How Does Recent Discontinuation of Antidepressants Affect MDMA-Assisted Therapy?

interaction mdma snri ssri Apr 28, 2021

Muted Experiences with SSRIs and MDMA

A number of small clinical trials have pre-treated persons with SSRI or SNRI medications before administering MDMA and found that despite higher blood concentrations of MDMA (due to CYP2D6 inhibition of MDMA metabolism in the liver) that subjective and most physiological effects of MDMA are diminished. However, laboratory drug interaction studies that combine antidepressants with MDMA don't tell us much about how recent discontinuation of antidepressants could affect things. Antidepressants like SSRIs produced long-term neuroadaptive effects that may involve downregulation of key targets of MDMA's mechanism of action such as the serotonin reuptake pump (SERT) or serotonin 2A receptors (5HT2ARs). This could result in diminished effects or benefits of MDMA even after SSRIs have left the body.

Muted Healing After Stopping SSRIs with MDMA

For example, In a recent post-hoc analysis of phase II data, it was found that 63.6% of persons not taking antidepressants at the time of trial enrollment no longer met PTSD criteria at the primary endpoint compared with 25% in the group that had to taper to be included in the trials. Clinical trials to date have required persons to be off of antidepressants for at least two weeks, this appears to not be long enough based on this analysis in which persons were off an average of ~25 days prior to administration of MDMA. Given it takes SSRIs 4-6 weeks to take full effects, it may be reasonable to consider this a minimum time from between abstaining from SSRI use prior to use of MDMA for therapeutic purposes. Antidepressants like SSRIs often require long and gradual dose reduction for successful tapering and stopping of use. 

Serotonin Syndrome with SSRIs and MDMA?

There is likely minimal risks of serotonin syndrome when combining MDMA and SSRIs, although it would still be considered a contraindicated combination because the effects of MDMA are so largely blunted that attempting (therapeutic) use makes little sense. Taking large doses of MDMA, abruptly stopping antidepressants in an attempt to get MDMA to work, or mixing SSRIs with ‘ecstasy’ are not good strategies and may be harmful. Now, check out the 'research corner' video that dives into the research behind the interaction post-antidepressant use with MDMA!

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