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Chemical structures of mitragynine (A), 7-hydroxymitragynine (B), and mitraphylline (C). 

Chemical structures of mitragynine (A), 7-hydroxymitragynine (B), and mitraphylline (C). 

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Mitragyna speciosa (kratom) is a popular herb in Southeast Asia, which is traditionally used to treat withdrawal symptoms associated with opiate addiction. Mitragynine, 7-hydroxymitragynine, and mitraphylline are reported to be the central nervous system active alkaloids which bind to the opiate receptors. Mitraphylline is also present in the bark...

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... It has been reported in the literature that 7HMG metabolizes to MTG (Manda et al., 2014), but no quantifiable MTG was found in any samples following oral administration of 50 mg/kg 7HMG indicating that the quantifiable conversion of 7HMG to MTG did not occur in mice in this study. These results are supported by the in vitro microsomal data as well as the results of a PK study in female beagle dogs (Maxwell et al., 2021). ...
Article
Kratom (Mitragyna speciosa), a Southeast Asian tree, has been used for centuries in pain relief and mitigation of opium withdrawal symptoms. Mitragynine (MTG), the major kratom alkaloid, is being investigated for its potential to provide analgesia without the deleterious effects associated with typical opioids. Concerns have been raised regarding the active metabolite of MTG, 7-hydroxymitragynine (7HMG), which has higher affinity and efficacy at µ-opioid receptors than MTG. Here we investigated the hotplate antinociception, pharmacokinetics, and tissue distribution of MTG and 7HMG at equianalgesic oral doses in male and female C57BL/6 mice to determine the extent to which 7HMG metabolized from MTG accounts for the antinociceptive effects of MTG and investigate any sex differences. The mechanism of action was examined by performing studies with the opioid receptor antagonist naltrexone. A population pharmacokinetic/pharmacodynamic model was developed to predict the behavioral effects after administration of various doses of MTG and 7HMG. When administered alone, 7HMG was 2.8-fold more potent than MTG to produce antinociception. At equivalent effective doses of MTG and 7HMG, there was a marked difference in the maximum brain concentration of 7HMG achieved, i.e., 11-fold lower as a metabolite of MTG. The brain concentration of 7HMG observed 4 hours post administration, producing an analgesic effect <10%, was still 1.5-fold higher than the maximum concentration of 7HMG as a metabolite of MTG. These results provide strong evidence that 7HMG has a negligible role in the antinociceptive effects of MTG in mice. SIGNIFICANCE STATEMENT: Mitragynine (MTG) is being investigated for its potential to aid in pain relief, opioid withdrawal syndrome, and opioid use disorder. The active metabolite of MTG, 7-hydroxymitragynine (7HMG), has been shown to have abuse potential and has been implicated in the opioid-like analgesic effect after MTG administration. The results of this study suggest a lack of involvement of 7HMG in the antinociceptive effects of MTG in mice.
... For the intestinal barrier, the Caco-2 cell line developed from human colorectal adenocarcinoma epithelium is commonly used to establish a model for the barrier, to determine intestinal absorption (Volpe, 2020). The model was used to investigate intestinal permeability of kratom alkaloids mitragynine (Manda et al., 2014;Rusli et al., 2019), 7-hydroxymitragynine, and mitraphylline (Manda et al., 2014). Mitragynine was found to be the most permeable across the Caco-2 cells, followed by 7hydroxymitragynine and mitraphylline with P app of 24.2 × 10 -6 cm/s, 16.1 × 10 -6 cm/s and 6.3 × 10 -6 cm/s respectively, when tested at 5 μM in the absorptive direction (apical to basolateral). ...
... For the intestinal barrier, the Caco-2 cell line developed from human colorectal adenocarcinoma epithelium is commonly used to establish a model for the barrier, to determine intestinal absorption (Volpe, 2020). The model was used to investigate intestinal permeability of kratom alkaloids mitragynine (Manda et al., 2014;Rusli et al., 2019), 7-hydroxymitragynine, and mitraphylline (Manda et al., 2014). Mitragynine was found to be the most permeable across the Caco-2 cells, followed by 7hydroxymitragynine and mitraphylline with P app of 24.2 × 10 -6 cm/s, 16.1 × 10 -6 cm/s and 6.3 × 10 -6 cm/s respectively, when tested at 5 μM in the absorptive direction (apical to basolateral). ...
... Mitragynine was found to be the most permeable across the Caco-2 cells, followed by 7hydroxymitragynine and mitraphylline with P app of 24.2 × 10 -6 cm/s, 16.1 × 10 -6 cm/s and 6.3 × 10 -6 cm/s respectively, when tested at 5 μM in the absorptive direction (apical to basolateral). P app values in the absorptive direction for the three compounds were similar when tested at 10 μM (Manda et al., 2014). Rusli et al. (2019) reported comparable mitragynine P app of 18.8 × 10 -6 cm/s. ...
