Drug & supplement interaction

Psilocybin + Esketamine

Esketamine brand name: Spravato.

No Known Interaction

Medically reviewed by Dr. Brian Staiger, PharmD, BCPS · Updated July 2026 · Pair last verified Sep 20, 2026

The bottom line No known interaction

We found no known interaction between Psilocybin and Esketamine in our sources. Absence of a documented interaction is not the same as proven safety, and does not guarantee one does not exist. Do not start, stop, or change a medication or supplement based on this page; confirm with your pharmacist or doctor first. Additionally, although there is no interaction, the two are separately associated with some of the same side effects, which would make a new symptom harder to attribute to one or the other.

Know someone taking this? Share

Facebook Post Reddit Email

On this page

Interaction report

Psilocybin and Esketamine

We checked these two against our interaction database. Here is what we found.

No Known Interaction Found

We did not find a documented interaction between Esketamine and Psilocybin in our sources. This does not guarantee that the combination is completely free of risk — there is often limited research on supplements and herbal products, especially around drug interactions.

If you decide to take both, the practical routine is simple: add one new thing at a time and note the date you started it. If the combination is going to disagree with you, it usually shows in the first days to a couple of weeks — and a start date turns “I’ve been feeling off” into something a pharmacist can actually work with. Do not stop a prescribed medicine on your own.

Always talk with your pharmacist or doctor before making changes to your medications or supplements, particularly if you take several medications or have an ongoing health condition.

Psilocybin safety at a glance

Psilocybin overall Avoid Psilocybin is a controlled substance with powerful mind-altering effects and is not a safe or legal dietary supplement.

Pregnancy Avoid There is no safety data; avoid during pregnancy.

Breastfeeding Avoid There is no safety data; avoid while breastfeeding.

Safety guidance is general; always confirm with your pharmacist or doctor for your situation.

Still wondering about combining Esketamine and Psilocybin? Ask Dr. Brian Staiger, PharmD, BCPS directly ›

How we checked

Why No Interaction Is Listed for Esketamine

Interactions in our licensed database are recorded against drug classes, not just single drug names. Esketamine is filed under 2 classifications — tricyclic antidepressants (tcas), antidepressant drugs. Psilocybin has documented interactions with 2 drug classes — the most serious being serotonergic drugs (moderate) and stimulant drugs (moderate) — and none of Esketamine’s classifications are among them.

Classification data comes from our licensed Natural Medicines dataset. A medication can belong to classes beyond those recorded there, so this describes how the check was run — it is not a safety guarantee.

Keep it in perspective

Psilocybin Does Interact With Other Medications

Psilocybin has 293 moderate known drug interactions in our database — Esketamine isn’t one of them. If you take anything else, check it against the full list below.

Moderate 293 No known interaction 2,537 (incl. Esketamine)

Taking anything else?

Check Another of Your Medications Against Psilocybin

Covers the 2,830 medications we’ve checked against Psilocybin. Pick one to open its full report.

What to actually watch for

No Interaction Found — But Data Suggests Psilocybin and Esketamine May Share Several of the Same Side Effects

This is not an interaction. Neither one changes how your body handles the other, and nothing here says they react together. What our sources do show is that each has separately been linked to the effects below — so taking both can make those effects more likely to turn up, and harder to pin on one or the other if they do. 3 of them are worth acting on rather than waiting out — marked below.

Thoughts of self-harm / Low mood Worth acting on reported in 7.6% of FDA reports for Esketamine Additional detail
Psilocybin
“Psilocybin has psychedelic or hallucinogenic effects, with side effects including visual, auditory, tactile, and other illusions, as well as changes in time and space perception, and "mystical experiences". The severity of some of these responses may be dose-dependent.”

