A Phase 2 interventional study of N-Acetylcysteine and Placebo Oral Capsule in Alcohol Drinking and Control, sponsored by Medical University of South Carolina. Completed at 1 site in United States. Open to participants aged 15 Years to 19 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-06-22.
Sponsored by Medical University of South Carolina · Phase 2, Interventional, and Basic science
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).
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.
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.
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 · Drug: Placebo Oral Capsule
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 · Drug: Placebo Oral Capsule
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.
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.
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)
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)
57 participants were screened for eligibility between October 16, 2017 and February 18, 2022 at the Medical University of South Carolina.
| Milestone | N-Acetylcysteine, Then Placebo | Placebo, Then N-Acetylcysteine |
|---|---|---|
| Started | 18 | 17 |
| Completed | 18 | 16 |
| Not completed | 0 | 1 |
| Withdrew: Physician decision | 0 | 1 |
| Milestone | N-Acetylcysteine, Then Placebo | Placebo, Then N-Acetylcysteine |
|---|---|---|
| Started | 18 | 16 |
| Completed | 18 | 16 |
| Not completed | 0 | 0 |
| Milestone | N-Acetylcysteine, Then Placebo | Placebo, Then N-Acetylcysteine |
|---|---|---|
| Started | 18 | 16 |
| Completed | 17 | 16 |
| Not completed | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 |
| Milestone | N-Acetylcysteine, Then Placebo | Placebo, Then N-Acetylcysteine |
|---|---|---|
| Started | 17 | 16 |
| Completed | 15 | 16 |
| Not completed | 2 | 0 |
| Withdrew: Lost to follow-up | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 |
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.
| mmol/kg | N-Acetylcysteine | Placebo |
|---|---|---|
| Quantifying the Difference in Glutamate Levels (mmol/kg) During N-Acetylcysteine Versus Placebo in the Anterior Cingulate Brain Region. | 15.7527667 ± 0.748460934 | 15.6265229 ± 0.778392692 |
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.
| Z-score | N-Acetylcysteine | Placebo Oral Capsule |
|---|---|---|
| Left Amygdala | 0.649576194 ± 0.968974541 | 0.3018234193548 ± 0.841575583 |
| Right Amygdala | 0.56294871 ± 0.999382512 | 0.210653871 ± 0.946731462 |
| Left Caudate | 0.137316806 ± 0.970053483 | 0.110683871 ± 0.826040069 |
| Right Caudate | 0.065642839 ± 1.100274051 | 0.031422161 ± 0.79443319 |
| Left Insula | -0.258198161 ± 1.142477966 | 0.058738871 ± 0.846769387 |
| Right Insula | -0.429143032 ± 1.2071406050607 | -0.169528194 ± 1.075103119 |
| Left Nucleus Accumbens | 0.347468645 ± 1.0725798 | 0.2095879354838 ± 0.697815244 |
| Right Nucleus Accumbens | 0.240204258 ± 1.151021574 | 0.072915871 ± 0.9231385308441 |
| Left Putamen | -0.138118065 ± 0.894080737 | 0.225092871 ± 0.989678164 |
| Right Putamen | -0.165481516 ± 0.818905961 | 0.058414516 ± 0.9453397543003 |
Collected over 31 days (10 days of first intervention, 11-day wash out, 10 days of second intervention) Intervention = N-acetylcysteine, then Placebo OR Placebo, then N-acetylcysteine. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| N-Acetylcysteine | 0/34 (0%) | 0/34 (0%) | 10/34 (29.4%) |
| Placebo Oral Capsule | 0/34 (0%) | 0/34 (0%) | 5/34 (14.7%) |
| Washout Period | 0/33 (0%) | 0/33 (0%) | 1/33 (3%) |
| Baseline | 0/35 (0%) | 0/35 (0%) | 2/35 (5.7%) |
| Event | N-Acetylcysteine | Placebo Oral Capsule | Washout Period | Baseline |
|---|---|---|---|---|
| NauseaGastrointestinal disorders | 4/34 | 0/34 | 0/33 | 0/35 |
| StomachacheGastrointestinal disorders | 3/34 | 0/34 | 0/33 | 0/35 |
| HeadacheNervous system disorders | 1/34 | 2/34 | 0/33 | 0/35 |
| Sore ThroatRespiratory, thoracic and mediastinal disorders | 0/34 | 0/34 | 1/33 | 0/35 |
| FatigueGeneral disorders | 0/34 | 1/34 | 0/33 | 0/35 |
| VomitingGastrointestinal disorders | 0/34 | 1/34 | 0/33 | 0/35 |
| ConjunctivitisEye disorders | 0/34 | 1/34 | 0/33 | 0/35 |
| Skin and subcutaneous tissue disorderSkin and subcutaneous tissue disorders | 1/34 | 0/34 | 0/33 | 0/35 |
| Nasal CongestionRespiratory, thoracic and mediastinal disorders | 1/34 | 0/34 | 0/33 | 0/35 |
| Gastrointestinal disorderGastrointestinal disorders | 0/34 | 0/34 | 0/33 | 1/35 |
| Age, Continuous(Years) | N-Acetylcysteine, Then Placebo | Placebo, Then N-Acetylcysteine | Total |
|---|---|---|---|
| Mean | 18.90 ± 0.75 | 18.79 ± 0.60 | 18.85 ± 0.67 |
| Sex: Female, Male(Participants) | N-Acetylcysteine, Then Placebo | Placebo, Then N-Acetylcysteine | Total |
|---|---|---|---|
| Female | 9 | 11 | 20 |
| Male | 9 | 6 | 15 |
| Race (NIH/OMB)(Participants) | N-Acetylcysteine, Then Placebo | Placebo, Then N-Acetylcysteine | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 2 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 18 | 15 | 33 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(Participants) | N-Acetylcysteine, Then Placebo | Placebo, Then N-Acetylcysteine | Total |
|---|---|---|---|
| United States | 18 | 17 | 35 |
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Medical University of South Carolina