FDA Releases CRL Detailing Safety Concerns for MDMA-Assisted Therapy in PTSD

On September 4, 2025, the US Food and Drug Administration (FDA) publicly released Lykos Therapeutics’ Complete Response Letter (CRL) on midomafetamine (MDMA) capsules for PTSD.1

The FDA had initially issued a CRL on August 9, 2024, after its Psychopharmacologic Drugs Advisory Committee (PDAC) raised concerns on June 4, 2024, about safety, cardiovascular risks, and functional unblinding in trials.2,3 The committee noted that pivotal trials lacked systematic documentation of abuse-related adverse events, as required by the FDA, and provided insufficient data to guide clinicians on the duration of MDMA’s effect.3 Other concerns included inconsistent therapy protocols, limited patient diversity, unclear separation of MDMA effects from psychotherapy, patient vulnerability due to acute impairment (i.e., impaired judgment), and inadequate therapist oversight.3

The CRL, now public, lists 3 main concerns, 8 safety components, and 9 trial suggestions that do not affect approvability.1

3 Main MDMA Concerns in the CRL

1. Failure to report positive or abuse potential adverse events.

The CRL noted that the study failed to collect important information deemed “positive” or “favorable” by participants, therapists, or investigators, and the FDA identified several unreported adverse events at multiple sites. Documenting such events is critical to assess abuse potential, as even seemingly positive experiences—like euphoria or mood changes—can signal risk.

The FDA also found inconsistencies between the MAPP2 protocol and the training/safety manual in defining adverse events. The manual excluded “positive or favorable effects,” while the protocol included any medical occurrence, whether related to the trial or not. The agency emphasized that all events relevant to abuse potential or impairment should have been reported.

2. Not evaluating MDMA’s durability beyond 18 weeks

The MAPP1 and MAPP2 trials did not test whether MDMA is durable beyond 18 weeks. Since PTSD is chronic, a durable benefit is required, especially given the proposed limited regimen of 3 treatment sessions.

The follow-up study (MPLONG) was inadequate due to design flaws: it had only 1 visit, variable timing (6 months–2 years), low enrollment with potential self-selection bias, and many participants received other therapies in the interim. As a result, the data do not establish whether MDMA’s benefits persist, if retreatment is needed, or how it should be managed long term—information essential for labeling and clinical use.

3. Selection bias with many participants having prior experience with MDMA

About 40% of participants had prior MDMA use, raising functional unblinding concerns. The FDA recommends a randomized, double-blind study excluding prior users, with pre-specified retreatment criteria, full adverse event reporting, and third-party data audit.

Safety Update

1. Detail any significant changes in the safety profile.
2. Present new safety data alongside original data, including adverse event frequencies for all indications and comparisons with prior reports.
3. Provide case report forms and narratives for participant deaths, discontinuations due to adverse events, and serious adverse events.
4. Highlight changes in common, less serious adverse events.
5. Update clinical study exposure information.
6. Summarize worldwide safety experience, including drug use in other countries.
7. Include English translations of current foreign labeling.

Additional Recommendations

Other recommendations include routine labs (i.e. liver analytes, electrolytes) and vital signs, psychotherapy contribution (i.e. including an arm without psychotherapy), improving diversity, assessing MDMA-SSRI interactions, PK studies in hepatic/renal impairment, and lactation and pre-/post-natal studies.

“Lykos will continue negotiations with the FDA,” said MAPS Founder & President Rick Doblin in a statement.4 “MAPS will keep driving forward: incubating and accelerating new MDMA-focused research, training therapists…catalyzing humanitarian projects in high trauma/low resource areas of the world and building the infrastructure for a future where psychedelic-assisted healing and personal growth is not delayed by shifting politics but delivered as a matter of compassion and justice.”

References

1. Complete Response, NDA 215455. US Food and Drug Administration. August 8, 2024. Accessed September 15, 2025. https://psychedelicalpha.com/wp-content/uploads/2025/09/CRL_NDA215455_20240808.pdf

2. Derman C. FDA Rejects Application for MDMA-Assisted Therapy in PTSD, Calls for Additional Trial. Hcplive. Published August 9, 2024. Accessed September 15, 2025. https://www.hcplive.com/view/fda-rejects-application-for-mdma-assisted-therapy-in-ptsd-calls-for-additional-trial

3. Kunzmann K. FDA Psychopharmacologic Advisory Committee Votes Against Supporting Effectiveness of MDMA for PTSD. HCP Live. Published June 4, 2024. https://www.hcplive.com/view/live-updates-fda-psychopharmacologic-advisory-committee-meeting-mdma-ptsd

4. MAPS Statement on FDA’s Public Release of Complete Response Letter for MDMA-assisted Therapy – Multidisciplinary Association for Psychedelic Studies – MAPS. Maps.org. Published September 5, 2025. Accessed September 15, 2025. https://maps.org/2025/09/04/fda-public-release-of-crl/