Opioid-like Effects Research Articles

Comparative Analysis of Mitragynine Content in Kratom Leaves (Mitragyna speciosa Korth) from Kabupaten Kapuas Hulu Using HPLC Method

Opioid drugs are common analgesics for managing chronic pain, but they have significant short- and long-term side effects. Despite this, opioid consumption continues to rise in high-income countries, raising concerns about dependency. Kratom (Mitragyna speciosa Korth), which has opioid-like effects, shows potential as an analgesic with fewer side effects. This study aimed to explore and compare the mitragynine content in Kratom leaves from various regions in Kabupaten Kapuas Hulu, Indonesia, using High-Performance Liquid Chromatography (HPLC). Kratom leaves from 14 regions in Kapuas Hulu were collected, dried, and ground. Mitragynine was extracted using 70% ethanol and analyzed with HPLC. The yield percentage and mitragynine content in both the powdered simplisia and ethanol extract were measured and compared. The study showed that the average ethanol extract yield was 28%, with the highest yield from Elis Menendang (31.20%) and the lowest from Nanga Lauk (23.86%). Mitragynine content was significantly higher in the ethanol extract (3.22%) compared to the powdered simplisia (1.46%). Samples from Lanjak, Jongkong, Bunut, and Putussibau Kota showed mitragynine content exceeding 4% in the ethanol extract. HPLC analysis indicated that ethanol extraction significantly increases the mitragynine content in Kratom leaves compared to powdered simplisia, up to twice as much.

Kratom: a primer for pain physicians.

Kratom is used commonly in the United States, usually to mitigate pain, opioid withdrawal, or fatigue. A comprehensive discussion on kratom, tailored to pain management physicians, is needed, given its associated risks and potential interactions. Kratom and its main metabolites, mitragynine and 7-OH-mitragynine, bind to a variety of receptors including mu opioid receptors. Still, kratom cannot be described as a classic opioid. Kratom has been utilized without FDA approval as an alternative to traditional medications for opioid use disorder and opioid withdrawal. Lower doses of kratom typically cause opioid-like effects while higher doses can have sedating effects. Tolerance, dependence and withdrawal still occur, although kratom withdrawal appears to be more moderate than opioid withdrawal. Contamination with heavy metals and biological toxins is concerning and there is potential for serious complications, including seizures and death. The use of kratom as an opioid-sparing alternative as a part of a multimodal pain regimen is not without significant risks. It is of utmost importance for pain physicians to be aware of the risks and adverse effects associated with kratom use.

Knowledge of Kratom among Alabama Pharmacists.

Kratom (Mitragyna speciosa) is a botanical substance whose leaves produce stimulant- and opioid-like effects. Kratom use has increased precipitously in the United States (U.S.) over the last decade, yet, in our experience, many pharmacists are unfamiliar with this herb. The purpose of this study was to assess pharmacists' awareness and knowledge of kratom. This cross-sectional study used an online questionnaire to preferentially solicit community pharmacists' knowledge of kratom and collect demographic information. The survey was sent via email to approximately 10,000 pharmacists, targeting those in the state of Alabama, U.S. Data were analyzed using descriptive statistics, and the Chi Square test was used to compare nominal data. A total of 257 participants responded to the survey. Almost 50% of participants had heard of kratom, and 50% had not. Compared to females, males were more likely to have heard of kratom (64% vs. 42%; p = 0.0015), as were pharmacists who worked for an independent pharmacy vs. a chain (61% vs. 41%; p = 0.025). Of the participants who had heard of kratom, only 14% considered themselves knowledgeable or very knowledgeable about the herb, and only 44% knew it was illegal in Alabama. These data indicate a need to further kratom education among community pharmacists in Alabama.

