Psilocybin Efficacy With or Without Pimavanserin Pretreatment

Official title

PRISMatic: A Phase 1b Randomized, Double-Armed, Parallel-Group, Placebo-Controlled Trial of Psilocybin Efficacy With or Without Pimavanserin Pretreatment

Overview

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.

Interventions

• Drug Psilocybin
  Psilocybin, 25 mg, oral, single dose
• Drug Pimavanserin
  Pimavanserin, 34 mg, oral, two doses
• Drug Inactive Placebo
  Inactive placebo, oral, two doses

Primary outcome measures

• Persisting Effects Questionnaire (PEQ) score [Time frame: Day 7, Day 30]

Secondary outcome measures (2)

• Amygdala Response to Stimuli in the Emotion Recognition Test [Time frame: Day -1 (baseline), Day 7, Day 30]
• Pharmacokinetics (PK) of Psilocybin metabolites [Time frame: 0-6 hours]

Eligibility criteria

Inclusion criteria

• Age 21 to 65 years old
• Provision of written informed consent
• Fluency in English
• At least high school level of education
• Right-handed
• 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 supplement, 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.
• 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.

Exclusion criteria

• 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)
• History of psychiatric diagnosis in adulthood (≥18 years), including, but not limited to, major depressive disorder, bipolar disorder I and II, psychotic disorders, and substance use disorder.
• Current use of neuropsychiatric medications, including but not limited to typical/atypical antidepressants, antipsychotics, and stimulants.
• Lifetime history of 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.
• Unable or unwilling to perform study procedures, or inappropriate for further study participation as determined by the PI and/or study clinicians

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Basic science

Study locations

United States · 1 center

• Johns Hopkins Center for Psychedelic and Consciousness Research — Baltimore

Publications

• 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
• 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
• 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

Identifiers

NCT: NCT07610135 · IRB00526000

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