The underlying neurobiological mechanisms of chronic alcohol consumption, particularly neuroinflammation and immune system dysregulation, have been extensively studied in recent years. In this process, the identification of objective biomarkers that can predict treatment response and enable personalized medicine approaches is of critical importance. This study aimed to evaluate the potential predictive value of tenascin-C (TNC), an extracellular matrix protein, neopterin, a marker of cellular immune activation and pro-inflammatory cytokines interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), during the treatment process for alcohol use disorder (AUD). This prospective observational cohort study included 30 patients admitted to an AUD treatment centre and 31 healthy controls. Serum TNC, IL-6, TNF-α and IFN-γ levels were measured using the ELISA method. Clinical outcomes were assessed using the SCL-90-R and API-K scales. Serum samples were collected from patients at admission and on the 7th day of detoxification treatment. Baseline serum TNC levels in the alcohol group (131.78 ± 50.92 ng/mL) were significantly higher than in the healthy control group (63.92 ± 23.85 ng/mL). In the alcohol group, TNC (p = 0.007) and AST (p = 0.025) levels decreased significantly, while vitamin B12 (p = 0.002) and platelet count (p = 0.012) increased. No significant difference was observed in neopterin and cytokine levels (TNF-α, IL-6 and IFN-γ) between baseline and follow-up measurements. Clinical assessments showed significant improvements in depression (p = 0.041), anxiety (p = 0.014) and total symptom scores (p = 0.026) on the SCL-90-R scale. ROC analysis showed that a reduction of 28.22% or more in TNC predicted clinical improvement with an overall accuracy rate of 73.33%.

Fentanyl is a potent synthetic opioid associated with overdose. However, little is known about fentanyl-induced molecular adaptations in the habenula and amygdala, two brain regions implicated in opioid use and withdrawal. We performed bulk RNA-sequencing in the rat habenula and amygdala to identify transcriptomic changes associated with fentanyl intake. Male rats self-administered intravenous saline or fentanyl over 22-24 days. Ninety minutes following the final session, brains were collected for transcriptomic profiling. In Hb, we identified 453 differentially expressed genes (DEGs) between saline and fentanyl rats, with upregulated genes associated with synaptic transmission and ionic conductance. In the amygdala, we identified 3041 fentanyl-associated DEGs with upregulated genes implicated in metabolic and vesicular functions. Downregulated genes in both regions were enriched for extracellular matrix functions. Integration of DEGs with single-cell RNA-sequencing data from rodents and humans revealed that fentanyl DEGs were enriched in specific habenula and amygdala cell type markers. Furthermore, fentanyl downregulated DEGs in the amygdala were enriched in genes associated with the risk for substance use disorders. Together, we define how fentanyl intake alters transcriptional programs in the rat habenula and amygdala, and we link these changes to specific human cell types and risk genes for neuropsychiatric disorders and addiction.

This study employed a network meta-analysis to evaluate and compare the efficacy of different exercise intensities (light, moderate and vigorous) on internet addiction and related psychological symptoms in adolescents and young adults. We systematically searched eight databases for relevant randomised controlled trials. A total of 22 studies with 1438 samples were included. A pairwise meta-analysis indicated that exercise interventions across all intensities were associated with improvements in internet addiction, anxiety and negative moods, with moderate-intensity additionally improving depression. The results of the network meta-analysis suggested that light-intensity exercise (SMD = -2.61, 95% CI [-4.29, -0.93], p = 0.002), moderate-intensity exercise (SMD = -2.74, 95% CI [-4.25, -1.22], p < 0.0001) and high-intensity exercise (SMD = -2.55, 95% CI [-4.88, -0.22], p = 0.032) may be associated with a reduction in adolescents' internet addiction. Only moderate-intensity exercise may be associated with a reduction in depression (SMD = -1.19, 95% CI [-2.20, -0.18], p = 0.021) and anxiety (SMD = -1.90, 95% CI [-3.50, -0.30], p = 0.02); light-intensity and high-intensity exercise were not significantly associated with a reduction in depression and anxiety. Light-intensity exercise (SMD = -1.63, 95% CI [-2.85, -0.41], p = 0.009) and moderate-intensity exercise (SMD = -1.55, 95% CI [-2.56, -0.54], p = 0.003) may be associated with reductions in other negative moods. According to the probability ranking of the likelihood of the optimal intervention effect, moderate-intensity exercise (SUCRA = 71) ranked highest for interventions in adolescents' internet addiction, depression (SUCRA = 70.2), anxiety (SUCRA = 68.4) and light exercise (SUCRA = 67.9) ranked highest for negative moods. However, owing to the limitations of sample size and the quality of individual studies, the strength of evidence needs to be further validated by more standardised, high-quality studies.

