OBJECTIVE:This review conceptualizes ethanol and methanol neurotoxicity through a tri-domain framework encompassing motivational, degenerative, and developmental mechanisms, and integrates decades of rodent research into a multidimensional map of how alcohol reshapes the brain. It emphasizes exposure route-specific paradigm, oral gavage, vapor inhalation, and intraperitoneal administration, as translational anchors linking behavioral, metabolic, and molecular signatures. METHOD:A literature search was conducted across PubMed, Scopus, and Web of Science databases for articles published between June 1999 and May 2026. Search terms integrated keywords related to alcohol exposure routes and neurotoxicity (e.g., ethanol, methanol, neurodegeneration, prenatal/adolescent exposure, oral gavage, vapor, and injection paradigms). Boolean operators and manual citation tracking were utilized. Out of 205 initially identified articles, 182 studies meeting selection criteria were included in the final synthesis. RESULTS:Chronic gavage models effectively capture nutrient-metabolic interactions under sustained drinking, vapor inhalation isolates central oxidative and inflammatory cascades under stress-neutral conditions, and injection paradigms offer mechanistic precision for acute mitochondrial dysfunction. Hybrid protocols reveal time-coded dynamics of degeneration and recovery. Developmental studies demonstrate that prenatal and adolescent alcohol exposure drives epigenetic remodeling, DNA methylation drift, histone acetylation, and microRNA dysregulation, leading to long-term deficits in cortical maturation and cognitive control. Methanol models extend this neuroenergetic spectrum through formate-driven mitochondrial failure and optic-cerebellar injury. CONCLUSIONS:The tri-domain framework integrates diverse rodent paradigms across exposure routes and life stages. To enhance clinical translation, future research should leverage multi-omics, connectomic mapping, and bioengineered platforms (e.g., organoids and brain-on-chip) to identify early molecular markers and targeted neuroprotective interventions.
OBJECTIVE:Opioid overdose deaths continue to increase among Black Americans, despite decreases in deaths overall nationwide. Older Black men (beginning in their 50s) have a heightened risk, dying from opioid overdoses at a five-fold increase from 2015-2023. However, research identifying differences in risk factors for opioid overdose among older Black men compared to younger Black men is limited. METHOD:The current study is a secondary analysis of survey data from a study highlighting drug misuse and treatment among Black adults in Kentucky, and compares Black men 51 and older (n = 125) to Black men 50 and younger (n = 271) on the following overdose risk factors: opioid use, stimulant use, polydrug use, stimulant and opioid co-use, injection drug use, pain, and having a doctor deny pain medication. The sample includes Black men residing in Kentucky, a state with the fourth highest opioid overdose rates in the U.S. RESULTS:Results indicate that Black men 51 and older report more stimulant use, U = 10740.50, p < .001, r = -.35; stimulant/opioid co-use, B = -1.23, p < .001; OR = .29, 95% CI = .18 - .47; polydrug use, t(223.14) = 2.46, p = .02; and pain, B = -.62, p = .008; OR = .54, 95% CI = .34 - .85; than men 50 and younger. CONCLUSIONS:Findings illustrate differential prevalence of overdose risk factors among Black men 51 and older compared to men 50 and younger. Opioid overdose prevention considerations are discussed, including assessing identified risk factors among older Black men.
