Clinical trial NCT03252756
Conditions: Alcohol Use Disorder
Keywords: Cannabidiol Alcohol Use Disorder
Sponsor: NYU Langone Health
Start date: 2019-09-01; Completion date: 2022-03-16
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of the proposed project is to begin rigorous study of the clinically relevant effects of non-psychoactive phytocannabinoid cannabidiol (CBD) in patients with severe alcohol use disorder (AUD). This double-blind, randomized proof-of-concept study (n = 40) is designed to assess feasibility and contrast effects of extended (8 weeks) treatment with CBD to those of placebo in AUD patients. Participants with AUD will be randomized to receive either placebo or 600mg CBD/day (PO) for 4 weeks, immediately followed by 1200mg CBD/day (PO) for an additional 4 weeks (8 total weeks). These doses were chosen to reproduce serum CBD levels reported to reduce alcohol-seeking behavior in animal studies. Measures will include circulating levels of CBD, safety measures (THC serum levels, adverse events, cognitive and motoric function), and physiological and psychological domains relevant to AUD (including self-reported craving, depression, and anxiety, and responses to personalized scripts designed to elicit stress- and cue-induced craving and anxiety). Assessments will be conducted following 1 day, 1 week, and 4 weeks of treatment with each dose of CBD vs. placebo, and 1 and 4 weeks after the cessation of treatment. Drinking outcomes across 8 weeks of treatment and 4 weeks of follow-up will also be assessed as an exploratory outcome.

Detailed description:
There is increasing recognition of the roles of the endocannabinoid system in neurobiological processes and behavioral domains relevant to addiction. The non-psychoactive phytocannabinoid cannabidiol (CBD) has attracted considerable attention due to its lack of abuse potential, its excellent safety profile, its unique and complex pharmacology, and evidence that it affects anxiety and stress response in animal models and humans. There is a growing body of preclinical data demonstrating that CBD produces marked and persisting decreases in alcohol self-administration and preference for alcohol, and alcohol-, cue- and stress-induced reinstatement of alcohol-seeking behavior, yet there are few studies of the effects of CBD in humans with addictive disorders, and none in alcohol dependent patients.

Arms: arm 1: 600mg/day Saline taken by mouth (PO) for 4 weeks, immediately followed by 1200mg saline/ day (PO) for an additional 4 weeks (8 total weeks). arm 2: 600mg CBD/day (PO) for 4 weeks, immediately followed by 1200mg CBD/day (PO) for an additional 4 weeks (8 total weeks).
Interventions: intervention 1: Placebo intervention 2: Phytocannabinoid cannabidiol (CBD)
Intervention descriptions: intervention 1: Saline taken by mouth (PO) intervention 2: CBD taken by mouth (PO)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Effects of Cannabidiol in Alcohol Use Disorder   
NCT Number: 
NCT03252756 
Study Number: 
17-01001 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
July 20, 2021 
 


 
 
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Tool Revision History: 
 
Version Number 
Version Date 
Summary of Revisions Made 
1.0 
June 13, 2018 
Original version 
1.1 
July 12, 2018 
Clarifications requested by the FDA as well as Local NYUSoM 
IRB prompting a revision of the protocol. The FDA requested 
adding exclusion for medications which are moderate to strong 
inhibitors of CYP3A4 or CYP2C19, or have a narrow 
therapeutic index and are substrates of UGT1A9, UGT2B7, 
CYP2C8, CYP2C9, CYP2C19, CYP1A2, or CYP2B6. The 
NYUSoM IRB requested clarity around drug storage and 
importation as well as the correction of a heading title. 
1.2 
July 20, 2018 
Clarifications requested by the NYUSoM IRB prompting a 
revision of the protocol. The study team removed all mention 
of the NYU-HHC CTSI Research Pharmacy as they will not be 
storing or dispensing the study medication. All mentions of 
medication compounding services were removed, as the 
investigational product will not require compounding. 
1.3 
July 25, 2018 
Clarification requested by the NYUSoM IRB to replace 
mention of’ pharmacy records’ from page 36 of the protocol 
with ‘study drug records’.  
2.0 
June 17, 2019 
Documentation of change from LM to M2 study drug 
formulation requested by study sponsor Tilray Canada Ltd. 
 
Clarification of pharmacokinetic timepoints, collection 
procedure and associated statistical analyses. Clarification of 
additional Case Report Forms and recruitment language. 
Addition of Medical Managament Manual for drug dispensation 
and accountability. Revision of study schema and addition of 
full study schedule for clarity. Addition of audio-visual data 
collection language and consent form. Addition of generalized 
phone screen and associated consent form to enhance study 
recruitment and improve flow. 
2.2 
September 13, 
2019 
Changes to study schedule to include: administration of C-
SSRS, urine drug screen and urine pregnancy test at every 
visit (except those under 24 hours from last visit) as safety 
measures, removal of Stroop tasks, removal of AUD-related 
measures from phone visits. 
 
Study reporting procedures for AEs/SAEs have been changed 
to reflect the DSMB’s recommendations. 
 
Inclusion/Exclusion criteria have been changed to more 
accurately reflect the target population of participants recruited 
to the study. 


 
 
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2.3 
October 1, 2019 
Inclusion/Exclusion criteria have been changed to enhance 
study recruitment within the safety parameters of the research. 
2.4 
November 11, 
2019 
The exclusionary medication list has been changed to reflect 
only the limitations put in place by the FDA; the other 
medication types have been removed to avoid redundancy.  
2.5 
December 10, 
2019 
Medical management has been removed from the 1-day, 4 
weeks+1 day and 9-week visits because no study drug will be 
dispensed at the aforementioned time points. The C-SSRS will 
no longer be administered at the 1-day and 4-weeks+1-day 
visits. The study figure has been revised to reflect these 
changes.  
2.6 
January 10, 
2020 
Drinking criteria has been changed from 10 heavy drinking 
days to 8 heavy drinking days in order to facilitate recruitment 
efforts and the attainment of target enrollment numbers. 
2.7 
July 26, 2020 
Option for remote e-consent was added; option to complete 
initial portion of screening visit remotely added; reimbursement 
schedule altered to reflect two-part screening visit option; 
consent updated to include risk of elevated liver enzymes; 
recruitment dates were updated; reference to COVID-19 safety 
procedures SOP was added 
2.8 
September 26, 
2020 
Website recruitment materials added 
2.9 
10/30/2020 
Changed heavy drinking inclusion from 8 heavy drinking days 
to 6 heavy drinking days  
3.0 
February 15, 
2021 
Removed exclusion of drugs that are weak-moderate 3A4 
substrates 
Clarified exclusion criterion #8 (Significant laboratory 
abnormalities, including significantly impaired liver function, 
serious abnormalities of complete blood count or metabolic 
panel). 
Added a new exclusion for Type I Diabetes, per the DSMB's 
review of risks associated with cannabis use and development 
of ketoacidosis in Type I Diabetes. 
3.1 
July 15, 2021 
Added to the procedure section 8 which states that study team 
may ask for release of health information if it is helpful or 
requested by the participant. 
 
 
 


 
 
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A PHASE I/II RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED TRIAL OF CANNABIDIOL FOR ALCOHOL USE 
DISORDER 
 
 
Principal Investigator: 
 
Michael Bogenschutz, M.D. 
NYU SoM Department of Psychiatry 
462 First Ave, 22N11 
Michael.Bogenschutz@nyumc.org 
646-501-4026 
NYULMC Study Number: 
s17-01001 
Funding Sponsor: 
National Institute on Alcohol Abuse and Alcoholism 
(NIAAA/NIH)  
IND/IDE Number: 
140108 
Regulatory Sponsor:  
Michael Bogenschutz, M.D. 
NYU SoM Department of Psychiatry 
462 First Ave, 22N11 
Michael.Bogenschutz@nyumc.org 
646-501-4026 
Study Product: 
Cannabidiol 
Study Product Provider:  
Tilray 
ClinicalTrials.gov 
Number: 
NCT03252756 
 
Initial version: June 13, 2018 
Amended: 
July 12, 2018 
Amended: 
July 20, 2018 
Amended: 
July 25, 2018  
Amended:  
June 17, 2019 
Amended:  
September 13, 2019 
Amended: 
October 1, 2019 
Amended: 
November 11, 2019 
Amended: 
December 10, 2019 
Amended:  
January 10, 2020 
Amended: 
July 26, 2020 
Amended: 
September 26, 2020  
Amended:          October 30, 2020 
Amended:          February 15, 2021 
 
 


Study number: s17-01001 
 
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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 


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Table of Contents 
STATEMENT OF COMPLIANCE ................................................................................................................ IV 
LIST OF ABBREVIATIONS....................................................................................................................... VIII 
PROTOCOL SUMMARY .............................................................................................................................. 9 
1 
SCHEMATIC OF STUDY DESIGN .................................................................................................... 10 
2 
KEY ROLES ....................................................................................................................................... 11 
3 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ..................... 11 
3.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE .............................................................. 11 
3.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT ............................................................ 13 
 
Preclinical Data...................................................................................................................... 13 
 
Clinical Data to Date .............................................................................................................. 13 
 
Dose Rationale (if applicable) ............................................................................................... 14 
3.3 
RATIONALE .................................................................................................................................. 14 
3.4 
POTENTIAL RISKS & BENEFITS ...................................................................................................... 15 
 
Known Potential Risks ........................................................................................................... 15 
 
Known Potential Benefits ...................................................................................................... 15 
4 
OBJECTIVES AND PURPOSE ......................................................................................................... 15 
4.1 
PRIMARY OBJECTIVE .................................................................................................................... 15 
4.2 
SECONDARY OBJECTIVES ............................................................................................................. 15 
5 
STUDY DESIGN AND ENDPOINTS .................................................................................................. 16 
5.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................. 16 
 
Primary Study Endpoints ....................................................................................................... 16 
 
Secondary Study Endpoints .................................................................................................. 16 
 
Exploratory Endpoints ........................................................................................................... 17 
6 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 17 
6.1 
INCLUSION CRITERIA .................................................................................................................... 17 
6.2 
EXCLUSION CRITERIA ................................................................................................................... 18 
6.3 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 18 
6.4 
DURATION OF STUDY PARTICIPATION ............................................................................................ 19 
6.5 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 19 
6.6 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 19 
 
Reasons for Withdrawal or Termination ................................................................................ 19 
 
Handling of Participant Withdrawals or Termination ............................................................. 19 
6.7 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 20 
7 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION ......................................................................................................................................... 20 
7.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 20 
 
Acquisition ............................................................................................................................. 20 
 
Formulation, Appearance, Packaging, and Labeling ............................................................ 20 
 
Product Storage and Stability ................................................................................................ 20 
 
Preparation ............................................................................................................................ 21 
 
Dosing and Administration .................................................................................................... 21 
 
Route of Administration ......................................................................................................... 21 
 
Starting Dose and Dose Escalation Schedule ...................................................................... 21 
 
Dose Adjustments/Modifications/Delays ............................................................................... 21 
 
Duration of Therapy ............................................................................................................... 21 
7.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................................. 21 
7.3 
STUDY BEHAVIORAL OR SOCIAL INTERVENTION(S) ......................................................................... 22 


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Administration of Intervention ................................................................................................ 22 
 
Assessment of Subject Compliance with Study Intervention ................................................ 23 
8 
STUDY PROCEDURES AND SCHEDULE ....................................................................................... 25 
8.1 
STUDY PROCEDURES/EVALUATIONS ............................................................................................. 25 
8.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................................... 27 
 
Specimen Preparation, Handling, and Storage ..................................................................... 27 
 
Specimen Shipment .............................................................................................................. 27 
8.3 
STUDY SCHEDULE ........................................................................................................................ 28 
 
Screening .............................................................................................................................. 28 
 
Enrollment/Baseline .............................................................................................................. 28 
 
Intermediate Visits ................................................................................................................. 28 
 
Final Telephone Follow-Up ................................................................................................... 30 
 
Unscheduled Visit .................................................................................................................. 30 
8.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................... 30 
8.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ........................................................ 30 
9 
DEFINITIONS OF KEY TERMS ......................................................................................................... 30 
10 
SPECIFICATION OF SAFETY VARIABLES .................................................................................... 31 
11 
GENERAL GUIDELINES ................................................................................................................... 31 
11.1 
SOLICITATION OF AES .................................................................................................................. 31 
11.2 
PREPLANNED HOSPITALIZATION OR PROCEDURE ........................................................................... 32 
11.3 
REPORTS OF CANCER .................................................................................................................. 32 
11.4 
SPECIFIC GUIDELINES FOR ASSESSING LABORATORY VALUES AS ADVERSE EVENTS .......................... 32 
12 
ASSESSMENT OF ADVERSE EVENTS ........................................................................................... 32 
12.1 
EXPECTEDNESS ........................................................................................................................... 32 
12.2 
SEVERITY .................................................................................................................................... 32 
12.3 
RELATEDNESS ............................................................................................................................. 32 
13 
MONITORING ADVERSE EVENTS .................................................................................................. 33 
14 
KNOWN POTENTIAL TOXICITIES OF STUDY DRUG .................................................................... 33 
15 
OTHER SIGNIFICANT ADVERSE EVENTS ..................................................................................... 33 
16 
REPORTING PROCEDURES ............................................................................................................ 33 
16.1 
AE REPORTING ............................................................................................................................ 33 
16.2 
SAE REPORTING ......................................................................................................................... 34 
16.3 
UP REPORTING ........................................................................................................................... 35 
16.4 
PREGNANCY REPORTING .............................................................................................................. 36 
17 
REPORTING OF INVESTIGATIONAL MEDICINAL PRODUCT QUALITY COMPLAINTS ............ 36 
17.1 
DEFECT OR POSSIBLE DEFECT IN THE IP ....................................................................................... 36 
17.2 
TEMPERATURE DEVIATIONS .......................................................................................................... 37 
18 
STUDY HALTING RULES ................................................................................................................. 37 
19 
SAFETY OVERSIGHT ....................................................................................................................... 37 
20 
CLINICAL MONITORING .................................................................................................................. 37 
21 
STATISTICAL CONSIDERATIONS .................................................................................................. 38 
21.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................................. 38 
21.2 
STATISTICAL HYPOTHESES ........................................................................................................... 38 
21.3 
DESCRIPTION OF STATISTICAL METHODS ...................................................................................... 38 
 
General Approach ............................................................................................................. 38 
 
Analysis of the Primary Endpoint(s) .................................................................................. 38 
 
Analysis of the Secondary Endpoint(s) ............................................................................. 38 


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Safety Analyses ................................................................................................................ 39 
 
Adherence and Retention Analyses .................................................................................. 39 
 
Baseline Descriptive Statistics .......................................................................................... 39 
 
Planned Interim Analysis .................................................................................................. 39 
 
Multiple Comparison/Multiplicity ........................................................................................ 40 
 
Tabulation of Individual Response Data ........................................................................... 40 
 
