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Clinical Pharmacology of the Dietary Supplement, Kratom (Mitragyna speciosa)
Abstract
Kratom (Mitragyna speciosa) consists of over 40 alkaloids with two of them, mitragynine (MG) and 7‐OH‐mitragynine (7‐OH‐MG) being the main psychoactive compounds. MG and 7‐OH‐MG each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the μ, δ, and κ opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a “legal high,” and numerous CNS disorders including anxiety depression and post‐traumatic stress disorder (PTSD). Kratom induces analgesia and mild euphoria with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects including liver toxicity, seizures, and death. These risks are often compounded by poly‐substance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P‐glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes (UGDT). In 2016 the U.S. Drug Enforcement Administration (DEA) took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other CNS conditions, kratom will likely remain available as a dietary supplement for the foreseeable future. This article is protected by copyright. All rights reserved
... The effects of kratom have been associated with the plant strain, which is visually characterized based on vein color, including white, green, or red (Suwanlert, 1975;Hartley et al., 2022). Vein color changes as the plant ages, from white at the young stage to green and finally to red after maturation (Ngernsaengsaruay et al., 2022). ...
... Kratom extracts and alkaloids, including mitragynine, have been reported to activate the pregnane X receptor in HepG2 cells (EC 50 , ~5 μg/mL and 1-5 μM, respectively) (Manda et al., 2017;Hartley et al., 2022), which may induce the expression of certain drug metabolizing enzymes and transporters, including CYP3A and P-gp (Tolson and Wang, 2010). Although mitragynine did not increase CYP3A4 mRNA expression nor enzyme activity, the oxindole This article has not been copyedited and formatted. ...
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 biological 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 (CYP) 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-gp. An iterative approach that includes clinical studies and PBPK modeling and simulation is recommended for further evaluation of the drug interaction potential of this increasingly popular botanical.
... Mitragynine (an active substance in kratom) exhibited an atypical epidemiology compared to the other NPS ( Kratom has significant opioid effects at higher doses [45], and is therefore sometimes self-administered as a remedy against opioid abstinence [46]. This may explain its negative correlation with heroin, and a trend for positive correlation with loperamide, which is used (at supra-pharmacological doses) as a legal self-medication for opioid abstinence [47]. ...
New psychoactive substances (NPS) are health‐hazardous through unpredictable toxicity and effects and largely unknown epidemiology, motivating studies of the latter.
Up to 138 NPS were retrospectively identified using liquid chromatography‐high resolution mass spectrometry data from all 34 183 oral fluid drug samples collected in one Swedish health care region 2019–2020 representing 9468 psychiatric and addiction care patients. In total, 618 findings representing 58 NPS were detected in 481 samples from 201 patients. Male gender and age ≥25 years correlated positively with NPS use. Ketamine correlated positively with all NPS classes except cannabinoids; additionally, fentanyl, methadone, tapentadol and clonazepam correlated with multiple NPS classes. More numerous traditional drugs of abuse (DoA) correlated positively with sedative/hypnotic NPS, indicating that these are used in broader patient groups than other NPS. Mitragynine correlated negatively with other NPS in general and with several traditional DoA, but positively with the potential opioid abstinence remedies buprenorphine, loperamide and tapentadol aside from ketamine. In conclusion, NPS use is infrequent but occur also at higher ages, certain traditional DoA and particularly ketamine could have clinical value as NPS use signals, and mitragynine exhibited an atypical NPS consumption pattern indicating significant use as an opioid abstinence remedy.
... The authors uncovered hundreds of fatalities attributed to consumption of products sold in the United States and vast, complicated intricacies of the currently unregulated US trade in products claimed to be derived from the kratom plant [7][8][9]. Several comprehensive reviews of kratom alkaloids pharmacology have been recently published [10][11][12]. ...
Purpose of review
Kratom plant, products derived from the plant, and plant phytochemicals are of great interest among researchers, clinicians, and consumers. However, there is a paucity of rigorously collected scientific data on their risk/safety profile and public health impact. This scoping review discusses original research articles published between 2022 and 2023. It focuses on identifying publication gaps on topics related to epidemiology, public health, and risk/safety profiles comparing evidence collected by researchers from Southeast Asia and the West.
Recent findings
Our review of the Scopus database identified a total of 55 publications, including clinical case reports and case series reports, surveys, studies enrolling human participants, and publications based on large-scale national surveys or large-scale national or international health system database records.
Summary
Overall, there is dearth of reliable data on key epidemiological factors, including the prevalence rates, and on objective and reliable indices of the risk/safety profiles. Rigorous and systematic studies including improved epidemiological surveillance, human laboratory, and controlled clinical studies are urgently needed to advance our understanding of public health consequences of consuming kratom and kratom-derived products and to improve our understanding of their risk/safety profile and additional analytical studies to better inform development of needed regulatory oversight.
... In places where it is legal, it is sold in various non-pharmaceutical formulations, and products are often prepared in a substandard quality (e.g., dietary supplements, powders, tablets, resin, tincture, gelatine capsules) containing Mitragyna speciosa extracts or dried leaves (Fleming et al. 2022;Sharma and McCurdy 2021;Sharma et al. 2019). Kratom products are typically advertised based on the leaves' place of origin, strains, and vein colors (Hartley, Bulloch, and Penzak 2021), and they are sold through multiple channels, including head shops, gas stations, and web shops (Prozialeck, Jivan, and Andurkar 2012;Swogger et al. 2022;Williams and Nikitin 2020). ...
... 23 Mitragynine is a partial m-opioid agonist and d-opioid antagonist that does not recruit b-arrestin-2 activity, 24,25 the pathway associated with tolerance and sympathetic nervous system activation. 26 In an observational study, no evidence of an Overall, biological plausibility, confirmed case reports, and substantial signals of disproportionate reporting raise public health concern regarding the proarrhythmic potential for both the over-thecounter drug loperamide and the recreational opioid kratom. needed. ...
Background:
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.
Objectives:
In this study, we sought to explore opioid-associated arrhythmia reporting in North America.
Methods:
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.
Results:
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.
Conclusions:
The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.
... Kratom has gained some interest in the past two decades due to its dose-dependent stimulant and opioid-like effects that appear to be mediated primarily by indole alkaloids present in the leaves with a diverse pharmacological profile acting on opioid receptors as well as adrenergic, serotonergic, and other neurotransmitter systems. 4 This article will summarize the traditional uses of kratom, its currently known pharmacology, modern use of kratom and global trends, potential benefits of kratom and its active constituents mitragynine, 7-hydroxymitragynine, and other alkaloids, as well as adverse health effects of kratom as reported in the literature or inferred from pre-clinical studies. ...
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.
The Pharmacist’s Manual: An Informational Outline on the Controlled Substances Act, is the primary source for federal information on controlled substances presented in this chapter [1]. It summarizes the basic requirements of handling and prescribing controlled substances in accordance with the Controlled Substances Act (CSA), Title 21 United States Code (21 U.S.C.) 801–971 and Drug Enforcement Administration (DEA) regulations, Title 21, Code of Federal Regulations (21 CFR), Parts 1300 to end. If the reader requires clarification or further insight into any of the topics addressed below, they are encouraged to refer to the electronic version of this document and follow the provided links for supplemental information. In addition, Alabama controlled substance laws are presented; these are found in the Alabama State Board of Pharmacy (ALBOP) Administrative Code Chapter 680-X-3 [2], Alabama Uniform Controlled Substances, and the Alabama Board of Medical Examiners (ALBME) Administrative Code Chapter 540-X-4 Controlled Substances Certificate [3].
As Kratom use increases, concerns about potential herb-drug interactions with liver enzymes, particularly UDP-glucuronosyltransferases (UGTs), have emerged. This study investigated the inhibitory effects of Kratom leaf constituents, mitragynine and 7-hydroxymitragynine, on 4-methylumbelliferone (4MU) glucuronidation by a panel of recombinant human UGT enzymes, including UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, and UGT2B15. The degree of inhibition exhibited by mitragynine and 7-hydroxymitragynine on UGTs varied. Mitragynine exhibited the highest inhibitory potency on UGT1A3 with an IC50 value of 72 µM. Moderate inhibition potency of mitragynine were observed for UGT1A6, UGT1A9 and UGT2B15, with IC50 value of 121, 131, and 152 µM, respectively, whereas the inhibition on UGT1A1 and UGT2B7 was low (IC50 > 200 µM). 7-Hydroxymitragynine exhibited the highest inhibitory potency on UGT1A9, with IC50 value of 51 µM, while moderate potency was observed for UGT1A1 and UGT1A3, with IC50 value of 196 and 141 µM, respectively. The inhibitory potency of 7-hydroxymitragynine on UGT2B15 was low (IC50 > 200 µM), while negligible effects were observed for UGT1A6 and UGT2B7. Kinetic inhibition study revealed that mitragynine noncompetitively inhibited UGT1A3 (Ki = 45 µM) and competitively inhibited UGT1A9 (Ki = 114 µM), while 7-hydroxymitragynine competitively inhibited UGT1A3 (Ki = 33 µM) and noncompetitively inhibited UGT1A9 (Ki = 29 µM). The experimental Ki values found here are relatively high compared to the maximum plasma concentrations of mitragynine and 7-hydroxymitragynine reported in humans, suggesting an unlikely potential for herb-drug interactions via UGT inhibition.