OBJECTIVE:This study evaluates whether pandemic-era "alcohol-to-go" laws, adopted in most U.S. states to support restaurants and bars, produced measurable effects on economic activity and impaired driving. METHODS:We used a staggered difference-in-differences design to compare outcomes in states that adopted alcohol-to-go laws between 2020 and 2021 to never-adopting states. Policy adoption dates were drawn from the Alcohol Policy Information System. Outcomes were measured using three complementary datasets: (1) SafeGraph Patterns for weekly restaurant and bar visits (2019-2022), (2) the National Incident-Based Reporting System (NIBRS) for non-fatal DUI arrests (2018-2022), and (3) the Fatality Analysis Reporting System (FARS) for alcohol-impaired traffic fatalities (2018-2022). Analyses were conducted at the county-month level. RESULTS:Alcohol-to-go laws did not produce consistent or durable changes in levels of restaurant or bar visitation. Average treatment effects on visits were small and statistically insignificant across adoption cohorts. Similarly, we found no systematic evidence that alcohol-to-go laws affected DUI arrest rates or alcohol-involved traffic fatalities. The instances where we found significant effects were limited to isolated adoption cohorts or settings and lacked broader generalizability. CONCLUSIONS:Alcohol-to-go policies neither delivered the economic relief anticipated by policymakers nor generated the public safety harms feared by critics. Findings suggest these laws produced limited, context-dependent effects. As states debate whether to make such provisions permanent, evidence indicates caution is warranted: benefits appear narrow while risks remain uncertain.
OBJECTIVE:The prevalence of cannabis use has increased sharply from adolescence through young adulthood in recent U.S. cohorts. However, little is known about how cannabis-specific risk factors and their associations with use vary during these developmental periods. Understanding these associations among Latinx youth, the fastest-growing ethnic minority group, and within urbanicity groups, which may influence risk, is critical. METHOD:Data were from Latinx participants ages 14-29 (N=29,061) in the 2015-2019 National Survey on Drug Use and Health. Time-varying effect models were used to estimate age trends in any and weekly 30-day cannabis use and three key risk factors: perceived risk of monthly and weekly cannabis use and perceived ease of access. Additional models assessed age-varying associations between each risk factor and cannabis use. All models were stratified by urbanicity (large urban, small urban, and rural). RESULTS:Cannabis use and perceived ease of access increased with age and peaked in early adulthood, whereas perceived risks of cannabis use declined with age. These developmental prevalence patterns were broadly similar across urbanicity groups. Risk factors were consistently associated with greater odds of cannabis use across the age range, with the strongest associations observed in early adolescence. Overall association patterns differed only slightly by urbanicity. CONCLUSIONS:Findings highlight important developmental shifts in cannabis use and associated risk factors from adolescence through young adulthood among Latinx youth. Developmentally timed prevention strategies are needed to address rising cannabis use during adolescence and young adulthood in this growing population.
OBJECTIVE:Evidence-based drug treatment is a vital component of an effective response to substance use inequities in the United States (US). Unfortunately, many drug treatment models were developed in western contexts and may fail to account for Indigenous cultures and values. The experiences of Indigenous peoples in drug treatment programs have not been well studied, leading to a dearth of knowledge about factors that facilitate or impede recovery. We aim to explore perceptions about drug treatment and associated experiences among Indigenous peoples in recovery in the northern Midwest US. METHOD:Semi-structured interviews with Indigenous peoples in recovery and residing in the northern Midwest US (n=17) were conducted to explore perceptions about drug treatment and associated experiences and challenges. Participants were recruited on or near the reservation lands of a collaborating Tribal Nation. Interviews were analyzed using an inductive thematic analysis. RESULTS:Indigenous peoples in recovery were often motivated to seek drug treatment after experiencing significant life events. Access to drug treatment was severely limited. Few participants reported having used medications for opioid use disorder (MOUD); however, many described conflicting attitudes about MOUD utilization with tensions arising between how they perceived it as a pathway to recovery and as replacing one form of drug dependence with another. People explained that they engaged in cultural practices while in drug treatment programs and emphasized the need for gender-specific services. CONCLUSIONS:Mitigating harms of the addiction crisis in Indigenous communities requires enhanced access to evidence-based drug treatment services.
