Alcohol and brain structure across the lifespan: A systematic review of large-scale neuroimaging studies.

Alcohol exposure affects brain structure, but the extent to which its effects differ across development remains unclear. Several countries are considering changes to recommended guidelines for alcohol consumption, so high-quality evidence is needed. Many studies have been conducted among small samples, but recent efforts have been made to acquire large samples to characterize alcohol's effects on the brain on a population level. Several large-scale consortia have acquired such samples, but this evidence has not been synthesized across the lifespan. We conducted a systematic review of large-scale neuroimaging studies examining effects of alcohol exposure on brain structure at multiple developmental stages. We included studies with an alcohol-exposed sample of at least N = 100 from the following consortia: ABCD, ENIGMA, NCANDA, IMAGEN, Framingham Offspring Study, HCP and UK BioBank. Twenty-seven studies were included, examining prenatal (N = 1), adolescent (N = 9), low-to-moderate-level adult (N = 11) and heavy adult (N = 7) exposure. Prenatal exposure was associated with greater brain volume at ages 9-10, but contemporaneous alcohol consumption during adolescence and adulthood was associated with smaller volume/thickness. Both low-to-moderate consumption and heavy consumption were characterized by smaller volume and thickness in frontal, temporal and parietal regions, and reductions in insula, cingulate and subcortical structures. Adolescent consumption had similar effects, with less consistent evidence for smaller cingulate, insula and subcortical volume. In sum, prenatal exposure was associated with larger volume, while adolescent and adult alcohol exposure was associated with smaller volume and thickness, suggesting that regional patterns of effects of alcohol are similar in adolescence and adulthood.

Alcohol First, Cannabis Last: Identification of an Especially Risky Use Pattern among Individuals Who Co-Use Alcohol and Cannabis.

Background: Alcohol and cannabis co-use is common and confers increased risk for potential harms, such as negative consequences and substance dependence. The existing evidence suggests that factors such as dose of delta-9-tetrahydrocannabinol (THC) consumed and order of use of each substance (i.e., using alcohol or cannabis first or last when co-using) may impact co-use outcomes. Existing co-use research has focused primarily on college-samples or young adults, and few studies have explored these nuanced relations among community samples. Methods: We examined survey data from 87 community members (mean age 32.9 years, 49.4% female) recruited from legal market cannabis dispensaries. Using a combination of regression techniques (i.e., OLS, negative binomial, censor-inflated) we modeled relations among co-use ordering patterns, THC dose and cannabis outcomes as well as interactions with sex assigned at birth and age. Results: Individuals who endorsed co-use reported significantly higher CUDIT scores than those who had never co-used (p < 0.01). Using alcohol first and cannabis last (a pattern we refer to as "AFCL") was more common among females than males (p < 0.01). In the context of typical substance use weeks, more frequently engaging in the AFCL pattern was associated with significantly higher CUDIT scores (p < 0.001) and negatively predicted positive consequences (p < 0.001). Other patterns predicted higher CUDIT scores during heavy use weeks. Conclusions: Results indicate that co-use ordering patterns are related to substance use outcomes. Further research leveraging within-subjects, longitudinal designs is needed to test causal relations between these variables.

Patterns of Simultaneous and non-Simultaneous Use of Cannabis and Alcohol Among American Indian Adolescents.

Background: American Indian (AI) adolescents report earlier initiation and higher rates of cannabis and alcohol use compared to their non-AI peers. Simultaneous cannabis and alcohol (SCA) use is increasingly common. A primary goal of our research was to identify profiles of cannabis and alcohol use, including SCA use, among AI adolescents using latent class analysis (LCA). Method: Data from 1,673 7th - 12th grade students attending 45 reservation-area schools throughout the U.S. who reported using alcohol and/or cannabis in the past year were used to identify the latent classes. Multinomial logistic regression analysis determined associations of sex, grade, and multiethnicity to class membership. Results: A four-class solution was found: 1) SCA-Heavier Use (16.1%); 2) SCA-Lighter Use (25.2%); 3) Primarily Cannabis Use (33.3%); and 4) Primarily Alcohol Use (25.4%). Multinomial regression showed higher grade, identifying as multiethnic, and being female were associated with higher likelihood of membership in the SCA class. Conclusion: AI adolescents were more likely to be classified in the Primarily Cannabis Use class as compared to all other classes. Characterizing profiles of use may help identify those engaging in risky or co-use and help researchers and clinicians better understand how AI adolescents engage with alcohol and marijuana.

