Systematic Reviews

Five good- to fair-quality systematic reviews were identified. Of those five reviews, Whiting et al. (2015) was the most comprehensive, both in terms of the target medical conditions and in terms of the cannabinoids tested. Snedecor et al. (2013) was narrowly focused on pain related to spinal cord injury, did not include any studies that used cannabis, and only identified one study investigating cannabinoids (dronabinol). Two reviews on pain related to rheumatoid arthritis did not contribute unique studies or findings (Fitzcharles et al., 2016; Richards et al., 2012). Finally, one review (Andreae et al., 2015) conducted a Bayesian analysis of five primary studies of peripheral neuropathy that had tested the efficacy of cannabis in flower form administered via inhalation. Two of the primary studies in that review were also included in the Whiting review, while the other three were not. It is worth noting that the conclusions across all of the reviews were largely consistent in suggesting that cannabinoids demonstrate a modest effect on pain. For the purposes of this discussion, the primary source of information for the effect on cannabinoids on chronic pain was the review by Whiting et al. (2015). Whiting et al. (2015) included RCTs that compared cannabinoids to usual care, a placebo, or no treatment for 10 conditions. Where RCTs were unavailable for a condition or outcome, nonrandomized studies, including uncontrolled studies, were considered. This information was supplemented by a search of the primary literature from April 2015 to August 2016 as well as by additional context from Andreae et al. (2015) that was specific to the effects of inhaled cannabinoids.

The rigorous screening approach used by Whiting et al. (2015) led to the identification of 28 randomized trials in patients with chronic pain (2,454 participants). Twenty-two of these trials evaluated plant-derived cannabinoids (nabiximols, 13 trials; plant flower that was smoked or vaporized, 5 trials; THC oramucosal spray, 3 trials; and oral THC, 1 trial), while 5 trials evaluated synthetic THC (i.e., nabilone). All but 1 of the selected primary trials used a placebo control, while the remaining trial used an active comparator (amitriptyline). The medical condition underlying the chronic pain was most often related to a neuropathy (17 trials); other conditions included cancer pain, multiple sclerosis, rheumatoid arthritis, musculoskeletal issues, and chemotherapy-induced pain. Analyses across 7 trials that evaluated nabiximols and 1 that evaluated the effects of inhaled cannabis suggested that plant-derived cannabinoids increase the odds for improvement of pain by approximately 40 percent versus the control condition (odds ratio [OR], 1.41, 95% confidence interval [CI] = 0.99–2.00; 8 trials). The effects did not differ significantly across pain conditions, although it was not clear that there was adequate statistical power to test for such differences.

Only 1 trial (n = 50) that examined inhaled cannabis was included in the effect size estimates from Whiting et al. (2015). This study (Abrams et al., 2007) also indicated that cannabis reduced pain versus a placebo (OR, 3.43, 95% CI = 1.03–11.48). It is worth noting that the effect size for inhaled cannabis is consistent with a separate recent review of 5 trials of the effect of inhaled cannabis on neuropathic pain (Andreae et al., 2015). The pooled ORs from these trials contributed to the Bayesian pooled effect estimate of 3.22 for pain relief versus placebo (95% CI = 1.59–7.24) tested across 9 THC concentrations. There was also some evidence of a dose-dependent effect in these studies.

Primary Literature

In the addition to the reviews by Whiting et al. (2015) and Andreae et al. (2015), the committee identified two additional studies on the effect of cannabis flower on acute pain (Wallace et al., 2015; Wilsey et al., 2016). One of those studies found a dose-dependent effect of vaporized cannabis flower on spontaneous pain, with the high dose (7 percent THC) showing the strongest effect size (Wallace et al., 2015). The other study found that vaporized cannabis flower reduced pain but did not find a significant dose-dependent effect (Wilsey et al., 2016). These two studies are consistent with the previous reviews by Whiting et al. (2015) and Andreae et al. (2015), suggesting a reduction in pain after cannabis administration.

Discussion of Findings

The majority of studies on pain cited in Whiting et al. (2015) evaluated nabiximols outside the United States. In their review, the committee found that only a handful of studies have evaluated the use of cannabis in the United States, and all of them evaluated cannabis in flower form provided by the National Institute on Drug Abuse that was either vaporized or smoked. In contrast, many of the cannabis products that are sold in state-regulated markets bear little resemblance to the products that are available for research at the federal level in the United States. For example, in 2015 between 498,170 and 721,599 units of medical and recreational cannabis edibles were sold per month in Colorado (Colorado DOR, 2016, p. 12). Pain patients also use topical forms (e.g., transdermal patches and creams). Thus, while the use of cannabis for the treatment of pain is supported by well-controlled clinical trials as reviewed above, very little is known about the efficacy, dose, routes of administration, or side effects of commonly used and commercially available cannabis products in the United States. Given the ubiquitous availability of cannabis products in much of the nation, more research is needed on the various forms, routes of administration, and combination of cannabinoids.

CONCLUSION 4-1 There is substantial evidence that cannabis is an effective treatment for chronic pain in adults.

Systematic Reviews

Using the committee's search strategy only one recent review was found to be of good to fair quality (Rocha et al., 2014).³ The review focused exclusively on the anti-tumor effects of cannabinoids on gliomas.⁴ Of the 2,260 studies identified through December 2012, 35 studies met the inclusion criteria. With the exception of a small clinical trial, these studies were all preclinical studies. All 16 of the in vivo studies found an antitumor effect of cannabinoids.

Primary Literature

The committee did not identify any good-quality primary literature that reported on cannabis or cannabinoids for the treatment of cancer that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

Clearly, there is insufficient evidence to make any statement about the efficacy of cannabinoids as a treatment for glioma. However, the signal from the preclinical literature suggests that clinical research with cannabinoids needs to be conducted.

CONCLUSION 4-2 There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for cancers, including glioma.

Systematic Reviews

Whiting et al. (2015) summarized 28 trials reporting on nausea and vomiting due to chemotherapy, most published before 1984, involving 1,772 participants. The cannabinoid therapies investigated in these trials included nabilone (14), tetrahydrocannabinol (6), levonantradol (4), dronabinol (3), and nabiximols (1). Eight studies were placebo controlled, and 20 included active comparators (prochlorperazine 15; chlorpromazine 2; dromperidone 2; and alizapride, hydroxyzine, metoclopramide, and ondansetron 1 each). Two studies evaluated combinations of dronabinol with prochlorperazine or ondansetron. The average number of patients showing a complete nausea and vomiting response was greater with cannabinoids than the placebo (OR, 3.82, 95% CI = 1.55–9.42) in 3 trials of dronabinol and nabiximols that were considered low-quality evidence. Whiting et al. (2015) concluded that all trials suggested a greater benefit for cannabinoids than for both active agents and for the placebo, although these did not reach statistical significance in all trials.

