FDA Declines to Approve MDMA-Assisted Therapy for PTSD (2024)

Table of Contents

1. What the FDA Did
2. The Application and the Terms Used
3. The Advisory Committee Meeting of 4 June 2024
4. The Committee’s Votes
5. The FDA’s Decision: the Complete Response Letter
6. Reason 1: Safety Data the Trials Did Not Capture
7. Reason 2: No Evidence the Effect Lasts
8. Reason 3: Selection and Expectation Bias
9. The New Trial the FDA Described
10. Other Gaps the Letter Listed
11. What the Decision Does Not Do
12. Dates and Status as of 11 October 2026
13. How the Decision Fits Earlier and Later FDA Actions
14. Primary Documents
15. Key Research Papers
16. Connections

1. What the FDA Did

The FDA took three public or recorded steps on this application in 2024:

• 8 May 2024 — meeting notice. A notice in the Federal Register (89 FR 38903, FR Doc. 2024-10053, Docket No. FDA-2024-N-1938) announced a public meeting of the Psychopharmacologic Drugs Advisory Committee for 4 June 2024 on midomafetamine capsules, and opened a public docket for comments.
• 4 June 2024 — advisory committee meeting. The committee discussed “new drug application 215455, for midomafetamine (MDMA) capsules … for the proposed indication of treatment of post-traumatic stress disorder” and was asked to discuss “the overall benefit-risk profile of the product, including the potential public health impact.” Its final summary minutes were approved on 26 July 2024.
• 8 August 2024 — complete response letter. The FDA wrote that it had “completed our review of this application, as amended, and have determined that we cannot approve this application in its present form.” The letter concluded that the application “does not provide substantial evidence of effectiveness or establish the safety of your product to support the approval of midomafetamine for the treatment of posttraumatic stress disorder (PTSD).”

The letter carries an electronic signature dated 08/08/2024, and 8 August 2024 is the date used on this page.

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2. The Application and the Terms Used

• Midomafetamine. The name used in the FDA documents for the drug in this application; the committee minutes write it as “midomafetamine (MDMA).” The FDA’s 2026 guidance on psychedelic drug trials spells MDMA out as 3,4-methylenedioxymethamphetamine and groups it with the “entactogens or empathogens.”
• New drug application (NDA). The formal request a company files asking the FDA to approve a drug for sale. This one is NDA 215455.
• Advisory committee. A panel of outside experts, plus consumer and patient representatives, that gives the FDA advice. The Federal Register notice describes the committee’s general function as “to provide advice and recommendations to FDA on regulatory issues.” Its votes are advice; the decision belongs to the FDA.
• Complete response letter. The letter the FDA sends when it finishes reviewing an application and cannot approve it. It lists the problems and, in the words of this letter, “where possible, our recommendations to address these issues.”
• REMS (risk evaluation and mitigation strategy). A set of required safety conditions attached to some drugs. The letter explains that section 505-1 of the Federal Food, Drug, and Cosmetic Act lets the FDA require one “if FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks.”
• Federal Register docket. A public file, numbered and kept on regulations.gov, where anyone can send comments on an FDA notice. The meeting notice says comments are posted there unchanged.
• Functional unblinding. In a “blinded” trial, neither participants nor staff are supposed to know who received the drug and who received a placebo. The FDA’s 2026 psychedelic guidance explains that the intense perceptual changes these drugs cause increase “the potential for bias due to functional unblinding of patients, therapists, monitors, or raters” — people can often tell who got the real drug, which can shape what they expect and report.

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3. The Advisory Committee Meeting of 4 June 2024

The meeting was held at the FDA’s White Oak campus in Silver Spring, Maryland, with the public taking part online. The notice set it for 8:30 a.m. to 4:30 p.m. Eastern Time; the minutes record that it adjourned at about 5:45 p.m. According to the minutes, about 1,570 people attended and there were 32 speakers in the open public hearing. Comments sent to the docket by 23 May 2024 were to be given to the committee; the docket closed on 3 June 2024.

