Combination therapies for opioid use disorder

Abstract

Provided herein are methods and compositions for the treatment of opioid use disorder (OUD). The methods and compositions can include cannabidiol (CBD), one or more medications for opioid use disorder (MOUDs), combinations thereof, and uses thereof.

Description

[0001] Attorney Docket No. 27527-0197WO1 COMBINATION THERAPIES FOR OPIOID USE DISORDER CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U. S. Provisional Application No. 63 / 789,228 filed April 15, 2025, the contents of which are herein incorporated by reference in their entirety'.

[0002] FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0003] This invention was made with government support under grant number UH3 DA050323, awarded by the National Institutes of Health. The government has certain rights in the invention.

[0004] TECHNICAL FIELD

[0005] The present disclosure relates to methods and compositions for the treatment of opioid use disorder (OUD). The methods and compositions can include cannabidiol (CBD). one or more medications for opioid use disorder (MOUDs), combinations thereof, and uses thereof.

[0006] BACKGROUND

[0007] The opioid epidemic has had devastating consequences leading to profound national burden. Research into the enhancement of treatment options for individuals with opioid use disorder (OUD) is a public health priority. Methadone, an opioid agonist, has been the traditional line of treatment for OUD. In recent years, buprenorphine, a partial opioid agonist, has been added to the treatment repertoire for OUD. While these life-saving medications for OUD (MOUDs) are important first line opioid agonist therapies (OATs) to attenuate opioid-induced “high’" and withdrawal syndrome, neither methadone nor buprenorphine sufficiently prevent and alleviate craving. Craving is a distressing symptom which is linked to anxiety, poor decision-making, relapse and ultimately the failure of treatments. Drug associated environmental cues that induce craving are strong triggers for opioid use thus treatments that reduce craving decrease the likelihood of drug misuse. Therefore, developing additional interventions that reduce craving can enhance the OUD treatments available for addressing the opioid epidemic.Attorney Docket No. 27527-0197WO1

[0008] Therefore, there exists a need for additional therapies for OUD, e.g., combination therapies including one or more MOUDs and one or more additional therapeutic agents. Provided herein are therapeutic methods and compositions for the treatment of OUD.

[0009] SUMMARY

[0010] Provided herein are methods and compositions for the treatment of OUD. The methods and compositions can include cannabidiol (CBD) and one or more medications for opioid use disorder (MOUDs). The methods and compositions disclosed herein can be more efficacious for the treatment of OUD than administration of the one or more MOUDs alone. Measures of efficacy for the treatment of OUD can include, for example, cravings associated with opioid use, anxiety associated with opioid use, opioid intake as measured by urine toxicology7, daytime stress, and deep sleep measurements. Additional features of the disclosed methods and compositions are provided in the appendices filed herewith.

[0011] In a first aspect, the disclosure provides methods of treating opioid use disorder (OUD) in a subject in need thereof, the methods including administering to the subject a medication for opioid use disorder (MOUD) and administering to the subject an adjunctive therapeutic agent including cannabidiol (CBD). In some embodiments, the subject previously did not respond, or responded poorly, to treatment with the MOUD. In some embodiments, the subject has ceased the use of opioids. In some embodiments, the subject has not ceased the use of opioids. In some embodiments, the subject has been administered the MOUD for at least 14 days prior to administration of the adjunctive therapeutic agent including CBD.

[0012] In some embodiments, the MOUD is selected from the group consisting of methadone, buprenorphine, and naltrexone. In some embodiments, the MOUD is methadone administered at a dose of between 10 mg and 250 mg per day. In some embodiments, the MOUD is buprenorphine administered at a dose of between 2 mg and 32 mg per day. In some embodiments, the MOUD is naltrexone administered at a dose of between 25 mg and 50 mg per day.

[0013] In some embodiments, the CBD is administered orally. In some embodiments, the CBD is administered at a dose of between 400 mg per day and 800 mg per day. In some embodiments, the CBD is administered once daily. In some embodiments, the CBD is administered orally at a dose of 400 mg daily. In some embodiments, the CBD is administered orally at a dose of 800 mg daily. In some embodiments, the CBD is administered twice daily. In some embodiments, the CBD is administered orally at a dose ofAttorney Docket No. 27527-0197WO1

[0014] 200 mg twice daily. In some embodiments, the CBD is administered orally at a dose of 400 mg twice daily. In some embodiments, the CBD is administered orally at a dose of 400 mg once daily. In some embodiments, the CBD is administered orally at a dose of 400 mg twice daily. In some embodiments, the CBD is administered orally at a dose of 800 mg once daily.

[0015] In some embodiments, the MOUD and the adjunctive therapeutic agent including CBD are co-administered. In some embodiments, the MOUD and the adjunctive therapeutic agent including CBD are administered separately.

[0016] In some embodiments, the CBD is measurable in plasma of the subject (ng / mL) at a level of between 50 ng / mL and 300 ng / mL after four weeks of administering to the subject the adjunctive therapeutic agent including CBD. In some embodiments, 7-carboxy cannabidiol (7-COOH-CBD) is measurable in plasma of the subject (ng / mL) at a level of between 1000 ng / mL and 4000 ng / mL after four weeks of administering to the subject the adjunctive therapeutic agent including CBD. In some embodiments, Cmaxof CBD as measured in plasma of the subject is between 150 and 550 after administration of CBD orally at a dose of 400 mg daily. In some embodiments, AUClastof CBD as measured in plasma of the subject is between 500 and 2000 after administration of CBD orally at a dose of 400 mg daily.

[0017] In some embodiments, cravings associated with opioid use are reduced in the subject. In some embodiments, anxiety associated with opioid use is reduced in the subject. In some embodiments, anxiety associated with opioid use is reduced in the subject, wherein the anxiety is measured by a biometric device.

[0018] In some embodiments, opioid intake as measured by urine toxicology7is reduced in the subject. In some embodiments, opioid intake as measured by urine toxicology7is reduced in the subject relative to a second subject that was not administered CBD. In some embodiments, opioid intake as measured by urine toxicology is reduced in the subject relative to opioid intake as measured by urine toxicology measured in the subject prior to administering the adjunctive therapeutic agent including cannabidiol (CBD).

[0019] In some embodiments, daytime stress associated with opioid use is reduced in the subject. In some embodiments, daytime stress associated with opioid use is reduced in the subject, wherein the daytime stress is measured by a biometric device. In some embodiments, number of daytime hours spent in a stressful state is decreased in the subject relative to a second subject that w as not administered CBD. In some embodiments, number of daytime hours spent in a stressful state is decreased in the subject relative to number of daytime hours spent in a stressful state in the subject prior to administering the adjunctive therapeutic agentAttorney Docket No. 27527-0197WO1

[0020] including cannabidiol (CBD). In some embodiments, daytime stress as measured by a biometric device includes one or more biometric measurements selected from the group consisting of heart rate data, body temperature data, and accelerometer data.

[0021] In some embodiments, deep sleep measurements are improved in the subject. In some embodiments, number of hours of deep sleep is increased in the subject relative to a second subject that was not administered CBD. In some embodiments, number of hours of deep sleep is increased in the subject relative to number of hours of deep sleep in the subject prior to administering the adjunctive therapeutic agent including cannabidiol (CBD). In some embodiments, deep sleep measurements are improved in the subject, wherein the deep sleep measurements are measured by a biometric device. In some embodiments, number of hours of deep sleep relative to number of hours of light sleep is increased in the subject relative to a second subject that was not administered CBD. In some embodiments, number of hours of deep sleep relative to number of hours of light sleep is increased in the subject relative to number of hours of deep sleep relative to number of hours of light sleep in the subject prior to administering the adjunctive therapeutic agent including cannabidiol (CBD). In some embodiments, the deep sleep measurements as measured by a biometric device include one or more biometric measurements selected from the group consisting of heart rate data, body temperature data, and accelerometer data.

[0022] In some embodiments, the duration of the treatment is at least 16 weeks.

[0023] In another aspect, the disclosure provides compositions including a cannabidiol (CBD) and a medication for opioid use disorder (MOUD) for use in the treatment of opioid use disorder (OUD). In some embodiments, the MOUD is methadone, buprenorphine, or naltrexone.

[0024] In some embodiments, the composition includes: (i) between 10 mg and 250 mg of methadone and between 200 mg and 800 mg of CBD; (ii) between 2 mg and 32 mg of buprenorphine and between 200 mg and 800 mg of CBD; or (iii) between 25 mg and 50 mg of naltrexone and between 200 mg and 800 mg of CBD.

[0025] In some embodiments, the composition includes between 10 mg and 250 mg of methadone and 200 mg of CBD. In some embodiments, the composition includes between 10 mg and 250 mg of methadone and 400 mg of CBD. In some embodiments, the composition includes between 10 mg and 250 mg of methadone and 800 mg of CBD. In some embodiments, the composition includes between 2 mg and 32 mg of buprenorphine and 200 mg of CBD. In some embodiments, the composition includes between 2 mg and 32 mg of buprenorphine and 400 mg of CBD. In some embodiments, the composition includes betweenAttorney Docket No. 27527-0197WO1

[0026] 2 mg and 32 mg of buprenorphine and 800 mg of CBD. In some embodiments, the composition includes between 25 mg and 50 mg of naltrexone and 200 mg of CBD. In some embodiments, the composition includes between 25 mg and 50 mg of naltrexone and 400 mg of CBD. In some embodiments, the composition includes between 25 mg and 50 mg of naltrexone and 800 mg of CBD.

[0027] BRIEF DESCRIPTIONS OF THE DRAWINGS FIG. 1 describes the experimental plan for a double-blinded, randomized, placebo control study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0028] FIG. 2 shows the general schematic overview of the double-blinded, randomized, placebo control study to determine whether CBD can reduce craving and anxiety7in individuals maintained on opioid agonist therapy treatment.

[0029] FIG. 3 shows a schematic of the consent, screening, study drug administration, and follow-up of the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0030] FIG. 4 describes the procedures and duration of visits 1-4 of the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0031] FIG. 5 describes the procedures and duration of visits 9-12 of the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0032] FIG. 6 describes the procedures and duration of visits 13-16 of the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0033] FIG. 7 shows a schematic of visits 2, 7, 12, and 16 for the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0034] FIG. 8 shows a schematic for visit 2 for the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0035] FIG. 9 shows a schematic overview of the cue-induced task measurements to be performed.

[0036] FIG. 10 provides a summary of study endpoints and outcome measures.Attorney Docket No. 27527-0197WO1

[0037] FIG. 11 provides a summary of preliminary' data relating to recruitment numbers for the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0038] FIG. 12 provides a summary of preliminary data relating to demographics of participants for the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0039] FIG. 13 shows a plot of mean cannabidiol (CBD) plasma toxicology across visit 2 (baseline) to visit 16.

[0040] FIG. 14 shows a plot of mean CBD-COOH plasma toxicology' across visit 2 (baseline) to visit 16.

[0041] FIG. 15 shows plots of data relating to preliminary’ data of cue-induced cravings (VASC).

[0042] FIG. 16 shows plots of data relating to preliminary' data of cue-induced cravings (VASC).

[0043] FIG. 17 shows plots of data relating to preliminary’ data of cue-induced anxiety (VASA).

[0044] FIG. 18 shows a plot of data relating to preliminary data of a general craving selfreport for subjects in the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0045] FIG. 19 shows a plot of data relating to preliminary data of a general anxiety selfreport for subjects in the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0046] FIG. 20 shows plots of data relating to biometric data of daytime stress across four weeks of twice daily 200 mg CBD or placebo.

[0047] FIG. 21 shows plots of data relating to biometric data of sleep measures across four weeks of twice daily 200 mg CBD or placebo.

[0048] FIG. 22 shows a plot of data relating to preliminary' data of urine toxicology' for subjects in the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0049] FIG. 23 shows data relating to preliminary data of safety' and report of adverse events for subjects in the study to determine whether CBD can reduce craving and anxiety7in individuals maintained on opioid agonist therapy treatment.Attorney Docket No. 27527-0197WO1

[0050] FIG. 24 shows data relating to preliminary data of electrocardiogram (EKG), respiration rate, and oxygen saturation for subjects in the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0051] FIG. 25 shows data relating to preliminary' data of plasma metabolites of opioid agonists for subjects in the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0052] FIG. 26 shows plots of data relating to preliminary’ data of methadone plasma concentrations for subjects in the study to determine whether CBD can reduce craving and anxiety in individuals maintained on opioid agonist therapy treatment.

[0053] DETAILED DESCRIPTION

[0054] The present disclosure relates to methods and compositions for treating opioid use disorder (OUD) through the administration of a medication for opioid use disorder (MOUD) in combination with an adjunctive therapeutic agent comprising cannabidiol (CBD). The disclosed methods and compositions provide clinically meaningful improvements in treatment outcomes relative to administration of MOUD alone.

[0055] In various embodiments, administration of CBD as an adjunct to MOUD results in one or more of the following outcomes: reduction of opioid cravings, reduction of anxiety associated with opioid use. reduction of daytime stress, improvement in sleep quality including increased deep sleep, and reduction of opioid intake as measured by objective toxicological assessments.

[0056] The disclosure provides methods and compositions for treating opioid use disorder through administration of a medication for opioid use disorder in combination with cannabidiol. The disclosed methods and compositions may provide enhanced therapeutic efficacy relative to administration of a MOUD alone.

[0057] In various embodiments, adjunctive administration of cannabidiol modulates one or more symptoms of OUD, including craving, anxiety, stress, sleep architecture, and opioid intake behavior. The methods described herein are applicable across a range of clinical contexts, including early stabilization, maintenance therapy, relapse prevention, and long-term management of OUD.

[0058] The disclosed methods and compositions provide clinically meaningful improvements in the treatment of opioid use disorder by addressing craving, anxiety, stress dysregulation. sleep disturbances, and opioid use behaviors that may not be fully mitigated by MOUD alone.Attorney Docket No. 27527-0197WO1

[0059] These improvements may enhance treatment adherence, reduce relapse risk, and improve long-term outcomes for individuals with opioid use disorder.

[0060] Methods of Treatment

[0061] In one aspect, provided herein are methods of treating opioid use disorder in a subject in need thereof, the methods comprising administering to the subject a medication for opioid use disorder and administering to the subject an adjunctive therapeutic agent comprising cannabidiol.

[0062] In certain embodiments, the subject has previously failed to achieve adequate symptom control with a MOUD alone, including subjects exhibiting persistent craving, anxiety, continued opioid use, or relapse despite MOUD therapy.

[0063] In some embodiments, the subject has ceased opioid use at the time cannabidiol is initiated. In other embodiments, the subject has not ceased opioid use prior to or during initiation of cannabidiol administration. The disclosed methods encompass harm-reduction, stabilization, and abstinence-oriented treatment paradigms.

[0064] In some embodiments, cannabidiol administration is initiated following a stabilization period on the MOUD. For example, the MOUD may be administered for at least about 14 days prior to initiation of cannabidiol, allowing the subject to achieve a stable MOUD dosing regimen before adjunctive therapy is introduced.

[0065] In certain embodiments, adjunctive cannabidiol therapy is administered for at least about 16 weeks. Longer durations, including extended maintenance administration, are contemplated.

[0066] Medications for Opioid Use Disorder

[0067] In various embodiments, the medication for opioid use disorder is selected from methadone, buprenorphine, naltrexone, or combinations thereof. In certain embodiments, the MOUD is methadone, which may be administered at daily doses ranging from about 10 mg to about 250 mg. In certain embodiments, the MOUD is buprenorphine, which may be administered at daily doses ranging from about 2 mg to about 32 mg. In certain embodiments, the MOUD is naltrexone, which may be administered at daily doses ranging from about 25 mg to about 50 mg.

[0068] The MOUD may be administered using any clinically appropriate formulation or route of administration, including oral, sublingual, injectable, transdermal, or implantable formulations.Attorney Docket No. 27527-0197WO1

[0069] Cannabidiol Administration

[0070] In various embodiments, cannabidiol is administered orally as part of the disclosed methods. Oral dosage forms include tablets, capsules, oils, solutions, suspensions, or other pharmaceutically acceptable formulations. In certain embodiments, cannabidiol is administered at a total daily dose of between about 400 mg and about 800 mg. In some embodiments, cannabidiol is administered once daily. In other embodiments, cannabidiol is administered twice daily in divided doses. Non-limiting dosing regimens include: about 400 mg once daily; about 800 mg once daily; about 200 mg twice daily; or about 400 mg twice daily.

[0071] Cannabidiol and the MOUD may be administered concurrently or separately, including administration at different times of day or via different routes of administration.

[0072] Pharmacokinetics

[0073] In certain embodiments, administration of cannabidiol according to the disclosed methods produces reproducible and measurable plasma concentrations of cannabidiol and cannabidiol metabolites.

[0074] In some embodiments, plasma cannabidiol concentrations measured after approximately four w eeks of administration range from about 50 ng / mL to about 300 ng / mL. In some embodiments, plasma concentrations of the cannabidiol metabolite

[0075] 7-carboxy-cannabidiol (7-COOH-CBD) range from about 1000 ng / mL to about 4000 ng / mL. In certain embodiments, oral administration of cannabidiol at about 400 mg daily results in a peak plasma concentration (Cmax) between about 150 and about 550 and an AUClast between about 500 and about 2000.

[0076] Therapeutic Outcomes

[0077] In various embodiments, the disclosed methods result in a reduction in cravings associated with opioid use. In some embodiments, anxiety associated with opioid use is reduced. Anxiety may be assessed subjectively, clinically, or through objective biometric measurements reflecting physiological correlates of anxiety. In certain embodiments, opioid intake is reduced, as measured by urine toxicology. Reduction may be assessed relative to baseline measurements prior to cannabidiol administration or relative to a comparator subject receiving MOUD without cannabidiol.Attorney Docket No. 27527-0197WO1

[0078] In certain embodiments, administration of cannabidiol reduces daytime stress associated with opioid use. Daytime stress may be assessed using biometric devices configured to measure physiological signals such as heart rate, body temperature, movement, or combinations thereof.

