Cannabidiol for Reducing Cigarette Use

The goal of this research is to evaluate the efficacy of cannabidiol (CBD) in reducing cigarette smoking. Although there are safe and effective treatments for smoking cessation, not everyone who attempts smoking cessation is successful, even with these treatments. Relapse rates are high, leaving a need for new approaches. Despite justification to evaluate CBD for this indication, human research on the topic is scant. Larger, more extended studies are warranted and essential.

We will recruit participants from CRI-Help, Inc., a substance abuse treatment program in North Hollywood, where residents who indicate the desire to stop smoking are prohibited from using other cannabis products which would affect recruitment.

The aims of this study are:

1. Evaluate the effects of CBD on reduction of cigarette use. The primary endpoint will be reduction in cigarette use, indexed by self-reported cigarettes/day and plasma cotinine.

   The secondary endpoint will be abstinence from smoking, indexed categorically by self-report and confirmed biochemically by expired carbon monoxide (CO) during the last 2 weeks of the trial.

2. Evaluate CBD effects on participant retention. The primary endpoint will be retention in the trial, indicated by number of days that participants continue in the trial.

   Secondary endpoints will be nicotine dependence and withdrawal (measured weekly on the Fagerström Test for Nicotine Dependence and Minnesota Withdrawal Scale, respectively), and mood states (measured weekly on the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 screener).

3. Exploratory Aims. Measure CBD and endocannabinoids. Plasma concentrations of CBD, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), will be measured at baseline and at specified times throughout the trial. The primary endpoint will be CBD plasma level.

Participants who meet eligibility criteria will take part in a 56-day treatment phase during which they receive the study medication under supervision (CBD or placebo twice daily) and complete questionnaires on side effects, withdrawal, craving and mood symptoms. Blood, breath, and urine tests will also be performed throughout the study. Participants who complete the treatment will also be assessed at 1-month and 3-month follow up visits.

This will be a randomized, double-blind, placebo-controlled, comparison study of Nantheia ATL5 (CBD) vs. placebo in participants who have Tobacco Use Disorder and indicate desire for smoking cessation. We will instruct participants and provide support for them using messages from the National Cancer Institute's (NCI) Smokefree.gov website. Smokefree.gov offers free text 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.

Recruitment and intervention will take place at CRI-Help, Inc., a community-based, private non-profit behavioral healthcare organization located in Southern California with several agency sites, including the one in north Hollywood, where this protocol will be conducted. CRI-Help's treatment team is composed of licensed and certified treatment professionals, including doctors, nurses, psychologists, therapists, and certified drug counselors. Additionally, CRI-Help is licensed and certified by the State of California, and accredited by the Commission on Accreditation of Rehabilitation Facilities (CARF). Clients take part in individual and group counseling, integrated health and counseling, and vocational assistance. Additional services include recreational and fitness activities, family education, neurofeedback, trauma groups, grief counseling, treatment for co-occurring mental health conditions, and daily 12-Step meetings. The rehabilitation treatment programs are designed to integrate 12-Step philosophy into daily life.

We will enroll up to 120 participants who have Tobacco Use Disorder, express a desire for smoking cessation, and are in residential treatment for substance use disorders.

A staff member of Cri-Help, Inc. will identify participants who meet the general recruitment criteria for the study, and will provide them with a flyer describing the study and inviting them to contact University of California Los Angeles (UCLA) staff at Cri-Help if they are interested in participating. Interested potential participants will meet with research staff for a description of the study in a private room, where informed consent will be taken remotely by Dr. Larissa Mooney. Participants will then complete questionnaires and will travel to UCLA for medical evaluation (blood and urine tests, ECG, history and physical) at the Clinical and Translational Research Center (CTRC). Dr. Mooney/CTRC Nurse Practitioners will review lab results (and History & Physical report) and will advise Dr. London (Principal Investigator) on medical aspects in determining eligibility.

TREATMENT PHASE

The treatment phase of the study will be performed in two cohorts of participants. The first cohort (60 participants) will receive CBD at a dose of 400 mg/day or matching placebo (n = 30/group). If efficacy in reducing smoking is indicated at 400 mg/day (group difference in change in cigarette use, either statistically significant at p < 0.05 or a trend at p < or = 0.1), the second cohort (60 participants) will be tested in a replication--400 mg/day vs. placebo (n = 30/group). However, if there is no indication of efficacy at 400 mg/day, the second cohort will be tested in a trial of 800 mg/day CBD vs. placebo.

Note: Blood will be drawn for clinical lab tests to determine safety of participation (25 ml each time), and also for assay of CBD, anandamide, 2 arachidonoylglycerol (2-AG) and cotinine (2 ml each time). Blood will be drawn on 6 days: at screening (Days -7 to 0: 25 ml for screening), at baseline (Day 0: 2 ml for assay of cotinine and cannabinoids), and during the intervention (Days 7, 14, 28, and 56: 27 ml each time for safety labs as well as cotinine + cannabinoids). The total volume of blood taken will be up to (135 ml over the course of the entire study).

RANDOMIZATION TO TREATMENT

We will randomize by sex and age (18-30, 31 years or older) to ensure equal representation across the groups. We will use an intention-to-treat analysis, including data from all participants who are randomized.

