Search Results (151)

Aim: There is an urgent need for systematic and well-designed studies to clarify the role of systemic inflammatory parameters, especially the neutrophil–lymphocyte-ratio (NLR), in the pathophysiology and clinical management of unregulated substance addiction. This review aims to synthesize current evidence on the relationship between unregulated substance addiction and systemic inflammatory parameters, focusing specifically on the NLR as a potential biomarker. Methods: To ensure a transparent approach in the collection of evidence, this review was carried out following the recommendations of the PRISMA 2020 guidelines and registered in PROSPERO (CRD420251151136). We searched the PubMed and Scopus databases in July2025 using combinations of MeSH terms and keywords related to unregulated substance use and inflammatory biomarkers. The strategy included terms such as “cocaine,” “cannabis,” “opioids,” “heroin,” “fentanyl,” “methadone,” “buprenorphine” “nitazene”, “MDMA”, and “methamphetamine,” combined with “neutrophil-to-lymphocyte ratio.” Filters were applied to limit results to human studies published between 2015 and 2025 in English. The methodological quality of the studies included was assessed using the STROBE 22-item checklist. Results: Fifteen studies were included in this review. Methamphetamine and opioid users showed higher NLR and MLR values. For cocaine abuse, although the evidence is limited to a single population-based study, a significant increase in NLR was reported. Controversial results were observed for cannabis use. Conclusions: Systemic inflammation markers are related to unregulated substance abuse disorders; however, the sparse available evidence encourages the need for well-designed large, prospective clinical trials. Full article

This review examines convergent neurobiological mechanisms linking stress and drugs that drive stress-induced drug-related behaviors. It first outlines the main theoretical frameworks explaining substance use disorders (SUDs), emphasizing vulnerability factors—particularly stressful life events—that increase addiction risk. The analysis integrates preclinical evidence demonstrating that chronic stress facilitates cross-sensitization to psychostimulants and accelerates drug self-administration, underscoring how stress and drugs converge on glutamatergic and dopaminergic transmission within the Nucleus Accumbens (NAc). Special attention is given to the glial cells, particularly microglia and astrocytes, in mediating stress-induced neuroimmune activation and glutamate dysregulation in the NAc. Three major themes related to microglia–astrocyte crosstalk are addressed: (i) the contribution of these glial cells to neuroimmune and glutamatergic alterations induced by stress; (ii) their role in synaptic and structural plasticity changes within the NAc; and (iii) the mechanisms by which stress and drug exposure reshape glial–neuronal communication, driving the comorbidity between stress and SUDs. A dedicated section focuses on key neuroimmune signaling pathways—particularly the TNF-α/NF-κB axis—and their involvement in stress-induced vulnerability to cocaine addiction. Finally, the review discusses preclinical evidence supporting the therapeutic potential of repurposed glutamate-modulating agents as promising pharmacological candidates for treating comorbid stress and cocaine-use disorder. Full article

Background: Adults with attention-deficit/hyperactivity disorder (ADHD) often have comorbid substance use disorders (SUDs). In Italy, individuals with both ADHD and heroin use disorder (HUD) are usually treated in addiction services with opioid agonist therapy (OAT), but stimulant medications are rarely prescribed. This may create a treatment gap for core ADHD symptoms. Aim: This study examined the clinical and behavioural profiles of ADHD patients with HUD who receive OAT but no stimulant treatment, compared to ADHD patients without opioid use disorder (ADHD/NoHUD) on standard pharmacotherapy. All participants were considered treatment responders in their respective services. Methods: Data were collected from two outpatient clinics and included 103 adult ADHD patients assessed using validated tools for symptom severity, emotional dysregulation, and global functioning. Differences between groups were analysed using univariate tests and logistic regression. Results: The ADHD+HUD group was significantly older and showed higher levels of emotional dysregulation, impulsivity, and current cocaine use. Despite clinical stability, these individuals presented a more severe psychopathological profile than their ADHD/NoHUD counterparts, who received stimulant-based treatment. Conclusions: Although limited by its cross-sectional nature and setting-related confounders, the study indicates that OAT alone may not be sufficient to manage neurodevelopmental symptoms in ADHD+HUD patients. Further research is necessary to assess the safety and efficacy of integrated stimulant-based treatments, ideally within dual disorder services combining psychiatric and addiction expertise. Full article

