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.
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.
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.
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.
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.
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.
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 (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.
Bovine β-casein (β-CN) is a major milk protein that exists as multiple genetic variants, distinguished by differences in their amino acid sequences. Among these, the A1 and A2 variants are the most extensively studied. They differ at position 67, where β-CN A2 contains a proline residue, whereas β-CN A1 has a histidine. This single amino acid substitution may influence the enzymatic hydrolysis of β-CN, potentially affecting bioactive peptide release during cheese ripening or human digestion, of most interest are the β-casomorphins (BCMs). These BCMs have opioid-like activity that could impact gastrointestinal signaling. There have been a couple of studies with small-scale experimental cheeses made from milk differing in the β-CN A1 or A2 variant, which have investigated a few types of BCMs. The cheese ripening process is very complicated and many factors influence proteolysis, which could impact the release of BCMs. Exploring commercially manufactured cheeses made from different variants of β-CN that had different levels of maturity could help clarify if there are significant differences in the types and concentrations of a wide range of BCMs. We investigated whether differences in the β-CN polymorphism influenced the proteolytic patterns of a wide range of commercial A1/A2 and A2/A2 Cheddar cheeses. A total of 26 Cheddar cheese samples, comprising β-CN A1/A2 (n = 16) and A2/A2 (n = 10) of different ages were sourced from individual US cheese manufacturers. The β-CN variant present in each sample was confirmed via capillary electrophoresis (CE). pH 4.6-soluble nitrogen (pH 4.6-SN/TN), levels of free amino acids (FAAs), and various types of BCMs were analyzed to assess proteolysis. No significant differences were observed in the composition of the 2 types of Cheddar except for fat levels. Cheeses made with A2/A2 milks tended to have higher fat levels; most current manufacturers of these cheeses tended to be smaller plants where milk standardization facilities may be limited. Although lab studies have suggested that milk from the A2 variant has poorer rennet coagulation properties, we did not observe any difference in moisture contents between the 2 cheese types. The moisture content of cheese can be impacted by alterations in the coagulation behavior. The A2/A2 cheeses exhibited increased levels of total FAAs, which was likely due to having several raw milk cheeses within that group. There were no significant differences in levels of total BCMs between cheese groups (P > 0.05). However, BCM-7 was only detected in A1/A2 cheeses (≤9.75 mg/kg). High levels of BCM-9 were found in both types of cheeses (≤127 mg/kg). The type of β-CN variant in milk impacted the release of individual BCMs in Cheddar cheese but did not alter the total concentration of BCMs.
Under normal circumstances, loperamide has minimal systemic absorption due to extensive first-pass metabolism and limited permeability across the intestinal mucosa. However, in the presence of severe gastrointestinal inflammation, compromised mucosal integrity may enhance loperamide's central opioid effects via altered pharmacokinetics. Although respiratory depression due to therapeutic loperamide use remains sparse, this case accentuates the risks in vulnerable patients. This case report describes a rare case of loperamide-induced respiratory depression in a patient with chemotherapy-induced gastrointestinal mucosal inflammation, and highlights the potential increased systemic absorption and opioid-like toxicity in vulnerable patients receiving high-dose loperamide therapy. A 75-year-old female who was undergoing active chemotherapy developed significant diarrhoea. Endoscopy revealed active inflammation from the oesophagus to the large bowel. She was treated with high-dose loperamide and octreotide. Subsequently, she developed respiratory depression and altered consciousness, which resolved rapidly with naloxone infusion without lasting effects. In such settings, clinicians should exercise caution with high-dose loperamide as compromised mucosal barriers can facilitate systemic drug accumulation and toxicity.
