The adolescent and young adult microbiome and its association with substance use: a scoping review.

AIMS: The microbiome is a critical factor in health throughout human development. The aims of this scoping review are to (i) elucidate the differences between the youth (post-natal day 21-65 for rodents, 2-7 years for non-human primates, and 10-25 years for humans) microbiome with other life stages and (ii) identify youth-specific microbial changes associated with substance use. METHODS: Peer-reviewed studies published up to May 2023 were identified in PubMed and SCOPUS and included gut and oral microbiome studies from rodents, non-human primates, and humans (N = 1733). Twenty-six articles were determined eligible based on inclusion criteria (aim 1: n = 19, aim 2: n = 7). RESULTS: The adolescent and young adult oral and gut microbiomes are distinct compared to other life stages, within both non-human and human models. While there is limited research in this area, the microbiome appears to be vulnerable to substance use exposure earlier in life, including substances commonly initiated and escalated during adolescence and young adulthood (i.e. alcohol, cannabis, and tobacco). CONCLUSIONS: Studies across the lifespan indicate that adolescence and young adulthood are distinct periods of development, where the microbiome is sensitive to exposures, including substance use. There is a need for more studies focused on the adolescent and young adult microbiome and substance use, as well as focused on the oral microbiome during this developmental period. Understanding the gut and oral microbiome during adolescence and young adulthood may provide insight into the pathophysiology of substance use disorders.

Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies.

Alcohol misuse and alcohol use disorder (AlUD) have neurobiological consequences. This meta-analysis of proton magnetic resonance spectroscopy (MRS) studies aimed to assess the differences in brain metabolite levels in alcohol misuse and AUD relative to controls (PROSPERO registration: CRD42020209890). Hedge's g with random-effects modeling was used. Sub-group and meta-regression techniques explored potential sources of demographic and MRS parameter heterogeneity. A comprehensive literature review identified 43 studies, resulting in 69 models across gray and white matter (GM, WM). Lower N-acetylaspartate levels were found in frontal, anterior cingulate cortex (ACC), hippocampal, and cerebellar GM, and frontal and parietal WM, suggesting decreased neuronal and axonal viability. Lower choline-containing metabolite levels (all metabolites contributing to choline peak) were found in frontal, temporal, thalamic, and cerebellar GM, and frontal and parietal WM, suggesting membrane alterations related to alcohol misuse. Lower creatine-containing metabolite levels (Cr; all metabolites contributing to Cr peak) were found in temporal and occipital cortical GM, while higher levels were noted in midbrain/brainstem GM; this finding may have implications for using Cr as an internal reference. The lack of significant group differences in glutamate-related levels is possibly related to biological and methodological complexities. The few studies reporting on GABA found lower levels restricted to the ACC. Confounding variables were age, abstinence duration, treatment status, and MRS parameters (echo time, quantification type, data quality). This first meta-analysis of proton MRS studies consolidates the numerous individual studies to identify neurometabolite alterations within alcohol misuse and AUD. Future studies can leverage this new formalized information to investigate treatments that might effectively target the observed disturbances.

Artificial food coloring affects EEG power and ADHD symptoms in college students with ADHD: a pilot study.

Objectives: Removing artificial food coloring (AFC) is a common dietary intervention for children with Attention-Deficit/Hyperactivity Disorder (ADHD), but has not been tested in young adults. This pilot study examined the effects of AFC on ADHD symptoms and electroencephalography (EEG) in college students with and without ADHD.Methods: At baseline, control and ADHD participants completed the Adult ADHD Self-Report Scale (ASRS), simple and complex attention measures, and resting-state EEG recordings. ADHD participants (n = 18) and a subset of controls (extended control group or EC, n = 11) avoided AFC in their diet for 2 weeks and then were randomized to a double-blind, placebo-controlled crossover challenge. Subjects received either 225 mg AFC disguised in chocolate cookies or placebo chocolate cookies for 3 days each week, with testing on the third day each week. Baseline comparisons were made using Student's t-test or Wilcoxon rank sum tests and challenge period analyses were run using General Linear Modeling.Results: The ADHD group had significantly greater scores on the ASRS (p < 0.001), confirming a symptom differential between groups; however, there were no differences in attentional measures or EEG at baseline. The AFC challenge resulted in an increase in posterior mean gamma power (p = 0.05), a decrease in posterior relative alpha power (p = 0.04), and a marginal increase in inattentive symptoms (p = 0.08) in the ADHD group. There were no effects of AFC in the EC group.Discussion: This study indicates that AFC exposure may affect brainwave activity and ADHD symptoms in college students with ADHD. Larger studies are needed to confirm these findings.

