Psilocybin Microdosing With Psychotherapy for Treatment-Resistant Depression

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.