Associations between alcohol and cannabis use order, frequency, quantity, and consequences in a college sample of individuals who co-use alcohol and cannabis.

BACKGROUND AND OBJECTIVES: Using both alcohol and cannabis (either at the same time or at different times) is common among college students, and is called "co-use." Using these substances simultaneously, such that their effects overlap, is thought to be an especially risky co-use pattern. Gaining a better understanding of how co-use patterns relate to substance use and consequences could aid prevention and intervention efforts. METHODS: We examined college students (N = 401) who reported using both alcohol and cannabis at least once in the past 30 days. Path analysis was used to explore relations among co-use patterns (number of days in a typical week that participants used both alcohol and cannabis; the number of days using alcohol first, cannabis first, alcohol last, and cannabis last; the number of days of simultaneous use), past-30-day alcohol and cannabis consequences, use frequency, and typical quantities used. RESULTS: Each additional day of using alcohol first was associated with fewer past-30-day cannabis consequences. Each additional day of using cannabis first was associated with fewer alcohol-related consequences. Each additional day of using alcohol and cannabis on the same day and each additional day of simultaneous use were both associated with less cannabis used and alcohol consumed in a typical week. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This study is among the first to identify associations between alcohol and cannabis order and outcomes (i.e., consequences and consumption). Results suggest that modifying which substance is used first on a given day could be a practical intervention strategy for individuals who co-use alcohol and cannabis.

Addendum to "Evaluating substance use outcomes of recreational cannabis legalization using a unique co-twin control design".

An earlier version of this article was published in error. Our prior publication was missing reference to a prior study on this topic. Our prior research has not found an association between recreational cannabis legalization (RCL) and negative psychosocial and psychiatric outcomes. We reported significant associations between RCL with greater cannabis frequency and fewer alcohol use disorder symptoms. The current study expands on our previous research by using a cross-sectional design and different measures of problems from cannabis and alcohol use and including additional substance use variables. The current study found similar results to our previous research.

Evaluating substance use outcomes of recreational cannabis legalization using a unique co-twin control design.

Background: As more states pass recreational cannabis legalization (RCL), we must understand how RCL affects substance use.Objectives: The current study aims to examine the effect of RCL on lifetime and past-year use of cannabis, alcohol, tobacco, and other drugs, frequency of cannabis, alcohol, and tobacco use, co-use of cannabis with alcohol and tobacco, and consequences from cannabis and alcohol use.Methods: We used a unique, co-twin control design of twin pairs who were discordant for living in a state with RCL between 2018 and 2021. The sample consisted of 3,830 adult twins (41% male), including 232 twin pairs discordant for RCL. Problems from alcohol and cannabis use were assessed via the Brief Marijuana Consequences Questionnaire and the Brief Young Adult Alcohol Consequences Questionnaire.Results: Results indicated that the twin living in an RCL state was more likely to endorse past-year cannabis use (OR = 1.56, p = .009), greater number of cannabis use days in the past 6 months (ß = 0.47, p = .019), but not more negative consequences from cannabis use (ß = 0.21, p = .456) compared to their co-twin in a non-RCL state. There were no differences within-twin pairs in frequency of alcohol use (ß=-0.05, p = .601), but the RCL twin reported fewer negative consequences from alcohol use (ß=-0.29, p = .016) compared to their co-twin in a non-RCL state. We did not observe any other differences within-twin pairs on other outcomes.Conclusion: These results suggest that living in an RCL state is associated with greater cannabis frequency but not more negative consequences from cannabis use than living in a non-RCL state.

Effects of cannabidiol in cannabis flower: Implications for harm reduction.