The United States is currently facing a drug overdose epidemic. The nucleus accumbens core (NAcore), a brain region critical for reward and aversion behaviors, undergoes structural and functional synaptic adaptations in response to chronic drug exposure. However, the molecular mechanisms underlying these adaptations remain poorly understood. In this study, we investigate the role of dual-specificity phosphatase 5 (DUSP5), a phosphatase known to deactivate extracellular signal-regulated kinase (ERK), in cocaine-induced neuroplasticity. While prior research has linked other DUSP family members to various drugs of abuse, the specific role of DUSP5 in cocaine addiction remains unexplored. We hypothesized that lack of DUSP5 contributes to cocaine-induced maladaptive synaptic plasticity in NAcore. To test this, we employed a rat cocaine self-administration model and molecular analyses and mined publicly available single-cell RNA sequencing data from cocaine-treated NAcore. Our findings reveal a role for DUSP5 in cocaine-related synaptic and behavioral adaptations, highlighting DUSP5 and DUSP5-associated signaling pathways as potential mechanisms underlying substance use disorders and as candidates for therapeutic intervention. Full article

The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms underlying these conditions. This review synthesizes recent advances in understanding how eCBS components—cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes—modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, opioids, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and protein aggregation—pathological features common to Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. These overlapping mechanisms disrupt neuronal integrity and contribute to progressive neurotoxicity, highlighting shared pathogenic pathways between addiction and neurodegeneration. Despite these advances, critical gaps remain in delineating how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be essential for harnessing the eCBS as a therapeutic target to mitigate addiction-driven neurotoxicity and age-related cognitive decline. Full article

Background: Exercise is a promising non-pharmacological intervention for cocaine addiction but molecular mechanisms of exercise-related genes in addiction remain unclear. This study aimed to identify exercise-related signature genes for cocaine addiction and to assess the potential causal relationship between exercise and cocaine addiction using two-sample Mendelian randomization (MR) analysis. Methods: Midbrain transcriptomic data were analyzed for differentially expressed genes (DEGs) and intersected with exercise-related genes. Functional enrichment, protein-protein interaction (PPI) and immune infiltration analyses explored their roles while signature genes were screened via LASSO/Random Forest and validated by ROC curves. GSEA explored pathways and MR confirmed exercise’s causal effect. Results: A total of 244 DEGs were identified, including 27 exercise-related, and six signature genes (CALM3, CCL2, CD44, CLIC1, JUN, VCAM1) showed AUC values between 0.714 and 0.868 in distinguishing cocaine-addicted individuals from controls. Functional analyses revealed enrichment in immune-inflammatory pathways, metabolic processes and neuro-immune interactions and immune infiltration analysis showed cocaine addicts had elevated pro-inflammatory cells, reduced regulatory cells and signature genes correlated with immune dysregulations. MR analysis suggested a statistically significant protective association between genetically proxied higher levels of exercise and cocaine addiction risk (p < 0.05). Conclusions: These six genes may be potential biomarkers and therapeutic targets, and exercise may protect against cocaine addiction by regulating immune-inflammatory responses, metabolic pathways and neuroplasticity, although further validation in larger, independent cohorts and experimental models is required. Full article

Interest in ketamine as a novel treatment for substance use disorders (SUDs) has been increasing due to its N-methyl-D-aspartate (NMDA) glutamate receptor antagonism and mounting evidence that glutamate neurotransmission is involved in the pathogenesis of both depression and addictions. This narrative review provides an outline of clinical evidence reported in the literature from the 1970s to 2025 that examines the efficacy of ketamine for the treatment of SUDs, focusing primarily on randomized blinded controlled trials (RBCTs). Key cohort studies, retrospective studies, secondary analyses, case reports, and relevant basic neuroscience studies are reviewed to complement the more rigorous human controlled trial data. Thus far, ketamine has been tested in nine RBCTs targeting cocaine (three studies), alcohol (three studies), opioid use disorder (two studies), and nicotine (one study), suggesting efficacy for addiction in combination with psychotherapies, and often when doses produce subjectively reported mystical or psychedelic experiences. This review highlights promising preliminary evidence, and the need for more rigorous studies to elucidate the scope of drug addictions ketamine may target, its optimal dosing or route of administration, the importance of concurrent psychotherapies, professional supervision and safety monitoring, and which psychiatric comorbidities or contexts may contraindicate its use for SUDs. Full article

Drug abuse is a chronic, relapsing disorder marked by compulsive drug-seeking behavior and profound neurobiological consequences. Each year, millions of individuals face serious social and legal repercussions due to addiction. This review synthesizes findings from both preclinical and clinical studies to examine how chronic exposure to substances such as alcohol, cocaine, methamphetamine, and opioids affects the central nervous system. Specifically, it explores the epigenetic modifications induced by these substances, including DNA methylation, histone modifications, and noncoding RNA regulation. The literature was selected using a thematic approach, emphasizing substance-specific mechanisms and their effects on gene expression, synaptic plasticity, and the brain’s reward circuitry. Emerging evidence links these epigenetic changes to long-term behavioral adaptations and even transgenerational inheritance. This review underscores the complex molecular pathways contributing to addiction, vulnerability, and relapse, offering insights into potential therapeutic targets. Full article

