Study of Psilocybin Under Anesthesia Controlled by EEG

NCT07479550 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 72097
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Major depressive disorder (MDD) affects millions of Americans and remains difficult to treat. Psilocybin, a psychedelic compound, has shown promise for reducing depression symptoms, but a key challenge in psychedelic research is that participants can usually tell whether they received the active drug - making it hard to conduct fully blinded studies. This study (Studying Psilocybin with Anesthesia Controlled by EEG \[SPACE\]) tests a new approach: administering psilocybin while participants are under general anesthesia, so that the noticeable psychological effects of psilocybin are masked. This allows both participants and outcome assessors to remain unaware of whether psilocybin or placebo was given, improving the scientific rigor of the research. Participants with MDD will be randomly assigned to receive either psilocybin or placebo across four dosing sessions conducted under general anesthesia. The study will assess whether this approach is safe and feasible, and will collect early data on whether it may reduce depression symptoms.

Conditions

Major Depression

Keywords

psilocybin; major depressive disorder; anesthesia; propofol; psychedelic-assisted therapy; blinding; masking

Outcome Measures

Primary Outcomes (2)

• Blinding Success - Correct Identification of Psilocybin at Final Dosing Session

  Percentage of participants who correctly guess whether they received a full dose of psilocybin during the final dosing session (Visit 20), assessed using the Blinding Survey at Visit 21.

  1 day after the final dosing session (Visit 21, Week 4)

• Blinding Success - Accuracy of Guessed Psilocybin Dose at Final Dosing Session

  The dose of psilocybin guessed by participants at Visit 21 compared to the dose actually received at Visit 20, assessed using the Blinding Survey.

  1 day after the final dosing session (Visit 21, Week 4)

Secondary Outcomes (3)

• Acute Drug Effects by Dose - Drug Effects Questionnaire (DEQ)

  Immediately after emergence at each of the 4 dosing sessions (Visits 5, 10, 15, 20; Weeks 1-4)

• Mystical-Type Experiences by Dose - Mystical Experiences Questionnaire (MEQ-30)

  Immediately after emergence at each of the 4 dosing sessions (Visits 5, 10, 15, 20; Weeks 1-4)

• Altered States of Consciousness by Dose - Three-Dimensional Altered States of Consciousness Scale (3D-ASCr)

  Immediately after emergence at each of the 4 dosing sessions (Visits 5, 10, 15, 20; Weeks 1-4)

Other Outcomes (27)

• Feasibility - Challenging Experiences Questionnaire (CEQ)

  Immediately after emergence at Visits 5, 10, 15, and 20 (Weeks 1-4)

• Safety - Incidence and Severity of Adverse Events

  Continuously from Visit 1 through Visit 25 (up to 7 weeks)

• Safety - PACU Discharge Readiness

  Within 4 hours of emergence at Visits 5, 10, 15, and 20 (Weeks 1-4)

Study Arms (2)

Sequence A

EXPERIMENTAL

Participants are randomized 1:1 to one of two dosing sequences. All participants receive all four dosing conditions across weekly sessions: placebo (0 mg), psilocybin 10 mg, and psilocybin 25 mg administered in two separate sessions. Sequences differ only in the order of the first two sessions. Specific sequence assignments are not disclosed to preserve blinding.

Drug: Psilocybin (Usona Institute); Drug: Propofol; Drug: Placebo

Sequence B

EXPERIMENTAL

Participants are randomized 1:1 to one of two dosing sequences. All participants receive all four dosing conditions across weekly sessions: placebo (0 mg), psilocybin 10 mg, and psilocybin 25 mg administered in two separate sessions. Sequences differ only in the order of the first two sessions. Specific sequence assignments are not disclosed to preserve blinding.

Drug: Psilocybin (Usona Institute); Drug: Propofol; Drug: Placebo

Interventions

Psilocybin (Usona Institute) DRUG

Oral psilocybin capsules administered at doses not disclosed to participants to preserve blinding. Each dose is administered approximately 30 minutes prior to induction of general anesthesia with propofol. Participants receive psilocybin or placebo across four weekly dosing sessions.

Sequence A; Sequence B

Propofol DRUG

Intravenous propofol administered by a board-certified anesthesiologist to induce and maintain general anesthesia during each of the four dosing sessions. Propofol is co-administered with psilocybin or placebo to mask the psychoactive effects of psilocybin and enable participant blinding.

Sequence A; Sequence B

Placebo DRUG

Oral placebo capsule identical in appearance to the psilocybin capsules, administered prior to induction of general anesthesia with propofol during one of the four dosing sessions.

