We report a case of severe opioid-like withdrawal symptoms following cessation of a commercially available beverage marketed as a "kava" product. A 36-year-old White male with opioid use disorder in sustained remission developed rapid tolerance, frequent redosing, nocturnal withdrawal, prominent gastrointestinal and autonomic symptoms, and generalized pruritus after heavy use of a gas-station-sold "kava" shot. Symptoms were refractory to benzodiazepines but improved rapidly with buprenorphine/naloxone; this suggests µ-opioid receptor-mediated dependence. The clinical presentation was inconsistent with kava withdrawal, which is typically mild and anxiety predominant. Review of product labeling indicated the presence of akuamma (Picralima nitida), a botanical containing μ-opioid receptor-active alkaloids; secondary qualitative testing of independently purchased samples of the same product by the UAB toxicology lab confirmed the presence of kratom (Mitragyna speciosa) derivatives and kavalactones. In the context of kratom prohibition in Alabama and overlapping manufacturer product lines, this case highlights the risks of mislabeled or adulterated polyherbal products and underscores the need for clinicians to consider opioid-mediated mechanisms and symptom-guided treatment when evaluating withdrawal from purported nonopioid supplements.
Milk and dairy products are a significant source of bioactive peptides, including β-casomorphin-7 (BCM-7), a heptapeptide released from the enzymatic cleavage of the A1 variant of β-casein. While some studies have suggested that BCM-7 may have detrimental effects on gastrointestinal physiology, the European Food Safety Authority found no established cause-and-effect relationship between the oral intake of BCM-7 and non-communicable diseases. This study aimed to investigate the biological effects of BCM-7 at physiologically relevant concentrations, corresponding to the estimated exposure levels in the European population, on the mucus-producing HT29-MTX-E12 intestinal cell line. Cells were treated with BCM-7 concentrations ranging from 4 to 120 µM for 4 hours, and various endpoints were assessed, including cytotoxicity, mucus production and secretion, opioid activity, inflammation, and peptide translocation across the intestinal barrier. BCM-7 treatment did not significantly affect cell viability, metabolic activity, or membrane integrity, except for a slight increase in LDH release at the highest concentration tested. No changes in mucin gene transcription levels (MUC5AC, MUC2) or mucus secretion were observed. However, BCM-7 treatment increased the expression of the µ-opioid receptor compared to the untreated control, confirming its opioid-like properties. While the IL-8 gene mRNA level increased at 120 µM, protein secretion remained unchanged, suggesting limited inflammatory effect. BCM-7 translocation across the intestinal barrier was minimal and inversely concentration-dependent, with most peptides likely degraded by dipeptidyl peptidase-4. These findings demonstrate that physiologically relevant BCM-7 concentrations exhibit opioid-like properties but have limited impact on mucus production, inflammation, and translocation of the intact peptide across the epithelial barrier in this in vitro intestinal model. The results provide mechanistic insights into BCM-7 effects while highlighting the need for further research considering individual dietary patterns and complex milk component interactions.
