The Cannabis Frontier: As Medical Cannabis Moves Mainstream, are Rheumatologists Prepared?

As any self-respecting American marijuana smoker can attest, the nation’s complicated relationship with the drug dates at least as far back as the Founding Fathers: Both George Washington and Thomas Jefferson were known to grow acres of hemp — marijuana’s far less-psychoactive cannabis cousin — on their Virginia plantations.

Although hemp was a known cash crop at the time, used in a variety of products including paper, lamp oil, ropes and sail canvasses, historians continue to clash on whether the Founding Fathers and other farmers at the time also utilized hemp for the more recreational or medicinal properties associated with cannabis today.

The potential benefits and harms of cannabis-based products have been alternately vilified and glorified by users, government officials and the scientific community alike for nearly 3 centuries. That argument has carried into the rheumatology sphere today, where increasing interest in tetrahydrocannabinol (THC) and cannabidiol (CBD) to manage inflammation and pain, among other disease characteristics, is leading to a growing body of research. However, that body of research is developing far too slowly, at least in the U.S., for one simple reason: Cannabis remains classified as a schedule I narcotic, which, according to the Drug Enforcement Agency, means that it has “no currently accepted medical use and a high potential for abuse.”

All of this creates a complicated equation for rheumatologists to untangle. As more and more patients are using the drug, either legally or illegally depending on the laws of the state in which they reside, they are approaching their doctors for advice.

Doctors, then, have to discuss the issue in the absence of hard, randomized, controlled data outlining potential benefits and harms, which makes it difficult to offer any kind of concrete recommendations. Factor in that there are now hundreds of strains and types of the marijuana plant as well as a growing number of ways to ingest it — smoking, vaping, oils and edibles — and most rheumatologists are at a loss for how to even begin a conversation about appropriate usage and dosing.

Philip J. Molloy, MD, a board-certified rheumatologist at Atrius and Nantucket Cottage Hospital, takes strong issue with the idea that there can be no medical use for cannabinoid products, as the schedule I classification states. “We have receptors that bind to cannabinoids all over our bodies, including in the central nervous system, as part of our endocannabinoid system,” he said. “Accordingly, research has shown cannabinoids as having clinical benefit, specifically an effect in inflammatory cells. But nobody can fund research, publicly or privately.”

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, suggested that basic science and preclinical studies have shown “astounding and promising” results for cannabinoids in the treatment of conditions and managing symptoms ranging from pain, sleep difficulties, mobility and mood disorders.

“But advocacy, anecdote, political agendas and big money have outrun science in this field,” she said. “To date, only about 200 persons with rheumatic diseases have been studied in randomized clinical trials — using pharmaceutical preparations only — with not a single clinical trial examining the effect of the herbal product in defined rheumatic diseases.”

Yet the tide is changing on both the legal and research fronts in the U.S., with similar changes seen internationally. Former FDA Commissioner Scott Gottlieb, MD, made a number of statements concerning the progress of cannabis toward acceptance and approval domestically, which many perceive to be an important step toward validating the drug as a viable clinical option. Recreational cannabis was legalized in Canada in October 2018, which may give way to a spike in research in North American patients. Likewise, restrictions have been greatly reduced across Europe and Australia, and as Fitzcharles noted, the preclinical data are setting the stage for further exploration.

More widespread use of synthetic CBD products such as dronabinol and nabilone may further grease the wheels toward approval of natural cannabinoid products. However, Molloy believes this has little bearing on regulatory issues for the marijuana that comes from the earth. “It is a natural substance, nobody has a patent on it,” he said. “There is not a lot of money to be made by pharma, so big name drug companies are not going to sink a billion dollars into it.”

Despite these hurdles, Fitzcharles believes the mission is to build on those preclinical data and determine whether the signals indicating anti-inflammatory effects and a capacity for pain management, among other possible impacts, hold up in real-world patients. Questions remain unanswered, despite the undeniable reality of widespread marijuana use in both medical and nonmedical contexts.

