Drug companies are spending millions to incorporate psychedelic agents into healthcare, working with research institutions and patient organisations, and gaining support in Congress, while mounting clinical evidence is paving the way for probable approval of new psychedelic medicines by the Food and Drug Administration (FDA).
FDA review is important because psychedelics are Schedule I controlled substances, which means the Drug Enforcement Administration considers them to have no currently accepted medical uses and a high potential for abuse, write Mason Marks and Glenn Cohen in New England Journal of Medicine.
Yet while approval would also promote rescheduling, they suggest some tweaks and adjustments to the FDA’s draft guidelines – published earlier this year – on psychedelics research, which includes recommendations for scientists and drug sponsors.
Although focused on research, the guidance may influence clinicians preparing to prescribe psychedelics. But, they suggest, several of its recommendations may be contentious.
They write:
Psychedelics produce changes in cognition, perception, and affect. The guidance recognises that some of them, like lysergic acid diethylamide (LSD), will be synthesised, and others may be botanical drugs consisting of plant or fungal material, such as psilocybin-producing mushrooms.
The FDA suggests that if previous human trials have involved extensive exposure to a psychedelic and haven’t identified serious safety concerns, it might allow sponsors to start new human trials without performing animal testing.
Although this policy wouldn’t affect ongoing trials for depression and post-traumatic stress disorder (PTSD), it might accelerate research on new indications.
The guidance discusses limitations associated with blinding in placebo-controlled psychedelics trials. Because psychedelics produce perceptual changes, participants and researchers can often identify the groups to which participants are assigned, which could potentially bias study results.
The FDA proposes minimising “functional unblinding” by administering sub-perceptual doses of psychedelics or other substances whose effects mimic those of psychedelics instead of placebos.
Because of a potential risk of valvular disease, which has been observed with drugs having a high affinity for serotonin 5-hydroxytryptamine 2B (5-HT2B) receptors and hypothesised for classic psychedelics such as psilocybin and LSD, the FDA suggests excluding participants with valvular disease or pulmonary hypertension.
It recommends baseline and follow-up echocardiography for studies involving long-term administration of 5-HT2B agonists.
We believe these components of the guidance are well founded.
Other more controversial recommendations deserve greater scrutiny, including those related to psychotherapy. Most psychedelics trials provide some form of psychological support during and after drug administration.
Clinician monitors who observe participants experiencing acute psychedelic effects typically provide this support using a range of methods. Researchers also provide support during follow-up sessions.
The FDA notes that these psychological elements of treatment are poorly characterised, however, and warns that they could complicate assessment of product efficacy and labelling.
The guidance urges sponsors to justify the inclusion of psychological support and describe plans to quantify its effects and reduce potential bias. It further states that because monitors can often identify the trial groups to which participants are assigned, different personnel should provide post-administration support.
Some stakeholders have expressed concern that the guidance misinterprets the role of psychological support, which many consider essential to psychedelic treatment. Support could reduce the risk of serious adverse events, including psychosis, suicidal ideation, and chronic perceptual disturbances.
Furthermore, because support relies on trust, having different people monitor participants and provide aftercare could undermine patient–clinician rapport and affect outcomes.
The FDA has been reluctant to regulate supportive aspects of drug therapies, leaving this responsibility to state licensing bodies. In May 2023, for example, the agency argued against making access to buprenorphine for people with opioid use disorder (OUD) contingent on their receiving supportive services.
It had previously lifted similar limits on access to Suboxone (buprenorphine–naloxone). The FDA concluded that although support should be offered with such therapies, lack of access to supportive services shouldn’t be a barrier to treatment.
To be sure, psychedelics have different indications and carry different risks from OUD medications. But both address important public health problems and have been provided alongside psychological support, which adds substantial expense.
Price estimates for post-approval MDMA (3,4-methylenedioxymethamphetamine) therapy range from $13 000 to $15 00), much of which is attributable to monitoring and psychological support.
Because of the need for effective mental health treatments, it’s important to have strong evidence from trials reinforcing the benefits of various approaches to support before requiring that such approaches be used.
