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The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research (2017)

Chapter:4 Therapeutic Effects of Cannabis and Cannabinoids

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Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

Chapter Highlights
  • In adults with chemotherapy-induced nausea and vomiting, oral cannabinoids are effective antiemetics.
  • In adults with chronic pain, patients who were treated with cannabis or cannabinoids are more likely to experience a clinically significant reduction in pain symptoms.
  • In adults with multiple sclerosis (MS)-related spasticity, short-term use of oral cannabinoids improves patient-reported spasticity symptoms.
  • For these conditions the effects of cannabinoids are modest; for all other conditions evaluated there is inadequate information to assess their effects.

Cannabis sativa has a long history as a medicinal plant, likely dating back more than two millennia (Russo et al., 2007). It was available as a licensed medicine in the United States for about a century before the American Medical Association removed it from the 12th edition of the U.S. Pharmacopeia (IOM, 1999). In 1985, pharmaceutical companies received approval to begin developing Δ 9 -tetrahydrocannabinol (THC) preparations—dronabinol and nabilone—for therapeutic use, and as a result, cannabinoids were reintroduced into the armamentarium of willing health care providers (Grotenhermen and Müller-Vahl, 2012). Efforts

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

are now being put into the trials of cannabidiol as a treatment for conditions such as epilepsy and schizophrenia, 1 although no such preparations have come to market at this time. Nabiximols, an oromucosal spray of a whole cannabis plant extract with a 1:1 ratio of THC to cannabidiol (CBD), was initially licensed and approved in Europe, the United Kingdom, and Canada for the treatment of pain and spasticity associated with multiple sclerosis (GW Pharmaceuticals, 2016; Pertwee, 2012), but it continues to undergo evaluation in Phase III clinical trials in the United States. 2 Efforts are under way to develop targeted pharmaceuticals that are agonists or antagonists of the cannabinoid receptors or that modulate the production and degradation of the endocannabinoids, although such interventions have not yet demonstrated safety or effectiveness. Nonetheless, therapeutic agents targeting cannabinoid receptors and endocannabinoids are expected to become available in the future.

The renewed interest in the therapeutic effects of cannabis emanates from the movement that began 20 years ago to make cannabis available as a medicine to patients with a variety of conditions. It was in 1996 that Arizona and California first passed medicinal cannabis legislation, although Arizona later rescinded the approval, so it would be California that paved the way. At the time that this report was written, in 2016, 28 states and the District of Columbia had legalized the medical use of cannabis; 8 states had legalized both medical and recreational use of cannabis; and another 16 states had allowed limited access to low-THC/high-CBD products (i.e., products with low levels of THC and high levels of CBD) (NCSL, 2016). A recent national survey showed that among current adult users, 10.5 percent reported using cannabis solely for medical purposes, and 46.6 percent reported a mixed medical/recreational use (Schauer et al., 2016). Of the states that allow for some access to cannabis compounds, cancer, HIV/AIDS, multiple sclerosis, glaucoma, seizures/epilepsy, and pain are among the most recognized qualifying ailments (Belendiuk et al., 2015; NCSL, 2016). There are certain states that provide more flexibility than others and that allow the use of medical cannabis for the treatment of any illness for which the drug provides relief for the individual. Given the steady liberalization of cannabis laws, the numbers of these states are likely to increase and therefore support the efforts to clarify the potential therapeutic benefits of medical cannabis on various health outcomes.

For example, the most common conditions for which medical cannabis is used in Colorado and Oregon are pain, spasticity associated with multiple sclerosis, nausea, posttraumatic stress disorder, cancer, epilepsy, cachexia, glaucoma, HIV/AIDS, and degenerative neurological

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

conditions (CDPHE, 2016; OHA, 2016). We added to these conditions of interest by examining lists of qualifying ailments in states where such use is legal under state law. The resulting therapeutic uses covered by this chapter are chronic pain, cancer, chemotherapy-induced nausea and vomiting, anorexia and weight loss associated with HIV, irritable bowel syndrome, epilepsy, spasticity, Tourette syndrome, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dystonia, dementia, glaucoma, traumatic brain injury, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, and schizophrenia and other psychoses. The committee is aware that there may be other conditions for which there is evidence of efficacy for cannabis or cannabinoids. In this chapter, the committee will discuss the findings from 16 of the most recent, good- to fair-quality systematic reviews and 21 primary literature articles that best address the committee’s research questions of interest.

As a reminder to the reader, several of the prioritized health endpoints discussed here in Part II are also reviewed in chapters of Part III; however, the research conclusions within these chapters may differ. This is, in part, due to differences in the study design of the evidence reviewed (e.g., randomized controlled trials [RCTs] versus epidemiological studies), differences in the characteristics of cannabis or cannabinoid exposure (e.g., form, dose, frequency of use), and the populations studied. As such, it is important that the reader is aware that this report was not designed to reconcile the proposed harms and benefits of cannabis or cannabinoid use across chapters.

CHRONIC PAIN

Relief from chronic pain is by far the most common condition cited by patients for the medical use of cannabis. For example, Light et al. (2014) reported that 94 percent of Colorado medical marijuana ID cardholders indicated “severe pain” as a medical condition. Likewise, Ilgen et al. (2013) reported that 87 percent of participants in their study were seeking medical marijuana for pain relief. In addition, there is evidence that some individuals are replacing the use of conventional pain medications (e.g., opiates) with cannabis. For example, one recent study reported survey data from patrons of a Michigan medical marijuana dispensary suggesting that medical cannabis use in pain patients was associated with a 64 percent reduction in opioid use (Boehnke et al., 2016). Similarly, recent analyses of prescription data from Medicare Part D enrollees in states with medical access to cannabis suggest a significant reduction in the prescription of conventional pain medications (Bradford and Bradford, 2016). Combined with the survey data suggesting that pain is one of the primary reasons for the use of medical cannabis, these recent reports sug-

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

gest that a number of pain patients are replacing the use of opioids with cannabis, despite the fact that cannabis has not been approved by the U.S. Food and Drug Administration (FDA) for chronic pain.

Are Cannabis or Cannabinoids an Effective Treatment for the Reduction of Chronic Pain?

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, rheuma-

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

toid 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 exam-

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

ple, 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.

CANCER

Cancer is a broad term used to describe a wide range of related diseases that are characterized by an abnormal, unregulated division of cells; it is a biological disorder that often results in tumor growth (NCI, 2015). Cancer is among the leading causes of mortality in the United States, and by the close of 2016 there will be an estimated 1.7 million new cancer diagnoses (NCI, 2016). Relevant to the committee’s interest, there is evidence to suggest that cannabinoids (and the endocannabinoid system more generally) may play a role in the cancer regulation processes (Rocha et al., 2014). Therefore, there is interest in determining the efficacy of cannabis or cannabinoids for the treatment of cancer.

Are Cannabis or Cannabinoids an Effective Treatment for Cancer?

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

3 Due to the lack of recent, high-quality reviews, the committee has identified that a research gap exists concerning the effectiveness of cannabis or cannabinoids in treating cancer in general.

4 Glioma is a type of tumor that originates in the central nervous system (i.e., the brain or spine) and arises from glial cells.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING

Nausea and vomiting are common side effects of many cytotoxic chemotherapy agents. A number of pharmaceutical interventions in various drug classes have been approved for the treatment of chemotherapy-induced nausea and vomiting. Among the cannabinoid medications, nabilone and dronabinol were initially approved in 1985 for nausea and vomiting associated with cancer chemotherapy in patients who failed to respond adequately to conventional antiemetic treatments (Todaro, 2012, pp. 488, 490).

Are Cannabis or Cannabinoids an Effective Treatment for the Reduction of Chemotherapy-Induced Nausea and Vomiting?

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,

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

(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/m 2 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,

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

ANOREXIA AND WEIGHT LOSS

Anorexia and weight loss are common side effects of many diseases, especially cancer. And prior to the availability of highly active antiretroviral therapy, a wasting syndrome was a frequent clinical manifestation in patients with human immunodeficiency virus (HIV) infection and advanced acquired immune deficiency syndrome (AIDS). The labeled indications for dronabinol were expanded in 1992 to include treatment of anorexia associated with weight loss in patients with AIDS (IOM, 1999, p. 156).

Are Cannabis or Cannabinoids an Effective Treatment for Anorexia and Weight Loss Associated with HIV/AIDS, Cancer-Associated Anorexia-Cachexia Syndrome, and Anorexia Nervosa?

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

5 Key issues that led to high ROB ratings were: high (n = 1) or unclear (n = 3) ROB for allocation concealment; unclear ROB (n = 3) for blinded outcome assessments; high (n = 1) or unclear (n = 1) ROB for randomization.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

IRRITABLE BOWEL SYNDROME

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder commonly associated with symptoms of abdominal cramping and changes in bowel movement patterns. Irritable bowel syndrome is classified into four types based on the types of bowel movements: IBS with diarrhea, IBS with constipation, IBS mixed, and IBS unclassified (NIDDK, 2015). Approximately 11 percent of the world’s population suffers from at least one type of this disorder (Canavan et al., 2014).

Type 1 cannabinoid (CB1) receptors are present in the mucosa and neuromuscular layers of the colon; they are also expressed in plasma cells and influence mucosal inflammation (Wright et al., 2005). In animal models, endocannabinoids acting on CB1 receptors inhibit gastric and small intestinal transit and colonic propulsion (Pinto et al., 2002). Studies in healthy volunteers have shown effects on gastric motility and colonic motility (Esfandyari et al., 2006). Thus, cannabinoids have the potential for therapeutic effect in patients with IBS (Wong et al., 2012).

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms of Irritable Bowel 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 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 BID 6 (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

6 BID is an abbreviation for the Latin phrase bis in die, which means twice per day.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

EPILEPSY

Epilepsy refers to a spectrum of chronic neurological disorders in which clusters of neurons in the brain sometimes signal abnormally and cause seizures (NINDS, 2016a). Epilepsy disorder affects an estimated 2.75 million Americans, across all age ranges and ethnicities (NINDS, 2016a). Although there are many antiepileptic medications currently on the market, about one-third of persons with epilepsy will continue to have seizures even when treated (Mohanraj and Brodie, 2006). Both THC and CBD can prevent seizures in animal models (Devinsky et al., 2014).

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms of Epilepsy?

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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

7 ClinicalTrials.gov: NCT02224560, NCT02224690, NCT02091375, NCT02324673.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

SPASTICITY ASSOCIATED WITH MULTIPLE SCLEROSIS OR SPINAL CORD INJURY

Spasticity is defined as disordered sensorimotor control resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles (Pandyan et al., 2005). It occurs in some patients with chronic neurological conditions such as multiple sclerosis (MS) and paraplegia due to spinal cord injury. Recent studies have shown that some individuals with MS are seeking alternative therapies, including cannabis, to treat symptoms associated with MS (Zajicek et al., 2012).

