Possible mechanisms
While the format of MDMA-assisted psychotherapy and the nondirective therapeutic approach we used are quite different from many existing treatments for PTSD, some elements of what occurs in MDMA-assisted therapy would be easily recognizable to many therapists. The first category of effects discussed above, in which MDMA appears to remove obstacles to effective trauma processing, can be understood in terms used by Foa and colleagues19 to describe obstacles to prolonged exposure therapy: overengagement and underengagement.
To be effective, exposure must be accompanied by a degree of emotional engagement or fear activation while avoiding dissociation or overwhelming emotion.20 This has been referred to as working within the optimal arousal zone, or window of tolerance.21-23 During MDMA sessions, we observed that patients with PTSD spontaneously engaged in “imaginal exposure,” and MDMA appeared to allow them to remain within an optimal arousal zone while doing so.
Further trials will determine whether the study results will evolve into clinical applications … it is likely that MDMA may find an important place in the future of psychopharmacology.
The pharmacological effects of MDMA include serotonin release; serotonin type 2 receptor stimulation; and an increase in levels of the neurohormones oxytocin(Drug information on oxytocin), prolactin, and cortisol.24-29 Serotonin release plays an important role in producing the subjective effects of MDMA.30-33 Pretreatment with SSRIs reduces most acute subjective and physiological effects of MDMA, including effects on mood and perception. Serotonin release directly or indirectly leads to an elevation in oxytocin levels, possibly by stimulating serotonin type 1A receptors.24,28,34 Studies suggest that oxytocin plays an important role in stress response, reduces the fear response, and increases social affiliation and trust35-39; thus, elevated oxytocin levels might help patients form a therapeutic alliance and revisit traumatic experiences in an emotionally engaged state.
Elevation in oxytocin levels after MDMA administration has been associated with greater sociability and more gregarious behavior.24 MDMA has recently been shown to decrease perception of negative emotions in others and perception of threat-related signals, such as fear, which might increase social approach behavior.40 It has been postulated that prolactin release following MDMA administration may contribute to a postorgasmic-like sense of relaxation and receptivity.41 The neurocircuitry model of PTSD postulates a deficit in extinction of fear conditioning mediated by the amygdala and the ventromedial prefrontal cortex, a model supported by findings of reduced hippocampal activity and volume, increased activity in the amygdala, and decreased activation of the medial prefrontal cortex in persons with PTSD.42,43
Gamma and colleagues44 used positron emission tomography to measure cerebral blood flow 75 minutes after MDMA was given to healthy volunteers. Their findings showed increases in cerebral blood flow in the ventromedial frontal and occipital cortex and decreases in the left amygdala. MDMA may produce some of its effects through these acute changes in brain activity, which may reverse abnormalities associated with PTSD and thereby allow effective processing of traumatic memories. The nature of the effects is consistent with much of what we observed in our clinical trial.
