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.
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.
Papers cited by this study that are also in Blossom
Baggot, M. J., Kirkpatrick, M. G., Bedi, G. et al. · Journal of Psychopharmacology (2015)
Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S. et al. · Journal of Psychopharmacology (2016)
Barrett, F. S., Griffiths, R. R. · Current Topics in Behavioral Neurosciences (2017)
Becker, A. M., Holze, F., Grandinett, T. et al. · Clinical Pharmacology and Therapeutics (2021)
Sarparast and colleagues situate this review within a renewed clinical interest in MDMA and psilocybin as adjuncts to psychotherapy for disorders such as post‑traumatic stress disorder and major depressive disorder. Both compounds differ from typical psychiatric medications in being administered only a few times during a treatment course and have advanced in the US FDA pipeline (MDMA with Breakthrough Therapy designation for PTSD; psilocybin for depression). Because current standard care for these indications frequently involves ongoing use of psychiatric medications and because MDMA and psilocybin both modulate serotonergic (and in MDMA's case noradrenergic and dopaminergic) systems, there is a plausible risk of pharmacokinetic and pharmacodynamic drug‑drug interactions that could alter safety, subjective effects, or therapeutic efficacy. This paper aims to systematically summarise human data on interactions between psychiatric medications and either MDMA or psilocybin. The stated objective was to compile evidence on pharmacokinetic measures (for example plasma drug and metabolite levels), physiological outcomes (for example vital signs, circulating catecholamines), and subjective effects when MDMA or psilocybin are co‑administered with drugs prescribed in psychiatry. The authors emphasise that prior reviews of MDMA interactions were not systematic and that no prior systematic review addressed psilocybin drug‑drug interactions, motivating the present work.
The researchers conducted a systematic review according to PRISMA guidelines and registered the protocol with PROSPERO (CRD42021233519). MEDLINE (via PubMed) was searched for English‑language human studies from 1958 through December 2020. The search strategy comprised 163 Title/Abstract terms: 22 pharmacologic class terms, 135 specific psychiatric medication terms, and six terms to capture MDMA/psilocybin. The PICOS framework specified participants as people exposed to MDMA or psilocybin together with a psychiatric medication; comparisons were typically MDMA or psilocybin with versus without the psychiatric drug; outcomes included pharmacokinetic, physiological and subjective measures; and eligible study designs were broad (RCTs, observational studies, case reports, reviews and meta‑analyses). Screening was performed by two independent reviewers with consensus decisions for disagreements; hand‑searching added 12 articles not retrieved by the database query. Ultimately 40 publications met inclusion: 26 randomized controlled trials (RCTs), 3 epidemiologic studies, and 11 case reports (the latter placed in supplemental materials). The authors standardised reported outcome differences using a percentage‑change formula to compare MDMA/psilocybin plus medication versus MDMA/psilocybin plus placebo. Most RCTs enrolled healthy adult volunteers, used single or short courses of the psychiatric medication (usually acute pretreatment or up to 14 days), had small samples (range 8–23 participants), and applied common exclusions such as pregnancy, age limits, extremes of BMI, psychiatric illness in self or first‑degree relatives, and active substance use. Some trials included pharmacogenetic measures such as CYP2D6 metaboliser status. The review synthesises findings by drug class and by the two index psychedelic drugs, integrating pharmacokinetic, physiological and subjective outcomes reported in the trials and epidemiologic studies.
The systematic search yielded 40 included publications: 26 RCTs, 3 epidemiologic studies (a post‑marketing association analysis, a cross‑sectional survey, and a quantitative analysis of online reports), and 11 case reports. Collective clinical trial enrolment exceeded 200 participants but individual RCTs were small and limited to healthy volunteers. RCTs examined MDMA combinations with SSRIs (citalopram, fluoxetine, paroxetine), SNRIs (duloxetine), NET inhibitors (reboxetine), bupropion, methylphenidate, haloperidol, memantine, and several adrenergic agents (carvedilol, pindolol, clonidine, doxazosin). Psilocybin RCTs studied co‑administration with chlorpromazine, haloperidol, risperidone, buspirone, ergotamine, and one trial with escitalopram. Adrenergic agents with MDMA: Pindolol (20 mg p.o.) given one hour before MDMA (1.6 mg/kg p.o.) reduced a small number of affective subscales and lowered MDMA peak heart rate but did not change mean arterial pressure, temperature, or neurocognitive impairment. Carvedilol (50 mg p.o.) plus MDMA (125 mg p.o.) markedly attenuated cardiostimulant and hyperthermic responses without significantly altering MDMA's subjective effects; circulating epinephrine and norepinephrine paradoxically rose, and MDMA/MDA plasma levels were unchanged. Clonidine (150 µg p.o.) reduced MDMA‑induced increases in circulating norepinephrine and blood pressure, but those reductions mirrored clonidine’s effects alone and did not alter temperature, mydriasis, mood, or adverse effects. Doxazosin (8 mg p.o. ~16 h prior) attenuated mean arterial pressure increases and mood‑heightening ratings yet enhanced tachycardia and circulating norepinephrine. Antipsychotics and other agents with MDMA: Intravenous haloperidol (1.4 mg i.v.) combined with MDMA (1.5 mg/kg p.o.) did not change cardiovascular or thermogenic effects but shifted MDMA’s psychological profile from pleasurable to dysphoric, reducing well‑being and “oceanic boundlessness” and increasing state anxiety. Bupropion XR (titrated to 300 mg) with MDMA (125 mg) moderately reduced norepinephrine and attenuated heart‑rate elevation but prolonged MDMA’s positive mood effects; pharmacokinetic changes included increased MDMA plasma and reduced metabolites (DHMA, HMMA, MDA), consistent with inhibition of CYP2D6 and CYP2B6 and reciprocal increases in bupropion levels. Memantine (20 mg) did not alter MDMA (75 mg) effects on memory or mood. Methylphenidate co‑administration delayed MDMA’s time to maximum concentration without changing MDMA or methylphenidate half‑lives. Serotonin reuptake inhibitors with MDMA: Acute pretreatment with SSRIs (citalopram, fluoxetine, paroxetine) attenuated MDMA’s subjective effects by approximately 30–80% and reduced physiological effects modestly (about 6–14% for most SSRIs; paroxetine showed larger physiological attenuation of ~40–60%). Fluoxetine and paroxetine, strong CYP2D6 inhibitors, increased MDMA plasma concentrations despite the blunted subjective response. The SNRI duloxetine markedly reduced circulating norepinephrine, heart rate, blood pressure, pupillary responses and many subjective measures (well‑being, extroversion, closeness, openness, alterations of consciousness); these reductions occurred despite higher MDMA plasma levels due to CYP2D6 inhibition. Reboxetine (8 mg) reduced norepinephrine, attenuated cardiovascular stimulation and several psychostimulant subjective effects, while not affecting drug “liking”; reboxetine also increased MDMA plasma, consistent with CYP2D6 inhibition. Psilocybin drug‑drug interactions: Antagonism at 5‑HT2A receptors attenuated psilocybin’s subjective and perceptual effects. Chlorpromazine (50 mg p.o.) reduced mydriasis and visual changes induced by psilocybin (0.2 mg/kg). Risperidone (0.5–1 mg p.o.) reduced multiple dimensions of the Altered States of Consciousness scale and lessened psilocybin‑induced reaction‑time delays; haloperidol increased dread of ego dissolution without attenuating perceptual changes. Buspirone (20 mg) reduced “visionary restructuralization” on the 5D‑ASC, while ergotamine (3 mg) had no effect. Escitalopram titrated to 20 mg over 14 days and given 2 hours before psilocybin (25 mg) did not significantly reduce ratings of altered states but did reduce several adverse subjective measures (bad drug effects, fear, anxiety, global adverse effects) and attenuated physiological responses (blood pressure, pupil dilation); escitalopram did not alter psilocin levels or QTc. Epidemiologic and case evidence: A cross‑sectional survey (n=216) of ecstasy users who co‑ingested pharmaceuticals found that 76% of those using antidepressants still reported euphoria but experienced higher rates of adverse effects (for example muscle rigidity, nystagmus, dizziness, headache, profuse sweating). A quantitative analysis of 96 online reports involving psychedelics plus mood stabilisers found two of six lithium‑plus‑psilocybin reports described seizures; lamotrigine reports (n=10) showed no seizures, although the authors judged this evidence low quality due to selection and verification biases. Case reports reviewed in the supplement highlighted severe morbidity and fatalities most commonly when MDMA was combined with MAO inhibitors, with presentations consistent with unrecognised serotonin‑toxicity syndromes.
