Research into the therapeutic benefits of psychedelic drugs is nothing new. In fact, research extends back 80 years with the discovery of lysergic acid diethylamide (LSD), when the Swiss chemist Albert Hofmann, looking to synthesize a migraine treatment, created the derivative of the ergot fungus. It wasn’t until several years later that he accidentally dosed himself and realized LSD’s psychedelic effect.
This initial research kicked off a wave investigating the therapeutic potential of psychedelics, but with the emergence of the secretive and unethical research by the Army and CIA and the rise of the counterculture, the federal government stepped in. The Controlled Substance Act subsection of the Comprehensive Drug Abuse Prevention and Control Act of 1970 classified LSD, heroin, marijuana and a few other drugs as having “a high potential for abuse, no current medical use, and a lack of safety for use under medical supervision,” classifying them as Schedule I substances and effectively killing research because of the hoops scientists would need to jump through, with both the U.S. Food and Drug Administration (FDA) and the Drug Enforcement Administration (DEA).
It would be nearly three decades before psychedelic medicine research re-emerged in a meaningful way, when researchers at Johns Hopkins obtained regulatory approval to reinitiate research in healthy, psychedelic-naïve volunteers. A subsequent study examining psilocybin administered in a supportive setting is widely recognized for igniting the current period of psychedelic research. This seminal study, which demonstrated long-term benefits of psilocybin (e.g., positive mood, life satisfaction, prosocial behavior) in healthy participants, is just one of many studies that have since confirmed the low toxicity and minimal addiction potential of psychedelics.
In the intervening years, legislative reform regarding psychedelics began to gain momentum. According to a study in JAMA Psychiatry, from January 2019 to September 2022, 25 states considered 74 bills to reform existing laws restricting access to psychedelic drugs or proposed further research into reform legislation. Ten of those bills were signed into law by seven states, with the vast majority (90 percent) specifically referring to psilocybin and 36 percent of the bills also including 3,4-methylenedioxy-methamphetamine (MDMA).
The foundation laid by Johns Hopkins has, over the last 20 years, spurred a wave of interest — and progress — into the benefits of psychedelic medicines.
In October 2022, mental health company Compass Pathways announced initiation of the first Phase 3 program of psilocybin therapy globally for treatment-resistant depression. Initiation of the program followed positive results from the company’s Phase 2b study, presented at the American Psychiatric Association annual meeting in May 2022. Likewise, earlier this year, the Multidisciplinary Association for Psychedelic Studies announced results of its Phase 3 clinical trial of MDMA-assisted therapy, which demonstrated statistically significant improvements in PTSD symptoms after three sessions.
This past June, the FDA published a new draft guidance to highlight considerations to researchers investigating the use of psychedelic drugs for potential treatment of medical conditions. This represented the first draft guidance that presents considerations for designing clinical trials for psychedelic drugs. It recognizes the interest in exploring their therapeutic potential, but also the unique challenges throughout the drug development process, including clinical trial conduct, data collection, subject safety and new drug application requirements.
Further, the draft guidance notes that, for psychedelics that are currently Schedule I controlled substances, activities associated with investigations under an Investigational New Drug Application must comply with applicable DEA regulatory requirements. Importantly, in providing a pathway for the research, this is a tacit signal that the FDA is also indicating to the biopharmaceutical industry that there is ultimately a pathway to approval. With the first approval possibly coming as soon as 2024, there will surely be increased interest in the space, even if it doesn’t translate into an immediate wave of approvals.
Yet, challenges remain.
These challenges are often logistical in nature. Given the psychedelic experience that accompanies treatment, which can last up to 12 hours in some cases, conducting clinical research is labor and resource intensive. FDA’s guidance requires two people to monitor clinical trial participants. One of these monitors needs to be at least a Ph.D.-level researcher and the secondary monitor still needs to have experience in the mental health space. This is something that will likely extend into treatment once these medicines are approved. Uptake could be a similar challenge, as it could require two people to guide patients through their psychedelic experience to make sure they remain safe, and if there are any adverse effects, that they can support them along their journey.
This is also new ground for the FDA, and the agency will likely take a very cautious approach to safeguard patients and minimize the risk for unforeseen treatment-emergent safety concerns. Compounding the challenge of uptake is that manufacturers and investigators will need to go through the process of securing DEA clearance to be authorized to administer these drugs in the research setting.
Despite decades of research, the FDA’s draft guidance is finally bringing psychedelics research into the light. As the space continues to progress, there could be a move toward fine tuning the experience for patients. That may mean minimizing the psychedelic effects of these drugs without compromising their therapeutic benefits or being more selective in the receptors researchers target to reduce their adverse potential. Along with this evolution, a meaningful step that could bring us closer to realizing the full potential of these important therapeutics would be for the Department of Health and Human Services (HHS) to initiate a review to consider recommending rescheduling of the individual drugs or the entire class. The precedent for such a move was recently set when HHS recommended in August 2023 to have cannabis moved to Schedule III from its current Schedule I. Doing so would greatly ease access for further research and eliminate the administrative burden on prospective researchers and the DEA that is currently required to review the paperwork from each researcher for each trial they plan to conduct.
Robert Bauer is executive director of operational strategy at Precision for Medicine.