MDMA-Assisted Therapy vs Cognitive Processing Therapy for PTSD

Overseen By Anna Donnelly

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Patricia Suppes

Must not be taking: Ketamine, MDMA, others

Disqualifiers: Cardiac conditions, Substance use disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 9-15 weeks

30 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial requires participants to stop or safely taper off certain prohibited medications, but it doesn't specify which ones. It's best to discuss your current medications with the study team to see if they are allowed.

What data supports the effectiveness of the drug MDMA-assisted therapy for PTSD?

Research shows that MDMA-assisted therapy can significantly reduce PTSD symptoms, with patients experiencing greater improvements compared to those receiving standard therapy. Studies found that MDMA helps patients feel more connected and open during therapy, leading to better outcomes. ^{1 2 3 4 5}

Is MDMA-assisted therapy safe for humans?

MDMA-assisted therapy has been found to be generally safe in clinical settings, with no serious drug-related adverse events reported in studies. However, it can increase blood pressure, heart rate, and body temperature, so careful monitoring is necessary. ^{2 6 7 8 9}

How is MDMA-assisted therapy different from other PTSD treatments?

MDMA-assisted therapy is unique because it combines the use of MDMA, a psychedelic drug, with psychotherapy to help patients process traumatic memories without feeling overwhelmed. This approach is particularly promising for those with treatment-resistant PTSD, as it can enhance emotional bonding and reduce distress during therapy sessions. ^{1 2 3 10 11}

What is the purpose of this trial?

This trial is testing a new treatment that uses MDMA along with therapy to help veterans with PTSD who haven't improved with other treatments. MDMA makes therapy sessions more effective by helping patients feel less fearful and more open. The study will compare this new method to another common PTSD therapy to see which works better. MDMA has been shown in several studies to enhance the effectiveness of psychotherapy for PTSD by reducing fear and increasing openness during therapy sessions.

Research Team

Trisha Suppes, MD, PhD

Principal Investigator

VA Palo Alto Healthcare System / Stanford University

Shannon Wiltsey Stirman, PhD

Principal Investigator

VA Palo Alto Healthcare System / Stanford University

Eligibility Criteria

This trial is for U.S. Military Veterans with severe PTSD lasting at least 6 months, who are fluent in English and weigh at least 48 kg. Participants must not be pregnant or breastfeeding, have a support person for post-session evenings, and can't have certain mental health conditions, unstable medical illnesses, serious heart issues, high suicide risk, or recent substance abuse.

Inclusion Criteria

I have had severe PTSD symptoms in the last month.

I have been diagnosed with severe PTSD for at least 6 months.

Participants must agree to have study visits audio and/or video recorded

Exclusion Criteria

I cannot or will not stop taking certain medications.

Participants who lack social support or a stable living situation

I have a condition that makes taking stimulant medications unsafe for me.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 8-15 virtual CPT sessions, including MDMA-assisted sessions for the experimental arm, over a 9-15 week period

9-15 weeks

8-15 virtual visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

Optional Crossover

Participants in the CPT arm have the option to crossover to the MDMA-aCPT arm 6 months after study completion

Treatment Details

Interventions

• Cognitive Processing Therapy
• MDMA

Trial Overview The study compares MDMA-assisted therapy with Cognitive Processing Therapy (CPT) to see which is better for treating PTSD in veterans. It will also look into how feasible it is to use this treatment within the VA system and its economic impact.

Participant Groups

Group I: MDMA-assisted Cognitive Processing Therapy (MDMA-aCPT) Experimental Treatment 2 Interventions

This arm consists of 8-15 virtual CPT sessions (average of 12), one 90-minute, non-drug Preparatory Session, three Experimental Sessions with MDMA (\~8 hours), and three 90-minute, non-drug Integration Sessions, occurring over a 9-15-week Treatment Period. Standardized homework is assigned at each CPT session to promote the practice of the skills taught in the session. Participants will receive 80mg MDMA HCl for the first Experimental Session and will have the option of a supplemental dose of 40mg MDMA HCI 1.5-2 hours after the initial dose. For the second and third Experimental Sessions, participants will receive either 80mg or 120mg MDMA HCl as the initial dose, and an optional supplemental dose of 40mg or 60mg MDMA HCl 1.5-2 hours after the initial dose. Participants interested in receiving CPT treatment alone after study completion will have the option to be referred to their local VA PTSD Clinical Team for services 6 months after all study visits are completed.

