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This study aimed to develop an antioxidative compound extraction method for Kratom (Mitragyna speciosa) leaves using cellulase and pectinase, in combination and alone. The enzymatic hydrolysis-assisted process (EA) successfully enhanced antioxidant extraction from kratom leaves. The single enzymatic hydrolysis-assisted process (SEA) with 6% cellulase (C6) provided the highest extraction yield. The mixed enzymatic hydrolysis-assisted process (MEA) was then developed using C6, mixed with different concentrations of pectinase. Based on the high extraction yield, the MEA using 6% cellulase and 2% pectinase (C6+P2) was selected for further studies in comparison with that from relevant SEA and the control (without EA). Different extraction processes altered the characteristics and antioxidative activities of resulting extracts. The antioxidative activity of C6+P2 was dramatically enhanced in the gastrointestinal tract model system. Fourier transform infrared (FT-IR) spectrometer results confirmed significant content of phenolic compounds, proteins, and polysaccharides in C6+P2. From in vitro cytotoxicity study, C6+P2 showed an IC 50 value of 22.86 and 4.76 µg/mL in RAW264.7 and Caco-2 cells, respectively. The bioactive compounds from C6+P2 should be identified in further studies to facilitate their application in the food and pharmaceutical industries. [Display omitted] • 6% Cellulase mixed with 2% pectinase (C6+P2) gave the highest extraction yield. • C6+P2 showed drastically increase in antioxidative activity after digestion. • FTIR spectra reconfirmed the complex form of antioxidative compounds. • Cytotoxicity of C6+P2 was evaluated as IC 50 on macrophage and epithelial cells. [ABSTRACT FROM AUTHOR]

This systematic review aimed to assess the association between neuropsychiatric effects of substance use and occurrence of ER stress and unfolded protein response (UPR) through comprehensive electronic search of existing literature and review of their findings. A comprehensive electronic literature search was carried out on research articles published between 1950 to July 2023 through major databases, such as Scopus, Web of Science, Google Scholar, PubMed, PsycINFO, EMBASE, Medline and Cochrane Library. A total of 21 research articles were selected for review, which were comprised of sixteen animal studies, four human studies and one study on postmortem human brain samples. The selected studies revealed that alcohol, methamphetamine, cocaine, opioid and kratom exposures contributed to neuropsychiatric effects: such as decline in learning and memory function, executive dysfunction, alcohol, methamphetamine, opioid, and kratom dependence. These effects were associated with activation and persistent of ER stress and UPR with elevation of BiP and CHOP expression and the direction of ER stress is progressing towards the PERK-eIF2α-ATF4-CHOP pathway and neuronal apoptosis and neurodegeneration at various regions of the brain. In addition, regular kratom use in humans also contributed to elevation of p-JNK expression, denoting progress of ER stress towards the IRE1-ASK1-JNK-p-JNK pathway which was linked to kratom use disorder. However, treatment with certain compounds or biological agents could reverse the activation of ER stress. The neuropsychiatric effects of alcohol, methamphetamine, cocaine, opioid and kratom use may be associated with persistent ER stress and UPR. • Neuropsychiatric effects of substance use are related to endoplasmic reticulum stress and unfolded protein response. • Alcohol, methamphetamine, cocaine, opioids and kratom use linked to protracted endoplasmic reticulum stress in brain neurons. • Protracted endoplasmic reticulum stress in the brain neurons were linked to dependence, tolerance and cognitive impairment. • PERK-CHOP, IRE1-XBP1 and ATF6 ER stress pathways were activated by alcohol, methamphetamine, cocaine, opioids and kratom use. • Increased expression of XBP1s was not related to substance dependence. [ABSTRACT FROM AUTHOR]

Alternative medicine supplements have become the second most common cause of drug-induced liver injury (DILI) in the US. Kratom is a herbal supplement that is popular for its psychotropic and opioid-like activity. It has become increasingly available in western countries, which often have no specific regulations on its use. However, reports of adverse events linked to kratom use have been increasing; it has been implicated in acute liver injury (mostly cholestatic), acute liver failure, organ dysfunction, toxicity, coma, seizures, and death. Herein, we aim to increase healthcare provider and public awareness of the risks posed by kratom and ultimately support increased regulation of its use. [ABSTRACT FROM AUTHOR]

Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied. In this study, we sought to explore opioid-associated arrhythmia reporting in North America. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory. Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS. The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America. [Display omitted] [ABSTRACT FROM AUTHOR]

Mitragynine (MTG) is a prominent indole alkaloid that is present abundantly in Mitragyna speciosa , commonly referred to as kratom. MTG has garnered significant attention due to its selective agonistic characteristics towards opioid receptors and related analgesic effects. In the circulatory system, the in vivo efficacy of MTG is dictated by its interaction with plasma proteins, primarily human serum albumin (HSA). In the present study, we utilized a broad methodology that included spectroscopic, calorimetric, microscopic, and in silico approaches to characterize the interaction between MTG and HSA. Alterations in the UV absorption spectrum of HSA by the presence of MTG demonstrated a ground-state complexation between the protein and the ligand. The K a values obtained for the MTG–HSA interaction were in the range 103–104 M−1 based on analysis of fluorescence and ITC data, respectively, indicating an intermediate binding affinity. The binding reaction was thermodynamically favorable as revealed by Δ H , Δ S , and Δ G values of −16.42 kJ mol−1, 39.97 J mol−1 K−1, and −28.34 kJ mol−1, respectively. Furthermore, CD spectroscopy results suggested MTG binding induced minimal effects on the structural integrity of HSA, supported by computational methods. Changes in the dimensions of HSA particles due to aggregation, as observed using atomic force microscopy in the presence of MTG. Competitive drug displacement results seemingly suggested site III of HSA located at subdomain IB as the preferred binding site of MTG, but were in inconclusive. However, docking results showed the clear preference of MTG to bind to site III, facilitated by hydrophobic (alkyl and pi-alkyl) and van der Waals forces, together with carbon hydrogen bonds. Additionally, the MTG–HSA complexation was demonstrated to be stable based on molecular dynamics analysis. The outcomes of this study shed light on the therapeutic potential of MTG and can help in the design of more effective derivatives of the compound. [Display omitted] • MTG binds to HSA with moderate affinity. • MTG likely binds to HSA at site III in subdomain IB. • Structural integrity of HSA is unaffected by MTG complexation. • MTG–HSA complexation is energetically favorable and stable. [ABSTRACT FROM AUTHOR]