The applicant presented its case on unmet need, efficacy, safety, the clinician’s perspective and benefit-risk. FDA staff then presented the regulatory history, the efficacy and safety analyses, and the FDA’s risk-management proposal. The committee discussed four questions before voting. The minutes summarize what members said:

• Effectiveness. Members “commented that functional unblinding and expectation bias may have played a role in the efficacy results,” and some said these biases “could account for what was seen in the clinical trial in the short term.” On durability, many said “there were too many confounders involved to tease the small data set apart.” On the role of psychotherapy, members suggested a two-by-two factorial design and some raised concerns about therapist unblinding and “the therapist power of suggestibility.”
• Safety data. The FDA asked members to consider “the limited data collected on events deemed positive, favorable, or neutral that would inform abuse potential” and missing laboratory tests. Members mentioned the risks of boundary violations and hyponatremia (low blood sodium), the lack of laboratory data and the lack of QTc and other cardiac data; some described the abuse-liability assessment as inadequate and raised concerns about diversion.
• Impairment. Members said impairment could last longer than had been studied and that a REMS would be needed; some raised concerns about tapering other psychiatric medicines beforehand, and some suggested an overnight stay.
• Risk controls. Many members said the risk “was not fully characterized,” and suggested measures including two licensed therapists, training by an independent outside group, medical staff on site, safety reporting outside the treatment centers, and fuller ECG, laboratory and vital-sign data.

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4. The Committee’s Votes

Eleven voting members took part: five standing committee members (including a consumer representative) and six temporary voting members (including a patient representative). An industry representative attended without a vote. The minutes record two votes:

• “Do the available data show that the drug is effective in patients with posttraumatic stress disorder?” Yes 2, No 9, Abstain 0. The minutes say many members found that “the functional unblinding, the lack of management of expectation bias and selection bias limited the interpretability of the efficacy analyses.” Those voting yes shared the concerns about unblinding and expectation bias but “could not overlook the fact the effect sizes were large.”
• “Do the benefits of midomafetamine with FDA’s proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD?” Yes 1, No 10, Abstain 0. Many members said more efficacy and safety data were needed. The one member voting yes said the REMS, “while not perfect, is on the right track to address the safety concerns,” and spoke of the need for new PTSD treatment options.

These votes were advice to the FDA. The agency’s decision came two months later in the letter described below.

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5. The FDA’s Decision: the Complete Response Letter

The FDA’s letter of 8 August 2024 states that the agency “identified several issues with the application that preclude its approval.” It lists three “complete response issues,” set out in the next three sections, and then a longer list of gaps that it says are not approvability issues on their own.

The letter also records that the FDA agreed with the applicant that, if the drug were ever approved, a REMS “will be necessary … to ensure that the benefits of the drug outweigh the risk of serious harm resulting from patient impairment.” Discussion of the proposed REMS was put off until a response to the letter is submitted.

The letter was not made public in 2024. The FDA released it later in its openFDA collection of complete response letters, where its record shows the letter date 08/08/2024 and the status “Unapproved.” Some passages in the released copy, including dates of earlier correspondence, are redacted.

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6. Reason 1: Safety Data the Trials Did Not Capture

The first issue is that the trials “did not collect important information on events that the participant, therapist, or study physician considered ‘positive’ or ‘favorable.’” The letter explains that the FDA needs this information “to assess signals of abuse potential and patient impairment.”

• What the inspection found. The protocol of one of the two phase 3 trials defined an adverse event as “any medical occurrence in a participant … whether or not considered related to participation in the research.” But the training slides and safety manual given to the study sites described an adverse event as an “undesirable, unfavorable, inappropriate, or untoward medical occurrence … NOT positive or favorable effects.” The letter says this “systematic training of not reporting ‘positive’ or ‘favorable’ effects as AEs raises concerns over the reliability of the safety data.”
• Earlier FDA advice. The letter quotes an earlier FDA communication: “For all Phase 1, 2 and 3 studies, AEs associated with potential abuse or overdose must be documented,” and notes that the FDA had pointed the applicant to its 2017 guidance on assessing abuse potential, which covers recording such events “even if they are considered desirable (e.g., euphoria-related experiences, mood changes).”
• Unreported events. FDA inspections “also identified several unreported adverse events for at least two sites.”
• Consequence. Because such events were not captured, the letter states, “the studies failed to adequately characterize the safety of midomafetamine, its acute effects, the duration of impairment, or signals of abuse potential.” The FDA concluded there are “substantial concerns about the reliability of the safety data.”

