The legalization of medical cannabis has facilitated the use of cannabis and cannabis-based extracts for pain management, but evidence for their benefits and harms in patients with rheumatologic disorders remains elusive. Documentation of the medicinal effects of Cannabis sativa were described as far back as 5000 years ago, when therapeutic uses of the plant were described in a Chinese pharmacopeia dating from 2737 BC.1 Yet difficulties in establishing clinical trial protocols and the status of cannabis as a controlled substance have impeded research into its effectiveness. One systematic review of clinical trials on the treatment of rheumatologic conditions with cannabinoids (phytocannabinoids derived from plant material or synthesized pharmaceutical preparations) showed analgesic effects in 2 of the 4 studies that qualified for inclusion, but there was also a high incidence of adverse effects, including drowsiness, dizziness, cognitive problems, and nausea.2 However, the review did not include the use of herbal cannabis, the most prevalent choice for today’s medical cannabis users. Population-based studies have demonstrated that approximately 10% to 40% of patients who use medical cannabis have musculoskeletal or arthritic diseases, with the majority stating that they experience therapeutic benefits with cannabis use.3

According to results from a survey of Canadian rheumatologists published in 2017, 4 out of 5 respondents reported at least 1 query per week from patients seeking advice on the use of medical cannabis, yet only 75% felt confident about their knowledge of cannabinoids or their ability to provide effective guidance.4 A position statement on medical cannabis and the rheumatology patient recently published by the Canadian Rheumatology Association takes a cautious view, stating that, “evidence is insufficient about the benefit of pharmaceutical cannabinoids in fibromyalgia, osteoarthritis, rheumatoid arthritis (RA), and back pain, but there is evidence of a high risk of harm.” Nonetheless, in acknowledgment that many patients with rheumatologic disorders are interested in using cannabis, the Canadian Rheumatology Association provides guidance for initiating trials of medical cannabis in patients seeking this modality after conventional treatment strategies for pain relief and sleep promotion have been tried, with an aim toward harm reduction.4

To date, 426 chemical entities have been identified in the cannabis plant. More than 60 of these are cannabinoid compounds.5 First isolated in the 1960s,3 the major active compounds in cannabis are delta-tetrahydrocannabinol (THC) and cannabidiol (CBD). Differing cannabis strains have varying concentrations of THC and CBD, compounds with pharmacologically and behaviorally opposing effects.6 The identification of cannabinoids in cannabis was followed by the discovery of the endogenous cannabinoid system, whose components include cannabinoid CB1 receptors in the central nervous system, CB2 receptors in the immune cells of peripheral tissues, and endogenous ligands for these receptors.7 THC is a partial agonist, while cannabidiol is an antagonist at CB1 and CB2 receptors. THC is primarily responsible for the drug’s psychoactive effects, whereas CBD has been proposed to attenuate these and the anxiety, paranoia, mental slowing, and tachycardia that sometimes accompany them.5,6,8 Additionally, CBD has analgesic effects, and may inhibit pro-inflammatory cytokine production and immune cell mobilization.9 Pharmacologic agents targeting the endocannabinoid system for numerous disorders are currently in development, including selective synthetic cannabinoid receptor agonists or antagonists and inhibitors of the reuptake of endogenous cannabinoid ligands.3

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In a recent paper, Torsten Lowin, PhD, of the Department of Rheumatology & Hiller Research Center for Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany, proposed that a CB1 receptor antagonist combined with CBD and a fatty acid amide hydrolase (FAAH) inhibitor to inhibit the degradation of endocannabinoids could be beneficial in the treatment of RA. In an interview with Rheumatology Advisor, Dr Lowin stated, “If a treatment regimen as the one described in my paper would be applied, then I would expect therapeutic effects comparable to biologics treatment with a better side effect profile. I think that manipulation of the cannabinoid system might get the immune system closer to the homeostatic set point where inflammation is effectively limited.”

Dr Lowin suggested that patients with RA wishing to try herbal cannabis to address their symptoms should start out with a low THC/high CBD variety and then titrate THC. “High THC might not be favorable because it does increase heart rate and patients with rheumatoid arthritis often develop atherosclerosis. Here THC might promote fatal heart failure,” he noted. “Medical cannabis, however, cannot provide the therapeutic effects when comparing it with my advised combination of CB1 antagonist, FAAH inhibitor, and CBD. While the latter can clearly be provided in medical cannabis preparations, the other two components are missing, at least with strains that are available right now. There might be a positive effect of cannabis at the very beginning of RA, where a decrease in adrenergic signaling might be beneficial; this might be provided by THC. GW Pharma, the company that made Sativex, is now investigating cannabis strains that have high amounts of other cannabinoids like tetrahydrocannabivarin, which is actually a CB1 antagonist. I am pretty sure that strain cross-breeding, and maybe also [Clustered Regularly Interspaced Short Palindromic Repeat] CRSPR, will eventually result in cannabis varieties with a specific mode of action that might mimic the action of a CB1 antagonist and a FAAH inhibitor. However, cannabis will never have an impact such as anti-TNF or JAK inhibitors and might be used mainly with arthritis comorbidities. I would consider it more as an adjuvant therapy that reduces side effects of NSAIDs such as stomach ulcers, or allows for overall reduction in pain medication, for example, reduction of opioids.”

References

1. Leal-Galicia P, Betancourt D, Gonzalez-Gonzalez A, Romo-Parra H. A brief history of marijuana in the western world [in Spanish]. Rev Neurol. 2018;67(4):133-140.

2. Fitzcharles M-A, Ste-Marie PA, Häuser W, et al. Efficacy, tolerability, and safety of cannabinoid treatments in the rheumatic diseases: a systematic review of randomized controlled trials. Arthritis Care Res (Hoboken). 2016;68(5):681-688.

3. Perrot S, Trouvin A-P. Cannabis for musculoskeletal pain and arthritis: evidence is needed. Joint Bone Spine. 2019;86(1):1-3.

4. Fitzcharles M-A, Niaki OZ, Hauser W, Hazlewood G, Canadian Rheumatology Association. Position statement: a pragmatic approach for medical cannabis and patients with rheumatic diseases. J Rheumatol. 2019;46(5):532-538.

5. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol. 2012;2(6):241-254.

6. Romero-Sandoval EA, Kolano AL, Alvarado-Vázquez PA. Cannabis and cannabinoids for chronic pain. Curr Rheumatol Rep. 2017;19(11):67.

7. Barrie N, Manolios N. The endocannabinoid system in pain and inflammation: its relevance to rheumatic disease. Eur J Rheumatol. 2017;4(3):210-218.

8. Halawa OI, Furnish TJ, Wallace MS. Chapter 56 – Role of Cannabinoids in Pain Management. In: Benzon HT, Raja SN, Liu SS, Fishman SM, Cohen SP, eds. Essentials of Pain Medicine (Fourth Edition). Elsevier; 2018:509-520.e2.

9. Lowin T, Schneider M, Pongratz G. Joints for joints: cannabinoids in the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2019;31(3):271-278.