Clinical trial NCT05317546
Conditions: Alcohol Use Disorder
Sponsor: Medical University of South Carolina
Start date: 2022-10-01; Completion date: 2024-06-25
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The goal of this study is to test cannabidiol (CBD) as a potentially effective candidate medication for youth alcohol use disorder (AUD). To accomplish this goal, this study will use a randomized, double-blind, within-subjects crossover design. In counterbalanced order, 50 youth (ages 16-22) will receive 600 mg of CBD or placebo three hours before a neuroimaging and behavioral assessment paradigm. The total amount of time the participant will be in the study is approximately one month.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Cannabidiol
Intervention descriptions: intervention 1: In counterbalanced order, 50 youth (ages 16-22) will receive 600mg of cannabidiol or placebo three hours before a neuroimaging and behavioral assessment paradigm, separated by an approximate 18-day washout period.

Protocol documents:
Prot_SAP_001.pdf: 
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PROTOCOL TITLE:  
Neurobehavioral Effects of Cannabidiol in Youth Alcohol Use Disorder 
 
PRINCIPAL INVESTIGATOR: 
Lindsay Squeglia, PhD 
 
 


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1.0 Objectives / Specific Aims 
Alcohol use is prevalent and problematic among youth, who are more likely than adults to initiate 
alcohol use, develop alcohol use disorder (AUD), and suffer lasting adverse alcohol-related 
consequences1,2. Despite the clear need for youth-targeted AUD treatments, established psychosocial and 
behavioral interventions offer limited efficacy, with very few youth achieving sustained alcohol abstinence 
or reduction3. Pharmacotherapies play a key role in bolstering substance use disorder treatment outcomes 
in adults, but to date, no medications for AUD in youth have merited FDA approval. The development of 
safe and effective adjunctive medications to treat adolescent AUD is needed to improve treatment 
outcomes and to potentially reduce the long-term consequences of adolescent use.  
Cannabidiol (CBD), one of the main phytocannabinoids in the Cannabis sativa plant4, is a potentially 
promising candidate pharmacotherapy for youth AUD. It is particularly appealing as a youth treatment 
option since it is non-intoxicating4,5, appears generally well-tolerated, and demonstrates no signal of abuse 
liability6. Further, young people tend to have a more positive attitude towards natural or alternative 
medicine7,8. CBD has many potential targets within the central nervous system that may mitigate the 
symptoms of AUD9,10 via modulation of the glutamatergic, GABAergic (gamma aminobutyric acid), 
dopaminergic, opioidergic, and endocannabinoid pathways11-14. Preclinical work has shown that CBD 
affects an array of drinking behaviors (e.g., reduces ethanol seeking and intake; mitigates symptoms of 
withdrawal, relapse, anxiety, and impulsivity)9,10,15, and recent clinical work has indicated CBD’s potential 
to reduce alcohol intake within adults who endorse alcohol and cannabis co-use16. CBD’s safety profile, 
potential mechanistic targets, and preliminary effects on alcohol-related behaviors in humans warrants 
research to assess the neural mechanisms and acute effects of CBD among youth with AUD.  
Translational medication screening studies have the potential to rigorously evaluate the acute effects 
of promising compounds, such as CBD, for neural and behavioral target engagement prior to initiating 
large-scale efficacy trials. Magnetic resonance spectroscopy (MRS) and functional MRI (fMRI) are two 
translational, developmentally appropriate techniques that can be used in humans to assess the neural 
mechanisms of pharmacotherapies17,18. MRS measures metabolite levels in the brain that are neural 
treatment targets (e.g., glutamate, GABA) and fMRI localizes and quantifies brain activity. Utilizing these 
neuroimaging methods will allow for investigation into the neural effects of CBD on two important aspects 
of AUD: modulation of 1) in vivo glutamate and GABA levels, two neurotransmitter systems involved in 
addictive behaviors19-21 that have been proposed as therapeutic targets of CBD13,14,22, and 2) brain 
reactivity to alcohol cues, which can be reliably measured with fMRI in heavy drinking youth23 and 
correlates with alcohol craving24. Establishing the acute neurometabolic and neurobehavioral effects of 
CBD in youth with AUD will be a critical first step in the pharmacotherapy development pipeline before 
initiating larger scale trials.  
Consistent with the trans-NIH initiative to identify neurally-informed novel substance use treatments for 
youth, the goal of this application is to test CBD as a potentially effective candidate medication for youth 
with AUD by leveraging developmentally informed neuroimaging methods (MRS, fMRI) and lab-based 
paradigm procedures. To accomplish this goal, this study will use a randomized, double-blind, within-
subjects crossover design. In counterbalanced order, 50 youth (ages 16-22) who meet criteria for AUD (³ 
2 symptoms) will receive 600mg of CBD25-30 or placebo with a standardized snack (to modulate CBD 
absorption rates) three hours before a neuroimaging and behavioral assessment paradigm, separated by 
an approximate 18-day washout period31.  
Aim 1: Quantify neurometabolic effects of CBD using MRS in youth with AUD: Youth with AUD will show 
increased levels of glutamate and GABA in the anterior cingulate after taking CBD compared to placebo. 
Aim 2: Quantify neurobehavioral effects of CBD using fMRI alcohol cue reactivity in youth with AUD: Youth 
with AUD will show decreased cue reactivity in reward-related neural regions after taking CBD compared 
to placebo. 
Aim 3: Examine psychophysiological effects of CBD during alcohol cues: In vivo response to olfactory 
alcohol cues (measured via heart rate, skin conductance, and subjective ratings) will be lower post CBD 
vs. placebo. 


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Adolescence and young adulthood are critical periods of time for intervention and treatment for emerging 
alcohol-related problems, and pharmacotherapies can provide significant support to evidence-based 
psychosocial interventions. In this proposal, we will leverage neuroimaging and behavioral data to examine 
the acute neurometabolic, neurobehavioral, and psychophysiological effects of CBD on youth with AUD to 
assess CBD’s promise as a potential adjunctive medication for youth AUD. Findings will bridge a critical 
translational gap (“the valley of death”32) in pharmacotherapy development for youth AUD, advancing 
methodology for rigorous neural-behavioral early efficacy testing of CBD. Effects established through this 
study could pave the way to a larger-scale clinical trial and, ultimately, improved long-term outcomes for 
young people suffering from AUD. 
 
2.0 
Background 
 
SIGNIFICANCE 
Alcohol use during adolescence and emerging adulthood is problematic and has long-term 
consequences. Alcohol is the most used substance among young people; 55% of 12th graders33 and 72% 
of 18-25 year olds34 endorsed past year alcohol use. Youth alcohol use is related to serious psychosocial 
problems, including comorbid psychopathology35-39, poorer academic success40, and detrimental 
neurocognitive consequences41,42. Further, early alcohol initiation increases the risk of subsequent alcohol 
use disorder (AUD) and related problems1,2,43. Nearly 15% of youth meet the diagnostic criteria for AUD 
by age 1844, and alarmingly, half of individuals that meet the criteria for lifetime AUD do so by the age of 
2145. 
Existing youth substance use treatments are inadequate. Effective treatments during adolescence and 
young adulthood are critical for improving long-term outcomes. Current treatments for youth AUD are 
primarily psychosocial, such as cognitive behavioral therapy, family-based therapy, and motivational 
interviewing3. Psychosocial interventions have shown small to medium effects on reducing substance use 
during adolescence46,47, and up to half of youth return to substance use within 12 months following 
treatment48-50. Given the modest efficacy of current psychosocial treatments, pharmacotherapy has been 
explored as a potential complement to the standard of care to improve outcomes51. However, there are 
limited data regarding the efficacy of pharmacotherapy in treating youth AUD, and the safety and efficacy 
of adult AUD medications cannot be extrapolated to youth52. This calls for the evaluation of treatments 
specifically for youth with AUD to improve treatment outcomes and to potentially reduce the long-term 
consequences of youth use. Natural or alternative medicine options may be particularly appealing for 
youth7,8. 
Cannabidiol (CBD) may be a promising pharmacotherapy for youth AUD. CBD is a non-intoxicating 
constituent of the Cannabis sativa plant that has garnered attention as an alternative therapy because of 
its wide range of therapeutic properties, including its effects on addictive behaviors53. Specifically, there is 
a growing preclinical literature9 indicating that CBD reduces: alcohol consumption and motivation to drink54-
57; alcohol relapse and withdrawal55,58; and alcohol-related neurotoxicity59,60. A study of adult alcohol and 
cannabis co-users found that high CBD cannabis (23% CBD, 1% THC) was related to a decrease in alcohol 
consumption over 5 days which was not seen in the THC (24% THC, 1% CBD) or THC plus CBD (9% 
THC, 10% CBD) groups16. 
CBD’s effects on alcohol consumption and AUD symptoms may be due to its multiple brain targets that 
overlap with systems underlying AUD. Inside the endocannabinoid system (ECS), CBD can act as an 
inverse agonist or negative allosteric modulator of cannabinoid receptors (CB1, CB2)12,61-63 and can 
change ECS signaling through inhibiting the enzymatic breakdown of anandamide (endogenous 
cannabinoid ligand)64,65. CB1 and CB2 receptors are expressed throughout the mesocorticolimbic pathway, 
which is highly implicated in addictive behaviors (e.g., reward, decision-making, substance intake, 
motivation, withdrawal, and relapse)66-69. Thus, CBD may exert its effects on AUD symptoms through 
indirect modulation of the ECS. Outside of the ECS, CBD has been shown to modulate glutamate13,22, 
gamma aminobutyric acid (GABA)14, dopamine70, serotonin71,72, and opioid73 neurotransmission, all of 
which are crucial systems implicated in AUD and have each been proposed as treatment targets for adult 
AUD15. While it is harder to assess neural mechanisms in humans, CBD has been shown to increase 
glutamate levels in individuals with psychosis25 and austim spectrum disorder26 through specialized 


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neuroimaging techniques (discussed more below). Overall, CBD’s mechanism of action makes it a 
promising potential candidate medication for youth with AUD. 
In addition to the preliminary behavioral and mechanistic data, CBD has a record of general safety and 
tolerability6,74 with limited adverse events75 or abuse liability6,76,77. Due to the lack of data in humans, which 
is even more pronounced in youth, it is important to rigorously test the acute neural and alcohol-related 
behavioral effects of CBD as a candidate medication for youth AUD before moving forward with large scale 
clinical trials. 
Lab-based paradigms can provide a critically important intermediary step in medication 
development, from preclinical to efficacy trials. There is a pressing need to accelerate the pace of 
medication development for youth AUD by focusing on moving candidate compounds through the drug 
development pipeline. Human medication screening paradigms can provide an essential bridge to test 
promising preclinical findings in humans before lengthy large-scale efficacy trials are initiated.  
Magnetic resonance imaging (MRI) techniques provide promising non-invasive methods to test neural 
mechanisms of a candidate medication78. Two techniques that are particularly relevant for medication 
development and are also developmentally-appropriate to use with youth are magnetic resonance 
spectroscopy (MRS) and functional MRI (fMRI)79. MRS quantifies metabolites in the brain, including 
glutamate and GABA levels, which are affected by substance use and are therefore targets for substance 
use medication development79-81. Alcohol alters glutamate neurotransmission82, which is related to 
GABAergic functioning, further supporting the use of MRS to test medications for AUD. fMRI localizes and 
quantifies brain activity, allowing for mechanistic understanding of neural substrates affected by the 
candidate medication. fMRI cue reactivity tasks activate incentive salience and reward circuitry83, and 
these cue-related brain activation patterns have been modulated by pharmacological intervention; 
predicted later relapse; and are associated with alcohol craving84. Cue reactivity can also be assessed 
during an olfactory cue reactivity task (measured via heart rate, skin conductance, and subjective ratings)85 
to better understand psychophysiological effects of potential medications. 
Summary. Adolescence and young adulthood are critical periods of time to intervene with emerging AUD 
and alcohol-related issues. Pharmacological interventions have the potential to bolster the efficacy of 
psychosocial treatments for youth AUD; however, they must be tailored to youth rather than extrapolating 
from the adult literature. CBD is a promising candidate pharmacotherapy for youth AUD due to its safety 
profile, proposed mechanisms, and signal for reducing alcohol-related behaviors in preclinical and clinical 
work. The purpose of this application is to conduct a translational pilot study to examine the neural, 
behavioral, and psychophysiological effects of CBD in youth with AUD for the first time. Effects established 
through this study could pave the way to a larger-scale clinical trial and, ultimately, improved long-term 
outcomes for youth suffering from AUD.  
 
