Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review

This review (2022) explores the drug-drug interactions between MDMA or psilocybin and conventional psychiatric medications. Publications of studies describe interactions between MDMA (n=24) or psilocybin (n=5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and several classes of antidepressants.

Abstract

“Rationale & objectives:  ± 3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin are currently moving through the US Food and Drug Administration’s phased drug development process for psychiatric treatment indications: posttraumatic stress disorder and depression, respectively. The current standard of care for these disorders involves treatment with psychiatric medications (e.g., selective serotonin reuptake inhibitors), so it will be important to understand drug-drug interactions between MDMA or psilocybin and psychiatric medications.

Methods: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the MEDLINE database via PubMed for publications of human studies in English spanning between the first synthesis of psilocybin (1958) and December 2020. We used 163 search terms containing 22 psychiatric medication classes, 135 specific psychiatric medications, and 6 terms describing MDMA or psilocybin.

Results: Forty publications were included in our systematic review: 26 reporting outcomes from randomized controlled studies with healthy adults, 3 epidemiologic studies, and 11 case reports. Publications of studies describe interactions between MDMA (N = 24) or psilocybin (N = 5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and several classes of antidepressants. We focus our results on pharmacodynamic, physiological, and subjective outcomes of drug-drug interactions.

Conclusions: As MDMA and psilocybin continue to move through the FDA drug development process, this systematic review offers a compilation of existing research on psychiatric drug-drug interactions with MDMA or psilocybin.”

Authors: Aryan Sarparast, Kelan Thomas, Benjamin Malcolm & Christopher S. Stauffer

Summary

MDMA and psilocybin are currently moving through the US Food and Drug Administration’s phased drug development process for psychiatric treatment indications.

We searched the MEDLINE database for human studies on psilocybin between 1958 and 2020 and found 6 studies describing MDMA or psilocybin.

We reviewed forty publications on drug interactions between MDMA and psilocybin, including 26 randomized controlled studies with healthy adults, 3 epidemiologic studies, and 11 case reports.

This article offers a compilation of existing research on MDMA interactions.

Psilocybin, stress disorders, post-traumatic depression, serotonin uptake inhibitors

Introduction

MDMA and psilocybin have been studied as augmentation to psychotherapy and are typically administered one to three times during a treatment course. However, the field of psychiatry has a limited understanding of their therapeutic use due to their Schedule I categorization. MDMA and psilocybin are Schedule I substances, but the FDA has granted Breakthrough Therapy designation to MDMA-assisted psychotherapy for Posttraumatic Stress Disorder (PTSD) and psilocybin-assisted psychotherapy for both Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD).

MDMA and Psilocybin have shown transdiagnostic therapeutic potential beyond PTSD and depression, and are frequently used in the treatment of anxiety disorders and substance use disorders.

MDMA

MDMA is a phenethylamine compound with psychostimulant effects. It promotes social engagement, openness, receptiveness to positive affect, heightened empathy, and increased disclosure of emotional content in dialogue.

MDMA reverses the action of monoamine transporters and competes with monoamines for sites on the vesicular monoamine transporter-2 (VMAT-2) in the brain, resulting in increased concentrations of intrasynaptic monoamines, predominantly serotonin (5-HT), to a lesser degree norepinephrine (NE), and to the least degree dopamine (DA). MDMA is metabolized by cytochrome P450 enzymes to produce inactive metabolites, including 4-hydroxy-3-methoxymethamphetamine (HMMA), cortisol, prolactin, and oxytocin. MDMA is also thought to lead to auto-inhibition of CYP2D6, resulting in nonlinear pharmacokinetics.

MDMA’s physiological effects include increased heart rate, blood pressure, temperature, pupil size, as well as adverse acute transient physical effects such as nausea, vomiting, bruxism, muscle aches, headache, sweating, fatigue, dizziness, and dry mouth. MDMA’s psychological effects include euphoria, anxiolysis, enhanced fear-extinction learning, and feelings of closeness or connectedness.

MDMA is often sold as “ecstasy” or “molly” and is often adulterated with other substances prior to sale. It is often coinested with other substances and involves situational risk factors such as heavy physical exertion, excessive heat, low water intake or water intoxication, and lack of screening for medical risk factors. In contrast to recreational use, clinical trials have involved carefully screened participants ingesting laboratory-grade MDMA at precise dosages. There has been only one reported serious adverse reaction to MDMA within a clinical trial setting.

