Search Results (136)

Substance use disorders (SUDs) remain a major public health concern and contribute substantially to compromised quality of life, mortality, and healthcare burden. In the United States alone, millions of individuals are affected by alcohol use disorder (AUD), tobacco use disorder (TUD), and opioid use disorder (OUD), with many cases complicated by co-existing anxiety and stress-related disorders. Piper methysticum G. Forst (kava), a traditional South Pacific plant preparation, has gained attention for its anxiolytic, sedative, and sleep-promoting properties. Its pharmacological effects are primarily attributed to a set of lipophilic compounds known as kavalactones, which have been reported to modulate GABA_A receptor activity, dopaminergic and adrenergic signaling pathways, monoamine oxidase-B activity, cannabinoid receptor type 1 activity, and voltage-gated ion channels. Peer-reviewed literature was identified through searches of PubMed, NIH resources, and other scientific databases using terms related to kava, kavalactones, addiction, anxiety, stress, insomnia, and SUDs. Both clinical and preclinical studies were reviewed, including investigations of neurotransmitter systems and addiction-related signaling pathways. The current literature suggests that the strongest rationale for kava use exists in AUD, where anxiety and stress are established contributors to relapse. Evidence supporting kava use in TUD and OUD is largely theoretical, while concerns regarding hepatotoxicity, cytochrome P450 interactions, product variability, and additive risk remain important barriers to its clinical application. In summary, current evidence does not support kava as a replacement for established therapies, while its unique pharmacological profile warrants further investigation as a potential adjunctive treatment for withdrawal and relapse in SUDs. Full article

Acute coronary syndrome (ACS) remains a leading cause of cardiovascular morbidity and mortality worldwide. Although traditional cardiovascular risk factors remain central to ACS development, recreational drug use is increasingly recognized as a clinically relevant trigger, particularly in younger patients with fewer conventional risk factors. This narrative review synthesized evidence identified through searches of PubMed/MEDLINE and Scopus up to June 2026, including clinical guidelines, systematic reviews, observational studies, mechanistic investigations, and clinically informative case-based evidence. Cannabis, cocaine, amphetamines, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), opioids, lysergic acid diethylamide (LSD), synthetic cannabinoids, and polysubstance use may promote myocardial ischemia and infarction through overlapping mechanisms, including sympathetic activation, coronary vasospasm, endothelial dysfunction, oxidative stress, inflammation, platelet activation, thrombosis, arrhythmogenesis, and myocardial oxygen supply–demand mismatch. Clinical presentation may be typical or atypical and may overlap with intoxication, withdrawal, anxiety, neurological symptoms, or non-cardiac chest pain, making diagnosis challenging. Underreporting of recreational drug use is common, and targeted toxicology screening may improve diagnostic accuracy and risk stratification, particularly in patients younger than 50 years, those with few traditional cardiovascular risk factors, or those presenting with otherwise unexplained ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), coronary vasospasm, arrhythmias, or cardiac arrest. Acute management should generally follow standard ACS guidelines, while considering drug-specific issues such as stimulant-induced vasospasm, sympathetic excess, cautious use of beta-blockers during acute intoxication, and preference for primary percutaneous coronary intervention when fibrinolysis carries increased risk. Long-term care should combine evidence-based secondary prevention with substance-use counseling, addiction medicine referral, cardiac rehabilitation, and behavioural interventions. This review summarizes the pathophysiology, clinical manifestations, epidemiology, treatment considerations, preventive strategies, and knowledge gaps related to recreational drug-associated ACS. Full article