Exploratory Analyses ........................................................................................................ 40 
21.4 
SAMPLE SIZE ............................................................................................................................... 40 
22 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 40 
23 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 41 
24 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 41 
24.1 
ETHICAL STANDARD ..................................................................................................................... 41 
24.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 41 
24.3 
INFORMED CONSENT PROCESS .................................................................................................... 41 
 
Consent/Assent and Other Informational Documents Provided to Participants ............... 41 
 
Consent Procedures and Documentation ......................................................................... 42 
24.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 42 
 
Research Use of Stored Human Samples, Specimens, or Data ...................................... 43 
24.5 
FUTURE USE OF STORED DATA .................................................................................................... 43 
25 
DATA HANDLING AND RECORD KEEPING ................................................................................... 44 
25.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 44 
25.2 
STUDY RECORDS RETENTION ....................................................................................................... 44 
25.3 
PROTOCOL DEVIATIONS ............................................................................................................... 44 
25.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 45 
26 
STUDY FINANCES ............................................................................................................................ 45 
26.1 
FUNDING SOURCE ........................................................................................................................ 45 
26.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 45 
26.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................ 46 
27 
CONFLICT OF INTEREST POLICY .................................................................................................. 46 
28 
REFERENCES ................................................................................................................................... 47 
29 
ATTACHMENTS ................................................................................................................................ 53 
 
 
 


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List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
LFT 
Liver Function Test 
MOP 
Manual of Procedures 
n 
Number (typically refers to participants) 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
US 
United States 
CBD 
Cannabidiol 
THC 
Tetrahydrocannabinol 
AUD 
Alcohol Use Disorder 
 
 


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Protocol Summary 
Title 
A Phase I/II Randomized, Double-Blind, Placebo-Controlled Trial of 
Cannabidiol for Alcohol Use Disorder 
Brief Summary 
The proposed study is a double-blind, randomized proof-of-concept study 
designed to assess feasibility and contrast effects of CBD treatment to those of 
placebo on drinking-related outcomes in patients with AUD. We will evaluate 
the safety of an extended daily CBD treatment regimen in an AUD population, 
assess the impact of CBD on neuropsychological and neurophysiological 
domains implicated in AUD, and generate preliminary data on the impact of 
CBD on alcohol consumption. Following screening and baseline assessments, 
40 participants will be randomized in 1:1 ratio to receive either placebo or 
600mg CBD/day (PO) for 4 weeks, immediately followed by 1200mg CBD/day 
(PO) for an additional 4 weeks (8 weeks in total). 
Phase 
Clinical study phase I/II 
Objectives 
To assess circulating cannabinoid (including CBD and THC) levels and safety 
of CBD administered to patients with AUD, to contrast the effects of CBD to 
those of placebo on several physiological and psychological domains relevant 
to AUD, and to assess the impact of CBD on drinking behavior 
Methodology 
Double-blind, placebo-controlled 
Endpoint 
Circulating concentrations of CBD and THC, AEs, and scores on psychomotor 
and cognitive tasks and alcohol consumption. 
Study Duration 
2 years 
Participant Duration 
12 weeks 
Duration of IP 
administration 
8 weeks 
Population 
n=40 18-65 year-old males and females with moderate to severe alcohol use 
disorder in the New York area  
Study Sites 
New York University School of Medicine 
Number of participants 
60 participants expected to be enrolled 
Description of Study 
Agent/Procedure 
Cannabidiol PO 600-1200mg/day 
Reference Therapy 
Placebo with medication management 
Key Procedures 
Blood draws 
Statistical Analysis 
Circulating levels of CBD, Anandamide, Delta-9 THC, 11-Hydroxy Delta-9 THC 
and Delta-9 Carboxy THC will be assessed in CBD-treated participants 45 
minutes after the initial administration (T1, T4), 1 day (T2, T5), 1 week (T3, 
T6), and 4 weeks (T4, T7) of treatment with each dose of CBD. Anandamide 
levels will also be assessed at these timepoints in placebo treated participants. 
Additionally, circulating levels of CBD and anandamide will be assessed in 
CBD-treated participants 12 hours after ingestion of the preceding evening 
dose following 1 week (T3, T6) and 4 weeks (T4, T7) of administration of each 
dose of CBD. Circulating levels of each analyte (mean and standard deviation) 
will be reported at each timepoint, and effects of dose and time-point will be 
evaluated. Between-group differences on psychomotor tasks (T1-T8), 
cognitive measures (T3, T6) and number of adverse events (T1-T9) will be 
assessed. 
 


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1 Schematic of Study Design 
 
 
 
 
 
 


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2 Key Roles 
Michael Bogenschutz, MD – Principal Investigator 
New York University School of Medicine 
Department of Psychiatry 
462 First Ave, 8th Fl. A Building 
(646) 501-4026 
Michael.Bogenschutz@nyumc.org 
 
John Rotrosen, MD Sub-Investigator 
New York University School of Medicine 
Department of Psychiatry 
One Park Ave, 8th Fl 
(646) 754-4763 
John.Rotrosen@nyumc.org 
 
Stephen Ross, MD Sub-Investigator 
New York University School of Medicine 
Department of Psychiatry 
462 First Ave, 8th Fl. A Building  
(212) 562-4097 
Stephen.Ross@nyumc.org  
 
Sarah Mennenga, PhD Sub-Investigator 
New York University School of Medicine 
Department of Psychiatry 
462 First Ave, 8th Fl. A Building  
(646) 501-4037 
Sarah.Mennenga@nyumc.org 
3 Introduction, Background Information and Scientific Rationale 
3.1 Background Information and Relevant Literature 
Need for improved treatments for alcohol use disorder (AUD). Of all drugs of abuse, alcohol is possibly 
the most damaging in the US and globally when factoring in preventable death, premature death, disability, 
healthcare/societal costs, adverse medical and neuropsychiatric complications, unintentional injuries, and its 
significant causal link to suicidal and violent behaviors. AUDs are highly prevalent in the US, affecting up to 
12% of the population at some point in their lifetimes [1]. AUDs are among the most disabling of all diseases 
worldwide, and alcohol use is responsible for approximately 4.6% of global disability-adjusted life-years and 
36.4% of neuropsychiatric disability-adjusted life-years in 2004 [2]. In the US alcohol accounts for 12.1% of 
disability-adjusted life-years in men, and 4.6% in women [2]. The economic cost of alcohol use is staggering, 
estimated at $185 billion per annum in the US alone, vs. $158 billion for nicotine and $280 billion for illicit drugs 
(higher because of costs related to criminalization) [3]. 
Substantial progress has been made in understanding the neurobiological and neuropsychological 
underpinnings of the loss of control that is the hallmark of addiction. A number of pharmacological and 
behavioral treatments have been developed that target specific aspects of addiction, including motivation, 
coping skills, social support, reward/punishment, and relapse due to stress, priming doses of the drug, or 
exposure to conditioned cues. However, the effects of currently available treatments remain disappointingly 
small [4]. Although combining effective treatments (multiple pharmacotherapies or pharmacotherapy plus 
behavioral therapy) is an obvious strategy to increase treatment effect sizes, attempts to improve outcomes by 
combination therapy have been largely disappointing as well [5]. Approximately one person achieves 
abstinence or avoids relapse for every 9 people treated with the most effective FDA-approved 
pharmacotherapies for alcohol use disorder [6, 7]. Currently available medications for alcohol use disorder 
require adherence to treatment for relatively long periods of time, which further limits their effectiveness.  


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Cannabidiol. CBD is a phytocannabinoid that lacks the rewarding properties and psychoactive effects of 
THC [8]. CBD exerts effects both through the endocannabinoid system and through several other 
signaling pathways. GW pharmaceuticals is developing CBD (Epidiolex®) as a medication for the 
treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, and completed 
successful Phase 3 trials in 2016 [9-11]. Over the past decade, a rapidly growing body of research, 
summarized below, has established that CBD affects processes and behavior relevant to anxiety 
disorders and substance use disorders, providing strong support for exploration of the effects of CBD in 
humans with alcohol use disorder. 
The endocannabinoid system and CBD. The endocannabinoid system includes several endogenous 
compounds with cannabis-like activity and their molecular targets: g-protein coupled cannabinoid receptor 
1 (CB1) and 2 (CB2), and the novel cannabinoid-sensitive g-protein coupled receptor, GPR-55 [12-14]. 
Both CB1 and GPR-55 are highly expressed in brain regions involved in the regulation of stress, sleep, 
learning, memory, and reward-seeking, including: the hippocampus, amygdala, striatum, nucleus 
accumbens, frontal cortex, and entorhinal cortex [15-18]. CB1 is primarily expressed pre-synaptically and 
regulates GABAergic and glutamatergic release [17, 19], whereas GPR-55 exerts agonist- and tissue-
specific actions, including regulation of intracellular calcium levels, extracellular signal-regulated kinases 
(ERKs), and nuclear factor of activated T-cells (NFAT), through coupling with Gαq/11 [20, 21], Gα12 [20], 
or Gα13 [22, 23] proteins (for review, see [24]). While the role of CB2 in the brain is unknown, neuronal 
expression of CB2 has been established in the substantia nigra and hippocampus, and CB2 is found in 
microglia [25-27].  
CBD has a low affinity for CB1 and CB2 receptors [28, 29], but acts as a weak inverse agonist at CB2 
receptors [30], and an antagonist at GPR-55 [22]. CBD may antagonize the effects of CB1 agonists 
through non-CB1 mediated mechanisms [31, 32], and indirectly facilitates endocannabinoid 
neurotransmission by inhibiting hydrolysis of the endocannabinoid anandamide by fatty acid amide 
hydrolase (FAAH) [33], and reducing anandamide uptake by the anandamide membrane transporter 
(AMT) [34].  
Other pharmacologic targets of CBD. In addition to its impact on the endocannabinoid system, CBD 
also acts as an agonist at the serotonin 1A (5-HT1A) receptor [35], produces allosteric modulation of 
ligand-binding kinetics at μ and δ opioid receptors [36], increases intracellular calcium through activation 
of transient receptor potential vanilloid type 1 (TRPV1) cation channels [34], and enhances adenosinergic 
neurotransmission via inhibition of the adenosine transporter [37]. Moreover, CB1 receptors have been 
shown to regulate 5-HT1A, 5-HT2A, and 5-HT2C receptor functions in rodents [38], and there is evidence 
that CB2 and 5-HT1A receptors may heterodimerize, modulating their function [39].  
Effects of CBD on anxiety and negative affect. In chronic addiction, increased negative affect occurs 
through the recruitment of the classic stress axis and aversive dynorphin-mediated systems, and negative 
reinforcement (relief from dysphoric states) plays an important role in maintenance of alcohol or drug use [40-
42]. In animal models, alcohol withdrawal is associated with increased activity in the extended amygdala, and 
pharmacological inhibition of extended amygdala activity reduces both anxiety and alcohol-seeking behaviors 
associated with withdrawal [41, 43-47]. Higher amygdala reactivity predicts future problem drinking In AUD 
patients who report alcohol use to mitigate negative emotions [48].  
Extensive research in animals and humans demonstrates that CBD dampens activity in circuits mediating 
anxiety and negative affect, suggesting a possible mechanism of its anti-addictive effects. In animal models, 
CBD produces anxiolytic, anti-compulsive, anti-fear-conditioning and pro-fear-extinction effects by acting at 5-
HT1a and CB1 receptors within the extended amygdala [49-53] and functionally connected brain regions [54-
57]. CBD indirectly increases endocannabinoid agonism at the CB1 receptor, reducing extended amygdala 
output and alcohol seeking [58]. In human experimental studies, CBD at doses between 300–600 mg rapidly 
(within 2 hours) reduces subjective anxiety in both healthy and social anxiety disorder subjects, and reduces 
threat-related amygdala activity and sympathetic arousal measured by skin conductance [57, 59]. 
Effects of CBD on other domains relevant to addiction. Several other effects of CBD may also act to 
combat addiction. CBD produces several pro-cognitive effects: it protects against binge ethanol consumption-
induced neurotoxicity [60], exerts neurogenerative effects in the hippocampus [61, 62], and attenuates 
cognitive impairments in several animal models of neurodegenerative disease, likely through its 
neurogenerative and anti-inflammatory properties [63-65]. In contrast to these pro-cognitive effects, CBD 
disrupts consolidation and facilitates extinction of fear memories [66, 67] and prevents reconsolidation of 


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contextual drug-related memories [68]. CBD decreases marble-burying in rodents, an analogue for obsessive-
compulsive behavior [69], alters reward-seeking behavior [70], and reduces amotivational symptoms 
associated with anxiety, depression, and addiction [71, 72]. 
3.2 Name and Description of the Investigational Agent  
CBD is a phytocannabinoid that lacks the rewarding properties and psychoactive effects of 
tetrahydrocannabinol (THC) [8]. CBD exerts effects both through the endocannabinoid system and through 
several other signaling pathways. GW pharmaceuticals is developing CBD (Epidiolex®) as a medication for the 
treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, and completed 
successful Phase 3 trials in 2016 [9-11].  
Existing data suggest CBD is highly non-toxic to humans. However, clinical data are limited, and its use in the 
treatment of AUD is experimental. The data and safety monitoring plan is therefore designed to ensure that the 
risks of medications and study-related procedures are minimized for patients. CBD is a schedule 1 drug, a class 
that includes compounds with high potential for abuse and no medical value. Contrary to this scheduling, CBD 
does not appear to possess a high abuse potential, nonetheless, it has not been FDA-approved for medical 
use. Therefore, this study will be performed under an Investigational New Drug Application (IND #140108). 
Refer to the Investigator’s Brochure for comprehensive drug information. 
 Preclinical Data 
In rodent models, CBD reduces cue-induced heroin seeking, potentiates extinction of cocaine- and 
amphetamine-induced conditioned place preference [73], and normalizes heroin-seeking-induced changes 
in glutamatergic GluR1-containing amino-hydroxy-methyl-isoxazolepropionic (AMPA) receptors and CB1 
receptor expression in the nucleus accumbens [74]. Work done in the laboratory of Friedbert Weiss 
(consultant on the current proposal) demonstrated that transdermal CBD at a dose yielding serum CBD 
concentrations of 300-400ng/ml reduces stress- and cue-induced alcohol- and cocaine- seeking in 
rodents, with effects lasting up to 138 days post-CBD treatment for alcohol [75]. This regimen also 
reduced anxiety-like behavior in alcohol-exposed, cocaine-exposed, and drug-naive rodents without 
impacting locomotor activity or cue- or stress- induced reinstatement for a sweet solution, and reversed 
impulsive-like behavior induced by alcohol intoxication in a delay discounting task 6-15 days after the 
cessation of treatment. Another recent report also demonstrated CBD’s ability to reduce the reinforcing 
effects of alcohol at an identical dose of CBD delivered subcutaneously in a microparticle formulation also 
designed to provide continuous controlled release of CBD [76]. 
 
