Highlights
- •Medical cannabis used for chronic pain over one year appears to have a reasonable safety profile.
- •The detailed listing of adverse events to medical cannabis will enhance clinical decision-making.
- •The average daily dose of dried herbal cannabis used by patients with chronic pain was 2.5g/day.
- •Medical cannabis use over one year was associated with improvements in pain, function, quality of life and cognitive function.
Abstract
Study registration
Perspective
Key words
Health Canada. Marihuana for medical purposes regulations. Available at: http://gazette.gc.ca/rp-pr/p2/2013/2013-06-19/html/sor-dors119-eng.php. Accessed May 14, 2014
Methods
Objectives
Study Design
Study Population
Study Drug
Outcome Measures
Primary Outcome
ICH: Definitions and standards for expedited reporting. Available at: http://www.ich.org/cache/compo/276-254-1.html. Accessed October 1, 2005
The use of the WHO-UMC system for standardised case causality assessment. Available at: http://who-umc.org/Graphics/24734.pdf. Accessed July 25, 2013.
Common terminology criteria for adverse events v3.0. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed July 25, 2013
Secondary Outcomes
Neurocognitive function
Pulmonary function
Other safety parameters
Efficacy measures
Study Procedures
Baseline Assessment
Follow-Up
AE Reporting
Sample Size and Power Considerations
Statistical Analysis
Primary Analysis
Subgroup Analysis
Secondary Analyses
Protocol Modifications
Ethics and Regulatory Approvals
Results

Characteristics | Cannabis Group (N = 215) | Control Group (N = 216) | P |
---|---|---|---|
Age at enrollment | 45.5 (19–82) | 52.4 (21–83) | <.001 |
Gender (% male) | 110 (51.2%) | 76 (35.2%) | <.001 |
Education (% university/college) | 111 (51.6%) | 122 (56.5%) | .14 |
Married; n (%) | 133 (61.9%) | 140 (64.8%) | .52 |
Disabled; n (%) | 129 (60.0%) | 102 (47.2%) | .01 |
Tobacco status | .01 | ||
Current tobacco users | 91 (42.3%) | 67 (31.0%) | |
Ex-tobacco users | 77 (35.8%) | 73 (33.8%) | |
Never users | 47 (21.9%) | 76 (35.2%) | |
Alcohol status | .05 | ||
Currently drinking | 166 (77.2%) | 149 (69.0%) | |
Not currently drinking | 49 (22.8%) | 67 (31.0%) | |
Past cannabis use ‖ “Current cannabis users” were those who reported using cannabis and were still using at the baseline interview; “Ex-cannabis users” were those who reported using cannabis but were not using at the baseline interview; “naive users” were those who reported never using cannabis before the baseline interview. | <.001 | ||
Current cannabis users | 141 (65.6%) | 0 | |
Ex-cannabis users | 58 (27.0%) | 70 (32.4%) | |
Naive users | 16 (7.4%) | 146 (67.6%) | |
Drug Abuse Screening Test | <.0001 | ||
N/A (DAST = 0) | 59 (27.4%) | 133 (62.1%) | |
Low (DAST = 1–5) | 153 (71.2%) | 81 (37.9%) | |
Intermediate (DAST = 6–10) | 3 (1.4%) | 0 | |
Substantial (DAST = 11–15) | 0 | 0 | |
Severe (DAST = 16–20) | 0 | 0 | |
Type of pain | .40 | ||
Nociceptive | 35 (16.3%) | 39 (18.1%) | |
Neuropathic | 83 (38.6%) | 70 (32.4%) | |
Both | 97 (45.1%) | 107 (49.5%) | |
Average pain intensity | 6.6 (0–10) | 6.1 (0–10) | .002 |
Duration of pain (years) | 8.0 (0–54) | 7.0 (0–82) | .42 |
