Addiction Biology

Maternal smoking during pregnancy is associated with adverse effects on offspring health through impaired placental structure and function. Nicotine and other tobacco-related compounds readily cross the placental barrier, disrupt metabolic pathways, and increase the risk of long-term developmental disorders in newborn. Here, placental metabolic alterations associated with maternal smoking exposure were examined with metabolomics. We used placental samples from the Kuopio Birth Cohort study from 23 nonsmoking controls pregnancies, 19 pregnancies with early smoking exposure (cotinine detected in first-trimester but not in at-term samples), and 13 pregnancies with continuous smoking-exposure (cotinine detected in both first-trimester and at-term samples). Differences in placental metabolomic profiles were seen between controls and both smoking-exposed groups. For example, increased activity of xenobiotic metabolism pathways showed as elevated CYP1A2-related metabolites, e.g., aminoamide local anesthetic metabolite detected in both smoking-exposure groups (p=0.0042 and 0.0019, respectively). Disruptions in amino acid metabolism were observed, e.g., reduced placental tryptophan levels (p=0.0209 and 0.0237). Placentas from women who quit smoking during showed markers of reduced oxidative stress, lower oxidized glutathione (p=0.0119) and higher ergothioneine (p=0.0426) levels. These findings indicate that many smoking-related effects on the placental metabolome persist beyond acute nicotine exposure, showing long-term biological effects of maternal smoking during pregnancy. Plain language summarySmoking during pregnancy can possibly change how the placenta functions, which also affects the newborns long-term health. In this study, we compared placentas from nonsmokers, women who quit during pregnancy, and those who kept smoking. Clear chemical differences were seen in the placentas of smoking exposed pregnant women. The main changes included lowered levels of tryptophan and glutathione, which are important for growth and protection from stress. These results show that smoking-related changes in the placenta can persist beyond active nicotine exposure.

BackgroundOral pouch products containing nicotine analogues such as 6-methyl nicotine (6MN) were recently introduced to evade federal and state regulations. Preclinical studies demonstrated that 6MN is more toxic than nicotine and binds to nicotinic receptors with higher potency. However, the nicotine analogue contents of oral pouch products and the associated health risks remain unknown. MethodsTwenty-five flavor varieties from three oral pouch product (OPP) brands (Aroma-King, Hippotine-Happy Hippo, MG-Upperdeckys) marketed to contain 6MN were purchased in 2024-25. 6MN was quantified by either GC-FID (Yale) or GC-MS (Duke) to assess the estimated exposure dose (EED) from OPP use. Health risks associated with acute 6MN exposure from a single pouch use were assessed by calculating (i) hazard quotient (HQ) for heart-rate increase, and (ii) margin of exposure (MOE) for convulsions, with HQ more than 1 considered a potential health risk and the acceptable safety threshold value of MOE for proconvulsive effects considered 10. For comparison, both risk measures were determined for Zyn nicotine pouch products. Results6MN contents in analyzed OPPs ranged from 2.96-14.5 mg and diverged significantly from labelled contents for some products. HQs for 6MN OPPs for heart-rate increase ranged from 74-381, compared to 95-162 for nicotine in Zyn. MOEs for convulsion risk ranged from 0.6-2.8, indicating elevated risk. MOEs for nicotine in Zyn products were 3.2-5.4 Conclusions6MN contents in novel pouch products are higher than in popular nicotine pouch products. Consumers using these products are exposed to 6MN levels that may exceed safety thresholds, potentially leading to adverse health effects. Nicotine analogues should be urgently addressed by lawmakers and regulators, and FDA should be authorized to regulate products containing them.

