Summary of Evidence

FDA-approved cannabinoid-based drugs may be available for certain Blue Cross Blue Shield of Minnesota benefit-eligible members. However, medical marijuana (cannabis), is considered experimental/investigative for all indications. This is due to the lack of FDA approval for marijuana as a safe and effective drug and the lack of published clinical evidence demonstrating an impact on improved health outcomes.

Rationale

There has been a growing interest in the development of therapies and other FDA-regulated consumer products derived from cannabis and its components, including cannabidiol (CBD). Products containing cannabis or cannabis-derived compounds are treated the same as any other FDA-regulated product.

At the federal level, cannabis and all derivatives of the plant, with the exception of the U.S. Food and Drug Administration (FDA)-approved drugs, are classified as a Schedule I substance under the Controlled Substances Act. Schedule I substances are considered to have no currently accepted medical use and a high potential for abuse. To date, the FDA has not approved a marketing application for cannabis for the treatment of any disease or condition.

Three synthetic THC products and a plant-based pharmaceutical product have received approval by the FDA for non-pain indications. Another plant-based pharmaceutical product (Sativex®) is approved for use outside of the U.S. and is considered an investigational drug by the FDA. Studies with these cannabinoids may provide indirect evidence of the effects of products sold at dispensaries.

• Marinol® (dronabinol) oral capsule is indicated in adults for the treatment of: (1) anorexia associated with weight loss in patients with acquired immune deficiency syndrome (AIDS), and (2) nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
• Syndros® (dronabinol) oral solution is indicated in adults for the treatment of: (1) anorexia associated with weight loss in patients with acquired immune deficiency syndrome (AIDS), and (2) nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
• Cesamet® (nabilone), a synthetic analog of THC, is an oral capsule indicated for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
• Epidiolex® (cannabidiol) is an oral solution containing CBD that is concentrated from cannabis plants. It is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.
• Sativex® (nabiximols) is a pharmaceutical product extracted from the whole cannabis plant that contains THC and CBD in a 1:1 ratio along with minor cannabinoids. It is considered an investigational drug by the FDA and has been studied in several Phase III trials for the treatment of cancer pain.

In 2019, the FDA announced steps for the agency's continued evaluation of potential regulatory pathways for the marketing of cannabis and cannabis-derived products under the FDA's existing authorities. As part of this effort, the FDA issued warning letters to companies marketing CBD products with "egregious and unfounded claims" that were aimed at vulnerable populations, including individuals with cancer, Alzheimer disease, fibromyalgia, and substance abuse disorders.

There are questions that need to be addressed to reach conclusions regarding the efficacy of medical cannabis for chronic pain. Further study is needed to identify if there are specific chronic pain types that can be effectively treated with medical cannabis, and to determine what doses and delivery modes are effective. In addition, long-term use of at least 1 year needs to be evaluated.

In 2018, Mücke et al published a Cochrane review of cannabis-based medications for chronic neuropathic pain. 16 randomized, double-blind controlled trials with 1750 participants of medical cannabis, plant-derived and synthetic cannabis-based medicines compared to placebo or any other active treatment of conditions with chronic neuropathic pain in adults met inclusion criteria. The reviewers rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis (a primary outcome) to be of very low quality (26% vs 21%; RD 0.09 [95% CI 0.01 to 0.17]; need to treat for an additional beneficial outcome [NNTB] 11 [95% CI 6 to 100]; 1092 participants, 6 studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 [95% CI 0.02 to 0.07]; need to treat for an additional harmful outcome [NNTH] 25 [95% CI 16 to 50]; 1848 participants, 13 studies, moderate-quality evidence). No information was found on long-term risks in the studies analyzed. There was evidence of publication bias, as there were studies with negative results that had not been published. The reviewers concluded that the potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms.

In 2015, Andreae et al conducted a patient-level Bayesian meta-analysis of 5 RCTs that evaluated inhaled cannabis for neuropathic pain. The primary outcome was the proportion of responders with more than 30% improvement in a patient reported instrument such as the VAS. Inhaled cannabis increased the proportion of responders with an OR of 3.2 and a Bayesian posterior probability of 99.7%. This analysis provides direct evidence of inhaled cannabis for neuropathic pain but is limited by the small population with multiple etiologies, and the variability in the short duration of the studies (from hours to weeks).