INNOVATION 
MRS- and fMRI-based biomarkers and lab-based paradigms offer novel translational testing of the 
neural mechanisms of CBD in humans. A key element in translating candidate medications from 
preclinical to human trials is evaluation of common neural effects; MRS and fMRI provide low-risk, non-
invasive means to safely and reliably assess the effects of CBD on youth with AUD. In vivo response to 
olfactory alcohol cues will help further illuminate CBD’s effect on cue reactivity to better understand the 
potential mechanism of CBD’s action.  
To our knowledge, there are no published trials examining CBD as a potential treatment for youth 
with AUD or any other substance use disorder during adolescence or young adulthood, and 
according to clinicaltrials.gov, no trials are currently underway. This will be the first trial examining 
CBD as a potential candidate medication for youth with AUD. Due to its reported safety profile and 
tolerability, CBD is well-suited for a youth-specific pharmacotherapy translational trial in AUD. 
 
APPROACH  
Pilot Data/Feasibility 


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Team. The interdisciplinary research team consists of a clinical neuropsychologist/neuroimager (Squeglia), 
a licensed child and adolescent psychiatrist (Gray), a clinical psychologist/statistician (Tomko), and a 
neuroimaging postdoctoral fellow (Kirkland) with complementary expertise in AUD, youth substance use, 
neuroimaging, assessment and psychometrics, statistical analysis, and alcohol biomarkers. Our team 
recently completed five randomized placebo-controlled trials of pharmacotherapy and cognitive 
interventions for youth with substance use disorder (SUDs)86-90 and currently have four studies underway. 
Several of the on-going studies will complete recruitment prior to the initiation of the proposed study, 
limiting competing enrollment across studies.  
Neuroimaging and behavioral measures. Our team has extensive experience neuroimaging youth with 
the proposed methods. Dr. Squeglia has performed over 200 scans on substance-using youth (ages 15-
21), using the proposed fMRI and MRS protocol, with over 95% usable data. In a pilot study using the 
same fMRI alcohol cue reactivity task proposed for this application91, 11 heavy drinking youth displayed 
robust activation in several brain regions including the anterior cingulate, insula, striatum, and amygdala 
during alcohol vs. non-alcohol cue trials, which is highly consistent with activation patterns seen in adult 
studies92. Participants will undergo an olfactory alcohol cue exposure procedure which is consistent with 
published procedures utilized with adolescents at MUSC85. 
 
3.0 
Intervention to be studied  
CBD is a promising candidate pharmacotherapy for youth AUD due to its safety profile, proposed 
mechanisms, and signal for reducing alcohol-related behaviors in preclinical and clinical work. This double 
blind crossover trial will compare one dose of acute oral CBD (600 mg25-27,29) and placebo, followed by an 
approximate 18 day washout to allow for CBD clearance31 (terminal half-life 18-32 hours after acute oral 
dose)93.  
 
Though CBD is often well-tolerated, it can cause side effects, such as dry mouth, diarrhea, reduced 
appetite, drowsiness, and fatigue. CBD can also interact with other medications that some people take, 
such as blood thinners. These side effects are usually mild and go away even with continued use of CBD.  
 
"Increased risk of suicidal thoughts or behavior" is a CBD risk per package insert. However, a recently 
published meta-analysis indicates no risk for increased suicidality with CBD at this dose or over chronic 
dosing periods (Klein et al., 2021). Consistent with all of our youth substance use medication studies, we 
carefully assess participant suicidality and manage appropriately in the event of any compromise to safety. 
 
We do not predict severe adverse events from a single 600 mg CBD dose. All participants will be evaluated 
by the study medical clinician. The DSMB will review adverse events every 6 months. Concurrent 
medications with potential interactions with CBD are included in the exclusion criteria. Medication response 
and tolerability/adverse events will be assessed at each visit.  
 
The suggested maximum target daily dosing for children with epilepsy is 25 mg/kg/day; therefore, even for 
a low-weight adolescent, the proposed single dose is well within target range of tolerability. A previous 
within-subjects study in adults with autism spectrum disorder used an acute oral dose of CBD (600 mg) 
and successfully prevented carry-over effects with a 13-day washout period 26. Further, a single dose of 
600 mg has been shown to modulate brain metabolite levels measured with MRS25,26 and blood oxygen 
level dependent (BOLD) signal measured with fMRI27-30 as compared to placebo in clinical populations 
(autism spectrum disorder, clinical high risk for psychosis, and psychosis) and healthy controls.  
 
Most studies in children, adolescents, or young adults are long-term studies examining the effects of CBD 
within epilepsy. CBD doses in those studies usually range between 0.5 mg/kg/day to 28.6 mg/kg/day, with 
37% reporting drowsiness and 16% reporting fatigue94. In adult studies giving an acute dose of 600 mg, 
there have been either no adverse events95-97 or low rates for sedation or tiredness (e.g., 15%98; 22%99). 
There are currently no studies on the effect of oral purified CBD on driving ability, but one study found no 
differences on driving performance when comparing higher CBD-cannabis flower (smoked) as compared 


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to placebo at 40 or 240 minutes after use100. We will carefully evaluate drowsiness and fatigue before 
participants are able to leave from the facility, and we will arrange safe transportation accordingly. 
 
The metabolism and absorption of CBD can be modulated by food intake, with a 4-to-5 fold increase in 
bioavailability after a high-fat meal74; thus, all participants will eat a standardized high-fat snack with each 
medication administration. Neuroimaging will be conducted 3 hours after CBD/placebo administration to 
allow for CBD to reach its peak plasma concentration26,101. PI Squeglia received an FD exemption for using 
Epidiolex (CBD) with adolescent substance users (IND161500).  
 
 
4.0 
Study Endpoints  
Type 
Endpoint 
Time 
Frame  
Brief Description 
Primary  Brain 
Metabolites  
Visit 1 and 
Visit 2 
MRS quantifies metabolites in the brain, including glutamate 
and GABA levels, which are affected by substance use and 
are therefore targets for substance use medication 
development79-81. 
Primary fMRI Alcohol 
Cue-Reactivity  
Visit 1 and 
Visit 2 
fMRI localizes and quantifies brain activity, allowing for 
mechanistic understanding of neural substrates affected by 
the candidate medication. fMRI cue reactivity tasks activate 
incentive salience and reward circuitry83, and these cue-
related brain activation patterns have been modulated by 
pharmacological intervention; predicted later relapse; and are 
associated with alcohol craving84 
Primary Psychophysiol
ogical cue 
reactivity  
Visit 1 and 
Visit 2 
Cue reactivity can also be assessed during an olfactory cue 
reactivity task (measured via heart rate, skin conductance, and 
subjective ratings)85 to better understand psychophysiological 
effects of potential medications. 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Youth (ages 16-22; 50% women) alcohol users (N=50) will be recruited for the current study. To promote 
consistency between human laboratory models and clinical trials, we will recruit youth who meet criteria 
for AUD (³ 2 symptoms)102. At the end of the trial, all participants will have the opportunity to meet with a 
trained clinician for a brief treatment session from NIAAA’s brief alcohol intervention, which includes 
motivational interviewing and setting individual goals and action plans, consistent with the current 
standard-of-care treatment. We will also offer referral to additional clinical services, as well as provide all 
participants with a handout listing all community mental health and substance use programs. 
 
Participants having completed a separate ongoing research study (PRO #94743) who have consented to 
future contact and meet study criteria will be offered participation.  
Inclusion Criteria  
(1) ages 16-22 
(2) participants ages 16-17: a parent or legal guardian must be able to provide 
informed consent and youth must be able to provide assent 
(3) participants ages 18-22: must be able to provide informed consent 
(4) AUD in the past year and at least one current (past 30 days) continued symptom 
besides craving 


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(5) have used alcohol in the past two weeks before screening. 
 
Exclusion Criteria 
(1) significant or acutely unstable medical, psychiatric, or substance use 
problems (e.g., current manic episode, positive psychotic symptoms, severe 
eating disorder, severe opioid use disorder) that would contraindicate research 
procedures, interfere with safety, compromise data integrity, or preclude 
consistent study participation 
(2) significant risk of homicide or suicide 
(3) currently enrolled in or acutely seeking treatment for AUD or any other SUD 
(4) pregnant, trying to become pregnant, or breastfeeding 
(5) known allergy or intolerance to CBD 
(6) current use of CBD or any supplement containing CBD 
(7) history of a serious medical or neurological problem that could affect neural 
response or brain development 
(8) non-correctable visual or hearing problems 
(9) MRI contraindications (e.g., braces, claustrophobia, irremovable metal 
implants or piercings) 
(10) acute drunkenness or consumption of alcohol within 12 hours of visit 
(11) ³10 on the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) 
(12) severe Cannabis Use Disorder (CUD) 
(14) concurrent medications with potential drug-drug interactions with CBD, 
including CYP3A4 and CYP2C19 substrates, inhibitors, and inducers, as well 
as CYP2C8/9 substrates. 
Age Range: This work emphasizes capturing neurobehavioral effects of CBD during early life AUD, which 
will require a broad age range as drinking habits and consequences can widely vary among youth, while 
limiting neural and AUD heterogeneity within the sample. The CDC defines adolescence as ages 10-24. 
While some youth initiate alcohol use before age 16, few meet criteria for AUD103. Therefore, we chose a 
lower age limit of 16 and upper limit of 22 to reduce heterogeneity, while still sampling across the period 
when substance use problems emerge and peak. We will complete exploratory analyses within age and 
education-level subgroups to probe the confounding effect of developmental heterogeneity. Creation of 
alcohol-focused interventions during adolescence could have substantial long-term implications by 
reducing acute and long-term negative social, academic, and cognitive consequences related to heavy 
teen drinking and by reducing the rate of youth transitioning from heavy drinking to more problematic 
alcohol dependence. While participants in this study are not treatment seeking, all participants will be given 
treatment referrals at the conclusion of the study. 
 
Diverse Population: In this cohort, approximately 50% of the participants will be female, and we aim to 
recruit participants to approximate the racial and ethnic composition of Charleston County.  
 
6.0 
Number of Subjects 
We propose to enroll 50 participants.  
 
7.0 
Setting 
Visits will take place at MUSC in the Institute of Psychiatry, Roper Office Medical Building, and the 
Biomedical Imaging MRI research facility at 30 Bee St (for those visits requiring an MRI). If a participant is 


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unable to attend or complete a visit due to unexpected conflict (e.g., transportation issues, travel, University 
closings), arrangements may be made to remotely complete as much of the visit procedures as possible 
to maintain data collection and study engagement. This will be done via Zoom and REDCap assessments. 
 