Substance use during pregnancy is an increasingly important yet under-recognized threat to maternal and child health. This narrative review synthesizes the current evidence available on the epidemiology, pathophysiology, clinical management, and policy landscape of prenatal exposure to alcohol, tobacco, opioids, benzodiazepines, cocaine, cannabis, methamphetamines, and other synthetic drugs. All major psychoactive substances readily cross the placenta and can remain detectable in breast milk, leading to a shared cascade of obstetric complications (hypertensive disorders, placental abruption, pre-term labor), fetal consequences (growth restriction, structural malformations), and neonatal morbidities such as neonatal abstinence syndrome and sudden infant death. Mechanistically, trans-placental diffusion, oxidative stress, inflammatory signaling, and placental vascular dysfunction converge to disrupt critical neuro- and cardiovascular developmental windows. Early identification hinges on the combined use of validated screening questionnaires (4 P’s Plus, CRAFFT, T-ACE, AUDIT-C, TWEAK) and matrix-specific biomarkers (PEth, EtG, FAEE, CDT), while effective treatment requires integrated obstetric, addiction, and mental health services. Medication for opioid use disorders, particularly buprenorphine, alone or with naloxone, confers superior neonatal outcomes compared to methadone and underscores the value of harm-reducing non-punitive care models. Public-health strategies, such as Mexico’s “first 1 000 days” framework, wrap-around clinics, and home-visiting programs, demonstrate the potential of multisectoral interventions, but are hampered by structural inequities and punitive legislation that deter care-seeking. Research gaps persist in polysubstance exposure, culturally tailored therapies, and long-term neurodevelopmental trajectories. Multigenerational, omics-enabled cohorts, and digital longitudinal-care platforms represent promising avenues for closing these gaps and informing truly preventive perinatal health policies. Full article

Cocaine use remains a major public health concern, with rising global prevalence and a well-established profile of neurotoxicity and addictive potential. While the central nervous system has been the primary focus of cocaine research, emerging evidence indicates that cocaine also disrupts male reproductive physiology. In the testis, cocaine alters the endocrine microenvironment, induces cell-specific damage, and disrupts spermatogenesis. Cocaine also interferes with epigenetic programming in germ cells and mature sperm, potentially leading to heritable epimutations. Epidemiology data reveal that approximately two-thirds of regular cocaine users are males of reproductive age, and preclinical models have documented numerous behavioral and molecular alterations in their offspring, often linked to paternal cocaine exposure—such as increased drug resistance or vulnerability, altered anxiety-like behavior, impaired learning/memory, disrupted social behaviors, and shifts in neural circuitry and gene expression in reward-related brain regions. This review aims to integrate findings from studies that have independently examined testicular dysfunction, germline epigenetic reprogramming, and offspring outcomes, offering a unified perspective on their potential interconnections and highlighting future directions for research in the field of epigenetic inheritance. Full article

Substance use disorders (SUDs) remain a major public health challenge, with existing pharmacotherapies offering limited long-term efficacy. Traditional treatments focus on dopaminergic systems but often overlook the complex interplay between metabolic signals, neuroplasticity, and conditioned behaviors that perpetuate addiction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have recently emerged as promising modulators of reward-related brain circuits. This review synthesizes current evidence on the role of glucagon-like peptide-1 (GLP-1) and its receptor in modulating craving and substance-seeking behaviors. We highlight how GLP-1 receptors are expressed in addiction-relevant brain regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), where their activation influences dopaminergic, glutamatergic, and GABAergic neurotransmission. In addition, we explore how GLP-1 signaling affects reward processing through gut–brain vagal pathways, hormonal crosstalk, and neuroinflammatory mechanisms. Preclinical studies demonstrate that GLP-1RAs attenuate intake and relapse-like behavior across a range of substances, including alcohol, nicotine, and cocaine. Early-phase clinical trials support their safety and suggest potential efficacy in reducing craving. By integrating findings from molecular signaling, neurocircuitry, and behavioral models, this review provides a translational perspective on GLP-1RAs as an emerging treatment strategy in addiction medicine. We propose that targeting gut–brain metabolic signaling could provide a novel framework for understanding and treating SUDs. Full article

Exposure to chronic stress creates vulnerability to drug misuse and presents a barrier to sustained recovery for many individuals experiencing substance use disorders (SUDs). Preclinical literature demonstrates that stress modulates psychostimulant intake and seeking, yet there are wide gaps in our understanding of the specific mechanisms by which stress promotes brain changes that may govern addiction-related behaviors. Recent data suggest that microglia, innate immune cells in the central nervous system, are highly responsive to chronic stressors, and several mechanistic links have been explored highlighting the critical role microglia play in stress-related brain adaptation. Importantly, psychostimulants may engage similar microglial machinery, which opens the door for investigation into how microglia may be involved in shaping motivation for psychostimulants, especially in the context of stress exposure. The aims of this review are threefold: 1. Offer a brief overview of microglial biology in the adult brain. 2. Review current methods of interrogating microglial function with a focus on morphometric analyses. 3. Highlight preclinical research describing how microglia contribute to brain changes following chronic stress and/or psychostimulant exposure. Ultimately, this review serves to prime investigators studying the intersection of stress and SUDs to consider the relevant impacts of microglial actions. Full article