Using a federally compatible, naturalistic at-home administration procedure, the present study examined the acute effects of three cannabis flower chemovars with different tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios, in order to test whether chemovars with a higher CBD content produce different effects. Participants were randomly assigned to ad libitum administration of one of three chemovars (THC-dominant: 24% THC, 1% CBD; THC+CBD: 9% THC, 10% CBD; CBD-dominant: 1% THC, 23% CBD); 159 regular cannabis users (male = 94, female = 65) were assessed in a mobile pharmacology lab before, immediately after, and 1 h after ad libitum administration of their assigned chemovar. Plasma cannabinoids as well as positive (e.g., high, elation) and negative (e.g., paranoia and anxiety) subjective effects were assessed at each time points. Participants who used the CBD-dominant and THC + CBD chemovars had significantly less THC and more CBD in plasma samples compared to participants who used the THC-dominant chemovar. Further, the THC + CBD chemovar was associated with similar levels of positive subjective effects, but significantly less paranoia and anxiety, as compared to the THC-dominant chemovar. This is one of the first studies to examine the differential effects of various THC to CBD ratios using chemovars that are widely available in state-regulated markets. Individuals using a THC + CBD chemovar had significantly lower plasma THC concentrations and reported less paranoia and anxiety while also reporting similar positive mood effects as compared to individuals using THC only, which is intriguing from a harm reduction perspective. Further research is needed to clarify the harm reduction potential of CBD in cannabis products.

Exploring relationships between alcohol consumption, inflammation, and brain structure in a heavy drinking sample.

BACKGROUND: Chronic alcohol consumption is associated with structural brain changes and increased inflammatory signaling throughout the brain and body. Increased inflammation in the brain has been associated with structural damage. Recent studies have also shown that neurofilament light polypeptide (NfL) is released into the systemic circulation following neuronal damage. Although NfL has thus been proposed as a biomarker for neurodegenerative diseases, its connection to alcohol use disorder has not been explored. For this secondary data analysis, we proposed a conceptual model linking alcohol consumption, the pro-inflammatory cytokine IL-6, brain structure, and NfL in heavy drinking participants. METHODS: Of the 182 individuals enrolled in this study, 81 participants had usable data on gray matter (GM) thickness and 80 had usable data on white matter (WM) diffusivity. A subset of participants had NfL (n = 78) and IL-6 (n = 117) data. An estimate of GM thickness was extracted from middle frontal brain regions using FreeSurfer. Estimated mean WM diffusivity values were extracted from Tract Based Spatial Statistics. NfL and IL-6 were measured in blood. Regression models were used to test individual linkages in the conceptual model. Based on significant regression results, we created a simplified conceptual model, which we tested using path analysis. RESULTS: In regressions, negative relationships emerged between GM and both drinks per drinking day (DPDD) (p = 0.018) and NfL (p = 0.004). A positive relationship emerged between WM diffusivity and DPDD (p = 0.033). IL-6 was not significantly associated with alcohol use, GM or WM. The final path model demonstrated adequate fit to the data and showed significant, negative associations between DPDD and middle frontal gyrus (MFG) thickness, and between MFG thickness and NfL, but the association between DPDD and NfL was not significant. CONCLUSIONS: This is the first study to show that heavy drinking is associated with lower GM thickness and higher WM diffusivity and that lower GM thickness is associated with higher circulating NfL. The analyses also show that the effects of drinking do not involve the pro-inflammatory cytokine IL-6.

Cannabinoids and the Microbiota-Gut-Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders.

The endocannabinoid system (ECS) has emerged in recent years as a potential treatment target for alcohol use disorders (AUD). In particular, the nonpsychoactive cannabinoid cannabidiol (CBD) has shown preclinical promise in ameliorating numerous clinical symptoms of AUD. There are several proposed mechanism(s) through which cannabinoids (and CBD in particular) may confer beneficial effects in the context of AUD. First, CBD may directly impact specific brain mechanisms underlying AUD to influence alcohol consumption and the clinical features of AUD. Second, CBD may influence AUD symptoms through its actions across the digestive, immune, and central nervous systems, collectively known as the microbiota-gut-brain axis (MGBA). Notably, emerging work suggests that alcohol and cannabinoids exert opposing effects on the MGBA. Alcohol is linked to immune dysfunction (e.g., chronic systemic inflammation in the brain and periphery) as well as disturbances in gut microbial species (microbiota) and increased intestinal permeability. These MGBA disruptions have been associated with AUD symptoms such as craving and impaired cognitive control. Conversely, existing preclinical data suggest that cannabinoids may confer beneficial effects on the gastrointestinal and immune system, such as reducing intestinal permeability, regulating gut bacteria, and reducing inflammation. Thus, cannabinoids may exert AUD harm-reduction effects, at least in part, through their beneficial actions across the MGBA. This review will provide a brief introduction to the ECS and the MGBA, discuss the effects of cannabinoids (particularly CBD) and alcohol in the brain, gut, and immune system (i.e., across the MGBA), and put forth a theoretical framework to inform future research questions.