Of the 23 trials summarized in a Cochrane review (Smith et al., 2015), 19 were crossover design and 4 were parallel-group design. The cannabinoids investigated were nabilone (12) or dronabinol (11), with 9 placebo-controlled trials (819 participants) and 15 with active comparators (prochlorperazine, 11; metoclopramide, 2; chlorpromazine, 1; domperidone, 1). In 2 trials, a cannabinoid added to a standard antiemetic was compared to the standard alone. While 2 of the placebo-controlled trials showed no significant difference in those reporting absence of nausea with cannabinoids (relative risk [RR], 2.0, 95% CI = 0.19–21), 3 showed a greater chance of having complete absence of vomiting with cannabinoids (RR, 5.7, 95% CI = 2.16–13) and 3 showed a numerically higher chance of complete absence of both nausea and vomiting (RR, 2.9, 95% CI = 1.8–4.7). There was no difference in outcome between patients who were cannabisnaïve and those who were not (P value = 0.4). Two trials found a patient preference for cannabinoids over the comparator. When compared to prochlorperazine, there was no significant difference in the control of nausea, vomiting, or both, although in 7 of the trials there was a higher chance of patients reporting a preference for the cannabinoid therapy (RR, 3.2, 95% CI = 2.2–4.7). In their review the investigators state that cannabinoids were highly effective, being more efficacious than the placebo and similar to conventional antiemetics in treating chemotherapy-induced nausea and vomiting. Despite causing more adverse events such as dizziness, dysphoria, euphoria, “feeling high,” and sedation, there was weak evidence for a preference for cannabinoids over the placebo and stronger evidence for a preference over other antiemetics. Despite these findings, however, the authors concluded that there was no evidence to support the use of cannabinoids over current first-line antiemetic therapies and that cannabinoids should be considered as useful adjunctive treatment “for people on moderately or highly emetogenic chemotherapy that are refractory to other antiemetic treatments, when all other options have been tried” (Smith et al., 2015, p. 23).

Only 3 of the 28 trials in a systematic review of antiemetic therapies in children receiving chemotherapy involved cannabinoid therapies (nabilone 2; THC 1) (Phillips et al., 2016). The comparators were prochlorperazine in the first nabilone trial, domperidone in the second, and prochlorperazine and metoclopramide in two separate randomizations in the THC trial. In 1 trial with unclear risk of bias, THC dosed at 10 mg/m² five times on the day of chemotherapy was superior to prochlorperazine in the complete control of acute nausea (RR, 20.7, 95% CI = 17.2–36.2) and vomiting (RR, 19.0, 95% CI = 13.7–26.3). Another trial reported better nausea severity scores for nabilone compared to domperidone (1.5 versus 2.5 on a 0 to 3 [none to worst] scale) (p = 0.01). The largest and most recent trial in this review compared THC to proclorperzine and found no benefit over the control on emesis (RR, 1.0, 95% CI = 0.85–1.17).

Primary Literature

An additional search of the primary literature since the review by Whiting et al. (2015) did not identify any additional studies. The primary literature was then searched in an effort to find studies of cannabinoids compared to the more widely used antiemetics. One trial conducted in 2007 investigated a cannabinoid therapy compared to the current generation of serotonin antagonist antiemetics, as opposed to the dopamine D2 receptor antagonists used in the earlier trials. This 64-patient study evaluated the frequently used antiemetic ondansetron versus dronabinol versus the combination of the two in delayed chemotherapy-induced nausea and vomiting (Meiri et al., 2007). The two agents appeared similar in their effectiveness, with no added benefit from the combination. Hence, the cannabinoid again fared as well as the current standard antiemetic in this more recent investigation.

Discussion of Findings

The oral THC preparations nabilone and dronabinol have been available for the treatment of chemotherapy-induced nausea and vomiting for more than 30 years (Grotenhermen and Müller-Vahl, 2012). They were both found to be superior to the placebo and equivalent to the available antiemetics at the time that the original trials were conducted. A more recent investigation suggests that dronabinol is equivalent to ondansetron for delayed nausea and vomiting, although no comparison to the currently more widely used neurokinin-1 inhibitors has been conducted. In the earlier trials, patients reported a preference for the cannabinoids over available agents. Despite an abundance of anecdotal reports of the benefits of plant cannabis, either inhaled or ingested orally, as an effective treatment for chemotherapy-induced nausea and vomiting, there are no good-quality randomized trials investigating this option. This is, in part, due to the existing obstacles to investigating the potential therapeutic benefit of the cannabis plant. Nor have any of the reviewed trials investigated the effectiveness of cannabidiol or cannabidiol-enriched cannabis in chemotherapy-induced nausea and vomiting. Such information is frequently requested by patients seeking to control chemotherapy-induced nausea and vomiting without the psychoactive effects of the THC-based preparations. Resolving this identified research gap may be a future research priority.

CONCLUSION 4-3 There is conclusive evidence that oral cannabinoids are effective antiemetics in the treatment of chemotherapy-induced nausea and vomiting.

AIDS Wasting Syndrome

Systematic Reviews Two good-quality systematic reviews included trials investigating cannabinoid therapies in patients with HIV/AIDS. Four randomized controlled trials involving 255 patients were assessed by Whiting et al. (2015), who described all of the trials to be at high risk of bias (ROB) for reasons not elaborated.⁵ All four studies included dronabinol, with one investigating inhaled cannabis as well. Three trials were placebo-controlled, and one used the progestational agent megestrol acetate as the comparator. The review authors concluded that there was some evidence suggesting that cannabinoids were effective in weight gain in HIV. A second systematic review focused on morbidity and mortality in HIV/AIDS as the primary outcomes, with changes in appetite and weight as secondary endpoints (Lutge et al., 2013). Seven RCTs conducted between 1993 and 2009 were included in the qualitative analysis. The trials compared dronabinol or inhaled cannabis with a placebo or with each other. In one study the individuals' weights increased significantly more (p <0.01) on higher doses of cannabis (3.9 percent THC) and dronabinol (10 mg) than on lower doses. In a second trial, median weight was increased with inhaled cannabis (3.5 percent) by 3.0 kg (p = 0.021) and dronabinol (2.5 mg) by 3.2 kg (p = 0.004) when compared with a placebo (a 1.1-kg increase over a 21-day exposure). In a study with 88 evaluable patients, the dronabinol group gained an average of 0.1 kg, while the placebo recipients lost a mean of 0.4 kg (p = 0.14). The proportion of patients gaining at least 2 kg was the same in both groups. Most of the weight gain was in the body fat compartment when this was investigated. Changes in appetite, food, and caloric intake were not deemed to be evaluable in any of the studies. These investigators concluded that the evidence for the efficacy and safety of cannabis and cannabinoids is lacking to support utility in treating AIDS-associated anorexia.

Primary Literature The committee did not identify any good-quality primary literature that reported on cannabis or cannabinoids as effective treatments for AIDS wasting syndrome that were published subsequently to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question. This is largely due to the virtual disappearance of the syndrome since effective antiretroviral therapies became available in the mid-1990s.

Cancer-Associated Anorexia-Cachexia Syndrome

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on cannabis or cannabinoids as effective treatments for cancer-associated anorexia-cachexia syndrome.