Intranasal administration of the neuropeptide oxytocin has been explored as a potential therapeutic agent for substance use disorder including opioid use disorder (OUD). This phase 1, crossover, randomized, double-blind, placebo-controlled trial tested the safety, tolerability, and efficacy of intranasal oxytocin (80 IU) twice a day for 7 days in participants (N = 20) with OUD who were taking an opioid agonist therapy. In the laboratory, participants underwent opioid cue exposure paired with noradrenergic activation produced by yohimbine (32.4 mg) or placebo. Assessments included, 1) subjective response: craving, withdrawal, anxiety, and stress; 2) biomedical markers: hypothalamic-pituitary-adrenal axis response (cortisol) and noradrenergic activation (α-amylase); and 3) safety measures: hemodynamics and adverse event evaluation. Generalized linear model with model-based estimator in the covariance matrix was used, with medication (oxytocin/placebo) and noradrenergic activation (yohimbine/placebo) as within-subject factors. Oxytocin significantly reduced opioid-like withdrawal, anxiety symptoms, and cortisol levels elicited by cue exposure under noradrenergic activation produced by yohimbine. This effect was specific because oxytocin did not reduce craving, hemodynamics, or α-amylase levels increased by yohimbine administration. A single dose of yohimbine elicited the noradrenergic stimulation, and 7-day oxytocin administration was safe and well tolerated among individuals diagnosed with OUD and taking opioid agonist therapy. The findings of this study suggest that oxytocin alleviates opioid-like withdrawal symptoms and anxiety by modulating the hypothalamic-pituitary-adrenal axis. Oxytocin was administered intranasally to 20 participants with opioid use disorder (OUD) to determine whether it reduced cravings for opioids and helped to improve symptoms of the disorder in general. The study sample included individuals with OUD who were currently abstinent from opioids and were receiving medication treatment to help maintain abstinence. Results indicated that after a stress-induced procedure, oxytocin was not effective in reducing opioid cravings, but it was able to reduce opioid-like withdrawal symptoms, and other markers of anxiety.
The development of multi-target opioids has emerged as a promising strategy to mitigate opioid-related side effects. We have previously designed a novel hybrid peptide BNT12 by combining opioid and neurotensin pharmacophores, which exhibited supraspinal antinociception. Herein, the antinociceptive properties of a novel hybrid peptide, BNT12, were evaluated across various preclinical pain models following intrathecal (i.t.) administration. Our results showed that spinal administration of BNT12 produced potent antinociception in acute pain. The antinociceptive effects of BNT12 were likely mediated through μ- and δ-opioid receptors, as well as the neurotensin receptor 1 (NTSR1) and 2 (NTSR2). BNT12 also exhibited significant antinociceptive activities in spared nerve injury (SNI)-induced neuropathic pain, complete Freund's adjuvant (CFA)-induced inflammatory pain, acetic acid-induced visceral and formalin-induced pain at the spinal level. Additionally, BNT12 significantly inhibited the microglial activation and decreased the mRNA expression levels of TNF-α and IL-1β in the spinal dorsal horn of SNI model. It is noteworthy that BNT12 exhibited substantially reduced acute and chronic antinociceptive tolerance. Furthermore, i.t. administered BNT12 showed minimal or no side effects on conditioned place preference response, naloxone-precipitated withdrawal response, acute hyperlocomotion, gastrointestinal transit, and motor coordination. The present investigation demonstrated that the hybrid peptide BNT12 exhibited potent and durable antinociception with minimal opioid-like side effects at the spinal level. Therefore, BNT12 might serve as a promising candidate to alleviate pain with a favourable side effect profile.
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.
International guidelines for the management of high output stoma (HOS) commonly involve the use of opioids and opioid-like derivatives, such as loperamide, to mitigate the risk or impact of intestinal failure. However, these agents often have significant drug-drug interactions that may reduce the efficacy of anti-diarrheal pharmacotherapy and risk prolonged dependency on parenteral nutritional and intravenous fluid replacement, if unrecognized. Two cases of patients prescribed rifampicin for differing indications demonstrate persistent HOS despite traditional management strategies, including maximal doses of anti-diarrheal agents. Rifampicin, a known cytochrome P450 enzyme inducer, increases metabolism of both codeine and loperamide, resulting, in these cases to reduced drug efficacy and intestinal failure. Prescribers must be mindful of the potential drug-drug interactions when co-administering drugs inducing cytochrome P450 expression with opioids commonly used in HOS management. Given the risk of opioid inefficacy and increased stomal outputs, close monitoring and careful drug titration is advised.