Exploring Cannabis and Alcohol Co-Use in Adolescents: A Narrative Review of the Evidence.

Objective: Amidst the evolving policy surrounding cannabis legalization in the United States, cannabis use is becoming increasingly prevalent as perceptions of harm decrease, particularly among adolescents. Cannabis and alcohol are commonly used by adolescents and are often used together. However, developmental research has historically taken a "single substance" approach to examine the association of substance use and adolescent brain and behavior rather than examining co-(or poly-substance) use of multiple substances, such as cannabis and alcohol. Thus, the acute effects of cannabis and alcohol, and the impact of co-use of cannabis and alcohol on the adolescent brain, cognitive function and subsequent psychosocial outcomes remains understudied. This narrative review aims to examine the effects of cannabis and alcohol on adolescents across a number of behavioral and neurobiological outcomes. Methods: The PubMed and Google Scholar databases were searched for the last 10 years to identify articles reporting on acute effects of cannabis and alcohol administration, and the effects of cannabis and alcohol on neuropsychological, neurodevelopmental, neural (e.g., structural and functional neuroimaging), and psychosocial outcomes in adolescents. When adolescent data were not available, adult studies were included as support for potential areas of future direction in adolescent work. Results: Current studies of the impact of cannabis and alcohol on adolescent brain and behavior have yielded a complicated pattern. Some suggest that the use of cannabis in addition to alcohol during adolescence may have a "protective" effect, yielding neuropsychological and structural brain outcomes that are better than those for adolescents who use only alcohol. However, other adolescent studies suggest that cannabis and alcohol co-use is associated with negative health and social outcomes such as poorer academic performance and impaired driving. Conclusion: Variation in study methodologies, policy-level limitations and our limited understanding of the developmental neurobiological effects of cannabis preclude the straightforward interpretation of the existing data on adolescent cannabis and alcohol use. Further research on this topic is requisite to inform the development of effective intervention and prevention programs for adolescent substance users, which hinge on a more comprehensive understanding of how cannabis-and its intersection with alcohol-impacts the developing brain and behavior.

DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity.

Studies have identified strong associations between D2 receptor binding potential and neural responses to rewarding stimuli and substance use. Thus, D2 receptor perturbations are central to theoretical models of the pathophysiology of substance dependence, and epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effects of alcohol exposure on the brain. We hypothesized that epigenetic alterations in the promoter region of the dopamine D2 receptor (DRD2) gene would be associated with cue-elicited activation of neural reward regions, as well as severity of alcohol use behavior. The current study leveraged functional neuroimaging (fMRI) during an alcohol reward paradigm (n = 383) to test associations among DRD2 promoter methylation in peripheral tissue, signal change in the striatum during the presentation of alcohol cues, and severity of alcohol use disorder (AUD). Controlling for age, DRD2 promoter methylation was positively associated with responses to alcohol cues in the right accumbens (partial r = 0.144, P = 0.005), left putamen (partial r = 0.133, P = 0.009), right putamen (partial r = 0.106, P = 0.039), left caudate (partial r = 0.117, P = 0.022), and right caudate (partial r = 0.133, P = 0.009), suggesting that DRD2 methylation was positively associated with robust activation in the striatum in response to reward cues. DRD2 methylation was also positively associated with clinical metrics of AUD severity. Specifically, controlling for age, DRD2 methylation was associated with Alcohol Use Disorders Identification Test total (partial r = 0.140, P = 0.002); Impaired Control Scale total (partial r = 0.097, P = 0.044) and Alcohol Dependence Scale total (partial r = 0.152, P = 0.001). Thus, DRD2 methylation may be a critical mechanism linking D2 receptors with functional striatal brain changes and clinical severity among alcohol users.

Investigating the Relationships Between Alcohol Consumption, Cannabis Use, and Circulating Cytokines: A Preliminary Analysis.

