more pronounced with higher doses of Δ9-THC.

A phase II, double-blind, placebo-controlled, crossover clinical trial of smoked cannabis for HIV-associated refractory neuropathic pain reported a 30% decrease in HIV-associated, distal sensory predominant, polyneuropathic pain in 46% of patients smoking cannabis for five days (1 – 8% Δ9-THC, four times daily), compared to a decrease of 18% in the placebo groupReference281. The NNT in this study was 3.5. Almost all of the subjects had prior experience with cannabis and were concomitantly taking other analgesics such as opioids, NSAIDs, anti-depressants or anti-convulsants. Adverse effects associated with the use of cannabis were reported to be frequent, with a trend for moderate or severe adverse effects during the active treatment phase compared to the placebo phase.

A randomized, double-blind, placebo-controlled, four-period, crossover clinical study of smoked cannabis for chronic neuropathic pain caused by trauma or surgery and refractory to conventional therapies reported that compared to placebo, a single smoked inhalation of 25 mg of cannabis containing 9.4% Δ9-THC (2.35 mg total available Δ9-THC per cigarette), three times per day (7.05 mg total Δ9-THC per day) for five days, was associated with a modest but statistically significant decrease in average daily pain intensityReference59. In addition, there were statistically significant improvements in measures of sleep quality and anxiety with cannabis. The majority of subjects had previous experience with cannabis and most were concomitantly taking other analgesics such as opioids, anti-depressants, anti-convulsants, or NSAIDs. Adverse effects associated with the use of cannabis included headache, dry eyes, burning sensation in the upper airways (throat), dizziness, numbness, and cough.

A clinical study examined the effects of vapourized cannabis on the pharmacokinetics, subjective effects, pain ratings and safety of orally-administered opioids in patients suffering from chronic pain (musculoskeletal, post-traumatic, arthritic, peripheral neuropathy, cancer, fibromyalgia, MS, sickle cell disease, and thoracic outlet syndrome)Reference280. The study reported that inhalation of vapourized cannabis (900 mg, 3.56% Δ9-THC), three times per day for five days, was associated with a statistically significant decrease in pain (-27%, CI = 9 – 46). Subjects were on stable doses of sustained-release morphine sulfate or oxycodone, and had prior experience with smoking cannabis. There was a statistically significant decrease in the Cmax of morphine sulfate, but not oxycodone, during cannabis exposure. No clinically significant adverse effects were noted, but all subjects reported experiencing a “high”. The study design carried a number of limitations including small sample size, short duration, a non-randomized subject population, and the lack of a placebo.

A double-blind, placebo-controlled, crossover study of patients suffering from neuropathic pain of various etiologies (SCI, CRPS type I, causalgia-CRPS type II, diabetic neuropathy, MS, post-herpetic neuralgia, idiopathic peripheral neuropathy, brachial plexopathy, lumbosacral radiculopathy, and post-stroke neuropathy) reported that inhalation of vapourized cannabis (800 mg containing either a low dose of Δ9-THC (1.29% Δ9-THC; total available amount of Δ9-THC 10.3 mg) or a medium dose of Δ9-THC (3.53% Δ9-THC; total available amount of Δ9-THC 28.2 mg)) during three separate 6 h sessions was associated with a statistically significant reduction in pain intensityReference598. Inhalation proceeded using a standardized protocol (i.e. the “Foltin procedure”): participants were verbally signaled to hold the vapourizer bag with one hand, put the vapourizer mouthpiece in their mouth, get ready, inhale (5 s), hold vapour in their lungs (10s), and finally exhale and wait before repeating the inhalation cycle (40s). Non-significant differences were observed between placebo and active treatments with respect to pain ratings at the 60 min time point following study session initiation. Following four cued inhalations of either dose of THC at the 60 min time point, a significant treatment effect was recorded 60 min later (i.e. at the 120 min time point following trial initiation). A second cued inhalation of vapourized cannabis, at the 180 min time point following trial initiation (four to eight puffs, flexible dosing, 2 h after first inhalation), was associated with continued analgesia lasting another 2 h. Both the 1.29% and 3.53% Δ9-THC doses were equianalgesic and significantly better in achieving analgesia than placebo. The NNT to achieve a 30% pain reduction was 3.2 for the low-dose vs. placebo, 2.9 for the medium-dose vs. placebo, and 25 for the medium- vs. the low-dose. The authors suggested that the NNT for active vs. placebo conditions is in the range of two commonly used anti-convulsants used to treat neuropathic pain (pregabalin, 3.9; gabapentin, 3.8). Using a Global Impression of Change rating scale, pain relief appeared to be maximal after the second dosing at 180 min, and dropped off between 1 and 2 h later. Both active doses had equal effects on ratings of pain “sharpness”, while the low-dose was more effective than either the placebo or medium-dose for pain described as “burning” or “aching”. All patients had prior experience with cannabis and were concomitantly taking other medications (opioids, anti-convulsants, anti-depressants, and NSAIDs). Cannabis treatment was associated with a small impairment of certain cognitive functions, with the greatest effects seen in domains of learning and memory. The study suffered from a number of drawbacks including a relatively small number of patients, a short study period, and the possibility of treatment unblinding.

A review of the use of smoked cannabis for the treatment of neuropathic pain suggested that the efficacy of smoked cannabis (NNT = 3.6, for a 30% reduction in pain) was comparable to that of traditional therapeutic agents (e.g. gabapentin, NNT = 3.8), slightly less than that observed with tricyclic antidepressants (NNT = 2.2), but better than lamotrigine (NNT = 5.4) and selective serotonin reuptake inhibitors (NNT = 6.7)Reference832. The author reports that the concentrations of THC in the smoked cannabis ranged between 2 and 9% with an average concentration of 4% yielding good efficacy. Furthermore, the author suggests that cannabis may present a reasonable alternative or adjunctive treatment for patients with severe, refractory peripheral neuropathy who have tried other therapeutic avenues without satisfactory results. This review, along with another more recent reviewReference275 provide a useful clinical algorithm for determining if a patient would be a candidate for treatment with cannabis for peripheral neuropathic pain (see Figure 3).

Figure 3. A Possible Clinical Algorithm for Physicians Considering Supporting Therapeutic Use of Cannabis for a Patient with Chronic, Intractable Neuropathic Pain. Figure adapted fromReference275Reference832
Figure 3. Text version below.

Figure 3 – Text description

Legend:

Standard medications include antidepressants, anticonvulsants, opioids, nonsteroidal anti-inflammatory drugs.

At least 30% reduction in pain intensity.

Consider past experience with cannabis or cannabinoids, potential for side effects or history of side effects, willingness to smoke/vapourize/ingest orally.

Determine substance abuse history; history of psychiatric or mood disorders. If yes or at high risk for substance abuse, proceed with caution and close observation (see Sections 2.45.0, and 6.0); coordinate with substance abuse treatment programs. If there is a history or risk of psychiatric disease (schizophrenia) or bipolar disorder see Section 7.7.3 and consult with a psychiatric specialist before proceeding.

Specific cannabinoid, dose, route of administration; symptoms treated and outcome; adverse effects.

Discuss the fact that there are not yet clear guidelines regarding efficacy, doses and toxicity; raise awareness of oral and vapourized routes of cannabis administration; refer patient to Health Canada website and documents regarding access to cannabis product(s); follow the usual clinical guideline to start low and titrate dose slowly.

g Efficacy should aim for at least 30% decrease in pain intensity.

A single-dose, open-label, clinical trial of patients with neuropathic pain and using very low doses of THC (from vapourized cannabis) reported a statistically significant improvement in neuropathic pain with minimal adverse effectsReference58. In this clinical study, 10 patients suffering from neuropathic pain of any type (SCI, CRPS, lumbosacral radiculopathy, pelvic neuropathic pain) of at least three months duration and on a stable analgesic regimen for at least 60 days (e.g. opioids, antidepressants, anticonvulsants, benzodiazepines, steroids, NSAIDs, cannabis) were administered a vapourized dose of 3 mg of THC (available in the device; ~ 1.5 mg THC actually delivered) resulting from vapourization of 15 mg of dried cannabis containing 20% THC. THC administration was associated with a statistically significant reduction in baseline VAS pain intensity of 3.4 points (i.e. a 45% reduction in pain) within 20 min of inhalation with a return to baseline within 90 min. Adverse effects were minimal but included lightheadedness for 10 min after inhalation which lasted approximately 30 min and then fully resolved. Subjects reported using between 2 and 40 g of cannabis per month (i.e. 0.067 g per day and 1.3 g per day). THC was detected in blood within 1 min following inhalation and reached a maximum within 3 min at a mean THC concentration of 38 ng/ml.

A Canadian multi-centre, prospective, cohort safety study of patients using cannabis as part of their pain management regimen for chronic non-cancer pain reported that cannabis use was not associated with an increase in the frequency of serious adverse events vs. controls, but was associated with an increase in the frequency of non-serious adverse eventsReference216. In this study, 216 patients with chronic non-cancer pain (nociceptive, neuropathic, or both) using cannabis and 215 control patients with chronic pain with no cannabis use were followed for a period of one year and evaluated for frequency and type of adverse effects associated with the use of a standardized herbal cannabis product (CanniMed 12.5% THC, <0.5% CBD). A significant proportion of study subjects were taking opioids, anti-depressants or anti-convulsants. Almost one third of study subjects who reported smoking cannabis at least once reported consuming it exclusively by smoking, 44% reported smoking and oral ingestion, 14% reported vapourizing, smoking or ingesting cannabis orally, and slightly less than 4% reported only smoking or vapourizing. Secondary objectives were to examine the effects of cannabis use on pulmonary and neurocognitive function and to explore the effectiveness of cannabis for chronic non-cancer pain, including pain intensity and QoL. For the primary outcome, the total number of serious adverse events was similar between the cannabis group and the control group and none of the serious adverse events were considered to be either “certainly” or “very likely” related to the cannabis provided by the investigators. One serious adverse event (convulsion) was considered to be “probably/likely” related to the study cannabis. Patients in the cannabis-treatment group experienced a median of three events per subject (vs. a median of two events per subject among controls). The incidence rate of adverse events in the cannabis treatment group was 4.61 events/person-year and was significantly higher than in the control group where the incidence rate was 2.85 events/person-year. The most common adverse event categories in the cannabis-treatment group were nervous system (20%), GI (13.4%), and respiratory disorders (12.6%) and the rate of nervous system disorders, respiratory disorders, infections, and psychiatric disorders was significantly higher in the cannabis group than in the control group. Furthermore, mild (51%) and moderate (48%) events were more common than severe ones (10%) in the cannabis-treatment group. Somnolence (0.6%), amnesia (0.5%), cough (0.5%), nausea (0.5%), dizziness (0.4%), euphoric mood (0.4%), hyperhidrosis (0.2%), and paranoia (0.2%) were assessed as being “certainly/very likely” related to treatment with cannabis. Increasing the daily dose of cannabis was not associated with a higher risk of serious or non-serious adverse events, although the recommended maximum daily amount of cannabis was set at 5 g per day (the median daily cannabis dose was 2.5 grams per day). With respect to secondary outcomes, no difference in neurocognitive function was found between cannabis users and controls, after one year of treatment and after controlling for multiple potential confounders. No significant changes were noted in certain pulmonary function tests (Slow Vital Capacity, Functional Residual Capacity, Total Lung Capacity) over the course of the study period, although reductions were noted in residual volume, forced expiratory volume in one second (FEV1) and in the FEV1/forced vital capacity (FVC) ratio (0.78% decrease). No changes were observed in liver, renal or endocrine functions. In terms of efficacy for pain, compared to baseline, there was a significant reduction in average pain intensity in the cannabis-treatment group but not in the control (difference = 1.10). Notably, patients using cannabis had higher baseline pain and disability than controls. While there was a significant improvement from baseline pain intensity in both the control and cannabis-treatment groups, greater improvement of physical function was observed in the cannabis group vs. control. Lastly, the sensory component of pain and total symptom distress score (Edmonton Symptom Assessment System) as well as the total mood disturbance scale of the Profile of Mood States all showed improvement in the cannabis group vs. control. Limitations of the study included relatively small sample size and short follow-up time which prevented the identification of rare serious adverse events, a significant drop-out rate attributable to adverse events (especially among cannabis naïve and former users), perceived lack of efficacy, and/or dislike of the study product. The majority (66%) of individuals in the cannabis group was composed of experienced cannabis users and the authors of the study suggest that a higher rate of adverse events for cannabis may have been observed if only new cannabis users had been included. Therefore, the study findings regarding safety of cannabis use for chronic non-cancer pain cannot be generalized to patients who are cannabis naïve. Lastly, the study was not a RCT and allocation was not blinded, therefore improvements in secondary efficacy measures should be interpreted with caution.