Recently in the USA, kratom consumers increasingly report use of the plant for self-treatment of mood ailments, the lack of energy, chronic pain, and opioid withdrawal and dependence. Several alkaloids are present in kratom leaves, but limited data are available on their pharmacokinetics/pharmacodynamics, except for mitragynine. To support clinical studies, a high-performance liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of 11 kratom alkaloids in human plasma was developed and validated. For calibration standards and quality control samples, human plasma was fortified with alkaloids at varying concentrations, and 200 µL were extracted employing a simple one-step protein precipitation procedure. The extracts were analyzed using LC-MS/MS including electrospray ionization (ESI) in positive multiple reaction monitoring (MRM) mode. The lower limit of quantification was 0.5 ng/mL, and the upper limit of quantification was 400 ng/mL for all analytes. Inter-day analytical accuracy and imprecision ranged from 98.4 to 113% of nominal and from 3.9 to 14.7% (coefficient of variance), respectively. The analysis of plasma samples collected during a clinical trial administering capsules containing kratom leaf extract showed that most samples had quantifiable concentrations of mitragynine, 7-OH-mitragynine, speciogynine, speciociliatine, and paynantheine and that mitragynine, speciogynine, and speciociliatine accumulated in human plasma after daily administration over 15 days. An LC-MS/MS assay for the specific quantification of kratom alkaloids including mitragynine and its main metabolites was developed and successfully validated in human plasma. Human plasma samples collected following multiple oral administrations of a controlled Kratom extract documented accumulation of kratom alkaloids over 15 days.
Kratom/ketum is a psychoactive herbal preparation that has been used for a long time as a remedy and performance-enhancing substance in Southeast Asia. The advancement of globalization is making kratom increasingly more available in the western world, where it is becoming increasingly more used.
The current research on kratom and its ingredients is presented.
An overview of the use and effects of kratom is exemplary given on the basis of reports. The instrumentalization of the drug and its consequences up to the development of addiction are discussed.
Consumption is accompanied by several instrumentalizeable effects so that kratom is used as a therapeutic substance in the self-management of pain, anxiety and depression as well as other substance addictions. Another benefit comes from the performance-enhancing effects on physical work and in a social context. Consumption is usually well controlled, rarely escalates and has few and mostly mild aversive side effects. The danger arises from consumption particularly when there is an escalation of the dose and from mixed consumption with other psychoactive substances. The main alkaloid mitragynine and the more potent 7‑hydroxy-mitragynine are considered mainly responsible for the effect. Both have a complex pharmacology that involves partial µ‑opioid receptor agonism.
Epidemiological, clinical and neurochemical studies have shown that kratom only has a limited addictive drug profile, which might suggest a medical use as a remedy or substitute in addiction treatment.
Kratom (Mitragyna speciosa) is used as a stimulant, an opioid-like analgesic, and a sedative. However, Kratom consumption has profound effects, such as seizures, withdrawal, hallucinations, coma, and cardiac or respiratory arrest. We tested Kratom's effects on pentylenetetrazole-induced seizures in adult zebrafish (D rerio) using hydroethanolic Kratom extracts. Kratom extracts have pro-convulsant effects at low concentrations (10-4-10-1 mg/mL), while sedation occurs at higher concentrations. In the open-field test, Kratom has no anxiolytic effects; however, "social" behavior was lost at high concentrations (1.0 mg/mL). Our results confirm the possible proconvulsant role of Kratom while questioning its anxiolytic effects.
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.
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.
Drug addiction is considered a chronic disorder affecting the individual’s life, his/her family and society. Up till now the treatment of drug addiction is considered a problematic issue. Synthetic drugs available for the treatment of drug addiction are few, of limited efficacy and associated with serious side effects. Therefore, there is a continuous search for better therapeutic agents for drug addiction. Natural products represent a promising source for drug addiction treatment. This review summaries drug addiction definition, its mechanism of action, its types, its diagnosis, factors affecting its development and different available approaches for its treatment especially the use of natural products. Six plants were discussed thoroughly in this review, including, Tabernanthe iboga Baill., Mitragyna speciosa Korth., Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep, Hypericum perforatum L., Panax ginseng C.A. Mey., and Withania somnifera (L.) Dunal.
Mitragyna speciosa, known as kratom, is a tropical tree native to Southeast Asia that has long been used to increase energy and in traditional medicine. Kratom leaves contain several indole alkaloids including mitragynine, mitraciliatine, speciogynine, and speciociliatine which have the same molecular formula and connectivity, but different spatial arrangements (i.e. diastereomers). A routine liquid-chromatographic-high-resolution mass-spectrometric (LC-HRMS) multi-analyte method for addictive and herbal drugs in urine did not separate mitragynine from speciogynine and speciociliatine. Separation and individual measurement of the four diastereomers was possible with an improved LC method. All diastereomers were detected in 29 patient urine samples who tested positive for mitragynine with the routine method, albeit at variable absolute amounts and relative proportions. The presence of all diastereomers rather than individual substances indicated that they originated from the intake of kratom (i.e. plant material). Speciociliatine dominated in most samples (66%), while mitragynine and mitraciliatine were the highest in 17% each. A kratom product (powdered plant material) marketed in Sweden contained all diastereomers with mitragynine showing the highest level. In Sweden, there are signs of an increasing use of kratom in society, based on the results from drug testing, the number of poisons center consultations on intoxications, and customs seizure statistics. Because there may be health risks associated with kratom use, including dependence, serious adverse reactions, and death, analytical methods should be able to identify and quantify all diastereomers. In Sweden, this is important from a legal perspective, as only mitragynine is classified while the other three diastereomers, and kratom (plant material), are not.
New psychoactive substances (NPS) are life‐threatening through unpredictable toxicity and limited analytical options for clinicians. We present the retrospective identification of NPS in raw data from a liquid chromatography‐high resolution mass spectrometry (LC‐HRMS) based multidrug panel analysis on 14,367 clinical oral fluid samples requested during 2019 mainly by psychiatric and addiction care clinics. Retrospectively analysed NPS included 48 notified originally in 2019 by the European Union Early Warning System (EU‐EWS) and 28 frequently reported in Sweden. Of 88 included NPS, 34 (mitragynine, flualprazolam, 3F/4F‐α‐P(i)HP, etizolam, 4F‐MDMB‐BINACA, cyproheptadine, 5F‐MDMB‐PICA, isotonitazene, isohexedrone, MDPEP, N‐ethylpentedrone, tianeptine, flubromazolam, 4′‐methylhexedrone, α‐P(i)HP, eutylone, mephedrone, N‐ethylhexedrone, 5F‐MDMB‐PINACA, ADB‐BUTINACA, 3‐methoxy PCP, 4F‐furanylfentanyl, 4F‐isobuturylfentanyl, acrylfentanyl, furanylfentanyl, clonazolam, norfludiazepam, 3F‐phenmetrazine, 3‐MMC, 4‐methylpentedrone, BMDP, ethylphenidate, methylone, α‐PVP) were identified as 219 findings in 84 patients. Eight NPS notified in 2019 were identified, five before EWS release. NPS occurred in 1.20% of all samples and 1.53% of samples containing traditional drugs, and in 1.87% of all patients and 2.88% of patients using traditional drugs. NPS use was more common in men and polydrug users. Legal (not scheduled) NPS were more used than comparable illegal ones. Retrospective identification could be useful when prioritizing NPS for clinical routine analysis and when studying NPS epidemiology.
Background: Kratom or Mitragyna speciosa (Korth.) has received overwhelming attention recently due to its alleged pain-relieving effects. Despite its potential therapeutic value, kratom use has been linked to many occurrences of multiorgan toxicity and cardiotoxicity. Accordingly, the current narrative review aimed to provide a detailed account of kratom’s adverse cardiovascular effects and cardiotoxicity risk, based on in vitro studies, poison center reports, coroner and autopsy reports, clinical case reports, and clinical studies.
Methods: An electronic search was conducted to identify all research articles published in English from 1950 to 2021 using the major research databases, such as Google Scholar, Web of Science, PubMed, Scopus, Mendeley, EMBASE, Cochrane Library, and Medline. We then analyzed the literature’s discussion of adverse cardiovascular effects, toxicity, and mortality related to kratom use.