BACKGROUND: In recent years, human and animal studies have converged to support altered inflammatory signaling as a molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD. Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation. Thus, the impact of cannabis on inflammation in AUDs in humans warrants examination. METHODS: We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-8, and IL-1ß in the blood. Among 66 regular drinkers (mean age = 30.08), we examined circulating cytokines and administered questionnaires assessing alcohol consumption and days of cannabis use over the past 90 days. We examined whether alcohol consumption, cannabis use, and gender were associated with changes in circulating cytokines, and whether there was a significant interaction between alcohol and cannabis use predicting blood levels of circulating cytokines. RESULTS: A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1ß. Follow-up moderation analyses indicated a cannabis by alcohol interaction predicting circulating IL-6, such that cannabis nonusers showed a stronger relationship between alcohol and IL-6 compared to cannabis users. CONCLUSIONS: These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use. In addition, the present results provide data to inform future investigations, with the goal of ultimately leveraging knowledge of the role of inflammation in AUDs to develop more effective treatments focused on novel immune targets.

Neural activation during delay discounting is associated with 6-month change in risky sexual behavior in adolescents.

Background: Identifying cognitive and neural mechanisms of decision making in adolescence can enhance understanding of, and interventions to reduce, risky health behaviors in adolescence. Delay discounting, or the propensity to discount the magnitude of temporally distal rewards, has been associated with diverse health risk behaviors, including risky sex. This cognitive process involves recruitment of reward and cognitive control brain regions, which develop on different trajectories in adolescence and are also implicated in real-world risky decision making. However, no extant research has examined how neural activation during delay discounting is associated with adolescents' risky sexual behavior. Purpose: To determine whether a relationship exists between adolescents' risky sexual behavior and neural activation during delay discounting. Methods: Adolescent participants completed a delay discounting paradigm during functional magnetic resonance imaging (fMRI) scanning, and they reported risky sexual behavior at baseline, 3-, 6-, 9-, and 12-month follow-up time points. Latent growth curve models were employed to determine relationships between brain activation during delay discounting and change in risky sexual behavior over time. Results: Greater activation in brain regions associated with reward and cognitive control (caudate, putamen, nucleus accumbens, anterior cingulate, insula, orbitofrontal cortex, inferior frontal gyrus, dorsolateral prefrontal cortex) during delay discounting was associated with lower mean levels of risky sexual behavior but greater growth over the period from baseline to 6 months. Conclusions: Neural activation during delay discounting is cross-sectionally and prospectively associated with risky sexual behavior in adolescence, highlighting a neural basis of risky decision-making as well as opportunities for early identification and intervention.

Interactions between TLR4 methylation and alcohol consumption on subjective responses to an alcohol infusion.

AIMS: Converging evidence has implicated perturbed inflammatory signaling in alcohol use disorders (AUDs), and both animal and human studies suggest that alcohol-induced inflammatory signaling is mediated by Toll-Like Receptor 4 (TLR4). We previously demonstrated that TLR4 is hypermethylated in subjects with AUD compared to control individuals. Examining the relationship between TLR4 methylation and subjective alcohol responses could shed light on the role of TLR4 in promoting AUDs, thereby highlighting its potential as a treatment target. SHORT SUMMARY: Significant interactions were demonstrated between Toll-like Receptor 4 (TLR4) methylation and human alcohol consumption patterns, such that greater methylation was associated with decreased positive and negative self-reported arousal during an alcohol infusion among light-to-moderate drinkers, but increased self-reported positive arousal and physiological arousal (i.e. systolic blood pressure) among heavy drinkers. METHODS: Latent growth models were used to examine the relationship between TLR4 methylation and subjective responses and physiological measures of arousal during an alcohol infusion across 222 drinkers. RESULTS: We observed significant interactions of TLR4 methylation and alcohol use (drinks per week) on intercepts for self-report and physiological arousal measures. Specifically, light-to-moderate drinkers had positive associations between methylation and stimulation and tension (r's = 0.21-0.24), and heavy drinkers had negative associations (r's = -0.15 to -0.21). There were also significant interaction effects on changes in tension (ß = 0.31, P < 0.01), systolic blood pressure (ß = 0.74, P < 0.01) and marginal effects on stimulation (ß = 0.15, P = 0.07) during the infusion, such that methylation was associated with decreased arousal among light-to-moderate drinkers (r's = -0.12 to -0.25) but stable or increased arousal among heavy drinkers (r's = 0.05-0.19). CONCLUSIONS: Findings suggest that the relationship between TLR4 methylation and subjective and physiological arousal during acute alcohol intoxication depends upon on self-reported alcohol use. These data demonstrate the influence of TLR4 on subjective responses to alcohol, thereby supporting the need for further research on its potential as a pharmacological treatment target.

Evaluating the Hispanic Paradox in the Context of Adolescent Risky Sexual Behavior: The Role of Parent Monitoring.