A meta-analysis of randomized, double-blind, placebo-controlled trials of smoked/vapourized cannabis for neuropathic pain reported that inhaled cannabis resulted in short-term reductions in chronic neuropathic pain for one in every five to six patients treated (NNT = 5.6)Reference833. Furthermore, the study results suggested that inhaled cannabis may be as potent as gabapentin (NNT = 5.9). In this study, one hundred and seventy-eight middle-aged participants with painful neuropathy of at least three months’ duration were enrolled in the five North American RCTs examined – two RCTs recruited only HIV+ individuals with HIV-related chronic painful neuropathy, while the remaining three RCTs recruited patients with neuropathy secondary to trauma, SCI, diabetes mellitus and CRPS. No studies investigated outcomes beyond two weeks. Therapeutic effects appeared to increase with increasing THC content. Study withdrawals due to adverse effects were rare. Subjective side effects included mild anxiety, disorientation, difficulty concentrating, headache, dry eyes, burning sensation, dizziness, and numbness. Psychoactive effects (e.g. “feeling high”) increased in frequency with increasing dose. Limitations of this study are mainly reflective of the limitations associated with the original studies (i.e. small number of available studies, small number of participants, shortcomings in allocation concealment, and attrition). The meta-analysis could not draw any conclusions regarding the long-term efficacy or safety of inhaled cannabis for chronic neuropathic pain, as the original studies did not extend past a maximum two-week period.

A randomized, double-blind, placebo-controlled, single-dose, cross over clinical trial of low, medium and high-dose vapourized cannabis in 16 patients with painful diabetic peripheral neuropathy measuring short-term efficacy and tolerability reported a statistically significant difference in spontaneous pain scores between doses and a statistically significant negative effect of the high dose on some neuropsychological measuresReference599. Study participants had diabetes mellitus type I or II and had at least a six-month history of painful diabetic peripheral neuropathy. Subjects participated in four sessions, separated by two weeks and were exposed to placebo, low (1% THC, <1% CBD, 400 mg total plant material), medium (4% THC, <1% CBD, 400 mg total plant material) and high (7% THC, <1% CBD, 400 mg total plant material) doses of THC; actual doses of THC available for inhalation were estimated at 0, 4, 16, or 28 mg THC per dosing session. Baseline measurements of spontaneous pain, evoked pain and cognitive testing were performed. There was a reported statistically significant difference in spontaneous pain scores between doses, with the average pain intensity scores with the low, medium and high doses being significantly different from the placebo, and the average pain score with the high dose being significantly different from the average pain score in the medium, low dose and placebo; no statistically significant difference in average pain intensity was noted between the medium and low dose. There was a statistically significant reduction in mean evoked pain scores between the placebo and high dose, between the low and high dose, and between the medium and high dose of cannabis. On average, the lowest minimum pain score was achieved with the high dose (7% THC), and the highest minimum pain score was seen with the placebo dose. While results showed a statistically significant reduction in both spontaneous and evoked pain between doses, comparison of the proportions of participants who achieved at least 30% reduction in spontaneous and evoked pain scores was not statistically significant between the different doses. Performance on selected neurocognitive tests (attention/working memory) showed statistically significant differences between doses, with some impairments lasting up to 120 min post-administration. There was a dose-dependent effect in subjective “highness” score that dissipated after 4 h. Furthermore, the study findings suggested a correlation between subjective “highness” score and spontaneous pain score, with every 1-point increase in “highness” score associated with a pain score decrease of 0.32 points. Euphoria was noted in 100% of individuals at the highest dose (7% THC), and there was a statistically significant difference in euphoria between the high dose and placebo and the medium dose and placebo. Somnolence was noted in 73% of individuals at the high dose and was only statistically significant for the high dose vs. placebo. Interestingly, 56% of individuals reported euphoria with the placebo dose, suggesting a high expectancy rate. Limitations of the study included small sample size, underpowering, brief duration, limited neuropsychiatric testing, and potential unblinding.

A systematic review of RCTs examining cannabinoids (nabilone, oral mucosal cannabis spray, oral cannabis extract, smoked or vapourized cannabis, and FAAH inhibitors) in the treatment of chronic non-cancer pain was conducted according to Preferred Reporting Items for Sytematic Reviews and Meta-Analyses (PRISMA) guidelines on health care outcomes and showed that the majority of the trials demonstrated a significant analgesic effect as well as improvements in secondary outcomes (e.g. sleep, muscle stiffness, spasticity)Reference176. Frequent adverse effects, likely caused by cannabis, included drowsiness, fatigue, dizziness, dry mouth, nausea and cognitive effects that were generally mild to moderate in severity and generally well tolerated. Serious adverse effects included urinary tract infection, head injury, and interstitial lung disease (oral cannabis extract), delirium (nabilone), and suicidal ideation and disorientation (oral mucosal cannabis spray). Limitations of the findings relate mainly to the short duration and small sample sizes of the included trials and the modest effect sizes. RCTs of longer duration and with a larger sample size are needed to confirm efficacy signals reported by the smaller “proof of concept” studies, and for longer term monitoring of patients to assess long-term safety.

Another systematic review of six RCTs (N = 226 patients) of smoked or vapourized cannabis for chronic non-cancer pain reported evidence for the use of low-dose cannabis in refractory neuropathic pain in conjunction with traditional analgesicsReference172. Five out of the six included RCTs were considered high quality (using the Jadad scale). Two-hundred and twenty-six adults (mean age 45 to 50) with chronic neuropathic pain (HIV-associated neuropathy, post-traumatic neuropathy, mixed neuropathy) were included in the analysis. All included trials excluded patients with a history of psychotic disorders, previous history of cannabis abuse or dependence. Four of the five trials that allowed patients to continue using opioids, anticonvulsants, and anti-depressants reported that more than 50% of subjects used concomitant opioids. Dose of THC ranged from about 1% to 9.4% (by dry weight) with the total daily THC amount delivered ranging from 1.9 mg/day to a maximum of 34 mg/day. The two trials open to cannabis-naïve subjects reported dropouts or withdrawals associated with potential adverse effects of smoked cannabis (e.g. psychosis, persistent cough, feeling “high”, dizziness, fatigue) with the remaining reasons for dropouts unrelated to adverse effects. All studies reported a statistically significant analgesic effect. Clinically meaningful analgesic effect (> 30% improvement in pain relief) was reported in only three of the included studies. Adverse effects included mainly neurologic or psychiatric events (e.g. headache, sedation, euphoria, dysphoria, poor concentration, attention and memory) and the incidence of these adverse effects appeared to increase in frequency with increasing dose of THC. The authors conclude that the short-term adverse cognitive effects reported in the included RCTs were similar to those experienced with opioids and suggest the same precautions used with opioids should be applied to cannabis. The authors suggest that low-dose THC (< 34 mg THC/day) is associated with an improvement in refractory neuropathic pain of moderate severity in adults using concurrent analgesics. Generalizability of the results in chronic non-cancer pain is limited by quality of the studies, small sample sizes, short duration, and dose and dose scheduling variability.

Clinical studies with orally administered prescription cannabinoids

Nabilone

An off-label, retrospective, descriptive study of 20 adult patients suffering from chronic non-cancer pain of various etiologies (post-operative or traumatic pain, reflex sympathetic dystrophy, arthritis, Crohn’s disease, neuropathic pain, interstitial cystitis, HIV-associated myopathy, post-polio syndrome, idiopathic inguinal pain, and chronic headaches) reported subjective overall improvement and reduced pain intensity with nabilone as an adjunctive pain-relief therapyReference822. Furthermore, beneficial effects on sleep and nausea were the main reasons for continuing use. Patients used between 1 and 2 mg of nabilone per day. Higher doses (3 – 4 mg/day) were associated with an increased incidence of adverse effects. These included dry mouth, headaches, nausea and vomiting, fatigue, cognitive impairment, dizziness, and drowsiness. Many patients were concomitantly taking other drugs such as NSAIDs, opioids, and various types of anti-depressants. Many of the subjects also reported having used cannabis in the past to manage symptoms. Limitations in study design included the lack of an appropriate control group and the small number of patients.

An enriched-enrolment, randomized-withdrawal, flexible-dose, double-blind, placebo-controlled, parallel-assignment efficacy study of nabilone as an adjuvant in the treatment of diabetic peripheral neuropathic pain reported a statistically significant decrease in pain compared to placebo, with 85% of the subjects in the nabilone group reporting a ≥ 30% reduction in pain from baseline to end point, and 31% of subjects in the nabilone group reporting a ≥ 50% reduction in pain from baseline to end pointReference612. Subjects taking nabilone also reported statistically significant improvements in anxiety, sleep, QoL, and overall patient status. Doses of nabilone ranged from 1 to 4 mg/day. Most subjects were concomitantly taking a variety of pain medications including NSAIDs, opioids, anti-depressants, and anxiolytics. Adverse events associated with the nabilone intervention included dizziness, dry mouth, drowsiness, confusion, impaired memory, lethargy, euphoria, headache, and increased appetite although weight gain was not observed.

Dronabinol

A randomized, double-blind, placebo-controlled, crossover trial of patients suffering from MS-associated central neuropathic pain reported a decrease in central pain with 10 mg maximum daily doses of dronabinolReference610. Dosing started with 2.5 mg dronabinol/day and employed gradual dose-escalation every other day; total trial duration was three weeks (range: 18 – 21 days). Pain medications, other than paracetamol, were not permitted during the trial. The NNT for 50% pain reduction was 3.5 (95% CI = 1.9 to 24.8). Fifty-four percent of patients had a ≥ 33% reduction in pain during dronabinol treatment compared with 21% of patients during placebo. The degree of pain reduction in this study was comparable to that seen with other drugs commonly used in the treatment of neuropathic pain conditions. There were no significant differences reported between the treatment group and placebo in thermal sensibility, tactile and pain detection, vibration sense, temporal summation, or mechanical or cold allodynia. However, there was a statistically significant increase in the pain pressure threshold in dronabinol-treated subjects. Self-reported adverse effects were common, especially during the first week of active treatment. These included lightheadedness, dizziness, drowsiness, headache, myalgia, muscle weakness, dry mouth, palpitations, and euphoria.

A phase I, randomized, single-dose, double-blind, placebo-controlled, crossover trial of 30 patients taking short- or long-acting opioids (68 mg oral morphine equivalents/day; range: 7.5 – 228 mg) for intractable, chronic non-cancer pain (of various etiologies) reported that both a 10 mg and 20 mg dose of dronabinol was associated with significant pain relief compared to placebo, although no difference in pain relief was observed between the two active treatmentsReference287. Pain intensity and evoked pain were also significantly reduced in subjects who received the active treatments compared to placebo. Significant pain relief compared to baseline was also reported in an open-label, phase II extension to the initial phase I trial. Subjects were instructed in a stepwise dosage schedule beginning with a 5 mg/day dose, and titrating upwards to a maximum of 20 mg t.i.d. Significant side effects were observed in the majority of patients in the single-dose trial, were consistent with those observed in other clinical trials, and occurred more frequently in subjects receiving the highest dosage of the study medication. The authors reported that compared to the single-dose phase I trial, the frequency of self-reported side effects in the phase II open-label study decreased with continued use of dronabinol. Limitations in the design of the study included the small number of study subjects, the large number of subjects with a history of cannabis use, the lack of appropriate comparison groups, and the lack of an active placebo. Other limitations specific to the open-label phase II trial included the lack of a control group or crossover arm.

