January 25, 2024Client Alert

FDA Publishes Guidance Document Discussing the Study of Investigational Psychedelic Drugs in Clinical Trials

Over the past two decades, efforts to relax and eliminate legal restrictions on cannabis have gained widespread backing in the United States. The normalization of marijuana, as well as an emphasis on responsible use, has likely contributed to the renaissance of psychedelics and their potential as therapeutic treatments for addiction, treatment-resistant depression, anxiety, and post-traumatic stress disorder (PTSD). Despite a resurgence in interest, current regulations and restrictions pose a major hurdle for psychedelics.

Psychedelics have not always been strictly regulated or designated as Schedule I drugs. Prior to the 20th century, mushroom extracts, cactus extracts, and toad excretions were used during shamanic rituals to induce sensory experiences for spiritual healing and divination. In 1938, lysergic acid diethylamide, colloquially known as “LSD”, was synthesized by Albert Hoffman; however, it was not until 1943 that the ability of LSD to alter visual and auditory perceptions of reality were identified. During the 1950’s, over 500 scientific publications were published on LSD. None of the publications during this time were directed towards LSD addiction or abuse. Rather, many of the publications cited LSD’s success in treating alcoholism.

During the 1960’s, the absence of regulatory control enabled unrestricted distribution and use of psychedelics. This coincided with the hippie counterculture movement, which advocated against war, capitalism, racism, and government imperialism. Rightfully or wrongfully, the use of psychedelics to dissociate (i.e., “trip”) to another dimension of reality became associated with the counterculture movement. Amid civil unrest and violent protests, psychedelics were hailed the culprit.

In 1970, President Richard Nixon enacted the United States Controlled Substance Act. This legislation created five Schedules (i.e., classifications) to which compounds could be designated based upon their acceptance for medical use and risk for abuse. Under the Controlled Substance Act, psychedelics, such as LSD and MDMA, were designated as Schedule I and considered to be compounds with a high risk of abuse and no accepted medical use. In the wake of the Controlled Substance Act, funding for research into the therapeutic potential of psychedelics ceased to exist. It was not until 2021 that the National Institute of Health (NIH) awarded its first grant in 50 years to study the therapeutic effects of psilocybin on tobacco addiction. John Hopkins Medicine Receives First Federal Grant For Psychedelic Treatment Research in 50 years (October 2021).

The re-emergence of research funding for psychedelics is concurrent with the U.S. Food and Drug Administration’s (FDA) response to the need for alternative therapies to address treatment resistant medical conditions. This past June the FDA took a big step by issuing a draft guidance for researchers wishing to develop psychedelic drugs for the treatment of medical conditions: Psychedelic Drugs: Considerations for Clinical Investigations Guidance for Industry (June 2023).

The creation of this draft is not the first time the FDA has signified their acknowledgement of the need for alternative therapeutics to combat treatment resistant mental health disorders. In 2019, the FDA approved esketamine (SPRAVATO®), the S-enantiomer of ketamine, in conjunction with an antidepressant for the treatment of depression in adults. Similar to psychedelics, esketamine possesses the ability to induce a dissociative, hallucinogenic state. Due to the potential risk of sedation, dissociation, abuse, and misuse, the FDA requires restricted distribution of esketamine under a Risk Evaluation and Mitigation Strategy (REMS) to reduce the frequency and/or severity of adverse events. For esketamine, compliance with the approved REMS requires that a patient receive esketamine at a certified doctor’s office or clinic and be monitored by a health care provider for at least two hours after receiving a dose. FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression (March 2019).

In parallel with the REMS established for esketamine, the FDA’s draft guidance on psychedelics emphasizes safety-monitoring guidelines. In particular, the guidance highlights that a patient receiving a psychedelic may be in a vulnerable state for as long as 12 hours. Additionally, the guidance indicates that safety-monitoring measures should include a healthcare provider with graduate-level professional training and an assistant monitor possessing a bachelor’s degree and at least one year of clinical experience in a licensed mental healthcare setting. Due to the similarity in the risks between esketamine and psychedelics, it is possible that the FDA’s approach to esketamine may serve as a framework for regulatory approval of psychedelics. The congruence between esketamine’s REMS and the draft guidance issued by the FDA for psychedelics. further substantiates this possibility.

Further, the FDA’s guidance includes information on trial conduct, data collection, and safety. Specifically, the FDA acknowledges unique considerations for psychedelics, especially related to the design of "adequate and well-controlled" clinical studies. The draft guidance underscores that a direct comparison of a traditional placebo control group to a treatment group may not appropriately assess efficacy due to the existence of perceptual disturbances in response to a psychedelic that may unblind study participants.

Of particular importance, the draft guideline emphasizes the significance of pharmacodynamic evaluation of psychedelic compounds at the serotonin 2B receptor subtype (5-HT2B). During the 1990’s, fenfluramine was later removed from the market in September 1997 due to an increased prevalence of valvular heart disease in patients taking fenfluramine. Researchers discovered that fenfluramine was a 5-HT2B receptor agonist and determined that 5-HT2B activation was responsible for adverse valvular heart disease in response to fenfluramine. Consequently, it is no surprise that the FDA’s guidance on psychedelics underscores that any psychedelic compound showing activation of the 5-HT2B receptor should be evaluated and assessed for its ability to cause heart valve thickening. The guidance also suggests that subjects with pre-existing valvulopathy or pulmonary hypertension should be excluded from clinical studies until the risk of 5-HT2B activation of the psychedelic compound is comprehensively addressed. Evidence for Possible Involve of 5-HT2B Receptors in Cardiac Valvulopathy Associated with Fenfluramine and Other Serotonergic Medications (December 2000).

While the creation of this draft by a federal agency in itself is historic, the FDA is not the first to publicly admit to the rising interest in psychedelics. Individuals, private companies, and even states have long realized the potential benefits of psychedelics' pharmacological use.

JAMA Psychiatry, part of the American Medical Association, released an analysis (Apr 2023) that estimated most states will legalize psychedelics by 2037. Additionally, while only two states have decriminalized the supervised use of psychedelics (CO/OR), half our country — 25 states — have considered legislation. Although analogies are often made to the legalization of cannabis we suspect that the regulatory scheme ultimately developed for psychedelics will be very different from that adopted for recreational and medical marijuana.   

The question, then, is, why does the FDA's draft matter? For the patient, a lot. Psychedelics, as prescribed by a doctor, means greater therapy choices and the potential for improved health.

For companies, psychedelics equals cash. "With more than $6.8 billion on the line by 2027, companies at the vanguard of the psychedelic therapeutic drug market could heap enormous benefits in the coming years." (Network News Wire, Oct 2020)

As the psychedelic therapeutic drug market valuation increases, the value of protecting intellectual property in the psychedelic space is becoming paramount. The growth of the psychedelic industry has increased the number of patent applications directed towards psychedelic subject matter. A particular challenge in the preparation of applications containing psychedelic subject matter pertains to patent prior art. An assessment of the patent prior art landscape can be challenging since newly filed patent applications do not publish to the public until at least 18 months after the effective filing date. As a result, it can be difficult to assess patent prior art that might be cited against the application during prosecution and strategically prepare an application in view of existing prior art. This challenge is not unique to psychedelics and exists in “hot” areas of technology and industries.

While a win-win scenario is still up in the air, the FDA’s draft guidance is definitely a positive step toward the treatment of complex and hard-to-treat mental health disorders.

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