Using ecological momentary assessment (EMA), we undertook a natural experiment wherein kratom-product variability was a tool to assess kratom dose-response relationships based on product form and alkaloid level. Between July-November 2022, 357 US kratom consumers (56.6 % male, 90.2 % non-Hispanic white) completed 15 days of EMA; 348 participants submitted samples of the products used most often during EMA. These were assayed for ten alkaloids using ultra-performance liquid chromatography-tandem mass spectrometry. Self-reported kratom effects were modeled as a function of kratom amount and alkaloid content. Participants used over 220 brands. The most-reported product forms were loose powder (55.8 %) and encapsulated powder (26.8 %); extracts were used less (419 uses across 9.48 % of participants). Of the 12,244 use-event entries, 7726 had follow-up data (15–180 minutes after use) on felt effects. Effects were stronger in participants with a higher average amount per use. Within-person dose-response relationships were obscured by highly-consistent within-person dosages. Effects of loose powder decreased over three hours; effects of extracts started higher but decreased more rapidly. Dose-response relationships for specific alkaloids could not be reliably established because total alkaloid content and relative levels of specific alkaloids showed limited variability between products. Higher levels of corynoxine alkaloids were associated with slightly stronger effects, possibly an artifact of modeling data with low alkaloid variability. Alkaloid content was surprisingly consistent across kratom products, and participants were consistent in the amount they used across events. Firm conclusions about alkaloid-effect relationships for kratom will require experimenter-controlled manipulations of agent and dose. • This study was the first to combine field reports of kratom use with product assays • 357 kratom consumers nationwide reported on 12,244 instances of use • 330 of their products were assayed for 10 major and minor kratom alkaloids • Results clarified kratom's effects and time course by amount and product type • Alkaloid profiles similar across products, obscuring effects of any specific alkaloid [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna Speciosa Korth.) is an indigenous tree native to Southeast Asia whose leaves have been traditionally ingested as a tea and has seen its popularity increase in the United States. Although kratom and its constituents presently have no approved uses by the Food and Drug Administration, its major alkaloids (e.g., mitragynine) have psychoactive properties that may hold promise for the treatment of opioid cessation, pain management, and other indications. 9-O-demethylmitragynine is a major metabolite formed from mitragynine metabolism (36 % total metabolism) and displays similar pharmacologic activity. Cytochrome P450 (CYP) 3A4 has been identified as a major enzyme involved in mitragynine metabolism; however, the in vitro metabolism parameters of 9-O-demethylmitragynine formation are not well defined and a risk of potential drug interactions exists. Using human liver S9 fractions, 9-O-demethylmitragynine formation was generally linear for enzyme concentrations of 0–0.25 mg/mL and incubation times of 5–20 min. 9-O-demethylmitragynine displayed a K m 1.37 μM and V max of 0.0931 nmol/min/mg protein. Known CYP inhibitors and compounds that might be concomitantly used with kratom were assessed for inhibition of 9-O-demethylmitragynine formation. Ketoconazole, a CYP3A index inhibitor, demonstrated a significant effect on 9-O-demethylmitragynine formation, further implicating CYP3A4 as a major metabolic pathway. Major cannabinoids (10 μg/mL) displayed minor inhibition of 9-O-demethylmitragynine formation, while all other compounds had minimal effects. Mixtures of physiological achievable cannabinoid concentrations also displayed minor effects on 9-O-demethylmitragynine formation, making a metabolic drug interaction unlikely; however, further in vitro, in vivo, and clinical studies are necessary to fully exclude any risk. • 9-O-demethylmitragynine formation shows linear formation with human liver fractions. • Mitragynine metabolism to 9-O-demethylmitragynine shows Michaelis-Menten kinetics. • A CYP3A inhibitor, ketoconazole, reduces formation of 9-O-demethylmitragynine • Cannabinoids had minor inhibitory effects on 9-O-demethylmitragynine formation. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Mitragynine, an alkaloid present in the leaves of Mitragyna speciosa (kratom), has a complex pharmacology that includes low efficacy agonism at μ-opioid receptors (MORs). This study examined the activity of mitragynine at adrenergic α 2 receptors (Aα 2 Rs) in vitro and in vivo. Mitragynine displaced a radiolabeled Aα 2 R antagonist ([3H]RX821002) from human Aα 2A Rs in vitro with lower affinity (K i = 1260 nM) than the agonists (−)-epinephrine (K i = 263 nM) or lofexidine (K i = 7.42 nM). Mitragynine did not significantly stimulate [35S]GTPγS binding at Aα 2A Rs in vitro , but in rats trained to discriminate 32 mg/kg mitragynine from vehicle (intraperitoneally administered; i.p.), mitragynine exerted an Aα 2 R agonist-like effect. Both α 2 R antagonists (atipamezole and yohimbine) and MOR antagonists (naloxone and naltrexone) produced rightward shifts in mitragynine discrimination dose-effect function and Aα 2 R agonists lofexidine and clonidine produced leftward shifts. In the mitragynine trained rats, Aα 2 R agonists also produced leftward shifts in discrimination dose-effect functions for morphine and fentanyl. In a separate rat cohort trained to discriminate 3.2 mg/kg i.p. morphine from vehicle, naltrexone produced a rightward shift, but neither an Aα 2 R agonist or antagonist affected morphine discrimination. In a hypothermia assay, both lofexidine and clonidine produced marked effects antagonized by yohimbine. Mitragynine did not produce hypothermia. Together, these data demonstrate that mitragynine acts in vivo like an Aα 2 R agonist, although its failure to induce hypothermia or stimulate [35S]GTPγS binding in vitro , suggests that mitragynine maybe a low efficacy Aα 2 R agonist. [ABSTRACT FROM AUTHOR]

Mitragynine, an alkaloid found in Mitragyna speciosa (kratom), shows promise as a potential alternative to opioids owing to its distinctive indole alkaloid structure and its capacity for pain relief, alleviation of opioid withdrawal symptoms, and anti-inflammatory effects. Recently the intricate process of mitragynine biosynthesis from the precursor strictosidine was elucidated, providing insights into the complex pathways responsible for synthesizing this opioid compound and its related diastereomers. As the search continues for the authentic hydroxylase and methyltransferase crucial for mitragynine formation, leveraging enzymes from other species and exploiting enzyme promiscuity has facilitated heterologous mitragynine biosynthesis in microbes. This highlights the extraordinary flexibility of enzymes in generating a spectrum of variations and analogs of kratom opioids within alternative biological systems. [ABSTRACT FROM AUTHOR]

Used in Southeast Asia for generations, kratom gained popularity in the United States and elsewhere over the past several decades. Derived from Mitragyna speciosa , kratom preparations including leaves, teas, powders, capsules, and extracts may yield stimulant, analgesic, and opioid-like effects that occur dose-dependently based on concentrations of kratom's key alkaloids, mitragynine and 7-hydroxymitragynine. Such effects are responsible for kratom's potential as a reduced-harm alternative to opiates and as a withdrawal treatment. But these properties are also associated with tolerance development and addictive potential. Given mitragynine and 7-hydroxymitragynine activity on cytochrome P450 isoforms and opioid receptors, adverse effects among polysubstance users are a concern. Current literature on the toxicology of kratom is reviewed, including product alkaloid concentrations, in vitro and in vivo data, epidemiological evidence, and human case data. The potential harms and benefits of kratom products are discussed within an exposure assessment framework, and recommendations for industry are presented. Current evidence indicates that kratom may have therapeutic potential in some persons and that products present few risks with typical, non-polysubstance use. However, few studies identified alkaloid doses at which adverse effects were expected in humans or animals. Such research is needed to inform future assessments of kratom's risks and benefits. • Kratom (Mitragyna speciosa) use continues to increase in the United States. • Toxicological and pharmacological data show kratom's potential benefits and harms. • Alkaloid concentration-informed risk assessments showed few hazards with most uses. • Product concentrations of mitragynine and 7-hydroxymitragynine vary considerably. • Improved quality control would benefit U.S. kratom processors and distributors. [ABSTRACT FROM AUTHOR]