Sarparast and colleagues interpret the literature as demonstrating clear, clinically relevant interactions between psychiatric medications and MDMA or psilocybin, while emphasising important limitations. The available evidence predominantly concerns MDMA; only a small number of studies addressed psilocybin drug‑drug interactions. Most clinical trials enrolled young, healthy volunteers who received acute or short‑term psychiatric medication exposure rather than chronic treatment, limiting generalisability to typical clinical populations who take medications for months or years. The authors note that some trials used atypical routes or dosing regimens (for example intravenous administration) and imposed exclusion criteria that further constrain extrapolation. Mechanistically, MDMA is susceptible to pharmacokinetic interactions via CYP2D6 (and to a lesser extent CYP2B6, CYP3A4 and others), and many psychiatric medications inhibit CYP2D6; several trials showed increased MDMA plasma concentrations with concomitant CYP2D6 inhibitors. Despite higher MDMA plasma levels, monoamine reuptake inhibitors (SSRIs, SNRIs, NRIs) frequently attenuated MDMA’s subjective and physiological effects, a pattern the authors attribute to pharmacodynamic competition at monoamine transporters preventing MDMA‑induced monoamine efflux. MAO inhibitors were highlighted as a distinct high‑risk class: case reports associate MAOI plus MDMA with severe serotonin toxicity and deaths. Stimulant co‑ingestion may potentiate cardiostimulant and adverse effects, whereas dopamine D2 antagonists altered the subjective profile toward dysphoria without changing cardiovascular measures. For psilocybin, the authors report that 5‑HT2A antagonists consistently attenuate subjective effects, while SERT blockade (escitalopram) did not abolish psychedelic experiences and actually reduced distress and physiological responses, consistent with psilocybin acting primarily via direct serotonin‑receptor agonism and being less dependent on transporter‑mediated increases in synaptic serotonin. The authors acknowledge limitations of the evidence base: small sample sizes, healthy volunteer samples, brief medication exposure, limited studies on benzodiazepines and atypical antipsychotics, sparse data on clinically relevant populations and on chronic medication use, lack of participant diversity reporting, and low‑quality signals from recreational use reports. They call for targeted research to guide clinical decision‑making, including studies of tapering strategies, safety in medically ill populations (for example with hepatic impairment), interactions with commonly used crisis medications such as benzodiazepines or antipsychotics, and investigations that include more diverse samples and account for hormonal influences on metabolism. The authors also highlight pharmacogenetic findings: CYP2D6 poor metaboliser status is associated with higher MDMA exposure and greater physiological and subjective responses, suggesting the value of genotypic or phenotypic considerations in future trials and clinical practice.
This systematic review compiles existing human data on interactions between psychiatric medications and MDMA or psilocybin, finding demonstrable pharmacokinetic and pharmacodynamic interactions that alter physiological and subjective responses. The literature is far richer for MDMA than for psilocybin. Because most controlled studies involved small samples of healthy volunteers with short‑term medication exposure, the findings are not directly applicable to typical clinical populations receiving chronic psychiatric medications. The authors conclude that additional clinical research is needed to inform safe and effective approaches to managing psychiatric medications in the context of MDMA‑assisted or psilocybin‑assisted psychotherapy.
Preliminary evidence for the use of ± 3,4-methylenedioxymethamphetamine (MDMA)) and psilocybin; Castro Santos and Gama Marques 2021;in the treatment of psychiatric disorders has been promising. Both drugs have been studied as augmentation to psychotherapy and are typically only administered one to three times during a treatment course. This represents a departure from traditional pharmacological treatment in psychiatry. MDMA and psilocybin were researched as clinical interventions beginning in the 1970s and 1960s, respectively. However, the field of psychiatry has a limited understanding of their therapeutic use due to their Schedule I categorization (i.e., drugs determined to lack safety even under medical supervision, have no currently accepted medical use, and are deemed to have a high potential for abuse). Despite MDMA and psilocybin's categorization as Schedule I substances, the US Food and Drug Administration (FDA) has more recently granted Breakthrough Therapy designation to MDMA-assisted psychotherapy (MAP) for Posttraumatic Stress Disorder (PTSD) as well as psilocybin-assisted psychotherapy (PAP) for both Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD). Breakthrough Therapy designation is a process designed to expedite the development and review of drugs intended to treat a serious or life-threatening condition for which preliminary clinical evidence suggests substantial improvement over available options. MAP and PAP are currently being studied in Phase III and Phase II manufacturer-sponsored clinical trials, respectively. Upon successful completion of Phase III trials, a manufacturer may submit a New Drug Application asking the FDA to consider a drug for marketing approval. MAP and PAP have shown transdiagnostic therapeutic potential beyond PTSD and depression, including as treatments for anxiety disorders) and substance use disorders. All of the above-mentioned indications are frequently treated with psychiatric medications, such as: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, psychostimulants, and antidepressants. In fact, a combination of multiple psychiatric medications (i.e., polypharmacy) is common in the clinical management of MDDand PTSD. With the number of clinical trials of MAP and PAP increasing exponentially, and potential FDA approval in the pipeline, it is important to compile what we know about the potential drug-drug interactions between psychiatric medications and MDMA or psilocybin.