The term "kratom" refers to a plant species formally known as Mitragyna speciosa. Kratom is composed of over 40 alkaloids, a type of organic compound that contains nitrogen. These compounds work primarily via binding to opioid receptors expressed on neurons, where they stimulate signal transduction mechanisms involving the activation of G proteins. Kratom has been shown to cause both a stimulant-like effect and a sedative effect in humans. These studies have shown that use is highest among European-American, middle-class men living in suburban areas. Additionally, individuals who have a history of opioid misuse are also more likely to take kratom. Kratom is used by many different people in the US for numerous different reasons. Some of the most often cited reasons include treating chronic pain conditions, depression, and anxiety. Individuals who used kratom for these reasons typically consumed kratom daily at a dose of 1-3 grams, with the kratom extracted into a powder to be consumed in a capsule. Additionally, there have been reports of kratom being used to treat opioid withdrawal symptoms, as kratom can bind to some of the same receptors as opioids. This manuscript specifically describes trends regarding the use of kratom in the US, pharmacokinetic and pharmacodynamic properties of kratom, potential therapeutic uses of kratom, adverse events caused by kratom, and case studies in the literature regarding patients using kratom.
In October 2025, the Alabama Poison Information Center and local addiction medicine providers identified a cluster of cases involving liquid products marketed as containing kava associated with opioid-like withdrawal symptoms. Kava is not typically associated with physical dependence, raising concern for opioid-active substances. Five unique retail products were submitted for laboratory analysis. Three underwent quantitative ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) testing for kavalactones, kratom alkaloids, and related semisynthetic derivatives, with additional screening for 260 substances. Two products underwent qualitative gas chromatography-mass spectrometry (GC-MS) testing for mitragynine and kavalactones. Qualitative GC-MS detected both mitragynine and kavalactones in one product, while another contained mitragynine with no detectable kavalactones. Quantitative UPLC-MS/MS identified both kavalactones and kratom alkaloids in three products, with mitragynine pseudoindoxyl predominating at concentrations of 0.16-0.21 mg per bottle. Detection of kratom alkaloids and related semisynthetic derivatives in products labeled as kava may explain the observed opioid-like withdrawal. Mitragynine pseudoindoxyl, which has greater opioid activity than mitragynine and 7-hydroxymitragynine, was identified as the predominant kratom-related compound. Unrecognized exposure to opioid-active kratom compounds may occur through products marketed as kava, highlighting the need for improved surveillance and increased awareness.
Kratom is increasingly used in the United States for pain, mood, anxiety, and opioid substitution. Traditional kratom produces mild, delayed withdrawal, but semisynthetic derivatives such as mitragynine pseudoindoxyl (MP) are highly potent μ-opioid receptor agonists with δ-opioid receptor antagonism, leading to rapid-onset, full-spectrum opioid-like withdrawal. We describe a 34-year-old man with long-term remission from heroin use disorder who presented with suicidal ideation and severe opioid-like withdrawal despite no recent opioid use. He progressed from powdered kratom to 7-hydroxymitragynine tablets and then MP tablets, averaging nine 20 mg doses daily, including nocturnal use. On presentation, he exhibited chills, tremors, diaphoresis, gastrointestinal distress, restlessness, with a Clinical Opiate Withdrawal Scale score of 31, blood pressure 168/107 mmHg, and heart rate 115 bpm. Supportive management with clonidine, hydroxyzine, gabapentin, loperamide, and antiemetics over 72-96 hours led to symptom resolution. Naltrexone, including a Vivitrol injection, was initiated without precipitating withdrawal, and the patient remained abstinent at one-month follow-up, despite a brief noneuphoric lapse. This case highlights MP as an emerging high-potency kratom derivative that poses unique diagnostic and management challenges. Clinicians should recognize its severe withdrawal profile, the limitations of standard toxicology, and the potential role of naltrexone in relapse prevention once an opioid-free interval is established.