Primary Literature A Phase III multicenter, randomized, double-blind placebo-controlled trial was conducted by the Cannabis-In-Cachexia-Study-Group in patients with cancer-related anorexia-cachexia syndrome (Strasser et al., 2006). Patients with advanced cancer and weight loss of greater than 5 percent over 6 months were randomized 2:2:1 to receive treatment with a cannabis extract (standardized to THC 2.5 mg and cannabidiol 1.0 mg), THC 2.5 mg, or a placebo twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily. Cancer-related quality of life and cannabinoid-related toxicity were also monitored. Only 164 of the 243 patients who were randomized completed the trial. An intent-to-treat analysis yielded no difference between the groups in appetite, quality of life, or toxicity. Increased appetite was reported by 73 percent of the cannabis-extract, 58 percent of the THC group, and 69 percent of the placebo recipients. Recruitment was terminated early by the data review board because it was believed to be unlikely that differences would emerge between the treatment arms. The findings in this study reinforce the results from an earlier trial investigating dronabinol, megestrol acetate, or the combination in 469 advanced cancer patients with a loss of appetite and greater than 5 pounds weight loss over the prior 2 months (Jatoi et al., 2002). Megestrol acetate was superior to dronabinol for the improvement of both appetite and weight, with the combination therapy conferring no additional benefit. Seventy-five percent of the megestrol recipients reported an improvement in appetite compared to 49 percent of those receiving dronabinol (p = 0.0001). Of those in the combination arm, 66 percent reported improvement. A weight gain greater than or equal to 10 percent over their baseline at some point during the course of the trial was reported by 11 percent of those in the megestrol arm, compared with 3 percent of the dronabinol recipients (p = 0.02). The combination arm reported a weight gain in 8 percent. These findings confirm a similarly designed trial that was conducted in patients with AIDS wasting syndrome (Timpone et al., 1997).

Anorexia Nervosa

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for anorexia nervosa.

Primary Literature Pharmacological interventions in the treatment of anorexia nervosa have not been promising to date. Andries et al. (2014) conducted a prospective, randomized, double-blind, controlled crossover trial in 24 women with anorexia nervosa of at least 5 years' duration attending both psychiatric and somatic therapy as inpatients or outpatients. In addition to their standard psychotherapy and nutritional interventions, the participants received dronabinol 2.5 mg twice daily for 4 weeks and a matching placebo for 4 weeks, randomly assigned to two treatment sequences (dronabinol/placebo or placebo/dronabinol). The primary outcome was weight change assessed weekly. The secondary outcome was change in Eating Disorder Inventory-2 (EDI-2) scores. The participants had a significant weight gain of 1.00 kg (95% CI = 0.40–1.62) during dronabinol therapy and 0.34 kg (95% CI = −0.14–0.82) during the placebo (p = 0.03). No statistically different differences in EDI-2 score changes were seen during treatment with dronabinol or the placebo, suggesting that there was no real effect on the participants' attitudinal and behavioral traits related to eating disorders. The authors acknowledged the small sample size and the short duration of exposure, as well as the potential psychogenic effects, but they concluded that low-dose dronabinol is a safe adjuvant palliative therapy in a highly selected subgroup of chronically undernourished women with anorexia nervosa.

Discussion of Findings

There is some evidence for oral cannabinoids being able to increase weight in patients with the HIV-associated wasting syndrome and anorexia nervosa. No benefit has been demonstrated in cancer-associated anorexia-cachexia syndrome. The studies have generally been small and of short duration and may not have investigated the optimal dose of the cannabinoid. In one study in HIV patients, both dronabinol and inhaled cannabis increased weight significantly compared to the placebo dronabinol. Cannabis has long been felt to have an orexigenic effect, increasing food intake (Abel, 1975). Small residential studies conducted in the 1980s found that inhaled cannabis increased caloric intake by 40 percent, with most of the increase occurring as snacks and not during meals (Foltin et al., 1988). Hence, the results of the clinical trials in AIDS wasting and cancer-associated anorexia-cachexia syndrome demonstrating little to no impact on appetite and weight were somewhat unexpected. One could postulate that perhaps other components of the plant in addition to THC may contribute to the effect of cannabis on appetite and food intake. There have not been any randomized controlled trials conducted studying the effect of plant-derived cannabis on appetite and weight with weight as the primary endpoint. This is, in part, due to existing obstacles to investigating the potential therapeutic benefit of the cannabis plant.

CONCLUSION 4-4

• 4-4(a) There is limited evidence that cannabis and oral cannabinoids are effective in increasing appetite and decreasing weight loss associated with HIV/AIDS.
• 4-4(b) There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for cancer-associated anorexia-cachexia syndrome and anorexia nervosa.

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for symptoms of irritable bowel syndrome.

Primary Literature

We identified a single relevant trial (Wong et al., 2012) evaluating dronabinol in patients with irritable bowel syndrome with diarrhea (IBS-D). This low-risk-of-bias trial enrolled 36 patients between the ages of 18 and 69 with IBS-D. Patients were randomized to dronabinol 2.5 mg BID⁶ (n = 10), dronabinol 5 mg BID (n = 13), or a placebo (n = 13) for 2 days. No overall treatment effects of dronabinol on gastric, small bowel, or colonic transit, as measured by radioscintigraphy, were detected.

Discussion of Findings

A single, small trial found no effect of two doses of dronabinol on gastrointestinal transit. The quality of evidence for the finding of no effect for irritable bowel syndrome is insufficient based on the short treatment duration, small sample size, short-term follow-up, and lack of patient-reported outcomes. Trials that evaluate the effects of cannabinoids on patient-reported outcomes are needed to further understand the clinical effects in patients with IBS.

CONCLUSION 4-5 There is insufficient evidence to support or refute the conclusion that dronabinol is an effective treatment for the symptoms of irritable bowel syndrome.

Systematic Reviews

We identified two systematic reviews of randomized trials assessing the efficacy of cannabis or cannabinoids, used either as monotherapy or in addition to other therapies, in reducing seizure frequency in persons with epilepsy. Gloss and Vickrey (2014) published a systematic review of randomized controlled trials. They identified four reports (including one conference abstract and one letter to the editor) of cannabinoid trials, all of which they considered to be of low quality. Combined, the trials included a total of 48 patients. The systematic review's primary prespecified outcome was freedom from seizures for either 12 months or three times the longest previous seizure-free interval. None of the four trials assessed this endpoint. Accordingly, Gloss and Vickrey asserted that no reliable conclusions could be drawn regarding the efficacy of cannabinoids for epilepsy.

Koppel et al. (2014) published a fair-quality systematic review. They identified no high-quality randomized trials and concluded that the existing data were insufficient to support or refute the efficacy of cannabinoids for reducing seizure frequency.

Primary Literature

We identified two case series that reported on the experience of patients treated with cannabidiol for epilepsy that were published subsequent to the systematic reviews described above. The first of these was an open-label, expanded-access program of oral cannabidiol with no concurrent control group in patients with severe, intractable childhood-onset epilepsy that was conducted at 11 U.S. epilepsy centers and reported by Devinsky et al. (2016) and by Rosenberg et al. (2015). Devinsky et al. (2016) reported on 162 patients ages 1 to 30 years; Rosenberg et al. (2015) reported on 137 of these patients. The median monthly frequency of motor seizures was 30.0 (interquartile range [IQR] 11.0–96.0) at baseline and 15.8 (IQR 5.6–57.6) over the 12-week treatment period. The median reduction in motor seizures while receiving cannabidiol in this uncontrolled case series was 36.5 percent (IQR 0–64.7).

Tzadok et al. (2016) reported on the unblinded experience of Israeli pediatric epilepsy clinics treating 74 children and adolescents with intractable epilepsy with an oral formulation of cannabidiol and tetrahydrocannabinol at a 20:1 ratio for an average of 6 months. There was no concurrent control goup. Compared with baseline, 18 percent of children experienced a 75–100 percent reduction in seizure frequency, 34 percent experienced a 50–75 percent reduction, 12 percent reported a 25–50 percent reduction, 26 percent reported a reduction of less than 25 percent, and 7 percent reported aggravation of seizures that led to a discontinuation of the cannabinoid treatment.

