How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale

This theory building paper (2009) suggests three potential mechanisms for the efficacy of MDMA as a treatment for anxiety disorders. These mechanisms are linked to oxytocin levels, amygdala and vmPFC activity, and norepinephrine and cortisol release.

Abstract

“Exposure therapy is known to be an effective treatment for anxiety disorders. Nevertheless, exposure is not used as much as it should be, and instead patients are often given supportive medications such as serotonin reuptake inhibitors (SSRIs) and benzodiazepines, which may even interfere with the extinction learning that is the aim of treatment. Given that randomized controlled trials are now investigating a few doses of ±3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) in combination with psychotherapy for treatment-resistant anxiety disorders, we would like to suggest the following three mechanisms for this potentially important new approach: 1) MDMA increases oxytocin levels, which may strengthen the therapeutic alliance; 2) MDMA increases ventromedial prefrontal activity and decreases amygdala activity, which may improve emotional regulation and decrease avoidance and 3) MDMA increases norepinephrine release and circulating cortisol levels, which may facilitate emotional engagement and enhance extinction of learned fear associations. Thus, MDMA has a combination of pharmacological effects that, in a therapeutic setting, could provide a balance of activating emotions while feeling safe and in control, as described in case reports of MDMA-augmented psychotherapy. Further clinical and preclinical studies of the therapeutic value of MDMA are indicated.”

Authors: Pål-Ørjan Johansen & Teri S. Krebs

Summary

Exposure therapy is known to be effective for anxiety disorders, but it is not used as much as it should be. MDMA may improve treatment by increasing oxytocin levels, improving therapeutic alliance, decreasing emotional regulation and decreasing avoidance.

PTSD is an anxiety disorder characterized by intrusive re-experiencing of the trauma and efforts to avoid triggers or reminders. It can persist for years in survivors of intrapersonal traumas such as rape, torture and combat.

Fear conditioning and extinction has been shown to be a successful model for the development and treatment of anxiety disorders.

PTSD patients who receive 10 weekly sessions of extinction-based exposure therapy have long-lasting and clinically meaningful responses, yet over 40% continue to meet diagnostic criteria. MDMA may be a promising new treatment option.

MDMA is a substituted phenethylamine with profound subjective effects including increased empathy and affiliation. MDMA binds and reverses mono-anime transporters, resulting in serotonin release, which seems to mediate most of the subjective effects of MDMA.

Three randomized placebo-controlled clinical trials are now testing MDMA as an augment to psychotherapy for chronic, treatment-resistant PTSD or anxiety associated with advanced-stage cancer. The preliminary results show initial promise.

MDMA increases oxytocin levels, which mediates the anxiety-regulating effect of social closeness and may strengthen the therapeutic alliance between the therapist and patient. Oxytocin has also been shown to enhance the encoding of positive social memories and increase the social support benefit of having a close-friend present during a psychosocial stress test.

MDMA increases activity in the ventromedial prefrontal cortex (vmPFC) and decreases activity in the amygdala, which are both involved in emotional regulation and extinction of conditioned fear.

MDMA increases norepinephrine and cortisol release, which may help with eliciting emotional recall of traumatic experiences and enhance the rate of extinction learning in some anxiety disorders. However, anxiety-reducing treatments can actually interfere with extinction learning.

MDMA could be used in therapy to reduce avoidance behaviour linked to emotions, and could improve the balance of activating emotions while feeling safe and in control.