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, plasma cotinine and expired carbon monoxide (CO) daily during the trial.

   The secondary endpoint will be abstinence from smoking, indexed categorically by self-report and confirmed biochemically by expired carbon monoxide (CO) daily during 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.

PROTOCOL

Glossary of Abbreviations in Protocol AE Adverse Event 2-AG 2-Arachidonoylglycerol AIDS Acquired Immunodeficiency Syndrome ALT Alanine transaminase AST Aspartate transaminase BID Twice a day BP Blood pressure CBD Cannabidiol cGMP Current good manufacturing practice CO Carbon monoxide C-SSRS Columbia Suicide Severity Rating Scale CV Coefficient of variation CYP3A4, CYP2C19 Cytochromes 3A4 and 2C19, which take part in drug metabolism CYPP450 Cytochrome P450 DEA Drug Enforcement Agency DSM-5 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition EKG Electrocardiogram FDA Food and Drug Administration FTND Fagerström Test for Nicotine Dependence GAD General Anxiety Disorder GAD-7 General Anxiety Screener GLMM Generalized linear mixed model HIPAA Health Insurance Portability and Accountability Act of 1996 HIV Human immunodeficiency virus HR Heart rate INR International Normalized Ratio LC/MS-MRM Liquid chromatography/mass spectrometry-multiple reaction monitoring MedHx/PsychHx Medical history and psychiatric evaluation MINI Mini International Neuropsychiatric Interview 7.0.2 for DSM-5 MNWS Minnesota Nicotine Withdrawal Scale Nantheia ATL5 Cannabidiol, 100 mg/ml NCI National Cancer Institute PHQ-9 Patient Health Questoinnaire-9 RADT Registered alcohol and drug technician SD Standard deviation T3 Triiodothyronine T4 Thyroxine TBL Total bilirubin level THC Tetrahydrocannabinol TUD Tobacco Use Disorder UGT1A9, UGT2B7 UDP-glucuronosyltransferases, catalyze conjugation of glucuronic acid to xenobiotics ULN Upper limit of normal

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

Endpoints: The primary endpoint for Aim 1 will be reduction in cigarette use, indicated by self-reported cigarettes per day and plasma levels of cotinine. The secondary endpoint will be abstinence from smoking during the last 2 weeks of the trial, indexed categorically by self-report and confirmed biochemically by a reading below 5 ppm of carbon monoxide (CO) in expired air. The primary endpoint in Aim 2 will be nicotine dependence (measured weekly on the Fagerström Test for Nicotine Dependence (Heatherton et al., 1991)). Secondary endpoints will be nicotine withdrawal measured on the Minnesota Nicotine Withdrawal Scale (Hughes & Hatsukami, 1986), and mood states (measured weekly on the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 screener). In an exploratory aim, we will measure plasma concentrations of CBD, anandamide and 2-AG (at screening and on days 7, 14, 28, and 56). The goals are to test associations of CBD levels with effects in Aims 1 and 2, the effects of CBD on anandamide and 2-AG, and the influence of the endocannabinoid levels on CBD effects in Aims 1 and 2.

Participants: We will study equal numbers of males and females, 18 - 65 years of age, who smoke cigarettes and are in residential treatment for substance use disorders. Recruitment will be from participants at Cri-Help Treatment Center in North Hollywood, CA. 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. We will include all racial and ethnic groups. Based on the population of the surrounding communities in the Los Angeles region, we 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.

Inclusion criteria:

• Smoking at least 5 cigarettes a day on average or at least moderate nicotine dependence.
• Although vaping is common among people who smoke cigarettes (Smith et al., 2022), vaping is not allowed at Cri-Help and will not confound our assessments of smoking.
• Age 18-65 years of age.
• All genders.