BackgroundObservational studies suggest smoking, cannabis use, alcohol consumption, cannabis use, and substance use disorders (SUDs) may play a role in the susceptibility for respiratory infections and disease, including coronavirus 2019 (COVID-2019). However, causal inference is challenging due to comorbid substance use. MethodsUsing genome-wide association study data of European ancestry (data from >1.7 million individuals), we performed single-variable and multivariable Mendelian randomization to evaluate relationships between smoking, cannabis use, alcohol consumption, SUDs, and respiratory infections. ResultsGenetically predicted lifetime smoking was found to be associated with increased risk for hospitalized COVID-19 (odds ratio (OR)=4.039, 95% CI 2.335-6.985, P-value=5.93x10-7) and very severe hospitalized COVID-19 (OR=3.091, 95% CI, 1.883-5.092, P-value=8.40x10-6). Genetically predicted lifetime smoking was also associated with increased risk pneumoniae (OR=1.589, 95% CI, 1.214-2.078, P-value=7.33x10-4), lower respiratory infections (OR=2.303, 95% CI, 1.713-3.097, P-value=3.40x10-8), and several others. Genetically predicted cannabis use disorder (CUD) was associated with increased bronchitis risk (OR=1.078, 95% CI, 1.020-1.128, P-value=0.007). ConclusionsWe provide strong genetic evidence showing smoking increases the risk for respiratory infections and diseases even after accounting for other substance use and abuse. Additionally, we provide find CUD may increase the risk for bronchitis, which taken together, may guide future research SUDs and respiratory outcomes.

The sense of smell plays a key role in guiding motivated behavior, and olfactory function is impaired in clinical populations with dysfunctional approach-avoidance behavior, including major depressive and alcohol use disorder (AUD). However, whether olfactory impairments are also observed in individuals with substance use disorders (SUDs) other than AUD is currently unknown. This study aimed to evaluate the relationship between olfactory function and SUDs. We tested olfaction in 40 individuals with substance use disorders (SUDs) other than AUD using the Sniffin Sticks odor identification and olfactory threshold tests, versus 112 controls. Group differences were assessed with linear regression models, with diagnosis (SUD vs. controls) as a predictor, controlling for age, sex and smoking. Across a diverse range of substances used, individuals with SUDs had significantly lower identification scores than those in the control group. In contrast, olfactory thresholds did not differ significantly by diagnosis overall. However, exploratory analyses showed that men with SUDs had lower olfactory threshold scores (i.e., higher thresholds) than men in the control group, a difference that was absent in women. These results suggest that olfactory function is impaired in individuals with SUDs relative to controls. There are several plausible pathways by which differences in olfaction could be related to differences in hedonic processing, but longitudinal studies are needed to clarify the timing of olfactory impairment relative to substance use or SUD symptomatology.

Alcohol use disorder (AUD) is known to have a significant genetic component, yet there remains a substantial gap between its heritability and findings from genome-wide association studies. One potential factor contributing to this gap may be genetic interactions, or epistasis, a largely unexplored aspect in the context of AUD. The aim of this study was to investigate the role of epistasis in AUD susceptibility and severity among American Indians, a population that exhibits the highest rates of AUD among all ethnic groups in the U.S. We began by identifying genes previously linked to alcohol dependence and AUD, then expanded this gene set through biological networks, ultimately comprising 3,736 genes and regulatory elements. The final gene set was mapped to over 476K variants in an American Indian cohort of 742 individuals. We performed a pairwise genetic interaction association analysis on the variant set, followed by a bi-clustering procedure to group the interacting SNP pairs into interacting intervals. A total of 114 interacting pairs of genes and regulatory elements were identified to be significantly associated with AUD severity. These genes were enriched for immune system, cell adhesion, neuronal, and disease pathways. Their expressions were particularly enriched in midbrain GABAergic neurons. Our study represents the first large-scale genetic interaction study of AUD in any population. Our findings suggest that epistasis may significantly contribute to the development and progression of AUD.