[0079] In some embodiments, the number of daytime hours spent in a stressful physiological state is reduced following cannabidiol administration.

[0080] In various embodiments, sleep quality is improved. Improvements may include increased deep sleep duration, increased ratio of deep sleep to light sleep, or other favorable changes in sleep architecture. Sleep may be assessed using wearable or bedside biometric devices.

[0081] Compositions

[0082] In another aspect, provided herein are compositions comprising cannabidiol and a medication for opioid use disorder for use in the treatment of opioid use disorder.

[0083] In some embodiments, the composition comprises methadone, buprenorphine, or naltrexone in combination with cannabidiol. The components may be formulated together in a single dosage form or provided as separate dosage forms intended for coordinated administration. Exemplary compositions include:

[0084] methadone (about 10 mg to about 250 mg) and cannabidiol (about 200 mg to about 800 mg);

[0085] buprenorphine (about 2 mg to about 32 mg) and cannabidiol (about 200 mg to about 800 mg); or

[0086] naltrexone (about 25 mg to about 50 mg) and cannabidiol (about 200 mg to about 800 mg).

[0087] The compositions may further comprise pharmaceutically acceptable excipients, carriers, stabilizers, or release-modifying agents.Attorney Docket No. 27527-0197WO1

[0088] EXAMPLES

[0089] Example 1: A Study for Adjunctive Cannabidiol for Recovery from Opioid Study (ACROS)

[0090] The study design and preliminary experimental data shown in Appendix 1 forms part of the present description and is incorporated herein in its entirety;

[0091] Example 2: A Double-blinded, Randomized, Placebo Control Study to Determine Whether CBD Can Reduce Craving and Anxiety in Individuals Maintained on Opioid Agonist Therapy Treatment (OAT)

[0092] Included in this study are individuals who are treated with at least a dose of methadone or buprenorphine that constitutes the lower threshold for a medium-dose maintenance treatment (i.e. > 40 mg methadone per day or > 8 mg buprenorphine per day). Thus this allow s studying a broad, naturalistic group of individuals who are treated with an adequate maintenance dose, while also providing the opportunity to study if the addition of CBD allows for a dose reduction in their opioid agonist therapy (OAT).

[0093] The study design and preliminary data associated with this study are presented in FIGs. 1-26.APPENDIX

[0094] Phase 3: Adjunctive Cannabidiol for Recovery from Opioid Study (ACROS)

[0095] Protocol Number IRB#: STUDY-21-00607

[0096] IND #155375

[0097] Principal Investigator: Yasmin Hurd, PhD

[0098] Funded by: National Institute on Drug Abuse (NIDA) (NIH) NIH Grant: UH3 DA050323

[0099] Icahn School of Medicine at Mount Sinai Seed Fund: 0285-5811 Version Number: v.8.0

[0100] 14 Feb 2025

[0101] Summary of Changes from Previous Version:

[0102]

[0103] Protocol Rev. 8.0: 02 / 13 / 2025

[0104]

[0105] STATEMENT OF COMPLIANCE.

[0106]

[0107]

[0108] 1.1 Synopsis

[0109]

[0110] 1.2 Schema>

[0111] 2 INTRODUCTION.

[0112]

[0113] 2.1 Study Rationale..

[0114]

[0115] 2.2 Background

[0116]

[0117] 2.3 Risk / Benefit Assessment..9 2.3.1 Known Potential Risks..9 2.3.2 Known Potential Benefits 11 2.3.3 Assessment of Potential Risks and Benefits> 11 3 OBJECTIVESAND ENDPOINTS. 12 STUDYDESIGN. 13 4.1 Overall

[0118]

[0119] 4.2 Scientific Rationale for Study Design.

[0120]

[0121] 4.3 Justification for Dose 14

[0122]

[0123] 5.1 Inclusion

[0124]

[0125] 5.2 Exclusion Criteria 16 5.3 Lifestyle

[0126]

[0127] 5.4 Screen Failures

[0128]

[0129] 5.5 Strategies for Recruitment and Retention..

[0130]

[0131] 6 STUDY PROCEDURE.

[0132]

[0133] 6.1

[0134]

[0135] 6.2 Schedule of Activities (SoA)

[0136]

[0137] 7 STUDY ASSESSMENTS AND PROCEDURES. 20 7.1 ASSESSMENT PROCEDURES.25 7.2 Safety and Other Assessments >.27 7.3 Study Intervention Compliance>

[0138]

[0139] 7.4 Concomitant Therapy >.28

[0140] Protocol Rev. 8.0: 02 / 13 / 20257.5 Study product Preparation / Handling / Storage / Accountability. 28

[0141] 7.5.1 Acquisition and accountability. 28 7.5.2 Formulation, Appearance, Packaging, and Labeling. 29 7.5.3 Product Storage and Stability. 30 7.5.4 Preparation. 30 8 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION / WITHDRAWAL. 30 8.1 Discontinuation of Study Intervention. 30 8.2 Participant Discontinuation / Withdrawal from the Study. 32 8.3 Lost to Follow-Up. 32 8.4 Adverse Events and Serious Adverse Events. 33 8.4.1 Definition of Adverse Events (AE). 33 8.4.2 Definition of Serious Adverse Events (SAE). 33 8.4.3 Classification of an Adverse Event. 33 8.4.4 Time Period and Frequency for Event Assessment and Follow-Up. 34 8.4.5 Adverse Event Reporting. 34 8.4.6 Serious Adverse Event Reporting. 35 8.5 Unanticipated Problems. 36 8.5.1 Definition of Unanticipated Problems (UP). 36 8.5.2 Unanticipated Problem Reporting. 36 8.5.3 Reporting Unanticipated Problems to Participants. 37 9 STATISTICAL CONSIDERATIONS. 37 9.1 Statistical Hypotheses. 35 9.2 Sample Size Determination. 38 9.3 POPULATIONS FOR ANALYSES. 35 9.4 Statistical Analyses. 38 9.4.1 General Approach. 38 9.4.2 Analysis of the Primary Efficacy Endpoint(s). 39 9.4.3 Analysis of the Secondary Endpoint(s). 39 9.4.4 Safety Analyses. 40 9.4.5 Planned Interim Analyses. 40 9.4.6 Sub-Group Analyses. 41 9.4.7 Tabulation of Individual participant Data. 41 9.4.8 Exploratory Analyses. 41 10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS. 41 10.1 Regulatory, Ethical, and Study Oversight Considerations 41 10.1.1 Informed Consent Process. 41 10.1.2 Study Discontinuation and Closure. 42 10.1.3 Confidentiality and Privacy. 42 10.1.4 Future Use of Stored Specimens and Data. 43 10.1.5 Key Roles and Study Governance. 43 10.1.6 Safety Oversight. 41 10.1.7 DSM Board Plan and Frequency of DSM reviews. 45 10.1.8 Clinical Monitoring - Oversight / Responsible Parties. 45 10.1.9 Quality Assurance and Quality Control. 45

[0142] Protocol Rev. 8.0: 02 / 13 / 202510.1.10 Data Handling and Record Keeping. 46

[0143] 10.1.11 Protocol Deviations. 47 10.1.12 Publication and Data Sharing Policy. 47 10.1.13 Conflict of Interest Policy. 47 10.2 Environmental assessment

[0144]

[0145] 10.3 Abbreviations

[0146]

[0147] 10.4 Protocol Amendment History. 51 11 REFERENCES. 53

[0148] Protocol Rev. 8.0: 02 / 13 / 2025Adjunctive Cannabidiol for Recovery from Opioid Study Version 8.0

[0149] (ACROS) 14 Feb 2025

[0150]

[0151] The trial will be carried out in accordance with International Conference on Harmonization Good Clinical Practice (ICH GCP) and the following:

[0152] • United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and / or 21 CFR Part 812)

[0153] National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP Training.

[0154] The protocol, informed consent form(s), recruitment materials, and all participant materials will be reviewed and approved by the Institutional Review Board (IRB). Approval of both the protocol and the consent form will be obtained before any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before the changes are implemented to the study. In addition, all changes to the consent form will be IRB- approved; a determination will be made regarding whether a new consent needs to be obtained from participants who provided consent, using a previously approved consent form.

[0155] Protocol Rev. 8.0, 02 / 14 / 2025Adjunctive Cannabidiol for Recovery from Opioid Study Version 8.0

[0156] (ACROS) 14 Feb 2025

[0157]

[0158] 1.1

[0159] Title: Cannabidiol in the Treatment of Opioid Use Disorder

[0160] Study Description: The long-term goal of the project is to determine whether cannabidiol (CBD) can reduce craving and relapse in individuals with opioid use disorder (OUD). The first phase of our project was an open cross-over design study in healthy individuals to confirm the safety and pharmacokinetic (PK) effects of CBD (BSPG CBD; Brains Bioceutical). The second phase was a double-blinded randomized controlled trial to determine whether CBD reduces craving and anxiety in individuals with OUD maintained on opioid agonist therapy. This next phase will determine whether CBD can serve as a potential adjunct treatment to reduce illicit opioid use in individuals with OUD maintained on opioid agonist therapy.

[0161] Objectives: To determine whether CBD (200 mg or 400 mg; BSPG CBD, Brains Bioceutical) taken twice daily (morning and evening), as compared to placebo, for 24 weeks reduces illicit opioid use and craving in individuals with OUD who are maintained on methadone or buprenorphine.

[0162] Endpoints: Primary outcomes: Percentage of individuals with negative toxicology for illicit opioid use during the study.

[0163] Secondary outcomes:

[0164] Concentration of illicit opioids in quantitative urine and plasma toxicology

[0165] Cue-induced craving and anxiety

[0166] General craving and anxiety self-report

[0167] Duration of first illicit opioid abstinence

[0168] Number of weeks of abstinence from illicit opioids

[0169] Substance use other than opioids

[0170] Concentration of methadone, buprenorphine and their metabolites

[0171] Retention in treatment

[0172] Change in opioid treatment dosage

[0173] Psychiatric symptomatology

[0174] Physiological measures (heart rate, blood pressure, body temperature, 02)

[0175] Sleep

[0176] Cognitive function

[0177] Quality of life

[0178] Safety:

[0179] Adverse events

[0180] Study Population: Individuals with OUD who are maintained on methadone or buprenorphine. Individuals will be randomized to one of four groups: 1 capsule CBD 200mg, 2 capsules CBD 400mg, 1 capsule placebo, 2 capsules placebo (1: 1:0.5:0.5 ratio). The total N= 450 (150 / group).

[0181] Phase: Randomized, double-blind, placebo-controlled Phase 3 trial

[0182] Description of

[0183] Sites / Facilities CODA, Inc., Icahn School of Medicine at Mount Sinai, University of Kentucky, University Enrolling Participants: of Pennsylvania, the University of Texas Southwestern Medical Center, University of New Mexico, and University of Illinois Chicago

[0184] Protocol Rev. 8.0, 02 / 14 / 2025Adjunctive Cannabidiol for Recovery from Opioid Study Version 8.0

[0185] (ACROS) 14 Feb 2025

[0186] Description of Study CBD (BSPG CBD; Brains Bioceutical) or placebo in capsules twice a day for 24 Intervention: weeks.

[0187] Study Duration: Estimated 3 years from when the study opens for enrollment until final completion of the data collection.

[0188] Participant Duration: Participants will be involved in the trial for approximately 30 weeks, including a screening and baseline period of ~ 1-2 weeks, 24-week treatment period, and 4-week follow-up assessment.

[0189] Protocol Rev. 8.0, 02 / 14 / 2025Adjunctive Cannabidiol for Recovery from Opioid Study Version 8.0

[0190] (ACROS) 14 Feb 2025

[0191] >

[0192] > >

[0193] 1.2 SCHEMA> >

[0194]

[0195] Figure 1. General schematic overview of the study.

[0196] OUD

[0197] Individ

[0198] maint

[0199] metha

[0200] bupre

[0201] (N=15

[0202] total N

[0203]

[0204]

[0205] Figure 2. General overview of the study activities.

[0206]

[0207] EMA, ecological momentary assessment; VASC, visual analog scale-craving; VASA, visual analog scale-anxiety.

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[0210]

[0211] 2.1

[0212]

[0213] Responding to the urgent calls for developing non-opioid therapeutics to address the opioid addiction epidemic, we have been investigating the therapeutic potential of cannabidiol (CBD), a non-intoxicating cannabinoid as a possible strategy. Our preclinical animal studies demonstrated that CBD decreases cue-induced heroin seeking behavior during drug abstinence, associated with the incubation of craving. Moreover, the effects of CBD to reduce heroin-seeking behavior was still evident even in animals that were maintained on methadone. We also showed in randomized, double-blind placebo- controlled design human clinical trials that acute CBD (Epidiolex) administration (400 mg and 800mg) decreased craving and anxiety associated with heroin cues in abstinent individuals with heroin use disorder, an effect that persisted even a week after the last CBD dose (given daily for 3 days). Moreover, another of our human studies showed that CBD was safe even in combination with a potent opioid agonist (fentanyl) to address a potential relapse condition suggesting negligible negative interaction with opioids. Building on those studies, we next set out to investigate the potential for CBD as an adjunctive treatment to methadone or buprenorphine in opioid use disorder (OUD). To that end, we first conducted Phase 1 pharmacokinetic studies with a CBD formulation in oral capsules (BSPG CBD; Brains Bioceutical) in healthy participants that showed that oral administration of BSPG CBD (400 mg) led to comparable pharmacokinetic parameters of the CBD plasma levels and its active metabolite as Epidiolex (400 mg), an FDA-approved comparator CBD product that previously reduced craving. In the Phase 2 clinical trial, we evaluated the effect of 200mg CBD (vs placebo) twice daily for 4 weeks and an additional 4 weeks of 400 mg CBD, twice daily, on cue-induced craving and anxiety in individuals with OUD who are maintained on methadone or buprenorphine. In the next phase of this IND application, we will extend the Phase 2 study to evaluate the effects of 200mg CBD, 400 mg CBD and placebo, taken twice daily, over a 24-week period in the OUD individuals maintained on methadone or buprenorphine. Our goals in this double-blinded randomized controlled clinical trial (RCT) are to investigate the potential of CBD to 1) decrease illicit opioid use and 2) reduce craving.

[0214] 2.2 BACKGROUND

[0215]

[0216] The opioid epidemic has had devastating consequences leading to profound national burden. Research into the enhancement of treatment options for individuals with OUD is clearly a major public health priority. Methadone, a full opioid agonist, has been the traditional line of treatment for OUD. In recent years, buprenorphine, a partial opioid agonist, has been added to the treatment repertoire for OUD. While these life-saving medications for OUD (MOUDs) are important first line opioid agonist therapies (OATs) to attenuate opioid-induced “high” and withdrawal syndrome, neither methadone nor buprenorphine sufficiently prevent and alleviate craving. Importantly, craving is a distressing symptom which is linked to anxiety, poor decision-making, relapse and ultimately the failure of treatments1-4. Significant evidence shows that drug- associated environmental cues that induce craving are strong triggers for opioid use thus treatments that reduce craving decrease the likelihood of drug misuse. Therefore, developing add-on interventions that reduce craving can enhance the OUD treatment arsenal critical for addressing the opioid epidemic.

[0217] To expand the medication toolbox for treating OUD, we began to evaluate the therapeutic potential of cannabidiol (CBD), a non-intoxicating cannabinoid5'9, since our preclinical rat studies showed that CBD decreases cue-induced heroin seeking behavior associated with incubation of craving during drug abstinence10. In subsequent clinical studies, we showed that CBD was safe even in combination with a potent opioid agonist to address a potential relapse condition11and that CBD decreased craving and anxiety associated with heroin cues in abstinent individuals with heroin use disorder1213, an effect that persisted even a week after the last CBD dose13. Our pioneering CBD studies have significant clinical relevance since craving is associated with relapse propensity that often contributes to the insidious cycle of heroin use and eventually treatment failure414'18. A recent study has also shown that CBD reduces craving in individuals maintained on buprenorphine or methadone19>20.

[0218] The current study, an NIH-funded UH3 double-blind (placebo-controlled) randomized controlled trial (RCT), will determine whether 200mg and 400mg CBD (BSPG CBD; Brains Bioceutical Laboratories) taken twice daily Protocol Rev. 8.0, 02 / 14 / 2025 5Adjunctive Cannabidiol for Recovery from Opioid Study Version 8.0

[0219] (ACROS) 14 Feb 2025

[0220] (morning and evening), as compared to placebo, over 24 weeks reduces illicit opioid use and craving in OUD individuals maintained on methadone or buprenorphine. This is a natural extension of our previous CBD studies. In our Phase 1 UG3 NIH study, a single administration of both 200 and 400 mg of B SPG CBD resulted in CBD plasma concentrations similar to 400mg Epidiolex within 2 hours which previously was shown to reduce cue-induced craving and anxiety12’13. The 400 mg BSPG CBD matched exactly the time course of plasma concentrations of CBD and CBD metabolite as 400 mg Epidiolex. Subsequently, the Phase 2 UG3 clinical trial evaluated OUD individuals who are maintained on OAT (methadone or buprenorphine) since this population remains sensitive to craving that contributes to their continued illicit opioid use. Moreover, focusing on individuals who are maintained on OAT reduces the potential for relapse and overdose as compared to OUD individuals who try to maintain abstinence without any clinical managed care. For this study, OAT- managed OUD individuals were monitored during two dosing periods — First period (4 weeks double-blinded RCT): CBD (200mg) or Placebo twice daily. Second period (4 weeks open label): Both cohorts receive CBD (400mg) twice daily. Participants were then monitored for an additional 4 weeks. A key component of this Phase 2 clinical trial was to determine the safety and tolerability of CBD taken over 8 weeks in OUD OAT-managed individuals. Cue (drug and neutral)-induced craving and anxiety were measured at baseline (visit 2), after 4 weeks 200mg CBD / placebo (visit 7) and after an additional 4 weeks 400mg CBD (visit 12). Our findings to date demonstrate that the twice daily CBD regimen provides stable CBD plasma levels, is safe in OUD individuals maintained on OAT and reduces cue-induced craving. Specific initial preliminary analysis of the data from the Phase 2 are presented below:

[0221] Preliminary Outcomes of UG3 Phase 2 Clinical Trial:

[0222] Demographics: No significant difference in demographic parameters was noted between the 200mg / twice daily CBD (n=26) and placebo (N=25) groups with regard to age (45.14 ± 11.06 SEM; 45.33 ± 12.08), sex / gender (20M / 5F / 1 transgender female; 20M / 4F / 1 transgender female), race / ethnicity (17 / 17 non-Hispanic; 9 / 8 Hispanic; 9 / 8 White; 10 / 10 Black; other 7 / 6), education (16 / 20 majority high school diploma or above), OAT (20 / 19 methadone; 6 / 6 buprenorphine).

