A Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD (MAPP2)

NCT ID: NCT04077437

Last Updated: 2025-06-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 121 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-02
• Study Completion Date: 2022-11-02

Brief Summary

The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective in people with at least moderate PTSD.

The main question it aims to answer is: Do three sessions of MDMA-assisted therapy reduce PTSD symptoms?

Researchers will compare three sessions of MDMA-assisted therapy with an initial dose of 80 to 120 mg to three sessions of placebo with therapy.

Participants will undergo three preparatory sessions without any study drug, followed by three MDMA-assisted therapy or placebo with therapy sessions. Each medication session will be followed by three integrative therapy sessions without study drug.

Detailed Description

This multi-site, double-blind, placebo-controlled, randomized Phase 3 study will assess the efficacy and safety of MDMA-assisted psychotherapy versus psychotherapy with placebo control in participants diagnosed with at least moderate PTSD. The study will be conducted in N ≈ 100 participants. Participants will be randomized into one of two groups (MDMA or placebo) in a 1:1 ratio. An initial dose of MDMA or placebo, followed by a supplemental half-dose unless contraindicated, will be administered during the Treatment Period with manualized psychotherapy in three monthly Experimental Sessions. This ~12-week Treatment Period is preceded by three Preparatory Sessions. Initial doses per Experimental Session include 80 mg or 120 mg of midomafetamine HCl or placebo followed 1.5 to 2 hours later by a supplemental half-dose (40 or 60 mg). Total amounts of midomafetamine HCl to be administered per Experimental Session range from 80 mg to 180 mg. Each Experimental Session will be followed by three Integrative Sessions of non-drug psychotherapy to help the participants process and understand their experiences during the Experimental Sessions.

The primary objective of this study is to evaluate the efficacy of MDMA-assisted psychotherapy for PTSD compared to identical psychotherapy with inactive placebo, as measured by change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Severity Score from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline) (Blake et al., 1995). The key secondary objective of this study is to evaluate the efficacy of MDMA-assisted psychotherapy for PTSD compared to identical psychotherapy with inactive placebo in clinician-rated functional impairment, as measured by the change in Sheehan Disability Scale (adapted SDS) item scores from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline) (Leon et al., 1997).

Conditions

Posttraumatic Stress Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Experimental: MDMA-assisted psychotherapy

Administration of 80 to 120 mg midomafetamine HCl in combination with manualized psychotherapy, followed by a supplemental half-dose 1.5 to 2 hrs after the initial dose of 40 or 60 mg, respectively.

Group Type: EXPERIMENTAL

Therapy

Intervention Type: BEHAVIORAL

Standardized non-directive therapy performed by therapist team.

Midomafetamine

Intervention Type: DRUG

Administration of 80 to 120 mg midomafetamine HCl, followed by a supplemental half-dose 1.5 to 2 hrs after the initial dose of 40 or 60 mg, respectively, during three sessions of MDMA-assisted psychotherapy.

Placebo Comparator: Placebo

Administration of inactive placebo in combination with manualized psychotherapy.

Group Type: PLACEBO_COMPARATOR

Therapy

Intervention Type: BEHAVIORAL

Standardized non-directive therapy performed by therapist team.

Placebo

Intervention Type: DRUG

Administration of placebo with therapy during three experimental sessions

Interventions

Therapy

Standardized non-directive therapy performed by therapist team.

Intervention Type: BEHAVIORAL

Midomafetamine

Administration of 80 to 120 mg midomafetamine HCl, followed by a supplemental half-dose 1.5 to 2 hrs after the initial dose of 40 or 60 mg, respectively, during three sessions of MDMA-assisted psychotherapy.