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, leading to its characterization as an "entactogen-empathogen." These effects distinguish MDMA from "classic psychedelics." The active dose range of MDMA in studies is 75-225 mg administered orally (Multidisciplinary Association for Psychedelic Studies 2021). The onset of pharmacological effects usually occurs 30-60 min after ingestion, with peak effects appearing 75-120 min after ingestion and a total duration of 3-6 h (Multidisciplinary Association for Psychedelic Studies 2021). The elimination half-life is 8-9 h. MDMA reverses the action of monoamine transporters, which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). MDMA also competes with monoamines for sites on the vesicular monoamine transporter-2 (VMAT-2), suggesting that MDMA leads to the displacement of monoamines from presynaptic vesicular stores as well. Together, transporter reversal and emptying of vesicular stores results in increased concentrations of intrasynaptic monoamines: predominantly serotonin (5-HT), to a lesser degree norepinephrine (NE), and to the least degree dopamine (DA). Additionally, MDMA displays some binding affinity as an agonist at 5-HT 1A , 5-HT 2A , 5-HT 2B and 5-HT 2C serotonin receptors; α 1 -, α 2A -and β-adrenergic receptors; D 1 -and D 2 -dopamine receptors; M 1 -and M 2 -muscarinic receptors; H 1 -histamine receptor; and minimally at the human trace amine-associated receptor 1 (TAAR1). The S( +)-MDMA enantiomer has a stronger binding affinity to radiolabeled brain serotonin and dopamine binding sites than R(-)-MDMA). Recent MAP clinical trials have used a racemic mixture of MDMA. MDMA's downstream effects include increased secretion of arginine vasopressin, adrenocorticotropic hormone (ACTH), cortisol, prolactin, and oxytocin. MDMA is metabolized by cytochrome P450 enzymes (Table), primarily CYP2D6 followed by catechol-O-methyltransferase to its main inactive metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA). MDMA also has a minor metabolism pathway via CYP3A4, CYP1A2, CYP2B6, and CYP2C19 to its only active metabolite 3,4-methylenedioxyamphetamine (MDA). MDMA is also thought to lead to auto-inhibition of CYP2D6, resulting in nonlinear pharmacokinetics. MDMA and its metabolites are primarily excreted as conjugates, such as sulfates and glucuronides. Common physiological effects of MDMA 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 (Multidisciplinary Association for Psychedelic Studies 2021). MDMA increases plasma epinephrine and NE). Common psychological effects of MDMA include euphoria, anxiolysis, enhanced fear-extinction learning, feelings of closeness or connectedness, an expanded emotional range, as well as adverse subjective effects such as fearfulness, dysphoria, confusion, sleeplessness, and decreased appetite). MDMA's properties as an 'empathogen-entactogen' may have specific advantages in the treatment of PTSD including promoting increases in the personality feature of openness, large magnitudes of posttraumatic growth (i.e. positive changes in self-perception, interpersonal relationships, or philosophy of life), fear extinction, widened window of tolerance, and reopening of the critical period for social reward learning possibly mediated by oxytocin release (in mice,. In recreational settings, MDMA is colloquially known as "ecstasy" or "molly." Past year illicit use among US persons aged 12 or older was approximately 1.0% of the population between 2015 and 2019 (Center for Behavioral Health Statistics and Quality 2020). Unverified recreational ecstasy pills often consist of variable doses ranging from no detectable MDMA to 280 mg or more. Ecstasy is frequently adulterated with other substances prior to sale. Additionally, ecstasy use is often intentionally coingested 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 these settings, several types of short and longer-term adverse effects have been reported, including seizures, rhabdomyolysis, cardiovascular events, neurocognitive dysfunction, psychiatric crisis, habituation and addiction, and death. Case reports and epidemiologic analyses of drug interactions from these recreational settings are much less reliable and present major limitations. In contrast to recreational use, clinical trials to date have involved carefully screened participants ingesting laboratory-grade MDMA at precise dosages. There has only been one reported serious adverse reaction to MDMA within a clinical trial setting: one participant experienced exacerbated ventricular extrasystoles after 125 mg of MDMA, which resulted in overnight hospital monitoring and full recovery within one day (Multidisciplinary Association for Psychedelic Studies 2021). Moderate doses utilized in MAP clinical trials, administered only two or three times during a course of treatment, have not resulted in persistently detectable deficits in neurocognitive function.
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a psychoactive tryptamine that naturally occurs in over 200 species of mushrooms, most notably from the genus Psilocybe. It is often referred to as a "classic psychedelic," since the drug-induced alterations of perception, emotion, and cognition are primarily related to 5-HT 2A receptor agonism, though it also binds to other 5-HT receptor subtypes. Pooled data from 579 oral psilocybin doses administered across completed clinical trials involved a broad range of dosing for psilocybin from "very low dose" (0.014 mg/kg) to "high dose" (0.6 mg/kg), corresponding to 3.15-42 mg in a 70-kg human (Usona Institute 2021). The subjective effects of psilocybin usually begin 20-40 min after ingestion, peak after 60-90 min, and have a total duration of 6 h. Psilocybin is a prodrug, rapidly dephosphorylated upon ingestion by alkaline phosphatase or non-specific esterases, to its active metabolite, psilocin. Psilocybin and psilocin lack clinically significant inhibitor activity at monoamine reuptake pumps, such as SERT or VMAT-2, thus do not result in substantially increased intrasynaptic serotonin. Due to minimal intrasynaptic serotonin release, psilocybin's mechanism of action is unlikely, even in high doses, to result in serotonin toxicity. Psilocin metabolism primarily occurs via UDP-glucuronyltransferase enzymes, UGT1A9 and UGT1A10 (Table) (Dinis-Oliveira 2017;. Psilocin also undergoes deamination and demethylation to form the inactive metabolite 4-hydroxy-indole-3-acetic acid (4HIAA). Physiologically, psilocybin is known to cause mild increases in blood pressure and heart rate. Common physical adverse effects include headache, nausea, dizziness, and fatigue (Usona Institute 2021). Psilocybin can elicit subjective experiences with mystical-type qualities, such as an increased sense of unity, transcendence of time and space, loss of self, and euphoria. Mystical-type experiences are correlated in the laboratory with diminished activity of functionally connected brain circuits collectively termed the default mode network (DMN) as well as long-term improvements in wellbeing, psychosocial function, symptoms of clinical illness, and mindfulness-related capacities. Psilocybin lacks dopamine-mediated reinforcement, and there is no evidence supporting potential for habituation or addiction despite development of rapid tolerance with repeated administration. Common adverse psychological effects include transient anxiety, dysphoria, impaired sleep, paranoia, grief, and preoccupation with death. While laboratory-made synthetic psilocybin is typically used in clinical trials, psilocybin is often ingested for personal use as "magic mushrooms." Pooled data from the 2015-2018 National Survey on Drug Use and Health shows that approximately 9.68% of US adults have ever used psilocybin in their lifetime. Psilocybin is known to have a wide margin of safety, with lethal doses of psilocybin estimated to be more than 1000-fold higher than therapeutic doses. There have been no serious adverse events related to psilocybin in clinical trials. Compared to personal use of other psychedelics, psilocybin appears to have the lowest rates of adverse events reported to poison control centers and very few reports of cardiovascular events.
Given that both MDMA and psilocybin modulate serotonin neurotransmission, there is a potential for drug-drug interactions with medications that also modulate the serotonin system, including Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Tricyclic Antidepressants (TCAs), Monoamine Oxidase Inhibitors (MAOIs), mirtazapine, trazodone, lithium, buspirone, atypical antipsychotics, and others. Some of these interactions may increase the risk of toxidromes such as serotonin syndrome. Another pharmacodynamic interaction that may occur is the attenuation of MDMA's subjective effects or reduced efficacy of MAP for PTSD in participants with recent exposure to antidepressant drugs that inhibit reuptake transporters. While a history of SSRI usage ever in one's lifetime does not seem to be associated with reduced MAP efficacy, the adequate washout period between SSRI use and MAP has not yet been delineated. Due to MDMA also acting on the NE and DA neurotransmitter systems, there are potential interactions with drugs that target these neurotransmitters as well, such as SNRIs, bupropion, and psychostimulants. There may also be relevant drug-drug interactions between psychiatric medications and MDMA or psilocybin through more indirect mechanisms. For example, GABAergic agents such as benzodiazepines have been advocated as an intervention to mitigate acute psychological or physiological adverse effects related to psychedelics. From a pharmacokinetic perspective, other medications may be substrates, inhibitors (e.g., CYP2D6, which could result in competitive interactions with MDMA), or inducers of drugmetabolizing enzymes. While interactions with UGTs are not as common, there are some medications that inhibit or induce UGT enzymes, which may theoretically affect the metabolism of psilocybin.