Results: Our findings revealed that, although in vitro studies have found kratom preparations’ most abundant alkaloid—mitragynine—to cause a prolonged QTc interval and an increased risk of torsades de pointes, a clinical study examining humans’ regular consumption of kratom did not report such a risk. However, this latter study did show that regular kratom use could induce an increased QTc interval in a dose-dependent manner. A few case reports also highlighted that kratom consumption is associated with ventricular arrhythmia and cardiopulmonary arrest, but this association could have ensued when kratom was co-administered with another substance. Similarly, analyses of national poison data showed that kratom’s most common adverse acute cardiovascular effects include tachycardia and hypertension. Meanwhile, coroner and autopsy reports indicated that kratom’s cardiovascular sequelae encompass coronary atherosclerosis, myocardial infarction, hypertensive cardiovascular disease, left ventricular hypertrophy, cardiac arrhythmia, cardiomegaly, cardiomyopathy, focal band necrosis in the myocardium, and myocarditis. Given the available data, we deduced that all cardiac eventualities reported in the literature could have been compounded by polysubstance use and unresolved underlying medical illnesses.
Conclusion: Although kratom use has been associated with death and cardiotoxicity, especially at higher doses and when associated with other psychoactive drugs, the dearth of data and methodological limitations reported in existing studies do not allow a definitive conclusion, and further studies are still necessary to address this issue.
Consumption of herbal supplements has been linked to multiorgan toxicities. Kratom is an herbal extract that has gained popularity for its analgesic and psychotropic properties. Several cases of kratom-induced liver injury have been reported, but data on multiorgan involvement remain scarce. We present the case of a 37-year-old woman who developed a mixed hepatocellular and cholestatic pattern of acute liver injury, acute kidney injury, and pancolitis after prolonged use of kratom-containing herbal supplements.
Multiorgan toxicities have been extensively reported in kratom (Mitragyna speciosa Korth) users in Western countries but not in Southeast Asia. Existing literature argued that this discrepancy may be due to underreporting of kratom-related toxicity cases in Southeast Asia. Hence, this case series filled the research gap by clinically assessing the cardiovascular functioning and serum mitragynine level of regular kratom users in its traditional settings in Malaysia. Nine regular kratom users without history of polysubstance use were recruited from the same community via snowball sampling and were subjected to electrocardiogram (ECG) and echocardiogram assessments. Serum mitragynine analysis was also performed by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The mean serum mitragynine level was 10.3 mg/L (SD = 6.9) and ranged from 2.5 mg/L to 22.4 mg/L. Those who consumed an average daily quantity of four or more glasses of brewed kratom juice (p = 0.045) and those who had prolonged QTc intervals (p = 0.017) had significantly higher serum mitragynine level. Echocardiographic findings of all the respondents were normal except one reported left ventricular hypertrophy and another had trivial tricuspid regurgitation with pulmonary artery systolic pressure (PASP) of 10 + 5 mmHg. Regular kratom use without concomitant use of other illicit substances may not provoke any risk of cardiovascular impairment or toxicity except for prolonged QTc interval, which appeared to be dose dependent. However, as this study was limited by a small sample size, future studies with larger sample size are warranted to confirm our findings.
Background: Kratom (Mitragyna speciosa Korth), a popular opioid-like plant holds its therapeutic potential in pain management and opioid dependence. However, there are growing concerns about the safety or potential toxicity risk of kratom after prolonged use.
Aim of the study: The study aimed to assess the possible toxic effects of kratom decoction and its major alkaloids, mitragynine, and speciociliatine in comparison to morphine in an embryonic zebrafish model.
Methods: The zebrafish embryos were exposed to kratom decoction (1,000–62.5 μg/ml), mitragynine, speciociliatine, and morphine (100–3.125 μg/ml) for 96 h post-fertilization (hpf). The toxicity parameters, namely mortality, hatching rate, heart rate, and morphological malformations were examined at 24, 48, 72, and 96 hpf, respectively.
Results: Kratom decoction at a concentration range of ≥500 μg/ml caused 100% mortality of zebrafish embryos and decreased the hatching rate in a concentration-dependent manner. Meanwhile, mitragynine and speciociliatine exposure resulted in 100% mortality of zebrafish embryos at 100 μg/ml. Both alkaloids caused significant alterations in the morphological development of zebrafish embryos including hatching inhibition and spinal curvature (scoliosis) at the highest concentration. While exposure to morphine induced significant morphological malformations such as pericardial oedema, spinal curvature (lordosis), and yolk edema in zebrafish embryos.
Conclusion: Our findings provide evidence for embryonic developmental toxicity of kratom decoction and its alkaloids both mitragynine and speciociliatine at the highest concentration, hence suggesting that kratom consumption may have potential teratogenicity risk during pregnancy and thereby warrants further investigations.
Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea “kratom” and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.
Leaves harvested from the Southeast Asian tree Mitragyna speciosa (kratom) have a history of use as a traditional ethnobotanical source of medicine to combat fatigue, improve work productivity, and to reduce opioid-related withdrawal symptoms. Kratom leaves contain an array of alkaloids thought to be responsible for the bioactivity reported by users. Interest in the consumptive effects of kratom has led to its recent popularity and use in North America, Western Europe, and Australia. Although the chemistry and pharmacology of select kratom alkaloids are understood, studies have not examined the influence of production environment on growth and alkaloidal content. To directly address this need, 68 kratom trees were vegetatively propagated from a single mother stock to reduce genetic variability and subjected to four varying fertilizer application rates. Leaves were analyzed for chlorophyll concentration, biomass, and alkaloidal content to understand the physiological response of the plant. While increasing rates of fertilizer promoted greater plant growth, relationships with alkaloidal content within leaves were highly variable. Fertility rate had little influence on the concentration of mitragynine, paynantheine, speciociliatine, mitraphylline, and corynoxine per leaf dry mass. 7-Hydroxymitragynine was below the lower limit of quantification in all the analyzed leaf samples. Low to medium rates of fertilizer, however, maximized concentrations of speciogynine, corynantheidine, and isocorynantheidine per leaf dry mass, suggesting a promotion of nitrogen allocation for secondary metabolism occurred for these select alkaloids. Strong correlations (r² = 0.86) between extracted leaf chlorophyll and rapid, non-destructive chlorophyll evaluation (SPAD) response allowed for development of a reliable linear model that can be used to diagnose nutrient deficiencies and allow for timely adjustment of fertilization programs to more accurately manage kratom cultivation efforts. Results from this study provide a greater understanding of the concentration and synthesis of nine bioactive alkaloids in fresh kratom leaves and provide foundational information for kratom cultivation and production.
BACKGROUND: Kratom is a psychoactive substance that is isolated from the plant Mitragyna speciosa. The leaves can be chewed fresh or dried, smoked, or infused similar to herbal teas. The plant leaves have been used by natives of Southeast Asia for centuries. The substance has been used for its stimulant activity at low doses, and as an opium substitute at higher doses due to a morphine like effect.
CASE SUMMARY: A 37-year-old female with a history of depression and obesity (body mass index: 32) presented to emergency room with a week-long history of nausea, decreased appetite, fatigue, and two days of jaundice. On admission bilirubin was markedly elevated. Her condition was thought to be due to consumption of Kratom 2 wk before onset of symptoms. Liver biopsy showed changes mimicking primary biliary cholangitis. Patient’s symptoms and jaundice improved quickly.
CONCLUSION: The use of Kratom has been on the rise in recent years across the United States and Europe. Several case reports have associated adverse health impact of Kratom-containing products including death due to its ability to alter levels of consciousness. Only a few case reports have highlighted the hepatotoxic effects of Kratom. Even fewer reports exist describing the detailed histopathological changes.
Commercially available Kratom (Mitragyna speciosa) is a dietary supplement that has gained popularity in the United States for its psychoactive effects and potential medicative properties as an opioid receptor agonist. Likewise, sudden discontinuation may be accompanied by an opioid-like withdrawal. We present the first case in the literature of the withdrawal manifesting in disturbing obsessive thoughts after the substance was used as an opioid replacement treatment by our patient, as well as the first case where lorazepam is utilized for mitigation of these thoughts.
Kratom (Mitragyna speciosa, Korth) is a tree-like plant 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. Recently, the United States Food and Drug Administration and Centers for Disease Control have raised concerns regarding the contamination of some kratom products with toxic metals (Pb and Ni) and microbes such as Salmonella. To further explore this issue, eight different kratom products were legally purchased from various “head”/”smoke” shops in the Western Suburbs of Chicago and then tested for microbial burden, a panel of metals (Ni, Pb, Cr, As, Hg, Cd), and levels of the main psychoactive alkaloid mitragynine. All of the samples contained significant, but variable, levels of mitragynine (3.9–62.1 mg/g), indicating that the products were, in fact, derived from kratom. All but two of the samples tested positive for the presence of various microbes including bacteria and fungi. However, none of the samples tested positive for Salmonella. Seven products showed significant levels of Ni (0.73–7.4 µg/g), Pb (0.16–1.6 µg/g) and Cr (0.21–5.7 µg/g) while the other product was negative for metals. These data indicate that many kratom products contain variable levels of mitragynine and can contain significant levels of toxic metals and microbes. These findings highlight the need for more stringent standards for the production and sale of kratom products.
