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

Not Applicable

Not yet recruiting

• Conditions: Healthy Volunteers
• Interventions: Drug: Psilocybin and D-Serine; Diagnostic Test: Physical Examination; Diagnostic Test: Vital signs; Diagnostic Test: ECG test; Diagnostic Test: Comprehensive Blood Panel; Diagnostic Test: Complete Blood Count; Diagnostic Test: Urinalysis; Diagnostic Test: Urine Toxicology Screen; Diagnostic Test: A pregnancy Urine test; Diagnostic Test: Electroencephalogram; Diagnostic Test: Plasma Amino Acid Levels; Diagnostic Test: Plasma Inflammation Markers; Diagnostic Test: Plasma Brain-Derived Neurotrophic Facto; Other: Mini International Neuropsychiatric Interview; Other: Family Psychiatric History Assessment; Other: Beck Depression Inventory; Other: State-Trait Anxiety Inventory; Behavioral: Profile of Mood States; Behavioral: Subjective Units of Distress Scale; Other: Five-Dimensional Altered States of Consciousness questionnaire; Behavioral: Integration

• Registration Number: NCT07079930
• Lead Sponsor: Hadassah Medical Organization

Brief Summary

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.

Study Timeline

• Status Verified: 2025-07
• Study First Submitted: 2025-07-15
• Study First Submitted QC: 2025-07-15
• Study First Posted: 2025-07-23
• Last Update Submitted: 2025-07-28
• Last Update Posted: 2025-07-31
• Study Start: 2025-11-01
• Primary Completion: 2026-11
• Study Completion: 2027-02-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

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

Exclusion Criteria

1. 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.
2. Family history (among first-degree relatives) of schizophrenia, bipolar disorder, or other psychotic disorder
3. History of cardiovascular disorders.
4. Pregnant or breastfeeding women or women of childbearing age not using effective contraception.
5. Use of psilocybin or other psychedelic compound in the 12 months preceding the study
6. Use of medications that interact with psilocybin or D-Serine.
7. Positive urinary drug screening.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
25 mg of Psilocybin and 7 gr of D-Serine	ECG test	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Comprehensive Blood Panel	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Complete Blood Count	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Urinalysis	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Urine Toxicology Screen	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	A pregnancy Urine test	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Electroencephalogram	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Plasma Amino Acid Levels	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Plasma Inflammation Markers	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Plasma Brain-Derived Neurotrophic Facto	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Mini International Neuropsychiatric Interview	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Family Psychiatric History Assessment	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Beck Depression Inventory	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	State-Trait Anxiety Inventory	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Profile of Mood States	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Subjective Units of Distress Scale	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Five-Dimensional Altered States of Consciousness questionnaire	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Integration	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Psilocybin and D-Serine	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Physical Examination	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Vital signs	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	ECG test	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Urinalysis	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Comprehensive Blood Panel	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Complete Blood Count	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Electroencephalogram	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Plasma Amino Acid Levels	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Plasma Inflammation Markers	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Urine Toxicology Screen	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	A pregnancy Urine test	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Plasma Brain-Derived Neurotrophic Facto	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Mini International Neuropsychiatric Interview	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Profile of Mood States	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Family Psychiatric History Assessment	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Beck Depression Inventory	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	State-Trait Anxiety Inventory	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Subjective Units of Distress Scale	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Five-Dimensional Altered States of Consciousness questionnaire	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
15 mg of Psilocybin and 5 gr of D-Serine	Integration	The investigational drug, 15 mg of Psilocybin and 5 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Psilocybin and D-Serine	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Physical Examination	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.
25 mg of Psilocybin and 7 gr of D-Serine	Vital signs	The investigational drug, 25 mg of Psilocybin and 7 g of D-Serine, will be administered as a single oral dose in solution form.

Primary Outcome Measures

Name	Time	Method
Incidence and severity of treatment-emergent adverse events (TEAEs) following administration of psilocybin and D-serine	From time of dosing (Day 1) through Day 84 (final follow-up visit)	The number, type, severity, timing, and relatedness of treatment-emergent adverse events following administration of psilocybin and D-serine. Adverse events will be assessed through continuous clinical monitoring, spontaneous reports, and structured instruments including the UKU Side Effect Rating Scale. Safety will also be evaluated via changes in vital signs, ECG, and laboratory tests (SMAC-20, CBC, urinalysis). Events will be classified using standard regulatory definitions and graded for severity and relatedness to study treatment.