[0223] Plasma CBD and CBD metabolite toxicology: Plasma levels are presented in Figure 3 for CBD and one of its main metabolite CBD-COOH. CBD taken at 200 mg twice daily maintained relatively stable plasma CBD levels across time.

[0224] Moreover, the plasma concentration se ng tes D- lar he

[0225]

[0226] ite proved to be a stable mark for CBD use Figure 3. Mean CBD (left) and CBD-COOH (right) plasma concentration across with a clear dose dependent profile. study visits for OUD individuals within the CBD 200mg / twice daily (n=21) and Placebo

[0227] (n=18) groups. White indicates levels during double-blinded phase; pink indicates levels Moreover, CBD levels showed more during 400 mg / twice daily open-label phase; green indicates levels during the follow-up variability than CBD-COOH perhaps phase when no CBD was given. due to individuals taking CBD at different times in the mornings before the plasma was taken in the lab. Thus CBD-COOH was also a good marker for adherence, which showed that all individuals had consumed CBD though two individuals showed initially very low CBD- COOH levels. Even if these individuals are considered initially non-adherent, that would still indicate a 90% adherence for participants taking the study drug (CBD / placebo).

[0228] Protocol Rev. 8.0, 02 / 14 / 2025 6Proportion of Individuals with reduced cue Induced Cue-induced craving and anxiety: Cue-induced craving and anxiety were craving scores at visit 7 vs 2 measured at in-person laboratory visits (2, 7 and 12). Although the groups showed no significant difference in demographic characteristics, at baseline ad se n ng in he ir nt by up

[0229]

[0230] a reported reduced craving to the drug cue compared to those in the:ebo group (P= 0.048; Figure 4).

[0231] General Opioid Craving and Anxiety: There was no significant difference in the opioid craving self-report across sessions with the heroin craving questionnaire (HCQ). Change from baseline in anxiety reported with the Generalized Anxiety Disorder Scale (GAD-7) was higher in the CBD group from baseline compared to the placebo group that continued throughout each visit. Nevertheless, there was a consistent larger

[0232] dec tha anx ran Re bio me var co

[0233]

[0234] and restored state during the day (Figure 5).

[0235] Urine opioid toxicology: No significant effects were observed for urine opioid toxicology. Nevertheless, the placebo group had increased positive urine opioid toxicology at visit 7 compared to baseline that was not seen in the 200mg CBD group.

[0236] Safety (Adverse events): Similar to what we and others have previously documented for CBD, there were no serious AEs with either the 200mg or 400mg BSPG CBD twice daily dosing regimen (Table 1). The events (related to GI and fatigue) were mild to moderate in the placebo group and resolved in a short time. The lack of significant AEs suggests that the 8-week exposure to CBD is safe in OAT-managed OUD individuals.

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[0240] Safety (OAT toxicology): Another aspect of safety examined relates to the potential of CBD to elevate the levels of methadone or buprenorphine through interactions with

[0241] common CYP-450 liver enzymes. As noted in Table 2, Table 2. Plasma methadone, buprenorphine and their

[0242] even after 4 weeks of twice daily administration of metabolites levels (mean and SD) at baseline and at end of the drug exposure period after twice daily 400mg CBD.

[0243] 400mg CBD, there was no significant change in either

[0244] methadone, buprenorphine or their metabolite levels as

[0245] compared to baseline, prior to any CBD administration.

[0246]

[0247] Fig

[0248] acr thi Sa me

[0249]

[0250] conducted 3 days after individuals initiated their CBD or

[0251] placebo dosing regimen. Neither the 200mg or 400mg twice daily CBD

[0252] re n t. al 5 n rt

[0253]

[0254] Overall, the Phase 2 trial provides a significant foundation for the next phase of this project by showing:

[0255] 1. CBD at the doses (200mg and 400mg twice daily) to be used in the Phase 3 study showed a good safety profile with no significant adverse events;

[0256] 2. CBD doses to be used in the Phase 3 study did not affect prolongation of the QTc interval, respiration or oxygen saturation (SpO2) in OUD OAT-managed participants;

[0257] 3. CBD doses to be used in the Phase 3 study did not significantly change methadone, buprenorphine or their metabolite plasma levels from baseline compared to even after 4 weeks of the higher dose 400mg CBD twice daily regimen;

[0258] 4. OUD OAT-managed participants tolerated the CBD doses (200mg and 400mg) twice daily regimen very well; 5. More than 90% retention over 12 weeks (8 weeks with CBD and 4 weeks follow up) which is outstanding for an OUD clinical trial especially given the numerous study visits;

[0259] 6. Plasma toxicology emphasized at least 90% adherence to the study drug and showed that CBD-COOH is a good marker for repeated CBD use;

[0260] 7. CBD 200 mg, twice daily, for 4 weeks tended to reduce drug cue-induced craving and reduced biophysiological stress measures.

[0261] 8. The 200 mg and 400 mg CBD, twice daily, are the doses and dose regimen to be used in the next UH3 phase.

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[0264] 2.3 RISK / BENEFIT ASSESSMENT

[0265]

[0266] 23.1 KNOWN POTENTIAL RISKS

[0267] Cannabidiol: Oral CBD has been administered in clinical trials to both healthy volunteers and patients with various medical conditions, as single or multiple doses ranging from 10 mg to 6000 mg811 21-38. In most of the studies, CBD was well tolerated, and no severe or serious adverse events (SAEs) were reported. Hence, CBD is generally considered to have a favorable safety profile. It is noteworthy, however, that since clinical trials are conducted under widely varying conditions, the observed adverse effects rates are difficult to compare and may not necessarily reflect those observed in practice. CBD safety has been further affirmed by the World Health Organization in a comprehensive monograph on this matter39. Any AEs have been considered more a result of drug-drug interactions between CBD and patients’ existing medications than anything else as likewise stated in a review of CBD for treating epilepsy40. We did not see an adverse interaction between Epidiolex CBD given at a dose of 400 mg and 800 mg and a potent opioid11.

[0268] In a study involving healthy volunteers, oral CBD doses of up to 6000 mg (single administration) and up to 1500 mg / d (multiple dose) were associated with only mild or moderate AEs, and none resulted in the early termination of participation22. The most common AEs in all the trial arms were diarrhea, nausea, headache, and somnolence. Diarrhea and headache were more common in participants taking CBD compared with placebo. The recommended dose of the FDA-approved Epidiolex® (to children) ranges from 5 mg / kg / day to 5 mg / kg twice daily (10 mg / kg / day). Occasionally 20 mg / kg / day have also been administered. The most common adverse reactions that occurred in Epidiolex®-treated patients (incidence at least 10% and greater than placebo) were somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise and asthenia; rash; insomnia, sleep disorder and poor sleep quality.

[0269] Increased hepatic transaminase levels is an important consideration for potential liver damage, but elevated liver enzymes do not necessarily signal a serious liver problem. There does not appear to be reports of CBD-treated patients who have experienced liver failure, and CBD may actually have therapeutic utility in treating liver conditions associated with alcohol, inflammation, oxidative stress and steatosis41. Identified risk factors for transaminase elevation included concomitant treatment with valproic acid (a medication used to treat seizure disorders, mood conditions and migraine headaches), elevated baseline liver function tests, and higher doses of CBD. Most events of transaminase elevation occurred within 30 to 90 days after initiation of CBD treatment although rare cases were observed up to 200 days after initiation of treatment, particularly in patients also taking valproic acid. These abnormalities generally resolved with discontinuation of CBD or dose decreases in CBD or valproic acid, yet elevated levels also resolved spontaneously without changing the dose of CBD42. Overall, while SAEs have been documented in epileptic patients especially in relation to the use of antiepileptic medication, no SAEs have been reported in studies with healthy volunteers43.

[0270] Cannabidiol Warnings and Precautions:

[0271] Relevant warnings and precautions are based on the Prescribing Information of the only FDA-approved CBD drug, Epidiolex.

[0272] Hepatocellular Injury: Epidiolex has been shown to cause transaminase elevations. Concomitant use of valproate and higher doses of CBD increase the risk of transaminase elevations.

[0273] Somnolence and Sedation: Monitor for somnolence and sedation and advise participants not to operate machinery or work at heights or be involved in extreme sports on dosing day, and to refrain from driving for at least 24 hours after each drug administration.

[0274] Suicidal Behavior and Ideation: Monitor participants for suicidal behavior and thoughts.

[0275] Hypersensitivity Reactions: Advise participants to seek immediate medical care if any signs of allergy or hypersensitivity develop outside the clinical trial site. Discontinue and do not restart CBD if hypersensitivity occurs.

[0276] Protocol Rev 8.0, 02 / 14 / 2025 9Cannabidiol Adverse Reactions:

[0277] The outcomes from our Phase 1 24hrs PK study in healthy study participants (Table 3) as well as our Phase 2 (Table 1) safety in OAT-maintained OUD with the BSPG CBD product to be used in the current study showed a good safety profile.

[0278] None of the AEs were Table 3. Reported Adverse Events (AE) to the BSPG CBD product in Healthy Individuals. serious and all were Evaluated in association with four PK sessions (at least a week apart) and at the follow-up considered mild to moderate period. All were mild to moderate. No severe AEs were reported. and quickly resolved.

[0279] BSPG CBD BSPG CBD Epidiolex CBD 400mg with N=24 Individuals given Epidiolex at 400 mg as a comparator in y in d s) d as D. or n g re er e:

[0280]

[0281] somnolence; decreased appetite; diarrhea; transai sleep quality; and infections. Cannabidiol Drug Interactions:

[0282] Moderate or strong inhibitors or inducers of CYP2C9, CYP2C19, or CYP3A4 (i.e., ketoconazole, rifampicin) may affect CBD blood concentration and should be avoided or used with caution (i.e., appropriate safety monitoring) within 30 days prior to the anticipated first drug administration and throughout the clinical trial duration.

[0283] Care should be taken with hypnotics, sedatives and drugs with potential sedating effects as there may be an additive effect on sedation.

[0284] We did not observe significant effects of CBD doses (200mg and 400mg, twice daily) to be used in this Phase 3 study with methadone or buprenorphine. We will nevertheless inform participants of these potential side effects, exclude individuals with potential risk factors and ensure an appropriate follow-up to minimize any potential physical and psychological risk related to the study, which appear to be minimal.

[0285] Overdose: Individuals with OUD have an increased risk for overdose and thus death. As such, study participants will have bi-weekly follow ups with a medical clinician (MD, PA, or NP) for the first 4 weeks and monthly thereafter that will also include a discussion on medication adherence and evaluation of concomitant use of other substances. Psychoeducation will also be provided including harm reduction interventions and overdose prevention. Naloxone kits and training as well as fentanyl and xylazine test strips will be provided by the medical clinician. Brief intervention and referral to additional counseling (including providing a list of community services) will occur for any participants who needs a higher level of care due to worsening of their substance use.

[0286] Blood draw: Blood sampling can cause bleeding, bruising, dizziness, infection, and pain. Participants will be warned of such potential risks.

[0287] Cue-induced craving in-lab session: It is possible that some individuals could experience prolonged elevation of desire for the drug following the craving sessions, but a safe environment will be provided to minimize the probability of adverseAdjunctive Cannabidiol for Recovery from Opioid Study Version 8.0

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[0289] events following a craving episode. To minimize any potential increase in craving beyond the laboratory session, previously established relaxation procedures known to decrease drug craving will be used to decrease cravings. In addition, psychological debriefing and relaxation procedures will be done with each patient after all sessions to ensure that patients are clinically stable when they leave the study site. The patients will be monitored in person during designated study sessions. Throughout the study, both objective (vitals, urine testing) and subjective (craving, stress, anxiety, feeling of imminent relapse) measures will be carefully assessed by the study medical clinicians. If relapse is imminent, or if any mental or physical symptom occurs that would require medical attention, participants will be offered to consult with a site physician or other mental health provider, as an outpatient, an inpatient or in the ER depending on the severity of the symptoms. A physician will be available at any time during the study for consultation or examination. Participants will also be provided with contact information of a research team’s member, as well as a list of resources and clear steps to follow in case of physical or psychological deterioration.

[0290] Questionnaires and self-report information: This study also involves interviews and self-report questionnaires (see Approach). These procedures do not deviate from standard practice and pose no major risk. One risk of the study is that some individuals may find certain questions in the research instruments uncomfortable or difficult to answer. Research staff are trained to clarify the questions and inform participants that they have the option of not answering specific questions, or not participating in the study at all. Furthermore, should any participant experience severe emotional distress during a study visit, they will be referred by the trained research staff to a prearranged mental health provider.

[0291] Confidential information: Social and economic risks exist whenever there is the possibility that participating in research or the revelation of data collected in the course of the research, if disclosed to individuals or entities outside of the research, could negatively impact others’ perceptions of the participant. Social risks can range from jeopardizing the individual’s reputation and social standing, to placing the individual at-risk of political or social reprisals. However, measures will be taken to minimize the risk of a breach of confidentiality. Participants will be assigned a unique identification number which is the only identifier that will be stored together with research data. A key linking unique identification numbers with participant identities will be stored at each site using methods accepted by the institution, e.g., kept in a locked filing cabinet in a locked office or on a secure server, completely separate from study data. The Clinical Coordinators will access this key in order to attach the correct unique identification number to data collected from participants at study visits.

[0292]

[0293] The immediate potential benefits to select participants include reduced relapse to illicit drug use and reduction of craving and anxiety. There could also be potential medium-term benefits given the 6-month duration of the study. The long-term results derived from this clinical trial could provide evidence to support the long-term development of CBD as a new evidence- based therapeutic tool to address the critical need for novel treatments of opioid use disorders. Such treatment would ultimately be beneficial to the study participants in the future. Adding additional medications to the treatment toolkit can have significant implications for the millions of people worldwide currently suffering from OUD. All participants will be monitored closely during the course of the study for psychiatric and medical outcomes that could potentially be a benefit. Given the extent of the burden associated with OUD and the minimal risk linked to CBD, the risk / benefit ratio appears to be acceptable.

[0294] 2,3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS

[0295] CBD is now widely being used by the public so accumulating more evidence in regard dose dependent effects related to tolerability and safety is extremely important. Moreover, there are few non-opioid treatments for OUD, so data relevant to the potential development of CBD medications has significant implications for the millions of people currently suffering from this disorder.

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[0298]

[0299] The primary aim of this study is to determine whether CBD can reduce illicit opioid use and craving in individuals maintained on opioid agonist therapy (methadone or buprenorphine) studied across 24 weeks in a double-blind, randomized, placebo-controlled clinical trial.

[0300] STUDY ENDPOINTS / OUTCOME MEASURES

[0301] Primary outcome and endpoints:

[0302] • Percentage of study participants with negative urine toxicology for illicit opioid use over the course of 24 weeks Secondary outcome:

[0303] • Concentration of illicit opioids in quantitative plasma toxicology (plasma every four weeks)

[0304] • Weeks of abstinence of illicit opioid use

[0305] • Number of weeks using other non-opioid illicit substances

[0306] • Duration of first opioid abstinence, defined as the number of weeks from randomization to first opioid test positive or urine test missed.

[0307] • Cue-induced Visual Analog Scale for craving (VASC) [12 and 24 weeks]

[0308] • Cue-induced Visual Analog Scale for anxiety (VASA) [12 and 24 weeks]

[0309] • Change in illicit opioids in plasma and urine toxicology over 24 weeks.

[0310] • Retention in study over 24 weeks

[0311] • General craving self-report [daily (EMA); every 4 weeks (OCQ)]

[0312] • General anxiety self-report [daily (EMA); every 4 weeks (GAD7)]

[0313] • Proportion of substance use other than opioids

[0314] • Methadone, buprenorphine and metabolite plasma concentrations

[0315] • Proportion retention in OAT clinical care

[0316] • Proportion change in opioid treatment dosage

[0317] • Safety and drug tolerability. Evaluation of safety and incidence of adverse effects will be performed with the Systematic Assessment for Treatment Emergent Events (SAFTEE).

[0318] • General clinical-behavioral measures

[0319] o Depression (PHQ-9)

[0320] o PANAS

[0321] o Sleep score

[0322] o Cognition

[0323] o Pain score

[0324] o Quality of life

[0325] o Psychosocial functioning

[0326] Physiological assessments:

[0327] Vital signs including heart rate, blood pressure, body temperature, 02, will be taken throughout all study procedures monitored at regular intervals.

[0328] Lab assessments (Hepatic Function Panel, safety labs): Safety hepatic function lab assessments will be conducted throughout the study. Participants will have follow-up laboratory and medical assessments that will be compared with initial laboratory assessments. Assessments will be comprehensive and include an evaluation of parameters described in the Warnings and Precautions section of the referenced drug labeling for Epidiolex (e.g., hepatic function, somnolence, mood changes).

[0329] Exploratory outcome: Biomarkers in peripheral blood (epigenomic chromatin accessibility and lipidomics). Peripheral blood mononuclear cells (PBMCs) will be processed from blood for the Assay for Transposase Accessible Chromatin-sequencing (ATAC-seq) and lipidomics will be carried out on plasma samples obtained at baseline and different timepoints throughout the study.