Movement on the Regulatory Front

In December 2018, Gottlieb released a statement on the Agriculture Improvement Act of 2018, a provision of which removed hemp from the dangerous substances list, noting that “We’re aware of the growing public interest in cannabis and cannabis-derived products, including cannabidiol. This increasing public interest in these products makes it even more important with the passage of this law for the FDA to clarify its regulatory authority over these products.”

Shortly before his tenure ended in April 2019, Gottlieb outlined a series of actions the FDA will be taking to gain deeper understanding of the true utility of cannabinoid products. Some of these actions include a public hearing to help understand pathways to appropriate regulation, an FDA working group to explore these topics further, and stricter oversight of all facets of the budding CBD industry.

Gottlieb also targeted what he called “egregious” claims about the efficacy of cannabinoid products. In short, parties who market medical cannabinoid products frequently overstate their potential impact. For example, companies have claimed that the products can slow Alzheimer’s disease progression, stop cancer cell growth, and treat substance abuse disorders. None of these claims has been sufficiently proven.

“Ultimately, we remain committed to exploring an appropriate, efficient, and predictable regulatory framework to allow product developers that meet the requirements under our authorities to lawfully market these types of products,” Gottlieb said. “The actions we’re announcing today will allow us to continue to clarify our regulatory authority over these products and seek input from a broad range of stakeholders and examine a variety of approaches and considerations in the marketing and regulation of cannabis or cannabis-derived products, while continuing to protect the public’s health and safety.”

Despite this progress on the regulatory front, Fitzcharles stressed that a number of nonlegal barriers to acceptance of cannabis as a medical therapy also remain deeply entrenched. “To date, cannabis had mostly been smoked, and, therefore, smoking is a deterrent,” she said. “Also, cannabis use in a household with young children and teenagers is not recommended.”

Although the drug is gaining more widespread and mainstream acceptance, Ronald Rapoport, MD, chief of the division of rheumatology at Southcoast Health in Falls River, Massachusetts, noted that since many patients do not have access to the medical product, they are paying for it themselves. “Cost is prohibitive in many cases,” he said. “Also, there are so many products to smoke, or eat, with hundreds of types of cannabis available. Patients ask me all the time: Which one do I use? It is difficult to give them an answer.”

Arun Swaminath, MD, associate professor at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and director of Inflammatory Bowel Disease at Lenox Hill Hospital, also finds himself in an uncomfortable position in the clinic due to varying properties and concentrations of THC and CBD. “It is not like prescribing a typical drug, that is identical, regardless of which state and which store a patient purchases it in,” he said. “And since the product is not prescribed, patients often get their information from various internet sources of unchecked quality as well as the pharmacists attached to cannabis dispensaries.”

Dealing With Misconceptions

Swaminath referred to pharmacists at dispensaries as “budtenders,” which could serve as a symbol of the extensive level of misunderstanding surrounding medical marijuana. A simple place to begin dispelling myths is the difference between THC and CBD, according to Rapoport. “Simply put, THC contains the psychoactive component of the marijuana plant, the part that gets you high,” he said. “CBD does not contain the psychoactive property.”

Whether patients understand this difference is up for debate. “Most patients have figured out that CBD is generally safe because in many — if not most — states, this is widely available over the counter and being purported to treat everything,” Daniel Clauw, MD, professor of anesthesiology, medicine (rheumatology) and psychiatry, and director of the Chronic Pain and Fatigue Research Center at the University of Michigan, told Healio Rheumatology. “Nonetheless, they still get some things wrong.”

The key concern with patients taking THC is that they might be taking too much, according to Clauw. “A low dose seems to work better than a high dose for pain,” he said. “If they go to a dispensary that caters to recreational users, they will likely get high THC cannabis products that will make them high but not improve their pain.”

Underscoring the THC-CBD discussion is the extent to which patients are simply looking to get high. “It can be hard for us as clinicians to separate those who really want pain relief vs. those who want to get high, or who want a combination of those things,” Rapoport said. “It is my experience that the majority of patients want pain relief, and they do not even want the THC.”

