Search Results (166)

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

Rapid methadone metabolism in patients with opioid use disorder could complicate methadone treatment. Toxicology screenings to monitor methadone levels may show negative for methadone, even with regular adherence to a regimen. A patient receiving treatment for opioid use disorder tested negative for methadone in 11 out of 22 toxicology screenings (50.0%). We hypothesized that the patient was a rapid methadone metabolizer. After tapering doses to a maintenance level and using supervised urine collection, the patient was negative for methadone in seven out of seven tests (100.0%), but positive for cocaine in five out of seven tests (71.4%) near the end of the maintenance period. Chronic cocaine use and genetic factors, particularly CYP2B6 polymorphisms, have been found to cause rapid methadone metabolism. Clinicians should be vigilant for unusual metabolic reactions and modify dose and monitoring schedules accordingly. More investigation into the physiological and genetic aspects of methadone metabolism is needed. Full article

Objective: To scope the available literature on antipsychotic treatment in substance-induced psychotic disorders, summarize evidence across substance categories, and highlight priorities for future research. Methods: This scoping review followed Arksey and O’Malley’s framework and PRISMA-ScR guidelines. A systematic search of PubMed, Scopus, Embase, PsycINFO, and Cochrane Library (January 1985–August 2025) identified studies examining antipsychotic treatment in cannabis-, stimulant-, and hallucinogen-induced psychoses. Two reviewers independently screened studies and extracted data using a standardized form. Given marked heterogeneity, findings were synthesized descriptively. Results: Seventeen studies met inclusion criteria: 3 randomized controlled trials (17.6%), 10 observational studies (58.8%), and 4 case series (23.5%). Most evidence involved cannabis-induced (n = 7) and methamphetamine-induced (n = 6) psychosis. Randomized trials showed comparable efficacy between risperidone and haloperidol for cannabis-induced psychosis, and between quetiapine and haloperidol for methamphetamine-induced psychosis. Case series suggested potential benefits of third-generation antipsychotics such as lurasidone and cariprazine. No controlled studies were identified for cocaine- or hallucinogen-induced psychoses. Conclusions: Evidence for antipsychotic treatment in substance-induced psychoses remains scarce and uneven. While conventional antipsychotics appear effective for cannabis- and methamphetamine-related presentations, other substances remain virtually unstudied. Substantial evidence gaps and limited methodological quality highlight urgent research needs. Full article

The appetite hormone ghrelin influences biological processes that are responsible for substance use disorder, which is related to alcohol and most abused drugs including cocaine, methamphetamine, nicotine, etc. In general, upregulation of the ghrelin system enhances drug cravings and substance use. Studies reported in the literature consistently demonstrated that the ghrelin system is associated with stimulants. However, research on opioids in combination with methamphetamine has not been reported. In this study, we examined the relationship of circulating ghrelin with the polydrug use of fentanyl and methamphetamine in male Sprague-Dawley rats, demonstrating for the first time that concurrent use of fentanyl and methamphetamine significantly increased plasma acyl-ghrelin (the active form of ghrelin) and total ghrelin concentrations. Additionally, the data also demonstrated for the first time that the use of fentanyl alone also significantly increased the plasma ghrelin concentrations. These findings imply that the ghrelin system could be a potential pharmacological target for the treatment of substance use disorders caused by polydrug use involving fentanyl and methamphetamine as well as the fentanyl use alone. Full article

Medical students are at elevated risk for psychoactive substance use and mental health challenges due to academic pressures and environmental stressors. This study aimed to determine the prevalence and trends of psychoactive substance use among medical students at Riga Stradins University (RSU) and to examine associations with symptoms of anxiety, depression, and resilience to stress. A bilingual, anonymous cross-sectional study was conducted using a SurveyMonkey-hosted questionnaire. The survey included a socio-demographic questionnaire, the Generalized Anxiety Disorder Questionnaire-7 (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), the Brief Resilience Scale (BRS), and the World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test (WHO ASSIST V3.1). A total of 559 RSU medical students participated (response rate: 31.8%). Lifetime substance use prevalence was highest for caffeine 98.7%, alcohol 93.9%, tobacco 68.4%, and cannabis 50.9%. High-risk use was noted for tobacco 6.8%, inhalants 4.2%, cocaine 3.6%, and alcohol 1.4%. Significant differences in total substance use were observed by gender (p = 0.006) and depression symptom severity by PHQ-9 (p < 0.001), which were predictors of the total involvement score. The findings suggest that further attention to mental health and substance use patterns among medical students may be beneficial for student well-being and professional development. Full article