The lack of a concurrent placebo control group and the resulting potential for regression to the mean and other sources of bias greatly reduce the strength of conclusions that can be drawn from the experiences reported by Devinsky et al. (2016), Rosenberg et al. (2015), and Tzadok et al. (2016) about the efficacy of cannabinoids for epilepsy. Randomized trials of the efficacy of cannabidiol for different forms of epilepsy have been completed,⁷ but their results have not been published at the time of this report.

Discussion of Findings

Recent systematic reviews were unable to identify any randomized controlled trials evaluating the efficacy of cannabinoids for the treatment of epilepsy. Currently available clinical data therefore consist solely of uncontrolled case series, which do not provide high-quality evidence of efficacy. Randomized trials of the efficacy of cannabidiol for different forms of epilepsy have been completed and await publication.

CONCLUSION 4-6 There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for epilepsy.

Systematic Reviews

We identified two recent systematic reviews that assessed the efficacy of cannabis or cannabinoids in treating muscle spasticity in patients with MS or paraplegia due to spinal cord injury—the systematic review by Whiting et al. (2015) that examined evidence for a broad range of medical uses of cannabis or cannabinoids and the systematic review by Koppel et al. (2014) that focused more narrowly on neurologic conditions. Both systematic reviews examined only randomized, placebo-controlled trials. Whiting et al. (2015) excluded from their primary analysis trials that did not use a parallel group design (i.e., they excluded crossover trials) and performed a quantitative pooling of results. In contrast, Koppel et al. (2014) included crossover trials but did not perform a quantitative pooling of results.

Whiting et al. (2015) searched for studies examining the efficacy of cannabinoids for spasticity due to MS or paraplegia. They identified 11 studies that included patients with MS and 3 that included patients with paraplegia caused by spinal cord injury. None of the studies in patients with paraplegia caused by spinal cord injury were reported as full papers or included sufficient data to allow them to be included in pooled estimates. Whiting et al. (2015) reported that in their pooled analysis of three trials in patients with MS, nabiximols and nabilone were associated with an average change (i.e., improvement) in spasticity rating assessed by a patient-reported numeric rating scale of −0.76 (95% CI = −1.38 to −0.14) on a 0 to 10 scale that was statistically greater than for the placebo. They further reported finding no evidence for a difference according to type of cannabinoid (i.e., nabiximols versus nabilone). Whiting et al. (2015) also reported that the pooled odds of patient-reported improvement on a global impression-of-change score was greater with nabiximols than with the placebo (OR, 1.44, 95% CI = 1.07–1.94).

The review by Koppel et al. (2014) restricted its focus on spasticity to that due to MS. Their conclusions were broadly in agreement with corresponding conclusions from the review by Whiting et al. (2015). In particular, Koppel et al. (2014) concluded that in patients with MS, nabiximols and orally administered THC are “probably effective” for reducing patient-reported spasticity scores and that oral cannabis extract is “established as effective for reducing patient-reported scores” for spasticity (Koppel et al., 2014, p. 1558).

A commonly used scale for rating spasticity is the Ashworth scale (Ashworth, 1964). However, this scale has been criticized as unreliable, insensitive to therapeutic benefit, and reflective only of passive resistance to movement and not of other features of spasticity (Pandyan et al., 1999; Wade et al., 2010). Furthermore, no minimally important difference in the Ashworth scale has been established. Whiting et al. (2015) calculated a pooled measure of improvement on the Ashworth scale versus placebo based on five parallel-group-design trials. They reported that nabiximols, dronabinol, and oral THC/CBD were associated with a numerically greater average improvement on the Ashworth scale than with a placebo but that this difference was not statistically significant. This conclusion is in broad agreement with corresponding conclusions reached by Koppel et al. (2014), who concluded in particular that nabiximols, oral cannabis extract and orally administered THC are “probably ineffective” for reducing objective measures of spasticity in the short term (6–15 weeks), although oral cannabis extract and orally administered THC are “possibly effective” for objective measures at 1 year.

Primary Literature

An additional placebo-controlled crossover trial of nabiximols for the treatment of spasticity in patients with MS was published after the period covered by the Whiting and Koppel systematic reviews (Leocani et al., 2015). This study randomized 44 patients but analyzed only 34 because of post-randomization exclusions and dropouts. Such post-randomization exclusions and dropouts reduce the strength of the evidence that is provided by this study. Patient-reported measures of spasticity were not assessed. After 4 weeks of treatment, response on the modified Ashworth scale (defined as improvement of at least 20 percent) was more common in the THC/CBD group (50 percent) than in the placebo group (23.5 percent), p = 0.041.

Discussion of Findings

Based on evidence from randomized controlled trials included in systematic reviews, an oral cannabis extract, nabiximols, and orally administered THC are probably effective for reducing patient-reported spasticity scores in patients with MS. The effect appears to be modest, as reflected by an average reduction of 0.76 units on a 0 to 10 scale. These agents have not consistently demonstrated a benefit on clinician-measured spasticity indices such as the modified Ashworth scale in patients with MS. Given the lack of published papers reporting the results of trials conducted in patients with spasticity due to spinal cord injury, there is insufficient evidence to conclude that cannabinoids are effective for treating spasticity in this population.

CONCLUSION 4-7

• 4-7(a) There is substantial evidence that oral cannabinoids are an effective treatment for improving patient-reported multiple sclerosis spasticity symptoms, but limited evidence for an effect on clinician-measured spasticity.
• 4-7(b) There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for spasticity in patients with paralysis due to spinal cord injury.

Systematic Reviews

We identified two good-quality systematic reviews (Koppel et al., 2014; Whiting et al., 2015) that evaluated medical cannabis for Tourette syndrome. Both good-quality reviews identified the same trials, and we focus on the more recent review by Whiting et al. (2015). The two RCTs (four reports), conducted by the same research group (Müller-Vahl et al., 2001, 2002, 2003a,b), compared THC capsules (maximum dose 10 mg daily) to a placebo in 36 patients with Tourette syndrome. Tic severity, assessed by multiple measures, and global clinical outcomes were improved with THC capsules. On a 0 to 6 severity scale, symptoms were improved by less than 1 point. These outcomes were assessed at 2 days (unclear-risk-of-bias trial) and 6 weeks (high-risk-of-bias trial). Neither trial described randomization or allocation concealment adequately, and the 6-week trial was rated high risk of bias for incomplete outcome data.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for Tourette syndrome, and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

No clear link has been established between symptoms of Tourette syndrome and cannabinoid sites or mechanism of action. However, case reports have suggested that cannabis can reduce tics and that the therapeutic effects of cannabis might be due to the anxiety-reducing properties of marijuana rather than to a specific anti-tic effect (Hemming and Yellowlees, 1993; Sandyk and Awerbuch, 1988). Two small trials (assessed as being of fair to poor quality) provide limited evidence for the therapeutic effects of THC capsules on tic severity and global clinical outcomes.

CONCLUSION 4-8 There is limited evidence that THC capsules are an effective treatment for improving symptoms of Tourette syndrome.

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for symptoms associated with amyotrophic lateral sclerosis.

