Usona Institute, Compass Pathways, and Resilient Pharmaceuticals (formerly MAPS-Lykos) represent the three most advanced psychedelic programs to have reached Phase 3, although their trajectories have diverged sharply. Usona has launched its Phase 3 uAspire trial. Compass has completed two Phase 3 trials with positive primary endpoints. Resilient reached Phase 3 with MDMA-assisted therapy before receiving an FDA rejection in 2024 and has not yet resubmitted. All three worked with the FDA on design. All three arrived at radically different answers to the same question: how much structured psychotherapy does a psychedelic drug actually need, and what does that mean for approval?
The divergence reflects three things: different theories of mechanism, different IP strategies, and different assessments of what the FDA will accept.
Usona's psilocybin program, now in Phase 3 under the uAspire trial, uses the least prescriptive therapeutic framework among advanced-stage programs: a single psilocybin session with psychosocial support oriented around set and setting, no proprietary therapeutic protocol, and no claim that a specific psychological modality is driving outcomes. As a non-profit, Usona has committed to making its clinical trial data available to other developers post-approval. There is no proprietary protocol to protect. This produces the cleanest possible label outcome: approval without a therapy manual attached. If Usona achieves approval on a minimal-support framework, any for-profit competitor whose valuation rests on the claim that its specific therapy protocol is what drives outcomes loses that argument. Mechanistically, Usona's bet is that the drug is sufficient. The IP position is open by design. And the regulatory read is that the FDA will accept a lean support model — a precedent that would quietly deflate the commercial logic of therapy-heavy programs across the field.
COMP360's Phase 2b trial (N=233, NEJM Evidence, 2022) used a framework Compass formally calls the Compass Psychological Support Model (CPSM): structured but limited therapist contact designed to facilitate the drug experience rather than constitute an independent therapeutic intervention. In practice, CPSM means preparation sessions before the drug day, a therapist present during the session acting as a safeguard with minimal intervention, and integration sessions afterward. No ongoing psychotherapy, no trauma processing, no therapeutic relationship sustained across months. Compass publishes this model under the language of "psychological support" rather than "therapy": a deliberate terminological choice that positions the drug, not the relationship, as the active agent.
The commercial logic is straightforward: a drug that works with modest support can scale. Specialist therapist dyads are expensive and scarce. If psilocybin's neuroplastogenic effects (5-HT2A-mediated DMN disruption, BDNF/TrkB-dependent synaptic remodeling) do the clinical work, the support wrapper can be standardized and minimized.
The Phase 2b data supported that bet. The 25mg dose produced a mean MADRS reduction of -12.0 points at week 3, versus -6.1 for the 1mg comparator, a statistically adjusted between-group difference of -6.6 points (Goodwin GM et al., 2022). For context, six weeks of SSRIs typically produce a drug-placebo difference of 2-3 points on the MADRS (Hengartner MP et al., 2020). The between-group difference for psilocybin at three weeks was more than twice that. Sustained response through week 12 was 20.3% of the 25mg arm versus 10.1% of the 1mg arm: real, but modest.
Both Phase 3 trials have now reported positive primary endpoints: COMP005 showed a -3.6 point adjusted MADRS difference at week 6 (25mg vs. placebo, p<0.001), and COMP006 a -3.8 point difference versus the 1mg comparator (Compass Pathways, press releases, June and February 2026), with durability maintained through at least week 26 in responders after one or two doses, ahead of a planned NDA submission in Q4 2026. Mechanistically, Compass is betting the drug carries the signal. The IP sits in the formulation and the CPSM framework. And the regulatory read is that a support-not-therapy model is approvable, a read that two Phase 3 wins are beginning to validate.
“The more contested question is whether psilocybin efficacy holds broadly over time without meaningful integration support.”
The Resilient protocol sits at the opposite extreme: three 90-minute preparatory sessions, three 6-8 hour MDMA sessions spaced roughly a month apart, and nine 90-minute integrative sessions afterward — approximately 42 hours of therapist contact per treatment course, delivered by a trained dyad of two co-therapists (Perivoliotis D et al., 2025). The underlying bet was that MDMA enables a therapeutic window, and the work done inside that window is what heals PTSD. The therapy is not the wrapper. The therapy is the co-product.
The FDA's August 2024 Complete Response Letter struck at precisely that logic. When the agency published the redacted letter in September 2025, the full scope of its concerns became public: functional unblinding, therapist allegiance effects, inadequate characterization of psychotherapy as an independent variable, unreported safety events at multiple sites, and no demonstrated durability past 18 weeks (FDA CRL to Lykos Therapeutics, September 2025). The agency did not say MDMA-AT does not work. It said the design could not establish what was working, and that the therapy component had become a confound rather than a mechanism. When therapy is positioned as core to efficacy, it must be treated like a drug: characterized, validated, and controlled for. Mechanistically, Resilient bet that drug and therapy are inseparable, that the synergy is necessary, or maybe is simply optimal. The IP sat in the protocol and the training infrastructure. And the regulatory read proved fatal: a therapy-as-product model that cannot blind its own intervention cannot satisfy FDA.
With two positive Phase 3 readouts in hand, the accumulating evidence suggests that psilocybin has standalone pharmacological efficacy. The more contested question is whether that efficacy holds broadly over time without meaningful integration support, and whether a lean support model is sufficient for the wider, less selected populations a commercial product will reach.
That framing, therapy as a potential durability lever rather than an efficacy prerequisite, has never been directly tested. No trial has run a drug-only arm alongside a drug-plus-therapy arm with equivalent populations. But it is the hypothesis most consistent with existing data, and it has a clear implication: drug-forward programs face residual durability risk as follow-up windows lengthen and populations broaden, therapy-heavy programs face regulatory design risk the FDA has now made explicit, and the program that cleanly quantifies the therapy contribution without confounding it with drug effect does not yet exist.
That is both the field's central unanswered question and, for whoever answers it first, a durable competitive position.
References
- Goodwin GM et al. Single-dose psilocybin for a treatment-resistant episode of major depression. NEJM Evidence, 2022.
- Hengartner MP, Jakobsen JC, Sørensen A, Plöderl M. Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials. PLoS ONE, 2020.
- Compass Pathways. COMP005 Phase 3 top-line results press release. June 2025. COMP006 Phase 3 top-line results press release. February 2026.
- Kirlić N, Lennard-Jones M, Atli M, Malievskaia E, Modlin NL, Knatz Peck S, Gaillard A, Goodwin GM, Koelpin D. Compass Psychological Support Model for COMP360 psilocybin treatment of serious mental health conditions. American Journal of Psychiatry, 2025.
- Perivoliotis D, Knopp K, Remick S, Kaigle A, Stauffer CS, Khalifian C, Wachsman TR, Chargin BE, Bismark AW, Alam A, Morland L. Bringing MDMA-assisted therapy for PTSD to traditional healthcare systems: tending to set and setting. Frontiers in Psychiatry, 2025.
- FDA. Complete Response Letter to Lykos Therapeutics re: midomafetamine (MDMA) capsules for PTSD. August 2024. Published September 2025.