Are Cannabis or Cannabinoids an Effective Treatment for Spasticity Associated with Multiple Sclerosis or Spinal Cord Injury?

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

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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 pro-

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

vided 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.

TOURETTE SYNDROME

Tourette syndrome is a neurological disorder characterized by sporadic movements or vocalizations commonly called “tics” (NINDS, 2014). While there is currently no cure for Tourette syndrome, recent efforts have explored whether cannabis may be effective in reducing symptoms commonly associated with the disorder (Koppel et al., 2014).

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Tourette Syndrome?

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons in the spinal cord, brain stem, and motor cortex, ultimately leading to complete paralysis (Rossi et al., 2010). The pathogenesis of ALS remains unclear, but the disease is thought to result from the interplay of a number of mechanisms, including neurofilament accumulation, excitotoxicity, oxidative stress, and neuroinflammation (Redler and Dokholyan, 2012), all of which may be amenable to manipulation of the endocannabinoid system and cannabinoid receptors.

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Amyotrophic Lateral 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 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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

HUNTINGTON’S DISEASE

Huntington’s disease is characterized by chorea (abnormal, involuntary movement) along with cognitive decline and psychiatric impairment (Armstrong and Miyasaki, 2012). Worsening chorea significantly impacts patient quality of life. The pathophysiology and neurochemical basis of Huntington’s disease are incompletely understood. Neuroprotective trials often investigate agents that may decrease oxidative stress or glutamatergic changes related to excitotoxic stress. There is some preclinical evidence and limited clinical evidence that suggest that changes in the endocannabinoid system may be linked to the pathophysiology of Huntington’s disease (Pazos et al., 2008; van Laere et al., 2010).

Are Cannabis or Cannabinoids an Effective Treatment for the Motor Function and Cognitive Performance Associated with Huntington’s Disease?

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

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the declines in motor function and cognitive performance associated with Huntington’s disease 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

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

PARKINSON’S DISEASE

Parkinson’s disease is a motor system disorder attributed to the loss of dopamine-producing brain cells. It is characterized clinically by tremor, rigidity, bradykinesia (slowness of movement), and impaired balance and coordination (PDF, 2016a). An estimated 60,000 Americans are diagnosed with this disorder each year (PDF, 2016b).

Although the disease is progressive and without cure, there are medications that can ameliorate some of the associated symptoms. Although levodopa has demonstrated efficacy for treating symptoms of Parkinson’s disease, long-term use of levodopa is associated with the development of side effects, especially dyskinesias (involuntary movements) (NINDS, 2015). Evidence suggests that the endocannabinoid system plays a meaningful role in certain neurodegenerative processes (Krishnan et al., 2009); thus, it may be useful to determine the efficacy of cannabinoids in treating the symptoms of neurodegenerative diseases.

Are Cannabis or Cannabinoids an Effective Treatment for the Motor System Symptoms Associated with Parkinson’s Disease or the Levodopa-Induced Dyskinesia?

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

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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

8 The Dyskinesia Disability Scale is a 0–4 scale (absent to most severe) measuring the severity of dyskinesia (Goetz et al., 1994).

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

DYSTONIA

Dystonia is a disorder characterized by sustained or repetitive muscle contractions which result in abnormal fixed postures or twisting, repetitive movements (NINDS, 2016b). Idiopathic cervical dystonia is the most common cause of focal dystonia. Oral pharmacological agents are generally ineffective, with repeated injections of botulinum toxin being the most effective current therapy. The pathophysiologic mechanisms of dystonia are poorly understood, but, as in other hyperkinetic movement disorders, underactivity of the output regions of the basal ganglia may be involved. Stimulation of the cannabinoid receptors has been postulated as a way to reduce dystonia (Zadikoff et al., 2011). Anecdotal reports have suggested that cannabis may alleviate symptoms associated with dystonia (Uribe Roca et al., 2005). In a 1986 preliminary open pilot study in which five patients with dystonic movement disorders received cannabidiol, dose-related improvements were observed in all five patients (Consroe et al., 1986).

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

Are Cannabis or Cannabinoids an Effective Treatment for Dystonia?

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.

DEMENTIA

Dementia is characterized by a decline in cognition that typically affects multiple cognitive domains such as memory, language, executive function, and perceptual motor function (NIH, 2013). Alzheimer’s disease, vascular dementia, and Parkinson’s disease with dementia are three prominent dementing disorders (NIA, n.d.). Behavioral and psychological symptoms, including agitation, aggression, and food refusal, are common

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

in the more advanced stages of dementia. These symptoms cause distress to the patient and caregivers and may precipitate the patient being placed in institutional care. Current treatments for dementia (e.g., cholinesterase inhibitors) have only modest effects, and treatments for behavioral disturbances such as antipsychotic medications have both modest benefits and substantial adverse effects (Krishnan et al., 2009).

CB1 receptors are found throughout the central nervous system, and the endogenous cannabinoid system is thought to be important in the regulation of synaptic transmission (Baker et al., 2003), a process that is disordered in patients with dementia. Accumulating evidence suggests that cannabinoids have the potential for neuroprotective effects (Grundy, 2002; Hampson et al., 1998; Shen and Thayer, 1998). This developing understanding of the endogenous cannabinoid system, along with cannabinoids anxiolytic and appetite-stimulating effects, provides a rationale for its study in patients with dementia.

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Dementia?

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).

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

GLAUCOMA

Glaucoma is one of the leading causes of blindness within the United States (Mayo Clinic, 2015). This disorder is characterized as a group of eye conditions that can produce damage to the optic nerve and result in a loss of vision. This damage is often caused by abnormally high intraocular pressure (NEI, n.d.). Because high intraocular pressure is a known major risk factor that can be controlled (Prum et al., 2016, p. 52), most treatments have been designed to reduce it. Research suggests that cannabinoids may have potential as an effective treatment for reducing pressure in the eye (Tomida et al., 2007).

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

Are Cannabis or Cannabinoids an Effective Treatment for Glaucoma?

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

TRAUMATIC BRAIN INJURY/INTRACRANIAL HEMORRHAGE

Traumatic brain injury (TBI) is an acquired brain injury that can result from a sudden or violent hit to the head (NINDS, 2016c). TBI accounts for about 30 percent of all injury deaths in the United States (CDC, 2016). Intracranial hemorrhage (ICH), bleeding that occurs inside the skull, is a common complication of TBI which is associated with a worse prognosis of the injury (Bullock, 2000; CDC, 2015). There is a small body of literature reporting the neuroprotective effects of cannabinoid analogues in preclinical studies of head injuries (Mechoulam et al., 2002) as well as in observational studies in humans (Di Napoli et al., 2016; Nguyen et al., 2014).

Are Cannabis or Cannabinoids an Effective Treatment or Prevention for Traumatic Brain Injury or Intracranial Hemorrhage?

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 Scale 9 (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.

9 The modified Rankin Scale is a clinical assessment tool commonly used to measure the degree of disability following a stroke. Outcome scores from the scale range from 0 (no symptoms) to 6 (death) (Di Napoli et al., 2016, p. 249).

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

ADDICTION

Drug addiction has been defined as a chronically relapsing disorder that is characterized by the compulsive desire to seek and use drugs with impaired control over substance use despite negative consequences (Prud’homme et al., 2015). The endocannabinoid system has been found to influence the acquisition and maintenance of drug-seeking behaviors, possibly through its role in reward and brain plasticity (Gardner, 2005; Heifets and Castillo, 2009). Furthermore, in laboratory settings orally administered dronabinol has been found to reduce cannabis withdrawal symptoms in cannabis users who were not seeking treatment to reduce cannabis use (Budney et al., 2007; Haney et al., 2004) and therefore may be expected to be useful as a substitute to assist to achieve and maintain abstinence of cannabis.

Are Cannabis or Cannabinoids an Effective Treatment for Achieving Abstinence from Addictive Substances?

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

10 Prud’homme (2015) is often categorized as a systematic review; however, the committee determined that the review lacks certain key elements of a systematic review, including a clearly stated research question, independent and duplicate data abstraction efforts, an assessment of the research quality and risk of bias, and a quantitative summary.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

ANXIETY

Anxiety disorders share features of excessive fear and anxiety which induce psychological and physical symptoms that can cause significant distress or interfere with social, occupational, and other areas of functioning (APA, 2013). In a given year, an estimated 18 percent of the U.S. adult population will suffer from symptoms associated with an anxiety disorder (NIMH, n.d.). Given the role of the endocannabinoid system in mood

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

regulation, the committee decided to explore the relationship between anxiety and cannabis.

Are Cannabis or Cannabinoids an Effective Treatment for the Improvement of Anxiety Symptoms?

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

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

DEPRESSION

Depression is one of the nation’s most common mental health disorders (ADAA, 2016). Across the many depressive disorders that exist (e.g., persistent depressive disorder, major depressive disorder, premenstrual dysphoric disorder) there are common symptomatic features of feelings of sadness, emptiness, or irritable mood, accompanied by somatic and cognitive changes that affect the individual’s capacity to function (APA, 2013, p. 155). The endocannabinoid system is known to play a role in mood regulation (NIDA, 2015, p. 9); therefore, the committee decided to explore the association between cannabis use and depressive disorders or symptoms.

Are Cannabis or Cannabinoids an Effective Treatment to Reduce Depressive Symptoms?

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

SLEEP DISORDERS

Sleep disorders can be classified into major groups that include insomnia, sleep-related breathing disorders, parasomnias, sleep-related movement disorders, and circadian rhythm sleep–wake disorders (Sateia, 2014). Fifty million to 70 million adults in the United States report having some type of sleep disorder (ASA, 2016). In 2010, insomnia generated 5.5 million office visits in the United States (Ford et al., 2014). There is some evidence to suggest that the endocannabinoid system may have a role in sleep. THC is associated in a dose-dependent manner with changes in slow-wave sleep, which is critical for learning and memory consolidation. Cannabis may also have effects on sleep latency, decreasing time to sleep onset at low doses and increasing time to sleep onset at higher doses (Garcia and Salloum, 2015). Thus, cannabinoids could have a role in treating sleep disorders.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

Are Cannabis or Cannabinoids an Effective Treatment for Improving Sleep Outcomes?

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

POSTTRAUMATIC STRESS DISORDER

Posttraumatic stress disorder (PTSD) falls within the broader trauma- and stressor-related disorders categorized by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). The diagnostic criteria of PTSD include an exposure to a traumatic event (e.g., the threat of death, serious injury, or sexual violence) and exhibiting psychological distress symptoms that occur as a result of that exposure (e.g., intrusion symptoms, such as distressing memories; avoidance of stimuli that are associated with the traumatic event; negative alterations in mood and cognition; alterations in arousal and reactivity associated with the traumatic event; functional impairment) (APA, 2013, pp. 271–272). Given the known psychoactive effects of cannabis, the committee decided to explore the association between PTSD and cannabis use.