The low glutamate diet improves cognitive functioning in veterans with Gulf War Illness and resting-state EEG potentially predicts response.

Objectives: Gulf War Illness (GWI) is a chronic, multi-symptom disorder with underlying central nervous system dysfunction and cognitive impairments. The objective of this study was to test the low glutamate diet as a novel treatment for cognitive dysfunction among those with GWI, and to explore if baseline resting-state electroencephalography (EEG) could predict cognitive outcomes.Methods: Cognitive functioning was assessed at baseline, after one-month on the diet, and across a two-week double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG) relative to placebo.Results: Significant improvements were seen after one-month on the diet in overall cognitive functioning, and in all other domains tested (FDR p < 0.05), except for memory. Challenge with MSG resulted in significant inter-individual response variability (p < 0.0001). Participants were clustered according to baseline resting-state EEG using k-means clustering to explore the inter-individual response variability. Three distinct EEG clusters were observed, and each corresponded with differential cognitive effects during challenge with MSG: cluster 1 had cognitive benefit (24% of participants), cluster 2 had cognitive detriment (42% of participants), and cluster 3 had mild/mixed effects (33% of participants).Discussion: These findings suggest that the low glutamate diet may be a beneficial treatment for cognitive impairment in GWI. Future research is needed to understand the extent to which resting-state EEG can predict response to the low glutamate diet and to explore the mechanisms behind the varied response to acute glutamate challenge.

Moving past antioxidant supplementation for the dietary treatment of multiple sclerosis.

Current research has demonstrated the definitive presence of oxidative stress in multiple sclerosis (MS). This finding has led to clinical trial research which has indicated that specific antioxidants have the ability to effectively reduce markers of oxidative stress. However, few interventions testing antioxidant supplements have shown efficacy for reducing the symptom burden in the disorder. This paper quickly reviews what is currently known about oxidative stress and antioxidants in MS, explains which nutrients are critical for the creation and maintenance of the myelin sheath, describes potential negative effectors in the diet which may be contributing to oxidative stress, and how these aspects of diet, combined with current knowledge on antioxidants, may be able to be combined into a whole food dietary intervention which can be tested for efficacy in MS.

Power and persuasion in the vaccine debates: an analysis of political efforts and outcomes in the United States, 1998-2012.

CONTEXT: This article examines trends in state-level childhood vaccine policies in the United States from 1998 to 2012 and explains the trajectories for both vaccine-critical and proimmunization legislative efforts. Successful mobilization by vaccine critics during the height of the autism and thimerosal scares (roughly 1998 to 2003) yielded a few state-level expansions for the most permissive type of exemption from vaccine mandates for public school attendance, those based on personal beliefs. Vaccine-critical positions, however, have largely become discredited. How has vaccine critics' ability to advance preferred policies and prevent the passage of unfavorable legislation changed over time? METHODS: We created a unique data set of childhood vaccine bills (n = 636), introduced from 1998 to 2012 across the 50 state legislatures, and coded them by type of effort (exemption, mandate, mercury ban, and information policies) and outcome. We then mapped out the trends in vaccine policies over time. In order to contextualize the trends we identified, we also reviewed numerous primary sources and conducted interviews with stakeholders. FINDINGS: In general, we found that vaccine critics' legislative success has begun to wane. In only 20 bills in our data set were vaccine critics able to change policy in their preferred direction via the legislative process. Only 5 of those wins were significant (such as obtaining a new philosophical exemption to vaccine mandates), and the last of these was in 2007. Critics were more successful at preventing passage of proimmunization legislation, such as mandates for the human papillomavirus (HPV) vaccine. CONCLUSIONS: Recent legislation in California, Oregon, and Washington that tightened philosophical exemptions by means of informational requirements suggests that vaccine politics may be entering another phase, one in which immunization supporters may be able to counter increasing opt-out rates, particularly in states with recent outbreaks and politicians favoring science-based policies.

Critical perspectives on wellness.

Workplace wellness programs are written into law as exceptions to otherwise protective antidiscrimination provisions, and the Patient Protection and Affordable Care Act expands employers' ability to treat workers differently based on their health. Rather than assume that wellness programs promote health and save money, here I approach them as legally sanctioned discrimination. What exactly wellness discrimination might look like in practice across many contexts is an open question, but there is good reason to be wary of the power of wellness to create and reproduce hierarchy, to promote homogeneity, narrow-mindedness, and moralism about how to live one's life, and to cover for discrimination based on health, weight, income, age, pregnancy, and disability.