Psilocybin

Psilocybin is a psychoactive tryptamine that naturally occurs in over 200 species of mushrooms. Its effects are primarily related to 5-HT2A receptor agonism, though it also binds to other 5-HT receptor subtypes.

Psilocybin is rapidly dephosphorylated upon ingestion to its active metabolite, psilocin, which lacks clinically significant inhibitor activity at monoamine reuptake pumps. Psilocin metabolism primarily occurs via UDP-glucuronyltransferase enzymes, UGT1A9 and UGT1A10.

Psilocybin causes mild increases in blood pressure and heart rate, headache, nausea, dizziness, and fatigue, and can elicit subjective experiences with mystical-type qualities. These experiences are correlated with diminished activity of the default mode network and long-term improvements in wellbeing, psychosocial function, and symptoms of clinical illness.

Psilocybin is a psychedelic drug used in clinical trials and is also used for personal use as “magic mushrooms”. It has a wide margin of safety and has been associated with very few reports of cardiovascular events.

Drug interaction potential

MDMA and psilocybin may interact with medications that also modulate the serotonin system, including SSRIs, SNRIs, TCAs, MAOIs, mirtazapine, trazodone, lithium, buspirone, atypical antipsychotics, and others, and may decrease the subjective effects of MDMA or reduce the efficacy of MAP for PTSD. There are potential interactions between MDMA and psychiatric medications, including SNRIs, bupropion, and psychostimulants. Some medications may also be substrates, inhibitors, or inducers of drug-metabolizing enzymes, which could affect the metabolism of MDMA.

Objective of systematic review

Although reviews of drug-drug interactions with MDMA and psilocybin have been published, none have been systematic. Therefore, this systematic review summarizes all existing data.

Methods

This systematic review included meta-analyses, systematic reviews, randomized controlled trials (RCTs), retrospective studies, cross-sectional studies, case – control studies, cohort studies, and case reports. The PICOS framework was used to guide the methods of this review.

A list of psychiatric medications was compiled using the APA Textbook of Psychopharmacology, 5th Edition, Appendix for the psychiatric pharmacopoeia in the United States, Martindale: The Complete Drug Reference, and Department of Veterans Affairs and Department of Defense practice guidelines.

Search strategy

We searched the MEDLINE database via PubMed for publications in English between 1958 and 2020 involving psilocybin and MDMA. A total of 455 abstracts were found using 163 terms, including 22 psychopharmacology classes and 135 psychiatric medications.

Study selection

We screened abstracts for inclusion by two independent reviewers, and assessed the remaining full-text articles in detail. Ultimately, 40 articles were included in this systematic review, including 26 RCTs and 3 epidemiologic studies.

Percent change calculation

A formula was utilized to standardize comparison of outcome measures when ingestion of MDMA or psilocybin was preceded by ingestion of another drug versus preceded by placebo.

Results

This review includes 26 publications of RCTs and 3 epidemiologic studies. The results include primary outcome publications for 17 original RCTs along with 9 additional analyses of secondary or exploratory outcome measures using the same sample from a previously-published RCT.

All of the RCTs enrolled only healthy adults, had limited sample sizes, and investigated pharmacogenetic biomarkers, such as CYP2D6 genotype. Some trials also investigated psychiatric illness in self or first-degree relatives, and active substance use.

Adrenergic agents & MDMA

Four RCTs were conducted combining MDMA with four different adrenergic agents. These medications may be relevant clinically in the management of common transient effects of MDMA such as elevated blood pressure.

Hasler et al. (2009) found that pindolol (20 mg p.o.) reduced MDMA-induced positive basic mood, mania-like experience, and dreaminess, but had no effect on MDMA-induced changes in mean arterial pressure, body temperature, or adverse effects.

Carvedilol, an adrenoreceptor antagonist, attenuated the cardiostimulant and hyperthermic effects of MDMA without affecting the subjective effects. However, circulating epinephrine and NE levels were increased.

Clonidine reduced MDMA’s effects by decreasing the exocytotic release of NE, but did not affect body temperature, mydriasis, self-reported mood effects or adverse effects from MDMA.

Hysek et al. (2013) hypothesized that pretreatment with doxazosin would reduce MDMA-induced increases in blood pressure and positive mood. Doxazosin pretreatment attenuated these effects, but not adverse effects or mydriasis.