B-330 Homogeneous Enzyme Immunoassay for Hydrocodone

Abstract Background Hydrocodone is a semi-synthetic derivative of codeine and produces opioid-like effects similar to morphine. Hydrocodone (Trade names: Vicodin, Lortab, Hycodan, Vicoprofen) is one of the most frequently prescribed opioids in the U.S. as an antitussive (cough suppressant) and narcotic analgesic agent for the treatment of moderate to severe pain. Its ease of prescription and opioid-like effects has led to widespread drug diversion and abuse. The two commercially available homogeneous immunoassays for the detection of hydrocodone in urine at a cutoff of 300 ng/mL suffer undesirable cross-reactivity to oxycodone and morphine at concentrations below 25 000 ng/mL. ARK Diagnostics has developed the ARK Hydrocodone Assay to detect hydrocodone at a cutoff of 300 ng/mL with no cross-reactivity to oxycodone, morphine, and codeine at concentrations below 100 000 ng/mL. Methods The ARK™ Hydrocodone Assay is a liquid stable homogeneous enzyme immunoassay, consisting of two reagents, with a cutoff of 300 ng/mL and semi-quantitative range up to 800 ng/mL. The performance of this assay was evaluated on the Beckman Coulter AU680 Automated Clinical Chemistry Analyzer. Precision, spiked recovery, specificity, Histogram Overlap Analysis of ±25% controls and the cutoff, and method comparison with LC-MS/MS were evaluated. Results In semi-quantitative mode, total precision ranged from 3.9% to 9.9%CV. Spiked recovery of hydrocodone ranged from 86.2% (720 ng/mL) to 102.9% (240 ng/mL). The active metabolite, hydromorphone, showed an approximate equivalence to the 300 ng/mL hydrocodone cutoff at 299 ng/mL (100.3% cross-reactivity). Histogram overlap analysis showed no overlap between cutoff and control levels. Method correlation with LC-MS/MS using authentic urine samples showed an excellent agreement with a specificity of 100% and sensitivity of 96.9% (98 positives and 128 negatives). Conclusion The ARKTM Hydrocodone Assay measures hydrocodone and its metabolite hydromorphone in human urine with acceptable performance. The assay is sensitive, rapid, and applicable to a wide range of clinical chemistry analyzers.

Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose.

Novel synthetic opioids (NSOs) are emerging in recreational drug markets worldwide. In particular, 2-benzylbenzimidazole 'nitazene' compounds are problematic NSOs associated with serious clinical consequences, including fatal respiratory depression. Evidence from in vitro studies shows that alkoxy chain length can influence the potency of nitazenes at the mu-opioid receptor (MOR). However, structure-activity relationships (SARs) of nitazenes for inducing opioid-like effects in animal models are not well understood compared to relevant opioids contributing to the ongoing opioid crisis (e.g., fentanyl). Here, we examined the in vitro and in vivo effects of nitazene analogues with varying alkoxy chain lengths (i.e., metonitazene, etonitazene, isotonitazene, protonitazene, and butonitazene) as compared to reference opioids (i.e., morphine and fentanyl). Nitazene analogues displayed nanomolar affinities for MOR in rat brain membranes and picomolar potencies to activate MOR in transfected cells. All compounds induced opioid-like effects on locomotor activity, hot plate latency, and body temperature in malemice, and alkoxy chain length markedly influenced potency. Etonitazene, with an ethoxy chain, was the most potent analogue in MOR functional assays (EC50 = 30pM, Emax = 103%) and across all in vivo endpoints (ED50 = 3-12μg/kg). In vivo SARs revealed that ethoxy, isopropoxy, and propoxy chains engendered higher potencies than fentanyl, whereas methoxy and butoxy analogues were less potent. MOR functional potencies, but not MOR affinities, were positively correlated with in vivo potencies to induce opioid effects. Overall, our data show that certain nitazene NSOs are more potent than fentanyl as MOR agonists in mice, highlighting concerns regarding the high potential for overdose in humans who are exposed to these compounds.

Kratom availability in California vape shops

Kratom products are derived from trees native to Southeast Asia and have dose-dependent stimulant and opioid-like effects. Despite being on the Drug Enforcement Administration “Drugs and Chemicals of Concern List,” kratom is legal for sale in most US states. However, there are scarce data on its availability. The goal of this study was to examine kratom availability in vape shops across the state of California and assess shop compliance with a local kratom sales ban (enacted in 2016) in San Diego City. As part of a larger study about retail tobacco marketing near colleges, availability of kratom was assessed in summer 2019 in a random sample of 614 vape shops that was stratified to compare stores near (≤ 3 miles) and distant (>3 miles) from colleges. Logistic regression examined kratom availability as a function of store type (stores that sold vape products only vs. stores selling other tobacco), nearness to college, and tract-level demographics. Kratom was available in 62.4% of observed stores and more often in vape-and-smoke (81.1%) than vape-only shops (11.5%, AOR = 40.4, 95% CI = 23.3–74.1). Kratom availability did not differ by nearness to colleges. In San Diego City, 46.2% of observed stores (95% CI = 28.8–64.5) sold kratom products. Findings indicate that kratom was available in the majority of vape shops and most commonly in vape-and-smoke shops. Widespread availability in tobacco specialty shops suggests the need for research on dual use with tobacco, kratom advertising and cross-product promotion, and the potential of state and local tobacco retail licensing to prohibit sales.