Although reviews of drug-drug interactions (DDI) with MDMA have been published, none have been systematic, and there have been no reviews of DDIs with psilocybin. Therefore, the objective of this systematic review is to summarize all existing data related to pharmacokinetic, physiological, and subjective effects of drug-drug interactions between medications prescribed in psychiatry and MDMA or psilocybin.
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PROSPERO 2021 registration ID: CRD42021233519. The PICOS (Participants-Intervention/ Exposure-Comparison-Outcomes-Study) framework was used to guide the methods of this review. Participants are people of any age who were exposed to, or ingested, MDMA or psilocybin in combination with a psychiatric medication. For clinical trials, comparison is made between MDMA or psilocybin in combination with a psychiatric drug versus MDMA or psilocybin alone. Outcomes include measures of pharmacokinetics (e.g., plasma drug and metabolite levels), physiology (e.g., vital signs, circulating catecholamines), and subjective outcomes (e.g., psychological effects, list of complaints). Study type was defined broadly to include meta-analyses, systematic reviews, randomized controlled trials (RCTs), retrospective studies, cross-sectional studies, case-control studies, cohort studies, and case reports. A list of psychiatric medications (see Table) was compiled using the APA Textbook of Psychopharmacology, 5 th Edition, Appendix for the psychiatric pharmacopoeia in the United States. Given that clinical research investigating MDMA and psilocybin is also being conducted outside of the United States (e.g., NCT01689740, NCT04670081), we referenced Martindale: The Complete Drug Reference) and included any internationally-approved pharmacotherapy for the treatment of PTSD and MDD that we had not already included. Lastly, we referred to the Department of Veterans Affairs and Department of Defense practice guidelines for PTSD and MDD to include additional medications that are not typically categorized as psychiatric drugs, but are used in the treatment of these disorders (e.g., prazosin, liothyronine) (VA/DOD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder 2017).
We searched the MEDLINE database via PubMed for publications in English between 1958 and 2020. This date range was chosen to capture relevant scientific literature beginning with the synthesis and formal research use of psilocybinas well as the early use of MDMA's therapeutic properties in psychotherapy starting in the 1970's. We utilized the PubMed Advanced Search Builder to conduct a query comprising 163 terms included in the Title or Abstract. A total of 22 search terms reflecting psychopharmacology classes and 135 search terms reflecting psychiatric medications (e.g., Tricyclic antidepressant OR Desipramine OR Nortriptyline) were combined using the logical operator AND with 6 search terms aimed to capture MDMA OR psilocybin ("psilocybin" OR "mdma" OR "ecstasy" OR "psychedelic" OR "entheogen" OR "3 4 methylenedioxymethamphetamine"). See Tablesand
Each abstract was screened for inclusion by two independent reviewers. Abstracts were excluded if they were an editorial, a duplicate, not available in the English language, or otherwise did not address the objective of this systematic review. Any discrepancies between independent reviewers were discussed among the authors of this systematic review, leading to a final decision to include or exclude a specific article based on unanimous consensus. We assessed the remaining full-text articles in detail, during which 12 additional handselected articles arose that had not been captured by our database query. Hand-selected articles were reviewed and met all study selection criteria. Ultimately, 40 articles were included in our systematic review. See Fig.for a PRISMA flow diagram. 26 RCTs and 3 epidemiologic studies were captured. We corresponded with any researchers who published more than one of the resulting RCT articles to seek unpublished or uncaptured data; no additional data were obtained this way. We included the 3 epidemiologic studies in this review due to their large sample sizes and implications for future hypothesis generation, despite their methodological limitations. In addition, 11 case studies were reviewed and placed in the Supplemental Materials.
The following formula was utilized to standardize comparison of outcome measures (e.g., Epinephrine nmol/l) when ingestion of MDMA or psilocybin was preceded by ingestion of another drug (e.g., carvedilol) versus preceded by placebo, resulting in a percentage change (e.g., ↑204.3%) in the outcome of interest. V PBO-MDMA refers to the value of the outcome of interest for the MDMA (or psilocybin) pretreatment with placebo condition, and V med-MDMA refers to the value of the outcome of interest for MDMA (or psilocybin) pretreatment with the psychiatric medication.
This review includes 26 publications of RCTs and 3 epidemiologic studies (1 post-marketing surveillance association study, 1 cross-sectional survey, and 1 quantitative analysis). RCTs (Table) include combinations of MDMA with SSRIs, SNRIs, bupropion, methylphenidate, haloperidol, memantine (de Sousa Fernandes, and adrenergic agents; and combinations of psilocybin with ergotamine or buspirone, haloperidol or risperidone, chlorpromazine, and escitalopram. Our 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. Exploratory analyses were on drug-drug interactions with MDMA and their effects on: immune response), drug metabolism, plasma copeptin, pupillary response, psychological effects, and habituation of startle response. All of the RCTs enrolled only "healthy" adults, often recruited from a university campus, and had limited sample sizes (range of 8-23 participants). Several trials also investigated pharmacogenetic biomarkers, such as CYP2D6 genotype, and categorized participants as extensive, intermediate, or poor metabolizers. Common exclusion criteria across clinical trials were pregnancy or nursing, age < 18 or > 45, BMI < 18.5 or > 25 kg/m 2 , presence of psychiatric illness in self or first-degree relatives, and active substance use. Many studies required female participants to be in the follicular phase of their menstrual cycle (day 2-14) during drug dosing due the potential for cyclic change in subjective reactivity to amphetamines. Refer to Tablefor additional details on study designs and study participants and to Tablesandfor pharmacokinetic, physiological, and subjective outcomes of the RCTs included in our systematic review.