Background
Kratom is a Southeast Asian plant, which is widely used in this region, and making an increasing appearance in Europe and the US.
Case report
We present the case of a 26-year-old man in Substitol-assisted treatment of excessive Kratom and Tilidin use expressing the wish for a drug-free management of a chronic pain condition. After an accidental calcaneus impression fracture, the patient was suffering from severe chronic pain and anxiety of further accidents. This was managed initially with Tilidin. Resulting from the wish to self-manage the pain condition in a way that permitted continuation of a job, the patient searched for a ‘natural’ treatment alternative obtained from an Internet vendor. He successfully instrumentalized Kratom for 3 years with daily consumption intermixed with occasional Tilidin for pain management. However, the dose of Kratom was increased considerably up to a level of effect reversal, when no analgesic and behaviorally activating effects occurred any more, but only intense drowsiness. The patient was treatment seeking and subsequently detoxified from Kratom and Tilidin. Pain management was shifted to retarded morphine.
Conclusion
Kratom instrumentalization for pain management might appear to be more problematic for addiction development than when its use is established for other consumption motives.
Mitragyna speciosa, otherwise known as kratom, is a plant in the coffee family (Rubiaceae) native to Southeast Asia and Thailand whose leaves have been shown to cause opioid-like and stimulant responses upon ingestion. The major pharmacologically active compounds present in kratom, mitragynine and 7-hydroxymitragynine (7-HMG), are both indole alkaloids and are responsible for its opioid-like activity. While kratom is most commonly known for its affinity for mu-opioid receptors, research has shown one of its active components has effects on the same receptors to which some antipsychotics bind, such as D2 dopamine, serotonin (5-HT2C and 5-HT7), and alpha-2 adrenergic receptors displaying possible indications of kratom to be used as both antipsychotics and antidepressants. Although studies to evaluate this effect are still lacking, several online and in-person surveys note relief of depression and anxiety symptoms among those who consume kratom products, and in fact identify it as a common reason for consumption. This then highlights the dire need for further research to be conducted on kratom, its mechanism of action and the constituents that elicit these antidepressant, anxiolytic, and antipsychotic properties.
Background: Kratom has a long history of traditional medicine use in Southeast Asia. Consumption of kratom products has also been reported in the US and other regions of the world. Pain relief is among many self-reported kratom effects but have not been evaluated in controlled human subject research. Methods: Kratom effects on pain tolerance were assessed in a randomized, placebo-controlled, double-blind study. During a 1-day inpatient stay, participants received a randomized sequence of kratom and placebo decoctions matched for taste and appearance. Pain tolerance was measured objectively in a cold pressor task (CPT) as time (seconds) between the pain onset and the hand withdrawal from the ice bath. Health status, vital signs, objective, and subjective indicators of withdrawal symptoms, self-reported data on lifetime kratom use patterns, and assessments of blinding procedures were also evaluated. Results: Twenty-six males with the mean (SD) age 24.3 (3.4) years were enrolled. They reported the mean (SD) 6.1 (3.2) years of daily kratom consumption. Pain tolerance increased significantly 1 hour after kratom ingestion from the mean (SD) 11.2 (6.7) seconds immediately before to 24.9 (39.4) seconds 1 hour after kratom consumption (F(2,53.7)=4.33, p=0.02). Pain tolerance was unchanged after consuming placebo drinks: 15.0 (19.0) seconds immediately before and 12.0 (8.1) seconds 1 hour after consumption of placebo (F(2,52.8)=0.93, p=0.40). No discomfort or signs of withdrawal were reported or observed during 10-20 hours of kratom discontinuation. Conclusions: Kratom decoction demonstrated a substantial and statistically significant increase in pain tolerance. Further rigorous research on kratom pain-relieving properties and a safety profile is needed.
Background
Opiate addiction is a major health problem in many countries. A crucial component of the medical treatment is the management of highly aversive opiate withdrawal signs, which may otherwise lead to resumption of drug taking. In a medication-assisted treatment (MAT), methadone and buprenorphine have been implemented as substitution drugs. Despite MAT effectiveness, there are still limitations and side effects of using methadone and buprenorphine. Thus, other alternative therapies with less side effects, overdosing, and co-morbidities are desired. One of the potential pharmacotherapies may involve kratom's major indole alkaloid, mitragynine, since kratom (Mitragyna speciosa Korth.) preparations have been reported to alleviate opiate withdrawal signs in self-treatment in Malaysian opiate addicts.
Methods
Based on the morphine withdrawal model, rats were morphine treated with increasing doses from 10 to 50 mg/kg twice daily over a period of 6 days. The treatment was discontinued on day 7 in order to induce a spontaneous morphine abstinence. The withdrawal signs were measured daily after 24 h of the last morphine administration over a period of 28 abstinence days. In rats that developed withdrawal signs, a drug replacement treatment was given using mitragynine, methadone, or buprenorphine and the global withdrawal score was evaluated.
Results
The morphine withdrawal model induced profound withdrawal signs for 16 days. Mitragynine (5–30 mg/kg; i.p.) was able to attenuate acute withdrawal signs in morphine dependent rats. On the other hand, smaller doses of methadone (0.5–2 mg/kg; i.p.) and buprenorphine (0.4–1.6 mg/kg; i.p.) were necessary to mitigate these effects.
Conclusions
These data suggest that mitragynine may be a potential drug candidate for opiate withdrawal treatment.
Kratom, or Mitragyna, is a tropical plant indigenous to Southeast Asia, with unique pharmacological properties. It is commonly consumed by preparing the leaves into decoction or tea, or by grinding them into a powder. Recent evidence has revealed that kratom has physiological effects similar to opioids, including pain relief and euphoria, as well as stimulant properties, which together raise potential concern for dependence and addiction. Moreover, growing evidence suggests that the prevalence of kratom use is increasing in many parts of the world, raising important considerations for healthcare providers. This manuscript will discuss the most current epidemiology, pharmacology, toxicity, and management related to kratom, while seeking to provide a contemporary perspective on the issue and its role in the greater context of the opioid epidemic.
Kratom or Mitragna speciosa is a tropical tree that is indigenous to Southeast Asia, where it has been used for various medicinal reasons. In the West, it is used in the self-treatment of opioid withdrawal, pain, and a variety of mood and anxiety states. Two active ingredients in kratom are mitragynine and 7-hydroxymitragynine, which have affinity at the mu-opioid receptor among others. Kratom is easily available over the Internet and its use is increasing in the United States. It is currently listed by the Drug Enforcement Administration as a drug of concern. In 2017, the U.S. Food and Drug Administration started issuing a series of warnings about kratom, and by early 2018, it released a statement identifying 44 deaths related to kratom use. The Centers for Disease Control and Prevention has also reported 91 deaths directly linked to kratom use in 2019. Although its safety profile needs additional research for clarification, there have been reports of kratom-induced or kratom-related respiratory depression, hypothyroidism, secondary hypogonadism, hyperprolactinemia, psychosis, and seizures. We report a case of kratom-induced tonic-clonic seizures in a 27-year-old Caucasian male with a psychiatric history of anxiety, attention-deficit/hyperactivity disorder, benzodiazepine use disorder, and opioid use disorder. He was hospitalized after a witnessed tonic-clonic seizure. There was no significant metabolic abnormality on laboratory testing. Spinal cord and brain imaging were unremarkable, whereas his urine toxicology was positive for opioids only, which was likely a false-positive result due to cross-reactivity with his sleeping aids. He was evaluated by the Consultation-Liaison Psychiatry team for psychotic symptoms. On evaluation, the patient's psychosis had resolved, but he endorsed racing thoughts, significant anxiety, and insomnia. He admitted to drinking three to four 8-mL bottles of Kratom daily for one-and-a-half years to self-medicate his anxiety after losing his health insurance. In the hospital, he was treated with anxiolytics, counseled to abstain from Kratom use, and was referred for substance use disorder treatment. This case highlights the life-threatening complications of Kratom that is easily available online.
Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.
Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding and metabolic stability. Mitragynine the major alkaloid in Mitragyna speciosa (kratom) had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.
Background and Purpose
Mitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids but is unregulated in most countries. Kratom is used in the self‐medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over β‐arrestin proteins. We hypothesized that kratom (alkaloids) can also reduce alcohol intake.
Experimental Approach
We pharmacologically characterized kratom extracts, kratom alkaloids (mitragynine, 7‐hydroxymitragynine, paynantheine, and speciogynine) and synthetic carfentanil‐amide opioids for their ability to interact with G proteins and β‐arrestin at μ, δ, and κ opioid receptors in vitro. We used C57BL/6 mice to assess to which degree these opioids could reduce alcohol intake and whether they had rewarding properties.
Key Results
Kratom alkaloids were strongly G protein‐biased at all three opioid receptors and reduced alcohol intake, but kratom and 7‐hydroxymitragynine were rewarding. Several results indicated a key role for δ opioid receptors, including that the synthetic carfentanil‐amide opioid MP102—a G protein‐biased agonist with modest selectivity for δ opioid receptors—reduced alcohol intake, whereas the G protein‐biased μ opioid agonist TRV130 did not.