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[0332]

[0333] 4.1

[0334]

[0335] This is a double-blinded, placebo-controlled randomized trial of BSPG CBD (200 and 400 mg twice daily) in OUD individuals who are maintained on an OAT with at least a dose of methadone or buprenorphine that constitutes a clinically relevant range of maintenance doses (i.e. > lOmg and < 250mg methadone per day or > 2mg and < 32mg buprenorphine per day). Assessors will be blind to the CBD / placebo treatment condition. A total of 450 participants will be randomized to treatment groups (1 capsule CBD (200 mg), 2 capsules CBD (400 mg), 1 capsule placebo and 2 capsules placebo) in a 1: 1:0.5:0.5 ratio. The two placebo groups will be combined for statistical analysis purposes. Baseline toxicology assessments will include methadone, buprenorphine and metabolite levels. Participants will complete a battery of clinical and psychophysiological assessments at baseline, every 4 weeks during treatment, and every 2 weeks during the 4-week followup period. Participants will be administered their first CBD / placebo in lab and studied for cue-induced craving and anxiety assessed with VASC and VASA, respectively. Participants will subsequently be given take-home CBD / Placebo bi-weekly supply. Participants will complete daily ecological momentary assessments (EMAs) no more than 3 times / day (morning, noon, and night) of symptoms and opioid use during treatment and during the 4 weeks follow-up period. EMA text reminders will also be used to remind participants to take the study drug and to document adherence of the at-home CBD / Placebo intake. Individuals will also be monitored with Oura Ring to obtain biophysiological parameters (e.g., sleep, motion).

[0336] Dosage:

[0337] 200 mg CBD, 400 mg CBD and placebo twice daily (morning and evening) studied across 24 weeks.

[0338] • Participants: OUD; OAT-managed (methadone or buprenorphine)

[0339] • Design: Double-blinded; Placebo controlled

[0340] • Dose / regimen: 2 CBD doses — 200 mg twice daily; 400 mg twice daily

[0341] • Duration: 24 weeks

[0342] • Follow-up period: 4 weeks

[0343] • Total = 150 x 3 groups = 450 study participants

[0344] From the point of treatment assignment, the primary endpoint will be analyzed by intention-to-treat; that is, the patients will be grouped by their assignments at randomization regardless of whether or not they actually received the treatment to which they were assigned. If CBD / placebo administration is discontinued due to SAE or lack of tolerability prior to the 24-week duration, the study participant will continue to be followed through the end of the trial per protocol.

[0345] Study details:

[0346] • Consent. Pre-screening: inclusion / exclusion assessments.

[0347] • Screening: health measures (vitals), electrocardiogram (EKG), routine lab work (urine); comprehensive metabolic panel and complete blood count (CBC); inclusion / exclusion assessments (including suicidality). • Randomization.

[0348] • Baseline:

[0349] o In-lab assessment; cue-induced VASC / VASA, behavioral / physiological measures (including suicidality); blood and urine sampling (toxicology). Given first take-home CBD / Placebo bi-weekly supply.

[0350] • Daily:

[0351] o Participants complete EMAs up to 3 times / day (morning, midday, and evening) of symptoms (craving, anxiety, and mood), and opioid use. EMA used to prime reminder for CBD / placebo administration. o Oura Ring physiological measures

[0352] • At 2-week visit and at 24-week visit: EKG and cardiovascular assessments.

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[0355] • Every 2 weeks for the first 4 weeks in-lab assessment:

[0356] o Behavioral / physiological measures (including suicidality); mine; participant receives the next biweekly supply of CBD / Placebo (which includes a few extra pills in case unexpected challenge with meeting the next in-lab visit).

[0357] • Every 2 weeks:

[0358] Urine toxicology

[0359] • Every 4 weeks:

[0360] o Clinical assessments (including suicidality)

[0361] o Blood

[0362] o Take-home CBD / placebo supply (every 4 weeks)

[0363] • Cue-induced VASC / VASA measures assessed at week 12 and 24.

[0364] • At baseline, week 12 and week 24: Social Needs Screening Tool.

[0365] • At end of study drug administration, a 4-week follow-up period with bi-weekly mine toxicology and clinical assessment at 4 weeks.

[0366] The detailed Schedule of Activities and procedme assessments are provided in Section 6.2.

[0367] 4.2 SCIENTIFIC

[0368]

[0369] Individuals who are treated with at least a dose of methadone or buprenorphine that constitutes a clinically relevant range of maintenance doses (i.e. > lOmg and < 250mg methadone per day or > 2mg and < 32mg buprenorphine per day)44-47will be included in the trial. This will allow for the inclusion a broad, naturalistic group of individuals who are treated with an adequate maintenance dose, while also providing the opportunity to study if the addition of CBD allows for a dose reduction in their OAT. Individuals who are maintained on OAT will be the focus since this population is safer regarding potential relapse and overdose over the course of studying CBD for an extended period (24 weeks plus 4 weeks follow-up). It also provides an opportunity to determine the degree to which opioid agonist dosing regimen can be reduced in combination with the CBD without negative consequences and thereby improve overall participant outcome. In addition to in-lab cue- induced craving and anxiety, assessments of the effects of CBD on the general use of illicit substances as well as safety and tolerability will be studied. EMA will be employed to obtain real-time and real-world measures of symptoms including craving, anxiety, and mood as well as to track adherence to usage of the study drug.

[0370] 4.3 JUSTIFICATION FOR DOSE

[0371]

[0372] We choose 200 and 400 mg of BSPG CBD administered orally based on our Phase 1 study with those doses and formulation resulted in CBD plasma concentrations within 2 hrs. that were similar to 400 mg Epidolex previously shown to reduce cue- induced craving and anxiety48. Moreover, the 400 mg BSPG CBD achieved similar time course of plasma CBD concentration, with Tmax and Cmax comparable to the comparator Epidiolex [4.27 ± 2.7 (mean ± SD), 4.97 ± 2.32, and 5.87 ±2.83 at 200 mg BSPG CBD, 400 mg BSPG CBD and 400 mg Epidiolex, respectively] See the full CBD plasma PK parameters in Table 4. Additionally, these doses, twice daily for a total of 8 weeks, in the Phase 2 study resulted in relatively stable plasma CBD and CBD-COOH levels (Table 1) and did not induce any adverse events in individuals maintained on OAT. Furthermore, the 200mg, twice daily, dosing regimen tended to reduce in-lab cue-induced craving (Figure 4) and ‘real-world’ biophysiological stress measures (Figure 5).

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[0375] Table 4. CBD plasma PK parameters: Assessed over a 24hr period following oral administration of 400 mg i Epidiolex and BSPG CBD at 200 mg and 400 mg under standard meal (SM) condition as well as at 400 mg high fat i (HF) breakfast condition in healthy volunteers in four PK sessions at least a week apart.

[0376]

[0377]

[0378] i rsq: coefficient of determination of the time points used for the estimate of the elimination constant in a semi-log plot; ti / i: apparent terminal i i half-life; tmax: time to maximum concentration; Cmax: maximum concentration; tlast: time to last quantifiable concentration; Clast: last i i quantifiable concentration; AUClast: area-under-the-concentration time curve over the observation period; AVCinf: area-under-the- i i concentration time curve extrapolated to infinity; MRT: mean residence time.

[0379] 4.4 END OF STUDY DEFINITION

[0380]

[0381] A participant is considered to have completed the study if he or she has completed all phases of the study including the last scheduled procedure shown in the Schedule of Activities (SoA) in Section 6.2.

[0382] The end of the study is defined as completion of all the procedures shown in the SoA in the trial globally.

[0383]

[0384] 5.1

[0385]

[0386] An individual who meets all of the following criteria will be eligible for study participation:

[0387] 1. Individuals between 18 and 65 years old.

[0388] 2. Ability to understand and give informed consent.

[0389] 3. Current opioid use disorder (OUD) or OUD in remission while on maintenance therapy with OAT, as determined by DSM-5 with the M. I. N. I. interview (Mini-International Neuropsychiatric Interview).

[0390] 4. Current opioid agonist maintenance treatment with methadone or buprenorphine for at least 14 days prior to consent. With the following more specific criteria for each of these two medications:

[0391] • Current methadone maintenance treatment with a dose of > lOmg / day, (maximum: 250mg / day), AND urinary toxicology positive for methadone and 2-ethylidene-l,5-dimethyl-3,3-diphenylpyrrolidine (EDDP).

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[0394] OR

[0395] • Current buprenorphine maintenance treatment with a dose of > 2mg / day (maximum: 32mg / day), AND urinary toxicology positive for buprenorphine.

[0396] 5.2

[0397]

[0398] An individual who meets any of the following criteria will be excluded from participation:

[0399] 1. Participants who are non-English speaking.

[0400] 2. Psychiatric conditions under DSM-5 (examined with the MINI) that would make study participation unsafe, or which would prevent adherence to study procedure; examples include: suicidal (i.e. high risk for suicide on the Columbia suicide severity rating scale (C-SSRS) screen version) or homicidal ideation requiring immediate attention, inadequately-treated mental health disorder (e.g., active psychosis, uncontrolled bipolar disorder). 3. Current diagnosis of a severe substance use disorder (except for opioid and nicotine / tobacco) in the past 3 months, based on the MINI interview, that would preclude safe participation in the study as determined by the study medical clinician.

[0401] 4. Signs of acute drug intoxication when arriving at the study site as determined by clinician assessment.

[0402] 5. Medical or psychiatric contraindications for CBD administration (e.g., history of hypersensitivity to cannabinoids);

[0403] or any of the ingredients in the product (gelatin or sesame oil).

[0404] 6. Showing signs of acute opioid withdrawal symptoms (as determined by the result of the Clinical Opiate Withdrawal Scale (COWS). A Score of > 5 or as interpreted by the investigator will be considered a positive result for withdrawal symptoms).

[0405] 7. Have a medical condition that would make study participation unsafe, which would make treatment compliance difficult, or would prevent adherence to study procedure. This includes but is not limited to the following criteria:

[0406] • < 30mL / min / 1.73m2 eGFR.

[0407] • QTc Fridericia > 500ms at screening.

[0408] • Elevated liver enzymes at screening. The exclusionary lab values are: >4x the upper limit of normal (ULN) per laboratory criteria for AST or ALT or >1.5x ULN for bilirubin.

[0409] 8. Participating in another pharmacotherapeutic trial in the past 3 months.

[0410] 9. Participants who have used (within 14 days prior to consent) or plan to use (during the 24-week treatment period) any medications, dietary supplements (and / or grapefruit juice), or combination of medications and supplements known to alter the metabolism of, or interact with CBD (buproprion, rifampin, barbiturates, phenothiazines, cimetidine, anticoagulants, antiplatelets, etc.).

[0411] 10. For women: being pregnant (positive urine test for pregnancy) or breastfeeding.

[0412] 11. Not using an appropriate method of contraception such as hormonal contraception (oral hormonal contraceptives, Depo-Provera, Nuva-Ring), intrauterine device (IUD), sterilization, or double barrier method (combination of any two barrier methods used simultaneously, i.e. condom, spermicide, diaphragm).

[0413] 12. Participants who have been court mandated to attend treatment centers.

[0414] 5.3 LIFESTYLE CONSIDERATIONS

[0415]

[0416] During this study, participants are asked to:

[0417] • Abstain from dietary supplements (and / or grapefruit juice), or combination of medications and supplements known to alter the metabolism of, or interact with CBD (bupropion, rifampin, barbiturates, phenothiazines, cimetidine, anticoagulants, antiplatelets, etc.) 14 days prior to consent and during the 24-week treatment period.

[0418] • Participants who use tobacco products will be instructed that use of nicotine-containing products (except nicotine patches) will not be permitted while they are in the clinical unit but can use the tobacco products in their daily life.

[0419] • Women of childbearing potential and all men will be asked to use an effective method of contraception including

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[0422] oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine system or device; a double barrier method of contraception; or true abstinence from the time consent is signed until 4 weeks after treatment discontinuation.

[0423] 5.4

[0424]

[0425] Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently randomized. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, and eligibility criteria. Individuals who do not meet the criteria for participation in this trial (screen failure) because of modifiable factors-may be rescreened. Rescreened participants will be assigned the same participant number as for the initial screening.

[0426] 5.5 STRATEGIES FOR RECRUITMENT AND RETENTION

[0427]

[0428] Participants will be recruited through IRB-approved advertisements and approved flyers as well as referrals in Opioid Treatment Programs and psychiatry clinical sites at each enrolling center.

[0429]

[0430] 6.1 STUDY INTERVENTION(S) ADMINISTRATION

[0431]

[0432] 6.1.1 SCREENING AND BASELINE

[0433] Participants will be individuals with OUD treated with OAT maintenance therapy between the age of 18 and 65 years old and will include both biological males and females. Potential study participants will be screened to determine inclusion / exclusion criteria. The absence of serious physical illness will be required to be included in the study, and participants may not take any treatment for a medical or psychiatric condition that would be contraindicative with CBD. Women of childbearing potential will be included provided that they are not pregnant and that they agree not to become pregnant during the study. Both men and women will agree to use an effective method of contraception with proven efficacy during the study. A breathalyzer and rapid urine drug screen will also be taken to document if individuals are acutely intoxicated with alcohol or other substances (e.g., cocaine, illicit opioid, tranquilizers, and hallucinogens) during the clinical lab sessions. We will also exclude participants who participated in another pharmacotherapeutic trial in the past 3 months.

[0434] Informed Consent: Informed consent will be initiated prior to a potential participant agreeing to participate in the study. A thorough explanation of the risks and benefits of the study will be outlined by the PI to the potential study participant, and all potential participants will be given adequate time to review the informed consent document and consider participation in the trial. All questions will be answered to the satisfaction of the participant prior to signing the informed consent document. Site source records will include documentation of the informed consent process for each participant. No study specific procedures will be performed prior to signing of the informed consent document and applicable revisions.

[0435] Physical Examination: A medical clinician (MD, PA, or NP) will perform a basic physical examination, medical history, EKG, and blood draw at the screening visit. This includes review of systems, medical history, confirming absence of serious physical illness, and treatment for medical conditions or psychiatric diagnoses that would interfere with study participation.

[0436] Biological specimen collection and laboratory evaluations: Plasma and urine samples will be taken from participants. A physical examination and blood work (e.g., drug toxicology, liver and renal function, EKG) will be conducted.

[0437] Physiological assessments: Vital signs including heart rate and blood pressure.

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[0440] See Schedule of Events table in Section 6.2.

[0441] 6.1.2 MEASURES TO MINIMIZE BIAS

[0442] Stratified block randomization

[0443] To minimize potential sources of confounding associated with unevenly distributed covariates (within each treatment group), which can influence the outcome, randomization will be carried out within each site using biological sex and race / ethnicity as additional stratification factors. We will have 2 strata for natal / biological sex and up to 4 strata for race / ethnicity; the study will have up to 8 strata per site.

[0444] Using stratified block randomization with randomly varying block sizes, participants who meet the eligibility requirements and provide informed consent will be randomly allocated to one of the study arms (1 capsule CBD (200 mg), 2 capsules CBD (400 mg), 1 capsule placebo and 2 capsules placebo) with a 1:1:0.5:0.5 allocation ratio. The placebo groups will be combined for statistical analysis purposes. Random permuted blocks sizes within stratification groups will be used to minimize the chance of selection bias. Investigators and blinded study staff will be blinded to the block size of each block.

[0445] Blinding:

[0446] Investigators and participants will be blinded to treatment assignment. The staff involved in primary outcome assessment and laboratory tests in local laboratories will also be blinded to treatment assignment.

[0447] Randomization will be generated centrally and performed through a Web-based data collection system that automates the delivery of the randomization codes. The treatment assignment will be sent to the unblinded pharmacist or unblinded study team electronically, in a secure fashion, and electronic verification of the treatment assignment will be required before proceeding with the treatment intervention.

[0448] Active drug and placebo will be identical to maintain study blinding.

[0449] 6.1.3 DOSING AND ADMINISTRATION

[0450] This is a double-blinded, randomized, placebo controlled clinical trial where participants (N=450) diagnosed with an OUD and on OAT maintenance therapy will receive CBD (200 mg or 400 mg twice daily; morning and evening) or placebo for a period of 24 weeks.

[0451] The first dose will be administered in the lab and individuals will be given take-home investigational product (IP) packages every 2 weeks for the first 4 weeks and then given 4- week IP packages for the remainder of the study during their visit to the lab for follow-up assessments. At-home adherence to the study drug intake will be monitored with EMA.

[0452] Participants will be evaluated by a medical clinician to identify any effects of the study drug administered during the session. If there is any indication of participant’s acute impairment, that person will be asked to stay at the study site and monitored clinically until these effects resolve.

[0453] 6.1. FOLLOW UP

[0454] After the dosing period the study participant will be evaluated every 2 weeks for 4 weeks for psychophysiological and urine toxicology assessments. Study participants who are discontinued at any stage will continue to be monitored, if they agree, along same the timeline as other participants.

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[0456] 6.2 SCHEDULE OF ACTIVITIES

[0457]

[0458]

[0459]

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[0462]

[0463]

[0464]

[0465]

[0466] Study assessments were chosen to minimize burden to the study participant yet collect adequate data to support analyses and ensure safety. Many of the measures are those that are similar to other recent studies with CBD and used in past studies that evaluated the effects of pharmacological interventions on OUD outcomes. Safety is assessed at each visit. Additional forms will be used to collect and document information such as dosing and protocol satisfaction. The NIDA endorsed Substance Abuse and Addiction common data elements from Core Tier 1 or the PhenX Toolkit (https: / / www.phenxtoolkit.org), which include demographic and other baseline information, will be captured directly or will be populated from the answers to questions from other assessments. Table 5 provides the Table of Assessments.

