Increasingly potent concentrated cannabis products containing high levels of Δ[9]-tetrahydrocannabinol (THC) are being consumed with alcohol. This combination is known to acutely impair cognitive and psychomotor abilities, although few studies have evaluated alcohol and cannabis co-use using neural measures. This naturalistic feasibility study explored the acute effects of co-intoxication on behavioural performance and brain activity, measured via electroencephalography (EEG), during a performance monitoring task administered three times over a 4.5-h period. Participants (N = 17, 65% male) were heavy drinking community members (age M = 31.7 years; SD = 10.27) who regularly use cannabis. EEG was recorded while participants completed a speeded visual-flanker task at baseline (sober) before consuming a standardized dose of alcohol and a cannabis concentrate product, followed by EEG recordings 1-h (intoxicated) and 4-h post co-consumption (recovery). Recordings were processed to obtain six event-related potential components: the stimulus-locked N1, P2, N2 and P3 and response-locked error-related negativity (ERN) and error positivity (Pe). Repeated measures ANOVAs revealed that behavioural measures at the intoxicated timepoint showed an increase in errors (p < 0.005; η[2] p = 0.35) and significant decrease in response time (RT) (p < 0.001; η[2] p = 0.50) compared to sober and recovery periods. Measures of brain activity also demonstrated significant change across time with largest amplitudes when sober, smaller amplitudes when intoxicated, then an increase in amplitude to near sober levels at recovery for stimulus-locked (P2, N2 and P3) and response-locked components (ERN and Pe). Thus, compared to sober and recovery periods, the behaviour at the intoxicated timepoint revealed significantly greater impulsivity (RT) leading to significantly higher error rates, while measures of cognitive processing (i.e., decision-making, error detection, performance monitoring/adaptation) showed significantly diminished levels of brain activity. Performance and neurophysiology measures remained diminished at recovery compared to baseline. Understanding neurocognitive functioning during co-intoxication may provide insights into specific cognitive processes that may impact function in everyday activities such as driving. Trial Registration: NCT06259916.

Alcohol use disorder (AUD) causes a high burden worldwide. The menstrual cycle and the progesterone-to-estradiol ratio are related to alcohol consumption in females and males with AUD. However, the underlying mechanisms triggering problem drinking in everyday life remain to be determined. This longitudinal multicentre study analysed associations of menstrual cycle phases (1316 of 70 naturally cycling females with AUD) and progesterone-to-estradiol ratios (quantified in 567 blood samples of 256 males with AUD) with real-world 12-month data on loss of control over alcohol consumption and craving measured via 17296 and 10482 smartphone entries using general linear mixed models. Females with severe AUD stated less frequent loss of control in the midluteal and late luteal phases characterized by high progesterone-to-estradiol ratios compared to the follicular phase. In the total female sample, craving was lower during the late luteal and menstrual phases compared to the follicular phase. Similarly, males with moderate and severe AUD reported less frequent loss of control in phases of a high progesterone-to-estradiol ratio. The identified biobehavioural interplay suggests that increasing progesterone relative to estradiol may assist individuals with AUD in re-establishing control over alcohol consumption and reducing craving. When employed in conjunction with customized just-in-time adaptive digital interventions, this approach has the potential to evolve into a novel precision medicine strategy for AUD. The findings also underscore the necessity for the development of treatments tailored to the phases of the menstrual cycle, thereby addressing the critical underrepresentation of females in AUD research.

Regulation of craving (ROC) by focusing on long-term negative consequences of drug use has been shown to successfully reduce subjective craving. This process is supported by the dorsolateral prefrontal cortex (dlPFC), which exerts control over reward and value signals in the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC). As stress impairs cognitive control and addiction is characterized by altered value computations manifesting in delay discounting, we examined how these factors interact with ROC and its neural correlates to better understand the use of ROC in high-risk situations. Sixty-eight male smokers underwent a delay discounting task and either a stress (socially evaluated cold pressor task) or a control condition. They subsequently completed a ROC task during fMRI while focusing on (1) long-term negative consequences (LATER) versus (2) short-term positive consequences (NOW). We found lower subjective craving ratings and attenuated neural responses in the VS (t = 4.33, p = 0.012) and vmPFC (t = 5.79, p < 0.001), as well as higher activation in the dlPFC (t = 4.09, p = 0.038) in the LATER compared to the NOW strategy. Although no neural or behavioural difference in ROC was observed between stress and control groups, both individual stress (cortisol) and delay discounting were positively related to vmPFC activity (NOW > LATER). We replicated previous results on ROC. Importantly, the association of vmPFC signals with stress response and delay discounting suggests that enhancing ROC success may involve reinforcing changes in self-referentiality of future thoughts to subjective value of drug use.

