New legislation may tame ‘wild west’ of cannabis research in rheumatology
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A law allowing for medical cannabis research could have far-reaching implications in rheumatology and across the health care spectrum, but there are still significant hurdles to clear before cannabinoids become part of routine care.
On Dec. 2, 2022, President Joseph R. Biden signed the Medical Marijuana and Cannabidiol Research Expansion Act, the first standalone legislation pertaining to cannabis approved by both the U.S. Senate and the House of Representatives.
The law allows for expanded research into the drug in myriad medical specialties. However, perhaps more importantly, it will free up rheumatologists to discuss — with data — cannabis with their patients, including those who have been using it off-label and recreationally to manage pain, improve sleep and minimize anxiety for years.
“This is huge,” Kaleb Michaud, PhD, of the University of Nebraska Medical Center, in Omaha, told Healio. “There are so many restrictions to studying the effects of cannabis that most in academia did not want to even start or participate with other larger studies. This will have the greatest impact on clinical trials that are greatly needed to better understand the effects of cannabis.”
Mark Bleackley, PhD, chief science officer at Incannex, which develops medical cannabis therapies, added that the legislation is a “game changer” for the rheumatology space.
“The pleotropic effects of cannabinoids provide advantages over currently available medicines for pain and inflammation,” he said. “However, the potential for cannabinoids will not be achieved with simple extracts of botanical material or people smoking cannabis.”
That said, despite the apparent optimism surrounding the legislation and subsequent impending research, there are some important reservations that must be considered.
According to Michael E. Schatman, PhD, of the department of anesthesiology, perioperative care and pain medicine, as well as the department of population health’s division of medical ethics, at the New York University Grossman School of Medicine — who applauded the passage of the legislation — chief among these is the issue of funding.
“My concern is that while the legislation may ease some of restrictions regarding doing the research, it does not say much about how the research is going to be funded,” Schatman said. “With no clear federal source of funding, it is possible that the research will be funded by industry. This can lead to poorer quality research that does not show the potential harms or adverse events.”
Beyond funding, other issues to consider include dosing and delivery, he added. Cannabinoid products can be applied topically, eaten, drank, smoked, sprayed and inhaled. Sorting out each of these approaches and applying them to individual disease states, as well as arriving at standardized treatment protocols, could be time-consuming and costly.
Moreover, most current research focuses on the difference between tetrahydrocannabinol (THC) — the component that has psychotropic effects and can provide a “high” — and cannabidiol (CBD), which generally has no known high associated with its use.
“These are only two of the more than 110 constituents in the cannabis plant,” Schatman said. “If you do conduct a study of one strain that has a particular balance of THC and CBD and you get positive findings, does that mean all medical cannabis is great for that indication or just that one strain? These are the questions we need to answer.”
Despite these reservations, many rheumatologists anxiously await the next step — when the legislation begins to yield actual research.
‘Long delay’
The consensus among many rheumatologists is that having a law in place is better than not having a law in place. According to Bleackley, this piece of legislation removes one of the many obstacles in the cannabinoid research setting.
“There are still a number of restrictions, and corresponding licenses and permits required to work with these molecules,” he said. “This acts as a barrier for many researchers as the administrative burden can be substantial.”
Bleackley added that, in some cases, the legislation governing non-clinical research is not well-defined.
“This leads to confusion on what the licenses and permits required to acquire and conduct research on cannabinoids are, and who needs to have them,” he said.
Meanwhile, if the law signed by the Biden administration eventually leads to research establishing the safety and efficacy of certain cannabinoid products, FDA approvals may follow.
“Then, there is also the potential for cannabinoid containing products to be covered by insurers and Medicare,” Bleackley said. “However, it will be important that legislation around possession and shipping of cannabinoids progresses with the development of cannabinoid therapeutics.”
That journey, from the current status quo to medical cannabis distribution at the federal level, promises to be long, according to Michaud.
“If we get randomized controlled trials showing if or how cannabis could help people seeing rheumatologists, then most definitely,” he said. “Unfortunately, there is still a long delay from research initiation to recommendations for clinical use.”