Background/Objectives: Alcohol consumption is a major public health concern, particularly among individuals with type 2 diabetes (T2D), due to its impact on morbidity and mortality. However, alcohol use disorder (AUD) among hospitalized T2D patients in Spain remains understudied. This study analyzed trends in AUD prevalence in adults hospitalized with T2D (2016–2023), identified associated factors, and assessed predictors of in-hospital mortality (IHM). Methods: We conducted a retrospective observational study using the Spanish National Hospital Discharge Database. Adults (≥18 years) with T2D were included. Joinpoint regression and multivariable logistic regression were applied. Results: Among 5,192,189 hospital admissions with T2D, 326,433 (6.29%) had AUD. Prevalence increased from 5.05% in 2016 to 7.52% in 2023 (annual percent change 5.95%; p < 0.05). AUD was more frequent in men (9.99%) than women (1.12%). Rising trends were observed for smoking (67.9% to 70.6%), cocaine use (2.0% to 3.15%), and cannabinoid use (1.08% to 1.78%) (all p < 0.001). Factors strongly associated with AUD included male sex (aOR 5.67; 95% CI 5.60–5.75), age 50–64 years, smoking (aOR 3.68 in men; 5.61 in women), cocaine use (aOR 4.55 in men; 7.68 in women), and mental disorders. IHM was 7.0% in T2D with AUD, peaking at 7.85% in 2020. Higher IHM was associated with age ≥ 80 years, hypoglycemia, and COVID-19, while obesity and mental disorders were linked to lower IHM. Conclusions: AUD prevalence in hospital admission with T2D in Spain is high and rising, particularly among women, with concomitant substance use also increasing. Comprehensive, sex-sensitive strategies are urgently needed in both hospital and outpatient care. Full article

Background: Insomnia is strongly associated with stimulant use across various populations and for a wide range of substances. It represents a significant clinical problem among individuals with stimulant use disorders, yet treatment guidelines for this specific population are limited. This gap underscores the need for a systematic review to analyze the pharmacological and non-pharmacological treatments for insomnia in individuals with stimulant use disorders. The aim of this review is to determine the efficacy, safety, and limitations of these approaches and their impact on psychiatric symptoms, stimulant use, and adverse events. Methodology: A systematic review was conducted through January–July 2025 using PubMed, Scopus, and Web of Science. The review focused on the management of chronic insomnia associated with stimulant use, including substances such as amphetamines, methylphenidate, nicotine, caffeine, and cocaine. The systematic review was structured in accordance with the PRISMA guidelines, and identified studies were assessed by title/abstract and full-text evaluation. Results: A total of twenty studies were included in the systematic review. Seven studies examined pharmacological interventions, including modafinil, naltrexone/buprenorphine-naloxone, varenicline, combination NRT, and ramelteon. Thirteen studies investigated non-pharmacological approaches, including Cognitive Behavioral Therapy (CBT), Repetitive Transcranial Magnetic Stimulation (rTMS), Electrical Vestibular Nerve Stimulation (VeNS), maximal strength training, electroacupuncture (EA), and probiotics. The majority of interventions demonstrated positive outcomes in reducing insomnia severity, with some participants achieving non-clinical levels. Commonly reported clinical symptoms related to insomnia included difficulty initiating or maintaining sleep, early morning awakening, and sleep dissatisfaction. Conclusions: Both pharmacological and non-pharmacological interventions showed promise. However, the lack of validated guidelines underscores the need for integrated therapeutic approaches that address the complex comorbidity of insomnia, stimulant use, and co-occurring psychiatric conditions. Full article

Kappa opioid receptor (KOR) antagonists may have therapeutic potential to prevent stress-induced relapse in abstinent individuals with cocaine use disorder (CUD). The macrocyclic peptide [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) is an orally bioavailable, brain–penetrant selective KOR antagonist that prevents stress-induced reinstatement of cocaine-seeking behavior in a mouse model of CUD. We synthesized and evaluated analogs of this lead compound with substitutions for the D-Trp residue to identify analogs that exhibit more potent central KOR antagonism following oral administration. The peptides were synthesized by a combination of solid phase and solution peptide synthetic methodologies, and their pharmacological activity was evaluated both in vitro (for KOR affinity, selectivity and antagonism) and in vivo (for antinociception and KOR antagonism), with promising analogs evaluated for their ability to prevent stress-induced reinstatement of cocaine-seeking behavior in the mouse conditioned place preference (CPP) assay. A variety of substituted D-Phe or modified D-Trp derivatives were tolerated by KOR with retention of significant KOR antagonism in vivo after oral administration. Macrocyclic peptide pretreatment, per os, significantly prevented stress-induced reinstatement of cocaine CPP at doses of 10 and 30 mg/kg of [D-Phe⁴]CJ-15,208, 4, and 30 mg/kg of [D-Trp(formamide)]CJ-15,208, 3, which are 6-fold and 2-fold lower, respectively, than that needed for {D-Trp]CJ-15,208. Full article