Studies of CBD’s effects on addiction-related behaviors in human participants are limited. The only study to 
assess the impact of CBD on alcohol-related behaviors found no impact of 200mg of CBD on symptoms of 
intoxication in healthy volunteers [77]. However, high concentrations of CBD in cannabis are related to lower 
attentional bias toward drug stimuli and lower self-rated liking of cannabis-related stimuli relative to cannabis 
with a low ratio of CBD to THC [78], CBD may reduce cigarette smoking in dependent humans [79], and a 
single case study reported that daily CBD prevented marijuana withdrawal symptoms [80]. 
 Clinical Data to Date 
Studies of CBD’s effects on addiction-related behaviors in human participants are limited. The only study to 
assess the impact of CBD on alcohol-related behaviors found no impact of 200mg of CBD on symptoms of 
intoxication in healthy volunteers [77]. However, high concentrations of CBD in cannabis are related to lower 
attentional bias toward drug stimuli and lower self-rated liking of cannabis-related stimuli relative to cannabis 
with a low ratio of CBD to THC [78], CBD may reduce cigarette smoking in dependent humans [79], and a single 
case study reported that daily CBD prevented marijuana withdrawal symptoms [80].  
 
CBD has also been shown to produce anxiolytic and anti-epileptic effects in human participants. CBD negates 
the anxiogenic effects of simulated public speaking both in healthy [81] and in anxious individuals [82], and also 
reduces the anxiogenic effects of THC [83, 84]. CBD alters regional cerebral blood flow in limbic and paralimbic 
regions important for anxiety and addiction in healthy [85], and anxious [86] individuals and attenuates blood 
oxygenation level-dependent signal in the same structures during response inhibition [87] and presentation of 


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fearful faces [59]. GW pharmaceuticals is developing CBD (Epidiolex®) as a medication for the treatment of 
seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, and completed successful Phase 3 
trials in 2016 [9-11]. 
 Dose Rationale (if applicable)  
CBD has been given up to 600 mg daily orally for cannabis dependence [80], and the one existing human 
study of CBD’s impact on the acute effects of alcohol used a dose of 200 mg [88]. CBD was given to patients 
with schizophrenia up to 1280 mg/day [89], and Phase 3 trials of CBD for seizure disorders used doses of 20 
mg/kg/day oral CBD solution (1400 mg/day for a 70 kg person) [9, 11]. 
Consistent and clinically significant effects on fear and anxiety in the absence of intoxicating, 
psychotomimetic, and psychotropic effects have been observed with oral dosing in the range of 300-600 
mg/day [90]. However, preliminary work performed by Dr. Weiss and others [76] indicates that higher doses 
(>30mg/kg/day transdermal/subcutaneous) yielding serum CBD concentrations in the range of 300-400ng/ml 
are required to reduce alcohol-reinforced reward-seeking behaviors in rodents.  
Oral dosing of CBD is complicated by limited oral absorption, which is similar to THC at approximately 6% 
[91], and by the possibility that high doses of CBD could convert to THC when delivered orally [92, 93]. 
However, oral delivery of CBD in a sesame-oil formulation at a dose of 12mg/kg (roughly equivalent to 
1000mg/day adjusted for average human body weight) was shown to yield serum concentrations within the 
targeted range in rats [94]. We therefore will administer CBD vs. Placebo orally in a lipid-based formulation at 
600mg/day for an initial period of 4 weeks, followed by 1200mg/day for an additional 4 weeks, to reach our 
target circulating levels of 300-400ng/ml in a human AUD sample. Two studies in humans have shown no 
progressive accumulation of CBD levels with repeated daily dosing, including following 6 weeks of oral 
administration of 700mg/day CBD [95, 96], and preliminary data with transdermal CBD up to 30mg/kg/day in 
rodents shows no serum accumulation over 7 days of treatment (Weiss, unpublished data). Therefore, under 
the proposed dosing regimen we expect to achieve steady-state circulating levels of CBD within a week.  
Plasma CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC, and Anandamide levels will be 
assessed prior to the first dose (T1), 45 min after ingesting the first dose (T1), and 45 min after ingesting the 
morning dose after 1 day (T2, T5), 1 week (T3, T6), and 4 weeks (T4, T7) of treatment with each dose of CBD 
(600mg/day, 1200mg/day). Anandamide levels will also be assessed at these timepoints in placebo treated 
participants. We will also assess pre-CBD dosing plasma levels of CBD and Anandamide prior to ingesting 
the morning dose after 1 week (T3, T6) and 4 weeks (T4, T7) of treatment with each dose of CBD. 
Anandamide levels will also be assessed at these timepoints in placebo-treated participants.  
3.3 Rationale 
There is increasing recognition of the role of the endocannabinoid system in neurobiological processes and 
behavioral domains relevant to the pathophysiology and treatment of addiction. The phytocannabinioid 
cannabidiol has attracted considerable attention due to its lack of intoxicating effects, low abuse potential, 
excellent safety, and unique pharmacological profile.  
CBD reliably reduces anxiety-like behavior in animals, attenuates anxiogenic effects of stressful stimuli in 
healthy and anxious individuals, and disrupts consolidation and facilitates extinction of fear memories. More 
directly relevant to addiction, CBD prevents reconsolidation of contextual drug-related memories and may 
decrease impulsive behaviors, craving, and withdrawal. Very recently, rodent studies have provided strong 
direct evidence of clinically relevant effects of CBD in models of alcohol use disorder (AUD). In two independent 
studies, treatment with CBD produced marked and persisting decreases in alcohol self-administration and 
preference for alcohol, and alcohol-, cue- and stress-induced reinstatement. These findings suggest that CBD 
could have potential as a treatment for AUD. However, there are few studies of the effects of CBD in humans 
with addictive disorders, and limited data on CBD’s safety in AUD populations, particularly at doses shown to 
be effective in animal models of AUD.  
The proposed study is a double-blind, randomized proof-of-concept study designed to assess feasibility and 
contrast effects of CBD treatment to those of placebo on drinking-related outcomes in patients with alcohol use 
disorder (AUD). We will evaluate the safety of an extended daily CBD treatment regimen in an AUD population, 
assess the impact of CBD on neuropsychological and neurophysiological domains implicated in AUD, and 


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generate preliminary data on the impact of CBD on alcohol consumption. Following screening and baseline 
assessments, 40 participants will be randomized in 1:1 ratio to receive either placebo or 600mg CBD/day (PO) 
for 4 weeks, immediately followed by 1200mg CBD/day (PO) for an additional 4 weeks (8 weeks in total). These 
doses are calculated to achieve the serum CBD levels reported to reduce alcohol-seeking behavior in animal 
studies. Assessments will be completed after 45 minutes, 1 day, 1 week and 4 weeks of treatment with each 
dose of CBD vs. placebo, and 1 and 4 weeks after the cessation of treatment. Outcomes will include circulating 
levels of CBD, Anandamide, Delta-9 THC, 11-Hydroxy Delta-9 THC and Delta-9 Carboxy THC, safety measures 
(adverse events, cognitive and motoric function), and physiological and psychological domains relevant to AUD 
including self-reported craving, depression, and anxiety; responses to personalized scripts designed to elicit 
stress- and cue-induced craving and anxiety; and drinking outcomes across 8 weeks of treatment and 4 weeks 
of follow-up. 
3.4 Potential Risks & Benefits 
 Known Potential Risks 
The available evidence suggests that CBD is safe and well-tolerated in human participants. Numerous 
studies, including several blinded, placebo-controlled trials, have revealed few adverse effects of CBD orally 
in doses ranging from 10 mg to 1500 mg per day; there have been no reported effects on blood pressure, 
heart rate, or respiratory rate, no negative mood effects, and no psychomotor slowing. Commonly reported 
treatment-emergent adverse events in Phase 3 trials of CBD for Lennox-Gastaut or Dravet Syndrome 
included diarrhea, somnolence, pyrexia, decreased appetite, vomiting, fatigue, lethargy, and convulsion. All 
participants in these trials were on concomitant anti-seizure medications. CBD is not noticeably psychoactive. 
 Known Potential Benefits 
Participants may or may not experience clinical benefit from this study. Pre-existing clinical data suggest a 
possibility that the study drug could produce anxiolytic and anti-addictive effects. Aspects of study 
participation likely to be beneficial include free medical and psychiatric evaluations, and the attention and 
support of participating in a clinical trial. 
4 Objectives and Purpose 
4.1 Primary Objective 
The primary objective of this study is to assess circulating cannabinoid levels and safety of CBD administered 
to patients with AUD at doses calculated to yield circulating CBD levels comparable to those that produced 
clinically relevant effects in animal models of AUD. We predict that within-group circulating CBD levels will 
stabilize within one week (i.e. pre-CBD dosing levels obtained after 1 week of treatment will not differ from 
those obtained after 4 weeks of treatment at each dose), that circulating CBD levels obtained at the 1200 
mg/day dose will be comparable to those associated with anti-addictive effects in animal models, (i.e., in the 
range of 200-400 ng/ml), and that no clinically significant cognitive or motoric impairments, CBD-related 
serious adverse events, or persisting adverse effects will be observed. 
4.2 Secondary Objectives 
A secondary objective of this study is to contrast the effects of CBD to those of placebo on several 
physiological and psychological domains relevant to AUD. Relative to placebo, we predict that CBD will 
improve self-report measures of craving, anxiety, mood, and self-efficacy, and attenuate stress- and alcohol 
cue-induced craving and physiological stress response. 
The final exploratory objective of this study is to assess the impact of CBD on drinking behavior. Relative to 
the placebo-treated group, we predict that CBD-treated participants will have fewer heavy drinking days 
during and for four weeks after treatment with 1200mg/day CBD vs. placebo.  


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5 Study Design and Endpoints 
5.1 Description of Study Design 
The proposed study is a phase I/II, single-center, double-blind, randomized proof-of-concept study designed 
to assess feasibility and contrast effects of CBD treatment to those of placebo on drinking-related outcomes in 
patients with alcohol use disorder (AUD). We will evaluate the safety of an extended daily CBD treatment 
regimen in an AUD population, assess the impact of CBD on neuropsychological and neurophysiological 
domains implicated in AUD, and generate preliminary data on the impact of CBD on alcohol consumption. 
Following screening and baseline assessments, 40 participants will be randomized in 1:1 ratio to receive 
either placebo or 600mg CBD/day (PO) for 4 weeks, immediately followed by 1200mg CBD/day (PO) for an 
additional 4 weeks (8 weeks in total). These doses are calculated to achieve the serum CBD levels reported 
to reduce alcohol-seeking behavior in animal studies.  
 Primary Study Endpoints 
Circulating cannabinoid levels 
Circulating levels of CBD, Anandamide, Delta-9 THC, 11-Hydroxy Delta-9 THC and Delta-9 Carboxy THC will 
be assessed in CBD-treated participants 45 minutes after the initial administration (T1, T4), 1 day (T2, T5), 1 
week (T3, T6), and 4 weeks (T4, T7) of treatment with each dose of CBD. Anandamide levels will also be 
assessed at these timepoints in placebo treated participants. Additionally, circulating levels of CBD and 
anandamide will be assessed in CBD-treated participants 12 hours after ingestion of the preceding evening 
dose following 1 week (T3, T6) and 4 weeks (T4, T7) of administration of each dose of CBD. Plasma CBD levels 
will be determined via High Performance Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS) by 
collaborators at the Nathan Kline Institute.  
 
Safety 
Safety will be assessed by collection of adverse events at all visits after treatment is initiated. LFTs will be 
obtained at screening, as well as weeks 4, 8, and 9 to assess liver function during and after treatment with 
study medication. Risk of suicidality will be assessed using the Columbia-Suicide Severity Rating Scale (C-
SSRS) [111] by a licensed Clinical Psychologist, NP or MD as part of each study visit (except for the 1-day/T2 
and 4 weeks+1-day/T5 visits). 
Psychomotor and subjective effects of CBD:  
Basic motoric and cognitive function will be evaluated throughout treatment with several established field 
sobriety tests, including a walk-and-turn task, one-leg stand, Romberg’s test, finger-finger test, and counting 
backwards [97]. The Addiction Resource Center Inventory (ARCI), 49-item version [98], will be used as a 
measure of the intoxicating effects and abuse potential of CBD. Breath Alcohol Concentration (BAC) will also 
be measured to ensure participants are not under the influence of alcohol during administration of these tasks. 
Between-group differences on psychomotor tasks (T1-T8), cognitive measures (T3, T6) and number of adverse 
events (T1-T9) will be assessed.  
 
Cognitive Function:  
Several established neuropsychiatric and cognitive tasks will be administered to evaluate the impact of CBD 
vs. placebo treatment on cognitive domains potentially affected by CBD and/or THC. The Rey Auditory Verbal 
Learning Task (RAVLT) will be used to assess episodic memory [99, 100], the Mental Rotation Task (MRT) will 
evaluate visuospatial ability [101, 102], a Time Reproduction Task (TRT) will measure encoding and retrieval 
of time intervals [88], and several WM Span tasks (OSpan, RSpan, SymSpan, RotSpan) will measure working 
memory capacity [103, 104].  
 Secondary Study Endpoints 
Additional outcomes will include physiological and psychological domains relevant to AUD including self-
reported craving, depression, and anxiety; responses to personalized scripts designed to elicit stress- and 
cue-induced craving and anxiety; and drinking outcomes across 8 weeks of treatment and 4 weeks of follow-
up. 