Intervention Type: DRUG

Placebo

Administration of placebo with therapy during three experimental sessions

Intervention Type: DRUG

Other Intervention Names

Manualized MDMA-assisted therapy; 3,4-methylenedioxymethamphetamine; MDMA; Inactive placebo

Eligibility Criteria

Inclusion Criteria

• Are at least 18 years old
• Are fluent in speaking and reading the predominantly used or recognized language of the study site
• Are able to swallow pills
• Agree to have study visits recorded, including Experimental Sessions, Independent Rater assessments, and non-drug psychotherapy sessions
• Must provide a contact (relative, spouse, close friend or other caregiver) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable
• Must agree to inform the investigators within 48 hours of any medical conditions and procedures
• If of childbearing potential, must have a negative pregnancy test at study entry and prior to each Experimental Session, and must agree to use adequate birth control through 10 days after the last Experimental Session
• Must not participate in any other interventional clinical trials during the duration of the study
• Must be willing to remain overnight at the study site after each Experimental Session and be driven home after, and commit to medication dosing, therapy, and study procedures
• At baseline, have moderate PTSD diagnosis

Exclusion Criteria

• Are not able to give adequate informed consent
• Have uncontrolled hypertension
• Have a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds [ms] in males and >460 ms in females corrected by Bazett's formula)
• Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
• Have evidence or history of significant medical disorders, such as myocardial infarction, cerebrovascular accident, or aneurysm
• Have symptomatic liver disease
• Have history of hyponatremia or hyperthermia
• Weigh less than 48 kilograms (kg)
• Are pregnant or nursing, or are of childbearing potential and are not practicing an effective means of birth control
• Have an active illicit or prescription drug use disorder
• Have used Ecstasy (material represented as containing MDMA) more than 10 times within the last 10 years or at least once within 6 months of the first Experimental Session; or have previously participated in a MAPS-sponsored MDMA clinical trial

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Lykos Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

New School Research

Los Angeles, California, United States

San Francisco Insight and Integration Center

San Francisco, California, United States

UCSF

San Francisco, California, United States

Aguazul Bluewater, Inc.

Boulder, Colorado, United States

Wholeness Center

Fort Collins, Colorado, United States

University of Connecticut

Farmington, Connecticut, United States

Ray Worthy Psychiatry LLC

New Orleans, Louisiana, United States

Trauma Research Foundation

Boston, Massachusetts, United States

New York University

New York, New York, United States

Nautilus Psychiatric Services

New York, New York, United States

Zen Therapeutic Solutions, LLC

Mt. Pleasant, South Carolina, United States

University of Wisconsin - Madison

Madison, Wisconsin, United States

Assaf Harofeh Research Fund

Beer Yaaqov, , Israel

Sheba Fund for Health Services and Research

Tel Litwinsky, , Israel

Countries

United States; Israel

References

Leon AC, Olfson M, Portera L, Farber L, Sheehan DV. Assessing psychiatric impairment in primary care with the Sheehan Disability Scale. Int J Psychiatry Med. 1997;27(2):93-105. doi: 10.2190/T8EM-C8YH-373N-1UWD.

Reference Type: BACKGROUND

PMID: 9565717 (View on PubMed)

Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, Keane TM. The development of a Clinician-Administered PTSD Scale. J Trauma Stress. 1995 Jan;8(1):75-90. doi: 10.1007/BF02105408.

Reference Type: BACKGROUND

PMID: 7712061 (View on PubMed)

Mitchell JM, Ot'alora G M, van der Kolk B, Shannon S, Bogenschutz M, Gelfand Y, Paleos C, Nicholas CR, Quevedo S, Balliett B, Hamilton S, Mithoefer M, Kleiman S, Parker-Guilbert K, Tzarfaty K, Harrison C, de Boer A, Doblin R, Yazar-Klosinski B; MAPP2 Study Collaborator Group. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med. 2023 Oct;29(10):2473-2480. doi: 10.1038/s41591-023-02565-4. Epub 2023 Sep 14.

Reference Type: DERIVED

PMID: 37709999 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

MAPP2

Identifier Type: -

Identifier Source: org_study_id