8.0 
Recruitment Methods 
All participants will be recruited from a pool of participants who have completed an ongoing Entryway 
Intake study (PRO #94743). Participants who have completed this protocol and who appear to meet 
eligibility criteria will be offered participation in this protocol. Individuals who participate in the Entryway 
Intake consent for their data to be carried forward into the study in which they ultimately enroll. The 
Entryway Intake includes, but is not limited to, a comprehensive substance use history assessment and a 
structured diagnostic interview for psychiatric conditions, including assessment of AUD and other 
substance use disorders, as well as bioassay collection. After completion of the Entryway Intake, 
participants who are eligible for the current study will be offered participation. They will consent to sharing 
data collected across both protocols for analysis. Since launching the shared Entryway Intake in 
September 2020, we have averaged 33 referrals per month of youth (ages 16-22) interested in participating 
in alcohol studies. In the past 10 months, we have had 74 youth in this age range complete our shared 
Intake process. Of the total intakes, 41 (55%) met criteria for AUD, of which 20 (49%; 2/month) met for 
moderate or severe AUD. This is consistent with our proposed recruitment rate of 1.8/month. Study staff 
may also use the following methods of advertising to promote recruitment: local publications, physician 
offices/local clinics, MUSC campus, local college and high school campuses as permissions are granted 
by the academic institution, internet, social media, TV commercials, and other locations (e.g., restaurants, 
movie theaters, malls, buses/transportation services) in the community that agree to post Brand and IRB 
approved recruitment materials for this study and that may reach our target population. 
 
Our team has been successful with optimizing participant retention via several well-established strategies. 
We maintain active communication with participants between visits via their preferred mode of contact 
(e.g., text message, e-mail). We strictly maintain confidentiality, a particularly significant issue in studies 
focused on youth substance use interventions, and our team has extensive experience in managing 
communication with study participants while maintaining appropriate bounds of confidentiality and 
managing issues of safety; the resultant trust and rapport supports participant adherence and retention.  
 
9.0 
Consent Process 
Prior to the initiation of any study procedures, the MUSC Institutional Review Board (IRB) written and 
approved Informed Consent (IC) and HIPAA authorization will be obtained by IRB-approved, trained, 
designated research staff in a private interview room. Potential participants (and parents/guardians, as 
appropriate) will be provided with a copy of the IRB-approved consent form prior to their visit. After the 
Entryway Intake and prior to initiating any specific study procedures, research staff will obtain written 
informed consent and provide a copy of HIPAA privacy practices to potential participants. 
Parents/guardians will participate in the informed consent/assent procedures for youth between the ages 
of 16-17. Participants 18 years and older will provide their own informed consent. The complex issues of 
informed consent and assent, and related limitations of confidentiality, as they apply to youth and their 
parents/guardians, are understood by the research team and will be communicated clearly during the visit. 
Trained research staff members complete online and lab-based training in HIPAA policy, human subjects’ 
research, and management of other research issues. During the consent phase, participants and parents 
are informed that all information provided is confidential within ethical and legal limits to facilitate 
disclosure. During the consenting process, parents are told that they will not be informed about their child’s 
substance use and that youth self-report and lab data are confidential, except for any acute safety issues 
(e.g., suicidality, abuse). After given the chance to answer any questions concerning the study, individuals 
who agree to participate will be asked to sign the informed consent form. As part of the informed consent 
procedures, participants will be asked to provide or decline consent to be contacted for future studies. The 
forms are reviewed with the interested parties and filed in a locked file cabinet in a locked office. Trained 
research staff members complete online and lab-based training in HIPAA policy, human subjects’ research, 
and management of other research issues.  
 


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We may also use several different methods to complete electronic informed consent, if applicable and 
necessary, that include the following: 1) REDCap electronic consent (e-consent) combined with a video 
discussion on software approved by IT Security) or 2) via MUSC’s doxy.me system (teleconsent). As a last 
resort, we will also email the consent document to the participant or parent/guardian and conduct the 
informed consent via video chat. Participants can then email or mail the signed consent back to the 
research team if needed. Video chat functionality will only be used if all parties have the capability and will 
be on software approved by the IT Security team at MUSC.  
 
E-consent via REDCap will be saved in a separate informed consent database. All doxy.me signed consent 
forms will be saved as PDF files within our study records. Using these systems, signatures on the consent 
form may be obtained electronically via REDCap/doxy.me. These procedures for consenting remote study 
participants have been established in prior studies at MUSC (e.g., Pro# 19201). In the case that 
participants mail back hard copies of the consent (in rare instances), those will be stored in locked file 
cabinets in the offices of research staff. 
 
During the consent process birth certificate information will be collected from the participant (ie, 
first/middle/last name, birthdate, biological sex, and city/municipality of birth). This is in a separate REDCap 
file from data collection and is not part of our study data collection. This information is to be used solely for 
creating a Global Unique Identifier (GUID) for the NIMH Data Archive (NDA). This data is not transmitted 
to NDA but rather used in their online GUID Tool to create the GUID. The GUIDs created will be used as 
the participants’ ID when submitting study data to the NDA. This is detailed in the consent form. 
 
Informed consent is viewed as an ongoing process, so participants will be given the opportunity to ask 
questions about their participation throughout the course of the visit. The consent document will contain a 
thorough review of potential risks associated with participation, including breach of confidentiality and 
privacy concerns. 
 
10.0 
Study Design / Methods 
Entryway Intake. All participants will complete a centralized Entryway Intake process for substance use 
studies at MUSC (i.e., the Entryway Intake (PRO #94743)) to determine eligibility before consenting for 
this project. This triaged approach allows for minimization of participant study shopping (“professional 
participants”) and assurance that participants are triaged to the most appropriate study, thereby increasing 
the confidence and validity of study-specific results104-106. Eligibility criteria for all Youth Collaborative 
studies (including the proposed study) will be concurrently assessed during the Intake and participants will 
only be offered study participation in studies for which they are eligible.  
 
Overview. Our primary goal is to test CBD as a potential candidate medication for youth with AUD, 
leveraging neuroimaging and behavioral data, to examine the acute neurometabolic, neurobehavioral, and 
psychophysiological effects. In counterbalanced order, youth (ages 16-22; 50% female) will receive 600 
mg of CBD25-30  or matched placebo with a standardized snack, separated by approximately 18 days31 (see 
Figure below). We will stratify by education level (high school vs post high school) to ensure that these 
developmental groups are represented equally between the randomized crossover orders within our final 
sample. Neuroimaging will be collected after each medication trial: MRS will examine glutamate and GABA 
levels in the anterior cingulate cortex, and fMRI alcohol cue reactivity will examine neural response in 
reward networks, post-CBD and placebo. In vivo response to olfactory alcohol cues will be measured via 
heart rate, skin conductance, and subjective ratings85.  
  


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Participant Procedures 
CBD or placebo administration. This double blind crossover trial will compare acute oral CBD (600 mg25-
27,29) and placebo, followed by an approximate 18 day washout to allow for CBD clearance31 (terminal half-
life 18-32 hours after acute oral dose)93. All participants will eat a standardized snack with each medication 
administration. Neuroimaging will be conducted 3 hours after CBD/placebo administration to allow for CBD 
to reach its peak plasma concentration26,101. Medication response and tolerability/adverse events will be 
assessed at each visit.  
 
Assessments 
We focused on inclusion of measures that are standardized for this age group, have good psychometric 
properties, and/or are part of the PhenX Toolkit or are included in the multisite Adolescent Brain and 
Cognitive Development study to yield comparable data to national datasets. See Study Timetable (Table 
1). 
 
Clinical assessments. In general, these measures will be used to assess and track mental health and 
substance use-related problems over the course of study participation. Adverse events will be 
documented, rated for severity and relatedness, and managed/reported appropriately via established 
procedures. Participants will also meet with a medical clinician at each in person study visit to ensure 
physical and mental wellbeing throughout the study.  
 
Primary Assessments: Entryway Intake Process (PRO #94743) 
 
Physiological and Biological Assessments 
Urine samples will be obtained from all participants to conduct pregnancy tests (female sex at birth only) 
and qualitative urine drug screens. For females, the pregnancy test will be completed first and a positive 
pregnancy test will immediately stop all subsequent procedures. No urine drug screen will be completed. 
An alcohol breath sample will be obtained from all participants to rule-out acute intoxication. A carbon 
monoxide sample will be collected via a carbon monoxide monitor. A saliva sample will be collected for 
profiling of microbial communities via 16S rRNA sequencing. Vital signs will be taken on all participants, 
including height, weight, blood pressure, and pulse. 
 
Self-Report Measures  
1. 
The Demographic Form was designed by our research team to assess basic demographics, including 
age, gender, race, and social history. 
 
2. 
The MacArthur Social Status Ladder is a brief, 2-item measure with good psychometric properties 
(Operario, Adler, & Williams, 2004). It is designed to assess how individuals perceive their relative 
status in their community and nationally.  
 


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Page 11 of 26 
 
3. 
The Health and Substance Use History Questionnaires were designed by our team to assess basic 
health functioning and lifetime substance use exposure. Age of substance use onset will also be 
detailed. 
 
4. 
The Treatment Services Utilization Forms were designed by our research team to assess history of 
substance use and psychiatric treatment utilization. 
 
5. 
The Pittsburgh Sleep Quality Index (PSQI; Buysee et al., 1989) is a brief instrument designed to 
assess typical duration and quality of sleep. 
  
6. 
The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF; Schechter, Endicott, & 
Nee, 2007) and the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q-
SF; Endicott, et al., 2006) are 16-item and 15-item measures, respectively, designed to assess the 
degree to which one experiences joy and satisfaction. The pediatric version will be administered to 
youth ages 12-17, and the adult version will be administered to participants ages 18 and older. 
 
7. 
The Everyday Discrimination Scale – Short Version (Williams et al., 1997) is a 6-item measure 
designed to assess experiences of discrimination due to race, ethnicity, gender, disability, physical 
appearance, or other attributes. 
 
8. 
The Beliefs about Medicines Questionnaire (Horne et al., 1999) subscale related to general beliefs 
will be administered to assess attitudes toward medications. Three positively valanced items regarding 
medications were created by the study team and added to the measure, resulting in 11 total questions. 
 
9. 
The Mini International Neuropsychiatric Interview (MINI; Sheehan et al., 1998; Sheehan et al., 2010) 
is a semi-structured interview designed to assess current, past, or lifetime history of major DSM 5 
psychiatric and substance use disorder diagnoses. Based on the original MINI, an expanded version 
(MINI Plus) and a pediatric version (MINI Kid) have been developed and validated. The appropriate 
instrument (MINI Plus for participants ≥18 years and MINI Kid for participants <18 years) will be 
administered by trained staff. 
 
10. The Patient Health Questionnaire (PHQ-9; Kroenke et al., 2001) is a 9-item scale used to assess 
DSM-IV symptoms of depression. 
 
11. The Generalized Anxiety Disorder scale (GAD-7; Spitzer et al., 2006) is a 7-item measure used to 
assess symptoms of generalized anxiety. 
 
12. The UPPS-Revised-Child Impulsivity Scale (Zapolski et al., 2010; Gunn et al., 2010) is a 40-item 
measure used to assess five facets of trait impulsivity among youth (administered to participants ages 
12-25). 
 
13. Difficulties in Emotion Regulation Scale Short Form (DERS-SF; Kaufman, et al., 2015) is an 18-item 
self-report measure designed to assess six facets of emotion regulation problems among adolescents 
and adults: lack of emotion regulation strategies, non-acceptance of emotions, difficulties in goal-
directed behavior, impulse control difficulties, lack of emotional awareness, and lack of emotional 
clarity.  
 