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[0468]

[0469]

[0470] 21

[0471]

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[0473]

[0474]

[0475]

[0476] Protocol Rev 8.0, 02 / 14 / 2025 23

[0477]

[0478] Medical / Physiological Measures:

[0479] Blood plasma collection: Collection and processing of blood plasma for CBD and metabolite levels, methadone / buprenorphine and their metabolites, as well as illicit drug toxicology.

[0480] Blood work: Blood will be drawn, and a complete blood count and a comprehensive metabolic panel will be reviewed by medical clinician prior to participant inclusion in study.

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[0483] CBD administration: On the day of randomization / first test day, the participant’s first dose will be administered by medical staff.

[0484] Concomitant Medication log: Updated at each encounter to document any prescribed medications or over the counter medications that are taken by the participant during the study.

[0485] Experimental session urine collection: Collection and processing of urine samples for CBD and metabolite levels.

[0486] Medication adherence review: Review and documentation of the participant’s past week adherence to medication will be done in person bi-weekly for the first 4 weeks and then every 4 weeks during their medical assessment.

[0487] Medical Evaluation: The medical clinician (MD or PA) will perform a basic physical examination, medical history, EKG, and blood draw at the screening visit. This includes review of systems, medical history, confirming absence of serious physical illness, and treatment for medical conditions or psychiatric diagnoses that would interfere with study participation.

[0488] Social Needs Screening Tool (SNST): a 15-item self-report questionnaire that measures health-related social needs, including housing status, food, transportation, utilities, and personal safety.

[0489] Systemic Assessment for Treatment Emergent Events (SAFTEE): The SAFTEE is designed to collect information on adverse health events occurring during a specified time period of a clinical trial, regardless of whether they are suspected to be drug related or not in order to reduce the under-reporting of unanticipated events compared to “known or expected” events. It has two forms, a General Inquiry and a Systematic Inquiry, which together takes approximately 10 minutes to administer. The General Inquiry is an open-ended inquiry about any physical or health problems and its impact on functioning. The Systematic Inquiry is a detailed and systematic inquiry regarding 78 adverse effects divided in 23 categories corresponding to organ system or body part.

[0490] Urine Pregnancy Test: A urine specimen will be obtained to evaluate for pregnancy.

[0491] Urine toxicology / Alcohol screen: A urine specimen will be obtained to evaluate for active substance use / alcohol use. A breathalyzer will be used to evaluate alcohol use if urine alcohol is positive or if active alcohol use is suspected.

[0492] Vital signs: Including heart rate, blood pressure, respiratory rate, oxygen levels, and body temperature. Vitals will be taken every visit to ensure monitoring on a regular basis.

[0493] Medical Check-in: A medical clinician will evaluate participant to evaluate for any changes in medications or health status, evaluate and manage adverse events, and encourage medication adherence (bi-weekly during the first 4 weeks, every 4 weeks during the rest of the study).

[0494] Biobehavioral measures:

[0495] Cue-induced session: The cue task follows a block design, presenting participants with 6-second videos according to the following three conditions: neutral videos, opioid-related drug cue videos for passive viewing, and opioid-related drug cue videos where participants are asked to inhibit their craving. Between videos, participants will be asked to fill out questions to measure their craving. This task takes in total about 7 minutes.

[0496] Addiction Severity Index 5th edition (ASI). The ASI is a 45-minute interview which yields composite scores, ranging from 0 to 1 of problem severity over the past 30 days in 7 areas: medical, employment, drug use, alcohol use, legal, family / social, and psychiatric. ASI composite scores will be used as secondary outcome measures.

[0497] Brief Pain Inventory Short Form (BPI-SF): A 9 item self-administered questionnaire that evaluates severity of pain and impact of pain on daily functioning.

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[0499] (ACROS) 14 Feb 2025 Columbia Suicide severity rating scale screen version: a clinician administered 5 minute questionnaire to assess suicidality.

[0500] Ecological Momentary Assessment (EMA): Daily queries of craving and mood (e.g., anxiety) that participants complete (3-7 minutes; up to 3 times / day) using a smartphone app to obtain real-time measures in their natural environment.

[0501] Fagerstrom Test for Nicotine Dependence (FIND): A 5 minute, 6-item semi-structured interview that assesses the intensity of physical addiction to nicotine.

[0502] Generalized Anxiety Disorder Scale (GAD-7): is a brief 7-item assessment of anxiety and anxiety symptom severity. Items are rated on a 3-point Likert scale (0=not at all, 3=nearly every day) for how bothersome anxiety symptoms have been in the last 2 weeks.

[0503] Opioid Craving Scale (OCQ): A 4 minute, 3 item self-administered measure evaluating opioid craving. Each item is rated on a 11-point Likert scale (ranging from 0 to 10).

[0504] Insomnia Severity Index (ISI): A 5-10 minute, 7 question self-administered screening tool for insomnia. Each item rates the nature and symptoms of their sleep problems of their sleep problems using a Likert-type scale.

[0505] Mini-International Neuropsychiatric Interview (M. I. N. L) is a 15 minute, clinician-administered, brief structured diagnostic interview, for major Axis I psychiatric disorders in DSM-V and ICD-10.

[0506] Montreal Cognitive Assessment (MoCA) is a 30-point cognitive test that can be administered in 10 minutes. The items are categorized in six domains: 1) memory, 2) executive functioning, 3) attention, 4) language, 5) visuospatial, and 6) orientation.

[0507] Patient Health Questionnaire (PHQ-9): is a brief 9-item assessment of depression and depression symptom severity. Items are rated on a 3-point Likert scale (0=not at all, 3=nearly every day) for how bothersome depression symptoms have been in the last 2 weeks.

[0508] Positive and Negative Affect Schedule (PANAS): A 20 item self-administered questionnaire evaluating current positive and negative affect. Each item is rated on a 5-point scale (0=not at all, 5=very much).

[0509] Reading subtest from the Wide Range Achievement Test (WRAT-4): Wrat-4 Reading subset measures letter and word decoding through letter identification and word pronunciation of 15 letters and 42 words.

[0510] Survey of Drugs and Alcohol (SODA): A 10-15 minute interview which inquiries about previous or current use of specific substances. These substances include cannabis, alcohol, nicotine, opioids, barbiturates, cocaine, amphetamines, hallucinogens, and inhalants.

[0511] The Digit Span Test subtest of the Wechsler Adult Intelligence Scale 4thedition: A 10- 15 minute 30-item assessment that includes Digit Span Forward (DSF) and Digit Span Backward (DSB). DSF measures short-term memory, not working memory. DSB measures auditory working memory.

[0512] The Digit Symbol Substitution Test (DSST) A 1.5-2 minute nonspecific cognitive test (processing speed, executive functioning, and working memory), offers high sensitivity to detect impairment.

[0513] The Symptom Check List 90 (SCL-90): A 12-15 minute, 90 item self-administered psychometric instrument yielding nine scores of primary symptom dimensions, along with three scores based on global distress measures.

[0514] Timeline Follow-Back Interview (TLFB): The TLFB is a 15-45 minute, semi-structured interview designed to measure

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[0517] self-reported drug use. It will be used at baseline to capture all drug use in the past 30 days including prescribed addictive medications (e.g. benzodiazepines). A TLFB will be administered at every test session to capture drug use since their last visit.

[0518] 7.2 SAFETY AND OTHER ASSESSMENTS

[0519]

[0520] We will assess safety and adverse effects with the Systematic Assessment for Treatment Emergent Events (SAFTEE)49. The SAFTEE is designed to collect information on adverse health events occurring during a specified time period of a clinical trial, regardless of whether they are suspected to be drug related or not in order to reduce the under-reporting of unanticipated events compared to “known or expected” events. It has two forms, a General Inquiry and a Systematic Inquiry, which together takes approximately 10 minutes to administer. The General Inquiry is an open-ended inquiry about any physical or health problems and its impact on functioning. The Systematic Inquiry is a detailed and systematic inquiry regarding 78 adverse effects divided in 23 categories corresponding to organ system or body part50.

[0521] Safety hepatic function lab assessments will be conducted throughout the study. Assessments will be comprehensive and include an evaluation of parameters described in the Warnings and Precautions section of the referenced drug labeling for Epidiolex (e.g., hepatic function, somnolence, mood changes).

[0522] Before each in-lab session, a breathalyzer and drug urinalysis including opiate metabolite screen will be administered to monitor active use of alcohol, or any psychoactive substances (cocaine, illicit opiates, benzodiazepines, barbiturates, amphetamines, methadone, methamphetamines, oxycodone, PCP, tricyclic antidepressant, THC, buprenorphine). Positive testing or clinical signs of intoxication will not result in the discontinuation of the session since study staff will monitor whether substance use may relate to treatment group differences. Vital signs (blood pressure and heart rate), respiratory function (oxygen saturation and respiratory rate) will be monitored throughout the test sessions.

[0523] Electrocardiogram prolongation of QTc interval and other potential adverse cardiovascular symptoms (dysrhythmias, tachycardia, and hypotension) will be checked 2 weeks after initiation of CBD and at the 24-week timepoint. Should QTc exceed >500msec or the individual exhibit other negative cardiovascular consequences, as determined by the clinician, they will be discontinued from the study and monitored for an additional 4 weeks.

[0524] For the cue-induced sessions, in order to minimize any potential increase in craving beyond the laboratory session, relaxation procedures known to decrease laboratory induced craving51>52will be conducted at the end of each session and psychological debriefing will be done with each participant after all sessions to ensure that participants are clinically stable when they leave the study site. Throughout the study, both objective (urine testing) and subjective (craving rating, distress, anxiety, feeling of imminent relapse) measures will be carefully assessed. In addition, ongoing monitoring of responses to EMA prompts regarding affect will be reviewed by study team members. If any mental or physical symptom occurs that would require medical attention, the participant will be offered to consult with Mount Sinai physician or other mental health provider, either as an outpatient, an inpatient or in the ER depending on the severity of the symptoms. Participants will also be provided with contact information of a research team member, and with a list of resources and clear steps to follow in case of physical or psychological deterioration.

[0525] All serious adverse events (SAEs) will be reported to the Institutional Review Board (IRB), United States Food and Drug Administration (US FDA), BSPG Laboratories and NIDA within required timelines, as indicated below. In the event of a SAE or unanticipated problem, the project Principal Investigator (PI) will follow the reporting requirements of the IRB.

[0526] Throughout the study, participants will be assessed for any mental or physical symptom occurs that would require medical attention. A psychiatrist and a physician will be available at any time during the study for consultation or examination. Participants will also be provided with contact information of a research team member, and with a list of resources and clear steps to follow in case of physical or psychological deterioration after they leave the study site. In such case, the participant will be offered to consult with Mount Sinai physician or other mental health provider, either as an outpatient, an inpatient or in the ER depending on the severity of the symptoms.

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[0529] All participants will be provided a letter to bring to their OAT prescriber stating their enrollment in the study, their start date of CBD and projected end date of the study. The letter will state the purpose of the study and a brief explanation of CBD, potential drug-drug interactions, and side effects, as well as the study contact information should they require additional information regarding the study product.

[0530] 73 STUDY INTERVENTION COMPLIANCE

[0531]

[0532] Adherence to the protocol (e.g., administration of study intervention, completion of questionnaires, etc.) will be assessed, and verified. All study assessments are mandatory to complete, and Case Report Form (CRF) source documents / records will be used to document study intervention compliance.

[0533] 7.4 CONCOMITANT

[0534]

[0535] For this protocol, a prescription medication is defined as a medication that can be prescribed only by a properly authorized / licensed clinician. Medications to be reported in the concomitant medication log section of the case report form in the electronic data capture are concomitant prescription medications including methadone and buprenorphine, over-the- counter medications and supplements. Participants may not have medications and supplements known to alter the metabolism of, or interact with CBD (bupropion, rifampin, barbiturates, phenothiazines, cimetidine, anticoagulants, antiplatelets etc.).

[0536] 7.5

[0537]

[0538] 7.5.1 ACQUISITION AND ACCOUNTABILITY

[0539] Ordering and Shipment of Investigational Product

[0540] Study product will be shipped by BSPG Laboratories to each study site’s research pharmacy where it will be stored.

[0541] The IDS will be responsible for ordering the investigational product (IP) from Brains Bioceutical, Inc.

[0542] Upon receipt of the investigational product, the IDS will ensure that the information on the packaging slip matches the product received. The pharmacy will verify the following:

[0543] • Amount of product received (number, concentration)

[0544] • Lot numbers

[0545] • Expiration dates

[0546] • IP in good condition

[0547] • IP was transported under proper storage conditions

[0548] Any evidence of breakage, compromised storage or product tampering will be reported to the supplier immediately, and the product will be quarantined and maintained under correct storage conditions until further instructions are given by the supplier / manufacturer.

[0549] Chain of custody documentation will be maintained for the transport, handling, and receipt of IP. The IDS pharmacy will keep all inventories and packing slips for their records but will provide a copy of all inventories and packing slips to the PI to be maintained along with other study records.

[0550] IP will not be dispensed until it is properly inventoried, and quality is verified.

[0551] Inventory and Accountability

[0552] All IP supplied will be accounted for and tracked in an accountability log. Accountability of IP will be documented from Protocol Rev 8.0, 02 / 14 / 2025 28Adjunctive Cannabidiol for Recovery from Opioid Study Version 8.0

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[0554] the time of initial receipt, through dispensational, and final disposal. The accountability log will indicate the amounts received from the supplier.

[0555] Each time the CBD (BSPG) or Placebo is dispensed to a participant, the occurrence will be documented in the accountability log. The log will indicate the amounts dispensed to each participant and the amount retumed / disposed. A balance of the remaining IP will be documented in the log.

[0556] Investigation Product Dispensation

[0557] The pharmacy or unblinded delegated study staff will dispense the investigational product. The IDS or unblinded staff will be provided with a copy of FDA Form 1572 for this study to certify that the prescribing clinician is authorized to prescribe the IP for this protocol. Prior to dispensing the IP to a participant, randomization assignment will be confirmed by the unblinded study staff, as well as an order / prescription for CBD or placebo issued by the prescribing clinician (PA / MD). Each site PI will designate on-site licensed clinicians (PA / MD) who will evaluate all potential participants for eligibility before randomization. Once eligibility is confirmed (i.e., the participant has consented to participate in the study and completes screening), the participant will be randomized in the Electronic Data Capture (EDC) system to either CBD 200mg, CBD 400mg, or placebo, and the clinicians will then write the orders / prescription for the CBD or placebo to be dispensed by the pharmacy or unblinded study staff. The order / prescription will serve to verify that the participant is enrolled in the clinical trial. The order will have the following information:

[0558] • Protocol number

[0559] • Order date

[0560] • Participant ID number

[0561] • Study product prescribed: CBD or Placebo

[0562] • Route of administration, dosage, and frequency

[0563] • Prescriber’s signature

[0564] Investigational Product Return

[0565] At the end of the study, the pharmacy will reconcile all remaining IP and once verified by the PI and BSPG Laboratories, Inc., the pharmacy will destroy all remaining IP per FDA guidelines. BSPG Laboratories will pay the associated fees for the destruction / disposal. The pharmacy will maintain study product accountability logs to note the amount destroyed / returned, lot numbers, expiration dates, and condition of product.

[0566] 7.5.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING

[0567] The CBD used in the BSPG investigational medicinal product for this clinical trial is produced from industrial hemp sourced from China where the initial extraction is conducted (see CMC CBD API for details). Industrial hemp is a variety of the Cannabis Sativa L plant and is specifically grown for industrial applications and derived products. Industrial hemp typically contains < 0.2% THC. The crude CBD extract is then purified (specification 98.0% to 102.0%) by BSPG Laboratories based in Sandwich, Kent, United Kingdom. The investigational medicinal product is a 200 mg green / white capsule (size "0") containing pure CBD manufactured in compliance with GMP. The capsule formulation is composed of Softisan 378 which contains capiylic / capric / myristic / stearic triglycerides and is a basic excipient / ingredient of magisterial preparations (see CMC CBD capsule product for details). Softisan 378 is widely used as a stable, odorless, capsule-filling base. It is a specialty blend of triglycerides of saturated even-numbered, unbranched natural fatty acids of vegetable origin with a chain length of C8-C 18. It is free from antioxidants and other stabilizing additives (see CMC and Softisan attachment for details).

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[0570] The pharmacy will repackage the capsules into the appropriate study-specific doses. The repackaged IP will be labeled with the following information:

[0571] • Name, address, and phone number of the dispensing research pharmacy

[0572] • Participant name

[0573] • Dispensing date

[0574] • Expiration date

[0575] • Directions

[0576] • Prescribing investigator’s name

[0577] • IRB Protocol Number

[0578] • Number of dosing units dispensed

[0579] • Labeled “for investigational use only”

[0580] 7.5.3 PRODUCT STORAGE AND STABILITY

[0581] The BSPG CBD capsules and matching Placebo investigational medicinal products will be stored at each site’s research pharmacy. The IP will be stored according to storage instructions provided by BSPG Laboratories., delineated below, as well as in accordance with Federal, State, and City regulations.

[0582] Previous stability studies show that the BSPG CBD capsules are very stable when stored below 25°C (see CMC CBD Capsule product). No significant changes were observed at any of the time points studied across 24 months. Based on the continued expected stability over the following months, the actual shelf life for 200 mg CBD capsules is set at 24 months. The capsules will be stored in white high-density polyethylene (HDPE) bottles, protected from light and stored below 25°C. If storage conditions have been compromised (i.e., temperature excursions from the allowable range) due to an inadvertent event, or if there is any suspicion that the IP has been stored improperly, the pharmacy will quarantine the IP and maintain the product under the correct storage conditions until further notice.

[0583] The pharmacy will contact the PI, and the PI will then notify BSPG Laboratories immediately and await further instructions. The occurrence will be documented by the IDS and a copy of the report will be given to the PI to file with study records. h.5 PREPARATION

[0584] The BSPG CBD capsule formulation will be supplied in white High Density Polyethylene (HDPE) plastic bottles and labelled according to the content (bottles containing 30 capsules). The clinical trial material will be packaged and labelled in compliance with the Good Manufacturing Practice for drugs used in clinical trials. The research pharmacy will repackage the investigational product with the appropriate dosing (200 mg and 400 mg CBD or placebo) to be used in the study.