Primary Literature

On the basis of proposed pathogenesis and anecdotal reports of symptomatic benefit from the use of cannabis in patients with ALS, two small trials of dronabinol have been conducted. In a randomized, double-blind crossover study, 19 patients with ALS were treated with dronabinol doses of 2.5 to 10 mg daily for 4 weeks (Gelinas et al., 2002). Participants noted improvement in appetite and sleep but not in cramps or fasiculations (involuntary muscle twitches). The second study enrolled 27 patients with ALS who had moderate to severe cramps (greater than 4 on a 0–10 visual analogue scale) in a randomized, double-blind trial of dronabinol 5 mg twice daily or a placebo, each given for 2 weeks with an intervening 2-week washout period (Weber et al., 2010). The primary endpoint was a change in cramp intensity with secondary endpoints of change in cramp number, intensity of fasciculations, quality of life, sleep, appetite, and depression. There was no difference between dronabinol and the placebo seen in any of the endpoints. The investigators reported that the dronabinol was very well tolerated and postulated that the dronabinol dose may have been too low as well as suggesting that a carryover effect in the crossover design may have obfuscated any differences in the treatment arms. The sample size was too small to discern anything but a large effect.

Discussion of Findings

Two small studies investigated the effect of dronabinol on symptoms associated with ALS. Although there were no differences from placebo in either trial, the sample sizes were small, the duration of the studies was short, and the dose of dronabinol may have been too small to ascertain any activity. The effect of cannabis was not investigated.

CONCLUSION 4-9 There is insufficient evidence that cannabinoids are an effective treatment for symptoms associated with amyotrophic lateral sclerosis.

Systematic Reviews

The systematic review from the American Academy of Neurology includes two studies on Huntington's disease (Koppel et al., 2014). A randomized, double-blind, placebo-controlled crossover pilot trial investigated nabilone 1 or 2 mg daily for 5 weeks followed by a placebo in 22 patients with symptomatic Huntington's disease (Curtis et al., 2009). An additional 22 patients were randomized to the placebo followed by nabilone. The primary endpoint was the total motor score of the Unified Huntington's Disease Rating Scale (UHDRS). Secondary endpoints included the chorea, cognitive performance, and psychiatric changes measured with the same instrument. No significant difference in the total motor score was seen in the 37 evaluable patients (treatment difference, 0.86, 95% CI = −1.8–3.52), with a 1-point change considered clinically significant. There was evidence of an improvement in the chorea subscore with nabilone (treatment difference, 1.68, 95% CI = 0.44–2.92). There was no difference between treatments for cognition, but there was evidence of an improvement in the two neuropsychiatric outcome measures in the nabilone arm—UHDRS behavioral assessment (4.01, 95% CI = −0.11–8.13) and neuropsychiatric inventory (6.43, 95% CI = 0.2–12.66). The small estimated treatment effect with wide confidence intervals reduces the level of evidence for nabilone's effectiveness from this pilot study. However, based on this trial, the American Academy of Neurology guideline concluded that “nabilone possibly modestly improves Huntington's disease chorea” (Armstrong and Miyasaki, 2012, p. 601). The second study included in the systematic review was a lower-quality, 15-patient randomized, double-blind, placebo-controlled trial investigating the effect of cannabidiol capsules at a dose of 10 mg/kg/day in two divided doses (Consroe et al., 1991). The endpoints in this study involving patients with Huntington's disease who were not on neuroleptics were chorea severity, functional limitations, and side effects. There were no statistically significant differences between cannabidiol and placebo in any outcomes, although the American Academy of Neurology considered the study to be underpowered.

Discussion of Findings

Two small studies have investigated the potential benefit of cannabinoids in patients with Huntington's disease. Although nabilone appeared to have some potential benefit on chorea, cannabidiol appeared to be equal to placebo in ameliorating symptoms. Both studies were of short duration and likely underpowered because of their small sample sizes. Cannabis has not been investigated in Huntington's disease.

CONCLUSION 4-10 There is insufficient evidence to support or refute the conclusion that oral cannabinoids are an effective treatment for chorea and certain neuropsychiatric symptoms associated with Huntington's disease.

Systematic Reviews

The systematic review of cannabis in selected neurologic disorders (Koppel et al., 2014) identified two trials of cannabinoid therapies in patients with levodopa-induced dyskinesias. Nineteen patients with levodopa-induced dyskinesia greater than or equal to 2 as determined by questions 32–34 of the Unified Parkinson's Disease Rating Scale (UPDRS) were randomized in a double-blind, placebo-controlled crossover trial to receive Cannador capsules (containing THC 2.5 mg and CBD 1.25 mg) to a maximum dose of 0.25 mg/kg of THC daily or placebo (Carroll et al., 2004). The primary endpoint was the effect of treatment on the dyskinesia score of the UPDRS. Secondary endpoints included the impact of dyskinesia on function, pathophysiologic indicators of dyskinesia, duration of dyskinesia, quality of life, sleep, pain, and overall severity of Parkinson's disease. The overall treatment effect was +0.52, which indicated a worsening with Cannador, although this worsening was not statistically significant (p = 0.09). No effects were seen on the secondary outcomes. Although there were more adverse events on the drug than on the placebo, the investigators felt that the treatment was well tolerated. The study had limited statistical power to detect anything but a large treatment effect due to its small sample size. The second study included in the systematic review was an even smaller low-quality, randomized, double-blind, placebo-controlled crossover trial involving seven patients with Parkinson's disease who had stable levodopa-induced dyskinesia present for 25–50 percent of the day (Sieradzan et al., 2001). Nabilone dosed at 0.03 mg/kg or a placebo was administered 12 hours and 1 hour before levodopa at a dose of 200 mg. The primary endpoint was total dyskinesia disability as measured using the Rush Dyskinesia Disability Scale.⁸ The median total dyskinesia score after treatment with levodopa and nabilone was 17 (range 11–25) compared to 22 (range 16–26) after levodopa and the placebo (p <0.05). The anti-Parkinsonian actions of levodopa were not reduced by nabilone pretreatment. Although the authors stated that “nabilone significantly reduced total levodopa-induced dyskinesia compared with placebo” (Sieradzan et al., 2001, p. 2109), the fact that the results were generated by only seven patients receiving only two doses clearly reduces the ability to draw such an enthusiastic conclusion. Koppel concludes that oral cannabis extract “is probably ineffective for treating levodopa-induced dyskinesias” (Koppel et al., 2014, p. 1560).

Primary Literature

Cannabidiol capsules were evaluated in a randomized, double-blind, placebo-controlled trial conducted in 21 patients with Parkinson's disease (Chagas et al., 2014). The study was an exploratory trial to assess the effect of CBD in Parkinson's disease globally with the UPDRS and the Parkinson's Disease Questionnaire-39 (PDQ-39) used to assess overall functioning and well-being. Possible CBD adverse events were evaluated by a side effect rating scale. Baseline data were collected 1 week before commencing treatment with CBD at 75 mg/day or 300 mg/day or with a placebo, and the same assessments were repeated during the sixth and final week of the trial. No statistically significant differences were seen in the UPDRS between the three study arms. There was a statistically significant difference in the variation between baseline and final assessment in the overall PDQ-39 score between the placebo (6.50 ± 8.48) and CBD 300 mg/day (25.57 ± 16.30) (p = 0.034), which suggests that there might be a possible effect of CBD on improving quality of life.

An open-label observational study of 22 patients with Parkinson's disease attending a motor disorder clinic at a tertiary medical center collected data before and 30 minutes after patients smoked 0.5 grams of cannabis (Lotan et al., 2014). The instruments utilized included the UPDRS, the McGill Pain Scale, and a survey of subjective efficacy and adverse effects of cannabis. In addition, the effect of cannabis on motor symptoms was evaluated by two raters. The investigators found that the total motor symptoms score on the UPDRS improved from 33.1 (± 13.8) to 23.2 (± 10.5) (p <0.001). Subcategories of the UPDRS that showed statistically significant improvement included tremor, rigidity, and bradykinesia. Pain and sleep were also reported to be improved after smoking cannabis. The results from this low-quality observational study prompted the investigators to propose that their findings should be confirmed in a larger, longer, randomized, double-blind, placebo-controlled trial.