Mesocorticolimbic circuits are central to theories of methamphetamine and other addictions. White-matter fibres are a necessary component of those circuits. However, the extent to which mesocorticolimbic white-matter tracts are altered in methamphetamine addiction is unknown. The current study addressed this gap as well as sought to determine relationships with neurofunctional and behavioural deficits concerning nondrug rewards. Multimodal MRI was acquired from 92 people with problematic methamphetamine-use experience (MA[+]) and 98 methamphetamine-naïve controls (MA[-]). Diffusion tractography mapped probabilistic fibre paths connecting midbrain presynaptic dopamine hubs to striatal and medial orbitofrontal areas highly sensitive to rewards. MA[+] exhibited microstructural alterations (via fractional anisotropy [FA]) along this mesocorticolimbic tract-in particular, white-matter segments running through anterior limb of the internal capsule (ALICFA: MA[+] > MA[-]) and near the medial orbitofrontal target area (mOFCFA: MA[+] < MA[-]). In addition, task-fMRI revealed that MA[+] exhibited reduced activations to monetary rewards within the striatal and mOFC area versus MA[-]. Moreover, MA[+] participants reported they attributed lower hedonic value and lesser motivational salience to broader nondrug rewards/pleasant experiences relative to MA[-]. Further, within MA[+] participants, those exhibiting decreased ALICFA or mOFCFA reported attributing lower hedonic value to nondrug rewards/experiences relative to their peers-with a similar correlation found for ALICFA and motivational-salience reports. Our findings identified microstructural alterations in a mesocorticolimbic white-matter tract plausibly supporting reward-related dopaminergic signalling in people experienced with methamphetamine. Such alterations may play a role in the lower valuation of nondrug rewards and diminished motivation to pursue typical/nondrug activities associated with methamphetamine use.

Chronic heavy alcohol use and alcohol withdrawal are known to diffusely damage white matter (WM), but it has remained rather unclear whether the damage sustained during a single withdrawal event is functionally relevant and whether WM damage also occurs during or after single episodes of heavy drinking. We therefore set out to investigate the effects of acute alcohol intoxication, alcohol hangover and (post)acute alcohol withdrawal on axonal injury (assessed via serum neurofilament light chain/NFL) and potentially associated cognitive-behavioural functioning (as assessed with the CANTAB test battery) in three separate studies. Acute intoxication and hangover effects were studied in healthy young men who underwent a standardized intoxication procedure aiming at an intoxication level of approx. 1.2‰ in two separate randomized experimental crossover studies. (Post)acute withdrawal effects were longitudinally observed in withdrawal patients during a 21-day inpatient qualified detoxification treatment. There was no significant effect of alcohol intoxication (n = 51) or alcohol hangover (n = 80) on NFL levels. In contrast, withdrawal patients (n = 31) revealed significant changes of NFL levels over the course of inpatient treatment; most prominently an increase from the first day of admission to the peak of withdrawal symptoms and a decrease from there to the day of hospital discharge. Higher NFL levels of withdrawal patients were associated with slower motor responses and lower risk taking/delay aversion in gambling, as assessed with the CANTAB test battery. In conclusion, the functionally relevant increase in axonal injury despite gold-standard inpatient treatment for alcohol withdrawal necessitates further investigation.