In 2017, Butler et al conducted a systematic review of cannabis use for treating chronic non-cancer pain for the Minnesota Department of Public Health Medical Cannabis program. Reviewers identified 21 studies of at least 2 weeks duration. The studies used broad categories of chronic pain, and nearly all used cannabis as an adjunctive treatment to other pain medications. The most commonly studied cannabis product was nabiximols. Low strength evidence favored nabiximols over placebo for peripheral neuropathic pain and suggested no difference between nabiximols and placebo in patients with multiple sclerosis or central neuropathic pain. There was insufficient evidence for other non-cancer chronic pain conditions. The review found that cannabinoids are associated with greater risk of any adverse events (AEs), serious AEs, withdrawals due to AEs, and other specified AEs, as compared to placebo. Only 1 study compared AEs between cannabinoids and opioids or other analgesics. Limitations of the body of evidence were that the botanical and synthetic treatments in the review provided only indirect evidence regarding the benefits and harms of whole plant medical cannabis, and treatment durations in the studies were too short to address benefits and harms from long-term use. The reviewers stated that overall, the literature for medical cannabis for chronic non-cancer pain is sparse, patchy, of low quality, and leads to generally insufficient evidence for most patient populations and treatments.

Sainsbury et al (2021) included 17 RCTs (n=861) in another systematic review of cannabis-based medicines for the management of chronic neuropathic pain. Cannabinoids were administered via a variety of methods and in various dosage forms for numerous different neuropathic pain etiologies. The reviewers found that THC, THC plus CBD, and dronabinol significantly reduce pain intensity (-6.624, -8.681, and -6.0 units, respectively; p<0.001, p<0.001, p<0.008, respectively). THC and THC plus CBD also increased the likelihood of a 30% reduction in pain by 1.917 and 1.756 times, respectively. The reviewers concluded that although THC and THC/CBD interventions provided a significant improvement in pain intensity and were more likely to provide a 30% reduction in pain, the evidence was of moderate-to-low quality and further research is needed.

A Cochrane review by Filippini et al (2022) assessed the benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing chronic neuropathic pain (and other symptoms) for adults with multiple sclerosis. Only 1 trial (n=48) was identified that measured the number of patients reporting substantial pain relief with a synthetic cannabinoid compared with placebo. The reviewers were uncertain whether cannabinoids reduce chronic neuropathic pain intensity. In addition, the evidence is limited by short-term duration of the study.

In 2020, Boland et al published a systematic review and meta-analysis of RCTs evaluating cannabinoids compared with placebo/other active agents for the treatment of cancer-related pain in adults. 6 RCTs were identified (n=1460) and 5 of the 6 trials (n=1442) were included in the meta-analysis. There was no significant difference between cannabinoids and placebo for the difference in the average NRS pain scores (mean difference, -0.21; p=0.14). Meta-analysis of the 3 phase 3 studies also showed no benefit of treatment (mean difference, -0.02; p=0.80). Results also showed that treatment with cannabinoids was associated with a higher risk of somnolence (OR 2.69; 95% CI, 1.54 to 4.71; p<0.001) and dizziness (OR 1.58; 95% CI, 0.99 to 2.51; p=0.05). Dropouts and mortality rates were high. The reviewers concluded that these studies with a low risk of bias showed that for adults with advanced cancer, the addition of cannabinoids to opioids did not reduce cancer pain.

Similar findings were reported by Hauser et al (2019) in a systematic review and meta-analysis of RCTs investigating medical cannabis and/or pharmaceutical cannabinoids for pain control in cancer patients. 5 RCTs with oromucosal nabiximols or tetrahydrocannabinol (THC) including 1534 participants with moderate and severe pain despite opioid therapy were identified. 4 studies with a parallel design and 1333 patients were available for meta-analysis. The quality of evidence was very low for all comparisons. Oromucosal nabiximols and THC did not differ from placebo in reducing pain, sleep problems, opioid dosages and in the frequency of combined responder, serious adverse events and psychiatric disorders side effects. The reviewers concluded that very low quality evidence suggests that oromucosal nabiximols and THC have no effect on pain, sleep problems, and opioid consumption in patients with cancer pain with insufficient pain relief from opioids.

The National Comprehensive Cancer Network (NCCN) guideline for Adult Cancer Pain does not provide recommendations for use of cannabinoids and medical marijuana/cannabis for pain management. The guideline states that while medical marijuana has been legalized in many states, it has not been FDA-approved for any indication. Furthermore, the U.S. Drug Enforcement Administration (DEA) classifies marijuana as a Schedule I substance, meaning that it has a high potential for misuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision. The NCCN provides a summary of evidence as the use of medical marijuana among cancer patients is common. The guideline notes that data supporting the use of cannabinoids as adjuvant analgesics for treatment of cancer pain are extremely limited and the results from what little data exists are somewhat conflicting.