Despite the misunderstandings, Rapoport strongly believes in the clinical benefit of CBD, largely because of CB1 and CB2 receptors found throughout the body as part of the endocannabinoid system. “They are in neuron terminals, in basal ganglia that can affect motor activity, in the cerebellum and in the neocortex, which can impact cognition,” he said. “We think that CB2 is in the T cells and B cells and can therefore affect inflammatory and immune activity. They are in leukocytes that modulate cell migration, in synovial cells. These receptors are all over the place.”

Early data bear out these associations. In their study in The International Journal of Biochemistry & Cell Biology, Navarini and colleagues looked at the endocannabinoid system in SLE. Liquid chromatography-mass spectrometry results showed that endocannabinoid levels highlighted that plasma levels of 2-arachidonoylglycerol (2-AG) were significantly higher in SLE patients compared with healthy controls (P = .0059). Moreover, SLE patients with the highest 2-AG had the lowest disease activity.

Patients with SLE also demonstrated a “deranged” 2-AG metabolism, according to gene expression analysis of metabolic enzymes. The researchers concluded that these alterations in the endocannabinoid system among patients with SLE provides proof of concept that cannabis-based medicines may be used in patients with immune-related diseases.

Rapoport warned, however, that patients should not believe those who claim that because of these associations, CBD has a “magical quality” to cure almost anything. “Just by seeing the promotional advertisements, cannabis and CBD are positioned as cure-alls,” Swaminath said. “Because it is not a regulated product, it exists in this gray area where it is not a medication, and it is not entirely clear whether the contents on the ingredient list are actually what is in the product.”

Swaminath acknowledged that preclinical animal models have shown that CB1/2 receptors have resulted in improved gastrointestinal motility, less abdominal pain and anti-inflammatory effects; however, he noted that it is simply too early to tell how these findings might play out in humans.

One further misunderstanding pertains to topical applications of cannabis oil, according to Clauw. “This is not likely to be of a great deal of benefit because it so poorly penetrates the skin, unless there is something else also applied to the skin at the same time, such as alcohol,” he said.

Limited Data

An ancillary concern to the schedule I classification is that a great deal of research zeroes in on the harms of cannabinoids, while considerably less focus is placed on potential benefits. For example, Donald I. Abrams, MD, professor of clinical medicine at University of California, San Francisco, was part of a 16-member team charged by the National Academies of Science, Engineering and Medicine to publish a nearly 500-page report about the effects of cannabis. “There were 15 chapters in the document,” he said. “Fourteen on the potential harms of cannabis, and one on the potential benefits.”

Yet scientists around the globe continue to explore the signals. In a study published in Journal of Pediatric Gastroenterology and Nutrition, Hoffenberg and colleagues investigated cannabis oil in a cohort of young adult patients with inflammatory bowel disease. The analysis included 15 cannabis users who reported perceived effects on sleep quality, nausea and appetite. The researchers suggested ongoing communication about the positive effects of cannabis until more rigorous studies can be conducted.

For Molloy, it is critical to develop a yardstick to measure all of these outcomes, and set to the work of rigorous clinical research. “Every disease state for which there is medical treatment has measuring tools,” he said. “We need to use the criteria by which we measure outcomes in rheumatoid arthritis, osteoarthritis, lupus, Crohn’s and colitis, and other conditions, and begin looking at how CBD performs by these metrics.”

A byproduct of a growing number of studies demonstrating benefit is that patients are less reticent about admitting cannabis use. “Our patients with various inflammatory diseases are getting more and more open about using cannabis because we are in Massachusetts, where it has been medically legal for a few years,” Molloy said. “We know that among the patients who admit trying it for various medical indications, it is unusual for a patient to say it did nothing for them.”