Kratom ( Mitragyna speciosa ) is a plant indigenous to Southeast Asia. This pilot study evaluated the pharmacodynamic (PD) effects, safety, and pharmacokinetics (PK) of kratom and several of its alkaloids. Recreational polydrug users (8 participants/cohort; 6 active: 2 placebo, N=40) completed the study. Participants had experience with opioids but were otherwise healthy. This study utilized a double-blind, between-subjects design where participants randomly received a single dose of placebo or kratom. The kratom used in the study had alkaloid levels representative of botanical kratom products (i.e., leaf) previously characterized in the literature and contained trace levels of 7-hydroxymitragynine (7-OH). The starting dose was 1 g and doses of 3, 8, 10, and 12 g were administered after safety reviews after each dose. After dosing, pupillometry and assessments of subjective effects were performed, and blood samples were collected. Safety assessments included adverse events (AE) monitoring, laboratory tests, vital signs, ECG assessments, physical examination findings, and assessment of suicidality. No deaths or serious adverse events (SAEs) occurred. Somnolence, vomiting, and nausea were the most common AEs reported. Kratom alkaloid concentrations showed generally orderly, dose-related effects. At doses ≥3 g, kratom produced pupillary constriction. Few dose-related effects were observed, although the 12 g dose of kratom produced increases on several subjective measures including ratings of "drug liking." This study investigated the safety of single-sourced botanical kratom; the results may not be representative of other kratom-containing products. Kratom produced some opioid-like effects including pupillary constriction, and the 12 g dose produced effects commonly associated with drugs of abuse such as visual analog scale (VAS) ratings of drug liking, good effects, and high.
This study aimed to report acute opioid withdrawal after an abrupt cessation of high-dose 7-hydroxymitragynine (7-OH) in a patient who transitioned from kratom and to outline pharmacist-focused assessment, management, and regulatory counseling strategies including a formal causality assessment. A 43-year-old male with opioid use disorder presented with nausea, diarrhea, abdominal cramping, restlessness, chills/clamminess, and anxiety after discontinuing concentrated 7-OH (360 mg/d, last 30 mg dose ∼ 48 hours earlier). Vital signs were blood pressure of 138/93 mm Hg, temperature of 37.7°C, heart rate of 84 beats/min, respiratory rate of 16 breaths/min, and pupils of 2-3 mm, with a clinical opioid withdrawal scale score of 5. He had transitioned from kratom to 7-OH approximately 18 months earlier. He met the DSM-V criteria for moderate opiate use disorder, although he never engaged in formal treatment. The patient reported that he transitioned from kratom to concentrated 7-OH products because he perceived stronger, faster opioid-like effects and required smaller quantities to avoid withdrawal. Emergency department management included sublingual buprenorphine-naloxone 4-1 mg, adjuncts (clonidine, ondansetron, loperamide, methocarbamol, nonsteroidal anti-inflammatory drugs, acetaminophen), counseling on precipitated withdrawal, and referral for treatment. A Naranjo assessment supported probable causality (score 6). Concentrated 7-OH products differ from kratom leaf and can produce dependence and withdrawal; pharmacists should screen for these products, time buprenorphine initiation to moderate withdrawal, provide harm-reduction counseling, and incorporate evolving state regulations into patient education.
Drug-induced hyperpigmentation accounts for 10%-20% of acquired pigmentary disorders and can be misdiagnosed for other causes such as melasma, post inflammatory changes, or heavy metal deposition. Kratom (Mitragyna speciosa), a Southeast Asian plant with an opioid-like profile, has been increasingly used in the United States for several conditions such as pain, mood disorders, and opioid withdrawal. While neuropsychiatric and liver toxicity adverse effects are documented, hyperpigmentation, and skin changes remain poorly recognized. We describe a 38-year-old female with a history of Hashimoto's thyroiditis and seizure disorder who developed a progressive blue-gray hyperpigmentation over 3 years. The hyperpigmentation was initially confined to the nose and subsequently spread to the face, neck, chest, upper back, and arms. It was initially diagnosed and treated as melasma without improvement. Skin biopsies revealed basal layer hyperpigmentation and dermal melanophages. Fontana-Masson staining demonstrated an admixture of black melanin granules and distinct red-brown intracytoplasmic pigment, consistent with Kratom-associated drug deposition. These findings were consistent with drug-induced hyperpigmentation. A comprehensive medication review history excluded commonly implicated drugs. Upon further questioning, the patient disclosed prior use of kratom tea for approximately 18 months, which was discontinued around the time of the clinical presentation. This case highlights the importance of thorough exposure history, including herbal supplements, in the workup of atypical hyperpigmentation and highlights novel histopathological features of Kratom-associated hyperpigmentation that expand the current understanding of drug-induced cutaneous changes.
