Psilocybin: A Clinician’s Guide to Pharmacological Interactions

SPECIAL REPORT: PSYCHEDELICS

An increasing body of evidence supports that psilocybin is effective for the treatment of depression and other psychiatric disorders, such as anxiety, obsessive-compulsive disorder, posttraumatic stress disorder, and substance use disorders.^1,2 The FDA has granted psilocybin a breakthrough therapy designation with multiple phase 2 and phase 3 trials currently underway. If the FDA approves psilocybin, it would be rescheduled from its current Drug Enforcement Administration (DEA) Schedule I status to a prescriptible classification (Schedule II-V) in the United States. At the state level, Oregon, Colorado, and New Mexico have legalized psilocybin for supervised or regulated therapeutic use, and Arizona, Alaska, Massachusetts, and Minnesota have drafted and proposed bills toward the same goal.

Research suggests that in moderate to severe depression, 2 doses of psilocybin administered over 6 weeks are noninferior to daily escitalopram use.² In patients meeting criteria for treatment-resistant depression, 1 or 2 doses of psilocybin have demonstrated efficacy when combined with psychological support.^3,4

Given current state-level efforts to approve regulated psilocybin use and the likelihood of FDA approval and DEA rescheduling, clinicians will benefit from familiarizing themselves with this medicine’s pharmacological interactions. To date, many studies have prioritized safety and have deprescribed participants prior to psilocybin administration. If psilocybin becomes approved, however, deprescribing will not be feasible and, at times, not clinically possible. Moreover, with ongoing efforts to legalize and decriminalize psilocybin for personal use, patients may choose to take it independently.

Because a good understanding of psilocybin’s pharmacological interactions will be crucial for safety and guidance, we will examine psilocybin’s main interactions, focusing on psychotropic and other relevant medications.

Psilocybin’s Pharmacological Interactions

Psilocybin is metabolized to psilocin, and its main action is related to agonism of 5HT2A serotonin receptors. Its most common adverse effects include anxiety, nausea, pupillary dilation, yawning, and transient increases in heart rate and blood pressure.⁵

Key pharmacological interactions and safety considerations when combining psilocybin with other substances include the following:

1. Selective serotonin reuptake inhibitors (SSRIs)/selective serotonin-norepinephrine reuptake inhibitors (SSNRIs): The primary interaction risk of SSRIs and SSNRIs is attenuating or blunting psilocybin effects, likely related to downregulation and desensitization of 5HT2A serotonin receptors, the main target of psilocybin.^6,7 Although patients taking SSRIs and SSNRIs have reported a less intense psychedelic experience, experimental evidence has not been supportive of these naturalistic findings.⁸ Moreover, although clinicians often recommend tapering and discontinuing these antidepressants prior to psilocybin use to prevent serotonergic overload, the risk of serotonin syndrome remains theoretical, with no solid evidence supporting it. Antidepressants such as fluoxetine, sertraline, and escitalopram are generally safe if given concomitantly with psilocybin.
2. Tricyclic antidepressants (TCAs): Although knowledge about interactions between psilocybin and TCAs is more limited, TCAs also may attenuate psilocybin effects. In addition, they have a higher risk of causing autonomic instability, such as heart rate and blood pressure fluctuations, and psilocybin is known to cause transient increases in blood pressure.^7,9
3. Monoamine oxidase inhibitors (MAOIs): The use of MAOIs has increased with the release of the selegiline transdermal system. In general, they pose a risk of hypertension and hyperthermia, so studies with psilocybin require a long washout of MAOIs before administration. MAO-A inhibition could also reduce psilocin breakdown and potentiate its effects, making psilocybin generally contraindicated with MAOIs.¹⁰
4. Lithium: Lithium is perhaps the most critical drug-drug interaction to consider with psilocybin. Lithium carries a significant risk of seizures and delirium, and through a mechanism not yet fully understood, psilocybin has been associated with an increased risk of both. Therefore, psilocybin is strongly contraindicated in patients taking lithium, and significant caution must be exercised.¹¹
5. Mood stabilizers: Anticonvulsants such as valproate, carbamazepine, or lamotrigine—used in psychiatry for mood stabilization—may attenuate psilocybin’s effects because psilocybin also acts via enhancement of cortical excitability. These interactions, however, have not been vigorously studied.
6. Antipsychotics: Medications such as olanzapine and risperidone block 5HT2A receptors and can reverse psilocybin-induced effects. In fact, they can be used to abort a psilocybin experience if the patient cannot tolerate it. These medications must be avoided when psilocybin is used therapeutically. Benzodiazepines are preferred for managing anxiety related to the psilocybin experience.
7. Benzodiazepines: Like anticonvulsants, benzodiazepines act on γ-aminobutyric acid A receptors and can decrease cortical excitability, potentially dampening psilocybin’s effects and therapeutic potential. Despite this, clinically, patients still report visual and time-perception changes. Benzodiazepines are preferred to manage anxiety during psilocybin experiences.¹²
8. Stimulants: Methylphenidate was historically studied as an enhancer of psychedelic experiences, but stimulants are now avoided because they can increase heart rate and blood pressure, resulting in autonomic instability.¹⁰
9. Medical settings: Psilocybin is metabolized via glucuronidation and has few interactions compared with other medical drugs. Nonsteroidal anti-inflammatory drugs, chemotherapy, steroids, and immunosuppressants have no known interactions, although these medications can be associated with neuropsychiatric symptoms, which could complicate a psilocybin experience. Careful neuropsychiatric evaluation must be done before considering psilocybin. Antiemetics such as ondansetron can be used to treat psilocybin-induced nausea, but metoclopramide should be avoided because it shares properties with antipsychotics. Linezolid may attenuate psilocybin effects due to its serotonergic action. Similarly, St John’s wort should also be avoided. β-Blockers and antihypertensives could be used to manage psilocybin’s autonomic adverse effects, although patients on diuretics should avoid dehydration. Inhalers and asthma medications are not contraindicated.