Tobacco use disorder (TUD) remains a leading cause of preventable mortality, and existing pharmacotherapies yield 12-month abstinence rates below 30%. As cannabis legalization expands, approximately 18-22% of people who use tobacco report concurrent cannabis use, yet the impact of co-use on cessation outcomes and the therapeutic potential of endocannabinoid system (ECS) modulation remain unclear. We conducted a translational systematic review and meta-analysis following PRISMA 2020 guidelines, searching Ovid MEDLINE, Embase, APA PsycInfo, and Web of Science through January 2026 (PROSPERO: CRD420250652724). Three study categories were eligible: observational studies of cannabis co-use and cessation outcomes; preclinical studies of cannabinoid modulators on nicotine-related behaviors; and human experimental studies of ECS-targeted interventions. Of 4,869 records screened, 52 studies met inclusion criteria. Meta-analysis of 18 observational studies (N=229,630) revealed that cannabis use was associated with 35% lower odds of achieving tobacco smoking cessation (OR=0.65; 95% CI: 0.55-0.78; p<0.0001; I{superscript 2}=88.1%). Preclinical evidence (15 studies) demonstrated that CB1 receptor antagonists robustly reduced nicotine self-administration and reinstatement, while cannabidiol (CBD) attenuated both nicotine intake and withdrawal without affecting food reinforcement. Clinical translation of CB1 receptor inverse agonists failed due to psychiatric adverse effects, but CBD showed promise by reducing cigarette consumption by 40%, reversing attentional bias to smoking cues, and alleviating withdrawal severity. These findings distinguish naturalistic cannabis exposure from potentially beneficial targeted ECS modulation, and support CBD as a promising candidate for adequately powered tobacco cessation trials.

Development and severity of alcohol use disorder (AUD) has been linked to variations in gut microbiota and their associated metabolites in both animal and human studies. However, the involvement of the gut microbiome in alcohol consumption of individuals with AUD undergoing treatment remains unclear. To address this, stool samples (n=48) were collected at screening (baseline) and trial completion from a single site of a multi-site double-blind, placebo-controlled trial of Zonisamide in individuals with AUD. Alcohol consumption, gamma-glutamyl transferase (GGT), and phosphatidylethanol (PEth)levels were measured both at baseline and endpoint of 16-week trial period. Fecal microbiome was analyzed via 16S rRNA sequencing and metabolome via untargeted LC-MS. Both sex (p = 0.003) and psychotropic medication usage (p = 0.025) are associated with baseline microbiome composition. The relative abundance of 12 genera at baseline was correlated with percent drinking reduction, baseline and endpoint alcohol consumption, and changes in GGT and PeTH over the course of treatment (p.adj < 0.05). Overall microbiome community structure at baseline differed between high and low responders (67-100% and 0-33% drinking reduction, respectively; p = 0.03). A positive relationship between baseline fecal GABA levels and percent drinking reduction (R=0.43, p < 0.05) was identified by microbiome function prediction and confirmed by ELISA and metabolomics. Predicted microbiome function and metabolomics analysis have found that tryptophan metabolic pathways are over-represented in low responders. These findings highlight importance of baseline microbiome and metabolites in alcohol consumption in AUD patients undergoing zonisamide treatment.