Group II: Cognitive processing therapy Experimental Treatment 1 Intervention

This arm consists of 8-15 virtual CPT treatment sessions lasting approximately 1-1.5 hours, occurring over a \~12-16-week Treatment Period. These sessions will take place approximately one week apart. Standardized homework is assigned at each session to promote the practice of the skills taught in the session. Participants will have the option to crossover to the MDMA-aCPT arm 6 months after all study visits are completed.

Cognitive Processing Therapy is already approved in United States, European Union for the following indications:

Approved in United States as Cognitive Processing Therapy for:

• Posttraumatic Stress Disorder (PTSD)

Approved in European Union as Cognitive Processing Therapy for:

• Posttraumatic Stress Disorder (PTSD)

Who Is Running the Clinical Trial?

Patricia Suppes

Lead Sponsor

Trials

1

Recruited

30+

Steven & Alexandra Cohen Foundation

Collaborator

Trials

5

Recruited

150+

VA Palo Alto Health Care System

Collaborator

Trials

97

Recruited

58,500+

Stanford University

Collaborator

Trials

2,527

Recruited

17,430,000+

Steven & Alexandra Cohen Foundation

Collaborator

Trials

10

Recruited

320+

Findings from Research

MDMA-assisted psychotherapy significantly reduced PTSD symptoms, as measured by the Clinician-Administered PTSD Scale (CAPS), showing a greater reduction compared to control psychotherapy, with a relative risk of achieving clinically significant improvements at 3.65.

The therapy was generally safe and well tolerated, although some side effects like bruxism and anxiety were reported; however, using unregulated MDMA outside a controlled therapeutic setting poses significant risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MDMA-Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta-Analysis. Smith, KW., Sicignano, DJ., Hernandez, AV., et al.[2022]

MDMA-assisted psychotherapy for treatment-resistant PTSD was found to be safe, with no serious adverse events reported during the trial involving 12 patients.

While there were no statistically significant reductions in PTSD symptoms measured by the Clinician-Administered PTSD Scale (CAPS), significant self-reported improvements were observed, and the effectiveness increased with more treatment sessions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Oehen, P., Traber, R., Widmer, V., et al.[2013]

In a clinical trial involving 20 patients with chronic PTSD who had not responded to other treatments, those receiving MDMA during psychotherapy showed a significantly greater reduction in PTSD symptoms compared to the placebo group, with an 83% response rate in the MDMA group versus 25% in the placebo group.

MDMA-assisted psychotherapy was found to be safe, with no serious adverse events or negative effects on neurocognitive function, suggesting it could be a beneficial treatment option for patients with treatment-resistant PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Mithoefer, MC., Wagner, MT., Mithoefer, AT., et al.[2021]

MDMA-assisted psychotherapy shows significant reductions in PTSD symptoms, as measured by the Clinician Administered PTSD Scale (CAPS-IV), particularly at doses of 75 mg and 125 mg, based on a meta-analysis of four randomized controlled trials involving treatment-resistant PTSD patients.

While MDMA treatment was associated with some adverse effects like low mood and nausea, the overall risk was minimal, suggesting that MDMA could be a promising option for patients who have not responded to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis. Illingworth, BJ., Lewis, DJ., Lambarth, AT., et al.[2022]

Cognitive Behavioral Conjoint Therapy (CBCT) combined with MDMA-assisted psychotherapy shows promise in reducing PTSD symptoms and improving relationship satisfaction, as demonstrated in a pilot trial with a representative couple.

