3,4-methylenedioxymethamphetamine (MDMA) impairs the extinction and reconsolidation of fear memory in rats

Abstract

Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

“…The substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) induces serotonin release by binding primarily to presynaptic serotonin transporters 12 . MDMA has been shown to enhance fear memory extinction, modulate fear memory reconsolidation (possibly through an oxytocin-dependent mechanism), and bolster social behavior in animal models 13 , 14 . Pooled analysis of six phase 2 trials of MDMA-assisted therapy for PTSD have now shown promising safety and efficacy findings 15 .…”

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…The other main interesting feature of S1R is its modulatory action over chromatin remodeling complexes, which lead to a rearrangement of gene expression (Demmerle et al, 2012;Tsai et al, 2015). Therefore, the positive outcomes on traumarelated fear-memory extinction and memory reconsolidation elicited by compounds such as ayahuasca and MDMA might result from the activation of this receptor (Feduccia and Mithoefer, 2018;Inserra, 2018;Hake et al, 2019).…”

Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine

“…MDMA may also modify the sensitivity to social reward in mice, an effect lasting weeks after a single dose (Nardou et al, 2019), reminiscent of the "integration therapy" process after an MDMA experience, wherein a patient is encouraged to consider how emotional shifts in the aftermath of their MDMA session may be integrated into daily life (Greer and Tolbert, 1986). Finally, MDMA disrupts fear memories in a widely used model for PTSD (Young et al, 2015(Young et al, , 2017Hake et al, 2019), wherein a conditioned fear memory is extinguished by re-cueing the memory in a safe context.…”