Microdosing Psychedelics to Improve Mood

NCT05259943 | Completed Phase 2

• 1 other identifier: ABC123DRM
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

This trial aims to examine the safety and efficacy of small (2mg) sub-hallucinogenic doses of psilocybin in people with Major Depressive Disorder.

Conditions

Major Depressive Disorder

Keywords

Psilocybin; Psychedelics; Creativity; Mindfulness; Depression

Outcome Measures

Primary Outcomes (1)

• Change in Patient Health Questionnaire Somatic-Anxiety-Depression

  The PHQ-SADS is a 32-item self-report subset of the full PHQ designed to detect the co-occurrence of somatic, anxiety, and depressive symptoms (the SAD triad). Responses are measured using a likert scale between 0 (not bothered) and 2 (bothered a lot). Higher scores suggest more severe depressive symptoms.

  Every week until week 4.

Study Arms (3)

Blinded Placebo

PLACEBO COMPARATOR

In this condition participants will receive an inert placebo once weekly for 4 weeks, but they will not know whether they receive placebo or psilocybin.

Drug: Placebo first

Blinded Psilocybin

EXPERIMENTAL

In this condition participants will receive psilocybin once weekly for 4 weeks, but they will not know whether they receive placebo or psilocybin.

Drug: Psilocybin first

Open Label

EXPERIMENTAL

In this condition participants will receive psilocybin once weekly for 4 weeks, and will be told that they are receiving psilocybin.

Drug: Psilocybin first; Drug: Placebo first

Interventions

Placebo first DRUG

Participants will receive 4 doses of placebo followed by 4 doses of 2mg psilocybin

Blinded Placebo; Open Label

Psilocybin first DRUG

Participants will receive 8 doses of 2mg psilocybin.

Blinded Psilocybin; Open Label

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must:
• Have given written informed consent.
• Have a high school level of education.
• Be fluent in speaking and reading the study site's predominantly used or recognized language (i.e., English).
• Be 18 to 65 years old.
• If of childbearing potential, must have a negative pregnancy test at study entry and must agree to use adequate birth control 10 days after the last Experimental Session (refer to section 9.4.2 for contraceptive guidelines).
• Have a preexisting diagnosis of MDD with dysthymic subtype or receive a diagnosis of MDD during screening.
• Agree that for one week preceding each psilocybin session, they will refrain from taking any nonprescription medication, nutritional supplements, or herbal supplement except when approved by the research team. Exceptions will be evaluated by the research team and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals with the exception of SAM-e, 5-HTP, L-tryptophan, and St. John's Wort.
• Agree to consume approximately the same amount of caffeine-containing beverage (i.e. coffee, tea) that they consume on a usual morning, before arriving at the research unit on the mornings of psilocybin session days. Caffeine consumption should not exceed more than ≥600mg/day. If the patient does not routinely consume caffeinated beverages, they must agree not to do so on psilocybin session days.
• Agree not to take any as needed (PRN) medications on the mornings of psilocybin sessions. Non-routine PRN medications for treating breakthrough pain that were taken in the 24 hours before the psilocybin session may result in rescheduling the treatment session, with the decision at the discretion of the investigators.
• Agree to refrain from using any psychoactive drugs, including alcoholic beverages, within 24 hours of each psilocybin administration. As described elsewhere, exceptions include daily use of caffeine.

You may not qualify if:

• The subject has participated in another investigational study within 60 days prior to the screening visit.
• Cardiovascular conditions: coronary artery disease, uncontrolled hypertension, angina, a clinically significant ECG abnormality (i.e. atrial fibrillation), TIA in the last 6 months, stroke, peripheral or pulmonary vascular disease (no active claudication).
• Blood pressure exceeding screening criteria described below:
• ○ Cardiovascular screening:
• At the screening and randomization visit, blood pressure will be assessed to qualify to proceed in the trial. Each assessment occasion will involve two or more blood pressure readings. To qualify for the study, the mean blood pressure (mmHg) of the two readings will not exceed 140 systolic and 90 diastolic.
• Blood pressure (BP) will be taken while subjects are at rest and have been seated or supine for at least 5 minutes. The assessment will involve the average of 2 or more readings separated by fifteen minutes. If the first 2 readings differ by more than 5 mmHg, additional readings will be obtained and averaged. During the BP assessment, the volunteer will be acclimated to the automated blood pressure monitoring equipment by repeatedly taking blood pressure (at least 3 readings) with the device.
• Epilepsy with a history of seizures.
• The subject has a history of cerebral ischemia, transient ischemic attack, intracranial aneurysm, or arteriovenous malformation.
• The subject has a clinically significant history of head injury or head trauma per the judgement of the investigator.
• The subject has a history of cancer.
• Unstable medical condition, severe renal disease (creatinine clearance \< 40 ml/min using the Cockcroft and Gault equation), hepatic disease (known history of liver disease, abnormal elevations in LFTs), or serious central nervous system pathology.
• Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia.
• Are pregnant (positive urine pregnancy test assessed at screening) or nursing, or are of childbearing potential and are not practicing an effective means of birth control (refer to section 9.4.2 for contraceptive guidelines).
• Currently taking on a regular (i.e. daily) basis any psychotropic medications including: investigational agents, psychoactive prescription medications (i.e. benzodiazepines), antidepressants, medications having a primary pharmacological effect on serotonin neurons (i.e. ondansetron), medications that are MAO inhibitors, opioid medications. If previously on antidepressants a minimum of five half lives must have passed from the last dose of medication plus an additional seven days of stabilization before first administration of the drug.
• Current use of any the following of potent metabolic inducers or inhibitors: Inducers - Rifamycin (rifampin, rifabutin, rifapentine), anticonvulsants (carbamazepine, phenytoin, Phenobarbital), Nevirapine, Efavirenz, Taxol, Dexamethasone), St John's Wort; All cytochrome P450 Inhibitors - including all HIV protease inhibitors, verapamil, diltiazem, itraconazole, ketoconazole, erythromycin, clarithromycin, azithromycin, and troleandomycin.

Sponsors & Collaborators

• Rotem Petranker: lead
• Nikean Foundation: collaborator

Study Sites (1)

Psych Research

Toronto, Ontario, Canada

Location

Related Publications (1)

• Beidas Z, Ragnhildstveit A, Blackman A, Anderson T, Fewster E, Syed OA, Sobolenko V, Kanca IK, Jaglinska M, Son T, Farb N, Petranker R. Microdosing psilocybin for major depressive disorder: study protocol for a phase II double-blind placebo-controlled randomised partial crossover trial. BJPsych Open. 2026 Feb 16;12(2):e65. doi: 10.1192/bjo.2025.10968.

  PMID: 41693474 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Participants will not know whether they received placebo or psilocybin in the first stage of the trial. Care providers and investigators will not know whether participants received placebo or psilocybin.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Director, Psychedelic Studies Research Program

Model Details: This trial starts as a placebo-control for 4 weeks and then becomes Open Label for 4 additional weeks. Follow-up assessments will be performed weekly for the first 4 weeks following the last Open Label week.

Study Record Dates

• First Submitted: February 15, 2022
• First Posted: March 2, 2022
• Study Start: July 15, 2023
• Primary Completion: December 21, 2024
• Study Completion: February 1, 2025
• Last Updated: December 30, 2025

Record last verified: 2025-12

Locations

CA (1)