Discussion of Findings

Small trials of oral cannabinoid preparations have demonstrated no benefit compared to a placebo in ameliorating the side effects of Parkinson's disease. A seven-patient trial of nabilone suggested that it improved the dyskinesia associated with levodopa therapy, but the sample size limits the interpretation of the data. An observational study of inhaled cannabis demonstrated improved outcomes, but the lack of a control group and the small sample size are limitations.

CONCLUSION 4-11 There is insufficient evidence that cannabinoids are an effective treatment for the motor system symptoms associated with Parkinson's disease or the levodopa-induced dyskinesia.

Systematic Reviews

The American Academy of Neurology systematic review (Koppel et al., 2014) identified one study that examined the effect of dronabinol on cervical dystonia. The review described the study as being underpowered to detect any differences between dronabinol and the placebo. Overall, nine patients with cervical dystonia were randomized to receive dronabinol 15 mg daily or a placebo in an 8-week crossover trial (Zadikoff et al., 2011). The primary outcome measure was the change in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) part A subscore at the beginning and the end of each 3-week treatment phase. There was no statistically significant effect of dronabinol on the dystonia compared with the placebo as measured by the TWSTRS-A (p = 0.24).

Primary Literature

Fifteen patients with a clinical diagnosis of primary dystonia received a single dose of nabilone or placebo (0.03 mg/kg to the nearest whole milligram) on the study day (Fox et al., 2002). The primary outcome measure was the dystonia-movement scale portion of the Burke-Fahn-Marsden dystonia scale. Treatment with nabilone produced no significant reduction in the total dystonia movement scale score when compared with placebo (p >0.05).

Discussion of Findings

Two small trials of dronabinol and nabilone failed to demonstrate a significant benefit of the cannabinoids in improving dystonia compared with placebo. Cannabis has not been studied in the treatment of dystonia.

CONCLUSION 4-12 There is insufficient evidence to support or refute the conclusion that nabilone and dronabinol are an effective treatment for dystonia.

Systematic Reviews

We identified two good-quality systematic reviews (Krishnan et al., 2009; van den Elsen et al., 2014) that evaluated cannabis for dementia. Both reviews identified the same two RCTs, which were synthesized qualitatively. A small randomized crossover trial (Volicer et al., 1997) evaluated dronabinol in 15 hospitalized patients with probable Alzheimer's disease who had behavior changes and were refusing food. Patients were randomized to dronabinol (2.5 mg twice daily) for 6 weeks and to a placebo for 6 weeks. Data in this trial with a high risk of bias were presented in such a way that they could not be abstracted for analysis by systematic review authors. The primary study authors reported: increased weight during the 12 weeks regardless of order of treatment (dronabinol, 7.0 [SD 1.5] pounds, and placebo, 4.6 [SD 1.3] pounds, during the first 6 weeks); decreased disturbed behavior during dronabinol treatment, an effect that persisted in patients treated first with dronabinol, then the placebo; decreased negative affect scores in both groups during the 12 weeks, more so when taking dronabinol than the placebo; and no serious adverse events attributed to dronabinol, although one patient suffered a seizure following the first dose. One other open-label pilot study (Walther et al., 2006), which evaluated six patients with severe dementia for the effects of dronabinol on nighttime agitation, did not meet eligibility criteria for the review by Krishnan et al. (2009).

Primary Literature

We identified one good-quality RCT that evaluated THC in 50 patients with Alzheimer's disease, vascular or mixed dementia, and neuropsychiatric symptoms (van den Elsen et al., 2015). THC 1.5 mg given three times daily for 3 weeks did not improve overall neuropsychiatric symptoms, agitation, quality of life, or activities of daily living versus a placebo. Although the study recruited less than one-half of the planned sample, the authors estimated that there was only a 5 percent chance that enrolling more participants would have shown a clinically important effect on neuropsychiatric symptoms.

Discussion of Findings

The authors of the good-quality Cochrane systematic review concluded that the “review finds no evidence that cannabinoids are effective in the improvement of disturbed behavior in dementia or treatment of other symptoms of dementia” (Krishnan et al., 2009, p. 8). Subsequently, a larger good-quality RCT found no benefit from low-dose THC. We agree that the evidence is limited due to the small number of patients enrolled, limits in the study design and reporting, and inconsistent effects. The current limited evidence does not support a therapeutic effect of cannabinoids.

CONCLUSION 4-13 There is limited evidence that cannabinoids are ineffective treatments for improving the symptoms associated with dementia.

Systematic Reviews

We identified one good-quality systematic review (Whiting et al., 2015) that evaluated medical cannabis for the treatment of glaucoma. This review identified a single randomized crossover trial (six participants) in patients with glaucoma. The trial compared THC (5 mg oromucosal spray), cannabidiol (20 mg oromucosal spray), cannabidiol spray (40 mg oromucosal spray), and a placebo, examining intraocular pressure intermittently up until 12 hours after treatment. Elevated intraocular pressure is one of the diagnostic criteria for glaucoma, and lowering intraocular pressure is a goal of glaucoma treatments (Prum et al., 2016). The trial was evaluated as “unclear” risk of bias. No differences in intraocular pressure were found between placebo and cannabinoids.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the symptoms of glaucoma and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

Lower intraocular pressure is a key target for glaucoma treatments. Non-randomized studies in healthy volunteers and glaucoma patients have shown short-term reductions in intraocular pressure with oral, topical eye drops, and intravenous cannabinoids, suggesting the potential for therapeutic benefit (IOM, 1999, pp. 174–175). A good-quality systemic review identified a single small trial that found no effect of two cannabinoids, given as an oromucosal spray, on intraocular pressure (Whiting et al., 2015). The quality of evidence for the finding of no effect is limited. However, to be effective, treatments targeting lower intraocular pressure must provide continual rather than transient reductions in intraocular pressure. To date, those studies showing positive effects have shown only short-term benefit on intraocular pressure (hours), suggesting a limited potential for cannabinoids in the treatment of glaucoma.

CONCLUSION 4-14 There is limited evidence that cannabinoids are an ineffective treatment for improving intraocular pressure associated with glaucoma.

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that evaluated the efficacy of cannabinoids as a treatment or prevention for traumatic brain injury or intracranial hemorrhage.

Primary Literature

There were two fair- to high-quality observational studies found in the literature. One study (n = 446) examined the TBI presentation and outcomes among patients with and without a positive THC blood test (Nguyen et al., 2014). Patients who were positive for THC were more likely to survive the TBI than those who were negative for THC (OR, 0.224, 95% CI = 0.051–0.991). The authors used regression analysis to account for confounding variables (e.g., age, alcohol, Abbreviated Injury Score, Injury Severity Score, mechanism of injury, gender, and ethnicity). In the only other observational study that examined the association between cannabis use and brain outcomes, a study of intracranial hemorrhage patients (n = 725) found that individuals with a positive test of cannabis use demonstrated better primary outcome scores on the modified Rankin Scale⁹ (adjusted common OR, 0.544, 95% CI = 0.330–0.895) (Di Napoli et al., 2016). In their analysis, the authors adjusted for confounding variables that are known to be associated with worse ICH outcomes, including age, sex, Glasgow Coma Scale as continuous variables, and anticoagulant use.