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AUD-Related Measures: 
The Penn Alcohol Craving Scale (PACS) [105] will be used to assess craving. This scale has 5 Likert-scaled 
items with excellent internal consistency and evidence of predictive, construct, and discriminant validity. Mood 
and Anxiety will be measured with the Beck Anxiety Inventory (BAI) [106] and Beck Depression Inventory-II 
(BDI-II) [107] scales before CBD treatment, at the end of treatment, and at the 2 week follow-up. Self-efficacy 
will be assessed using the Alcohol Abstinence Self-Efficacy Scale (AASE) [108], a self-report questionnaire 
which has been used widely in the alcohol treatment research, both as a predictor of outcome and as a 
patient-treatment matching variable [109, 110].  
The Cue and Stress Response Task will be performed at the 5- week time-point using methodology 
developed in Rajita Sinha’s lab, similar to those in used in past studies with alcohol dependent patients [112, 
113]. Dr. Sinha will provide consultation on the implementation of these methods. Briefly, imagery scripts will 
be developed at baseline and again following 4 weeks of treatment. Stress imagery scripts will be based on a 
recent highly stressful situation the participant has experienced unrelated to alcohol use. Alcohol cue scripts 
will be derived from a recent event that included alcohol-related stimuli and led to alcohol use. Neutral or 
relaxing scripts will also be developed. All scripts will be developed by obtaining specific details of stimulus 
and response, including contextual details, cognitive and verbal content, affective experience, and bodily 
sensations. These details form the basis of a 5-minute imagery script, which will be developed for each of the 
three conditions. Imagery sessions will be structured with a 5-minute pre-imagery period, a 5-minute imagery 
period, and a 5-minute recovery period. Pulse, skin conductance, heart rate variability, and blood pressure will 
be monitored during each imagery session with an ADInstruments PowerLab 4/30 Galvanic Skin Response 
device and a Contec Patient Monitor. In Human laboratory studies with CBD, skin conductance and amygdala 
activation were reduced by CBD in a closely correlated manner [59], suggesting threat-related sympathetic 
arousal may serve as a proxy for amygdala activation [114]. Participants will complete Likert scale ratings of 
vividness, craving, anxiety, and the 30-item Differential Emotion Scale [112, 113] following each of the three 
periods. After each condition, a progressive relaxation procedure will be implemented to facilitate return to 
baseline of vital signs, craving and anxiety, an approximate period of 10 minutes, as shown in previous 
research from the Sinha lab [112, 113]. The entire imagery protocol will take 120 minutes. The order of the 
sessions will be randomized and counterbalanced among participants. This task will be completed at 5 
weeks, i.e. after 1 week of treatment at 1200mg daily. At this point, we expect steady-state circulating CBD 
levels to have been reached. It is important to assess stress- and cue- response at the high dose because it 
is possible that anxiolytic effects decrease at high doses of CBD, while effects on alcohol consumption are 
expected to increase with dose.  
 Exploratory Endpoints 
Alcohol consumption will be assessed with Time-line Follow-back (TLFB) [115] and percent carbohydrate-
deficient transferrin (CDT) in serum. History of trauma will be assessed with the Trauma History 
Questionnaire (THQ) [116] at baseline. 
6 Study Enrollment and Withdrawal 
6.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1) Males and females age 18-65 
2) DSM-5 diagnosis of moderate or severe AUD 
3) Able to provide voluntary informed consent 
4) At least 6 heavy drinking days (4 or more drinks for a woman, 5 or more drinks for a man) in the 30 days 
prior to screen 
6) If of childbearing potential (male or female), are willing to use approved form of contraception from 
screening for duration of the trial 
7) Able to provide at least two locators 
8) Endorse desire to cut down or stop drinking 
9) Agrees to abstain from all other cannabinoid use for duration of the study 
 


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6.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1) Current alcohol withdrawal (CIWA-Ar score >7) 
2) Exclusionary medical conditions (e.g. current severe alcohol withdrawal requiring medical 
hospitalization, significantly impaired liver function, Type I Diabetes) 
3) DSM-5 diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder 
4) High risk of adverse emotional or behavioral reaction based on investigator’s clinical evaluation (e.g., 
evidence of serious personality disorder, antisocial behavior, serious current stressors, lack of meaningful 
social support) 
5) Current significant suicidality (assessed using the C-SSRS), any suicidal behavior in the past 12 
months, or any history of serious suicide attempts requiring hospitalization, or current significant 
homicidality 
6) History of severe Traumatic Brain Injury (LOC > 24 hours) 
7) DSM-5 diagnosis of current mild cannabis use disorder and/or moderate or severe substance use 
disorder for a substance other than alcohol or nicotine 
8) Significant laboratory abnormalities, including significantly impaired liver function*, serious 
abnormalities of complete blood count or metabolic panel 
9) Active legal problems likely to result in incarceration within 12 weeks of treatment initiation 
10) Pregnancy or lactation 
 
11) Current use of exclusionary medications, including cannabinoids; treatments for addictions including 
alcohol; moderate to strong inhibitors of CYP3A4 or CYP2C19; medications metabolized primarily by 
CYP3A5, or CYP3A7; and medications with a narrow therapeutic index which are substrates of 
CYP3A4,UGT1A9, UGT2B7, CYP2C8, CYP2C9, CYP2C19, CYP1A2, or CYP2B6. 
12) Allergy to any ingredient of the study compound. 
13) Current treatment for AUD, with exception of AA/12-step treatment 
14) No inpatient psychiatric treatment in the last 12 months, with the exception of detox and extended 
Emergency Department stays 
15) A positive urine drug screen for THC, cocaine and/or opioids at screen 
 
*Significantly impaired liver function will be operationalized as alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), or alkaline phosphatase (All Phos) > 2.5 × upper limit of normal (ULN), or Total 
bilirubin > 2.0 × ULN in the absence of Gilbert's syndrome. 
 
6.3 Strategies for Recruitment and Retention 
Subjects will be approximately 60 women and men, age 18 or greater, with moderate to severe AUD, recruited 
from the public through local media advertisements, 40 of whom will be randomized and complete the treatment 
portion of the study. Participants will be recruited between approximately September 2019 and August 2021. 
Informed consent will be given at NYUSoM space occupied by the PI within Bellevue Hospital in New York, NY, 
following an initial telephone consent and screen to determine potential eligibility for the study. Participants will 
be asked to share information about their drinking and use of any other drugs, anxiety and mood, and undergo 
a full medical and psychiatric evaluation at screen by licensed providers. Participants will have the option of 
completing the initial portion of the screening visit remotely. In this case, participants will be asked to share 
information about their drinking and use of any other drugs, anxiety and mood, and undergo a full psychiatric 
evaluation by licensed providers remotely via Webex. If inclusion and exclusion criteria continue to be met 
following the remote portion of the screening visit, participants will be invited to undergo a full in-person medical 
evaluation by licensed providers to complete the screening visit. 
Active recruitment will also take place through social media sources, including Facebook and  Twitter, 
at social service agencies, community mental health clinics, community organizations, local  professional 
organizations, residential treatment facilities, consenting support and recovery centers,  regional employee 
assistance programs, religious organizations, cultural centers, social clubs, and local  universities. 
Recruitment materials will also be posted to the laboratory’s website (centerforpsychedelicmedicine.com). 
Clinicians will provide study staff with names and contact info for interested patients, who will sign an 


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authorization form allowing the clinic to release only their contact information to study staff (no clinical or 
diagnostic information will be shared). Once referrals are given, the study team will access EPIC to determine 
the participant’s initial eligibility. Subjects will also be recruited through advertisements in local newspapers. 
Additionally, the study team will use NYU’s DataCore service to gather information from EPIC for current NYU 
patients who may be eligible.  
 
Active recruitment will also take place through social media sources, including Facebook, ResearchMatch, 
Craigslist, and Instagram, at social service agencies, community mental health clinics, community 
organizations, local professional organizations, residential treatment facilities, consenting support and 
recovery centers, regional employee assistance programs, religious organizations, cultural centers, social 
clubs, and local universities.  
 
Potential participants contacted through any of the above channels will be asked to complete a brief pre-
screening interview either in person or by telephone, using an IRB approved, and scripted pre-screening form 
describing the basic facts of the study and inquiring about inclusion and exclusion criteria. Participants who 
pass the pre-screening interview (i.e., those who appear likely to qualify for the study and remain interested in 
participating) will be scheduled for an in-person screening visit or for the remote portion of the screening visit, 
followed by the remaining in-person portion of the screening visit, if inclusion and exclusion criteria continue to 
be met. 
6.4 Duration of Study Participation 
Including screening and follow-up visits, the total duration of participant involvement will be approximately 12 
weeks. Total time of contact during these 12 weeks is estimated at 28 hrs. 
6.5 Total Number of Participants and Sites  
Recruitment will end when approximately 60 participants are enrolled. It is expected that approximately 60 
participants will be enrolled in order to produce 40 randomized participants.  
6.6 Participant Withdrawal or Termination 
 Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request. An investigator may 
terminate participation in the study if: 
• 
Any clinical adverse event (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 
• 
The participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation 
• 
The participant fails to adhere to protocol requirements 
 Handling of Participant Withdrawals or Termination 
Every effort will be made to undertake the protocol-specified safety follow-up procedures to capture AEs, 
SAEs, and UPs. The investigator will attempt to obtain at a minimum survival data on all participants lost to 
follow-up. If a participant is lost to follow-up, they study team will attempt to contact the participant 3 times by 
telephone and twice by email. If the participant fails to respond, locators identified by the participant at 
screening will be contacted in the method specified by the participant. If participants withdraw, are terminated, 
or are lost to follow-up prior to the end of the 8-week treatment phase (prior to T7), they will not be replaced to 
allow for 40 participants to complete the 8-week treatment phase (through T7), and their partial data will be 
handled according to the statistical analysis plan (SAP). 
 


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6.7 Premature Termination or Suspension of Study 
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 by the 
suspending or terminating party to Dr. Bogenschutz, NIH/NIAAA, the FDA, the DEA, and the NY State BNE. If 
the study is prematurely terminated or suspended, the PI will promptly inform the IRB and will provide the 
reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance with protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy 
the sponsor, IRB and/or FDA. 
7 Study Agent (Study drug, device, biologic, vaccine etc.) and/or 
Procedural Intervention  
7.1 Study Agent(s) and Control Description 
 
The TN-C200M2 Oral Capsules and matching placebo for this study are provided by TilrayTM. The CBD is 
derived from cannabis and processed according to CGMP standards (see Quality Overall Summary 
document provided by Tilray). The active capsules will include CBD (the active ingredient) at a quantity of 
200mg per capsule, as well as a mixture of surfactants, co-surfactants, co-solvents and carrier oils. The 
placebo capsules will contain no CBD.  
 Acquisition 
 
The investigational product, CBD, will be imported from Tilray, which is located at 1100 Maughan Road, 
Nanaimo, British Columbia, Canada V9X 1J2. The IND & DEA schedule I researcher, Michael P. 
Bogenschutz, MD, will acquire a New York State Bureau of Narcotic Enforcement Class 9 license to import 
controlled substances as well as a DEA Schedule I import permit. Tilray will then obtain a DEA export permit 
that will allow them to ship CBD to Michael P. Bogenschutz, MD. Once all permits and licensure is in place, 
Michael P. Bogenschutz will send a DEA 222 form to Tilray requesting the shipment of the investigational 
product. All shipping, importation and exportation of the investigational product will occur in line with local, 
state and federal regulations.  
 Formulation, Appearance, Packaging, and Labeling 
 
The drug product to be used in this study (TN-C200LM Oral Capsule) is a formulation of CBD dissolved in 
a mix of surfactants, co-surfactants, co-solvents and carrier oils at a concentration of 400mg/g. The 
formulation is designed to act as a self-emulsifying drug delivery system (SEDDS). Hard gelatin size-zero 
capsules are filled with the formulation to a fill weight of 500mg, providing a single capsule dose of 200mg 
CBD. This product in investigational and will be acquired as described above in 6.1.1. The TN-C200M2 
Oral capsules are packaged in pharmaceutical grade 100mL polyethylene terephthalate (PET) bottles and 
lid, with a fill of 20 capsules. 
 Product Storage and Stability 
 
The study drug, CBD, will be stored securely by study personnel under the PI’s individual schedule 1 DEA 
registration and New York Bureau of Narcotics Enforcement (BNE) class 7 license in accordance with all 
applicable laws and regulations. Additionally, a NYS BNE class 9 importer license and a DEA importer permit 
will be obtained prior to importation of study drug and study initiation. CBD will be stored in a double-locked 


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refrigerator. The refrigerator is located in a designated research room with limited access to the PI and study 
staff only, within the NYU-HHC CTSI Facility, which is located at 462 1st Avenue, 27th Street, C-D Building 4th 
floor, New York, NY 10016. The drug is to be stored between 2-8 degrees Celsius. It is recommended that the 
investigational product be reassayed at 9-months. The Principal Investigator will oversee the appropriate 
storage, accountability and dispensing of the study medication and all study drug administration to the patients 
will be done by the PI or treating co-investigators.   
 
TilrayTM has provided stability data for RSM-CBD Lots P56/8/116, P56/8/116, p56/17/017 and P56/44/057 at 4, 
25 and 40 degrees Celsius. 12-months data has been generated on the first two batches and 9-months data 
has been generated on the second two batches. There is no evidence of degradation for any of the samples 
stored at 4, 25 and 40 degrees Celsius after 9-months. Additional and detailed stability data can be found in 
the accompanying Quality Overall Summary (QOS) document. 
 Preparation 
 
Because the investigational product is going to be shipped and received in its ready-for-dispensation 
formulation, there will not be any preparation required prior to dispensation. The study drug will be dispensed 
by qualified study personnel.  
 Dosing and Administration 
Participants will self-administer CBD vs Placebo twice daily for a total of 600mg/day CBD vs. Placebo for the 
first four weeks of treatment and 1200mg/day CBD vs. Placebo for weeks 5-8 of treatment. For the first four 
weeks of treatment, participants will self-administer two 200mg capsules every morning following a light meal 
at approximately the same time of day, and an additional single 200mg capsule approximately 12 hours later 
following a light meal. During weeks 5-8 of treatment, participants will self-administer three 200mg capsules 
every morning following a light meal at approximately the same time of day, and an additional three 200mg 
capsules approximately 12 hours later following a light meal.  
 Route of Administration 
CBD will be administered orally in capsules that each contain 200mg CBD vs. Placebo. 
 Starting Dose and Dose Escalation Schedule 
All participants will receive 600mg/day CBD vs. Placebo for weeks 1-4 of treatment, unless contraindicated, 
and will be escalated to 1200mg/day CBD vs. Placebo for weeks 5-8 of treatment, unless contraindicated.  
 Dose Adjustments/Modifications/Delays 
If participants report AEs that are determined by the PI to be treatment-related during administration of study 
medication and are intolerable to the participant or represent a significant risk to the participant, daily 
administration will be reduced by 200-400mg/day every two days until symptoms are resolved or tolerable. 
Dose may be titrated back up toward the full dose by 200 mg/day/week as tolerated. Individuals who cannot 
tolerate the 600mg dose will remain on their maximum tolerable dose during the second 4-week period of the 
study. Treatment will be discontinued immediately if continuing the medication places the participant at 
significant risk in the medical judgement of the PI. 
 Duration of Therapy 
The duration of the active treatment portion of the study is 8 weeks, followed by an additional 4-week follow-
up period. In order for participants to be included in the primary statistical analyses, they must complete the 8-
week treatment phase of the study (through T7).  
7.2 Study Agent Accountability Procedures 
CBD will be stored by the study personnel securely under the PI’s individual schedule 1 DEA registration and 
New York Bureau of Narcotics Enforcement (BNE) class 7 license in accordance with all applicable laws and 
regulations. Additionally, a NYS BNE class 9 importer license and a DEA importer permit will be obtained by 


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the schedule I license and registration holder prior to importation of study drug and study initiation. CBD will be 
stored in a double-locked refrigerator. The refrigerator is located in a designated research room, with limited 
access to the PI and study staff only, within the NYU-HHC CTSI Facility, which is located at 462 1st Avenue, 
27th Street, C-D Building 4th floor, New York, NY 10016. The Primary Investigator will oversee the appropriate 
storage, accountability and dispensing of the study medication and all study drug administration to the patients 
will be done by the PI or treating co-investigators. In order to preserve the blind, medication will be administered 
in identical capsules containing 0 or 200 mg of CBD dissolved in a mixture of self-emulsifying excipients; 
participants will be delivered multiple 200mg capsules/day for a total of 0, 600, or 1200 mg CBD/day. 
 
Study medication will be received under a Schedule 1 import license obtained by the PI and will be logged into 
the approved storage facility upon arrival. Study medication will be re-packaged by unblinded study personnel 
from the original Tilray bottles into blinded and appropriately labeled bottles for dispensation. The re-bottled, 
blinded study medication will then be dispensed to participants under the direct supervision of the PI or a 
designated coinvestigator, as approved by the BNE and DEA. Participants will be required to return all un-used 
medication, which will be kept securely at the drug storage site until it is sent to a reverse distributor for 
destruction. 
 
