Cannabidiol for Reducing Cigarette Use

General Experimental Design: This will be a randomized, double-blind, placebo-controlled, comparison study of Nantheia ATL5 (CBD) vs. placebo on smoking behavior in participants who have Tobacco Use Disorder (TUD) and have a desire for smoking cessation, conducted at CRI-Help, Inc., a residential substance use treatment center in N. Hollywood, CA. The investigators will instruct participants and provide support via text messages from the National Cancer Institute's Smokefree.gov website. Smokefree.gov offers free messaging programs that give encouragement, advice, and tips for becoming smoke-free and being healthier. The NCI website also helps people who smoke create a personalized quit plan that makes it easier to stay on track, get through hard times, and quit for good. Creating this plan will be part of baseline procedures.

Randomization to Treatment, Sample Size: Participants will receive CBD at a dose of 800 mg per day or placebo (n = 40/group). The investigators will randomize by sex and age (18-30, greater than/equal to 31 years) to ensure equal representation across the groups. The investigators will use an intention-to-treat analysis, including data from all participants who are randomized (see below for power analysis).

Dosing and Testing Schedule: After screening (Days -7 to 0) and baseline (Day 0) assessments, the study will comprise a 56-day (8-week) treatment period with follow up assessments at 1 and 3 months after termination of treatment as part of this trial. Measurements will be obtained at daily and weekly assessments during the 8-week treatment period.

Measures Collected: A baseline assessment will include assay of blood plasma cotinine to indicate heaviness of smoking, and self-reports of smoking-related behaviors on the following smoking-related questionnaires:

• Fagerström Test for Nicotine Dependence (FTND). This 6-item survey (~2 min) is closely linked to nicotine intake.
• Smoking History Questionnaire. Developed in Dr. London's Lab, this 25-item survey (~5 min) queries age at initiation, longest quit attempt, number of quit attempts, reasons for quitting, and current smoking behavior (e.g., preferred brand, cigarettes per day, etc.).
• Minnesota Nicotine Withdrawal Scale (MNWS) measures withdrawal symptoms: craving, irritability, anxiety, difficulty concentrating, restlessness, headache, drowsiness, and GI disturbances. These symptoms are scored on an ordinal scale [0 (not present) to 3 (severe)].
• General Anxiety Screener (GAD-7). This is a self-administered seven-item questionnaire that is used to measure or assess the severity of generalized anxiety disorder (GAD). The GAD-7 takes ~1-2 min to complete.
• Patient Health Questoinnaire-9 (PHQ-9). This self-administered nine-item scale measures the degree of depression. The PHQ-9 only takes ~1-2 min to complete.
• State-Trait Anxiety Inventory Y1 (STAI-Y1). This self-administered 20-item scale measures the degree of anxiety and takes ~1-2 min to complete.
• Positive and Negative Affect Schedule (PANAS). This self-administered 30-item scale measures current affective state and takes ~2-3 min to complete.

Participants will self-report cigarette use and adverse events (AEs) each day using structured questionnaires. At screening and on days 7, 14, 28 and 56, the investigators will take vital signs and draw blood for clinical laboratory tests for safety, to assay cotinine as an index of nicotine intake, and assay cannabinoids (CBD, anandamide, 2-AG) from screening and day 7; participants will complete the FTND, MNWS, GAD-7, PHQ-9, STAI-Y1, and PANAS. At 1- and 3-month follow up, the investigators will take vital signs, measure CO in breath, and take the same behavioral/self-report measures as on Days 7, 14, 28 and 56.

Assay of CBD, anandamide, 2-AG and cotinine: The investigators will use liquid chromatography/mass spectrometry-multiple reaction monitoring (LC/MS-MRM) assays. Internal standards are added after sample extracts are processed and injected onto a multi-mode column with reversed phase, cation and anion exchange capabilities. After equilibration and elution, column effluents are passed through an electrospray ion source attached to a triple quadrupole mass spectrometer, and MRM signals are recorded. Each compound is quantified by interpolation from response curves using data from internal standards and increasing concentrations of unlabeled authentic analytes.

Risks and Minimization of Risk

Risks associated with taking CBD include:

• Increase in liver alanine aminotransferase enzymes (ALT test)
• Increase in blood clotting (International Normalized Ratio, INR).

Given the possibility that individuals with substance use disorders will participate in the study and may exhibit abnormality in liver function at baseline, liver function tests will be performed in screening, and individuals with abnormal values will be excluded.

