Cannabinoids for Medical UseA Systematic Review and Meta-analysis

Importance  Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear.

Objective  To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids.

Data Sources  Twenty-eight databases from inception to April 2015.

Study Selection  Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome.

Data Extraction and Synthesis  Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis.

Main Outcomes and Measures  Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs.

Results  A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

Conclusions and Relevance  There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

Cannabis is a generic term used for drugs produced from plants belonging to the genus Cannabis.¹ It is one of the most popular recreational drugs; worldwide, an estimated 178 million people aged 15 to 64 years used cannabis at least once in 2012.² Cannabis was included as a controlled drug in the United Nations’ Single Convention on Narcotic Drugs, held in 1961,³ and its use is illegal in most countries.

Medical cannabis refers to the use of cannabis or cannabinoids as medical therapy to treat disease or alleviate symptoms. Cannabinoids can be administered orally, sublingually,or topically; they can be smoked, inhaled, mixed with food, or made into tea. They can be taken in herbal form, extracted naturally from the plant, gained by isomerisation of cannabidiol, or manufactured synthetically.⁴ Prescribed cannabinoids include dronabinol capsules, nabilone capsules, and the oromucosal spray nabiximols.⁴ Some countries have legalized medicinal-grade cannabis for chronically ill patients. Canada and the Netherlands have government-run programs in which specialized companies supply quality-controlled herbal cannabis.⁵ In the United States, 23 states and Washington, DC (May 2015), have introduced laws to permit the medical use of cannabis⁶; other countries have similar laws. The aim of this systematic review was to evaluate the evidence for the benefits and adverse events (AEs) of medical cannabinoids across a broad range of indications.

This review followed guidance published by the Centre for Reviews and Dissemination and the Cochrane Collaboration.^7,8 We established a protocol for the review (eAppendix 1 in Supplement 1).

Randomized clinical trials (RCTs) that compared cannabinoids with usual care, placebo, or no treatment in the following indications were eligible: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis (MS) or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, intraocular pressure in glaucoma, or Tourette syndrome. These indications were prespecified by the project funders, the Swiss Federal Office of Public Health. If no RCTs were available for a particular indication or outcome (eg, long-term AEs such as cancer, psychosis, depression, or suicide), nonrandomized studies including uncontrolled studies (such as case series) with at least 25 patients were eligible.

Twenty-eight databases and gray literature sources were searched from inception to April 2015 without language restriction (Embase search strategy and details of databases searched available in eAppendix 2 in Supplement 2). The search strategy was peer reviewed⁹ by a second information specialist. Reference lists of included studies were screened. Search results and full-text articles were independently assessed by 2 reviewers; disagreements were resolved through consensus or referral to a third reviewer.

We extracted data about baseline characteristics and outcomes (patient-relevant and disease-specific outcomes, activities of daily living, quality of life, global impression of change, and specified AEs). For dichotomous data such as number of patients with at least 30% improvement in pain, we calculated the odds ratio (OR) and 95% CI. For categorical data, we extracted details about each category assessed and the numbers of patients with an outcome in each category. Continuous data such as the Ashworth spasticity score¹⁰ were extracted as means and SDs at baseline, follow-up, and the change from baseline and used to calculate mean differences with 95% CIs. Results (mean difference, 95% CIs, and P values) from the between-group statistical analyses reported by the study were also extracted. All relevant sources were used for data extraction including full-text journal articles, abstracts, and clinical trial registry entries. Where available, the journal article was used as the primary publication because it had been peer reviewed.

RCTs were assessed for methodological quality using the Cochrane Risk of Bias tool.¹¹ If at least one of the domains was rated as high, the trial was considered at high risk of bias. If all domains were judged as low, the trial was considered at low risk of bias. Otherwise, the trial was considered as having unclear risk of bias. Data extraction and risk-of-bias assessment were performed independently by 2 reviewers; disagreements were resolved by a third reviewer.