Designated study personnel will keep a log of the study drug accountability and dispensing in accordance with 
New York State Bureau of Narcotic Enforcement and DEA policies (see below). This process will provide strict 
safeguarding and accounting of the agent both for internal and external regulatory agencies. 
 
As per Schedule I drug compliance, a biennial inventory shall be prepared and maintained in accordance with 
New York State and federal statutes. A copy of the inventory will be kept on file with other controlled substance 
records and shall be kept available for inspection for at least 5 years. The number of study drug-containing 
capsules will be checked on a weekly basis by two designated study staff members and it will be recorded on 
a Controlled Substance Accountability Log which includes the following information: 1) date and time of 
recording, 2) name of controlled substance, 3) amount received (number of capsules), 4) amount dispensed, 
and 5) amount returned. All other information will be included in the Study Drug Dispensation Log as each 
individual subject's dose is dispensed. The information included in the Study Drug Dispensation Log is: 1) 
subject initials/number (plus date of birth as a double identifier), 2) date and time of study drug dispensation, 3) 
drug name, 4) lot number, and 5) dose. Two designated study team members will sign the Study Drug 
Dispensation Log. The balance of the remaining medication and any amount returned will be recorded in the 
Controlled Substance Accountability Log (see above). 
7.3 Study Behavioral or Social Intervention(s) 
All participants will receive Medical Management from a licensed MD or NP listed as study personnel, based 
on the model developed for the NIAAA COMBINE trial [117]. This model provides a low intensity intervention 
that has some efficacy over no intervention, and is designed to enhance compliance in the context of a clinical 
trial. Brief counselling sessions provided by a study clinician focus on: support for recovery, treatment 
participation, reporting possible adverse effects, and medication compliance. The PI has experience adapting 
this model in a prior alcohol pharmacotherapy trial [118]. 
 Administration of Intervention 
CBD (or placebo) will be administered daily for 8 weeks. The first administration of each dose of CBD vs. 
placebo (at T1 and T4) will take place at the study site. Participants will remain at the study site with a study 
team member for approximately 2 hours following the initial administration of each dose of CBD, and 
participants will not be permitted to leave the study site until they are able to pass a standard field sobriety 
test (a walk-and-turn task, one-leg stand, Romberg’s test, finger-finger test, and counting backwards [97]). If 
there are no AEs during this time period or lasting intoxicating effects of the study drug (i.e. participants are 
able to pass field sobriety tests 2-3 hours after study drug administration), participants will be dispensed the 
proper quantity of study drug (CBD or placebo) to self-administer daily at home until the next scheduled study 
visit (i.e. a 1- or 3-week supply, depending on the visit).  


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 Assessment of Subject Compliance with Study Intervention 
To maximize medication compliance, we will implement a smartphone-assisted medication adherence 
platform [119] in which the subject takes a video of drug administration at each dose, and transmits this to 
study personnel. This program has been used successfully in previous studies and includes security 
provisions that ensure protection of confidentiality and privacy. 
 
 
 
 
 
 


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8 Study Procedures and Schedule 
8.1 Study Procedures/Evaluations 
Inclusion/exclusion criteria:  
Medical screening by a licensed NP or MD will include medical history and physical exam, liver function 
tests (LFTs), complete blood count, serum chemistries, urinalysis, serum pregnancy test, and weight. The 
licensed provider will also review participants’ controlled substance prescription history using the online 
Prescription Monitoring Program (PMP) Registry to inform study eligibility. The Structured Clinical Interview 
for DSM-5 (SCID) will be used to determine substance use disorder diagnoses and exclusionary psychiatric 
disorders [120]. Individuals will have the option to be audiotaped during the interview. If a participant voices 
that he/she is uncomfortable with the audiotaped interview, he/she can tell a study team member that he/she 
does not wish to participate in this component of the study. In that case, the participant could still participate 
in the study but would not complete the audiotaped interview.  
 
PhenX Tier 1 measures and a Locator form will completed at screening to collect contact information, 
demographics, BMI, quality of life, HIV risk and status, and substance use measures (age of onset, past 30-
day quantity and frequency, lifetime use for alcohol, tobacco, and other substances; www.phenxtoolkit.org). 
The Clinical Institute Withdrawal Scale- Alcohol, revised (CIWA-Ar) will be used to verify lack of alcohol 
withdrawal [121], a Urine drug screen (UDS) will be done at each in-person study visit to verify lack of recent 
cannabinoid and other drug use, and a Urine pregnancy test will be done at each in-person study visit (for 
women of childbearing potential) to verify lack of pregnancy. History of trauma will be assessed at baseline 
with the Trauma History Questionnaire (THQ) [116].  
 
Confirmation of target CBD levels and determination of other cannabinoid levels:  


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Plasma levels of cannabinoids including CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC and Delta-9 Carboxy 
THC will be obtained at baseline, as well as 45 minutes, 1 day, 1 week and 4 weeks after starting each dose 
of treatment with CBD only. Plasma levels of anandamide will be obtained at the aforementioned timepoints 
after starting each dose of treatment with CBD or placebo. Anandamide and Cannabidiol will be analyzed 
by LC/MS/SIM. Other analytes by Capillary GC/MS/SIM/NCI in one column. Both systems using deuterated 
analytes as internal standards i.e. isotope dilution procedure. These analyses will be performed at the 
Nathan Kline Institute (NKI). 
 
Safety:  
Safety will be assessed by collection of adverse events using the Systemic Assessment for Treatment of 
Emergent Events (SAFTEE) [124] measure at all visits after treatment is initiated. LFTs will be obtained at 
screening, as well as weeks 4, 8, and 9 to assess the liver function during and after treatment with study 
medication. Risk of suicidality will be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
[111] by a licensed psychologist, NP or MD as part of each study visit (except for the 1-day/T2 and 4 weeks+1-
day/T5 visits), including screening and baseline.  
  
Release of Health Information  
The Authorization for Release of Study Information form permits research staff to communicate to listed family 
members designated by the participant until their participation in the study has ended. The Authorization of 
Release form will only release research related data. Patient's request to have family members notified of 
specified study related information may be useful for a variety of occasions. For example, designated family 
could be notified of medication related information or laboratory blood results if the participant requests such 
information to be shared to their designated family member. The visit schedule and medication compliance 
aspects of the study may be easier to navigate if unexpected situations occur, such as abnormal lab results or 
missed visits to pick up study medication. Hence, participants may like to have designated family members 
involved. The study related health information that is reported on the Authorization of Release form to be 
discussed with designated family members is the only information that study team members will be allowed to 
discuss or share. Study team members that will communicate with participant family members include the study 
coordinator, PI, and NP. Communication with family members will happen via phone call and email 
correspondence. Release of health information and study information will be done in a manner that does not 
un-blind participants, study staff, or designated family members. Information will be released to ensure subject 
confidentiality. The Authorization of Release form allows study participant’s to specify health information from 
the study that will be released to their designated family member. Other study related information that is not 
designated on the release form will not be released to their designated family member. The Authorization of 
Release form will be kept and filed with the Informed Consent forms in the ICF Study binder for CBD-AUD. In 
addition, a study participant log will be kept and updated accordingly to keep track of participants who have 
submitted this form. 
 
Psychomotor and subjective effects of CBD:  
Basic motoric and cognitive function will be evaluated throughout treatment with several established field 
sobriety tests, including a walk-and-turn task, one-leg stand, Romberg’s test, finger-finger test, and counting 
backwards [97]. The Addiction Resource Center Inventory (ARCI), 49-item version [98], will be used as a 
measure of the intoxicating effects and abuse potential of CBD. Breath Alcohol Concentration (BAC) will 
also be measured to ensure participants are not under the influence of alcohol during administration of these 
tasks. 
 
Cognitive Function:  
Several established neuropsychiatric and cognitive tasks will be administered to evaluate the impact of CBD 
vs. placebo treatment on cognitive domains potentially affected by CBD and/or THC. The Rey Auditory 
Verbal Learning Task (RAVLT) will be used to assess episodic memory [99, 100], the Mental Rotation Task 
(MRT) will evaluate visuospatial ability [101, 102], a Time Reproduction Task (TRT) will measure encoding 
and retrieval of time intervals [88], and several WM Span tasks (OSpan, RSpan, SymSpan, RotSpan) will 
measure working memory capacity [103, 104].  
 


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AUD-related domains:  
The Penn Alcohol Craving Scale (PACS) [105] will be used to assess craving. This scale has 5 Likert-scaled 
items with excellent internal consistency and evidence of predictive, construct, and discriminant validity. 
Mood and Anxiety will be measured with the Beck Anxiety Inventory (BAI) [122] and Beck Depression 
Inventory-II (BDI-II) [107] before CBD treatment, 1, 4, 5, and 8 weeks into treatment, and at the end of 
treatment. Self-efficacy will be assessed using the Alcohol Abstinence Self-Efficacy Scale (AASE) [108], a 
self-report questionnaire which has been used widely in the alcohol treatment research, both as a predictor 
of outcome and as a patient-treatment matching variable [109, 110].  
 
The Cue and Stress Response Task will be performed at the 5- week time-point using methodology developed 
in Rajita Sinha’s lab, similar to those in used in past studies with alcohol dependent patients [112, 113]. Dr. 
Sinha will provide consultation on the implementation of these methods. Briefly, imagery scripts will be 
developed at baseline and again following 4 weeks of treatment. Stress imagery scripts will be based on a 
recent highly stressful situation the participant has experienced unrelated to alcohol use. Alcohol cue scripts 
will be derived from a recent event that included alcohol-related stimuli and led to alcohol use. Neutral or 
relaxing scripts will also be developed. All scripts will be developed by obtaining specific details of stimulus and 
response, including contextual details, cognitive and verbal content, affective experience, and bodily 
sensations. These details form the basis of a 5-minute imagery script, which will be developed for each of the 
three conditions. Imagery sessions will be structured with a 5-minute pre-imagery period, a 5-minute imagery 
period, and a 5-minute recovery period. Pulse, skin conductance, heart rate variability, and blood pressure will 
be monitored during each imagery session with an ADInstruments PowerLab 4/30 Galvanic Skin Response 
device and a Contec Patient Monitor. In Human laboratory studies with CBD, skin conductance and amygdala 
activation were reduced by CBD in a closely correlated manner [59], suggesting threat-related sympathetic 
arousal may serve as a proxy for amygdala activation [114]. Participants will complete Likert scale ratings of 
vividness, craving, anxiety, and the 30-item Differential Emotion Scale [112, 113] following each of the three 
periods. After each condition, a progressive relaxation procedure will be implemented to facilitate return to 
baseline of vital signs, craving and anxiety, an approximate period of 10 minutes, as shown in previous research 
from the Sinha lab [112, 113]. The entire imagery protocol will take 120 minutes. The order of the sessions will 
be randomized and counterbalanced among participants. This task will be completed at 5 weeks, i.e. after 1 
week of treatment at 1200mg daily. At this point, we expect steady-state circulating CBD levels to have been 
reached. It is important to assess stress- and cue- response at the high dose because it is possible that 
anxiolytic effects decrease at high doses of CBD, while effects on alcohol consumption are expected to increase 
with dose.  
 
Alcohol use:  
Alcohol consumption will be assessed with Time-line Follow-back (TLFB) [115] and percent carbohydrate-
deficient transferrin (CDT) in serum. 
8.2 Laboratory Procedures/Evaluations 
Plasma will be collected at baseline, as well as 45 minutes, 1 day, 1 week and 4 weeks after starting each 
dose of treatment with CBD or placebo for measurement of circulating cannabinoid levels. Serum will be 
collected at baseline, at 4 weeks, and at 8 weeks for measurement of CDT. 
 Specimen Preparation, Handling, and Storage 
Blood will be drawn at several time points to establish 45 minutes post- and pre-CBD dosing levels of CBD, 
according to the study’s SOP. Briefly, we will measure circulating cannabinoid levels at 45 minutes, 1 day, 1 
week and 4 weeks after treatment with each dose of CBD. Plasma (1ml/sample) will be stored at -20 °C for no 
longer than 6 months, and will be labeled with study number, participant number, and timepoint. Plasma CBD 
levels will be determined via High Performance Liquid Chromatography/Tandem Mass Spectrometry (LC-
MS/MS) by the Nathan Kline Institute (NKI).  
 Specimen Shipment 
Specimens will be shipped monthly on dry ice with appropriate labeling for shipment of biological specimens 
on dry ice, according to the study’s SOP. A specimen tracking log will be utilized to record dates and times 


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that each specimen was collected and shipped. Specimens may be shipped overnight between 9:00am and 
5:00pm on business days except Fridays.  
8.3 Study Schedule 
Procedures for minimizing COVID-19 risk among participants and study team members during required in-
person visits (including routine temperature checks, use of personal protective equipment, symptom checks, 
etc.) are outlined in the COVID Safety Procedures SOP (R:\etc-research-01\CBD-Alcohol\1. CBD-AUD\SOPs 
(Standard Operating Procedure)\ SOP_17-01001_COVIDSafety_Procedures_07.20.2020.docx). 
 Screening  
Option 1: In-person Screening Visit (T0) 
• 
Obtain informed consent of potential participant verified by signature on written informed consent for 
screening form. 
• 
Review medical and psychiatric history to determine eligibility based on inclusion/exclusion criteria. 
• 
Review concurrent medications to determine eligibility based on inclusion/exclusion criteria. 
• 
Perform medical examinations needed to determine eligibility based on inclusion/exclusion criteria. 
• 
Obtain demographic information, alcohol, drug, and tobacco use history 
• 
Collect urine for urine drug analysis, urinalysis, urine pregnancy test 
• 
Collect blood for LFTs, complete blood count, serum chemistries, serum pregnancy test 
Schedule study visits for participants who are eligible and available for the duration of the study 
Option 2: Two-part Remote and In-person Screening Visit (T0a/b) 
Part a: Remote Screening 
• 
Obtain informed consent of potential participant verified by signature on written informed consent for 
screening form. 
• 
Review medical and psychiatric history to determine eligibility based on inclusion/exclusion criteria. 
• 
Review concurrent medications to determine eligibility based on inclusion/exclusion criteria. 
• 
Obtain demographic information, alcohol, drug, and tobacco use history 
• 
test 
Part a: In-person Screening 
• 
Perform medical examinations needed to determine eligibility based on inclusion/exclusion criteria. 
• 
Collect urine for urine drug analysis, urinalysis, urine pregnancy test 
• 
Collect blood for LFTs, complete blood count, serum chemistries, serum pregnancy  
• 
Schedule study visits for participants who are eligible and available for the duration of the study  
 