Exclusion criteria:

• Current use of any illicit drugs or substances, including cannabis. Use of these substances is not allowed at Cri-Help.
• Physiological dependence on alcohol or any drug, requiring medical detoxification and/or showing signs of acute withdrawal symptoms from opioids, alcohol or benzodiazepines.
• Use of standard medications for smoking cessation, specifically nicotine (e.g., nicotine patch), varenicline, or bupropion.
• Based on data obtained using Epidiolex® (CBD) oral solution label section 7, "Drug Interactions", we 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.
• Receiving therapy for opioid use disorder with buprenorphine or methadone to avoid potential drug-drug interactions because CBD interacts with CYP3A (Welty et al., 2014). Opioid drugs metabolized by cytochrome P450 (CYP450), and cytochrome P450 isoenzyme CYP3A4 (CYP3A4) in particular, include fentanyl, methadone, oxycodone, and buprenorphine (Kotlinska Lemieszek et al., 2015).
• AIDS or current HIV medication treatment with antiviral and/or non-antiviral therapy (due to the interaction of CBD with antiviral therapy).
• 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.
• Clinically significant cardiovascular, hematologic, hepatic, renal, neurological, or endocrine abnormalities [specific exclusion criteria: AST or ALT greater than or equal to 3Xs ULN, Bilirubin greater/equal to 1.5 X ULN, Prothrombin time/International Normalized Ratio (INR) > 1.5].
• Pregnancy and/or lactation.
• 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.

Participant Recruitment: We will enroll participants who have Tobacco Use Disorder, express a desire for smoking cessation, and are in residential treatment for substance use disorders. We will conduct the study at Cri-Help, where we have a long-standing relationship and where we have conducted other research protocols. We will not recruit from the general population because most potential participants in the greater Los Angeles area, who smoke cigarettes, also have significant use of cannabis, which would be a major confound in evaluating the therapeutic effects of CBD. This problem is avoided by studying participants who are receiving treatment at a facility where cannabis use is not allowed.

Randomization to Treatment, Sample Size. Participants will receive CBD at a dose of 800 mg per day or placebo (n = 60/group). We will randomize by sex and age (18-30, greater than/equal to 31 years) to ensure equal representation across the groups. We 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 during daily and weekly assessments for the duration of the 8-week treatment period.

Measures Collected: A baseline assessment will include blood sampling for assay of plasma 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 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 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). It takes ~1-2 min to complete.
• Patient Health Questoinnaire-9 (PHQ-9). This self-administered nine-item scale measures the degree of depression. It only takes ~1-2 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, 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 FTND, MNWS, GAD-7, and PHQ-9. At 1- and 3-month follow up, we will take vital signs, measure CO in breath, and take the same behavioral/self-report measures as on Days 7, 14, 28 and 56.

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.

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

Assay of CBD, anandamide, 2-AG and Cotinine. We 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 some abnormality in liver function at baseline, tests indicative of liver function will be performed in screening, and individuals with abnormal values will not be allowed to participate.

*Abuse Potential of CBD: The DEA has classified CBD as a Schedule I drug In the United States. This suggests 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 specific 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). It 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 the effects of CBD on fetal development; however, studies in animals suggest that long-term use is safe, with a very low potential for effects on a developing fetus at doses typically 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. She may still continue to receive treatment as usual at Cri-Help.

Risk of ovarian suppression. Animal studies have indicated this possibility. Female participants will undergo a hormonal battery at screening with ultrasound in the case of abnormal findings. Participants who show evidence of ovarian suppression will not be allowed to participate. Ovarian function also will be tested during the treatment phase, and any abnormality will be 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 from the protocol for safety (see stopping criteria above). Decisions regarding safety will be made by the PI with advice from Co-Investigator Larissa Mooney, M.D. Participants also can be withdrawn if they leave inpatient treatment at Cri-Help. In addition, participants can decide on their own to withdraw from the protocol at any time without prejudice. If a participant is withdrawn or decides on their own to withdraw, this will not affect their treatment at Cri-Help. If a participant leaves the protocol for any of these reasons, they 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:

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). 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. They 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 who will receive CBD or placebo (1:1). The treatment period with CBD or placebo will be 56 days (8 weeks). Participants will be in the study for up to 24 weeks, including follow-up evaluations at 1 and 3 months after completion of the treatment protocol. The CBD dose will be 800 mg/day. Dose Justification: CBD will be tested at a daily dose of 800 mg/day vs. placebo. 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 (Devinsky et al., 2016); and doses between 300 and 1500 mg have been used in humans without toxicity or serious adverse events (Borgward et al., 2008; Consroe et al., 1991; Fusar-Poli et al., 2009; Zuardi, 2008; Zuardi et al., 1993; Zuardi et al., 2006; Zuardi et al., 1995). Forty-two subjects received 200 mg of CBD four times daily (total 800 mg per day as in this protocol) for 2 to 4 weeks to treat schizophrenia without notable side effects (Leweke et al., 2012). 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 (Bergamaschi et al., 2011).

