"Is Psychedelic Euphoria an Adverse Event?" - PSA's Sunday Sound-Off: October 25, 2026

PSA’s Sunday Sound-Off: October 25th, 2026

The Sunday Rundown

1. Is Psychedelic Euphoria an Adverse Event?
2. Introducing PSA's New Global Psychedelic Policy Tracker
3. PSA NewsWire Highlights of the Week: October 25, 2026

Is Psychedelic Euphoria an Adverse Event?

By Jim Tate

Source: The Chronicles of Kykeon on Substack

In August 2024 the Food and Drug Administration turned down MDMA as a medicine, and one of its reasons will shape every psychedelic that reaches approval in the years ahead. In the agency’s view, the feeling of euphoria itself is an adverse event.

I have read the FDA’s briefing document for the June 4, 2024 advisory committee meeting on Lykos Therapeutics’ application for MDMA-assisted therapy for PTSD. A large part of the answer to why that application failed is buried in a single word: “untoward”.

The Phase 3 trials were sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS) and run by its public benefit corporation, the company later renamed Lykos. Investigators worked from a training manual that defined an adverse event as any undesirable, unfavorable, inappropriate, or untoward medical occurrence. The manual said plainly that positive or favorable effects did not count. A headache, jaw clenching, and nausea counted. A veteran on a mat weeping with relief and feeling connected to other people for the first time in years, did not.

To a drug regulator that was a hole in the data. When FDA reviewers went looking for reports of euphoria or elated mood, they found almost nothing. Those are the signals the agency uses to predict misuse. FDA clinical reviewer David Millis told the committee he noticed a “striking lack of abuse-related adverse events.” The briefing document was blunter. The sponsor likely did not record these effects because adverse events are defined as untoward. MAPS had said as much in print. Its 2021 Nature Medicine paper on the first Phase 3 trial states that anticipated effects such as euphoria, stimulation, and feelings of closeness were intentionally not solicited as adverse events, and the same paper reported that MDMA did not induce adverse events of abuse potential.

The FDA told MAPS what it wanted in 2017, more than a year before the first Phase 3 participant was recruited in November 2018. During negotiations over the trial design, the agency wrote that adverse events associated with potential abuse or overdose must be documented in every phase, and pointed MAPS to its 2017 guidance on abuse potential. Federal regulations define an adverse event in a drug trial as any untoward medical occurrence associated with the drug, whether or not it is considered drug related.

MAPS read “untoward” through the eyes of the patient and the therapist. The FDA read it through the eyes of someone who has to imagine the same molecule sold as ecstasy on the street.

The Complete Response Letter, which the FDA made public in September 2025, put this at the top of its list of concerns. The trials failed to capture effects that participants, therapists, or investigators viewed as positive. FDA inspections turned up unreported adverse events at the study sites. The MAPP2 protocol and the training manual did not even agree with each other on what an adverse event was. MAPS said the FDA moved the goalposts, but the documents are public. The goalposts were set in 2017. What MAPS can fairly argue is that “abuse-related” was vague, and that nobody said clearly enough that pleasure itself had to be written down.

The literature won’t let us pin this on one organization. A 2022 systematic review in the Journal of Psychopharmacology looked at 44 published articles on clinical treatment with MDMA, psilocybin, LSD, and ayahuasca and concluded that adverse events in psychedelic treatment are poorly defined and probably underreported. A 2024 meta-analysis in JAMA Psychiatry from the Johns Hopkins group found that of 68 classic psychedelic studies published since 2005, only 16 described a systematic way of assessing adverse events. Only 20 reported every adverse event rather than just the ones judged to be drug reactions.

To be fair, the same Hopkins review carried good news, though it covered the classic psychedelics, not MDMA. Serious adverse events turned up in about 4 percent of participants with existing psychiatric conditions and in none of the healthy volunteers. There were no suicides, no persistent psychoses, and no cases of hallucinogen persisting perception disorder in modern trials. Psilocybin, LSD, and their cousins may well be reasonably safe in screened, supervised settings. The field was still measuring that safety with a loose net.

And there is a kind of harm that slips through both definitions. It is the long, slow aftermath. In 2023, Jules Evans and colleagues published accounts from 608 people who reported extended difficulties after psychedelic experiences that included anxiety, fear, existential struggle, social disconnection, and the unsettling sense that the self or the world was no longer real. For about a third of them, it lasted more than a year. Fewer than 3 percent of them had their experience in a clinic or medical trial, and all of them chose to answer the survey, so the study tells us these outcomes exist, not how often they follow treatment. A guided setting was associated with a narrower range of difficulties. Narrower is not none.

The FDA has since made its position official. Its June 2023 draft guidance on psychedelic trials already told investigators to track abuse-related adverse events such as euphoria and hallucinations. The final version, issued July 13, 2026, goes further. Euphoria, hallucinations, perceptual distortions, and altered thinking should be recorded as adverse events even when patients do not describe them that way, and even when they are believed to be part of the cure. It also tells sponsors to plan for a possible Risk Evaluation and Mitigation Strategy and favors about twelve months of blinded follow-up.

You can already see what this looks like on paper. Compass Pathways expects to complete its application for COMP360 psilocybin in treatment-resistant depression by the end of this year. In its second Phase 3 trial, visual hallucination is listed among the most common adverse events. To a casual reader that sounds like a warning label. It is the drug doing what it does, logged in the column where the regulators want it. Lawyers at King & Spalding see a scheduling strategy here, a dataset the DEA can use to decide how tightly to control an approved psychedelic. That is their reading, not the agency’s stated purpose.

So, what does this mean for the medical model? Three things, I think. Patients and prescribers are going to see safety labels that look alarming, with euphoria and hallucination sitting next to nausea and headache, and someone will have to explain why. The legal definition of an adverse event has not changed, but the FDA’s reading of it is now wide enough to catch pleasure. It is still not built to catch the slow existential aftermath that Evans and the former participants describe. And the therapy manual is now a safety document. If it disagrees with the protocol, the FDA will find it.

Is ecstasy an adverse event? Under the medical model, yes. MAPS defined harm from inside the session room. The FDA defined it from the street. Any psychedelic that hopes to reach patients will have to answer to both.

Editor’s Note: This essay was originally published by The Chronicles of Kykeon over on Substack. Be sure to like, share, and subscribe!

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