 Enrollment/Baseline 
Enrollment/Baseline Visit (T1) 
• 
Collect urine for urine drug analysis and urine pregnancy test 
• 
Record vital signs, results of examinations, other assessments 
• 
Record results of evaluations of safety, psychomotor effects and AUD-related domains 
• 
Collect blood for CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC and 
Anandamide levels (pre-CBD levels, before dosing, and post-CBD levels, 45 minutes after dosing) 
• 
Collect blood for CDT (carbohydrate deficient transferrin) levels 
• 
Administer the study treatment 
• 
Record adverse events as reported by participant or observed by investigator 
• 
Provide participants with sufficient study medication to administer daily until the next scheduled visit, 
and instructions for how to use the study medication and document their use 
 Intermediate Visits 
8.3.3.1 
Visit 2 
1 day (T2)  


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• 
Collect blood for CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC and 
Anandamide levels (45 minutes post-CBD levels) 
• 
Record adverse events as reported by participant or observed by the coordinator 
• 
Record vital signs, results of evaluations of safety, and psychomotor effects 
8.3.3.2 
Visit 3 
1 week (T3)  
• 
Collect urine for urine drug analysis and urine pregnancy test 
• 
Collect blood for CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC and 
Anandamide levels (pre-CBD and 45 minutes post-CBD levels) 
• 
Record adverse events as reported by participant or observed by investigator 
• 
Record vital signs, results of evaluations of safety, psychomotor/subjective effects, cognitive function, 
AUD-related domains and drinking 
• 
Provide additional medication to the participant according to the study’s MOP requirements 
• 
Record participant’s adherence to treatment program 
8.3.3.3 
Visit 4 
4 weeks (T4)  
• 
Collect urine for urine drug analysis and urine pregnancy test 
• 
Collect blood for CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC and 
Anandamide levels (pre-CBD and 45 minutes post-CBD levels), LFTs 
• 
Collect blood for CDT levels 
• 
Record adverse events as reported by participant or observed by investigator 
• 
Record vital signs, results of evaluations of safety, psychomotor/subjective effects, AUD-related 
domains, and drinking 
• 
Provide additional medication to the participant according to the study’s MOP requirements 
• 
Record participant’s adherence to treatment program 
8.3.3.4 
Visit 5 
4 weeks + 1 day (T5)  
• 
Collect blood for CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC and 
Anandamide levels (45 minutes post-CBD levels) 
• 
Record adverse events as reported by participant or observed by coordinator 
• 
Record vital signs, results of evaluations of safety, psychomotor/subjective effects 
8.3.3.5 
Visit 6 
5 weeks (T6)  
• 
Collect urine for urine drug analysis and urine pregnancy test 
• 
Collect blood for CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC and 
Anandamide levels (pre-CBD and 45 minutes post-CBD levels) 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, results of evaluations of safety, psychomotor/subjective effects, cognitive function, 
AUD-related domains, cue/stress response task, and drinking 
• 
Provide additional medication to the participant according to the study’s MOP requirements 
• 
Record participant’s adherence to treatment program 
8.3.3.6 
Visit 7 
8 weeks (T7)  
• 
Collect urine for urine drug analysis and urine pregnancy test 
• 
Collect blood for CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC and 
Anandamide levels (pre-CBD and 45 minutes post-CBD levels), LFTs 
• 
Collect blood for CDT levels 
• 
Record adverse events as reported by participant or observed by investigator 


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• 
Record vital signs, results of evaluations of safety, psychomotor/subjective effects, AUD-related 
domains, and drinking 
• 
Provide additional medication to the participant according to the study’s MOP requirements 
• 
Record participant’s adherence to treatment program 
8.3.3.7 
Visit 8 
9 weeks (T8)  
• 
Collect urine for urine drug analysis and urine pregnancy test 
• 
Collect blood for CBD, Delta-9 THC, 11-Hydroxy Delta-9 THC, Delta-9 Carboxy THC and 
Anandamide levels (pre-CBD levels), LFTs 
• 
Record adverse events as reported by participant or observed by coordinator 
• 
Record vital signs, results of evaluations of safety, psychomotor/subjective effects, AUD-related 
domains, and drinking 
 Final Telephone Follow-Up 
12 weeks (T9)  
• 
Record adverse events as reported by participant  
• 
Record drinking 
 Unscheduled Visit 
Unscheduled visits will be documented on an unscheduled visit form. 
 
8.4 Concomitant Medications, Treatments, and Procedures 
All concomitant prescription medications taken during study participation will be recorded on the case report 
forms (CRFs). 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 CRF are concomitant 
prescription medications, over-the-counter medications and non-prescription medications. 
8.5 Prohibited Medications, Treatments, and Procedures 
Treatment with medications including cannabinoids; treatments for addictions including alcohol; moderate to 
strong inhibitors of CYP3A4 or CYP2C19; medications metabolized primarily by CYP3A4, CYP3A5, or 
CYP3A7: and medications with a narrow therapeutic index which are substrates of UGT1A9, UGT2B7, 
CYP2C8, CYP2C9, CYP2C19, CYP1A2, or CYP2B6 will not be permitted unless discussed with and 
approved by the PI. 
9 Definitions of Key Terms 
An adverse event (AE; also referred to as an adverse experience) is any untoward medical occurrence 
associated with the use of a drug (pharmaceutical investigational product) in humans, which does not 
necessarily have a causal relationship with that treatment. An AE can therefore be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding or test result), symptom, disease, accident, or 
worsening (increase in severity or frequency) of a pre-existing abnormality, temporally associated with the use 
of the drug, whether or not considered related to the drug. An AE can arise from any use of the drug (e.g., off-
label use, use in combination with another drug and from any route of administration, formulation, or dose, 
including overdose). 
A serious adverse event (SAE) is an adverse drug or biologic or device experience occurring during any study 
phase (i.e., screening, admission, treatment, or follow-up), and at any dose of the study drug, comparator or 
placebo, that results in one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening*  
• 
Requires in-patient hospitalization (i.e., admission) or prolongation of existing hospitalization 


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• 
Results in persistent or significant disability** or incapacity 
• 
Is a congenital abnormality or birth defect (in an offspring) 
• 
Is an important medical event that may not result in death, be life-threatening, or require or prolong 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the 
event may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of important medical events include events requiring intensive 
treatment in an emergency department, convulsions that do not require in-patient hospitalization, or 
the development of drug dependency or drug abuse (see Section 8, Other Significant Adverse 
Events). 
*Life-threatening: Any AE that places the subject, in the view of the investigator, at immediate risk of death 
from the reaction as it occurred; it does not include a reaction that, had it occurred in a more severe form, 
might have caused death. 
**Disability: A substantial disruption of a person’s ability to conduct normal life functions. 
10 Specification of Safety Variables 
Safety and toxicity monitoring will be performed throughout the study for all subjects. Safety variables to be 
assessed include AEs, vital signs, and safety laboratory values, when collected.  
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. At each study 
visit following screening, designated study team members will inquire about the occurrence of AE/SAEs since 
the last visit.  
11 General Guidelines 
All AEs, regardless of causality or severity, must be immediately recorded on the AE CRF when volunteered 
by the subject or solicited through a study assessment questionnaire. The CRC will record all AEs, regardless 
of causality or severity, with start dates occurring any time after informed consent is obtained until 7 (for AEs) 
or 30 (for SAEs) days after the last day of study participation on the AE case report forms (CRF). Information 
to be collected includes event description, time of onset, clinician’s assessment of severity, relationship to 
study product (assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event.  
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.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. AEs characterized as intermittent require documentation of onset and 
duration of each episode. 
At the last scheduled visit, the CRC should instruct each subject to report any subsequent event(s) that the 
subject, or the subject’s personal physician, believes might reasonably be related to participation in this study.   
11.1 Solicitation of AEs 
At all follow-up visits occurring after study medication has been administered, the SAFTEE questionnaire 
[124] will be used to assess AEs through the following three prompts: 
“Have you had any physical or health problems since our last visit?” 
“Have you noticed any changes in your physical appearance since our last visit?” 
“Have you cut down on the things you usually do because of not feeling well physically since our last 
visit?” 
If the subject responds “yes” to any of these questions then the following question will be asked: 


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“Could you describe in more detail what this effect means to you?”  
The presence or absence of specific AEs should not be solicited from subjects. 
11.2 Preplanned Hospitalization or Procedure 
During the study, if a subject has a hospitalization or procedure (e.g., elective surgery) that was due to a 
preexisting condition that has not worsened since enrollment in the study (i.e., since the subject [or the 
subject’s legal representation] signed the informed consent), the hospitalization or procedure is considered a 
therapeutic intervention and not the results of an AE. However, if the event/condition worsens during the 
study, it must be reported as an AE (or SAE, if the event/condition results in a serious outcome, such as 
hospitalization). 
11.3 Reports of Cancer 
Cancer is no longer considered an FDA criterion for an SAE (unless an event occurs with a serious outcome). 
If a new diagnosis of cancer has a serious outcome, then the reporting time frame for an SAE (48 hours) must 
be met. Progression of disease is not considered new cancer and is therefore not an AE. 
11.4 Specific guidelines for assessing laboratory values as adverse events 
Any laboratory abnormality, including leukopenia, absolute neutropenia, or thrombocytopenia, will not be 
considered an AE unless this abnormal laboratory value results in clinical sequelae, such as infection, 
bleeding, or an intervention. If an abnormal laboratory value results in a clinical event, then the clinical event, 
not the abnormal laboratory value, must be recorded as an AE. The clinical event must be reviewed to 
determine if it meets the criteria for an SAE. 
12 Assessment of Adverse Events 
The following definitions, developed in accordance with the US Code of Federal Regulations (CFR) and the 
International Committee on Harmonization (ICH), will be used for the purpose of identifying AEs in this clinical 
study. 
12.1 Expectedness 
Unexpected: An AE is considered unexpected if it is not listed in the Investigator Brochure (IB) or is not 
listed at the specificity or severity that has been observed, or not previously observed in animal toxicity 
studies for psilocybin. Unexpected also refers to AEs that are mentioned in the IB as occurring with a class 
of drugs or as anticipated from the pharmacologic properties of the drug, but are not specifically mentioned 
as occurring with psilocybin.  
12.2 Severity 
The determination of severity must be made with the appropriate involvement of a medically qualified 
investigator. The investigator will evaluate the severity of each AE using the following three terms and 
definitions: 
Minimal: single occurrence that is not distressing and does not limit activities 
Mild: multiple occurrences, awareness of sign or symptom but easily tolerated, usually does not require 
intervention or limit activities 
Moderate: discomfort sufficient to cause interference with normal activities; intervention may be needed 
Severe: incapacitating, with inability to perform normal activities; treatment or other intervention usually 
needed 
12.3 Relatedness 
This category provides the opportunity to indicate the reasons for suspecting a drug-related effect. If no such 
effect is suspected, check “No.” The following reasons for possible relationship to drug are to be assessed by 
the medically qualified investigator. 


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Dose-response: indicates that the intensity of the event is related to the dosage level.  
Timing of onset: is used if the onset of the event has some regular relationships to drug administration (e.g., 
it always occurs 1 hour after taking the drug). 
Known drug effect: is another reason for suspecting a drug relationship. 
The relationship of each AE to study drug will be assessed using the following terms and definitions: 
Probable (must have first two): This category applies to AEs that are considered, with a high degree of 
certainty, to be related to the study drug. An AE may be considered probable, if: 
• 
It follows a reasonable temporal sequence from administration of the drug. 
• 
It cannot be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the subject. 
• 
It follows a known pattern of response to the suspected drug. 
Possible: This category applies to those AEs in which the connection with the study drug administration is 
possible. An AE may be considered possible if, or when, any of the above reasons have been selected.  
Unrelated: This category is applicable to those AEs that are judged to be due only to extraneous causes (e.g., 
disease, environment, etc.) and do not meet any of the criteria for a possible drug relationship. 
The determination of the relationship of the AE to the use of the study drug(s) rests on careful medical 
consideration of the PI.  
13 Monitoring Adverse Events 
The investigator will follow all AEs until the event is resolved, stabilized, or the subject is lost to follow-up. 
Relevant clinical assessments and laboratory tests may be performed as determined by the PI or a qualified 
designee, appropriate medical intervention should be provided and, if necessary, the subject may be 
excluded from additional treatment with the study drug. 
Any actions taken and follow-up results must be recorded on the appropriate page of the CRF and in the 
subject’s source documentation. Follow-up laboratory results should be filed with the subject’s source 
documentation. 
For all AEs that require the subject to be discontinued from the study, relevant clinical assessments and 
laboratory tests will be repeated as clinically appropriate, until final resolution or stabilization of the event(s). 
14 Known Potential Toxicities of Study Drug 
Overall, no preclinical results have been identified that preclude the development of cannabidiol for the 
treatment of alcohol use disorder, or suggest that serious AEs are likely in clinical studies. Refer to the IB for 
toxicology findings and information on AEs observed to date.  
15 Other Significant Adverse Events 
Should any AE occur that is considered significant, but does not meet the criteria for an SAE, the CRC and PI 
should be notified immediately. 
16 Reporting Procedures  
16.1 AE Reporting  
To the FDA: In accordance with FDA reporting requirements, all AEs occurring during the course of the 
clinical trial will be collected, documented, and reported by the PI or IND Sponsor. On an annual basis, as 
part of the update to the study IND, the IND Sponsor will submit to the FDA:  


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• 
A list of all AEs that have occurred during the reporting period 
• 
A summary of all IND safety reports submitted during the past year 
• 
A list of all subjects who died during the participation in the investigation, listing cause of death for 
each,  
• 
And a list of subjects who dropped out during the course of the investigation in association with any 
adverse experience, whether or not thought to be drug related. 
To the IRB: In accordance with local IRB requirements, all AEs occurring during the course of the clinical trial 
regardless of relationship to study activities will be collected, documented, and reported by the PI or designee 
to the IRB on an annual basis in the application for the study’s continuation renewal. Staff education, re-
training or appropriate corrective action plan will be implemented when unreported or unidentified AEs or 
SAEs are discovered, to ensure future identification and timely reporting.  
To the DSMB: All AEs occurring during the course of the clinical trial regardless of relationship to study 
activities will be reported to the DSMB at regular meetings. Prior to each DSMB meeting, the PI will prepare a 
report to the Board including review of aggregate analysis of AEs and SAEs. 
Following each meeting, the board will provide the PI with a report including a recommendation to continue 
the study unchanged, continue with modifications of the protocol and/or the consent form to protect participant 
safety, or terminate the study. This report will then be submitted to the FDA as part of the annual report to the 
study IND, and the IRB in the application for the study’s annual continuation renewal.  
To the Study Sponsors:  
Tilray 
The PI shall promptly inform Tilray of any significant safety issues occurring during the course of the study 
that might affect the performance of the study and of any AEs and SAEs experienced by subjects during the 
study. The PI shall share with Tilray any associated CRFs and source data, safety reports related to such AEs 
and SAEs, and permit access to anonymized pharmacokinetic data of study subjects. 
PI shall provide all reports issued by the DSMB according to protocol (e.g. annually for the duration of the 
trial, including following completion of treatment for the first 5 completers, after completion of treatment for the 
first 20 completers, and upon completion of enrollment for the trial).  
NIH/NIAAA 
All AEs occurring during the course of the clinical trial regardless of relationship to study activities will be 
collected, documented, and reported by the PI or designee to NIH/NIAAA on an annual basis in the annual 
Research Performance Progress Report (RPPR). 
16.2 SAE Reporting 
SAEs will be promptly reported to the CRC and PI. The PI or qualified designee will distinguish Serious 
Adverse Events (SAEs) from Adverse Events (AEs). The details of the event will be documented and reported 
as follows: 
To the FDA: The PI is required to report certain study events in an expedited fashion to the FDA. These 
written notifications of AEs are referred to as IND/IDE safety reports.  
The following describes the IND safety reporting requirements by timeline for reporting and associated type of 
event: 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected, and 
– fatal or life-threatening 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 


