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This narrative review identifies the sex- and gender-related factors that influence individual vulnerability to developing addictive disorders. Addiction arises from the complex interaction between neurobiological and psychosocial factors. Sex-based brain dimorphisms, shaped by genetic, hormonal, and epigenetic influences, lead to differences in neural circuits involved in reward, emotional regulation, and executive functioning. Pharmacokinetic differences, such as higher blood alcohol levels, faster nicotine metabolism, and slower μ-opioid receptor internalization in women, contribute to earlier medical complications and faster addiction progression. Gender, understood as a system of socially constructed roles and expectations, further modulates these vulnerabilities. Traditional masculine norms are associated with higher substance use, while certain aspects of femininity may increase risk (e.g., emotional repression or partner dependence) or serve as protective factors through help-seeking behavior. Sexual and gender minorities experience the most significant disparities. Lesbian and bisexual women show the highest rates of substance use disorders; gay and bisexual men report greater illicit drug use; and bisexual individuals consistently display the highest overall risk. Transgender and non-binary populations exhibit increased prevalence of tobacco, stimulant, and chemsex-related substance use, often as a response to minority stress and exclusion from cisnormative care systems. Psychiatric comorbidity affects 50-80% of cases. Women show higher rates of anxiety, trauma histories, and adverse clinical outcomes. Many face "triple stigma" due to their gender, mental health condition, and substance use. Addressing these disparities requires an intersectional, gender-informed, and culturally competent approach to prevention, diagnosis, and treatment.

Adolescence is a critical developmental window during which exposure to stress and alcohol can induce long-lasting neurobiological alterations. Binge-like alcohol consumption is particularly disruptive to corticostriatal circuits, but the extent to which prior stress history modulates these effects remains poorly understood. Here, we investigated how acute versus repeated restraint stress before intermittent alcohol exposure during adolescence shapes transcriptional changes in the dorsal striatum of male rats. Animals were exposed either to a single (acute) or five-day (repeated) restraint stress at postnatal day (PND) 32-36, followed by four weeks of intermittent intragastric ethanol (3 g/kg) or saline administration. At adult age, striatal mRNA expression of dopaminergic (Drd1, Drd2, Th), glutamatergic (Gls, Gls2, Gria2, Grin2a, Grin2b), endocannabinoid (Cnr1, Cnr2, Napepld, Faah, Dagla, Daglb, Mgll), neurotrophic (Bdnf, Ntrk2), and glial (Gfap, Aif1) genes was quantified. Alcohol exposure upregulated genes associated with glutamate synthesis and receptor signaling, endocannabinoid metabolism, and astrocytic activation. Acute stress amplified alcohol-induced expression of Gls, Gls2, Gria2, Napepld, Faah, Daglb, Ntrk2, and Gfap, while repeated stress blunted these effects and selectively enhanced Drd1, Drd2, Grin2a, and Bdnf expression. Microglial activation (Aif1) was increased by alcohol independently of stress. These results suggest that acute stress sensitizes glutamatergic and endocannabinoid pathways to alcohol, whereas repeated stress engages adaptive mechanisms consistent with the stress inoculation hypothesis. Overall, stress history critically determines the neurobiological outcomes of adolescent alcohol exposure, with implications for resilience and vulnerability to alcohol-induced psychopathology.