Nabiximols

Health Canada has approved Sativex® (with conditions) as an adjunct treatment for the symptomatic relief of neuropathic pain in MSReference431.

A number of randomized, placebo-controlled, double-blind crossover and parallel studies have shown a significant reduction in central or peripheral neuropathic pain of various etiologies (e.g. brachial plexus avulsion, MS-related) following treatment with nabiximols (Sativex®)Reference433Reference834Reference835. In all three studies, patients were concomitantly using other drugs to manage their pain (anti-epileptics, tricyclic anti-depressants, opioids, NSAIDs, selective serotonin reuptake inhibitors, benzodiazepines, skeletal muscle relaxants). The NNT for 30% pain reduction (deemed clinically significant) varied between 8 and 9, whereas the NNT for 50% pain reduction for central neuropathic pain was 3.7, and 8.5 for peripheral pain. In two of the three studies, the majority of subjects had prior experience with cannabis for therapeutic or non-medical purposesReference834Reference835. Furthermore, the majority of subjects allocated to the active treatment experienced minor to moderate adverse effects compared to the placebo group. These included nausea, vomiting, constipation, dizziness, intoxication, fatigue, and dry mouth among other effects.

According to the updated consensus statement and clinical guidelines on the pharmacological management of chronic neuropathic pain published by the Canadian Pain Society in 2014, cannabinoid-based therapies (e.g. dronabinol, nabiximols, smoked cannabis) are now considered to be third-line treatments (in 2007 they were considered fourth-line treatments) for neuropathic pain; mostly as adjuvant analgesics for pain conditions refractory to standard drugsReference836Reference837 (but also see Section 4.8.3 andReference838 for updated clinical guidelines on the use of cannabinoids for the treatment of symptoms associated with fibromyalgia).

A nine-month (38-week) open-label, add-on extension study investigated the long-term efficacy, safety and tolerability of nabiximols in 380 patients (234 completed) with peripheral neuropathic pain associated with diabetes mellitus or allodynia and concomitantly using other analgesic therapyReference839. One hundred and sixty-six patients had previously been taking nabiximols under a parent RCT (mean daily doses for allodynia, 8.9 sprays; mean daily doses for diabetic neuropathy, 9.5 sprays). Mean daily dose of nabiximols in the add-on extension trial was between six and eight pump actuations (16.2 mg THC and 15 mg CBD and 21.6 mg THC and 20 mg CBD) and no increase in pump actuations was noted over time suggesting the absence of tolerance to the study medication. Eleven percent of patients who had received nabiximols during the parent RCT study withdrew from the extension study due to adverse events while 27% of patients taking placebo during the parent study withdrew from the extension study due to adverse events. Thirteen percent of patients who had received nabiximols in the parent RCT withdrew because of lack of efficacy. Concomitant analgesic medication was used by 84% of patients. The most commonly used analgesic medications included anticonvulsants, tricyclic anti-depressants, opioids, and NSAIDs. Non-analgesic concomitant medications included 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, angiotensin-converting enzyme (ACE) inhibitors, biguanides, and platelet aggregation inhibitors. The vast majority of patients had a history of previously trying and failing at least one analgesic for their peripheral neuropathic pain (i.e. anticonvulsants and NSAIDs). All patients showed an improvement in pNRS score over time, from an initial score of 6.9 at baseline in the parent RCTs to a score of 4.2 at the end of the nine-month open-label extension trial period. At least half of the patients reported a 30% clinically significant improvement in pain compared to parent RCT baseline, and a minimum of 30% of patients demonstrated a 50% improvement in pain over time. The maximum reduction in pain scores occurred between 14 and 26 weeks during the extension trial. Improvements in sleep quality NRS scores and EQ-5D health questionnaire outcomes were maintained into and over the course of the add-on extension study period. The most common all-cause adverse events reported by system organ class were nervous system disorders (44%), GI disorders (36%), general disorders and administration site conditions (24%), infections and infestations (23%), and psychiatric disorders (21%). The most common treatment-related adverse events were dizziness (19%), nausea (9%), dry mouth (8%), dysgeusia (7%), fatigue (7%), somnolence (7%), and feeling drunk (6%). The majority (74%) of treatment-related adverse events resolved without consequence by the end of the study period. However, adverse events that were reported to be continuing at study end included fatigue, dizziness, and insomnia. Eleven percent of patients experienced a serious adverse event during the study, with 1% experiencing a treatment-related adverse event. The serious adverse events that were considered to be treatment-related included nervous system disorders and psychiatric disorders: two patients experienced amnesia, and there was one event of paranoia and one suicide attempt. Eighteen percent of patients ceased study medication due to treatment-related adverse events. The majority of these events occurred within the first week of treatment.

4.7.2.3 Cancer pain
  • The limited available clinical evidence with certain cannabinoids (dronabinol, nabiximols) suggests a modest analgesic effect of dronabinol and a modest and mixed analgesic effect of nabiximols on cancer pain.

Clinical studies with dronabinol

Two randomized, double-blind, placebo-controlled clinical studies suggested oral Δ9-THC (dronabinol) provided an analgesic benefit in patients suffering from moderate to severe continuous pain due to advanced cancer. The first study was a small dose-ranging study of 5, 10, 15, and 20 mg Δ9-THC, given in successive days, to 10 cancer patientsReference840. Significant pain relief was found at the 15 and 20 mg dose levels, but at these higher doses patients were heavily sedated and mental clouding was common. A second, placebo-controlled study compared 10 and 20 mg oral Δ9-THC with 60 and 120 mg codeine in 36 patients with cancer painReference285. While the lower and higher doses of THC were equianalgesic to the lower and higher doses of codeine, respectively, statistically significant differences in analgesia were only obtained between placebo and 20 mg Δ9-THC, and between placebo and 120 mg codeine. The 10 mg Δ9-THC dose was well tolerated, and despite its sedative effect appeared to have mild analgesic potential. The 20 mg Δ9-THC dose induced somnolence, dizziness, ataxia, and blurred vision. Extreme anxiety was also observed at the 20 mg dose in a number of patients.

Clinical studies with nabiximols

A randomized, double-blind, placebo-controlled, parallel-group clinical trial of patients suffering from intractable cancer pain (mixed, bone, neuropathic, visceral, somatic/incident) suggested that an orally administered THC: CBD extract (nabiximols), containing 2.7 mg of Δ9-THC and 2.5 mg CBD per dose, is an efficacious adjunctive treatment for such cancer-related pain which is not fully relieved by strong opioidsReference138. Baseline daily median morphine equivalents ranged from 80 to 120 mg. Forty-three percent of patients (n = 60) taking the extract achieved a ≥ 30% improvement in their pain score, which was twice the number of patients who achieved this response in the THC only (n = 58) and placebo (n = 59) groups. Both the nabiximols and the THC medications were reported to be well tolerated in this patient population, and adverse events were reported to be similar to those seen in other clinical trials of nabiximols (e.g. somnolence, dizziness, and nausea).

This study was followed-up by an open-label extension study that evaluated the long-term safety and tolerability of nabiximols (as well as oro-mucosal THC spray) as an adjuvant pain treatment in patients with terminal cancer pain refractory to strong opioid analgesicsReference283. Patients who had taken part in, fully complied with the study requirements of, had not experienced an unacceptable adverse event in the initial parent study, and that were expected to receive clinical benefit from nabiximols (with acceptable tolerability) were enrolled in the extension study. The most commonly reported (50%) pain type was mixed pain (nociceptive and neuropathic), followed by neuropathic pain (37%), and bone pain (28%). The median duration of treatment with nabiximols (n = 39 patients) was 25 days (range: 2 – 579 days) while the mean duration of treatment with oro-mucosal THC spray (n = 4 patients) was 151.5 days (range: 4 – 657 days). The average number of sprays/day for nabiximols during the last seven days of dosing was 5.4 vs. 14.5 for THC only. No dose escalation was noted in patients taking nabiximols beyond six months and up to one year following treatment initiation. Although the study was a non-comparative, open-label study with no formal hypothesis testing and mostly used descriptive statistics, a decrease from baseline in mean score on the Brief Pain Inventory Short-Form was observed for both “pain severity” and “worst pain” over the five weeks of treatment. However, the authors noted that the clinical investigators considered that their patients’ pain control was sub-optimal. A negative change from baseline (i.e. indicating a worsening) was also reported in the physical functioning score on the EORTC QLQ-C30, although some improvements in scores for sleep and pain, between baseline and week five of treatment, were reported. Eight percent of the patients on nabiximols developed a serious nabiximols-associated adverse event. The most commonly reported adverse events for nabiximols were nausea/vomiting, dry mouth, dizziness, somnolence, and confusion.

In contrast to the above-mentioned studies using nabiximols, a randomized, double-blind, placebo-controlled, parallel group clinical trial of opioid-treated cancer patients with intractable chronic cancer pain (e.g. bone, mixed, neuropathic, somatic, visceral) reported no statistically significant difference between placebo and the nabiximols treatment group in the primary endpoint of 30% relief from baseline pain at study endReference284. However, when using a continuous responder rate analysis as a secondary endpoint (i.e. comparing the proportion of active drug vs. placebo responders across the full spectrum of response from 0 to 100%), the study was able to report a statistically significant treatment effect in favour of nabiximols. Patients were taking median opioid equivalent doses ranging between 120 and 180 mg/day. Adverse events were dose-related, with only the highest dose group comparing unfavourably to placebo. The authors noted that the trial was a dose-ranging study, and that confirmatory studies are strongly warranted. The study design also did not permit the evaluation of a therapeutic index.

A randomized, placebo-controlled, cross-over pilot clinical trial of nabiximols for the alleviation of established chemotherapy-induced neuropathic pain reported no statistically-significant difference between the treatment and the placebo groups on a numerical rating scale for pain intensity (NRS-PI)Reference282. The authors noted that five participants (responders) experienced a 2-point or greater drop in NRS-PI during treatment which was statistically significant compared to placebo. The mean dose of medication used in the treatment arm was eight sprays per day (range: 3 – 12) and 11 sprays in the placebo arm with most patients titrating to maximum dose in the placebo arm. Medication-related side effects were reported by the majority of participants and included fatigue, dry mouth, dizziness, nausea, headache, “fuzzy thinking” or “foggy brain”, increased appetite and diarrhea. Ten participants continued into the extension phase of the trial and pain levels continued to decrease from a baseline of 6.9 to 5.0 at three months and 4.2 at six months. Average dose was 4.5 sprays per day (range: 2 – 10 sprays per day).

In Canada, nabiximols (Sativex®) is approved (with conditions) as an adjunctive analgesic in adults with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background painReference431. Current dosing recommendations for nabiximols suggest a maximum daily dose of 12 sprays (32.4 mg THC and 30 mg CBD) over a 24 h periodReference122Reference138Reference431, although higher numbers of sprays/day have been used or documented in clinical studiesReference284Reference431. It should be noted that increases in the number of sprays/day were accompanied by increases in the incidence of adverse effects.

4.7.2.4 “Opioid-sparing” effects and cannabinoid-opioid synergy
  • While pre-clinical and case studies suggest an “opioid-sparing” effect of certain cannabinoids, epidemiological and clinical studies with oral THC and nabiximols are mixed.
  • Observational studies suggest an association between U.S. states with laws permitting access to cannabis (for medical and non-medical purposes) and lowered rates of prescribed opioids and opioid-associated mortality.

The “opioid-sparing” effect refers to the ability of a non-opioid medication (e.g. cannabis, THC) to confer adjunctive opioid analgesia with the use of a lower dose of the opioid, thereby decreasing opioid-associated side effects. While there are some pre-clinical data and data from case studies supporting such an effect for cannabinoids, this is less well-established in published clinical studies. Furthermore, there is some evidence from epidemiological/observational studies to suggest that individuals using opioids for chronic non-cancer pain may also use cannabis to manage distress from unmanaged pain, and that a certain portion of individuals using higher doses of opioids for chronic non-cancer pain may also have greater problems across a number of domains, including greater risk of a CUD.

