Safety and Psychological Effects of Psilocybin and D-Serine Formulation in Healthy Volunteers

Overview

The goal of this open-label, dose-escalation, prospective study is to evaluate the safety and psychological effects of a Psilocybin and D-Serine formulation in healthy volunteers. The main objectives are: 1. To assess the psychological and physiological effects of psilocybin administered with D-Serine in healthy adults. 2. To determine whether D-Serine modulates or attenuates the psychedelic effects of psilocybin. 3. To evaluate the safety and tolerability of psilocybin and D-Serine co-administration. Study population includes: 10 healthy male or female volunteers aged 25-60 years with no history of psychiatric or major medical disorders and no current evidence of such disorders. The study includes two cohorts. The first cohort of 5 participants will receive 15 mg of Psilocybin and 5 g of D-Serine. Safety data will be collected and submitted in an interim report to the Ethics Committee. If no safety concerns arise, the second cohort will receive an increased dose of 25 mg of Psilocybin and 7 g of D-Serine to help determine the optimal dose for a future Phase IIa clinical trial.

Detailed description

This is a first-in-human, Phase I, exploratory clinical trial designed to evaluate the safety, tolerability, and initial psychological and physiological responses to a single administration of psilocybin in combination with D-Serine in healthy adult volunteers. The rationale for this combination stems from preclinical evidence indicating that D-Serine, a naturally occurring co-agonist at the NMDA receptor, may attenuate the acute psychedelic effects of psilocybin while preserving its neuroplastic and therapeutic properties.

Preclinical studies demonstrated that D-Serine reduced the psilocybin-induced head-twitch response (HTR) in rodent models and enhanced the expression of synaptic plasticity markers (e.g., GAP43, PSD95, SV2A, synaptophysin) across multiple brain regions, with effects sustained up to 12 days post-treatment. These findings suggest that the combination may improve the safety and tolerability of psilocybin, particularly for populations sensitive to its psychoactive effects.

The trial will consist of four sequential components:

Screening Phase - to assess eligibility.

Preparation Phase - to establish therapeutic rapport and baseline assessments.

Administration Phase - involving a single oral administration of the investigational combination (psilocybin + D-Serine).

Follow-up Phase - including in-person follow-up visits on Day 2, Day 7, Day 28, and Day 84 post-treatment to monitor safety outcomes, subjective responses, and potential delayed effects.

Interventions

• Drug Psilocybin and D-Serine
  A single administration of the drug, with dosage divided as follows: Cohort 1: 15 mg of Psilocybin and 5 gr of D-Serine Cohort 2: 25 mg of Psilocybin and 7 gr of D-Serine
• Diagnostic test Physical Examination
  The physical examination will include diagnosis and documentation of any significant clinical abnormalities or diseases. It will be performed during the baseline rating visit (preparation phase).
• Diagnostic test Vital signs
  Vital sign measurements (blood pressure, pulse, and oxygen saturation) will be taken at screening, preparation, baseline rating, administration day, day 2, day 28, and day 84. Vital signs will be assessed at the following time points on the administration day and on day 2: pre-administration, and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours post-administration.
• Diagnostic test ECG test
  A 12-lead ECG will be performed to rule out underlying cardiac abnormalities. An ECG will be conducted for each patient during the screening and Day 2 visits.
• Diagnostic test Comprehensive Blood Panel
  A comprehensive blood panel will be performed to assess kidney and liver function, electrolyte balance, and glucose levels. It will be conducted during the Screening visit, and on Day 2, Day 28, and Day 84.
• Diagnostic test Complete Blood Count
  Complete Blood Count will be performed to check for hematological abnormalities. It will be conducted during the Screening visit, and on Day 2, Day 28, and Day 84.
• Diagnostic test Urinalysis
  Urinalysis will be conducted during the Screening visit, and on Day 2, Day 28, and Day 84.
• Diagnostic test Urine Toxicology Screen
  Urine Toxicology Screen will be performed to rule out illicit drug use. It will be conducted during the Screening visit, and on Day 2, Day 28, and Day 84.
• Diagnostic test A pregnancy Urine test
  A urine pregnancy test will be performed for women of childbearing potential only. It will be conducted during the screening and baseline rating visits. If the urine test is positive, a serum β-hCG test will be performed for confirmation.
• Diagnostic test Electroencephalogram
  EEG will be performed during the baseline rating scale and Day 7 visits to evaluate brain activity

Primary outcome measures

• Incidence and severity of treatment-emergent adverse events (TEAEs) following administration of psilocybin and D-serine [Time frame: From time of dosing (Day 1) through Day 84 (final follow-up visit)]

Secondary outcome measures (9)

• Change in subjective psychedelic experience measured by the 5D-ASC scale [Time frame: 6 hours post-dosing and Day 2 follow-up]
• Change in mood states assessed by the Profile of Mood States (POMS) [Time frame: Baseline, 8 and 20 hours post-dosing, Day 2, Week 1, and Day 84]
• Change in anxiety and stress measured by the Subjective Units of Distress Scale (SUDS) [Time frame: Baseline, 8 and 20 hours post-dosing, Day 2]
• Change in plasma D-serine concentration [Time frame: Baseline and Week 1 (Day 7)]
• Change in plasma inflammatory markers concentration. [Time frame: Baseline and Week 1 (Day 7)]
• Change in plasma BDNF concentration [Time frame: Baseline and Week 1 (Day 7)]
• Change in plasma glutamate concentration [Time frame: Baseline and Week 1 (Day 7)]
• Beck Depression Inventory-II (BDI-II) total score [Time frame: Baseline (Day -1), Day 2, Day 7, and Day 84]
• State-Trait Anxiety Inventory (STAI) - State and Trait scores [Time frame: Baseline (Day -1), Day 2, Day 7, and Day 84]

Eligibility criteria

Inclusion criteria

• Aged 25-60 years, male or female.
• Medically healthy, as confirmed by a comprehensive clinical assessment.
• Written informed consent provided.

Exclusion criteria

• History of any Axis 1 psychiatric disorder requiring pharmacotherapy such as schizophrenia, schizoaffective disorder, any other psychotic disorder, bipolar disorder, as well as non-psychotic disorders such as generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, posttraumatic stress disorder.
• Family history (among first-degree relatives) of schizophrenia, bipolar disorder, or other psychotic disorder
• History of cardiovascular disorders.
• Pregnant or breastfeeding women or women of childbearing age not using effective contraception.
• Use of psilocybin or other psychedelic compound in the 12 months preceding the study
• Use of medications that interact with psilocybin or D-Serine.
• Positive urinary drug screening.

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

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Israel · 1 center

• Hadassah Medical Organization, Jerusalem, Israel — Jerusalem

Identifiers

NCT: NCT07079930 · Ps-PD-24-01-HMO-CTIL

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