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Identification of a Safe and Non-Psychedelic Dose of Psilocybin

This Phase I, randomised, double-blind, placebo-controlled single ascending dose trial (n=56) evaluated oral psilocybin in healthy adults to identify a safe, non-psychedelic threshold dose and to assess safety, tolerability, pharmacodynamic effects and pharmacokinetics. Participants received single doses of psilocybin from 0.5 mg up to 5 mg, with matching placebo, in a parallel-group design. The study enrolled up to 10 cohorts of 8 subjects, with 6 assigned to psilocybin and 2 to placebo in each cohort. Dosing took place during a 3-day/2-night inpatient treatment phase, with safety monitoring and pharmacodynamic assessments collected through 24 hours after dosing and follow-up about 7±2 days later. Outcome measures included adverse events, vital signs, ECGs, laboratory tests, the 5D-ASC, STAI, reaction time, rapid visual information processing, spatial working memory, and multiple visual analogue scales for perceived drug effects, alongside blood sampling for pharmacokinetic analysis and possible pharmacogenetic testing.

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Target Enrollment
56 participants
Study Type
Phase I interventional
Design
Randomized, quadruple Blind

Detailed Description

This randomized, double-blind, placebo-controlled, single ascending dose study will evaluate psilocybin in healthy adult subjects. Each subject will complete Screening within 28 days before admission, a 3-day/2-night inpatient Treatment Phase from Day -1 to Day 2, and Follow-Up 7±2 days after dosing.

Up to 80 subjects will be enrolled in up to 10 cohorts of 8 subjects. In each cohort, 6 will receive a single oral dose of psilocybin and 2 matching placebo. The first cohort will receive 0.5 mg psilocybin or placebo. The DSRC will determine subsequent dose levels after each completed cohort. Proposed doses are 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and up to 5 mg; lower doses, repeated levels, or smaller increments such as 0.25 mg may be used based on emerging data.

Within each cohort, safety and pharmacodynamic data will be collected through 24 hours post dose. Safety monitoring will include adverse events, vital signs, ECGs, laboratory tests, physical examinations, concomitant medications, and C-SSRS results. Pharmacokinetic blood samples will be collected before and after dosing, and blood for possible retrospective pharmacogenetic analysis will be collected on Day -1.

Pharmacodynamic assessments will include Alertness/Drowsiness, Agitation/Relaxation, Hallucinations, Any Effects, Bowdle, Bond-Lader, 5D-ASC, and STAI measures. Cognitive and psychomotor testing will include RTI, RVP, and SWM tasks. Pupil diameter will be measured as an objective marker. Other subject-reported effects may be recorded as adverse events at the investigator's discretion.

Subjects will be discharged on Day 2 if medically appropriate and will receive a 24-hour/7-day emergency clinic contact number. After each cohort, the DSRC will review available blinded safety and pharmacodynamic data through 24 hours post dose before the next cohort begins. Escalation and any decision to stop will follow prespecified rules.

The study aims to identify a safe threshold dose (TD) that does not elicit psychoactive effects. The TD will be the dose immediately before the dose at which escalation stops because of neuropsychiatric adverse events and/or a pharmacodynamic response pattern indicating a dose above the nonpsychoactive level. The study will end when a TD is identified or the 5 mg maximum dose is reached.

Study Arms & Interventions

Psilocybin 0.5 mg or Placebo

experimental

Psilocybin 0.5 mg in 5 mL sucralose randomly administered to 6 participants and placebo (5 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 1.0 mg or Placebo

experimental

Psilocybin 1 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 1.5 mg or Placebo

experimental

Psilocybin 1.5 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 2.0 mg or Placebo

experimental

Psilocybin 2.0 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 2.5 mg or Placebo

experimental

Psilocybin 2.5 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 3.0 mg or Placebo

experimental

Psilocybin 3.0 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 3.5 mg or Placebo

experimental

Psilocybin 3.5 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 4.0 mg or Placebo

experimental

Psilocybin 3.5 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 4.5 mg or Placebo

experimental

Psilocybin 4.5 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Psilocybin 5.0 mg or Placebo

experimental

Psilocybin 5.0 mg in 10 mL sucralose randomly administered to 6 participants and placebo (10 mL sucralose) randomly administered to 2 participants.