Psilocybin · Natural Medicines adverse-effect record, reported in anxiety.
6 sources cited

106129. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 2016;30(12):1181-1197. PubMed

106137. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol 2015;29(3):289-99. PubMed

106138. 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):71-8. PubMed

106146. Brown RT, Nicholas CR, Cozzi NV, et al. Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Clin Pharmacokinet 2017;56(12):1543-1554. PubMed

106150. Griffiths RR, Johnson MW, Richards WA, et al. Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial at

106154. Carbonaro TM, Bradstreet MP, Barrett FS, et al. Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. J Psychopharmacol 2016;30(12):1268-1278. PubMed
Esketamine

Listed in the ADVERSE REACTIONS section of the FDA label for Esketamine, and in voluntary FDA adverse-event reports. Read the label on DailyMed ›
Raised blood pressure Worth acting on reported in 4.8% of FDA reports for Esketamine Additional detail

Psilocybin

“Orally, psilocybin seems to be generally well tolerated when single doses are used with appropriate medical supervision. However, the United States Drug Enforcement Administration (DEA) lists psilocybin as a Schedule I controlled substance and a thorough evaluation of safety outcomes related to its use without medical supervision, including in micro dosing amounts, has not been conducted.

Most Common Adverse Effects:…”

Psilocybin · Natural Medicines adverse-effect record, reported in anxiety.

Esketamine

Listed in the ADVERSE REACTIONS section of the FDA label for Esketamine, and in voluntary FDA adverse-event reports. Read the label on DailyMed ›
Drowsiness / Dizziness reported in 15.3% of FDA reports for Esketamine Additional detail
Psilocybin
“Orally, single doses of psilocybin have resulted in mild to moderate headache in numerous case studies and experimental studies. Headaches have been reported in up to 50% of individuals, starting a mean of 7 hours after intake and lasting for 1-2 days. Severity and duration seem to be dose-dependent.”

Psilocybin · Natural Medicines adverse-effect record, reported in anxiety.
6 sources cited

106129. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 2016;30(12):1181-1197. PubMed

106131. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl) 2018;235(2):399-408. PubMed

106132. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 2016;30(12):1165-1180. PubMed

106134. 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):619-27. PubMed

106135. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry 2021;78(5):481-489. PubMed

106137. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol 2015;29(3):289-99. PubMed
Esketamine

Listed in the ADVERSE REACTIONS section of the FDA label for Esketamine, and in voluntary FDA adverse-event reports. Read the label on DailyMed ›
Anxiety or restlessness / Nausea / Headache reported in 5.4% of FDA reports for Esketamine Additional detail
Psilocybin
“Orally, single doses of psilocybin have resulted in nausea, and rarely, vomiting and diarrhea. Analysis from a large clinical trial that evaluated single doses of psilocybin 1 mg, 10 mg, and 25 mg suggests that for every 5 patients treated with psilocybin 25 mg over psilocybin 1 mg, one additional case of nausea will occur.”

Psilocybin · Natural Medicines adverse-effect record, reported in anxiety.
6 sources cited

106129. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 2016;30(12):1181-1197. PubMed

106131. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl) 2018;235(2):399-408. PubMed

106132. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 2016;30(12):1165-1180. PubMed

106134. 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):619-27. PubMed

106137. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol 2015;29(3):289-99. PubMed

106161. Carbonaro TM, Johnson MW, Griffiths RR. Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan. Psychopharmacology (Berl) 2020;237(8):2293-2304. PubMed
Esketamine

Listed in the ADVERSE REACTIONS section of the FDA label for Esketamine, and in voluntary FDA adverse-event reports. Read the label on DailyMed ›
Tiredness Additional detail
Psilocybin
“Orally, single doses of psilocybin have resulted in unspecified types of physical discomfort, abnormal feelings, and fatigue.”

Psilocybin · Natural Medicines adverse-effect record, reported in fatigue.
2 sources cited

106129. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 2016;30(12):1181-1197. PubMed

113870. Peck SK, Shao S, Gruen T, et al. Psilocybin therapy for females with anorexia nervosa: a phase 1, open-label feasibility study. Nat Med 2023;29(8):1947-1953. PubMed
Esketamine

Listed in the ADVERSE REACTIONS section of the FDA label for Esketamine. Read the label on DailyMed ›
Vomiting Additional detail

Psilocybin

Recorded for Psilocybin in the same Natural Medicines adverse-effect record shown under Anxiety or restlessness / Nausea / Headache above.