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Parallel to the growing use of kratom, there is a wealth of evidence from self-report, preclinical, and early clinical studies on therapeutic benefits of its alkaloids in particular for treating pain, managing substance use disorder, and coping with emotional or mental health conditions. On the other hand, there are also reports on potential health risks concerning kratom use. These two aspects are often discussed in reviews on kratom. Here, we aim to highlight specific areas that are of importance to give insights into the mechanistic of kratom alkaloids pharmacological actions. This includes their interactions with drug-metabolizing enzymes and predictions of clinical drug-drug interactions, receptor-binding properties, interactions with cellular barriers in regards to barrier permeability, involvement of membrane transporters, and alteration of barrier function when exposed to the alkaloids.
... Mitragynine is a drug of intermediate lipophilicity (log P, 1.7; Ramanathan et al., 2015). Although this might favor high blood-brain barrier penetration, both mitragynine and 7-hydroxymitragynine are reported to be highly protein bound (>90%) which may restrict their passage (Manda et al., 2014). ...
... There are currently no in-vivo studies regarding the metabolism of 7-hydroxymitragynine in humans. However, Manda reported that 7-hydroxymitragynine converted to mitragynine in the presence of human liver microsomes (HLMs) and in alkaline intestinal fluid (pH 6.8; Manda et al., 2014). It has been reported that although 7-hydroxymitragynine may not be present in all kratom products, it is predominantly found in dry leaf materials that have been exposed to air and sun for long periods of time (Kruegel et al., 2016). ...
... Mitragynine and 7-hydroxymitragynine have also been shown to inhibit P-glycoprotein. This indicates the possibility of a drug interaction if mitragynine and 7-hydroxymitragynine are co-administered with drugs that are Pglycoprotein substrates (Manda et al., 2014). Mitragynine has also been shown to have toxicokinetic interactions with permethrin by inhibiting hydrolysis, increasing the risk of developing neurotoxicity (Srichana, Janchawee, Prutipanlai, Raungrut, & Keawpradub, 2015). ...
Article
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 high clearance of 43.2 ± 3.5 mL/min/kg in the presence of human liver microsomes results in low bioavailability and limited distribution to tissues. Mitragynine and 7-hydroxymitragynine exhibited significant P-gp (P-glycoprotein) inhibition, similar to verapamil, indicating the possibility of drug-drug interactions when coadministered with drugs that are P-gp substrates [62]. ...
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Plant-based indole alkaloids are very rich in pharmacological activities, and the indole nucleus is considered to contribute greatly to these activities. This review's fundamental objective is to summarize the pharmacological potential of indole alkaloids that have been derived from plants and provide a detailed evaluation of their established pharmacological activities, which may contribute to identifying new lead compounds. The study was performed by searching various scientific databases, including Springer, Elsevier, ACS Publications, Taylor and Francis, Thieme, Wiley Online Library, ProQuest, MDPI, and online scientific books. A total of 100 indole compounds were identified and reviewed. The most active compounds possessed a variety of pharmacological activities , including anticancer, antibacterial, antiviral, antimalarial, antifungal, anti-inflammatory, anti-depressant, analgesic, hypotensive, anticholinesterase, antiplatelet, antidiarrheal, spasmolytic, an-tileishmanial, lipid-lowering, antimycobacterial, and antidiabetic activities. Although some compounds have potent activity, some only have mild-to-moderate activity. The pharmacokinetic profiles of some of the identified compounds, such as brucine, mitragynine, 7-hydroxymitragynine, vindoline, and harmane, were also reviewed. Most of these compounds showed promising pharmacological activity. An in-depth pharmacological evaluation of these compounds should be performed to determine whether any of these indoles may serve as new leads.
... In contrast, mitragynine exhibited a multiexponential profile after C max . Manda et al. (2014) reported that 7-hydroxymitragynine metabolized about 45% to mitragynine in human liver microsomes but we did not observe any conversion of 7-hydroxymitragynine to mitragynine in dogs [22]. Dogs were chosen as a preclinical species for pharmacokinetic testing because of their well-understood physiology and similarities to humans [19]. ...
... In contrast, mitragynine exhibited a multiexponential profile after C max . Manda et al. (2014) reported that 7-hydroxymitragynine metabolized about 45% to mitragynine in human liver microsomes but we did not observe any conversion of 7-hydroxymitragynine to mitragynine in dogs [22]. Dogs were chosen as a preclinical species for pharmacokinetic testing because of their well-understood physiology and similarities to humans [19]. ...
