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MDMAAssistedPsychotherapy.pptx

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MDMA Assisted Psychotherapy: Pitfall & Promises What a PMHNP Should Know

Tatiana Green

MH 708 Psychotherapy

September 1, 2025

Learning Objectives

Define MDMA assisted therapy and its core principles

Summarize evidence based, safety and controversies

Apply MDMA assisted therapy to PTSD and compare with Prolonged Exposure (PE standard therapy)

History of MDMA

1912

MDMA synthesized in 1912 (Merck) (DEA, n.d.)

1970s-80s

used in psychotherapy informally then criminalized in 1985 (Yazar-Klosinski & Mithoefer, 2017)

2019

Multidisciplinary Association for Psychedelic Studies (MAPS) research led to Phase 2 and Phase 3 trials published in Nature Medicine (MAPS

Theory & Model

MDMA acts as an enactogen: promotes openness, empathy, and fear reduction

Lowers avoidance, enhance memory reconsolidation, and increases trust in therapy (Yazar-Klosinski & Mithoefer, 2017)

Therapy Protocol: Prep sessions Dosing Sessions Integration (MAPS, 2019)

Mechanism of Action

MDMA serotonin, dopamine, and norepinephrine (Yazar-Klosinski & Mithoefer, 2017)

Oxytocin bonding/trust (Yazar-Klosinski & Mithoefer, 2017)

Amygdala reactivity reduced fear response (StatPearls Publishing, 2024)

Facilitates trauma processing

Protocol & Technique

2-3 dosing sessions (6-8 hours each) with 2 therapist (Mitchell et al., 2021)

Music, eye shades, and supportive therapy

Integration sessions after each dose (MAPS, 2019)

Safety & Monitoring

Common Side Effects: anxiety, nausea, increased HR/BP (Mitchell et al., 2023)

Rare Risk: Hyperthermia & Hyponatremia (StatPearls Publishing, 2024)

Contraindications: Cardiovascular disease, liver disease, and pregnancy (StatPearls Publishing, 2024)

Medical monitoring required

Complexity, Scope, & Usefulness

Complexity: moderately structured requiring intensive training (Yazar-Klosinski & Mithoefer, 2017)

Scope: Conceptual model (MAPS, 2019)

Usefulness: Today, limited to research settings

Cultural & Lifespan Issues

Trials included mostly adults age 18-65 (Mitchell et al., 2023)

Older adults, teens, and children excluded from trials

More research needed to address how cultural differences affect engagement or outcomes (ICER, 2024)

Evidence (Key Trials)

Phase 3 MAPP1 & MAPP2: MDMA-AT + therapy > therapy + placebo (Mitchell et al., 2021)

Dropout rates lower than in traditional trauma therapy……promising!

Critiques of Evidence

Expectancy issues for blind trials (MDMA effects are obvious) (ICER, 2024)

Therapist allegiance effects

Concerns about trial conduct (bias, irregularities).

FDA Advisory Committee voted against approval (FDA, 2024)

Regulatory Status

FDA issued Complete Response Letter in August 2024 rejection (FDA, 2024)

MDMA remains Schedule I (DEA, n.d.)

Expanded access only in research programs

Application to PTSD

Section II

DSM-5-TR PTSD

Core clusters: intrusion, avoidance behaviors, negative cognitions/mood shifts, and increased arousal symptoms

Onset usually within 3 months but can be delayed (American Psychiatric Association, 2022)

Epidemiology

Lifetime prevalence ~6-8%; women > men (NIMH, 2022)

Higher rates in veterans and trauma exposed groups (VA/DoD, 2023)

Assessment

Screening Tools (VA/DoD, 2023):

CAPS-5 structured interview = diagnostic goal standard

PC-PTSD-5 = brief

PCL-5

Clinical Course & Presentation

Symptoms may remit or persist chronically (intrusion, avoidance, negative mood) (American Psychiatric Association, 2022)

Common comorbidities: depression, chronic pain, substance use disorder complicates treatment (NIMH, 2022)

Differential Diagnosis

Acute stress disorder, Adjustment Disorder, Major Depressive Disorder, Obsessive Compulsive Disorder, Traumatic Brain Injury (American Psychiatric Association, 2022)

To differentiate use structured assessments (VA/DoD, 2023)

Standard Treatments

First line: trauma-focused psychotherapies (Prolonged exposure, Cognitive processing therapy, EMDR) (VA/DoD, 2023; Schnurr et al., 2022)

Second line: SSRIs, SNRIs (VA/DoD, 2023)

Prazosin for nightmares

Where does MDMA-AT fit?