OBJECTIVE: In the United States, Hispanic adolescents are at elevated risk for negative outcomes related to risky sexual behavior. To evaluate potential protective factors for this group, we examined the fit of the Hispanic Paradox for sexual behavior among high-risk youth and the moderating role of parent monitoring. METHOD: We enrolled 323 justice-involved Hispanic youth (73% male; mean age 16 years), and measured generational status, parent monitoring (monitoring location, who children spend time with outside of school, family dinner frequency), and sexual risk behavior. RESULTS: There were no main effects for generational status on sexual behavior. Parent monitoring of location moderated the relationship between generational status and sexual behavior, such that greater monitoring of location was associated with less risky sexual behavior, but only for youth second generation and above. CONCLUSIONS: Rather than direct evidence supporting the Hispanic Paradox, we found a more nuanced relationship for generational status in this sample.

Clinical neuroscience of addiction: similarities and differences between alcohol and other drugs.

BACKGROUND: Existing pharmacological treatments for alcohol use disorder (AUD) and other substance use disorders (SUDs) have demonstrated only modest efficacy. Although the field has recently emphasized testing and developing new compounds to treat SUDs, there are numerous challenges inherent to the development of novel medications, and this is particularly true for SUDs. Thus, research to date has tended toward the "repurposing" approach, in which medications developed to treat other mental or physical conditions are tested as SUD treatments. Often, potential treatments are examined across numerous drugs of abuse. Several repurposed medications have shown promise in treating a specific SUD, but few have shown efficacy across multiple SUDs. Examining similarities and differences between AUD and other SUDs may shed light on these findings and offer directions for future research. METHODS: This qualitative review discusses similarities and differences in neural circuitry and molecular mechanism(s) across alcohol and other substances of abuse, and examines studies of pharmacotherapies for AUD and other SUDs. RESULTS: Substances of abuse share numerous molecular targets and involve much of the same neural circuitry, yet compounds tested because they putatively target common mechanisms have rarely indicated therapeutic promise for multiple SUDs. CONCLUSIONS: The lack of treatment efficacy across SUDs may be partially explained by limitations inherent in studying substance users, who comprise a highly heterogeneous population. Alternatively, medications may fail to show efficacy across multiple SUDs due to the fact that the differences between drug mechanisms are more important than their commonalities in terms of influencing treatment response. We suggest that exploring these differences could support novel treatment development, aid in identifying existing medications that may hold promise as treatments for specific SUDs, and ultimately advance translational research efforts.

Methylation of a CpG site near the ALDH1A2 gene is associated with loss of control over drinking and related phenotypes.

BACKGROUND: The pathophysiology of alcohol use disorders (AUDs) may be influenced by epigenetics processes such as DNA methylation, but the identification of DNA methylation patterns associated with AUDs has largely been limited to a handful of candidate genes. METHODS: Participants were hazardous drinkers from the local community (n = 309). All participants completed a baseline clinical interview in which they reported on their loss of control over drinking. A subsample participated in an ethanol (EtOH) infusion experiment (n = 50). DNA was extracted from saliva samples and assayed on the Illumina Infinium HumanMethylation27 DNA Analysis BeadChip. RESULTS: We identified significant associations between loss of control over drinking and DNA methylation at multiple CpG sites. In follow-up analyses of one of our top results, a CpG site near the ALDH1A2 gene, we found that methylation was negatively associated with rate of intoxication and self-reported feelings of intoxication, consistent with the view that DNA methylation at ALDH1A2 may be associated with changes in alcohol metabolism. CONCLUSIONS: While these findings require replication, they provide evidence that DNA methylation at multiple CpG sites is associated with loss of control over drinking. It may be useful to examine DNA methylation patterns using several related phenotypes to establish the biological coherence of results and to help prioritize markers for further study.

Simultaneous cannabis and psychedelic use among festival and concert attendees in Colorado: characterizing enhancement and adverse reactions using mixed methods.