Are Cannabis or Cannabinoids an Effective Treatment for PTSD Symptoms?

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

11 ClinicalTrials.gov: NCT02102230, NCT02874898, NCT02517424, NCT02759185.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

SCHIZOPHRENIA AND OTHER PSYCHOSES

Schizophrenia spectrum disorders and other psychotic disorders are mental health disorders characterized by three different classes of symptoms: positive symptoms (e.g., delusions, hallucinations, or disorganized or abnormal motor behavior), negative symptoms (e.g., diminished emotional expression, lack of interest or motivation to engage in social settings, speech disturbance, or anhedonia), and impaired cognition (e.g., disorganized thinking) (APA, 2013, p. 87; NIMH, 2015). Evidence suggests that the prevalence of cannabis use among people with schizophrenia is generally higher than among the general population (McLoughlin et al., 2014). In most of the studies reviewed below, schizophrenia, schizophreniform disorder, schizoaffective disorder, and psychotic disorders are used as aggregate endpoints.

Are Cannabis or Cannabinoids an Effective Treatment for the Mental Health Outcomes of Patients with Schizophrenia or Other Psychoses?

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.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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.

RESEARCH GAPS

In reviewing the research evidence described above, the committee has identified that research gaps exist concerning the effectiveness of cannabidiol or cannabidiol-enriched cannabis in treating the following:

  • cancer in general
  • treating chemotherapy-induced nausea and vomiting
  • symptoms of irritable bowel syndrome
  • epilepsy
  • spasticity due to paraplegia from spinal cord injury
  • symptoms associated with amyotrophic lateral sclerosis
  • motor function and cognitive performance associated with Huntington’s Disease
  • motor system symptoms associated with Parkinson’s disease or levodopa-induced dyskinesia
  • achieving abstinence or reduction in the use of addictive substances, including cannabis itself
  • sleep outcomes in individuals with primary chronic insomnia
  • posttraumatic stress disorder symptoms

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

  • mental health outcomes in individuals with schizophrenia or schizophreniform psychosis
  • cannabidiol short-term relief from anxiety symptoms

SUMMARY

This chapter outlines the committee’s efforts to review the current evidence base for the potential efficacy of cannabis or cannabinoids on prioritized health conditions. The health conditions reviewed in this chapter include chronic pain, cancer, chemotherapy-induced nausea and vomiting, anorexia and weight loss associated with HIV, irritable bowel syndrome, epilepsy, spasticity, Tourette syndrome, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dystonia, dementia, glaucoma, traumatic brain injury, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, and schizophrenia and other psychoses. The committee has formed a number of research conclusions related to these health endpoints; however, it is important that the chapter conclusions be interpreted within the context of the limitations discussed in the Discussion of Findings sections above. See Box 4-1 for a summary list of the chapter’s conclusions.

We found conclusive or substantial evidence (ranging in modest to moderate effect) for benefit from cannabis or cannabinoids for chronic pain, chemotherapy-induced nausea and vomiting, and patient-reported symptoms of spasticity associated with multiple sclerosis. For chemotherapy-induced nausea and vomiting and spasticity associated with multiple sclerosis, the primary route of administration examined was the oral route. For chronic pain, most studies examined oral cannabis extract, although some examined smoked or vaporized cannabis. It is unknown whether and to what degree the results of these studies can be generalized to other products and routes of administration. For many of the other conditions discussed above, there is insufficient or no evidence upon which to base conclusions about therapeutic effects. The potential efficacy of cannabinoids for several of these conditions, such as epilepsy and posttraumatic stress disorder, should be prioritized, given the substantial number of persons using cannabis for those conditions (Cougle et al., 2011; Massot-Tarrús and McLachlan, 2016). As identified in the chapter’s Discussion of Findings sections, there are common themes in the type of study limitations found in this evidence base. The most common are limitations in the study design (e.g., a lack of appropriate control groups, a lack of long-term follow-ups), small sample sizes, and research gaps in examining the potential therapeutic benefits of different forms of cannabis (e.g., cannabis plant). These limitations highlight the need for substantial research to provide comprehensive and conclusive evidence on the therapeutic effects of cannabis and cannabinoids.

Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

BOX 4-1
Summary of Chapter Conclusions *

There is conclusive or substantial evidence that cannabis or cannabinoids are effective:

  • For the treatment of chronic pain in adults (cannabis) (4-1)
  • As antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids) (4-3)
  • For improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids) (4-7a)

There is moderate evidence that cannabis or cannabinoids are effective for:

  • Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis (cannabinoids, primarily nabiximols) (4-19)

There is limited evidence that cannabis or cannabinoids are effective for:

  • Increasing appetite and decreasing weight loss associated with HIV/AIDS (cannabis and oral cannabinoids) (4-4a)
  • Improving clinician-measured multiple sclerosis spasticity symptoms (oral cannabinoids) (4-7a)
  • Improving symptoms of Tourette syndrome (THC capsules) (4-8)
  • Improving anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders (cannabidiol) (4-17)
  • Improving symptoms of posttraumatic stress disorder (nabilone; a single, small fair-quality trial) (4-20)

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 (4-15)

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Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

There is limited evidence that cannabis or cannabinoids are ineffective for:

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Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

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Suggested Citation:“4 Therapeutic Effects of Cannabis and Cannabinoids.” National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.

Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system

* Author for Correspondence: Dr. Keith Sharkey, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada, Tel: 403-220-4601, Fax: 403-283-2700, [email protected]

Abstract

Nausea and vomiting (emesis) are important elements in defensive or protective responses that animals use to avoid ingestion or digestion of potentially harmful substances. However, these neurally-mediated responses are at times manifested as symptoms of disease and they are frequently observed as side-effects of a variety of medications, notably those used to treat cancer. Cannabis has long been known to limit or prevent nausea and vomiting from a variety of causes. This has led to extensive investigations that have revealed an important role for cannabinoids and their receptors in the regulation of nausea and emesis. With the discovery of the endocannabinoid system, novel ways to regulate both nausea and vomiting have been discovered that involve the production of endogenous cannabinoids acting centrally. Here we review recent progress in understanding the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system, and we discuss the potential to utilize the endocannabinoid system in the treatment of these frequently debilitating conditions.

1. Introduction

Reflex mechanisms that serve to protect a host from injury and disability represent important and frequently well-conserved adaptations to a hostile external environment. Rarely do these adaptations, such as blinking or sneezing, become “hijacked” by physiological or pathophysiological processes in the body, not involving the organ they evolved to protect. Unfortunately, that is not the case for nausea and vomiting. Nausea is an aversive experience that often precedes emesis (vomiting), but is distinct from it (Borison and Wang, 1953; Carpenter, 1990; Horn, 2008; Andrews and Horn, 2006; Stern et al., 2011). Retching and vomiting lead to the forceful expulsion of gastric and/or upper intestinal contents, the primary function of which is to remove ingested materials or food that may be contaminated or potentially harmful. Nausea associated with emesis serves as an unconditioned stimulus for learning and memory; food that becomes associated with nausea and vomiting will be avoided in future encounters (Borison and Wang, 1953; Carpenter, 1990; Horn, 2008; Andrews and Horn, 2006; Stern et al., 2011).

In the natural environment, as a protective reflex, nausea and vomiting are very important adaptations found in most vertebrate species (Borison et al., 1981). However, possibly because of its importance, the sensitivity of this reflex is very low, making it easily activated. In various disease states, e.g. diabetes and labyrinthitis (Koch, 1999; Schmäl, 2013), the inappropriate activation of this reflex leads to severe and debilitating symptoms. Many central nervous system conditions, including elevated intracranial pressure, migraine headache and concussion also cause nausea and vomiting (Edvinsson et al., 2012; Mott et al, 2012; Stern et al., 2011). Nausea and vomiting are frequent, unwanted, side-effects of a range of medications used to treat a variety of conditions, notably cancer chemotherapeutic agents (Hesketh, 2005; Rojas and Slusher, 2012). Pregnancy-induced nausea and vomiting are reportedly adaptive mechanisms, but hyperemesis gravidarum can severely compromise both the health of the mother and the developing fetus (Patil et al, 2012; Sanu and Lamont, 2011; Sherman and Flaxman, 2002). Finally, motion sickness, which results from a sensory conflict between visual and vestibular stimuli, can be of immense discomfort, and severely limit certain activities (Schmäl, 2013; Yates et al., 1998). Nausea and vomiting are significant in our society and understanding them represents both an important goal and a major challenge; the former because of the substantial health implications, but the latter because it is hard to judge if an experimental animal is nauseated and commonly used laboratory animals are some of the few species that do not vomit! Nevertheless, significant progress has been made in our understanding of the processes of nausea and vomiting, which has led to new and improved pharmacological treatments for these disorders in the last 20–30 years, as described in many of the accompanying articles in this volume and previous reviews (Rojas and Slusher, 2012; Sanger and Andrews, 2006; Schmäl, 2013).

One of the oldest pharmacological remedies for nausea and vomiting is the plant cannabis (Kalant, 2001). In clinical trials, cannabis-based medicines have been found to be effective anti-emetics and even surpass some modern treatments in their potential to alleviate nausea (Cotter, 2009; Tramèr et al., 2001). However, it was not until the early 1990s that the mechanism of action of cannabis was established following the cloning of the “cannabinoid” (CB) receptors (Howlett et al., 2002; Pertwee et al., 2010). The significance of this discovery was enhanced when it was realized that these receptors were part of an endogenous cannabinoid (endocannabinoid) system in the brain and elsewhere in the body (Di Marzo and De Petrocellis, 2012; Izzo and Sharkey, 2010; Mechoulam and Parker 2013; Piomelli, 2003). The endocannabinoid system serves to modulate the expression of nausea and vomiting when activated by central or peripheral emetic stimuli (Darmani and Chebolu, 2013; Parker et al., 2011).

In this article we will outline the endocannabinoid system and then describe what is known about this system in relation to the neural circuits of nausea and vomiting. We will describe recent findings on the anti-emetic effects of cannabinoids and show how manipulation of elements of the endocannabinoid system can modify the expression of emesis. We will discuss at some length the evidence that cannabinoids and the endocannabinoid system can regulate nausea, because this is an area that has been not been considered so fully in the past. We will then briefly describe the paradoxical effect of chronic exposure to high doses of cannabis that in some people causes a cyclic vomiting syndrome. Finally, we will conclude with some future directions for this research by identifying gaps in our knowledge of the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system.

