Aryan Sarparast, M.D.
Latest posts by Aryan Sarparast, M.D. (see all)
Chris Stauffer, M.D.
Latest posts by Chris Stauffer, M.D. (see all)
Kelan Thomas, PharmD, MS, BCPS, BCPP
Benjamin Malcolm, PharmD, MPH, BCPP
Latest posts by Benjamin Malcolm, PharmD, MPH, BCPP (see all)

Introduction

If MDMA or psilocybin is approved by the FDA for treatment of PTSD and depression, then what will happen to individuals prescribed common psychiatric medications like antidepressants, antipsychotics, and mood stabilizers?

If MDMA or psilocybin is approved by the FDA for treatment of PTSD and depression, then what will happen to individuals prescribed common psychiatric medications like antidepressants, antipsychotics, and mood stabilizers? This was the question that led to our review, which looked at how psychiatric medications may interact with MDMA or psilocybin. We felt this was important to understand the efficacy and safety of various medication combinations, but also to encourage future clinical trials to investigate drug-drug interactions. Currently, most psychedelic clinical trials require discontinuation of psychiatric medications, which may pose unique risks, like acute psychiatric decline and medication discontinuation syndrome symptoms.

Join Chacruna’s workshop Reducing the Impact of Bias on Therapy, Education, & Training

Methods

We cast a wide net (163 search terms, including 135 specific psychiatric medications) to identify all the published human studies that involve co-administration of a psychiatric medication and MDMA or psilocybin since 1958, when psilocybin was first synthesized in a lab. These were evaluated according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to determine which studies to include in the review.

Results

We included 26 randomized controlled studies (RCTs) describing interactions between psychiatric medications and three large population-based epidemiologic studies. There were also 11 case studies described in Supplemental Materials. Several highlights emerged from the research to date. First, serotonin syndrome from co-ingestion of psilocybin and a psychiatric medication has not been documented in these studies and is not considered a major clinical concern. Serotonin syndrome from MDMA and a psychiatric medication is a rare, but potentially lethal risk that occurred with monoamine oxidase inhibitors (MAOIs) like phenelzine and resulted in case reports of death. Based on self-reported trip accounts that are considered “low quality evidence,” there may be a risk of seizures when lithium is combined with psilocybin (Nayak et al., 2021). Also, nearly all of the studies were with MDMA (N=24), which demonstrated a clear pattern of serotonin reuptake inhibitors (SSRIs) blunting the effects of MDMA. The one RCT of psilocybin plus an SSRI (Becker et al., 2022) demonstrated the psychedelic effects of psilocybin were not blunted, but SSRI pre-treatment was only two weeks, and this is likely an insufficient duration to cause receptor homeostatic changes that could blunt psilocybin effects. Lastly, MDMA has a more complex metabolism prone to drug-drug interactions that can increase plasma levels of MDMA while, at the same time, blunting its physical and psychological effects. 

Limitations

There are two major limitations of the current evidence. First, all the studies were with young healthy individuals, potentially limiting the generalizability to participants with mental or physical illnesses. Second, all drug-drug interaction studies administered a psychiatric medication for only a brief period of time, ranging from a single dose, hours prior, to multiple daily doses for two weeks prior to administration of MDMA or psilocybin. This is problematic since certain psychiatric medications like antidepressants can take six or more weeks to take full effect and the current evidence has not evaluated the effect of long-term psychiatric medication use on psychedelic efficacy.

Conclusion

This systematic review demonstrates that the combination of psilocybin with most psychiatric medications confers minimal safety risks, with the exception of lithium, which may cause seizures. It is also clear that MDMA’s risk of serotonin toxicity is exacerbated in combination with MAOIs and that SSRIs blunt the effects of MDMA, even though some SSRIs, like fluoxetine and paroxetine, increase plasma levels of MDMA.

Discover the Indigenous Reciprocity Initiative of the Americas

This systematic review demonstrates that the combination of psilocybin with most psychiatric medications confers minimal safety risks, with the exception of lithium, which may cause seizures. It is also clear that MDMA’s risk of serotonin toxicity is exacerbated in combination with MAOIs and that SSRIs blunt the effects of MDMA, even though some SSRIs, like fluoxetine and paroxetine, increase plasma levels of MDMA.

We urge researchers to investigate co-administration of psilocybin with SSRIs after an adequate duration for full antidepressant efficacy of the SSRI (e.g., >2 months), first and foremost. We also urge researchers to continue investigating how psychiatric medications and MDMA or psilocybin interact when treating participants with mental illness.

Art by Trey Brasher.

References

Becker A. M., Holze F., Grandinetti T., Klaiber A., Toedtli V. E., Kolaczynska K. E., … & Liechti. (2022). Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double‐blind, placebo‐controlled, crossover study in healthy subjects. Clinical Pharmacology and Therapeutics. 111(4), 886–895. doi:10.1002/cpt.2487

Nayak S. M., Gukasyan N., Barrett F. S., Erowid E., Erowid F., Griffiths R. R. (2021). Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports. Pharmacopsychiatry. 54(05):240–245. doi: 10.1055/a-1524-2794

Sarparast, A., Thomas, K., Malcolm, B., Stauffer C. S. (2022). Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review. Psychopharmacology, 239, 1945–1976. doi:10.1007/s00213-022-06083-y

Note:

Dr.’s Aryan Sarparast, Chris Stauffer, Kelan Thomas, and Benjamin Malcolm, recently published the first systematic review of drug interactions between psychiatric medications and psychedelics: “Drug-drug interactions between psychiatric medications and MDMA or psilocybin: A systematic review.” In this article, the authors offer a synopsis of their systematic review.


Take a minute and buy our books and goods:


Did you enjoy reading this article?

Please support Chacruna's work by donating to us. We are an independent organization and we offer free education and advocacy for psychedelic plant medicines. We are a team of dedicated volunteers!

Can you help Chacruna advance cultural understanding around these substances?

Become a Chacruna Member

To make a direct donation click the button below:



Wednesday, June 9th, 2021 from 12-1:30pm PST REGISTER FOR THIS EVENT HERE There is growing enthusiasm in Jewish communities about possible ancient use and modern applications of plant medicine in Jewish spiritual development.  Psychedelic Judaism introduce new potential modes of  healing...