Search Results (175)

Background/Objectives: A sub-anesthetic dose of ketamine has shown promise in reducing craving, withdrawal symptoms, and use of drugs such as alcohol, cocaine, and opioids among individuals with substance use disorders. Ketamine’s therapeutic potential for tobacco use is unknown. Here, we investigated a single sub-anesthetic dose among adults with tobacco use disorder who were not interested in changing their smoking behavior. Methods: Utilizing a randomized, within-subject crossover, double-blinded, counter-balanced, midazolam-controlled design, participants (n = 18) received a 0.71 mg/kg infusion of ketamine and a 0.025 mg/kg infusion of midazolam (i.e., active placebo) at least two weeks apart. Participants were asked to abstain from smoking after the infusions until the post-infusion sessions, 1 day following infusion, where participants completed measures of smoking behavior, craving, and withdrawal symptoms. Participants continued to record their smoking behavior over the 7 days following infusion. Participants also completed a semi-structured qualitative interview regarding their experiences. Results: Compared to midazolam, ketamine infusion led to a non-significant reduction (p = 0.10, η_p² = 0.153) in the number of cigarettes smoked during the requested abstinence period. Following this period, there were no significant differences in ad lib smoking. Ketamine showed no effect on craving or withdrawal symptoms. Participants reported more intense psychological experiences following ketamine infusion (p < 0.001, η_p² = 0.830) and about half reported it felt easier to abstain from smoking after the ketamine infusion. Conclusions: While well tolerated, these findings suggest ketamine has little to no direct effect on quantitative measures of cigarette smoking, craving, or withdrawal. However, the qualitative measures suggest ketamine improves mood and reduces craving in some individuals for several days. Future studies should investigate whether ketamine can indirectly support smoking cessation among individuals with comorbid psychiatric indications for ketamine treatment. Full article

Background/Objectives: Research has shown a high prevalence of co-occurring trauma-related disorders and cocaine use disorder (CUD). However, there remains a need for preclinical studies to determine how traumatic event exposure influences vulnerability to CUD development and relapse. In this study, we assessed the impact of traumatic event exposure using a threat conditioning (TC) paradigm, which models traumatic event exposure through associative threat learning on cocaine-seeking behavior in adult male and female rats. Methods: Adult male and female rats were exposed to a single TC session. After TC, the rats underwent cocaine self-administration (SA), extinction training, cue-primed reinstatement, and cocaine-primed reinstatement testing. A parallel cohort was subjected to a sucrose SA cohort to assess whether TC altered non-drug reward seeking in the form of sucrose SA. Results: In the cocaine cohort, stressed male rats exhibited greater cue- and cocaine-primed reinstatement relative to non-stressed males, whereas no reinstatement differences emerged in female rats. In the sucrose cohort, stressed females displayed increased sucrose pellet delivery during self-administration compared to non-stressed females, but no differences were observed during sucrose reinstatement in either male or female rats. Conclusions: These findings indicate that trauma exposure prior to cocaine use influences cocaine relapse-related behavior, as well as non-drug reward reinforcement earning, in a sex-specific manner. Overall, these results highlight the value of associative stress models such as TC for studying trauma–addiction comorbidity and the need to investigate the neurobiological mechanisms driving these sex-specific outcomes. Full article

HIV-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART) and can be exacerbated by repeated cocaine (COC) exposure. Because COC, HAND, and cART independently disrupt medial prefrontal cortex (mPFC) function, their combined neurotoxic impact is a critical clinical concern. Using patch-clamp electrophysiology in HIV-1 transgenic (Tg) and non-Tg rats, we examined mPFC pyramidal neuron activity following repeated exposure to COC and/or cART. In non-Tg rats, COC and cART independently increased neuronal firing, trending toward an additive hyperactive effect when combined. Conversely, HIV-1 Tg rat neurons exhibited plateaued excitability, with no further firing elevations induced by COC or cART. Under intense depolarizing stimuli, treated neurons displayed overactivation-induced firing declines. These findings indicate that while COC and cART additively disrupt mPFC function in non-Tg rats, excitability mechanisms appear saturated in the HIV-1 Tg model. This restricted experimental context highlights the overlapping neurobiological impacts of cART and stimulant use, providing foundational insights into the comorbidity of COC use disorder and HAND. Full article

Graves’ disease (GD) is an autoimmune disorder characterized by hyperthyroidism and a hypermetabolic state involving complex endocrine, metabolic, and immune interactions. Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide involved in energy balance, neuroendocrine signaling, and neuroimmune modulation; however, its circulating levels and clinical relevance in GD remain unclear. In this single-center prospective study, serum CART levels were evaluated in 44 patients with GD and 44 age- and sex-matched healthy controls. Associations with thyroid function, autoimmune markers, metabolic parameters, and thyroid ultrasound heterogeneity were analyzed. Serum CART concentrations were measured using an enzyme-linked immunosorbent assay, and clinical, biochemical, and ultrasonographic data were recorded. Serum CART levels did not differ significantly between GD patients and healthy controls. However, within the GD group, CART levels varied significantly according to thyroid ultrasound heterogeneity, with lower levels observed in patients with severe parenchymal heterogeneity. Serum CART levels showed positive correlations with body mass index and insulin resistance indices, while inverse correlations were observed with thyrotropin receptor antibody and anti-thyroid peroxidase antibody levels. No significant associations were identified between serum CART levels and circulating thyroid hormone concentrations. These findings suggest that serum CART may reflect metabolic and autoimmune heterogeneity rather than hypothalamic–pituitary–thyroid axis activity in GD, supporting its role as a context-sensitive, hypothesis-generating biomarker. Full article

Background/Objectives: To evaluate whether medical cannabis (MC) use following dysuria diagnosis is associated with increased risk of developing substance use disorder (SUD), given rising cannabis prescriptions for urologic symptoms and concerns about long-term consequences. Methods: We conducted a retrospective cohort study using the TriNetX Research Network, a federated electronic health record database with over 120 million patients. Adult patients newly diagnosed with dysuria between 2003 and 2024 were identified and stratified by subsequent cannabis exposure. MC users were defined by a cannabis-related diagnostic code within 90 days of dysuria diagnosis. Propensity score matching (PSM) was performed 1:1 by age, sex, and race. The primary outcome was a new diagnosis of SUD (cannabis, opioid, or cocaine use disorders) within 12 months. Secondary analysis included Kaplan–Meier (KM) survival estimates over 5 years. Risk ratios (RR), odds ratios (OR), and hazard ratios (HR) were calculated. OR and RR estimated the likelihood of SUD within 12 months, and HR reflected relative hazard over 5 years. Results: After excluding patients with prior SUD, the final sample included 60,544 MC patients and 98,715 general dysuria (GD) patients. The MC group had a significantly higher incidence of new SUD diagnoses (11.13%) than the GD group (2.28%), yielding a risk difference of −8.85% (95% CI: −9.11 to −8.58; p < 0.0001), relative risk 0.205, and OR 0.186. KM analysis showed lower SUD-free survival in MC (80.96%) versus GD (96.35%; log-rank p < 0.0001). MC exposure was associated with nearly fivefold increased odds of SUD within 12 months (OR = 0.186) and sixfold higher hazard over 5 years (HR = 0.163). Conclusions: Medical cannabis use after dysuria is linked to markedly increased risk and earlier onset of SUD. Careful patient selection, counseling, and monitoring are essential when prescribing MC for urologic symptoms. Full article

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

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