OBJECTIVE:Δ9-THC edibles are widely marketed as federally compliant industrial hemp under the 2018 Farm Bill (≤0.3% Δ9-THC by dry weight). We evaluated whether the labeled Δ9-THC content in edibles marketed as "hemp" could be supplied using cannabis material meeting that threshold without exceeding the mass of the edible. METHOD:From October 2025 to February 2026, we identified online retailers marketing Δ9-THC edibles as hemp to U.S. consumers. For each product, we examined Δ9-THC content (mg), unit weight (g), and sugar content (g) from product labels and/or laboratory reports. We calculated the minimum cannabis mass required to supply the Δ9-THC content, assuming the maximum legal concentration (0.3%). Products were classified as mathematically infeasible when required cannabis mass exceeded available non-sugar mass (primary test) or total product mass (ultra-conservative test). Prevalence estimates used bootstrap confidence intervals (2,000 replications; clustered by brand). RESULTS:80% of products would have to contain mathematically impossible portions of cannabis (95% CI: 72-88%; n=297); the median product required cannabis material equal to 160% of available non-sugar mass. 2% required more cannabis than the total product mass (95% CI 0%-4%; n=380). Across all edible types, most appear unable to obtain their Δ9-THC content from lawful hemp material. CONCLUSIONS:Most Δ9-THC edibles marketed as "hemp" appear infeasible to manufacture using cannabis material containing ≤0.3% Δ9-THC by dry weight without exceeding the available product mass, even under highly conservative assumptions. Thus, most appear to depend on marijuana as an ingredient, which has substantial regulatory and public health implications.
OBJECTIVE:Reliable measurement of adolescent substance use is critical for accurately characterizing developmental risk, yet the consistency of commonly use self-report methods remains uncertain. Here, consistency of past 30-day substance use self-report data (alcohol, cannabis, nicotine) was compared between the timeline follow-back and monthly retrospective surveys in a sample of adolescents and young adults. METHOD:N=94 participants (19-21-years-old, 62% female) were drawn from an ongoing longitudinal study. Measurements consisted of in-person timeline follow-back interview and mobile monthly retrospective surveys assessing past 30-day substance use; these timelines were harmonized to assess full overlap in reporting between modalities. Dimensions of reliability between modalities and concurrent validity with measures of substance use consequences, craving, and use disorder symptoms were analyzed. RESULTS:Across substances (alcohol use days, cannabis use episodes, nicotine use episodes) rank correlations ranged from strong to very strong; however, significant within-person differences were observed for nicotine and cannabis. Nicotine use had poor agreement between the in-person and mobile survey modalities (ICC=0.30), while alcohol (ICC=0.91) and cannabis (ICC=0.88) were excellent and good, respectively. Concurrent validity differed between modalities for cannabis symptoms and problem outcomes but were comparable for alcohol and nicotine. CONCLUSIONS:Findings reflect nuanced measurement considerations for substance-specific patterns. While largely no differences between modalities and within-subjects were observed for alcohol use days, self-report differences emerged for cannabis and nicotine use, depending on the outcome assessed. Implications are discussed in the context of prospective, longitudinal studies of adolescents and young adults, while attempting to reduce participant burden and maintain reporting accuracy.
OBJECTIVE:Alcohol use plays a role in college sexual assaults. Given that more restrictive state alcohol policy environments have been associated with less binge drinking we tested whether these environments were associated with reduced risk of sexual assault victimization in college students. METHOD:Repeated cross-sectional National College Health Assessment surveys of 876,326 students (ages 18-24) from 2008-2019 were linked to time-varying, state-level Alcohol Policy Scale (APS) scores indexing the efficacy and implementation of 29 policies. Students reported five past-year sexual victimization experiences, formed into a binary composite, as well as 2-week binge drinking. RESULTS:Binge drinking was associated with significantly higher odds of sexual assault (OR = 2.22, p<0.0001 for the composite measure). In states with higher APS scores (more restrictive) students had lower odds of experiencing unwanted sexual touching [OR = .93 for women; OR = .81 (stronger) for men, p<.0001] and men had lower odds of experiencing attempted non-consensual penetration (OR = .81, p<.0001). CONCLUSIONS:State alcohol policies that reduce the prevalence of binge drinking may play a role in preventing some forms of sexual assault. Findings are consistent with the importance of multi-level (state-, community-, campus-level) and multi-target (e.g., alcohol misuse, bystander training) prevention approaches.
