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

Abstract

Case reports indicate that psychiatrists administered ±3,4-methylenedioxymethamphetamine (MDMA) as a catalyst to psychotherapy before recreational use of MDMA as ‘Ecstasy’ resulted in its criminalization in 1985. Over two decades later, this study is the first completed clinical trial evaluating MDMA as a therapeutic adjunct. Twenty patients with chronic posttraumatic stress disorder, refractory to both psychotherapy and psychopharmacology, were randomly assigned to psychotherapy with concomitant active drug (n = 12) or inactive placebo (n = 8) administered during two 8-h experimental psychotherapy sessions. Both groups received preparatory and follow-up non-drug psychotherapy. The primary outcome measure was the Clinician-Administered PTSD Scale, administered at baseline, 4 days after each experimental session, and 2 months after the second session. Neurocognitive testing, blood pressure, and temperature monitoring were performed. After 2-month follow-up, placebo subjects were offered the option to re-enroll in the experimental procedure with open-label MDMA. Decrease in Clinician-Administered PTSD Scale scores from baseline was significantly greater for the group that received MDMA than for the placebo group at all three time points after baseline. The rate of clinical response was 10/12 (83%) in the active treatment group versus 2/8 (25%) in the placebo group. There were no drug-related serious adverse events, adverse neurocognitive effects or clinically significant blood pressure increases. MDMA-assisted psychotherapy can be administered to posttraumatic stress disorder patients without evidence of harm, and it may be useful in patients refractory to other treatments.

Altered Insula Connectivity under MDMA

“…Furthermore, propranolol-another pharmacological agent investigated as an adjunct for PTSD therapy (Brunet et al, 2008, but see Wood et al, 2015;Steenen et al, 2016)-decreases connectivity within the salience network (Hermans et al, 2011). Thus, it is worth considering whether action at the salience network might be an important component of the mechanism by which MDMA operates in MDMA-assisted psychotherapy for PTSD (Mithoefer et al, 2011;Mithoefer et al, 2012;Oehen et al, 2013).…”

“…In light of recent hypotheses suggesting an 'insular view of anxiety' (Paulus and Stein, 2006), further understanding of how MDMA affects the insula might be crucial to elucidating the neurobiological underpinnings of re-emerging interest in MDMA as a therapeutic adjunct to psychotherapy in the treatment of anxiety disorders including PTSD (Mithoefer et al, 2011;Oehen et al, 2013, see Amoroso andWorkman, 2016 for a preliminary meta-analysis).…”

“…The first randomized controlled trials (RCTs) of MDMAassisted psychotherapy for treatment-resistant PTSD demonstrated decreases in both clinician-and participant-rated symptom severity (Mithoefer et al, 2011;Oehen et al, 2013). The efficacy of these interventions persisted at follow-up (Mithoefer et al, 2012), and effect sizes surpassed even those demonstrated by prolonged exposure therapy, the most widely accepted treatment for PTSD (Amoroso and Workman, 2016).…”

Perspectives on Zebrafish Models of Hallucinogenic Drugs and Related Psychotropic Compounds

“…21,22 Thus, the use of hallucinogenic drugs can lead to new sensitive experimental models of brain disorders. 23 Moreover, mounting evidence indicates that hallucinogens may have some clinical value in treating selected brain disorders, 24 including obsessive compulsive disorder, 25,26 posttraumatic stress disorder, 27,28 and depression. 29−31 Therefore, this line of research can lead to widening and innovating the spectrum of potential therapeutic approaches to some serious debilitating pathological conditions (see refs 10, 24, and 32 for discussion).…”

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction

“…Variability in temperature responses may explain the large individual differences in the emergence of adverse psychological and cognitive symptoms seen in some longterm MDMA users (for review, see Parrott, 2013b). Therefore, despite the modest hyperthermic responses to MDMA seen in humans under standard laboratory conditions (Freedman et al, 2005;Liechti, 2014), and its potential as a therapeutic agent for post-traumatic stress disorder (Mithoefer et al, 2011(Mithoefer et al, , 2013, our study underscores the possible dangers of 'recreational' MDMA use.…”