Depressive symptoms are highly prevalent among individuals with substance use disorders, particularly opioid use disorder (OUD), yet their clinical meaning is often difficult to determine. In routine practice, these symptoms are commonly interpreted within a binary framework, either as manifestations of an independent mood disorder or as substance-induced states related to intoxication, withdrawal, or early abstinence. Although clinically useful, this distinction may not fully capture a third configuration in which depressive psychopathology emerges within the chronic addictive process itself. This Perspective proposes a tripartite model of depressive states in OUD informed primarily by clinical and dimensional studies conducted in populations with heroin use disorder. First, substance-induced depression refers to mood symptoms temporally linked to the acute or subacute pharmacological effects of substances and generally expected to improve with stabilization or sustained abstinence. Second, an independent mood disorder may coexist with OUD, with particular attention warranted for bipolar-spectrum presentations characterized by affective instability, cyclothymic or irritable temperaments, mixed features, and mood-related patterns of substance use. Third, addiction-related depression describes a persistent depressive configuration associated with reward dysregulation, hypophoria, motivational depletion, cognitive inefficiency, and the Worthlessness/Being Trapped dimension identified primarily in dimensional studies of heroin use disorder. These configurations should not be regarded as rigid or mutually exclusive categories, but as longitudinal clinical formulations that may predominate at different stages of the addictive trajectory. Distinguishing among them may improve diagnostic clarity and support a hierarchical clinical approach in which stabilization of OUD is generally an initial therapeutic priority, while antidepressant and mood-stabilizing interventions are guided by symptom severity, temporal course, psychopathological organization, and evidence of an independent mood disorder. Full article

Background: Online communities such as Reddit can reveal critical information needs (CINs) among people who discuss opioid use for chronic or acute pain under conditions of stigma and uncertainty. Methods: We used a mixed-method design to analyze 3428 unique Reddit posts from 1 January to 31 December 2022. Sentence-BERT embeddings and K-means clustering identified eight dominant themes, followed by qualitative analysis of a random subsample of 400 posts. Results: The most prevalent theme was seeking alternatives to opioids for pain relief (28.00%), followed by medications for chronic pain (19.84%) and kratom use experiences (14.64%). Qualitative findings showed recurrent concerns about addiction, stigma in clinical encounters, withdrawal, treatment access, and peer-to-peer discussion of kratom, tianeptine, cannabis, and other substitute substances. Conclusions: The study suggests an unmet need for accessible, nonstigmatizing, and clinically grounded information on pain management, tapering, and lower-risk alternatives to opioid use. These results have implications for addiction prevention, harm reduction, and patient-facing communication strategies for clinical practice and community health. Full article

Misuse of over-the-counter (OTC) and prescription-only medicines (POMs) is increasingly recognised as a public health and medicine-safety concern. Although specialist substance misuse services (SMS) increasingly support people affected by OTC/POM misuse, little is known about how SMS staff perceive the characteristics, challenges, and treatment needs of this population. This study explored the experiences of SMS staff to address this evidence gap and inform pharmacy practice and service development. Confidential semi-structured interviews were conducted with staff across five community adult English SMS. Audio recordings were transcribed verbatim and analysed thematically using NVivo^®. Twenty interviews with varied professionals achieved data saturation. Three overarching themes emerged: (1) characteristics of OTC/POM misuse; (2) staff-perceived patterns among people who misuse OTC/POM; and (3) negative experiences and concerns. Dependence on orally administered opioids (particularly codeine-containing products), benzodiazepines and gabapentinoids predominated. Polypharmacy including illicit substance use was also reported. Withdrawal symptoms frequently perpetuated misuse, and abrupt supply cessation created additional risks. Routine enquiry about OTC/POM misuse and provision of tailored harm-reduction interventions are essential. The findings suggest that pharmacists may have an important role in early identification of problematic OTC/POM use, harm-reduction interventions, medicine review and facilitating referral into appropriate treatment pathways. Further research should examine whether dedicated OTC/POM pathways are required and explore differences in demographic and treatment needs across medicine types. Full article