RCTs were conducted combining MDMA with four different adrenergic agents: carvedilol, pindolol, clonidine, and doxazosin. These studies were among those handselected for inclusion as these medications, or medications from the same class, are occasionally used in clinical psychiatric practice as augmentation treatment (e.g., α 1 -adrenergic receptor blockers for the treatment of PTSD) and may be relevant clinically in the management of common transient effects of MDMA such as elevated blood pressure (De.hypothesized that pindolol (20 mg p.o.), a mixed β-adrenergic and 5HT 1A receptor antagonist, administered one hour prior to MDMA (1.6 mg/kg p.o.) would affect MDMA-induced affective, cognitive, and cardiovascular responses. It was found that pindolol pretreatment on average affected experience for only a few subscales of the affective measures (i.e., reduction in MDMA-induced "positive basic mood," "mania-like experience," and "dreaminess") and had no significant effect on MDMA-induced impairments when performing neurocognitive tasks. Pindolol pretreatment reduced MDMA-induced increases in peak heart rate, but had no effect on MDMA-induced change in mean arterial pressure, body temperature, or adverse effects.examined the combination of carvedilol (50 mg p.o.), an α 1 -and β-adrenoreceptor antagonist, with MDMA (125 mg p.o.) and found a large reduction in MDMA's cardiostimulant and hyperthermic effects without significantly affecting MDMA's subjective effects. Selfreported acute and subacute complaints from MDMA were not significantly affected by carvedilol. Despite the attenuation of MDMA's physiological effects, there was a significant rise in circulating epinephrine and NE. Carvedilol and MDMA are both CYP2D6 substrates, while MDMA is also an autoinhibitor; however, MDMA and MDA plasma levels were unchanged when coadministered with carvedilol compared to MDMA alone.hypothesized that the α 2 -adrenergic receptor agonist clonidine (150 μg p.o.), when administered one hour prior to MDMA (125 mg p.o.), would modulate the exocytotic release of NE and thus reduce MDMA's effects. It was found that clonidine did indeed reduce MDMAinduced elevation in circulating NE and blood pressure, but decreased by the same magnitude as clonidine alone. Body temperature, mydriasis, self-reported mood effects and adverse effects from MDMA were not significantly affected by clonidine pretreatment.hypothesized that pretreatment with the α 1 -adrenergic receptor antagonist doxazosin (8 mg p.o. ~ 16 h prior) would reduce MDMA-induced (125 mg p.o.) increases in blood pressure and positive mood. Indeed, doxazosin pretreatment, on average, reduced MDMAinduced increases in mean arterial pressure (MAP), despite enhancing circulating NE and tachycardia. Doxazosin pretreatment also attenuated MDMA-induced heightened mood ratings as predicted, and moderately attenuated increased body temperature. Self-reported adverse effects and mydriasis from MDMA were not significantly affected by doxazosin pretreatment.
One RCT was identified that combined MDMA with an antipsychotic. Researchers hypothesized that the D 2 antagonism effects of haloperidol (1.4 mg i.v.) would attenuate some of the stimulant-like effects of MDMA (1.5 mg/kg p.o.). No changes were observed in MDMA-induced cardiovascular or thermogenic effects, nor responsiveness to startle. In contrast to their hypothesis, this drug combination resulted in reduced well-being, reduced "oceanic boundlessness", and a higher rate of state anxiety. Overall, researchers noted an alteration in the psychological profile of MDMA's usually pleasurable state to a dysphoric one.studied the combination of bupropion XR (titrated to 300 mg p.o. over 7 days) with MDMA (125 mg p.o. administered concurrently with bupropion XR 300 mg on day 7). The researchers hypothesized that DAT and NET blockade by bupropion pretreatment would attenuate the mood and cardiostimulant effects of MDMA. There was a moderate reduction in NE as well as an attenuation in heart rate elevation. No other significant cardiovascular, mydriatic, or hormonal changes occurred compared to MDMA alone. Bupropion did affect self-reported subjective complaints from MDMA, although bupropion significantly prolonged the positive mood effects of MDMA. There was an increase in MDMA levels and reduction in the primary metabolites, DHMA and HMMA, suggesting inhibition of CYP2D6 by bupropion. There was also reduction in MDA levels, suggesting inhibition of CYP2B6 by bupropion. MDMA increased bupropion levels when co-administered due to MDMA's autoinhibition of CYP2D6.
de Sousa Fernandesstudied pretreatment with the NMDA-antagonist memantine (20 mg p.o. 2 h prior) to determine if this would alter MDMA's (75 mg p.o.) effects on memory and mood. The researchers hypothesized that memantine pretreatment may potentially reverse MDMA-induced memory impairment since this had been demonstrated in animal models. The study determined that memantine pretreatment had no effect on MDMA-induced acute memory impairment or effects on mood. Psychostimulants & MDMAconducted an RCT combining MDMA with methylphenidate. Researchers hypothesized that MDMA and methylphenidate may have pharmacodynamic interactions given that they both act on NET and DAT. MDMA and methylphenidate levels and half-lives were unaffected by co-administration; however, researchers found that methylphenidate delayed the time it took for MDMA to reach maximum concentration. The researchers remark this may be due to methylphenidate reducing the absorption of Duplicates removed (n = 0)
Given that MDMA increases intrasynaptic 5HT, partially by inhibiting SERT, researchers hypothesized that the SERTblocking effects of SSRIs carry the potential for pharmacodynamic interactions when co-administered with MDMA. In addition, several SSRIs are also substrates or inhibitors of cytochrome P450 enzymes, which may result in pharmacokinetic interactions with MDMA. Three primary RCTs, and four additional analyses of exploratory outcomes from the primary RCTs, have been published looking at the combination of MDMA with citalopram) fluoxetineand paroxetine. All three SSRIs attenuated the subjective effects of MDMA by ~ 30-~ 80%, while physiological effects were attenuated by ~ 6-~ 14% (with the exception of paroxetine, which was on the order of ~ 40-~ 60%). Both fluoxetine and paroxetine are strong inhibitors of CYP2D6, and plasma concentrations of MDMA were increased despite the effects of MDMA being attenuated. Exploratory studies demonstrated that paroxetine both blunted MDMA-induced immunosuppression, especially cytokine release), and may interact with multiple cytochrome P450 enzymes involved in MDMA metabolism.studied the effect of duloxetine, an SNRI, on MDMA because of its potent inhibition of both SERT and NET, without substantial activity at DAT. Compared to MDMA alone, the addition of duloxetine reduced circulating NE and attenuated MDMA-induced increases in heart rate and blood pressure. There was a near complete elimination of MDMA's effects on the pupillary light reflex. Exploratory hormone measures with female participants found that MDMA-induced elevations in copeptin were reduced by duloxetine, while there was no significant change in males. Subjectively, many of MDMA's effects, including those on mood-such as well-being, extroversion, closeness, openness, as well as alterations in consciousness-were significantly reduced by duloxetine. Participants given MDMA alone had 5.56 more acute complaints than baseline, while duloxetine co-administered with MDMA resulted in having less acute and subacute complaints than their pre-drug baseline. These reductions of MDMA's pharmacodynamic, physiological, and subjective effects occurred despite increased MDMA plasma levels due to CYP2D6 inhibition by duloxetine, suggesting that pharmacokinetics are not responsible for these attenuating effects.were interested in studying the effects of a NE specific reuptake inhibitor, reboxetine (8 mg p.o.), on MDMA (125 p.o.). Researchers hypothesized that reboxetine inhibition of NET would outcompete MDMA's effects on NET, resulting in attenuation of MDMA's effects. Confirming their hypothesis, they found reductions in circulating NE and attenuation of the cardiovascular stimulant effects of MDMA. Subjectively, the addition of reboxetine attenuated MDMA's psychostimulant properties, such as emotional excitation, feeling "stimulated," state anxiety, and blissful feelings such as closeness and boundlessness. There were no significant effects on other psychological parameters such as drug "liking" or "good drug effect." Reboxetine reduced MDMA-induced acute and subacute complaints, such as tremor and restlessness. These attenuations in MDMA's effects occurred despite increased plasma MDMA, likely due to reboxetine's CYP2D6 inhibition. Ex vivo plasma examination showed that reboxetine co-administered with MDMA reduced NET binding and had no effect on SERT or DAT binding.