Discussion of Findings

The two studies discussed above (Di Napoli et al., 2016; Nguyen et al., 2014) provide very modest evidence that cannabis use may improve outcomes after TBI or ICH. However, more conclusive observational studies or randomized controlled trials will be necessary before any conclusions can be drawn about the neuroprotective effect of cannabinoids in clinical populations.

CONCLUSION 4-15 There is limited evidence of a statistical association between cannabinoids and better outcomes (i.e., mortality, disability) after a traumatic brain injury or intracranial hemorrhage.

Systematic Reviews

We identified two recent published reviews that examined randomized trials evaluating the effects of cannabis or cannabinoids on the use of addictive drugs, including cannabis: one systematic review by Marshall et al. (2014) and one comprehensive review by Prud'homme et al. (2015).¹⁰

The review by Marshall et al. (2014) is a high-quality systematic review of randomized and quasi-randomized trials assessing the efficacy of drug therapies specifically for cannabis dependence. They identified two trials examining THC: one published by Levin et al. (2011), examining dronabinol, and one published by Allsop et al. (2014), examining nabiximols.

The trial by Levin et al. (2011) was a randomized, placebo-controlled double-blind trial, which assigned cannabis-dependent adults to receive dronabinol (n = 79) or a placebo (n = 77) for 8 weeks, followed by a 2-week taper. Both groups received weekly individual therapy plus motivational enhancement therapy. Retention in the treatment program at the end of the maintenance phase was 77 percent in the dronabinol group and 61 percent in the placebo group (p-value for difference between groups = 0.02). Withdrawal symptoms declined more quickly in the dronabinol group than in the placebo group (p = 0.02). However, the primary outcome, the proportion of participants who achieved 2 consecutive weeks of abstinence at weeks 7 to 8, was 17.7 percent in the dronabinol group and 15.6 percent in the placebo group, which were not statistically significantly different from one another (p = 0.69).

The trial by Allsop et al. (2014) was randomized, placebo-controlled, and double-blind, and it enrolled adults seeking treatment for cannabis dependence. Subjects were patients who were hospitalized for 9 days and who received a 6-day regimen of nabiximols oromucosal spray (n = 27) or a matching placebo (n = 24) together with standardized psychosocial interventions. The primary outcome was a change in the Cannabis Withdrawal Scale, which is a 19-item scale that measures withdrawal symptom severity on an 11-point Likert scale for the previous 24 hours. Over the 6-day treatment period, subjects in the nabiximols group reported a mean 66 percent reduction from baseline in the cannabis withdrawal scale, while patients in the placebo group reported a mean increase in the cannabis withdrawal scale of 52 percent (p-value for between-group difference = 0.01). The median time between hospital discharge and relapse to cannabis use was 15 days (95% CI = 3.55–26.45) in the nabiximols group and 6 days (95% CI = 0–27.12) in the placebo group. The difference between these times was not statistically significant (p-value for between-group difference = 0.81).

Based on the Levin et al. (2011) and Allsop et al. (2014) trials, Marshall et al. (2014) concluded that there was moderate-quality evidence that users of THC preparations were more likely to complete treatment than those given a placebo (RR, 1.29, 95% CI = 1.08–1.55). However, the systematic review further concluded that, based on these two trials, the studied THC preparations were not associated with an increased likelihood of abstinence or a greater reduction in cannabis use than a placebo.

The review by Prud'homme et al. (2015) is a comprehensive review that broadly examined evidence on the effects of cannabidiol on addictive behaviors. The only randomized trial assessing the role of cannabis in reducing the use of an addictive substance was published by Morgan et al. (2013). That study was a pilot placebo-controlled trial that randomized cigarette smokers who wished to quit smoking to receive 400 µg inhaled cannabidiol (n = 12) or inhaled placebo (n = 12) for 1 week. Participants were instructed to use the inhaler when they felt the urge to smoke. The reduction in the number of cigarettes smoked per week was higher in the cannabidiol group than in the placebo group, although the difference was not statistically significant (p = 0.054). Rates of abstinence were not reported.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the reduction in use of addictive substances and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

Based on the systematic reviews, neither of the two trials evaluating the efficacy of a cannabinoid in achieving or sustaining abstinence from cannabis showed a statistically significant effect. However, given the limited number of studies and their small size, their findings do not definitively rule out the existence of an effect. The only study examining the efficacy of a cannabinoid in cigarette smoking cessation was a pilot study that did not examine rates of abstinence. Thus, its efficacy for smoking cessation has not been thoroughly evaluated.

CONCLUSION 4-16 There is no evidence to support or refute the conclusion that cannabinoids are an effective treatment for achieving abstinence in the use of addictive substances.

Systematic Reviews

The review by Whiting et al. (2015) was the most recent good-quality review. This review identified one randomized trial with a high risk of bias that compared a single 600 mg dose of cannabidiol to a placebo in 24 participants with generalized social anxiety disorder. Cannabidiol was associated with a greater improvement on the anxiety factor of a 100-point visual analogue mood scale (mean difference from baseline −16.52, p = 0.01) compared with a placebo during a simulated public speaking test. Four other randomized controlled trials (232 participants) enrolled patients with chronic pain and reported on anxiety symptoms. The cannabinoids studied were: dronabinol, 10–20 mg daily; nabilone, maximum dose of 2 mg daily; and nabiximols, maximum dose of 4–48 sprays/day. Outcomes were assessed from 8 hours to 6 weeks after randomization; three of the four trials were judged to have a high risk of bias. These trials suggested greater short-term benefit with cannabinoids than a placebo on self-reported anxiety symptoms.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the improvement of anxiety symptoms and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

There is limited evidence that cannabidiol improves anxiety symptoms, as assessed by a public speaking test, in patients with social anxiety disorder. These positive findings are limited by weaknesses in the study design (e.g., an inadequate description of randomization and allocation concealment), a single dose of CBD, and uncertain applicability to patients with other anxiety disorders. Limited evidence also suggests short-term benefits in patients with chronic pain and associated anxiety symptoms. In contrast, evidence from observational studies found moderate evidence that daily cannabis use is associated with increased anxiety symptoms and heavy cannabis use is associated with social phobia disorder (see Chapter 12).

CONCLUSION 4-17 There is limited evidence that cannabidiol is an effective treatment for the improvement of anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders.

Systematic Reviews

The review by Whiting et al. (2015) was the most recent good-quality review. No RCTs were identified that specifically evaluated cannabis in patients with a depressive disorder. Five RCTs (634 participants) enrolled patients for other conditions (chronic pain or multiple sclerosis with spasticity) and reported on depressive symptoms. Only one study reported depressive symptoms at baseline; symptoms were mild. Nabiximols (n = 3; maximum dose ranged from 4–48 doses/day), dronabinol (10 mg and 20 mg daily), and nabilone capsules (maximum of 8 mg) were compared to placebo; nabilone was also compared to dihydrocodeine. Outcomes were assessed from 8 hours to 9 weeks following randomization. Three of the five trials were judged to have a high risk of bias and the other two as unclear risk. Three studies (nabiximols, dronabinol) showed no effect using validated symptom scales. One study that evaluated three doses of nabiximols found increased depressive symptoms at the highest dose (11–14 sprays/day), but no difference compared to the placebo at lower doses. The comparison of nabilone to dihydrocodone showed no difference in depressive symptoms.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment to reduce depressive symptoms and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

Although patients report using cannabinoids for depression, our search for a good-quality systematic review did not identify any RCTs evaluating the effects of medical cannabis in patients with depressive disorders. Trials in patients with chronic pain or multiple sclerosis with uncertain baseline depressive symptoms did not show an effect. There are no trial data addressing the effects of cannabinoids for major depressive disorder.

