Alcohol Drinking, Control
Conditions
Keywords
adolescent
Brief summary
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).
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.
Interventions
DRUGN-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.
DRUGPlacebo 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.
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
15 Years to 19 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region. | 31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between) | 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. |
| Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | 31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between) | 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. |
Countries
United States
Participant flow
Recruitment details
57 participants were screened for eligibility between October 16, 2017 and February 18, 2022 at the Medical University of South Carolina.
Pre-assignment details
35 of 57 were randomized. Of those not randomized, 12 were ineligible, 6 declined to participate, and 4 withdrew or were withdrawn during the baseline visit.
Participants by arm
| Arm | Count |
|---|---|
| N-Acetylcysteine, Then Placebo N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days. After washout for 11 days, placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days. | 18 |
| Placebo, Then N-Acetylcysteine Placebo capsules mimicking N-Acetylcysteine (two pills, twice daily) will be taken for 10 days. After washout for 11 days, N-Acetylcysteine 600mg capsules by mouth, two pills twice daily will be taken for 10 days | 17 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Baseline (Before Intervention) | Physician Decision | 0 | 1 |
| Second Intervention (10-Days) | Lost to Follow-up | 1 | 0 |
| Second Intervention (10-Days) | Withdrawal by Subject | 1 | 0 |
| Washout Period (11-Days) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | N-Acetylcysteine, Then Placebo | Total | Placebo, Then N-Acetylcysteine |
|---|---|---|---|
| Age, Continuous | 18.90 Years STANDARD_DEVIATION 0.75 | 18.85 Years STANDARD_DEVIATION 0.67 | 18.79 Years STANDARD_DEVIATION 0.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 33 Participants | 15 Participants |
| Region of Enrollment United States | 18 Participants | 35 Participants | 17 Participants |
| Sex: Female, Male Female | 9 Participants | 20 Participants | 11 Participants |
| Sex: Female, Male Male | 9 Participants | 15 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 34 | 0 / 33 | 0 / 35 |
| other Total, other adverse events | 10 / 34 | 5 / 34 | 1 / 33 | 2 / 35 |
| serious Total, serious adverse events | 0 / 34 | 0 / 34 | 0 / 33 | 0 / 35 |
Outcome results
Primary
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.
Time frame: 31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Amygdala | 0.56294871 Z-score | Standard Deviation 0.999382512 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Insula | -0.429143032 Z-score | Standard Deviation 1.2071406050607 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Putamen | -0.165481516 Z-score | Standard Deviation 0.818905961 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Nucleus Accumbens | 0.347468645 Z-score | Standard Deviation 1.0725798 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Amygdala | 0.649576194 Z-score | Standard Deviation 0.968974541 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Nucleus Accumbens | 0.240204258 Z-score | Standard Deviation 1.151021574 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Caudate | 0.065642839 Z-score | Standard Deviation 1.100274051 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Putamen | -0.138118065 Z-score | Standard Deviation 0.894080737 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Insula | -0.258198161 Z-score | Standard Deviation 1.142477966 |
| N-Acetylcysteine | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Caudate | 0.137316806 Z-score | Standard Deviation 0.970053483 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Putamen | 0.058414516 Z-score | Standard Deviation 0.9453397543003 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Amygdala | 0.3018234193548 Z-score | Standard Deviation 0.841575583 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Amygdala | 0.210653871 Z-score | Standard Deviation 0.946731462 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Caudate | 0.110683871 Z-score | Standard Deviation 0.826040069 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Caudate | 0.031422161 Z-score | Standard Deviation 0.79443319 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Insula | 0.058738871 Z-score | Standard Deviation 0.846769387 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Insula | -0.169528194 Z-score | Standard Deviation 1.075103119 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Nucleus Accumbens | 0.2095879354838 Z-score | Standard Deviation 0.697815244 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Right Nucleus Accumbens | 0.072915871 Z-score | Standard Deviation 0.9231385308441 |
| Placebo | Change in Neural Reactivity (as Measured by BOLD: Blood Oxygen Level-Dependent Response) in Reward Regions During Alcohol-cue Reactivity Task. | Left Putamen | 0.225092871 Z-score | Standard Deviation 0.989678164 |
Comparison: Contrast of interest was alcohol beverages vs. non-alcohol beverages. We used linear mixed effects models with random intercepts with medication, visit, and sequence. Baseline reactivity levels for each ROI, cannabis use (days), and an alcohol use covariate (quantity, frequency, AUD status, or AUD severity - depending on which best fit the model) were included as covariates. ROIs included were (left and right hemisphere): amygdala, caudate, insula, putamen, and nucleus accumbens.p-value: >0.05Mixed Models Analysis
Primary
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.
Time frame: 31 days total (levels compared after 10 days on N-Acetylcysteine and 10-days of placebo with 11 day washout period in between)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region. | 15.7527667 mmol/kg | Standard Deviation 0.748460934 |
| Placebo | Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region. | 15.6265229 mmol/kg | Standard Deviation 0.778392692 |
Comparison: With 31 participants, the study has 99% power to detect such effects on glutamate levels (calculated based on d =1.13 \[reported in Schmaal et al., 2012\], α = 0.05, two-tailed).~We used linear mixed effects models with random intercepts with medication, visit, and sequence. Baseline metabolite levels and brain tissue composition \[GM:BM = GM/(GM+WM)\], cannabis use (days), and alcohol use disorder status (Yes/No) were included as covariates.p-value: >0.0595% CI: [0, 0.22]Mixed Models Analysis