Kratom (<i>Mitragyna speciosa</i> 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.

<h4>Context</h4>Kratom <i>(Mitragyna speciosa),</i> native to Southeast Asia, has traditionally been consumed as fresh leaves or teas. Under those conditions, exposure to 7-hydroxymitragynine (7-OH)-a potent μ-opioid receptor agonist-is minimal, as it occurs only at trace levels in leaf material. By contrast, the U.S. market offers chemically enriched or semi-synthetic 7-OH products, often marketed as 'kratom' yet chemically distinct from botanical preparations.<h4>Methods</h4>'7-OH', '7-hydroxymitragynine', and 'kratom' were used as keywords; relevant literature was obtained from PubMed, Web of Science, and Google Scholar.<h4>Results</h4>Pharmacological studies consistently identify 7-OH as a partial μ-opioid receptor agonist with nanomolar affinity, greater efficacy than mitragynine, and often exceeding the potency of morphine. Animal experiments demonstrate robust antinociceptive effects, respiratory depression, tolerance, dependence, and reinforcing properties characteristic of opioids. Human pharmacokinetic studies show systemic exposure after kratom ingestion, but concentrated 7-OH products bypass metabolic formation, producing markedly higher exposures. Regulatory surveillance, poison-center data, and marketplace audits confirm a rapid increase in availability and use of these products. State health departments have reported severe intoxications and fatalities. Clinical cases describe escalating use, medically managed withdrawal, and psychiatric destabilization, while forensic investigations document postmortem concentrations consistent with fatal opioid toxicity. Pediatric risk is amplified by developmental susceptibility, absence of age restrictions, and marketing in confectionary formats. Emerging analogues such as MGM-15 further extend this trajectory.<h4>Conclusion</h4>Collectively, the evidence demonstrates that concentrated 7-OH products are pharmacologically and toxicologically distinct from kratom leaf and pose significant risks of morbidity and mort Conclusion Collectively, the evidence demonstrates that concentrated 7-OH products are pharmacologically and toxicologically distinct from kratom leaf and pose significant risks of morbidity and mortality under typical conditions of use. Keywords 7-OH 7-hydroxymitragynine kratom mytragynine opioids National Institute of General Medical Sciences 10.13039/100000057 P20GM109096 IK is supported by the National Institute of General Medical Sciences, Grant/Award Number: P20GM109096. Botanically related to coffee, kratom thrives in wetland areas and has been traditionally cultivated for its psychoactive and medicinal properties (Heywood et al. 2024 ; Begum et al. 2025 ). The earliest Western descriptions of kratom use date back to the early nineteenth century, but ethnobotanical evidence indicates that local communities have used it for centuries. In its traditional context, fresh leaves were chewed to stave off fatigue among laborers or brewed into teas to relieve pain, diarrhea, and fever (Hossain et al. 2023 ; Heywood et al. 2024 ). Its products now include powders, capsules, tablets, concentrated extracts, gummies, and energy drinks (Heywood et al. 2024 ; Grundmann et al. 2025 ). These formulations contrast sharply with traditional Southeast Asian use and enable higher, more concentrated, and more frequent dosing (Heywood et al. 2024 ; Begum et al. 2025 ; Vadiei et al. 2025 ). Contemporary marketing emphasizes self-treatment for chronic pain, anxiety, depression, fatigue, and opioid withdrawal (Heywood et al. 2024 ; McCurdy et al. 2024 ). National survey data suggest that pain relief, relaxation, stress reduction, and energy enhancement are the leading reasons for use, with kratom often positioned as a ‘natural’ alternative to prescription opioids or stimulants (Green et al. 2025 ; Grundmann et al. 2025 ). Methods Literature was identified through structured searches of PubMed, Web of Science Core Collection, and Google Scholar, supplemented by targeted web searches. Database queries combined controlled vocabulary and free-text terms for kratom and its alkaloids (e.g., ‘Mitragyna speciosa’, ‘7-hydroxymitragynine’, ‘7-OH’, ‘mitragynine pseudoindoxyl’), with field limits applied to title/abstract where available. No language filters were imposed at the search stage, but only English-language sources were included in the analysis. Limitations include potential under-ascertainment of emerging products not yet indexed, heterogeneity of analytic panels that may miss 7-OH, and incomplete age-stratified data in public-health summaries. From mitragynine to 7-hydroxymitragynine: phytochemical and metabolic pathways Phytochemically, kratom leaves contain a complex array of indole and oxindole alkaloids with more than 40 identified to date (Hossain et al. 2023 ). The major constituent is mitragynine, typically comprising 12–66% of the total alkaloid content, depending on geography, harvest, and processing conditions (Pohanka 2023 ). Mitragynine is metabolized to 7-hydroxymitragynine (7-OH), a minor natural alkaloid but pharmacologically far more potent at the μ-opioid receptor (Obeng et al. 2022 ; Chiang et al. 2025 ). Other significant alkaloids include speciogynine, speciociliatine, paynantheine, and corynantheidine, which display variable affinities for opioid, adrenergic, and serotonergic receptors (Green et al. 2025 ). Federal review similarly notes widespread internet and brick-and-mortar sales of concentrated 7-OH products despite the absence of any approved drug indications and despite the compound’s potent μ-opioid receptor pharmacology (US Food and Drug Administration 2025 ). Surveillance and clinical evidence of emerging 7-hydroxymitragynine risk Population-level data specific to 7-OH remain limited; however, triangulation from regulatory surveillance, marketplace audits, poison center reporting, and clinical observations indicates a sharp recent increase in availability and exposure in the United States. The U.S.