Substance Use Disorders (SUDs) are frequently associated with impairments in emotional regulation and behavioural control. Among the most prevalent substances of abuse, alcohol and cocaine are known to exert distinct effects on neuropsychological functioning. This study aimed to compare individuals with Alcohol Use Disorder (AUD) and Cocaine Use Disorder (CUD) in terms of impulsivity and alexithymia, and to examine the clinical implications of poly-substance use involving both alcohol and cocaine. Participants completed standardized psychometric assessments, including the Barratt Impulsiveness Scale (BIS-11), the Brief Psychiatric Rating Scale (BPRS), and the Toronto Alexithymia Scale (TAS-20). Group comparisons were conducted using non-parametric tests, and logistic regression models were applied to control for demographic covariates. The findings showed that impulsivity levels were comparable across groups, whereas alexithymia scores were significantly higher in individuals with AUD and in those with poly-substance use, relative to CUD-only participants. These findings underscore the relevance of targeting emotional regulation difficulties, particularly alexithymia, in the assessment and treatment of SUDs. Integrating emotion-focused interventions may enhance treatment outcomes, especially for individuals with co-occurring substance use patterns. Future research is needed to clarify the underlying neuropsychological mechanisms contributing to these differences and to inform more personalized approaches to addiction care. Full article

Background/Objectives: This review examines the role of pharmacogenomics in individual responses to the pharmacotherapy of various drugs of abuse, including alcohol, cocaine, and opioids, to identify genetic variants that contribute to variability in substance use disorder treatment outcomes. In addition, it explores the pharmacomicrobiomic aspects of substance use, highlighting the impact of the gut microbiome on bioavailability, drug metabolism, pharmacodynamics, and pharmacokinetics. Results: Research on pharmacogenetics has identified several promising genetic variants that may contribute to the individual variability in responses to existing pharmacotherapies for substance addiction. However, the interpretation of these findings remains limited. It is estimated that genetic factors may account for 20–95% of the variability in individual drug responses. Therefore, genetic factors alone cannot fully explain the differences in drug responses, and factors such as gut microbiome diversity may also play a significant role. Drug microbial biotransformation is produced by microbial exoenzymes that convert low molecular weight organic compounds into analogous compounds by oxidation, reduction, hydrolysis, condensation, isomerization, unsaturation, or by the introduction of heteroatoms. Despite significant advances in pharmacomicrobiomics, challenges persist including the lack of standardized methodologies, inter-individual variability, limited understanding of drug biotransformation mechanisms, and the need for large-scale validation studies to develop microbiota-based biomarkers for clinical use. Conclusions: Progress in the pharmacogenomics of substance use disorders has provided biological insights into the pharmacological needs associated with common genetic variants in drug-metabolizing enzymes. The gut microbiome and its metabolites play a pivotal role in various stages of drug addiction including seeking, reward, and biotransformation. Therefore, integrating pharmacogenomics with pharmacomicrobiomics will form a crucial foundation for significant advances in precision and personalized medicine. Full article

An electrochemical sensor for identification and monitoring of alcoholism was preclinically validated by analyzing plasma from polydrug-consuming rats (alcohol and cocaine). The sensor measures by adsorptive transfer square wave voltammetry the glycosylation level of transferrin, which is an alcoholism biomarker, through a recently reported parameter called the electrochemical index of glycosylation (EIG). Three rat groups were designed: saline group, cocaine group, and cocaine–alcohol group. Moreover, two periods of withdrawal were studied, after 2 days and 30 days. The alcohol–cocaine group after 2 days of withdrawal showed significantly lower EIG values (p < 0.1) than the rest of groups and also alcohol–cocaine group after 30 days of withdrawal, so the sensor was able to identify the alcohol consumption in rats and to monitor the recovery of glycosylation level after 30 days of withdrawal, even combined with cocaine. Furthermore, the effect of sex was also considered. Receiver operating characteristic (ROC) curves were developed for each sex and the corresponding cut-off values were determined. The sensor showed a clinical sensitivity of 70% for male and 75% for female, and a specificity of 67% for both sexes. This preclinical validation demonstrated the possibilities of this sensor for point of care testing of alcoholism, even in cocaine addicts, making it a potential tool for diagnosis and monitoring of alcohol consumption in detox treatments for humans. Full article