OBJECTIVE:The Acquired Preparedness Model (APM) theorizes that psychosocial learning is a mechanism linking impulsive personality traits to various risky behaviors. Prior research on acquired preparedness has predominantly examined between-person associations, enrolled civilian samples, and focused on one behavior (e.g., alcohol use). This secondary analysis used three waves of biannual survey data to test temporal relations among impulsivity, alcohol and cannabis use expectancies, and quantity/frequency among Veterans deployed post-9/11/2001. METHOD:Veterans reporting lifetime cannabis use (N=361) completed measures of urgency (UPPS-P), alcohol and cannabis use expectancies, and past-month alcohol and cannabis frequency and quantity at baseline, 6 and 12-months. Four separate Random Intercept Cross-Lagged Panel Models tested between- and within-person associations among urgency, alcohol/cannabis expectancies, and alcohol/cannabis use frequency or quantity. RESULTS:Within persons, 6-month alcohol or cannabis expectancies did not mediate associations between baseline urgency and 12-month alcohol or cannabis use indices. Urgency was not associated with positive alcohol or cannabis expectancies at any assessment. Between persons, urgency was associated with more positive alcohol and cannabis expectancies. Positive expectancies were associated with higher use frequency and quantity across both substances, whereas negative expectancies were associated with lower cannabis use frequency and quantity. CONCLUSIONS:Acquired preparedness may be more applicable to predicting alcohol and cannabis use behaviors between rather than within Veterans over time. Future research should consider how sociocultural factors may impact acquired preparedness among Veterans, and whether these processes unfold differently in relation to substance use outcomes during shorter time periods and across unique developmental stages.
OBJECTIVE:Cannabis co-use is common among people with HIV (PWH) who smoke cigarettes yet is infrequently measured in smoking cessation trials. We report the relationship of baseline co-use status, HIV-related variables, and factors associated with tobacco treatment success (e.g., psychosocial characteristics) among PWH enrolled in an ongoing RCT evaluating a tailored app-based smoking cessation treatment. METHOD:U.S. adults who smoked ≥5 cigarettes per day and were willing to set a quit date were recruited nationally online and via community-based HIV clinics in Florida. At baseline, HIV-related variables, socio-demographics, psychosocial characteristics, tobacco use history, cannabis use history and modality, and other substance use were assessed. Participants were classified as co-using at baseline if they reported using any form of cannabis in the past 30 days. RESULTS:Participants who co-used cannabis (n=142, 28%) vs. did not (n=370, 72%) were more likely to be younger, Black, lesbian, gay, or bisexual, live in a household with another person who smokes, use other combustible tobacco products, report other recreational drug use in the past year, and have higher self-reported health. Compared to participants who did not use cannabis, co-use participants more often reported missed doses of ART in the past month (53% vs. 37%), loss of appetite or change in the taste of food (48% vs. 38%), frequent alcohol use, financial strain, loneliness, discrimination, and better perceived general health (p values < .05). They frequently reported blunt use and same-occasion cannabis and tobacco use. CONCLUSIONS:Study findings indicate that PWH who co-use experience elevated behavioral and psychosocial risk factors associated with reduced smoking cessation success and worse HIV-related outcomes.