The following information summarizes the results from pre-clinical, epidemiological and clinical studies investigating cannabinoid-opioid interactions and the potential “opioid-sparing effect” of cannabinoids.

Pre-clinical data

There is a fair amount of evidence to suggest a functional interaction between the cannabinoid and the opioid systems, although additional research is needed to understand precisely how the two systems communicate with one another. The evidence supporting a putative interaction between the cannabinoid and opioid systems comes from a number of observations. First, it is known that cannabinoids and opioids produce similar biological effects such as hypothermia, sedation, hypotension, inhibition of GI motility, inhibition of locomotor activity, and anti-nociceptionReference841Reference843. Furthermore, neuroanatomical studies in animals have demonstrated overlapping tissue distribution of the cannabinoid and opioid receptors, with both receptor types found in nervous system tissues associated with the processing of painful stimuli, namely the periaqueductal gray, raphe nuclei, and central-medial thalamic nucleiReference841Reference843. There is also some evidence that the CB1 and mu-opioid receptors can co-localize in some of the same neuronal sub-populations such as those located in the superficial dorsal horn of the spinal cordReference841. This co-localization may play an important role in spinal-level modulation of peripheral nociceptive inputsReference841. Both receptors also share similar signal transduction molecules and pathways, the activation of which generally results in the inhibition of neurotransmitter releaseReference841Reference843. The role of these receptors in inhibiting neurotransmitter release is further supported by their strategic localization on pre-synaptic membranesReference841. Evidence from some pre-clinical studies also suggests that acute administration of cannabinoid receptor agonists can lead to endogenous opioid peptide release, and that chronic THC administration increases endogenous opioid precursor gene expression (e.g. preproenkephalin, prodynorphin, and proopiomelanocortin) in different spinal and supraspinal structures involved in the perception of painReference841. A few studies have even demonstrated the existence of cannabinoid-opioid receptor heteromers, although the exact biological significance of such receptor heteromerization remains to be fully elucidatedReference844Reference845. Taken together, these findings suggest the existence of cross-talk between the cannabinoid and opioid systems. Furthermore, pre-clinical studies using a combination of different opioids (morphine, codeine) and cannabinoids (THC), at acute or sub-effective doses, have reported additive and even synergistic analgesic effectsReference846Reference848Reference848Reference851. A recent systematic review and meta-analysis of pre-clinical studies examining the strength of the existing evidence for the “opioid-sparing” effect of cannabinoids in the context of analgesia concluded that there was a significant opioid-sparing effect between morphine and THC when co-administered, although there was significant heterogeneity in the dataReference852. Nevertheless, when compared to morphine administration alone, the median ED50 of morphine was 3.6 times lower when given in combination with THC. A significant “opioid-sparing” effect was also reported for THC when co-administered with codeine (ED50 9.5 times lower when THC combined with codeine vs. codeine alone).

Clinical case series and epidemiological data

A recent cross-sectional on-line survey of 2 897 participants from a databse of 67 422 medical cannabis patients in the state of California gathered data about the use of cannabis as a substitute for opioid and non-opioid-based pain medicationReference853. The majority of the participant sample reported being able to decrease the amount of opioids they consumed when they also used cannabis. Limitations of this study included self-report and very low response rate (4%) and a biased sample population.

Analysis of patients case-series reported a reduction in opioid dose with cannabis use in the treatment of chronic non-cancer painReference854. In one case, a 47-year-old woman with a 10-year history of chronic progressive MS with headache, multi-site joint pain, bladder spasm, and leg spasticity on a daily regimen of 75 mg of long-acting morphine, 24 mg tizanidine, and 150 mg sertraline at bedtime began also using cannabis at bedtime. Over the next six months, the patient began smoking two to four puffs of cannabis at bedtime on a regular basis and reported a reduction of morphine to 45 mg per day, tizanidine to 6 mg per day, and sertraline to between 100 and 150 mg at bedtime. The patient reported improvement in pain, spasticity, bladder spasm, and sleep. The patient also reported not experiencing any adverse effects other than feeling somewhat “high” if she smoked more than four puffs at a time. Another patient, a 35-year-old male with HIV, who experienced HIV-related painful peripheral neuropathy involving the lower limbs and hands and who was taking 360 mg of long-acting morphine per day with an additional 75 mg of morphine sulfate four times daily for breakthrough pain and gabapentin at 2 400 mg per day began using smoked cannabis in a dose of three to four puffs, three to four times per day. Over the next four months, the patient’s dose of morphine decreased to 180 mg per day, and by nine months the patient discontinued the morphine followed by discontinuation of gabapentin. The patient also did not report any side effects associated with cannabis use. Lastly, a 44-year-old man with a six-year history of low back pain and left leg pain taking long-acting morphine at 150 mg per day and cyclobenzaprine 10 mg, t.i.d. with poor pain control began smoking cannabis, at a dose of several puffs to one joint, four to five times per day. After smoking cannabis on a regular basis for two weeks, the patient was able to decrease his morphine to 90 mg per day with a further reduction to 60 mg morphine per day and a reduction in cyclobenzaprine to 10 mg once daily with reported improvement in pain control. The authors of the case-series report that taken together, the three patients were able to reduce their opioid dose by 60 to 100% after starting the cannabis regimen. In addition, patients self-reported experiencing better pain control with the introduction of cannabis into their pain management strategy. All patients reported previous cannabis use before onset of morbidity.

A prospective, non-randomized, and unblinded observational case-series study assessing the effectiveness of adjuvant nabilone therapy in managing pain and symptoms experienced by 112 advanced cancer patients in a palliative care setting reported that those patients using nabilone had a lower rate of starting NSAIDs, tricyclic anti-depressants, gabapentin, dexamethasone, metoclopramide, and ondansetron and a greater tendency to discontinue these drugsReference288. Patients were prescribed nabilone for pain relief (51%), for nausea (26%), and for anorexia (23%). Treated patients were started on 0.5 or 1 mg nabilone at bedtime during the first week and titrated upwards in increments of 0.5 or 1 mg thereafter. At follow-up, the majority of patients were on a 2 mg daily nabilone dose with a mean daily dose of 1.79 mg. The two primary outcomes of the study, pain and opioid use in the form of total morphine sulfate equivalents were reduced significantly in treated patients compared to untreated patients. Side effects from nabilone consisted mainly of dizziness, confusion, drowsiness, and dry mouth. Patients also demonstrated less tendency to initiate additional new medications and could reduce or discontinue baseline medications.

A time-series analysis that examined death certificate data over time (1999-2010) between U.S. states with medical cannabis programs and those without, to determine if there was an association between the presence of state medical cannabis laws and opioid analgesic overdose mortality rates, reported that age-adjusted opioid analgesic overdose death rate per 100 000 population in states that enacted medical cannabis laws was almost 25% lower than in states without such laws (95% CI = -37.5%, -9.5%)Reference855. This association appeared to strengthen over time, with a decrease in the mean annual opioid overdose mortality rate of 19.9% in the first-year and a decrease in the mean annual opioid overdose mortality rate of 33.3% in year six after enactment of state medical cannabis laws. This study appears to suggest that medical cannabis laws are associated with reductions in opioid analgesic overdose mortality on a population level, however the mechanisms by which this appears to occur is unclear at this time and requires further investigation.

A time-series analysis that examined the association between Colorado’s legalization of cannabis for non-medical purposes and opioid-related deaths (2000-2015) reported a 0.7 deaths/per month reduction in opioid-related deaths (b = -0.68; 95% CI = -1.34, -0.03). Specifically, there was a 6% decrease in opioid-related deaths two years following legalization of non-medical cannabis when compared to two control states (one allowing cannabis for medical purposes, one not allowing cannabis for medical or non-medical purposes). However, the authors note that the two-year follow-up window post-legalization is relatively short and further research involving longer follow-up periods (and examining additional states that have legalized cannabis for non-medical purposes) are needed to determine if these reductions are sustained or dissipate over timeReference856.

Two recent observational studies using U.S health care data (Medicare and Medicaid) examined the difference in opioid prescription rates in U.S. states with and without legal access to cannabis. Bradford and colleaguesReference857 longitudinally (2010-2015) found that states that implemented medical cannabis laws reported fewer daily doses of prescribed opioids (2.21 million/year) compared to states without medical cannabis laws. Parallel to this finding, Wen and HockenberryReference858 cross-sectionally found that states with medical cannabis laws reported a 5.88% lower rate of prescribed opioids. This study further examined opioid prescribing patterns in states with laws regarding cannabis for non-medical purposes, and found that access to cannabis was also associated with reductions in opioid prescribing rates (i.e., 6.38% lower compared to states without non-medical cannabis legalization). Key limitations across these studies are the associative nature of the findings meaning that causality cannot be established, and the inability to determine if cannabis actually replaced or substituted for opioid use, as users potentially could have accessed and used opioids from other non-medical sources.

A cross-sectional retrospective survey of 244 patients accessing cannabis for medical purposes at a Michigan dispensary reported that the use of cannabis for medical purposes was associated with a significant decrease in opioid use, as well as a decrease in the number of other medications used and in the number of side effects associated with the use of other medications, as well as improvements in QoLReference859. The majority (80%) of the study participants reported smoking cannabis daily. The mean decrease in self-reported opioid use among all study respondents was 64%. Furthermore, there was a statistically significant decrease in the number of other non-opioid medications (e.g. NSAIDs, disease-modifying anti-rheumatic drugs, anti-depressants, serotonin-norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors) after cannabis use. Limitations of the study include potential recall bias, a self-selected population, self-report, and changes in the rates of physician prescription of opioids.

A prospective, open-label, single-arm, longitudinal study of 274 patients with treatment-resistant chronic pain (i.e. musculoskeletal widespread pain, peripheral neuropathic pain, radicular low back pain, cancer pain), examined the long-term effect of medicinal cannabis treatment on pain and functional outcomesReference582. Intention-to-treat analysis was conducted on 206 patients who provided baseline data and 176 subjects completed the study and were included in the final analysis. Patients could use smoked cannabis, baked cookies or an olive oil extract as drops (up to a maximum equivalent of 20 g per month, but with the possibility of increasing this amount if warranted). Patients were instructed to titrate their cannabis dose starting with one cigarette puff (or one drop of cannabis oil) per day and increase by increments of one puff or drop per dose up to three times per day until satisfactory pain relief was achieved or side effects appeared. Subjects were instructed to refrain from driving for at least 6 h after consuming cannabis or longer if they felt disoriented or drowsy. THC concentrations in the smoked product were estimated at 6 – 14% THC and between 11 – 19% in the oral formulations, with the CBD concentrations between 0.2 – 3.8% in the smoked product and 0.5 – 5.5% in the oral formulations. Mean monthly-prescribed amount of cannabis at follow-up was 43 g (average of 1.4 g per day). Cannabis treatment was added to the existing analgesic regimen. Median daily dose among opioid users (in daily oral morphine sulfate equivalents) was 60 mg. At follow-up (mean of seven months from treatment start), pain symptom score improved from a median score of 83.3 to a median score of 75.0 (p < 0.001) on the Short-Form Treatment Outcomes in Pain Survey (S-TOPS) questionnaire with 66% of subjects reporting improvement, 8% reporting no change, and 26% reporting deterioration. In subgroup analyses, no differences were noted in the primary outcome between neuropathic and non-neuropathic pain, or between male and female patients. Improvements were also noted in Brief Pain Inventory (BPI) scores of pain severity and pain interference as well as with most social and emotional disability scores (i.e. S-TOPS scores for family-social disability, role-emotional disability, satisfaction with outcomes, sleep problem index). Opioid consumption at follow-up also decreased by 44%. The median (daily) oral morphine equivalent dose among subjects still receiving opioids at follow-up decreased from 60 mg to 45 mg but did not reach statistical significance. Nine subjects discontinued treatment due to mild to moderate adverse effects, mainly sedation, heaviness, nervousness, and difficulty concentrating. Two additional subjects discontinued treatment due to serious side effects: one because of elevated liver transaminases, and one elderly subject admitted to emergency care and hospitalized for confusion. Total rate of cannabis discontinuation was 5.3%. Study limitations included lack of a control group and open-label design, lack of frequent periodic assessment of all adverse events, and under-representation by women.