Background/Objectives: The recreational use of fentanyl (FT) combined with xylazine (XZ), known as “tranq-dope,” poses a growing public health threat due to its high toxicity and mortality. This study evaluated the effectiveness of naloxone (NX), its lipophilic prodrug NX90, and their combinations with the mixed κ-agonist/µ-antagonist nalbuphine (NB) in reversing overdose and restoring respiratory function in a rat model. Methods: Male and female Wistar rats received intramuscular FT (0.104 mg/kg) + XZ (1 mg/kg) to induce overdose, followed by intranasal administration of NX, NX90, or combinations with NB. Physiological parameters, reflex recovery, time to overdose, and reversal outcomes were assessed during individualized clinical monitoring. Results: At the low FT dose (0.052 mg/kg), adding XZ (1 mg/kg) shortened time to overdose by ~2600 s compared with FT alone, whereas onset times were similar at medium and high FT doses. In the dose-finding cohort, FT + XZ co-administration was associated with a higher respiratory rate than FT alone at the highest fentanyl dose tested, an exploratory finding warranting confirmation in larger studies. Most interventions did not significantly shorten time to reversal; however, NX + NB (females) and NX90 + NB (both sexes) showed shorter reversal times than NX alone. However, respiratory rate at reversal was significantly improved with NX + NB, ½NX90 + NB and NX90 + NB (90 ± 6, 86 ± 5 and 92 ± 5 breaths/min) compared with naloxone alone (80 ± 6 breaths/min). Interventions containing nalbuphine (κ-agonist/µ-antagonist) yielded higher RR and HR at reversal than NX alone, consistent with an interpretive framework in which κ–µ opioid balance may influence observed physiological recovery patterns. Conclusions: Comparable or improved reversal outcomes could be achieved using half-doses of NX or NX90 with NB—potentially reducing the total dose of naloxone and mitigating the risk of precipitated withdrawal in individuals with opioid use disorder. Full article

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

Venlafaxine, a serotonin–norepinephrine reuptake inhibitor, shows analgesic effects in rodents, but its efficacy and pharmacological profile in acute stimulus-evoked nociception may depend on the nociceptive test used and the pharmacological context. The aim of this review was to identify the receptors implicated in venlafaxine antinociceptive effects and to examine which molecular processes most consistently explain its acute antinociceptive profile. We reviewed in vivo rodent studies testing venlafaxine in acute nociceptive assays (writhing, tail-flick, hot-plate, and other eligible acute tests) as monotherapy or associated with other pharmacologically active substances. PubMed/MEDLINE and Web of Science were searched from 1993 to 5 January 2026, and reference lists were also screened. Outcomes were synthesized and stratified by type of nociceptive test and interaction class. Fourteen studies were identified as relevant to the scope of this review. Venlafaxine produced dose-dependent antinociception across tests, reducing writhing and increasing thermal withdrawal latency. Central administration generally yielded effects at lower absolute doses than systemic routes. Interaction studies most consistently supported modulation of opioid receptors (e.g., leftward opioid dose–response shifts and attenuation of morphine tolerance in repeated-exposure designs), with convergent evidence implicating opioid and α₂-adrenergic mechanisms and context-dependent serotonergic contributions. Additional pathways were variably implicated, including nitric oxide—cyclic guanosine monophosphate (NO–cGMP) signaling and oxidative/mitochondrial processes in opioid tolerance paradigms. Preclinical evidence supports venlafaxine as a modulator of acute nociceptive control with notable opioid-interaction potential. Standardized pharmacodynamic reporting and translationally oriented studies are needed. Full article

Kratom (Mitragyna speciosa) is a botanical candidate for pain management with potentially reduced opioid-related risks, partly through modulation of neuroimmune pathways involving Toll-Like Receptor 4 (TLR4). This study aimed to characterize the phytochemical profile of kratom ethanol extract and evaluate its effects on TLR4 signalling, neuroinflammatory cytokines, analgesic activity, withdrawal behaviours, and organ safety in morphine-dependent mice. Metabolite profiling was conducted using UHPLC–Q-Exactive Orbitrap HRMS, followed by molecular docking of major constituents to the TLR4 complex. In vivo assessments included flow cytometry and gene expression analyses of TLR4-mediated cytokines (NF-κB, IL-1β, IL-6), behavioural assays for antinociception, endurance, and withdrawal symptoms, and histopathological and biochemical evaluation of liver, kidney, and spleen tissues. More than 100 metabolites were identified, including mitragynine and flavonoids such as rutin and isoquercetin, which showed interactions with key TLR4 residues. Selected fractions suppressed pro-inflammatory cytokine expression, increased tail-pinch latency comparable to morphine, reduced withdrawal manifestations, and demonstrated nephroprotective and immunomodulatory effects, although mild reversible hepatic alterations were observed in specific fractions. Overall, kratom ethanol extract exhibited fraction-dependent analgesic and anti-neuroinflammatory activities associated with TLR4 modulation, supporting its potential as a botanical analgesic candidate while emphasizing the importance of safety optimization and standardized fraction development. Full article