Wernicke's encephalopathy (WE) is caused by thiamine deficiency (TD) whose main risk factor is alcohol use disorder. Pathogenic mechanisms associated with WE include mitochondrial dysfunction, oxidative stress and neuroinflammation. This study aims to explore the gene expression signature of certain candidate genes related to neuroinflammation, mitochondrial dysfunction and thiamine metabolism in the hippocampus from animals exposed to chronic alcohol consumption, thiamine deficiency or the combination of both. Male Wistar rats (n=42) were randomly assigned to 4 experimental groups: control (C) receiving tap water or tap water plus thiamine (0.2 g/L), chronic alcohol (CA) forced ingestion for 36 weeks, TD diet and pyrithiamine for 12 days (TDD) and CA combined with TDD. The relative gene expression of neurotrophic factors (Ptn, Mdk, Ptprz), proinflammatory molecules (Tlr4, Ccl2 and Hmgb1), mitochondrial homeostatic factors (Mfn1 and Mfn2) and thiamine metabolism (Tpk1) was analyzed in RNA isolated from the hippocampus across all experimental groups. Differences in gene expression were assessed using non-parametric tests (Kruskal-Wallis). Ptprz mRNA levels tended to be downregulated in the TDD group compared to controls (p=0.06, non-significant) and levels were significantly decreased related to the CA+TDD group (p<0.05). TDD group showed the lowest expression levels of Ptn across all experimental groups, and this decrease was statistically significant compared to the control and CA groups (p<0.05). Our findings indicate a differential gene expression profile of the PTN-MDK-PTPRZ axis in the hippocampus of rats receiving a TD diet but not in the rest of the WE models analyzed (CA and CA+TDD).

Soybeans contain different isoflavones (mainly daidzein) which work as reversible inhibitors of aldehyde-dehydrogenase-2 enzyme (ALDH2). This activity has been related in animal experiments with a reduction of cocaine use. Our aim was to carry out an open-label pilot study to evaluate the possible efficacy of soy isoflavones as natural inhibitor of ALDH2 in cocaine use disorder. Nine subjects with severe cocaine use disorder participated in a single-center, open, non-controlled trial during 12 weeks of treatment and 4 of follow-up. The Substance Use Report (SUR) showed that three subjects (33.3%) reported a cocaine consumption of less than 20% (80% non-use days) from 10 to 12 weeks of the treatment period, from two (22.2%) at baseline, although non-significant. A finding that could not be confirmed by the detection of urine metabolites of cocaine. Seven participants (77.8%) completed the study at 16 weeks and one (1.11%) at 12 weeks. Urine concentrations of isoflavones, demonstrated that eight participants (88.9%) followed the treatment along the study. The Severity Dependence Scale (SDS) score showed a significant decrease between baseline to 12 weeks, baseline to 16 weeks and 12 to 16 weeks; the Brief Substance Craving Scale (BSCS) and Cocaine Selective Severity Assessment (CSSA) decreased their values but not significantly. Significant improvements in different areas of the SF-36 scale were observed: body pain scores decreased from baseline to 16 weeks statistically significant; social function improved its scores from baseline to 12 weeks and from baseline to 16 weeks significantly; the rest of areas increased their scores but not significantly. These findings show lower ratios of cocaine use days, and high retention and adherence to treatment although the acquisition of complete abstinence was not observed. Soy isoflavones could be considered a potential treatment in future research, to be confirmed by placebo-controlled studies with adequate sample size.

Adolescent binge drinking has detrimental effects on brain function, leading to long-lasting impairments in synaptic plasticity, cognition, and behavior. These effects are mediated, in part, by disruption of the endocannabinoid system (ECS) and its cannabinoid type-1 (CB1) receptor. Alcohol consumption also depletes omega-3 fatty acids, which are essential for maintaining cell membrane integrity and supporting brain function. This depletion impairs synaptic plasticity by disrupting endocannabinoid signaling and reducing CB1 receptor expression and function. Conversely, enhancement of the ECS can restore brain function and reverse the loss of endocannabinoid-dependent synaptic plasticity associated with omega-3 deficiency. Notably, omega-3 supplementation has been shown to restore CB1 receptor expression in specific brain regions in adult mice following adolescent alcohol exposure. However, despite the established interplay between alcohol, omega-3, and the ECS, the direct impact of omega-3 supplementation on the subcellular localization of CB1 receptors after alcohol exposure remains poorly understood. In this study, we used immunoelectron microscopy to investigate whether omega-3 supplementation influences CB1 receptor distribution in the hippocampal CA1 region following alcohol withdrawal in adolescent male mice. Our results demonstrate that omega-3 partially restore the excitatory/inhibitory balance disrupted by alcohol, as evidenced by an increased number of excitatory terminals and a significant reduction in inhibitory terminals. However, the distribution and density of CB1 receptors within neuronal and glial compartments remain unchanged following alcohol exposure and omega-3 supplementation. These findings highlight novel structural effects of omega-3 in mitigating alcohol-induced brain damage.