A metabolism-dependent mechanism helps to understand mitragynine’s opioid pharmacology and its analgesic activity. ACS Cent Sci ACS Cent Sci 2967 acscentsci 101660035 oc ACS Central Science 2374-7943 2374-7951 American Chemical Society PMC6598155 PMC6598155.1 6598155 6598155 31263752 10.1021/acscentsci.9b00462 1 First Reactions Unveiling 7-Hydroxymitragynine as the Key Active Metabolite of Mitragynine and the Promise for Creating Novel Pain Relievers Spetea Mariana Schmidhammer Helmut Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria E-mail: helmut.schmidhammer@uibk.ac.at ; mariana.spetea@uibk.ac.at . pmc-status-qastatus 0 pmc-status-live yes pmc-status-embargo no pmc-status-released yes pmc-prop-open-access yes pmc-prop-olf no pmc-prop-manuscript no pmc-prop-legally-suppressed no pmc-prop-has-pdf yes pmc-prop-has-supplement no pmc-prop-pdf-only no pmc-prop-suppress-copyright no pmc-prop-is-real-version no pmc-prop-is-scanned-article no pmc-prop-preprint no pmc-prop-in-epmc yes document-id-old-9 oc9b00462 document-id-new-14 oc-2019-00462u ccc-price Debilitating pain is a constant backdrop of daily life, resulting in personal suffering, substantial health costs, and an economic burden for society. Pain is not only a disabling symptom of many medical conditions but also a disease state in its own right. With its prevalence in 20–30% of the adult population, chronic pain affects more people than heart disease, cancer, and diabetes combined and will continue to grow as our population ages. 1 Pain medicine represents one of the most rapidly developing medical specialties of today, with effective pain control being a therapeutic priority. Chronic pain is still poorly managed because of the lack of efficacious therapies and significant adverse side effects of currently available analgesic drugs. 2 Now, the article of Kruegel et al. presents different pain therapeutics based on a natural product, Mitragyna speciosa , and new insights into its pharmacology and analgesic activity. 3 Opioids are highly effective analgesics and the most widely prescribed class of medications in the US. 4 Most opioid analgesics (e.g., morphine, fentanyl, and oxycodone) used in clinical practice target mu-opioid receptors. 2 Medical use and misuse of opioids have strongly increased in the past decades. It has emerged as a major public health threat due to the dramatic rise in opioid-related overdose deaths (over 47 000 in 2017 or 67.8% of all drug overdose deaths) and diagnoses of opioid-use disorder (addiction) associated with prescription opioids (1.8 million in 2016). The cost of the opioid epidemic in the US is estimated to be $80 billion annually. 4 , 5 Medicinal plants are tremendous sources of new drug candidates. Lately, there has been a renewed interest in natural product research due to the failure of alternative drug discovery methods to deliver many lead compounds in key therapeutic areas such as pain. Mitragyna speciosa , known as “kratom”, a plant native to Southeast Asia, has been used traditionally as a stimulant and analgesic and for the treatment of opioid addiction. 6 During the past years, kratom use has become increasingly popular in the US, where the consumption of kratom leaves was reported as an efficacious treatment of pain, particularly in cases where other available treatments have either failed or caused intolerable side effects. In their report, the authors rationalized the importance of 7-hydroxymitragynine (7-OH) as an active metabolite of mitragynine and a key mediator of its analgesic activity, thus providing the essential in vivo link signifying the pharmacological relevance of 7-OH ( Figure 1 ). Figure 1 Metabolic transformations of mitragynine to 7-hydroxymitragynine (7-OH), with 7-OH as an active metabolite of mitragynine and a key mediator of its analgesic activity. 6 Using genetic approaches, the authors demonstrated in vivo that mitragynine and 7-OH produce analgesic effects acting through a mu-opioid receptor-dependent mechanism. 