Findings from a two-year, prospective, cross-sectional, cohort study of 1 514 individuals prescribed pharmaceutical opioids for chronic non-cancer pain (the Pain and Opioids IN Treatment study) examined the extent to which cannabis is used by this groupReference214. The study reported that one in six (16%) enrolled individuals had used cannabis for pain relief and 25%, reported they would have used it for pain relief if they had access. Among those using cannabis for pain, the average pain relief they reported from using cannabis was 70%, which was in contrast to the 50% average pain relief reported for opioid medications. Almost half (43%) had used cannabis for non-medical purposes at some time and 12% of the entire cohort met the criteria for an International Classification of Diseases (ICD) CUD in their lifetime. Those individuals reporting using cannabis for pain relief were on average younger and male, and were significantly more likely to have met criteria for a range of other licit and illicit substance use disorders and to meet criteria for moderate or severe depression and generalized anxiety. Individuals who had used cannabis for pain were more likely to have reported back and neck problems and had been living with pain for a significantly longer period compared to those not using cannabis for pain. Those who had used cannabis for pain reported greater pain severity, greater interference from and poorer coping with pain, and more days out of role in the past year compared to those who had not used. In addition, these individuals had been prescribed opioids for longer, were on higher opioid doses, were more likely to also have been prescribed benzodiazepines, and were more likely to be non-adherent with their opioid use. According to the authors, those individuals using cannabis for pain appeared to be a group with greater problems across a number of domains including psychological distress and substance use problems such that the use of cannabis for pain may reflect those characteristics. Alternatively, the authors suggest that the adjunctive use of cannabis for pain could reflect attempts by those individuals to manage distress, given the experience of greater interference from reported pain. Limitations of the study include potential for under-reporting, potential bias associated with self-reporting, and lack of information on amount of cannabis consumed and potency.

In support of the above findings, a study looking at the rates of CUD in a national sample of Veterans Health Administration patients (N = 1 316 464) with chronic non-cancer pain diagnoses and receiving opioid medications, suggested that greater numbers of prescription opioid fills were associated with greater likelihood of a diagnosis of a CUDReference860. Patients prescribed opioids and diagnosed with a CUD were found to be significantly younger and more likely to be homeless. Those diagnosed with a CUD were also more likely to be diagnosed with hepatic disease and HIV, though less likely to be diagnosed with dementia and renal disease compared to those without a CUD. Patients diagnosed with a CUD were also more likely to be diagnosed with schizophrenia, other psychotic disorders, bipolar disorder, major depressive disorder, anxiety disorders, adjustment disorder, personality disorder, and dual diagnosis. Those with a CUD were also more likely to have been diagnosed with abuse or dependence of hallucinogens, cocaine, tobacco, amphetamine, opioids or alcohol. The authors conclude that the results of this study suggest that rather than cannabis functioning as an opioid substitute (i.e. CUD would be associated with less opioid use), these substances appear to complement each other as greater opioid medication use is associated with increased risk of CUD. Limitations of this study included a mostly homogenous population sample (male military veterans), and reliance on non-standardized semi-structured diagnostic interviews, raising the possibility that the actual prevalence of CUD in this patient population was under-estimated.

An epidemiological study using data gathered from wave 1 and 2 of NESARC (2001 – 2002 and 2004 – 2005) prospectively examined the association between cannabis use and incident non-medical prescription opioid use and disorder 3 years later, as well as whether cananbis use among adults with non-medical prescription opioid use was associated with subsequent decrease in non-medical opioid useReference861. Cannabis use at wave 1 was associated with a significant increase in the odds of prevalent non-medical prescription opioid use during the follow-up period at wave 2 which persisted even after adjusting for confounders. This association was observed among adults without past-year cannabis use disorder and among adults with moderate or more severe pain at wave 1. Furthermore, among individuals without non-medical opioid use during the 12 months prior to the wave 1 interview, there was a significant association between cannabis use at wave 1 and incident non-medical opioid use during the follow-up period. Cannabis use also appeared to be associated with lower odds of decreasing levels of opioid use but decreases were markedly more common than increases in opioid use. After adjustment for other covariates, significant associations persisted between wave 1 cannabis use and prevalent and incident non-medical opioid use disorder at wave 2. Among adults with moderate or more severe pain at wave 1, cannabis use was associated with prevalent opioid use disorder in adjusted analyses. Despite the above findings, the great majority of adults who used cannabis did not go on to initiate or increase non-medical opioid use.

A preliminary, historical, small cohort study examined the association between enrollment in a medical cannabis program and prescription opioid useReference862. Enrollment in a medical cannabis program was associated with a statistically significant higher odds of ceasing opioid prescriptions (OR = 17.27, CI = 1.89, 157.36), an OR = 5.12 of reducing daily opioid doses (CI = 1.56, 16.88). Improvements were noted in pain reduction, quality of life, social life, activity levels, and concentration with few side effects.

Data from clinical trials

A recent systematic review and meta-analysis of clinical studies examining the strength of the existing evidence for the “opioid-sparing” effect of cannabinoids in the context of analgesia concluded that there was an absence of randomized, well-controlled clinical studies that provide evidence of an “opioid-sparing” effect of cannabinoidsReference852. Furthermore, the existing data from clinical trials looking at the “opioid-sparing” ability of cannabis are mixed. One double-blind, placebo-controlled, crossover clinical study of healthy human volunteers given low doses of THC, morphine, or a combination of the two drugs failed to find any differences between subjects’ ratings of sensory responses to a painful thermal stimulusReference863. However, the study did report that the combination of morphine and THC was associated with a decrease in the subjects’ affective response to the painful thermal stimulus. The authors suggested that morphine and THC could combine to yield a synergistic analgesic response to the affective aspect of an experimentally-evoked pain stimulus.

A recent double-blind, placebo-controlled, within-subject clinical study examined if cannabis enhances the analgesic effects of (low dose) oxycodone and the impact of combining cannabis and oxycodone on abuse liability. Eighteen healthy ‘current’ cannabis smokers (at least 3 times/week; assessed by urine toxicology and self-report) were given oxycodone (0, 2.5, and 5.0 mg, P.O.) with smoked cannabis (0.0, 5.6% THC), and the analgesic effects were measured by the Cold-Pressor Test. Results revealed that oxycodone alone (5.0 mg) significantly increased pain threshold (F [1, 17] = 7.5, p ≤ 0.01) and tolerance (F [1, 17] = 5.4, p ≤ 0.05) compared to placebo (inactive cannabis and 0.0mg oxycodone). When administered with active cannabis, 5.0 mg oxycodone also increased pain tolerance compared to the placebo condition and active cannabis alone (F [1, 17] = 5.5, p ≤ 0.05). The combination of active cannabis and 2.5 mg oxycodone increased pain threshold and tolerance relative to the placebo condition (F [1, 17] = 5.9, p ≤ 0.05 and F [1, 17] = 6.5, p ≤ 0.05, respectively) and active cannabis alone (F [1, 17] = 5.2, p ≤ 0.05 and F [1, 17] = 5.5, p ≤ 0.05, respectively). In terms of abuse liability oxycodone did not increase subjective ratings of cannabis abuse or cannabis self-administration. However, a combination of oxycodone (2.5 mg) and cannabis yielded small but significant increases in oxycodone abuse liability (p ≤ 0.05). The researchers concluded that the findings demonstrate opioid-sparing effects of cannabis for analgesia that may be accompanied by increases in potential abuse liability pertaining to oxycodoneReference864.

Another clinical studyReference287 reported that patients suffering from chronic non-cancer pain and not responding to opioids experienced increased analgesia, decreased pain intensity, and decreased evoked pain when given either 10 or 20 mg dronabinol (for additional details see Section 4.7.2.2, under Clinical Studies With Orally Administered Prescription Cannabinoids).

In another study, it was reported that patients suffering from chronic pain of various etiologies, unrelieved by stable doses of opioids (extended release morphine or oxycodone), experienced a statistically significant improvement in pain relief (-27%, CI = 9 – 46) following inhalation of vapourized cannabis (900 mg, 3.56% THC, t.i.d. for five days)Reference280 (for additional details see Section 4.7.2.2, under Clinical Studies With Smoked or Vapourized Cannabis). The findings from this study suggest that addition of cannabinoids (in this case inhaled vapourized cannabis) to existing opioid therapy for pain may serve to enhance opioid-associated analgesia.

In contrast, another study did not note a statistically significant decrease in the amounts of background or breakthrough opioid medications consumed by the majority of patients suffering from intractable cancer-related pain and taking either nabiximols or THCReference138. Similarly, no statistically significant changes were observed in the amounts of background or breakthrough opioid doses taken by patients suffering from intractable cancer-related pain who were administered nabiximolsReference284. However, the design of the latter study did not allow proper assessment of an “opioid-sparing effect” of nabiximols.

In summary, pre-clinical and case studies appear to support an “opioid-sparing” effect of THC but results from clinical and epidemiological studies are mixed. While “cannabinoid-opioid synergy” has been proposed as a way to significantly increase the analgesic effects of opioids while avoiding or minimizing tolerance to the effects of opioid analgesics and circumventing, or attenuating, the well-known undesirable side effects associated with the use of either cannabinoids or opioids, some of the evidence is mixed and requires further studyReference841Reference843.

4.7.2.5 Headache and migraine
  • The evidence supporting using cannabis/certain cannabinoids to treat headache and migraine is very limited and mixed.

With regard to migraine, an endocannabinoid deficiency has been postulated to underlie the pathophysiology of this disorderReference865; however, the evidence supporting this hypothesis is limited and mixed. Clinical studies suggest that the concentrations of anandamide are decreased in the CSF of migraineurs, while the levels of calcitonin-gene-related-peptide and nitric oxide (normally inhibited by anandamide and implicated in triggering migraine) are increasedReference866Reference867. In contrast, the activity of the anandamide-degrading enzyme FAAH is significantly decreased in chronic migraineurs compared to controlsReference868.

While historical and anecdotal evidence suggest a role for cannabis in the treatment of headache and migraineReference869, no controlled clinical studies of cannabis or prescription cannabinoids to treat headache or migraine have been carried out to dateReference870Reference871.

In one case-report, a patient suffering from pseudotumour cerebri and chronic headache reported significant pain relief after smoking cannabisReference293. In another case-report, a patient complaining of cluster headaches refractory to multiple acute and preventive medications reported improvement with smoked cannabis or dronabinol (5 mg)Reference291. However, these single-patient case-studies should be interpreted with caution.

A report indicated that cannabis use was very frequent among a population of French patients with episodic or chronic cluster headache, and of those patients who used cannabis to treat their headache, the majority reported variable, uncertain, or even negative effects of cannabis smoking on cluster headacheReference290.

A retrospective chart review of 121 adults with a primary diagnosis of migraine headaches who were recommended migraine treatment or prophylaxis with cannabis for medical purposes by a physician from among two medical cannabis specialty clinics in Colorado reported that migraine headache frequency decreased from 10.4 to 4.6 headaches per month (p < 0.0001) with the use of cannabis for medical purposesReference289. Forty percent of the patients reported positive effects with the most common effect being prevention of migraine headache, decreased frequency, and aborted migraine headache. Inhaled cannabis was reported as being more effective than oral ingestion. Negative effects were reported in 12% of patients, with edibles being associated with more negative effects (i.e. problems with timing and effect intensity).