Translating Kratom-Drug Interactions: From Bedside to Bench and Back.

Kratom is a botanical natural product belonging to the coffee family, with stimulant effects at low doses and opioid-like effects at higher doses. During the last two decades, kratom has been purported as a safer alternative to pharmaceutical and illicit drugs to self-manage pain and opioid withdrawal symptoms. Kratom alkaloids, typically mitragynine, have been detected in biologic samples from overdose deaths. These deaths are often observed in combination with other drugs and are suspected to result from polyintoxications. This review focuses on the potential for kratom to precipitate pharmacokinetic interactions with object drugs involved in these reported polyintoxications. The legal status, chemistry, pharmacology, and toxicology are also summarized. The aggregate in vitro and clinical data identified kratom and select kratom alkaloids as modulators of cytochrome P450 (P450) enzyme activity, notably as inhibitors of CYP2D6 and CYP3A, as well as P-glycoprotein-mediated efflux activity. These inhibitory effects could increase the systemic exposure to co-consumed object drugs, which may lead to adverse effects. Collectively, the evidence to date warrants further evaluation of potential kratom-drug interactions using an iterative approach involving additional mechanistic in vitro studies, well designed clinical studies, and physiologically based pharmacokinetic modeling and simulation. This critical information is needed to fill knowledge gaps regarding the safe and effective use of kratom, thereby addressing ongoing public health concerns. SIGNIFICANCE STATEMENT: The botanical kratom is increasingly used to self-manage pain and opioid withdrawal symptoms due to having opioid-like effects. The legal status, chemistry, pharmacology, toxicology, and drug interaction potential of kratom are reviewed. Kratom-associated polyintoxications and in vitro-in vivo extrapolations suggest that kratom can precipitate pharmacokinetic drug interactions by inhibiting CYP2D6, CYP3A, and P-glycoprotein. An iterative approach that includes clinical studies and physiologically based pharmacokinetic modeling and simulation is recommended for further evaluation of potential unwanted kratom-drug interactions.

Chronic tianeptine induces tolerance in analgesia and hyperlocomotion via mu-opioid receptor activation in mice.

Tianeptine is approved in some countries to treat depression and anxiety. In addition to its activity on serotonin and glutamate neurotransmission, tianeptine has been proven to be a mu-opioid receptor (MOR) agonist, but only a few preclinical studies have characterized the opioid-like behavioral effects of tianeptine. In this study, we tested tianeptine activity on G protein activation using the [S35] GTPγS binding assay in brain tissue from MOR+/+ and MOR-/- mice. Then, to determine whether tianeptine behavioral responses are MOR-dependent, we characterized the analgesic, locomotor, and rewarding responses of tianeptine in MOR+/+ and MOR-/- mice using tail immersion, hot plate, locomotor, and conditioned place preference tests. Using the [S35] GTPγS binding assay, we found that tianeptine signaling is mediated by MOR in the brain with properties similar to those of DAMGO (a classic MOR agonist). Furthermore, we found that the MOR is necessary for tianeptine's analgesic (tail immersion and hot plate), locomotor, and rewarding (conditioned place preference) effects. Indeed, these behavioral effects could only be measured in MOR+/+ mice but not in MOR-/- mice. Additionally, chronic administration of tianeptine induced tolerance to its analgesic and hyperlocomotor effects. These findings suggest that tianeptine's opioid-like effects require MOR and that chronic use could lead to tolerance.

Analysis of heavy metals content in commercially available kratom products in Richmond, Virginia

Kratom is a novel psychoactive substance that has gained popularity within the past ten years. Originating from Southeast Asia, the leaves of the Mitragyna speciosa tree contain two principal alkaloids, mitragynine and 7-hydroxy-mitragynine, that play a key role in opioid-like effects. Due to its effects, the use of kratom products has increased drastically. However, reports describing concerns about the heavy metal content of these products for safe consumption are still scarce. i Twenty-seven kratom products were obtained from tobacco shops in the Richmond, Virginia area, including powders, teas, extracts, and a carbonated beverage. Kratom samples were subjected to an acid digestion followed by Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES) analysis. Aluminum (Al), arsenic (As), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), nickel (Ni), and lead (Pb) were quantitated using yttrium as the internal standard. Kratom tea samples were found to have up to 20 times the tolerable upper intake of manganese. Overexposure to manganese can lead to manganism, a syndrome that presents Parkinsonian symptoms including tremors, dystonia, and facial muscle spasms. As kratom products become more mainstream, stricter regulations of these products must be set in place. The presence of toxic metals in kratom products is a public health concern.