4F-ABUTINACA, a fourth-generation synthetic cannabinoid, has been identified in branded herbal smoking mixtures and e-cigarettes seized in China. However, its potential for abuse and its corresponding neurotoxic effects remain poorly understood. In the present study, we evaluated the abuse potential of 4F-ABUTINACA using the intravenous self-administration (IVSA) model and assessed anxiety-like behaviour using the open-field test (OFT) and the elevated plus maze test (EPM). Additionally, neuronal injury, apoptosis, alterations in glia expression and the BDNF-TrkB-AKT signalling pathway in multiple brain regions were assessed simultaneously. Rats acquired stable nose-poke operant response for self-administering 4F-ABUTINACA (0.00625 mg·kg-1·infusion-1) and showed significant drug-seeking behaviour induced by conditioned cues. Persistent anxiety-like behaviours were observed both immediately after drug-taking (SA group) and cue-induced reinstatement testing after a 14-day extinction period (CIR group). Histochemical analysis revealed more pronounced neuronal injury and apoptosis in the hippocampus, prefrontal cortex (PFC) and nucleus accumbens (NAc) in the SA group than in the CIR group. Reactive astrogliosis and microgliosis were observed in the hippocampus and the PFC in the SA group, whereas the numbers of microglia and astrocytes decreased in the NAc of the CIR group. We also found the distinct region-specific alterations in the BDNF-TrkB-AKT signalling pathway expression profile between the SA and CIR groups. The present results demonstrate that 4F-ABUTINACA exhibits significant potential for abuse and produces anxiety-like behaviour during both the active drug-taking and cue-induced relapse stages, which are associated with the neuropathological alterations in specific brain regions.

Alcohol use disorder (AUD) is linked to cognitive deficits that can persist even after prolonged abstinence. Research highlighted associations between plasma apolipoproteins and cognition in AUD. This study examines the longitudinal evolution of plasma apolipoproteins and inflammation in AUD patients during early and prolonged abstinence and their association with cognitive recovery. Thirty-three AUD patients from an outpatient hospital alcoholism programme were evaluated at baseline (t = 0), 6 months (t = 1) and 12 months (t = 2), along with 34 healthy controls. Cognitive performance was assessed using the TEDCA test, which measures general cognitive function (GCF). Biological assessments included plasma pro-inflammatory biomarkers (LPS and LBP) and several apolipoproteins (APOAI, APOAII, APOB, APOCII, APOE, APOJ and APOM). AUD patients showed elevated plasma LPS, APOAI, APOE, APOJ and downregulated APOM, which all normalized at t = 1, whereas cognitive improvement was significant at t = 2 compared to controls. Mixed-effects models including all covariates and within-between person decomposition, followed by correlation matrix and reduced mixed models sensitivity analysis support robust associations between better GCF and (1) the duration of abstinence and (2) within-person reductions in LPS, although apolipoprotein changes should be considered exploratory at this level. Prolonged abstinence in AUD patients normalizes plasma peripheral inflammation and apolipoprotein levels and improves cognition. Although APOAI and APOM showed opposite trajectories, as opposite biomarkers in AUD diagnosis reported previously, only the duration of abstinence and normalization of within-person blood LPS levels over time emerged as predictors of cognitive recovery.