It should also be noted that cannabis use has been associated with reversible cerebral vasoconstriction syndrome and severe headacheReference292. In addition, headache is an often-observed adverse effect associated with the use of cannabis or prescription cannabinoid medicationsReference59Reference227Reference431Reference492Reference688Reference716, and headache is also one of the most frequently reported physical symptoms associated with cannabis withdrawalReference872.

A recent review of the use of cannabis for headache disorders reported that there is insufficient evidence from well-controlled clinical trials to support the use of cannabis for headache, despite sufficient anecdotal and preliminary results as well as plausible neurobiological mechanisms to warrant clinical studiesReference873.

4.8 Arthritides and musculoskeletal disorders

  • The evidence from pre-clinical studies suggests stimulation of CB1 and CB2 receptors alleviates symptoms of osteoarthritis (OA), and THC and CBD alleviate symptoms of rheumatoid arthritis (RA).
  • The evidence from clinical studies is very limited, with a modest effect of nabiximols for RA.
  • There are no clinical studies of cannabis for fibromyalgia, and the limited clinical evidence with dronabinol and nabilone suggests a modest effect on decreasing pain and anxiety, and improving sleep.
  • The role of cannabinoids in osteoporosis has only been investigated pre-clinically and is complex and conflicting.

The arthritides include a broad spectrum of different disorders (e.g. osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, gout, and many others) all of which have in common the fact that they target or involve the joints. Scientific studies have demonstrated that joints, bone, and muscle all contain a working ECS, that some arthritides such as OA and RA are associated with changes in the functioning of the ECS, and that modulation of the ECS may help alleviate some of the symptoms associated with certain arthritidesReference40Reference42Reference778Reference874Reference882. The section below summarizes the evidence for cannabis/cannabinoids in OA and RA. Also covered are musculoskeletal disorders such as fibromyalgia and osteoporosis.

Information from surveys

The 2011 Canadian Alcohol and Drug Use Monitoring Survey (CADUMS) indicated that a significant proportion of Canadians aged 15 and over who reported using cannabis for medical purposes reported using it for chronic pain associated with, for example, arthritisReference883.

In addition, one study that explored the experiences of Australian individuals using cannabis for medical purposes reported that out of 128 participants in the survey, 35% said they used cannabis to treat symptoms associated with arthritisReference884.

A self-administered survey of 947 individuals in the U.K. who reported ever having used cannabis for medical purposes revealed that 21% of the individuals surveyed said they had used cannabis for symptoms associated with arthritis. Seven percent of these individuals had been using cannabis continuously for a median of four yearsReference579.

A survey of 628 Canadian individuals who self-reported using cannabis for medical purposes asked about individuals’ use of cannabis for medical purposesReference885. Approximately 15% of individuals reporting using cannabis for medical purposes used it to treat symptoms associated with arthritis pain, inflammation, insomnia, anxiety, depression, and spasms. Most reported preferring smoking (53%) compared to vapourizing or oral ingestion (both at 39%). The majority (47%) of individuals using cannabis for arthritis reported using cannabis four or more times per day and an equal proportion reported using at least 2 g per day or more; the median gram amount among those that used 2 g per day or more was approximately 4 g per day.

4.8.1 Osteoarthritis

Among the arthritides, OA is by far the most common type of arthritis and is the leading cause of disability in those over the age of 65 years in developed countriesReference886. OA results from damage to the articular cartilage induced by a complex interplay of genetic, metabolic, biochemical and biomechanical factors followed by activation of inflammatory responses involving the interaction of the cartilage, subchondral bone and synovium resulting in further damage and degradation of the articular cartilage and subchondral bone, variable synovitis, and capsular thickeningReference877Reference878. The eventual outcomes are joint disability and severe painReference877Reference878. The pain associated with OA is generally inadequately or safely controlled with current analgesics, which has spurred the search for alternative therapeutic approachesReference878. The disease affects both men and women, although it appears to occur more frequently in womenReference877. In addition, OA most commonly affects people in middle age and the elderly, even though younger people may also be affected due to injury or overuseReference877. The pain associated with OA includes both nociceptive and non-nociceptive components, as well as neuropathic and inflammatory components, and is associated with abnormally excitable pain pathways in the peripheral nervous system and the CNSReference877. The pain and physical disability associated with OA are also accompanied by anxiety, depression and changes in cognition all of which have a negative impact on QoLReference876. Neuroimaging studies have shown that several brain regions are involved in the processing of OA pain including bilateral activation of primary and secondary somatosensory cortices as well as the insular, cingulate, pre-frontal and orbito-frontal cortices, and the thalamus, as well as unilateral activation of the putamen and amygdalaReference887Reference888.

Pre-clinical studies

Animal models of OA suffer from a number of limitations such as differences in anatomy, functionality, dimensions, cartilage repair processes, and thickness in comparison with human jointsReference877. In addition, the lesions that develop in animal models of OA correspond to those found in humans only in a particular stage of the diseaseReference877. Furthermore, no animal model of OA completely reproduces the whole variety of signs and symptoms of human OA. Taken together, these factors all pose a number of significant challenges in translating findings obtained in animal models of OA to OA patients. Nevertheless, animal models of OA are useful in understanding the potential therapeutic effects of cannabis and cannabinoids.

There is increasing evidence that suggests an important role for the ECS in the pathophysiology of joint pain associated with OAReference877. With regard to endocannabinoid tone, one animal study reported elevated levels of the endocannabinoids anandamide and 2-AG, and the “entourage” compounds PEA and OEA in the spinal cord of rats with experimentally-induced knee joint OAReference889. While no changes were observed in the levels or the activities of the endocannabinoid catabolic enzymes FAAH or MAGL in the spinal cord of the affected rats, protein levels of the major enzymes responsible for endocannabinoid synthesis were reported to be significantly elevated in these animalsReference889.

Both CB1 and CB2 receptors have been localized in knee joints confirming that local control of joint pain is achievable without the need to involve central cannabinoid receptorsReference890Reference891. Downregulation of CB1 and CB2 receptor gene expression was reported in the lumbar spinal cord of osteoarthritic mice, likely in response to an elevated endocannabinoid tone coming from the affected osteoarthritic jointsReference892.

A study in rats reported that intra-articular injection of the CB1 receptor agonist arachidonyl-2-chloroethylamide in control animals was associated with a reduction in firing rate and suppression of nociceptive activity from pain fibers innervating the joints when the joints were subjected to either normal or noxious joint rotationReference893. Furthermore, animals with osteoarthritic joints produced an augmented response to articular CB1 receptor activation. The anti-nociceptive effect was blocked by co-administration of a CB1 receptor antagonist in osteoarthritic joints, but not in control joints.

Local administration of URB597 (a FAAH inhibitor) by intra-arterial injection proximal to an osteoarthritic joint was associated with decreased mechanosensitivity of joint afferent fibres in two different rodent models of OAReference894. Behavioural experiments carried out in OA rats suggested that treatment with the inhibitor also decreased joint pain measured by a decrease in hindlimb incapacitanceReference894. In addition to an antinociceptive response to FAAH inhibition, URB597 has been shown to reduce leukocyte trafficking in the synovium indicating that endocannabinoids could have anti-inflammatory properties in jointsReference880.

Systemic administration of a CB2 receptor agonist in a rat model of OA was associated with a dose-dependent reversal of decreased grip force in the affected limb, a proxy measure for painReference895. The maximal analgesic efficacy was comparable to that seen with celecoxib in this animal model of OAReference895.

In another animal study, the spinal lumbar CB2 receptor was shown to play a significant role in the modulation of osteoarthritic painReference892. Furthermore, upregulation of CB2 receptor expression in the spinal lumbar cord was associated with attenuation of joint pain. In addition, lumbar spinal cord mu-opioid receptor expression was downregulated, while delta and kappa-opioid receptor expression was upregulated, suggesting functional interactions between the endocannabinoid and opioid systems. The decreased mu-opioid receptor expression and concomitant increase in kappa and delta opioid receptor expression could additionally contribute to the nociceptive component of the disease.

One animal study conducted in a rat model of OA reported that CB2 receptor mRNA levels were significantly increased in spinal cord of osteoarthritic ratsReference896. Furthermore, selective stimulation of the CB2 receptor by systemic dosing with a synthetic cannabinoid receptor agonist was associated with significant attenuation of the development and maintenance of pain behaviour and spinal neuronal responses. Levels of pro-inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF) α, and IL-10 were also significantly attenuated following treatment with the CB2 receptor agonist. Rats also did not appear to develop tolerance to the anti-nociceptive effects of the CB2 receptor agonist after multiple administrations of the drug. The study also showed a negative association between CB2 mRNA levels and chondropathy in post-mortem samples of human spinal cord.

An animal study of OA in mice reported that the condition was associated with significant increases in 2-AG levels in the prefrontal cortex, the area of the brain implicated in pain, cognitive and emotional processing, as well as in the plasmaReference876. OA in this mouse model was also associated with increases in stress and anxiety-like behaviour in affected wild-type mice and in mice lacking CB1 receptor expression, but not in mice lacking CB2 receptor expression suggesting distinct roles for these two receptors in the pathophysiology of OA. Selective stimulation of CB1 and CB2 receptors was associated with improvements in mechanical allodynia. Lastly, patients with OA were shown to have significant increases in their plasma levels of 2-AG, but not anandamide, compared to healthy controls consistent with the findings obtained in the mouse model. Furthermore, expression of CB1 and CB2 receptors was upregulated in blood lymphocytes of these patients and significant positive correlations were noted between plasma levels of 2-AG, knee pain, and depression scores as well as significant negative correlations with SF-36 (QoL) and memory performance scores.

Further support for a role for the CB2 receptor in the pathophysiology of OA comes from a pre-clinical study in mice lacking CB2 receptor expressionReference897. These mice developed significantly more severe OA compared with wild-type controls. Furthermore, treatment of wild-type mice with a CB2 receptor agonist was associated with partial protection from OA. In contrast, another study found that local delivery of a CB2 receptor agonist actually increased joint nociceptor activity and the resulting heightened pain response was thought to involve TRPV1 ion channelsReference891.

A pre-clinical study in rats that investigated the effects of CBD on intravertebral disc degeneration showed that direct intradiscal injection of 120 nmol of CBD, but not lower doses of 30 or 60 nmol CBD, immediately after disc lesion significantly attenuated the extent of disc injury and the beneficial effect was maintained up to 15 days’ post-injuryReference898.

Clinical studies

There are no published clinical studies of cannabis for OA. In humans, one study found that the levels of the endocannabinoids anandamide and 2-AG in the synovial fluid of patients with OA were increased compared to non-inflamed normal controls, although the significance of these findings remains unclearReference42.

One multi-centre, randomized, double-blind, double-dummy, placebo- and active-controlled crossover clinical trial of a FAAH inhibitor reported a lack of analgesic activity (Western Ontario and McMaster Universities pain score) in patients with OA of the kneeReference899. In contrast, administration of naproxen in the study was associated with significant analgesia. Importantly, this clinical trial raised serious questions about the translatability of findings from animal studies to those conducted with humans since the FAAH inhibitor had shown efficacy in the animal model but not in humans. In addition, other issues of concern include the testing of the FAAH inhibitor on a heterogeneous population of OA patients and off-target effects (e.g. at TRPV1).

4.8.2 Rheumatoid arthritis

RA is a destructive, systemic, auto-immune inflammatory disease that affects a smaller, but not insignificant, proportion of the adult populationReference886. It is characterized by chronic inflammatory infiltration of the synovium leading to progressive synovitis, and eventual cartilage and joint destruction, functional disability, significant pain, and systemic complications (e.g. cardiovascular, pulmonary, psychological, and skeletal disorders such as osteoporosis)Reference879Reference900Reference901. As with OA, the ECS plays an important role in the pathophysiology of the disorder and manipulation of the ECS holds therapeutic promise.