If the FDA concludes that psychedelics can safely treat PTSD, addiction, or treatment-resistant depression with limited support, it could be standard practice to offer but not uniformly require psychological support after FDA approval.
We interpret the FDA’s guidance not as dismissing the therapeutic role of psychological support and continuity of care, but rather as underscoring the need to rigorously study these variables.
It suggests that researchers compare various supportive approaches, which may reveal that some approaches are safer and more effective, and others are unnecessary. Furthermore, because receiving psychological support can be emotionally intense and cathartic, even without psychedelics, any observed benefits could stem largely from support rather than the substances under investigation.
So far, clinical trials haven’t compared various levels of support or compared psychedelics alone with psychedelics plus support. Probably, some baseline level of support is advisable, and additional layers may prove beneficial.
Peer support could be helpful and economical, as it is in outpatient OUD treatment. Researchers could study these questions, and the FDA should remain open-minded about revisiting this issue.
Another point of contention is the FDA’s discussion of adverse events.
The guidance classifies the subjective effects of psychedelics, such as hallucinations and emotional changes, as “abuse-related adverse events”, It urges sponsors to report these events as safety concerns “even if they are hypothesised to be associated with the therapeutic response”.
We believe characterising subjective effects as “abuse-related” is unwarranted. Classic psychedelics are non-addictive and may have anti-addictive properties, and their subjective effects could inhibit long-term consumption of psychedelics and substances like alcohol, cocaine, and tobacco.
The situation is less clear-cut for ketamine and MDMA, which have different mechanisms of action from, and greater addiction potential than, classic psychedelics.
The FDA could consider how the framing of subjective psychedelic effects might affect treatment outcomes. Describing common occurrences such as perceptual changes and mystical experiences as adverse events could exacerbate stigma surrounding psychedelics. It could also undermine products’ therapeutic effects.
If clinicians inform trial participants that adverse events may include having strong emotions and mystical experiences, participants may become distressed when these events occur.
Because such events are common, frequently benign, and potentially beneficial, it may be preferable to describe them as side effects. If such effects are shown to be crucial to clinical benefit, however, they should instead be viewed as part of a drug’s therapeutic mechanism.
Meanwhile, the FDA should acknowledge clinician abuse of research participants as a potential serious adverse event.
Abuse of a participant receiving psychedelic treatment allegedly occurred during a Canadian MDMA trial sponsored by the Multidisciplinary Association for Psychedelic Studies. The final guidance could describe how drug sponsors should document, report, and respond to abuse.
The recommended credentials for clinician monitors are also controversial. The FDA advises sponsors to employ at least one primary monitor and one assistant monitor and outlines the training and experience that each should have. For example, primary monitors can include psychologists, physicians, social workers, and psychiatric nurse practitioners.
The range of credentials may be too specific, however. Nurse anaesthetists can practice independently in some states, and they are qualified to monitor patients in altered states of consciousness. But under the FDA’s recommendations, they couldn’t be primary or assistant monitors.
The FDA could expand the list of eligible monitors to include chaplains and nurses who have expertise in critical care, hospice, emergency medicine, and anaesthesia. The skill sets of these professionals are well-suited to monitoring psychedelic medicine sessions, and there is a projected shortage of clinicians in this area.
Expanding trial-monitor eligibility would increase the range of possible research that can be conducted and help prepare a diverse workforce to meet anticipated post-approval demand.
The FDA’s guidance for psychedelics research is a policy landmark and reflects shifting attitudes toward controversial substances. We believe most of the guidance is well reasoned.
But the FDA could consider changes in several areas, including changes regarding recommendations for psychological support, adverse-event reporting, and clinician credentials, to help improve psychedelics research.
Mason Marks, MD, JD, and I. Glenn Cohen, JD: From the Project on Psychedelics Law and Regulation, Petrie–Flom Centre for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School (M.M., I.G.C.), and Harvard Law School (I.G.C.) – both in Cambridge, MA; and Florida State University College of Law, Tallahassee (M.M.).
Psychedelic-Drugs
NEJM article – How Should the FDA Evaluate Psychedelic Medicine? (Restricted access)
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