Abuse Potential of CBD: The DEA has classified CBD as a Schedule I drug In the United States, suggesting that CBD has a high potential for abuse, but the World Health Organization Expert Committee on Drug Dependence concluded that no abuse potential could be confirmed based on findings from animal and human research. The type of CBD used here is derived from hemp and contains less than 0.3% tetrahydrocannabinol (THC; i.e., the primary psychoactive ingredient in cannabis). CBD used in Nantheia ATL-5 is not considered a scheduled drug by the DEA.

Note: Careful screening at baseline and ongoing monitoring of plasma levels for potential emergence of adverse events will be practiced, ensuring minimization of all risks.

In addition, trial stopping rules were developed with the following criteria applied.

Patient safety dose stopping and discontinuation criteria (no re-challenge):

• ALT or AST >3 x ULN and [total bilirubin level (TBL) >2 x ULN or INR >1.5).
• ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

Other risks of CBD administration Possible effects on a fetus: There are no long-term studies in humans on CBD effects on fetal development; however, animal studies suggest that long-term use is safe, with very low potential for effects on a fetus at doses associated with human treatment. To minimize this potential risk, pregnancy is an exclusion criterion, and a participant who becomes pregnant will be withdrawn from the study.

Risk of ovarian suppression: Animal studies have indicated this possibility. Female participants will undergo a hormonal battery at screening with ultrasound upon abnormal findings. Participants with evidence of ovarian suppression will be excluded. Ovarian function will also be tested during the treatment phase, and any abnormality followed up with referral for further investigation.

This study will be conducted in a residential treatment facility. Thus, participants will be closely monitored, dosing will be controlled, and clinical and laboratory assessments will be done on a regular schedule.

Participant Withdrawal from the Protocol: Participants can be withdrawn for safety (see stopping criteria above) and noncompliance with medication administration protocols. Decisions regarding safety will be made by the PI with advice from Co-Investigator Larissa Mooney, M.D. Participants will also be withdrawn upon leaving inpatient treatment at CRI-Help. Participants can decide on their own to withdraw from the protocol at any time without prejudice, and this will not affect their treatment at CRI-Help. All participants will receive compensation for all of the procedures/assessments completed.

Drug Administration Details

Investigational Product and Mode of Administration: Nantheia ATL5, which is CBD, extracted from hemp, at a 10% strength (softgel capsules with 100 mg/ml of CBD per capsule) or matching placebo. The formulation that was selected for this clinical trial contains CBD and excipients as here:

• emulsifying agents: Cremophor EL (Polyoxyl 35 castor oil), Tween 80 (Polysorbate 80), Plurol® Oleique (polyglyceryl-3 dioleate);
• cwe o-surfactant: propylene glycol;
• oil: Labrosol® (caprylocapryol polyoxyl-8 glycerides), medium chain triglycerides;
• antioxidant: BHT (butylated hydroxytoluene).

Nantheia ATL5 Softgel Capsules will be manufactured by Baxco Pharmaceutical Inc. (California, USA), under cGMP conditions for Ananda Therapeutics. Ananda will supply Nantheia ATL5 Softgel Capsules and matching placebo for this study. Capsules will be administered orally as indicated below. Ananda Therapeutics is FDA-approved to supply this product.

Dosage and Duration of Treatment: This study will evaluate Nantheia ATL5 in participants given CBD or placebo (1:1). The treatment period will be 56 days (8 weeks). Participants will be in the study for up to 24 weeks, including follow-up at 1 and 3 months after completion of the treatment protocol. The CBD/placebo dose will be 800 mg/day. Dose Justification: A daily dose of 600 mg is being evaluated in our ongoing trial of CBD for opioid use disorder (ClinicalTrials.gov Identifier: NCT03787628). Doses of CBD as high as 50 mg/kg (i.e., 3500 mg for a 70-kg participant) were well tolerated; and doses between 300 and 1500 mg have been used in humans without serious adverse events. Forty-two subjects received 200 mg of CBD 4x daily (total 800 mg per day) for 2-4 weeks to treat schizophrenia without notable side effects. Additionally, a review of 132 reports including animal and human studies concluded that CBD was well-tolerated in humans, at doses of up to 1500 mg/day.

Regulatory Considerations: CBD will be administered in this protocol as Nantheia ATL5, a hemp-derived product that contains < 0.3% tetrahydrocannabinol (THC). Nantheia ATL5 is not a Schedule 1 controlled substance because Nantheia ATL5 is hemp-derived CBD with a THC concentration of no more than 0.3%. The investigators have obtained FDA approval for this project. The investigators will receive oversight and obtain approval from the UCLA Institutional Review Board.