Conclusion and Implications
Our results suggest that kratom extracts can decrease alcohol intake but still carry significant risk upon prolonged use. Development of more δ opioid‐selective synthetic opioids may provide a safer option than kratom to treat alcohol use disorder with fewer side effects.
Mitragyna speciosa, commonly known as the kratom tree, has been utilized in Southeast Asia for centuries for its opioid-like effects. Kratom has been available in the United States for the past decade and has grown increasingly popular despite a lack of clinical research to determine its safety. With its widespread use, there have been an increasing number of fatalities. This study aims to establish a potential lethal range for mitragynine, the active compound in kratom, by investigating the toxicology reports of 35 deaths in Northern Nevada between 2015 and 2020. Mitragynine concentrations ranged from 8.7 to 1800 ng/mL (n = 27) in cases with drug toxicity as the cause of death; in 1 case, the sole intoxicant was mitragynine with a blood concentration of 950 ng/mL. In cases with nonmitragynine causes of death, the concentration was 110 to 980 ng/mL (n = 8). There was no statistically significant difference in blood concentrations between cases where mitragynine was not listed as a cause of death (mean, 315 ± 297.2 ng/mL) and cases in which mitragynine contributed to death (mean, 269.4 ± 382.5 ng/mL; P < 0.201). A literature review is also presented.
We report a case series of young adults who were admitted to hospital with seizures after regular kratom beverage consumption. This study aimed to determine kratom consumption habits and seizure characteristics and to explore whether chronic kratom ingestion without concomitant drug abuse leads to recurrent seizure or epilepsy. All patients underwent blood investigations, a brain computed tomography (CT) scan, electroencephalography, and urine testing for mitragynine and drug toxicology. Eleven participants who had a positive urine mitragynine test were included in the study. The longest duration of kratom consumption was 84 months: – most drank more than eight times per month (>200 mL/drink). Seizure developed within 10 minutes or up to 72 hours post-ingestion. Seizure occurred one to three times per year in most cases. Four patients had a focal to bilateral tonic-clonic seizure whereas the remaining participants had a generalized tonic-clonic seizure. Four patients mixed kratom with diphenhydramine syrup, and one patient took methamphetamine. Two patients had positive urine results for recreational drugs (opioid and amphetamine).
This study provided indirect evidence that chronic kratom use with or without concomitant drug abuse can cause recurrent seizures in susceptible individuals, which may progress to epilepsy or require antiepileptic medication.
Kratom is a botanical substance derived from the leaves of Mitragyna speciosa. Although kratom has been used traditionally in Southeast Asia for over a century, recreational use and non‐medically supervised use of the drug in the West has escalated considerably over the past decade. Viewed as a legal, “safe” or “natural” alternative to opioids, kratom has gained widespread use for the non‐medically supervised treatment of chronic pain, anxiety, and opioid withdrawal. Kratom consists of a complex mixture of more than 50 alkaloids, of which mitragynine and 7‐hydroxymitragynine are the principal compounds of interest due to their abundance and heightened affinity for the mu opioid receptor, respectively. Mitragynine, which is structurally and pharmacologically distinct from traditional opioids, exhibits a multimodal mechanism of action which accounts for its complex adrenergic, serotonergic, and opioid‐like effects. Adverse effects including fatalities have been associated with kratom's use, often in combination with other drugs. While users report numerous benefits associated with its use, lack of regulatory control and escalating use among individuals with opioid use disorder has attracted widespread concern. In this review the origins, pharmacology, uses, effects, and analysis of the drug are reviewed from a toxicological standpoint.
This article is categorized under:
• Toxicology > New Psychoactive Substances
• Toxicology > Opioids
• Toxicology > Plants and Poisons
Abstract
Kratom: A systematic review of toxicological issues.
The development of a method for the rapid screening of food and drug products for constituents such as mitragynine, the most abundant alkaloid found in Mitragyna speciosa (kratom) plant leaves, has become increasingly important. The use of kratom is said to produce stimulant or narcotic effects and poses risks of addiction, abuse, and dependence, much like other opioids. Direct Analysis in Real Time with thermal desorption mass spectrometry (DART-TD-MS), hand-held mass spectrometry, portable ion mobility spectrometry (IMS), and portable Fourier-transform infrared spectroscopy (FT-IR) were each evaluated as field-deployable screening techniques for the detection of mitragynine in food and drug products. These devices offer the potential for rapid, early detection of mitragynine in suspect products entering the United States through international mail facilities and other ports of entry. Ninety-six kratom products, including capsules, bulk powder, and bulk plant material, were analyzed by either direct sampling of the solid material or by solvent extraction. True and false positive and negative results are reported, based on comparison to results from qualitative screening using gas chromatography with mass spectral detection (GC-MS), liquid chromatography with mass spectral detection (LC-MS), and/or quantitative screening using high-performance liquid chromatography with ultraviolet detection (HPLC-UV), with a discussion of the assessment of each technique for use in the field. Each device demonstrated attributes that would be favorable for use in screening of suspected mitragynine-containing products at places like ports of entry, and simultaneous deployment of two or more of these devices as part of a workflow would be the most effective for rapid screening of these products. This combination of rapid screening orthogonal techniques suited to a non-laboratory environment will allow onsite destruction of products found to contain mitragynine.
Introduction. Kratom is a plant with partial opioid agonist effects, and its use has become popular to ameliorate symptoms of opioid withdrawal. Use, however, 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 US population.
Methods. Data were examined from the 2019 National Survey on Drug Use and Health, a nationally representative probability sample of noninstitutionalized individuals age >12 in the US (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 US 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: 2.60-7.19) 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.
Kratom is an unregulated kappa-opioid receptor agonist available for order on the internet that is used as a remedy for chronic pain. We present a case of a middle-aged man who suffered a cardiac arrest in the setting of kratom ingestion.
Illicit drugs are used to produce a sense of euphoria in the user. Like marijuana, kratom is a plant-based substance. The leaves of the Mitragyna speciosa tree were used to treat mild medical conditions in Thailand and Malaysia as a stimulant in low doses, and sedative and analgesic at high doses. Over recent years, kratom gained popularity as a recreational drug among younger individuals in Southeast Asia due to its availability as a cheap and easily assessable substance with euphoric effects. This trend has rapidly made its way to the West. Unlike marijuana, in the United States kratom’s use as an inexpensive herbal recreational “supplement” is poorly popularized. However, emerging reports garnished from use as a recreational drug reveals a potential health hazard. Seizures and neurological consequences have been reported from kratom abuse. Complex pharmacokinetics place patients at further risk of side effects and drug interactions. Still, individuals can legally purchase kratom at stores and through online distributers in capsule form or as teas, powders, and extracts under the veil of a harmless herbal remedy. Without United States Food and Drug Administration oversight, kratom has a high potential for abuse and without regulatory control threatens public safety.
Kratom is a legal, widely available substance that contains opioid agonist alkaloids. Due to the marketing of kratom as an opioid alternative for treatment of pain, anxiety, depression, or to reduce opioid withdrawal symptoms, the use of kratom has increased among persons in the USA including pregnant women. This systematic review of the peer-reviewed literature regarding kratom in relation to maternal and infant outcomes resulted in analysis of six case reports of prenatal kratom exposure. Maternal and infant withdrawal from kratom exposure was described in each case, resulting in pharmacologic treatment for both mothers and infants.
Introduction: This is the 37th Annual Report of the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS). As of 1 January, 2019, all 55 of the nation’s poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 6.52 [6.12, 8.68] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.
Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.
Results: In 2019, 2,573,180 closed encounters were logged by NPDS: 2,148,141 human exposures, 68,711 animal exposures, 351,163 information requests, 5,078 human confirmed nonexposures. Total encounters showed a 1.70% increase from 2018, while health care facility (HCF) human exposure cases remained nearly steady with a slight decrease of 0.495%. All information requests decreased by 4.58%, medication identification (Drug ID) requests decreased by 29.7%, and human exposure cases increased by 2.30%. Human exposures with less serious outcomes have decreased 2.08% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.61% per year since 2000.
Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (11.0%), household cleaning substances (7.13%), cosmetics/personal care products (6.16%), antidepressants (5.32%), and sedatives/hypnotics/antipsychotics (5.21%). As a class, antidepressant exposures increased most rapidly, by 1,957 cases/year (3.90%/year) over the past 10 years for cases with more serious outcomes.
The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (11.4%), household cleaning substances (10.5%), analgesics (8.97%), foreign bodies/toys/miscellaneous (7.17%), and dietary supplements/herbals/homeopathic (5.06%). Drug identification requests comprised 13.4% of all information contacts. NPDS documented 2,619 human exposures resulting in death; 2,048 (78.2%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).
Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information contacts. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.