Article
Background and Objectives7-Hydroxymitragynine (7-HMG) is an oxidative metabolite of mitragynine, the most abundant alkaloid in the leaves of Mitragyna speciosa (otherwise known as kratom). While mitragynine is a weak partial µ-opioid receptor (MOR) agonist, 7-HMG is a potent and full MOR agonist. It is produced from mitragynine by cytochrome P450 (CYP) 3A, a drug-metabolizing CYP isoform predominate in the liver that is also highly expressed in the intestine. Given the opioidergic potency of 7-HMG, a single oral dose pharmacokinetic and safety study of 7-HMG was performed in beagle dogs.Methods Following a single oral dose (1 mg/kg) of 7-HMG, plasma samples were obtained from healthy female beagle dogs. Concentrations of 7-HMG were determined using ultra-performance liquid chromatography coupled with a tandem mass spectrometer (UPLC-MS/MS). Pharmacokinetic parameters were calculated using a model-independent non-compartmental analysis of plasma concentration-time data.ResultsAbsorption of 7-HMG was rapid, with a peak plasma concentration (Cmax, 56.4 ± 1.6 ng/ml) observed within 15 min post-dose. In contrast, 7-HMG elimination was slow, exhibiting a mono-exponential distribution and mean elimination half-life of 3.6 ± 0.5 h. Oral dosing of 1 mg/kg 7-HMG was well tolerated with no observed adverse events or significant changes to clinical laboratory tests.Conclusions These results provide the first pharmacokinetic and safety data for 7-HMG in the dog and therefore contribute to the understanding of the putative pharmacologic role of 7-HMG resulting from an oral delivery of mitragynine from kratom.
... Several adverse effects have been documented to be associated with mitragynine use in humans. These include dry mouth, constipation, changes in urination pattern, vomiting, nystagmus, tremor, anorexia and weight loss [108]. Anorexia and weight loss are side effects which are most prominent in chronic users of the drug [109], and this observation has influenced the use of mitragynine-a psychoactive plant extract-as an anorectic [110]. ...
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Purpose This paper examines the scope of anorectics in counterfeit weight-reducing formulations and provides insight into the present state of research in determining such adulterants. Analytical techniques utilised in profiling adulterants found in slimming products, including limitations and mitigation steps of these conventional methods are also discussed. The current legal status of the anorectics and analogues routinely encountered in non-prescription slimming formulations is also explored. Methods All reviewed literature was extracted from Scopus, Web of Science, PubMed, and Google Scholar databases using relevant search terms, such as, ‘counterfeit drugs’, ‘weight loss drugs’, ‘weight-reducing drugs’, ‘slimming drugs’, ‘anorectic agents’, and ‘counterfeit anorexics’. Legislation related to anorectics was obtained from the portals of various government and international agencies. Results Anorectics frequently profiled in counterfeit slimming formulations are mostly amphetamine derivatives or its analogues. Five routinely reported pharmacological classes of adulterants, namely anxiolytics, diuretics, antidepressants, laxatives, and stimulants, are mainly utilised as coadjuvants in fake weigh-reducing formulations to increase bioavailability or to minimise anticipated side effects. Liquid and gas chromatography coupled with mass spectrometric detectors are predominantly used techniques for anorectic analysis due to the possibility of obtaining detailed information of adulterants. However, interference from the complex sample matrices of these fake products limits the accuracy of these methods and requires robust sample preparation methods for enhanced sensitivity and selectivity. The most common anorectics found in counterfeit slimming medicines are either completely banned or available by prescription only, in many countries. Conclusions Slimming formulations doped with anorectic cocktails to boost their weight-reducing efficacy are not uncommon. Liquid chromatography combined with mass spectrometry remains the gold standard for counterfeit drug analysis, and requires improved preconcentration methods for rapid and quantitative identification of specific chemical constituents. Extensive method development and validation, targeted at refining existing techniques while developing new ones, is expected to improve the analytical profiling of counterfeit anorectics significantly.
... Links to the specific experiments are provided in Supplemental Table S3. Data from nine published in vitro studies were entered into the repository (Hanapi et al., 2010(Hanapi et al., , 2013Kong et al., 2011;Haron and Ismail, 2014;Manda et al., 2014;Meyer et al., 2015;Kamble et al., 2019Kamble et al., , 2020Rusli et al., 2019). One study using recombinant CYP enzymes reported that a methanolic extract of kratom inhibited CYP2D6 but not CYP2C9 or CYP3A4 (Hanapi et al., 2010). ...
... Three studies reported inhibition of P-glycoprotein by mitragynine, two using Caco-2 cells (Meyer et al., 2015;Rusli et al., 2019) and one using MDCK transfected cells (Manda et al., 2014). The same MDCK transfected cell study reported inhibition of P-glycoprotein by 7hydroxymitragynine. ...