Pre-clinical studies

A pre-clinical study in a rat model of RA reported that treatment with either THC or anandamide was associated with significant anti-nociception in the paw-pressure testReference382. Another study in two different mouse models of RA (acute and chronic) reported that systemic administration (i.p.) of a range of doses of CBD (2.5 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg per day), after onset of acute arthritic symptoms, for a period of 10 days, was associated with the cessation of the progression of such symptomsReference902. The daily 5 mg/kg i.p. dose was deemed to be the optimal dose for both acute (10 days) and chronic models (5-weeks) of arthritis. No obvious side effects were noted at any of the tested doses. Oral administration of 25 mg/kg of CBD for 10 days after onset of acute arthritic symptoms was associated with suppression of the progression of these symptoms, although the 50 mg/kg daily oral dose was almost equally effective. The 25 mg/kg daily oral dose was also effective in suppressing the progression of chronic arthritic symptoms when administered over a five-week period. Protective effects associated with exposure to CBD included the prevention of additional histological damage to arthritic hind-paw joints, suppression of TNF release from arthritic synovial cells, attenuation of lymph node cell proliferation, suppression of production of reactive oxygen intermediates and attenuation of lymphocyte proliferation.

The results from a study examining the anti-nociceptive effects of THC in a rat model of RA suggested that intraperitoneal administration of 4 mg/kg THC was associated with a significant decrease in the levels of spinal dynorphin, an increase in kappa-opioid receptor-mediated analgesia, and a decrease in NMDA-receptor-mediated hyperalgesiaReference903. Another study by the same group and using the same animal model demonstrated that THC was equipotent and equiefficacious to morphine with regard to anti-nociception in the paw-pressure test, and that there was a synergistic anti-nociceptive interaction between THC and morphine in both arthritic and non-arthritic rats in the same paw-pressure testReference384. A follow-up study again using the same animal model suggested an important role for the CB2 receptor in modulating the anti-nociceptive effects of THCReference904.

Indeed, a number of additional studies have continued to support an important role for the CB2 receptor in RAReference874Reference879Reference905. Tissue samples taken from human rheumatoid joints showed increased CB2 receptor expression compared to osteoarthritic joints, with expression of the CB2 receptor localized to the lining layer and interstitial sub-lining layer as well as follicle-like aggregatesReference879Reference905. Furthermore, CB2 receptor activation on fibroblast-like synoviocytes derived from rheumatoid joints was associated with inhibition of the production of a variety of inflammatory mediators seen in RA including IL-6, matrix metalloproteinase (MMP)-3, MMP-13, and chemokine (C-C motif) ligand (CCL) 2Reference879Reference905. CB2 receptor activation was also associated with dose-dependent amelioration of arthritis severity in a mouse model of RAReference905. Selective stimulation of the CB2 receptor significantly decreased joint swelling, synovial inflammation, and joint destruction, as well as serum levels of anti-collagen II antibodies in a mouse model of RAReference874. However, others have reported that stimulation of joint CB2receptors causes synovial hyperaemia through a mechanism involving TRPV1 ion channelsReference906. The vasodilator effect of these CB2 receptor agonists is attenuated in models of acute and chronic arthritis suggesting that CB2 receptors are downregulated in inflamed joints.

A recent pre-clinical study examined the efficacy of transdermal CBD for the reduction of inflammation and pain in a rat model of RAReference907. In this study, gel preparations containing increasing doses of CBD (0.6, 3.1, 6.2, 62.3 mg/day) were applied to the dorsal skin surface for four consecutive days after induction of rheumatoid-like arthritis. Transdermal absorption resulted in dose-dependent increases in plasma concentrations of CBD. Four consecutive days of application resulted in mean plasma concentrations of 3.8 ng/mL, 17.5 ng/mL, 33.3 ng/mL, and 1 629.9 ng/mL, respectively. The three lower doses exhibited linear pharmacokinetic correlations, but not the highest dose. Furthermore, the 6.2 mg and the 62.3 mg gel doses of CBD significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane. The 6.2 mg dose of CBD optimally reduced swelling and synovial membrane thickness. CBD treatment was not associated with changes in exploratory behaviour suggesting the lack of psychoactive effects.

Clinical studies

In humans, one study found that the levels of the endocannabinoids anandamide and 2-AG in the synovial fluid of patients with RA were increased compared to non-inflamed normal controls, although the significance of these findings remains unclearReference42.

There are no published clinical studies of cannabis for RA.

A preliminary clinical study assessing the effectiveness of nabiximols (Sativex®) for pain caused by RA reported a modest but statistically significant analgesic effect on movement and at rest, as well as improvement in quality of sleepReference383. Administration of nabiximols was well tolerated and no significant toxicity was observed. The mean daily dose in the final treatment week was 5.4 pump actuations (equivalent to 14.6 mg THC and 13.5 mg CBD/day, treatment duration was three weeks). The differences observed were small and variable across the participants.

A Cochrane Collaboration review conducted in 2012 concluded that the evidence in support of the use of oro-mucosal cannabis (e.g. nabiximols) for the treatment of pain associated with RA is weak and given the significant side effect profile typically associated with the use of cannabinoids, the potential harms seem to outweigh any modest benefits achievedReference900.

4.8.3 Fibromyalgia

Fibromyalgia is a disorder characterized by widespread pain (allodynia and hyperalgesia) and a constellation of other symptoms including sleep disorders, fatigue, and emotional or cognitive disturbancesReference908. While the underlying pathophysiology of fibromyalgia remains unclear, disturbances in the recruitment or functioning of peripheral and central pain processing pathways and in the levels of several important neurotransmitters (serotonin, noradrenaline, dopamine, opioids, glutamate and substance P) have been noted in fibromyalgia patientsReference909Reference912. Co-morbid depressive symptoms have also been associated with a more pronounced deficit in pain inhibition, as well as increased pain in fibromyalgia patientsReference913.

Clinical studies with smoked or orally ingested cannabis

There are no clinical trials of smoked or ingested cannabis for the treatment of fibromyalgia. However, a cross-sectional survey of patients suffering from fibromyalgia found that the patients reported using cannabis (by smoking and/or eating) to alleviate pain, sleep disturbance, stiffness, mood disorders, anxiety, headaches, tiredness, morning tiredness, and digestive disturbances associated with fibromyalgiaReference184. Subjects (mostly middle-aged women who did not respond to current treatment) reported statistically significant decreases in pain and stiffness, and statistically significant increases in relaxation and well-being 2 h after cannabis self-administration. Side effects included somnolence, dry mouth, sedation, dizziness, high, tachycardia, conjunctival irritation, and hypotension. The study suffered from a number of limitations including the study design, small sample size, variability in frequency and duration of cannabis use, and a biased subject population.

Clinical studies with prescription cannabinoid medications

There are relatively few properly controlled clinical studies examining the role of cannabinoids in the treatment of fibromyalgia. The available evidence is summarized below.

Dronabinol

A non-placebo controlled pilot study examining the effect of dronabinol monotherapy (2.5 – 15 mg Δ9-THC/day; with weekly increases of 2.5 mg Δ9-THC, up to a maximum of 15 mg THC/day) on experimentally-induced pain, axon reflex flare, and pain relief in patients suffering from fibromyalgia reported that a sub-population of such patients experienced significant pain relief (reduced pain perception) with 10 and 15 mg/day Δ9-THC, but no changes were observed in axon reflex flareReference385. Touch-evoked allodynia and pinprick-induced hyperalgesia were also not significantly affected by Δ9-THC. Subjects who completed a three-month course of therapy (15 mg/day Δ9-THC) reported a > 50% decrease in pain. The study however suffered from low power due to the high rate of patient drop-out caused by intolerable side effects of the treatment.

A multi-center, retrospective study of patients suffering from fibromyalgia who were prescribed an average daily dose of 7.5 mg Δ9-THC, over an average treatment period of seven months, reported a significant decrease in pain score, a significant decrease in depression, and a reduction in the intake of concomitant pain-relief medications such as opioids, anti-depressants, anti-convulsants, and NSAIDs following treatment with Δ9-THCReference386. It is important to note that the study had a number of considerable limitations (method of data collection, heterogeneous patient selection criteria, and high subject dropout rate) and as such, the results should be interpreted with caution.

Nabilone

A randomized, double-blind, placebo-controlled clinical trial of nabilone (1 mg b.i.d.) for the treatment of fibromyalgia showed statistically significant improvements in a subjective measure of pain relief and anxiety, as well as on scores on the fibromyalgia impact questionnaire, after four weeks of treatmentReference596. However, no significant changes in the number of tender points or tender point pain thresholds were observed (note: the use of the “tender point” as a diagnostic criterion for fibromyalgia is no longer an absolute requirement)Reference914. Patients were taking concomitant pain medications such as NSAIDs, opioids, anti-depressants, and muscle relaxants. Nabilone did not have any lasting benefit in subjects when treatment was discontinued.

A two-week randomized, double-blind, active-control, crossover clinical study of 29 patients suffering from fibromyalgia reported that nabilone (0.5 – 1.0 mg before bedtime) improved sleep in this patient populationReference597.

The Canadian Clinical Guidelines for the Diagnosis and Management of Fibromyalgia Syndrome (endorsed by the Canadian Pain Society and the Canadian Rheumatology Association) indicate that with regards to possible treatments, a trial of a prescribed pharmacologic cannabinoid may be considered in a patient with fibromyalgia, particularly in the setting of important sleep disturbance (this recommendation was based on Level 3, Grade C evidence)Reference838. For additional information regarding the use of cannabis/cannabinoids to alleviate sleep disorders or disturbances, please consult Section 4.9.5.2.

A Cochrane systematic review of the available evidence on the efficacy, safety and tolerability of cannabis products from randomized, double-blind, clinical trials of at least four week’s duration for the treatment of fibromyalgia in adults reported that 1 mg nabilone at bedtime was not associated with high to moderate quality evidence for an outcome of efficacy (participant-reported pain relief of > 50%, and Patient Global Impression of Change much or very much improved), tolerability (withdrawal due to adverse events), and safety (serious adverse events)Reference915. Low quality evidence was found for nabilone over placebo in pain relief and health-related quality of life, but not in fatigue, and nabilone over amitriptyline in improving sleep quality but not for pain and health-related quality of life. Non-serious adverse events associated with nabilone use included dizziness/drowsiness, dry mouth and vertigo and the incidence of non-serious adverse events with nabilone was higher compared with placebo or amitriptyline.

4.8.4 Muscular pain

Muscular pain affects a large share of the population and is a major clinical problemReference916Reference917. Findings from pre-clinical studies using two animal models of acute muscle pain suggest that both systemic (0.3 – 5 mg/kg i.p.) and local administration (0.0125 – 0.1 mg/kg i.m.) of THC is associated with a dose-dependent reduction in frequency of paw shaking and a reduction in time spent in nocifensive behaviour following a noxious muscular stimulusReference916. Differences in the types of cannabinoid receptors engaged were observed according to the route of administration: systemic administration of THC was associated with engagement of CB1 and/or CB2 receptors, while local administration of THC in the paw was predominantly associated with engagement of CB2 receptorsReference916. No human experimental or clinical studies exist with cannabinoids for muscular pain.

4.8.5 Osteoporosis

Osteoporosis is a disease characterized by reduced bone mineral density and an increased risk of fragility fracturesReference918. It occurs when the normal cycle of bone remodelling is perturbed, leading to a net decrease in bone deposition and a net increase in bone resorptionReference919.

Pre-clinical studies

CB1 and CB2 receptors have been detected in mouse osteoblasts and osteoclasts, although CB1 is expressed at very low levels compared to CB2Reference20Reference920Reference921. In fact, it appears that CB1 receptors are expressed more abundantly in skeletal sympathetic nerve terminals in close proximity to osteoblastsReference922. Besides the receptors, the endocannabinoids 2-AG and anandamide have been detected in mouse trabecular bone and in cultures of mouse osteoblasts and human osteoclastsReference921Reference923Reference924. Taken together, these findings suggest the existence of a functional ECS in bone.