Kratom is a herbal substance belonging to the group of new psychoactive substances. It contains psychoactive indole alkaloids mitragynine and 7-hydroxymitragynine. At low doses, they act as psychostimulants and at higher doses they mediate an opioid-like effect. The increasing misuse of kratom requires the development of analytical methods that will accurately and reliably identify and quantify its psychoactive alkaloids in biological samples. Therefore, the development of effective, precise, and reliable green analytical methods that are easy to implement in practice is of great importance. On-line combination of capillary zone electrophoresis with tandem mass spectrometry (CZE-MS/MS) seems to be a promising solution. We present a novel green approach based on capillary zone electrophoresis – tandem mass spectrometry (CZE-MS/MS) method with on-line dynamic pH junction sample pretreatment to identify and determine mitragynine and 7-hydroxymitragynine in urine samples. The separation was performed in a background electrolyte composed of 100 mM formic acid (pH 2.39). The dynamic pH junction was ensured by injection of a short plug of 12.5 % NH 4 OH before the sample. Under optimal conditions, the developed method was validated and parameters such as linearity (r2 > 0.99), precision (2.2–8.7 %), accuracy (89.2–102.5 %) or stability of the sample (86.6–114.7 %) met the defined FDA guideline criteria (%RSD and %RE values where within ±15 %). Introduction of a simple in-capillary preconcentration strategy based on dynamic pH junction enabled significant improvement in analytical signal intensity and also the applicability of the method. Applying the presented approach, high sensitivity was achieved as indicated by limit of detection values, which were 0.5 ng mL−1 and 2 ng mL−1 for mitragynine and 7-hydroxymitragynine, respectively. Greenness of the proposed approach was confirmed by the AGREE metrics (score 0.63). The application potential of the developed method was successfully verified using blinded urine model samples. For the first time a fully validated CZE-MS/MS method for kratom alkaloids determination was introduced. The presented novel method is a cheaper and more ecological alternative to conventionally used chromatographic techniques what was clearly confirmed by its greenness evaluation and comparison with previously published liquid chromatography (LC) approaches. In-capillary sample pretreatment (dynamic pH junction) has been demonstrated to be an effective and fast tool in bioanalysis, minimizing the number of pretreatment steps and the manipulation with the sample. Moreover, LOD values comparable to those obtained by LC methods were recorded. High potential for the implementation of this approach into the toxicology environment in the near future is expected. [Display omitted] • The first validated CZE-MS/MS method for the determination of mitragynine and 7-hydroxymitragynine in biological samples. • Effective in-capillary sample pretreatment based on dynamic pH junction. • a suitable tool to prove the presence of kratom alkaloids in urine for toxicological purposes. • Green analytical method in toxicology. [ABSTRACT FROM AUTHOR]

Kratom is an herbal supplement that has drawn attention for its use in the self-treatment of opioid withdrawal, and its widespread availability with minimal restrictions. Past Web-based research has attempted to determine patterns and trends of use, but generalizability to underserved populations is unclear. The purpose of this study was to characterize behavior related to kratom, attitudes toward kratom, and knowledge of kratom in a rural, underserved population. We developed, refined, and administered a cross-sectional, 36-item survey to examine use, attitudes, and knowledge of kratom. We recruited participants and administered the survey alongside medical office appointments between January and April 2023. Data were summarized using descriptive statistics. A convenient sample of 186 patients (of the 907-patient clinic panel) were invited to participate and 150 returned the survey. Most patients were female (52.0%) and white (86.6%), and approximately half had an income below the federal poverty level (48.5%). Seventeen participants reported previous experience with kratom use, with one actively using kratom. The most commonly reported reasons for use were pain (47.1%) and mental health (41.2%). Kratom knowledge was low regardless of kratom use history, with most respondents correctly answering between 1 and 3 questions (n = 71 of 86; 82.3%) of the 5 knowledge-focused items. Results suggest that although active kratom use is uncommon in this Oregon population, 1 in 10 surveyed had used kratom. Regardless of past use, respondents had limited knowledge of kratom. Future research should focus on understanding trends in kratom use behaviors in underserved populations, addressing patient knowledge gaps, and evaluating patient safety and health equity implications. [ABSTRACT FROM AUTHOR]

During spring 2018, the U.S. Food and Drug Administration (FDA), Centers for Disease Control and Prevention, and state and local public health agencies responded to a multistate outbreak of gastrointestinal illnesses caused by multiple Salmonella serovars and associated with consumption of kratom, a product harvested from a tropical tree native to Southeast Asia. The outbreak included 199 case-patients reported by 41 U.S. states, with illness onset dates ranging 11 from January 2017 to 8 May 2018, leading to 54 hospitalizations and no deaths. Case-patients reported purchasing kratom products from physical and online retail points of service (POSs). Products distributed to 16 POSs where 24 case-patients from 17 states purchased kratom were selected for traceback investigation. Traceback revealed that the kratom was imported from several countries, the most common being Indonesia. Local and state officials collected product samples from case-patients and retail POSs. The FDA collected 76 product samples from POSs and distributors, of which 42 (55%) tested positive for Salmonella. The positive samples exhibited a range of pulsed-field gel electrophoresis patterns and whole genome sequence genetic heterogeneity, and 25 (60%) of 42 samples yielded at least one isolate indistinguishable from one or more outbreak-related clinical isolates. Although it does not exclude a possibility of a single contamination source, the extent of genetic diversity exhibited by the Salmonella isolates recovered from product samples and a lack of traceback convergence suggested that kratom was widely contaminated across multiple sites from which it was grown, harvested, and packaged. As a result of the contamination, kratom products were recalled by numerous firms (both voluntarily and mandatory). Epidemiologic, traceback, and laboratory evidence supported the conclusion that kratom products were associated with illnesses. Epidemiology investigations showed that multiple salmonella illnesses were associated with consumption of kratom, harvested from a tree native to Southeast Asia. Traceback investigations revealed that kratom was imported from several countries, most common being Indonesia. Extent of Salmonella genetic diversity from kratom samples and lack of traceback convergence, suggested that the products were widely contaminated. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa) is an opioid-like psychoactive substance not approved by the U.S. Food and Drug Administration that could be used due to its euphoric, stimulant, and analgesic effects. Kratom is gaining popularity in the U.S. and becoming a reason of concern among pediatricians. Data from the 2019 National Survey on Drug Use and Health were analyzed to estimate the prevalence and identify correlates of lifetime and past 12-month kratom use among 13,397 U.S. adolescents. Multivariable logistic regression models were conducted to assess the associations of interest. Lifetime and past 12-month prevalence of kratom use was.44% (95% confidence interval [CI].32–.60) and.27% (95% CI.18–.40), respectively. Past 12-month cigarette use was associated with lifetime kratom use (adjusted odds ratio 2.60, 95% CI 1.07–6.35). Past 12-month cannabis use was associated with past 12-month kratom use (adjusted odds ratio 2.48, 95% CI 1.15–5.35). This first report on the epidemiology of adolescent kratom use provides a baseline to assess kratom use trends in future years and identify potential correlates of use among adolescents. [ABSTRACT FROM AUTHOR]