RCTs were conducted combining psilocybin with three antipsychotics: chlorpromazine, haloperidol, and risperidone. An early study co-administered the typical antipsychotic chlorpromazine (50 mg p.o), which antagonizes both D 2 and 5HT 2A receptors, with psilocybin (0.2 mg/kg p.o.), resulting in attenuation in psilocybin-induced mydriasis and visual perceptual changes.examined the role of the D 2 antagonist haloperidol (0.021 mg/kg i.v.) and the mixed 5HT 2A /D 2 antagonist risperidone (0.5 mg p.o., 1 mg p.o.) when separately combined with psilocybin (0.25 mg/kg p.o.). In contrast to risperidone, haloperidol had no effects on psilocybin-induced perceptual changes but did increase the "dread of ego dissolution" parameter of the Altered States of Consciousness (APZ-OAV) scale. Risperidone reduced all the parameters of the APZ-OAV, demonstrating attenuation in psilocybin-induced alterations in consciousness, including a reduction in dread of ego dissolution. Working memory was tested using the delayed-response task, where a brief visual stimulus is presented then withdrawn, and after a several second delay, the participant is asked to identify the location of the visual stimulus. Psilocybin alone delayed reaction time during its peak effects, though co-administration with risperidone attenuated the delay in reaction time.
We found only one RCT combining psilocybin with serotonin agonists. Due to psilocybin's binding affinity for 5-HT 1A and 5-HT 2A , the researchers independently examined the effects of combining psilocybin (170 μg/kg p.o.) with buspirone (20 mg p.o.) or ergotamine (3 mg p.o.), both of which have 5-HT 1A and 5-HT 2A affinity. It was found that buspirone reduced visionary restructuralization, a subscale of the 5-Dimensions of Altered States of Consciousness Rating Scale (5D-ASC). This suggests that buspirone attenuated psilocybin-induced visual perceptual changes. Ergotamine had no effect on psilocybin-induced subjective effects, perhaps due to different functional selectivity profiles at these receptors.
To date, there has been only one RCT combining psilocybin with an SSRI. Participants were titrated to 20 mg of escitalopram over 14 days and then administered one dose of psilocybin (25 mg p.o., day 14) 2 h after final escitalopram administration. Due to prior case reports on SSRI-induced attenuation of the effects of LSD) researchers hypothesized a significant reduction in the subjective effects of psilocybin. Contrary to their hypothesis, escitalopram pretreatment did not significantly attenuate ratings of altered states of consciousness from psilocybin. Escitalopram pretreatment was associated with significant reductions in subjective ratings of bad drug effects, fear, talkativeness, openness, anxiety, ineffability, and global adverse effects. Physiologically, escitalopram pretreatment also significantly attenuated psilocybin-induced elevations in blood pressure and pupil dilation. Psilocybin alone did not alter the QTc interval and its co-administration with escitalopram had no effect on QTc. Escitalopram did not alter levels of psilocin.conducted a cross-sectional survey study of 216 adults who co-ingested ecstasy and a pharmaceutical drug within the previous 6 months. The mean age of the participants was 26 years, mostly male (63%), with an average of 11 days of ecstasy use in the prior 6 months. 28% of the participants intentionally co-ingested a pharmaceutical drug to augment the effects of ecstasy, in particular sildenafil (77% reported use was to gain or maintain an erection) and benzodiazepines. 76% of participants who concomitantly used ecstasy and antidepressants still experienced euphoria; however, they experienced higher rates of adverse effects, including: muscle rigidity (0% vs 45%), nystagmus (0% vs 33%), dizziness (19% vs 42%), headache (21% vs 62%, and profuse sweating (28% vs 53%). Notably, antidepressants were not analyzed based on pharmacologic class and included MAOIs which may have contributed to the frequency of the aforementioned adverse effects.conducted an epidemiologic quantitative analysis, which was hand-selected by the authors as it was pre-published online shortly after the initial PubMed query and met inclusion criteria. Analysis of 96 first-or second-person accounts posted online (i.e., Erowid, the Shroomery, and Reddit) involving co-ingestion of a psychedelic and a mood stabilizer (i.e., lithium, lamotrigine, valproic acid, carbamazepine, and oxcarbazepine). The researchers looked at numerous psychedelic substances, including psilocybin, however most reports involved lysergic acid diethylamide (LSD), another "classic psychedelic." Of the mood stabilizers, there was only data on lamotrigine and lithium being co-ingested with psilocybin. They found that 2 of the 6 reports of lithium plus psilocybin resulted in seizures. None of the 10 reports of lamotrigine plus psilocybin resulted in seizures. "Low quality evidence due to lack of standardization, selection bias, and lack of clinical verification" was acknowledged by the study authors.
To our knowledge, this is the first systematic review of drug-drug interactions between psychiatric medications and MDMA or psilocybin. Forty publications met our inclusion criteria, including 22 RCTs of MDMA administered with and without a psychiatric medication and 4 RCTs of psilocybin administered with and without a psychiatric medication. Cumulatively, these clinical trials included over 200 participants. We also identified 3 epidemiologic studies: one large cross-sectional survey, one large post-marketing surveillance association study involving ecstasy co-ingestion with medications, and one quantitative analysis of online "trip reports." This review demonstrates that the existing data on drugdrug interactions between a psychiatric medication and MDMA or psilocybin predominantly pertains to MDMA. There are only 2 studies on psilocybin captured in this review that were published within the last decade, highlighting a limited body of scientific literature related to drugdrug interactions with psilocybin. It is important to note that the clinical trials in this review were primarily designed to ascertain the mechanisms of MDMA or psilocybin. Therefore, all the study participants were young healthy adults who were either administered a psychiatric medication only once or, rarely, over several days for a maximum of 14 days. Therefore, these studies are limited in their extrapolation to real world clinical settings where psychiatric medications are often taken daily for months or years. Other factors that limit the extrapolation of these studies to clinical settings is that some studies instituted less common routes of administration of psychiatric medications, such as intravenous haloperidolor intravenous citalopram. Some studies had unique exclusion criteria that may limit the generalizability of outcomes further, such as high levels of neuroticism)which recently has been shown to predict negative psychological responses to MDMA)-or inclusion of only individuals with prior recreational ecstasy use.
Pharmacokinetic interactions-MDMA MDMA's pharmacokinetics are complex, involving several cytochrome P450 enzymes, which makes MDMA particularly susceptible to drug-drug interactions with strong pan-CYP inhibitors like ritonavir-which has resulted in significant toxicity. Many psychiatric medications have significant inhibitory effects on CYP2D6, and it is also an enzyme that displays a wide range in metabolic capacity throughout the population. The studies included in this review had numerous instances of CYP2D6 interactions with MDMA including paroxetine, fluoxetine, duloxetine, reboxetine, and bupropion.