Historically, PTSD treatments have evolved to include various evidence-based options, with cognitive behavioral therapies achieving significant symptom improvement in 50-60% of patients, highlighting the potential benefits of integrating new approaches like MDMA with established therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining Cognitive-Behavioral Conjoint Therapy for PTSD with 3,4-Methylenedioxymethamphetamine (MDMA): A Case Example. Wagner, AC., Mithoefer, MC., Mithoefer, AT., et al.[2020]

In a small study of six women with chronic PTSD due to sexual assault, low doses of MDMA (50-75 mg) were found to be safe both psychologically and physiologically.

The study highlights the need for further research with larger sample sizes and higher doses to better understand the safety and efficacy of MDMA-assisted psychotherapy for PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. Bouso, JC., Doblin, R., Farré, M., et al.[2013]

MDMA-assisted psychotherapy has been recognized as a promising treatment for PTSD, receiving 'breakthrough therapy' status from the FDA in 2017, and is currently undergoing Phase III trials with potential approval expected in late 2023.

This treatment aims to address the limitations of existing PTSD therapies by combining the effects of MDMA with psychotherapy, although the article also highlights the need to consider risks and limitations in the current evidence base.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of MDMA-Assisted Therapy for Posttraumatic Stress Disorder. Lewis, BR., Byrne, K.[2023]

The deuterium-substituted form of MDMA (d2-MDMA) shows similar effectiveness to MDMA in producing desired interoceptive effects, which are important for its therapeutic use in PTSD treatment.

d2-MDMA has a reduced potential for causing hyperthermia compared to MDMA, suggesting it may have a better safety profile while maintaining therapeutic benefits, warranting further research into its cardiovascular effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation. Berquist, MD., Leth-Petersen, S., Kristensen, JL., et al.[2021]

MDMA-assisted psychotherapy has shown promise in treating PTSD, particularly in patients who do not respond to traditional therapies, based on results from six phase II randomized controlled trials.

The FDA has designated MDMA as a 'breakthrough therapy' for PTSD, as it can significantly reduce symptoms by enhancing levels of neurohormones like dopamine and serotonin, and by affecting brain regions related to fear and anxiety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MDMA-Based Psychotherapy in Treatment-Resistant Post-Traumatic Stress Disorder (PTSD): A Brief Narrative Overview of Current Evidence. Riaz, K., Suneel, S., Hamza Bin Abdul Malik, M., et al.[2023]

In a study involving six couples where one partner had PTSD, MDMA-facilitated cognitive-behavioral conjoint therapy (CBCT) showed significant improvements in PTSD symptoms and relationship satisfaction, with effect sizes ranging from 1.85 to 3.59.

The treatment was safe and well-tolerated, with no serious adverse events reported, suggesting that MDMA can enhance the effectiveness of therapy for both individual and relational functioning in PTSD cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial. Monson, CM., Wagner, AC., Mithoefer, AT., et al.[2021]

MDMA, when used in a controlled clinical setting with specialized psychotherapy, can help patients with PTSD recall traumatic memories without overwhelming negative emotions, making trauma-focused therapy more accessible.

Recent studies indicate that MDMA-assisted psychotherapy may be a promising treatment for individuals with treatment-resistant PTSD, showing potential benefits in managing this chronic condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MDMA and PTSD treatment: "PTSD: From novel pathophysiology to innovative therapeutics". Sessa, B.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

MDMA-Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta-Analysis. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). [2013]

3. United States pubmed.ncbi.nlm.nih.gov

The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Combining Cognitive-Behavioral Conjoint Therapy for PTSD with 3,4-Methylenedioxymethamphetamine (MDMA): A Case Example. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

A Review of MDMA-Assisted Therapy for Posttraumatic Stress Disorder. [2023]

8. Ireland pubmed.ncbi.nlm.nih.gov

In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

MDMA-Based Psychotherapy in Treatment-Resistant Post-Traumatic Stress Disorder (PTSD): A Brief Narrative Overview of Current Evidence. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial. [2021]

11. Ireland pubmed.ncbi.nlm.nih.gov

MDMA and PTSD treatment: "PTSD: From novel pathophysiology to innovative therapeutics". [2018]