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7. Reason 2: No Evidence the Effect Lasts

The letter states that the applicant had not shown “that the effect observed with midomafetamine is durable beyond the 18-week end-of-study assessments (8 weeks after the last dose).” It explains why that matters: “As PTSD is a chronic condition, any drug indicated for the treatment of PTSD is expected to provide a durable treatment effect,” and the proposed regimen was a limited course of three treatment sessions.

The application relied on a separate long-term follow-up study for durability. The FDA listed its problems:

• it consisted of a single visit;
• the timing of that visit varied widely, from 6 months to up to 2 years after treatment;
• only some trial participants enrolled, so people may have selected themselves in or out;
• many participants had used “potentially therapeutic interventions” in the time between the trial and the follow-up visit.

The letter concludes that the data “fails to establish how MDMA should be used to treat this chronic disease, whether treatment with a single treatment cycle is adequate or if retreatment is necessary.”

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8. Reason 3: Selection and Expectation Bias

The trial protocols allowed people who had taken MDMA before to enroll. The letter reports that “approximately 40% of the enrolled participants reported prior use,” which it calls “much higher than the background use” among people with PTSD.

• The comparison figure. The FDA analyzed data from the 2022 National Survey on Drug Use and Health. Among people with past-year moderate or severe mental illness, lifetime use of MDMA was 16.2% and 20.5% respectively.
• Prescreening. Inspections also “detected very high rates of failures during the ‘prescreening’ process prior to the formal screening.”
• Why it matters. Together, the letter says, these suggest “the possibility of selection bias, with the enrolled population not being representative of the general PTSD population.” It adds that participants who had taken the drug before “are more likely to recognize the effects of midomafetamine (i.e., leading to functional unblinding) and anticipate a treatment benefit.”

The FDA concluded that these limits, together with the follow-up study’s failure to show a lasting effect, “preclude the ability to establish substantial evidence of effectiveness.”

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9. The New Trial the FDA Described

The letter states the FDA’s view that “the most efficient path to address the clinical issues above would be to conduct a new clinical trial.” It describes the “most informative design” as “a randomized, double-blind study which includes the initial treatment sessions followed by blinded long-term follow-up with pre-specified criteria for retreatment, if needed.” The elements the FDA listed:

• Durability: keep following participants in a blinded way after the treatment period; set criteria in advance for when PTSD symptoms count as returning and when a participant is retreated, taking into account whether the participant seeks other treatment; and schedule follow-up assessments at least monthly.
• Bias: exclude or reduce the number of participants who have used MDMA or other psychedelics; measure what participants expect at the start; measure at the end whether participants and raters or therapists could tell which treatment was given; and consider a low-dose midomafetamine group as the control.
• Safety: capture all abuse-related adverse events “regardless of perceived emotional valence,” and develop standard criteria, both psychological and physiological, for deciding when a participant is ready to go home after a session.

Citing “the serious nature of the concerns raised about the reliability of the safety data” — and acknowledging concerns about study conduct raised in the open public hearing and the public docket — the FDA recommended that the applicant consider “an independent third-party data audit of all study records and reports, including the recordings of the treatment sessions, to identify unreported or under-reported adverse events.” The letter notes that some inspection-related activities were still ongoing.