Esketamine

Listed in the ADVERSE REACTIONS section of the FDA label for Esketamine. Read the label on DailyMed ›

Reported for Psilocybin but not commonly for Esketamine: a heart attack, a slow heartbeat, dependence or withdrawal symptoms and mood changes or irritability.

Effects for Esketamine come from the ADVERSE REACTIONS section of its FDA label; effects for Psilocybin come from the Natural Medicines adverse-effect record, quoted above. Where a percentage is shown, it is the share of 17,728 voluntary FDA FAERS reports for Esketamine that mention that effect — a reporting proportion, not an incidence rate and not evidence the drug caused it. Wording is matched across sources by our own clinical vocabulary, so treat this as a prompt to pay attention, not a diagnosis.

Overlapping uses

What Esketamine Is Prescribed For, and What Psilocybin Has Been Studied For

These two come up together because they touch the same health topic — not because they do the same job. Esketamine is a prescription medicine with approved uses on its FDA label. Psilocybin is a supplement: what follows is what researchers have looked at it for, and how strong that evidence is.

Esketamine is prescribed for: Spravato nasal spray is approved for two uses in adults. First, it treats treatment-resistant depression (TRD) — depression that has not responded to other antidepressants — either on its own or alongside an oral antidepressant. Second, it treats depressive symptoms in adults with major depressive disorder (MDD) who have acute suicidal ideation or behavior, always used together with an oral antidepressant in this case. Important limits: Spravato has not been shown to prevent suicide or reduce suicidal thoughts or behavior on its own.

Read the rest of what Esketamine is prescribed for

It is not a replacement for hospitalization if that is clinically needed, and it is not approved as an anesthetic.

Psilocybin has been studied for:

Depression Natural Medicines rates the evidence for Psilocybin: Possibly Effective Read what the research shows

Psilocybin for depression

Clinical research in patients with major depressive disorder (MDD) or depression associated with cancer suggests that pure psilocybin, typically taken as a single 25 mg dose in combination with supportive or integrative psychotherapy by trained therapists, may improve symptoms of depression and increase the likelihood of remission.

Effectiveness ratings and the research summaries above are the verbatim record from the Natural Medicines database, which grades evidence from “Effective” down to “Insufficient Reliable Evidence To Rate”. A rating below the top of that scale means researchers have looked at it — not that it works, and never that it can stand in for a prescribed medicine. Do not stop or replace Esketamine on your own; if you are taking Psilocybin for the same health topic, tell your prescriber, especially if the medicine is being adjusted to a target.

Everything else you take

See Every Supplement That Interacts With Esketamine

This page covers Psilocybin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Esketamine page lists 11 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Scopolia (major), Cowhage (moderate), Dhea (moderate), Griffonia Simplicifolia (moderate) and Indian Snakeroot (moderate).

By severity: 1 major · 6 moderate · 4 minor.

From our pharmacist’s overview on the Esketamine page

“Esketamine (Spravato) is the nasal spray for depression that hasn't responded to standard treatment, and its supplement list deserves genuine respect. Scopolia carries the only major rating and is the entry to understand before any other; pairing it with the medication can raise the risk of anticholinergic effects, meaning dry mouth, b…”

Reviewed by 2 · Jul 18, 2026

Open the Esketamine interaction page

How much people look this up

Where Psilocybin and Esketamine Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Psilocybin

Top half

#499 of 1,452 supplements looked up here in the last 7 days

29 days ago today

Medication Esketamine

Steady interest

#2,247 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Where does our data come from?

