The purpose of this Phase I non-therapeutic trial is to examine the neurological effects of cannabis on stress reactivity and inhibition in healthy cannabis users. We expect differences between high ratio CBD:THC cannabis oil, low ratio CBD:THC cannabis oil, and/or placebo on outcome measures.

Purpose: To examine the neurological effects of cannabis on stress reactivity and inhibition in healthy adults using recreational cannabis. This is a phase I/pilot healthy subjects trial.

Primary Hypotheses:

1. The intervention will be feasible to implement
2. Cannabis oil will attenuate stress, measured via biological and self-report data, including salivary molecules, functional Magnetic Resonance Imaging, and standardized psychosocial assessments.

Justification: Current cannabis research focuses on medical uses for cannabis, clinical populations and/or non-commercially available products. There remains limited experimental research on the effects of commercial products in non-clinical regular users of cannabis. Further, most drug use research excludes polysubstance users. Given the high number of people using cannabis to cope with stress, biological evidence is needed to determine the validity of this claim. Stress is known to negatively impact daily functioning and has been linked to poorer mental and physical health outcomes. The effects of cannabinoids on cognitive functioning also have implications for daily functioning.

Objectives: Determine a causal link between commercially available cannabinoid products and mechanisms involved with stress response in polysubstance users, specifically weekly cannabis users with heavy drinking (males: minimum 5 drinks, females: minimum 4 drinks on at least one occasional per month for the past 12 months). Examine the short-term effects of cannabinoids on sleep quality in this population.

Study Design: The study is a Phase I non-therapeutic pilot trial and will utilize a double-blind, placebo-controlled, within-subjects design. The acute effects of the investigational products (IPs) will be examined. Each participant will undergo an initial phone screen and 5 sessions, with sessions 2-4 involving drug administration. There will be three investigational product arms for the drug administration sessions: cannabis oil with a high ratio of THC to CBD, cannabis oil with a high ratio of CBD to THC, and placebo. Each participant will be exposed to all three arms, one per drug administration session. The order of arm will be randomized. Each drug administration session will be a minimum of10 days apart to ensure a sufficient washout period.

Inclusion criteria:

1. Are 19-35 years old at the start of the study
2. Have used oral cannabis, including at least 5mg of THC, at least once in their life
3. Have used cannabis at least once in the past year
4. Used cannabis less than 3 times per week on average, in the past 3 months
5. Are using an effective and/or highly effective method of contraception and will continue to do so for the duration of participation in the study. Health Canada's definition of effective methods of contraception include barrier methods of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge). Health Canada's definition of highly effective methods of contraception includes hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy and tubal ligation.
6. Females: are not undergoing alternative fertility methods, such as IVF, or otherwise trying to start a family for the duration of participation
7. Males: will not be donating sperm at some point during the duration of participation
8. Are able to provide informed consent
9. Are able to complete assessments in English
10. Are able to attend sessions according to the study schedule
11. Will provide proof of 2 doses of an approved COVID-19 vaccination

Exclusion criteria:

1. Are left-handed or ambidextrous

2. Females: are pregnant, nursing, or not on safe pregnancy protection

3. Are trying to conceive

4. Have a known or suspected allergy to cannabinoids and/or palm/coconut oil

5. Are hypersensitive to CBD and/or THC and/or have ever had an adverse reaction (an unwanted and unexpected reaction), to less than 40mg of CBD and/or 10mg THC

6. Have had an adverse reaction (unwanted, unexpected reaction or symptoms) to cannabis within last 6 months

7. Have a major physical problem/health concern, including:

   1. Liver-cirrhosis or other liver disease
   2. Diabetes
   3. Chronic illness that may increase risk for adverse reactions to cannabis
   4. Chronic pain
   5. Genetic glucuronidation disorders (e.g., Gilbert's disease)
   6. Cardiovascular disease, including ischemic heart disease with unstable angina or recent acute coronary syndrome in the last 3 months, uncontrolled arrhythmias, poorly controlled hypertension or high blood pressure (e.g., 130/80), or severe heart failure
   7. Delirium: active delirium or recent delirium < 7 days, or at significant risk of delirium due to multiple comorbidities (e.g., very elderly, cognitive impairment, cerebrovascular disease) and contributing drugs (e.g., alcohol, stimulants, high doses of benzodiazepines, opioid, sedatives, psychoactive medications)