BackgroundGenetic influences account for a substantial proportion of individual differences in alcohol use behaviors (AUBs). However, multiple distinct sets of genes are linked to different AUBs, which may explain their dramatic variability in risk factors and manifestations. In this study, we explore whether intermediate neurobiological traits and alcohol-related cognitions mediate the relationship between polygenic scores (PGS) and multiple AUBs, with the aim to better understand processes captured by different genetic profiles. MethodsUsing results from prior genome-wide association studies, we derived PGS for 6 AUBs in participants from Spit for Science, a longitudinal study of college students in the U.S. (n=4,549). Self-report measures included personality traits, alcohol expectancies, drinking motivations, and alcohol sensitivity measures as well as drinking frequency, drinking quantity, alcohol use disorder (AUD) symptoms, and maximum drinks in 24 hours. Using linear regression and multiple mediation models, we investigated the direct and indirect effects of PGS on AUBs. ResultsIn univariable regression results, PGSs indexing broad AUB dimensions such as drinks per week (DPW) and AUD predicted higher levels of sensation-seeking and multiple drinking motives, while BeerPref PGSs (indexing a variable pattern of alcohol problems associated with a preference for beer) predicted higher negative urgency and lower alcohol sensitivity. Mediational models indicated strong direct and indirect effects of DPW PGSs on multiple AUBs via social/enhancement drinking motives and alcohol sensitivity, indirect effects of AUD PGSs on AUD symptoms via coping motives, and indirect effects of BeerPref PGS on all AUBs via the joint effect of mediators including alcohol sensitivity. ConclusionsThese findings provide initial evidence that the genetic influences on different AUBs are associated with and partially mediated by intermediate neurobiological and cognitive factors, which may be more amenable to intervention. Greater focus on drinking motives and alcohol sensitivity is warranted in genetic research, as well as attention to the heterogeneous pathways linking genes to alcohol use outcomes.

Associations between the fat mass and obesity-associated (FTO) gene and obesity are well-established. However, recent studies have linked FTO to addiction phenotypes and dopaminergic signaling, thus suggesting broader psychiatric implications. We explored this assumption by conducting a phenome-wide association study (PheWAS) across 4,756 genome-wide association studies (GWASs), identifying 26 psychiatric traits associated with FTO at the multiple-corrected significance level. These traits clustered into four categories: substance use, chronotype/sleep, well-being, and neuroticism. To validate these findings, we analyzed a functionally suggestive FTO variant (rs1421085) in a separate cohort, examining its impact on (i) alcohol use based on the Alcohol Use Disorders Identification Test (AUDIT), (ii) subjective well-being based on the WHO (Ten) Well-Being Index, and (iii) neuroticism based on Schafers Five Factor Model (FFM) or the Karolinska Scales of Personality (KSP). Our results confirmed a direct association between rs1421085 and neuroticism that was independent of age, sex, alcohol use, body mass index (BMI), and childhood adversities. Interestingly, while no direct association with alcohol intake was observed, both cross-sectional and lagged longitudinal mediation analyses uncovered indirect relationships between rs1421085 and problematic alcohol use (AUDIT-P), with increased neuroticism acting as the intermediary. Mediation analyses also supported an indirect effect of rs1421085 on lower well-being through the pathways of increased neuroticism and BMI. Our study is the first to validate a direct association between FTO and neuroticism. However, additional studies are warranted to affirm the causal pathways linking FTO to well-being and alcohol use through neuroticism.

Binge drinking is a relatively common pattern of alcohol use among youth with normative frequency trajectories peaking in emerging and early adulthood. Frequent binge drinking is a critical risk factor for not only the development of alcohol use disorders (AUDs) but also increased odds of alcohol-related injury and death, and thus constitutes a significant public health concern. Changes in binge drinking across development are strongly associated with changes in impulsive personality traits (IPTs) which have been hypothesized as intermediate phenotypes associated with genetic risk for heavy alcohol use and AUD. The current study sought to examine the extent to which longitudinal changes in binge drinking and intoxication frequency across adolescence and early adulthood are associated with genetic influences underlying dual-systems IPTs (i.e., top-down [lack of self-control] and bottom-up [sensation seeking and urgency] constructs) alongside genetic risk for alcohol consumption and AUD. Associations were tested using conditional latent growth curve polygenic score (PGS) models in three independent longitudinal samples (N=10,554). Results suggested consistent significant and independent associations across all samples between sensation seeking PGSs and model intercepts (i.e., higher frequency of binge drinking at first measurement occasion) and alcohol consumption PGSs and model slopes (i.e., steeper increases toward peak binge drinking frequency). Urgency PGSs were not significantly associated with changes in binge drinking or intoxication frequency. Collectively, these findings highlight the role of unique but correlated IPT and alcohol-specific genetic factors in the emergence and escalation of binge drinking during adolescence and early adulthood.

