FDA Issues Psychedelic Research Guidance for Industry

Covers clinical trials of psilocybin, MDMA, and LSD, including the role of therapy, abuse potential, adverse events, participant blinding, investigator qualifications, and theoretical cardiac risk

Yesterday, the U.S. Food and Drug Administration (FDA) announced new draft guidance for psychedelic research. I offer some thoughts on this new document, primarily related to the role of therapy in psychedelic medicine, the abuse potential of the substances, the risk and language surrounding adverse events, blinding of research subjects, suggested researcher qualifications, and the theoretical risk of cardiac valve thickening.

Technically, industry guidance does not legally bind regulated industries. It’s supposed to allow agencies to make non-binding recommendations, which lack the force of administrative rules.

Perhaps more than any other agency, the FDA often issues guidance instead of rules. Some have criticized it for doing so to circumvent the more burdensome requirements surrounding rule making.

Despite the fact that guidance constitutes mere recommendations, industry stakeholders might interpret guidance as though it is binding. In other words, like legally-enforceable rules, FDA guidance can shape pharmaceutical industry norms and practices.

In any case, this version of the FDA’s guidance is a draft, and the agency seeks input for potential incorporation into subsequent versions.

Many researchers and psychedelic advocates are hailing the guidance as a significant milestone. I have a slightly less enthusiastic take. Like the recent creation of a CPT code for psychedelic therapy by the American Medical Association (a CPT code does not guarantee insurance reimbursement), I’d say the new guidance is to be expected and is not particularly noteworthy. The FDA frequently issues guidance or action plans for emerging industries involving new technologies like gene therapies and medical AI.

Much of the new guidance would apply to any drug industry. For instance, it states that psychedelics must be produced using current good manufacturing practices (CGMP) under the Food, Drug, and Cosmetic Act. However, several notable aspects warrant discussion. Some are merely interesting. Others could potentially influence the course of future psychedelic research.

The FDA’s Use of Psychedelic Language

In the guidance, the FDA differentiates classic psychedelics like psilocybin and LSD, which activate the 5-HT2 receptor, from entactogens or emphathogens like MDMA, which have different effects and mechanisms. Up front, the FDA says it will use the general term psychedelics as shorthand to reference both groups.

There are psychedelic language police out there who bristle at the inclusion of MDMA and ketamine within the scope of the term psychedelics. But I don’t think that’s a problem, and the FDA guidance handles it well (perhaps excluding ketamine from the discussion because it is already FDA approved).

The Role of Therapy in Psychedelic Medicine

One of the most interesting aspects of the guidance addresses the contributions of therapy or psychological support. Interestingly, the FDA acknowledges that these factors’ contributions to therapeutic outcomes remains uncharacterized. That’s notable because many actors in the psychedelic landscape swear that therapy and integration are essential to achieving therapeutic benefits. Some even claim the extent and duration of therapy and integration positively correlate with the extent of benefits and negatively correlate with the risks. Of course, many commenters have a financial interest in promoting specific therapy protocols and training programs that may be required to utilize them. The potential influence of these ties should not be overlooked.

The FDA offers a more sobering take. We simply don’t know the importance of therapy and various forms of psychological support. The agency even suggests that psychotherapy could negatively impact trial validity by increasing participant expectancy and performance biases (where participants or researchers behave differently because they have inferred the study arm to which a participant belongs). Accordingly, the FDA encourages researchers to design trials that evaluate the impact of therapy and other modes of support.

One FDA suggestion has already drawn criticism from researchers on Twitter. The guidance suggests that to minimize performance biases, the researchers providing therapy (often called integration) after a psychedelic session should potentially be different from the researchers who support participants while under the influence of a psychedelic (during an administration session). Critics of this view argue that such an approach could undermine rapport between researchers and trial participants. Though superficially appealing, like the role of therapy itself, this claim has not been empirically tested.

I find the FDA’s somewhat agnostic position on the role of therapy refreshing. It takes nothing for granted and puts the burden on researchers to prove that their therapies enhance safety and efficacy. The psychedelic industry has been too quick to adopt the loaded term psychedelic-assisted therapy (or psychedelic therapy), and the FDA’s guidance appears to walk that back. I expect that some industry stakeholders will lobby the agency to reconsider its position in future versions of the guidance.

I don’t mean to minimize the importance of support or aftercare. It’s worth noting that Indigenous communities often have elaborate systems that support people having psychedelic experiences. These practices have been honed for centuries. However, I would not confuse these longstanding, community-based practices with the psychedelic therapies promoted by drug makers to accompany their proprietary compounds. The latter should be rigorously evaluated to determine the extent to which they are helpful. They add significant cost to psychedelic medicine, and to the extent that they don’t enhance safety and efficacy, they should be modified, pared back, or eliminated.

Abuse Potential

Another notable section of the FDA’s guidance covers the topic of abuse. I should emphasize that the agency references abuse in terms of the potential for people to abuse psychedelics. It does not address the potential abuse of vulnerable participants by researchers, a serious concern that is often overlooked.

The Controlled Substances Act, which lists classic psychedelics as Schedule I controlled drugs, perpetuated the notion that all drug consumption outside the medical system constitutes abuse. The FDA’s new guidance appears to reinforce this view. Further, it states that some core features of the psychedelic experience, such as cognitive changes and hallucinations, reflect a drug’s potential for abuse.