Fentanyl analog structure-activity relationships demonstrate determinants of diverging potencies for antinociception and respiratory depression

Opioid overdoses, particularly those involving fentanyl-related substances (FRS), present a significant public health challenge in the United States. This structure-activity relationship (SAR) study evaluated the relationship between the chemical structure of seventeen FRS and their in vivo mu-opioid-receptor (MOR) mediated effects. SAR evaluations included fluorine substitutions on the aniline or phenethyl ring and variations in N-acyl chain length. Adult male Swiss Webster mice were administered fluorinated regioisomers of fentanyl, butyrylfentantyl and valerylfentanyl, and compared to MOR standards including morphine, buprenorphine, and fentanyl to determine if they would elicit prototypical opioid-like effects including hyperlocomotion (open-field test), antinociception (warm-water tail-withdrawal test), and hypoventilation (whole-body plethysmography test). To determine if the MOR was the pharmacological mechanism responsible for these effects, naltrexone or naloxone pretreatments were administered to evaluate their actions on FRS-induced antinociception and hypoventilation. There were three main findings. First, FRS elicited hyperlocomotion, antinociception, and hypoventilation in mice to varying degrees, similar to prototypical MOR standards. Second, the rank order of potencies for hypoventilatory effects of FRS were different for each series including FRS with increasing N-acyl chain length (i.e., acetylfentanyl, fentanyl, butyrylfentanyl, valerylfentanyl, hexanoylfentanyl), phenethyl-fluorinated regioisomers (e.g., 2′-fluorofentanyl, 3′-fluorofentanyl, 4′-fluorofentanyl), and aniline-fluorinated regioisomers (e.g., ortho-fluorofentanyl, meta-fluorofentanyl, para-fluorofentanyl). Third, the degree of separation in potencies observed for the antinociceptive and hypoventilatory effects of these drugs did not always follow that which was observed for their antinociceptive and hyperlocomotor effects. This study clarifies the in vivo activities for these FRS and elucidates a SAR for MOR-mediated effects among structural isomers.

Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom.

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (Cmax ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (KI , ~4 μM; kinact , ~0.07 min-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

Upregulation of Brain's Calcium Binding Proteins in Mitragynine Dependence: A Potential Cellular Mechanism to Addiction.

Background: Mitragyna speciosa Korth or Kratom is widely used traditionally for its medicinal values. The major alkaloid content of kratom leaves is mitragynine, which binds to opioid receptors to give opioid-like effects. This study aimed to analyse the brain proteome of animals that displayed addictive behaviors. Design and Methods: Six groups (n=6-8) of rats made up of negative control, positive control using morphine (10 mg/kg), and treatment groups at low (1mg/kg) and high doses of mitragynine (30 mg/kg) for 1 and 4 days. The rats' behaviors were evaluated and subsequently the rats' brains were harvested for proteomic analysis that was performed by using 2D gel electrophoresis and LC/MS/MS. Results: The rats developed physical dependence only on day 4 following morphine and mitragynine (1 and 30mg/kg) treatments. Among the proteins that were up-regulated in treatment groups were four calcium-binding proteins, namely calretinin, F-actin, annexin A3 and beta-centractin. Conclusions: Upregulation of calretinin acted as low Ca2+ buffering upon the blockage of Ca2+ ion channel by mitragynine in the brain, which subsequently caused a reduction of GABA released and inversely increased the dopamine secretions that contributed to dependence indicators.

Application of Proteomics in Diagnosis of Kratom Addiction

Kratom (Mitragyna speciosa) is a medicinal plant grown wildly in Southeast Asian. It has been used traditionally for its analgesic and relaxing effects after hard day of labors. The main alkaloid of kratom, mitragynine binds to opioid receptors to give opioid-like effects, therefore it has been widely utilized as opiate substitute.