Introduction: Kratom is a plant with partial opioid agonist effects, and its use has become popular to ameliorate symptoms of opioid withdrawal. However, use has been linked to thousands of poisonings, although most have involved use of other drugs. Little is known regarding prevalence and correlates of use in the general U.S.Population: Methods: Data were examined from the 2019 National Survey on Drug Use and Health, a nationally representative probability sample of non-institutionalized individuals aged ≥12 years in the U.S. (N=56,136). Prevalence and correlates of past-year kratom use were estimated. Data were analyzed in 2020.Results: An estimated 0.7% (95% CI=0.6, 0.8) of individuals in the U.S. have used kratom in the past year. Past-year proxy diagnosis of prescription opioid use disorder was associated with increased odds for kratom use (AOR=3.20, 95% CI=1.38, 7.41), with 10.4% (95% CI=6.7, 15.9) of those with use disorder reporting use. Opioid misuse not accompanied with use disorder was not associated with kratom use. Those reporting past-year cannabis use both with (AOR=4.33, 95% CI=2.61, 7.19) and without (AOR=4.57, 95% CI=3.29, 6.35) use disorder and those reporting past-year cocaine use (AOR=1.69, 95% CI=1.06, 2.69) and prescription stimulant misuse (AOR=2.10, 95% CI=1.44, 3.05) not accompanied with use disorder were at higher odds for kratom use.Conclusions: Kratom use is particularly prevalent among those with prescription opioid use disorder, but it is also prevalent among people who use other drugs. Research is needed to determine reasons for use and potential dangers associated with adding kratom to drug repertoires. [ABSTRACT FROM AUTHOR]

Mitragyna speciosa , more commonly known as kratom, has emerged as an alternative to treat chronic pain and addiction. However, the alkaloid components of kratom, which are the major contributors to kratom's pharmaceutical properties, have not yet been fully investigated. In this study, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry was used to map the biodistribution of three alkaloids (corynantheidine, mitragynine, and speciogynine) in rat brain tissues. The alkaloids produced three main ion types during MALDI analysis: [M + H]+, [M − H]+, and [M − 3H]+. Contrary to previous reports suggesting that the [M − H]+ and [M − 3H]+ ion types form during laser ablation, these ion types can also be produced during the MALDI matrix application process. Several strategies are proposed to accurately map the biodistribution of the alkaloids. Due to differences in the relative abundances of the ions in different biological regions of the tissue, differences in ionization efficiencies of the ions, and potential overlap of the [M − H]+ and [M − 3H]+ ion types with endogenous metabolites of the same empirical formula, a matrix that mainly produces the [M + H]+ ion type is optimal for accurate mapping of the alkaloids. Alternatively, the most abundant ion type can be mapped or the intensities of all ion types can be summed together to generate a composite image. The accuracy of each of these approaches is explored and validated. [Display omitted] • Biodistribution of kratom alkaloids is mapped in rat brains using imaging mass spectrometry. • Alkaloids produced three main ion types during MALDI mass spectrometry analysis. • Dehydrogenated ion formation is an artifact of MALDI, and not due to endogenous metabolism. [ABSTRACT FROM AUTHOR]

Kratom, Mitragyna speciosa , is one of the most popular herbs in the West and Southeast Asia. A number of previous works have focused on bioactive alkaloids in this plant; however, non-alkaloids have never been investigated for their biological activities. Antiviral and virucidal assays of a methanol leaf extract of Kratom, M. speciosa , revealed that a crude extract displayed virucidal activity against the SARS-CoV-2. Activity-guided isolation of a methanol leaf extract of Kratom led to the identification of B-type procyanidin condensed tannins of (−)-epicatechin as virucidal compounds against SARS-CoV-2. The fraction containing condensed tannins exhibited virucidal activity with an EC 50 value of 8.38 μg/mL and a selectivity index (SI) value >23.86. LC-MS/MS analysis and MALDI-TOF MS identified the structure of the virucidal compounds in Kratom as B-type procyanidin condensed tannins, while gel permeation chromatograph (GPC) revealed weight average molecular weight of 238,946 Da for high molecular-weight condensed tannins. In addition to alkaloids, (−)-epicatechin was found as a major component in the leaves of M. speciosa , but it did not have virucidal activity. Macromolecules of (−)-epicatechin, i.e., procyanidin condensed tannins, showed potent virucidal activity against SARS-CoV-2, suggesting that the high molecular weights of these polyphenols are important for virucidal activity. • High amount of (−)-epicatechin was found in leaves of Kratom, Mitragyna speciosa. • Virucidal compounds in Kratom were identified as condensed tannins of (−)-epicatechin. • Procyanidin condensed tannins exhibited virucidal activity against COVID-19 virus with EC 50 value of 8.38 μg/mL. • This work first reports bioactive non-alkaloid compounds in Kratom. [ABSTRACT FROM AUTHOR]

Kratom products are widely used in the United States, with inadequate understanding of how dosing amounts/frequencies relate to outcomes. Between July-November 2022, we enrolled 395 active US adult kratom consumers into a remote study with a baseline survey. We examined self-reported typical dose amounts and frequencies across people and product types, and their associations with outcomes: multiple regression was used to examine whether amounts and frequencies (doses/day) were associated with acute effects, withdrawal symptoms, scores on the Subjective Opioid Withdrawal Scale (SOWS), and addiction (operationalized as DSM-5-based symptoms of kratom-use disorder, KUD). Participants were 54.9% male, aged 38.1 on average, and 81.3% White. Mean length of kratom use was 5.7 years. Most (95.9%) reported regularly using whole-leaf kratom products; 16 (4.1%) reported regular extract use. SOWS scores were mild to moderate on average (13.5, SD 11.9). KUD symptom counts were mostly in the mild/moderate range (80.7%). Withdrawal and KUD symptoms were more closely associated with dose frequency than dose amount. Men reported more acute effects, withdrawal symptoms with cessation, and KUD symptoms than women. Greater dose amount and frequency were systematically related to the number of withdrawal symptoms upon cessation and to KUD symptoms; the relationship was stronger for dose frequency than amount. Men may have more acute effects and more withdrawal and KUD symptoms than women. Although kratom may be used nonproblematically by some consumers, physical dependence (tolerance, withdrawal, or use to avoid withdrawal) and KUD become more likely with increasing dose frequency. • Some kratom outcomes (e.g., withdrawal symptoms) were related more to dose frequency than amount. • Substance use disorder for kratom was primarily mild to moderate in frequent users. • Kratom physical dependence was common but largely without psychosocial impairment. • Men evinced more withdrawal symptoms than women, independent of dosing. • Participants primarily used whole-plant products, not concentrated extracts. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa) is a species of large tree that grows in Southeast Asia and is part of the Rubiaceae family. Its fresh leaves are harvested for their medicinal properties and used for their psychoactive effects. Kratom contains many biologically active alkaloids, including mitragynine and 7-OH-mitragynine, which are considered the two most important psychoactive components and constitute approximately 66% and 2% of the total alkaloid content. Other alkaloids are present in the plant, such as speciogynine, speciociliatine and paynantheine, but have less psychoactive activity. Over the past decade, the sale of kratom powder has increased on the Internet. This led to a significant increase in forensic cases. Given the lack of data existing in the literature, and the total absence of data in nails, the authors report a study to determine the best target alkaloids for documenting kratom consumption in this matrix. Fingernail clippings from a supposed kratom powder user were analyzed after liquid-liquid extraction, chromatography separation using a HSS C18 column and performed on an ultra-high performance liquid chromatography coupled to a tandem mass spectrometer. In the specimen, mitragynine was quantified at 229 pg/mg, speciogynine and paynantheine were both quantified at 2 pg/mg, and speciociliatine was quantified at 19 pg/mg. 7-OH-mitragynine was not detected. The interpretation of these concentrations is complex, since there is currently no reference in the literature, as this is the first identification of mitragynine and other kratom alkaloids in nails. Nevertheless, in view of the high concentration of mitragynine, the subject seems to be a repetitive user of kratom. According to the measured concentrations, it seems that mitragynine remains the best target to document kratom consumption, but the identification of the other alkaloids would enhance the specificity of the test. • Kratom contains many biologically active alkaloids, including mitragynine and 7-OH-mitragynine. • Other alkaloids are present in the plant, such as speciogynine, speciociliatine and paynanthetine. • Given the lack of data, the authors report a study to determine the best target alkaloids for documenting a kratom consumption. • According to the measured concentrations, mitragynine remains the best target to document kratom consumption. • The identification of the other alkaloids would enhance the specificity of the test. [ABSTRACT FROM AUTHOR]

