Psilocybin Microdosing With 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

Objective:

To assess the safety and efficacy of a six-week microdosing regimen of psilocybin combined with short-term, experience-based psychotherapy in patients with treatment-resistant depression who have not responded to previous pharmacological or long-term psychological interventions.

Hypothesis:

Compared to baseline, the group that begins with psilocybin will exhibit a more rapid reduction in depressive symptoms after six weeks, compared to the group that begins with placebo and receives only psychotherapy. Following the crossover between conditions, the placebo-first group will also show an accelerated reduction in these measures after the subsequent six weeks.

Alternative hypothesis: No difference will be observed between groups in the rate of symptom reduction.

Objective:

To examine biological markers that may mediate potential improvements in depressive symptoms among participants receiving psilocybin microdosing compared to placebo.

Hypothesis:

Compared to baseline, six weeks of active psilocybin dosing will result in decreased levels of cortisol and inflammatory markers, and increased levels of oxytocin and BDNF in saliva.

Objective:

To assess psychological factors that may mediate potential improvements in depressive symptoms among participants receiving psilocybin microdosing compared to placebo.

Hypothesis:

Compared to baseline, six weeks of active psilocybin dosing will lead to increased cognitive flexibility, greater self-compassion, and enhanced present-moment awareness.

Objective:

To explore a subpopulation of women experiencing premenstrual symptom exacerbation (PMS) and the potential for improvement in depressive symptoms in the days preceding menstruation, if any.

Hypothesis:

Among women with worsened premenstrual symptoms, psilocybin will reduce premenstrual symptoms, specifically depressive symptoms, compared to baseline.

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.