Stress hormones and corticosteroid signalling influence dopaminergic transmission and reward-related behaviours. The present study investigated whether pharmacological manipulation of corticosteroid signalling within the dorsal striatum influences morphine-induced conditioned place preference (CPP) and dopamine transporter (DAT) regulation. Male Wistar rats were implanted with bilateral intra-dorsal striatal cannulae and subjected to the CPP paradigm. Before conditioning sessions, animals received bilateral intra-dorsal striatal infusions of corticosterone, the glucocorticoid receptor (GR) antagonist RU-38486 or the mineralocorticoid receptor (MR) antagonist spironolactone. Behavioural preference, locomotor activity and DAT immunoreactivity were subsequently assessed. Morphine reliably induced CPP and reduced DAT immunoreactivity in the dorsal striatum. Corticosterone, RU-38486 and spironolactone each significantly attenuated morphine-induced CPP and prevented the reduction in DAT immunoreactivity without altering locomotor activity. The convergence of these pharmacologically distinct manipulations on similar behavioural and DAT outcomes suggests that perturbation of corticosteroid-sensitive signalling within the dorsal striatum modulates opioid reward and associated dopaminergic plasticity. Importantly, the present findings do not establish whether corticosterone's effect is mediated by classical GR signalling, rapid corticosteroid actions or GR-independent mechanisms. Given the role of the dorsal striatum in addiction-related learning and the transition towards habitual and compulsive drug seeking, these findings identify corticosteroid-dopamine interactions within this region as an important mechanism for further investigation in opioid use disorders.

Alcohol use disorder (AUD) is a preventable condition that impacts more than 28 million adults in the United States. The neurocognitive correlates of AUD have been extensively studied, but their interaction with psychosocial contributors remains less clear. Social mistreatment is common in human society, and negative social experiences can lead to poor health behaviours, such as binge drinking. Inhibitory control and error processing are cognitive functions facilitating self-regulation, which may mitigate the influence of social mistreatment on alcohol misuse. This study examined the longitudinal relationship between general social mistreatment (GSM) and alcohol use problems across 3 years among 133 college students (64.7% females) via self-report surveys. Inhibitory control- and error processing-related behavioural performance and brain network activation during a Stop-Signal Task at baseline were explored as moderators of the GSM-alcohol association. Our sample showed significantly increased risky drinking behaviours between the baseline and final follow-up 3 years later, and this slope became steeper as a function of increased GSM. Behaviourally, stop-signal reaction time (SSRT) but not post-error slowing interacted with time and GSM, such that faster SSRT was associated with attenuated alcohol misuse slope (independent of GSM) and a lower impact of GSM on alcohol misuse (independent of time). Additionally, the effect of GSM on the slope of alcohol misuse was moderated by error-related subcortical network activation, but not by inhibition-related networks. Slope contrasts demonstrated that reduced subcortical activation (associated with greater behavioural slowing) was protective against alcohol misuse development among individuals with lower GSM but not those with higher GSM. This study conforms with the existing literature that GSM exacerbates risky drinking in college students. Our results suggest that the detrimental effect of psychosocial risk is attenuated by motor response inhibition, and neural sensitivity to error is protective only in the context of lower social mistreatment.

Relapse to alcohol use is frequently triggered by re-exposure to alcohol-associated cues, and extinction-based interventions can reduce this vulnerability. However, the striatal cellular mechanisms through which extinction alters later alcohol seeking remain unclear. Using a mouse model of operant alcohol self-administration, we examined two distinct direct-pathway medium spiny neuron (dMSN) populations in the dorsomedial striatum. Extinction reduced cue-induced alcohol seeking and decreased the probability that acquisition-recruited dMSNs were reactivated during relapse testing. Chemogenetically maintaining activity in acquisition-recruited dMSNs during extinction slowed the reduction in alcohol-seeking and enhanced subsequent relapse. In contrast, increasing activity in μ-opioid receptor (MOR)-expressing dMSNs, a striosome-enriched population, accelerated the reduction in responding and decreased later relapse without altering inactive-lever responding or locomotor activity. These findings indicate that extinction is associated with reduced re-engagement of acquisition-related dMSN ensembles, whereas enhancing activity in a MOR-defined, striosome-enriched output population can facilitate extinction-related behavioural change. Together, the results identify two complementary striatal processes that regulate alcohol extinction and relapse.