Source: the Natural Medicines (TRC Healthcare) clinical database — the evidence-graded professional reference for herb & supplement interactions.
Citation library: 103,510 references behind our interaction content, 65,311 of them resolved to verified PubMed/DOI sources. See every Psilocybin reference on this page ↓
Freshness: we automatically re-check this combination every week — this pair was last verified September 20, 2026. The Psilocybin and Esketamine records this page draws on were last updated July 10, 2026.
What “no known interaction” means: no documented interaction in the sources above — not a guarantee of safety. Supplements are studied far less than prescription drugs, so we say exactly what the evidence supports, and nothing more.

Data structure & sourcing designed and verified by Dr. Brian Staiger, PharmD, BCPS.

Supplement

About Psilocybin

What is Psilocybin?

Depression
Anxiety (including in serious illness)
Substance use disorders
Post-traumatic stress
Spiritual or psychological exploration

Psilocybin is a powerful psychedelic compound found in certain mushrooms and is being studied for hard-to-treat depression, anxiety, and addiction, but it is still investigational and not an approved supplement. It is illegal in most places, can cause intense and unpredictable mental effects, and should never be used outside of a supervised clinical setting.

Psilocybin is a compound found in certain mushrooms (often called 'magic mushrooms') · Dried mushrooms, capsules, isolated/synthetic psilocybin (used in clinical trials)

An interaction check asks whether these two react with each other — it does not ask whether Psilocybin is a good idea for someone in your situation. Here is what our Psilocybin record says about it on its own.

Psilocybin: dosing

There is no established, safe over-the-counter dose of psilocybin. In research studies, doses are carefully measured, purified, and given under medical supervision with psychological support before, during, and after.Mushroom strength varies widely, so there is no reliable way to know how much you are taking from wild or non-medical sources. Because psilocybin is illegal in most places and can cause strong reactions, we cannot recommend any home dose.

From our Psilocybin monograph — the full record covers uses, side effects and every documented interaction.

Read the full Psilocybin monograph & all interactions

Medication

About Esketamine Nasal Spray

What Is Esketamine Nasal Spray Used For?

Brand name: Spravato

Spravato nasal spray is approved for two uses in adults. First, it treats treatment-resistant depression (TRD) — depression that has not responded to other antidepressants — either on its own or alongside an oral antidepressant. Second, it treats depressive symptoms in adults with major depressive disorder (MDD) who have acute suicidal ideation or behavior, always used together with an oral antidepressant in this case.

Important limits: Spravato has not been shown to prevent suicide or reduce suicidal thoughts or behavior on its own. It is not a replacement for hospitalization if that is clinically needed, and it is not approved as an anesthetic.

Most-Reported Side Effects for Esketamine

From FAERS, the FDA’s public side-effect reporting system (17,728 reports, all brands). Reports are voluntary and are not proof the drug caused the effect.

Dissociation 3,733 reports

Sedation 2,706 reports

Suicidal ideation 1,351 reports

Nausea 957 reports

Depression 873 reports

See full Esketamine Nasal Spray drug information

Keep checking

Other Drugs & Psilocybin

Browse every other medication we’ve checked against Psilocybin — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major

293Moderate

0Minor

2,536No known interaction

293 Moderate 2,536 No interaction

Moderate

293 interactions

Showing 60 of 293 moderate interactions — see all 293 on the Psilocybin page.

No interaction 2,536 drugs checked — show the list

We also checked Psilocybin against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 2,536 medications checked with no known interaction — see the full Psilocybin list.

See the full Psilocybin interactions page

See every supplement checked against Esketamine, ranked by severity

Evidence & sources

Psilocybin References

The 65 references that drive our Psilocybin monograph and interaction data, from the evidence-graded Natural Medicines (TRC Healthcare) database. Citations with a link open the study on PubMed or the publisher’s site.

Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 2016;30(12):1181-1197. PubMed
Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl) 2018;235(2):399-408. PubMed
Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 2016;30(12):1165-1180. PubMed
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):619-27. PubMed
Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry 2021;78(5):481-489. PubMed
Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol 2015;29(3):289-99. PubMed
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):71-8. PubMed
Vargas AS, Luís Â, Barroso M, Gallardo E, Pereira L. Psilocybin as a new approach to treat depression and anxiety in the context of life-threatening diseases-A systematic review and meta-analysis of clinical trials. Biomedicines 2020;8(9):331. PubMed
Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 2014;28(11):983-92.
Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology 2018;142:143-166. PubMed
Brown RT, Nicholas CR, Cozzi NV, et al. Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Clin Pharmacokinet 2017;56(12):1543-1554. PubMed
Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry 2006;67(11):1735-40. PubMed
Griffiths RR, Johnson MW, Richards WA, et al. Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial at
Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory controlled study of the migraine-suppressing effects of psilocybin. Neurotherapeutics 2021;18(1):534-543. PubMed
Carbonaro TM, Bradstreet MP, Barrett FS, et al. Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. J Psychopharmacol 2016;30(12):1268-1278. PubMed
Barrett FS, Carbonaro TM, Hurwitz E, Johnson MW, Griffiths RR. Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition. Psychopharmacology (Berl) 2018;235(10):2915-2927. PubMed
Studerus E, Kometer M, Hasler F, Vollenweider FX. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol 2011;25(11):1434-52. PubMed
Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology (Berl) 2004;172(2):145-56. PubMed
Bienemann B, Ruschel NS, Campos ML, Negreiros MA, Mograbi DC. Self-reported negative outcomes of psilocybin users: A quantitative textual analysis. PLoS One 2020;15(2):e0229067. PubMed
Rosenbaum D, Weissman C, Anderson T, et al. Microdosing psychedelics: Demographics, practices, and psychiatric comorbidities. J Psychopharmacol 2020;34(6):612-622. PubMed
Carbonaro TM, Johnson MW, Griffiths RR. Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan. Psychopharmacology (Berl) 2020;237(8):2293-2304. PubMed
Anderson BT, Danforth A, Daroff PR, et al. Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine 2020;27:100538. PubMed
Dahmane E, Hutson PR, Gobburu JVS. Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Psilocybin/Psilocin. Clin Pharmacol Drug Dev 2021;10(1):78-85. PubMed
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. PubMed
Carbonaro TM, Johnson MW, Hurwitz E, Griffiths RR. Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences. Psychopharmacology (Berl) 2018;235(2):521-534. PubMed
Higgins GA, Carroll NK, Brown M, et al. Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property. Front Pharmacol 2021;12:640241. PubMed
Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci U S A 2021;118(17):e2022489118. PubMed
Bravermanová A, Viktorinová M, Tyl &scaron; F, et al. Psilocybin disrupts sensory and higher order cognitive processing but not pre-attentive cognitive processing-study on P300 and mismatch negativity in healthy volunteers. Psychopharmacology (Berl) 201 PubMed
Winter JC, Rice KC, Amorosi DJ, Rabin RA. Psilocybin-induced stimulus control in the rat. Pharmacol Biochem Behav 2007;87(4):472-80. PubMed
Johnson MW, Sewell RA, Griffiths RR. Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers. Drug Alcohol Depend 2012;123(1-3):132-40. PubMed
Nicholas CR, Henriquez KM, Gassman MC, et al. High dose psilocybin is associated with positive subjective effects in healthy volunteers. J Psychopharmacol 2018;32(7):770-778. PubMed
Kometer M, Schmidt A, Bachmann R, Studerus E, Seifritz E, Vollenweider FX. Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychia PubMed
Hasler F, Bourquin D, Brenneisen R, Vollenweider FX. Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. J Pharm Biomed Anal 2002;30(2):331-9. PubMed
Wackermann J, Wittmann M, Hasler F, Vollenweider FX. Effects of varied doses of psilocybin on time interval reproduction in human subjects. Neurosci Lett 2008;435(1):51-5. PubMed
Bickel M, Ditting T, Watz H, et al. Severe rhabdomyolysis, acute renal failure and posterior encephalopathy after 'magic mushroom' abuse. Eur J Emerg Med 2005;12(6):306-8. PubMed