Mitragyna speciosa (commonly known as kratom) is a tropical tree native to Southeast Asia, ethnobotanically used for pain relief and fatigue management. Kratom has gained popularity in Western countries for its dose-dependent stimulant and opioid-like effects, and its reported use in the self-treatment of opioid withdrawal. Kratom leaves accumulate over 50 monoterpene indole alkaloids (MIAs) and oxindole alkaloids that have pharmaceutical significance, to which many of these effects are attributed. In this study, we characterized eight kratom accessions originating from Central and Southern Thailand which exhibited phenotypic variation in leaf morphology, including differences in shape, margins, and vein coloration. To authenticate and evaluate genotypic variation among these accessions, we employed DNA barcoding using four loci: the nuclear ITS, and three plastid barcodes including rbcL, MatK, and trnH-psbA. No polymorphisms were detected using ITS and rbcL barcodes. However, sequence analyses revealed insertion-deletion polymorphisms in trnH-psbA, and single nucleotide polymorphisms in both MatK and trnH-psbA, resolving intraspecific variation and separating the accessions into two distinct haplotypes. Targeted metabolite profiling was conducted using UPLC-MS to quantify 17 MIAs and oxindole alkaloids from both young and mature leaves across all kratom accessions. Mitragynine was the most predominant alkaloid in mature leaves, reaching up to 1.19% w/w of leaf dry mass, whereas juvenile leaves accumulated speciociliatine as the major alkaloid, at levels up to 1.14% w/w. Notably, strictosidine, the central precursor of MIA biosynthesis, was detected exclusively in juvenile leaves, which also exhibited significantly higher levels of upstream intermediates including corynantheidine, and iso-corynantheidine compared with mature leaves. In addition, juvenile leaves were dominated by 3R MIAs, whereas mature leaves accumulated higher levels of 3S MIAs. However, the relative distribution of 3S and 3R stereoisomers remained consistent across accessions. Under the conditions examined, leaf developmental stage exerted a greater influence on alkaloid composition than accession or haplotype variation. Despite visible distinction in leaf vein coloration, alkaloid profiles at maturity remained largely consistent across all accessions. The developmental chemotype patterns presented in this study provide a valuable framework for targeted breeding, metabolic engineering, and controlled cultivation strategies aimed at optimizing specific MIA profiles, particularly those of pharmacological interest.
Kratom (Mitragyna speciosa) is increasingly used in the United States as a dietary supplement for pain, mood regulation, and opioid withdrawal. Its alkaloids, mitragynine and 7-hydroxymitragynine (7-OH), demonstrate μ-opioid receptor activity, with 7-OH exhibiting substantially greater opioid-like potency than mitragynine. There are concerns from the US Food and Drug Administration (FDA) regarding dependence and adverse effects. Purified 7-OH products may bypass metabolic pathways and deliver disproportionately strong opioid effects compared with natural kratom preparations, increasing the risk of dependence. Despite these concerns, 7-OH remains federally unscheduled, though listed as a "Drug of Concern" by the DEA. Although there is no standardized clinical guidance, buprenorphine has been used to manage kratom and 7-OH withdrawal with varying initiation strategies. To describe the clinical course and outcomes of buprenorphine initiation among patients with problematic 7-OH use, focusing on initiation timing, dosing strategies, and symptom monitoring. Retrospective chart review of patients treated at a low-barrier telehealth addiction medicine clinic between April and October 2025. Nine patients with purified 7-OH product use (as opposed to kratom use) met the inclusion criteria. The mean age was 33.5 years; 7 patients were identified as male. Low-dose initiation was used in 6 cases and standard initiation in 3 cases. Successful initiation and stabilization occurred in 88.9%, with no precipitated withdrawal or adverse events. Symptom improvement was reported in 8 of the total cases at a median 6-week follow-up. Buprenorphine initiation for problematic 7-OH use was feasible, well tolerated, and associated with symptom improvement, supporting development of pragmatic clinical approaches for this emerging substance use disorder.
