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

Kratom is a natural psychoactive product known primarily in Southeast Asia, including Thailand, Malaysia, etc. It is also known as krathom, kakuam, ithang, thom (Thailand), biak-biak, ketum (Malaysia) and mambog (Philippines) and is sometimes used as an opium substitute. It is stimulant at doses of 1-5 g, analgesic at doses of 5-15 g and euphoric and sedative at doses of >15 g. Mitragynine is the most abundant indole compound in kratom (Mitragyna speciosa) and is metabolized in humans to 7-hydroxymitragynine, the more active metabolite. Adverse effects include seizures, nausea, vomiting, diarrhea, tachycardia, restlessness, tremors, hallucinations and death. There are few studies on the analytical method for the detection of mitragynine and 7-hydroxymitragynine in hair. Therefore, this study proposes a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the analysis of kratom in hair. Hair samples were first weighed to ∼10 mg and washed with methanol. Then the washed hair samples were cut into pieces and incubated in methanol with stirring and heating (16 h/38℃). Extracts were then analyzed by LC-MS-MS. This method was validated by determining the limit of detection (LOD), limit of quantification, linearity, intra- and inter-day accuracy and precision, recovery and matrix effects. The intra- and inter-day precision (CV%) and accuracy (bias%) were within ±20%, which was considered acceptable. Using this newly developed LC-MS-MS method, the simultaneous detection of mitragynine and 7-hydroxymitragynine in six authentic hair samples was achieved to provide the direct evidence of kratom use in the past. Mitragynine concentrations ranged from 16.0 to 2,067 pg/mg (mean 905.3 pg/mg), and 7-hydroxymitragynine concentrations ranged from 0.34 to 15 pg/mg (mean 7.4 pg/mg) in six authentic hair samples from kratom abusers. This may be due to the higher sensitivity of the LOD in this study, with values of 0.05 pg/mg for mitragynine and 0.2 pg/mg for 7-hydroxymitragynine in hair.

Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500-4000 mg dried kratom leaf powder (6.65-53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine Cmax increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine Tmax was 1.0-1.3 h after single and 1.0-1.7 h after multiple doses; for 7-hydroxymitragynine Tmax, it was 1.2-1.8 h and 1.3-2.0 h. Steady-state mitragynine concentrations were reached in 8-9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T1/2 was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20-0.31 after a single dose and decreased (0.15-0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations.

Kratom (Mitragyna speciosa Korth. Havil) has been considered a narcotic drug for years, barred by the law in many parts of the world, while extensive research over the past few decades proves its several beneficial effects, some of which are still in ambiguity. In many countries, including Thailand, the indiscriminate use and abuse of kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from kratom, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at other central receptors. Mitragynine is also credited to be one of the modulatory molecules for the Keap1-Nrf2 pathway and SOD, CAT, GST, and associated genes\' upregulatory cascades, leading it to play a pivotal role in neuroprotective actions while evidently causing neuronal disorders at high doses. Additionally, its anti-inflammatory, antioxidative, antibacterial, and gastroprotective effects are well-cited. In this context, this review focuses on the research gap to resolve ambiguities about the neuronal effects of kratom and demonstrate its prospects as a therapeutic target for neurological disorders associated with other pharmacological effects.

Kratom (Mitragyna speciosa) is a Southeast Asian plant containing various alkaloids that induce pharmacological effects in humans. In Western countries, online vendors sell a variety of different kratom strains which are marketed to have distinct effect profiles. However, as of yet such marketing claims are unsubstantiated, and therefore the current study investigated whether differently colored kratom products can induce distinct effects, as self-reported by users. Six hundred forty-four current kratom users were anonymously surveyed to compare the self-reported effects of and motivations for using kratom products sold as red, green, and white strains. Most of the survey respondents were customers of the same kratom vendor, the products of which had been analyzed for their alkaloid content by an independent laboratory. The survey respondents reported distinct subjective experiences for different kratom strains, in a manner congruent with common marketing descriptions. However, the product analyses revealed no significant cross-strain differences in alkaloid content, suggesting that the reported effect differences might be disproportionally influenced by marketing narratives and anecdotal reports. Future studies should engage a more diverse population and include kratom strains from various vendors. Controlled, blinded experiments could assess whether the reported effect differences stem from a placebo effect or from alternative factors, e.g., minor alkaloids and terpenes.