van Poorten JF, Stienstra R, Dworacek B, Moleman P, Rupreht J. Physostigmine reversal of psilocybin intoxication. Anesthesiology 1982;56(4):313. PubMed
Borowiak KS, Ciechanowski K, Waloszczyk P. Psilocybin mushroom (Psilocybe semilanceata) intoxication with myocardial infarction. J Toxicol Clin Toxicol 1998;36(1-2):47-9.
Hendin HM, Penn AD. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disord 2021. PubMed
Anderson T, Petranker R, Christopher A, et al. Psychedelic microdosing benefits and challenges: an empirical codebook. Harm Reduct J 2019;16(1):43. PubMed
Fadiman J, Korb S. Might Microdosing Psychedelics Be Safe and Beneficial? An Initial Exploration. J Psychoactive Drugs 2019;51(2):118-122. PubMed
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. PubMed
Kotts WJ, Gamble DT, Dawson DK, Connor D. Psilocybin-induced takotsubo cardiomyopathy. BMJ Case Rep 2022;15(5):e245863. PubMed
Müller F, Kraus E, Holze F, et al. Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants. Psychopharmacology (Berl) 2022. PubMed
Rucker JJ, Marwood L, Ajantaival RJ, et al. The effects of psilocybin on cognitive and emotional functions in healthy participants: Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparati
Holze F, Ley L, Müller F, et al. Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology 2022;47(6):1180-1187. PubMed
Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial [published online ahead of print, 20 PubMed
Cavanna F, Muller S, de la Fuente LA, et al. Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study. Transl Psychiatry. 2022;12(1):307. PubMed
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.
Breeksema JJ, Kuin BW, Kamphuis J, van den Brink W, Vermetten E, Schoevers RA. Adverse events in clinical treatments with serotonergic psychedelics and MDMA: A mixed-methods systematic review. J Psychopharmacol 2022;36(10):1100-1117. PubMed
von Rotz R, Schindowski EM, Jungwirth J, et al. Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial [published correction appears in EClinicalMedicine. 2023 Jan 30;56:101841.
Ledwos N, Rosenblat JD, Blumberger DM, et al. A critical appraisal of evidence on the efficacy and safety of serotonergic psychedelic drugs as emerging antidepressants: Mind the evidence gap. J Clin Psychopharmacol 2022;42(6):581-588. PubMed
Suleiman M, Basu A, Belal S, Jacob T. From mushrooms to myolysis: A case of rhabdo in psilocybin-induced mood and psychotic disorder. J Nerv Ment Dis 2022;210(8):638-639. PubMed
Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial. Headache 2022;62(1 PubMed
Barber G, Nemeroff CB, Siegel S. A case of prolonged mania, psychosis, and severe depression after psilocybin use: Implications of increased psychedelic drug availability. Am J Psychiatry 2022;179(12):892-896. PubMed
Schneier FR, Feusner J, Wheaton MG, et al. Pilot study of single-dose psilocybin for serotonin reuptake inhibitor-resistant body dysmorphic disorder. J Psychiatr Res. 2023;161:364-370. PubMed
Raison CL, Sanacora G, Woolley J, et al. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA 2023;330(9):843-853. PubMed
Haikazian S, Chen-Li DCJ, Johnson DE, et al. Psilocybin-assisted therapy for depression: A systematic review and meta-analysis. Psychiatry Res 2023;329:115531. PubMed
Perez N, Langlest F, Mallet L, et al. Psilocybin-assisted therapy for depression: A systematic review and dose-response meta-analysis of human studies. Eur Neuropsychopharmacol 2023;76:61-76. PubMed
Goodwin GM, Croal M, Feifel D, et al. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacology 2023;48(10):1492-1499. PubMed
Agrawal M, Emanuel E, Richards B, Richards W, Roddy K, Thambi P. Assessment of Psilocybin Therapy for Patients With Cancer and Major Depression Disorder. JAMA Oncol 2023;9(6):864-866. PubMed
Bahji A, Lunsky I, Gutierrez G, Vazquez G. Efficacy and Safety of Four Psychedelic-Assisted Therapies for Adults with Symptoms of Depression, Anxiety, and Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis. J Psychoactive Drugs. 2023;1-1 PubMed
Peck SK, Shao S, Gruen T, et al. Psilocybin therapy for females with anorexia nervosa: a phase 1, open-label feasibility study. Nat Med 2023;29(8):1947-1953. PubMed
Lewis BR, Garland EL, Byrne K, et al. HOPE: A Pilot Study of Psilocybin Enhanced Group Psychotherapy in Patients With Cancer. J Pain Symptom Manage 2023;66(3):258-269. PubMed
Wong S, Kwan ATH, Teopiz KM, et al. A comparison between psilocybin and esketamine in treatment-resistant depression using number needed to treat (NNT): A systematic review. J Affect Disord 2024;350:698-705. PubMed
Ho C, Crawford JR. Neuroimaging features of psilocybin-induced toxic-metabolic encephalopathy in an adolescent. BMJ Case Rep 2024;17(3):e259721. PubMed