Sixty subjects were dosed to date in a pediatric pharmacokinetic trial with doses ranging from 10 mg/kg/day up to 40 mg/kg/day (Wheless et al., 2019); these doses were generally well tolerated, and no clinically significant safety concerns were identified, even in adolescents. In addition, 24 adults received doses of 20 mg/kg CBD (up to ~2000 mg as a single dose) (INS011-15-043) in a study evaluating the effects of food (fasting and a high-fat meal) on absorption of CBD. In that study and in another that evaluated food effects on CBD absorption in 8 healthy adults (INS011-16-093), there were no safety issues and very few adverse events.

Statistical Analysis Efficacy Endpoints: Statistical analyses will be conducted on the Intent to Treat (ITT) population (all participants who are randomized). We will use graphical and numerical summaries to screen the data for outliers and violations of model assumptions. Any identified problems will be taken into account in all analyses by transformations or non-parametric methods. Our primary analytic tool will be the generalized linear mixed model (GLMM), using group (CBD, placebo) and time (baseline, end of intervention), and their interactions as the primary predictors along with subject-level random effects to account for individual differences. The GLMM properly accounts for correlations induced by repeated measurements within subjects and ensures unbiased estimates and accounts for randomly missing data, minimizing effects of loss to follow-up. Our primary hypotheses (Aims 1 and 2) correspond to significant interactions, modeling the difference in change over time on measures of cigarette use and FTND score.

Aim 1: CBD and cigarettes per day: we will test for a Group X Time interaction with cigarettes per day as the dependent variable. We expect a significant interaction with treatment group, showing a reduction in smoking in participants who receive CBD relative to controls treated with placebo. Aim 2: CBD and nicotine dependence; As for Aim 1, we will test for a Group X Time interaction with cigarettes per day as the dependent variable. We expect a significant interaction with treatment group, showing a reduction in smoking in participants who receive CBD relative to controls treated with placebo.

Other Analyses: Plasma concentrations of CBD, anandamide and 2-AG at each sampling time will be summarized by descriptive statistics (e.g., mean, SD, CV, minimum, median, maximum, and geometric mean), and will be compared during the steady-state CBD phase (Days 7, 14, 28 and 56) to baseline.

Sex as a Biological Variable: We will perform a preliminary assessment of the effects of sex on the outcome measures in Aims 1 and 2. If significant effects are revealed, biological sex will be retained as a covariate to evaluate its influence on the effects of CBD.

Power analysis. This study was powered for the primary endpoint in Aim 1 - reduction in cigarette smoking from baseline to the end of the trial. Preliminary data regarding the effect of CBD on cigarette use, the primary endpoint of our study, are limited. We estimate power based on this limited information, but also on data with varenicline. Power calculations are based on n=30/group, but power will be higher because our GLMM structure allows us to use data from non-completers. A two-sided significance of α=0.05 and a within-subject autocorrelation of r=0.5 (a likely conservative lower bound) are assumed. Our primary aims will be tested by evaluating Group X Time interactions. Our design provides sufficient power to detect interaction effects as small as f=0.18 with >80%power. This minimum detectable effect size is between Cohen's definition of a small (f=0.10) and medium effect (f=0.25). A pilot study showed a 40% reduction in cigarette use for individuals receiving aerosolized CBD vs. placebo (n=12/group), with a large effect size (f=0.39) (Morgan et al., 2013). Assuming that the correlation between baseline and post-treatment scores is ≥ 0.5, the power to detect such an effect is >99%. If the effect size is instead comparable to that of varenicline (f=0.30 meta-analysis) (Wu et al., 2006), we will have >99% power to detect such an effect. Overall, our study has sufficient power to detect effect sizes of the magnitude, which would motivate further study of CBD for TUD.

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 it is hemp-derived CBD with a THC concentration of no more than 0.3%. We have obtained approval from the FDA for this project as we have for another clinical trial that we are conducting with Nantheia ATL5 (IND 152888, E.D. London, sponsor). We will receive oversight and will 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 sachets containing four, 1-mL softgels each for testing of 800 mg CBD vs. placebo. It will be stored at room temperature, 59-86°F (15-30°C), in locked cabinet in a locked office of a staff member, who is blinded to its identity (CBD or placebo).

