Psilocybin Efficacy With or Without Pimavanserin Pretreatment

NCT07610135 | Not Yet Recruiting Phase 1 FDA Drug

• 1 other identifier: IRB00526000
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Twenty healthy adults (≥21 years old) will be enrolled to evaluate the efficacy of a single oral dose of psilocybin (25 mg) administered with or without pretreatment using oral pimavanserin (34 mg) or placebo. Outcome assessments will occur at 1 week and 1 month following psilocybin administration. The purpose of this study is to clarify the receptor-level mechanisms underlying psilocybin's effects on mood and well-being, along with the associated neurophysiologic signatures. These mechanisms will be examined using psychometric scales, autonomic and fMRI-based neurophysiologic markers, and integrated pharmacokinetic/pharmacodynamic modeling.

Conditions

Mood (Psychological Function); Well Being; Mood; Healthy

Keywords

Psilocybin; Randomized Controlled Trial; Tryptamine; Pimavanserin; Indoles; Indole Alkaloid

Outcome Measures

Primary Outcomes (1)

• Persisting Effects Questionnaire (PEQ) score

  Persisting effects will be assessed using the single item well-being item from the Persisting Effects Questionnaire (PEQ) at 1-week (primary inferential contrast) and 1-month post-dosing. The PEQ is an instrument designed to measure participants' retrospective attributions regarding the longer-term impact of the psilocybin experience, including effects on mood, behavior, and overall well-being. The item is rated on a 7-point Likert scale (-3 = decreased very much; -2 = decreased moderately; -1 = decreased slightly; 0 = no change; 1 = increased slightly; 2 = increased moderately; 3 = increased very much). Score range -3 to 3.

  Day 7, Day 30

Secondary Outcomes (2)

• Amygdala Response to Stimuli in the Emotion Recognition Test

  Day -1 (baseline), Day 7, Day 30

• Pharmacokinetics (PK) of Psilocybin metabolites

  0-6 hours

Study Arms (2)

Psilocybin + Pimavanserin

EXPERIMENTAL

Two oral pretreatment doses of pimavanserin (34 mg each) followed by a single oral dose of psilocybin (25 mg)

Drug: Psilocybin; Drug: Pimavanserin

Psilocybin + Placebo

PLACEBO COMPARATOR

Two oral pretreatment doses of inactive placebo followed by a single oral dose of psilocybin (25 mg)

Drug: Psilocybin; Drug: Inactive Placebo

Interventions

Psilocybin DRUG

Psilocybin, 25 mg, oral, single dose

Psilocybin + Pimavanserin; Psilocybin + Placebo

Pimavanserin DRUG

Pimavanserin, 34 mg, oral, two doses

Also known as: Nuplazid

Psilocybin + Pimavanserin

Inactive Placebo DRUG

Inactive placebo, oral, two doses

Psilocybin + Placebo

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged 21 to 65 years old
• Fluency in English
• At least high school level of education
• Right-handed
• Female participants of childbearing potential must agree to use a highly effective method of contraception throughout the study. Highly effective methods are defined as those that, when used consistently and correctly (alone or in combination), are associated with a failure rate of less than 1% per year. Condoms alone are not considered highly effective. Abstinence is not considered a highly effective method. However, at the investigator's discretion, abstinence may be accepted if, based on the investigator's judgment and knowledge of the participant's usual and preferred lifestyle, it can be reasonably expected to result in 100% effectiveness.
• Agree to abstain from any psychoactive drugs on the day prior to and the day of the drug administration session as demonstrated by a negative toxicology report.
• Agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at the research unit on the mornings of drug session days. If the participant does not routinely consume caffeinated beverages, he/she must agree not to do so on session days.
• Agree not to take any PRN medications on the mornings of drug sessions
• Agree that for one week before the drug session, he/she will refrain from taking any nonprescription medication, nutritional or herbal supplement except when approved by the study investigators. Exceptions will be evaluated by the study investigators and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals.

You may not qualify if:

• Non-English speakers and those with language or hearing impairments
• Left-handedness (assessed by the Edinburgh Handedness Inventory)
• Any lifetime history of psychedelic use, including serotonergic compounds (e.g., psilocybin, LSD, mescaline, DMT, 5-MeO-DMT) and nontraditional psychedelics (e.g., MDMA, ketamine, ibogaine)
• Presence of cardiac, pulmonary, vascular, renal, hepatic, or other significant medical comorbidities
• Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, and HR \>90 bpm), a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e., QTc \> 450 msec), heart valve, or TIA in the past year
• Lifetime history of serious psychiatric or neurological disorders, including bipolar disorder, psychosis, or seizure disorder
• Lifetime history of severe substance use disorder
• Current (within past six months) substance use disorder of moderate or greater severity
• Clinically significant suicidal ideation (with strong intent or means) within the past 6 months or lifetime history of suicide attempt, current suicidal ideation, or otherwise judged by a study clinician to be more than low risk for suicidality
• Current use/positive toxicology for illicit drugs at screening and prior to drug administration session (includes illicit, non-prescribed, or prohibited substances such as amphetamines, barbiturates, buprenorphine, benzodiazepines, cocaine, MDMA, methadone, opioids, phencyclidine (PCP), and tetrahydrocannabinol (THC))
• Nicotine user consuming the equivalent of ≥ 10 cigarettes/day
• Altered gastrointestinal anatomy \[history of surgeries that promote a general intestinal malabsorption (e.g., jejunoileal bypass, jejunocolic bypass, roux-en-Y gastric bypass, vertical banded gastroplasty, gastric band, gastric stapling, sleeve gastrectomy, biliopancreatic diversion with partial gastrectomy, distal gastric bypass, duodenal switch)\]
• Weight \< 40kg
• Have a first degree relative with schizophrenia or other psychotic disorders (except substance/medication-induced or due to another medical condition), or bipolar I disorder
• MRI contraindications (e.g., claustrophobia incompatible with MRI scanning, medical device or implant incompatible with MRI, prior history as a metal worker and/or certain metallic objects in the body). Must complete MRI screening form and be approved by MRI technologist before each scan.

Sponsors & Collaborators

• Johns Hopkins University: lead

Study Sites (1)

Johns Hopkins Center for Psychedelic and Consciousness Research

Baltimore, Maryland, 21224, United States

Location

Related Publications (3)

• Barrett FS, Doss MK, Sepeda ND, Pekar JJ, Griffiths RR. Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci Rep. 2020 Feb 10;10(1):2214. doi: 10.1038/s41598-020-59282-y.

  PMID: 32042038 BACKGROUND

• Atiq MA, Baker MR, Voort JLV, Vargas MV, Choi DS. Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties. Psychopharmacology (Berl). 2025 Jul;242(7):1481-1506. doi: 10.1007/s00213-024-06599-5. Epub 2024 May 14.

  PMID: 38743110 BACKGROUND

• Yaden DB, Griffiths RR. The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol Transl Sci. 2020 Dec 10;4(2):568-572. doi: 10.1021/acsptsci.0c00194. eCollection 2021 Apr 9.

  PMID: 33861219 BACKGROUND

MeSH Terms

Interventions

Psilocybin; pimavanserin

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines

Study Officials

• David B. Yaden, PhD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Arozo Azimi

CONTACT

410-550-0007; aazimi2@jh.edu

Mazen A. Atiq, MD

CONTACT

matiq3@jh.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2026
• First Posted: May 27, 2026
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: June 8, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)