14. Mental Health Treatment Utilization Form. This assessment includes a series of questions adapted 
from the National Survey on Drug Use and Health (a nationally representative SAMHSA-administered 
study) designed to assess adolescent current, past year, and lifetime mental health service utilization 
and reasons for service utilization. 
 
15. The Eating Disorder Screen for Primary Care (ESP) (Cotton et al., 2003) is a 5-item measure to quickly 
screen for the presence of an eating disorder. 


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Page 12 of 26 
 
 
16. The Timeline Follow Back (TLFB; Sobell & Sobell, 1992) is a calendar-based assessment designed 
to enhance retrospective recall of substance use for the past 60 days. Quantity and frequency of 
alcohol, cannabis, tobacco/nicotine products (cigarettes, ENDS, other tobacco/nicotine products), and 
other drug use will be assessed. Grams of cannabis will be estimated. Cannabis Methods. This 
assessment is conducted concurrently with the TLFB and includes a series of questions to determine 
which routes of administration participants are employing to use cannabis. 
 
17. The Rapid Eating Assessment for Participants- Shortened Version (REAP-S; Segal-Isaacson 2004) 
is a brief validated questionnaire designed to quickly assess nutrient intake.  
 
Secondary Assessments: Entryway Intake Process 
(The following measures will be administered depending on responses to TLFB): 
 
18. The Marijuana Assessment Problem Inventory (MAPI; Johnson & White, 1989) is a 23-item scale 
assessing consequences of cannabis use. This will be administered if past 60-day cannabis use is 
endorsed on TLFB. 
 
19. Rutgers Alcohol Problem Index (RAPI; White & Labouvie, 1989) is a 23-item questionnaire assessing 
consequences of alcohol use. This will be administered if past 60-day alcohol use is endorsed on 
TLFB. 
 
20. The Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES; Miller & Tonigan, 
1996) is a 19-item questionnaire designed to assess readiness to change drug use. Instructions will 
be modified for cannabis and alcohol use. These will be administered if past 60-day cannabis or 
alcohol use is endorsed on TLFB, respectively. 
 
21. Thoughts About Abstinence Scale (e.g., Substance Use Goals; Hall et al., 1991) assesses whether 
participants are interested in total abstinence, reduced use, or no change in substance use behavior 
for each of the following substances: alcohol, cannabis, e-cigarettes/nicotine vaping, regular 
cigarettes. There are 4 items in total (one for each substance).  
 
22. Reasons for Quitting Questionnaire-Cannabis (Steinberg et al., 2005) is a 27-item scale designed to 
assess common reasons for wanting to quit using cannabis. The scale will be modified to reflect 
quitting or reducing cannabis use and will only be administered to participants who report an 
abstinence or reduced use goal for cannabis on the “Thoughts About Abstinence Scale”. Note that 
only items 1-27 will be administered. 
 
23. The Motivation to Quit Measure (Turner & Mermelstein, 2004) is a single item assessing motivation 
to quit smoking. This has been adapted to additionally assess motivation to quit vaping or e-cigarette 
use in the current study. These will be administered if past 60-day cigarette or e-cigarette use is 
endorsed on TLFB, respectively. 
 
24. The Addiction Growth Mindset Questionnaire (Burnette et al., 2019) is a 3-item questionnaire 
designed to assess whether individuals see their substance use and behaviors as malleable or static 
in nature. 
 
25. The Modified Fagerström Tolerance Questionnaire (mFTQ; Prokhorov et al., 2000) is a 7-item self-
rating questionnaire assessing nicotine dependence in the adolescent population and it will be given 
to participants that endorse tobacco use in the past 60 days on TLFB. 
 
26. Penn State Electronic Cigarette Dependence Index (Foulds et al., 2015) is a 10-item questionnaire 
assessing electronic cigarette dependence, given to participants that endorse past 60-day e-cigarette 
use on TLFB. 


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Page 13 of 26 
 
                                                                                                                      
Additional Study Specific Assessments 
 
27. Clinical Institute Withdrawal Assessment for Alcohol (CIWA): Alcohol withdrawal will be assessed at 
the beginning of each session using the CIWA. A score >10 will result in referral to a higher level of 
clinical care. 
 
28. Columbia Suicide Severity Rating Scale assesses for suicidal ideation at each visit and if a higher 
level of clinical care is needed. 
 
29. Prior/concomitant medication will assess for eligibility at each medication visit (see exclusion criteria). 
 
30. Adverse events will be assessed after each medication dose. 
 
31. Penetration of the Blind will be assessed after each medication dose to assess the participant’s belief 
about whether they received the placebo or active condition. 
 
32. Cash Choice task is a brief measure of motivation, inhibition, impulsivity. 
 
33. Alcohol Purchase Task (17 items; Murphy et al., 2006) is a behavioral economic measure of motivation 
for alcohol. 
 
34. Alcohol Urge Questionnaire (Drobes & Thomas, 1999) is a measure that assesses alcohol urges.  
 
35. Barratt Impulsiveness Scale (BIS-11) is a 30-item self-report scale used to measure impulsiveness. 
 
 
Entryway 
Intake 
Study 
Screener 
Visit 1 
Visit 2 
Visit 3 
(remote) 
Study Visit Information 
 
 
 
 
 
Informed Consent 
X 
X 
 
 
 
Locator Form and Updates 
 
X 
X 
X 
X 
Penetration of the Blind 
 
 
X 
X 
 
Demographics, Health, Experiences, and Functioning 
 
 
 
 
 
Demographics 
X 
 
 
 
 
MacArthur Social Ladder 
X 
 
 
 
 
Health and Substance Use History Questionnaires 
X 
 
 
 
 
Treatment Services Utilization (substance use) 
X 
 
X 
X 
X 
Treatment Services Utilization (mental health) 
X 
 
 
 
 
Pittsburgh Sleep Quality Index 
X 
 
X 
X 
 
Quality of Life Enjoyment and Satisfaction (Pediatric and 
Adult Versions) 
X 
 
 
 
 
Everyday Discrimination Scale 
X 
 
 
 
 
Beliefs About Medicines Questionnaire 
X 
 
 
 
 
Biological Samples 
 
 
 
 
 
Pregnancy test 
X 
 
X 
X 
 
Urine sample 
X 
 
X 
X 
 
Alcohol breathalyzer 
X 
 
X 
X 
 
Carbon monoxide sample 
X 
 
 
 
 
Saliva sample 
X 
 
X 
X 
 
Blood sample 
 
 
X 
X 
 
Medical Assessments 
 
 
 
 
 
Meet with Medical Clinician 
 
X 
X 
X 
X (optional) 
Brief Medical History & Physical Exam 
 
X 
 
 
 
Adverse Events 
 
X 
X 
X 
 
Prior/Concomitant Meds 
 
X 
X 
X 
X 


Version 10; 12/11/2023 
 
Page 14 of 26 
 
 
Visits. On the day of the Entryway assessment, we will conduct an additional in-person Screening Visit, 
to set up and trial daily texting, ensure inclusion/exclusion criteria, and collect additional study-specific 
information. Visits 1 and 2 will be in-person and include neuroimaging. There will be a brief Visit 3 about 
two and a half weeks after Visit 2 that will be via phone or video to update the participant’s information. 
 
Daily texts. After Visits 1 and 2, participants will receive a daily text for the next 18 days with a maximum 
of 30 days if necessary due to scheduling. The text will have a link to an on-line REDCap survey that will 
ask about the prior day’s use of alcohol, cannabis, tobacco, CBD, and other substances. The link can also 
be e-mailed if the participant prefers. 
 
Alcohol cue exposure procedure. Consistent with published procedures utilized with youth at MUSC, all 
participants will undergo an olfactory alcohol cue exposure procedure85 before the neuroimaging session. 
In a counterbalanced order, participants will smell water, a bottle or can of the participant’s preferred 
alcoholic beverage, and a cup of apple juice (as this is not typically used as a mixer with alcohol107) for 
three minutes each, with three minute rest periods in between each liquid. Heart rate, skin conductance, 
and self-reported craving (via the Alcohol Urges Questionnaire) will be acquired based on previously used 
protocols107.  
Clinical Institute Withdrawal Assessment for Alcohol 
 
X 
X 
X 
 
Vitals Signs/Body Mass Index 
X 
 
X 
X 
 
General Mental Health and Psychological 
Assessments 
 
 
 
 
 
MINI International Neuropsychiatric Interview-DSM 5 
X 
 
 
 
 
MINI Alcohol Use Disorder Past 30 Day Module 
 
X 
 
 
 
PHQ-9 
X 
 
X 
X 
 
GAD-7 
X 
 
X 
X 
 
UPPS-R-C Impulsivity Scale 
X 
 
 
 
 
Difficulties in Emotion Regulation Scale Short Form 
(DERS-SF) 
X 
 
 
 
 
Eating Disorder Screen for Primary Care (ESP) 
X 
 
 
 
 
Barratt Impulsiveness Scale (BIS-11) 
 
X 
 
 
 
Columbia Suicide Severity Rating Scale 
 
X 
X 
X 
 
Cash Choice Task 
 
X 
X 
X 
 
Substance Use 
 
 
 
 
 
TLFB (Past 60 Days at baseline & Past number of days 
since prior TLFB at visits 1, 2, & 3) 
X 
 
X 
X 
X 
Cannabis Methods 
X 
 
 
 
 
Rutgers Alcohol Problems Index (RAPI) 
X 
 
 
 
 
Marijuana Assessment Problem Inventory (MAPI) 
X 
 
 
 
 
SOCRATES (Alcohol) 
X 
 
X 
X 
 
SOCRATES (Cannabis) 
X 
 
 
 
 
Thoughts About Abstinence Scale (e.g., Substance Use 
Goals) 
X 
 
 
 
 
Reasons for Quitting Questionnaire (Cannabis) 
X 
 
 
 
 
Motivation to Quit (Cigarettes and E-cigarettes) 
X 
 
 
 
 
Ecig Use Questionnaire 
X 
 
 
 
 
Addiction Growth Mindset Questionnaire 
X 
 
 
 
 
Modified Fagerström Tolerance Questionnaire 
X 
 
 
 
 
Penn State Electronic Cigarette Dependence Index 
X 
 
 
 
 
Alcohol Purchase Task 
 
X 
X 
X 
 
Alcohol Urge Questionnaire 
 
 
X 
X 
 
Lab Procedures  
 
 
 
 
 
Alcohol Olfactory Cue Reactivity Task 
 
 
X 
X 
 
Magnetic Resonance Imaging  
 
 
X 
X 
 
Estimated Visit Length (hours) 
2-3 
1-1.5 
5 
5 
0.5 


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Biological assessments. Combined use of ethanol metabolites and traditional biomarkers [i.e. alcohol 
breathalyzer, urine ethyl glucuronide (EtG), and blood phosphatidylethanol (PEth)] will be utilized to 
corroborate self-report alcohol use108-111. THC and CBD assays will be collected through urine to corroborate 
cannabis use. Blood samples will also be used to detect peripheral cytokines. Saliva samples will be 
collected for profiling of microbial communities via 16S rRNA sequencing. Urine drug tests (comprehensive 
panel testing for cotinine, cannabinoids, amphetamines, opioids, and benzodiazepines) will be used to 
monitor other substance use. Urine pregnancy tests will be conducted with participants assigned female at 
birth. Participants will also be asked to sniff a scented candle and report whether they can smell it and 
identify the scent, to check basic ability to smell. 
 