SAFETY ASSESSMENTS AND MONITORING

The following tests and procedures will be performed for safety monitoring throughout the study:

1. Comprehensive metabolic panel, Complete Blood Count (CBC) with differential, and urinalysis Key tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and international normalized ratio (INR) levels Sampling times: Days -7 to 0 (screening), Days 7, 14, 28 and 56 (treatment).
2. Electrocardiogram Safety parameters: evidence of arrhythmia, recent myocardial infarction (MI), and 3rd degree heart block. Assessment times: Days -7 to 0 (screening).

3. Ovarian hormone battery Hormone assays: estradiol, follicle-stimulating hormone (FSH), free thyroxine (T4), luteinizing hormone (LH), prolactin, thyroid-stimulating hormone (TSH), total thyroxine (T4) , total triodothyronine (T3). If abnormality is seen, ultrasound will be obtained.

   Assessment times: Days -7 to 0 (screening), Days 7, 14, 28 and 56 (treatment).

4. Suicidality Assessment: Columbia Suicide Severity Rating Scale (C-SSRS) Assessment times: Days -7 to 0 (screening), and weekly during the Treatment phase, and also at the 1- and 3-month follow-up.
5. Pregnancy A urine pregnancy test will be administered once during Days -7 to 0, weekly during the treatment period (Days 1-56).

DOSING AND TESTING SCHEDULE

The investigational product will be 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 to be used in for this trial contains CBD and the following excipients:

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

ATL5 Softgel Capsules will be manufactured by Baxco Pharmaceutical Inc., (California, USA) under current good manufacturing practice (cGMP) conditions. They will be administered orally as indicated below.

DOSAGE AND DURATION OF TREATMENT

The planned study will evaluate Nantheia ATL5 (400 and 800 mg per day; 200 mg and 400 mg twice a day (BID), respectively). The treatment period with CBD or placebo will be 56 days. Participants will be in the study for up to 24 weeks (8 weeks intervention + 4-week and 12-week follow-up) 16 weeks.

DOSE JUSTIFICATION

CBD will be tested at 400 and 800 mg daily. These doses were selected on the basis of safety data from human studies. In a previous clinical trial, doses of CBD as high as 50 mg/kg (i.e., 350 mg for a 70-kg participant) were well tolerated. Doses between 300 and 1500 mg have been used in humans without toxicity or serious adverse events. Forty-two subjects received 200 mg of CBD four times daily (total 800 mg per day) for 2 to 4 weeks to treat schizophrenia without notable side effects. Additionally, a review of 132 reports, which included animal and human studies, concluded that CBD was well-tolerated in humans, at doses of up to 1500 mg/day for 4 weeks to treat schizophrenia without notable side effects; and 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.

MEASURES COLLECTED:

Following screening, a baseline assessment will include sampling blood for assay of cotinine as an indication of 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 (Heatherton et al., 1991).
• Smoking History Questionnaire. Developed in Dr. London's Lab, this 25-item survey (~5 min) queries age at of 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) (Hughes & Hatsukami, 1986) measures withdrawal symptoms: craving, irritability, anxiety, difficulty concentrating, restlessness, headache, drowsiness, and gastrointestinal (GI) disturbances.

These symptoms are scored on an ordinal scale [0 (not present) to 3 (severe)].

• Generalized Anxiety Disorder-7 (GAD-7). This is a self-administered seven-item questionnaire that is used to measure or assess the severity of generalized anxiety disorder (GAD). It takes ~1-2 min to complete.
• Patient Health Questionnaire-9 (PHQ-9). This self-administered nine-item scale measures the degree of depression. It takes ~1-2 min to complete.

Participants will self-report cigarette use and adverse events at each visit using structured questionnaires. On Days 7, 14, 28 and 56, we will take vital signs, and draw blood for clinical laboratory tests (to assure safety) and to assay cotinine as an index of heaviness of smoking and for assay of cannabinoids (CBD, anandamide, 2-AG); participants will complete the Anti-depressant Side Effect Checklist (ASEC), FTND, MNWS, GAD-7, PHQ-9.

At 1- and 3-month follow up, we will take the same self-report and behavioral measures, and vital signs (no blood assays).

ADHERENCE TO MEDICATION

Participants will report to the nursing station in the morning and evening according to the CRI-Help medication schedule. They will receive the investigational product (CBD or placebo) and will take it under the direct observation of a Residential Technician (Registered Alcohol and Drug Technician, RADT, certified by the California Consortium of Addiction Programs and Professionals). Any unused or missed medication will be collected weekly and will be returned to the manufacturer.

PARTICIPANT RETENTION

The index of retention will be number of days a participant remains in the study.

ASSAYS OF CBD, ANANDAMIDE, 2-AG AND COTININE

We will use liquid chromatography/mass spectrometry-multiple reaction monitoring (LC/MS-MRM) assays that we have developed for these compounds in plasma. 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 nuclear magnetic resonance (NMR) signals are recorded. Peak areas, measured with manufacturer-supplied software, are checked and adjusted if needed. Each compound is quantified by interpolation from response curves from data obtained using internal standards and increasing concentrations of unlabeled authentic analytes.