2. The endocannabinoid system

The isolation of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) as the major psychoactive ingredient in cannabis was an important milestone in neuropharmacology (Howlett et al., 2002; Pertwee et al., 2010). This discovery provided the impetus for extensive investigations that led to an understanding of many of the central and peripheral sites of action of cannabis and ultimately to the cloning of the two G-protein coupled cannabinoid receptors; CB1 and CB2. CB1 receptors are distributed throughout the central and peripheral nervous system, but also in many other sites throughout the body (Howlett et al., 2002; Pertwee et al., 2010). In the brain they are frequently expressed in high density on presynaptic nerve terminals of both inhibitory and excitatory nerves, depending on the region (Katona and Freund, 2012). CB2 receptors are expressed on cells and organs of the immune system, but they are also found in the brain and at other sites in the body (Onaivi et al., 2012; Pacher and Mechoulam, 2011). The actions of cannabinoids can largely be accounted for by these two receptors, however, there are some well-described non-cannabinoid1-, non-CB2 receptor-mediated actions of cannabinoids. To date there is limited evidence for a third cannabinoid receptor, though some cannabinoids act at the GPR55 receptor (Pertwee et al., 2010). Whether GPR55 has any role in nausea and vomiting is not known and has not been examined to date.

Both cannabinoid receptors signal through Gi/o proteins, inhibiting adenylyl cyclase and activating mitogen-activated protein kinase. Activation of the cannabinoid receptors limits calcium entry into cells by inhibiting N- and P/Q-type calcium currents and further inhibits cellular excitability by activating A-type and inwardly rectifying potassium channels (Howlett et al., 2002; Pertwee et al., 2010).

Shortly after the discovery of the CB1 receptor, two endogenous cannabinoid receptor ligands, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) were isolated (Di Marzo and De Petrocellis, 2012). Unlike many preformed intercellular mediators, endocannabinoids are made on demand when cells are stimulated with either an increase in intracellular calcium (Alger and Kim, 2011), or following metabotropic receptor activation involving Gq/11 or possibly Gs proteins (Gyombolai et al., 2012). These ligands are found in the brain and in the periphery, for example, in the gastrointestinal tract (Izzo and Sharkey, 2010), where they act at cannabinoid and other receptors (see below).

Both endocannabinoids are made by enzymatic pathways that have specific localization patterns in the brain that give important clues to their functional roles. Best characterized are the biosynthetic and degradative pathways for the formation and hydrolysis of 2-AG (Blankman and Cravatt, 2013; Long and Cravatt, 2011; Ueda et al., 2010, 2011). The most important pathway for the synthesis of 2-AG begins with activation of a phosphoinositol (PI)-phospholipase C (PLC) which hydrolyzes inositol phospholipids at the sn-2 position producing diacylglycerol (DAG). The hydrolysis of DAG via sn-1-selective diacylglycerol lipases (DAGL)-α and DAGL-β then leads to the formation of 2-AG. Alternatively, but less well characterized, is the sequential hydrolysis of PI by phospholipase A1 to make lyso-PI which is then further hydrolysed to 2-AG by lyso PI-specific PLC. In the brain, endocannabinoid signaling is abolished in DAGL-α −/− mice (Gao et al., 2010), suggesting this form of the enzyme is the key physiological rate limiting enzyme for 2-AG biosynthesis. The metabolism of 2-AG is complex and potentially can involve enzymatic oxygenation, acylation, or phosphorylation; but probably the most important pathway for 2-AG metabolism is hydrolysis (Blankman and Cravatt, 2013; Ueda et al., 2011). Using a functional proteomic approach, Blankman et al. (2007) showed that the majority (~85%) of the 2-AG hydrolyzing activity in the brain was due to the serine hydrolase, monoacylglycerol lipase (MAGL) (Dinh et al., 2002). The remaining hydrolytic activity was due to the enzymes α/β-hydrolase domain-containing protein-6 (ABHD-6) and ABHD-12 (Marrs et al., 2010; Savinainen et al., 2012). MAGL is located presynaptically (Gulyas et al., 2004), but ABHD6 is found in postsynaptic sites (Marrs et al., 2010), suggesting their roles in the regulation of 2-AG are distinct, and possibly important for the establishment of different pools of 2-AG in cellular compartments in the brain. The distribution of these enzymes elsewhere in the body is not well understood.

The major biosynthetic enzyme for the formation of 2-AG in the brain, DAGL-α, was identified in the plasma membranes of postsynaptic dendritic spines in various brain regions (Yoshida et al., 2006). In contrast, as noted above, CB1 receptors are located presynaptically. This anatomical arrangement is entirely consistent with 2-AG being a retrograde synaptic neurotransmitter in the CNS: being synthesized and released from a postsynaptic site and acting to limit neurotransmitter release from presynaptic terminals via CB1 receptor activation, and then having its action terminated by hydrolysis (Alger and Kim, 2011; Castillo et al., 2012). There is some evidence for a basal pool of 2-AG in neurons, since DAGL inhibitors do not block all the synaptic endocannabinoid signaling in some situations, whereas endocannabinoid signaling is completely blocked in DAGL −/− mice (Min et al., 2010). However, the significance of this observation remains to be determined.

Anandamide is the other major endocannabinoid ligand. Anandamide acts not only at CB1 receptors but strong evidence supports the idea that it is also an “endovanilloid”, acting on the ligand-gated transient receptor potential (TRP) vanilloid 1 receptor, and possibly other TRP receptor ion channels (Di Marzo and De Petrocellis, 2012). It should be noted that both anandamide and 2-AG might also be natural ligands for receptors other than the cannabinoid receptors, as data is accumulating that they can modulate receptor binding at a variety of receptors including the G protein-coupled muscarinic cholinergic and mu opioid receptors, nuclear peroxisome proliferator-activated receptors and ligand-gated ion channels such as the 5-HT3 receptor, albeit with relatively low potency and/or efficacy in many cases (Pertwee et al., 2010).

An important route of anandamide synthesis begins with the membrane phospholipid precursor, N-arachidonoylphosphatidylethanolamine (NAPE), which is formed by the transfer of arachidonic acid from the sn-1 position of a donor phospholipid to phosphatidylethanolamine by N–acyltransferase. Hydrolysis of NAPE by an N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) produces anandamide (Blankman and Cravatt, 2013; Di Marzo and De Petrocellis, 2012; Ueda et al., 2010). That said, the levels of anandamide in NAPE-PLD −/− mice are very similar to those of wild type animals and the increase in anandamide seen in the brain after blocking its degradation in vivo is also similar, suggesting that another biosynthetic pathway can completely compensate for the NAPE-PLD pathway or that there are at least two parallel pathways for anandamide synthesis in the brain (Leung et al., 2006). These additional enzymatic pathways for the production of anandamide include the sequential deacylation of NAPE by the enzyme alpha beta-hydrolase 4 and the cleavage of glycerophosphate to yield anandamide, and a PLC-mediated hydrolysis of NAPE which produces phosphoanandamide, which is then dephosphorylated to produce anandamide (Blankman and Cravatt, 2013; Di Marzo and De Petrocellis, 2012; Liu et al., 2006, 2008; Ueda et al., 2010). Little is known about the distribution of these additional biosynthetic enzymatic pathways in the brain, but the distribution of NAPE-PLD has recently been described.

NAPE-PLD has been localized in many regions of the brain, and its distribution is similar to the distribution of the CB1 receptor, but unlike DAGL-α, it has been localized in both pre- and post-synaptic structures (Egertová et al., 2008). Furthermore, it appears to be localized intracellularly on organelles including the smooth endoplasmic reticulum, suggesting that anandamide may act as both an anterograde signaling molecule and/or as an intracellular regulator. Since the binding site for anandamide on TRPV1 receptors is intracellular (Di Marzo and De Petrocellis, 2012), and anandamide is a full agonist of TRPV1 (whereas it is only a partial agonist at the CB1 receptor; Howlett et al., 2002; Pertwee et al., 2010) it seems possible that its primary function in the brain may be distinctly different from that of the synaptic retrograde signaling function of 2-AG (Alger and Kim, 2011; Castillo et al., 2012). In support of this idea, anandamide has been shown to be released tonically in the hippocampus and seems to be responsible for regulating inhibitory network activity in a homeostatic manner (Kim and Alger, 2010). In this case, its actions appear to be retrograde in nature, and so given the distribution of NAPE-PLD noted above, perhaps this is not the source of the anandamide, which has still to be resolved. Much more work is needed to establish the enzyme systems responsible for the production of endocannabinoids in specific brain regions. But as we will see later, both CB1 and TRPV1 receptors are responsible for the antiemetic actions of the endocannabinoid anandamide and the related compound N-arachidonoyl-dopamine (Sharkey et al., 2007).

The principal enzyme for the degradation of anandamide is fatty acid amide hydrolase (FAAH). FAAH is found in neurons throughout the brain, where its postsynaptic distribution is consistent with the idea that the function of anandamide may be primarily to mediate anterograde or intracellular signaling (Gulyas et al., 2004; Tsou et al., 1998). A surprising finding is that levels of anandamide are not only regulated by FAAH, but are reduced in DAGL-α −/− mice, pointing to a convergence in endocannabinoid signaling pathways where 2-AG production regulates the levels of anandamide (Gao et al., 2010). Exactly how this is occurs is not known. Convergence of endocannabinoid signaling was also revealed using dual FAAH and MAGL inhibitors and MAGL inhibitors in FAAH −/− mice (Long et al., 2009; Wise et al., 2012). These studies suggest there is significant cross-talk between these ligand systems and the cannabinoid receptors.

In summary, the endocannabinoid system is responsible for shaping and refining synaptic signaling in the brain and the peripheral nervous system. There is considerable complexity to this system and in only a few areas have systematic studies of all of its many components been conducted. To date, the endocannabinoid system in the peripheral and central neural circuits responsible for the nausea and vomiting have not been extensively studied. In the next section we will outline what is known of the functional neuroanatomy of this system in relation to the reflex circuitry of the brain-gut circuit mediating emesis.