Antipsychotics & MDMA

Researchers combined MDMA with an antipsychotic to attenuate some of the stimulant-like effects. However, the combination led to reduced well-being, reduced “oceanic boundlessness”, and a higher rate of state anxiety.

Bupropion & MDMA

Schmid et al. (2015) studied the combination of bupropion XR and MDMA and found that bupropion attenuated the mood and cardiostimulant effects of MDMA, but did not affect any other significant cardiovascular, mydriatic, or hormonal changes compared to MDMA alone.

De Sousa Fernandes Perna et al. (2014) studied the effect of memantine pretreatment on MDMA-induced memory impairment and mood.

Psychostimulants & MDMA

Hysek et al. (2014b) conducted an RCT combining MDMA with methylphenidate. They found that the combination increased cardiovascular and adverse effects, and attenuated the effect of MDMA on “happy” affect recognition and mental concentration.

Serotonin reuptake inhibitors & MDMA

Researchers hypothesized that SSRIs could interact with MDMA by inhibiting SERT, and that SSRIs might also interact with cytochrome P450 enzymes. Three primary RCTs and four additional analyses of exploratory outcomes from the primary RCTs were published looking at the combination of MDMA and SSRIs.

Duloxetine, an SNRI, attenuates many of MDMA’s effects, including those on mood, well-being, extroversion, closeness, openness, and alterations in consciousness. This occurs despite increased MDMA plasma levels due to CYP2D6 inhibition by duloxetine.

Reboxetine & MDMA

Hysek et al. (2011) found that reboxetine (8 mg p.o.) reduced circulating NE and attenuated the cardiovascular stimulant effects of MDMA, and had no effect on other psychological parameters such as drug “liking” or “good drug effect”.

Antipsychotics & psilocybin

RCTs were conducted combining psilocybin with three antipsychotics: chlorpromazine, haloperidol, and risperidone. Risperidone reduced all parameters of the APZ-OAV scale and attenuated psilocybin-induced alterations in consciousness, including a reduction in dread of ego dissolution.

Serotonin agonists & psilocybin

We found only one RCT combining psilocybin with serotonin agonists, and it was found that buspirone attenuated psilocybin-induced visual perceptual changes. Ergotamine had no effect on psilocybin-induced subjective effects.

Serotonin reuptake inhibitors & psilocybin

To date, there has been only one RCT combining psilocybin with an SSRI. Escitalopram did not significantly attenuate ratings of altered states of consciousness from psilocybin, but did significantly attenuate subjective ratings of bad drug effects, fear, talkativeness, openness, anxiety, ineffability, and global adverse effects.

Epidemiologic studies

Cohen et al. (2021) conducted a post-marketing surveillance association study on 946 unique recreational ecstasy use reports from the FDA Adverse Event Reporting System (FAERS) database from 2000 – 2020. They found that several concomitant drug class ingestions were associated with an increased multivariate adjusted odds ratio of death.

A cross-sectional survey study of 216 adults who co-ingested ecstasy and a pharmaceutical drug within the previous 6 months found that 76% experienced euphoria, but had higher rates of adverse effects, including muscle rigidity, nystagmus, dizziness, headache, and profuse sweating.

Nayak et al. (2021) conducted an epidemiologic quantitative analysis of 96 first- or second-person accounts posted online involving co-ingestion of a psychedelic and a mood stabilizer. They found that 2 of the 6 reports of lithium plus psilocybin resulted in seizures.

Discussion

This systematic review identified forty publications involving 22 RCTs of MDMA and 4 RCTs of psilocybin administered with and without a psychiatric medication.

This review demonstrates that most studies on drug-drug interactions between psychiatric medications and MDMA pertain to MDMA, and there are only 2 studies on psilocybin that were published within the last decade. These studies are limited in their extrapolation to real world clinical settings.

Pharmacokinetic interactions—MDMA

MDMA’s pharmacokinetics are complex, involving several cytochrome P450 enzymes. Ritonavir and other strong pan-CYP inhibitors can cause significant toxicity, and MDMA has been shown to interact with several psychiatric medications.

Pharmacodynamic interactions—MDMA

MDMA acts as a substrate for SERT and NET, resulting in reverse transport and exocytotic release of 5HT and NE. Antidepressants inhibit SERT, NET, and DAT, preventing substrate binding.

