Cannabis for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease that commonly affects joints in the hands, wrists, and knees. Chronic inflammation damages joint tissue, which can cause chronic pain, unsteadiness, and deformity. RA can also affect other tissues throughout the body, causing problems in organs such as the heart, blood vessels, lungs, and eyes. The pain and damage from RA frequently lead to disability, affect mental health, result in poor quality of life, and can significantly increase mortality.1 There is no cure for the disease, and current treatments fail to adequately meet patients’ needs, leading many to look at alternative treatments, including cannabis and cannabis-related therapies.

RA Pain
Pain is a major concern and priority in patients with rheumatoid diseases, which are a leading cause of chronic pain, defined as that which lasts for longer than three to six months.2 Treatment that improves pain has consistently been rated as the highest priority among health outcomes for patients with RA.3 However, the treatment of chronic pain is challenging, and even when rheumatic diseases are in a state of remission, pain frequently is not entirely eliminated; it’s the most common residual symptom associated with RA remission or low disease activity.4 Further complicating treatment are concerns that exist about many long-term treatments for pain. Opioid use carries the risk of potentially significant adverse events, addiction, and overdose. Further, long-term use of opioids can result in hyperalgesia, and their use has been shown to be associated with more severe symptoms and unemployment in those with rheumatoid disease fibromyalgia.5 And while antidepressants are potentially useful for chronic pain, certain side effects, such as increased cardiovascular events with tricyclic antidepressants as well as increased falls with all antidepressants, may limit their use in many older adults.

Increasing Cannabis Use for RA
A growing interest in cannabis and cannabis-based therapies, along with the need for adequate pain relief, has contributed to significantly increased cannabis use in persons with rheumatic disease. Researchers evaluated more than 11,000 rheumatoid patients from FORWARD, the United States patient-reported research bank for rheumatic disorders.6 The patients were surveyed about their past and current cannabis use. From 2014 to 2019, the number of patients using cannabis for rheumatic disease nearly tripled from 6.3% to 18.4%, with the greatest prevalence of use in states where cannabis use is legal. Most users (74% in 2014; 62% in 2019) reported that cannabis was effective in relieving arthritis symptoms. The survey also found that patients with rheumatic diseases who try cannabis are often those persons whose pain management needs are not adequately addressed with other therapies. Cannabis users were more likely to be taking weak opioids, such as codeine, tramadol, or hydrocodone (vs strong opioids like morphine, fentanyl, or oxycodone), to have a history of smoking tobacco, and have worse measures on all assessed patient-reported outcomes.

Nabiximols Study
In the first controlled trial of a cannabis medication for RA, a significant analgesic effect was observed, and disease activity was significantly suppressed following nabiximols (Sativex) treatment—a pharmaceutical grade cannabis oral mucosal spray product containing 2.7 mg of THC and 2.5 mg of CBD in each 10 ml bottle.7 In the randomized, double-blind study, parallel-group study investigators compared nabiximols with placebo in 58 patients over five weeks of treatment. Thirty-one were randomized to the nabiximols and 27 to placebo. Nabiximols was administered in the evening, and assessments were made the following morning. In comparison with placebo, the nabiximols produced statistically significant improvements in efficacy outcomes, including pain on movement, pain at rest, quality of sleep, and measure of disease activity. There was no effect on morning stiffness, but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group.

However, other interpretations of current cannabis data have been less positive. In a recent meta-analysis, researchers conducted a review to examine whether cannabis, cannabis-derived products, and synthetic cannabinoids are effective in treating RA.8 In all, it involved 26 systematic reviews—including the above-mentioned nabiximols (Sativex) study, which was the only randomized, controlled trial in the analysis. Data from the review was extracted and reanalyzed by the researchers, who provided a summary of their key findings, including the following:

• Cannabis, cannabis-derived products, and synthetic cannabinoids may slightly reduce disease activity.
• The evidence suggests that cannabis, cannabis-derived products, and synthetic cannabinoids result in little to no difference in pain reduction.
• No studies were found that examined physical disability.
• No studies were found that assessed quality of life.
• The evidence is very uncertain about the effect of cannabis, cannabis-derived products, and synthetic cannabinoids on serious adverse events risk.

The researchers also indicated that additional studies with cannabinoids other than nabiximols are needed, that the lack of articles on the topic contrasts with increasing interest of RA patients in medicinal cannabis, and that clinicians need stronger evidence to properly address patients’ questions about benefits and risks of cannabis products for RA.