3. The endocannabinoid system at sites in the brain and gastrointestinal tract involved in nausea and vomiting

The key components of the brain-gut circuitry mediating emesis have been well described (Andrews and Horn, 2006; Hornby, 2001). As outlined above, emesis can be initiated peripherally or centrally. However, most commonly, emesis is evoked from the gastrointestinal tract by ingestion of toxins, including bacteria or bacterial products, or food that is not tolerated. It may also be caused by drugs such as the cancer chemotherapeutic agent cisplatin and radiation. In most of these examples, the initial trigger for emesis is the release of serotonin (5-HT) from enterochromaffin cells that are distributed throughout the epithelium of the gastrointestinal tract (Andrews and Bhandari, 1993; Naylor and Rudd, 1996; Rojas and Slusher, 2012). Serotonin activates 5-HT3 and/or 5-HT4 receptors on vagal primary afferent nerves, whose cell bodies are located in the nodose ganglia. Vagal afferents innervating the proximal gastrointestinal tract may also be activated by distension and/or the release of enteric neurotransmitters in the vicinity of vagal afferent endings in the mucosa, myenteric plexus or muscle layers of the wall of the gut. When effectively stimulated, vagal afferents activate circuits in the dorsal vagal complex of the brainstem (Boissonade et al., 1994; Hornby, 2001; Miller and Ruggiero, 1994). The dorsal vagal complex consists of the nucleus of the solitary tract, area postrema and dorsal motor nucleus of the vagus. Circulating emetogens can also directly activate neurons in the area postrema, which is a circumventricular organ that lies outside of the blood-brain barrier (Miller and Leslie, 1994). Cerebral and vestibular inputs are also integrated at the level of the nucleus of the solitary tract. The integrative circuitry of the nucleus of the solitary tract initiates appropriate motor responses that involve activation of the respiratory, gastric, salivatory, esophageal, laryngeal and hypoglossal neural centres in the brainstem and spinal cord (Carpenter, 1990; Miller, 1999). These motor centres elicit the characteristic and stereotyped behaviours of emesis.

The brain centres that elicit nausea are far less clearly defined than those involved in emesis. They are clearly distinct from those involved in emesis and are certainly localized in the forebrain. Early studies from Penfield and Faulk (1955) revealed that stimulation of the insular cortex elicited nausea in some patients undergoing surgery for intractable epilepsy. As well, stimulation of the insular cortex has been shown to produce vomiting in humans (Fiol et al., 1988; Catenoix et al., 2008) and other animals (Kaada, 1951). In rats, inactivation of the visceral insular cortex (granular) reduced lithium chloride (LiCl)-induced malaise (Contreras et al., 2007). Contreras et al. (2007) suggested that this region of the insular cortex (which is also involved in craving for drugs; Naqvi and Bechara, 2009; Forget et al., 2010) may be responsible for sensing strong deviations from a “well-being state” (e.g., Craig, 2002). However, recent functional magnetic resonance imaging studies have revealed an extensive network of brain regions activated by visually-evoked nausea (Napadow, 2013). Phasic and sustained increases in BOLD signals were identified with increasing degrees of nausea. Increasing nausea was associated with increasing phasic activation in the ventral putamen, amygdala and the locus coeruleus; brain regions known to process emotion, stress and fear conditioning. With higher levels of nausea intensity, sustained activation was noted in the insular, anterior cingulate, premotor, and orbitofrontoal cortices and the primary and secondary somatosensory cortices. In addition, subcortical activation was noted in the putamen, ventral tegmental area and nucleus accumbens; a broad network of interoceptive, limbic, somatosensory, and cognitive processing brain areas (Napadow, 2013). Some of these regions are also important in integrating vestibular inputs, and so are likely the common centres for the development of nausea, but further experimental studies are required to substantiate whether nausea evoked from different stimuli activate the same brain regions. Of particular relevance to this paper are findings discussed in more detail below that the anti-nausea effects of a CB1 receptor agonist are mediated by an action in the insular cortex (Limebeer et al, 2013), suggesting it may have a prominent role as a central substrate for nausea.

CB1 receptors are widely distributed in the brain and periphery and are in essence found in all the brain regions and peripheral neural structures described above. Direct evidence for the presence of CB1 receptors on 5-HT containing enterochromaffin cells is lacking, but in both rats (that do not vomit) and the house musk shrew (that does vomit) CB1 receptor agonists reduce intestinal 5-HT release, suggesting that enterochromaffin cells express functional CB1 receptors (Hu et al., 2007; Rutkowska and Gliniak, 2009). Of particular interest are the observations that the CB1 agonist WIN 55,212-2 reduced 5-HT release evoked by the emetogenic Staphylococcal enterotoxin (Hu et al., 2007). These results suggest that 5-HT release from enterochromaffin cells might be selectively targeted to reduce emesis triggered by peripheral stimuli, cancer chemotherapeutics or radiation treatment. It remains to be determined if this strategy would be effective. CB1 receptors are found on the vagal afferent neurons in the nodose ganglion (Burdyga et al., 2004; Partosoedarso et al., 2003). Of interest is the fact that these receptors are regulated by the feeding state of the animal. Fed animals have low levels of CB1 expression whereas the levels of CB1 receptor increase with fasting (Burdyga et al., 2004). The expression of these receptors are not only regulated by circulating hormones such as leptin, but also cannabinoid receptor agonists including anandamide (Burdyga et al., 2004, 2010; Jelsing et al., 2009). Whether CB1 receptors on vagal afferent neurons are involved in the control of nausea and vomiting is not well understood.

CB1 receptors are found in the forebrain, midbrain and brainstem regions described above, in differing densities and in varying locations in the cell. For example, in the locus coeruleus, CB1 receptors were not only found presynaptically, as expected, but also on postsynaptic somatodendritic compartments (Scavone et al., 2010). The highest density of CB1 receptors are in the cortex, amygdala and basal ganglia, with lower densities in the nucleus accumbens, ventral tegmental area and brainstem regions (Mackie, 2005). In the cortex the density of distribution of CB1 receptors varies according the different layers. Throughout the brain there are varying degrees of colocalization with the two main classical transmitters; CB1 seems universally to colocalize with GABA, where it regulates inhibitory transmitter release, but in only some locations does it colocalize with glutamate to regulate excitation (Freund et al., 2003; Kano et al., 2009; Mackie, 2005). Moreover, in neurons the efficiency of the coupling of CB1 receptor to the G protein signaling molecules differs: in GABA neurons it is weakly coupled, whereas in glutamate neurons this coupling is far stronger (Steindel et al., 2013). This implies that lower doses of cannabinoids may elicit effects on glutamatergic synapses whilst GABA synapses may require higher doses of cannabinoids to be effective. Currently, the specific synaptic pathways regulating nausea have not been defined well enough to know which neuronal populations control this sensory experience. Likewise for vomiting, whilst the synaptic circuitry of the dorsal vagal complex is well understood, the specific synaptic events underlying this behavior have not yet been defined. CB1 receptors are nevertheless found in the DVC (Derbenev et al., 2004; Moldrich and Wenger, 2000; Partosoedarso et al., 2003; Sharkey et al., 2007; Suárez et al., 2010; Van Sickle et al., 2001; 2003). CB1 receptors are also found on dopaminergic, noradrenergic and other transmitter containing neurons in the brain regions involved in the control of nausea and vomiting (Freund et al., 2003; Kano et al., 2009; Mackie, 2005).

In general, a detailed description of the other components of the endocannabinoid system in the brain regions regulating nausea and vomiting is lacking. Van Sickle et al. (2005) made the discovery that CB2 receptors were present in the dorsal vagal complex of the ferret and were involved in the regulation of emesis. These functional and neuroanatomical studies have not been extended with regard to nausea. Nevertheless, CB2 receptors are more widely distributed in the brain, including in some of the regions identified above that are involved in nausea, such as the amygdala, striatum, nucleus accumbens and cortex (Brusco et al., 2008; Gong et al., 2006). Interestingly, they have also been described in the vestibular nuclei (Baek et al., 2008), but the functional implications of this for motion sickness remain to be determined. It is not yet clear if they are present in the insular cortex of emetic species. Unlike CB1 receptors, CB2 receptors appear to be postsynaptically localized and may regulate neuronal excitability by unique mechanisms, as well as through more traditional cannabinoid signaling. For example, CB2 receptors were recently described in the prefrontal cortex to be intracellular, regulating neuronal excitability though calcium-activated chloride channels (den Boon et al., 2012). Another interesting feature of the CB2 receptor in the brain is that it may form functional heteromers with the CB1 receptor (Callén et al., 2012). One specific characteristic of these heteromeric receptors is that they are bidirectionally cross-antagonized with both CB1 and CB2 receptor antagonists. This opens up interesting possibilities for therapeutics, but needs to be examined more thoroughly since clearly both receptors need to be in the same anatomical location for this to be happening – and in many brain regions they appear distinct.

Far less is known of the other components of the endocannabinoid system, namely the biosynthetic and degradative enzyme systems involved in the production and breakdown of the endocannabinoids. FAAH was described in neurons of the dorsal motor nucleus of the vagus and it appears also to be expressed in the ferret area postrema (Van Sickle et al., 2001), but not that of the rat (Suárez et al., 2010). MAGL is expressed in the area postrema in the rat (Suárez et al., 2010), but has not been anatomically localized in species that vomit, but it is present in brain of house musk shrews by whole brain analysis (Sticht et al., 2012). DAGLα is not found in the area postrema, and NAPE-PLD and DAGLβ are only weakly expressed, suggesting endocannabinoids are not major transmitters in this region of the brain (Suárez et al., 2010). In other brainstem nuclei involved in emesis, DAGL and NAPE-PLD have not been examined. In the brain regions involved in nausea there have not been extensive examinations of the distribution of the enzymes of endocannabinoid biosynthesis, though FAAH and MAGL are present in some of these regions, such as the nucleus accumbens and the amygdala (Dinh et al., 2002; Gulyas et al., 2004; Tsou et al., 1998).

Much more work is required to examine in detail the endocannabinoid system in the brain regions involved in nausea and vomiting, despite the functional evidence for the effectiveness of this system in regulating these functions, as we shall describe below.

4. Anti-emetic effects of cannabinoids and endocannabinoids

Cannabis is a well-known anti-emetic whose actions have been extensively reviewed (Cotter, 2009; Darmani and Chebolu, 2013; Izzo and Sharkey, 2010; Parker et al., 2011; Tramèr et al., 2001). Following the isolation of Δ 9 -THC, the mechanism and site of action of cannabinoids were established. In humans and animal models, plant-derived cannabinoids, synthetic cannabinoids and endocannabinoids inhibit emesis evoked peripherally or centrally with drugs or natural stimuli. Cannabinoids block both acute and delayed emesis. Where it has been examined, these effects are mediated by CB1 receptors in the DVC (Darmani, 2001a, 2001b; Darmani et al., 2003b; Ray et al., 2009; Van Sickle et al., 2003). Interestingly, there is dissociation between the antiemetic doses of Δ 9 -THC and effects of Δ 9 -THC on impairing motor function (Darmani, 2001b; Darmani and Crim, 2005).

The role of CB2 receptors in the anti-emetic actions of cannabinoids is less well established. Van Sickle et al. (2005) demonstrated that in the ferret the anti-emetic actions of the endocannabinoid 2-AG were blocked by a CB2 receptor antagonist, which did not block the anti-emetic effects of anandamide or Δ 9 -THC. Neither were the effects of the synthetic cannabinoid WIN55,212-2 blocked by a CB2 receptor antagonist in the ferret or Δ 9 -THC and synthetic cannabinoids CP55,940 and WIN55,212-2 in the least shrew (Darmani, 2001c; Darmani et al., 2003b; Simoneau et al., 2001). Because they lack psychotropic effects, CB2 receptor agonists represent potential anti-emetic therapeutics, but this has yet to be tested clinically.