Medication overviews come from MedlinePlus (NIH); supplement label data from the NIH Dietary Supplement Label Database. Content is written and reviewed by licensed HelloPharmacist pharmacists — see our data sources and editorial standards.

Related: nutrient depletion

Esketamine Is Linked to Lower Levels of One Nutrient

Natural Medicines records Esketamine as a medicine that can lower these. This is not an interaction with Psilocybin — it is a separate effect of the medicine, and it is a reason some people are advised to supplement rather than to avoid one:

SODIUM›

Read the full Esketamine nutrient depletion report ›

Depletion records come from the licensed Natural Medicines database. Do not start a supplement on the strength of this page — ask your pharmacist or doctor whether it applies to you.

Pharmacist Counseling Corner

Taking Psilocybin and Esketamine Together: Common Questions

Is it safe to take Psilocybin with Esketamine?

We do not list a known interaction between Psilocybin and Esketamine. That does not guarantee the combination is risk-free, so confirm with your pharmacist or doctor — especially if you take other medications or have a health condition.

Do Psilocybin and Esketamine have any of the same side effects?

Yes — our sources link each of them separately to 10 of the same effects. That is not an interaction: neither changes how your body handles the other. It does mean that if one of those effects turns up, it can be harder to tell which one is behind it. They are listed on this page with the source behind each.

Are Psilocybin and Esketamine used for the same thing?

They overlap in purpose, which usually means the real question is whether you need both rather than whether they are safe together. This page lists the shared uses and how strong the evidence is for Psilocybin in each. That is a conversation for your prescriber, especially if Esketamine is being adjusted to a target.

How was the Psilocybin and Esketamine combination checked?

Interactions in our licensed database are recorded against drug classes. Esketamine is filed under 2 classifications, and Psilocybin has documented interactions with 2 drug classes — none of Esketamine's classifications are among them. A medication can belong to classes beyond those recorded in our dataset, so this describes how the check was run rather than guaranteeing safety.

Does Psilocybin interact with any other medications?

Yes. Psilocybin has 293 documented drug interactions in our database — Esketamine is simply not one of them. If you take anything else, it is worth checking each one; they are all listed on this page.

Does Esketamine interact with any supplements?

Yes. Esketamine has documented interactions with 11 supplements in our database — Psilocybin is not one of them. The Esketamine interaction page linked on this page lists every one, ranked by severity.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Where next

Keep Exploring

Psilocybin monograph Uses, safety profile, and every drug interaction in one place Esketamine Nasal Spray drug information The full plain-English guide to this medication Esketamine supplement interactions Every supplement checked against Esketamine, ranked by severity Supplement interaction checker Check any supplement or product against your medications Browse medications A–Z Every drug we’ve checked against herbs & supplements References The 65 citations behind this page Ask a pharmacist Free, personal answer from our licensed team

Still Have a Question About Esketamine and Psilocybin?

Our pharmacists answer your medication & supplement questions — free.

Ask a pharmacist

This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.