8. Are taking any of the following medications:

   1. Any medication that impacts the central nervous system, brain, and/or metabolic system
   2. Psychotropic medications, sedatives, and central nervous system depressants, including sleeping pills, tranquilizers, some pain medications, some allergy and cold medications, and anti-seizure medications
   3. Medications otherwise affecting the central nervous system, including amphetamines and other sympathomimetics
   4. Allergy medications (antihistamines; within 24 hours)
   5. Heart medications
   6. Blood pressure medication
   7. Steroid medications
   8. Opioids or other pain medications
   9. Anticholinergics: drugs that block acetylcholine, a chemical signal that plays a role in memory and learning.
   10. Drugs metabolized by cytochrome P450 enzymes, including amitriptyline, fentanyl, sufentanil, and alfentanil
   11. Highly protein-bound drugs, including warfarin, cyclosporine, and amphtericin
   12. Drugs metabolized by UGT enzymes, including propofol, antivirals
   13. Antiretroviral drugs
   14. Stomach acid inhibitors
   15. Antibiotics and antifungal medications
   16. Heart medications
   17. Other medications/substances interfering with CYP2C19 receptors

   i. Inhibitors: Fluvoxamine, isoniazid (INH), ritonavir ii. Inducers: Carbamazepine, phenytoin, rifampin iii. Substrates: Omeprazole (Prilosec), phenobarbital, phenytoin r. Other medications/substances interfering with CYP3A4 receptors: i. Inhibitors: Clarithromycin (Biaxin), diltiazem (Cardizem), erythromycin, grapefruit juice, itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), ritonavir, telithromycin (Ketek), verapamil (Calan) ii. Inducers: Carbamazepine, Hypericum perforatum (St. John's wort), phenobarbital, phenytoin, rifampin iii. Substrates: Alprazolam (Xanax), amlodipine (Norvasc), atorvastatin (Lipitor), cyclosporine (Sandimmune), diazepam (Valium), estradiol (Estrace), simvastatin (Zocor), sildenafil (Viagra), verapamil, zolpidem (Ambien)

9. Other MRI contraindications (conditions that make MRI procedure inadvisable):

   a. Have implanted metal clips or wires, including: i. Implanted electronic device (e.g., pacemaker, defibrillator implanted medication infusion pump, electrical stimulator, and/or ear or eye implant) including retained wires that has been removed (e.g., pacemaker wires not attached to a pacemaker) ii. Stainless steel intrauterine device (IUD) iii. Metal in eye or orbit, or metal slivers iv. Ferromagnetic aneurysm clip v. Coil, catheter, or filter in any blood vessel vi. Orthopedic hardware (artificial joint, plate, screw, rod) vii. Shrapnel, bullets, or other metal fragments (i.e., metal in eye or orbit) 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. Surgery, medical procedure or tattoos (including tattooed eyeliner) in the last six weeks xiv. Other metallic prostheses b. Have a personal or family history of seizures c. Have any significant neurological disorder including, but not limited to: i. Any condition likely to be associated with increased intracranial pressure ii. Space-occupying brain lesion iii. Seizure iv. Cerebral aneurysm v. Parkinson's disease vi. Huntington's chorea vii. Multiple sclerosis viii. Significant head trauma with loss of consciousness for greater than or equal to 5 minutes 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.

10. Work nightshifts

11. Have any diagnosed sleep disorders

12. Have dyscalculia

13. Have a neurodevelopmental disorder or cognitive impairments, including:

    1. Autism Spectrum Disorder
    2. Attention Deficit/Hyperactivity Disorder (ADHD)

14. Have schizophrenia spectrum disorder and/or history of psychosis

15. Meet criteria for potential mental health disorder in the Mini International Neuropsychiatric Interview (M.I.N.I.) Screen Version 7.0.2, except for alcohol and cannabis use disorders

16. Any diagnosed current mental health disorder and/or diagnosis of a mental health disorder within the past year

17. Have a non-correctable clinically significant sensory impairment (e.g., cannot hear well enough to cooperate with interview)

19) Are unable to attend sessions according to the study schedule 20) Have used opiates more than twice in the past 30 days

Double-blinded masking.