Kratom is an herbal supplement which is used for its stimulating properties and pain reduction due to interaction with opioid receptors. Kratom overdose may cause fatality. A 56-year-old man was admitted to the emergency department with severe jaundice and liver failure. His total bilirubin reached at 70.6 mg/dL, but extensive workup did not show any liver mass. Family informed that the patient was taking Kratom. Plasma exchange was suggested as an unconventional therapy and consent from the patient was obtained because this procedure has never been performed to treat Kratom toxicity before. After four procedures, his total bilirubin was reduced to 23.9 mg/dL and his clinical condition improved significantly. Finally on day 5 he was discharged at stable condition with a total bilirubin value of 21.3 mg/dL. There is no antidote for Kratom, and treatment is supportive. To our knowledge this is the first report of reversing Kratom poisoning using plasma exchange. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mitragynine is a frequently used drug with potential therapeutic applications. • Here we evaluate the effects of mitragynine withdrawal on protein expression. • Mitragynine withdrawal was associated with an upregulation of Rab35 in the brain. • Rab35 may serve as a marker for previously high mitragynine exposure. Mitragyna speciosa, also known as kratom, has been used for mitigating the severity of opioid withdrawal in humans. Its main indole alkaloid, mitragynine, has been considered as a pharmacotherapy for pain conditions and opioid replacement therapy. However, at high doses, chronic mitragynine may also have an addiction potential. The effects of chronic action of mitragynine in the brain are still unknown. The present study developed a mitragynine withdrawal model in rats and used it for a proteomic analysis of mitragynine withdrawal effects. Mitragynine (30 mg/kg, i.p.) was administered daily over a period of 14 days and then withdrawn. A proteomic analysis revealed that from a total of 1524 proteins identified, 31 proteins were upregulated, and 3 proteins were downregulated in the mitragynine withdrawal model. The Rab35 protein expression increased most profoundly in the mitragynine withdrawal group as compared to vehicle group. Therefore, it is proposed that Rab35 in the brain might be considered as a potential biomarker during mitragynine withdrawal and might be valuable target protein in developing new pharmacotherapies in the future. [ABSTRACT FROM AUTHOR]

Background: Kratom (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 Report: A 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. [ABSTRACT FROM AUTHOR]

Background: Kratom is a South Eastern Asian tree whose leaves are used to make tea-like brews or swallowed in powdered form for various health and well-being reasons including to relieve pain and opioid withdrawal. It is important to learn more about the potential public health impact of kratom in the context of the opioid epidemic.Methods: An anonymous online survey of kratom users (2867 current users and 157 former users) was conducted in September 2017 through the American Kratom Association and associated social media sites.Results: Kratom was used primarily to relieve pain (endorsed by 48% of respondents), for anxiety, PTSD, or depression (22%), to increase energy or focus (10%) and to help cut down on opioid use and/or relieve withdrawal (10%). Over 90% of respondents who used it in place of opioids indicated that it was helpful to relieve pain, reduce opioid use, and relieve withdrawal. The reported incidence of bad adverse reactions was 13%, and reactions were overwhelmingly mild and self-managed.Conclusions: Respondents reported using kratom for conditions which often require use of opioids, including pain and reduction of opioid use. The high self-reported efficacy and low incidence of adverse reactions associated with kratom use suggest that it may provide a potential alternative to opioids for some persons even though it has not been evaluated in multi-center clinical trials or approved for any therapeutic purpose. Further study of kratom, including systematic characterization of its safety and efficacy for various conditions is warranted. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa) is a tree-like plant indigenous to Southeast Asia. Its leaves, and the teas brewed from them have long been used by people in that region to stave off fatigue and to manage pain and opioid withdrawal. Evidence suggests kratom is being increasingly used by people in the United States and Europe for the self-management of opioid withdrawal and treatment of pain. Recent studies have confirmed that kratom and its chemical constituents have potentially useful pharmacological actions. However, there have also been increasing numbers of reports of adverse effects resulting from use of kratom products. In August 2016, the US Drug Enforcement Administration announced plans to classify kratom and its mitragynine constituents as Schedule I Controlled Substances, a move that triggered a massive response from pro-kratom advocates. The debate regarding the risks, and benefits and safety of kratom continues to intensify. Kratom proponents tout kratom as a safer and less addictive alternative to opioids for the management of pain and opioid addiction. The anti-kratom faction argues that kratom, itself, is a dangerous and addictive drug that ought to be banned. Given the widespread use of kratom and the extensive media attention it is receiving, it is important for physicians, scientists and policy makers to be knowledgeable about the subject. The purpose of this commentary is to update readers about recent developments and controversies in this rapidly evolving area. All of the authors are engaged in various aspects of kratom research and it is our intention to provide a fair and balanced overview that can form the basis for informed decisions on kratom policy. Our conclusions from these analyses are: (a) User reports and results of preclinical studies in animals strongly suggest that kratom and its main constituent alkaloid, mitragynine may have useful activity in alleviating pain and managing symptoms of opioid withdrawal, even though well-controlled clinical trials have yet to be done. (b) Even though kratom lacks many of the toxicities of classic opioids, there are legitimate concerns about the safety and lack of quality control of purported "kratom" products that are being sold in the US. (c) The issues regarding the safety and efficacy of kratom and its mitragynine constituent can only be resolved by additional research. Classification of the Mitragyna alkaloids as Schedule I controlled substances would substantially impede this important research on kratom. [ABSTRACT FROM AUTHOR]

The opioid epidemic has left its toll on the United States with millions suffering from an opioid use disorder and tens of thousands dying from overdoses each year. With intentions to combat the crisis, health providers have been prescribing less opioids, which resulted in an unintentional increase in the abuse of other opioid-like substances. Three emerging drugs of abuse have been noted in the literature as having increased abuse potential in light of recent trends. Kratom, an herbal supplement, gabapentin, a prescription nerve pain and anticonvulsant medication, and loperamide, an over-the-counter antidiarrheal medication. These have all displayed opioid-like properties at high doses and used to alleviate opioid withdrawal. Healthcare clinicians and patients might not be aware of the potential risks involved with misusing or abusing these opioid substitutes. This article discusses the increased usage of kratom, gabapentin, and loperamide, the abuse potential, adverse effects and withdrawal symptoms of each drug, and nursing implications that impact inpatient safety and management. • With less opioids being prescribed, opioid-like substances are being abused. • Misuse or abuse of kratom, gabapentin, and loperamide can cause dependence. • Standard drug screens might not detect opioid-like substances. [ABSTRACT FROM AUTHOR]