Kratom is the common term for Mitragyna speciosa and its products. Its major active compounds are mitragynine and 7-hydroxymitragynine. An estimated 2.1 million US residents used kratom in 2020, as a \"legal high\" and self-medication for pain, opioid withdrawal, and other conditions. Up to 20% of US kratom users report symptoms consistent with kratom use disorder. Kratom use is associated with medical toxicity and death. Causality is difficult to prove as almost all cases involve other psychoactive substances. Daily, high-dose use may result in kratom use disorder and opioid-like withdrawal on cessation of use. These are best treated with buprenorphine.

A number of alkaloids found in Mitragyna species belonging to the Rubiaceae family have been shown to have potent biological activity such as analgesic properties. Here, we report the asymmetric total syntheses of mitragynine, speciogynine, and 7-hydroxymitragynine, which are classified as corynantheine-type monoterpenoid indole alkaloids, isolated from Mitragyna speciosa. These syntheses were accomplished within 12 steps and in >11% total yield from commercial 3-(trimethylsilyl)propanal using an organocatalytic anti-selective Michael reaction and bioinspired transformations.

Kratom (Mitragyna speciosa) is an easily accessible dietary supplement gaining notoriety in medicine for its use as a surrogate form of self-driven opioid use disorder treatment, albeit one with a lack of evidence and significant risks. Both misuse and withdrawal from kratom have been appreciated in the literature and addressed in a fashion analogous to that of opioids. Because of this, it has largely been studied through the looking glass of its properties of agonizing μ-opioid and likely α2-adrenergic receptors. While an important area of study, the correlation with kratom and stimulant use, reflected in the National Survey on Drug Use and Health, is one that often gets neglected clinically. In our manuscript we present three unique cases, demonstrative of the overlap kratom misuse may have with stimulant use disorders in distinct settings. We provide a discussion and review of this correlation in light of kratom use increasing in the United States.

Kratom products have been historically and anecdotally used in south Asian countries for centuries to manage pain and opioid withdrawal. The use of kratom products has dramatically increased in the United States. More than 45 kratom alkaloids have been isolated, yet the overall pharmacology of the individual alkaloids is still not well characterized. The purpose of this chapter is to summarize in vitro and in vivo opioid activities of the primary kratom alkaloid mitragynine and its more potent metabolite 7-hydroxymitragynine. Following are experimental procedures described to characterize opioid receptor activity; receptor binding and functional assays, antinociceptive assays, operant conditioning assays, and respiratory plethysmography. The capacity of kratom alkaloids to confer tolerance and physical dependence as well as their pharmacokinetic properties are also summarized. The data reviewed here suggest that kratom products and mitragynine possess low efficacy agonist activity at the mu-opioid receptor in vivo. In addition, kratom products and mitragynine have been demonstrated to antagonize the effects of high efficacy mu-opioid agonists. The data further suggest that 7-hydroxymitragynine formed in vivo by metabolism of mitragynine may be minimally involved in the overall behavioral profile of mitragynine and kratom, whereas 7-hydroxymitragynine itself, at sufficiently high doses administered exogenously, shares many of the same abuse- and dependence-related behavioral effects associated with traditional opioid agonists. The apparent low efficacy of kratom products and mitragynine at mu-opioid receptors supports the development of these ligands as effective and potentially safe medications for opioid use disorder.

Mitragyna is a genus belonging to the Rubiaceae family and is a plant endemic to Asia and Africa. Traditionally, the plants of this genus were used by local people to treat some diseases from generation to generation. Mitragyna speciosa (Korth.) Havil. is a controversial plant from this genus, known under the trading name \"kratom\", and contains more than 40 different types of alkaloids. Mitragynine and 7-hydroxymitragynine have agonist morphine-like effects on opioid receptors. Globally, Mitragyna plants have high economic value. However, regulations regarding the circulation and use of these commodities vary in several countries around the world. This review article aims to comprehensively examine Mitragyna plants (mainly M. speciosa) as potential pharmacological agents by looking at various aspects of the plants. A literature search was performed and information collected using electronic databases including Scopus, ScienceDirect, PubMed, directory open access journal (DOAJ), and Google Scholar in early 2020 to mid-2021. This narrative review highlights some aspects of this genus, including historical background and botanical origins, habitat, cultivation, its use in traditional medicine, phytochemistry, pharmacology and toxicity, abuse and addiction, legal issues, and the potential of Mitragyna species as pharmaceutical products.