We will focus the rest of this section on compounds that alter the levels of endogenous cannabinoids and the role of the endocannabinoid system in the regulation of emesis. Administration of CB1 receptor antagonists to humans is frequently associated with nausea and vomiting (Després et al., 2009; Kipnes et al., 2010; Pi-Sunyer et al., 2006). In animals that vomit, CB1 receptor antagonists either initiate vomiting or potentiate emesis evoked by an emetogen (Darmani, 2001a; Sharkey et al., 2007; Van Sickle et al., 2001). Taken at face value, these results initially suggested that there is a tonic release of endocannabinoids giving rise to anti-emetic tone, presumably in the brainstem sites that regulate emesis. However, in these studies the receptor antagonists used are in fact “inverse agonist / receptor antagonists” (Bergman et al., 2008; Pertwee et al., 2010) and these findings were subsequently challenged when it was shown that the centrally acting “neutral” CB1 receptor antagonist AM4113 did not potentiate emesis (and similar compounds do not cause nausea, as we discuss below) (Chambers et al., 2007). Exactly what property of the inverse agonists is responsible for their pro-emetic action has not been discovered, although they do release serotonin and dopamine in the brainstem of the least shrew (Darmani et al., 2003a), which may contribute to these actions. Assuming it is the inverse agonist activity that causes this effect, these data are consistent with the notion that there is constitutive receptor activity in the brainstem. But it still remains to be determined where in the synaptic circuitry CB1 receptors are acting and whether or not this is the case, because, as we shall illustrate below, further evidence supports the notion of an anti-emetic endocannabinoid tone.

Compounds that increase the availability of endogenous cannabinoids have the potential to harness the anti-emetic power of the endocannabinoid system in a locally restricted manner, given the “on demand” nature of endocannabinoid release (Alger and Kim, 2011). That is, when the emetic circuitry is activated the local release of endocannabinoids acting at cannabinoid receptors would limit the extent of this activation. This concept has been tested and whilst it holds true in some circumstances, there are some conflicting data.

Early studies using the compound VDM11 that was initially reported as an endocannabinoid transport inhibitor revealed efficacious anti-emetic actions in both ferrets and the least shrew against morphine 6-glucuronde and apomorphine, respectively (Darmani et al., 2005; Van Sickle et al., 2005). In the ferret, this effect was interestingly inhibited by both CB1 and CB2 receptor antagonists (Van Sickle et al., 2005). Similarly, AM404, an analogous compound to VDM11, blocks acute but not delayed emesis induced by cisplatin, but not that caused by copper sulphate or apomorphine (Chu et al., 2010); the receptor mechanism of action of AM404 was not examined. These compounds and others like them were recently shown to inhibit the association of anandamide with fatty acid binding proteins, rather than a membrane transporter (Kaczocha et al., 2012). So exactly where it is having an effect and how this action occurs remains an enigma. One possible explanation is that they are acting as FAAH inhibitors and raising the local levels of endocannabinoids. The FAAH inhibitor, URB597, is a particularly promising compound in treatment of nausea and vomiting, because it has no known psychoactive effects (Fegley et al, 2003; Gobbi et al, 2005). URB597 was shown to be anti-emetic against morphine 6 glucuronide in the ferret (Van Sickle et al., 2005), but not against apomorphine in this species (Percie du Sert et al., 2010); but in the least shrew, it is pro-emetic and does not prevent vomiting evoked by cisplatin or apomorphine (Darmani et al., 2005), which argues against this possibility in this species.

More recently, URB597 was tested in the house musk shrew against cisplatin- and nicotine-induced emesis (Parker et al., 2009). URB597 given alone or together with anandamide blocked cisplatin-induced emesis, whilst anandamide (5mg/kg) was ineffective when given alone. Nicotine-induced emesis was also attenuated by URB597 and this effect was reversed by the CB1 receptor antagonist rimonabant, in a dose that alone was not pro-emetic (Parker et al., 2009). Further support for the role of endocannabinoids in the regulation of emesis was obtained by blocking MAGL. Raising 2-AG levels with the selective inhibitor JZL184 was also an effective strategy to block LiCl-induced vomiting in the house musk shrew (Sticht et al., 2011). As before, this was shown to be sensitive to CB1 receptor antagonists, but in neither case were the effects of CB2 receptor antagonists examined with either JZL184 or URB597 (Parker et al., 2009; Sticht et al., 2011). These data tell us that FAAH and MAGL inhibitors, and drugs like VDM11 offer the potential for new anti-emetic strategies. Why the least shrew behaves differently in response to these treatments remains slightly unclear. It may be that endocannabinoids are metabolized differently in this species or that for some reason the emetic circuitry is subtly different in these animals. However, it should also be said, that in most of the studies noted above in the ferret and the house musk shrew, full dose-response curves for the various cannabinoid agonists and antagonists, as well as enzyme inhibitors have not be performed. Different conclusions might be drawn depending on the nature of the results obtained conducting such studies.

Before moving on to discuss the anti-nausea effects of cannabinoids and endocannabinoids, it is important to consider possible synergistic actions with other receptor systems, notably 5-HT3 and TRPV1. As noted above, anandamide is an intracellular TRPV1 agonist and acts at these receptors to inhibit emesis in the ferret (Sharkey et al., 2007). Similarly, Δ 9 -THC at low doses was more efficacious against cisplatin-induced emesis in the house musk shrew when combined with a low dose of a 5-HT3 antagonist, than when given alone (Kwiatkowska et al., 2004), but full dose-response studies were not conducted. In the least shrew, limited potentiation at low doses of Δ 9 -THC was also observed (Wang et al., 2009). These studies suggest there is a potential that some of the actions of the endocannabinoid system involve other receptor systems – not limited only to these two. However, the extent to which such interactions actually occur are not clear and future studies should consider them in order to explain more fully the potential of utilizing the endocannabinoid system in novel anti-emetic strategies.

5. Cannabinoids and endocannabinoids in the control of nausea in humans

There is clearly a need of treatments for acute, delayed and anticipatory nausea in chemotherapy treatment (e.g., Poli-Bigelli et al., 2003). One of the first recognized medicinal benefits of cannabis was for the treatment of nausea (Iversen, 2008). The most investigated compound has been Δ 9 -THC (see Cotter, 2009; Tramèr et al., 2001 for reviews); however, other nonpsychoactive compounds in the cannabis plant have recently been reported to also have benefits in preclinical models of nausea and vomiting.

Nabilone (Cesamet) an orally active, synthetic analogue of Δ 9 -THC, was licensed for management of chemotherapy-induced nausea and vomiting in 1985, but today is only prescribed after conventional anti-emetics fail. To our knowledge, studies have only compared nabilone with dopamine receptor 2 (D2) receptor antagonists for their anti-emetic/anti-nausea effects in chemotherapy patients. When compared with D2 receptor antagonists in double blind cross-over designs, such as metoclopramide, nabilone treatment resulted in fewer vomiting episodes (Ahmedzai et al., 1983; Herman et al., 1979; Pomeroy et al., 1986; Steele et al., 1980) and reports of nausea on a 3 point scale of severity (Ahmedzai et al., 1983; Dalzell et al., 1986; Herman et al., 1979) in patients taking moderately toxic chemotherapy treatments; however, when given to cancer patients receiving cisplatin chemotherapy, nabilone was only as effective as the D2 receptor antagonist in reducing vomiting (Crawford and Buckman, 1986). Therefore, nabilone is superior to D2 receptor antagonists for the treatment of moderate emesis but probably not for the treatment of severe emesis.

Another orally active, synthetic Δ 9 -THC known as dronabinol (Marinol), has also been used as an anti-emetic and was later used as an appetite stimulant (Pertwee, 2009). When compared with Prochlorperazine (a D2 receptor antagonist) or a combination of dronabinol and the D2 receptor antagonist, those patients given the combination treatment had less severe nausea and the duration was significantly shorter than with either agent alone, when they were being treated with moderately emetogenic chemotherapy (Lane et al., 1991). Most recently, Namisol, a tablet containing pure Δ 9 -THC, was designed to improve absorption after ingestion. Evidence in healthy adults indicates its rapid onset may be beneficial for rapid therapeutic effects, but no clinical trials have yet been completed to demonstrate its clinical efficacy (Klumpers et al., 2012).

In cancer patients, administration of oral Δ 9 -THC has been shown to significantly suppress the experience of nausea and vomiting, in comparison to placebo controls (Chang et al., 1979; Frytak et al., 1979; Orr et al., 1980; Sallan et al., 1975; Sweet et al., 1981) and when compared to the D2 receptor antagonists available at the time, Δ 9 -THC was at least as effective (Carey et al., 1983; Crawford and Buckman, 1986; Cunningham et al., 1988; Frytak et al., 1979; Tramèr et al., 2001; Ungerleider et al., 1984) if not more effective (Ekert et al., 1979; Orr and McKernan, 1981) at reducing nausea and vomiting. Clinical evidence suggests that Δ 8 -THC suppresses anticipatory nausea in child patients (Abrahamov et al., 1995).

Only one published clinical trial has directly compared the anti-emetic and anti-nausea effects of a cannabinoid with a 5-HT3 receptor antagonist. Meiri et al. (2007) compared dronabinol, ondansetron, or their combination, for efficacy in reducing delayed chemotherapy-induced nausea and vomiting. Dronabinol and ondansetron alone were equally effective in reducing nausea and vomiting, but the combined therapies were no more effective than either agent alone. When assessing severity of nausea alone, dronabinol was more effective than ondansetron for mildly to moderately severe nausea produced by chemotherapy treatments, but not for severe emetogenic treatments. However, there has been no report of a direct comparison of Δ 9 -THC and the current first line treatment of 5-HT3 receptor antagonist/dexamethasone/neurokinin 1 receptor antagonist on acute or delayed chemotherapy-induced nausea or vomiting in human chemotherapy patients.

Another chemical compound in cannabis is cannabidiol (CBD), this non-psychoactive cannabinoid is now available as a sublingual spray called Nabidiolex (GW Pharmaceuticals). There are no reports of any specific evaluation of CBD alone to reduce nausea and vomiting in human chemotherapy patients. Interestingly, there have been no reports of the evaluation of combined Δ 9 -THC and CBD on emesis or nausea in animal models. However, in humans, a phase II clinical trial evaluated Sativex (an oromucosally administered cannabis-based medicine containing Δ 9 -THC and CBD in a 1:1 ratio), taken in conjunction with standard anti-emetic therapies (5-HT3 receptor antagonists), for its ability to control delayed chemotherapy-induced nausea and vomiting (Duran et al., 2010). When compared with placebo, Sativex reduced the incidence of delayed nausea and vomiting and was well tolerated by patients. Fifty-seven percent of Sativex patients experienced no delayed nausea compared to 22% in the placebo group. In terms of emesis, 71% of Sativex patients versus 22% of placebo patients experienced no delayed emesis. These results indicate that Δ 9 -THC and CBD in combination may be useful in managing delayed nausea and vomiting in human patients.