Neuroimaging protocol (1 hour).  
Mock scanner: On Visit 1, participants will be introduced to the mock scanner to help them become 
acclimated to the MR environment and give them the opportunity to practice remaining still while in the 
magnet, which will minimize motion-related confounds in the imaging data. 
Participants will undergo 2 neuroimaging scans (1 scan three hours after CBD, 1 scan three hours after 
placebo). Breath and urine toxicology samples will be collected before every scan. Saliva samples will be 
collected before and after every scan. Scans will be performed with a Siemens 3T Prismafit MRI scanner. 
Imaging sessions (~60 minutes) consist of: 
 
1. T1-weighted structural: A high-resolution anatomical scan will be acquired, to allow subsequent 
registration to functional images and region-of-interest (ROI) definition. 
2. The Alcohol Cue Reactivity Task: 91,92. During the alcohol cue reactivity task, participants are 
shown pseudorandomly interspersed images of alcoholic (i.e., beer, wine, and hard liquor) and 
non-alcoholic (e.g., soft drink, juice) beverages, visual control images (i.e., blurred images), and a 
fixation cross. A magnetic fieldmap will also be acquired to allow geometric unwarping and cost-
function masking of EPI images induced by magnetic field inhomogeneities. 
3. Magnetic Resonance Spectroscopy: The magnetic resonance spectroscopy protocol proposed 
will be utilizing previously published methods. 
 
Participants will be compensated $25 for the Screening Visit, $300 for completing both imaging visits ($150 
V1 and $150 V2), as well as an additional $1 per day for submitting their daily text questionnaire for a 
maximum of 60 days total. Participants will also be eligible for a $30 referral bonus for everyone they refer 
who successfully randomizes into this study. Mileage reimbursement will be available to participants who 
live >25 miles away; the current mileage reimbursement rate, which is updated each year by the state, will 
be offered. 
 
11.0 
Specimen Collection and Banking  
 
Biological Assessments. Urine samples will be obtained from all participants to conduct pregnancy tests 
(only those assigned female at birth) and qualitative urine drug screens. Necessary pregnancy tests will 
be completed first and a positive pregnancy test will immediately stop all subsequent procedures. The 
Clinical Neurobiology Lab (CNL) at MUSC will analyze urine and blood samples (urine ethyl glucuronide 
(EtG)), and blood phosphatidylethanol (PEth)). CNL will also process and store blood samples for analysis 
or peripheral cytokines. Participants will provide saliva samples using all-in-one collection kits and the 
samples will be immediately stored in a freezer until analysis. 
 
12.0 
Data Management  
All data will be managed via REDCap. Research staff and participants will enter data in REDCap; a secure, 
web-based 
application 
designed 
exclusively 
to 
support 
data 
capture 
for 
research 
studies. REDCap provides: 1) an intuitive interface for data entry (with data validation); 2) audit trails for 


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tracking data manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages (SPSS, SAS, R); 4) procedures for importing data from external 
sources; and 5) advanced features, such as branching logic and calculated fields. These procedures are 
effective in minimizing data entry errors (e.g., missing or errant data). Direct entry of data by study 
participants (self-reports) will also be conducted in this study. This is done through a front-end survey 
interface that allows the participant to enter data on select questionnaires/assessments, but not access 
any other study records or data in REDCap. Server maintenance will be conducted by Information 
Technology Specialists at MUSC. 
 
Accuracy and completeness of the data collected will be ensured by weekly review in team meetings. The 
REDCap system does not accept outliers, illogical response patterns, etc., thus minimizing data entry 
errors during participant direct entry. The PI will have weekly meetings with the research coordinator and 
research assistants to discuss qualitative comments received during data collection and any problems in 
data collection or entry. Dr. Squeglia will periodically examine the database to look for irregularities. Initial 
data analyses will examine distributions of variable scores and comparability of baseline characteristics 
across conditions in case analyses need to be adjusted for these characteristics. Dr. Squeglia will be 
responsible for maintaining signed consent forms as source documents for quality assurance review and 
regulatory compliance. 
 
Data Analysis 
Crossover designs are highly cost-efficient and powerful designs112. Laboratory studies can enroll more 
participants and minimize statistical noise through greater experimental control32. The primary outcome 
measures of interest will be glutamate and GABA levels (MRS; Aim 1), alcohol cue reactivity (fMRI; Aim 
2), and in vivo response to olfactory alcohol cues (heart rate, skin conductance, subjective rating; Aim 3). 
For all outcomes, a generalized linear mixed effects regression model will be developed accounting for 
clustering within subject. Additionally, study day (scan 1 vs. scan 2), condition (CBD vs. placebo), and 
condition order (CBD/placebo, placebo/CBD) will be included to ensure the crossover design and washout 
period were successful. During model development, random intercepts will be included to account for 
variations in baseline response levels for individual participants and random slopes to account for varying 
responses to treatment. For all models, baseline characteristics will be assessed for association with study 
outcomes (e.g., sex, baseline alcohol use rates, alcohol craving) and when significant, will be added in a 
covariate adjusted model. Model based interactions will assess any differential effect of sex on the 
relationship between medication condition and study outcomes.  
 
Power and sample size. The proposed study is primarily powered to assess the relationship between 
treatment with CBD as compared to placebo on glutamate and GABA levels in the anterior cingulate (Aim 
1) and neural response to alcohol cues (Aim 2). In a cross-over study of the effects of CBD as compared 
to placebo on glutamate in the hippocampus in a population of patients with schizophrenia, significant 
increases were found (d= 0.48; p=0.035)25. To our knowledge, the effects of CBD on cue reactivity have 
not been assessed using fMRI. However, several studies have demonstrated that CBD can modulate 
resting-state28,29 or task-based5,27,30,113-116 BOLD signal under similar study design (acute dosing, 600 mg 
CBD) with sample sizes smaller than our proposed sample. Given limited literature in this area, we were 
not able to run a power analysis for Aim 3; this pilot study will provide data to power further analyses/effect 
sizes. Due to the number of tests run within the fMRI and MRS aims, the study will be powered at 80% 
with a corrected α=.0005 (.05/100). Thus, in a crossover randomized controlled trial, n=27 study 
completers would be necessary. Although the proposed project is of relatively short duration (1.5 months), 
we anticipate an attrition rate of up to 7 participants (~23%) due to head motion or other artifacts, thus 
requiring a total of n=50 participants enrolled and randomized.  
 
Rigor and Transparency. The proposed study is rigorous and will achieve robust and unbiased results 
by using explicit inclusion/exclusion criteria (commensurate with AUD trials for youth); use of validated 
measures and methods; explicit hypotheses and corresponding planned statistical analyses; power 
estimates; planned handling of retention/attrition and missing data; and careful consideration of potential 


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confounds. Key biological variables such as sex and age are considered and are incorporated into the 
proposed data analytic plan. All experimental details are reported in a detailed and fully transparent manner 
for replication. 
 
13.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
All aspects of the study will be run through the MUSC Department of Psychiatry and Behavioral Sciences. 
Consistent with the guidelines of the MUSC IRB, an internal Data and Safety Monitoring Plan (DSMP) will 
be used. An internal DSMP is appropriate for this study because 1) it does not involve a multi-site trial and 
2) it presents minimal risks to participants. 
Prior to the start of the study, the protocol will be registered on the clinical trials registry (clinicaltrials.gov). 
Final modifications will be made to the study application with the MUSC Institutional Review Board (IRB) 
prior to the start of any study procedures and participant enrollment. During study enrollment, all serious 
adverse events (SAE; defined as any untoward medical occurrence that results in death, is life-threatening, 
requires or prolongs hospitalization, causes persistent or significant disability/incapacity, results in 
congenital anomalies/birth defects, or in the opinion of the investigators represents other significant 
hazards or potentially serious harm to research subjects or others) will be reported to the MUSC IRB within 
24 hours of learning of the event. Follow-up of all SAEs will be reported as well. All adverse events (AEs) 
will be reviewed weekly by the PI and every 6 months by both the appointed Data and Safety Monitoring 
Board (DSMB) and the IRB. Any significant actions taken by the local IRB, including significant protocol 
changes, will be relayed to NIH. We anticipate the SAE rate to be low. If monitoring indicates otherwise, 
we will convene a special meeting of the DSMB to evaluate further.  
The potential risks and benefits and methods to minimize these risks are outlined in Human Subjects 
Sections. Guidelines have been developed for managing and reporting of AEs, including SAEs. Dr. 
Squeglia will serve as the Program Manager for AEs. The Adverse Event Log will be used to document all 
AEs. If an AE is non-serious (self-limited with no intervention needed), no further action will be necessary. 
However, in the case of a serious, unresolved event, an AE follow-up log will be completed. The clinician 
will then call Dr. Squeglia with initial reports within 24 hours of the start of the SAE. The clinician will record 
the information on SAE Notification Form. The clinician will forward hard copies of the complete report 
(SAE Notification Form, Concomitant Medication Log, and AE Log) to Dr. Squeglia, who will, in turn notify 
the IRB, DSMB, and NIH about the SAE. Additionally, Dr. Squeglia will communicate summary reports of 
DSMB discussion of the SAE, or any deliberations of IRB regarding the review of the SAE or the trial itself, 
to NIH. If the event is “Serious, Unexpected and Associated” (an SAE is considered unexpected if it is not 
described in the Package Insert), Dr. Squeglia will complete Food and Drug Administration (FDA) Form 
3500A and will forward it to the FDA. Dr. Squeglia also will inform the IRB and the study participants (and 
parents/guardians, as appropriate) about the SAE. In all of these reviews and reports, strict patient 
confidentiality will be maintained. 
AEs will be coded on a weekly basis using Medical Dictionary for Regulatory Activities (MedDRA) rules 
and entered into a database. For each weekly study meeting, the research assistants will prepare a 
summary of all AEs, including their severity and presumed relation to study medication. The PI will review 
this at the weekly study meeting (or before if more urgent). 
Study procedures will follow as much as possible the FDA’s Good Clinical Practice Guidelines. We will 
encourage participants (and parents/guardians as appropriate) to notify their physicians that a) they are in 
a randomized controlled research study evaluating CBD for adolescent AUD, and b) the physician should 
contact the PI directly if the physician has any questions. 
The research assistants will be instructed not to reveal whether a person is a participant in the study and 
will report to the PI any outside requests for information about a participant or any breaches in 


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Page 18 of 26 
 
confidentiality. All requests by participants’ physicians and other medical providers will be referred directly 
to the PI.  
The Data and Safety Monitoring Board may request a blinded interim efficacy report (blinded to the PI and 
research team) for review while the trial is ongoing. Final (fully unblinded) efficacy analysis will occur after 
all participants have completed all visits. 
Dr. Squeglia will have overall responsibility for safety and data monitoring on a day-to-day basis for this 
trial, including weekly checks of the AE database prepared by research assistants during study meetings 
to determine if particular categories are being endorsed more frequently than anticipated and to determine 
if severity is greater than anticipated for this trial. Dr. Gray will also serve as the primary medical monitor 
for this study and will provide guidance and input on a scheduled and as-needed basis throughout the trial. 
Co-I Dr. Tomko will examine the outcomes database twice annually for missing data, unexpected 
distributions or responses, and outliers. Annual data and safety monitoring reports will be written and 
submitted to the IRB and to NIH. This information will include, but may not be limited to, a brief description 
of the trial, baseline sociodemographic characteristics of participants accrued, retention of study 
participants, quality assurance issues, and reports of adverse events, significant/unexpected adverse 
events and serious adverse events. 
 