BackgroundWith cannabis legalization spreading to more countries for both medicinal and recreational use, grasping its effects on the human body is vital. The endocannabinoid system, governed by natural and external cannabinoid compounds, significantly impacts host metabolism. Working alongside the hosts immunomodulation, it shapes the gut microbiota, yielding benefits for the GI and immune systems. ObjectiveTo assess the link between cannabis treatment and the gut/oral microbiome. MethodsWe extensively searched PubMed, Embase, and Cochrane Librarys CENTRAL until December 9, 2023, for English studies involving adults with clinical abnormalities. Identified studies were analyzed, categorizing by different clinical aspects. Data was then qualitatively and quantitatively synthesized. ResultThe study involved 10 studies encompassing 2511 participants, comprising 2 clinical trials and 8 observational studies. The review provided a range of microbiota by the influence of cannabis usage within different clinical contexts: HIV infection, pain/inflammation, systemic aspergillosis, obesity, cognitive deficits, and oral diseases. Users with anhedonia and HIV infection showed lower -diversity, but those with knee arthritis showed higher -diversity. According to research, 21.4% of MJ cigarette users experienced adverse outcomes; however, these lessened once they stopped smoking. ConclusionThese findings shed light on the complex effects of cannabis use on the human microbiota, underscoring the need for future research on the therapeutic potential of cannabis. This review provides valuable insights to guide future investigations in this field. Registration IDPROSPERO 2022 CRD42022354331 Short SummaryWith the global expansion of cannabis legalization, understanding the effects of cannabis on the human body, particularly among individuals with diverse clinical conditions, is of paramount importance. Through a meticulous systematic review utilizing comprehensive data, our findings uncover that cannabis consumption in adults with varied clinical conditions leads to discernable alterations in the human microbiome. These noteworthy modifications necessitate careful consideration in future investigations exploring the potential beneficial or adverse effects of cannabis treatment on patients.

A family history (FH) of alcohol use disorder (AUD) is associated with increased personal risk for alcohol misuse and AUD. FH is also related to increased impulsivity as evidenced by performance on delay discounting tasks, representing a potential mechanistic link between FH and alcohol misuse. Delay discounting tasks assess individual differences in preferences for smaller, immediate versus larger, delayed rewards, the former being linked to substance misuse. Decision-making on such tasks is underpinned by multiple neural systems, including those supporting reward valuation, cognitive control, and future-oriented thinking. We hypothesized that FH would be associated with differences in one or more neural systems related to delay discounting, with these differences being related to increases in alcohol misuse in young adulthood. We tested 163 first-year college students (ages 18-19) with varying levels of familial risk for AUD on an fMRI delay discounting task. Alcohol misuse was self-reported at baseline and in three yearly follow-up surveys using the Alcohol Use Disorders Identification Test (AUDIT). Alcohol misuse was modeled using a latent growth model, and we examined mediation between FH and alcohol misuse trajectory (AUDIT intercept and slope) through functional activation of brain regions implicated in reward valuation (nucleus accumbens), cognitive control (middle frontal gyrus), and future-oriented thinking (hippocampus). FH was associated with greater activation of the nucleus accumbens, which in turn predicted a steeper AUDIT slope. No other mediators were significant. Our results demonstrate that nucleus accumbens function may be a key mechanism by which FH increases risk for alcohol misuse and AUD.

As the global burden of addiction intensifies, the neurobiological commonalities and distinctions between substance use disorders (SUDs) and behavioral addictions (BAs) remain poorly characterized. This coordinate-based meta-analysis of 59 fMRI articles (n = 2,951) mapped the neural signatures of visual cue-reactivity across the addictive disorders. Our results revealed a universal core network shared by SUDs and BAs centered in the bilateral opercular inferior frontal gyrus, suggesting a shared disruption in inhibitory control. Distinctively, SUDs exhibited a stronger recruitment of a subcortical salience pathway, with greater involvement of the left thalamus ventral anterior nucleus than BAs, potentially reflecting pharmacologically amplified bottom-up salience attribution. Notably, recovery-related patterns diverged in the left medial superior frontal gyrus. Alcohol use disorder was associated with neural restoration, whereas heroin use disorder showed neural decompensation. These neural signatures establish a rigorous neurobiological basis for differentiating substance and behavioral phenotypes, supporting tailored circuit-based precision treatments.

