Inclusion Criteria:
1. Are between 20 and 35 years old at the start of the study
2. Are enrolled in the UBC SCANS (H24-02776) study
3. Use e-cigarettes containing nicotine ≥5 (greater than or equal to) days/week for at least 1 year
4. Meet criteria for moderate nicotine dependence, as determined by the research team
5. Can verify e-cigarette use status with a saliva test
6. If they are a person able to become pregnant (PABP):
1. Be of non-childbearing potential, defined as (i) self-reported postmenopausal status (12 months of spontaneous amenorrhea and ≥ 45 years of age); or (ii) documented surgical sterilization (i.e., tubal ligation, hysterectomy, or bilateral oophorectomy); or
2. Have a negative pregnancy test at screening and prior to each psilocybin session, and must agree to use adequate contraception through 10 days after the psilocybin session. Adequate contraception methods include intrauterine devices, oral hormones plus barrier contraception, abstinence, injectable or implanted hormonal methods, or vasectomized/non-sperm carrying sole partner. Barrier methods alone are not considered effective methods of contraception.
7. Willing to abstain from any nicotine use for ≥12 (greater than or equal to) hours and additional substance use (excluding caffeine) for ≥24 (greater than or equal to) hours before the drug and MRI sessions.
8. Can verify nicotine and additional substance use abstinence with a breathalyzer, saliva, and urine test
9. Are not actively trying to quit or cut down on your level of e-cigarette use
10. Are able to provide informed consent
11. Be able to understand, communicate and speak English
Exclusion Criteria:
1. Are left-handed or ambidextrous
2. Have any medical condition that would be contraindicated, including but not limited to:
* seizure disorder or history of seizures;
* a history of significantly impaired hepatic function;
* a history of unstable or uncontrolled cardiovascular disease (coronary artery disease, heart failure, clinically significant ECG abnormality);
* uncontrolled hypertension, resting blood pressure \> 140/90 mmHg;
* baseline prolongation of QTc interval: \>450 msec in both males and females;
* a history of major central nervous system disease (history of cerebrovascular accident, masses, aneurysm);
* a history of uncontrolled obstructive airway disease or significant respiratory compromise;
* a history of uncontrolled thyroid disease;
* a history of uncontrolled insulin dependent diabetes that may preclude safe participation in the study;
* a history of narrow-angle glaucoma;
* gastrointestinal conditions which may affect psilocybin absorption (i.e. stenosing peptic ulcer, pyloroduodenal obstruction);
* a history of active obstructive urological conditions (i.e. symptomatic prostatic hypertrophy, bladder-neck obstruction) that may preclude safe participation in the study.
3. Have any reported diagnosed mental health disorder (current or in the past year) or potential mental health disorder, as determined by the MINI.
4. Have other moderate-to-severe substance use disorders (other than nicotine), as determined by the MINI.
5. Have a first- or second-degree relative with psychotic or bipolar disorder.
6. Have a personality disorder deemed to be high risk (, antisocial, borderline, narcissistic) assessed via the MINI.
7. Have a history of suicide attempt within the last 10 years or a suicidal ideation in the last year.
8. Have used classic psychedelic drugs (e.g., psilocybin, LSD, DMT, ayahuasca, or mescaline) in the last 12 months or more than 25 times in lifetime, based on self-report.
9. Are currently taking medications with known interactions with psilocybin (e.g., antidepressants, antipsychotics) or that may significantly affect research performance
10. Are pregnant, breastfeeding, or they are a PABP and not practicing an adequate form of birth control
11. Have Autism Spectrum Disorder or other cognitive impairment that would affect performance on research tasks, as determined by the research team
12. Have a non-correctable clinically significant sensory impairment (e.g., cannot hear well enough to complete an interview).
13. Are pregnant, breastfeeding, or they are a PABP and not practicing an adequate form of birth control
14. Any other finding(s) based on the screening process that the investigator determines makes the candidate unsuitable for the study
15. Results from safety laboratory tests (CBC, AST and ALT, TSH, HbA1c) are not within normal limits
16. Have baseline heart rate outside of normal limits (e.g., \>100 beats per minute).
17. Have any history of Hallucinogen Persisting Perceptive Disorder
18. Subjects currently on medications with serotonergic activity, or taking inhibitors of UGT1A9, UGT1A10, MAO and aldehyde or alcohol dehydrogenase.
19. Have any other conditions that make MRI procedure inadvisable that may include:
a. Have implanted metal clips or wires, or other conditions including: i. Retained wires from an electronic implant that has been removed (i.e. pacemaker wires not attached to a pacemaker) ii. Cardiac pacemaker or defibrillator iii. Metal in eye or orbit iv. Ferromagnetic aneurysm clip v. Pregnancy vi. Makeup tattoos that are not designed to fade over time vii. Stainless steel intrauterine device (IUD) viii. Artificial heart valve ix. Ear or eye implant x. Brain aneurysm clip xi. Implanted electronic device (i.e. drug infusion pump, electrical stimulator) xii. Coil, catheter, or filter in any blood vessel xiii. Orthopedic hardware (artificial joint, plate, screw, rod) xiv. Shrapnel, bullets, or other metal fragments xv. Surgery, medical procedure or tattoos (including tattooed eyeliner) in the last six weeks xvi. Other metallic prostheses b. Have a personal or family history of seizures c. Have any significant neurological disorder, including any condition likely to be associated with increased intracranial pressure, space-occupying brain lesion, and cerebral aneurysm d. Claustrophobia (i.e., feel uncomfortable in small spaces), or fear of loud, repetitive sounds, or inability to lay still. Participants will have to lie still in the confined space of the MRI scanner.