Clinical heterogeneity was assessed by grouping studies by indication, cannabinoid, and outcome. If there were 2 or more trials within a single grouping, data were pooled using random-effects meta-analysis.¹² For continuous outcomes, we analyzed the mean difference in change from baseline; if this was not reported and could not be calculated from other data, we used the mean difference at follow-up.¹³ For dichotomous data, we used the OR. In order to avoid double counting, we selected a single data set from each study to contribute to the analysis. For studies evaluating multiple interventions, we selected the intervention or dose that was most similar to the other interventions being evaluated in the same analysis. Heterogeneity was investigated using forest plots and the I² statistic. Where data were considered too heterogeneous to pool or not reported in a format suitable for pooling (eg, data reported as medians), we used a narrative synthesis.

Sensitivity analyses were used to assess the statistical effect of trial design. The primary analysis included only parallel-group trials, results from crossover trials were included in an additional analysis. For the analysis of AEs, data for all conditions were combined. We conducted stratified analyses and meta-regression to investigate whether associations varied according to type of cannabinoid, study design (parallel group vs crossover trial), indication (each of the indication categories included in this report), comparator (active vs placebo), and duration of follow-up (<24 hours, 24 hours-1 week, >1 week-4 weeks, >4 weeks) for the outcome of any AE. Statistical analyses were performed using Stata statistical software (version 10).

GRADE (Grading of Recommendations Assessment, Development and Evaluation) was used to rate the overall quality of the evidence for risk of bias, publication bias, imprecision, inconsistency, indirectness, and magnitude of effect. The GRADE ratings of very low–, low-, moderate-, or high-quality evidence reflect the extent to which we are confident that the effect estimates are correct.¹⁴

The searches identified 23 754 hits (records) of which 505 were considered potentially relevant, based on title and abstract screening, and obtained as full-text studies. A total of 79 studies (6462 participants), available as 151 reports, were included; 3 studies (6 reports) were included in multiple indication categories (Figure 1). Thirty-four studies were parallel-group trials (4436 participants), and 45 were crossover trials (2026 participants). Four studies were available only as an abstract,^15- 18 a further 3 were available only as abstracts^19- 21 but with additional details available on trial registries including full results in one,¹⁹ and details of 2 trials (including full trial results) were available only as trial registry entries^22,23; all other trials were reported in full-length journal articles. Where reported, the proportion of participants who were men ranged from 0% to 100% (median, 50% [57 studies]), and the proportion of white participants ranged from 50% to 99% (median, 78% [18 studies]). Publication dates ranged from 1975 to 2015 (median, 2004 [with one-third of trials published before 1990]). Studies were conducted in a wide range of countries. A variety of cannabinoids were evaluated and compared with various different active comparators or placebos; most active comparators were included in the nausea and vomiting indication (Table 1). eAppendices 3 to 12 in Supplement 1 provide an overview of the included studies and their findings.

Four (5%) trials were judged at low risk of bias, 55 (70%) were judged at high risk of bias, and 20 (25%) at unclear risk of bias (eAppendix 13 in Supplement 2). The major potential source of bias in the trials was incomplete outcome data. More than 50% of trials reported substantial withdrawals and did not adequately account for this in the analysis. Selective outcome reporting was a potential risk of bias in 16% of trials. These studies did not report data for all outcomes specified in the trial register, protocol, or methods section or changed the primary outcome from that which was prespecified. Most studies reported being double-blinded but only 57% reported that appropriate methods had been used for participant blinding and only 24% reported that outcome assessors had been appropriately blinded.

Full results from included studies are presented in eAppendices 3-12 in Supplement 2; pooled results and GRADE ratings are presented in Table 2.