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– serious, but not fatal or life-threatening 
-or- 
– a previous AE that was not initially deemed reportable but is later found to fit the criteria for 
reporting (reporting within 15 calendar days from when event was deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
Each written notification must be submitted on an FDA Form 3500A. The PI is also required to identify in IND 
safety reports all previous reports concerning similar AEs and to analyze the significance of the current event 
in light of the previous reports. 
To the IRB: The IRB Chair or Administrator will be notified immediately for SAEs that are at least possibly 
related to study participation only. If the IRB administrator determines that reporting of the incident/issue is 
required, it will be submitted to the IRB within 48 hours of the IRB direction/response.  
The team will also submit summary information related to all SAEs, AEs, and UPs in the annual application 
for continuation to the IRB. 
To the Study Sponsors:  
NIH/NIAAA 
SAEs considered at least possibly related to study participation will be documented and reported to NIAAA 
within 48 hours with copies included in the participant’s file. 
Tilray 
If an SAE occurs after the subject signs informed consent through the end of study participation, the PI or a 
qualified designee will complete the Tilray SAE Form and send it via email to contacts designated by Tilray 
within 24 hours of the site becoming aware of the SAE. The form must be completed and submitted to Tilray 
any time a serious medical event has occurred in a participant during the clinical trial, whether or not it is 
considered related to the study treatment, including active comparators and placebo. 
Ensure that an investigator has reviewed and signed the SAE form prior to submission. 
Every exposure during pregnancy (participant) should be reported on an SAE worksheet as a case of special 
interest from the time of study enrolment to the end of study participation. 
The following timelines describe when Tilray, as the manufacturer of IP, has to report ADRs to Health 
Canada: 
• 
Fatal or life-threatening unexpected ADRs require notification of regulatory agencies as soon as 
possible but no later than 7 calendar days after first knowledge by Tilray that a case qualifies, 
followed by as complete a report as possible within 8 additional calendar days. The report will include 
an assessment of the importance and implication of the findings, including relevant previous 
experience with the same or similar medicinal products. 
• 
All other serious, unexpected ADRs must be filed as soon as possible but no later than 15 calendar 
days after first knowledge by Tilray that the case meets minimum criteria for expedited reporting. 
16.3 UP Reporting 
Incidents or events that meet the OHRP criteria for UPs involving risks to subjects or others require 
notification of the local IRB. The phrase “unanticipated problems involving risks to subjects or others” is found 
but not defined in the HHS regulations at 45 CFR part 46. Any incident, experience, or outcome that 
meets all of the following criteria is considered to be Reportable New Information (RNI) and is required to be 
promptly reported to the local IRB: 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied; 


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related or possibly related to participation in the research (in this guidance document, possibly 
related means that, in the opinion of the PI, the incident, experience, or outcome was more likely than 
not caused by procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
OHRP recognizes that it may be difficult to determine whether a particular incident, experience, or outcome is 
unexpected and whether it is related or possibly related to participation in the research. OHRP notes that an 
incident, experience, or outcome that meets the three criteria above generally will warrant consideration of 
substantive changes in the research protocol or informed consent process/document or other corrective 
actions in order to protect the safety, welfare, or rights of subjects or others.  
The RNI report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
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 response to the UP. 
UPs must be reported using the following timeline: 
• 
UPs that are SAEs will be reported to the IRB and to the study sponsor according to SAE reporting 
procedures described above (within 48 hours of the investigator becoming aware of the event). 
• 
UPs that meet the requirements for RNI will be reported to the IRB as soon as possible and within 5 
working days of the site becoming aware of the event. 
• 
All other UPs not related to study activities or that do not result in harm to participants will be reported 
to the IRB annually in the application for the study’s continuation renewal.  
16.4 Pregnancy Reporting 
Pregnancy information on clinical study subjects is collected by the investigator. If a subject should become 
pregnant during the course of the study, the investigator or qualified designee will contact the IRB within 5 
working days of the PI or qualified designee first becoming aware of the pregnancy.  
Tilray Pregnancy Reporting Requirements: Every exposure during pregnancy (participant) should be reported 
on a Tilray SAE worksheet within 24 hours of the site becoming aware of the pregnancy as a case of special 
interest from the time of study enrollment to the end of study participation. If an SAE occurs in conjunction 
with the pregnancy, then the Tilray reporting timeframe for an SAE (24 hours) must be met. In the event of a 
pregnancy, administration of study medication will be discontinued, but all other follow-up data, including 
safety data, will be collected. 
Pregnancies resulting in congenital abnormalities or birth defects in offspring meet the requirements for an 
SAE and will be collected, documented, and reported according to the procedures outlined above for SAEs. 
17 Reporting of Investigational Medicinal Product Quality Complaints 
17.1 Defect or Possible Defect in the IP 
Any defect or possible defect in the investigational medicinal product (defined as a pharmaceutical form of an 
active substance or placebo being tested or used as a reference in a clinical trial) must be reported by the PI 
or qualified designee to Tilray within 48 hours of first becoming aware of the possible defect. This report to 
Tilray may be made by telephone or by email. The product and packaging components in question, if 
available, must be stored in a secure area under specific storage conditions until it is determined whether the 
product is required to be returned for investigation of the defect. If the product complaint is associated with an 
SAE, the SAE must be reported separately in accordance with the protocol, and the SAE report should 
mention the product quality complaint. 


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17.2 Temperature Deviations 
In the event that the temperature at which the IP is stored is less than 2°C or greater than 8°C, the CRC and 
PI will be notified immediately and a temperature deviation form will be completed and sent via email to 
contacts designated by Tilray as soon as possible. Tilray will provide further guidance on how to proceed on a 
case-by-case basis. 
18 Study Halting Rules 
When three severe AEs are determined to be “probably related” to the study agent, the DSMB will be 
informed and asked to convene in order to determine whether action should be taken. The Principal 
Investigator will inform the DSMB members within 24 hours of this occurrence and will provide the DSMB 
with AE listing reports. The DSMB will convene an ad hoc meeting by teleconference or in writing as soon 
as possible. The DSMB will provide recommendations for proceeding with the study to the Principal 
Investigator. The Principal Investigator will inform the FDA of the DSMB’s decision and the disposition of 
the study. If the DSMB finds it is likely that CBD is contributing to negative outcomes, they will consider 
solutions including protocol changes or potentially stopping the study. 
19 Safety Oversight 
Medical and Safety Monitoring 
The research team (project manager, coordinators, and research assistants) will submit any adverse events 
to the PI. The PI is responsible for reviewing all AEs and serious adverse events (SAEs) reported. All SAEs 
will be reviewed at the time they are reported in the electronic data capture system. All AEs will be reviewed 
on a weekly basis to observe trends or unusual events. 
 
The PI will generate and present reports for Data Safety Monitoring Board (DSMB) meetings. The DSMB will 
receive listings of AEs and summary reports of all SAEs at a frequency requested by the DSMB, but at least 
annually.  Furthermore, the DSMB will be informed of expedited reports of SAEs. 
 
Data and Safety Monitoring Board (DSMB) 
A Data and Safety Monitoring Board (DSMB) will be established, comprising three individuals appointed by 
the PI. The members of the DSMB will have the following backgrounds/expertise: one member with expertise 
in clinical trials for alcohol use disorder, one member with expertise in clinical trials involving pharmacological 
interventions, one member with expertise in clinical trials for mood disorders, and one member with expertise 
in clinical trials for anxiety disorders. This committee will meet (in person or by teleconference) prior to 
enrollment of the first participant, and at least annually thereafter, including meetings following completion of 
treatment of the first 5 completers, after completion of treatment of the first 20 completers, and upon 
completion of enrollment for the trial. Prior to each meeting, the PI will prepare a report to the Board including 
review of: 
 
• 
Protocol and ICF changes 
• 
Protocol violations and deviations 
• 
Documentation of informed consent  
• 
Enrollment and retention 
• 
Investigator or key personnel changes 
• 
Aggregate analysis of adverse events/serious adverse events 
• 
Protection of confidentiality 
 
Following each meeting, the board will provide the PI with a report including a recommendation to continue 
the study unchanged, continue with modifications of the protocol and/or the consent form to protect participant 
safety, or terminate the study. 
20 Clinical Monitoring 
Site staff will be required to audit source documentation, including informed consent forms and HIPAA forms, 
regulatory documents and case report forms on a biannual basis. Site staff will be responsible for local quality 


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assurance and will verify that study procedures are properly followed and that site staff are trained and able to 
conduct the protocol appropriately. If the site staff’s review of study documentation indicates that additional 
training of study personnel is needed, this will be arranged as per the PI. Study team members will review 
each other’s data for completeness, accuracy, and fidelity to the protocol. 
21 Statistical Considerations 
21.1 Statistical and Analytical Plans (SAP) 
A formal SAP will be developed prior to database lock and unblinding.  
21.2 Statistical Hypotheses 
Hypothesis 1a: Within-group circulating CBD levels will stabilize within one week, i.e. pre-CBD dosing (12 
hour) levels obtained after 1 week of treatment will not differ from those obtained after 4 weeks of treatment at 
each dose.  
Hypothesis 1b: Circulating CBD levels obtained at the 1200 mg/day dose will be comparable to those 
associated with anti-additive effects in animal models, i.e., in the range of 200-400 ng/ml. 
Hypothesis 1c: No clinically significant cognitive or motoric impairments, CBD-related serious adverse events, 
or persisting adverse effects will be observed. 
Hypothesis 2a: Relative to placebo, CBD will improve self-report measures of craving, anxiety, mood, and 
self-efficacy. 
Hypothesis 2b: Relative to placebo, CBD will be associated with decreased stress- and alcohol cue-induced 
craving and physiological stress response 
Hypothesis E: Relative to the placebo-treated group, CBD-treated participants will have fewer heavy drinking 
days during and for four weeks after treatment with 1200mg/day CBD vs. placebo. 
21.3 Description of Statistical Methods 
 General Approach 
The distributional characteristics of the measures used to investigate the aims of the study will be assessed 
and data transformations will be explored if necessary. For all hypotheses, linear mixed effects models will be 
constructed including treatment group as a fixed between-subjects factor, time (T0-T9) as a fixed within-
subjects factor, and subject as a random effect. Treatment groups will also be compared on baseline 
measures of alcohol consumption (% drinking days and % heavy drinking days), alcohol craving (PACS), 
anxiety (BAI), mood (BDI-II), and self-efficacy (AASE), and baseline scores on these measures will be utilized 
as covariates for hypothesis evaluation. 
 Analysis of the Primary Endpoint(s) 
For Hypothesis 1a, acute circulating levels of CBD will be assessed in CBD-treated participants 45 minutes 
after initial administration (T1, T4), and 45 minutes after administration of the morning dose of medication 
following 1 day (T2, T5), 1 week (T3, T6), and 4 weeks (T4, T7) of treatment with each dose of CBD. 
Additionally, circulating levels of CBD will be assessed in CBD-treated participants 12 hours after ingestion of 
the preceding evening dose following 1 week (T3, T6) and 4 weeks (T4, T7) of administration of each dose of 
CBD. Levels of CBD (mean and standard deviation) will be reported at each timepoint and effects of dose and 
timepoint will be evaluated. For Hypothesis 1b, circulating CBD levels (mean and standard deviation) 45 
minutes after administration of the morning dose of medication following 1 week (T3, T6) and 4 weeks (T4, 
T7) of treatment with each dose of CBD will be reported in CBD-treated participants. For Hypothesis 1c, 
between-group differences on psychomotor tasks (T1-T8), cognitive measures (T3, T6) and number of 
adverse events (T1-T9) will be assessed. 
 Analysis of the Secondary Endpoint(s) 
For Hypothesis 2a, between- and within- group differences on measures of craving, anxiety, depression, and 
self-efficacy (T1, T3, T4, T6, T7, T8) will be evaluated. For Hypothesis 2b, linear mixed effects models will be 
constructed as described by Sinha et al. [123] with treatment group (CBD vs. placebo) included as a fixed 


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between-subjects factor, time (nested factor including pre-imagery, imagery, and recovery periods at both T3 
and T6) and script type (stress, alcohol cue, neutral) as fixed within-subjects factors, with subject as a random 
effect. Between- and within- group comparisons and interactions for measures of craving, anxiety, and 
physiological stress response will be assessed. 
 Safety Analyses 
Means and standard deviations of acute circulating CBD and THC levels within CBD-treated participants 45 
minutes after initial administration (T1, T4), and 45 minutes after administration of the morning dose of 
medication following 1 day (T2, T5), 1 week (T3, T6), and 4 weeks (T4, T7) of treatment with each dose of 
CBD will be assessed to determine whether target circulating levels of CBD have been achieved, and whether 
metabolic transformation of CBD to THC has occurred.  
Means and standard deviations of change in 12 hour circulating CBD levels from 1 week to 4 weeks of 
treatment (T3 to T4, and T6 to T7) within CBD-treated participants will be presented to determine whether 
extended treatment with CBD results in accumulation of CBD.  
The number of participants within each treatment group that were able to pass a battery of psychomotor field 
sobriety tasks (walk-and-turn task, one-leg stand, Romberg’s test, finger-finger test, and counting backwards  
[97]) within 2 hours of the initial administration of each dose of CBD vs. placebo (T1 and T4) will be analyzed 
as summary statistics during treatment. 
AEs and SAEs, when present, will be collected on an AE Case Report Form at study visits. The form will 
include an assessment of clinical significance and study relatedness. Serious Adverse Events (SAEs) will be 
documented on an additional SAE form. These CRFs will be based on those used in recent NIDA Clinical 
Trials Network trials. To further assess abuse potential, visual analog scales will be used to assess abuse 
potential. Scales will include desire to use the study medication again, desire to use the study medication 
again for pleasurable intoxication (“to get high”), and craving for the study medication. 
The study may be stopped if there are untoward and concerning levels of Adverse Event (AE) or Serious 
Adverse Event (SAE) outcomes attributable to CBD or study participation. If the DSMB finds it is likely that 
CBD is contributing to negative outcomes, they will consider solutions including protocol changes or 
potentially stopping the study. 
 Adherence and Retention Analyses 
Adherence to the protocol will be assessed with a smartphone-assisted medication adherence platform [119] 
in which the subject takes a video of drug administration at each dose, and transmits this to study personnel. 
This program has been used successfully in previous studies, and includes security provisions that ensure 
protection of confidentiality and privacy. Circulating concentrations of CBD will also be collected at T1-T8 to 
verify treatment adherence. 
 