In Chapter 12 (Mental Health), the committee reviews epidemiological evidence to examine the association between cannabis use and the development of depressive disorders as well as the impact of cannabis use on the disorder's course or symptoms.

CONCLUSION 4-18 There is limited evidence that nabiximols, dronabinol, and nabilone are ineffective treatments for the reduction of depressive symptoms in individuals with chronic pain or multiple sclerosis.

Systematic Reviews

The review by Whiting et al. (2015) was the most recent good-quality review. Two RCTs (54 participants) evaluated cannabinoids (nabilone, dronabinol) for the treatment of sleep problems. A trial deemed to have a high risk of bias conducted in 22 patients with obstructive sleep apnea showed a greater benefit of dronabinol (maximum dose of 10 mg daily) than with a placebo on sleep apnea/hypopnea index (mean difference from baseline −19.64, p = 0.02) at 3 weeks follow-up. A crossover trial deemed to have a low risk of bias in 32 patients with fibromyalgia found improvements for nabilone 0.5 mg daily compared with 10 mg amitriptyline in insomnia (mean difference from baseline, −3.25, 95% CI = −5.26 to −1.24) and greater sleep restfulness (mean difference from baseline, 0.48, 95% CI = 0.01–0.95) at 2 weeks follow-up. Although the antidepressant amitriptyline is an established treatment for fibromyalgia, it is not FDA approved for insomnia, and its use is limited by adverse effects.

Nineteen trials (3,231 participants) enrolled patients with other conditions (chronic pain or multiple sclerosis) and reported on sleep outcomes. Nabiximols (13 studies), THC/CBD capsules (2 studies), smoked THC (2 studies), and dronabinol or nabilone were compared to a placebo. Sleep outcomes were assessed at 2–15 weeks after randomization. Eleven of the 19 trials were judged to have a high risk of bias, 6 had an uncertain risk of bias, and the other 2 were judged to have a low risk of bias. The meta-analysis found greater improvements with cannabinoids in sleep quality among 8 trials (weighted mean difference [WMD], −0.58, 95% CI = −0.87 to −0.29) and sleep disturbance among 3 trials (WMD, −0.26, 95% CI = −0.52 to 0.00). These improvements in sleep quality and sleep disturbance were rated on a 10-point scale and would be considered small improvements. The summary estimate showing benefit was based primarily on studies of nabiximols.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment to improve sleep outcomes and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

A high-quality systematic review found moderate evidence suggesting that cannabinoids (primarily nabiximols) improve short-term sleep outcomes in patients with sleep disturbance associated with obstructive sleep apnea, fibromyalgia, chronic pain, or multiple sclerosis. However, the single study using an active comparator used a drug (amitriptyline) that is considered second-line treatment due to the availability of newer, more effective treatments that have fewer adverse effects. The committee did not identify any clinical trials that evaluated the effects of cannabinoids in patients with primary chronic insomnia.

CONCLUSION 4-19 There is moderate evidence that cannabinoids, primarily nabiximols, are an effective treatment to improve short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis.

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for PTSD symptoms.

Primary Literature

We identified a fair-quality double-blind, randomized crossover trial (Jetly et al., 2015) conducted with Canadian male military personnel with trauma-related nightmares despite standard treatments for PTSD. Ten participants were randomized to either nabilone 0.5 mg that was titrated to a daily maximum of 3.0 mg or else to a placebo for 7 weeks. Following a 2-week washout period, subjects were then treated with the other study treatment and followed for an additional 7 weeks. Effects on sleep, nightmares, and global clinical state were assessed by the investigators; sleep time and general well-being were self-reported. Nightmares, global clinical state, and general well-being were improved more with nabilone treatment than with the placebo treatment (p <0.05). There was no effect on sleep quality and quantity. Global clinical state was rated as very much improved or much improved for 7 of 10 subjects in the nabilone treatment period and 2 of 10 subjects in the placebo treatment period.

Discussion of Findings

A single, small crossover trial suggests potential benefit from the pharmaceutical cannabinoid nabilone. This limited evidence is most applicable to male veterans and contrasts with non-randomized studies showing limited evidence of a statistical association between cannabis use (plant derived forms) and increased severity of posttraumatic stress disorder symptoms among individuals with posttraumatic stress disorder (see Chapter 12). A search of the grey literature identified several recently initiated randomized controlled trials examining the harms and benefits of marijuana for PTSD.¹¹ One trial examines the effects of four different types of cannabis with varying THC and CBD content on PTSD symptoms in 76 veterans (Bonn-Miller, 2016). Another trial is a Canadian study that evaluates different formulations of THC and CBD in 42 adults with PTSD (Eades, 2016). If these trials are successfully completely, they will add substantially to the knowledge base, expanding the range of cannabinoids evaluated and the opportunity to examine the consistency of effects across studies.

CONCLUSION 4-20 There is limited evidence (a single, small fair-quality trial) that nabilone is effective for improving symptoms of posttraumatic stress disorder.

Systematic Reviews

Two good-quality reviews (McLoughlin et al., 2014; Whiting et al., 2015) evaluated cannabinoids for the treatment of psychosis. We focus on the good-quality review by Whiting et al. (2015) as it is more current. Two RCTs with high risk of bias (71 total participants with schizophrenia or schizophreniform psychosis) compared cannabidiol to the atypical antipsychotic amisulpride or a placebo. One trial reported no difference on mental health between CBD (maximum dose 800 mg/day) and amisulpride (maximum dose 800 mg/day) at 4 weeks (brief psychiatric rating scale mean difference, −0.10, 95% CI = −9.20–8.90) or on mood (positive and negative syndrome scale mean difference, 1.0; 95% CI = −12.6–14.6). A crossover trial showed no difference in effect on mood between CBD (maximum dose 600 mg/day) and placebo (positive and negative symptom scale mean difference, 1, 95% CI = −12.60–14.60; scale range 30–210).

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the mental health outcomes of patients with schizophrenia or other psychoses and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

Good-quality systematic reviews identified only two small, unclear-to high-risk-of-bias trials evaluating cannabinoids for the treatment of schizophrenia. These studies provide only limited evidence due to the risk of bias, the short-term follow-up, and the evaluation of a single cannabinoid. Furthermore, the larger trial was designed to detect a moderate benefit of cannabidiol compared to the antipsychotic amisulpride, but it enrolled only 60 percent of the planned sample. Thus, it did not have the statistical power to detect small or moderate differences between CBD and amisulpride. Overall, the evidence is insufficient to determine if cannabidiol is an effective treatment for individuals with schizophrenia or schiophreniform psychosis.

In Chapter 12, the committee reviews epidemiological evidence to examine the association between cannabis use and the development of schizophrenia and other psychoses, as well as the impact of cannabis use on the disorder's course or symptoms.

CONCLUSION 4-21 There is insufficient evidence to support or refute the conclusion that cannabidiol is an effective treatment for the mental health outcomes in individuals with schizophrenia or schizophreniform psychosis.