Nausea and vomiting due to chemotherapy was assessed in 28 studies (37 reports; 1772 participants).^{15,16,24- 58} Fourteen studies assessed nabilone and there were 3 for dronabinol, 1 for nabiximols, 4 for levonantradol, and 6 for THC. Two studies also included a combination therapy group of dronabinol with ondansetron or prochlorperazine. Eight studies included a placebo control, 3 of these also included an active comparator, and 20 studies included only an active comparator. The most common active comparators were prochlorperazine (15 studies), chlorpromazine (2 studies) and domperidone (2 studies). Other comparators (alizapride, hydroxyzine, metoclopramide and ondansetron) were evaluated in single studies (Table 1). Of all 28 studies, risk of bias was high for 23 or unclear for 5. All studies suggested a greater benefit of cannabinoids compared with both active comparators and placebo, but these did not reach statistical significance in all studies. The average number of patients showing a complete nausea and vomiting response was greater with cannabinoids (dronabinol or nabiximols) than placebo (OR, 3.82 [95% CI, 1.55-9.42]; 3 trials). There was no evidence of heterogeneity for this analysis (I² = 0%) and results were similar for both dronabinol and nabiximols.

Appetite stimulation in HIV/AIDS was assessed in 4 studies (4 reports; 255 participants).^59- 62 All studies assessed dronabinol, 3 compared with placebo (1 of which also assessed marijuana), and 1 compared with megastrol acetate. All studies were at high risk of bias. There was some evidence that dronabinol is associated with an increase in weight when compared with placebo. More limited evidence suggested that it may also be associated with increased appetite, greater percentage of body fat, reduced nausea, and improved functional status. However, these outcomes were mostly assessed in single studies and associations failed to reach statistical significance. The trial that evaluated marijuana and dronabinol found significantly greater weight gain with both forms of cannabinoid when compared with placebo.⁵⁹ The active comparison trial found that megastrol acetate was associated with greater weight gain than dronabinol and that combining dronabinol with megastrol acetate did not lead to additional weight gain.⁶⁰

Chronic pain was assessed in 28 studies (63 reports; 2454 participants).^{19,20,22,23,63- 120} Thirteen studies evaluated nabiximols, 4 were for smoked THC, 5 for nabilone, 3 for THC oromucosal spray, 2 dronabinol, 1 vaporized cannabis (included 2 doses), 1 for ajuvenic acid capsules, and 1 for oral THC. One trial compared nabilone with amitriptyline⁶⁴; all other studies were placebo controlled. One of these studies evaluated nabilone as an adjunctive treatment to gabapentin.¹²¹ The conditions causing the chronic pain varied between studies and included neuropathic pain (central, peripheral, or not specified; 12 studies), 3 for cancer pain, 3 for diabetic peripheral neuropathy, 2 for fibromyalgia, 2 for HIV-associated sensory neuropathy, and 1 study for each of the following indications: refractory pain due to MS or other neurological conditions, for rheumatoid arthritis, for noncancer pain (nociceptive and neuropathic), central pain (not specified further), musculoskeletal problems, and chemotherapy-induced pain.

Two studies were at low risk of bias, 9 at unclear risk, and 17 at high risk of bias. Studies generally suggested improvements in pain measures associated with cannabinoids but these did not reach statistical significance in most individual studies.

The average number of patients who reported a reduction in pain of at least 30% was greater with cannabinoids than with placebo (OR, 1.41 [95% CI, 0.99-2.00]; 8 trials; Figure 2). One trial assessed smoked THC⁷⁷ and reported the greatest beneficial effect (OR, 3.43 [95% CI, 1.03-11.48]), and 7 trials assessed nabiximols (Figure 2). Pain conditions evaluated in these trials were neuropathic pain (OR, 1.38 [95% CI, 0.93-2.03]; 6 trials) and cancer pain (OR, 1.41 [95% CI, 0.99-2.00]; 2 trials), with no clear differences between pain conditions. Nabiximols was also associated with a greater average reduction in the Numerical Rating Scale (NRS; 0-10 scale) assessment of pain (weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), brief pain inventory-short form, severity composite index (WMD, −0.17 [95% CI, −0.50 to 0.16]; 3 trials), neuropathic pain scale (WMD, −3.89 [95% CI, −7.32 to −0.47]; 5 trials), and the proportion of patients reporting improvement on a global impression of change score (OR, 2.08 [95% CI, 1.21 to 3.59]; 6 trials) compared with placebo. There was some evidence to support this based on continuous data but this was not consistent across trials. There was no difference in average quality-of-life scores as measured by the EQ-5D health status index (WMD, −0.01 [95% CI, −0.05 to 0.02]; 3 trials) between nabiximols and placebo. Two of the studies included in the meta-analysis for the NRS (0-10 scale) assessed patients with cancer pain, all other studies assessed patients with neuropathic pain. There were no clear differences based on cause of pain in the meta-analysis of NRS. Sensitivity analyses that included crossover trials showed results consistent with those based on parallel-group trials alone.