[0585]

[0586] 8.1 DISCONTINUATION OF STUDY INTERVENTION

[0587]

[0588] If a clinically significant finding is identified (including, but not limited to changes from baseline) after enrollment, the investigator or qualified designee will determine if any change in participant management is needed. Any new clinically relevant finding will be reported as an adverse event (AE).

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[0591] Since the primary endpoint will be analyzed by intention-to-treat (ITT) and thus, patients will be grouped by their assignments at randomization regardless of whether or not they actually received the treatment to which they were assigned, study participants will continue to be followed through the end of the trial per protocol even if study drug is discontinued. Study participants will have follow-up laboratory and medical assessments throughout the study and 4 weeks following the final CBD / placebo administration that will be compared with initial assessments. These assessments will follow the parameters described in the Warnings and Precautions section of the referenced drug labeling for Epidiolex (e.g., hepatic function, somnolence, mood changes) as indicated below. The study participant will be evaluated by the study clinician if vitals are outside of the following limits, and study clinician will evaluate if further study participation is safe. If hepatic or renal function laboratory results are outside of the following limits, or if QTc is >500ms, study drug will be discontinued (patient would continue to be followed through the end of the trial per protocol).

[0592] Normal limits for vital signs:

[0593] Blood pressure: 85 / 55 mm Hg to 170 / 120 mm Hg

[0594] Respiratory rate: 11 to 22 breaths per minute

[0595] Pulse: 50 to 120 beats per minute

[0596] Temperature: 95.0°F to 101.1 °F

[0597] Cardiac parameters:

[0598] QTc Frederica > 500ms

[0599] Laboratory outcomes:

[0600] Participants will discontinue IP if lab values are: >4x the upper limit of normal (ULN) per laboratory criteria for AST or ALT,

[0601] >1,5x ULN for total bilirubin or eGFR <30mL / min / l,73m2eGFR.

[0602] The following normal limits for laboratory values are used for the calculation of the upper limits of normal ( LN') for the laboratory tests mentioned above:

[0603] Bilirubin, Total: 0.0 - 1.2 mg / dL

[0604] AST (SGOT): 0 - 40 IL7L

[0605] ALT (SGPT): 0 - 44 IU / L

[0606] Epidiolex Safety and Monitoring Parameters:

[0607] Recommended safety and monitoring parameters for Epidiolex include ALT, AST, and total bilirubin at baseline within the levels provided above and consider monitoring individuals more frequently if there are elevated baseline ALT / AST, concurrent hepatotoxic medical changes, signs / symptoms of depression, behavior changes, and suicidality. Participants will discontinue IP if any of the following common reactions occur and are graded as serious, or if any of the following serious adverse reactions occur:

[0608] Common and Serious Reactions for Epidiolex

[0609] Most Common Reactions in descending order:

[0610] • Somnolence / sedation

[0611] • Anemia

[0612] • Decreased appetite

[0613] • Diarrhea

[0614] • ALT, AST, bilirubin elevations

[0615] • Rash

[0616] • Fatigue

[0617] • Insomnia

[0618] • Infection

[0619] • Increased creatinine

[0620] • Irritability

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[0623] • Lethargy

[0624] • Aggression

[0625] • Weight loss

[0626] • Sialorrhea

[0627] • Gastroenteritis

[0628] • Abdominal discomfort / pain

[0629] • Hypoxia

[0630] • Gait disturbance

[0631] Serious Reactions include:

[0632] • Hepatocellular injury

[0633] • Suicidality

[0634] • CNS depression

[0635] • Respiratory failure

[0636] • Withdrawal seizures if abrupt discontinuation

[0637] Participants may withdraw from the study at any time. Participants who wish to withdraw from the study will do so through contacting the PI or research personnel.

[0638] 8.2 PARTICIPANT

[0639]

[0640] Participants are free to withdraw from participation in the study at any time upon request. An investigator may discontinue or withdraw a participant from the study for the following reasons:

[0641] • Pregnancy

[0642] • Significant study intervention non-compliance

[0643] • If any clinical AE, laboratory abnormality, or other medical condition or situation occurs such that continued participation in the study would not be in the best interest of the participant

[0644] • Disease progression which requires discontinuation of the study intervention

[0645] • Consent withdrawal

[0646] • If the participant meets an exclusion criterion (either newly developed or not previously recognized) that precludes further study participation

[0647] • Participant is no longer able to receive study intervention

[0648] The reason for participant discontinuation or withdrawal from the study will be recorded on the Case Report Form (CRF).. The analysis will be ITT and therefore every subject randomized will remain in the trial analysis and will not be replaced. Study subjects that discontinue study drug will be followed as per protocol-defined follow-up.

[0649] 8.3

[0650]

[0651] All efforts should be made to locate a participant before this option is chosen on the CRF and these efforts must be documented. Lost to follow-up should only be used as a last resort and preferably not until end of study. It is preferable that a visit is marked as not done if a participant is unable to be reached, and the study site staff should attempt to contact the participant again at the following scheduled visit.

[0652] The following actions will be taken if a participant fails to return to the clinic for a required study visit:

[0653] • All attempts will be made to contact the participant and reschedule the missed visit within 24 hours. The participant will be counseled on the importance of maintaining the assigned visit schedule and ascertain if the participant wishes to continue in the study.

[0654] •, The investigator or designee will make every effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter to the participant’s last known mailing address or local equivalent methods). These contact attempts will be documented in the participant’s medical record or study file.

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[0657]

[0658] Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).

[0659] 8.4.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)

[0660] Serious Adverse Events (SAE): A SAE is any event that: is fatal, is life-threatening (life threatening is defined as the participant was at immediate risk of death from the adverse event as it occurred), is significantly or permanently disabling, requires inpatient hospitalization or prolongs hospitalization, is a congenital anomaly or birth defect. Discontinuation is the date a participant and / or investigator determines that the participant can no longer comply with the requirements for any further study visits or evaluations (e.g., the participant is prematurely discontinued from the study).

[0661] An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly / birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization.

[0662] 8.4.3 CLASSIFICATION OF AN ADVERSE EVENT

[0663]

[0664] Adverse events will be assessed with the SAFTEE questionnaire. For AEs not included in the protocol defined grading system, the following guidelines will be used to describe severity.

[0665] Participants will be questioned and / or examined by the investigator(s) / Physicians for evidence of adverse events. All adverse events will be recorded in the participant’s research records. The severity of the adverse event and its attribution will be assessed according to the following systems:

[0666] Grading: For the severity of adverse events, the following definitions will be used:

[0667] Minimal: Low awareness of the sign, symptom, or event, and easily tolerated.

[0668] Mild. Awareness of sign, symptom, or event, but easily tolerated.

[0669] Moderate-. Discomfort enough to interfere with usual activity and may warrant intervention.

[0670] Severe: Incapacitating with inability to do usual activities or significantly affects clinical status, and warrants intervention.

[0671] Very Severe: Immediate risk of death.

[0672] Attribution / Drug Related: Assess the relationship of drug to event:

[0673] Dose Response: Indicates that the intensity of the event is related to the dosage level.

[0674] Timing of onset: If the onset of the event has some regular relationship to drug administration (e.g., it always occurs 1 hour after taking the drug).

[0675] Known drug effect. Adverse event is a known effect of the drug.

[0676] Other: Other reasons are possible for the adverse event.

[0677] Don ’t know: It is unknown if the adverse event is related to the drug.

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[0680]

[0681] All AEs will have their relationship to study drug assessed by the Principal Investigator or delegated clinician who will examine and evaluate the participant based on temporal relationship and his / her clinical judgment. The degree of certainty about causality will be graded using the following categories: unrelated, unlikely related, possibly related, probably related, and definitely related.

[0682]

[0683] An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously described for the study drug in the Investigational Brochure. The Medical Monitor will be responsible for determining whether an AE is expected or unexpected.

[0684] 8.4.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP

[0685] The occurrence of an AE or SAE may come to the attention of study personnel during study visits and interviews of a study participant presenting for medical care, or upon review by a study monitor.

[0686] All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate case report form (CRF). Information to be collected includes event description, time of onset, clinician’s assessment of severity, relationship to study product (assessed only by the Principal Investigator or delegated clinician), and time of resolution / stabilization of the event. All AEs occurring while on study will be documented appropriately regardless of relationship. All AEs will be followed to adequate resolution.

[0687] Any medical condition that is present at the time that the participant is screened will be considered as baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, it will be recorded as an AE.

[0688] AEs will be captured from event onset to event resolution, and changes can be made to the AE CRF as needed. One event per CRF should be recorded. AEs characterized as intermittent will be documented in regard to the onset and duration of each episode.

[0689] Study medical clinician or Clinical Research Coordinator will record all reportable events with start dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day the participant is treated with study drug or completes the trial, whichever is longer. Participants who stop study drug should continue to be monitored for AEs and SAEs.

[0690] At each study visit, the investigator will inquire about the occurrence of AE / SAEs since the last visit. Events will be followed for outcome information until resolution or stabilization.

[0691]

[0692] All adverse events must be reported to the Data Coordinating Center (DCC) via the EDC. Throughout the study, all identified adverse events (serious and non-serious) will be recorded on all appropriate source document and adverse event case report forms regardless of their severity or relation to the study. A complete description of all adverse events will include event description, time of onset, investigator assessment of severity, relationship to study agent or procedures, time of resolution / stabilization of the event, expectedness, determination of whether the AE qualifies as a SAE, and action taken. A change in the severity of the AE will also be documented. Assessment of severity and relationship will be documented on the source documents or on the CRF.

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[0695] Serious, unexpected and possibly related adverse events will be reported per expedited timelines to the FDA and NIDA. All other events will be reported at least annually. In the event of an SAE or unanticipated problem, investigators are required to notify BRANY promptly of any unanticipated problems involving risks to subjects or others that occur in research, as well as of any serious adverse event that is reported to the FDA or NIDA / DCC in accordance with FDA requirements. Furthermore, the investigators must follow regulatory requirements related to the reporting of suspected unexpected serious adverse drug reactions (SUSARs) to the regulatory authority and the IRB. Lastly, depending on the institutional requirements, the clinical sites must adhere to their local IRB guidelines for adverse event reporting. The project PI will follow the reporting requirements of the IRB, FDA, and other regulatory bodies.

[0696] The project staff will also utilize the following reporting procedures:

[0697] 1. When the staff and / or PI becomes aware of a SAE, reporting requirements will be implemented as per the timelines outlined in section 8.4.6.

[0698] 2. Project staff will complete the “Adverse Event Reporting Form” and submit the form to the DCC.

[0699] 3. The event will be reviewed to determine whether it is an SAE or unanticipated problem. All reportable events under BRANY policy will be reported in the specified time frame.

[0700] All other reportable AEs must be reported to the sponsor within 10 working days of the site becoming aware of the event. Lastly, depending on the institutional requirements, the clinical sites must adhere to their local IRB guidelines for adverse event reporting.

[0701]

[0702] Throughout the study, participants will be assessed for any mental or physical symptom that would require medical attention. A psychiatrist and a physician specialized in toxicology will be available at all times during the study for consultation or examination. Participants will also be provided with contact information of a research team member, and with a list of resources and clear steps to follow in case of physical or psychological deterioration after they leave the study site. In such case, the participant will be offered to consult with Mount Sinai physician or other mental health provider, either as an outpatient, an inpatient or in the ER depending on the severity of the symptoms.

[0703] The study clinicians will report within 24 hours of knowledge of the event via the EDC any SAE, whether or not considered study drug related, including those listed in the protocol or Investigator Brochure and will include an assessment of whether there is a reasonable possibility that the study drug caused the event. Study endpoints that are SAEs (e.g., all-cause mortality) will be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the study intervention and the event (e.g., death from anaphylaxis). In that case, the investigator will report the event to CBD drug manufacturer, BSPG Laboratories, within 24 hours of knowledge of the event. SAEs will be recorded on the adverse event case report form and must include a narrative of the event signed and dated by the site principal investigator.

[0704] According to BRANY’s requirements, the IRB of record for the study, SAEs that are both unexpected and related (SUSARs) must be reported as soon as possible, but no later than 5 business days of the study staff becoming aware of the event. Suspected unexpected serious adverse reactions are defined as any experience that has not been described in the package insert for a given product / device or investigator’s brochure, protocol, or the informed consent document.

[0705] Please find below a summary of all SAE reporting timeframes (redacted applicable source must be uploaded to the EDC for all events):

[0706] • All SAEs, regardless of expectedness and relatedness to study drug, must be reported via the EDC within 24 hours of knowledge of the event.

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[0709] • Mortalities must be reported via the EDC within 24 hours of knowledge of the event.

[0710] • SUSARs must be reported to BRANY within 5 days of knowledge of the event, and to the site’s local IRB as per local reporting requirements. Additionally, all SUSARs will be reported to NIDA within 72 hours, and the drug manufacturer within 24 hours of initial receipt of information by Dr. Hurd and the DCC. For all other SAEs, sites are required to follow their own local IRB reporting requirements.

[0711] • All other AEs not subject to expedited reporting as outlined above must be reported via the EDC within 10 business days of knowledge of the event.

[0712] • Events that meet expedited reporting to the FDA and NIDA will be submitted to the respective regulatory authorities by the IND Principal Investigator (Dr. Hurd) and DCC.

[0713] o FDA Initial Reporting: Any suspected adverse reaction or adverse reaction to study treatment that is both serious and unexpected will be reported to the FDA as follows:

[0714] ■ Unexpected serious suspected adverse reactions and observations from animal studies suggesting significant risk to human participants will be reported to FDA as soon as possible but no later than within 15 calendar days following the Pi’s initial receipt of the information.

[0715] ■ Unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the Pi’s initial receipt of the information.

[0716] o FDA Follow-up Reporting:

[0717] ■ Any relevant additional information obtained by the PI that pertains to a previously submitted IND safety report will be submited as a Follow-up IND Safety Report. Such report will be submited without delay, as soon as the information is available but no later than 15 calendar days after the PI receives the information.

[0718] All SAEs will be followed until satisfactory resolution or until the investigator deems the event to be chronic or the participant is stable.

[0719] 8.5 UNANTICIPATED

[0720]

[0721] DEFINITION OF UNANTICIPATED PROBLEMS (UP)

[0722] The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to participants or others to include, in general, any incident, experience, or outcome that meets all of the following criteria:

[0723] • Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved research protocol and informed consent document; and (b) the characteristics of the participant population being studied;

[0724] • Related or possibly related to participation in the research (“possibly related” means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and • Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

[0725] §.5.2 UNANTICIPATED PROBLEM REPORTING

[0726] The investigator will report unanticipated problems (UPs) to BRANY and to the DCC. The UP report will include the following information:

[0727] • Protocol identifying information: protocol title and number, Pi’s name, and the IRB project number;

[0728] • A detailed description of the event, incident, experience, or outcome;

[0729] • An explanation of the basis for determining that the event, incident, experience, or outcome represents an UP; • A description of any changes to the protocol or other corrective actions that have been taken or are proposed in

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[0732] response to the UP.

[0733] To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:

[0734] • UPs that are serious adverse events (SAEs) will be reported to the IRB and to BSPG Laboratories in accordance with BRANY / institutional IRB / NIH policy upon the investigator becoming aware of the event.

[0735] • Any other UP will be reported to the IRB and to BSPG Laboratories in accordance with BRANY / institutional IRB / NIH policy upon the investigator becoming aware of the problem.

[0736] • All UPs will be reported to appropriate institutional officials (as required by an institution’s written reporting procedures), the supporting agency head (or designee), and the Office for Human Research Protections (OHRP) 8.5.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS

[0737] If unanticipated problems to participants develop, potentially affected participants would be notified (if applicable), and the cons IND would be modified / updated as appropriate.

[0738]

[0739] The primary objective of this trial is to determine whether the administration of CBD (200 mg or 400 mg) twice daily, for 24 weeks reduces illicit opioid use and craving in individuals with OUD who are maintained on methadone or buprenorphine, as compared to placebo.

[0740] 9.1 STATISTICAL HYPOTHESES

[0741]

[0742] Primary Hypotheses:

[0743] Two hypotheses will be tested in the order presented below using a sequential strategy:

[0744] 1. The percentage of individuals with negative toxicology for illicit opioid use across 24 weeks in the combined groups of subjects assigned to BSPG CBD (200 mg or 400 mg) will be greater than the percentage of individuals with negative toxicology in the placebo group.

[0745] Ho: (% Negative toxicology) BSPG CBD = (% Negative toxicology) PLACEBO

[0746] Hi: (% Negative toxicology) BSPG CBD (Negative toxicology) PLACEBO

[0747] If the null hypothesis is rejected at the 0.05 significance level in this test, then we will proceed with testing each BSPG CBD dose against placebo.

[0748] 2. The percentage of individuals with negative toxicology for illicit opioid use across 24 weeks in each of the BSPG CBD group will be greater than the percentage of individuals with negative toxicology in the placebo group.

[0749] Ho: (Negative toxicology) BSPG CBD-200 = (Negative toxicology) PLACEBO

[0750] Hi: (Negative toxicology) BSPG CBD-200 (Negative toxicology) PLACEBO

[0751] Ho: (Negative toxicology) BSPG CBD-400 = (Negative toxicology) PLACEBO

[0752] Hi: (Negative toxicology) BSPG CBD-400 (Negative toxicology) PLACEBO

[0753] Each of these hypotheses will also be tested at the 0.05 significance level.

[0754] No direct comparison between the two CBD doses will be conducted.

[0755] Secondary Hypotheses:

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[0758] 1. Compared to placebo, OUD individuals maintained on OAT receiving BSPG CBD will show:

[0759] a. reduced concentrations of illicit opioids in urine and plasma.

[0760] b. reduced craving.