In 2020, the American Academy of Neurology (AAN) updated their position statement on the use of medical marijuana for neurologic disorders (first published in 2014). The AAN does not support the use of, nor any assertion of therapeutic benefits of, cannabis products as medicines for neurologic disorders in the absence of sufficient scientific peer-reviewed research to determine their safety and specific efficacy. The FDA-approved plant-based cannabidiol product is an example that has now proven to be sufficiently safe and effective for the treatment of seizures for certain epilepsy patients. The AAN notes that existing limited medical research does not support the present and proposed legislative policies across the country that promote cannabis-based products as treatment options for the majority of neurologic disorders. The AAN supports conducting rigorous Institutional Review Board-approved research and reclassification of cannabis used for medical purposes from its current Schedule I status to Schedule II to allow for medical research. Lastly, the AAN also recommends that each product and formulation of cannabis used in treating medical conditions demonstrate safety and efficacy via scientific study similar to the process required by the FDA for the approval of any drug and it is not appropriate to extrapolate the results of trials of standardized preparations to other non-standardized, non-regulated medical cannabis products.

The AAN also published an evidence-based guideline in 2014 on complementary and alternative medicine in multiple sclerosis (MS). The guideline makes the following recommendations for use of cannabinoids in multiple sclerosis:

• Clinicians might offer oral cannabis extract for spasticity symptoms and pain (excluding central neuropathic pain) (Level A). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity (short-term)/tremor (Level B) and possibly effective for spasticity and pain (long-term) (Level C).
• Clinicians might offer synthetic THC for spasticity symptoms and pain (excluding central neuropathic pain) (Level B). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity (short-term)/tremor (Level B) and possibly effective for spasticity and pain (long-term) (Level C).
• Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols) for spasticity symptoms, pain, and urinary frequency (Level B). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity/urinary incontinence (Level B). Clinicians might choose not to offer these agents for tremor (Level C).
• Data are inadequate to support or refute use of smoked cannabis for spasticity, pain, balance/posture, and cognition.

In 2020, the American Society of Clinical Oncology (ASCO) published a guideline on antiemetics. The guideline states that evidence remains insufficient for a recommendation regarding medical marijuana for the prevention of nausea and vomiting in patients with cancer receiving chemotherapy or radiation therapy. Evidence is also insufficient for a recommendation regarding the use of medical marijuana in place of the tested and FDA approved cannabinoids dronabinol and nabilone for the treatment of nausea and vomiting caused by chemotherapy or radiation therapy.

The American Cancer Society published the following statements on marijuana and cancer on their website: 

• The American Cancer Society supports the need for more scientific research on cannabinoids for cancer patients and recognizes the need for better and more effective therapies that can overcome the often debilitating side effects of cancer and its treatment.
• Medical decisions about pain and symptom management should be made between the patient and his or her doctor, balancing evidence of benefit and harm to the patient, the patient’s preferences and values, and any laws and regulations that may apply.
• The American Cancer Society Cancer Action Network (ACS CAN), the Society’s advocacy affiliate, has not taken a position on legalization of marijuana for medical purposes because of the need for more scientific research on marijuana’s potential benefits and harms. However, ACS CAN opposes the smoking or vaping of marijuana and other cannabinoids in public places because the carcinogens in marijuana smoke pose numerous health hazards to the patient and others in the patient’s presence.

In 2023, the American Medical Association (AMA) issued the following revised policy statements on cannabis legalization for medicinal use and cannabis/cannabinoid research:

• Our AMA believes that scientifically valid and well-controlled clinical trials conducted under federal investigational new drug applications are necessary to assess the safety and effectiveness of all new drugs, including potential cannabis products for medical use;
• Our AMA calls for further adequate and well-controlled studies of marijuana and related cannabinoids in patients who have serious conditions for which preclinical, anecdotal, or controlled evidence suggests possible efficacy and the application of such results to the understanding and treatment of disease;
• Our AMA supports research to determine the consequences of long-term cannabis use, especially among youth, adolescents, pregnant women, and women who are breastfeeding;
• Our AMA urges that marijuana's status as a federal schedule I controlled substance be reviewed with the goal of facilitating the conduct of clinical research and development of cannabinoid-based medicines, and alternate delivery methods. This should not be viewed as an endorsement of state-based medical cannabis programs, the legalization of marijuana, or that scientific evidence on the therapeutic use of cannabis meets the current standards for a prescription drug product;
• Our AMA believes cannabis for medicinal use should not be legalized through the state legislative, ballot initiative, or referendum process; 
• Our AMA encourages hospitals and health systems to not recommend patient use of non-FDA approved cannabis or cannabis derived products within healthcare facilities until such time as federal laws or regulations permit its use;
• Our AMA encourages hospitals and health systems to educate medical staffs on cannabis use, effects and cannabis withdrawal syndrome;
• Our AMA urges legislatures to delay initiating the legalization of cannabis for recreational use until further research is completed on the public health, medical, economic, and social consequences of its use.

Reference List

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