In rodent models, incubated craving for drugs and natural reinforcers is characterized by a time-dependent increase in cue-elicited operant responding, which posits that common biochemical mechanisms gate incubated craving across different types of reinforcers. Recently, our laboratory identified heightened mTOR activity in the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) as being associated with incubated craving for cocaine and sucrose, respectively. Importantly, Everolimus, an FDA-approved mTOR inhibitor, blocked the expression of incubated craving for both reinforcers. Hence, our current study investigated whether mTOR signalling also underpins cue-induced methamphetamine (METH)-seeking by evaluating the "therapeutic potential" of Everolimus to block incubated METH-craving. Male and female rats were trained under extended-access procedures (6-h/day × 10 days) to self-administer intravenous METH (0.1 mg/kg/0.1 mL infusion), paired with the presentation of a 20-s light + tone compound stimulus and then were subjected to a withdrawal period of 1 or 30 days (WD1 or WD30). Rats tested on WD30 were gavage-infused with either vehicle (VEH; 1% DMSO in water; vol: 1 mL/kg) or Everolimus (1 or 10 mg/kg), whereas WD1 rats were infused with VEH to index baseline craving. Thirty minutes later, rats underwent a 2-h test to measure cue-elicited responding. Akt/mTOR activity in the PL and IL was examined via immunoblotting procedures. Male and female rats exhibited comparable METH intake and craving, with no effect of estrous cycle observed for either measure in females. Unlike previous findings for incubated cocaine- and sucrose-craving, Everolimus did not reduce incubated METH-craving. Further, incubated METH-craving was not associated with changes in Akt/mTOR activation within mPFC subregions nor did Everolimus lower mTOR pathway activation below baseline levels in either METH-experienced or -naive rats. Together, these findings demonstrate that elevated mTOR signalling within mPFC is not involved in incubated METH-craving, highlighting the potential need for drug-specific targeted treatments for curbing incubated craving in protracted withdrawal.

In 2024, approximately 30% of US adolescents reported having consumed alcohol at least once in their lifetime, with about 25% of these individuals engaging in binge drinking. Adolescent alcohol use is associated with neurodevelopmental impairments, elevated risk of later alcohol use and mental health disorders. Therefore, it is important to identify the variables driving adolescent alcohol use and leverage them for early identification and targeted intervention. Previous studies have typically developed machine learning classification models that use neuroimaging data in combination with limited clinical measurements. Neuroimaging data are expensive and difficult to obtain at scale, whereas clinical measures are more practical for large-scale screening due to their low cost and widespread accessibility. However, clinical-only approaches for alcohol drinking classification remain largely underexplored. Furthermore, prior studies have often focused on adults, limiting generalizability to the broader adolescent population. Additionally, confounding factors such as age and substance use, which are strongly correlated with alcohol consumption, have often been inadequately addressed, potentially inflating classification performance. Finally, class imbalance remains a persistent challenge, with prior attempts yielding only limited improvements. To address these limitations, we propose FocalTab, a framework that integrates TabPFN with focal loss for robust generalization and effective mitigation of class imbalance. The approach also incorporates an initial preprocessing step to remove confounding factors to account for age and substance use. We compare FocalTab against state-of-the-art methods across different variable selections and dataset settings. FocalTab achieves the highest accuracy (0.841 ± 0.011) and specificity (0.803 ± 0.055) in the most stringent setting, in which both age and substance use variables were excluded, whereas competing models drop to near-chance specificity (12%-24%). We further applied SHapley Additive exPlanations (SHAP) analysis to identify key clinical predictors of drinker classification, supporting enhanced screening and early intervention.

Internet gaming disorder (IGD) is a behavioural addiction characterized by substantial clinical heterogeneity. The present study aimed to investigate this heterogeneity by analysing the deviation patterns of interindividual brain functional connectivity. Resting-state functional magnetic resonance imaging (fMRI) data from 87 patients with IGD and 56 healthy controls (HCs) were included. First, functional connectivity matrices were constructed, and the interindividual deviation of functional connectivity (IDFC) of each patient with IGD relative to the HC group was quantified at the network level. K-means clustering was then applied to identify IGD subtypes. Edge-wise functional connectivity analysis with network contingency analysis (NCA) was used to characterize subtype-specific patterns of altered connections. Finally, support vector regression (SVR) based on network-level IDFC features was used to predict Internet Addiction Test (IAT) scores in the overall IGD cohort. Two distinct IGD subtypes were identified based on IDFC patterns. Compared with HCs, Subgroup 1 showed a widespread hypoconnectivity pattern, whereas Subgroup 2 showed a relative hyperconnectivity pattern. Network-level IDFC features also predicted IAT scores in the overall IGD cohort using SVR (r = 0.391, one-tailed permutation p = 0.038). Patients with IGD exhibit substantial interindividual variability in brain functional connectivity. Subtyping IGD based on these connectivity deviation patterns may improve the understanding of its neurobiological heterogeneity and facilitate the development of more precise individualized interventions.