Mitragynine is a major psychoactive alkaloid in leaves of kratom (Mitragyna speciosa Korth.). To understand its disposition in organs, this study aimed to develop a physiologically based pharmacokinetic (PBPK) model that predicts mitragynine concentrations in plasma and organ of interests in rats and humans. The PBPK model consisted of six organ compartments (i.e. lung, brain, liver, fat, slowly perfused tissues, and rapidly perfused tissue). From systematic searching, three pharmacokinetic studies of mitragynine (two studies in rats and 1 study in humans) were retrieved from the literature. Berkeley Madonna Software (version 8.3.18) was used for model development and model simulation. The developed PBPK model consisted of biologically relevant features following involvement of (i) breast cancer-resistant protein (BCRP) in brain, (ii) a hepatic cytochrome P450 3A4 (CYP3A4)-mediated metabolism in the liver, and (iii) a diffusion-limited transport in fat. The simulations adequately describe simulated and observed data in the two species with different dosing regimens. PBPK models of mitragynine in rats and humans were successfully developed. The models may be used to guide optimal mitragynine dosing regimens.
Kratom (Mitragyna speciosa) is a plant extract that exhibits opioid agonistic activity at the μ-opioid receptor. The use of this substance has increased recently due to widespread local availability across the United States (US), primarily at gas stations. Repeated kratom use has been shown to have major adverse effects leading to physiological dependence and addiction similar to other opioids. We used a novel contingency management (CM) program utilizing nonmonetary reinforcers along with medication-assisted treatment (MAT) using buprenorphine in an office-based setting to treat kratom use disorder in two cases. MAT with buprenorphine in a CM-based setting was found to be an effective strategy for treating kratom use disorder.
Background
: Kratom is a botanical product used as an opium substitute with abuse potential.
Methods
: Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort.
Results
: Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients.
Conclusion
: Kratom can cause severe liver injury with jaundice.
Preparations from the leaves of the kratom plant (Mitragyna speciosa) are consumed for their opioid-like effects. Several deaths have been associated with kratom used concomitantly with some drugs. Pharmacokinetic interactions are potential underlying mechanisms of these fatalities. Accumulating in vitro evidence has demonstrated select kratom alkaloids, including the abundant indole alkaloid mitragynine, as reversible inhibitors of several cytochromes P450 (CYPs). The objective of this work was to refine the mechanistic understanding of potential kratom-drug interactions by considering both reversible and time-dependent inhibition (TDI) of CYPs in the liver and intestine. Mitragynine was tested against CYP2C9 (diclofenac 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), and CYP3A (midazolam 1'-hydroxylation) activities in human liver microsomes (HLMs) and CYP3A activity in human intestinal microsomes (HIMs). Comparing the absence to presence of NADPH during preincubation of mitragynine with HLMs or HIMs, an ∼7-fold leftward shift in IC50 (∼20 to 3 μM) toward CYP3A resulted, prompting determination of TDI parameters (HLMs: K
I
, 4.1 ± 0.9 μM; k
inact
, 0.068 ± 0.01 min-1; HIMs: K
I
, 4.2 ± 2.5 μM; k
inact
, 0.079 ± 0.02 min-1). Mitragynine caused no leftward shift in IC50 toward CYP2C9 (∼40 μM) and CYP2D6 (∼1 μM) but was a strong competitive inhibitor of CYP2D6 (K
i
, 1.17 ± 0.07 μM). Using a recommended mechanistic static model, mitragynine (2-g kratom dose) was predicted to increase dextromethorphan and midazolam area under the plasma concentration-time curve by 1.06- and 5.69-fold, respectively. The predicted midazolam area under the plasma concentration-time curve ratio exceeded the recommended cutoff (1.25), which would have been missed if TDI was not considered. SIGNIFICANCE STATEMENT: Kratom, a botanical natural product increasingly consumed for its opioid-like effects, may precipitate potentially serious pharmacokinetic interactions with drugs. The abundant kratom indole alkaloid mitragynine was shown to be a time-dependent inhibitor of hepatic and intestinal cytochrome P450 3A activity. A mechanistic static model predicted mitragynine to increase systemic exposure to the probe drug substrate midazolam by 5.7-fold, necessitating further evaluation via dynamic models and clinical assessment to advance the understanding of consumer safety associated with kratom use.
Background
Made as a tea, the Thai traditional drug “kratom” reportedly possesses pharmacological actions that include both a coca-like stimulant effect and opium-like depressant effect. Kratom has been used as a substitute for opium in physically-dependent subjects. The objective of this study was to evaluate the antinociception, somatic and physical dependence produced by kratom tea, and then assess if the tea ameliorated withdrawal in opioid physically-dependent subjects.
Methods
Lyophilized kratom tea (LKT) was evaluated in C57BL/6 J and opioid receptor knockout mice after oral administration. Antinociceptive activity was measured in the 55 °C warm-water tail-withdrawal assay. Potential locomotor impairment, respiratory depression and locomotor hyperlocomotion, and place preference induced by oral LKT were assessed in the rotarod, Comprehensive Lab Animal Monitoring System, and conditioned place preference assays, respectively. Naloxone-precipitated withdrawal was used to determine potential physical dependence in mice repeatedly treated with saline or escalating doses of morphine or LKT, and LKT amelioration of morphine withdrawal. Data were analyzed using one- and two-way ANOVA.
Results
Oral administration of LKT resulted in dose-dependent antinociception (≥1 g/kg, p.o.) absent in mice lacking the mu-opioid receptor (MOR) and reduced in mice lacking the kappa-opioid receptor. These doses of LKT did not alter coordinated locomotion or induce conditioned place preference, and only briefly reduced respiration. Repeated administration of LKT did not produce physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice.
Conclusions
The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.
Objectives:
Little is known about the cardiotoxic effects of kratom (Mitragyna speciosa Korth.), a medicinal plant. This analytical cross-sectional study investigated the prevalence of electrocardiogram (ECG) abnormalities and QTc intervals in regular kratom users compared with non-kratom-using control subjects.
Methods:
We enrolled regular kratom users and non-kratom-using control subjects from three communities. Demographic data, clinical data, kratom use characteristics, and ECG findings were recorded. The mitragynine content of kratom juice was quantified using a validated gas chromatography-mass spectrometry (GC-MS) method.
Results:
A total of 200 participants (100 kratom users and 100 control subjects) participated in this study. The prevalence of ECG abnormalities in kratom users (28%) did not differ from that of control subjects (32%). Kratom use was not associated with ECG abnormalities, except for significantly higher odds of sinus tachycardia (OR = 8.61, 95% CI = 1.06-70.17, p = 0.035) among kratom users compared with control subjects. The odds of observing borderline QTc intervals were significantly higher for kratom users compared with control subjects, regardless of the age of first use, the duration of use, the daily quantity consumed, and the length of time that had elapsed between last kratom use and ECG assessment. Nevertheless, there were no differences in the odds of having prolonged QTc intervals between kratom users and controls. The estimated average daily intake of mitragynine consumed by kratom users was 434.28 mg.
Conclusion:
We found no link between regular kratom use and electrocardiographic abnormalities with an estimated average daily intake of 434.28 mg of mitragynine.
Introduction:
Some opioid use disorder (OUD) patients attempt to self-treat using herbal remedies such as kratom. However, kratom use itself can paradoxically cause physical dependence and OUD. Currently, there are no guidelines for treating patients with OUD stemming from kratom use. Our empirically-based hypothesis was that there would be a correlation between the amount of kratom used and the amount of buprenorphine-naloxone required for opioid agonist therapy.
Methods:
This study includes a systematic review assessing treatment of kratom-dependent patients with buprenorphine-naloxone; a case series of our kratom-dependent patients; calculation of the correlation between the kratom dose and the buprenorphine-naloxone dose required to treat kratom-associated OUD; and our proposed starting doses for using buprenorphine-naloxone to treat kratom OUD.
Results:
The OVID MEDLINE (1946-2020) database was searched using the terms "kratom," "buprenorphine," and "case report." This search yielded 3 relevant cases of patients having kratom OUD who were treated with buprenorphine-naloxone with the amounts of all substances reported. Review of the bibliographies, citing articles, and Google Scholar turned up three additional cases, yielding 6 literature cases that were analyzed. We also analyzed 2 patients from our clinic, giving a total of 8 patients included in the Pearson correlation coefficient calculation. We found a strong correlation of 0.84 between these variables, consistent with our hypothesis.
Conclusions:
Based on our analysis, patients using <20 g of kratom/d could be initiated on opioid agonist therapy with 4/1 mg-8/2 mg buprenorphine-naloxone/d, while patients using kratom doses >40 g/d could be initiated with 12/3 mg-16/4 mg of buprenorphine-naloxone/day.