Dr. Squeglia will create a DSMB, comprised of multidisciplinary faculty with expertise in adolescent-
focused clinical trials. The DSMB will meet every 6 months (more frequently as needed for emergency 
situations) to review any AEs related to the study, as well as review of any data management related 
errors. The board may be called at any point if needed for SAEs, etc. Modification will be made in the 
procedures and/or the protocol, if necessary, based on the findings of the board. 
 
Reports provided to the DSMB on an annual basis will address the following areas: 1) the progress of the 
research study, including assessments of data quality and participant recruitment, accrual, and retention; 
2) review of outcome and adverse event data to determine whether there is any change to anticipated 
benefit-to-risk ratio of study participation, and whether the study should continue as originally designed, 
should be changed, or should be terminated; 3) assessment of external factors or relevant information; 
and 4) review of study procedures designed to protect the privacy of the research participants and the 
confidentiality of their data. Following review of the annual update on the study, the DSMB will provide a 
written report that will be submitted annually with the IRB renewal.  
 
14.0 
Withdrawal of Subjects  
 
Participants will be informed that they may discontinue the study at any time during the visit without penalty 
and that they will be pro-rated for completed research activities. Participants may also be withdrawn from 
the study by the PI if it is determined that it is in the participant’s best interest (e.g., safety concern, requiring 
intervention). Finally, participants may withdraw consent of use of their biospecimen samples for additional 
purposes at any time.  
 
15.0 
Risks to Subjects 
The risks associated with participation in this study include adverse events related to study medication and 
the potential loss of confidentiality. Potential risk details are described below, and the PI will ensure that 
all risks are clearly defined for study participants and are thoroughly understood during the informed 
consent process and throughout the study period. 
In the unlikely event that participants are significantly distressed by any aspect of study participation, they 
will be offered the opportunity to discuss these issues with one of the PIs and/or the designated medical 
clinician (Kevin Gray) and may withdraw from the study at any point. If the distress is more serious and 
requires psychiatric attention, they will meet with a designated medical clinician on the study team. If 
participants require longer-term intervention, they will be referred to psychiatric treatment at MUSC, where 


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they will pay the standard fee. Should any participant report suicidal ideation at any time during study 
participation, they will be immediately referred to a PI or medical clinician to determine the appropriate 
course of action. Suicidal ideation as measured via the PHQ-9 will automatically trigger an email alert in 
REDCap to go to the PIs and/or the clinicians in the study for follow-up. Events of this nature are not 
expected to occur at greater frequency because of the current protocol, but procedures will be in place to 
ensure the safety of all study participants.  
 
Adverse Events Related to Study Medication. CBD has a generally benign adverse effect profile. It is non-
intoxicating4,5, appears generally well-tolerated, and demonstrates no signal of abuse liability6. Preclinical 
work has shown that CBD affects an array of drinking behaviors (e.g., reduces ethanol seeking and intake; 
mitigates symptoms of withdrawal, relapse, anxiety, and impulsivity)9,10,15, and recent clinical work has 
indicated CBD’s potential to reduce alcohol intake within adults who endorse alcohol and cannabis co-
use16.  
 
Loss of Confidentiality. There is the risk of breach of confidentiality. The research team has procedures in 
place to minimize the risk of any confidentiality breach. Participant records are stored in locked files within 
locked offices, or in password-protected databases. Much of the data collected, including all neuroimaging 
data, is de-identified and uses a participant ID. No specific or general participant information will be left in 
public access areas, and no oral communication regarding participants with identifiers will be made in any 
public areas. Research staff members have been given extensive training in maintaining confidentiality as 
well as HIPAA regulations. Participants will be informed of these potential risks during the informed consent 
process and will have the option to leave the study at any point. 
 
Other Minimal Risks. Risks associated with MRI are minimal for individuals who do not have metal in their 
body and are not claustrophobic. Some discomfort may result from lying in the scanner for up to 60 
minutes. There is some psychological risk inherent in testing participants for recent substance use, 
psychiatric symptomatology, and pregnancy, especially if results are contrary to participants' expectations. 
 
Protections Against Risk.  
 
Adverse Events Related to Study Medication. The informed consent process will be used to thoroughly 
educate participants and parents/guardians about potential medication-related risks, including adverse 
events. This discussion will include thorough review of adverse events associated with CBD treatment, 
which are minimal. Rigorous screening procedures and strict exclusion criteria are designed to exclude 
potential participants at elevated risk for adverse events. The study medical clinician will conduct serial 
adverse events monitoring as part of medication management. Participants and parents/guardians will 
have access to a study medical clinician 24 hours, 7 days a week for emergencies. Co-I Gray has full 
hospital admitting privileges in the event of an adverse event requiring hospitalization. Urine pregnancy 
tests will be conducted at baseline and serially during visits for participants assigned female at birth. 
   
Loss of Confidentiality. The research team has established procedures in place to minimize the risk of any 
confidentiality breach. To minimize this risk, all data will be stored in secure locations, including locked file 
cabinets and password-protected computers and databases. Any adverse events will be reported to the 
IRB, NIH, and others, as appropriate, to ensure the safety of study participants. Research staff are given 
extensive training in maintaining confidentiality as well as HIPAA regulations. 
 
Policy on neuroimaging data. Participants and their family (for those under age 18) are informed that this 
is a research study and therefore does not include clinical imaging to confirm clinical findings. If the 
research staff note a structural irregularity on a scan, a neuroradiologist will review it (fully de-identified) 
and note if it is of clinical significance or not. If the finding has the potential of clinical significance, the 
participant or parents (depending on age) will be notified to follow up with his or her doctor. There is a 
minimal risk of undue stress or concern if the finding is determined to be benign or not clinically significant.  
 
Since this study involves minors, particular caution will be exercised in obtaining informed adolescent 


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Page 20 of 26 
 
assent separately and independently from parental consent. To this end, an initial step in participant 
recruitment involves obtaining parental/legal guardian permission for participation by the adolescent. Once 
parental consent is secured, participants will be asked separately and independently for informed consent 
(i.e., parental consent will not be used to persuade teens to participate). This approach is considered very 
effective in minimizing coercion to participate. 
 
16.0 
Potential Benefits to Subjects or Others 
Potential benefits of participation in this study may include a reduction in alcohol use. However, there is 
no guarantee or promise that participants will receive any benefit from participation in this study. 
Participation in this study involves minimal risk for participants yet has the potential for minimizing alcohol 
use.  
 
17.0 
Sharing of Results with Subjects 
Aggregated study results can be shared with subjects or others in the form of peer-reviewed manuscripts, 
as relevant, upon request.  
 
18.0 
Drugs or Devices   
Epidiolex (CBD) will be dispensed by the MUSC Investigational Drug Service. The matched placebo liquid 
will be compounded and dispensed by the MUSC Investigational Drug Service. PI Squeglia received an 
FD exemption for using Epidiolex (CBD) with adolescent substance users (IND161500).  
 
 
 
 
 
 


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future research opportunities. Alcohol Clin Exp Res. 2010;34(6):955-967. 
111. 
Lowe JM, McDonell MG, Leickly E, et al. Determining ethyl glucuronide cutoffs when detecting 
self-reported alcohol use in addiction treatment patients. Alcoholism, clinical and experimental 
research. 2015;39(5):905-910. 
112. 
Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: Part 18 of a 
series on evaluation of scientific publications. Dtsch Arztebl Int. 2012;109(15):276-281. 
113. 
Winton-Brown TT, Allen P, Bhattacharrya S, et al. Modulation of auditory and visual processing 
by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology. 
2011;36(7):1340-1348. 
114. 
Borgwardt SJ, Allen P, Bhattacharyya S, et al. Neural basis of Δ-9-tetrahydrocannabinol and 
cannabidiol: effects during response inhibition. Biological psychiatry. 2008;64(11):966-973. 
115. 
Fusar-Poli P, Crippa JA, Bhattacharyya S, et al. Distinct effects of Δ9-tetrahydrocannabinol and 
cannabidiol on neural activation during emotional processing. Archives of general psychiatry. 
2009;66(1):95-105. 
116. 
Bhattacharyya S, Crippa JA, Allen P, et al. Induction of psychosis byδ9-tetrahydrocannabinol 
reflects modulation of prefrontal and striatal function during attentional salience processing. 
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ICF_000.pdf: 
Neurobehavioral Effects of Cannabidiol in Youth Alcohol Use Disorder 
 
NCT05317546 
 
08/08/2023 


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Medical University of South Carolina 
CONSENT TO BE A RESEARCH SUBJECT 
 
TITLE OF RESEARCH: 
Neurobehavioral Effects of Cannabidiol in Youth Alcohol Use Disorder 
 
If participants include those under 18 years of age: 1) The subject's parent(s) or legal guardian(s) will 
be present when the informed consent form is provided. 2) The subject will be able to participate only 
if the parent or legal guardian provides permission and the adolescent provides his/her assent. 3) In 
statements below, the word "you" refers to your child or adolescent who is being asked to participate 
in the study. 
 
You are being asked to volunteer for a research study. Research studies are voluntary and include 
only people who choose to take part. The purpose of the study includes evaluation of both the safety 
and the effectiveness of the study medication, which is called cannabidiol (or CBD).  
 
Specifically, we are evaluating how CBD versus an inactive substance (i.e., flavored sesame oil) affects 
the brain in adolescents who may use alcohol. CBD has been approved by the Food and Drug 
Administration (FDA) for use in adults and children for other uses, but little is known about its effect on 
brain function in youth or on youth who may use alcohol. After eating a snack, participants will receive 
one dose of CBD (600mg) or inactive flavored sesame oil before two different magnetic resonance 
imaging (MRI) brain scans separated by approximately 2.5 weeks. We will collect saliva samples; 
blood, breath, and urine samples; you will be asked to smell alcoholic beverages while being 
monitored, and you will fill out several questionnaires at each in-person visit. You will be sent daily 
texts questionnaires while you are in the study. The full study will last approximately 1.5 months. 
 
There are risks to the study drug that are described in this document. Some of the risks include dry 
mouth, diarrhea, reduced appetite, drowsiness, and fatigue. There is a risk of loss of confidentiality, 
but the researchers will code the samples and research information to protect privacy. There are no 
direct benefits to the participant, but we hope the information will help us develop treatments for youth 
who use alcohol. This is not a treatment study; however, all participants will have access to a trained 
clinician throughout the study. 
 
If you are interested in learning more about this study, please continue to read below. 
 
A. PURPOSE OF THE RESEARCH 
 
The purpose of this study is to understand if CBD may be an effective medication for youth who have 
problems with their alcohol use. You are being asked to participate in this study because you are 
between 16-22 years old and have used alcohol. A grant from the National Institutes of Health (NIH) 
will sponsor this study. Portions of Dr. Squeglia and her research team’s salaries will be paid by this 
grant. This study is being conducted at one site, the Medical University of South Carolina, and will 
involve 35 volunteers. 
 


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B. PROCEDURES 
 
Overview: For this study, you will complete two magnetic resonance imaging (MRI) scans over the 
course of one month. Before each scan, you will take CBD or an inactive substance (flavored sesame 
oil; also referred to as “placebo”). You will not know when you will be receiving the CBD or the inactive 
substance. We will collect saliva samples, blood, breath, and urine samples and you will fill out several 
questionnaires at each in-person visit. You will be sent daily text questionnaires for approximately a 
month of the study. If you are unable to attend or complete a visit due to unexpected conflict (e.g., 
transportation issues, travel, University closings), arrangements may be made to remotely complete 
as much of the visit procedures as possible.  
 
Parents will not be informed about their child’s substance use and youth self-report and lab data are 
confidential except for any acute safety issues (e.g., suicidality, abuse). 
 