3 They have demonstrated that metabolic conversion of mitragynine to 7-OH occurred also in vivo, where both alkaloids were detected in the plasma and brain, confirming that 7-OH is formed as a metabolite of mitragynine and that it enters the brain. Further, the authors have proven in mice that 7-OH contributes to the analgesic activity of mitragynine as a metabolite when comparing the pain response of compounds given at equianalgesic s.c. doses and confirmed this by quantifying concentrations of 7-OH in the brain, thus being consistent with 7-OH as the primary mediator of central analgesic activity. At the same time, other groups independently described the formation of 7-OH as a metabolite of mitragynine in vitro and in vivo. 9 , 10 However, pharmacokinetic studies will be required to elucidate the importance of 7-OH as a mitragynine metabolite in man, where the interspecies differences in the metabolic processes must be carefully considered. Overall, this work provides knowledge that can be used for creating novel pain therapeutics based on kratom.

Leaves harvested from kratom [Mitragyna speciosa (Korth.)] have a history of use as a traditional ethnobotanical medicine to combat fatigue and improve work productivity in Southeast Asia. In recent years, increased interest in the application and use of kratom has emerged globally, including North America, for its potential application as an alternative source of medicine for pain management and opioid withdrawal syndrome mitigation. Although the chemistry and pharmacology of major kratom alkaloids, mitragynine and 7-hydroxymitragynine, are well documented, foundational information on the imp Abstract Leaves harvested from kratom [ Mitragyna speciosa (Korth.)] have a history of use as a traditional ethnobotanical medicine to combat fatigue and improve work productivity in Southeast Asia. In recent years, increased interest in the application and use of kratom has emerged globally, including North America, for its potential application as an alternative source of medicine for pain management and opioid withdrawal syndrome mitigation. Although the chemistry and pharmacology of major kratom alkaloids, mitragynine and 7-hydroxymitragynine, are well documented, foundational information on the impact of plant production environment on growth and kratom alkaloids synthesis is unavailable. To directly address this need, kratom plant growth, leaf chlorophyll content, and alkaloid concentration were evaluated under three lighting conditions: field full sun (FLD-Sun), greenhouse unshaded (GH-Unshaded), and greenhouse shaded (GH-Shaded). Nine kratom alkaloids were quantified using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Leaf content of four alkaloids to include speciociliatine, mitraphylline, corynantheidine, and isocorynantheidine were not significantly impacted by lighting conditions, whereas 7-hydroxymitragynine was below the lower limit of quantification across all treatments. However, mitragynine, paynantheine, and corynoxine concentration per leaf dry mass were increased by 40%, 35%, and 111%, respectively, when cultivated under GH-Shaded compared to FLD-Sun. Additionally, total alkaloid yield per plant was maximized and nearly tripled for several alkaloids when plants were cultivated under such conditions. Historically, kratom was used in Thailand, Malaysia, and Indonesia to serve as a mild herbal stimulant, pain reliever, and to treat diarrhea and opium addiction [ 1 – 3 ]. Given its historical use as an analgesic and a medicine to mitigate opioid withdrawal symptoms, research on kratom cultivation and use is warranted. In Southeast Asia, kratom leaves are harvested and consumed fresh by chewing or steeping in water to make tea [ 3 ]. In the Western hemisphere where fresh kratom is unavailable, kratom is sold in the form of dried and ground powder or as a concentrated liquid extract for easier transportation and consumption [ 4 ]. Kratom produces an array of psychoactive compounds. So far more than 54 compounds including alkaloids, flavonoids, and terpenoids have been identified within kratom [ 5 – 7 ]. Although kratom’s alkaloids are likely produced by the plant to aid in defense of environmental challenges, they have demonstrated activity upon human central nervous system targets and may be medically valuable for the improvement of human health [ 8 – 10 ]. Of the wide array of alkaloids found in kratom leaves, mitragynine and 7-hydroxymitragynine are the best understood and considered the most psychoactive [ 6 ]. Mitragynine can constitute up to 38.7% in traditional and commercial kratom products [ 5 , 11 , 12 ]. 