Secondary Outcome Measures

Name	Time	Method
Change in subjective psychedelic experience measured by the 5D-ASC scale	6 hours post-dosing and Day 2 follow-up	Assessment of subjective altered states of consciousness using the 5-Dimensional Altered States of Consciousness scale.; Full questionnaire consists of 94 items, each item reflects a subjective experience during the altered state.; Each rated on a visual analog scale from 0 to 100, where: 0 = "not at all" 100 = "extremely"; The items are grouped into 5 empirically derived dimensions, each representing a core aspect of altered consciousness: Oceanic Boundlessness- Positively experienced ego dissolution, unity, bliss High scores = mystical-type experiences Anxious Ego Dissolution- Anxiety, loss of ego control, cognitive impairment High scores = difficult or fearful experiences Visionary Restructuralization -Visual imagery, hallucinations, synesthesia High scores = complex visual phenomena Auditory Alterations - Changes in auditory perception, e.g., hearing sounds or voices Reduction of Vigilance- Reduced alertness or drowsiness (less relevant in classic psychedelic states)
Change in mood states assessed by the Profile of Mood States (POMS)	Baseline, 8 and 20 hours post-dosing, Day 2, Week 1, and Day 84	Change in emotional and mood states as measured by the POMS scale. Participants complete the questionnaire at multiple time points to evaluate transient mood fluctuations in response to treatment.; The administered version of the POMS questionnaire consists of 28 adjectives describing various feelings and emotions, and participants rate the extent to which they have experienced each over a specified period (e.g., the past week), typically using a 5-point Likert scale ranging from 0 ("not at all") to 4 ("extremely").
Change in anxiety and stress measured by the Subjective Units of Distress Scale (SUDS)	Baseline, 8 and 20 hours post-dosing, Day 2	Subjective assessment of distress and anxiety using the SUDS, a self-report scale ranging from 0 (no distress) to 100 (extreme distress). Assessed multiple times to track acute and residual anxiety responses.
Change in plasma D-serine concentration	Baseline and Week 1 (Day 7)	Measurement of plasma D-serine (in micromoles per liter (µmol/L)) to explore potential neurobiological correlates of treatment. Blood collected at baseline and follow-up.
Change in plasma inflammatory markers concentration.	Baseline and Week 1 (Day 7)	Measurement of plasma inflammatory markers to explore potential neurobiological correlates of treatment. Blood collected at baseline and follow-up.
Change in plasma BDNF concentration	Baseline and Week 1 (Day 7)	Measurement of plasma PLASMA Brain-Derived Neurotrophic Factor (in micromoles per picograms per milliliter (pg/mL)) to explore potential neurobiological correlates of treatment. Blood collected at baseline and follow-up.
Change in plasma glutamate concentration	Baseline and Week 1 (Day 7)	Measurement of plasma glutamate (in micromoles per liter (µmol/L)) to explore potential neurobiological correlates of treatment. Blood collected at baseline and follow-up.
Beck Depression Inventory-II (BDI-II) total score	Baseline (Day -1), Day 2, Day 7, and Day 84	Self-reported symptoms of depression will be assessed using the 21-item Beck Depression Inventory-II, which provides a standardized index of depressive severity.; Each corresponding to a symptom of depression, rated on a scale from 0 to 3 based on intensity. The total score ranges from 0 to 63, with higher scores indicating more severe depressive symptoms. Score interpretation is as follows: 0-13 = minimal depression, 14-19 = mild depression, 20-28 = moderate depression, and 29-63 = severe depression.
State-Trait Anxiety Inventory (STAI) - State and Trait scores	Baseline (Day -1), Day 2, Day 7, and Day 84	Anxiety symptoms will be measured using the STAI, which provides separate scores for State Anxiety (how participants feel in the moment) and Trait Anxiety (how they generally feel).; The STAI consists of 40 items - 20 assessing state anxiety and 20 assessing trait anxiety - each rated on a 4-point Likert scale. Scores for each subscale range from 20 to 80, with higher scores indicating greater levels of anxiety. Generally, a score of 20-37 suggests low anxiety, 38-44 moderate anxiety, and 45-80 high anxiety.

Trial Locations

Locations (1)

Hadassah Medical Organization, Jerusalem, Israel; 🇮🇱 Jerusalem, Israel