This review (2022) assessed the literature on the basic and clinical neuroscience of the interactions between the class of antidepressants known as SSRIs and MDMA. SSRIs could dampen the therapeutic effects of MDMA-assisted therapy for PTSD. Further research is needed to elucidate the biological mechanisms underlying these interactions.
Abstract
“Background: Among the renewed applications of psychedelic medicines in psychiatry, 3,4-methylenedioxymethamphetamine (MDMA)–assisted therapy for posttraumatic stress disorder (PTSD) has demonstrated the most promise in early small-scale studies. Recent exploratory analyses from prior clinical trials of MDMA-assisted therapy for PTSD have suggested that recent use of selective serotonin reuptake inhibitors (SSRIs)—the only medication class with United States Food and Drug Administration (FDA) approval to treat PTSD—can significantly dampen the efficacy of this novel therapy. Although psychedelic medicines are not yet FDA approved, MDMA is very likely to be the first to achieve FDA approval—perhaps within the next 2 years. Given this timeline, the field would benefit from more knowledge about potential interactions between this novel therapy and our current treatments.
Methods: This brief report reviews selected literature in the basic and clinical neurosciences relevant to the interaction of SSRIs and MDMA.
Findings: The possibility that SSRI use could dampen future responses to MDMA-assisted therapy for PTSD raises many important questions about the biological mechanisms as well as ethical implications around the most appropriate way to counsel patients. In this brief report, we compare the evidence for SSRIs and MDMA-assisted therapy in the treatment of PTSD and discuss what is known about the neurobiological interactions between these 2 medicines.
Conclusions: There is strong neurobiological plausibility for the hypothesis that chronic SSRI use dampens response to MDMA-assisted therapy, although current knowledge in the field is limited and primarily relates to acute pharmacodynamic interactions. Our commentary highlights the urgent need for future work dedicated to addressing this important clinical topic.”
Authors: Colin Price, Allison Feduccia & Katrina DeBonis
Summary
Recent studies suggest that SSRIs can significantly dampen the efficacy of MDMA-assisted therapy for posttraumatic stress disorder, and more knowledge about potential interactions between this novel therapy and our current treatments would be helpful.
This brief report reviews the evidence for SSRIs and MDMA in the treatment of PTSD and discusses the possible neurobiological interactions between these 2 medicines.
Chronic SSRI use may dampen response to MDMA-assisted therapy. Future research is needed to address this important clinical topic.
MDMA-assisted therapy for PTSD may be effective.
(JClinPsychopharmacol2022;42: 464 – 469)
The treatment of posttraumatic stress disorder (PTSD) has long been an area of weakness in the field of psychiatry. The current evidence-based treatments for PTSD include medications and trauma-focused psychotherapies, but the treatments are insufficient to address the burden of suffering and disability for most people with PTSD.
The FDA has designated 3,4-methylenedioxymethamphetamine (MDMA) – assisted therapy for PTSD as a “breakthrough therapy” based on impressive results from phase 2 studies. There has been only 1 phase 3 trial of MDMA-assisted therapy in patients with severe PTSD. The large effect size seen in this positive study has bolstered hope for this novel therapy, but questions remain about how this therapy may interact with current first-line medication treatments for PTSD.
MDMA-assisted therapy for PTSD is a safe, well-tolerated, and effective intervention for chronic PTSD. It works by reversing monoamine transporters and increasing serotonin and dopamine levels.
To survey the clinical evidence of MDMA-assisted psychotherapy for PTSD, we searched for registered clinical trials on ClinicalTrials.gov using the diagnosis term “PTSD” and additional term “MDMA”, along with synonyms. We found 11 completed studies, 2 that were terminated, and 1 that was withdrawn before recruitment began.
A pooled analysis of 6 phase 2 studies showed that participants receiving MDMA had significantly greater improvement on the Clinician Administered PTSD Scale (CAPS)-IV than participants receiving placebo, with a large between-group Cohen d effect size of 0.8. A recent meta-analysis found a nearly 3-fold higher chance of remission in the MDMA group. Mitchell and colleagues demonstrated significant improvement in PTSD symptoms with MDMA-assisted therapy in a phase 3 study. The participants had chronic PTSD with significant symptom burden, and 67% achieved remission compared with 32% in the placebo group.
3,4-METHYLENEDIOXYMETHAMPHETAMINE– ASSISTED THERAPY VERSUS SSRIS FOR PTSD
MDMA-assisted therapy is far more effective than current pharmacotherapy for PTSD, with effect sizes 2 to 3 times larger than for current pharmacotherapies. Participants who had previously taken SSRIs were also more likely to achieve remission with MDMA-assisted therapy. MDMA-assisted therapy is likely at least as effective as SSRIs in the treatment of PTSD, and may be even more effective, given that it requires fewer medication administrations.
CURRENT SSRI USE AND MDMA
Current SSRI use can significantly dampen or abolish the subjective effects of MDMA and serotonergic hallucinogens, although this was not always observed. Controlled studies beginning in the 2000s began to shed further light on this phenomenon by examining the impact of SSRI and MDMA coadministration in healthy controls. Animal models suggest that blockage of the serotonin reuptake transporter (SERT) by SSRIs attenuates MDMA’s effects, and preserves serotonin metabolite concentrations and SERT binding that is normally depleted by MDMA after 1week.
Participants who were required to taper off all antidepressants before entering phase 2 MDMA assisted therapy trials had a significantly reduced response to the active intervention.
Feduccia and colleagues36 examined the impact of recent antidepressant use among participants in four phase 2 studies of MDMA for PTSD. They could not draw any conclusions regarding the effects of specific subclasses of antidepressants.
Participants who did not have to taper an antidepressant showed a significantly greater response to the intervention, with larger reductions in CAPS-IV and depression severity scores and higher rates of PTSD remission compared with the taper group.
The authors hypothesized that the decreased efficacy of MDMA-assisted therapy in the taper group may be related to neurobiological changes associated with long-term antidepressant use, and that prior use of antidepressants may have been correlated with comorbidities, such as anxiety and substance use disorders.
NEUROBIOLOGICAL CHANGES ASSOCIATED WITH ANTIDEPRESSANT USE
A large body of research has examined the effect of antidepressant administration on the expression of neural proteins that play a role in monoamine signaling. The results suggest that SSRIs may cause desensitization of 5-HT1A autoreceptors and changes in expression patterns of 5-HT1 and 5-HT2 receptors.
Changes in SERT and 5-HT receptor expression may also help explain the phenomenon of antidepressant discontinuation syndrome, which can be challenging to detect because of the significant symptom overlap with depression itself.
Recent observations suggest that tapering from antidepressants is associated with reduced efficacy of MDMA-assisted therapy, and that this may be explained by decreased densities of SERT and 5-HT receptors after SSRI use.
CONCLUSIONS AND FUTURE DIRECTIONS
SSRI use may interfere with MDMA response, and evidence of a diminished physiologic and clinical response was present in the exploratory pooled analyses of phase 2 data of MDMA-assisted therapy for PTSD. Further research is needed to better understand these interactions.
Patients will increasingly turn to physicians for guidance on treatment options for PTSD, and they must be able to communicate their most up-to-date understanding of this complicated issue, including potential risks of antidepressants reducing the efficacy of MDMA-assisted therapy.
People experiencing symptoms of PTSD may soon be able to receive more effective treatments, depending on how current first-line treatments interact with MDMA-assisted therapy.