BACKGROUND: Most studies examining the simultaneous use of cannabis with other drugs have focused on cannabis and alcohol, with fewer studies examining simultaneous use of cannabis with other drugs. The United States is currently experiencing an upward trend in psychedelic use and there is an increasing need to characterize cannabis and psychedelic drug interactions to best inform public health recommendations. MATERIALS AND METHODS: A mixed methods field study design was used to survey participants (N = 128) on their lifetime co-use of cannabis with other drugs. Participants who reported lifetime co-use of cannabis and psychedelics (N = 63) were then asked open-ended questions about their most recent simultaneous co-use experience (i.e., how cannabis enhanced their psychedelic experience and whether they experienced any adverse reactions). We conducted a thematic analysis of responses describing how cannabis enhanced the psychedelic experience (N = 54). However, due to low response rate for participants reporting an adverse reaction (N = 7, 11.1%), responses to this question were not analyzed thematically and are instead presented individually. RESULTS: Themes included tension reduction and balancing of drug effects (N = 27, 50%), enhancement to psychological processes (N = 11, 20.4%), intensified psychedelic drug effects (N = 12, 22.2%), enhanced psychedelic come-down experience (N = 8, 14.8%), and overall ambiguous enhancement (N = 7, 13%). Among participants reporting an adverse reaction, individual responses included increased anxiety and intensity of the experience, decreased sociability, increased negative affect, sleepiness, disassociation, and confusion. CONCLUSION: Additional research is warranted to better characterize cannabis and psychedelic drug interactions to best inform public health recommendations.

Daily diary study of associations between alcohol, cannabis, co-use and sleep quality in individuals with intentions to use cannabis to cope with anxiety.

INTRODUCTION: Sleep problems and anxiety conditions are common comorbidities and may be influenced by cannabis and alcohol use. This study examined daily within-person variation in subjective sleep quality among individuals with anxiety symptoms after cannabis or alcohol were used alone, and after co-use. METHODS: A total of 347 individuals with intentions to use cannabis to cope with anxiety reported their cannabis and alcohol use in the previous 24 h and their previous nights' sleep quality for 30 consecutive days. Mixed-effects models examined whether the within-person daily variation in use of cannabis and alcohol (alone and co-use) was associated with subjective sleep quality. Models also examined whether daily cannabis and alcohol use associations with sleep were moderated by frequency of cannabis, alcohol and co-use during the study period. RESULTS: Compared to non-use, participants reported better sleep after cannabis-use-only and after co-use, but not after alcohol-use-only. People who more frequently use alcohol and cannabis reported sleeping better after cannabis-use-only days compared to those who use cannabis and alcohol less frequently. DISCUSSION AND CONCLUSIONS: The study's utilisation of naturalistic data among individuals with anxiety symptoms replicated previously reported experimental findings among individuals without sleep and anxiety problems that overall, cannabis is associated with higher subjective sleep quality. The results expand upon other research to suggest that more frequent use of alcohol and cannabis may moderate daily associations of cannabis use and sleep, potentially through pharmacokinetics and cross-sensitisation.

Probing the Paradox: Investigating the Impact of Affect, Exercise Type, and Cannabis Use on the Alcohol-Exercise Relationship in College Students.

Alcohol has previously shown a paradoxical positive relationship with exercise behaviors. However, the relationship has not been explored according to type of exercise (aerobic vs. anaerobic), nor has the research considered other contextual variables that commonly co-occur with alcohol use, such as cannabis and mood. This study sought to expand upon previous research to understand how the alcohol-exercise relationship may vary based on exercise type. Additionally, this study included cannabis use and mood as moderators of the alcohol-exercise association. Cross-sectional survey data was collected from college students (N = 335). Negative binomial regression was used to test associations between exercise and alcohol consumption, cannabis use, positive affect (PA), negative affect (NA), and moderating effects of these factors on the alcohol-exercise relationship. Effect sizes are reported from an Incidence Rate Ratio (IRR). Sex assigned at birth (male = 1, female = 0; IRR = 1.34, p = .017), PA (IRR = 1.57, p = .001), and alcohol consumption (IRR = 1.94, p = .037) exhibited positive relationships with exercise. Significant main effects were not observed for negative affect (IRR = 1.17, p = .230), or cannabis use (IRR = 1.00, p = .988). There was a significant interaction between positive affect and alcohol consumption (IRR = 0.87, p = .044) predicting exercise minutes. Alcohol was positively associated with exercise for those with low positive affect (n = 42, b = 12.61, p = .096) and this effect was attenuated as levels of positive affect increased (mean positive affect: n = 232, b = 0.55, p = .926; high positive affect: n = 61, b = -15.86, p = .146). These findings suggest that low positive affect may contribute to the positive link between alcohol use and exercise (especially aerobic exercise) in young people.