Dispensation of the IP

• A staff member who is not involved in data entry or any other aspects of the study will distribute the IP into study-provided containers that will be labeled with the subject-ID number and/or patient initials and doses will be clearly divided and labeled for AM or PM:
• a) The investigational product (CBD or placebo) will be taken under staff supervision at the Cri-Help treatment center.
• b) A Residential Technician 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.

Relevant and Cited Literature Ananda Scientific (2021). ATL-5 Investigator's Brochure. Baker, T. B., Piper, M. E., Smith, S. S., Bolt, D. M., Stein, J. H., & Fiore, M. C. (2021). Effects of combined varenicline with nicotine patch and of extended treatment duration on smoking cessation: Arandomized clinical trial. JAMA, 326(15), 1485-1493.

Bergamaschi, M., Helena Costa Queiroz, R., Waldo Zuardi, A., & Crippa, A. S. (2011). Safety and side effects of cannabidiol, a cannabis sativa constituent. Curr. Drug Saf., 6(4), 237-249.

Borgwardt, S. J., Allen, P., Bhattacharyya, S., Fusar-Poli, P., Crippa, J. A., Seal, M. L, Franccaro, V., Atakan, Z, Martin-Santos, R., O'Carroll, C. O., Ribia, K., & McGuire, P. K. (2008). Neural basis of Δ-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol. Psychiatry, 64(11), 966-973.

Burggren, A. C., Shirazi, A., Ginder, N., & London, E. D. (2019). Cannabis effects on brain structure, function, and cognition: considerations for medical uses of cannabis and its derivatives. Am. J. Drug Alcohol Abuse, 45(6), 563-579.

Businelle, M.S., Kendzor, D.E., Kesh, A. et al. (2014). Small financial incentives increase smoking cessation in homeless smokers: a pilot study. Addict. Behav., 39(3), 717-720 Centers for Disease Control and Prevention (CDC) (2019). Current cigarette smoking among adults in the United States. Atlanta: U.S. Department of Health & Human Services.

Consroe, P., Laguna, J., Allender, J., Snider, S., Stern, L., Sandyk, R., Kennedy, K., & Schram, K. (1991). Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacol. Biochem. Behav., 40(3), 701-708.

Devinsky, O., Marsh, E., Friedman, D., Thiele, E., Laux, L., Sullivan, J.,Miller, I., Flamini, R., Wilfong, A., Fillous, F., Wong, M., Tilton, N., Bruno, P,M., Bluvstein, J., Hedlund, J., Kamens, R., Maclean, J., Nanoia, S., Sinohal, N., S., Wilson, C. A., Patel, A., & Cilio, M. R. (2016). Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol., 15(3), 270-278.

Dos Santos, R. G., Hallak, J. E. C., & Crippa J. A. S. (2021). Neuropharmacological effects of the main phytocannabinoids: a narrative review. Adv. Exp. Med. Biol., 1264:29-45.

Elmes, M. W., Kaczocha, M., Berger, W. T., Leung, K., Ralph, B. P., Wang, L., Sweeney, J., M., Tsirka, S. E., Ojima, I., & Deutsch, D. G. (2015). Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J. Biol. Chem., 290(14), 8711-8721.

Fusar-Poli, P., Crippa, J. A., Bhattacharyya, S., Borgwardt, S. J., Allen, P., Martin-Santos, R., Seal, M., Surguladze, S. A., Carroll, C., O., Atakan, A, Zuardi, A., W., & McGuire, P. K. (2009). Distinct effects of Δ9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch. Gen. Psychiatry, 66(1), 95-105.

Gamaleddin, I. H., Trigo, J. M., Gueye, A. B., Zvonok, A., Makriyannis, A., Goldberg, S. R., Le Foll, B. (2015). Role of the endogenous cannabinoid system in nicotine addiction: novel insights. Front. Psychiatry, 6:41.

García-Gómez, L., Hernández-Pérez, A., Noé-Díaz, V., Riesco-Miranda, J. A., & Jiménez-Ruiz, C. (2019). Smoking cessation treatments: current psychological and pharmacological options. Rev. Invest. Clin., 71(1), 7-16.