Evaluation of Phytochemical Composition, Antioxidant and anti-Diabetic Activities of Mitragyna speciosa Methanolic Extract (MSME)

Introduction: The therapeutic potential of plant-based or herbal medicine has been widely embraced by the public as a prevention and remedy for many illnesses. Mitragyna speciosa is one of the medicinal plant that exhibit the opioid-like effects of analgesia. This study aimed to evaluate the phytochemical content, antioxidant activity, and alpha-amylase enzyme inhibition of Mitragyna speciosa methanolic extract (MSME). Methods: The phytochemical composition of MSME was analyzed for secondary metabolites using UHPLC-TWIMS-QTOF-MS/MS. The total phenolic content (TPC), total flavonoid content (TFC), antioxidant scavenging activities (2,2-diphenyl-1-picrylhydrazyl [DPPH] and 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) [ABTS] assays) and α-amylase enzyme inhibition activities of MSME were analyzed in comparison to positive control Pterostilbene and acarbose, respectively. Results: Analysis of UHPLC-TWIMS-QTOF-MS/MS has characterized the presence of at least five different bioactive compounds, mostly derivatives of flavonoids and polyphenols. A significantly higher level of TFC (347.72±15.97 mg QE/g extract; p = 0.0005), but a significantly lower level of TPC (167.43±13.50 mg GAE/g extract; p = 0.002) was detected in MSME (1 mg/mL) compared to Pterostilbene. MSME presented antioxidant activity which has no significant difference compared to Pterostilbene as determined by DPPH (MSME IC50 = 4.34±1.79 µg/mL; p = 0.727) and ABTS (MSME IC50 = 4.25±1.59 µg/mL; p = 0.311) assays. Moreover, MSME also exhibited anti-diabetic effects through inhibition of α-amylase activity (IC50 = 0.01±7.18 mg/mL) which shows a significant difference (p = 0.009) compared to acarbose. Conclusion: This finding suggests that MSME has bioactive phytochemicals and exhibits potential antioxidant and anti-diabetic properties.

Social, psychological, and substance use characteristics of U.S. adults who use kratom: Initial findings from an online, crowdsourced study.

Kratom, a plant that produces opioid-like effects, has gained popularity in the U.S. for self-treating symptoms of chronic pain, mood disorders, and substance-use disorders (SUDs). Most data on kratom are from surveys into which current kratom-using adults could self-select; such surveys may underrepresent people who have used kratom and chosen to stop. Available data also do not adequately assess important psychosocial factors surrounding kratom use. In this study, U.S. adults who reported past 6-month alcohol, opioid, and/or stimulant use (N = 1,670) were recruited via Amazon Mechanical Turk between September and December 2020. Of the 1,510 evaluable respondents, 202 (13.4%) reported lifetime kratom use. Kratom-using adults, relative to others, were typically younger, male, unpartnered, without children, and had lower income. They had higher rates of chronic pain (31.7% vs. 21.9%, p = .003), childhood adversity, anxiety, and depression (p < .001), and lower perceived social rank (d = .19, .02-.22) and socioeconomic status (d = .37 .16-.26). They also reported higher use rates for most substances (except alcohol); this included medically supervised and unsupervised use of prescription opioids and diverted opioid agonist therapy (OAT) medications. Most (83.2%) met diagnostic criteria for any past-year SUD. Those reporting kratom use were less likely to reside in an urban/suburban area. The strongest predictors of kratom use were use of other drugs: cannabidiol (OR = 3.73), psychedelics (OR = 3.39), and nonmedical prescription opioids (OR = 1.72). Another strong predictor was lifetime OAT utilization (OR = 2.31). Despite seemingly poorer psychosocial functioning and health among respondents reporting lifetime kratom use, use of other substances may be the strongest indicators of kratom use. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The association between E-cigarette use and Kratom use among US adults

Kratom, an herbal substance with stimulant and opioid-like effects commonly used in capsules or powder to be ingested or brewed as a tea, has been gaining popularity in the United States (US). US e-cigarette use (i.e., vaping) has exponentially increased in recent years. Given the potential risks of kratom (e.g., poisonings) and the increasing prevalence of e-cigarette use, understanding the association between them is important to inform prevention strategies and regulatory policies. We harnessed data from the 2020 National Survey on Drug Use and Health (NSDUH; n = 27,170) to examine past-year kratom use by past-year e-cigarette use among adults. We ran a logistic regression model on kratom use by e-cigarette use adjusting for associated factors with substance use. Among all respondents, the estimated prevalence of past-year kratom use was 0.9% and an estimated 9.7% reported past-year e-cigarette use. Our multivariable model found those with e-cigarette use (vs. not) had 4.80 higher odds of using kratom in the past year (aOR = 4.80; 95% CI = 2.62, 8.80). These findings might help inform the need for continuing education for physicians and healthcare providers related to practice in managing patients with kratom use, future studies for regulatory policies on e-cigarettes (e.g., e-liquids), or other FDA policies related to kratom.

