Amid growing cannabis access, data for rheumatology benefit still 'fraught with bias'
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There is no doubt that patients with rheumatic and autoimmune diseases are taking full advantage of relaxed laws in the United States surrounding recreational cannabis use.
The question, however, is whether or not the improvements in pain, inflammation or sleep they are experiencing are attributable to true medicinal effects.
In their recent study in Arthritis Care & Research, Wipfler and colleagues conducted a trial of 11,006 patients with various arthritic conditions in the U.S. Results showed an increase in cannabis use from 6.3% in 2014 to 18.4% in 2019. The steepest increases were seen in states where recreational marijuana use is legalized.
Similarly, Mary-Ann Fitzcharles, MD, senior physician in the division of rheumatology at the Louise and Alan Edwards Pain Management Center at McGill University Health Center, Montreal, and colleagues, conducted an online survey of 1,047 rheumatology patients in Canada after recreational legalization of marijuana. Results published in ACR Open Rheumatology showed that cannabis use tripled in this group after legalization.
Despite this uptick, Fitzcharles explained why there are still far more questions than answers surrounding cannabis use in the rheumatology space. “The preclinical models of pain and inflammation, even joint inflammation, have shown excellent effect of cannabinoids,” she said. “But a preclinical study does not directly translate into the clinical setting.”
While a true analgesic effect is indeed possible with cannabis use, Fitzcharles suggested that an “expectation of a positive effect” could also be influencing how patients feel. “There may also be a true placebo effect for some patients,” she added.
But the issue, in fact, is actually much more complicated than that, according to Donald Abrams, MD, professor in the department of medicine and integrative oncologist at the University of California, San Francisco. “It is an impossible effort to try to study anything about cannabis because of the laws in this country,” he said.
But prohibitive regulations are just one factor, according to Abrams, who talked at length about the various forms of tetrahydrocannabinol (THC) and cannabidiol (CBD) available both legally and illegally in the U.S.
“There is CBD, THC, Delta-9 THC, Delta-8 THC; there are various concentrations of THC and CBD in different products; patients may take it orally and there are creams and vapors,” Abrams said. “There is too much variety in the products available, which makes any attempt to understand their impact fraught with bias.”
That said, Abrams noted that some form of cannabis has been used therapeutically for “thousands of years.” He believes that this potentially “useful botanical” is almost certainly safer than tobacco and alcohol and should be studied rigorously to answer the questions of whether it has benefit, and what those benefits are. “Stop demonizing it,” he said.
The first step in this process may be to further understand why cannabis products may or may not have a positive impact on rheumatology patients in the first place.
Understanding the Mechanism
For Ronald J. Rapoport, MD, FACR, chief of the division of rheumatology at Southcoast Health in Massachusetts, the fact that there is an endocannabinoid system in the human body is the obvious place to start. “The cannabinoids that are made in our body’s endocannabinoid system are involved in the normal functioning of such things as the nervous system,” he said, noting that the endocannabinoid system may be involved in everything from Alzheimer’s disease to multiple sclerosis.
“There are two confirmed receptor subtypes for cannabis in humans,” Rapoport continued. “The cannabinoid (CB)-1 receptor agonists may act on nociceptors in the dorsal horn of the spinal cord and may reduce pain because of this. The CB-2 receptor may have a positive effect on reducing inflammation and autoimmunity.”
CB-2 is not as ubiquitous as CB-1, according to Rapoport. However, there is some evidence that CB-2 binds to immune cells. “The CB-2 receptor has a high density on immune modulating cells and may influence such things as immune cell migration and cytokine release,” he said.
There is another component of the cannabinoid system that may be of particular interest to rheumatologists. “CB-2 also seems to be involved in maintaining skeletal integrity as it is noted to be found in osteocytes, osteoclasts and osteoblasts,” Rapoport said.
Rapoport also described the mechanism by which the endocannabinoid system may impact pain. “We have to emphasize that the CB-2 selective agonist may be helpful not only in reducing inflammation but also potentially in reducing established hypersensitivity in such things as skin disorders and peripheral pain,” he said.
Daniel Clauw, MD, director of the Chronic Pain and Fatigue Research Center and professor of medicine in the Division of Rheumatology at Michigan Medicine at the University of Michigan, summed up the conventional thinking on the possible impacts of THC and CBD on the endocannabinoid system and, by association, the impacts patients may or may not feel. “Current evidence is suggesting that CBD might have more of an anti-inflammatory effect whereas THC might be more so working in the brain to modify pain processing,” he said.
But in putting all of these theories and assumptions into context, Rapoport repeated the refrain voiced by many experts. “More data is needed to support this strongly,” he said.
Less Pain, More Sleep
Abrams led research from the National Academies of Sciences, Engineering and Medicine that included a comprehensive review of recent literature on cannabis and cannabinoids. With some 10,000 abstracts included, it is the largest analysis to date looking at the impact of these products.
“In the therapeutics chapter reviewed here, the report concluded that there was conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment of pain in adults,” Abrams wrote. “Moderate evidence was found for secondary sleep disturbances.”
The evidence for a number of other conditions that underwent analysis — ranging from Tourette syndrome, anxiety and post-traumatic stress disorder to cancer, irritable bowel syndrome, epilepsy and a variety of neurodegenerative disorders — was described as “limited, insufficient or absent.”
Regarding pain relief, because of the mechanism and the nature of the endocannabinoid system, Abrams suggested that it is “not a mystery” various cannabinoid products can have an analgesic effect.
“Most patients with rheumatic diseases are using cannabinoids primarily for pain management, with some experiencing added benefits of improved sleep,” Fitzcharles said. “However, while the effect on sleep is reported by many patients, the systematic reviews do not support an important effect on sleep. This may be in part explained that the formal studies have not been done or published.”