The role of endocannabinoids in nausea and vomiting has typically been investigated in animal models with human data rather scarce. However, Choukèr et al. (2010) recently reported lower blood endocannabinoid levels among participants experiencing motion sickness while undergoing parabolic flight maneuvers, whereas anandamide and 2-AG levels were higher among participants who did not experience motion sickness. Moreover, CB1 receptor expression was reduced among participants experiencing motion sickness compared to those unaffected by parabolic flight maneuvers. Interestingly, anandamide increases were observed early during the flight, whereas the 2-AG increases were observed following the flight, suggesting that endocannabinoids may play different roles in reducing both motion sickness and stress induced by parabolic flights (Choukèr et al., 2010).

6. Cannabinoid and endocannabinoid regulation of nausea in animal models

Animal models of vomiting have been valuable in elucidating the neural mechanisms of the emetic reflex (Hornby, 2001); however, the central mechanisms regulating nausea are still not well understood (Andrews and Horn, 2006). Considerably greater progress has been made toward the control of vomiting than the control of nausea. One reason is that nausea is much more difficult to quantify than is vomiting, and therefore, preclinical model development has been challenging. Although vomiting is a gastrointestinal event under control of brainstem structures (Hornby, 2001), it is generally agreed that activation of central forebrain structures is required to produce the distinct sensation of nausea (see above). The gastrointestinal visceral inputs to the brain are well characterized (Cechetto and Saper, 1987), but the way in which they are processed in the forebrain, leading to the sensation of nausea, is only beginning to be understood. One limitation in the preclinical assessment of nausea has been the lack of a reliable animal model of nausea. Of course, we can never know if an animal experiences nausea in the same manner as humans, however, here we describe the current models used to determine the nauseating potential of compounds and to determine the potential of anti-nausea agents that reverse nausea. Such models are essential if we hope to develop new treatments for this distressing disorder in humans. These models do not require the use of an animal capable of vomiting and have been primarily employed in rodents, which lack an emetic reflex. Although rodents lack an emetic reflex, their gastric afferents respond in the same manner to physical and chemical (intragastric copper sulphate and cisplatin) stimulation that precedes vomiting in ferrets, presumably resulting in nausea that precedes vomiting (Billig et al., 2001; Hillsley and Grundy, 1998). Indeed, 5-HT3 receptor antagonists that block vomiting in ferrets also disrupt this preceding neural afferent reaction in rats (Horn et al., 2004), suggesting that the rat detects nausea, but that the vomiting reaction is absent in this species. Indeed, laboratory rats failed to display any of the common coordinated actions indicative of retching or vomiting after emetic stimulation as compared with the musk shrew, using an in-situ brainstem preparation (Horn et al., 2013).

6.1 Pica

Consumption of non-nutritive kaolin clay, an example of pica (the eating of a non-food substance), is a putative direct indicator of nausea in rodents. Pica consumption may ameliorate the effects of toxins in the diet (e.g. Mitchell et al., 1976; Rudd et al., 2002). Pica has been reported in several strains of rats and mice exposed to emetic compounds (e.g. Stern et al., 2011); however, in emetic species, such as the house musk shrew, pica has not been demonstrated (Liu et al., 2005; Stern et al., 2011; Yamamoto et al., 2004). Although Δ 9 -THC has not been specifically evaluated for its anti-nausea effects in the pica model of increased intake of kaolin, the synthetic CB1 receptor agonist, WIN55,212-2 did not modify pica produced by chronic administration of cisplatin (Vera et al., 2007). To our knowledge, there have been no investigations of the potential of endocannabinoid manipulations to modify pica in rats or mice. Pica has the advantage of being a measure of unconditioned nausea, but it has poor temporal resolution (Stern et al., 2011). In addition, it may be difficult to apply to a species when intake is small, and it can be produced by factors other than nausea, such as stress or pain (Burchfield et al., 1977); therefore, it may not be selectively produced by nausea.

6.2 Lying on Belly

Lying on belly in rats (e.g. Bernstein et al., 1992; Parker et al., 1984) or flopping in ferrets (Stern et al., 2011) is another behavior that has been characterised as a nausea-induced response. In rats, this behavior has only been evaluated as a measure of LiCl-induced nausea (e.g. Bernstein et al., 1992; Contreras et al., 2007; Tuerke et al., 2012b). No other emetic agents have been evaluated using this measure. Both area postrema lesions (Bernstein et al. 1992) and interoceptive insular cortex lesions (Contreras et al. 2007) reduce LiCl-induced lying on belly. As well, pretreatment with the 5-HT3 receptor antagonist, ondansetron, reduces LiCl-induced lying on belly in rats (Tuerke et al., 2012b). There have been no reports of the effect of cannabinoid manipulations on the behavior of lying on belly in rats. A major limitation in this measure of nausea-induced behavior, however, is the difficulty in discriminating lying on belly from non-specific locomotor suppression (e.g. Tuerke et al., 2012b); therefore, this measure may not be a specific model of nausea-induced behavior.

6.3 Conditioned Flavor Avoidance and Conditioned Gaping

Other commonly employed rodent measures of nausea are conditioned flavor avoidance learning (e.g. Garcia et al., 1974) and conditioned gaping reactions in the taste reactivity test (Grill and Norgren, 1978). These are not direct measures of nausea, but rely upon conditioning. Conditioned flavor avoidance is a measure of an animal’s reluctance to consume flavors of foods that have been previously paired with nausea-inducing treatments. Indeed, high doses (8–10 mg/kg) of the CB1 inverse agonists AM251 (McLaughlan et al., 2005) and rimonabant (DeVry et al., 2004) have been shown to produce conditioned avoidance of flavored solution as well as conditioned gaping reactions (McLaughlan et al., 2005), but lower doses (3 and 5 mg/kg) that are also effective in reducing food intake failed to produce conditioned avoidance of flavored food pellets in a two choice test, even after 4 conditioning trials (Chambers et al., 2006). On the other hand, CB1 receptor neutral antagonists, AM6545 (Cluny et al., 2010), AM6527 (Limebeer et al., 2010) and AM4113 (Sink et al., 2008) all failed to produce both conditioned flavor avoidance and conditioned gaping at a high dose (10 mg/kg). These results suggest that it is the inverse agonist effect of rimonabant that is responsible for the side effect of nausea in human clinical trials (Després et al., 2009; Kipnes et al., 2010; Pi-Sunyer et al., 2006). Somewhat paradoxically, the CB1agonists CP55,940 (0.1 mg/kg; McGregor et al., 1996) and Δ 9 -THC (1.5 mg/kg −2.5 mg/kg; Parker and Gilles, 1995; Schramm-Sapyta et al., 2007) also produce conditioned flavor avoidance and conditioned place avoidance. Yet, low doses of Δ 9 -THC (0.3 and 1 mg/kg) and nabilone (0.01 and 0.03 mg/kg), but not levonantrodol (0.03 an 0.06 mg/kg) have also been reported to attenuate flavor avoidance induced by cyclophosphamide in CD-1 mice (Landauer et al., 1985). Since conditioned flavor avoidance can be produced even by rewarding drugs in non-emetic rodents it is not a particularly selective measure of nausea (see Parker review in current issue).

In contrast to conditioned flavor avoidance, conditioned gapingreactions appear to be more selective measure of conditioned nausea which is only produced by emetic drugs and consistently prevented by anti-emetic drugs (see Grill and Norgren, 1978; Pelchat et al., 1983; Parker review in present volume). Much of the work on the effects of cannabinoids and endocannabinoids on nausea in rodents using this model is reviewed by Parker et al. (2011). Here we update this review.

Clearly, low doses of CB1 agonists (0.5 mg/kg Δ 9 -THC, Limebeer and Parker, 1999; 0.001–0.01 HU-210, Parker et al., 2003) attenuate nausea in the conditioned gaping model, an effect that is reversed by rimonabant (see Parker et al., 2011). At low doses (1–5 mg/kg, i.p.) the nonpsychoactive phytocannabinoid, CBD, also reduces these nausea-induced behaviors (without affecting any measures of motor activity) by its action as an indirect agonist of 5-HT1A receptors in the dorsal raphe nucleus (Rock et al., 2012; Parker et al., 2011). By acting as an agonist of the somatodendritic 5-HT1A autoreceptors located in the dorsal raphe, CBD would be expected to reduce the release of 5-HT in forebrain regions (e.g. possibly the interoceptive insular cortex, Tuerke et al., 2012a) to ultimately suppress toxin-induced nausea. The currently employed anti-anxiety compound buspirone acts as a partial 5-HT1A agonist. In humans, buspirone resulted in a reduction of self-report nausea scores in healthy human patients participating in nutrient drink test to assess gastric functioning (Chial et al., 2003). In this test, participants consume the maximum tolerated volume of a nutrient drink at the rate of 30 ml/min and 30 min later symptoms of bloating, fullness, nausea and pain are assessed. Buspirione (10 mg twice orally) selectively lowered nausea ratings in this test. On the other hand, intravenously administered busprione was ineffective in preventing postoperative nausea and vomiting (Kranke et al., 2012).

The non-psychoactive carboxylic acidic precursor of CBD, cannabidiolic acid (CBDA), is present in the fresh cannabis plant and slowly loses its acidic function (decarboxylates) in the plant in response to heating (e.g. when cannabis is smoked). Recent evidence indicates that CBDA (0.1 and/or 0.5 mg/kg, i.p.) potently interferes with motion-, LiCl-, and cisplatin- induced vomiting in the house musk shrew (Bolognini et al., 2012). CBDA also reduced acute nausea produced by LiCl, an effect that was prevented by pretreatment with the 5-HT1A receptor antagonist, WAY100635, and not by rimonabant. CBDA also increased the ability of the 5-HT1A receptor agonist, 8-OH-DPAT, to potently stimulate [ 35 S]GTPγS binding to rat brainstem membrane, again without activating CB1 receptors in vitro or in vivo. More recently, CBDA has been shown to reduce acute nausea at a dose as low as 0.5 μg/kg (Rock and Parker, 2013a). As well, a subthreshold dose of CBDA (0.1 μg/kg, i.p.) enhanced the ability of a mildly effective dose of ondansetron (1 μg/kg) (Rock and Parker, 2013a) and an ineffective dose (0.3 mg/g) of metoclopramide (Rock and Parker, 2013b) to reduce LiCl-induced acute nausea in the rat flavor induced gaping model. Interestingly, both CBD (Mechoulam et al., 2002) and CBDA (Rock and Parker, 2013a) have no effect on locomotor activity or any of the commonly measured CB1 mediated psychoactive behaviors.