Genetic liability to substance use disorders can be parsed into loci conferring general and substance-specific addiction risk. We report a multivariate genome-wide association study that disaggregates general and substance-specific loci for problematic alcohol use, problematic tobacco use, and cannabis and opioid use disorders in a sample of 1,025,550 individuals of European and 92,630 individuals of African descent. Nineteen loci were genome-wide significant for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries PDE4B was significant (among others), suggesting dopamine regulation as a cross-trait vulnerability. The addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into the genetic architecture of general and substance-specific use disorder risk that may be leveraged as treatment targets.

Any increase in alcohol use is associated with an increase in risk of illness and mortality and consequences of chronic alcohol use include cancer, hypertension, heart and liver disease, and Alcohol Use Disorder. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective anti-glycemic and weight-loss medications with a strong safety record. There is substantial preclinical evidence and mounting retrospective and prospective randomized controlled trial evidence that GLP-1RAs could be effective for reducing alcohol consumption. However, the mechanism by which GLP-1RAs reduce alcohol intake remains unclear. While medications that reduce alcohol intake such as naltrexone and acamprosate have central nervous system action, disulfiram reduces alcohol intake through peripheral mechanisms. Here, we test whether GLP- 1RAs alter alcohols peripheral pharmacokinetics as a potential mechanism of action for their alcohol intake suppressive effects. In this pilot study, twenty participants with obesity in the GLP-1RA or control group consumed a challenge dose of alcohol, and we measured breath alcohol (BrAC) and the subjective effects of alcohol. We observed a delayed rise in BrAC and subjective effects in the GLP-1RA group as compared to controls, that was not explained by nausea. These data provide preliminary evidence that GLP-1RAs could act through peripheral mechanisms to suppress alcohol intake.

BackgroundSmoking is a serious public health issue linked to more than 8 million deaths per year worldwide. It also may lead to nicotine dependence (ND). Smoking can induce long-lasting epigenetic changes. Although epigenetic alterations related to tobacco smoke have been largely studied, few works have investigated ND and its interaction with smoking status (SS). ObjectiveWe investigated the peripheral epigenomic profile of SS and ND in a U.S. male veteran cohort. MethodsDNA from saliva was collected from 1,135 European American (EA) male U.S. military veterans. DNAm was assessed using the Illumina Infinium Human MethylationEPIC BeadChip array. SS was evaluated as: current smokers (n=137; 12.1%) and non-current smokers (never and former smokers; n=998; 87.9%). ND was assessed using the Fagerstrom Test for Nicotine Dependence (FTND). EWAS and co-methylation analyses were conducted for SS and ND. ResultsA total of 450 and 22 genome-wide significant differentially methylated sites (DMS) were associated with SS and ND, respectively (fifteen overlapped sites). We identified 97 DMS (43 genes) in SS-EWAS previously reported in the literature, including AHRR, and F2RL3 genes (p-value range: 1.95x10-83 to 4.5x10-33). ND novel DMS mapped to NEUROG1, ANPEP, and SLC29A1. Co-methylation analysis identified 386 modules (11 SS-related and 19 ND-related). SS-related modules showed enrichment for alcoholism, chemokine signaling pathway, and neurogenesis; while ND-related modules were enriched for cellular adhesion, and nicotine addiction. ConclusionsThis study confirms previous findings and identifies novel and -potentially specific - epigenetic signatures for SS and ND in a sample of EA male veterans.

Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology.