Here is a visual overview of the study: 
 
 
 
 
If you agree to be in this study, the following will happen: 
 
Screening (1 hour): If you have completed the Entryway Intake study in the past 30 days, portions of 
this screening will have been completed. Data collected during the Entryway Intake will be carried over 
and included to avoid repeating any data collection. Examples of such data include answers to 
completed surveys and questionnaires about your substance use.  
 
Additional screening for this study will include a brief medical history and a review of medications by a 
trained clinician. A urine sample will be collected for a urine drug test and pregnancy test (only 
participants assigned female at birth). The pregnancy test will be completed prior to the drug testing. 
Individuals testing positive on the pregnancy test or those who plan to become pregnant during the 
study period cannot participate in the study and no further study procedures will be completed. 
Participants will need to take steps to avoid becoming pregnant during the study. We will also check 


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your pulse, blood pressure, temperature, and weight (vitals). You will be asked questions about your 
general substance use, mood, and alcohol use and craving. 
 
The research team will use several methods of contact to keep in touch with you. We will ask you to 
provide us with phone numbers, e-mail addresses, current addresses, and contact information of family 
and friends who may know how best to reach you. 
 
Visit 1 (5 hours): When you come in for your visit, you will be given Epidiolex (i.e., CBD) or the inactive 
substance (i.e., flavored sesame oil) to be taken with a snack which you will choose. You will receive 
both Epidiolex and the inactive substance, but the order you receive them will be determined by 
chance. You will have a 50:50 chance (like the flip of a coin) of receiving either CBD or the inactive 
substance during the first visit. For the second visit, you will receive whichever substance you did not 
receive the first time. Neither you nor your study team will know the order of the substances you are 
receiving; however, the researchers can find out what you are taking if there is a need to do so. 
 
Before the scan, you will be asked to complete questionnaires, provide saliva (to measure the 
microorganisms in your body, such as fungi, bacteria, and viruses), and provide urine, breath, and 
approximately one tablespoon of blood  to measure alcohol and other substance use. You will complete 
a task where you smell an alcohol of your choice and rate how you feel. You will then have a 1-hour 
MRI scan. A second saliva sample will be collected after the scan. 
 
During the MRI scan the following will happen: 
1. If you would like, you may first be introduced to the mock (fake) MRI scanner. This is a model of a 
scanner that is not magnetically active. It is used to introduce people (that may or may not have 
ever been in an MRI scanner) to the size, shape, and sounds associated with the scanning 
procedure. During the introduction to the mock scanner, you will be asked to lay down on the 
scanner bed. This bed will then be slowly pushed back into the tube of the scanner and we make 
sure you are comfortable enough to participant in the actual scan. 
2. Before you go in the scan room, we will make sure you have no metal on your clothes or body. You 
will then lay down on the MRI scanner bed and your head and shoulders will be inside the MRI tube 
during the scan. You will be given earplugs to wear while you are in the scanner. You will be able 
to speak to and hear the research staff during the scan. While you are in the MRI scanner, we will 
take pictures of your brain during several scanning sessions. You will be asked to lay still in the 
MRI scanner during this time. In between each scanning session we will talk to you through the 
speakers in the MRI scanner to see how you are feeling. You will be given a pressure-sensitive ball 
which you can squeeze at any time to end the MRI scan if you feel uncomfortable. Furthermore, 
we will be able to hear you and will be talking with you over a speaker periodically to make sure 
that you are feeling well. 
3. Several tasks will be completed during the 1-hour MRI scan. These tasks involve looking at different 
images on a screen and occasionally providing responses with a hand pad. 
 
These procedures are completely non-invasive and painless. There is no radiation with MRIs. 
 


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Visit 2 (5 hours): About 18 days after Visit 1, you will go through the same procedures as the first visit. 
The study substance you receive the second time will be determined by which substance you have 
already received. If you already received CBD, you will take the inactive substance and vice versa.  
 
Daily Texts: Beginning the day after your first MRI visit, you will be sent daily text questionnaires. These 
will continue until approximately 18 days after your second scan when your final remote visit is 
completed. 
 
Final remote visit (30 minutes):  About 18 days after Visit 2, you will have a phone or video visit. This 
will be a short visit consisting of some follow-up questions. 
 
At any point in the study, you will have the opportunity to meet with a clinician if you would like to change 
your alcohol or other substance use. You can request this at any point. You will also be asked if you 
would like to meet with a clinician at the end of the study. Meeting with the clinician is optional. 
 
At each MRI visit, you will be closely monitored for excessive drowsiness and fatigue prior to leaving 
the research facility. 
 
You may be withdrawn from this study without your consent if the researchers believe it is in your best 
interest or if you fail to follow study procedures. 
 
You may withdraw from the study at any time. If you decide to stop participating in the study, you are 
encouraged to talk to study staff first so that stopping can be done safely. Another reason to tell study 
staff that you are thinking about stopping is to discuss what follow-up care and testing could be most 
helpful to you. 
 
C. COLLECTION OF SPECIMENS 
 
As part of this study, we would like to store blood and saliva specimens collected from you for future 
research on youth alcohol use. This future research may be conducted by Dr. Lindsay Squeglia or by 
other researchers who obtain IRB approval for their research. This research may involve genome 
sequencing studies. There are several things you should know before allowing your blood and saliva 
to be studied or to be stored. 
1. The specimens will be labeled with a code that only study personnel can link back to you. 
Researchers outside of this study will not be given a link between the code number and your 
name or any other identifying information. While we hope this will prevent any potential loss of 
privacy or confidentiality, we cannot make any guarantees. 
2. In addition to your name, other information about you might be connected to your sample. For 
instance, information about race, ethnicity, sex, your medical history, and so forth might be 
available to investigators studying your specimen. Such information might be important for 
research or public health. It is possible that this information (including genetic information) might 
come to be associated with your racial or ethnic group. 
3. The specimens obtained from you in this research may help in the development of a future 
commercial product. There are no plans to provide financial compensation to you should this 
occur. Research results from any additional research will not be placed in your medical record. 


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4. Loss of privacy or confidentially is a risk of collection of specimens; however, we have 
procedures in place to minimize this risk (see C.1 above, Section E.5 below). There are no direct 
benefits to you for the collection, storage, and subsequent research use of specimens.  
In this study, investigators will not tell you what they find out about you, nor will they contact you for 
additional consent nor if a test becomes available to diagnose a condition you might have or later 
develop.  
You may request at any time that your research samples be removed from storage and not be used for 
future research. If you decide you want your samples removed, you may contact Dr. Lindsay Squeglia 
at the following email address: squegli@musc.edu. Once the request is received, and if your samples 
have not already been used for other research, they will be destroyed. If you do not make such a 
request, your specimens will be stored indefinitely or until completely used. 
 
D. DURATION 
 
Participation in the study will include a brief screening visit (less than one hour), 2 MRI visits (4-5 hours 
each), a remote follow-up visit, and daily text questionnaires (less than 3 minutes per survey) over a 
period of approximately 1.5 months. No more than 60 total daily text questionnaires will be sent if there 
are scheduling delays. 
 
E. RISKS AND DISCOMFORTS 
 
There are risks involved with participating in this study, including risks associated with CBD, the MRI 
scan, study procedures, emotional distress from answering personal questions, and loss of 
confidentiality. 
 
In this study, you will be taking Epidiolex (CBD) orally (by mouth) one time. All medications may cause 
side effects and there are some risks and discomforts associated with CBD. You will be monitored 
closely by the medical clinician associated with the study. If the medical clinician or you decide to stop 
your participation in the study due to unwanted experiences or side effects, you will receive appropriate 
follow-up care as determined by the medical clinician. 
 
1) Adverse Effects of Epidiolex (CBD) 
Though Epidiolex (CBD) is often well-tolerated, it can cause side effects, such as dry mouth, 
diarrhea, reduced appetite, drowsiness, and fatigue. CBD can also interact with other 
medications that some people take, such as blood thinners. These side effects are usually mild 
and go away even with continued use of CBD. Current medications will be reviewed by the 
clinician to assess for any potential interactions with CBD. 
 
Because CBD has not been evaluated in combination with many other medications, it will be 
important for you to report to the research staff any medications you may be taking before, 
during, or after the study. Medications include prescription medications from a doctor, over-the-
counter medications that you may buy in a drug store, herbal medications that you may buy in 
a health food store, or any other drugs you are using. 


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"Increased risk of suicidal thoughts or behavior" is listed as a potential risk in the package insert 
of CBD, though a recent published review of multiple CBD clinical trials found no increased 
suicidality even at higher doses or with repeated dosing. Regardless, our team includes 
experienced clinicians who will carefully assess for suicidality and will manage any safety 
concerns. 
 
2) Risks associated with MRI 
We are performing imaging solely for the research purposes described above. It is not a clinical 
scan intended for diagnostic or therapeutic purposes. If you want your scan to be reviewed by 
a physician so that the physician can look for medical issues, you can request a copy of your 
scan. We will provide an electronic copy at no charge. 
 
The risks associated with MRI are minimal for individuals who do not have metal and are not 
claustrophobic. Some discomfort may result from lying in the scanner for up to 60 minutes. You 
will be welcome to take short breaks between the various tasks. During the MRI scan, there are 
potential risks that are detailed below. 
 
Potential Risks of MRI: 
• Although the risks from magnetic resonance imaging (MRI) are low, it is critical that 
participants do not have metal in the skull, metal implants, a cardiac or brain pacemaker, 
or old metal fragments in the eye or retina. If participants have a question about metal 
their body, they should inform the researchers and they will determine whether it is safe 
in an MRI scan.  
• Some discomfort may occur from having to remain still while in the MRI scanner. During 
the scanning, an emergency ball will be given to squeeze if there are any feelings of 
discomfort or desire to be pulled out of the scanner. 
• Although the MRI scanner is open on both ends, some people become anxious or 
claustrophobic (fear of small spaces) when entering the MRI scanner due to the feeling 
of being enclosed. If participants have a history of experiencing this, they should inform 
the study personnel. 
• There is a chance that the technologist doing the scan could see something that does not 
look normal, in which case they would ask a radiologist to review the scan. If the 
radiologist recommends further action, we will contact you regarding their suggestion. 
This may cause you anxiety while you wait for further information or follow-up. 
 
3) Interviews/Rating Scales (Questionnaires) 
The questions that will be asked may be sensitive in nature and make you feel uncomfortable. 
You may be asked personal questions that you find distressing. You may refuse to answer any 
question(s) that you do not wish to answer. 
 
4) Blood Draw 
Risks associated with drawing blood from your arm include momentary discomfort and/or 
bruising. Infection, excess bleeding, clotting, or fainting is possible, although unlikely. 
 


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5) Risk of Loss of Confidentiality 
All study records will be placed in a locked, secure, limited access location. Your participation 
in the study and the information you provide will be treated as confidential. The information we 
collect will contain a code and not your name to protect your confidentiality. Codes linking 
numbers and names will be kept in a password-protected secure database and will not be 
accessible to anyone outside the research team. 
 
The information you share with us is confidential. That means we do not share information you 
tell us with anyone outside our research team. This helps us maintain privacy so we are able to 
get honest answers. However, you should also know that if you threaten to harm yourself or 
others or give information about child or elder abuse or neglect, this information will be reported 
to appropriate clinical staff and other persons outside the research program as necessary to 
protect yourself and others as mandated by law. 
 
6) Unknown Risks 
The experimental procedures may have unknown side effects. The researchers will let you know 
if they learn anything during the study that might make you change your mind about participating 
in the study. 
 