Medications | |||
Opioids | 118 (54.9%) | 143 (66.2%) | .02 |
Antidepressants | 101 (47.0%) | 128 (59.3%) | .01 |
Anticonvulsants | 94 (43.7%) | 118 (54.6%) | .02 |
AEs
SAEs
Serious AEs | Cannabis Group | Control Group | ||
---|---|---|---|---|
System Organ Class (MedDRA) | Number of Events | Rate | Number of Events | Rate |
Surgical and medical procedures | 10 | 5.65 | 11 | 5.39 |
Gastrointestinal disorders | 10 | 5.65 | 7 | 3.43 |
Musculoskeletal and connective tissue disorders | 5 | 2.82 | 6 | 2.94 |
Injury, poisoning, and procedural complications | 4 | 2.26 | 1 | .49 |
Renal and urinary disorders | 3 | 1.69 | 1 | .49 |
Nervous system disorders | 2 | 1.13 | 4 | 1.96 |
Respiratory, thoracic, and mediastinal disorders | 1 | .56 | 7 | 3.43 |
Infections and infestations | 1 | .56 | 5 | 2.45 |
Vascular disorders | 1 | .56 | 3 | 1.47 |
Metabolism and nutrition disorders | 1 | .56 | 2 | .98 |
Psychiatric disorders | 1 | .56 | 2 | .98 |
Investigations | 1 | .56 | 0 | .00 |
General disorders and administration site conditions | 0 | .00 | 3 | 1.47 |
Blood and lymphatic system disorders | 0 | .00 | 1 | .49 |
Eye disorders | 0 | .00 | 1 | .49 |
Hepatobiliary disorders | 0 | .00 | 1 | .49 |
Immune system disorders | 0 | .00 | 1 | .49 |
Total | 40 | 22.60 | 56 | 27.45 |
Total number of patients | 28 | 13.02% | 42 | 19.44% |
Non-serious AEs
Non-serious AEs | Cannabis Group | Control Group | ||||
---|---|---|---|---|---|---|
System Organ Class (MedDRA) | Number of Persons Reporting Symptoms | Number of Events Reported | Rate (Events/Person-Year) | Number of Persons Reporting Symptoms | Number of Events Reported | Rate (Events/Person-Year) |
Nervous system disorders | 101 | 165 | .93 | 71 | 93 | .46 |
Gastrointestinal disorders | 66 | 109 | .62 | 70 | 101 | .50 |
Respiratory, thoracic, and mediastinal disorders | 77 | 103 | .58 | 49 | 67 | .33 |
Infections and infestations | 63 | 89 | .50 | 49 | 68 | .33 |
Musculoskeletal and connective tissue disorders | 49 | 77 | .44 | 50 | 67 | .33 |
Psychiatric disorders | 47 | 57 | .32 | 21 | 24 | .12 |
General disorders and administration site conditions | 29 | 35 | .20 | 20 | 23 | .11 |
Injury, poisoning, and procedural complications | 23 | 31 | .18 | 21 | 23 | .11 |
Renal and urinary disorders | 23 | 29 | .16 | 18 | 22 | .11 |
Skin and subcutaneous tissue disorders | 18 | 22 | .12 | 17 | 18 | .09 |
Investigations | 21 | 21 | .12 | 8 | 8 | .04 |
Eye disorders | 16 | 20 | .11 | 13 | 14 | .07 |
Reproductive system and breast disorders | 11 | 15 | .08 | 5 | 6 | .03 |
Metabolism and nutrition disorders | 14 | 14 | .08 | 7 | 7 | .03 |
Vascular disorders | 8 | 8 | .05 | 9 | 9 | .04 |
Surgical and medical procedures | 6 | 7 | .04 | 10 | 12 | .06 |
Cardiac disorders | 4 | 4 | .02 | 7 | 7 | .03 |
Blood and lymphatic system disorders | 4 | 4 | .02 | 0 | 0 | .00 |
Ear and labyrinth disorders | 3 | 3 | .02 | 5 | 5 | .02 |
Immune system disorders | 1 | 2 | .01 | 3 | 3 | .01 |
Hepatobiliary disorders | 2 | 2 | .01 | 1 | 1 | .00 |
Endocrine disorders | 1 | 1 | .01 | 0 | 0 | .00 |
Neoplasms benign, malignant, and unspecified (including cysts and polyps) | 0 | 0 | .00 | 3 | 3 | .01 |
