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.

Effects of Selective Serotonin Reuptake Inhibitor Use on 3,4-Methylenedioxymethamphetamine–Assisted Therapy for Posttraumatic Stress Disorder

“…In these studies, participants received MDMA in one or a handful of nondirective, supportive psychotherapy sessions, with multiple nondrug sessions preceding and following each drug session for preparation and integration. Across more than 600 experimental sessions, MDMA was found to be safe and well tolerated, with only one serious adverse event deemed possibly related to drug administration (increase in premature ventricular contractions without significant long-term sequalae) 12 . Mild treatment-associated adverse events were more common in the MDMA arm of the phase 3 study, with the most common being muscle tightness, decreased appetite, and nausea 10 …”

“…Long-term follow-up data from the same 6 studies found a large within-subjects effect size of d = 1.58 at treatment exit (1–2 months after the last active dose MDMA session) compared with baseline, which further improved between treatment exit and long-term follow-up (approximately 1 year later) with a small effect size of d = 0.23 14 . A recent meta-analysis including 10 phase 2 trials found a large overall effect size of d = 0.93 when comparing active MDMA intervention versus control groups, with a relative risk for remission of 2.96 (95% confidence interval, 1.63–5.39) indicating a nearly 3-fold higher chance of remission in the MDMA group 12 . Finally, in the only phase 3 study to date, Mitchell and colleagues demonstrated significant improvement in PTSD symptoms with MDMA-assisted therapy 10 .…”

“…14 A recent meta-analysis including 10 phase 2 trials found a large overall effect size of d = 0.93 when comparing active MDMA intervention versus control groups, with a relative risk for remission of 2.96 (95% confidence interval, 1.63-5.39) indicating a nearly 3-fold higher chance of remission in the MDMA group. 12 Finally, in the only phase 3 study to date, Mitchell and colleagues demonstrated significant improvement in PTSD symptoms with MDMA-assisted therapy. 10 As with all prior studies, the population had chronic PTSD with significant symptom burden, indicated by a baseline CAPS-Vof 44.1, greater than 97% having received prior psychotherapy, and an average illness duration of 14.1 years.…”

“…Across more than 600 experimental sessions, MDMA was found to be safe and well tolerated, with only one serious adverse event deemed possibly related to drug administration (increase in premature ventricular contractions without significant long-term sequalae). 12 Mild treatment-associated adverse events were more common in the MDMA arm of the phase 3 study, with the most common being muscle tightness, decreased appetite, and nausea. 10 A pooled analysis of 6 of the initial phase 2 studies showed that by the end of treatment, the active groups (receiving MDMA doses of 75, 100, or 125 mg) had significantly greater improvement on the Clinician Administered PTSD Scale (CAPS)-IV as compared with the active-placebo groups (receiving MDMA doses of 0-40 mg), with a large between-group Cohen d effect size of 0.8.…”

The Efficacy of Psychedelic-Assisted Therapy in Managing Post-traumatic Stress Disorder (PTSD): A New Frontier?

“…Post-traumatic stress disorder (PTSD) is a complex mental disorder that affects 7.7 million adults in the United States annually, with one in 11 individuals being diagnosed with PTSD at some point in their lives. More than twice as many women (10%) as men (4%) have PTSD, with sexual assault being the most common traumatic incidence [ 1 ]. According to the DSM-5 criteria, PTSD is a mental health disorder that can develop after exposure to a traumatic event, such as death, serious injury, or sexual violence [ 2 ].…”