Adenylyl cyclase 1 (AC1) plays an integral role in the excitatory signaling in the anterior cingulate cortex underlying chronic pain pathophysiology. Upon chronic nociceptive input, sustained Ca2+/calmodulin (CaM)-stimulated AC1 activity leads to the development of chronic pain. In this study, we characterize our recently reported series of pyrazolopyrimidinone amine analogs that selectively inhibit Ca2+/CaM-stimulated AC1 activity. Lead compounds AC10136A, AC10142A, and AC10172A exhibited potent AC1 inhibition (IC50 = 140-290 nM) and complete selectivity over AC2, AC5, and AC8. All compounds showed high therapeutic indices (>300) and minimal cytotoxicity up to 100 μM. Lead compounds displayed no functional agonism at κ-opioid receptor. Further, compounds prevented and reversed μ-opioid receptor-mediated heterologous sensitization of AC1, highlighting potential utility in mitigating opioid-induced dependence. Further, chronic treatment with lead compounds failed to induce opioid-like adaptations, such as heterologous sensitization, and did not modulate expression of AC1. Mechanistic studies revealed that inhibition is Ca2+/CaM dependent but independent of Gαs, suggesting preferential targeting of the active AC1 conformation. In mice, AC10142A demonstrated analgesic efficacy in the complete Freund adjuvant model of chronic inflammatory pain. Acute and repeated dosing at 48-120 h after complete Freund adjuvant treatment increased mechanical paw withdrawal thresholds and sustained analgesia over this repeated dosing. By targeting Ca2+/CaM-bound AC1, these inhibitors preferentially inhibit increased AC1 activity to its normal activity, demonstrating a state-dependent mechanism ideal for chronic pain treatment. Together, these findings establish AC10136A, AC10142A, and AC10172A as potent, selective, and well-tolerated AC1 inhibitors, with promising therapeutic potential for chronic pain and potentially opioid use disorder. SIGNIFICANCE STATEMENT: Adenylyl cyclase 1 (AC1) plays a key role in chronic pain sensitization and opioid use disorder, making it a promising therapeutic target. Selective pyrazolopyrimidinone amine inhibitors of AC1 potently block Ca2+/calmodulin-dependent activation (with IC50 values of 140-290 nM), exhibit excellent in vitro safety profiles, prevent μ-opioid receptor-mediated AC1 sensitization in vitro, and demonstrate robust antiallodynic effects in vivo, positioning this compound series as a compelling nonopioid strategy for managing chronic pain and potentially addressing opioid use disorder.
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.
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.
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.
Kratom (Mitragyna speciosa) is a traditional Southeast Asian botanical long used for alleviating pain and boosting energy. Its chief bioactive compound, mitragynine (MG), exhibits both opioid-like and stimulant properties and has prompted interest in its potential role in pain management and opioid withdrawal support. However, its safety profile and underlying mechanisms remain incompletely understood. This systematic review critically synthesizes preclinical evidence on kratom's molecular, pharmacological, and epigenetic effects. Guided by PRISMA 2020 criteria, studies indexed in Scopus and Web of Science (2000-2024) were analyzed, focusing on receptor activity, intracellular signaling, and gene regulation in in vitro and in vivo models. Among 20 eligible studies, key findings indicate that kratom alkaloids engage μ-opioid, adrenergic, and serotonergic receptors; modulate dopaminergic and glutamatergic systems; and exert anti-inflammatory and analgesic effects. Under chronic exposure followed by withdrawal, MG was associated with reduced histone acetylation and increased HDAC2 expression, while Rab35 emerged as a potential withdrawal-associated biomarker. MG also inhibited cardiac ion channels and altered CYP450 enzyme expression, highlighting safety concerns related to cardiotoxicity and drug-drug interactions. Despite these mechanistic insights, limitations in pharmacokinetic data, standardized dosing, and long-term safety preclude clinical application. Future research should prioritize controlled human studies, omics-driven biomarker discovery, and evidence-based regulatory evaluation to clarify kratom's therapeutic potential and risk profile.
Kratom (Mitragyna speciosa) and its active alkaloids, mitragynine and 7-hydroxymitragynine, can produce opioid-like dependence and withdrawal meeting DSM-5 criteria for opioid use disorder (OUD). While buprenorphine has been described for kratom use disorder (KUD), published experience with methadone is limited. We identified 14 patients across multiple Opioid Treatment Programs (OTPs) with KUD who were treated with methadone between January 2024 and October 2025. Demographic, dosing, and urine toxicology data were reviewed. The mean age was 36.8 years; 71% were male. Sixty-four percent reported using both kratom and 7-OH. The mean first-day methadone dose was 27.5 mg (range 15-30), and the mean maximum dose was 98.6 mg (range 35-190). Thirteen patients (93%) remained in treatment at the last follow-up. No adverse events were reported. Methadone was well tolerated and effective in stabilizing patients with KUD, supporting its use as a viable alternative when buprenorphine is not suitable.
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.