Researchers conducted a series of clinical trials on MDMA and various monoamine reuptake blocking agents to ascertain the relative contributions of different monoamine systems to MDMA’s mechanism of action.

MDMA’s physiological and subjective effects were attenuated by monoamine reuptake inhibitors, even in instances of higher MDMA plasma levels by means of CYP2D6 inhibition. Exceptions to this trend included the combined NET and DAT inhibitor, bupropion, which prolonged the subjective effects and heightened the positive mood effects of MDMA. While no serious adverse effects were observed in clinical trial settings, combining SSRIs or bupropion with MDMA in uncontrolled settings may increase the risk of seizures, stimulant toxicity, or serotonin syndrome.

MDMA and monoamine reuptake inhibitors may be combined without increasing the risk of serotonin syndrome. This is because the inhibition of monoamine transporters by most antidepressants negates MDMA’s reversal of monoamine transporters.

SSRI and SNRI use in conjunction with MDMA can result in attenuation of subjective effects and reduced MAP treatment efficacy, but discontinuation of psychiatric medications poses a risk of antidepressant discontinuation syndromes or relapse of psychiatric symptoms.

Stimulants like MDMA induce exocytotic release of monoamines via DAT and NET, while methylphenidate only inhibits DAT and NET reuptake. The combination of methylphenidate and MDMA results in synergistic effects.

Adrenergic agents reduce MDMA-induced cardiostimulant and hyperthermic effects without influencing MDMA’s psychological effects. However, doxazosin attenuates MDMA’s mood heightening effects and increases MDMA-induced tachycardia.

Pharmacogenetics & MDMA

CYP2D6 poor metabolizers reaching an average maximum concentration of 19% higher and an initial drug exposure of 25% higher than extensive metabolizers reaching only *1 and *2 alleles reached a more rapid onset of subjective effects and elevated blood pressure.

Pharmacokinetic interactions—psilocybin

Psilocybin is less likely to cause drug interactions than MDMA because its metabolism involves UGT1A10 and UGT1A9. However, there is no evidence to confirm this hypothesis beyond shared metabolism.

Pharmacodynamic interactions—psilocybin

Research into drug interactions with psilocybin is sparse yet paints an interesting picture of its mechanism. It is hypothesized that SERT blockers, such as sertraline, would reproduce similar findings as Becker et al. (2021), while 5HT2A blockade would attenuate psilocybin’s effects, both subjectively and physiologically.

Trends in case studies

We identified 11 case study manuscripts that involve the recreational ingestion of ecstasy and provide helpful insights on the implications of co-ingestion in the context of illicit use. These case studies reveal a trend that the highest rates of morbidity occurred from the combination of MDMA with MAOIs. Combining SSRIs with ecstasy may attenuate the effects of MDMA, but may also drive individuals to take higher doses to achieve effects.

Limitations

This review focuses on MDMA and psilocybin, and does not include literature on other psychedelic substances, ketamine, or repeated dosing of MDMA or psilocybin. It is also limited to psychiatric medications, and does not include information on other forms of collective knowledge.

Considerations for future research

Modern research protocols for MAP and PAP have excluded participants taking psychiatric medications or discontinued psychiatric medications prior to administration of MDMA or psilocybin. Additional clinical research is needed to develop optimal strategic approaches for patients who may benefit from MAP or PAP, but are currently prescribed psychiatric medications.

Certain groups were excluded from the clinical trial samples described in this systematic review, including individuals with particular psychiatric symptoms or medical illnesses. Additionally, none of the included studies reported on the race or ethnicity of participants nor commented on the inclusion of sexual or gender minorities.

Benzodiazepines have been suggested by guidelines to address extremely challenging psychedelic experiences that don’t respond to behavioral interventions, but there are no studies on the concomitant use of benzodiazepines with MDMA nor psilocybin. Atypical antipsychotics may also be an appropriate approach to manage psychological distress related to MDMA or psilocybin, but more research is needed.

The mechanism in which MAP or PAP lead to psychiatric recovery remains unclear as does the mechanism in which psychiatric drugs affect MAP or PAP outcomes. However, a sub-analysis of pooled Phase 2 MAP studies demonstrated that participants who recently tapered off of prescription antidepressants had higher PTSD symptom burden.

Conclusions

As MDMA and psilocybin continue to move through the FDA drug development process, there are clear acute pharmacokinetic and pharmacodynamic interactions between these substances and many common psychiatric medications.