Neurobiological Effects of Psilocybin in Treatment Resistant Bipolar Depression

Inclusion Criteria: 1. Adults 18 to 65 years old. 2. Must be deemed to have capacity to provide informed consent; 3. Must sign and date the informed consent form; 4. Stated willingness to comply with all study procedures; 5. Ability to read and communicate in English, such that their literacy and comprehension is sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent; 6. Primary DSM-5 diagnosis of Bipolar II Disorder (BD-II) currently experiencing a Major Depressive Episode (MDE) without psychotic features as diagnosed by a mood disorder specialist and confirmed using the Mini-International Neuropsychiatric Interview (MINI); 7. Current MDE must be moderate to severe, as determined by the Hamilton Depression Rating Scale (HDRS-17) score greater than 20 with inadequate response to two or more adequate evidence-based treatment trials for bipolar depression, as per the 2018 CANMAT Bipolar Disorder Guidelines. Treatment trials are specific to current MDE rather than lifelong trials; 8. Ability to take oral medication; 9. Must be currently taking lamotrigine or planning on starting lamotrigine outside of the trial for the duration of the study, including the 1-month follow-up period, without changes in the medication; 10. Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 3 months prior to screening and agreement to use such a method during study participation; 11. Individuals who are capable of fathering a child: use of condoms or other methods for the duration of study participation to ensure effective contraception with partner; 12. Individuals who are willing to taper off current medications for a minimum of 1-month prior to Baseline (V3, Day -1) and whose physician confirms that it is safe for them to do so; 13. Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study duration. Exclusion Criteria: 1. Pregnant as assessed by a urine pregnancy test at Screening (Visit 1) or individual's that intend to become pregnant during the study or are breastfeeding; 2. Treatment with another investigational drug or other intervention within 30 days of Screening (Visit 1); 3. Current symptoms of mania, hypomania or mixed features, as determined by the Young Mania Rating Scale (YMRS) score greater than 12; 4. History of mania or hypomania in the past 6 months as determined by psychiatric history; 5. Have a DSM-5 diagnosis of substance use disorder (excluding use of tobacco) within the preceding 12 months; 6. Have active suicidal ideation as determined by the C-SSRS and/or clinical interview Significant suicide risk is defined by suicidal ideation as endorsed by items 4 or 5 of the C-SSRS, OR active suicidality requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months; 7. Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder; psychotic disorder (including but not limited to during previous mood episodes or substance-induced psychosis), bipolar I disorder, paranoid personality disorder, borderline personality disorder, or neurocognitive disorder as determined by medical history, the MINI clinical interview, and the International Personality Disorder Examination (IPDE) administered at V1; 8. Have contraindications to fMRI as determined by the MRI questionnaire; 9. Have a history of seizures; 10. Are taking anticonvulsants (with the exception of lamotrigine) or benzodiazepines (lorazepam up to 2mg/day is acceptable); 11. History of Steven-Johnson Syndrome (SJS) or suspected SJS as determined by medical history; 12. Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I disorder as determined by the family medical history form and discussions with the participant; 13. Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal or hepatic impairment; 14. Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG or a history of long QTc syndrome or related risk factors; 15. History of allergy to lamotrigine or psilocybin, or inability to tolerate lamotrigine during trial. 16. Participants who are unwilling or unable to take their lamotrigine (as prescribed by their most responsible physician) throughout the duration of the study, including up to the four-week post-dose visit, will be excluded from the study. 17. Use of classic psychedelic drugs (e.g., psilocybin, DMT, LSD, mescaline) within the previous 6 months of singing the informed consent form; 18. Use of intravenous or oral steroids within one week of the administration of psilocybin; 19. Use of S-Adenosyl methionine (SAM-e), 5-Hydroxytryptophan (5-HTP), L-tryptophan, and St. John's Wort one week prior to administration of psilocybin; and 20. Any other clinically significant physical illness including chronic infectious diseases or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study.