Gómez-Coronado, N., Walker, A. J., Berk, M., & Dodd, S. (2018). Current and emerging pharmacotherapies for cessation of tobacco smoking. Pharmacotherapy, 38(2), 235-258.

Halperin, A. C., .McAfee, T. A., Jack, L., M., M.A., Catz, S., L., McClure, J., B., Deprey, T., M., Richards, J., Zbikowski, S., M., & Swan, G. E. (2009). Impact of symptoms experienced by varenicline users on tobacco treatment in a real world setting. JSAT, 36(4), 428-434.

Hindocha, C., Freeman, T. P., Grabski, M., Stroud, J. B., Crudgington, H., Davies, A. C., Das, R., K., Lawn, W., Morgan, C.J. A., & Curran, H. V. (2018a). Cannabidiol reverses attentional bias to cigarette cues in a human experimental model of tobacco withdrawal. Addiction, 113(9), 1696-1705.

Hindocha, C., Freeman, T. P., Grabski, M., Crudgington, H., Davies, A. C., Stroud, J. B., Das, R., K., Lawn, W., Morgan, C.J. A., & Curran, H. V. (2018b). The effects of cannabidiol on impulsivity and memory during abstinence in cigarette dependent smokers. Sci. Rep., 8(1), 1-7.

Hughes, J. R., Keely, J., & Naud, S. (2004). Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction, 99(1), 29-38.

Jordan, C. J. & Xi, Z. X. (2018). Discovery and development of varenicline for smoking cessation. Expert Opin. Drug Discov., 13(7):671-683.

Karimi-Haghighi, S., Razavi, Y., Iezzi, D., Scheyer, A. F., Manzoni, O. &, Haghparast, A. (2022). Cannabidiol and substance use disorder: Dream or reality. Neuropharmacology 2022 Apr 1:207:108948. doi: 10.1016/j.neuropharm.2022.108948. Epub 2022 Jan 13.

Kathmann, M., Flau, K., Redmer, A., Tränkle, C., & Schlicker, E. (2006). Cannabidiol is an allosteric modulator at mu-and delta-opioid receptors. Naunyn-Schmiedeb. Arch. Pharmacol., 372(5), 354-361.

Kendzor, D. E., Businelle, M. S., Poonawalla, I. B., et al. (2015). Financial incentives for abstinence among socioeconomically disadvantaged individuals in smoking cessation treatment. Am. J. Public Health, 105(6), 1198-1205.Kotlinska-Lemieszek, A., Klepstad, P., Haugen, D. F. (2015) Clinically significant drug-drug interactions involving opioid analgesics used for pain treatment in patients with cancer: A systematic review. Drug Des Devel Ther, 9, 5255-5267.

Kotlinska-Lemieszek, A., Klepstad, P., Haugen, D. F. (2015). Clinically significant drug-drug interactions involving opioid analgesics used for pain treatment in patients with cancer: a systematic review. Drug Des Devel Ther. 16(9), 5255-5267 Le Foll, B., Forget, B., Aubin, H. J., & Goldberg, S. R. (2008). Blocking cannabinoid CB1 receptors for the treatment of nicotine dependence: insights from pre-clinical and clinical studies. Addict. Biol., 13, 239-52.

Leweke, F. M., Piomelli, D., Pahlisch, F., Muhl, D., Gerth, C. W., Hoyer, C., Klosterkötter, J., Hellmich, M., & Koethe, D. (2012). Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry, 2(3), e94-e94.

Maione, S., Piscitelli, F., Gatta, L., Vita, D., De Petrocellis, L., Palazzo, E., de Novellis, V. & Di Marzo, V. (2011). Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. Br. J. Pharmacol., 162(3), 584-596.

McPherson, M., Burduli, E, Smith, C., Herron, J., Oluwoye,O., Hirchak, K., Orr, M., McDonell, M., Roll, J. (2018). A review of contingency management for the treatment of substance-use disorders: adaptation for underserved populations, use of experimental technologies, and personalized optimization strategies. Subst. Abuse Rehabil. 9, 43-57, Mitrirattanakul, S., Ramakul, N., Guerrero, A. V., Matsuka, Y., Ono, T., Iwase, H., Mackie, K., Faull, K., F.,