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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments for post-traumatic stress disorder (PTSD): Cognitive Processing Therapy (CPT) and MDMA-assisted Cognitive Processing Therapy (MDMA-aCPT). The researchers aim to determine if adding MDMA, a drug that may aid emotional processing, to therapy sessions can improve outcomes for those with severe PTSD. U.S. veterans with PTSD symptoms for at least six months and receiving care from specific VA healthcare systems may qualify to participate. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that MDMA-assisted therapy, which uses a drug sometimes called ecstasy, can be safely administered to people with PTSD. Past studies have demonstrated its effectiveness in reducing PTSD symptoms, particularly in those unresponsive to other treatments. MDMA may enhance therapy by increasing certain brain chemicals.

Regarding safety, studies generally find MDMA-assisted therapy well-tolerated, with most participants not experiencing serious side effects. Common side effects include anxiety or headaches. Participants should discuss any concerns with the medical team conducting the trial.

Cognitive Processing Therapy (CPT), the other treatment in this study, is a well-known therapy for PTSD. It does not involve drugs and helps patients change their thoughts about the trauma. CPT is considered safe and is widely used.

In summary, both treatments have shown safety in past studies, though MDMA-assisted therapy might have some mild side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about MDMA-assisted therapy for PTSD because it introduces a novel approach by combining psychotherapy with the psychoactive effects of MDMA. Unlike standard treatments like cognitive processing therapy (CPT) alone, MDMA is believed to enhance emotional engagement and processing, potentially leading to more profound therapeutic breakthroughs. The unique mechanism of MDMA targets the brain’s serotonin system, which is thought to help reduce fear and defensiveness, making therapy sessions more effective. Additionally, the integration of MDMA with CPT could accelerate healing, offering the potential for quicker symptom relief compared to traditional methods.

What evidence suggests that this trial's treatments could be effective for PTSD?

This trial will compare MDMA-assisted Cognitive Processing Therapy (MDMA-aCPT) with Cognitive Processing Therapy (CPT) alone for PTSD. Research has shown that combining MDMA with Cognitive Processing Therapy can significantly reduce PTSD symptoms. Specifically, studies found that nearly 70% of participants no longer had PTSD after completing this treatment. This method appears safe and effective for individuals with long-term PTSD that hasn't improved with other treatments.

Cognitive Processing Therapy alone is also effective for PTSD, significantly improving symptoms with long-lasting benefits. One study demonstrated a substantial reduction in PTSD symptoms among those who underwent CPT. Both treatments in this trial offer promising options for individuals dealing with PTSD. ^{6 7 8 9 10}

Who Is on the 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

Are You a Good Fit for This Trial?

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

Participants with an active alcohol or substance use disorder

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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, 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]

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]

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]

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 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]

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]

Citations

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Cognitive Processing Therapy for Posttraumatic Stress ... The CPT-TAU group showed a mean (SE) reduction in CAPS-5 scores of 14.00 (1.92) points, with a low dropout rate (2 of 29 [6.9%]). Patients in ...

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