MDMA's effects on monoamine transporters, namely SERT and NET, are unique. MDMA acts as a SERT and NET substrate, resulting in reverse transport and exocytotic release of 5HT and NE). In contrast: antidepressants (i.e., SSRIs, SNRIs, NRIs, and NDRIs) capture the monoamine transporter (i.e., SERT, NET, and DAT) in an inhibitor-bound conformation, preventing substrate bindingand resulting in higher monoamine concentrations in the synaptic cleft. Researchers primarily from the same laboratory group systematically conducted a series of clinical trials on drugdrug combinations of MDMA with various monoamine reuptake blocking agents to ascertain relative contributions of different monoamine systems to MDMA's mechanism of action. SERT inhibitors (SSRIs), including citalopram, paroxetine, and fluoxetine, reduce MDMA's physiological and subjective effects broadly. NET-specific inhibition by reboxetine reduced MDMA's NE-mediated cardiostimulant properties and some psychological outcomes; while combined NET and SERT inhibition by duloxetine broadly attenuated physiological and psychological outcomes, similar to outcomes from SSRI + MDMA combinations. Overall, monoamine reuptake inhibitors resulted in attenuation of MDMA's physiological and subjective effects, even in instances of higher MDMA plasma levels by means of CYP2D6 inhibition. This consistent outcome may suggest that, when administered together, monoamine reuptake inhibitors outcompete MDMA by binding to monoamine transporters (i.e., SERT, NET, DAT), preventing the efflux of monoamines into the synaptic cleft, thus attenuating the effects of MDMA. Exceptions to this trend include the combined NET and DAT inhibitor, bupropion, which prolonged the subjective effects and heightened the positive mood effects of MDMA. In this case, CYP2D6 and CYP2B6 pharmacokinetic interactions and bupropion's relatively low ability to inhibit NET or DAT) may explain this outcome. While no serious adverse effects of these combinations were observed in clinical trial settings, there are risks to combining SSRIs or bupropion with MDMA in uncontrolled settings. For example, a recent large-scale surveillance study of data from the FDA's Adverse Event Reporting Systems (FAERS) reviewed reports of co-ingestion of MDMA in non-clinical settings with medications, finding that several antidepressant + MDMA combinations increased mortality, with bupropion having the highest odds ratio for death of any antidepressant. It is plausible that the combination of bupropion and MDMA increases the risk of seizures, stimulant toxicity, or serotonin syndrome given that both drugs are stimulants capable of lowering seizure thresholds and that they increase blood concentrations of each other when taken together. Relevant to the co-administration of monoamine reuptake inhibitors and MDMA, there has been ongoing attention paid to the risk of serotonin syndrome with the combination of SSRIs and MDMA, theorized to be related to a rise of 5HT in the central nervous system. The RCTs in this review show attenuation of MDMA's physiological effects, suggesting a reduced odds of serotonin syndrome, at least with acute SSRI dosing. This is corroborated by at least one other scientific review positing SSRIs, SNRIs, and TCAs are not likely to increase serotonin to life-threatening toxicity when combined with MDMA). This may be due to the fact that MDMA's reversal of monoamine transporters is negated by the inhibition of monoamine transporters by most antidepressants; therefore, there is not an increase in intrasynaptic serotonin which is the hallmark mechanism for serotonin toxicity to occur. A notable downside of SSRI or SNRI use in conjunction with MDMA is attenuation of subjective effects and the potential for reduced MAP treatment efficacy). However, discontinuation of psychiatric medications poses a risk of antidepressant discontinuation syndromes or relapse of psychiatric symptoms that must be weighed in clinical decision-making by the prescribing provider. An important outlier when it comes to serotonergic agents and MDMA is the MAOI class. MAOIs prevent breakdown of monoamines and, when combined with MDMA, result in dangerous elevations in intrasynaptic serotonin. This has contributed to the majority of deaths cited in published case studies (see summary of case studies in Supplementary Materials). Stimulants have been proposed to induce exocytotic release of monoamines via DAT and NET, similar to MDMA, or to only inhibit DAT and NET reuptake similar to methylphenidate. In fact, the combination of methylphenidate and MDMA resulted in synergistic effects: higher rates of self-reported complaints and heightened cardiostimulant effects. Dopamine blockade via coadministration of haloperidol did not alter MDMA's physiological effects, which is unsurprising given MDMA's limited impact on the dopamine system. However, it is intriguing that MDMA's typically euphoric effects were absent, while trait anxiety and dysphoria were exaggerated, potentially related to haloperidol's dysphoric effects. Regarding adrenergic agents and MDMA: carvedilol) dramatically reduced MDMA-induced cardiostimulant and hyperthermic effects without influencing MDMA's psychological effects, while clonidine and doxazosin had a minimal effect on physiology. It is not fully clear if combining an adrenergic agent with MDMA reflects additive effects or a pharmacodynamic interaction. The notion of additive effects is supported by the fact that carvedilol, pindolol, and clonidine) reduced adrenergic activity but did not significantly alter the subjective effects of MDMA. However, doxazosin is an outlier as it attenuated attenuated MDMA's mood heightening effects. Doxazosin also increased MDMA-induced tachycardia which may be a result of its α 1 specific blockade resulting in compensatory activation of other α-and β-adrenoreceptors as described elsewhere in the literature. Regardless, the interaction between adrenergic agents and MDMA would be a valuable area of additional research, as well as clinically useful information in choosing an antihypertensive or antipyretic to address MDMA-related adverse effects in the setting of MAP treatment without compromising the potentially beneficial affective effects of MDMA.
It has been demonstrated that CYP2D6 poor metabolizers carrying only *3, *4, or *5 alleles administered MDMA reached an average maximum concentration (C max ) that is 19% higher and an initial drug exposure (AUC 0-6 h ) that is 25% higher than extensive metabolizers carrying only *1 and *2 alleles, which corresponded to a more rapid onset of subjective effects and elevated blood pressure. Recent pooled RCT data demonstrated that the physiological and psychological effects of MDMA were most strongly dependent on plasma concentration, while higher activity scores for CYP2D6 metabolizer status predicted a lower MDMA plasma concentration.
Compared to MDMA, psilocybin is less likely to contribute to pharmacokinetic drug-drug interactions given that its metabolic pathway predominantly involves UGT1A10 and UGT1A9. Diclofenac and probenecid are examples of UGT1A9/10 inhibitors that may hypothetically alter psilocybin metabolism if co-ingested; however, there is no evidence to confirm this hypothesis beyond shared metabolism. There are few pharmacologic agents that influence UGT1A9 and UGT1A10. Furthermore, the pharmacokinetics of psilocin, the active metabolite of psilocybin, is linear and is minimally affected by renal clearance.
Research into drug interactions with psilocybin is sparse yet paints an interesting picture of its mechanism. When 5HT 2A is blocked pharmacologically, such as by buspirone, chlorpromazine, ketanserin, or risperidone, there is a consistent pattern of attenuation of psilocybin's subjective effects. However, 5HT 2A and 5HT 1A agonism, such as from ergotaminedoes not seem to have an effect on psilocybin nor LSD's subjective effects. D 2 antagonism alone, in the case of haloperidol, does not attenuate psilocybin's effects, and, in fact, exacerbates anxiety and produces dysphoria. Interestingly, when blocking SERT pharmacologically with escitalopram, there is no attenuation of psilocybin's psychedelic effects and in fact reduced measures of anxious distress and participant complaints. Collectively, this data points towards psilocybin's unique mechanism of action which is contingent on direct serotonin receptor agonism that does not compete nor rely on SERT activity. We would hypothesize that other SERT blockers, such as sertraline, in combination with psilocybin would reproduce similar findings aswhile 5HT 2A blockade would attenuate psilocybin's effects, both subjectively and physiologically.
