Psilocybin, LSD, Other Psychedelics Move to FDA Approval

Six months before his death at 27, Cindy Crawford’s son Presley Gerber described taking ibogaine for addiction. He hoped to find his way back to himself. His cause of death remains under investigation. His hope deserves respect. People with addiction want their lives back. But an old A.A. saying captures the challenge: “Once you are a pickle, you can never be a cucumber again.” Recovery is possible. Turning back the clock is another matter.

Failed treatments, craving, and suffering can make a new treatment irresistible. Some describe spiritual awakening and turning the clock back with psychedelics. But feeling transformed and sustained recovery are different things.

Listen to patients.

Then test the treatment. Randomized clinical trials (RCTs) help answer what patients deserve to know: Does it work? For whom? For how long? At what risk? Compared with what?

Different Drugs, Different FDA Timetables

Phase 1 studies assess initial safety, tolerability, and dosing. Phase 2 asks whether treatment is promising and warrants larger studies. Phase 3 RCTs examine efficacy, safety, and other outcomes more extensively. With this data, the FDA evaluates and weighs a new treatment’s benefits and risks.

Psychedelic drugs are quite different in their effects. While they are often lumped together, they differ in RCT evidence and progress toward FDA approval. Progress in depression and anxiety does not establish efficacy for SUDs. Each drug needs evidence for each condition. Relieving withdrawal or craving is encouraging. Preventing relapse and overdose over months and years is another test.

Esketamine (Spravato) is now FDA-approved for TRD. The FDA added guardrails with supervised administration and monitoring under a REMS safety program. Spravato is a logical comparison. Psilocybin and LSD deserve the same scientific bar; no psychedelic discount nor a psychedelic penalty.

Progress Towards FDA Approval

COMP360 psilocybin met its primary endpoints in two treatment-resistant depression Phase 3 trials. Its sponsor reports a rolling FDA application and initial review is underway. LSD’s sponsor also reported positive results from its second Phase 3 GAD trial in September. But company announcements aren’t FDA approval.

Psychedelics: Promise, Progress, and Proof

Source: Mark Gold, MD with permission

A September 29 JAMA Network Open study of 1,964 U.S. adults adds a warning. Across 13 assessed adverse effects, the higher reported adverse-effect rates were among ibogaine or 5-MeO-DMT users. These findings signal concern, but this was not a controlled drug-safety study. Still, limited evidence of benefit alongside greater reported harm deserves attention. Ibogaine also carries a specific cardiac danger: QT prolongation and potentially fatal arrhythmias. Screening and monitoring matter, but cannot make the drug risk-free. RCTs are needed.

The Blindfold Slips

In a double-blind RCT, neither patients nor outcome assessors should know who received the experimental treatment or placebo. The profound psychedelic “trip” makes that difficult.

Randomization still matters. The drug may genuinely help. But failed masking makes it harder to judge how much benefit comes from pharmacology versus expectations, psychological support, or their interaction. Therapists may behave differently if they know who did/did not take the drug, and symptom ratings may also shift.

Orsini and colleagues reviewed 112 randomized trials and found that only 33 even assessed blinding. Psilocybin, LSD, and ayahuasca studies frequently reported blinding failures exceeding 90 percent among participants and raters. This doesn’t prove ineffectiveness, but it weakens confidence in estimates of the drug’s efficacy

University of Michigan’s Dr. Jacob Aday and colleagues propose that RCTs use active placebos that better reproduce a psychedelic’s mental and physical effects, onset, and duration, while remaining safe and avoiding therapeutic effects of their own. Kevin Yang, M.D., and researchers from UCSF, UC San Diego, and Stanford University call for a more aggressive approach to preserving masking in psychedelic clinical trials. In the September 16 JAMA Psychiatry, they proposed carefully selected control cocktails of psychoactive drugs. They also suggest that participants authorize researchers to withhold selected study-design details, making treatment assignment harder to infer. Their argument: An RCT studying an intense psychedelic experience needs a credible, comparably intense control, with similar supervision and monitoring. But these combinations could themselves cause serious adverse effects, including cardiovascular instability and respiratory depression. Whether these risks are justified—and whether the approach works—remains to be established.

Compared to Existing Treatments

Patients also need direct comparisons with established, effective treatments. Head-to-head RCTs—not percentages from unrelated studies—can tell us which treatment works better and for whom.

Head-to-head RCTs with random assignment—not comparisons of percentages from unrelated studies—are needed to determine which treatment works better, for whom, for how long, and at what risk.

Psychedelic mechanism research is advancing. Joshua Siegel and colleagues showed psilocybin temporarily disrupts usual brain network patterns, with some connectivity changes lasting weeks. A new Nature study of 62 adults found brain activity became more aligned with context—music, meditation, or a movie—and tracked feelings of connection and next-day psychological changes. We still need to establish which changes produce lasting recovery.

A Trial Is Different from Self-Treatment

Compass reports that COMP360 psilocybin met its primary endpoints in two Phase 3 trials for treatment-resistant depression. On September 14, Definium announced the second positive Phase 3 LSD trial in GAD. Other psychedelic trials are moving at their own speed.

A positive RCT does not establish the safety or effectiveness of self-treatment. Researchers study a known drug and dose in selected patients, with supervision, monitoring, and follow-up. Taking mushrooms at home or recreational LSD does not reproduce those conditions.

Selection matters. Trials often exclude people with psychosis or bipolar risk; some also exclude active substance use disorders. Results cannot simply be extended to patients the researchers excluded. Safety assessments must also account for those who worsen or drop out.

The safeguards may disappear. The drug’s risks have not taken a vacation.

Some Patients Cannot Wait

Some patients with OUD remain ill despite evidence-based, FDA-approved treatments. Relapse and continued suffering may deepen depression and hopelessness. The President’s executive order calls for faster psychedelic research and development of access pathways.

VA trials can expand access and help establish whether these treatments work. FDA expanded access may permit investigational treatment for serious or life-threatening conditions when satisfactory alternatives are unavailable.

These routes may allow treatment before FDA approval. Access is not proof that it works. Nor does a pathway guarantee that a patient can get the treatment. Patients deserve compassion and access when justified. They also deserve the truth about what we know, what we do not know, and what could go wrong.

Defining Success

Screen carefully. Put safety first. Continue care. Patients in altered states are vulnerable. No sexual contact. No exploitation. No pushing a therapist’s beliefs.

Registries can help identify uncommon harms and track whether improvements last.

For addiction, a memorable trip is not enough. Neither is easier opioid withdrawal. Can patients rebuild their lives? Use less? Function better? Stay in care? Avoid overdose? Survive? How do outcomes compare with established treatments?

We should move quickly enough to help suffering people. But carefully enough to learn what actually works.

Hope deserves a hearing. Patients deserve the evidence to decide.