OBJECTIVE:Attrition can bias longitudinal findings, including those on alcohol use. We examined predictors of follow-up engagement in a multi-site neuroimaging cohort of youth. METHOD:Data were drawn from the first nine annual waves of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), which recruited 831 participants aged 12-21 years in 2013-2014 (52% female). Follow-up engagement was modeled as the total number of completed follow-up visits (0-9, excluding baseline) using Poisson regression with multiple imputation and family-cluster-robust standard errors. Secondary analyses examined categorical engagement levels. Primary predictors included exceeding age- and sex-specific baseline alcohol use thresholds, externalizing symptoms, race, and demographic and family factors. RESULTS:Overall engagement was high, with participants completing an average of approximately 9 of 10 possible visits. In Poisson models, exceeding baseline alcohol use thresholds was associated with a modest reduction in follow-up visits, although this did not reach statistical significance (IRR = 0.940, 95% CI: 0.881-1.004, p = .064). Externalizing symptoms were not significantly associated with engagement (IRR = 1.001, 95% CI: 0.998-1.003, p = .647). Sibling co-enrollment was associated with greater engagement (IRR = 1.058, 95% CI: 1.021-1.097, p = .002), while other factors showed small or non-significant associations. CONCLUSIONS:Follow-up engagement was generally high across adolescence into young adulthood. Exceeding baseline alcohol use thresholds showed a modest association with reduced engagement, although not statistically significant in the count model. Externalizing symptoms were not associated with engagement. Categorical analyses suggested a stronger association between exceeding baseline alcohol use thresholds and lower engagement groups. These findings may help identify participants who could benefit from additional engagement efforts.
OBJECTIVE:Impulsivity, a complex construct linked to addictions, is often inconsistently assessed and conceptualized, making it difficult to effectively target in addiction treatment. The current study aimed to identify neural substrates underlying distinct impulsivity domains and explore their relationships with alcohol use and stress in both women and men. METHOD:We utilized a whole-brain machine learning strategy, connectome-based predictive modeling (CPM), to investigate brain networks linked to four composite impulsivity-related domains previously identified in the NIAAA-funded Brain and Alcohol Research in College Students dataset: impulsive action, approach/appetitive motivation, impulsivity/compulsivity, and behavioral inhibition/punishment sensitivity (BIPS). CPM (5-fold cross-validation, 100 repeats, and permutation testing) was applied using Monetary Incentive Delay Task fMRI data from 287 undergraduates. Identified networks were examined in relation to alcohol use and stress across sexes. RESULTS:The CPM model predicting BIPS was significant (r = 0.24, p = .001). Higher BIPS was associated with increased connectivity between default mode, motor/sensory, and cerebellar networks, and decreased connectivity among medial frontal, frontoparietal, default mode, and motor/sensory networks. BIPS network strength differed by sex (t(285) = 8.26, p < .001), with negative associations with alcohol use (p < .05) in men and positive associations with stressful life events (p < .05) in women. CONCLUSIONS:Identifying a neuromarker of BIPS in young adults may inform targeted interventions for impulsive behaviors, considering sex differences. Future research should explore whether neuromodulation or other interventions targeting this network could mitigate problem drinking in men and stress-related concerns in women.
OBJECTIVE:This study sought to test whether negative urgency moderates the relationship between Posttraumatic Stress Disorder (PTSD) and alcohol demand. METHOD:In this secondary data analysis, participants (N=101; 58.2% female) completed an online procedure which included, a trauma cue manipulation (expressive writing exercise), pre- and post-cue versions of the Alcohol Purchase Task (APT, measuring alcohol demand), and self-report measures of trauma history, alcohol use, and PTSD symptoms. Five indices of alcohol demand data were calculated: intensity, breakpoint, Omax, Pmax, and elasticity. Participants were grouped based on PTSD symptom severity (PTSD vs. No PTSD). Path analyses were used to examine negative urgency as a moderator of the association between PTSD and each index of alcohol demand. RESULTS:Negative urgency was a significant moderator for intensity, breakpoint, Omax, and Pmax, such that high negative urgency in the PTSD group was associated with greater alcohol demand post- trauma cue controlling for pre-cue demand. In contrast, low negative urgency in the PTSD group was associated with lower intensity and Pmax post-cue controlling for pre-cue ratings. CONCLUSIONS:Individuals with PTSD and high negative urgency value alcohol more in the context of trauma-cue elicited negative affect. Trait-levels of negative urgency are important for identifying those with PTSD who are at greatest risk for problematic alcohol use and impulsive decision making in the context of a trauma cue.