Sequence A; Sequence B

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• People 25 to 65 years of age at screening;
• Able to read, understand, and provide dated, informed consent, either in writing or electronically, prior to screening. Patients will be deemed likely to comply with study protocol and communicate with study staff about adverse events and other clinically important information;
• Fluent in English;
• Able to commit to attend all study visits and participate in all remote data collection procedures;
• Be stable in background psychotherapy for at least 4 weeks prior to enrollment outside of the study and able to access mental healthcare for the duration of the study;
• Body mass index between 17-35 kg/m2.
• Participant has a current diagnosis of MDD during a current Major Depressive Episode (MDE) (single or recurrent episode as defined by DSM-5-TR \[if single episode, duration of ≥4 weeks\] and verified after evaluation by a qualified member of the investigative team using the QuickSCID-5 (Quick Structured Clinical Interview for DSM-5 Disorders).
• Able to physically tolerate general anesthesia, as determined by American Society of Anesthesiologists (ASA) Physical Status Class I or II. ASA Class III participants whose functional impairment is directly related to a psychiatric diagnosis (depression) will be included.
• Agree that for one week preceding the psilocybin sessions and throughout the study, they will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the study staff. Exceptions will be evaluated by the study staff and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals.
• Agree not to consume any food or drink after midnight preceding dosing days.
• Agree not to consume alcoholic beverages for 48 hours prior to and 24 hours following the dosing sessions.
• Agree not to use cannabis in any form for the duration of the study.
• Non-smoker, or abstained at least 6 weeks.
• For people who can become pregnant: agree to use highly effective contraception from entry into the trial through the end of the study.
• a. A person with a uterus is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterilized (i.e. has had a hysterectomy, bilateral salpingectomy or bilateral oophorectomy).

You may not qualify if:

• A potential participant will NOT be eligible for participation in this study if any of the following criteria are met:
• Has any ongoing legal or disability claim such as Worker's Compensation
• Is taking a medication belonging to any of the following classes:
• a. TCAs, MAOIs, SSRIs, SNRIs. (Other antidepressants including mirtazapine, nefazodone, trazodone, vilazodone, vortioxetine, and bupropion are allowed.) b. Typical or atypical antipsychotics c. Anticonvulsants such as valproate, topiramate, oxcarbazepine, carbamazepine. (Gabapentinoids and lamotrigine are allowed.) d. Other agents that may be associated with serotonin syndrome: i. St. John's Wort ii. S-adenosyl-methionine (SAM-e) iii. 5-Hydroxytryptophan (5-HTP) iv. Lithium v. Dextromethorphan vi. Linezolid vii. Buspirone viii. Efavirenz ix. Lorcaserin e. Agents that may interact with psilocybin metabolism/effects: i. Modulators of uridine diphosphate (UDP) or glucuronosyltransferase (UGT) (e.g., COMT inhibitors, ethinyl estradiol, valproate, diclofenac, mefenamic acid, verapamil, ketoconazole, itraconazole, probenecid, phenobarbital, protease inhibitors) ii. L-Methylfolate (\>/= 7.5mg/day) iii. Alcohol or aldehyde dehydrogenase inhibitors
• Is taking benzodiazepine medication such that patient cannot tolerate withholding doses 8 hours before through 6 hours after planned study intervention
• Is taking agents that may interact with psilocybin metabolism effects such that the patient cannot tolerate withholding doses 8 hours before through 6 hours after planned study intervention.
• For individuals who can become pregnant:
• a. Currently pregnant (confirmed or suspected) b. Currently breastfeeding c. Positive urinary pregnancy test at screening or immediately before dosing d. Unwilling or unable to use highly effective contraception (defined as methods with failure rate \<1% per year) from the time of consent through 30 days following the last dosing session e. Planning to become pregnant within 30 days following the psilocybin or placebo administration sessions
• Participation in a clinical trial within 30 days of entry into this trial, or during the trial, or treatment with another investigational drug or other intervention within 30 days or 5 half-lives, whichever is longer, that may interfere with psilocybin metabolism/effects.
• Currently receiving electroconvulsive therapy (ECT). Previous treatment with ECT is permitted; last treatment must be at least 30 days prior to entry into this trial.
• History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms, mania, or bipolar affective disorder
• A positive urine toxicology screen including amphetamines, cocaine, MDMA, cannabis, opioids, ketamine, and benzodiazepines at screening visit and on the morning of the dosing session.
• Use of psychedelics in the previous 6 months prior to screening (psilocybin, LSD, DMT, 5-Meo-DMT, MDMA, Ibogaine).
• History of meeting DSM-5 criteria for Hallucinogen Use Disorder (Moderate or Severe) or Hallucinogen Persisting Perception Disorder (HPPD),or has ever had a negative reaction to or experience with a psychedelic (e.g., "bad trip").
• Current diagnosis of a Substance Use Disorder over the last 12 months (SUD; Abuse or Dependence, as defined by DSM-V) per QuickSCID-5. Participants who are at risk of alcohol or cannabis withdrawal will be excluded (e.g. those who endorse tolerance or who have experienced previous withdrawal). The following categories of SUD will NOT be excluded: nicotine dependence; alcohol or cannabis substance use disorder rated "mild".