Interventions

  • Psilocybin

Participants

Ages
18 – 55
Sexes
Male & Female

Inclusion Criteria

  • Subjects must meet each of the following inclusion criteria to be eligible for participation in the study:
  • 1. Must provide written informed consent prior to the initiation of any protocol-specific procedures.
  • 2. Male and female adults, between 18 and 55 years of age, inclusive.
  • 3. Body mass index (BMI) within 18.0 to 34.0 kg/m2, inclusive (minimum weight of at least 50.0 kg).
  • 4. Systolic blood pressure between 95-140 mmHg, inclusive; diastolic blood pressure between 55-90 mmHg, inclusive; and heart rate between 50-100 bpm, inclusive, unless deemed otherwise by the investigator.
  • 5. Clinical laboratory values within the clinical site's most recent acceptable laboratory test ranges, and/or values are deemed by the investigator as not clinically significant.
  • 6. Non-smoker, for at least 6 months prior to first study drug administration.
  • 7. Agrees not to receive the COVID-19 vaccination from 7 days prior to the first study drug dose until at least 7 days after the last study drug administration.
  • 8. Female subjects must be non-pregnant and non-lactating and must fulfil at least one of the following:
  • * Be surgically sterile for a minimum of 6 months (achieved through hysterectomy, oophorectomy, or bilateral salpingectomy; note that tubal ligation is not considered a method of permanent sterilization).
  • * Post-menopausal for a minimum of 1 year (confirmed by follicle-stimulating hormone test).
  • * Agree to avoid pregnancy and use a medically acceptable method of contraception with male sexual partners from at least 30 days prior to the study until 30 days after the study has ended (last study procedure).
  • Medically acceptable methods of contraception include any of the following:
  • * double-barrier methods (e.g., male condom, spermicide with diaphragm or spermicide with cervical cap)
  • * oral contraceptives; hormonal patch, implant or injection; or hormonal or non-hormonal intrauterine device. The male partner should use, at all times, a male condom with spermicide, should the female subject choose to use any of these methods
  • * complete abstinence, should it be in line with the subject's preferred and usual lifestyle
  • 9. Males who are able to father children must agree to use medically acceptable methods of contraception during the study and for 30 days after the last study drug administration. If a subject's partner should become pregnant during his participation in the study and for 30 days after he has completed his last study drug administration, the subject must inform BioPharma Services Inc. staff immediately. Medically acceptable methods of contraception include:
  • * using a condom with a female partner of child-bearing potential who is using oral contraceptives; hormonal patch, implant or injection; hormonal or non-hormonal intrauterine device; or diaphragm or cervical cap with spermicide
  • * complete abstinence, should it be in line with the subject's preferred and usual lifestyle.
  • 10. Male subjects must refrain from sperm donation from clinic admission to at least 30 days after the last dose of study drug.
  • 11. Must be able to speak, read, and understand English sufficiently to allow completion of all study assessments.
  • 12. Must be willing to comply with the requirements and restrictions of the study.

Exclusion Criteria

  • Subjects will not be eligible to participate in this study if any of the following exclusion criteria is met:
  • 1. History or presence of any clinically significant cardiac, psychiatric, endocrine, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal, or other disease at Screening, which, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results.
  • 2. Clinically significant abnormality on ECG, including a QT interval corrected for heart rate (Bazett; QTcB interval) of \>440 milliseconds in males and \>460 milliseconds in females.
  • 3. History of allergies to the investigational product or excipients.
  • 4. History of seizures, family history of seizures, history of head trauma, history of neurosurgery, or close family history of idiopathic generalized epilepsy or other congenital epilepsies.
  • 5. Positive for hepatitis B virus surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV) antibody.
  • 6. Positive urine drug screen (UDS) for opioids, amphetamines, cocaine, tetrahydrocannabinol (THC), barbiturates, phencyclidine, or benzodiazepines upon any admission into the clinic.
  • 7. Positive breath alcohol test at admission to the clinic.
  • 8. Current or history of drug or alcohol dependence (excluding caffeine and nicotine) within the past 2 years, or lifetime history of participation in a drug rehabilitation program (other than treatment for smoking cessation).
  • 9. Has used CNS drugs with perception-altering properties (e.g., ketamine, lysergic acid diethylamide \[LSD\], phencyclidine \[PCP\], dextromethorphan, 3,4 methylenedioxymethamphetamine \[MDMA\], mescaline, psilocybin, tryptamine derivatives, or ring-substituted amphetamines with perception-altering effects) for non-therapeutic purposes (i.e., for psychoactive effects) within the past 5 years and/or ≥5 lifetime uses.
  • 10. Personal or immediate family history of schizophrenia, bipolar affective disorder, delusion disorder, paranoid disorder, schizoaffective disorder, or personality disorder.
  • 11. History of suicidal ideation or active suicidality, based on C-SSRS results.
  • 12. Concurrent or recent (within 5 years) history of major depression, obsessive-compulsive disorder, panic disorder, general anxiety disorder, social anxiety disorder, anorexia nervosa, or bulimia nervosa.
  • 13. Has donated \>500 mL of blood within 30 days prior to study drug administration.
  • 14. Requires concomitant treatment with any prescription or non-prescription medications (with the exception of acetaminophen) or natural health products (herbal remedies) within 14 days prior to receiving study drug.
  • 15. Has unsuitable or difficult venous access or is unwilling or unable to undergo direct venipuncture or catheter insertion.
  • 16. Is currently using an investigational drug or device or has used such in the 30 days prior to receiving study drug.
  • 17. Female subject is pregnant, breastfeeding, or has had a recent positive pregnancy test.
  • 18. Subject, in the investigator's opinion, is unsuitable for clinical study participation.

Study Protocol, Arms & Participants

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Study Details

Study Team

Sponsors & Collaborators

Locations

BioPharma Services Inc. — Toronto, Ontario, Canada

Related Publications

Open AccessindividualPrimary

A randomized, double-blind, placebo-controlled single-ascending-dose study to identify a non-hallucinogenic dose of psilocybin in healthy adults

This Phase I randomised, double-blind, placebo-controlled single-ascending-dose trial (n=56) in healthy adults tested low doses of psilocybin and found dose-related subjective effects and pupil dilation, but no serious side effects, hallucinations, or measurable cognitive decline. Subjective effects became distinguishable from placebo at 2.5 mg or below, suggesting low doses may separate psilocybin’s pharmacology from its hallucinogenic effects.

Published
Journal
MedRvix
Authors
Levy-Cooperman, N., Sellers, E., Glue, P., Szeto, I., Brown, D., Jarecki-Smith, J., Tyler, W. J., McDonnell, M. B.

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