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10. Other Gaps the Letter Listed

The FDA also listed gaps that it said were “not approvability issues at this time” but would be expected to be addressed in a resubmission or future studies:

• Laboratory and heart data. The application “did not include laboratory data (e.g., liver analytes, electrolytes) from the phase 3 studies and the cardiac safety assessment was incomplete.” Future studies are to include routine blood tests before and after dosing, and blood pressure and heart rate at baseline, after each dose and at the end of each session. The FDA called the in vitro hERG assessment (a laboratory heart-safety test) inadequate, asked for the drug’s major metabolites to be evaluated in it, and recommended a dedicated ECG study with continuous Holter monitoring.
• The role of psychotherapy. The FDA asked the applicant to show how much the psychotherapy contributes to any benefit and whether it is necessary; it noted that the psychotherapy regimen used in the trials “may not be generalizable to all types of psychotherapy practices,” suggested an evidence-based standard-of-care psychotherapy instead, and suggested considering a factorial design with an arm that has no psychotherapy.
• Diversity. Improve the diversity of the study population, with reference to the FDA’s draft guidance on diversity action plans.
• Further studies. A study of interactions with SSRI drugs, to determine whether they need to be tapered before treatment; drug-level studies in people with impaired liver function and in people with severe kidney impairment; a lactation study of how much drug passes into breast milk; and a pre- and postnatal development study, because “literature suggests there may be an effect of MDMA on the developing brain” and reliable human pregnancy data are lacking.

The letter closes with a standard statement: “The product may not be legally marketed until you have been notified in writing that this application is approved.”

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11. What the Decision Does Not Do

• It is not a finding that MDMA cannot work for PTSD. The letter describes a path to resubmission, a new trial design and an audit, and says a future review would still consider data from the existing phase 3 trials.
• The committee vote was not the decision. The votes of 4 June 2024 were advice; the FDA’s decision is the 8 August 2024 letter.
• It does not change how MDMA is controlled. The letter is a decision on one drug application and does not address scheduling under the Controlled Substances Act. The FDA’s 2026 psychedelic guidance explains that a Schedule I drug that the FDA approves is then found to have a currently accepted medical use and is placed within Schedules II through V; no such approval has happened here.
• It does not decide on other psychedelic drugs. The letter concerns this single application for this single condition.
• It does not end the application by itself. The letter gives the applicant one year to resubmit or take another action under the regulations (21 CFR 314.110), and says that without a response the FDA may treat the silence as a request to withdraw; an extension of time can also be requested.

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12. Dates and Status as of 11 October 2026

• 8 May 2024: Federal Register notice of the advisory committee meeting; public docket FDA-2024-N-1938 opened.
• 23 May 2024: last day for docket comments to be passed to the committee.
• 3 June 2024: docket closed.
• 4 June 2024: advisory committee meeting; votes of 2–9 on effectiveness and 1–10 on benefit-risk.
• 26 July 2024: final summary minutes approved.
• 8 August 2024: FDA complete response letter.

Status as of 11 October 2026: not approved; final FDA action on this application (complete response). openFDA’s complete-response-letter record for NDA 215455 still lists the status “Unapproved,” and openFDA’s Drugs@FDA database returns no approved application for midomafetamine. A check of the Federal Register from 2024 through 11 October 2026 found no later FDA document on midomafetamine. The documents reviewed for this page do not say whether the application was resubmitted.

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13. How the Decision Fits Earlier and Later FDA Actions

Breakthrough Therapy designation. An FDA notice of 14 July 2026 (91 FR 43095) records that the agency had granted Breakthrough Therapy designation to MDMA for the treatment of PTSD (2017). The notice explains that this designation speeds development and review of drugs for serious conditions where early evidence suggests a substantial improvement, and that it does not “constitute an FDA determination of safety or effectiveness” and is not “a substitute for marketing approval.” The 2024 letter shows the difference in practice.

2023 draft and 2026 final guidance. The FDA issued a draft guidance, “Psychedelic Drugs: Considerations for Clinical Investigations,” on 26 June 2023, and finalized it on 14 July 2026 (91 FR 43101, Docket No. FDA-2023-D-1987). The final guidance addresses the same issues the 2024 letter raised, as general advice for all psychedelic drug developers. It states that expected psychoactive effects such as euphoria and changes in perception and thinking are to be recorded as adverse events because of their link to abuse potential, “even if subjects do not describe these effects as adverse”; that enrolling people with prior psychedelic use “raises the possibility of expectation bias”; that an expectancy questionnaire before randomization and at the end of treatment may help; and that developers plan to evaluate “the durability of response.” It is described on the site’s FDA Final Guidance on Psychedelic Drug Trials (2026) page.

