Psilocybin microdosing plus short-term psychotherapy for treatment-resistant depression.

A Double-blind, Phase II Feasibility Study to Assess the Safety and Efficacy of Psilocybin Microdosing Combined With Psychotherapy in Treatment-resistant Depression

This trial will test whether six weeks of low-dose psilocybin together with short-term, experience-based psychotherapy can reduce symptoms in adults whose depression has not improved with prior treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: Beersheva Mental Health Center (Government)
• Locations: 1 site (Beersheba)
• Trial ID: NCT07183748 on ClinicalTrials.gov

What this trial studies

Participants with treatment-resistant major depression will be enrolled for a six-week microdosing regimen of psilocybin or matched placebo combined with brief, experience-based psychotherapy, followed by a crossover to the alternate condition. The design includes a placebo-controlled phase and a subsequent crossover so each participant receives both conditions at different times. Safety, symptom ratings, and biological markers will be measured at baseline and throughout the study to track response and possible mediators of effect. Concomitant psychiatric medications, recreational drugs and licensed cannabis must be stopped prior to and during participation, and participants will attend in-person visits at the study site.

Who should consider this trial

Good fit: Adults aged 18–65 with DSM-defined treatment-resistant major depression who are willing and able to discontinue psychiatric medications and recreational drugs, use contraception if applicable, and attend in-person psychotherapy sessions are the intended participants.

Not a fit: People who cannot safely stop psychiatric medications, are pregnant, are using illicit drugs or licensed cannabis during the study period, or cannot attend in-person visits are not eligible and may not benefit.

Why it matters

Potential benefit: If successful, this approach could produce faster symptom improvement for people with treatment-resistant depression and help identify biological markers linked to response.

How similar studies have performed: Full-dose psilocybin trials have shown promising signals for depression, but evidence specifically for microdosing is limited and mixed, making this approach relatively novel.

Eligibility criteria

Inclusion Criteria:

* Age range between 18-65 years.
* Diagnosis of treatment-resistant major depression as defined by the DSM-IV criteria (309.81) (ASA 1994) and determined by the BDI (BDI-II, 1996).
* Willingness to discontinue psychiatric medication starting two weeks prior to the beginning of the study and throughout its duration, as well as to cease the use of drugs and licensed cannabis, and to suspend psychotherapy for the duration of the study. Participants also commit not to initiate psychiatric medication or psychotherapy during the study without consulting the research team. All under supervision within a day treatment framework.
* Abstinence from drugs and other psychiatric medications.
* Negative pregnancy test for women, and use of contraception by both men and women during the study period.
* Willingness to sign a confidentiality waiver allowing the research team to consult with the participant's treating physician.
* Willingness to provide the contact information of a close and relevant person in case suicidal ideation arises.
* Commitment to participate in all stages of the study, including follow-up assessments.
* Willingness not to participate in another study during the current study period.

Exclusion Criteria:

* Investigators and their immediate family members are not permitted to participate in the study. Immediate family is defined as the investigator's spouse, parent, child, grandparent, or grandchild.
* Pregnant women, breastfeeding women, or women of childbearing age who are not using medically approved contraceptive methods (e.g., condoms).

Men who are sexually active and may cause pregnancy but are unwilling to use contraception.

* Significant unstable physical illness (including cardiac, hepatic, renal, respiratory, endocrinological, neurological, or hematological conditions), based on the investigator's judgment.
* Psychotic spectrum disorders.
* Bipolar disorder.
* Post-traumatic disorder involving dissociative symptoms.
* Uncontrolled anxiety disorder.
* Chronic perceptual disorder (HPPD).
* Head injury or cognitive impairment (including intellectual disability or dementia).
* Severe suicidal risk or aggressive behavior toward others, as assessed by the investigator and standardized depression/suicide assessment questionnaires.

History of chronic benzodiazepine use (at least 4 mg lorazepam daily for over two years), or signs and symptoms of benzodiazepine use within two weeks prior to randomization.

* Alcohol and/or substance abuse within the past 6 months, based on the clinical judgment of the investigator.
* Any active addiction (substance use disorder).
* Current or past epilepsy.
* Individuals with focal or generalized encephalopathy (e.g., tumor, stroke, meningitis, encephalitis), or head trauma that may be epileptogenic.

Where this trial is running

Beersheba

• Mental Health Center Beer Sheva — Beersheba, Israel (Recruiting)

Study contacts

• Study coordinator: Oded Arbel, MD

Conditions Treatment Resistant Depression