[0761] c. reduced stress.

[0762] 2. All CBD doses will be well-tolerated and will show no serious adverse effects.

[0763] 9.2 SAMPLE SIZE DETERMINATION

[0764]

[0765] Based on previously published data and the results of the second phase of the study, we assume that 14% of patients in the placebo group will have negative toxicology at 24 weeks post randomization. We believe a meaningful effect worth detecting is at least a 100% relative increase, to 28%, in subjects assigned to the CBD group. Sample size is based on the ability to detect this difference in the comparison of each of the CBD groups against placebo. A total of 450 subjects, randomized with equal probability to each arm (150 per arm), provides approximately 85% power to detect such a difference. Sample size calculations are based on a 0.05 level two-tailed test for independent proportions. Power for the primary hypothesis of a difference between the combined CBD (200 and 400 mg) groups against placebo will be also 85%, assuming that the average response in the two doses groups is around 28%. The sample size takes account a single interim analysis to be performed in addition to the final analysis.

[0766] 9.3 POPULATIONS

[0767]

[0768] Intention-to-treat (ITT) population:

[0769] All analyses will be conducted according to an intent-to-treat principle. Therefore, all participants will be analyzed in the group to which they were randomly assigned, regardless of whether they complete the intervention or are compliant with the treatment assigned. As noted, all participants will be assessed for the study outcomes even if they elect to stop the study intervention. If the participant withdraws consent to participate in the trial, no further follow-up will be conducted. An exception will be females who get pregnant since that would require discontinuation from the study. Additionally, court- mandated treatment incompatible with the study requirements, incarceration or death not related to participation in the trial would be cause for discontinuation.

[0770] Modified ITT population: Study participants who received at least one dose of CBD / placebo.

[0771] Per protocol (PP) population: defined as study participants who received at least 12 weeks of CBD / placebo dosage and toxicological assessments during that dosing period.

[0772] 9.4 STATISTICAL

[0773] 19.4.1 GENERAL APPROACH

[0774] Participant demographics and their OUD characteristics, including duration of OUD, other significant exposures, will be summarized overall as well as by treatment group (CBD 200 mg, CBD 400 mg and placebo). Descriptive statistics will be calculated for study outcome variables at baseline, and at 4- week intervals (study end point at 24 weeks) and 4 weeks after treatment until end of follow-up. All analyses will be conducted on the Intent-to-Treat (ITT) population unless otherwise stated, while key sensitivity analyses may be performed as needed. For endpoints measured repeatedly over time, linear mixed models will be used. Hypothesis testing will follow a close test procedure to control for the experiment wise type I error: first, the combined CBD group (200 mg + 400 mg) will be compared to placebo. If the null hypothesis is rejected in this comparison, separate pairwise comparisons (200 mg vs. placebo and 400 mg vs. placebo) will be conducted. A two-sided alpha of 0.05 will be used, with additional adjustments (Holm’s or other familywise corrections) applied when multiple comparisons arise within the same endpoint family.

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[0777] Following the data preprocessing, we will assess the validity of normality assumption by using the Shapiro-Wilk normality test. Outcome variables that require transformation to a Gaussian distribution, will be transformed and parametric tests will be used for analysis. Non-parametric tests will be used otherwise. The primary hypothesis will be investigated by using two- sample t-tests based on an alpha of 0.05 comparing individual CBD arms against placebo and separately against each other.

[0778] 9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S)

[0779] This analysis will evaluate the effect of the treatment on the percentage of participants with negative urine toxicology throughout the study. If a participant does not have toxicology results in one or more of the study visits, those missing values will be imputed as positive toxicology.

[0780] A log binomial regression model will be used to estimate and test differences between randomization groups. Similar to the logistic regression model, the log-binomial model is a generalized linear model.

[0781] The basic form of the log binomial models is:

[0782]

[0783] where Y, is a binary indicator of treatment failure for the ith patient, Xu is a binary indicator of randomization assignment for the ith patient, and u and X3 / are an indicators of sex and ethnicity at baseline, factors by which randomization will be stratified. Sex is a biological factor of interest (30% of individuals recruited will be biological females based on AIMS patient demographics, allowing sex comparisons). While randomization will also be stratified by randomizing center, the analysis will not adjust for center due to their relatively large number compared to the proposed sample size. The exponentiated estimate of pi (e(piin this model is the risk ratio for the endpoint for patients randomized to the combined CBD (200 mg + 400 mg) group compared to patients randomized placebo. The risk ratio and its associated 95% confidence interval will be used to quantify the relative risk of the endpoint.

[0784] Differences between randomization groups in the risk of the endpoint will be determined by testing the null hypothesis Ho: i= 0 versus a two-sided alternative (Hi: Pi 0) using a 0.05 level intention-to-treat normal approximation test (i.e., the Wald test). If this test will reject the null hypothesis, a similar model in which the two CBD groups will be compared to the placebo group will be used.

[0785] Assessment of Balance of the Randomization

[0786] The success of the randomization procedure in balancing important covariates between randomization groups will be assessed. Continuous measures will be compared using t-tests, while chi-square tests will be used to compare categorical variables. As 450 patients will be randomized, no substantial imbalances are expected. However, should any covariate differ significantly between treatment groups at the 0.01 level, and be substantively large, we will adjust for those covariates in a secondary analysis of the primary endpoint.

[0787] 9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S)

[0788] A variety of secondary endpoints will be assessed, with different statistical methods appropriate depending on the nature of the outcome variable and frequency of measurements. For repeated continuous measures — such as illicit opioid concentrations in plasma, cue-induced craving and anxiety (VASC / VASA), vitals, and certain biomarker or pharmacokinetic values (e.g., plasma levels of methadone, buprenorphine, CBD, and its metabolites) — mixed- effects models, often incorporating baseline adjustment will be used. A treatment-by-visit interaction will be used to determine whether patterns of change differ by study arm.

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[0791] Secondary endpoints measured as binary outcomes — including retention in the study, retention in opioid agonist therapy, dosage changes, and the presence of any non-opioid illicit drug use — will be analyzed primarily with two- proportion z-tests. Similarly, for the discrete count of total weeks of abstinence and total weeks of non-opioid use, initial goodness-of-fit checks performed via Pearson chi-square testing will determine if the data reasonably follow a binomial distribution. If so, binomial regression models will be used; if not, a non-parametric approach, namely, a Mann- Whitney U test, will be employed. Time-to-event analysis methods will be used, such as the duration of first opioid abstinence. Kaplan-Meier curves will estimate the cumulative event-free rates across treatment groups, and log-rank tests will compare combined CBD versus placebo. For the daily self-reported craving and anxiety data collected via Ecological Momentary Assessment (EMA), a growth curve analysis53will be used to examine the effect of treatment on: 1) trajectories of momentary craving and affect; 2) relationships among these variables over time; and 3) how trajectories in craving and affect may predict variations in illicit opioid use in separate autoregressive latent trajectory models. Growth curve models will be specified with fixed effects consisting of a time factor and between-subjects treatment factor, whereby the treatment X time interaction is the fixed effect of primary interest.

[0792] For the vital signs collected at a subset of study visits, continuous descriptive statistics (e.g., mean, standard deviation, median) will be presented by treatment group and visit. The primary analysis will compare changes from baseline in each vital sign across the scheduled visits using a linear mixed effects model, including fixed effects for treatment group, visit, and their interaction, with baseline value as a covariate. Model-based least squares means and 95% confidence intervals will be estimated for each treatment group at each post-baseline time point. If normality assumptions appear substantially violated, appropriate transformations or nonparametric methods may be considered.

[0793] 9.4.4 SAFETY ANALYSES

[0794] Modified ITT population will be included in this analysis.

[0795] AEs will be assessed and coded using the SAFTEE. The SAFTEE has two forms, a General Inquiry (GI) and a Systematic Inquiry (SI). The GI is an open-ended inquiry about any physical or health problems and its impact on functioning. The SI is a detailed and systematic inquiry regarding 78 adverse effects divided in 23 categories corresponding to organ system or body part. All SAEs will be reported to the IRB, US FDA and NIDA within required timelines, as indicated above. In the event of a SAE or unanticipated problem, the project PI will follow the reporting requirements of the IRB.

[0796] Each AE will be counted once for a given participant. AEs will be documented in terms of severity, seriousness, and frequency; onset / stop date and time; duration (minutes); pattern (isolated, intermittent, continuous); functional impairment (minimal, mild, moderate, severe, very severe); and outcome / action taken. Relationship of AEs to study intervention will be presented by system organ class (SOC), i.e., headache, eye irritation, dry mouth, nasal congestion, cardiovascular symptoms such as chest pain, stomach / abdominal discomfort, nausea / vomiting, diarrhea, constipation, appetite issues, muscle / bone / joint, urinary symptoms, tiredness / fatigue, cognitive and mood symptoms, etc.

[0797] For safety and tolerability, incidence of all adverse events, serious adverse events, and unexpected serious adverse reactions will be reported by study arm as number and rate of adverse events per patient / time in each study arm. Participant-level reporting of the adverse events will be used for reporting the number and percentage of participants who experienced any serious and serious unexpected adverse events.

[0798] Differences in the rate of individual serious AEs will be compared between randomization groups using Poisson regression. Ninety-five percent confidence intervals for the rate ratios for individual SAEs for the three treatment groups will be computed.

[0799]

[0800] We plan to perform a single interim analysis with respect to the primary endpoint to give the option of stopping early should results strongly favor one arm or the other. The proposed timing of this analysis is at 0.5 on the information scale, i.e., after

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[0803] one-half of patients (225 or approximately 75 in each group) reach the primary endpoint. The utility of performing this analysis will depend on the rate of accrual of patients into the trial. As the decision to terminate early would likely occur after most, if not all, patients were randomized, the principal benefit of early termination would be prompt suspension of treatment, and no further randomization to an inferior treatment. A group sequential procedure will be used to allow for flexibility in the number and timing of interim analyses should the DSMB choose to modify the proposed plan, or should accrual mitigate the usefulness of an interim assessment. We will use the Lan-DeMets approach, implementing an O'Brien-Fleming-type spending function that allots most of the type I error to the final look. The resulting critical values to be used for each analysis are 2.963 at the first interim analysis, 1.969 at the final analysis, with corresponding p-values of 0.003 and 0.05.

[0804] 9.4.6 SUB-GROUP ANALYSES

[0805] A subgroup analysis of the primary endpoint will be performed with subgroups defined by gender and race / ethnicity. These analyses will be performed in the same manner as that described for the primary analysis.

[0806] 9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA

[0807] Individual participant data will be listed by measure as well as averaged effects.

[0808] 9.4.8 EXPLORATORY ANALYSES

[0809] We will explore epigenetic state in peripheral blood mononuclear cell (PBMCs) using the Assay for Transposase Accessible Chromatin-sequencing (ATAC-seq) since this technique provides an unbiased agnostic assessment of the epigenome. We will use analytical strategies we have performed in the past in studying ATAC-seq datasets obtained from the brains of human heroin users.54Briefly, ATAC-Seq peak regions will be identified using a Model-based Analysis for chromatin immunoprecipitation-sequencing. We will retain peaks passing a p-value cutoff 4.7x1 O'6based on Irreproducibility Discovery Rate analysis [https: / / github.com / nboley / idr] on technical replicates. Various QC conditions will be applied. Peak regions will be merged to create a map of open chromatin regions and used to extract a read count matrix of all samples using Htseq.55For differentially accessible regions, we will use generalized linear models, implemented in edgeR, where differential open chromatin accessibility will be performed for each open chromatin region. Multiple hypothesis testing will be adjusted using a 5% FDR threshold. For lipidomic analysis, targeted high performance liquid chromatography with tandem mass spectrometry (HPLC-MS / MS) will be used to screen for 60 unique lipoamines (including the endocannabinoid anandamide), 2-acyl-sn-glycerol classes (including 2-AG) and free fatty acids.56’57Chromatin accessibility and levels of endocannabinoid-related lipids will be correlated with clinical and behavioral outcomes.

[0810]

[0811] 10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS

[0812] 10. LI INFORMED CONSENT PROCESS

[0813] 10.1.1.1 CONSENT / ASSENT AND OTHER. INFORMATIONAL DOCUMENTS PROVIDED TO FARTIClPAN’rS

[0814] Consent forms approved by the IRB, describing in detail the study intervention, study procedures, and risks will be given to the participant and written documentation of informed consent prior to starting intervention / administering study intervention.

[0815] [ 10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION

[0816] Informed consent will be initiated prior to the individual’s agreeing to participate in the study and continue throughout the individual’s study participation. Consent forms will be approved by the IRB and the participant will be asked to read and review the document. The investigator will explain the research study to the participant and answer any questions that may Protocol Rev. 8.0, 02 / 14 / 2025 41Adjunctive Cannabidiol for Recovery from Opioid Study Version 8.0

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[0818] arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes, procedures, and potential risks of the study and of their rights as research participants. Participants will have the opportunity to carefully review the written consent form and ask questions prior to signing. The participants will have the opportunity to discuss the study with their family or surrogates or think about it prior to agreeing to participate. The participant will sign the informed consent document prior to any procedures being done specifically for the study. Participants will be informed that participation is voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the informed consent document will be given to the participants for their records. The informed consent process will be conducted and documented in the source document (including the date), and the form signed, before the participant undergoes any studyspecific procedures. The rights and welfare of the participants will be protected by emphasizing to them that the quality of their medical care will not be adversely affected if they decline to participate in this study.

[0819] 10,1.2 STUDY DISCONTINUATION AND CLOSURE

[0820] This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided to the study participants, funding agency, the drug manufacturer and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the IRB, and drug manufacturer and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule.

[0821] Circumstances that may warrant termination or suspension include, but are not limited to:

[0822] • Determination of unexpected, significant, or unacceptable risk to participants. If two study participants experience a serious adverse event that is at least possibly related to the study drug, ongoing dosing of the study drug will be paused pending a safety review

[0823] • Demonstration of efficacy that would warrant stopping

[0824] • Insufficient compliance to protocol requirements

[0825] • Data that are not sufficiently complete and / or evaluable

[0826] • Determination that the primary endpoint has been met

[0827] • Determination of futility

[0828] • IRB & Data Safety Monitoring Board inspection of SAEs can also lead to a trial stop

[0829] The study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the drug manufacturer, IRB and / or FDA.

[0830] pO.l J CONFIDENTIALITY AND PRIVACY

[0831] Participant confidentiality and privacy is strictly held in trust by the participating investigators and their staff. This confidentiality is extended to cover testing of biological samples in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study, or the data will be released to any unauthorized third party without prior written approval of the sponsor (i.e., Principal Investigator). In addition, no information about the study participant will be provided to their OAT prescriber without approval of the study participant.

[0832] All research activities will be conducted in as private a setting as possible.

[0833] The study monitor, representatives of the IRB, the DCC, and regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records.

[0834] The study participant’s contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB and Institutional policies.

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[0837] Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be stored at the Icahn School of Medicine at Mount Sinai. This will not include the participant’s contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by staff will be secured and password protected. At the end of the study, all study databases will be de-identified and archived at Mount Sinai.

[0838] Certificate of Confidentiality

[0839] To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It will allow the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, the Certificate of Confidentiality will help to achieve the research objectives and promote participation in the study by helping assure confidentiality and privacy to participants.

[0840] 10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA

[0841] Data collected for this study will be analyzed and stored at the Icahn School of Medicine at Mount Sinai. Urine and blood samples will be sent to an external laboratory for toxicological testing (e.g., iC42 Labs, Colorado) and PBMCs (which will only be collected at select sites in addition to the Mount Sinai Clinical site) will be processed from blood for epigenetic measures (Hurd lab and sequencing core) as well as for specific genetic marks (Hurd lab and core). Participants will be assigned a unique identification number which is the only identifier that will be stored together with research data. A key linking unique identification numbers with participants identities will be kept in a file saved on the secure network drive, completely separate from study data. All hard copies of questionnaires and source documents containing the data obtained from every study session will be kept in a locked cabinet or secure server. Only authorized study staff will have access to information about the participants that is identifiable. All data will be entered in the electronic data capture database. Only authorized personnel named in this protocol will have access to the database.

[0842] H0. L5 KEY ROLES AND STUDY GOVERNANCE

[0843] As overall Principal Investigator, Dr. Hurd is responsible for the general oversight for all research activities and will inform the IRB, FDA, drug manufacturer and NIDA about all changes and adverse events.

[0844] ISMMS Principal Monitor: Overall PI

[0845] Check One: PI:[X] Team Member:

[0846] Last Name: Hurd

[0847]

[0848] FirstName: Yasmin

[0849] Title: Professor

[0850] Department: Psychiatry, Neuroscience, Pharmacological Sciences

[0851] Mailing Address: One Gustave L. Levy Place, Box 1639

[0852] Phone: 212-824-9314

[0853] Fax: 646-537-9598

[0854] E-mail:

[0855]

[0856] ISMMS Additional Monitor: Medical Monitor

[0857] Check One: On-Site PI: EJ Team Member: Independent: [X]

[0858] Last Name: Manini

[0859]

[0860] FirstName: Alex

[0861] Title: MD

[0862] Department: Emergency Medicine

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[0865] Mailing Address: 3E 101 St, 3rdfloor, Room 319

[0866] Phone: 212-241-6794

[0867] E-mail:

[0868]

[0869] Data and Clinical Coordinating Center (DCC)

[0870] A university-based DCC (InCHOIR) will collaborate with the overall Principal Investigator and their team. The DCC bears responsibility for monitoring interim data and analyzing the study's results in conjunction with the investigators and the sponsor.