Sleep disturbances are common in individuals with Internet gaming disorder (IGD), yet the neurobiological links between poor sleep quality and addictive symptoms remain unclear. The glymphatic system contributes to cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, processes that are closely related to sleep physiology. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) provides a non-invasive MRI-based marker related to glymphatic system function. In parallel, middle frontal gyrus (MFG)-centred functional connectivity may reflect prefrontal network alterations associated with cognitive control and addiction severity in IGD. The study included 30 individuals with IGD and 37 demographically matched healthy controls (HCs). All participants underwent diffusion tensor imaging and resting-state functional MRI. DTI-ALPS was used to assess glymphatic system-related function. Resting-state functional connectivity analysis was performed using the MFG as the seed region. Group differences in ALPS indices were tested while controlling for age, education years and mean framewise displacement. Within the IGD group, correlation analyses were conducted to examine associations among ALPS indices, PSQI scores, MFG-centred functional connectivity and IAT scores. Individuals with IGD showed significantly lower mean and left ALPS indices than HCs. The right ALPS index showed a non-significant trend towards reduction. Within the IGD group, higher PSQI scores were associated with lower mean, left and right ALPS indices, suggesting that poorer subjective sleep quality was related to reduced glymphatic system-related function. MFG-centred functional connectivity analysis showed increased connectivity mainly involving medial and superior frontal regions and decreased connectivity involving subcortical regions. Stronger MFG-centred functional connectivity was positively correlated with IAT scores, indicating an association with greater addiction severity. This study integrates DTI-ALPS and MFG-centred resting-state functional connectivity to examine sleep-related glymphatic alterations and prefrontal network changes in IGD. Lower ALPS indices were associated with poorer sleep quality, whereas stronger MFG-centred connectivity was associated with greater addiction severity. These findings support a potential sleep-glymphatic-prefrontal network framework for understanding IGD. Longitudinal and interventional studies are needed to clarify the directionality of these associations.

Cocaine use disorder (CUD) is a serious global public health problem, characterized by compulsive drug seeking and impaired cognitive control. Previous studies using voxel-based morphometry (VBM) or surface-based morphometry (SBM) have identified regional alterations in grey matter volume and cortical thickness (CT); purely local morphological analyses are insufficient to capture coordinated patterns of interregional change. In this study, we employed structural covariance networks (SCNs) analysis to investigate abnormalities in the macroscopic topological organization of the brain in individuals with CUD, based on CT measures. A total of 68 patients with CUD and 52 healthy controls (HCs) were included from the OpenNeuro database. The results demonstrated that the CUD group exhibited a significantly reduced global clustering coefficient and a shift in small-world properties, with network topology becoming more closely aligned with a lattice-like configuration. In addition, CUD showed disrupted rich-club connectivity, particularly within core frontoparietal regions. Notably, no significant group differences were observed in network robustness against random failure or targeted attack. Together, these findings indicated an imbalance between network integration and segregation in the structural brain networks of individuals with CUD, providing a novel network-level perspective on the pathophysiology of addiction and suggesting potential utility as a diagnostic neurobiological marker.

Underage drinking has become a global public health concern. One of the major causes of underage drinking is stress. The orexin system has been reported to be involved in both alcohol addiction and stress. However, few studies have examined this system, especially among adolescents. Therefore, we constructed protein-protein interaction (PPI) networks to confirm that orexin receptors are connected to stress- and alcohol dependence-related genes, providing a theoretical basis for our experimental approach. Animal experiments employed the conditioned place preference (CPP), the foot-shock stress model and the enzyme-linked immunosorbent assay (ELISA), to elucidate the role of the orexin system in the stress-induced alcohol addiction-related behaviour among adolescent mice. Our results revealed that there were interactions among orexin system, chronic/acute stress and alcohol dependence related proteins. Otherwise, chronic stress can increase the animals' vulnerability to alcohol addition-related behaviour. Additionally, acute foot-shock can promote alcohol-seeking behaviour reinstatement and facilitate orexin concentrations in brain regions that have been shown to be associated with reward and addiction. Moreover, the inhibition of orexin receptors can attenuate the formation and reinstatement of alcohol addiction-like behaviour among adolescent mice. Collectively, our findings indicate that orexin system may be a pivotal target for preventing stress-induced alcohol addiction and reinstatement among the adolescents.