‘Not relevant to the real world’
According to Bleackley, “best practices” should be instituted moving forward if research into cannabis products is going to reach full fruition. This begins with attitudes surrounding the product.
“Due to the history of CBD and cannabis there are a lot of preconceived notions about the molecules that are based on low quality evidence, such as anecdotal reports and experiments that lack appropriate controls,” Bleackley said.
Well-designed prospective trials are critical, according to Schatman.
“There needs to be a control group and a study group,” he said. “Ideally, the study would be double blind, or at least single-blind, to minimize bias.”
The issue is that this kind of research is costly and time-consuming, which adds to the many obstacles surrounding the study of cannabinoids.
The next consideration pertains to the strength of the product. For decades, the only cannabis that was allowed to be studied in medical trials had to be farmed at the University of Mississippi, which maintains a maximum THC level of 7% in its products.
“This raises the question of what constitutes medical-grade product,” Schatman said. “These days, on the street and in dispensaries, the weakest products patients are getting are 20% or 25% THC. Cannabis of the strength that has been studied from the University of Mississippi is not relevant to the real world.”
In addition to the strength, the quality of the product also should be rigorously regulated, according to Bleackley.
“The products need to meet pharmaceutical specifications,” he said. “Synthetic manufacturing of cannabinoids according to current Good Manufacturing Practice and formulation using pharmacopeial excipients are examples of how to achieve this.”
That said, quality evidence in cannabinoid products does, in fact, currently exist. Bleackley stressed the importance of sorting the good from the bad in this regard, so that future research can be held to the proper standards as data emerge across health care specialties — including rheumatology.
‘Impact on pain’
“We need randomized controlled trials examining the impact on pain — both intensity and interference — in our rheumatology patient community,” Michaud said. “It is also important to understand whether there is a difference in impact by rheumatic disease, from the primary inflammatory arthritides to osteoarthritis, to those where the causes of pain symptoms are less understood.”
Personal titration of CBD and THC levels also need to be considered to determine thresholds for symptom relief and side effects, he added.
“There is also a need to additionally understand the pharmacokinetics of these levels through various forms of treatment,” Michaud said, noting that inhaled, topical and edible products all can have different effects and should therefore undergo rigorous individual analysis. “Each has different timing and intensity of effect by individual.”
Finally, for each of these delivery methods and dosing thresholds, it is critical to determine if there are any safety concerns for cannabinoid products administered in combination with the many medications common to those with rheumatic diseases, according to Michaud.
To that point, Bleackley noted that IHL-675A (Incannex), a novel treatment that combines CBD and hydroxychloroquine sulfate, may have the capacity to treat chronic inflammatory conditions including rheumatoid arthritis.
“A phase 2 trial in rheumatoid arthritis patients is currently underway at 10 trial sites in Australia,” he said. “The study is investigating IHL-675A in patients with RA who have residual pain and reduced function, even if they are on approved medications for their disease.”
The results of that study could be the beginning of more evidence-based and fruitful conversations between rheumatologists and their patients.
Taming the ‘wild west’
Understanding the patient experience with cannabis will be critical in both the clinical and research arenas, according to Michaud.
“For research purposes, it may be difficult to find people who are truly naïve to the treatment, since exposure has been possible for over a lifetime and overall exposure has increased dramatically in the past decade through non-medical access,” he said. “Not accounting for attitudes and perceptions of the medication affects willingness to participate as well as placebo effects.”
Preconceived notions can be both positive and negative regarding the safety and efficacy of cannabis and cannabinoids, Bleackley added.
“Changing people’s minds is always more difficult than presenting them with a new idea,” he said.
However, there are steps one can take to improve conversations surrounding cannabis, and perhaps even change some minds.
“Our medical community needs and wants to learn more about the actual science to date, so that we can be more helpful in these discussions with our patients,” Michaud said, adding that he is hoping for a future that is clearer and more organized than the present.
“It is still a bit of the ‘wild west’ in the United States when it comes to cannabis product quality and reliability,” he said. “We have much to learn from randomized clinical trials to come.”
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