Background: Mitragynine pseudoindoxyl (MP) is a semi-synthetic kratom metabolite increasingly sold online and over-the-counter, marketed misleadingly as “kratom” or “7-OH,” despite lacking FDA approval and safety data in humans. Methods: This case report describes a 44-year-old male with polysubstance use history who developed opioid withdrawal symptoms after regular MP use (400 mg daily for pain management following neck injury). Vital signs, alcohol and opioid withdrawal scores and clinical outcomes were recorded. Results: The patient presented exhibiting symptoms of moderate opioid withdrawal in the absence of other opioid use. A buprenorphine macro-induction protocol was initiated. Following pre-treatment using chlorpromazine as an anti-emetic and diazepam to treat concomitant alcohol withdrawal, 32 mg buprenorphine were provided (16 mg × 2) on day one, with subsequent maintenance dosing and adjunctive medications. The patient demonstrated significant symptomatic improvement with decreased COWS scores and expressed interest in long-acting injectable buprenorphine maintenance therapy. Discussion: This represents the first documented case of suspected MP withdrawal successfully managed with buprenorphine macro-induction, demonstrating the potential efficacy of this approach for novel semi-synthetic kratom metabolites when standard withdrawal management protocols are insufficient. Further studies should evaluate long term outcomes and validate findings. Full article

This study investigated temporal group-level changes in gut microbiome composition and fecal metabolic markers in Wistar rats following a 10-day administration of morphine. Fecal samples were collected at predefined post-discontinuation time points and analyzed using 16S rRNA gene sequencing and GC×GC-TOF/MS-based metabolomics, with a focus on short-chain fatty acids (SCFAs). Morphine exposure was associated with transient alterations in gut microbiome structure at early post-treatment time points, including changes in alpha diversity and shifts in the relative abundance of major bacterial taxa. Unsupervised multivariate analysis of fecal metabolomic profiles revealed substantial inter-individual variability without persistent global separation between control and morphine-treated groups. Targeted analysis identified transient reductions in the relative signal intensities of selected SCFAs shortly after morphine withdrawal, while no significant differences were observed at later time points. These findings suggest that morphine-associated perturbations of the gut microbiome and fecal metabolome are predominantly time-dependent and tend to diminish during extended post-discontinuation phases. Full article

Long-Acting Buprenorphine Formulations (LAIB) have emerged as an alternative pharmacological approach for opioid use disorder, offering potential benefits extending beyond clinical stabilisation. Narrative medicine provides a unique approach to understand patients’ perspectives and experiences with sublingual buprenorphine and LAIB dispensed to fourteen patients across different Italian Addiction Services, examining how they impact the emotional, social, and motivational dimensions of recovery. Narratives were analysed by thematic content across eight domains: dependence on daily treatment regimen, emotional impact, self-perception, determination to change, quality of life, craving and withdrawal symptoms, treatment adherence, social burden, and therapeutic relationship. Statements were categorised by valence; experiential patterns were qualitatively analysed. Sublingual buprenorphine, although effective, was associated with reduced autonomy, symptom control, and difficulties in balancing treatment, work and life. These aspects were correlated with worse adherence. The stigma and burden of daily intake can reduce motivation and hinder identity reconstruction. In this setting, transitioning to LAIB resulted in improved self-autonomy, emotional balance, symptom control, self-esteem, and reduced daily and psychological burden, craving and stigma, facilitating social reintegration, and strengthening the therapeutic relationship. The results emphasise the importance of including both experiential and narrative elements in clinical care, as this helps create more tailored, recovery-focused treatment pathways. Full article