I suppose the implication is that the more a drug causes these effects, the more likely it is to be used illicitly. However, as many knowledgeable about psychedelics know, some of these features are equally likely to deter repeated use or abuse. For instance, the subjective effects of some substances are relatively unpleasant, potentially deterring repeated consumption. These subjective experiences also appear to have anti-addictive effects. Research participants have reported receiving subjective insights that helped them stop consuming addictive substances like heroin. Consequently, the subjective effects of a psychedelic could potentially reduce the drug’s abuse potential. The FDA’s guidance overlooks this perspective, but does not entirely preclude it.

I recommend that in future drafts, the FDA acknowledge the potential for physical, emotional, sexual, and financial abuse of research participants by investigators. It should urge researchers to develop systems to mitigate these risks. The agency should also acknowledge the role that the subjective effects of psychedelics may play in reducing their abuse potential, as well as the undesired use of other substances.

Side Effects Versus Adverse Events

Interestingly, the FDA’s guidance also frames core features of psychedelic experiences, such as hallucinations and emotional changes, as abuse-related adverse events to be reported as safety concerns, “even if they are hypothesized to be associated with the therapeutic response.” That may sound strange to experienced psychonauts and even some clinical researchers.

Because many of these symptoms are common to psychedelic experiences, they might better be categorized as side effects rather than adverse events. Side effects are often expected (some can even be beneficial), and it would be strange to administer a psychedelic without expecting some change in thought patterns or perception, which is often a goal of administering the substances.

In contrast, adverse events are more unexpected and harmful. However, some believe the term side effect should be eliminated in favor of adverse drug reaction. That too may have an overly negative connotation, but it could be an improvement over the FDA’s current recommendation within its guidance.

One potential concern is that by framing cognitive and perceptual changes as adverse events, the guidance furthers the narrative that psychedelic effects should be engineered out of these substances. This narrative overlooks the possibility that the subjective effects of psychedelics are necessary for their efficacy, or at least contribute to it. Of course, this too remains unproven. But just as the FDA has taken a neutral approach to the role of therapy and support in psychedelic medicine, it might also take a more neutral approach to the subjective effects of these substances.

Blinding in Clinical Trials

The guidance addresses concerns about blinding in psychedelic clinical trials, which have been extensively discussed elsewhere (including the psychedelic Twittersphere). Accordingly, there’s not much new within the guidance, and I won’t go into much depth. Suffice to say, the FDA acknowledges the challenges of blinding. It contemplates including control arms with sub-perceptual psychedelic doses, or drugs that mimic aspects of the psychedelic experience. The FDA did not mention the somewhat bizarre and arguably inconclusive trial where researchers administered ketamine to people under general anesthesia.

The Qualifications of Researchers

Another interesting aspect of the guidance is its discussion of researcher qualifications. The FDA included a range of professionals as potential lead monitors, including nurse practitioners, marriage and family therapists, social workers, and licensed professional counselors. The guidance suggests the presence of two monitors throughout a psychedelic session. However, an assistant monitor could hold “a bachelor’s degree and at least 1 year of clinical experience in a licensed mental healthcare setting.”

According to the guidance, if the lead monitor is not a physician, it suggests a physician be on-call and located within 15 minutes of the clinical site. These recommendations are sensible and a welcome change from some previous suggestions that at least one or two physicians be present at all times.

Valvulopathy and the 5-HT2B Receptor

For several years, some researchers (often pharmacists and pharmacologists) have expressed concerns that classic psychedelics like psilocybin could contribute to cardiac valve thickening. This concern is based on observations that other substances that bind to the 5-HT2B receptor have been linked to valvular dysfunction. The most well-known example is fenfluramine, which was marketed as fen-phen when combined with phentermine.

It must be noted that researchers have not observed valve thickening in association with psychedelics. For now, this risk remains theoretical, based on the observed action of psychedelics at the same receptor as fentermine and other 5-HT2B agonists. Though the risk remains theoretical, that doesn’t mean precautions should not be taken.

The FDA guidance suggests baseline and follow-up echocardiograms to assess valve structure and function before and after psychedelic administration. The agency also recommends measuring pulmonary artery pressures if psychedelics are administered for extended periods.

The FDA further recommends excluding people with existing valvular disease or pulmonary hypertension from clinical trials until heart-related risks are better understood.

For the most part, these precautions are sensible. However, there may be patients at the end of life for whom the risk-benefit analysis tips in favor of accessing psychedelics to alleviate end-of-life depression, anxiety, or existential distress. The FDA’s guidance should not be interpreted as a universal ban on providing psychedelics to these individuals, provided they are fully informed of the risks.

It will be interesting to see further reactions to the FDA’s guidance and read future drafts of the document. Follow Psychedelic Week for in-depth analysis of this and other psychedelic news, policies, and events.

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*The views expressed on Psychedelic Week do not represent the views of Harvard University, POPLAR at the Petrie-Flom Center at Harvard Law School, Florida State University, or the Florida State University College of Law. Psychedelic Week is an independent project unaffiliated with these programs and institutions.

Mason Marks, MD, JD is the Florida Bar Health Law Section Professor at the Florida State University College of Law. He is the senior fellow and project lead of the Project on Psychedelics Law and Regulation (POPLAR) at the Petrie-Flom Center at Harvard Law School and an affiliated fellow at the Information Society Project at Yale Law School. Marks teaches drug law, psychedelic law, constitutional law, and administrative law. Before moving to Florida, he served on the Oregon Psilocybin Advisory Board where he chaired its Licensing Subcommittee. Marks has drafted drug policies for state and local lawmakers. His forthcoming book on psychedelic law and politics will be published by Yale University Press. He tweets at @MasonMarksMD and @PsychedelicWeek.