Development and validation of ELISA for screening of Kratom (Mitragyna speciosa) habitual users using urinary AZ122 biomarker.

Kratom (Mitragyna speciosa Korth) has been used traditionally in Southeast Asia for its therapeutic properties. The major alkaloid of kratom, mitragynine, binds to opioid receptors to give opioid-like effects that causes addiction. In our previous study, we have identified AZ122 as a unique biomarker in habitual or regular kratom users through analysis of their urinary protein profiles. We aimed to develop and validate a screening method by means of enzyme-linked immunosorbent assay (ELISA) for detection of kratom habitual users. An ELISA approach was applied for the development of a screening method using urinary AZ122 as biomarker. Method validation was carried out using three quality control materials at different concentration of AZ122. The data was analyzed statistically using SPSS (Version 25). The ELISA was presented with Pearson correlation coefficient of 0.9993. The repeatability and reproducibility were presented at CV <7%, while the accuracy ranged from 78 to 96% at various AZ112 concentrations. Upon testing on 176 male respondents (n=88 regular kratom users and n=88 healthy controls), the specificity and sensitivity of the assay were both 100%. The ELISA has been validated and can be potentially used as a reliable screening test for detection of kratom habitual users.

Public Health Implications and Possible Sources of Lead (Pb) as a Contaminant of Poorly Regulated Kratom Products in the United States.

Kratom (Mitragyna speciosa) is a tropical tree that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression, and opioid use disorder (OUD). Recent studies from the United States Food and Drug Administration (FDA, Silver Spring, MD, USA) and our laboratory have shown that many kratom products being sold in the United States are contaminated with potentially hazardous levels of lead (Pb). In this commentary, we discuss the public health implications of the presence of Pb in kratom products, particularly as they relate to the predicted levels of Pb exposure among kratom users. We also considered the specific toxic effects of Pb and how they might relate to the known physiologic and toxicologic effects of kratom. Finally, we consider the possible sources of Pb in kratom products and suggest several areas for research on this issue.

Acute Renal Insufficiency Associated With Consumption of Hydrocodone- and Morphine-Adulterated Kratom (Mitragyna Speciosa)

BackgroundKratom (Mitragyna speciosa), an evergreen tree native to Southeast Asia, contains alkaloids that cause both stimulant and opioid-like effects. In the United States, its use continues to grow. Kratom products, however, are unregulated and nonstandardized, and reports of adulteration have been described previously. Case ReportA 21-year-old African-American woman with a history of occasional headaches and self-treatment with internet-purchased kratom presented to the emergency department with the chief symptoms of nausea, vomiting, and left flank pain. Laboratory tests showed a markedly elevated serum creatinine of 4.25 mg/dL (reference range 0.6–1.2 mg/dL) and proteinuria. A computed tomography scan of the abdomen and pelvis was unrevealing. A standard urine screen for drugs of abuse was positive for opiates. A confirmatory testing revealed the presence of hydrocodone and morphine in the urine. Hydrocodone, morphine, and mitragynine were identified in a sample of kratom leaves provided by the patient. The patient's renal function improved with supportive care and normalized 1 month post discharge after kratom discontinuation. Why Should an Emergency Physician Be Aware of This?Despite widespread use, relatively little is known about kratom's adverse effects, particularly regarding its potential to cause renal insufficiency. This case illustrates the vital importance of recognizing that adulteration of unregulated products is certainly a possibility and clinicians may continue to see a rise in adverse effects, given kratom's increasing popularity.

Kratom: History, pharmacology, current user trends, adverse health effects and potential benefits

Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with dose-dependent stimulant and opioid-like effects. Dried, powdered leaf material is among the kratom products most commonly consumed in the US and Europe, but other formulations also exist including enriched extracts, resins, tinctures, and edibles. Its prevalence in the US remains debated and the use pattern includes self-treatment of mood disorders, pain, and substance use disorders. Most of the adverse effects of kratom and its alkaloid mitragynine have been reported in the literature as case reports or part of surveys necessitating confirmation by clinical trials. Toxicities associated with kratom consumption have focused on hepatic, cardiac, and CNS effects with the potential to cause fatalities primarily as part of polydrug exposures. Kratom may also present with drug-drug interactions primarily through CYP 3A4 and 2D6 inhibition, although the clinical significance remains unknown to date. The variability in composition of commercially available kratom products complicates generalization of findings and requires further investigation by employing clinical trials. Healthcare professionals should remain cautious in counseling patients on the use of kratom in a therapeutic setting.