Kratom is widely consumed in the United States for self-treatment of pain and opioid withdrawal symptoms. Mitragynine is the most abundant alkaloid in kratom and is a mu-opioid receptor agonist. 7-Hydroxymitragynine (7-HMG), is a mitragynine metabolite that is a more potent and efficacious opioid than parent mitragynine. 7-HMG contributes to mitragynine’s antinociceptive effects in mice, but evidence suggests it may also have a higher abuse potential. This in vitro study demonstrates that 7-HMG is stable in rodent and monkey plasma but is unstable in human plasma. Surprisingly, in human plasma 7-HMG is converted to mitragynine pseudoindoxyl, an opioid that is even more potent than either mitragynine or 7-HMG. This novel metabolite is formed in human plasma to a much greater extent than in the preclinical species tested (mouse, rat, dog, and cynomolgus monkey) and, due to its mu-opioid potency, may substantially contribute to the pharmacology of kratom in humans to a greater extent than in other tested species.
Kratom, or Mitragyna speciosa Korth., is a tropical plant prevalent in Southeast Asia, and it is utilized as a traditional remedy for symptomatic relief of various illnesses. It has been labeled as an atypical opioid with significant narcoticlike properties, capable of inducing kratom dependence among those who misuse or abuse it. The prevalence of kratom use has drastically increased worldwide, raising concerns among healthcare providers, particularly regarding the availability of efficacious treatment options for kratom dependence. This manuscript provides a comprehensive narrative review of literature focusing on the psychoactive alkaloids of kratom, the possible neurobiological and pathophysiological models underlying the occurrence of kratom dependence, and the clinical presentations and effective treatment options available for kratom dependence. The psychoactive alkaloids of kratom, such as mitragynine (MG) and 7-hydroxymitragynine (7-HMG), act as partial mu opioid agonists and induce kratom dependence. As a result, regular kratom use leads to withdrawal symptoms on abstinence, along with craving, tolerance, and cross-tolerance to morphine. The psychological withdrawal symptoms reported include depressed mood, anxiety, restlessness, irritability, and feeling tense, while the physical withdrawal symptoms are myalgia and body ache, joint pain, lacrimation, running nose, yawning, insomnia, diarrhea, feverish sensation, loss of appetite, tremors, itching over the body, loss of concentration, and chills. Neonatal withdrawal symptoms, such as oral intolerance, restlessness, irritability, and vomiting, are also reported in newborns of women who are on regular kratom use. Sublingual buprenorphine-naloxone (Suboxone) is reported as a promising treatment for detoxification and maintenance replacement therapy for kratom-dependent users. Alternative treatments for in-patient detoxification include intravenous clonidine and a combination of oral dihydrocodeine and lofexidine. We conclude by adding a note on the research gap concerning kratom dependence, which future studies should focus on.
An enzyme-linked immunosorbent assay for detection of mitragynine, other closely related Kratom alkaloids and metabolites was developed using polyclonal antibodies. Mitragynine was conjugated to a carrier protein, cationized-bovine serum albumin using Mannich reaction. The synthesized antigen was injected into rabbits to elicit specific polyclonal antibodies against mitragynine. An enzyme conjugate was synthesized for evaluating its performance with the antibodies produced. The assay had an IC50 of 7.3 ng/mL with a limit of detection of 15 ng/mL for mitragynine. Antibody produced have high affinity for mitragynine (100%), other closely related Kratom alkaloids such as paynantheine (54%), speciociliatine (63%), 7α-hydroxy-7H-mitragynine (83%) and cross-reacted with metabolites 9-O-demethyl mitragynine (79%), 16-carboxy mitragynine (103%), 9-O-demethyl mitragynine sulfate (263%), 9-O-demethyl mitragynine glucuronide (60%), 16-carboxy mitragynine glucuronide (60%), 9-O-demethyl-16-carboxy mitragynine sulfate (270%) and 17-O-demethyl-16,17-dihydro mitragynine glucuronide (34%). It showed cross-reactivity less than 0.01% to reserpine, codeine, morphine, caffeine, methadone, amphetamine, and cocaine. Ten-fold dilution urine was used in the assay to reduce the matrix effects. The recovery ranged from 83% to 112% with variation coefficients in intraday and interday less than 8% and 6%, respectively. The ELISA turned out to be a convenient tool to diagnose mitragynine, other closely related Kratom alkaloids and metabolites in human urine samples.
Background and aims
Mitragyna speciosa (“kratom”) contains mu opioid partial agonists. It is widely available, and occasionally used as a home remedy for opioid use disorder. The Drug Enforcement Agency considers kratom a Drug of Concern; however, prevalence of use and role in drug misuse are unknown. This study aimed to characterize kratom use in the United States (U.S.).
Design
Cross‐sectional Survey of Non‐Medical Use of Prescription Drugs (NMURx) Program, 2018 3rd quarter and 2019 1st quarter.
Setting
A validated non‐probability online survey in the U.S.
Participants
A total of 59,714 respondents 18 years or older, weighted to represent the adult U.S. population (N=252,063,800).
Measurements
In addition to prevalence of past‐year kratom and other drug use, behavior proportions were estimated. The Drug Abuse Screening Test (DAST‐10) estimated consequences of drug abuse.
Findings
Estimated prevalence of past‐year kratom use in the adult U.S. population was 0.8% (95% CI 0.7‐0.9), representing 2,031,803 adults. Lifetime prevalence was 1.3% (95% CI 1.2‐1.4), representing 3,353,624 adults. Kratom users were younger (mean 35 years, p<0.001), with higher proportions of males (61.0 vs. 48.6%, p<0.001), students (14.1 vs. 7.5%, p<0.001), and healthcare professionals (9.7 vs. 4.5%, p<0.001), and fewer bachelor's/advanced degree graduates (33.4 vs. 42.6%, p<0.001), compared with non‐users. Results were inconclusive on whether there was a difference in kratom use by race, household income, or employment status. Among those with past‐year kratom use, 36.7% (95% CI 32.1‐41.3) non‐medically used prescription opioids, 21.7% (95% CI 18.0‐25.5) used illicit opioids, 54.4% (95% CI 49.5‐59.3) used another illicit drug, and 67.1% (95% CI 62.5‐71.8) used cannabis. The DAST‐10 profile was more often substantial/severe in kratom users (21 vs. 1%, p<0.001) compared with non‐users.
Conclusions
Estimated United States past‐year prevalence of kratom use is 0.8%, and kratom users tend to have more serious substance abuse profiles than non‐users or users of cannabis, alcohol, or cigarettes. This is the first description of kratom use at the national level.
Mitragyna speciosa (Kratom) has emerged as a recreational drug and a substance of medicinal intrigue. Although the drug was initially used recreationally for its sedating and euphoric effects, more recently its use has been associated with the non-medically supervised treatment of opioid abstinence syndrome. Mitragynine is the principal pharmacologically active alkaloid in kratom. Although metabolites of mitragynine have been identified, the cytochrome P450 (CYP450) enzymes responsible for its biotransformation are still under investigation. The goal of this study was to contribute further knowledge regarding CYP450 activity as it relates to mitragynine. Recombinant cytochrome P450 enzymes (rCYPs) were used to investigate the isoforms involved in its metabolism. Biotransformational products were identified using liquid chromatography-quadrupole/time of flight-mass spectrometry. Four rCYP enzymes (2C18, 2C19, 2D6 and 3A4) were found to contribute to the metabolism of mitragynine. 7-Hydroxymitragynine (which has an affinity for the mu-opioid receptor >10-folds that of morphine) was produced exclusively by 3A4. 9-O-demethylmitragynine, the most abundant metabolite in vitro (and the most prevalent metabolite in urine among kratom users) was produced by 2C19, 3A4 and 2D6. 16-Carboxymitragynine was produced by rCYPs 2D6, 2C19 and 2C18. 2C19 was solely responsible for the formation of 9-O-demethyl-16-carboxymitragynine. In vitro rCYP studies were compared with phase I metabolites in urine from cases involving mitragynine.
Background:
Kratom, a Southeast Asian plant with opioid-receptor mediated effects, has emerged as a potential substance of abuse, with limited data on its use and effects. This study characterized kratom user demographics, use patterns, and perceived drug effects.
Methods:
A cross-sectional, anonymous online survey was conducted between January and December 2017.
Results:
2,798 kratom users - mean age 40 (SD = 12); predominantly White (90 %), female (61 %), and located in the US (97 %) - completed the survey. Kratom was primarily taken orally in doses of 1-3 g (49 %), with daily use (59 %) being most common. Kratom was used for pain (91 %), anxiety (67 %), and depression (65 %), with high ratings of effectiveness. 1,144 (41 %) used kratom to stop or reduce prescription or illicit opioid use, citing decreased opioid withdrawal and craving related to kratom use, with 411 reporting >1-year continuous abstinence from opioids attributed to kratom use. Roughly one-third of respondents reported adverse effects of kratom, largely rated as mild in severity and lasting ≤24 h. Seventeen participants (0.6 %) sought treatment for adverse effects. Fifty-six individuals (2 %) met DSM-5 criteria for a past-year moderate or severe kratom-related substance use disorder (SUD). When asked how troubled they felt regarding their kratom use, the mean (SD) rating was 3.2 (9.8) on a scale from 0 to 100.
