Abstract

Introduction:
Post‐traumatic stress disorder ﴾PTSD﴿ is characterized by intrusive, emotional memories, sympathetic hyperactivation, and trauma related avoidance. Enhanced fear learning and decreased fear extinction ﴾with potential synaptic maladaptation to stress﴿ contribute to PTSD pathophysiology, as reflected, in humans, by amygdala hyperactivity and reduced hippocampal‐amygdala connectivity. Compared to current treatment approaches, early studies with 3,4,‐methylenedioxymethamphetamine ﴾MDMA﴿ assisted psychotherapy demonstrate superior and longer lasting therapeutic effects following a limited number of administrations.

Methods:
To elucidate the interaction between MDMA pharmacology and PTSD pathophysiology we adapted the question‐based drug‐development ﴾QBD﴿ framework in a narrative review. Based on published preclinical and clinical data, we summarized the cascade of potentially relevant pharmacological effects of MDMA to PTSD, from the molecular to the phenomenological level of central nervous system ﴾CNS﴿ ﴾dys﴿function.

Results:
MDMA crosses the blood‐brain barrier and potently releases presynaptic serotonin ﴾5‐HT﴿, norepinephrine, and to a limited extent dopamine, via reversal of the corresponding transporter proteins. Additionally, it also facilitates central and peripheral release of oxytocin, prolactin, cortisol and vasopressin. Importantly, MDMA acts as a 5‐HT2A agonist as well. Recent in‐vitro experiments with serotonergic psychedelic drugs such as lysergic acid diethylamide ﴾LSD﴿, support rapid, 5‐HT2A mediated synaptogenesis ﴾potentially via AMP mediated trkB/ mTOR downstream signaling﴿, even after transient exposure. Therefore, on the molecular level, MDMA might share 5‐HT2A mediated facilitation of neuronal growth with such compounds. On a CNS functional level, MDMA administration acutely modulates emotional and memory related circuits in humans, as indicated by increased resting state fMRI hippocampal‐amygdala connectivity, decreased amygdala activation during fear processing. Also, and consistent with classical psychedelics, MDMA decreases resting state fMRI connectivity in the default‐mode ﴾DMN﴿ and sensorimotor networks. As a result, MDMA also increases positive mood and emotions, such as trust, openness, insight, euphoria and well‐being, while it decreases fear and defensiveness. MDMA‐mediated release of oxytocin may further affect social relatedness and social reward learning by increasing empathy and connectedness.
Consequently, MDMA can assists psychotherapy by increasing the availability of positive feelings, provide a corrective experience with diminished fear during exposure ﴾enhancing fear extinction﴿, and strengthen therapeutic alliance. Findings from rodent studies between MDMA, of 5HT2a, 5HT5a, 6, 7, agonists, and low doses of psilocybin, converge on fear extinction enhancement and memory reconsolidation disruption. In humans, amphetamine like stimulants acting on the dopaminergic and noradrenergic systems do not share the effects on emotional memory, social processing, or DMN connectivity. Hence, 5‐HT activity is likely an important candidate to mediate MDMA’s therapeutic effects.

Conclusion:
Emerging clinical evidence shows, that MDMA’s acute effects can assist psychotherapy for PTSD. MDMA can aid in restoring dysfunctional emotional network connectivity by enhancement of 5‐HT2A mediated synaptogenesis. In turn, monoamine and particularly 5‐HT release, facilitates key psychotherapeutic processes such as boosting of positive emotions, disruption of traumatic memory reconsolidation, fear extinction and successful exposure. The neuroendocrine effects during psychotherapy may further enhance the therapeutic relationship. These combined effects on the therapeutic experience during MDMA assisted psychotherapy could further lead to the development of novel coping mechanisms that might sustain long‐term therapeutic effects.