Substance Spotlight — Psychedelics & empathogens: the Compass-Lykos fork

The story of psychedelic medicine in the United States changed twice in the last six weeks, and the two changes pointed in opposite directions. On April 24, Compass Pathways announced that the FDA had granted COMP360 — its synthetic psilocybin formulation for treatment-resistant depression — a rolling NDA review and selected the program for the Commissioner’s National Priority Voucher (CNPV). On April 14, Lykos Therapeutics confirmed it had reduced its workforce by roughly 75% and committed to running a third Phase 3 trial of MDMA-assisted therapy for PTSD before resubmitting its NDA. Both companies are still in the game. They are no longer in the same game.

Why Compass got the runway

Compass’s announcement is meaningful for two reasons. First, the rolling NDA pathway means the FDA will review sections of the application as they are submitted, rather than waiting for a complete package — a structural acknowledgement that the agency considers the data mature. Second, the CNPV designation, explained by PharmExec, shortens the formal post-filing review window to one to two months, if the package holds together. Compass’s clinical case rests on two Phase 3 trials with more than 1,000 participants combined, showing a 3.8-point MADRS difference between the 25-mg and 1-mg arms at the primary endpoint, with statistical significance (p<0.001). The company expects to complete its NDA submission in Q4 2026.

Why Lykos got the Complete Response Letter

The contrasting Lykos story has been a slow unwinding. The FDA’s Complete Response Letter, published in detail by Psychedelic Alpha and covered by AJMC, asked Lykos for a third Phase 3 trial to better characterize the safety profile of MDMA-assisted therapy for PTSD. The agency raised concerns about functional unblinding, the role of therapy in outcomes, and adverse-event reporting. Lykos has restructured to a small core team focused exclusively on running that trial and preparing a resubmission. A realistic timeline puts a potential market entry in the late 2020s or early 2030s.

Where the field actually disagrees

The Compass-Lykos divergence is not, in the simplest read, about psychedelics being good or bad medicines. It is about the distinction between a pharmacotherapy with a clearly defined drug-effect endpoint (Compass: psilocybin with light psychological support, depression rating scale) and a more entangled therapeutic protocol where drug effect is harder to separate from psychotherapy effect (Lykos: MDMA + structured therapy across multiple sessions). The field disagrees genuinely about which framing better serves patients. The FDA, for the moment, has indicated which one it can regulate.

The other tension is access. Even if Compass clears the NDA, the question of who will be able to afford a psilocybin course — and who will be eligible under insurance — is unresolved. Psychiatric Times’s analysis of the Lykos decision questioned whether the U.S. clinical infrastructure for either drug is yet capable of safe, equitable delivery at scale.

Resources

The Multidisciplinary Association for Psychedelic Studies (MAPS), the parent organization that spun out Lykos, continues to publish on the field’s evolution. ClinicalTrials.gov lists active psilocybin, ketamine, and DMT-related studies for depression, alcohol use disorder, and other indications. Ketamine remains the only legally accessible psychedelic-adjacent medicine in U.S. psychiatry today — through Spravato (esketamine, FDA-approved) and compounded racemic ketamine clinics, which we covered in yesterday’s spotlight.

Crisis footer

If you are in psychiatric distress or crisis, call 988 (Suicide & Crisis Lifeline) or text HOME to 741741. SAMHSA’s National Helpline: 1-800-662-HELP. Psychedelic experiences during clinical trials are not a substitute for crisis care, and unsupervised use of psychedelic substances carries real risks — particularly for people with personal or family histories of psychosis or bipolar disorder.