Fourteen studies (33 reports; 2280 participants) assessed spasticity due to MS or paraplegia.^{17,19,65,87,91,122- 149} Eleven studies (2138 participants) included patients with MS and 3 included patients with paraplegia (142 participants) caused by spinal cord injury. Six studies assessed nabiximols, 3 for dronabinol, 1 for nabilone, 4 for THC/CBD (2 of these also assessed dronabinol), and 1 each for ECP002A and smoked THC. All studies included a placebo control group; none included an active comparator. Two studies were at low risk of bias, 5 were at unclear risk of bias, and 7 were at high risk of bias. Studies generally suggested that cannabinoids were associated with improvements in spasticity, but this failed to reach statistical significance in most studies. There were no clear differences based on type of cannabinoid. Only studies in MS patients reported sufficient data to allow summary estimates to be generated. 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 (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials; Figure 3). Cannabinoids (nabilone and nabiximols) were also associated with a greater average improvement in spasticity assessed using numerical rating scales (mean difference, −0.76 [95% CI, −1.38 to −0.14]; 3 trials). There was no evidence of a difference in association according to type of cannabinoid for either analysis. Other measures of spasticity also suggested a greater benefit of cannabinoid but did not reach statistical significance (Table 2). The average number of patients who reported an improvement on a global impression of change score was also greater with nabiximols than placebo (OR, 1.44 [95% CI, 1.07 to 1.94]; 3 trials); this was supported by a further crossover trial of dronabinol and oral THC/CBD that provided continuous data for this outcome.¹³² Sensitivity analyses that included crossover trials showed results consistent with those based on parallel group trials alone.

No studies evaluating cannabinoids for the treatment of depression fulfilled inclusion criteria. Five studies included for other indications reported depression as an outcome measure; 4 evaluated chronic pain and 1 evaluated spasticity in MS patients.^{67,73,75,80,129} One trial assessed dronabinol (2 doses), 3 assessed nabiximols, and 1 assessed nabilone. Two studies were rated as having unclear risk of bias and 3 as having high risk of bias. Three studies suggested no difference between cannabinoids (dronabinol and nabiximols) and placebo in depression outcomes. One parallel-group trial that compared different doses of nabiximols with placebo reported a negative effect of nabiximols for the highest dose (11-14 sprays per day) compared with placebo (mean difference from baseline, 2.50 [95% CI, 0.38 to 4.62]) but no difference between placebo and the 2 lower doses.⁶⁷

One small parallel-group trial, judged at high risk of bias, evaluated patients with generalized social anxiety disorder.¹⁵⁰ The trial reported that cannabidiol was associated with a greater improvement on the anxiety factor of a visual analogue mood scale (mean difference from baseline, −16.52; P value = .01)compared with placebo during a simulated public speaking test. Additional data about anxiety outcomes provided by 4 studies (1 parallel group) in patients with chronic pain also suggested a greater benefit of cannabinoids (dronabinol, nabilone, and nabiximols) than placebo but these studies were not restricted to patients with anxiety disorders.^73- 75,80