Currently: experimental only (FDA, 2024)

Future (if approved): potential adjunct for severe, treatment resistant PTSD (ICER, 2024)

Would require therapist training, clinic infrastructure, controlled setting

MDMA-AT for PTSD (Efficacy & Risk)

Benefit vs therapy + placebo (CAPS-5) low dropout (Mitchell et al., 2021; Mitchell et al., 2023)

Safety profile favorable in trials with monitoring

Strict inclusion/exclusion criteria for patients (exclusion of high suicide rate, CVD, pregnancy, liver disease) (Jerome et al., 2020)

Alternative Strategies

CPT, EMDR, PE, Written exposure therapy (VA/DoD, 2023)

Tailor based on patient’s readiness, comorbidities, and cultural context

Comparison: MDMA-AT vs Prolonged Exposure (PE)

Section III

Why Compare

Prolonged Exposure: gold standard = guideline endorsed, widely available (VA/DoD, 2023)

MDMA-AT: experimental, promising but unproven

Evidence Snapshot

MDMA-AT: Phase 3 promising but concerns about bias; FDA rejected (Mitchell et al., 2021; Mitchell et al., 2023; FDA, 2024)

PE: dozens of RCTs, guideline endorsed, durable effects, PE ≥ CPT in some trials (Schnurr et al., 2022)

Pros & Cons

MDMA-AT Pros: strong effect sizes, low dropout, potential for rapid change

MDMA-AT Cons: medical risk, legal battles, high resource needs, intensive clinic time, cost/logistics

(Mitchell et al., 2021; Mitchell et al., 2023)

PE Pros: strong evidence, scalable, guideline recommended

PE Cons: dropout risk d/t exposure avoidance, emotionally taxing, requires skilled supervision

(Schnurr et al., 2022)

Patient Matching

MDMA-AT: highly treatment-resistant patients willing to engage in all day dosing; potential for refractory, severe PTSD (ICER, 2024)

PE: suitable as first line; adaptable to groups, primary care, telehealth (VA/DoD, 2023; Schnurr et al., 2022)

Risk of Misapplication

MDMA-AT: Medical complications, misuse/diversion, boundary issues, inadequate monitoring hyponatremia/hyperthermia (StatPearls Publishing, 2024)

PE: too-intense exposure dropout/worsening if poorly managed (VA/DoD, 2023)

Bottom Line

MDMA-AT: experimental, not yet ready for clinical practice (FDA, 2024)

PE: remains first line for PTSD (VA/DoD, 2023)

PMHNP role: use evidence based therapies, stay informed, educate patients

This project ties to AACN & NONPF competencies (usefulness, EBP, safety/efficacy, psychotherapy ordering)

References

American Psychiatric Association. (2022). Diagnostic and statistical manual of mental disorders (5th ed., text rev.; DSM-5-TR). American Psychiatric Publishing.

Institute for Clinical and Economic Review. (2024, June 27). MDMA-assisted therapy for PTSD: Final evidence report. ICER. https://icer.org

Jerome, L., Schuster, S., & Yazar-Klosinski, B. (2020). Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: A longitudinal pooled analysis of six phase 2 trials. Psychopharmacology, 237(8), 2485–2497. https://doi.org/10.1007/s00213-020-05548-2

Mitchell, J. M., Bogenschutz, M., Lilienstein, A., Harrison, C., Kleiman, S., Parker-Guilbert, K., … Doblin, R. (2021). MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled Phase 3 study. Nature Medicine, 27(6), 1025–1033. https://doi.org/10.1038/s41591-021-01336-3

Mitchell, J. M., Sexton, M., Jerome, L., Feduccia, A. A., Emerson, A., Schenberg, E. E., … Ot’alora, G. M. (2023). MDMA-assisted therapy for moderate to severe PTSD: A randomized, double-blind, placebo-controlled Phase 3 trial. Nature Medicine, 29(8), 1736–1745. https://doi.org/10.1038/s41591-023-02565-4

Multidisciplinary Association for Psychedelic Studies (MAPS). (2019). MDMA-assisted psychotherapy treatment manual for the treatment of PTSD. MAPS Public Benefit Corporation. https://maps.org

National Institute of Mental Health. (2022). Post-traumatic stress disorder. NIMH. https://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd

Schnurr, P. P., Wiltsey Stirman, S., Rodriguez, T., Guzman, D., & Kim, M. (2022). Comparative effectiveness of Prolonged Exposure vs Cognitive Processing Therapy for PTSD in female veterans and active-duty service members: A randomized clinical trial. JAMA Network Open, 5(9), e2232034. https://doi.org/10.1001/jamanetworkopen.2022.32034

StatPearls Publishing. (2024). 3,4-Methylenedioxymethamphetamine (MDMA) toxicity. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK430885/

U.S. Department of Veterans Affairs & U.S. Department of Defense. (2023). VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder. U.S. Government Publishing Office. https://www.healthquality.va.gov/guidelines/MH/ptsd/

U.S. Drug Enforcement Administration. (n.d.). Drug scheduling: MDMA (Ecstasy/Molly). DEA. https://www.dea.gov/drug-information/drug-scheduling

U.S. Food and Drug Administration. (2024, August 9). FDA issues complete response letter to Lykos Therapeutics regarding MDMA-assisted therapy for PTSD. FDA.gov. https://www.fda.gov

Yazar-Klosinski, B., & Mithoefer, M. C. (2017). Developing MDMA-assisted psychotherapy for PTSD: Results of phase 2 trials and research plans for phase 3. Journal of Psychopharmacology, 31(10), 1106–1117. https://doi.org/10.1177/0269881117725915