Effect of N-acetylcysteine on neural alcohol cue reactivity and craving in adolescents who drink heavily: A preliminary randomized clinical trial.

BACKGROUND: Alcohol craving is related to problematic alcohol use; therefore, pharmacotherapies that modulate alcohol craving are of interest. N-acetylcysteine, an over-the-counter antioxidant, is a candidate pharmacotherapy for adolescent alcohol use with the potential to impact craving. Cue-reactivity paradigms using functional magnetic resonance imaging (fMRI) can identify neural regions implicated in craving and serve as a screening tool for novel pharmacotherapy options. METHODS: This preliminary study examined the effect of N-acetylcysteine on neural reactivity to alcohol cues and subjective craving among 31 non-treatment-seeking adolescents (17.6-19.9 years old, 55% female) who use alcohol heavily. In a randomized cross-over design, participants completed three fMRI sessions: baseline and after a 10-day course of N-acetylcysteine (1200 mg twice daily) and matched placebo. The primary outcome was neural response to alcohol versus non-alcohol beverage cues after N-acetylcysteine versus placebo, with a secondary outcome of self-reported subjective craving. RESULTS: In the full sample (n = 31), there was no effect of N-acetylcysteine versus placebo on neural alcohol reactivity (ps ≥ 0.49; η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ s = 0.00-0.07) or self-reported acute alcohol craving (p = 0.18, η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ = 0.06). However, N-acetylcysteine did reduce self-reported generalized alcohol craving (p = 0.03, η p 2 $$ {\upeta_{\mathrm{p}}}^2 $$ = 0.15). In a subsample of youth who met criteria for past-year alcohol use disorder (n = 19), results remained unchanged. CONCLUSIONS: N-acetylcysteine may not alter neural reactivity to alcohol cues or acute craving; however, it may reduce general subjective alcohol craving among adolescents who consume alcohol heavily.

Multi-modal neuroimaging reveals differences in alcohol-cue reactivity but not neurometabolite concentrations in adolescents who drink alcohol.

BACKGROUND: The objective of this multi-modal neuroimaging study was to identify neuroscience-informed treatment targets for adolescent alcohol use disorder (AUD) by examining potential neural alterations associated with adolescent alcohol use. METHODS: Adolescents (ages 17-19) who heavily used (n=49) or did not use alcohol (n=22) were recruited for a multi-modal neuroimaging protocol, including proton magnetic resonance spectroscopy within the dorsal anterior cingulate cortex (dACC) and an fMRI alcohol cue-reactivity task. The alcohol cue-reactivity task was analyzed across 11 a priori regions-of-interest (ROI), including the dACC, and in an exploratory whole-brain approach. Correlations were run between neurometabolite levels and alcohol cue-reactivity in the dACC. RESULTS: There were no significant group differences in absolute neurometabolite concentrations. Compared to the control group, the alcohol-using group exhibited heightened alcohol cue reactivity in the left amygdala ROI (p=0.04). The whole-brain approach identified higher alcohol cue reactivity in the alcohol-using group compared to controls in the amygdala and occipital regions, and lower reactivity in the parietal lobe. Whole-brain sex effects were noted, with females displaying higher reactivity regardless of group. No significant correlations were found between neurometabolite levels and alcohol cue-reactivity in the dACC. CONCLUSIONS: The null neurometabolic findings may be due to age, relatively low severity of alcohol use, and non-treatment-seeking status of the participants. Females showed overall higher reactivity to alcohol cues, indicating a sex effect regardless of alcohol use history. Higher amygdala reactivity in alcohol-using adolescents suggests that emotional processing related to alcohol cues may be a useful target for future adolescent AUD interventions.

Predictors of Substance Use Initiation by Early Adolescence.