Two studies (5 reports; 54 participants) evaluated cannabinoids (nabilone) specifically for the treatment of sleep problems. One was a parallel-group trial judged at high risk of bias. This reported a a greater benefit of nabilone compared with placebo on the sleep apnea/hypopnea index (mean difference from baseline, −19.64; P value = .02). The other was a crossover trial judged at low risk of bias in patients with fibromyalgia and compared nabilone with amitriptyline. This suggested that nabilone was associated with improvements in insomnia (mean difference from baseline, −3.25 [95% CI, −5.26 to −1.24]) and with greater sleep restfulness (mean difference from baseline, 0.48 [95% CI, 0.01 to 0.95]). Nineteen placebo-controlled studies included for other indications (chronic pain and MS) also evaluated sleep as an outcome.^{22,23,65,67- 69,75,76,79- 81,87,88,123- 125,129- 131} Thirteen studies assessed nabiximols, 1 for nabilone, 1 for dronabinol, 2 for THC/CBD capsules, and two assessed smoked THC (one at various doses). Two of the studies that assessed nabiximols also assessed oral THC and the trial of dronabinol also assessed oral THC/CBD. There was some evidence that cannabinoids may improve sleep in these patient groups. Cannabinoids (mainly nabiximols) were associated with a greater average improvement in sleep quality (WMD, −0.58 [95% CI, −0.87 to −0.29]; 8 trials) and sleep disturbance (WMD, −0.26 [95% CI, −0.52 to 0.00]; 3 trials). One trial assessed THC/CBD, all others assessed nabiximols, results were similar for both cannabinoids.

Psychosis was assessed in 2 studies (9 reports; 71 participants) judged at high risk of bias, which evaluated cannabidiol compared with amisulpride or placebo.^21,151- 158 The trials found no difference in mental health outcomes between treatment groups.

One very small crossover trial (6 participants)¹⁵⁹ judged at unclear risk of bias compared tetrahydrocannabinol (THC; 5 mg), cannabidiol (20 mg), cannabidiol (40 mg) oromucosal spray, and placebo. This trial found no difference between placebo and cannabinoids on measures of intraocular pressure in patients with glaucoma.

Two small placebo-controlled studies (4 reports; 36 participants)^160- 163 suggested that THC capsules may be associated with a significant improvement in tic severity in patients with Tourette syndrome.

Data about AEs were reported in 62 studies (127 reports). Meta-regression and stratified analysis showed no evidence for a difference in the association of cannabinoids with the incidence of “any AE” based on type of cannabinoid, study design, indication, comparator, or duration of follow-up^{15,16,18,22- 26,28- 31,33- 38,41,42,44- 47,51,57,58,60,62,64- 69,72- 85,87,88,123- 127,129- 131,159,160,162}; further analyses were conducted for all studies combined. Figure 4 shows the results of the meta-analyses for the number of participants experiencing any AE compared when compared with controls, stratified according to cannabinoid. Cannabinoids were associated with a much greater risk of any AE, serious AE, withdrawals due to AE, and a number of specific AEs (Table 3). No studies evaluating the long-term AEs of cannabinoids were identified, even when searches were extended to lower levels of evidence.

We conducted an extensive systematic review of the benefits and AEs associated with medical cannabinoids across a broad range of conditions. We included 79 RCTs (6462 participants), the majority of which evaluated nausea and vomiting due to chemotherapy or chronic pain and spasticity due to MS and paraplegia. Other patient categories were evaluated in fewer than 5 studies.

Most studies suggested that cannabinoids were associated with improvements in symptoms, but these associations did not reach statistical significance in all studies. Based on the GRADE approach, there was moderate-quality evidence to suggest that cannabinoids may be beneficial for the treatment of chronic neuropathic or cancer pain (smoked THC and nabiximols) and spasticity due to MS (nabiximols, nabilone, THC/CBD capsules, and dronabinol). There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy (dronabinol and nabiximols), weight gain in HIV (dronabinol), sleep disorders (nabilone, nabiximols), and Tourette syndrome (THC capsules); and very low-quality evidence for an improvement in anxiety as assessed by a public speaking test (cannabidiol). There was low-quality evidence for no effect on psychosis (cannabidiol) and very low-level evidence for no effect on depression (nabiximols). There was an increased risk of short-term AEs with cannabinoid use, including serious AEs. Common AEs included asthenia, balance problems, confusion, dizziness, disorientation, diarrhea, euphoria, drowsiness, dry mouth, fatigue, hallucination, nausea, somnolence, and vomiting. There was no clear evidence for a difference in association (either beneficial or harmful) based on type of cannabinoids or mode of administration. Only 2 studies evaluated cannabis.^59,77 There was no evidence that the effects of cannabis differed from other cannabinoids.