Pavlovian and operant learning mechanisms promote and maintain alcohol intake despite aversive consequences. Here, we review the evidence for drug-associated modifications of basic learning mechanisms during the initiation and maintenance of alcohol use disorders in humans. We discuss how neuroadaptive effects elicited by chronic alcohol intake in the so-called brain reward system can bias learning and decision making towards drug consumption and contribute to the relapse risk after detoxification. Robustness of results and limitations of the respective neurobiological or imaging techniques are addressed. We opine that studying the effects of alcohol intake on Pavlovian and reinforcement learning can inform psychotherapeutic interventions and help to better understand some new neurobiological interventions. We argue that a focus on drug effects biassing basic learning mechanisms can help to reduce the stigma associated with drug consumption and emphasize behavioural and neurobiological interventions that take individual learning mechanisms into account when promoting alternative coping strategies.

Longer treatment engagement is associated with improved recovery outcomes in alcohol use disorder (AUD), making patient retention a critical determinant of reduced return to drinking. This study aimed to identify factors predicting outpatient treatment engagement, operationalized as the number of follow-up visits, among individuals with AUD following inpatient care. We applied a five-step analytic framework integrating random forest modelling (RFM) and Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify predictors of outpatient visit frequency. Clinical, psychological and physiological variables (n = 177 per participant) collected during inpatient treatment prior to discharge were included. RFM ranked variables associated with follow-up visits, with LASSO used for validation and complementary selection. Over a 5-year period, 119 treatment-seeking patients with AUD (mean age = 45.8) returned for outpatient care, averaging 5.14 visits, following a medical treatment inpatient stay. Positive urgency (VIP = 44.31) and positive life events (VIP = 41.19) emerged as the strongest predictors; both inversely associated with visit frequency. LASSO confirmed positive urgency as a significant predictor (coefficient: -0.03296). Greater alcohol use severity and higher haemoglobin levels were also associated with fewer outpatient visits, whereas higher depressive symptom severity predicted increased follow-up engagement. Using complementary machine learning and regression approaches, this study identified affective traits, alcohol use severity and physiological factors as key determinants of outpatient engagement following inpatient AUD treatment. Interestingly, positive urgency and positive life events, often considered markers of recovery or resilience, were linked to reduced outpatient attendance, suggesting that certain personality or motivational factors may diminish perceived need for continued care. These findings highlight the importance of integrating psychological and motivational variables into postdischarge planning to enhance retention and improve early recovery outcomes.

Despite sedative-hypnotic use disorder (SHUD) being a major public health priority due to its high abuse liability, the underlying causal neurobiological mechanisms of individual susceptibility remain largely unknown. We conducted a large-scale, bidirectional two-sample Mendelian randomization (MR) study utilizing genome-wide association study (GWAS) summary statistics for 3935 brain imaging-derived phenotypes (IDPs) from the UK Biobank (N = 33 000 participants) and SHUD data from the FinnGen R10 release (N = 2258 cases). Causal effects were primarily estimated using the inverse-variance weighted (IVW) method, which was supplemented by a suite of sensitivity analyses including MR-Egger, weighted median and MR-PRESSO. Multiple testing was controlled via Benjamini-Hochberg false discovery rate (FDR) correction (q < 0.05 $$ q<0.05 $$). Forward MR identified 34 brain IDPs with significant causal associations with SHUD risk. Specifically, increased susceptibility was linked to structural metrics in the temporal and limbic regions, including higher cortical thickness in the left transverse temporal sulcus (OR = 1.35, 95% CI 1.09-1.67, FDR = 0.04) and right middle temporal gyrus (OR = 1.30, 95% CI 1.07-1.58, FDR = 0.04), as well as elevated white-to-grey matter intensity contrast in the right insula (OR = 1.31, 95% CI 1.13-1.51, FDR = 0.02) and left parahippocampal gyrus (OR = 1.29, 95% CI 1.08-1.54, FDR = 0.04). Conversely, protective effects were observed for brainstem volume (OR = 0.74, 95% CI 0.61-0.91, FDR = 0.04) and white matter integrity in the left cingulum (OR = 0.73, 95% CI 0.57-0.92, FDR = 0.04). Functional connectivity analyses revealed that higher node activity in the salience network (OR = 0.70, 95% CI 0.53-0.92, FDR = 0.04) and strengthened connectivity between the visual and somatomotor networks (OR range: 0.54-0.74) predicted reduced risk. In contrast, specific edges within the default mode network and visual network were positively associated with SHUD susceptibility (OR = 1.56 and 1.48, respectively). Reverse MR analysis provided limited evidence for a causal effect of genetically predicted SHUD on right middle temporal gyrus thickness. Although a nominal association was observed (OR = 1.03, 95% CI 1.00-1.05, p = 0.02), this finding did not survive multiple testing correction (FDR = 0.56) and lacked robustness across sensitivity models. This research establishes a causal link between SHUD susceptibility and specific cortical morphologies, subcortical volumes and functional network topographies, emphasizing the pivotal roles of the temporal-limbic and salience systems. These findings provide novel mechanistic insights into the neurobiological foundations of SHUD while identifying potential imaging biomarkers for risk stratification and the advancement of therapeutic targets.