[0871] InCHOIR Data Coordinating Center Key Roles:

[0872] Principal Investigator

[0873] Last Name: Liu

[0874] FirstName: Sean

[0875] Title: MD

[0876] Department: Infectious Disease

[0877] Phone: 212-241-2724

[0878] E-mail:

[0879]

[0880] Statistician

[0881] Last Name: Irizar

[0882] FirstName: Aritz

[0883] Title: Statistician

[0884] Department: Population Health Science and Policy

[0885] Phone: 917-601-3097

[0886] E-mail: Aritz.irizar@mssm.edu

[0887] 10. L6 SAFETY OVERSIGHT

[0888] The Data Safety Monitoring (DSM) Board will provide bi-annual reviews and we will have a yearly review of its Data Safety Monitoring Plan (DSMP) outlining the following points: Reassessment of the risks and benefits to study participants; Participant recruitment, accrual, and retention; Data quality and completeness; Consideration of external scientific or therapeutic developments with impact on the safety of participants or the ethics of the study; Review safety data.

[0889] Members of the DSMB will be independent from the study conduct and free of conflict of interest. At the establishment of the DSM Board, and priorto eachmeeting, the members will submit their completed Conflict of Interest (COI) disclosure forms. COI information will be reviewed and approved before a new DSM Board member can be officially empaneled, and it will be submitted annually thereafter.

[0890] The DSM Board meetings will consist of an Open Session, Closed Session, and Executive Session. During the Open Session, general baseline and enrollment data will be presented. All investigators, monitors, statisticians and the DSM Board members may be present. After the Open Session, DSM Board members, and only the statistician when requested, will remain for the Closed Session to review safety data and, if available, efficacy data. Lastly, during the Executive Session, only the DSM Board members will remain to determine recommendations. Their recommendations may include continuation of the trial, a halt to enrollment, additional data tables, or other requests for future meeting materials. DSM reports will be conveyed to NIDA annually.

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[0893] 19.1.7 DSMB PLAN AND FREQUENCY OF DSMB REVIEWS

[0894] There will be a DSMB which will consist of a clinical addiction physician, a clinical pharmacologist and a medical ethicist who will all be independent from the project. An additional independent and ongoing study monitoring will be conducted by external Clinical Trials experts, not involved in the ongoing study conduct including the following functions to ensure data integrity and compliance in monitoring this study:

[0895] Oversight of Clinical Trial Operations: responsibility include coordination and monitoring of site recruitment, site initiation, site training, participant enrollment, and participant retention. This function will oversee EAC meetings and support the DSMB reports and meetings.

[0896] Regulatory oversight: track all deaths and serious AEs (including unexpected SAEs, the relatedness of AEs to the intervention and study) and the necessary AE reporting activities for the trial. This function is responsible for IRB oversight, preparation of protocol amendments and revision logs, reporting of events to the NIH, FDA and CIHR, quality assurance (including document control) of IND / fDE filings, FDA minutes, and tracking of regulatory reports and submissions. This function will manage the trial monitors and the regulatory compliance coordinator.

[0897] Compliance Coordinator: schedule site initiations, site visits, and trial-specific operational meetings. The coordinator will maintain meeting minutes, and will work under the regulatory manager, to track regulatory documents, and assists in the preparation of FDA submissions and scheduling of EAC meetings.

[0898] Trial Quality Monitor: performs remote electronic monitoring. The trial quality monitor will schedule site monitoring visits, monitor all deaths and serious AEs (including unexpected SAEs, the relatedness of AEs to the intervention), review supporting source documentation, review regulatory documents, write monitoring reports, and help prepare for the EAC and DSMB meetings.

[0899] 1QJ A CLINICAL MONITORING - OVERSIGHT / RESPONSIBLE PARTIES

[0900] The lead PI and site Pls will be responsible for ensuring that the rights and well-being of trial participants are protected, that the reported trial data are accurate, complete, verifiable, and that the conduct of the trial is in compliance with the currently approved protocol / amendment(s), with International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirements).

[0901] 10. L9 QUALITY ASSURANCE AND QUALITY CONTROL

[0902] A limited number of team members (physicians, physician assistants, and research coordinators) will be involved with participants in the study, which will reduce the inter-rater variability and facilitates its monitoring. We utilize structured and validated measures, where applicable, to enhance data integrity. For the measures that will be collected by more than one team member, it is the responsibility of the sites to ensure that the measurement tools are administered per their instructions in a homogeneous manner. Also, all team members will be provided with training through 1) informal teaching by qualified members of Dr. Yasmin Hurd’s research groups who have themselves experience in research and clinical activities related to the addiction field; 2) the DCC and 3) formal education through seminars and courses available at Mount Sinai and other local or national institutions. The clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion.

[0903] Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be

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[0906] run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification / resolution.

[0907] Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonization Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP).

[0908] The investigational site will provide direct access to all trial related sites, source data / documents, and reports for the purpose of monitoring and auditing and inspection by local and regulatory authorities.

[0909] 10.1,10 DATA HANDLING AND RECORD KEEPING

[0910] 10.1.10.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES

[0911] Data collection will be the responsibility of the clinical trial staff under the supervision of the site investigator. The investigator will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. All source documents will be completed in a structure, legible manner to ensure accurate interpretation of data.

[0912] Data recorded in the electronic Case Report Form (eCRF) derived from source documents will be consistent with the data recorded on the source documents. PDF files of the trial eCRFs will be provided to each site.

[0913] Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data) and clinical laboratory data will be entered into a web-based 21 CFR Part 11 -compliant Electronic Data Capture (EDC) system provided by the InCHOIRData Coordinating Center at the Icahn School of Medicine at Mount Sinai. The data system includes password protection and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source documents.

[0914] Study personnel requiring access to the EDC will have their own Login / Password. Access to clinical study information will be based on individuals' roles and responsibilities. The EDC will generate a unique participant identification code that will identify the patient throughout the course of the study. The application provides hierarchical user permission for data entry, viewing, and reporting options. For optimum security, the system operates Secure Socket Layer (SSL) 128-bit encryption protocol over Virtual Private Networks (VPN). This application is designed to be in full compliance with International Conference on Harmonization and Good Clinical Practices (ICH-GCP), the FDA’s Code of Federal Regulations (CFR) Number 21 Part 11 Electronic Record and Electronic Signatures, the FDA's " Guidance: Computerized Systems Used in Clinical Trials, and the Privacy Rule of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).

[0915] Quality Assurance

[0916] The data quality assurance tool has been designed as an automatic feature of the EDC system. When a form is submitted the system conducts instantaneous validation and cross-form validation checks. A query is generated and sent to the site coordinator electronically so that data may be verified and corrected. All changes made to a form are stored in an audit log. Additional external cross-form checks for data consistency and validation will be made by the DCC’s data management team. Data will be monitored remotely at the DCC on an ongoing basis to check for inconsistencies in information across forms and for data outliers (typically values that fall in the highest or lowest 10% of the accumulated data and / or values that are outside the range of what is typically considered to be physiologically possible). Monitors will enter these queries through the EDC system for site coordinators to either correct or verify. O

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[0919] 10.1.10.2 STUDY RECORDS RETENTION

[0920] Study documents will be retained for a minimum of 2 years after the last approval of a marketing application in an International Conference on Harmonization (ICH) region and until there are no pending or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development of the study intervention.

[0921] 10.1.11 PROTOCOL DEVIATIONS

[0922] A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by the site and implemented promptly.

[0923] These practices are consistent with ICH GCP:

[0924] • 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3

[0925] • 5.1 Quality Assurance and Quality Control, section 5.1.1

[0926] • 5.20 Noncompliance, sections 5.20.1, and 5.20.2.

[0927] It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations. All deviations will be addressed in study source documents and reported to NIH / NIDA per their policies. Protocol deviations will be sent to the reviewing IRB per their policies. The site investigator will be responsible for knowing and adhering to the reviewing IRB requirements. Further details about the handling of protocol deviations will be included in the manual of procedures (MOP).

[0928] 10.1.12 PUBLICATION AND DATA SHARING POLICY

[0929] This study will be conducted in accordance with the following publication and data sharing policies and regulations:

[0930] The National Institutes of Health (NIH) Public Access Policy ensures that the public has access to the published results of NIH funded research. We will therefore submit final peer-reviewed journal manuscripts that arise from our NIH-funded project to the digital archive PubMed. Central upon acceptance for publication.

[0931] This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers 5 years after the completion of the primary endpoint by contacting the PI.

[0932] 10.1.13 CONFLICT OF INTEREST POLICY

[0933] The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with NIH / NIDA has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.

[0934] 10.2 ENVIRONMENTAL ASSESSMENT

[0935]

[0936] An Environmental Assessment is not required because the action requested qualifies for a categorical exclusion per 21 CFR Protocol Rev. 8.0, 02 / 14 / 2025 47Adjunctive Cannabidiol for Recovery from Opioid Study Version 8.0 (ACROS) 14 Feb 2025

[0937] 25.31€. To the applicant’s knowledge, no extraordinary circumstances exist per 21 CFR 25.15(d).

[0938] 10.3 ABBREVIATIONS

[0939]

[0940]

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[0942]

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[0944]

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[0946] 10.4 PROTOCOL The table below is in change and rationale

[0947]

[0948]

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[0950]

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[0953]

[0954] 1 Sinha, R. New findings on biological factors predicting addiction relapse vulnerability. Curr Psychiatry Rep 13,

[0955] 398-405, (2011).

[0956] 2 Wang, G. B., Zhang, X. L., Zhao, L. Y., Sun, L. L., Wu, P., Lu, L. & Shi, J. Drug-related cues exacerbate decision making and increase craving in heroin addicts at different abstinence times. Psychopharmacology (Berl) 221, 701-708, (2012).

[0957] 3 Martel, M. O., Dolman, A. J., Edwards, R. R., Jamison, R. N. & Wasan, A. D. The association between negative affect and prescription opioid misuse in patients with chronic pain: the mediating role of opioid craving. J Pain 15, 90-100, (2014).

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[1023] 57 Maciel, I. S., Abreu, G. H. D., Johnson, C. T., Bonday, R., Bradshaw, H. B., Mackie, K. & Lu, H. C. Perinatal CBD or THC Exposure Results in Lasting Resistance to Fluoxetine in the Forced Swim Test: Reversal by Fatty Acid Amide Hydrolase Inhibition. Cannabis Cannabinoid Res 7, 318-327, (2022).

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Claims

Attorney Docket No. 27527-0197WO1WHAT IS CLAIMED IS:

1. A method of treating opioid use disorder (OUD) in a subject in need thereof, the method comprising administering to the subject a medication for opioid use disorder (MOUD) and administering to the subject an adjunctive therapeutic agent comprising cannabidiol (CBD).

2. The method of claim 1, wherein the subject previously did not respond, or responded poorly, to treatment with the MOUD.

3. The method of claim 1 or claim 2, wherein the subject has ceased the use of opioids.

4. The method of any one of claims 1-3, wherein the subject has not ceased the use of opioids.

5. The method of any one of claims 1-4, wherein the subject has been administered the MOUD for at least 14 days prior to administration of the adjunctive therapeutic agent comprising CBD.

6. The method of any one of claims 1-5, wherein the MOUD is selected from the group consisting of methadone, buprenorphine, and naltrexone.

7. The method of claim 6, wherein the MOUD is methadone administered at a dose of between 10 mg and 250 mg per day.

8. The method of claim 6, wherein the MOUD is buprenorphine administered at a dose of between 2 mg and 32 mg per day.

9. The method of claim 6, wherein the MOUD is naltrexone administered at a dose of between 25 mg and 50 mg per day.

10. The method of any one of claims 1-9, wherein the CBD is administered orally.Attorney Docket No. 27527-0197WO111. The method of any one of claims 1-10. wherein the CBD is administered at a dose of between 400 mg per day and 800 mg per day.

12. The method of any one of claims 1-11, wherein the CBD is administered once daily.

13. The method of any one of claims 1-12, wherein the CBD is administered orally at a dose of 400 mg daily.

14. The method of any one of claims 1-12, wherein the CBD is administered orally at a dose of 800 mg daily.

15. The method of any one of claims 1-11, wherein the CBD is administered twice daily.

16. The method of claim 15, wherein the CBD is administered orally at a dose of 200 mg twice daily.

17. The method of claim 15, wherein the CBD is administered orally at a dose of 400 mg twice daily.

18. The method of claim 11, wherein the CBD is administered orally at a dose of 400 mg once daily.

19. The method of claim 15, wherein the CBD is administered orally at a dose of 400 mg twice daily.

20. The method of claim 12, wherein the CBD is administered orally at a dose of 800 mg once daily.

21. The method of any one of claims 1-20, wherein the MOUD and the adjunctive therapeutic agent comprising CBD are co-administered.

22. The method of any one of claims 1-20, wherein the MOUD and the adjunctive therapeutic agent comprising CBD are administered separately.Attorney Docket No. 27527-0197WO123. The method of any one of claims 1-22. wherein the CBD is measurable in plasma of the subject (ng / mL) at a level of between 50 ng / mL and 300 ng / mL after four weeks of administering to the subject the adjunctive therapeutic agent comprising CBD.

24. The method of any one of claims 1-23, wherein 7-carboxy cannabidiol (7-COOH-CBD) is measurable in plasma of the subject (ng / mL) at a level of between 1000 ng / mL and 4000 ng / mL after four weeks of administering to the subject the adjunctive therapeutic agent comprising CBD.

25. The method of any one of claims 1-24. wherein Cmax of CBD as measured in plasma of the subject is between 150 and 550 after administration of CBD orally at a dose of 400 mg daily.

26. The method of any one of claims 1-25, wherein AUClastof CBD as measured in plasma of the subject is between 500 and 2000 after administration of CBD orally at a dose of 400 mg daily.

27. The method of any one of claims 1-26, wherein cravings associated with opioid use are reduced in the subject.

28. The method of any one of claims 1-27, wherein anxiety associated with opioid use is reduced in the subject.

29. The method of claim 28, wherein anxiety’ associated with opioid use is reduced in the subject, wherein the anxiety is measured by a biometric device.

30. The method of any one of claims 1-29, wherein opioid intake as measured by urine toxicology is reduced in the subject.

31. The method of claim 30, wherein opioid intake as measured by urine toxicology is reduced in the subject relative to a second subject that was not administered CBD.

32. The method of claim 30 or 31, wherein opioid intake as measured by urine toxicology is reduced in the subject relative to opioid intake as measured by urine toxicology measuredAttorney Docket No. 27527-0197WO1in the subject prior to administering the adjunctive therapeutic agent comprising cannabidiol (CBD).

33. The method of any one of claims 1-32, wherein daytime stress associated with opioid use is reduced in the subject.

34. The method of claim 33, wherein daytime stress associated with opioid use is reduced in the subject, wherein the daytime stress is measured by a biometric device.

35. The method of claim 34, wherein number of daytime hours spent in a stressful state is decreased in the subject relative to a second subject that was not administered CBD.

36. The method of any one of claims 33-35, wherein number of daytime hours spent in a stressful state is decreased in the subject relative to number of daytime hours spent in a stressful state in the subject prior to administering the adjunctive therapeutic agent comprising cannabidiol (CBD).

37. The method of any one of claims 33-36, wherein daytime stress as measured by a biometric device includes one or more biometric measurements selected from the group consisting of heart rate data, body temperature data, and accelerometer data.

38. The method of any one of claims 1-37, wherein deep sleep measurements are improved in the subject.

39. The method of claim 38, wherein number of hours of deep sleep is increased in the subject relative to a second subject that was not administered CBD.

40. The method of claim 38 or 39, wherein number of hours of deep sleep is increased in the subject relative to number of hours of deep sleep in the subject prior to administering the adjunctive therapeutic agent comprising cannabidiol (CBD).

41. The method of any one of claims 38-40, wherein deep sleep measurements are improved in the subject, wherein the deep sleep measurements are measured by a biometric device.Attorney Docket No. 27527-0197WO142. The method of any one of claims 38-41, wherein number of hours of deep sleep relative to number of hours of light sleep is increased in the subject relative to a second subject that was not administered CBD.

43. The method of any one of claims 38-42, wherein number of hours of deep sleep relative to number of hours of light sleep is increased in the subject relative to number of hours of deep sleep relative to number of hours of light sleep in the subject prior to administering the adjunctive therapeutic agent comprising cannabidiol (CBD).

44. The method of any one of claims 38-43, wherein the deep sleep measurements as measured by a biometric device include one or more biometric measurements selected from the group consisting of heart rate data, body temperature data, and accelerometer data.

45. The method of any one of claims 1-44, wherein the duration of the treatment is at least 16 weeks.

46. A composition comprising a cannabidiol (CBD) and a medication for opioid use disorder (MOUD) for use in the treatment of opioid use disorder (OUD).

47. The composition of claim 46, wherein the MOUD is methadone, buprenorphine, or naltrexone.

48. The composition of claim 46 or 47, comprising:(i) between 10 mg and 250 mg of methadone and between 200 mg and 800 mg of CBD;(ii) between 2 mg and 32 mg of buprenorphine and between 200 mg and 800 mg of CBD; or(iii) between 25 mg and 50 mg of naltrexone and between 200 mg and 800 mg of CBD49. The composition of any one of claims 46-48, comprising between 10 mg and 250 mg of methadone and 200 mg of CBD.Attorney Docket No. 27527-0197WO150. The composition of any one of claims 46-48, comprising between 10 mg and 250 mg of methadone and 400 mg of CBD.

51. The composition of any one of claims 46-48, comprising between 10 mg and 250 mg of methadone and 800 mg of CBD.

52. The composition of any one of claims 46-48, comprising between 2 mg and 32 mg of buprenorphine and 200 mg of CBD.

53. The composition of any one of claims 46-48, comprising between 2 mg and 32 mg of buprenorphine and 400 mg of CBD.

54. The composition of any one of claims 46-48, comprising between 2 mg and 32 mg of buprenorphine and 800 mg of CBD.

55. The composition of any one of claims 46-48, comprising between 25 mg and 50 mg of naltrexone and 200 mg of CBD.

56. The composition of any one of claims 46-48, comprising between 25 mg and 50 mg of naltrexone and 400 mg of CBD.

57. The composition of any one of claims 46-48, comprising between 25 mg and 50 mg of naltrexone and 800 mg of CBD.

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