Methamphetamine (METH) is a globally prevalent, highly addictive synthetic psychostimulant, for which no FDA-approved pharmacotherapy is currently available for METH use disorder (MUD). The microbiota-gut-brain axis has been well established as a key regulatory pathway in substance use disorders, yet its specific mechanistic basis and translational potential in METH addiction remain to be systematically elucidated. This review synthesizes current preclinical and clinical evidence demonstrating that METH exposure induces profound gut microbiota dysbiosis, characterized by the depletion of beneficial genera such as Faecalibacterium and Lactobacillus, enrichment of proinflammatory phylum Proteobacteria and concurrent dysregulation of microbial metabolites including short-chain fatty acids (SCFAs), tryptophan derivatives and bile acids. These microbial signals mediate bidirectional gut-CNS crosstalk through neuroimmune, neuroendocrine (hypothalamic-pituitary-adrenal (HPA) axis) and vagal pathways, thereby exacerbating the core central pathologies of METH addiction: neurotransmitter system imbalance, neuroinflammation and oxidative stress and dysfunction of addiction-related neural circuits. We further elaborate that gut microbiota-driven epigenetic modifications and transgenerational effects reinforce the persistence and heritability of addictive phenotypes. Importantly, microbiota-targeted interventions, including probiotics, prebiotics, faecal microbiota transplantation (FMT) and dietary modulation, can alleviate METH-induced affective disturbances (anxiety/depression-like behaviours), multiorgan damage (neurotoxicity, reproductive impairment) and relapse risk, via restoring gut microbial homeostasis, repairing intestinal barrier integrity and normalizing gut-brain axis signalling. Collectively, this review positions the gut microbiota as a critical peripheral regulatory node in METH addiction, providing a robust preclinical foundation for the development of gut-brain axis-targeted combination therapies for MUD.

Craving is one of the most robust proximal predictors of both treatment dropout and relapse during early recovery for alcohol use disorder (AUD). Craving can onset rapidly, and the ability to accurately detect or modulate cravings varies significantly within- and between-persons. Because of this, craving management is a central feature of most current AUD treatment models. However, impaired interoceptive awareness, which is common in early AUD recovery, can stymie individuals' capacity to implement craving management strategies. Measurement and detection of craving through passive biosensor monitoring could support novel just-in-time adaptive interventions that can mitigate this vulnerability. This study sought to characterize the biosignatures of craving through the measurement of heart rate variability (HRV) using a combination of ambulatory electrocardiogram (ECG) monitoring and ecological momentary assessment (EMA) in individuals in the first year of a current AUD recovery attempt (N = 40, observations = 400). A multilevel negative binomial regression analysis was conducted to estimate correlations between craving and HRV. Results demonstrated that, at the within-person level, high-frequency HRV (HF-HRV; IRR = 1.01, p = 0.013) and SD1 (IRR = 0.97, p = 0.020) were associated with craving at the same moment. Findings highlight HRV as a viable target for passive monitoring in interventions aimed at supporting craving mitigation in early AUD recovery, particularly at the momentary level.

Betel quid (BQ) is classified as a Group 1 carcinogen, underscoring a significant public health challenge. Neuroimaging evidence demonstrated that betel quid dependence (BQD) was linked to alterations in reward-related brain regions. However, resting-state functional connectivity (FC) in the reward circuit and their neural correlates with pathophysiological characteristics of BQD remain largely unexplored. We recruited 53 male BQD chewers and 53 male healthy controls (HCs) to participate in this study. Eleven reward circuit seeds, such as ventral striatum (VS), ventromedial prefrontal cortex (VMPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and others, were selected. Resting-state functional magnetic resonance imaging (rs-fMRI) data were analysed to evaluate FC between predefined seed regions and the whole brain. Association between aberrant FC and clinical features was further investigated. Relative to HCs, individuals with BQD exhibited altered FC in the reward circuit, mainly in VS, VMPFC, ACC, PCC and thalamus (Th). Correlation analysis indicated that FC between right Th and PCC was negatively correlated with BQD scales and dosage of BQ use in BQD subjects. Our findings provided the first empirical evidence that individuals with BQD showed aberrant resting-state FC in the reward circuit. Additionally, decreased connectivity between right Th and PCC was negatively associated with dependence degree and dosage of BQ use. These results highlighted the importance of the reward circuit in the pathophysiology of BQD and suggested that reward circuit dysfunction could serve as a potential circuit-level biomarker.