It is for this reason that Clauw described the possible benefits of CBD and THC on sleep as “theoretical.”
The potential effect on sleep quality also varies depending upon the patient, according to Rapoport. “Using either CBD or THC, starting with a lower dose and advancing is usually what is suggested,” he said. “The data to support a clear improvement in sleep is also lacking and studies are needed to better support this. There is no doubt that, clinically, a very high percentage of the population that has tried cannabinoids to help with sleep have had a positive response.”
Whether the positive responses on pain and sleep are real or, as Fitzcharles suggested, some sort of placebo effect, remains to be seen. In the meantime, rheumatologists are left wondering whether CBD and THC can have a positive benefit on the inflammation and mood disorders experienced by their patients.
Controlling Inflammation, Improving Mood
“Even though we would like to have a reduction in inflammation, the evidence supporting this is still not totally convincing,” Rapoport said. “The idea of binding to a receptor where decreased inflammation is an end result has been shown, but not enough randomized and controlled clinical trials have been published.”
The issue for Fitzcharles is that the studies showing the impact of cannabinoids on inflammation, like the studies in pain, are preclinical. “The effect on inflammation has not been studied in the clinical setting with rheumatology patients,” she said.
With that in mind, Fitzcharles offered a hard-boiled warning about the use of these products for controlling inflammation. “Rheumatology patients must be warned that cannabis in any form should not be used as a substitute for standard rheumatic disease treatment such as the disease modifying anti-rheumatic drugs,” she said.
Similar considerations must be in place for the use of cannabis to treat anxiety, depression or other mood disorders. “Some patients also report that cannabinoids have some effect on mood,” Fitzcharles said.
However, this picture may be slightly more complicated. Fitzcharles described a “vicious cycle” of pain, poor sleep and subsequent mood disturbance associated with many rheumatic and autoimmune diseases and noted that many patients use cannabis to temper these mood-related issues. However, it is uncertain whether improvements in mood are actually curative to anxiety or depression, or whether they are simply byproducts of less pain and a good night’s sleep.
For Abrams, the practicalities of studying the potentially mood-altering impacts of THC may just be too steep a hill to climb, for one important reason. “In this puritanical society, too many people think that euphoria is a bad idea,” he said.
What is most frustrating to Abrams is that fear of the euphoria associated with THC has pushed scientific and medical communities to make use of an inferior alternative. “People have glommed on to CBD in the absence of data showing that it does anything,” he said.
As a parting shot, Fitzcharles offered one final caveat for cannabis use in mood disorders. “It must also be remembered that cannabis can induce anxiety in some patients,” she said.
Potential Drawbacks
For Fitzcharles, a number of possible disadvantages of cannabinoid use should be kept in mind as the research community moves forward. One is whether tolerance to cannabinoids will develop over time. Another is whether long-term cannabinoid use will lead to broader substance use disorders.
“Some data indicate an addiction rate of up to 9% of people using higher doses,” Rapoport said. “But these data have been challenged.”
Another concern pertains to cardiovascular safety with use of THC compounds, according to Fitzcharles. “There are also concerns for cognitive, psychomotor effects in the elderly, especially falls,” she said.
While Fitzcharles believes that drug-drug interactions with other therapies are, at the moment, theoretical, this possibility should also be on the radar. “We also have to consider societal risks and safety concerns,” she said. “For example, driving under the influence is an issue, along with children and pets accessing products.”
“It is clear we would like to avoid their use in adolescents and those younger because they may cause issues in a developing brain,” Rapoport added.
Clauw believes that CBD is “fairly safe,” so he has fewer concerns about these products. “THC has a lot of side effects,” he said. “It is becoming more and more clear that a low dose works better than high doses. But most patients are not getting good guidance, so they often use too much THC and, as such, have a lot of side effects.”
Available data point to an oral dose of CBD at 50 mg to 100 mg twice daily, according to Clauw. “If this does not work and they want to try a bit of THC to see if this helps, use a low dose,” he said.
Rapoport built on this point. “The downside of the use of cannabinoids is usually based upon the amount consumed,” he said. “Using these products in large amounts and on a daily basis may lead to difficulties.”
Beyond individual patient concerns, Fitzcharles described more structural barriers to increased evidence-based use of cannabinoid products. “The cannabis industry is not supportive of medical research initiatives,” she said. “Even governments who are benefitting from taxation of recreational cannabis products have given limited support to medical research.”
But it is likely that science will march on despite this lack of support, according to Fitzcharles. “Perhaps we will never have the luxury of well-designed RCTs and will have to accrue evidence in more non-traditional ways, such as surveys and cohort studies,” she said.
Depending on the nature and extent of that evidence, rheumatology patients may someday use cannabinoid products to target, with effective results. In the meantime, off-label and recreational use is likely to remain the status quo.
For more information:
Donald Abrams, MD, can be reached at donald.abrams@ucsf.edu.
Daniel J. Clauw, MD, can be reached at 325 E Eisenhower Pkwy Ste. 100, Burlington Building, Ann Arbor, MI 48108; email: dclauw@med.umich.edu.
Mary-Ann Fitzcharles, MD, can be reached at 1650 Pine Ave. West, Montreal, Quebec, Canada H3G 1A4; email: mfitzcharles@sympatico.ca.
Ronald J. Rapoport, MD, FACR, can be reached at 1030 President Ave., Suite 221, Fall River, MA 02720; email: rappie12@aol.com.
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Abrams DI. Eur J Intern Med. 2018; doi: 10.1016/j.ejim.2018.01.003.
Fitzcharles MA, et al. ACR Open Rheumatol. 2020;doi:10.1002/acr2.11138.
Wipfler K, et al. Arth Care & Res. 2021;doi: 10.1002/acr.24752.
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