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Stanford University

Stanford, California, 94304, United States

Location

Related Publications (11)

• Stocker K, Hartmann M, Schmid Y, Vogt SB, Becker AM, Ley L, Straumann I, Arikci D, Klaiber A, Erne L, Vizeli P, Holze F, Liechti ME. The 3D-ASCr scale: A revalidation of the core dimensions of the Altered States of Consciousness Rating Scale 5D(11)-ASC for psychedelic research. J Psychopharmacol. 2025 Dec 26:2698811251397328. doi: 10.1177/02698811251397328. Online ahead of print.

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• Maclean KA, Leoutsakos JM, Johnson MW, Griffiths RR. Factor Analysis of the Mystical Experience Questionnaire: A Study of Experiences Occasioned by the Hallucinogen Psilocybin. J Sci Study Relig. 2012 Dec;51(4):721-737. doi: 10.1111/j.1468-5906.2012.01685.x.

  PMID: 23316089 BACKGROUND

• Yerubandi A, Thomas JE, Bhuiya NMMA, Harrington C, Villa Zapata L, Caballero J. Acute Adverse Effects of Therapeutic Doses of Psilocybin: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024 Apr 1;7(4):e245960. doi: 10.1001/jamanetworkopen.2024.5960.

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• Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008 Aug;22(6):603-20. doi: 10.1177/0269881108093587. Epub 2008 Jul 1.

  PMID: 18593734 BACKGROUND

• Lii TR, Smith AE, Flohr JR, Okada RL, Nyongesa CA, Cianfichi LJ, Hack LM, Schatzberg AF, Heifets BD. Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nat Ment Health. 2023 Nov;1(11):876-886. doi: 10.1038/s44220-023-00140-x. Epub 2023 Oct 19.

  PMID: 38188539 BACKGROUND

• Szigeti B, Heifets BD. Expectancy Effects in Psychedelic Trials. Biol Psychiatry Cogn Neurosci Neuroimaging. 2024 May;9(5):512-521. doi: 10.1016/j.bpsc.2024.02.004. Epub 2024 Feb 20.

  PMID: 38387698 BACKGROUND

• Aday JS, Heifets BD, Pratscher SD, Bradley E, Rosen R, Woolley JD. Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials. Psychopharmacology (Berl). 2022 Jun;239(6):1989-2010. doi: 10.1007/s00213-022-06123-7. Epub 2022 Apr 1.

  PMID: 35359159 BACKGROUND

• Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016 Jul;3(7):619-27. doi: 10.1016/S2215-0366(16)30065-7. Epub 2016 May 17.

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• von Rotz R, Schindowski EM, Jungwirth J, Schuldt A, Rieser NM, Zahoranszky K, Seifritz E, Nowak A, Nowak P, Jancke L, Preller KH, Vollenweider FX. Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. EClinicalMedicine. 2022 Dec 28;56:101809. doi: 10.1016/j.eclinm.2022.101809. eCollection 2023 Feb.

  PMID: 36636296 BACKGROUND

• Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, Bird C, Blom RE, Brennan C, Brusch D, Burke L, Campbell-Coker K, Carhart-Harris R, Cattell J, Daniel A, DeBattista C, Dunlop BW, Eisen K, Feifel D, Forbes M, Haumann HM, Hellerstein DJ, Hoppe AI, Husain MI, Jelen LA, Kamphuis J, Kawasaki J, Kelly JR, Key RE, Kishon R, Knatz Peck S, Knight G, Koolen MHB, Lean M, Licht RW, Maples-Keller JL, Mars J, Marwood L, McElhiney MC, Miller TL, Mirow A, Mistry S, Mletzko-Crowe T, Modlin LN, Nielsen RE, Nielson EM, Offerhaus SR, O'Keane V, Palenicek T, Printz D, Rademaker MC, van Reemst A, Reinholdt F, Repantis D, Rucker J, Rudow S, Ruffell S, Rush AJ, Schoevers RA, Seynaeve M, Shao S, Soares JC, Somers M, Stansfield SC, Sterling D, Strockis A, Tsai J, Visser L, Wahba M, Williams S, Young AH, Ywema P, Zisook S, Malievskaia E. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med. 2022 Nov 3;387(18):1637-1648. doi: 10.1056/NEJMoa2206443.

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MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Psilocybin; Propofol

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Dr. Boris Heifets, MD, PhD

  Stanford University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr. Boris Heifets, MD, PhD

CONTACT

4157161585; bheifets@stanford.edu

Dr. Pilleriin Sikka, PhD

CONTACT

sikka@stanford.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Participants are masked to treatment assignment through the use of general anesthesia - because they are unconscious during drug administration, they cannot detect the psychoactive effects of psilocybin. Outcomes assessors conducting blinded depression symptom ratings (MADRS) are kept unaware of treatment assignment throughout the study. The pharmacist preparing study drug is aware of treatment assignment for safety purposes but is otherwise not involved in outcome assessment.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: This is a within-subject, randomized sequence crossover design. Each participant receives all four dosing conditions - placebo (0 mg), psilocybin 10 mg, and psilocybin 25 mg administered across two separate sessions - in a randomized order. Dosing sessions are spaced one week apart.

Study Record Dates

• First Submitted: March 8, 2026
• First Posted: March 18, 2026
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: May 6, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)