This paper investigates the state of substance use disorder (SUD) and the frequency of substance use by utilizing three unsupervised machine learning techniques, based on the Diagnostic and Statistical Manual 5 (DSM-5) of mental health disorders. We used data obtained from the National Survey on Drug Use and Health (NSDUH) 2019 database with random participants who had undergone clinical assessments by mental health professionals and whose clinical diagnoses were not known. This approach classifies SUD status by discovering patterns or correlations from the trained model. Our results were analyzed and validated by a mental health professional. The three unsupervised machine learning techniques that we used comprised k-means clustering, hierarchical clustering, and density-based spatial clustering of applications with noise (DBSCAN), which were applied to alcohol, marijuana, and cocaine datasets. The clustering results were validated using the silhouette score and the 95% confidence interval (CI). The results from this study may be used to supplement psychiatric evaluations. Full article

Background and Clinical Significance: Cocaine use disorder (CUD) is characterized by recurrent, cue-triggered and intrusive urges to use cocaine (craving), compulsive drug-seeking despite adverse consequences, and impaired control over intake, often co-occurring with excess weight and hedonic overeating. A dual-target rationale supports the fixed-dose naltrexone–bupropion (NB) combination: μ-opioid receptor (MOR) antagonism may mitigate opioid-facilitated mesolimbic reinforcement, while bupropion’s catecholaminergic effects and POMC activation support satiety and weight loss. Case Presentation: We describe a case study from an Italian outpatient setting of a 35-year-old man with a 10-year history of CUD, multiple failed detoxifications, and class I obesity (body mass index [BMI] 31 kg/m²) who initiated fixed-dose NB and was followed for 12 weeks under routine care. NB was associated with progressive attenuation of cue-reactive cocaine craving and improved appetite control, alongside clinically meaningful weight reduction, without psychiatric destabilization or emergent safety concerns; medication adherence remained stable. The patient maintained abstinence throughout follow-up and reported improved psychosocial functioning. Quantitatively, CCQ-B scores decreased from 7.2 at baseline to 2.1 at Week 12 (≈70% reduction), while BMI decreased from 31.0 to 25.5 kg/m² (≈−17.7%), with clinically meaningful weight loss and stable adherence. Conclusions: This case study supports the mechanistic rationale that dual NB therapy can simultaneously attenuate cocaine craving and facilitate weight control, addressing two clinically relevant targets in CUD. Although evidence for NB in CUD remains limited and mixed across stimulant populations, this observation highlights a plausible, testable therapeutic hypothesis that integrates mesolimbic and hypothalamic pathways and may inform the design of controlled trials in patients with co-occurring CUD and obesity. Full article

Background: Myocardial infarction (MI) in young adults, once a rarity, is increasingly recognized as a distinct clinical entity. Unlike traditional MI patients, younger individuals often present without established risk factors or advanced atherosclerosis, prompting a reevaluation of pathophysiologic paradigms and risk assessment strategies. Objective: This review synthesizes current evidence on the epidemiology, pathophysiology, and diagnostic challenges of MI in adults under 55 years, with emphasis on risk factor profiles. We distinguish between traditional cardiovascular risk factors—smoking, dyslipidemia, hypertension, diabetes, obesity, and family history—and emerging contributors, including elevated lipoprotein(a), recreational drug use (cocaine, cannabis, amphetamines), autoimmune and inflammatory conditions, psychosocial stress, sleep disorders, genetic predisposition, and non-atherosclerotic mechanisms such as myocardical infarction with non-obstructive coronary arteries, spontaneous coronary artery dissection, SCAD and Takotsubo syndrome. Methods: A narrative literature review was conducted, focusing on studies from the last five years addressing MI in young adults, including data from large registries, cohort studies, and recent experimental findings. 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