The recent rise in the recreational use of plant-based "legal highs" has prompted the development of methods for the identification of the bulk material, and quantification of their psychoactive components. One of these plants is Mitragyna speciosa, commonly referred to as Kratom. While traditional use of this plant was primarily for medicinal purposes, there has been a rise in its recreational use, and as a self-prescribed medication for opioid withdrawal. Although Kratom contains many alkaloids, mitragynine and 7-hydroxymitragynine are unique psychoactive biomarkers of the species, and are responsible for its psychoactive effects. A rapid validated method for the quantification of mitragynine in Kratom plant materials by direct analysis in real time-high-resolution mass spectrometry (DART-HRMS) is presented. It has a linear range of 5-100 μg mL-1, and a lower limit of quantification of 5 μg mL-1. The protocol was applied to determination of the mitragynine content of 16 commercially available Kratom plant products purchased online. The mitragynine amounts in these materials ranged from 2.76 to 20.05 mg g-1 of dried plant material. The utilization of DART-HRMS affords a mechanism not only for the preliminary identification of bulk plant material as being M. speciosa-derived (with no sample preparation required), but also provides the opportunity to quantify its psychoactive components using the same technique. [ABSTRACT FROM AUTHOR]

• Mitragynine is a major psychoactive and analgesic alkaloid found in kratom (Mitragyna speciosa). This compound plays a major role in pharmacological actions of kratom as well as toxicity and addiction. • Mitragynine can be orally administered but it has a poor oral bioavailability. Nonetheless, a salt form of the alkaloid has a significantly higher oral bioavailability value. • Mitragynine can be rapidly transported into the brain due to its high lipid solubility and permeability. Mitragynine can be metabolized by liver CYP450 isozymes, primarily by CYP3A4. • Based on our systematic review, there are limited numbers of pharmacokinetic studies of mitragynine both in animals and humans. Thus, to understand more about pharmacokinetics of this important alkaloid, more research studies are needed. Kratom (Mitragyna speciosa) is a tropical tree found in southern Thailand and northern states of the Malay Peninsula. Kratom is commercially available and used as an alternative to treat opioid withdrawal. Mitragynine is the major indole alkaloid found in kratom leaves. This review aimed to summarize available pharmacokinetic information about mitragynine. PubMed, Scopus, and Web of Science were systematically searched from their inceptions to June 2018. All types of pharmacokinetic studies of mitragynine were included for further systematic review. Seventeen articles were reviewed. Mitragynine is a lipophilic weak base passively transported across the intestinal wall and blood brain barrier. 85–95% is bound to plasma protein and extensively metabolized by phase I and particularly phase II enzymes. Actions on CYP enzymes are unlikely to impact drug metabolism at concentrations likely to exist in kratom-consuming humans. In rats and humans, mitragynine is rapidly absorbed after orally administration (T max ˜1.5 h, C max ˜0.3−1.8 μM). V d was 37–90 L/kg; t 1/2 was 3–9 hr; mostly excreted as metabolites in urine. Bioavailability was estimated as 21%. It also rapidly penetrated and redistributed in brain. A quality assessment tool tailored for pharmacokinetic studies was also created which rated some studies of lower value. Rudimentary pharmacokinetics of mitragynine was described in this systematic review. However, the discovered studies provided scant information on the role of metabolism and redistribution into tissues nor the rate of excretion. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance The leaves of Mitragyna speciosa (Korth.) or kratom have been traditionally used in Malaysia and Thailand mainly to enhance work productivity, as a folk remedy for treating common ailments, and as a mood enhancer. Aim of the study This present study sought to investigate kratom use motives among regular kratom users in Malaysia. Materials and methods A total of 116 regular kratom users were recruited for this cross-sectional survey. The Drinking Motives Questionnaire (DMQ) was administered to measure kratom use motives. Results Our results indicate that heavy (>3 glasses daily, each glass contains 48.24–50.4 mg of mitragynine) kratom use was associated with coping (t 87.09 =3.544, p < 0.001), and enhancement (t 114 =2.180, p = 003). Single subjects had higher mean scores on the coping domain, relative to married subject (t 113.89 =3.029, p < 0.003), while those earning more than RM1500 per month had higher mean scores on the enhancement domain, compare to those earning less than RM1500 per month (t 107 =2.151, p < 0.034). Higher scores on the co p ing domain was significantly associated with higher (>3 glasses daily) kratom consumption (p < 0.0045). Conclusions Coping was associated with high (>3 glasses daily) kratom consumption among regular kratom users in traditional, rural settings. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Recreational drug toxicity is a rapidly evolving aspect in clinical practice. The prevalence of recreational drug abuse in the past decade has achieved an epidemic scale due to invention of new agents and ease of accessibility to the abused drugs. "Unconventional recreational drugs" is the term that includes new psychoactive drugs and medications diverted for recreational goals. Misuse of unconventional recreational drugs during pregnancy can affect both the pregnant woman and the fetus. However, the problems are usually unrecognized and overlooked by healthcare professionals. In this articles, obstetric complications, teratogenicity and neonatal abstinence syndrome from exposure during pregnancy to synthetic cannabinoids, synthetic cathinones, tramadol, kratom, olanzapine, quetiapine, ketamine and ketamine are reviewed. The main purpose is to create awareness about maternal, fetal and neonatal effects of these unconventional recreational drugs, so healthcare professionals will have improved vigilance for these under-recognized issues. [ABSTRACT FROM AUTHOR]

The use of herbal tea infusions is widespread in ethnomedicine throughout the world. One such ethnobotanical is kratom (Mitragyna speciosa Korth., Rubiaceae) which has gained considerable interest as an herbal supplement in recent years in the West beyond its native Southeast Asia. Traditional, kratom leaves are either chewed fresh or made into a tea infusion to treat fatigue, pain, or diarrhea. However, dried kratom leaf powder and hydroalcoholic extracts are more commonly used in Western countries, raising the question of exposure to kratom alkaloids and related effects. A specific kratom tea bag product was analyzed for mitragynine content using tea infusion preparation and methanolic extraction. Consumers of both the tea bag product and other kratom products completed an online anonymous survey to determine demographics, kratom use patterns, and self-reported beneficial and detrimental effects. Kratom tea bag samples were extracted using pH-adjusted water or methanol and analyzed using an established LC-QTOF method. A modified kratom survey was distributed to consumers of the kratom tea bag products and other kratom products over a 14-month period. Tea infusion extraction of tea bag samples resulted in lower mitragynine levels (0.062–0.131% (w/w)) compared to methanolic extraction (0.485–0.616% (w/w)). Kratom tea bag consumers did report similar, although often milder beneficial effects compared to consumers using other kratom products. Overall self-reported health was better among kratom tea bag consumers whereas improvement of a diagnosed medical condition was less in tea bag consumers compared to those using other kratom products. Traditional tea infusions of Mitragyna speciosa dried leaves provide benefits to consumers despite substantially lower mitragynine content. These effects may be less pronounced but indicate that tea infusions provide a potentially safer formulation compared to more concentrated products. [Display omitted] • Kratom is traditionally used as a tea infusion for alleviation of fatigue and pain. • Exposure to mitragynine is lower with tea infusions than other kratom products. • Reported effects from kratom tea infusions is less intense than other products. • Kratom tea infusions may provide benefits while being safer than other products. [ABSTRACT FROM AUTHOR]