The role of the ECS in bone physiology has been investigated using mice carrying genetic deletions of either the CNR1 or CNR2 genes. The skeletal phenotypes of CB1 receptor knockout mice appear to vary depending on the gene targeting strategy used, the mouse strain, gender, time points at which the phenotypes were assessed, and the different experimental methodologies used to measure bone densityReference20. In one CB1-deficient mouse strain, young female mice had normal trabecular bone with slight cortical expansion whereas young male mice had high bone massReference920Reference922. Loss of CB1 receptor function was associated with protection from ovariectomy-induced bone lossReference920. In addition, antagonism of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivoReference920.

A subsequent study by the same group reported that CB1 knockout mice had increased peak bone mass but eventually developed age-related osteoporosisReference918. The increased peak bone mass was attributed to a reduction in osteoclast formation and activity, with preservation of normal osteoblast activity. In contrast, age-related bone loss in the knockout mice appeared to be caused by preferential formation and accumulation of adipocytes at the expense of osteoblasts within the bone-marrow space, as well as decreased bone formationReference918. In contrast to these studies, another study using a different gene targeting strategy and mouse strain reported that both male and female CB1 knockout mice exhibited low bone mass, increased numbers of osteoclasts, and a decrease in the rate of bone formationReference922. The effects of ovariectomy in this mouse line were not examined, most likely because the baseline bone mass was too small to properly measure differences between mice subjected to ovariectomy and controls.

Another pre-clinical study in younger and older rats reported that blockade of CB1 receptor activity, by administration of rimonabant, had differential effects on glucocorticoid-induced cortical bone thickness and mean trabecular bone densityReference925. In young rats, rimonabant attenuated the osteoporotic effects of chronic glucocorticoid treatment whereas in older rats, the opposite effect was noted. Furthermore, the findings from this study further support the idea that the CB1receptor plays an age-related differential role in bone turnover processes.

In mice, activation of CB1 receptors by THC has been shown to significantly slow bone elongation and possibly overall body size, at least in female adolescent miceReference926. The concentration of systemic THC administered in the mice (5 mg/kg/day) was reported to be similar to that described for human daily cannabis smokers.

A pre-clinical study in rats measuring the impact of cannabis smoke on bone healing around titanium implants reported that chronic exposure to cannabis smoke reduced cancellous bone healing around the implants by reducing bone filling and bone-to-implant contact inside the implant threadsReference388. No such effect was observed for cortical bone.

The skeletal phenotypes of CB2 receptor knockout mice have also been investigated. Ofek reported that CB2-deficient mice display a low bone mass phenotype as well as age-related trabecular bone lossReference927. These deficits were associated with increased numbers of osteoclasts and decreased numbers of osteoblast precursors. Furthermore, a selective CB2 receptor agonist was reported to increase osteoblast proliferation and activity and to decrease the formation of osteoclast-like cells in vitro, and administration of this agonist attenuated ovariectomy-induced bone loss in vivoReference927. While a more recent study supported the finding of age-related bone loss, it failed to find any significant differences in peak bone mass between wild-type and knockout miceReference928. Furthermore, in contrast to the study by OfekReference927, selective stimulation of the CB2 receptor was associated with an increase in osteoblast differentiation and function rather than proliferation. Another study reported no differences in peak bone mass between CB2 receptor knockout mice and wild-type mice under normal conditionsReference929. Age-related bone loss was not measured in this study. Genetic ablation of the CB2 receptor appeared to protect against ovariectomy-induced bone loss, an effect mimicked by administration of a CB2-selective antagonistReference929. Conversely, results from in vitro studies suggested that CB2-selective agonists significantly increased osteoclast formation and osteoclast sizeReference929. It may be relevant to note here that single nucleotide polymorphisms (SNPs) and SNP haplotypes located in the coding region of the CB2 receptor gene have also been associated with osteoporosis in humansReference930Reference932.

4.9 Other diseases and symptoms

4.9.1 Movement disorders

The individual components of the ECS are particularly abundant in areas of the brain that control movement, such as the basal gangliaReference933. Motor effects generally arise as a consequence of changes in ECS activity, with activation of the CB1 receptor typically resulting in inhibition of movementReference933. A number of studies have reported changes in CB1 receptor levels and CB1 receptor activity in motor diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD)Reference934Reference937, and the findings from such studies suggest a complex link between the ECS and the pathophysiology of these and other neurological diseases.

A systematic review of the efficacy and safety of cannabinoids in movement disorders such as HD, PD, cervical dystonia and TS suggests that cannabinoids are either probably ineffective or of unknown efficacy and that the risks and benefits of cannabinoid treatment should be carefully weighedReference671. In addition, comparative efficacy of cannabinoid vs. other therapies is unknown for these indicationsReference671.

4.9.1.1 Dystonia
  • Evidence from limited pre-clinical studies suggests that a synthetic CB1 and CB2 receptor agonist may alleviate dystonia-like symptoms, and CBD delays dystonia progression.
  • Evidence from a limited number of case studies and small placebo-controlled or open-label clinical trials suggests improvement in symptoms of dystonia with inhaled cannabis, mixed effects of oral THC, improvement in symptoms of dystonia with oral CBD, and lack of effect of nabilone on symptoms of dystonia.

Dystonia involves overactivity of muscles required for normal movement, with extra force or activation of nearby but unnecessary muscles, and is often painful in addition to interfering with functionReference938. Dystonia can be primary, including torticollis and blepharospasm/orofacial dyskinesias or dystonias (Meige syndrome) or part of another condition such as HD, and tardive dyskinesia after dopa-blocking drugsReference938.

Pre-clinical data

A pre-clinical study in a hamster model of primary generalized dystonia reported a dose-dependent decrease in disease severity with administration of the synthetic CB1 and CB2 receptor agonist WIN 55,212-2Reference939. However, anti-dystonic doses of the agonist were associated with severe side effects including depression of spontaneous locomotor activity and catalepsy. In addition, this CB receptor agonist increased the anti-dystonic effect of diazepamReference939. A follow-up study by the same group confirmed the anti-dystonic efficacy of WIN 55,212-2 and also showed that CBD delayed the progression of dystonia, but only at a very high doseReference940. A pre-clinical study of anti-psychotic-induced acute dystonia and tardive dyskinesia in monkeys showed that oral dyskinesia, but not dystonia, was dose-dependently reduced by the synthetic CB1 receptor agonist CP 55,940Reference941.

Clinical data

While anecdotal reports suggest cannabis may alleviate symptoms associated with dystonia in humansReference248, no properly controlled clinical studies of cannabis to treat dystonia have been published.

One case-study reported improvement in torticollis after smoking cannabisReference942. Another case study reported improvement in a patient with central thalamic pain and right hemiplegic painful dystonia who smoked one joint in the morning once per week for three weeksReference943. Following smoking, the patient reported complete pain relief and relief of paresthesia and marked improvement in dystonia with improved ability to write and take a few steps without support. Pain relief appeared to persist for up to 48 h after each episode of cannabis smoking. No tolerance to the effects of cannabis was noted and the patient discontinued opioid analgesic therapy. Another case report of a 25-year-old patient using cannabis for generalized dystonia secondary to Wilson’s disease reported that smoking 3 or 4 g of cannabis per day was associated with significant improvement in his dystoniaReference248. Physician observation supported the patient’s claims: cannabis decreased the score on the Burke-Fahn-Marsden dystonia rating scale and the disability scale by 50% each. Therapeutic effects did not appear to persist beyond each 24 h period, requiring the patient to administer cannabis daily.

A placebo-controlled, single-dose trial with 5 mg of Δ9-THC administered orally to a musician with focal dystonia (“Musician’s Dystonia”) reported an improvement in motor control in the subject’s affected hand, with tiredness and poor concentration cited as side effects associated with the use of Δ9-THCReference250. The therapeutic effect persisted until 2 h after intake, with a progressive return to baseline values after 5 h.

An eight-week, phase IIa, cross-over, randomized, placebo-controlled trial of dronabinol (15 mg/day) in nine patients with cervical dystonia reported a lack of effect of dronabinol compared to placebo on any outcome measure (Toronto Western Spasmodic Torticollis Rating Scale – TWSTRS, VAS of pain, global impression of change)Reference244. Most subjects experienced an adverse event, none of which was deemed serious. Adverse events with dronabinol included light-headedness, sleepiness, dry mouth, blurred vision, bitter-taste and vertigo, and were deemed mild.

Another case-study reported that dronabinol (2.5 mg, b.i.d. initially, then 5 mg, b.i.d.) was associated with improvement in dystonia in a patient with MS, paroxysmal dystonia, complex vocal tics, and cannabis dependence (minimum daily consumption of five cannabis joints) and who had previously reported symptom improvement after smoking cannabisReference247. The patient also reported a significant reduction in cannabis craving, an improvement in quality of sleep, decreased vocalizations, decreased anxiety and decreased frequency of paroxysmal dystonia with dronabinol.

A six-week, open-label, pilot trial of five patients taking 100 to 600 mg/day of CBD reported modest dose-related improvements in dystonic movements in all study subjects, but a worsening of tremor and hypokinesia in two patients with co-existing PD administered doses of CBD > 300 mg/dayReference261. Side effects of CBD were mild and included hypotension, dry mouth, psychomotor slowing, light-headedness, and sedation.

Results of a double-blind, randomized, placebo-controlled study of 15 patients taking a single 0.03 mg/kg dose of nabilone and not taking any other anti-dystonia medication showed no significant reduction in dystoniaReference253.

4.9.1.2 Huntington’s disease
  • Evidence from pre-clinical studies reports mixed results with THC on Huntington’s disease (HD)-like symptoms.
  • Limited evidence from case studies and small clinical trials is mixed and suggests a lack of effect with CBD, nabilone and nabiximols, and a limited improvement in HD symptoms with smoked cannabis.

Pre-clinical and human experimental data

Results from studies carried out in animal models of HD as well as post-mortem studies carried out in deceased HD patients suggest that brain CB1 receptors, especially those found in the basal ganglia, are downregulated and/or desensitized as a result of the expression of the mutant Huntingtin protein, and that this occurs early in the course of the disease and prior to the appearance of overt clinical symptomsReference934Reference944Reference953. In vivo positron emission topography (PET) study of HD patients supports these findings, demonstrating profound decreases in CB1 receptor availability throughout the gray matter of the cerebrum, cerebellum, and brainstem of HD patients even in early stages of the diseaseReference954. Additional pre-clinical and post-mortem studies in deceased HD patients indicate that the decrease in CB1 receptor levels appears to be accompanied by an increase in CB2 receptor levels in glial elements, astrocytes, and in reactive microglial cellsReference949Reference955. Thus, a significant amount of pre-clinical evidence and some limited clinical evidence suggests that changes in the ECS are tightly linked to the pathophysiology of HDReference949Reference952Reference954.

One pre-clinical study in a mouse model of HD reported no beneficial effects of Δ9-THC (10 mg/kg/day)Reference956, while another study reported that Δ9-THC (2 mg/kg/day) was associated with decreased pathology and delayed onset of HD-like symptoms compared to untreated HD miceReference951. Another pre-clinical animal study in a rat model of HD showed that CBreceptor activation was associated with reduction in inflammatory markers associated with an HD-like phenotype and protection of striatal projection neuronsReference957. A pre-clinical study has also reported that a restricted population of CB1 receptors selectively located on glutamatergic terminals in corticostriatal projections may play a potentially protective role in attenuating excitotoxic damage associated with excessive glutamate release in HD, raising the possibility that selective targeting of this receptor population may help attenuate neurodegeneration in patients with HDReference958.

Clinical data

The results from single-patient case studies are mixed. In one study, daily doses of 1.5 mg nabilone increased choreatic movementsReference256, while in another case improved mood and decreased chorea were noted in a patient who had smoked cannabis and who then continued on 1 mg nabilone b.i.d.Reference959.

With regard to clinical studies, one double-blind, placebo-controlled, 15-week, crossover trial of 15 patients with HD taking 10 mg/kg/day of oral CBD did not report improvement in symptoms associated with HDReference258. A randomized, double-blind, placebo-controlled, crossover pilot study found little or no beneficial effect of 1 or 2 mg nabilone over placebo in 37 patients with HD