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There are many gaps in scientific knowledge about the clinical significance of pharmacokinetic natural product-drug interactions (NPDIs) in which the NP is the precipitant and a conventional drug is the object. The National Center for Complimentary and Integrative Health created the Center of Excellence for NPDI Research (NaPDI Center) (www.napdi.org) to provide leadership and guidance on the study of pharmacokinetic NPDIs. A key contribution of the Center is the first user-friendly online repository that stores and links pharmacokinetic NPDI data across chemical characterization, metabolomics analyses, and pharmacokinetic in vitro and clinical experiments (repo.napdi.org). The design is expected to help researchers more easily arrive at a complete understanding of pharmacokinetic NPDI research on a particular NP. The repository will also facilitate multidisciplinary collaborations, as the repository links all of the experimental data for a given NP across the study types. The current work describes the design of the repository, standard operating procedures (SOPs) used to enter data, and pharmacokinetic NPDI data that have been entered to date. To illustrate the usefulness of the NaPDI Center repository, more details on two high-priority NPs, cannabis and kratom, are provided as case studies.
... Additionally, a study by Lim et al. (50) reported that mitragynine was a significant in vitro 1A2 inducer, weak 3A4 inducer and a weak 3A4 enzyme inhibitor. Studies have also shown that mitragynine and 7-hydroxymitragynine could have potential drugdrug interactions with drugs that are P-glycoprotein substrates and can activate the pregnane X receptor, which could then lead to an increase in the activity of 3A4, 1A2 and P-glycoprotein (51,52). ...
Article
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.
... Information regarding the stability of the Mitragyna alkaloids is relatively sparse. Manda et al. (29) reported the stability of MG and MG-OH in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF). Both matrices were fortified with 5,000 ng/mL of MG and MG-OH and for up to 2.5 hours at 37 • C. For MG, samples in SGF (pH 1.2) were reported to be unstable (>26% loss) in 2 hours. ...
... Although all samples experienced a significant loss at the highest temperatures (80 and 60 • C) regardless of pH, degradation rates were pH-dependent. A loss of 100% was observed for pH 2 and a near complete loss (93% loss) was observed for pH 4 at 80 • C. The findings are consistent with earlier studies by Manda et al. (29), who reported that MG-OH was unstable in SGF (pH 1.2, 37 • C), but stable in SIF (pH 6.8, 37 • C) after ∼2 hours. Like MG, MG-OH was observed to be unstable at elevated temperatures in a pH-dependent manner. ...
Article
Mitragynine is the principal psychoactive alkaloid in kratom. The drug produces a variety of dose-dependent effects that appeal to recreational drug users and individuals seeking therapeutic benefits in the absence of medical supervision. In light of documented intoxications, hospitalizations and fatalities, mitragynine and other alkaloids from Mitragyna speciosa are of growing importance to the forensic toxicology community. However, the chemical stability of these compounds has not been thoroughly described. In this report, the stability of mitragynine (MG), 7-hydroxymitragynine (MG-OH), speciociliatine (SC), speciogynine (SG) and paynantheine (PY) are investigated. Short-term stability of the Mitragyna alkaloids was determined over a range of pH (2-10) and temperature (4-80 °C) over 8 h. Liquid chromatography time-of-flight mass spectrometry (LC-Q/TOF-MS) was used to estimate half-lives and identify degradation products where possible. The stability of mitragynine and other alkaloids was highly dependent on pH and temperature. All of the Mitragyna alkaloids studied were acid labile. Under alkaline conditions mitragynine undergoes chemical hydrolysis of the methyl ester to produce 16-carboxymitragynine. 7-Hydroxymitragynine was the most unstable alkaloid studied, with significant drug loss at 8 hours experienced at temperatures of 40 °C and above. No significant drug losses were observed for mitragynine in aqueous solution (pH 2-10) at 4, 20 or 40 °C. Diastereoisomers of mitragynine (speciociliatine and speciogynine) demonstrated even greater stability. These findings are discussed within the context of the identification of Mitragyna alkaloids in toxicological specimens.
... They are both selective μ-opioid receptor partial agonists. 5,10,13,14 Mitragynine is the most abundant alkaloid of Kratom with about 66% of the total alkaloid content, while 7-Hy-Mitra is present at lower concentrations of about 2% of the total alkaloids. 15 The concentrations have been reported to be strongly dependent on the strain and origin of the Kratom. ...
... 16 It is possible that 7-Hy-Mitra is a metabolite of mitragynine but there are contradictory reports. 5,14 During a recently published study, 17 Kratom. The method was applied to gain insight into the concentration distribution across the scalp, as the sampling site could have a strong impact on the test results as previously demonstrated (Meier et al., 2019). ...
Article
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.