Alcohol approach bias, a tendency to approach rather than to avoid alcohol and alcohol-related cues regardless of associated negative consequences, is an emerging key characteristic of alcohol use disorder (AUD). Reaction times from the Approach-Avoidance Task (AAT) can be used to quantify alcohol approach bias. However, only a handful of studies have investigated the neural correlates of implicit alcohol approach behavior. Graph Theory Analysis (GTA) metrics, specifically, weighted global efficiency (wGE), community detection, and inter-community information integration were used to analyze functional magnetic resonance imaging (fMRI) data of an in-scanner version of the AAT from 31 heavy drinking Veterans with AUD (HDV) engaged in out-patient treatment and 19 healthy Veterans as controls (HC). We found a functional imprint of alcohol approach bias in HDVs. HDVs showed significantly higher wGE values for approaching than for avoiding alcohol, indicating that their brain was more efficiently organized or functionally set to approach alcohol in the presence to alcohol-related external cues. In contrast, Brains of HCs did not show such a processing advantage for either the approach or avoid condition. Further post-hoc analyses revealed that HDVs and HCs differed in how they implemented top-down control when approaching/avoiding alcohol and in how the fronto-parietal control network interacted with subsystems of the default mode network. These findings contribute to understanding the complex neural underpinnings of alcohol approach bias and lay the foundation for developing more potent and targeted interventions to modify these neural patterns in AUD patients.

Cannabis has effects on the insulin/glucose metabolism. As the use of cannabis and the prevalence of type 2 diabetes increase worldwide, it is important to examine the effect of cannabis on the risk of diabetes. We conducted a Mendelian randomization study by using 19 single-nucleotide polymorphisms as instrumental variables for lifetime cannabis use and 14 SNPs to instrument cannabis use disorder, and linking these to type 2 diabetes risk using genome-wide association study data (lifetime cannabis use [N = 184,765]; cannabis use disorder [2,387 cases / 48,985 controls], type 2 diabetes [74,124 cases / 824 controls]). The MR analysis suggested no effect of lifetime cannabis use (inverse variance weighted odds ratio [95% confidence interval] = 1.00 [0.93-1.09], P-value = 0.935) and cannabis use disorder (OR = 1.03 [0.99-1.08]) on type 2 diabetes. Sensitivity analysis to assess potential pleiotropy led to no substantive change in the estimates. This study adds to the evidence base that cannabis use does not play a causal role in type 2 diabetes.

Background and AimsIncreasing evidence suggests that a ketogenic (high-fat, low-carbohydrate) diet intervention reduces alcohol withdrawal severity and alcohol craving in individuals with alcohol use disorder (AUD) by shifting brain energetics from glucose to ketones. We hypothesized that the ketogenic diet would reduce a brain craving signature when individuals undergoing alcohol detoxification treatment were exposed to alcohol cues. MethodsWe performed a secondary analysis of functional magnetic resonance data of n=33 adults with an AUD were randomized to a ketogenic diet (n=19) or a standard American diet (n=14) and underwent three weeks of inpatient alcohol detoxification treatment. Once per week, participants performed an alcohol cue-reactivity paradigm with functional magnetic resonance imaging. We extracted brain responses to food and alcohol cues and quantified the degree to which each set of brain images shared a pattern of activation with a recently validated Neurobiological Craving Signature (NCS). We then performed a group-by-time repeated measures ANOVA to test for differences in craving signature expression between the dietary groups over the three-week treatment period. We also correlated these expression patterns with self-reported wanting ratings for alcohol cues. ResultsFor alcohol relative to food cues, there was a main effect of group, such that the ketogenic diet group showed lower NCS expression across all three weeks of treatment. The main effect of time and the group-by-time interaction were not significant. Self-reported wanting for alcohol cues reduced with KD compared to SA but did not correlate with the NCS score. ConclusionsA ketogenic diet reduces self-reported alcohol wanting, and induced lower brain craving signatures to alcohol cues during inpatient treatment for AUD.