Conclusion:
Kratom is used among White, middle-aged Americans for symptoms of pain, anxiety, depression, and opioid withdrawal. Although regular use was typical, kratom-related SUD and serious adverse effects were uncommon. Additional research on kratom epidemiology and pharmacology is imperative in light of the present opioid epidemic.
The entire scalp hair of a self‐declared Kratom consumer of 3 grams per day was acquired during an ethical committee approved study. As no concentration values in hair of the two Kratom alkaloids mitragynine or 7‐hydroxymitragynine were found in the literature, an already established method for the analysis of benzodiazepines/z‐substances was extended for the detection of mitragynine and 7‐hydroxymitragynine with LC‐MS/MS, and successfully validated. The limits of detection and quantification for mitragynine were 2 pg/mg and 4 pg/mg, respectively. Those of 7‐hydroxymitragynine were 20 pg/mg and 30 pg/mg, respectively. The method was applied to the entire scalp hair, divided in 91 regions, of the study participant. A narrow mitragynine concentration distribution with values between 1054 pg/mg and 2244 ng/mg (mean 1517 ng/mg) and no clear scalp region associated distribution pattern was obtained. 7‐Hydroxymitragynine was not detected in any hair sample. After validation, the method was established as routine and subsequently 300 samples (mainly abstinence controls for drugs of abuse) were analyzed, allowing the investigation of the prevalence of Kratom consumption in our population. None of the analyzed routine hair samples were positive for mitragynine or 7‐hydroxymitragynine, providing no evidence that Kratom consumption is prevalent in the investigated population.
Ethnopharmacological relevance:
Kratom (Mitragyna speciosa) is a native medicinal plant of Southeast Asia widely reported to be used to reduce opioid dependence and mitigate withdrawal symptoms. There is also evidence to suggest that opioid poly-drug users were using kratom to abstain from opioids.
Aim of the study:
To determine the patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia.
Materials and methods:
A total of 204 opioid poly-drug users (142 current users vs. 62 former users) with current kratom use history were enrolled into this cross-sectional study. A validated UPLC-MS/MS method was used to evaluate the alkaloid content of a kratom street sample.
Results:
Results from Chi-square analysis showed that there were no significant differences in demographic characteristics between current and former opioid poly-drug users except with respect to marital status. Current users had higher odds of being single (OR: 2.2: 95%CI: 1.21-4.11; p < 0.009). Similarly, there were no significant differences in the duration (OR: 1.1: 0.62-2.03; p < 0.708), daily quantity (OR: 1.5: 0.85-2.82; p < 0.154) or frequency of kratom use between current and former opioid poly-drug users (OR: 1.1: 0.62-2.06; p < 0.680). While both current and former opioid users reported using kratom to ameliorate opioid withdrawal, current users had significantly higher likelihood of using kratom for that purpose (OR: 5.4: 95%CI: 2.81-10.18; p < 0.0001). In contrast, former opioid users were more likely to be using kratom for its euphoric (mood elevating) effects (OR: 1.9: 95%CI: 1.04-3.50; p < 0.035). Results from the UPLC-MS/MS analysis indicated the major alkaloids present in the representative kratom street sample (of approximately 300 mL of brewed kratom) were mitragynine, followed by paynantheine, speciociliatine and speciogynine, as well as low levels of 7-hydroxymitragynine.
Conclusions:
Both current and former opioid poly-drug users regularly used kratom (three glasses or about 900 mL daily or the equivalent of 170.19 mg of mitragynine) to overcome opioid poly-drug use problems.
Introduction: This is the 36th Annual Report of the American Association of Poison Control Centers’ (AAPCC) National Poison Data System (NPDS). As of 1 January, 2018, 55 of the nation’s poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.72 [6.90, 12.0] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.
Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.
Results: In 2018, 2,530,238 closed encounters were logged by NPDS: 2,099,751 human exposures, 57,017 animal exposures, 368,025 information requests, 5,346 human confirmed nonexposures, and 99 animal confirmed nonexposures. United States PCs also made 2,621,242 follow-up calls in 2018. Total encounters showed a 2.96% decline from 2017, while health care facility (HCF) human exposure cases remained nearly steady with a slight decrease of 0.261%. All information requests decreased by 15.5%, medication identification (Drug ID) requests decreased by 30.2%, and human exposure cases decreased by 0.729%. Human exposures with less serious outcomes have decreased 2.33% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.45% per year since 2000.
Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (10.8%), household cleaning substances (7.28%), cosmetics/personal care products (6.53%), sedatives/hypnotics/antipsychotics (5.53%), and antidepressants (5.22%). For cases with more serious outcomes, sedative/hypnotics/antipsychotics exposures were the class that increased most rapidly, by 1,828 cases/year (9.21%/year) over the past 18 years. Over just the past 10 years (for cases with the most serious outcomes) antidepressant exposures increased most rapidly, by 1,887 cases/year (7.02%/year).
The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (12.1%), household cleaning substances (10.7%), analgesics (9.04%), foreign bodies/toys/miscellaneous (6.87%), and topical preparations (4.69%). Drug identification requests comprised 18.2% of all information requests. NPDS documented 3,111 human exposures resulting in death; 2,582 (83.0%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).
Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information requests. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.
Introduction
Kratom is derived from the plant Mitragyna speciosa which is indigenous to Southeast Asia. Active compounds, mitragynine and 7-hydroxymitragynine, cause mild stimulant and opioid agonist effects. Although reported to have potential benefits in the treatment of opioid use disorder, efficacy remains uncertain while adverse health effects have been reported. A compounding concern is the presence of adulterants given that this is an unregulated product.
Case Details
A 54-year-old fitness instructor who used an online purchased kratom product regularly for one year developed stimulatory effects and suffered a large hemorrhagic stroke with a close temporal relationship to ingestion of a different kratom product from the one he regularly used. A collaborative investigation by medical toxicologists, a regional poison center, the state public health laboratory, and public health officials determined that his new kratom product was adulterated with phenylethylamine (PEA).
Discussion
We report a case of PEA adulterated kratom purchased and used with resultant adverse effects. PEA is structurally similar to amphetamine and is known to produce sympathomimetic effects. It is possible the stimulatory effect of PEA resulted in a marked and transient increase in blood pressure resulting in hemorrhagic stroke.
Conclusion
Medical toxicologists should form working relationships with laboratories and public health officials to aid in early identification of adulterated products that carry risk to the general population.
In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC50) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (Ki) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC50, 2.2 and 4.2 µM, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the Ki were found to be 1.1 and 2.8 µM, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.
Kratom use appears to be increasing across the United States, increasing attention to deaths in which kratom use was detected. Most such deaths have been ascribed to fentanyl, heroin, benzodiazepines, prescription opioids, cocaine and other causes (e.g., homicide, suicide and various preexisting diseases). Because kratom has certain opioid-like effects (e.g., pain relief), and is used by some people as a substitute for opioids for pain or addiction, kratom has been compared to "narcotic-like opioids" (e.g., morphine) with respect to risk of death despite evidence that its primary alkaloid, mitragynine, carries little of the signature respiratory depressing effects of morphine-like opioids. This commentary summarizes animal toxicology data, surveys and mortality data associated with opioids and kratom to provide a basis for estimating relative mortality risk. Population-level mortality estimates attributed to opioids as compared to kratom, and the per user mortality risks of opioids as compared to kratom are provided. By any of our assessments, it appears that the risk of overdose death is >1000 times greater for opioids than for kratom. The limitations of the mortality risk estimate warrants caution in individuals with unknown factors such as use of other substances and medications, or other preexisting conditions. More research on kratom safety and risks is needed, as is regulation of commercial kratom products to ensure that consumers are informed by FDA labeling and that kratom products are not contaminated or adulterated with other substances.
Purpose
This article presents updated information on kratom (Mitragyna speciosa), a natural opioid with stimulant properties that is currently sold in the United States without a prescription.
Summary
Kratom exerts opioid and alpha-2 agonistic effects, as well as anti-inflammatory and mild stimulant effects. Respiratory depression has not been commonly reported, but kratom does cause a host of adverse effects. While kratom may have a role in patients who are in chronic pain or dependent on opioid painkillers or heroin, this needs to be established in clinical trials. Kratom may have drug interactions as both a cytochrome P-450 system substrate and inhibitor. Kratom does not appear in normal drug screens and, especially when ingested with other substances of abuse, may not be recognized as an agent of harm. There are numerous cases of death in kratom users, but many involved polypharmaceutical ingestions. There are assessments where people have been unable to stop using kratom therapy and withdrawal signs/symptoms occurred in patients or their newborn babies after kratom cessation. Both banning and failure to ban kratom places people at risk; a middle-ground alternative, placing it behind the pharmacy counter, might be useful.
Conclusion
Kratom has a unique pharmacologic profile that might offer advantages over other opioids, but its high abuse liability, potential for drug interactions and adverse events, and inadequate research into the balance of benefits to harm are concerning. There is mounting information on the adverse events associated with kratom use and potential treatments that can be useful to clinicians.