Abuse of new psychoactive substances (NPSs) among youths is increasing at an unprecedented rate all over the world. In Asia, abuse of synthetic cannabinoids (SCs), kratom, and poppers has been reported, but up to date information related to abuse of these three NPSs is lacking. This literature review focuses on the recent abuse of these three NPS among Asian youth. Many studies have been conducted to investigate the abuse statuses of SCs in Asian youth in Turkey, Japan, and Korea, and many cases of kratom abuse have been reported in Malaysia and Thailand. In addition, concerns have been expressed about the use of kratom in combination with other substances by teenagers. Popper abuse has been reported among many young people in Asia, including Korea and China, and many studies on popper abuse have focused on men who have sex with men in China and Malaysia. Since NPS abuse can have severe adverse effects and create social problems, there is a continuing need to investigate NPS abuse status continuously among young people. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Mitragyna speciosa (Korth.) also known as kratom, is a native medicinal plant of Southeast Asia with opioid-like effects. Kratom tea/juice have been traditionally used as a folk remedy and for controlling opiate withdrawal in Malaysia. Long-term opioid use is associated with depletion in testosterone levels. Aim of the study Since kratom is reported to deform sperm morphology and reduce sperm motility, we aimed to clinically investigate the testosterone levels following long-term kratom tea/juice use in regular kratom users. Methods A total of 19 regular kratom users were recruited for this cross-sectional study. A full-blood test was conducted including determination of testosterone level, follicle stimulating hormone (FSH) and luteinizing hormone (LH) profile, as well as hematological and biochemical parameters of participants. Results We found long-term kratom tea/juice consumption with a daily mitragynine dose of 76.23–94.15 mg did not impair testosterone levels, or gonadotrophins, hematological and biochemical parameters in regular kratom users. Conclusion Regular kratom tea/juice consumption over prolonged periods (>2 years) was not associated with testosterone impairing effects in humans. [ABSTRACT FROM AUTHOR]

There has been significant research to develop an ideal synthetic opioid. Opioids with variable properties possessing efficacy and with reduced side effects have been synthesized when compared to previously used agents. An opioid modulator is a drug that can produce both agonistic and antagonistic effects by binding to different opioid receptors and therefore cannot be classified as one or the other alone. These compounds can differ in their structures while still possessing opioid-mediated actions. This review will discuss TRV130 receptor modulators and other novel opioid receptor modulators, including Mitragyna "Kratom," Ignavine, Salvinorin-A, DPI-289, UFP-505, LP1, SKF-10,047, Cebranopadol, Naltrexone-14-O-sulfate, and Naloxegol. In summary, the structural elucidation of opioid receptors, allosteric modulation of opioid receptors, new opioid modulators and agonists, the employment of optogenetics, optopharmacology, and next-generation sequencing of opioid receptor genes and related functionality should create exciting new avenues for research and therapeutic development to treat conditions including pain, opioid abuse, and addiction. [ABSTRACT FROM AUTHOR]

The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacological profile of raw kratom extracts, although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiological effects in man based on this preclinical data and comparison to both anecdotal human experience and multiple epidemiological surveys. Kratom exposure alone has not been causally associated with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential. This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’ [ABSTRACT FROM AUTHOR]

Mitragyna speciosa (Kratom) is a psychoactive plant that has recently emerged as a recreational drug. Mitragyna alkaloids are not within the scope of traditional forensic toxicology screening methods, which may contribute to under-reporting. Solid phase extraction (SPE) and liquid chromatography-quadrupole/time of flight mass spectrometry (LC-Q/TOF-MS) were used to identify five alkaloids in urine. Target analytes included the two known psychoactive compounds, mitragynine and 7-hydroxymitragynine, in addition to speciociliatine, speciogynine, and paynantheine. Two deuterated internal standards (mitragynine-D 3 and 7-hydroxymitragynine-D 3 ) were employed. Using traditional reversed phase chromatography all compounds and isomers were separated in 10 min. The procedure was validated in accordance with the Scientific Working Group for Forensic Toxicology (SWGTOX) Standard Practices for Method Validation. Extraction efficiencies were 63–96% and limits of quantitation were 0.5–1 ng/mL. Precision, bias and matrix effects were all within acceptable thresholds, with the exception of 7-hydroxymitragynine, which is notably unstable and unsuitable for quantitative analysis. In this paper we present a simultaneous quantitative analytical method for mitragynine, speciociliatine, speciogynine and paynantheine, and a qualitative assay for 7-hydroxymitragynine in urine using high resolution mass spectrometry (HRMS). [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Kratom ( Mitragyna speciosa Korth.) from the Rubiaceae family is an indigenous tropical medicinal tree of Southeast Asia. Kratom leaves have been used for decades in Malaysia and Thailand in traditional context for its perceived vast medicinal value, and as a mild stimulant among manual labourers. Kratom consumption has been reported to cause side-effects in kratom users. Aim of the study To evaluate kratom's effects towards hematological and clinical-chemistry parameters among regular kratom users in Malaysia. Methods A total of 77 subjects (n=58 regular kratom users, and n=19 healthy controls) participated in this cross-sectional study. All the surveys were conducted through face-to-face interview to elicit subject's socio-demographic characteristics and kratom use history. A full-blood test was also administered. Laboratory analysis was conducted using GC-MS to determine mitragynine content in the acquired kratom samples in order to relate mitragynine consumption with possible alterations in the blood parameters of kratom users. Results Findings showed that there were no significant differences in the hematological and clinical-chemistry parameters of traditional kratom users and healthy controls, except for HDL and LDL cholesterol values; these were found to be above the normal reference range for the former. Similarly, long-term kratom consumption (>5 years), and quantity of daily kratom use (≥3 ½ glasses; mitragynine content 76.3–114.8 mg) did not appear to alter the hematological and biochemical parameters of kratom users. Conclusion These data suggest that even long-term and heavy kratom consumption did not significantly alter the hematological and clinical-chemistry parameters of kratom users in a traditional setting. [ABSTRACT FROM AUTHOR]

Background: Kratom (Mitragyna speciosa) is a psychoactive plant native to Southeastern Asia that is receiving increased international attention as a potential therapeutic agent. While much of the limited scientific research on kratom is focused on its analgesic potential, kratom use also has important risks and benefits in the domain of mental health.Methods: We conducted a comprehensive systematic review of all studies on kratom use and mental health published between January 1960 and July 2017.Results: Findings indicate kratom's potential as a harm reduction tool, most notably as a substitute for opioids among people who are addicted. Kratom also enhances mood and relieves anxiety among many users. For many, kratom's negative mental health effects - primarily withdrawal symptoms - appear to be mild relative to those of opioids. For some users, however, withdrawal is highly uncomfortable and maintaining abstinence becomes difficult.Conclusion: Results inform clinicians working in the mental health and substance use fields, policy-makers, and researchers about the mental health effects of this plant. [ABSTRACT FROM AUTHOR]