A sex perspective in the behavioural effects induced by alcohol binge exposure during youth or early adulthood remain limited. This study aimed to evaluate the effects of high doses of ethanol on emotional behaviour and cognition in 8-weeks old rats, from a sex perspective. Male and female animals were exposed to ethanol binges (3 g/kg, i.g.; 3 times/day x 4 days) in a 2days on-2days off paradigm and assessed in the elevated plus maze (EPM), forced swimming test (FST), saccharin preference test (SPT), Morris water maze (MWM) and novel object recognition (NOR) test. Baseline differences between control male and females were observed in emotional, motivational and cognitive tasks. Additionally, Intensive Alcohol Exposure (IAE) exerted sex-specific effects in: a) EPM: males showed anxiety and no effect in females; b) FST: depressive-like symptoms in both sexes but more pronounce immobility time in females; c) NOR test: impairment in a short-term memory in both sexes but females displayed improved performance in a long-term versus their controls. No IAE-related effects were found in the SPT or MWM. These results suggest inherent sex-differences in rodent performance in behavioural tests assessing emotional, motivational and cognitive behaviours. Additionally, IAE may impact male and females differently during abstinence in early adulthood. These findings underscore the importance of considering sex as a critical variable for preclinical studies.

Loss of eating control is a crucial factor in developing obesity, which has become a global health concern, causing important cardiovascular, metabolic, emotional, and cognitive co-morbidities. A major cognitive alteration associated with loss of eating control and obesity is the impairment of cognitive flexibility and inhibitory control. An increasing number of studies confirm that gut microbiota is a significant contributor to loss of eating control, obesity, and cognitive function. Therefore, we have investigated whether gut microbiota transfer from humans with impaired/not impaired cognitive flexibility could substantially affect this behavioral response in mice in the context of obesogenic versus standard diet. Mice were pretreated with an antibiotic cocktail and later received a gut microbiota transplant from human subjects. The transferred microbiota was maintained in mice for seven weeks. Afterward, behavioral tests were performed to evaluate different cognitive responses, locomotor activity, anxiety-like, and depression-like behaviors. Antibiotic treatment significantly impaired short-term memory in mice, as previously reported. Furthermore, mice that received microbiota from high and low cognitive flexibility subjects modified their short-term and long-term memory performance depending on the diet exposure. Slight changes were observed in the locomotor activity, primarily in the high-fat diet-fed antibiotic-treated mice, and no significant alterations were observed in anxiety-like or depressive-like behaviors. In summary, this study shows that gut microbiota is a major contributor to cognitive flexibility, which may open novel therapeutic strategies for combating loss of eating control and related metabolic co-morbidities.

Preclinical studies suggest that stimulation of the brain's reward system by high-fat diets (HFD) could act as an alternative reinforcer. The main aim of the present study was to evaluate the effect of a limited and intermittent exposure to an HFD administered during and after exposure to Social Defeat (SD) on a non-effective dose of cocaine-induced Conditioned Place Preference (CPP). Experiment 1 consisted of modulating SD episodes with three different patterns of HFD access: 1h access before each session of SD; 2h access three days a week during the two weeks of SD exposure; and 2h access 4h after each SD. Experiment 2 consisted of modulating the effects of stress on CPP acquisition with three patterns of HFD access: 1h access before each conditioning session; 2h access three days a week throughout the two-week period of the CPP; and 2h access three days a week from the last SD episode to the end of CPP. HFD administered during the period of SD episodes counteracted the increased sensitivity that SD produces on the reinforcing effects of cocaine. Access to HFD before the conditioning session or three days a week (CPP-SD-MWF) during the acquisition of CPP blocked this increased sensitivity. In the striatum, SD induced a decrease in the cannabinoid 1 receptor (Cb1r) gene expression, not affected by HFD, and increased corticotrophin releasing hormone receptor 1 (Crhr1) gene expression, except for those mice fed on HFD after SD encounters. Our findings indicate that a small intake of HFD may attenuate the social stress-induced increase in the rewarding properties of cocaine.