OBJECTIVE:This study aims to understand the characteristics of people who inject drugs approached by others for injection assistance. METHOD:Peer-referral and outreach were used to recruit rural adults who recently injected drugs in Appalachian Kentucky (n=435). Interviewer-administered questionnaires elicited data on participant characteristics and injection assistance. Descriptive statistics and generalized estimating equations clustered on peer-referral recruitment chain were used for analysis. RESULTS:Nearly one-third (30.1%) reported others had come to them for injection assistance. People approached for assistance were slightly younger (prevalence ratio [PR]: 0.91, 95% confidence interval [CI]: 0.85-0.99) but otherwise, demographically similar to their counterparts. Those approached for assistance were more likely to have tested HCV antibody positive (PR: 1.65, 95%CI: 1.08-2.51), recently (past six months) engaged in distributive syringe sharing (PR: 1.33, 95%CI: 1.05-1.69), used buprenorphine "to get high" (PR: 1.32, 95%CI: 1.01-1.75), witnessed an overdose (PR: 1.71, 95%CI: 1.25-2.32), and used fentanyl test strips (PR: 1.54, 95%CI: 1.14-2.08). They were also more likely to have received safer injection education (PR: 1.43, 95%CI: 1.08-1.84) and less likely to believe that sterile syringes were easy to access (PR: 0.60, 95%CI: 0.40-0.88). Among those who visited the syringe services program (SSP), those approached for injection assistance provided more people with SSP-issued syringes (PR: 1.02, 95%CI: 1.01-1.03) than those not approached. CONCLUSIONS:Injection assistance is common in rural Appalachian Kentucky and those approached for assistance have unmet harm reduction needs. Interventions that improve syringe coverage and strengthen efforts to provide support to peers in this population are needed.
OBJECTIVE:Retail sales of intoxicants, including derived intoxicating cannabis products (DICPs) such as delta-8 tetrahydrocannabinol (THC) and hallucinogenic mushrooms, have rapidly increased throughout the US, despite their sale being federally illegal. This study assessed DICP and hallucinogenic mushroom availability in US smoke shops with differing DICP and psilocybin laws. METHODS:In May-October 2025, using Google's Incognito mode, we searched "smoke shop in [city, state]" across eleven cities in states (California, Colorado, Florida, Maryland, New York, Nevada, Oregon, Pennsylvania, Texas, Virginia, Washington) with differing legal contexts for THC and mushrooms (7 explicitly prohibited DICP sales, 2 decriminalized psilocybin, Amanita was not explicitly illegal in any). We called each store (n=1,023) to assess product availability. Bivariate tests assessed differences by state laws. RESULTS:73.0% (n=747/1,023) answered the phone and responded about DICP availability: 51.4% (n=384/747) reported selling DICPs (39.6% DICPs illegal vs. 80% not explicitly illegal, p<.05; range: 2.0% in New York City to 93.8% in Jacksonville, FL). Overall, 70.2% (n=718/1,023) answered questions about mushroom availability: 59.7% (n=414/718) sold mushrooms (56.6% decriminalized psilocybin vs. 57.9% illegal psilocybin, p=.786; range: 0% in New York City to 84.0% in Las Vegas, NV). Among those selling mushrooms, 54.1% specified they sold Amanita mushrooms, 28.5% did not know mushroom type, and 17.4% said 'something else'. CONCLUSIONS:DICPs were sold widely, including in states where they were expressly illegal (~40%). One-third of retailers were unable to identify mushroom type sold. Collectively, findings suggest the need for greater retail surveillance, education, and enforcement.