OBJECTIVE: Substance use initiation during early adolescence is associated with later development of substance use and mental health disorders. This study used various domains to predict substance use initiation, defined as trying any nonprescribed substance (e.g., alcohol, tobacco, cannabis), by age 12, using a large longitudinal data set. METHODS: Substance-naive youths from the Adolescent Brain Cognitive Development Study (ages 9-10; N=6,829) were followed for 3 years. A total of 420 variables were examined as predictors of substance use initiation, using a penalized logistic regression with elastic net; domains spanned demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, culture and environment, hormones, neurocognitive functioning, and structural neuroimaging. RESULTS: By age 12, 982 (14.4%) children reported substance initiation, with alcohol being the most common. Models with only self-report predictors had similar prediction performance to models adding hormones, neurocognitive factors, and neuroimaging predictors (AUCtest=0.66). Sociodemographic factors were the most robust predictors, followed by cultural and environmental factors, physical health factors, and parenting behaviors. The top predictor was a religious preference of Mormon (coefficient=-0.87), followed by a religious preference for Jewish (coefficient=0.32), and by Black youths (coefficient=-0.32). CONCLUSIONS: Sociodemographic variables were the most robust predictors of substance use initiation. Adding resource-intensive measures, including hormones, neurocognitive assessment, and structural neuroimaging, did not improve prediction of substance use initiation. The application of these large-scale findings in clinical settings could help to streamline and tailor prevention and early intervention efforts.

Adolescent alcohol use is associated with differences in the diversity and composition of the oral microbiome.

BACKGROUND: Adolescence is a sensitive stage of oral microbial development that often coincides with the initiation and escalation of alcohol use. Thus, adolescents may be particularly susceptible to alcohol-induced alterations in the oral microbiome, though minimal research has been done in this area. Understanding the connection between the oral microbiome and alcohol use during adolescence is important to understand fully the biological consequences of alcohol use to mitigate potential adverse outcomes. METHODS: Saliva samples were collected from adolescents aged 17-19 who used alcohol heavily (n = 21, 52.4% female) and those who did not use alcohol or any other substances (n = 18, 44.4% female). We utilized 16S rRNA sequencing to examine differences in microbial diversity and composition between the groups. RESULTS: For alpha diversity, evenness was significantly lower in the drinking group than the control group as indicated by Pielou's evenness, Shannon, and Simpson indices. There were no statistically significant findings for beta diversity. Differential abundance analyses revealed higher abundances of Rothia and Corynebacterium in the alcohol-using group using both centered-log-ratio and relative abundance normalization. These genera are known for their high capacity to convert alcohol into acetaldehyde, a toxic metabolite reported to play a role in the neurobiological effects of alcohol. An unclassified Clostridia UCG-014, Streptobacillus, Comamonas, unclassified Lachnospiraceae, and Parvimonas were also identified as significantly different between groups when using only one of the normalization techniques. CONCLUSIONS: This is the first study designed specifically to compare the oral microbiome of adolescents who use alcohol with that of control participants. Our findings reveal distinct alcohol-related differences in microbial composition and taxon abundance, emphasizing the importance of understanding the impact on the oral microbiome of alcohol use during adolescence. Because the oral microbiome is malleable, this study provides foundational work for future prevention and intervention studies.

Pairwise comparisons of three medication adherence outcomes in adolescents who use alcohol.

BACKGROUND: Accurate assessment of medication adherence is important for understanding pharmacotherapy outcomes across all phases of adolescent substance use disorder (SUD) clinical trials. The objective of this study was to describe and assess the pairwise concordance between three commonly used non-biological medication adherence assessment methods in adolescents who use alcohol to inform the selection of medication adherence measures for use in future youth SUD trials. METHODS: Participants (N = 32, 17-19-years-old) took N-acetylcysteine and placebo, in a randomized cross-over design, for 10 days each. Medication adherence was assessed (20 days total) via pill count, medication videos submitted twice daily, and the Medication Event Monitoring System (MEMS®). Lin's Concordance Correlation Coefficient (CCC) assessed concordance and Bland-Altman plots are reported. Linear mixed-effects models with main effects of medication, treatment block (first medication, second medication), and sequence were also run. RESULTS: Medication videos yielded the lowest (64%) and pill count yielded the highest (89%) adherence estimates. CCC values indicated poor correspondence, except between pill count and MEMS. The Bland-Altman plots showed good pairwise agreement between all methods. Linear mixed-effects models indicated a difference between the first and second cross-over medication, with adherence estimates being lower for the second medication, regardless of whether it was N-acetylcysteine or placebo. CONCLUSIONS: The study yielded important and practical information. First, incorporating more than one method of adherence assessment may capture estimated floor and ceiling adherence in the absence of a biological marker. This is particularly relevant for remote or hybrid studies where bio-marker collection is challenging. Selection of the assessment methods will depend on study goals. Second, the continuation of medication adherence research can benefit each phase of clinical trials and inform rigorous pharmacotherapy evaluation.

