Rethinking Evidence for Psychedelics in Medicine

According to popular accounts, the U.S. Drug Enforcement Administration’s (DEA) scheduling of LSD and other psychedelics in 1968 shut down promising research for decades. However, as historian Matthew Oram has shown, the Kefauver-Harris Amendment (1962) to the Food, Drugs, and Cosmetics Act slowed research well before the DEA got involved. As Oram argues, the new emphasis on Randomized Controlled Trials (RCT) — was essentially incompatible with psychedelics. 

The trouble lay with double blinding: the requirement that neither researchers nor participants know who receives the active drug or placebo, a condition psychedelics defied by their unmistakable and self-evident effects.

In September 2025, as part of new transparency policies, the U.S. Food and Drug Administration (FDA) released a series of previously confidential Complete Response Letters (CRLs) detailing reasons for its rejection of New Drug Applications (NDAs) by pharmaceutical companies. One of these letters, concerning Lykos Therapeutics’ application for MDMA for PTSD, included, in the context of minimizing bias, the directive:“Assess both participant and therapist/rater unblinding at the end of the study.”

However, fewer than 10 percent of psychiatric studies assess blinding integrity. Reporting guidelines like the Consolidated Standards of Reporting Trials (CONSORT) originally encouraged researchers to evaluate and report blinding integrity, but since 2010 the guideline has only included on its checklist a statement whether such an assessment was done.

In academic circles, random assignment and blinding are usually referred to as the ‘gold standard’ and are often assumed to be essential and absolutely necessary, a sine qua non, for successful regulatory approval. However, if we carefully look at the U.S. Code of Federal Regulations (CFR), particularly CFR 21 514.117, we find that the concept of an “Adequate and Well Controlled” trial (AWC) is not identical to a RCT:

“The primary purpose of conducting adequate and well-controlled studies of a new animal drug is to distinguish the effect of the new animal drug from other influences, such as spontaneous change in the course of the disease, normal animal production performance, or biased observation. One or more adequate and well-controlled studies are required to establish, by substantial evidence, that a new animal drug is effective.”

In the second paragraph, we find that:

“Within the broad range of studies conducted to support a determination of the effectiveness of a new animal drug, certain of the controls listed below would be appropriate and preferred depending on the study conducted”, and goes on to list and briefly describe four options: i) placebo concurrent control, ii) untreated concurrent control, iii) active treatment concurrent control, and iv) historical control. In addition, a waiver may be requested, provided the sponsor “state why the studies so conducted will yield, or have yielded, substantial evidence of effectiveness, notwithstanding nonconformance with the criteria for which waiver is requested.”

This is critical since the RCT is not a one-size-fits-all method. Indeed, philosophers of science have repeatedly highlighted the limitations of RCTs and shown there are serious problems with ‘magical thinking’ that treats RCTs as perfectly objective or infallible, as if they were an all-powerful method capable of total control of confounding variables — thus resulting in unequivocal causal relationships, which could simply be extrapolated from small and homogenous study samples to large and heterogeneous populations. The COVID pandemic made it crystal clear: Public policy based on RCTs of masking were misleading, to drastic detrimental consequences.

The language from the “Adequate and Well Controlled” regulation thus seems to anticipate the need, in certain cases, for alternatives to the classical randomized double-blind placebo controlled trials. Thus there is acknowledging that no single method is perfect. And indeed not all medical interventions, including drug treatments, can necessarily be adequately assessed using this trial methodology as single or main evidence.

A general lack of examination of unblinding in psychiatry means we know far less about its consequences on the interpretation of clinical trial data. That unblinding increases risk of bias interpreting drug’s effects is certain, but risk is not the same as an actual bias.

Problematically, there are no established standards on how to proceed when different rates or reasons for unblinding are identified. For the FDA to dismiss a New Drug Application (NDA) on this basis risks the perception that the intervention lacks therapeutic benefit — thereby depriving patients of potentially effective treatments. On the other hand, approving interventions that appear effective but whose effects were largely due to confounding factors, may expose patients to ineffective or unnecessary treatments. 

In the specific case of MDMA, the NDA included data not of a drug-only treatment, but on a model of drug-assisted therapy, complicating that case further. We believe solutions require a variety of study approaches and evidence assessment procedures. One strategy that is rapidly gaining traction in philosophy of science is called Evidence Based Medicine Plus (EBM+), also known as evidential pluralism.

To help advance scientific understanding, we are launching the Independent Psychedelic Evidence Assessment Working Group (IPEA-Working Group). This project convenes a multidisciplinary team of experts to examine available frameworks for evidence assessments and specifically consider their adequacy, reliability and feasibility for the case of psychedelic drugs as therapeutics. Members of the working group include scientists, philosophers and health experts who have made major contributions to the field of evidence assessment, but who are not involved in psychedelic research. IPEA Working Group sessions will consist of presentations to the working group from leading psychedelic researchers from diverse fields — cell biology, neuroimaging, clinical trials, causal inference, psychotherapy — as well as patients with lived experiences as psychedelic clinical trial participants, and an Indigenous expert. 

The IPEA Working Group’s mission is to offer sound, multidisciplinary recommendations — rooted in the pluralistic advances of the philosophy of evidence and causality in medicine — to help strengthen the evidentiary foundations needed for the safe, effective, and responsible integration of psychedelics into medical practice. By grounding scientific and regulatory discussions in this broader framework, the Working Group aims to help shape a more mature and conceptually coherent phase in the evolution of psychedelic medicine.