In the mid-1960s, the Grateful Dead were the house band for Ken Kesey’s Acid Tests, parties in which people were “tripping out” on LSD, parties that helped bring psychedelics into the counterculture. Psychedelic drugs have been the focus of extensive clinical research since then, and their potential therapeutic benefits have seen renewed interest in recent years. It’s been a long, strange trip for certain because, despite extensive research, there are currently no FDA-approved psychedelic medications on the market.
The initial wave of psychedelic research in the 1960s was not only closely tied to counterculture movements, it was endorsed and funded by the CIA, which was looking for a mind control drug. However, experimentation with psychedelics, whether sanctioned or not, led to political and social backlash and the classification of many psychedelics as Schedule I substances under the Controlled Substances Act in 1970. This classification severely restricted research and development, and lingering concerns have plagued the process ever since. The BMJ placed an expression of concern on a meta-analysis about a methodological error that likely overestimated the benefits of psilocybin for treating symptoms of depression.
The most recent blow was dealt by an FDA advisory committee meeting in June 2024. The Psychopharmacologic Drugs Advisory Committee voted 9-2 that the available data failed to show MDMA, commonly known as ecstasy, was effective in treating patients with PTSD. And by a vote of 10-1, it was deemed that its risks outweighed the benefits, even with a proposed risk evaluation and mitigation strategy (REMS). The FDA was not bound to accept the recommendations of the Committee; nevertheless, two months later, it declined to approve the treatment without another study and other stipulations.
The rigorous process of FDA approval involves multiple phases of clinical trials to demonstrate safety and efficacy, and psychedelics present unique challenges in designing and conducting these trials due to their complex effects on the brain. One significant challenge is clinical trial design, particularly with regard to functional unblinding, a situation in clinical trials where participants and/or researchers can infer which treatment a participant is receiving, despite efforts to maintain blinding.
Psychedelics typically produce intense and unmistakable psychoactive effects, such as altered perception, mood, and cognition. These effects are usually quite different from those of a placebo, making it relatively easy for both participants and researchers to guess whether a participant has received the active drug or a placebo. This awareness can introduce bias, as participants’ expectations and researchers’ observations may be influenced, potentially skewing the trial’s results.
Addressing functional unblinding in psychedelic research often requires innovative trial designs. Some strategies include using active placebos (substances that produce mild psychoactive effects but are not expected to have therapeutic benefits) or incorporating more rigorous and objective outcome measures that are less susceptible to bias. These approaches aim to preserve the blinding and ensure that the results of the trial are reliable and valid. Moreover, the FDA’s own regulatory code outlines several other study design options that could be used.
Another hurdle in psychedelic research is the difficulty in finding the “ideal agent.” Different psychedelics have varying effects, durations, and safety profiles. Identifying a compound that offers the most therapeutic benefit with the least risk is a complex and ongoing process. The leading contenders today in clinical trials are MDMA, psilocybin, and LSD. Apart from their powerful psychological effects, some may have significant effects on blood pressure, heart rate, and rhythm.
Additionally, the therapeutic use of psychedelics often requires a combination of the drug with psychotherapy. This integrated approach, sometimes referred to as psychedelic-assisted therapy, necessitates trained therapists and specialized settings, further complicating the clinical trial process and eventual implementation in standard clinical practice.
It is generally accepted that most clinical trials involving the use of psychedelics should be conducted by academics and in conservative, safe environments. However, this has not allayed concerns about misconduct during the trials – underreporting of serious adverse events and, in one incident, alleged sexual misconduct by an unlicensed therapist with a patient – prompting the scientific journal Psychopharmacology to retract three papers for “protocol violations amounting to unethical conduct” by the researchers.
Ethical concerns do indeed play a significant role in psychedelic research. The hallucinogenic effects of psychedelics can lead to challenging experiences, and there is a moral responsibility to ensure that participants are not harmed. This includes thorough screening, informed consent, and providing adequate support during and after the experience, which is why a REMS program would most certainly be a requirement of any FDA-approved agent. Researchers are also hopeful that the FDA will clarify how psychotherapy should be utilized in future psychedelic trials.
Historically, limited funding for psychedelic research due to stigma and regulatory barriers has been an issue, though this is beginning to change as more private and public entities recognize the potential benefits of these substances. Recent studies have shown promising results in treating conditions such as depression, PTSD, and substance use disorders. Organizations like MAPS (Multidisciplinary Association for Psychedelic Studies) and academic institutions are conducting rigorous research to build a strong evidence base.
Growing interest from patients and the public in alternative treatments for mental health conditions is driving demand for further research and potential approval of psychedelic therapies. Considering only PTSD, there are 13 million Americans who live with the disorder, and there have been no new drug treatments this century (the FDA approved sertraline and paroxetine for PTSD in 1999). While there are no FDA-approved psychedelic medications currently available, the landscape is rapidly evolving, and ongoing research, increasing funding, and shifting societal attitudes may pave the way for future approvals and broader acceptance of psychedelics in clinical practice.
Arthur Lazarus is a former Doximity Fellow, a member of the editorial board of the American Association for Physician Leadership, and an adjunct professor of psychiatry at the Lewis Katz School of Medicine at Temple University in Philadelphia, PA. He is the author of several books on narrative medicine, including Medicine on Fire: A Narrative Travelogue and Narrative Medicine: Harnessing the Power of Storytelling through Essays.