N-acetylcysteine does not alter neurometabolite levels in non-treatment seeking adolescents who use alcohol heavily: A preliminary randomized clinical trial.

Current treatments for adolescent alcohol use disorder (AUD) are mainly psychosocial and limited in their efficacy. As such, pharmacotherapies are being investigated as potential adjunctive treatments to bolster treatment outcomes. N-acetylcysteine is a promising candidate pharmacotherapy for adolescent AUD because of its tolerability and demonstrated ability to modulate glutamatergic, GABAergic, and glutathione systems. The primary objective of this double-blind, placebo-controlled, within-subjects crossover preliminary investigation was to measure potential changes within glutamate + glutamine (Glx), GABA, and glutathione levels in the dorsal anterior cingulate cortex (dACC) using proton magnetic resonance spectroscopy during 10-days of N-acetylcysteine (1200 mg twice daily) compared to 10-days of placebo in non-treatment seeking adolescents who use alcohol heavily (N = 31; 55% female). Medication adherence was confirmed via video. Effects on alcohol use were measured using Timeline Follow-Back as an exploratory aim. Linear mixed effects models controlling for baseline metabolite levels, brain tissue composition, alcohol use, cannabis use, and medication adherence found no significant differences in Glx, GABA, or glutathione levels in the dACC after N-acetylcysteine compared to placebo. There were also no measurable effects on alcohol use; however, this finding was underpowered. Findings were consistent in the subsample of participants who met criteria for AUD (n = 19). The preliminary null findings in brain metabolite levels may be due to the young age of participants, relatively low severity of alcohol use, and non-treatment seeking status of the population investigated. Future studies can use these findings to conduct larger, well-powered studies within adolescents with AUD.

Sex and Gender Differences in Simultaneous Alcohol and Cannabis Use: a Narrative Review.

Purpose of Review: The aim is to review recent literature on sex and gender differences in patterns of use, motives, pharmacological effects, and consequences of simultaneous alcohol and cannabis use (SAC). Recent Findings: Men engage in SAC more frequently than women. Women may have more substance-specific motives for use, while men tend to consistently endorse social/enhancement motives for both alcohol and cannabis. Regarding pharmacological effects, women experience the same subjective effects as men do at lower levels of use, with some evidence that women modulate cannabis use during simultaneous use episodes to avoid greater subjective intoxication. Finally, women appear more vulnerable to experiencing a range of positive and negative consequences from SAC relative to men. Summary: Research has identified several important sex/gender differences in SAC and its correlates and consequences. However, research has primarily focused on white and cisgender populations, with a need for more research among racial/ethnic and gender minorities.

The legitimacy of vaccine critics: what is left after the autism hypothesis?

The last dozen years have seen a massive transnational mobilization of the legal, political, and research communities in response to the worrisome hypothesis that vaccines could have a link to childhood autism and other developmental conditions. Vaccine critics, some already organized and some composed of newly galvanized parents, developed an alternate world of internally legitimating studies, blogs, conferences, publications, and spokespeople to affirm a connection. When the consensus turned against the autism hypothesis, these structures and a committed membership base unified all the organizations in resistance. This article examines the relationship between mobilization based on science and the trajectory of legitimacy vaccine criticism has taken. I argue that vaccine critics have run up against the limits of legitimate scientific argument and are now in the curious position of both doubling down on credibility-depleting stances and innovating new and possibly resonant formulations.

Credibility battles in the autism litigation.

That vaccines do not cause autism is now a widely accepted proposition, though a few dissenters remain. An 8-year court process in the US federal vaccine injury compensation court ended in 2010 with rulings that autism was not an adverse reaction to vaccination. There were two sets of trials: one against the measles-mumps-rubella (MMR) vaccine and one against the mercury-based preservative thimerosal. The MMR story is more widely known because of publicity surrounding the main proponent of an MMR-autism link, British doctor Andrew Wakefield, but the story of thimerosal in court is largely untold. This study examines the credibility battles and boundary work in the two cases, illuminating the sustaining world of alternative science that supported the parents, lawyers, researchers, and expert witnesses against vaccines. After the loss in court, the families and their advocates transformed their scientific arguments into an indictment of procedural injustice in the vaccine court. I argue that the very efforts designed to produce legitimacy in this type of lopsided dispute will be counter-mobilized as evidence of injustice, helping us understand why settling a scientific controversy in court does not necessarily mean changing anyone's mind.