The carboxylic acidic precursor of Δ 9 -THC is tetrahydrocannabinolic acid (THCA, Gaoni and Mechoulam, 1964). In the fresh plant, THCA is decarboxylated to Δ 9 -THC by heating or burning. Interestingly, no psychotomimetic activity was observed when THCA was administered to: rhesus monkeys at doses up to 5 mg/kg (intravenously, i.v.), mice at doses up to 20 mg/kg (i.p.), and dogs at doses up to 7 mg/kg (Grunfeld and Edery, 1969). Recent results (Rock et al., 2013) indicate that THCA (0.5 and 0.05 mg/kg, i.p.) reduced LiCl-induced vomiting in the house musk shrew, an effect that was reversed with rimonabant pretreatment. THCA (0.05 mg /kg, i.p.) also reduced conditioned gaping elicited by a flavour, without modifying saccharin palatability or conditioned taste avoidance. The suppression of LiCl-induced gaping was not simply the result of conversion of the THCA to THC once administered, because when administered at a dose of 0.05 mg/kg, i.p., Δ 9 -THC did not suppress this nausea induced behaviour.

Endocannabinoids are also effective in reducing conditioned gaping in rats. As reviewed by Parker et al. (2011) inhibition of FAAH-mediated hydrolysis of anandamide by URB597 has been shown to suppress LiCl-induced conditioned gaping in rats, with an even greater suppressive effect when co-administered with exogenous anandamide (Cross-Mellor et al., 2007). As well, most recently, inhibition of anandamide reuptake by ARN272 also suppresses this nausea-induced behavior (O’Brien et al., 2013). Both of these effects were reversed by the rimonabant, indicating a CB1 mediated effect. More recently, the endocannabinoid, 2-AG, like anandamide, has been shown to reduce nausea in rats. Pretreatment with exogenous 2-AG dose-dependently suppresses the establishment of LiCl induced conditioned gaping (Sticht et al., 2011). However, unlike the anti-nausea effects of anandamide, those of 2-AG do not seem to be entirely dependent on CB1 receptors since they can be reversed by the cyclooxygenase inhibitor, indomethacin (Sticht et al., 2011), but not by the CB1 or CB2 receptor antagonists, AM251 and AM630, respectively. Interestingly, the suppression of conditioned gaping following concomitant pretreatment with the MAGL inhibitor, JZL184, and exogenous 2-AG was partially reversed by a CB1 receptor antagonist (Sticht et al., 2011), suggesting that decreased 2-AG turnover reduces nausea, in part, through an action at CB1 receptors. However, since cyclooxygenase inhibition blocks the anti-nausea effects of 2-AG, it appears that 2-AG acts through several mechanisms to modulate LiCl-induced nausea. Further research is necessary to clarify the precise role of downstream endocannabinoid metabolites in the suppression of nausea.

As described above, rimonabant and AM251 produce both vomiting and nausea at high doses by acting as CB1 inverse agonists. At lower doses than those that produce the nausea-induced behavior of gaping (2.5 mg/kg), both AM251 (Limebeer et al., 2010) and rimonabant (Parker et al., 2003) potentiated the gaping produced by LiCl. On the other hand, the CB1 receptor neutral antagonists (without inverse agonist effects), AM4113 (Sink et al., 2007), AM6527 (Limebeer et al., 2010) and AM6545 (Cluny et al., 2010; Limebeer et al., 2010) do not produce conditioned flavor avoidance, nausea-induced conditioned gaping or potentiated LiCl-induced conditioned gaping reactions. Therefore, the nausea inducing effects of rimonabant and AM251 appear to be mediated by their inverse agonism effects at the CB1 receptor.

As indicated above, it is generally understood that nausea is regulated by central forebrain regions. Recent evidence indicates that at least one the forebrain region regulating nausea is the visceral insular cortex. Ablation of this region (Kiefer and Orr, 1992) and selective serotonin lesions of this region (Tuerke et al., 2012a) prevents LiCl-induced conditioned gaping reactions. As well, intracranial administration of ondansetron to this region attenuates nausea induced gaping reactions (Tuerke et al., 2012). Of particular interest, the location of the CB1 receptors mediating the anti-nausea actions appear to be in the visceral insular cortex (Limebeer et al., 2012). Delivery of the CB1 agonist, HU-210, to the visceral insular cortex, but not to the gustatory insular cortex, interfered with the establishment of LiCl-induced gaping reactions in rats. Such interference was prevented by co-administration of the CB1 inverse agonist/antagonist AM251 at a dose that had no effect on its own. Interestingly, however, the nausea-inducing effects of the CB1 inverse agonist/antagonist AM251 was not evoked by administration into this brain region (Limebeer et al., 2012).

7. Contextually-elicited conditioned gaping reactions: A model of anticipatory nausea

Rats not only display conditioned gaping reactions when re-exposed to a flavor previously paired with a nausea-inducing drug, but they also display conditioned gaping reactions when re-exposed to a context previously paired with a nausea-inducing drug (Chan et al., 2009; Limebeer et al., 2008; Rock et al., 2008;). As well, the house musk shrew also displays conditioned retching when re-exposed to a context previously paired with toxin-induced vomiting (Parker and Kemp, 2001; Parker et al., 2006). These contextually elicited conditioned gaping or retching reactions represent animal models of anticipatory nausea analogous to that experienced by human chemotherapy patients, which can be produced following 3–4 conditioning trials. In human chemotherapy patients, when anticipatory nausea develops, the classic anti-emetic agent ondansetron is ineffective in reducing this symptom (Hickok et al., 2003); likewise rats and shrews pretreated with ondansetron do not show a suppression of contextually-elicited gaping and retching reactions, respectively (Limebeer et al., 2006; Parker and Kemp, 2001; Parker et al., 2006; Rock et al., 2008). On the other hand, Δ 9 – THC, URB597 and CBD all reduce these contextually-elicited conditioned nausea reactions (Parker et al., 2011). More recently, it has been shown that CBDA (Bolognini et al., 2012) were more potent than CBD and Δ 9 -THC respectively in attenuation of contextually-elicited conditioned gaping in rats. CBDA potently suppresses nausea and vomiting in a 5-HT1A receptor dependent manner (Bolognini et al., 2012). Since these compounds are both non-psychoactive, they are promising candidates for the treatment of anticipatory nausea, as there is no current therapeutic available once anticipatory nausea does develop. Currently, patients are given non-specific anti-anxiety drugs.

Similarly, endocannabinoid enzyme inhibitors reduce contextually-elicited conditioned gaping in rats. The FAAH inhibitor, URB597, interfered with both the establishment and expression of conditioned gaping to an illness-paired context in a dose dependent manner (Rock et al., 2008). Since rimonabant reversed these effects, they were most likely mediated by elevated anandamide. Recently, Limebeer et al. (2013) evaluated the potential of the dual FAAH /MAGL inhibitor, JZL195, on its own and combined with anandamide and 2-AG, to reduce anticipatory nausea in the rat model. JZL195 suppressed conditioned gaping and by elevation of anandamide, but not 2-AG, an effect that was reversed by rimonabant (Limebeer et al., 2013). The suppressant effect of JZL195 was potentiated by co-administration of anandamide or 2-AG. On its own anandamide, but not 2-AG, also suppressed contextually elicited gaping, again reversed by rimonabant.

8. Cannabis and hyperemesis: the paradoxical effect of chronic exposure to cannabis

Heavy chronic cannabis use in some people, frequently young ones, leads to a constellation of symptoms that include abdominal pain, recurrent nausea and intractable cyclic vomiting (Galli et al, 2011; Nicolson et al., 2012; Simonetto et al., 2012). This syndrome was first reported about 10 years ago (Allen et al., 2004). These symptoms are, of course, exactly the opposite of what has been outlined above and hence represent a paradoxical effect of cannabis. Relief from these symptoms can be obtained from hot baths and showers, but standard anti-emetic treatments are not particularly effective (Galli et al, 2011; Nicholson et al., 2012; Simonetto et al., 2012). The mechanisms underlying these effects are entirely unknown, but are speculated to be either the buildup of a toxic chemical from the cannabis plant, or are due to a downregulation of cannabinoid receptors due to the high exposure to ligand. There are no animal models for this syndrome, which perhaps warrants further investigations. Given the relatively recent appearance of this condition, it would seem likely that recent developments in the horticulture of the plant may be responsible.

9. Future directions in using the endocannabinoid system in the treatment of nausea and vomiting

As can be appreciated from the discussion in the previous sections, we believe that the endocannabinoid system has the potential to be used for the treatment of nausea and likely as an adjunct therapy for the treatment of emesis, particularly delayed emesis, where current therapies are limited in their degree of efficacy. There are, however, many gaps in our knowledge, most of which were highlighted above. One of the biggest limitations is the very widespread nature of the CB1 receptor and the many critical functions in the synaptic control of neurotransmission that it subserves. Any compounds that either act directly at the receptor or increase (or reduce) ligand availability, have the potential to radically alter brain functions beyond that of nausea and vomiting. So, for example, enhancing endocannabinoid biosynthesis, which would, on the face of it, seem like a good anti-emetic strategy, is unlikely to be specific and might lead to many unwanted side-effects. Reducing endocannabinoid metabolism seems to carry with it a lot of potential and to date, side-effects of FAAH and MAGL inhibitors seem to be rather minimal, at least in animal models. Currently, another major limitation of advancing endocannabinoid therapies for the treatment of nausea and vomiting is actually our knowledge of the specific roles played by the two endocannabinoids anandamide and 2-AG. By inference from use of FAAH and MAGL inhibitors, both seem to be important, but more sophisticated approaches are required to identify the specific functional contributions of each. As noted above, understanding the role of CB2 receptors, particularly in nausea, also remains an important direction in research. There may be an opportunity to utilize these receptors for treatments, though as for CB1 receptors, their widespread nature may limit or restrict the use of such therapies.

Nausea and vomiting are frequently debilitating conditions that require substantial effort and cost to manage. Advances in recent progress in understanding the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system have revealed significant potential for therapeutic approaches to be developed. Future efforts aimed at developing new endocannabinoid-based anti-nausea and anti-emetic therapies are clearly warranted.

Acknowledgments

Original work in the authors’ laboratories is supported by the Canadian Institutes of Health Research (KAS), the Natural Sciences and Engineering Research Council of Canada (LAP) and NIH grants-NIDA 12605 and CA115331 (ND). KAS is the recipient of a Killam Annual Professorship and holds the Crohn’s & Colitis Foundation of Canada Chair in Inflammatory Bowel Disease Research at the University of Calgary. LAP is the recipient of a Tier 1 Canada Research Chair in behavioural neuroscience at University of Guelph.

Footnotes

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