We identified 11 case study manuscripts, all of which involve the recreational ingestion of ecstasy and provide helpful insights on the implications of co-ingestion in the context of illicit use. However, these data are limited by the inability to ascertain drug levels of MDMA or other potential adulterants in most cases; therefore, case studies are described in Supplemental Materials. These case studies reveal a trend that the highest rates of morbidity occurred from the combination of MDMA with MAOIs, such as moclobemide or phenelzine. A number of these cases involved significant hyperthermia, seizure-like activity, and altered mental status, suggestive of unrecognized symptoms of serotonin syndrome, many of which resulted in fatality. In several cases, coronary artery disease was noted upon autopsy and was a suggested risk factor in the cause of death. In one notable case of a young man with bipolar disorder prescribed moclobemide and lithium who ingested ecstasy, the symptoms of serotonin syndrome were misattributed by his peers to a "psychotic episode" whereupon he was left unaccompanied for 4 h and after which he was found deceased. The combination of SSRIs with ecstasy in case reports are consistent with lab data, suggesting attenuation of MDMA's effects. However, the attenuated subjective effects of MDMA from SSRIs may drive individuals to take escalating drug doses to achieve effects, resulting in the elevated odds-ratio for mortality observed by) in instances of concomitant MDMA use with SSRIs.
This review focuses on MDMA and psilocybin, thus did not include literature on other psychedelic substances, such as: lysergic acid diethyladmide (LSD), ayahuasca or N, N-demethyltryptamine (DMT), mescaline, or designer drugs. Ketamine can be used in combination with psychotherapy for its psychedelic effects; we included ketamine in our search as an antidepressant rather than a psychedelic, but did not find any literature on interaction with MDMA or psilocybin. We also did not include the effects of repeated dosing of MDMAor psilocybin on subsequent effects. Additionally, our scope was limited to psychiatric medications rather than other medications that may have the propensity for drug-drug interactions with MDMA and psilocybin. Although this review attempts to capture all relevant clinical data to date on co-administration of a psychiatric medication with MDMA or psilocybin, the window of permissible scientific study on psychedelics has been narrow in comparison to groups who have implemented psychedelics into their cultural and spiritual practices for longer than psychiatric medications have been around (e.g., the Mazatec people of Oaxaca) or in comparison to other forms of collective knowledge (e.g., the Erowid Experience Vaults).
Modern research protocols for MAP and PAP have either excluded participants taking psychiatric medications or discontinued psychiatric medications prior to administration of MDMA or psilocybin. Tapering psychiatric medications before MAP or PAP poses unique challenges and vulnerabilities to those suffering from psychiatric illnesses by way of increased risk of illness relapse, serotonin discontinuation syndrome, and reduced treatment efficacy. It is apparent that developing optimal strategic approaches for patients who may benefit from MAP or PAP, but are currently prescribed psychiatric medications, will require additional clinical research. In particular, there is a dearth of studies on psilocybin drug-drug interactions, signaling a need for additional research on how psychiatric medications and psilocybin interact. Additionally, of the psilocybin RCTs in this review, none included measures of physiological outcomes. Additional studies of psilocybin drug-drug interactions are pending completion, including a cross-sectional online survey being conducted by the Johns Hopkins Center for Psychedelic and Consciousness Research investigating psilocybin mushrooms taken with antidepressants (nspsy chede lic. org/ adsur vey). Certain groups have been excluded from the clinical trial samples described in this systematic review, including those with particular psychiatric symptoms or medical illnesses such as uncontrolled hypertension, cardiovascular disease, and liver disease. It remains unclear how to safely administer MAP or PAP to medically ill individuals, including individuals with hepatic impairment that would affect drug metabolism. At this time, research is underway to ascertain how hepatic impairment may affect MDMA's pharmacokinetics (NCT03606538), which is an FDA requirement for drug development and may broaden inclusion in future studies. Additionally, none of the included studies reported on the race or ethnicity of participants nor commented on the inclusion of sexual or gender minorities. This corresponds to the lack of diverse participants in MAP and PAP clinical trials. Additionally, there is evidence that estradiol up-regulates expression of UGT1A9 resulting in increased glucuronidation of UGT1A9 substrates. This suggests that hormone replacement therapy, oral contraceptives, and cyclical hormonal changes may affect the metabolism of psilocybin, highlighting the need for more inclusive research. There are a number of psychiatric medications commonly used in the management of acute psychological distress sometimes experienced acutely with MDMA or psilocybin administration. Benzodiazepines have been suggested by guidelines, informed by research on management of LSDrelated psychological distress, to address extremely challenging psychedelic experiences that don't respond to behavioral interventions. We did not find any studies on the concomitant use of benzodiazepines with MDMA nor psilocybin. In fact,found that, among several other drug class co-ingestions with recreational MDMA, benzodiazepines were associated with an increased multivariate adjusted odds ratio of death-higher than that of co-ingested opioids, ethanol, or antidepressants. Online communities have encouraged using olanzapine as a "trip terminator"; in other words, a pharmacologic technique for self-management of psychedelic crises. However, it remains unclear if atypical antipsychotics would be an appropriate approach to manage psychological distress related to MDMA or psilocybin. Recent data fromdemonstrated that olanzapine had an increased univariate unadjusted odds ratio of death among adverse reports of MDMA co-ingestion, while there were no cases of death with risperidone co-ingestion. It is notable that the study bywas in regards to unregulated ecstasy use in uncontrolled non-clinical settings. The absence of clinical trials on the combination of benzodiazepines or atypical antipsychotics with MDMA, and mixed data regarding heightened risk with psilocybin, suggest that it would be valuable to investigate these drug-drug interactions in future research. The mechanism in which MAP or PAP lead to psychiatric recovery remains unclear as is the mechanism in which psychiatric drugs affect MAP or PAP outcomes. Of the current body of literature, 5HT 2A serotonin receptor modulation (Carhart-Harris and Nutt 2017), changes in resting state functional connectivity in the default mode network, and neuroplasticity) are among some of the prevailing hypotheses. Whether or not combinations of psychiatric medications with MDMA or psilocybin would interfere with these processes specifically has not been studied. However, there are surprising results from a sub-analysis of pooled Phase 2 MAP studies demonstrating that participants who recently tapered off of prescription antidepressants (e.g. SSRIs, SNRIs, etc.) had a higher PTSD symptom burden and were more likely than the non-taper group to still meet PTSD criteria at the primary study endpoint (63.6% vs. 25.0%), despite completing the taper by an average of 25.1 days before their first MDMA administration session. This suggests that mechanisms beyond direct and immediate pharmacodynamic interactions may have an influence on how drug-drug interactions affect MAP and PAP outcomes. It would be valuable to further study how lifelong psychiatric medication adherence or enduring psychedelic use would affect MAP or PAP outcomes.
As MDMA and psilocybin continue to move through the FDA drug development process, this systematic review offers a compilation of existing research on psychiatric drugdrug interactions with MDMA or psilocybin. There are clear acute pharmacokinetic and pharmacodynamic interactions between many common psychiatric medications and MDMA or psilocybin which affect their physiological and subjective effects and help us better understand the mechanisms of action of these substances. However, the existing body of literature is not readily applicable to the clinical setting, prompting the need for additional research on the topic of drug-drug interactions with MDMA or psilocybin.
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