2026 public hearing. The same July 2026 notice announced a public hearing on 14 September 2026 on the “potential future therapeutic use of drug products containing a psychedelic drug substance in supervised and supportive settings” (Docket No. FDA-2026-N-7542). It also records that in April 2026 the FDA issued national priority vouchers to programs studying psilocybin for depression and methylone for PTSD.

2026 ibogaine notice. In October 2026 the FDA asked for information on the design and safety of early clinical trials of ibogaine, a plant alkaloid; see FDA Ibogaine Research Notice (2026).

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14. Primary Documents

1. Food and Drug Administration, HHS (2024). Psychopharmacologic Drugs Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments—Midomafetamine Capsules. Federal Register 89:38903–38905, 8 May 2024. Docket No. FDA-2024-N-1938 — FR Doc. 2024-10053
2. U.S. Food and Drug Administration, CDER (2024). Final Summary Minutes of the Psychopharmacologic Drugs Advisory Committee Meeting, 4 June 2024 (approved 26 July 2024) — fda.gov final summary minutes (PDF)
3. U.S. Food and Drug Administration (2024). Complete Response letter, NDA 215455, midomafetamine capsules, signed 8 August 2024; released through the openFDA complete response letter collection (addressee omitted here) — openFDA CRL PDF
4. Food and Drug Administration, HHS (2026). Psychedelic Drugs: Considerations for Clinical Investigations; Guidance for Industry; Availability. Federal Register 91:43101–43103, 14 July 2026. Docket No. FDA-2023-D-1987 — FR Doc. 2026-14158
5. U.S. Food and Drug Administration, CDER (2026). Psychedelic Drugs: Considerations for Clinical Investigations. Guidance for Industry, July 2026 — fda.gov guidance (PDF)
6. Food and Drug Administration, HHS (2026). Considerations for Potential Future Therapeutic Use of Psychedelic Drugs; Public Hearing; Request for Comments. Federal Register 91:43095–43098, 14 July 2026. Docket No. FDA-2026-N-7542 — FR Doc. 2026-14155

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Key Research Papers

1. Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, et al. (2021). MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine 27(6):1025-1033. A multi-site phase 3 trial in 90 participants with severe PTSD, comparing manualized therapy with MDMA or with placebo; symptoms were measured 2 months after the last session — PubMed PMID: 33972795
2. Mitchell JM, Ot’alora G M, van der Kolk B, Shannon S, Bogenschutz M, Gelfand Y, et al. (2023). MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature Medicine 29(10):2473-2480. A confirmatory phase 3 trial in 104 participants with moderate to severe PTSD; an author correction was published in 2024 (Nat Med 30(11):3382) — PubMed PMID: 37709999
3. Muthukumaraswamy SD, Forsyth A, Lumley T (2021). Blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Review of Clinical Pharmacology 14(9):1133-1152. A systematic review reporting that psychedelic trials had generally not measured pre-trial expectancy or whether blinding held — PubMed PMID: 34038314
4. Soliman PS, Curley DE, Capone C, Eaton E, Haass-Koffler CL (2024). In the new era of psychedelic assisted therapy: A systematic review of study methodology in randomized controlled trials. Psychopharmacology 241(6):1101-1110. A review of 16 publications on placebo choice, design and blinding in psychedelic-assisted therapy trials, including MDMA — PubMed PMID: 38683460

PubMed Topic Searches

1. PubMed: MDMA-assisted therapy for PTSD
2. PubMed: blinding and expectancy in psychedelic trials
3. PubMed: MDMA abuse potential and adverse events

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Connections

• FDA Actions of 2024
• FDA and Regulation
• FDA Final Guidance on Psychedelic Drug Trials (2026)
• FDA Ibogaine Research Notice (2026)
• Xanomeline–Trospium for Schizophrenia (2024)
• Donanemab Alzheimer’s Approval (2024)
• Tianeptine Retailer Warning (2024)
• 7-OH Kratom Scheduling Steps (2026)
• Post-Traumatic Stress Disorder (PTSD)
• Psychiatry
• Ibogaine
• SIADH and Low Blood Sodium

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