Relapse is a defining feature of substance use disorders, yet relapse risk varies widely across individuals. This variability has been linked to individual differences in incentive salience attribution to drug-related cues. We used fMRI to identify cortical and subcortical circuits underlying individual differences in incentive salience attribution among people with tobacco use disorder. Fifty daily cigarette users viewed pleasant, unpleasant, cigarette-related and neutral images during task-based fMRI and completed a resting-state scan. We extracted per-condition BOLD activity from a functionally defined extended visual region (Emotional > Neutral) and applied k-means clustering (k = 2) to derive neuroaffective profiles. Whole-brain voxelwise tests assessed Group × Content (cigarette vs. pleasant) effects. We compared groups' resting-state connectivity at the network level and for subcortical-cortical pairs. Individuals were clustered based on neuroaffective reactivity to drug-related and pleasant stimuli: The C > P profile showed larger BOLD responses to cigarette cues than to pleasant stimuli, whereas the P > C profile showed the opposite pattern. Whole-brain analyses showed significant Group × Content interactions that mirrored these profiles across left dorsolateral and medial prefrontal cortices and amygdala-hippocampal regions. At rest, individuals in the C > P profile showed weaker within-network connectivity of the frontoparietal control network (FPCN) and, in exploratory analyses, reduced FPCN-nucleus accumbens coupling. By replicating and extending prior psychophysiological work, this study identifies neuroaffective profiles that reflect the variation in incentive salience attribution central to neurobehavioral models of relapse. These findings provide convergent neurobiological markers that characterize distinct motivational pathways in substance use disorders.

Comorbid substance use disorders (SUDs) are common but difficult to study due to the complex, interacting and overlapping mechanisms through which they affect brain networks. Many datasets collected to investigate a specific SUD include participants with comorbid SUDs. Although most studies treat comorbid SUDs as covariates of no interest, these covariates also contain untapped information. This is particularly relevant as cannabis use disorder (CanUD) has become increasingly prevalent and comorbid with other SUDs that have been more thoroughly studied. While pharmacotherapies have been established for multiple SUDs, none have been approved for CanUD, although naltrexone (NTX) has been associated with reduced use. Here, we conducted a retrospective secondary analysis of functional magnetic resonance imaging (fMRI) data from individuals with primary opioid use disorder (OUD-only, N = 25 pre-NTX, N = 20 on-NTX) with comorbid CanUD (N = 10), alcohol use disorder (AUD, N = 6) or cocaine use disorder (CocUD, N = 7). All participants underwent imaging prior to receiving a therapeutic dose of long-acting intramuscular NTX (Vivitrol), an approved treatment for OUD and AUD but not for CocUD, and again 2 weeks postadministration. At baseline, OUD individuals with comorbid CanUD, AUD or CocUD exhibited distinct functional connectivity (FC) alterations compared to those with OUD-only. These differences were greater in younger participants and primarily involved the default mode network. Following NTX administration, FC differences between the comorbid CanUD and OUD-only groups globally diminished. A similar FC response to NTX was observed in the comorbid AUD group, whereas little change in FC was observed in comorbid CocUD. These findings, combined with prior evidence that NTX reduces cannabis use by dampening reward, suggest NTX may hold promise as a treatment for CanUD.