F. BENEFITS 
 
As part of the study, you can meet with a licensed clinician, which you may find to be beneficial. Given 
the investigational nature of this study, benefit cannot be guaranteed or promised. Information gained 
from this study may help other investigators have a better understand how CBD affects the brain. 
 
G. COSTS 
 
You will be receiving daily texts with a link to an online survey, which could result in charges on your 
phone service plan. We can also send the link via email if preferred. Otherwise, there will be no cost 
to you because of participation in this study. 
 
H. PAYMENT TO PARTICIPANTS 
 
In return for your time and effort, you will receive $300 for completing the two MRI visits ($150 V1 and 
$150 V2) and $25 for the screening. Also, you can earn a bonus of $1 per day for completing the 
remote text questionnaires (up to a maximum of $60). Mileage reimbursement may be available for 
participants who live who live more than 25 miles away. You will be reimbursed based on the state’s 
most updated reimbursement mileage rate. 
 
You have the choice between being paid in cash or through a pre-paid debit card, called ClinCard. 
ClinCard works like a bank debit card and you may use the card to purchase goods or services 
everywhere Debit MasterCard is accepted. If you choose to be paid via ClinCard, you will be given a 
ClinCard at the beginning of the study. Each time you receive payment for participation in this study, 
the money will be added to the card, as outlined in the payment schedule above.  
 


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Payments that you receive from MUSC for participating in a research study are considered taxable 
income per IRS regulations. Payment types may include, but are not limited to: checks, cash, gift 
certificates/cards, personal property, and other items of value. If the total amount of payment you 
receive from MUSC reaches or exceeds $600.00 in a calendar year, you will be issued a Form 1099. 
 
I. AUTHORIZATION TO USE AND DISCLOSE (RELEASE) MEDICAL INFORMATION 
 
As part of this research study, your study doctor and his/her research team will keep records of your 
participation in this study. 
 
The health information MUSC may use or disclose (release) for this research study includes 
information in your medical record, results of physical exams, medical history, lab tests or certain 
health information indicating or relating to your condition.  
 
Your study doctor and his/her research team will use and disclose (release) your health information to 
conduct this study. The health information listed above may be used by and/or disclosed (released) to 
the following, as applicable: 
• 
The sponsor of the study including its agents such as data repositories or contract research 
organizations monitoring the study; 
• 
Other institutions and investigators participating in the study; 
• 
Data Safety Monitoring Boards; 
• 
Accrediting agencies; 
• 
Clinical staff not involved in the study whom may become involved if it is relevant; 
• 
Parents of minor children if less than 16 years old. Parents of children 16 years old or older 
require authorization from the child; or 
• 
Health insurer or payer in order to secure payment for covered treatment; 
• 
Federal and state agencies and MUSC committees having authority over the study such 
as: 
 
o The Institutional Review Board (IRB) overseeing this study;  Committees with 
quality improvement responsibilities;  Office of Human Research Protections; 
Food and Drug Administration;  National Institutes of Health or Other 
governmental offices, such as a public health agency or as required by law. 
 
Those persons who receive your health information may not be required by Federal privacy laws 
(such as the Privacy Rule) to protect it and may share your information with others without your 
permission, if permitted by laws governing them. You do not have to sign this consent form. If you 
choose not to sign, it will not affect your treatment, payment or enrollment in any health plan or affect 
your eligibility for benefits. However, you will not be allowed to be a participant in this research study. 
 


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You will be given a copy of this consent form. Your authorization will expire at the conclusion of this 
study or, if you are participating in a study designed for the development of a drug or device, your 
authorization will remain in effect until the drug or device is approved by the FDA or until the 
company’s application to study the drug/device is withdrawn. You have the right to withdraw your 
agreement at any time. You can do this by giving written notice to your study doctor. If you withdraw 
your agreement, you will not be allowed to continue participation in this research study. However, the 
information that has already been collected will still be used and released as described above. You 
have the right to review your health information that is created during your participation in this study. 
After the study is completed, you may request this information. 
 
Your health information will be used or disclosed when required by law. Your health information may 
be shared with a public health authority that is authorized by law to collect or receive such information 
for the purpose of preventing or controlling disease, injury or disability and for conducting public 
health surveillance, investigations or interventions. No publication or public presentation about the 
research study will reveal your identity without another signed authorization from you.  
 
If you have questions or concerns about this Authorization or your privacy rights, please contact 
MUSC’s Privacy Officer at (843) 792-8740.  
 
J. ALTERNATIVES 
 
Participants who wish to receive information on mental health and/or substance use treatments will be 
referred clinically. Participation in this study is voluntary, and you may refuse to participate or 
discontinue participation at any time. If you choose not to participate, it will not affect your relationship 
with any current treatment provider or your right to health care or other services to which you are 
otherwise entitled. 
 
K. CERTIFICATE OF CONFIDENTIALITY 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. The researchers can use this Certificate to legally refuse to disclose information 
that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, for example, if there is a court subpoena. The researchers will use the Certificate to resist 
any demands for information that would identify you, except as explained below. 
 
The Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of federally funded projects or for information that 
must be disclosed to meet the requirements of the study sponsor and related agents participating in 
the study. 
 


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A Certificate of Confidentiality does not prevent you or a member of your family from voluntarily 
releasing information about yourself or your involvement in this research. If an insurer, employer, or 
other person obtains your written consent to receive research information, then the researchers may 
not use the Certificate to withhold that information. The Certificate of Confidentiality will not be used to 
prevent disclosure to state or local authorities of child abuse and neglect, or harm to self or others. 
 
L. NIAAA DATA ARCHIVE (NIAAADA)  
 
Data from this study will be submitted to the National Institute on Alcohol Abuse and Alcoholism 
Database (NIAAADA) at the National Institutes of Health (NIH). NIAAADA is a large database where 
deidentified study data from many NIAAA studies is stored and managed. Deidentified study data 
means that all personal information about you (such as name, address, birthdate, and phone number) 
is removed and replaced with a code number. The date of your visits though, will be linked with your 
code number to support appropriate secondary use of the data. Sharing your deidentified study data 
helps researchers learn new and important things about alcohol problems more quickly than before. 
 
During and after the study, the study researchers will send deidentified study data about your health 
and behavior to the NIAAADA. Other researchers across the world can then request your deidentified 
study data for other research. Every researcher (and institutions to which they belong) who requests 
your deidentified study data must promise to keep your data safe and promise not to try to learn your 
identity. Experts at the NIH who know how to keep your data safe will review each request carefully to 
reduce risks to your privacy. Sharing your study data does have some risks, although these risks are 
rare. Your study data could be accidentally shared with an unauthorized person who may attempt to 
learn your identity. The study researchers will make every attempt to protect your identity. 
 
You may not benefit directly from allowing your study data to be shared with NIAAADA. The study data 
provided to NIAAADA may help researchers around the world learn more about alcohol problems and 
how to help others who have problems with alcohol. NIAAA will also report to Congress and on its 
website about the different studies using NIAAADA data. You will not be contacted directly about the 
study data you contributed to NIAAADA. 
 
You may decide now or later that you do not want your study data to be added to the NIAAADA. You 
can still participate in this research study even if you decide that you do not want your data to be added 
to the NIAAADA. If you know now that you do not want your data in the NIAAADA, please tell the study 
researcher before leaving the clinic today. If you decide any time after today that you do not want your 
data to be added to the NIAAADA, call or email the study staff who conducted this study, and they will 
tell NIAAADA to stop sharing your study data. Once your data is part of the NIAAADA, the study 
researchers cannot take back the study data that was shared before they were notified that you 
changed your mind. If you would like more information about NIAAADA, this is available on-line at 
https://nda.nih.gov/niaaa. 
 
M. SIGNIFICANT NEW FINDINGS 
 
If there are significant new findings during the study, you will be notified. 
 


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N. STUDENT PARTICIPATION 
 
Your participation or discontinuance will not constitute an element of your academic performance, nor 
will it be a part of your academic record at this Institution. 
 
O. EMPLOYEE PARTICIPATION 
 
Your participation or discontinuance will not constitute an element of your job performance or 
evaluation, nor will it be a part of your personnel record at this Institution. 
 
P. CLINICAL TRIALS.GOV 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
Q. FUTURE CONTACT 
 
The researcher in charge of this study might like to contact you in the future about other research 
opportunities. Please initial by your choice below or if consenting electronically, scroll down to the 
bottom of the screen and select your choice: 
 
_____Yes, I agree to be contacted 
 
_____No, I do not agree to be contacted 
 
Results of this research will be used for the purposes described in this study. This information may be 
published, but you will not be identified. Information that is obtained concerning this research that can 
be identified with you will remain confidential to the extent possible within State and Federal law. The 
sponsor and the Food and Drug Administration (FDA) will receive copies of the research records. The 
investigators associated with this study, employees of the sponsor, the FDA, and the MUSC Institutional 
Review Board for Human Research will have access to identifying information. All records in South 
Carolina are subject to subpoena by a court of law. 
 
In the event that you are injured as a result of participation in this study, you should immediately go to 
the emergency room of the Medical University Hospital, or in case of an emergency go to the nearest 
hospital, and tell the physician on call that you are in a research study. They will call your study doctor 
who will make arrangements for your treatment. If the study sponsor does not pay for your treatment, 
the Medical University Hospital and the physicians who render treatment to you will bill your insurance 
company. If your insurance company denies coverage or insurance is not available, you will be 
responsible for payment for all services rendered to you. 
 
Your participation in this study is voluntary. You may refuse to take part in or stop taking part in this 
study at any time. You should call the investigator in charge of this study if you decide to do this. Your 


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IRB Number: Pro00119770 
Date Approved 8/8/2023 
 
 
decision not to take part in the study will not affect your current or future medical care or any benefits 
to which you are entitled. 
 
The investigators and/or the sponsor may stop your participation in this study at any time if they decide 
it is in your best interest. They may also do this if you do not follow the investigator’s instructions. 
 
Volunteer’s Statement 
I have been given a chance to ask questions about this research study. These questions have been 
answered to my satisfaction. If I have any more questions about my participation in this study or study 
related injury, I may contact Dr. Lindsay M. Squeglia at (843) 792-5451. I may also contact the Medical 
University of SC Patient and Family Care Liaison (843) 792-5555 concerning medical treatment. 
 
If I have any questions, problems, or concerns, desire further information or wish to offer input about 
my rights as a research subject in this study, I may contact the Medical University of SC Institutional 
Review Board for Human Research IRB Manager or the Office of Research Integrity Director at (843) 
792- 4148.  
 
I agree to participate in this study. I have been given a copy of this form for my own records. 
 
Signature of Person Obtaining 
Consent 
 
Date 
 
If you wish to participate, you should sign below for paper consents, or scroll down to the bottom of 
the screen and sign electronically: 
 
 
 
Signature of Adult Participant (18 years or 
older)  
 
Date 
If minors (ages 16-17) are research participants, both parents must sign this 
consent form, unless one parent is deceased, unknown, incompetent, or not 
reasonably available, or when only one parent has legal custody of a child. 
Name of Authorized Representative #1 
 
Relationship to minor participant: 
 Parent   
 Legal Guardian 
Signature of Authorized Representative #1 
 
Date 
 


Page 13 of 13 
Version Date: 08/04/2023 
 
 
IRB Number: Pro00119770 
Date Approved 8/8/2023 
 
 
Name of Authorized Representative #2 
 
Relationship to minor participant: 
 Parent   
 Legal Guardian 
Signature of Authorized Representative #2 
 
Date 
 
For Minors 12-17 years of age: “My participation has been explained to me, and 
all my questions have been answered. I am willing to participate.” 
 
 
Signature