7-Hydroxymitragynine is produced by oxidation of mitragynine and is a minor constituent (< 0.01% in fresh leaves) found at concentrations of up to 2% in leaf extracts and commercial kratom products [ 13 , 14 ]; however, it is believed to be the major contributor to the known addictive potential of kratom given its activity as a potent μ-opioid receptor agonist [ 15 – 18 ]. In the U.S., commercially available, imported kratom products (in the format of capsules, dried leaves, powders, resins, and concentrated extracts) have variable concentrations of mitragynine (1.2–38.74%) and 7-hydroxymitragynine (0.01–0.75%) on a weight basis [ 11 , 19 ] . SPAD index measurements were pooled from four random replicates per treatment for four months (n = 48) and chlorophyll correlation data were pooled from nine random replicates for four months (n = 36). Plants were cultivated from September to December 2018 under different radiation treatments. Means sharing the same letter are not statically different by Tukey’s honest significant difference test at P < 0 . 05 . Error bars indicate the standard error. Alkaloid concentration 7-hydroxymitragynine was not detected in any of our samples ( Table 1 ). Treatment Alkaloid Alkaloid concentration per leaf dry mass (%w/w) Total alkaloid content per plant (g) FLD-Sun GH-Unshaded GH-Shaded FLD-Sun GH-Unshaded GH-Shaded Mitragynine 0.015±0.001 b 0.016±0.001 b 0.021±0.001 a 0.79±0.04 c 1.60±0.14 b 2.10±0.11 a 7-Hydroxymitragynine Below LLOQ * Below LLOQ Below LLOQ Below LLOQ Below LLOQ Below LLOQ Speciogynine 0.135±0.008 a 0.112±0.006 b 0.113±0.006 ab 7.35±0.44 b 11.28±0.64 a 11.41±0.59 a Paynantheine 0.020±0.001 b 0.022±0.001 b 0.027±0.001 a 1.04±0.04 c 2.23±0.13 b 2.83±0.16 a Speciociliatine 0.021±0.001 0.024±0.002 0.023±0.001 Despite the range of lighting conditions imposed in this study, no 7-hydroxymitragynine was detected in any leaf samples, suggesting low abuse liability potential when compared to previously examined imported commercial kratom product and reinforcing the opinion that this alkaloid is produced from mitragynine as a post-harvest artifact [ 5 ]. Although historically regarded as a field crop, data from our study indicated that greenhouse production of kratom may be economically valuable given significant increased alkaloid concentrations and greater total alkaloid yield.

Mitragyna speciosa (Rubiaceae), commonly known as kratom, is a tropical tree with a long history of traditional use in parts of Africa and Southeast Asia. In recent years, kratom has gained popularity for use as a recreational drug across the globe. Relatively new to the illicit market and used in a manner different from its traditional applications, preparations of kratom are touted by many as a safe and legal psychoactive product that improves mood, relieves pain, and may provide benefits in opiate addiction. Available literature was reviewed for M. speciosa via PubMed, Google Scholar, CINAHL, and EBSCO to summarize its traditional uses, phytochemical composition, pharmacology and toxicology of proposed active constituents, and potential for misuse and abuse. Research has demonstrated that both stimulant and sedative dose-dependent effects do exist, but a growing concern for the drug's effects and safety of use has resulted in national and international attention primarily due to an increase in hospital visits and deaths in several countries that are said to have been caused by extracts of the plant. The main active alkaloid substances in kratom, mitragynine and 7-hydroxymitragynine, present with a range of CNS stimulant and depressant effects mediated primarily through monoaminergic and opioid receptors. Recently, Palm Beach County, located in the southeastern corridor of Florida, has considered regulating kratom due to public safety concerns following the death of a young adult. At the local, state, and even federal levels, governments are now being confronted with the task of determining the safety and the possible regulation of kratom extracts. There are currently no standard analytical screening techniques for mitragynine and its metabolites following ingestion limiting its detection to more sophisticated techniques like liquid chromatography-mass spectrometry to determine kratom use. The growing concern of the abuse potential of kratom requires careful evaluation of its benefits and potential toxicities.