Improved Pain and Sleep Quality
In another recent study, researchers evaluated the effects of medical cannabis on 319 persons with rheumatic disease and other health issues and concluded that medical cannabis had a favorable effect on pain and sleep quality.9 For the study, 319 questionnaires were completed and used to assess how medical cannabis use affected the participants’ pain and sleep quality. Of the 319, 76% of the participants were female, 82% had fibrinoids, 9% had mechanical problems, 4% had inflammatory problems, 4% had neurological problems, and 1% had other problems. The average monthly consumed dose of medical cannabis was 31 g, 35 g, 36 g, and 32 g, with mean pain level reduction of 77%, 82%, 83%, and 57%, and mean sleep quality improvement of 78%, 71%, 87%, and 76% among patients with fibromyalgia, mechanical, neuropathic, and inflammatory problems, respectively. Mean THC and CBD contents were 18.38% ± 4.96 and 2.62% ± 4.87, respectively. The THC concentration, duration of medical cannabis consumption, and medical cannabis consumption dose had independent significant correlations with pain reduction, while only the duration of medical cannabis consumption had an independent and significant correlation with sleep quality improvement. Medical cannabis was found to have a favorable effect on pain level and sleep quality among nearly the entire spectrum of patients with resistant “chronic pain syndromes” seen or referred to rheumatology clinics, including those with inflammatory diseases resistant to biological treatment. The study authors suggested that cannabis should be seriously considered in every “chronic pain condition” whenever the accepted modalities of treatment are insufficient for alleviating patient’s pain and sleep problems.

Role of Cytokines in RA
Cytokines—also referred to as interleukins (ILs), chemokines, or growth factors, among many other names—are cell signaling molecules that aid cell-to-cell communication in immune responses and stimulate the movement of cells toward sites of inflammation, infection, and trauma.10 Antigen-activated CD4+ T cells stimulate monocytes, macrophages, and synovial fibroblasts, also referred to as RA synovial fibroblasts (RASFs), to produce the proinflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α). These have been widely implicated in the inflammatory responses seen in inflammatory and autoimmune diseases and have also been described as the master regulators of chronic inflammation and tissue destruction.11 In addition, many cytokines, including TNFα, IL-6, and IL-10, are known to influence RA pain.12

Rationale for Cannabinoid Use in RA
Although the long-term efficacy and safety data on cannabis is limited, there’s an accumulation of evidence that cannabis and cannabis-related compounds possess immune-modulatory and analgesic properties desirable for the treatment of rheumatic diseases. By modulating the inflammatory processes seen in RA, cannabinoids may be potential treatment options and may help control pain, minimize joint damage, and improve or maintain function and quality of life. RASFs express not only cannabinoid receptors type I and II (CB1 and CB2) but also transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 (TRPA1).13 These RASF receptors are sensitive to the action of different cannabinoids that individually or in combination (the entourage effect) interact with the receptors, leading to beneficial anti-inflammatory effects.

Systematic Review of Cannabinoids
In a systematic review of 26 in vivo studies, the effects of cannabinoids on pro- and anti-inflammatory cytokines and disease severity were examined.14 Studies looked at CBD (n=20), cannabigerol (CBG; n=1), THC (n=2), THC and CBD separately (n=1), and THC and CBD in combination (n=2). TNF-α, IL-1β, IL-6, and interferon gamma were the most commonly studied proinflammatory cytokines. In 22 studies in which CBD, CBG, or CBD in combination with THC were administered, a reduction in the levels of at least one inflammatory cytokine was observed, and in 24 studies, some improvements in disease or disability were apparent. Cytokine levels were consistently reduced after treatment with CBD, CBG, or CBD+THC, but not with THC alone. THC alone did not reduce proinflammatory cytokine levels in three studies but did result in improvements in neuropathic pain in one study. The study’s authors suggest that this information could be used to inform human clinical trials of cannabinoids, focusing on CBD and CBG to reduce inflammation across a range of pathophysiological processes.