Reducing Pain and Inflammation

While randomized controlled trials in humans are lacking, case reports of the remarkable consequences of the human endocannabinoid system regularly appear in peer-reviewed journals. Most recently in the British Journal of Anesthesia, Habib and colleagues reported on a 66-year-old woman in Scotland who, essentially, felt no pain, with “nil requirement for postoperative analgesia after a normally painful orthopedic hand surgery” and “a lifelong history of painless injuries.” Investigation revealed enhanced endocannabinoid signaling and a loss of function of the FAAH chromosomal region.

“It should be very clear that, at least for some conditions and some patients, something in cannabis is good for pain in no small part because of our endocannabinoid system,” Richard J. Miller, MD, Alfred Newton Richards Professor in the department of pharmacology at Northwestern University Medical School, said in an interview. “It is frustrating that we still do not know exactly what components of THC or CBD may be interacting with that system. There are indications that both could be helpful, but we still do not know.”

CB2 receptors were initially identified in the spleen and macrophages, which may carry associations with immunity, according to Abrams. “The CB1 region contains one of the most densely populated receptor regions in the human brain,” he said. “But when I am speaking to residents and fellows and ask who has learned about this in medical school, almost no one ever raises their hand.”

Miller suggested that it is important for the research and clinical communities to understand the parameters of pain. “If we are going to effectively use cannabinoids to manage pain, it is important to understand that there are many different types of pain our patients can experience,” he said. “Patients can experience spontaneous pain, allodynia, hypoalgesia, mechanical pain, and all of these have different aspects. From there, we have to ask our patients: You have taken this drug for your specific pain. How do you feel?”

“So far, the strongest data are for chemotherapy-induced nausea and vomiting,” Abrams added. “There are also strong data showing that cannabis can be useful in peripheral neuropathy and other types of neuropathic pain.”

In their study in Pain Research and Treatment, Habib and colleagues investigated cannabis consumption habits among 383 patients with fibromyalgia in Israel. Results showed that 94% of cannabis users reported pain relief, while 93% reported improvement in sleep, 87% reported improvement in depression, while anxiety improved in 62%. The adverse event rate was 12%, with 8% reporting dependence on the drug.

Molloy warned that studies should attempt to control for self-reported outcomes. “Patients perceive improvements in all kinds of parameters, but how much of that is a placebo effect and how much is due to biologic activity is hard to sort out,” he said.

Because of the legal situation in the U.S., patients with chronic pain are often simply taking cannabinoid products at their own risk, at their own dosing levels, at their own discretion. “If I was a patient with chronic joint pain and I had tried a number of other types of analgesics, I would definitely try it,” Miller said. “But patients should not be in a position where they have to decide to give it a try and find a product on their own. We should have a clearer understanding of how to dose and prescribe it.”

Many physicians like Swaminath are concerned that patients may drop their effective standard therapies for what they may consider a natural and safer alternative, all the while allowing their underlying disease to progress while their symptoms are minimized and hidden. “A patient might feel they have made the right choice, but eventually the disease catches up,” he said.

Possible Red Flags

In terms of potential harms, other comments from Fitzcharles and colleagues in Journal of Rheumatology suggested that short-term risks of psychomotor effects may occur. However, long-term risks of this kind have not been determined. “Evidence is insufficient about the benefit of pharmaceutical cannabinoids in fibromyalgia, osteoarthritis, rheumatoid arthritis and back pain, but there is evidence of a high risk of harm,” they wrote.

Abrams disagrees. “Cannabis is something you do not need to worry about,” he said. “It is rather benign compared to many of the pharmaceuticals that are out there.”

Looking more closely at specific effects, Swaminath suggested that impaired motor coordination can lead to an uptick in traffic accidents, particularly when cannabis is combined with alcohol. However, data are inconclusive on this, largely because there is currently no way to test for cannabis at the site of a traffic accident.

Thinking about other potential harms, Fitzcharles cited findings in the International Review of Psychiatry from Cooper and colleagues, who provided a possible explanation for potential addiction risk. “These findings suggest that cannabis is addictive via the rewarding effects of CB1 receptors and dopamine release in mesolimbic-dopamine reward pathway,” she said. “Addiction rates are as follows: for recreational users overall, it is 9% for all users, 17% for onset adolescence, 25% to 50% for daily users.”

