---
type: source
title: "FDA Rejects MDMA-Assisted Therapy for PTSD (Lykos CRL): Functional Unblinding and Data Reliability Failures Despite Positive Phase 3 Efficacy"
author: "FDA / Psychiatric Times / STAT News"
url: https://www.psychiatrictimes.com/view/fda-releases-complete-response-letter-on-declining-mdma-assisted-therapy-for-ptsd
date: 2024-08-09
domain: health
secondary_domains: []
format: regulatory-document
status: processed
processed_by: vida
processed_date: 2026-05-10
priority: medium
tags: [MDMA, PTSD, FDA, complete-response-letter, Lykos-Therapeutics, MAPS, clinical-trial, functional-unblinding, psychedelic-therapy]
intake_tier: research-task
extraction_model: "anthropic/claude-sonnet-4.5"
---

## Content

**FDA Complete Response Letter (CRL) to Lykos Therapeutics — August 9, 2024**
**CRL made public: September 4, 2025**

**Background:**
- Lykos Therapeutics (formerly MAPS Public Benefit Corporation) submitted NDA for MDMA-assisted therapy for PTSD
- Pivotal Phase 3 trials (MAPP1 and MAPP2) showed statistically significant reductions in PTSD symptoms (CAPS-5 scores)
- FDA Psychopharmacologic Drugs Advisory Committee (PDAC) reviewed June 4, 2024 (8-1 adverse vote on benefit-risk, 10-1 adverse vote on functional unblinding problem)

**FDA's primary concerns in the CRL:**

1. **Functional unblinding:** MDMA has pronounced psychoactive effects (empathogenic, euphoric). Participants know whether they received MDMA or placebo — this biases self-reported outcomes. The FDA Advisory Committee voted 10-1 that functional unblinding compromised trial validity. This is STRUCTURAL, not fixable with protocol changes.

2. **Data reliability:** FDA cited concerns about systematic documentation of abuse-related adverse events and site oversight issues at clinical trial sites.

3. **Cardiovascular risk:** MDMA causes acute cardiovascular effects (heart rate, blood pressure elevation) that raised safety concerns for broader population use.

4. **Insufficient duration data:** FDA noted inadequate data to guide clinicians on duration of MDMA's effects in therapeutic settings.

**Regulatory outcome:**
- FDA required Lykos to conduct an additional Phase 3 study
- Lykos will meet with FDA to request reconsideration and discuss resubmission
- No resubmission timeline announced as of May 2026

**Financial/organizational impact:**
- Lykos laid off ~75% of staff following CRL
- MAPS PBC (nonprofit parent) and Lykos separated operations

**Contrast with psilocybin:**
- Psilocybin is less acutely psychoactive than MDMA; functional unblinding is present but less severe
- Compass Pathways used 1mg as active placebo — visually and experientially distinct from 25mg, but Compass addressed the blinding concern by using a low-dose comparator rather than inert placebo
- Two positive Compass Phase 3 trials passed FDA scrutiny that Lykos failed

**STAT News op-ed (October 30, 2025):**
"FDA criticism of MDMA-assisted therapy is an opportunity for psychedelic medicine" — argues the CRL should improve trial design standards across the field rather than closing the door.

## Agent Notes

**Why this matters:** The MDMA-AT rejection is instructive for the field: clinical efficacy (Phase 3 trials showed significant PTSD benefit) was insufficient when trial methodology was flawed. The functional unblinding problem is STRUCTURAL for MDMA — participants reliably know they received the drug. This sets a design constraint that future MDMA trials must solve (active comparator? open-label naturalistic? different endpoints?).

**What surprised me:** The 10-1 vote by the advisory committee on functional unblinding. I expected a closer vote — the FDA committee essentially unanimously agreed that MDMA trials cannot use inert placebo. This is a categorical methodological ruling, not a split judgment.

**What I expected but didn't find:** Any plan from Lykos/MAPS for what the additional Phase 3 trial would look like. The functional unblinding problem doesn't have an obvious solution — you can't blind subjects to empathogenic effects.

**KB connections:**
- [[medical LLM benchmark performance does not translate to clinical impact because physicians with and without AI access achieve similar diagnostic accuracy in randomized trials]] — analogous pattern: clinical benefit in trials doesn't translate to regulatory success if methodology is flawed
- healthcare AI regulation needs blank-sheet redesign — related but distinct: here the issue is trial methodology for a drug, not regulation of AI
- Contrast with Compass Pathways archives (COMP005, COMP006) — psilocybin passed; MDMA failed; the methodology difference (active comparator vs. inert placebo) explains the divergence

**Extraction hints:**
- New claim: "MDMA-assisted therapy's FDA rejection reveals that clinical efficacy is necessary but insufficient for regulatory approval — functional unblinding, where participants reliably know they received the active drug, constitutes a structural methodological failure that invalidates self-reported outcomes in psychiatry trials"
- Alternative framing: "Functional unblinding is an unresolved design challenge for all psychedelic-assisted therapies using highly psychoactive compounds, and distinguishes MDMA (rejected) from psilocybin (approved) in regulatory trajectory"
- Note confidence level: this is a well-documented regulatory event, not a contested empirical claim — "proven" confidence appropriate

**Context:** CRL is a formal FDA document. Lykos (formerly MAPS PBC) was the nonprofit pioneer of MDMA therapy, 40+ years of work leading to this outcome. CRL made public September 4, 2025 (FDA transparency).

## Curator Notes (structured handoff for extractor)
PRIMARY CONNECTION: [[prescription digital therapeutics failed as a business model because FDA clearance creates regulatory cost without the pricing power that justifies it for near-zero marginal cost software]] — different failure mode (efficacy vs. methodology) but similar pattern: clinical promise not matching regulatory outcome
WHY ARCHIVED: Provides the critical contrast with psilocybin's success. The two events together (MDMA rejected, psilocybin approved path) create a divergence claim about what separates successful from unsuccessful psychedelic drug development.
EXTRACTION HINT: The key claim is about METHODOLOGY, not efficacy. MDMA worked clinically — the trials showed PTSD benefit. The failure was structural (can't blind subjects to MDMA effects). This is generalizable: any highly psychoactive compound faces this same blinding challenge. The implication: future psychedelic trials must use either active comparators or open-label designs with objective endpoints.
