Psychotherapy-supported MDMA treatment for PTSD

Krystal, John H.; Kelmendi, Benjamin; Petrakis, Ismene L.

doi:10.1016/j.xcrm.2021.100378

Cited by 12 publications

(12 citation statements)

References 9 publications

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“…A recent confirmatory phase III study (MAPP2) involving participants with moderate PTSD was recently concluded ( NCT04077437 ), but results had not been reported at the time of writing. As with any nascent clinical literature, these exciting findings should be tempered by bearing in mind that additional studies of safety (including abuse liability) are still awaited ( Krystal et al, 2021 ).…”

Section: Monoamines: Poly-pharmacology and Psychedelicsmentioning

confidence: 99%

Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder

Singewald¹,

Sartori²,

Reif

et al. 2023

Neuropharmacology

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Section: Monoamines: Poly-pharmacology and Psychedelicsmentioning

confidence: 99%

Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder

Singewald¹,

Sartori²,

Reif

et al. 2023

Neuropharmacology

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“…Mechanistically different, amphetamines and their derivatives are substrates of SERT that induce efflux of the cognate intracellular substrate by reverse transport 21 . Among them, the illicit drug 3,4-methylenedioxy-N-methylamphetamine (MDMA) 22 , 23 has recently shown therapeutic potential and entered Phase III clinical trials for the treatment of post-traumatic stress disorder 22 , 24 , 25 .…”

Section: Introductionmentioning

confidence: 99%

Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors

Gradisch,

Schlögl,

Lazzarin

et al. 2024

Nat Commun

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The presynaptic serotonin transporter (SERT) clears extracellular serotonin following vesicular release to ensure temporal and spatial regulation of serotonergic signalling and neurotransmitter homeostasis. Prescription drugs used to treat neurobehavioral disorders, including depression, anxiety, and obsessive-compulsive disorder, trap SERT by blocking the transport cycle. In contrast, illicit drugs of abuse like amphetamines reverse SERT directionality, causing serotonin efflux. Both processes result in increased extracellular serotonin levels. By combining molecular dynamics simulations with biochemical experiments and using a homologous series of serotonin analogues, we uncovered the coupling mechanism between the substrate and the transporter, which triggers the uptake of serotonin. Free energy analysis showed that only scaffold-bound substrates could initiate SERT occlusion through attractive long-range electrostatic interactions acting on the bundle domain. The associated spatial requirements define substrate and inhibitor properties, enabling additional possibilities for rational drug design approaches.

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“…There has been a resurgence of interest in the therapeutic potential of psychedelic substances such as tryptamines (e.g., psilocybin), ketamine, and phenethylamines (e.g., 3,4-methylenedioxymethamphetamine (MDMA)) [ 1 , 2 ]. Based on its positive performance with significant and sustained reductions in PTSD symptoms and acceptable safety profiles, the FDA has designated MDMA-assisted therapy as a breakthrough therapy for PTSD.…”

Section: Introductionmentioning

confidence: 99%

Effects of MDMA-assisted therapy for PTSD on self-experience

van der Kolk,

Wang,

Yehuda

et al. 2024

PLoS ONE

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Introduction There is a resurgence of interest in the therapeutic potential of psychedelic substances such as 3,4-methylenedioxymethamphetamine (MDMA). Primary findings from our randomized, double-blind, placebo-controlled, multi-site Phase 3 clinical trial of participants with severe PTSD (NCT03537014) showed that MDMA-assisted therapy induced significant attenuation in the Clinician-Administered PTSD Scale for DSM-5 compared to Therapy with placebo. Deficits in emotional coping skills and altered self-capacities constitute major obstacles to successful completion of available treatments. The current analysis evaluated the differential effects of MDMA-assisted therapy and Therapy with placebo on 3 transdiagnostic outcome measures and explored the contribution of changes in self-experience to improvement in PTSD scores. Methods Participants were randomized to receive manualized therapy with either MDMA or placebo during 3 experimental sessions in combination with 3 preparation and 9 integration therapy visits. Symptoms were measured at baseline and 2 months after the last experimental session using the 20-item Toronto Alexithymia Scale (TAS-20), the 26-item Self Compassion Scale (SCS), and the 63-item Inventory of Altered Self-Capacities (IASC). Results 90 participants were randomized and dosed (MDMA-assisted therapy, n = 46; Therapy with placebo, n = 44); 84.4% (76/90) had histories of developmental trauma, and 87.8% (79/90) had suffered multiple traumas. MDMA-assisted therapy facilitated statistically significant greater improvement on the TAS-20, the SCS, and most IASC factors of interpersonal conflicts; idealization disillusionment; abandonment concerns; identity impairment; self-awareness; susceptibility to influence; affect dysregulation; affect instability; affect skill deficit; tension reduction activities; the only exception was identity diffusion. Conclusion Compared with Therapy with placebo, MDMA-assisted therapy had significant positive effects on transdiagnostic mental processes of self-experience which are often associated with poor treatment outcome. This provides a possible window into understanding the psychological capacities facilitated by psychedelic agents that may result in significant improvements in PTSD symptomatology.

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Psychotherapy-supported MDMA treatment for PTSD

Abstract: A promising new Phase III study of MDMA plus psychotherapy for PTSD treatment by Mitchell and colleagues that appeared in Nature Medicine raises important new questions about the biology and optimal treatment of this disorder.

Cited by 12 publications

References 9 publications

Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder

Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder

Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors

Effects of MDMA-assisted therapy for PTSD on self-experience

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