The Efficacy of MDMA (3,4-Methylenedioxymethamphetamine) for Post-traumatic Stress Disorder in Humans: A Systematic Review and Meta-Analysis

Abstract

Background: 3,4-methylenedioxymethamphetamine (MDMA), known recreationally as "Molly" or "Ecstasy", is a triple monoamine reuptake inhibitor. MDMA specifically acts as a weak 5-HT1 and 5-HT2 receptor agonist, targeting 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Its potential use for therapeutic purposes with these pharmacological profiles remains a controversial subject. Studies have shown the potential benefits in clinical trials for post-traumatic stress disorder (PTSD). A larger amount of data has been provided for the push in support of MDMA-assisted psychotherapy in these patients. Objective: The aim of this article is to compute a meta-analysis and conduct a systematic review of the effects of MDMA on PTSD, discussing the potential benefits and adverse events relative to dosing and stability of treatment. Methods: Articles were collected and analyzed for systematic review: 16 articles were included in the systematic review that met the criteria for the use of MDMA in the treatment of PTSD as well as assessing the safety and efficacy of the drug in human participants. Ten studies were used for the meta-analysis, with a cumulative sample size of 168 patients. The significance of the findings on dosing and efficacy of MDMA in healthy human participants was quantified based on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and PTSD symptom scores. Results: The disorders for which MDMA demonstrated a net positive or net negative effect on symptoms are presented separately. Adverse events in patients across all disease classes are presented. The therapeutic index for patients who demonstrated a benefit is also presented. An odds ratio for beneficial and adverse events is used to determine treatment-resistant patients who may benefit from clinical trials of MDMA. Discussion: Findings show promising evidence for the potential therapeutic use of MDMA alongside psychotherapy in the treatment of PTSD. The pharmacological profile of MDMA may provide direction for future drug developments to treat patients with treatment-resistant psychiatric disorders.

Keywords: mdma; mdma-assisted psychotherapy; posttraumatic stress; ptsd; ptsd diagnosis and treatment.

Figure 1. Systematic Review Protocol

MDMA: 3,4-methylenedioxymethamphetamine; PTSD: post-traumatic stress disorder

Figure 2. PRISMA Study Flow Diagram

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Figure 3. Risk of Bias Graph for All Included Studies

[3,8,18-25]

Figure 4. Risk of Bias Graph for Nonrandomized Trials MP-16, MP-17, MPVA-1 using ROBINS-I tool

ROBINS-I: Risk Of Bias In Non-randomized Studies of Interventions [21-23]; MPVA-1 (Monson et al. 2019) [21]; MP-16: NCT03282123 [22]; MP-17: NCT03485287 [23]

Figure 5. Risk of Bias Summary for Nonrandomized Trials MP-16, MP-17, MPVA-1 Using ROBT RevMan 5.4

ROBT: risk of bias tool; RevMan 5.4: Cochrane Review Manager version 5.4 MPVA-1 (Monson et al. 2019) [21]; MP-16: NCT03282123 [22]; MP-17: NCT03485287 [23]

Figure 6. Risk of Bias Summary

[3,8,18-25]; MP-16: NCT03282123 [22]; MP-17: NCT03485287 [23]; MP-4: NCT01958593 [24]; MP-9: NCT01689740 [25]

Figure 7. Funnel Plot of Risk Ratio of Responders to MDMA-Assisted Psychotherapy

MDMA: 3,4-methylenedioxymethamphetamine [3,8,18-25]

Figure 8. Funnel Plot of Standardized Mean Difference of Pre- Versus Post-Effect of MDMA-Assisted Psychotherapy

MDMA: 3,4-methylenedioxymethamphetamine [3,8,18-25]

Figure 9. Funnel Plot of Standardized Mean Difference of Pre- Versus Follow-up Effect of MDMA-Assisted Psychotherapy

MDMA: 3,4-methylenedioxymethamphetamine [3,8,18-25]

Figure 10. Funnel Plot for Those Who Went Into Remission

[3,8,18-25]

Figure 11. Forest Plot of Risk Ratio of Responders to MDMA (versus-control) Using Random Effects Meta Analysis

MDMA: methylenedioxymethamphetamine [3,8,18-25]; MP-16: NCT03282123 [22]; MP-17: NCT03485287 [23]; MP-4: NCT01958593 [24]; MP-9: NCT01689740 [25]

Figure 12. Forest plot for meta-analysis of remission of PTSD diagnostic status with MDMA-assisted psychotherapy

MDMA: 3,4-methylenedioxymethamphetamine; PTSD: post-traumatic stress disorder [3,8,18-25]; MP-16: NCT03282123 [22]; MP-17: NCT03485287 [23]; MP-4: NCT01958593 [24]; MP-9: NCT01689740 [25]

Figure 13. Forest plot of Standardized Mean Difference (SMD) of effect of MDMA (versus control) on PTSD symptoms score using random-effects meta analysis.

MDMA: 3,4-methylenedioxymethamphetamine; PTSD: post-traumatic stress disorder [3,8,18-25]; MP-16: NCT03282123 [22]; MP-17: NCT03485287 [23]; MP-4: NCT01958593 [24]; MP-9: NCT01689740 [25]

Figure 14. Forest plot of Standardized Mean Difference (SMD) of Pre-vs-Follow-up Effect of MDMA (versus control) on PTSD Symptoms Score using random-effects meta-analysis

MDMA: 3,4-methylenedioxymethamphetamine; PTSD: post-traumatic stress disorder [3,8,18-25]; MP-16: NCT03282123 [22]; MP-17: NCT03485287 [23]; MP-4: NCT01958593 [24]; MP-9: NCT01689740 [25]