Kratom ( Mitragyna speciosa ) is a psychoactive herbal product increasingly used for pain, anxiety, and opioid withdrawal. Although marketed as a natural dietary product, concerns have emerged regarding adverse effects like cardiotoxicity, seizures, opioid-like physical dependence, and, particularly, liver toxicity. We conducted a systematic review following PRISMA 2020 guidelines of all studies on kratom use and liver toxicity. Thirty-one studies were included, comprising 32 cases of kratom-associated liver injury. Most reports originated from the United States and were single-patient case reports. Most patients were adult males, with frequent co-occurrence of polysubstance use and comorbid conditions. Concomitant exposures were commonly reported but variably characterized across studies. Baseline liver disease was present in 3 patients (9%). Kratom dose, form, frequency, and duration were inconsistently reported. Only 7 cases (22%) provided complete exposure details, whereas the remainder lacked one or more elements. Kratom use was temporally associated with the onset of liver injury, commonly presenting with jaundice and elevations in liver enzymes. The patterns of injury were predominantly cholestatic. In most cases, liver enzymes and function improved after cessation of kratom use. In 4 cases, the patient's liver function did not improve and progressed to liver transplantation. Although formal causality assessments were inconsistently reported, many reports supported an association based on exclusion of alternative etiologies and, in some cases, rechallenge episodes. Further research is needed to better characterize kratom's mechanisms of liver injury and to inform clinical decision-making and public health policy.
Kava (Piper methysticum), a central nervous system depressant derived from a plant in the pepper family native to the Pacific Islands, is traditionally consumed in religious, cultural, political, and social ceremonies. In the United States, kava emerged in the late 1990s and has experienced renewed growth and product diversification since the 2010s, with increasing availability of concentrated extracts and ready-to-drink beverages. These commercial products are commonly marketed as healthy alternatives to alcohol, sold near college campuses, and increasingly being combined with kratom, a psychoactive botanical with opioid-like effects, raising safety concerns. Data on kava-related use during January 2000-December 2025 that resulted in a report to the National Poison Data System (i.e., kava exposure report) were analyzed to assess trends by users' demographic characteristics, exposure type, and outcomes. Kava-related exposure reports declined sharply after a 2002 Food and Drug Administration advisory on kava-associated severe liver injury but have risen steadily since 2011, reaching 203 reported exposures in 2025. Reports primarily involved adults aged ≥20 years, but demographic characteristics have changed over time. During 2000-2001, reports primarily involved females and included more children aged ≤12 years, whereas exposure reports since 2013 have predominantly involved men; reports involving children have been rare. Since 2017, reports involving combined use of kava and kratom have increased, reaching 30% (61) of all kava reports in 2025. These increases have coincided with higher rates of serious reported clinical outcomes in recent years (32% in 2025 compared with 12% in 2000). These data indicate a resurgence of overall kava exposure reports to poison centers, as well as an increase in kratom-related kava reports, which has coincided with higher rates of serious clinical outcomes. The findings in this report suggest the need for enhanced surveillance for, clinical awareness of, and public education regarding commercial products containing kava.