Background and Clinical significance: This case describes a patient with a complex medical history who develops an active Mycobacterium tuberculosis (MTB) infection. The complex multidrug regimen has led to significant drug–drug interactions (DDIs) and adverse effects. This case highlights an urgent need for standardized guidelines on dose adjustment and therapeutic monitoring for opioid substitution therapy (OST) and antiretroviral therapy (ART) during MTB treatment to prevent adverse health outcomes and ensure clinical success. Case Presentation: A 43-year-old man with medical history including human immunodeficiency virus (HIV), chronic hepatitis C virus (HCV), psychotic disorder, and opioid dependence maintained on buprenorphine (24 mg/day) presented with acute psychosis and respiratory symptoms. During hospitalization, he was diagnosed with MTB infection and was started on an empirical rifampicin-based anti-MTB regimen. His clinical course was complicated by reduced buprenorphine efficacy caused by rifampicin, which precipitated opioid withdrawal symptoms. Conclusions: The successful clinical stabilization with resolution of withdrawal syndrome, reduced agitation, and normalization of vital signs, including heart rate and blood pressure of this patient, was achieved through targeted management of pervasive DDIs. A strategic ART switch and careful buprenorphine dose titration during rifampicin therapy was the key factor. This case highlights that co-managing HIV, MTB, and opioid use disorder presents a significant challenge where unaddressed DDIs directly threaten treatment efficacy, a patient’s safety, and adherence, and may result in increased toxicity. The case underscores the critical need for proactive DDI assessment, interdisciplinary collaboration, and guideline development for medication optimization in people living with HIV receiving OST. Full article

Buprenorphine (BUP) is widely used in the treatment of neonatal opioid withdrawal syndrome (NOWS). However, the most compounded formulation contains 30% ethanol, despite regulatory and clinical concerns regarding ethanol exposure in pediatric patients. Thus, this research aimed to develop an ethanol-free sublingual (SL) gel formulation of BUP that would be safe, stable, and suitable for NOWS. Multiple polymers were screened as gelling agents, with hydroxypropyl methylcellulose (HPMC) emerging as the ideal base polymer for the formulation due to its optimal pH, rheological characteristics, and stability. The formulated gels were stored at room temperature and refrigerated conditions for 30 days and evaluated for stability using pH, rheology, and liquid chromatography-mass spectrometry. BUP content was between 90–110% of the labeled amount of the dosage form (75 µg/mL) at all time-points, and the pH remained close to physiological values. Release studies demonstrated a drug release of 23–24% for SL gels without surfactants stored at room temperature and refrigerated conditions, respectively. Incorporation of non-ionic surfactants (Tween 20 and Tween 80) significantly increased drug release to 33% and 40%, respectively, reflecting enhanced solubilization and improved mucosal penetration. The ethanol-free formulation demonstrated physicochemical stability and favorable release characteristics suitable for neonatal administration. These findings represent a meaningful advance in the development of safer pediatric formulations for NOWS. Full article

Substance Use Disorder (SUD) constitutes a major and persistent global public health burden, accounting for approximately 600,000 deaths annually, largely driven by opioid use. Despite substantial advances in addiction neuroscience, currently approved therapeutic strategies remain limited in efficacy, as they predominantly target isolated neurobiological processes and fail to concurrently address core mechanisms such as glutamatergic hyperactivity, mesolimbic hypodopaminergic, and dysfunction of cortical and executive control networks. This mechanistic fragmentation contributes to persistently high relapse rates and underscores the need for integrative and multitarget therapeutic approaches. Within this context, ibogaine has re-emerged as a clinical candidate due to its distinctive multimodal neuropharmacological profile and its reported capacity to modulate multiple pathways implicated in addictive behaviours. However, the clinical translation of ibogaine remains substantially constrained by fragmented and heterogeneous evidence, the absence of regulatory frameworks in several jurisdictions, limited phytochemical validation and standardization of available formulations, and unresolved concerns regarding cardiac safety. This scoping review critically synthesizes the available preclinical and clinical literature on ibogaine in the treatment of SUD, with particular emphasis on reported effects on withdrawal symptoms and craving, dose–response relationships, and the occurrence of cardiac adverse events. By clarifying the current state of the evidence and delineating key translational constraints, this review defines the conditions under which ibogaine, an indole alkaloid isolated from Tabernanthe iboga Baill. (Apocynaceae), may warrant continued investigation. The hypothesis of a neurobiological “reset”, supported by emerging preclinical and clinical data, positions ibogaine as a compound of relevance in addiction research and highlights the need for rigorous pharmacological, toxicological, and regulatory evaluation to inform safer and more standardized clinical pathways. Full article