Neuroscience-Informed Treatment Development for Adolescent Alcohol Use

This study will examine the effect of N-Acetylcysteine (NAC), an over-the-counter antioxidant supplement, on brains of youth (ages 15-19) using magnetic resonance imaging (MRI).

Study Overview

• Status: Completed
• Conditions: Alcohol Drinking; Control
• Intervention / Treatment: Drug: N-Acetylcysteine; Drug: Placebo Oral Capsule

Detailed Description

55 adolescents will receive, in a counterbalanced order, a 10-day course of NAC 1200 mg twice daily and a subsequent 10-day course of matched placebo twice daily, separated by 11 days. Urine and blood samples will be collected at baseline and urine samples again before and after each course of medication treatment. Participants will receive a 1- hour MRI scan at baseline and after each treatment trial.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 19 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria: Participants were between the ages of 15-19 and may or may not have used alcohol. All participants in the alcohol-using group met criteria for heavy drinking, based on quantity and frequency of drinking (Squeglia et al. 2011; Squeglia et al. 2012) (see Figure 2).

Exclusionary criteria: Not having a parent to consent (for those under age 18); history of alcohol treatment or treatment-seeking; current DSM-5 diagnosis of moderate or severe substance use disorder other than alcohol or cannabis (American Psychiatric Association 2013); positive urine toxicology screen for narcotics, amphetamines, sedatives, hypnotics, or opiates (not prescribed by a doctor); alcohol withdrawal (> 10 on the Clinical Institute Withdrawal Assessment for Alcohol (Sullivan et al. 1989); medical conditions or medications that contraindicate taking NAC; current use of N-acetylcysteine or any supplement containing N-acetylcysteine (must agree not to take any such supplement throughout study participation); medical history of severe asthma (uncontrolled with medication); history of a serious medical, psychiatric, or neurological problem that could affect neural response, brain development, or study participation, including diabetes, seizure disorder, and severe head injury with loss of consciousness; history of learning disability, pervasive developmental disorder, or other condition requiring special education; current use of psychoactive medications that affect cerebral blood flow; non-correctable visual or hearing problems; non-fluent in English; MRI contraindications (e.g., braces, claustrophobia, irremovable metal implants or piercings); (for females) pregnancy or refusal to use reliable methods of birth control; refusal of blood draw, abstinence from alcohol for >14 days before participation, and use of alcohol <12 hours before scanning (confirmed with breathalyzer). While cigarette and marijuana use will not be exclusionary, we will exclude any participants who are daily users of cannabis or tobacco.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N-Acetylcysteine, then Placebo; Participants first received N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days. After washout for 11 days, they then received placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days.	Drug: N-Acetylcysteine; N-Acetylcysteine; 600mg capsules by mouth, two pills twice daily (total 2400 mg/day). Participants will undergo MRI (including magnetic resonance imaging and functional MRI during an alcohol cue reactivity task) at baseline, after 10 days of N-Acetylcysteine and after 10 days of placebo.; Drug: Placebo Oral Capsule; N-acetylcysteine-matched placebo tablet two pills twice daily. Participants will undergo MRI (including magnetic resonance imaging and functional MRI during an alcohol cue reactivity task) at baseline, after 10 days of N-Acetylcysteine and after 10 days of placebo.
Experimental: Placebo, then N-Acetylcysteine; Participants first received placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days. After washout for 11 days, they then received N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days.	Drug: N-Acetylcysteine; N-Acetylcysteine; 600mg capsules by mouth, two pills twice daily (total 2400 mg/day). Participants will undergo MRI (including magnetic resonance imaging and functional MRI during an alcohol cue reactivity task) at baseline, after 10 days of N-Acetylcysteine and after 10 days of placebo.; Drug: Placebo Oral Capsule; N-acetylcysteine-matched placebo tablet two pills twice daily. Participants will undergo MRI (including magnetic resonance imaging and functional MRI during an alcohol cue reactivity task) at baseline, after 10 days of N-Acetylcysteine and after 10 days of placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region.	Using magnetic resonance spectroscopy and a within-subjects design, we will determine the effect of N-Acetylcysteine versus placebo on modulating anterior cingulate glutamate levels in adolescents. Values provided are absolute values (mmol/kg) at the end of each intervention period. Due to complexities of this method, "normal" levels of glutamate are not known; thus, we cannot make conclusions about the meaning of "higher" or "lower" glutamate levels when comparing N-acetylcysteine to placebo.	31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)
Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task.	Assessing the change in neural reactivity to alcohol cues after each round of medication: Placebo vs. N-Acetylcysteine. Cue reactivity is a type of learned response which is observed in individuals who use substances (e.g., alcohol) and involves significant physiological reactions to presentations of substance-related stimuli (i.e., alcohol images) in comparison to neutral images (e.g., non-alcoholic beverages ) measured by BOLD (Blood Oxygen Level-Dependent response). ROIs were (left and right hemisphere): amygdala, caudate, insula, nucleus accumbens, and putamen. Change in BOLD signal are reported in Z-scores. A Z-score of 0 would indicate there is no statistical difference in BOLD signal between alcohol images and non-alcohol beverage images. A higher Z-score would indicated a higher BOLD signal during alcohol images compared to non-alcohol beverage images. A lower Z-score would indicate a lower BOLD signal during alcohol images compared to non-alcohol beverage images.	31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in neural reactivity (as measured by BOLD: Blood Oxygen Level-Dependent response) in reward regions during alcohol-cue reactivity task.	Assessing the change in neural reactivity to alcohol cues at baseline and after each round of medication: Placebo vs. N-Acetylcysteine.	31 days total (levels compared to baseline after 10 days on N-Acetylcysteine and placebo with 11 day washout period in between)

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Lindsay M Squeglia, PhD, Medical University of South Carolina

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2017
• Primary Completion (Actual): March 1, 2022
• Study Completion (Actual): March 1, 2022

Study Registration Dates

• First Submitted: July 31, 2017
• First Submitted That Met QC Criteria: August 2, 2017
• First Posted (Actual): August 3, 2017

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: adolescent
• Additional Relevant MeSH Terms: Drinking Behavior; Alcohol Drinking; Underage Drinking; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: Pro00058771; K23AA025399 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No