Tianeptine is an atypical tricyclic antidepressant with mu-opioid receptor agonist activity. Although marketed as an unregulated "nootropic" in the United States, its use has been increasingly associated with misuse, dependence, and toxicity. We conducted a systematic review following PRISMA 2020 guidelines. MEDLINE, Embase, Cochrane, PsycInfo, and Scopus were searched from inception through July 2025 for human studies describing tianeptine misuse, toxicity, withdrawal, or overdose. Eligible designs included randomized controlled trials, observational studies, and case reports. Data were extracted on clinical presentation and management. Study quality was assessed using Joanna Briggs Institute tools, and findings were narratively synthesized. Fifty-three publications met inclusion criteria (48 case reports and 5 retrospective series; N = 1055). Among individual cases (n = 52), 26/52 (50%) presented with withdrawal and 23/52 (44%) with overdose. Long-term treatment for withdrawal included buprenorphine 5/26 (19%) and methadone 1/26 (4%). Overdose presentations commonly involved central nervous system depression, respiratory failure, and rhabdomyolysis; among overdose cases with detailed data (n = 22), naloxone was administered in 6/22 (27%), and fatalities occurred in 7/22 (32%). Retrospective studies (n = 1007) described mixed toxicity and withdrawal presentations; 227/1007 (22%) requiring intensive care. Tianeptine misuse is associated with opioid-like dependence, withdrawal, and toxicity. Continued clinical and epidemiological observation is warranted.
Kratom (Mitragyna speciosa) is a plant-derived supplement increasingly used in the United States for chronic pain and mood elevation due to its opioid-like effects. While systemic side effects have been described, cutaneous manifestations have rarely been reported. We report a case of striking photodistributed dyspigmentation in a chronic kratom user, with a detailed description of the histologic and elemental analysis findings. A 37-year-old Soldier taking kratom for lower back pain presented with asymptomatic blue-gray pigmentation involving his face, neck, and dorsal hands. Biopsy revealed pigment-laden macrophages within the superficial dermis, a mild perivascular and periadnexal lymphohistiocytic infiltrate, and a slightly thickened basement membrane. Special stains confirmed the pigmented particles as melanin-like. Scanning electron microscopy with energy-dispersive X-ray analysis (SEM-EDXA) demonstrated sulfur-containing material, consistent with phaeomelanin and/or a drug metabolite melanin-like complex. This case expands the clinicopathologic understanding of kratom-associated dermatoses and illustrates the utility of SEM-EDXA in identifying exogenous or drug-induced pigmentation.
Synthetic opioids pose a significant public health risk due to their rapid synthesis and potentially lethal potency. New compounds are emerging continuously, meaning current testing platforms struggle to keep pace. Consequently, there is a critical need for simple, rapid, translatable models to provide an in vivo platform for the functional hazard assessment of opioid-like compounds following chemical identification, and test potential intervention strategies. Here, we exposed 4 days post-fertilization (dpf) larval zebrafish to a range of concentrations of the prototypical class representative, fentanyl, to investigate behavioral and neural responses. Fentanyl caused low concentration hyperactivity, and high concentration hypolocomotion (sedation) which was reversed by the opioid antagonist naloxone. We confirmed predictive validity by replicating the behavioral responses with other class representatives (diacetylmorphine [heroin] and remifentanil). We also confirmed, pharmacologically, that low concentration hyperlocomotion was mediated by dopamine D2 receptors, replicating effects observed in mammals. Further mechanistic investigation using whole-brain in vivo imaging revealed disrupted connectivity in opioid-related circuits, such as the habenulae and dorsal thalamus, alongside novel pathways, including circuits associated with the pineal gland, torus semicircularis and eminentia granularis, potentially highlighting previously uncharacterized sensory and cerebellar neuronal networks. These findings support the use of the larval zebrafish as a scalable model for the assessment of synthetic opioids to provide novel insights into opioid-induced behaviors and candidate brain regions that may guide future mechanistic work to aid in the growing challenge of finding interventive treatments for synthetic opioid intoxication.
Kratom (Mitragyna speciosa) is a commonly used over-the-counter supplement with opioid-like and dopaminergic activity. Cutaneous side effects have been incompletely characterized; only limited case reports describe its associated hyperpigmentation. We describe two cases of kratom-induced photodistributed brown-gray patches with biopsies that show circular, orange-brown granules in the dermis that stain positive with Fontana-Masson and negative for iron. In conjunction with existing literature, our cases suggest a possible distinct clinicopathologic pattern for which kratom use can be suspected.