CBD
RASFs lead the way to eventual joint erosion in RA and actively contribute to inflammation through the production of chemokines and cytokines and matrix-degrading enzymes.15 CBD has been described as a killer of inflammatory RASFs.16 Investigation into CBD’s beneficial effects in RA found that CBD reduces cell viability and proliferation of RASF. More specifically, it increases intracellular calcium levels and reduces cell viability and IL-6/IL-8/matrix metalloproteinase-3 (MMP-3) production of RASF. It was also found that the pretreatment of RASF with TNF, a major contributor to the excess inflammation that drives RA, resulted in CBD’s anti-inflammatory effects being more pronounced. This suggests that CBD possesses antiarthritic activity and might selectively ameliorate arthritis by targeting synovial fibroblasts under inflammatory conditions. It’s also been suggested that CBD may be beneficial as an adjuvant treatment in RA that might support the action of currently used disease-modifying antirheumatic drugs.

THC
THC, which is responsible for marijuana’s psychoactive side effects such as euphoria, dizziness, and intensified visual and auditory sensations, has also been shown to possess anti-inflammatory properties through inhibition of prostaglandin E-2 synthesis, decreased platelet aggregation, and stimulation of lipoxygenase.17 THC’s anti-inflammatory properties are 20 times the potency of aspirin and twice that of the steroid hydrocortisone.18 A recent study was conducted to determine the effects of THC at various concentrations on RASF and peripheral blood mononuclear cells (PBMC), which are immune cells that, in the context of RA, initiate the autoimmune inflammatory process directed against target organs.19 In RASF, THC (≥5 μM) increased intracellular calcium levels/PoPo3 uptake in a TRPA1-dependent manner and reduced IL-8 and matrix metalloprotease 3 production at high concentrations (25 μM). Proliferation was slightly enhanced at intermediate THC concentrations (1–10 μM) but was completely abrogated at 25 μM. In PBMC alone, THC decreased IL-10 production and increased immunoglobulin G. In PBMC/RASF coculture, THC decreased TNF production when cells were stimulated with interferon-γ or CpG. THC provides pro- and anti-inflammatory effects in RASF and PBMC, which appear to be dependent on the activating stimulus and concentration of THC. Therefore, THC might be used to treat inflammation in RA, but it might need titrating to determine the effective concentration. The researchers also found that in addition to CB1 and CB2, TRPA1 is a target receptor of THC that increases intracellular calcium levels and drug uptake in RASF. Despite RASF cytokine production not being altered at lower concentrations, THC may still be appropriate as an adjuvant to other antirheumatic drugs and may provide benefits in the treatment of comorbid conditions, such as pain, depression, and sleep disturbances.

Synthetic Cannabinoids
Synthetic cannabinoids may also prove to be beneficial in the treatment of RA. The synthetic cannabinoid WIN55,212-2 mesylate has demonstrated strong anti-inflammatory effects in monocytes and synovial fibroblasts modulating cytokine and MMP-3 production in RASFs.20 Animal models using a murine model with collagen-induced arthritis have shown a beneficial effect of the synthetic cannabinoid CB2 receptor agonists JWH-133 and HU-308. JWH-133 is a potent synthetic CB2 receptor agonist that was found to be associated with a decrease in serum antibody levels, decreased cytokine production, and reduced bone destruction.20 HU-308, also a CB2 receptor agonist, was associated with less joint swelling and destruction, reduced synovial inflammation, along with a decrease in serum antibody levels.21

Mental Health
Chronic pain conditions, including rheumatic diseases, can negatively affect a person’s quality of life and mental health with an increase in comorbidities as well as an increased prevalence of anxiety, depression, and sleep disturbances.22 RA is associated with a higher prevalence of both depression and anxiety (estimated to affect 39% and 20% respectively).23 An estimated 30% of RA patients will develop depression within five years, with women being about 60% more likely to be diagnosed with depression compared with men.24 Possible explanations for the increased rate of depression and anxiety include functional impairments, increased levels of pain, helplessness due to uncertainty associated with the disease, proinflammatory cytokines, and TNF-α and IL-1, which may also have a pathological link to depression.25 It’s thought that chronic stress inhibits the production of endocannabinoids by the brain, which may lead to depression and anxiety. Based on this concept, supplementing the body’s endogenous cannabinoids may facilitate the restoration of optimal function, thus easing depression symptoms.

Final Thoughts
Despite limited clinical studies supporting the widespread use of cannabis and cannabis-derived products for RA, the anecdotal evidence, including a significant increase in the use of cannabis by persons with RA, suggests that cannabis provides a number of desirable properties. While larger controlled studies are needed, health care providers should continue to broaden their awareness and understanding of this drug so that they’re better equipped to advise their patients about potential benefits and risks.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

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