Number of participants that complete the treatment phase of the study (through T8), complete the follow-up 
phase of the study (through T9), and are lost to follow-up will be collected. Frequency of and reasons for 
discontinuation of the intervention or study follow-up will also be tallied.  
 Baseline Descriptive Statistics 
Treatment groups will be compared on several baseline characteristics, including sex, age, race/ethnicity, 
education level, baseline measures of alcohol consumption (% drinking days and % heavy drinking days), 
alcohol craving (PACS), anxiety (BAI), mood (BDI-II), and self-efficacy (AASE). Categorical data will be 
tallied, and means and standard deviations of continuous scores will be calculated. 
 Planned Interim Analysis 
21.3.7.1 Safety Review 
The DSMB will meet (in person or by teleconference) following completion of treatment of the first 5 completers, 
after completion of treatment of the first 20 completers, and upon completion of enrollment for the trial. Prior to 


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each meeting, the PI will prepare a report to the Board including review of the aggregate analysis of adverse 
events/serious adverse events. 
Following each meeting, the board will provide the PI with a report including a recommendation to continue the 
study unchanged, continue with modifications of the protocol and/or the consent form to protect participant 
safety, or terminate the study. The study may be stopped if there are untoward and concerning levels of AE or 
SAE outcomes attributable to CBD or study participation. If the DSMB finds it is likely that CBD is contributing 
to negative outcomes, they will consider solutions including protocol changes or potentially stopping the study. 
 Multiple Comparison/Multiplicity 
Because our primary outcomes are safety data, in which we hypothesize a null difference between treatment 
groups, we will not employ a correction for Type I error/alpha inflation. 
 Tabulation of Individual Response Data 
Aside from AEs/SAEs, individual response data will not be presented.  
 Exploratory Analyses 
Hypothesis E will be assessed by comparing within- and between- group differences in percent heavy 
drinking days from baseline (T1) to week 8 of treatment with study medication (T7) and during the 4-week 
period following administration of study medication (T8-T9) 
21.4 Sample Size 
We will enroll approximately 60 participants, and randomize approximately 40 participants to meet our 
recruitment goal (through week 8/T7). Sensitivity to detect effects with the proposed study design was 
calculated for each hypothesis at power = 0.95 for univariate outcomes with 40 participants in 2 groups at 
alpha = 0.05 for the analyses described above. Hypotheses 1a and 1c are powered to detect effect sizes of 
approximately d = 0.2. Hypothesis 2a and 2b are powered to detect effect sizes of d = 0.2 and d = 0.3, 
respectively. Hypothesis E (exploratory hypothesis) is powered to detect an effect size of d = 0.6, therefore 
we are only powered to detect substantial impacts on drinking outcomes for this exploratory aim. 
22 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, study medication 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the dispensation site, at the laboratories, and at medico-
technical departments involved in the clinical trial. It is acceptable to use CRFs as source documents. If this is 
the case, it should be stated in this section what data will be collected on CRFs and what data will be 
collected from other sources. 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the item, then initial 
and date it. 
Access to study records will be limited to IRB-approved members of the study team. The investigator will 
permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government regulatory 
bodies, and University compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator will ensure 


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the capability for inspections of applicable study-related facilities (e.g. dispensation site, diagnostic laboratory, 
etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
23 Quality Assurance and Quality Control 
Data quality assurance (QA) includes all those planned and systematic actions that are established to ensure 
that the trial is performed and the data are generated, documented (recorded), and reported in compliance 
with GCP and the applicable regulatory requirements(s) (ICH E6 1.46). Data quality control (QC) includes the 
operational techniques and activities undertaken within the quality assurance system to verify that the 
requirements for quality of the trial-related activities have been fulfilled (ICH E6 1.47).  
 
QC procedures will be implemented beginning with the data entry system, and data QC checks on the 
database will be generated. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The 
investigational site will provide direct access to all trial related sites, source data/documents, and reports for 
the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
24 Ethics/Protection of Human Subjects 
24.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for the Protection of 
Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH 
E6. 
24.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted 
to the IRB for review and approval. Approval of both the protocol and the consent form must 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. All changes to the consent form will be IRB approved; a 
determination will be made regarding whether previously consented participants need to be re-consented. 
24.3 Informed Consent Process 
 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to starting intervention/administering study 
product.  
 
The following consent materials are submitted with this protocol: 
• 
Advertisement 
• 
Telephone Screening Consent Form 
• 
Telephone Screening Script 
• 
Informed Consent Form 
• 
Consent Quiz 
• 
Audio-Visual Release Form 


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 Consent Procedures and Documentation 
An IRB-approved pre-screening form will be used to pre-screen individuals expressing interest in the study, to 
assess whether they are likely to qualify for the study. Interested patients who pass the pre-screening will be 
referred for informed consent.  
Interested patients will be provided with an informed consent form including all pertinent details of the study 
including description of the following: the assessment interview and questionnaires; the follow-up interviews; 
description of experimental treatment; risks and benefits of study procedures; alternatives to participation in 
the study; confidentiality; emergency treatment and compensation for injury; payment for participation; a 
statement that patients will be informed of any new findings affecting the risks or benefits of the study; a 
statement that participation is voluntary and that the patient may withdraw at any time; and information about 
whom to contact with questions or in case of emergency. The consent form will also include assurances of 
confidentiality and a statement that participation is entirely voluntary, that the decision to participate will in no 
way influence other aspects of the patient’s treatment, and that the participant is free to withdraw participation 
at any time. The investigator will explain the research study to the participant and answer any questions that 
may arise. All participants will receive a verbal explanation in terms suited to their 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. 
In the event the participant cannot be at the study site to participate in the consent process in person, it can 
be conducted via telephone or NYULH-approved Secure Video Conferencing (i.e. WebEx). An electronic copy 
of the consent form will be shared with the participant via SendSafe email and participants will still be given 
adequate time to read, review and ask questions about the informed consent document. Participants can 
electronically sign and date the consent form and authorization documents by typing their names, initials and 
date and/or using a valid electronic signature wherever indicated. Once signed, participants will return the 
informed consent form and authorization documents to the consenting study team member via SendSafe 
email. The consenting study team member will then electronically sign the informed consent form and 
authorization forms where indicated and return the completed and double-signed consent documents to the 
participant for their personal record keeping via SendSafe email correspondence. Should the participant 
prefer, they can print and sign a hard copy of the document to be mailed or scan and email the documents via 
SendSafe back to the consenting study team member. 
The participants may withdraw consent at any time throughout the course of the trial. A copy of the signed 
informed consent document will be given to the participants for their records. 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. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The consent 
process, including the name of the individual obtaining consent, will be thoroughly documented in the 
subject’s research record. Any alteration to the standard consent process (e.g. use of a translator, consent 
from a legally authorized representative, consent document presented orally, etc.) and the justification for 
such alteration will likewise be documented.  
 
Patients who consent to participate in the study will also be invited to consent to having their remote and/or in-
person screening assessments (i.e. SCID) audio-recorded at the initial visit (see Audio Recording Consent). If 
a patient does not sign the Audio Recording Consent, then we will not audio-record the patient’s interview. 
24.4 Participant and Data Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and genetic 
tests 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. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product 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 
study drug records for the participants in this study. The clinical study site will permit access to such records. 
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 local IRB and Institutional regulations. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at NYU Langone Medical Center. 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 NYU Langone Medical Center research staff will be secured and password protected. At the end of the 
study, all study databases will be de-identified and archived at the NYU Langone Medical Center. 
Confidentiality of research material will be ensured by storing the research materials in locked cabinets. Material 
will be available only to project staff, and only as needed. All project staff will be thoroughly trained in issues 
relating to confidentiality. Participants will be identified in case report forms (CRFs) by initials and an 
identification code. Data will be entered into TrialMaster® and REDCap, programs designed specifically to 
protect patient privacy and confidentiality. Published reports will be based on group data; no individual data will 
be reported.  
To further protect the privacy of study participants, a Certificate of Confidentiality will be obtained from the 
NIH. This certificate protects identifiable research information from forced disclosure. It allows 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, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to participants. 
 Research Use of Stored Human Samples, Specimens, or Data 
• Intended Use: Samples and data collected under this protocol may be used to evaluate study eligibility 
and plasma concentrations of cannabinoids. No genetic testing will be performed. 
• Storage: Access to stored samples will be limited by storing samples in a securely locked area. 
Samples and data will be stored using codes assigned by the investigators. Data will be kept in 
password-protected computers. Only investigators will have access to the samples and data. 
• Tracking: Data will be tracked using electronic logs. 
o 
Disposition at the completion of the study: All stored samples will be sent to GRM Document 
Management. Study participants who request destruction of samples will be notified of 
compliance with such request and all supporting details will be maintained for tracking. 
24.5 Future Use of Stored Data 
Data collected for this study will be analyzed and in locked cabinets in NYU space within the A, C-D, and H 
buildings of Bellevue Hospital Center. After the study is completed, the de-identified, archived data will be 
transmitted to and stored at GRM Document Management for use by other researchers including those 


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outside of the study. Permission to transmit data to GRM Document Management will be included in the 
informed consent. 
 
When the study is completed, access to study data will be provided through GRM Document Management. 
25 Data Handling and Record Keeping 
25.1 Data Collection and Management Responsibilities 
Data collection, interpretation, analysis, review, and reporting is the responsibility of the clinical trial staff at 
the site under the supervision of the site PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of data. 
Black ink will be used to ensure clarity of reproduced copies. When making changes or corrections, cross out 
the original entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from source 
documents will be consistent with the source documents or the discrepancies will be explained and captured 
in a progress note and maintained in the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into “Research Electronic Data Capture” (TrialMaster®), a 21 CFR Part 11-
compliant data capture system. 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. 
 
The audiotaped recordings will be kept as confidential as possible. No individual identities will be used in any 
reports or publications resulting from this study. The researchers are committed to protecting the 
confidentiality of subject responses and have taken a number of steps in this regard. For example, the audio 
recordings will be coded with a code number unique to the study and all information will be kept on secure 
servers and/or in locked files. Only NYU study personnel, with the permission of the principal investigator, will 
have access to the file linking the subject name and study ID code. All digital data will be double pass code 
protected and stored on a secure server at NYU. Digital video and audio recordings of clinical interviews 
conducted at NYU as part of this study will be stored on the secure NYU server. 
25.2 Study Records Retention 
Study documents and/or recordings will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the last approval of a marketing application is approved for the drug for 
the indication for which it is being investigated or 2 years after the investigation is discontinued and FDA is 
notified if no application is to be filed or if the application has not been approved for such indication. No 
records will be destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
25.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, 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. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 


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• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the scheduled 
protocol-required activity. 
 
All protocol deviations must be addressed in study source documents and reported to NIAAA Program 
Official. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. Further details about the handling of protocol 
deviations will be included in the MOP. 
25.4 Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control groups 
to study the cause-and-effect relationship between a medical intervention and a health outcome. Medical 
interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, 
and the like. Health outcomes include any biomedical or health-related measures obtained in patients or 
participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and the Section 
801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical trials be 
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of 
Medicine. Other biomedical journals are considering adopting similar policies. For interventional clinical trials 
performed under NIH IC grants and cooperative agreements, it is the grantee’s responsibility to register the 
trial in an acceptable registry, so the research results may be considered for publication in ICMJE member 
journals. The ICMJE does not review specific studies to determine whether registration is necessary; instead, 
the committee recommends that researchers who have questions about the need to register err on the side of 
registration or consult the editorial office of the journal in which they wish to publish. 
 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register 
and report results of certain "applicable clinical trials": 
 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations of a 
product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation (other 
than small feasibility studies) and pediatric postmarket surveillance studies. 
• NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 
26 Study Finances 
26.1 Funding Source 
This study is financed through a grant from the US National Institutes of Health (NIH)/National Institute on 
Alcohol Abuse and Alcoholism (NIAAA). 
26.2 Costs to the Participant 
Participants will not incur any costs as a result of participating in the study. 


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26.3 Participant Reimbursements or Payments 
Participants will receive monetary compensation for research assessments as follows:  
Screen: 
Option 1 (T0): In-person = $40,  
Option 2 (T0a/b): Two-part Remote and In-person Screen: 
 
Part a: Remote portion = $20 
 
Part b: In-person portion = $20 
 
Total = $40 
Baseline (T1) = $60,  
1-day assessment (T2) = $20,  
1-week assessment (T3) = $60,  
4-week assessment (T4) = $60,  
4-week+1-day assessment (T5) = $20,  
5-week assessment (T6) = $60,  
8-week assessment (T7) = $40,  
9-week assessment (T8) = $40.  
 
Participants completing all of the assessments would therefore receive a total of $400, equivalent to roughly 
$20 per hour of time required to complete the assessments.  
27 Conflict of Interest Policy 
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 trial. The study leadership in conjunction with the NIAAA 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.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the NYU 
Langone Conflict of Interest Management Unit (CIMU) with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study. All 
NYULMC investigators will follow the applicable conflict of interest policies. 
 
 


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28 References 
 
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dependence in the United States: results from the National Epidemiologic Survey on Alcohol and 
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Rehm, J., et al., Global burden of disease and injury and economic cost attributable to alcohol use 
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Volkow, N.D. and T.K. Li, Drugs and alcohol: treating and preventing abuse, addiction and their 
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Berglund, M., A better widget? Three lessons for improving addiction treatment from a meta-analytical 
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Anton, R.F.O.M., S. S.; Ciraulo, D. A.; Cisler, R. A.; Couper, D.; Donovan, D. M.; Gastfriend, D. R.; 
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W. R.; Pettinati, H. M.; Randall, C. L.; Swift, R.; Weiss, R. D.; Williams, L. D.; Zweben, A., Combined 
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Di Marzo, V. and F. Piscitelli, The Endocannabinoid System and its Modulation by 
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Adrenal Axis. Comprehensive Physiology, 2017. 7: p. 1-156. 
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Katona, I., et al., Presynaptically Located CB1 Cannabinoid Receptors Regulate GABA Release from 
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Lauckner, J.E.J., J. B.; Chen, H. Y.; Lu, H. C.; Hille, B.; Mackie, K., GPR55 is a cannabinoid receptor 
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Waldeck-Weiermair, M., et al., Integrin clustering enables anandamide-induced Ca2+ signaling in 
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22. 
Ryberg, E., et al., The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol, 
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29 Attachments 
These documents are relevant to the protocol, but they are not considered part of the protocol.  They are 
stored and modified separately. As such, modifications to these documents do not require protocol 
amendments. 
 
• Investigator Agreement (for any investigator, other than sponsor-investigator, who participates in the 
study) 
• Informed Consent Form 
• Study Procedures Flowchart/Table 
• Study Monitoring Plan 
• Specimen Preparation And Handling (e.g. for any specialized procedures that study team must follow 
to process a study specimen, and/or prepare it for shipment)