Receipt and Storage of the Investigational Product (IP). The IP will be delivered by the manufacturer in bottles containing 28 1-mL softgels each for testing of 800 mg CBD vs. placebo. Nantheia ATL5 will be stored at room temperature, 59-86°F (15-30°C), in a locked cabinet in a locked office of a staff member blinded to its identity (CBD or placebo).

Dispensation of the IP: Staff not involved in data entry or any other aspects of the study will distribute the IP into containers labeled with the subject-ID number and/or patient initials and doses will be divided for AM or PM. The investigational product (CBD or placebo) will be taken under staff supervision at the CRI-Help treatment center. A nurse (LVN) will be responsible for supervising and recording patient's self-administration of the IP. Unused or missed medication will be collected once weekly and prepared for return to the manufacturer.

Inclusion criteria

The investigators will study equal numbers of males and females betweeen 18 - 65 years of age who have Tobacco Use Disorder and express a desire for smoking cessation. Participants will be recruited from the clientele base at Cri-Help Treatment Center in North Hollywood, CA, where the investigators have a long-standing relationship and where the investigators have conducted other research protocols. This study will be conducted at Cri-Help Treatment Center.

Participants will not be recruited from the general population for this study because common use of cannabis in the greater Los Angeles area would confound measurements of CBD, interfering with evaluation of the association of plasma level from treatment with efficacy. This problem is avoided in studying participants who are receiving treatment at a facility where cannabis use is not allowed.

The investigators will include all racial and ethnic groups. Based on the population of the surrounding communities in the Los Angeles region, the investigators anticipate a racial and ethnic makeup of approximately 26% White, 9% Black/African American, 49% Hispanic/Latino, 14% Asian American, and 2% multi-racial/unknown. These percentages align with our recent studies.

Smoking cigarettes and at least moderate nicotine dependence, as indicated by smoking 5 or more cigarettes per day and/or a score of at least 4 on the Fagerström Test for Nicotine Dependence are inclusion criteria. Although vaping is popular and a high proportion of participants who vape also report cigarette smoking (58%), the investigators will exclude participants who vape nicotine. Vaping is not allowed at Cri-Help, Inc.

Exclusion criteria

• Physiological dependence on alcohol or any drug, requiring medical detoxification and/or showing signs of acute withdrawal symptoms from opioids, alcohol or benzodiazepines.
• Treatment of Opioid Use Disorder with buprenorphine or methadone to avoid potential drug-drug interactions. CBD interacts with CYP3A. Opioid drugs metabolized by cytochrome P450 (CYP450), and cytochrome P450 isoenzyme CYP3A4 (CYP3A4) in particular, include fentanyl, methadone, oxycodone, and buprenorphine.
• Meeting DSM-5 criteria for schizophrenia, Bipolar I disorder, psychotic disorder, having active suicidal ideation, or suicide attempt in the past 12 months. NOTE: Participants with other psychiatric conditions, such as major depression, generalized anxiety, dysthymia, social phobia or specific phobia can enroll if they are clinically stable.
• AIDS or current HIV medication treatment with antiviral and/or non-antiviral therapy (due to the interaction of CBD with antiviral therapy).
• Clinically significant abnormalities on EKG (such as evidence of arrhythmia or MI).
• Clinically significant cardiovascular, hematologic, hepatic, renal, neurological, or endocrine abnormalities [specific exclusion criteria: AST greater than or equal to 3Xs ULN, Bilirubin greater or equal to 1.5 X ULN, Prothrombin time/International Normalized Ratio (INR) > 1.5.
• Pregnancy and/or lactation. Contraception methods required at time of enrollment, and throughout the duration of the study medication period include abstinence, oral contraceptives, depot contraceptives, condom with spermicide, cervical cap with spermicide, diaphragm with spermicide, intrauterine device, surgical sterilization (e.g. tubal ligation, vasectomy).
• Because of evidence that CBD affects ovarian function in rats, women with values outside the reference ranges on a hormonal battery [estradiol, follicle- stimulating hormone, free thyroxine index, luteinizing hormone, prolactin, total T3 and total T4, thyroid-stimulating hormone], followed by an abnormal ovarian ultrasound finding will be excluded.
• Based on data obtained using Epidiolex® (CBD) oral solution label section 7, "Drug Interactions", the investigators will exclude participants who are taking the following medications: a) strong inducers of CYP3A4 or CYP2C19, which may decrease CBD plasma levels; and b) substrates of UGT1A9, UGT2B7, CYP2B6, CYP2C19 due to the potential of CBD to inhibit enzyme activity.