This review followed recommendations for rigorous systematic reviews.^7,8 In order to identify as many relevant studies as possible and reduce the risk of publication bias, a highly sensitive search strategy was used and an extensive range of resources were searched including electronic databases, guidelines, and systematic reviews. Both published and unpublished trials were eligible for inclusion. There were no date or language restrictions. In order to minimize bias and errors, the main Embase strategies were peer reviewed by a second independent information specialist¹⁶⁵ and all stages of the review process were performed independently by 2 reviewers. We used the Cochrane risk of bias tool¹¹ to assess the included RCTs. This highlighted a number of methodological weaknesses in the included trials including failure to appropriately handle withdrawals, selective outcome reporting, and inadequate description of methods of randomization, allocation concealment, and blinding. An additional limitation of many included studies was their very small sample sizes. This was particularly the case for the trial of glaucoma (N = 6), Tourette syndrome (average N = 18), sleep disorder (average N = 27), and anxiety disorder (N = 24), which means these studies may have lacked the power to detect differences between treatment groups.

The synthesis combined a narrative discussion of individual study results with meta-analysis (for studies in which suitable data were available), supplemented by interpretation (following guidance of the GRADE Working Group).¹⁴ The data analysis was complicated by a number of issues. The included studies used a large variety of measures to evaluate outcomes, and even very similar outcomes were often assessed using different measures. Furthermore, a wide range of time points were reported in the included trials, which limited the applicability of the findings of these studies. Multiple different cannabinoids were evaluated in the included studies. We stratified analyses based on type of cannabinoid to investigate whether there were differences in associations based on type of cannabinoid. The majority of the studies were 2-group trials with a placebo control group; however, some studies included active comparisons and multiple groups comparing more than 1 form of cannabinoid, different doses of cannabinoids, or active and placebo comparator groups. This necessitated selecting a single result from each trial to contribute to the meta-analysis to avoid double counting of studies. Where possible, we selected the result for the treatment or dose most similar to the other studies contributing to that meta-analysis and for placebo-controlled comparisons rather than active comparisons. For the short-term AE analysis, we selected the highest-reported cannabinoids dose because we hypothesized that this would be most likely to be associated with AEs—additionally, this analysis would present a worst-case scenario. Studies evaluated various forms of cannabis administered via various routes (oral capsules, smoked, vaporized, oromucosal spray, intramuscular injection) and active comparators differed across trials. These differences in form, combined with the variety of outcome measures and the broad indication groupings considered by this review, resulted in a very heterogeneous set of included studies, which meant that meta-analysis was not always possible or appropriate. Many studies reported insufficient information to allow meta-analysis (eg, reporting only P values for group differences) or no information on the analysis performed. A further difficulty with the continuous data were that even for the same outcomes, some studies reported results as difference between groups at follow-up and others reported results for difference in change from baseline. As advised by the Cochrane Handbook for Systematic Reviews of Interventions, we combined both types of data when estimating summary mean differences.⁷ A potential problem with RCTs using crossover designs is the possible unblinding due to strong treatment or AEs. Additionally, studies of this design were rarely analyzed appropriately and none reported the required data accounting for their crossover design to permit appropriate inclusion in meta-analyses.¹⁶⁶ Primary analyses were therefore based on parallel-group studies, with crossover trials included as sensitivity analyses.

Our search identified a number of existing reviews that assessed the use of medical cannabinoids for MS,^167- 170 nausea and vomiting due to chemotherapy,^171- 175 pain,^176- 191 psychosis,^192- 194 and Tourette syndrome.^195,196 Almost all previous reviews focused on single indications and all but one (which evaluated cannabinoids in 4 trials in patients with pain due to rheumatoid arthritis)¹⁸⁸ did not use the GRADE approach to rating the quality of the evidence. As far as we are aware, our review is the first comprehensive review to evaluate the safety and efficacy of cannabinoids across a broad range of indications. A key strength of review was that it allowed us to conduct pooled analysis for the AEs associated with medicinal cannabinoids, adding considerable power to this analysis.