Mitragynine (MG) is an indole alkaloid found in the extract of Mitragyna speciosa Korth native to Southeast Asia. Although MG is known for its pain-relieving and psychoactive effects, reports have suggested that it has therapeutic potential against neoplasms and psychiatric disorders. However, no evidence currently exists to support the effect of MG on brain tumors. This study aimed to investigate the antitumor effects of MG in C6 rat glioma and SH-SY5Y human neuroblastoma tumor cell lines compared with those in the non-tumor HT22 mouse hippocampal neuronal cell line. MTT assay for cell viability, clonogenic and wound healing assays for cell migration, Hoechst 33342/propidium iodide staining for nuclear morphology, and cell cycle distribution using flow cytometry were performed. MG at 125.47 μM (50 μg/ml) significantly reduced the viability of all cell lines, and the clonogenicity of C6 glioma cells began decreasing at 75.28 μM (30 μg/ml) of MG. Cell migration was inhibited in C6 and HT22 cells treated with 75.28 μM (30 μg/ml) of MG. Apoptotic nuclear condensation and fragmentation were observed in all cell lines treated with 125.47 μM (50 μg/ml) MG, whereas late-phase apoptotic cells were predominant in the group treated with 250.94 μM (100 μg/ml) of MG. The cell cycle assay results suggest that MG arrested the S phase in the C6 cell line and the G2/M phase in the HT22 cell lines. This study showed that MG induces cell death and cell cycle arrest, disrupting cell migration and reducing the clonogenicity of brain tumor cells. [ABSTRACT FROM AUTHOR]

Kratom, (Mitragyna Speciosa Korth.) is a plant indigenous to Southeast Asia whose leaves are cultivated for a variety of medicinal purposes and mostly consumed as powders or tea in the United States. Kratom use has surged in popularity with the lay public and is currently being investigated for possible therapeutic benefits including as a treatment for opioid withdrawal due to the pharmacologic effects of its indole alkaloids. A wide array of psychoactive compounds are found in kratom, with mitragynine being the most abundant alkaloid. The drug-drug interaction (DDI) potential of mitragynine and related alkaloids have been evaluated for effects on the major cytochrome P450s (CYPs) via in vitro assays and limited clinical investigations. However, no thorough assessment of their potential to inhibit the major hepatic hydrolase, carboxylesterase 1 (CES1), exists. The purpose of this study was to evaluate the in vitro inhibitory potential of kratom extracts and its individual major alkaloids using an established CES1 assay and incubation system. Three separate kratom extracts and the major kratom alkaloids mitragynine, speciogynine, speciociliatine, paynantheine, and corynantheidine displayed a concentration-dependent reversible inhibition of CES1. The experimental K i values were determined as follows for mitragynine, speciociliatine, paynantheine, and corynantheidine: 20.6, 8.6, 26.1, and 12.5 μM respectively. Speciociliatine, paynantheine, and corynantheidine were all determined to be mixed-type reversible inhibitors of CES1, while mitragynine was a purely competitive inhibitor. Based on available pharmacokinetic data, determined Ki values, and a physiologically based inhibition screen mimicking alkaloid exposures in humans, a DDI mediated via CES1 inhibition appears unlikely across a spectrum of doses (i.e., 2–20g per dose). However, further clinical studies need to be conducted to exclude the possibility of a DDI at higher and extreme doses of kratom and those who are chronic users. • Kratom extracts and its major alkaloids demonstrate a reversible inhibition of carboxylesterase 1, in vitro. • Using kratom products and medications metabolized by carboxylesterase 1 are unlikely to precipitate drug-drug interactions. • To exclude drug interaction risk, clinical pharmacokinetic studies with kratom at higher and chronic usage are warranted. [ABSTRACT FROM AUTHOR]

Mitragynine (MG) is the primary active constituent of Mitragyna speciosa Korth (kratom), a psychoactive Southeast Asian plant with potential therapeutic use. Numerous studies support roles of dopaminergic system in drug reward. However, the involvement of the dopaminergic system in mediating MG reward and drug-seeking is poorly understood. Using conditioned place preference (CPP) paradigm, the present study aims to evaluate the roles of the dopamine (DA) D1 receptor in the acquisition and expression of MG-induced CPP in rats. The effects of SCH-23390, a selective DA D1 receptor antagonist, on the acquisition of MG-induced CPP were first investigated. Rats were pre-treated systemically with SCH-23390 (0, 0.1 and 0.3 mg/kg, i.p.) prior to MG (10 mg/kg) conditioning sessions. Next, we tested the effects of the DA D1 receptor antagonist on the expression of MG-induced CPP. Furthermore, the effects of a MG-priming dose (5 mg/kg) on the reinstatement of extinguished CPP were tested. The results showed that SCH-23390 dose-dependently suppressed the acquisition of a MG-induced CPP. In contrast, SCH-23390 had no effect on the expression of a MG-induced CPP. The findings of this study suggested a crucial role of the DA D1 receptor in the acquisition, but not the expression of the rewarding effects of MG in a CPP test. Furthermore, blockade of the D1-like receptor during conditioning did not prevent MG priming effects on CPP reinstatement test, suggesting no role for the DA D1 receptor in reinstatement sensitivity. [ABSTRACT FROM AUTHOR]

Mitragynine (MG) is an alkaloid found in Mitragyna speciosa (kratom), a plant used to self-treat symptoms of opioid withdrawal and pain. Kratom products are commonly used in combination with cannabis, with the self-treatment of pain being a primary motivator of use. Both cannabinoids and kratom alkaloids have been characterized to alleviate symptoms in preclinical models of neuropathic pain such as chemotherapy-induced peripheral neuropathy (CIPN). However, the potential involvement of cannabinoid mechanisms in MG's efficacy in a rodent model of CIPN have yet to be explored. Prevention of oxaliplatin-induced mechanical hypersensitivity and formalin-induced nociception were assessed following intraperitoneal administration of MG and CB1, CB2, or TRPV1 antagonists in wildtype and cannabinoid receptor knockout mice. The effects of oxaliplatin and MG exposure on the spinal cord endocannabinoid lipidome was assessed by HPLC-MS/MS. The efficacy of MG on oxaliplatin-induced mechanical hypersensitivity was partially attenuated upon genetic deletion of cannabinoid receptors, and completely blocked upon pharmacological inhibition of CB1, CB2, and TRPV1 channels. This cannabinoid involvement was found to be selective to a model of neuropathic pain, with minimal effects on MG-induced antinociception in a model of formalin-induced pain. Oxaliplatin was found to selectively disrupt the endocannabinoid lipidome in the spinal cord, which was prevented by repeated MG exposure. Our findings suggest that cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid MG in a model of CIPN, which may result in increased therapeutic efficacy when co-administered with cannabinoids. • Cannabinoid mechanisms contribute to the efficacy of MG against CIPN. • MG is effective against persistent inflammatory pain. • Cannabinoid mechanisms do not contribute to the effects of MG on inflammatory pain. • Oxaliplatin and MG modulate the spinal cord endocannabinoid lipidome. [ABSTRACT FROM AUTHOR]