Concluding Thoughts

Overall, psilocybin is safe, well tolerated, and has few adverse effects or interactions. MAOIs are the main exception because they can inhibit MAO-A, a secondary metabolic route, and potentially cause serotonin toxicity. Most psychotropic medications can attenuate psilocybin’s effects, and benzodiazepines are the preferred option for managing anxiety during psilocybin experiences in controlled clinical settings.¹² Of all interactions, psilocybin’s pharmacological contraindication with lithium is the most clinically relevant due to the risk of seizures and other serious adverse events.¹¹ Clinicians need to monitor vital signs and other physical effects on a case-by-case basis.

It's important for clinicians to become familiar with psilocybin’s pharmacological interactions because the drug has been legalized in some states for supervised or regulated therapeutic use and is advancing toward FDA approval and DEA rescheduling. Many individuals in the community are also seeking psilocybin experiences to manage symptoms, for therapy, or for personal growth.

Dr Espí Forcén works at McLean Hospital in Lincoln, Massachusetts, focusing on innovative treatments for depression. He is also an assistant professor of psychiatry at Harvard Medical School in Boston and the creator of the Spanish-language psycho-podcast El último humanista.

References

1. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68(1):71-78.

2. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384(15):1402-1411.

3. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619-627.

4. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387(18):1637-1648.

5. Marinis J, Clarke ST, Guerin AA, Guastella AJ, Bedi G. Reporting of side-effects in clinical trials of psilocybin-assisted psychotherapy for psychiatric conditions: systematic review. BJPsych Open. 2025;11(6):e261.

6. Gukasyan N, Griffiths RR, Yaden DB, Antoine DG II, Nayak SM. Attenuation of psilocybin mushroom effects during and after SSRI/SNRI antidepressant use. J Psychopharmacol. 2023;37(7):707-716.

7. Sarparast A, Thomas K, Malcolm B, Stauffer CS. Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review. Psychopharmacology (Berl). 2022;239(6):1945-1976.

8. Becker AM, Holze F, Grandinetti T, et al. Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clin Pharmacol Ther. 2022;111(4):886-895.

9. Halman A, Kong G, Sarris J, Perkins D. Drug-drug interactions involving classic psychedelics: a systematic review. J Psychopharmacol. 2024;38(1):3-18.

10. Barnett BS, Koons CJ, Van den Eynde V, Gillman PK, Bodkin JA. Hypertensive emergency secondary to combining psilocybin mushrooms, extended release dextroamphetamine-amphetamine, and tranylcypromine. J Psychoactive Drugs. 2025;57(3):297-303.

11. Nayak SM, Gukasyan N, Barrett FS, Erowid E, Erowid F, Griffiths RR. Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports. Pharmacopsychiatry. 2021;54(5):240-245.

12. Nicholas CR, Banks MI, Lennertz RC, et al. Co-administration of midazolam and psilocybin: differential effects on subjective quality versus memory of the psychedelic experience. Transl Psychiatry. 2024;14(1):372.