Total | 191 | 818 | 4.62 | 186 | 581 | 2.85 |
Unadjusted OR (95% CI) | 1.28 (.72–2.28) | 1 | ||||
Unadjusted IRR (95% CI) | 1.62 (1.34–1.97) | 1 |

Multiple Regression Analyses
Cannabis | Control | Unadjusted IRR (95% CI) | Adjusted IRR (95% CI) | |
---|---|---|---|---|
All patients | ||||
Number of patients | 215 | 216 | – | – |
Cumulative person-years | 176.9 | 204.1 | – | – |
Number of SAEs | 40 | 56 | .82 (.46–1.46) | 1.08 (.57–2.04) |
Number of AEs | 818 | 574 | 1.64 (1.35–1.99) | 1.74 (1.42–2.14) |
Patients excluding “current cannabis users” at baseline | ||||
Number of patients | 74 | 216 | – | – |
Cumulative person-years | 52.2 | 204.1 | – | – |
Number of SAEs | 20 | 56 | 1.40 (.66–2.93) | 1.77 (.72–4.32) |
Number of AEs | 316 | 574 | 2.15 (1.69–2.74) | 2.07 (1.59–2.70) |
Neurocognitive Tests
Group | Number of Patients | Baseline | 6 Months | 12 Months | |
---|---|---|---|---|---|
WMS-III | |||||
Verbal paired associates I | |||||
Recall (max 32 points) | Cannabis | 77 | 16.92 (7.69) | 20.97 (8.01) | 22.97 (7.56) |
Control | 53 | 17.42 (7.85) | 19.25 (8.70) | 22.72 (8.53) | |
Verbal paired associates II | |||||
Recall (max 8 points) | Cannabis | 76 | 5.67 (2.35) | 6.29 (2.05) | 6.54 (1.81) |
Control | 53 | 5.45 (2.55) | 6.02 (2.45) | 6.64 (1.95) | |
Recognition (max 24 points) | Cannabis | 76 | 23.80 (.80) | 23.92 (.32) | 23.78 (1.41) |
Control | 53 | 23.94 (.23) | 23.98 (.14) | 23.98 (.14) | |
WAIS-III | |||||
Digit symbol-coding (max 133 points) | Cannabis | 72 | 52.21 (21.60) | 53.31 (23.64) | 55.90 (23.11) |
Control | 53 | 49.94 (18.82) | 54.64 (20.26) | 55.00 (17.65) | |
Picture arrangement (max 22 points) | Cannabis | 76 | 11.64 (3.91) | 13.67 (5.03) | 14.18 (4.36) |
Control | 53 | 11.42 (4.65) | 13.32 (5.14) | 14.24 (5.53) |
Pulmonary Function Tests
Blood Tests
Efficacy Measures
Pain Intensity

Quality of Life
Pain and Other Symptoms
Discussion
Acknowledgments
Supplementary data
- Supplementary Material
References
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Article info
Publication history
Footnotes
The study was funded by the Canadian Institutes of Health Research (MOL-66262). M.A.W. receives salary support from the FRQS and the Louise and Alan Edwards Foundation and has a research grant to his institution from CanniMed. M.L. is a founding board member of Panag Pharm Inc, a start-up company researching topical non-psychotropic cannabinoids for pain and inflammation, a medical advisor to Abide Therapeutics researching agents to modulate the endocannabinoid system for the treatment of pain, and a co-investigator on a clinical trial sponsored by Prairie Plant Systems. D.E.M. has received speaker's honoraria and/or consulting fees from Pfizer Canada, Eli Lilly Canada Inc, Janssen Pharmaceuticals, and Purdue Pharma Canada. A.B. discloses consultancies or advisory boards to Bedrocan, CanniMed, Jansen, Johnson & Johnson, Lilly, Merck, Mettrum, Pfizer, and Purdue Pharma. T.W., S.S., J.-P.C., A.G., C.O., and J.M.E. report no conflicts.
Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com.
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