Again, Abrams took issue with the idea of addiction to cannabis. “It has less potential for addiction than coffee,” he said.

A companion to addiction is increasing tolerance to the effect of THC or CBD, and how that might impact whatever clinical benefit may occur, according to Rapoport. “Patients have to titrate how much they are using,” he said, and noted that the onset of effect is dramatically different if patients are smoking, vaping or eating the product. “Patients often find it difficult to control the effects, at least at first.”

Fitzcharles noted concerns beyond usage and dosing issues. “The impact on brain development in young persons with rheumatic diseases is of concern,” she said. “Neurodevelopment continues into the early 20s with the endocannabinoid system playing an important role in development and maturation of cortical pathways, especially those projecting to the frontal cortex.”

Regular cannabis use negatively impacts this critical brain maturation, according to Fitzcharles, who cited findings from Njoo and colleagues in PLOS Biology. “At the axonal growth cones of nerve terminals, the CB1 receptor aligns with WAVE1 complexes to affect actin alignment,” she said. “This, thereby, directs and modulates the collapse and navigation of axonal growth cones and synaptic spines to create specific and secure circuitry for developing and maturation of neurons.”

Despite the unanswered questions and broad concerns, Fitzcharles and colleagues summed up the issue in a recent paper in European Journal of Pain. “Medical cannabis has entered mainstream medicine and is here to stay,” they wrote. – by Rob Volansky

• References:
• Cooper ZD, et al. Int Rev Psychiatry. 2009;doi:10.1080/09540260902782752.
• Fitzcharles MA, et al. Eur J Pain. 2018;doi:10.1002/ejp.1185.
• Fitzcharles MA, et al. J Rheumatol. 2019;doi:10.3899/jrheum.181120.
• Habib G, et al. Pain Res Treat. 2018;doi:10.1155/2018/7829427.
• Habib AM, et al. Brit Journ Anesthesia. 2019;doi:10.1016/j.bja.2019.02.019.
• Hoffenberg EJ, et al. J Pediatr Gastroenterol Nutr. 2019;doi:10.1097/MPG.0000000000002189.
• Navarini L, et al. Int J Biochem Cell Biol. 2018;doi: 10.1016/j.biocel.2018.04.010.
• Njoo C et al. PloS Biol. 2015;doi:10.1371/journal.pbio.1002286.

• For more information:
• Donald I. Abrams, MD, can be reached at 995 Potrero Ave., San Francisco, CA 94110; email: donald.abrams@ucsf.edu.
• Daniel Clauw, MD, can be reached at 24 Frank Lloyd Wright Dr.; PO Box 385; Ann Arbor, MI 48105; 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.
• Richard J. Miller, MD, can be reached at 303 E. Superior St., Chicago, IL 60611; email: r-miller10@northwestern.edu.
• Philip Molloy, MD, can be reached at 110 Long Pond Rd., Plymouth, MA 02360; email: pjm4pjm@hotmail.com.
• Ronald J. Rapoport, MD, can be reached at 1030 President Ave., Rm 221, Fall River, MA 02720; email: rappie12@aol.com.
• Arun Swaminath, MD, can be reached at 100 East 77th St., 2nd Floor, New York, NY 10026; email: aswaminath@northwell.edu.

Disclosures: Abrams reports being a scientific advisor to AXIM Biotechnologies, Cannformatics, Intec Pharma, Lumen, Maui Wellness Group, Scriptyx, Tikun Olam USA, and Vivo Cannabis. Clauw reports associations with a number of pharmaceutical companies, including Aptynix, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, Williams & Connolly, and Zynerba. Fitzcharles and Miller report no relevant financial disclosures. Molloy reports being an advisor and investor in Solar Therapeutics. Rapoport reports being a medical advisor for Solar Therapeutics. Swaminath reports being on the advisory board of Pfizer and receiving grant funding from Abbvie, Janssen, Pfizer and Takeda.