Further large, robust, RCTs are needed to confirm the effects of cannabinoids, particularly on weight gain in patients with HIV/AIDS, depression, sleep disorders, anxiety disorders, psychosis, glaucoma, and Tourette syndrome are required. Further studies evaluating cannabis itself are also required because there is very little evidence on the effects and AEs of cannabis. Future trials should adhere to the CONSORT (Consolidated Standards of Reporting Trials) reporting standards¹⁹⁷ and ensure that appropriate methods are used for randomization, allocation concealment, patient and outcome assessor blinding, handling of withdrawals, and avoiding selective outcome reporting. Future studies should assess patient-relevant outcomes (including disease-specific end points, quality of life, and AEs) using standardized outcome measures at similar time points to ensure inclusion in future meta-analyses.

There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

Corresponding Author: Penny Whiting, PhD, NIHR CLAHRC West, University Hospitals Bristol NHS Foundation Trust, Ninth Floor, Whitefriars, Lewins Mead, Bristol BS1 2NT, United Kingdom (penny.whiting@bristol.ac.uk).

Author Contributions: Dr Whiting had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Whiting, Wolff, Misso, Kleijnen.

Acquisition, analysis, or interpretation of data: Whiting, Wolff, Deshpande, Di Nisio, Duffy, Hernandez, Keurentjes, Lang, Misso, Ryder, Schmidlkofer, Westwood.

Drafting of the manuscript: Whiting, Keurentjes, Ryder.

Critical revision of the manuscript for important intellectual content: Whiting, Wolff, Deshpande, Di Nisio, Duffy, Hernandez, Keurentjes, Lang, Misso, Ryder, Schmidlkofer, Westwood, Kleijnen.

Statistical analysis: Whiting, Wolff, Di Nisio, Hernandez, Keurentjes, Schmidlkofer.

Obtained funding: Kleijnen.

Administrative, technical, or material support: Deshpande, Lang, Ryder.

Study supervision: Whiting, Kleijnen.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and declare support from the Swiss Federal Office of Public Health (FOPH) for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. Dr Whiting reports that part of her time on this review was supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care West at University Hospitals Bristol NHS (National Health Service) Foundation Trust. No additional disclosures were reported.

Funding/Support: This funded by the Swiss Federal Office of Public Health (FOPH) under grant agreement 14.001443/204.0001/-1257.

Role of the Funder/Sponsor: The FOPH had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The decision to submit the article for publication was a condition of the funding and was made before any results were available.

Additional Author Contributions: Dr Whiting drafted the article, produced tables and figures and performed the analysis. Drs Whiting, Wolff, and Kleijnen and Ms Misso and Mr Duffy drafted the protocol. Mr Duffy and Ms Misso conducted the literature searches. Drs Whiting, Wolff, and Lang screened searched results and selected full-text studies for inclusion. Drs Whiting, Wolff, Lang, Westwood, Keurentjes, Di Nisio, Hernandez, and Messrs Deshpande and Ryder, and Ms Schmidlkofer performed data extraction and risk-of-bias assessment. Dr Wolff performed the GRADE assessments. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Disclaimer: The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Additional Contributions: We would like to thank Julie Harker (MRes, Kleijnen Systematic Reviews at the time of this project) for help with inclusion screening and data extraction and Gillian Worthy (MSc, Kleijnen Systematic Reviews) for advice on data analysis. Neither of these individuals received additional compensation in association with their work on this article.

Correction: This article was corrected online June 26, 2015, for incorrect axis labeling in Figure 4; on July 13, 2015, for a corrected average reduction to the Ashworth spasticity scale (as reported in the Abstract); on November 5, 2015, for an incorrect nonproprietary name and approved use for a drug in Table 1; and on April 12, 2016, for an incorrect effect estimate.