Kratom

'''Kratom''' ('''''Mitragyna speciosa''''' Korth., Rubiaceae) is a tropical tree native to Southeast Asia whose leaves contain over 40 [[substance_class:chemical/indole-alkaloid|indole alkaloids]]. Its dominant constituent, [[substance:mitragynine]], is a G-protein-biased [[glossary:partial-agonist]] at the [[glossary:mu-opioid-receptor]] that also engages α₂-adrenergic [[glossary:receptor|receptors]]{{cite|pubmed=28830758|anchor=1b1a52eb}}. Mitragynine produces its principal effects by partially activating [[substance_class:psychoactive/opioid]] and adrenergic pathways, generating a dose-dependent spectrum from mild [[effect:stimulation]] to opioid-like [[effect:sedation]]. First described by Pieter Willem Korthals in 1841{{cite|url=https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:756303-1|anchor=ba324e47}}, kratom was used for centuries as a work aid and folk medicine in Thailand and Peninsular Malaysia{{cite|pubmed=26640804|anchor=2584bf60}}. The plant entered Western markets around 2005–2010 and became a focus of regulatory debate after the US [[glossary:drug-enforcement-administration|DEA]] proposed — then withdrew — [[glossary:schedule-i]] classification in 2016. [[index:effects|Subjective effects]] include stimulation, mood [[glossary:elevation]], [[effect:pain-suppression|analgesia]], sedation, and [[effect:euphoria]], shifting from functional energy at lower doses to opioid-like [[glossary:warmth]] and cognitive slowing at higher doses{{cite|pubmed=35300296|anchor=37606447}}. The defining quality is a dual adrenergic-opioid character absent from conventional opioids, though preparation type and alkaloid content — which varies more than 50-fold across commercial products — profoundly shape the experience{{cite|pubmed=30997725|anchor=0feda863}}. Common unsought effects include [[effect:nausea]], [[effect:constipation]], and [[effect:pupil-constriction]]. Prolonged use carries clinically significant opioid-type '''dependence''' risk, with a [[glossary:withdrawal]] marked by myalgia, [[effect:insomnia]], [[effect:anxiety]], and [[effect:irritability]]{{cite|pubmed=24698080|anchor=bed234ff}}. '''Hepatotoxicity''' — predominantly cholestatic — has been documented at a median latency of roughly three weeks{{cite|pubmed=31919755|anchor=e16ab268}}. The principal contemporary safety concern is the divergence between botanical leaf and commercially enriched [[substance:7-hydroxymitragynine]] products, which carry substantially greater [[effect:respiratory-depression]] and [[glossary:dependence]] risk{{cite|pubmed=41275505|anchor=b142100b}}; no formal human [[glossary:dose-finding-study|dose-finding]] trials have been completed, and long-term safety data remain limited to observational studies and [[glossary:case-report|case reports]].

'''Kratom''' (''Mitragyna speciosa'' Korth., Rubiaceae) is a tropical tree native to Southeast Asia whose leaves contain over 40 alkaloids. Its dominant constituent, [[substance:mitragynine]], activates both [[substance_class:psychoactive/opioid]] and [[substance_class:psychoactive/stimulant]] pathways in the brain. At low doses this produces alertness and energy; at higher doses, [[effect:sedation]] and [[effect:pain-suppression]] dominate. Kratom has been used in Thailand and the Malay Peninsula for centuries — chewed by farm laborers to ease [[glossary:fatigue]] and manage pain{{cite|pubmed=26640804|anchor=c4389ede}}. The Dutch botanist Pieter Willem Korthals first formally described the plant in 1841{{cite|url=https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:756303-1|anchor=8930821f}}. It entered Western markets around 2005–2010 and has remained subject to unresolved regulatory debate. [[index:effects|Subjective effects]] include [[effect:stimulation]], mood [[glossary:elevation]], pain relief, sedation, and [[effect:euphoria]] — shifting from sociable energy at lower doses to opioid-like [[glossary:warmth]] and cognitive slowing at higher doses{{cite|pubmed=35300296|anchor=2df25a55}}. The defining quality is a dose-dependent inversion absent from conventional stimulants or opioids, though preparation type and alkaloid concentration shape the experience considerably{{cite|pubmed=30997725|anchor=8142417e}}. Common unwanted effects include [[effect:nausea]], [[effect:constipation]], and [[effect:pupil-constriction]]. Prolonged use carries significant opioid-type [[glossary:physical-dependence]] risk, and kratom is a documented cause of drug-induced liver injury{{cite|pubmed=24698080|anchor=5471af46}}{{cite|pubmed=31919755|anchor=f4616fe9}}. The highest-risk pattern is combining kratom with opioids or sedatives — additive opioid signaling can slow breathing to a dangerous or fatal degree{{cite|pubmed=37753815|anchor=ed8ddbfe}}{{cite|pubmed=21513619|anchor=31c0e5c1}}. Alkaloid concentrations vary more than 50-fold across commercial products{{cite|pubmed=30997725|anchor=a8e204aa}}, and no formal human [[glossary:dose-finding-study|dose-finding]] trials have been completed.

'''Kratom''' ('''''Mitragyna speciosa''''' Korth.) is a tropical tree in the family Rubiaceae native to Southeast Asia, from southern Indochina to New Guinea. Its pharmacology is driven by the [[substance_class:chemical/indole-alkaloid]] [[substance:mitragynine]] and its hepatic [[glossary:metabolite]] [[substance:7-hydroxymitragynine]], which together produce a dose-dependent spectrum from [[substance_class:psychoactive/stimulant]] to [[substance_class:psychoactive/opioid]]-like effects. Principal preparations — dried leaf powder, aqueous tea, and concentrated extracts — yield total effect durations of 2–6 hours depending on preparation type{{cite|pubmed=35300296|anchor=ab4a4dfe}}. First described by the Dutch botanist Pieter Willem Korthals in 1841{{cite|url=https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:756303-1|anchor=300de564}}, kratom has been used as a traditional work aid and folk medicine in Thailand and the Malay Peninsula for centuries{{cite|pubmed=26640804|anchor=5c24d245}}. The plant entered Western markets around 2005–2010 and became a focus of intensive pharmacological research after the US [[glossary:drug-enforcement-administration]] proposed — then withdrew — [[glossary:schedule-i]] classification in 2016. Current investigational domains include pain management, [[glossary:substance-use-disorder|opioid use disorder]] treatment, and the therapeutic implications of G-protein-biased [[glossary:mu-opioid-receptor]] agonism. Mitragynine acts as a G-protein-biased [[glossary:partial-agonist]] at the μ-opioid receptor that does not significantly recruit β-arrestin-2, and simultaneously binds α₂-adrenergic [[glossary:receptor|receptors]]{{cite|pubmed=28830758|anchor=03cbf6ca}}. Its metabolite 7-hydroxymitragynine is a potent full μ-opioid [[glossary:agonist]], but occurs at only trace levels in natural leaf — commercially enriched products contain dramatically higher concentrations, producing a fundamentally different pharmacological and risk profile{{cite|pubmed=41275505|anchor=21889597}}. At lower doses, users report [[effect:stimulation]], enhanced focus, and mood [[glossary:elevation]]; at higher doses, opioid-like [[effect:pain-suppression|analgesia]], [[effect:sedation]], and [[effect:euphoria]] predominate. [[effect:nausea]], [[effect:constipation]], and [[effect:pupil-constriction]] are common dose-dependent [[glossary:adverse-effects]]. Effects and duration vary substantially by preparation method, and alkaloid content varies more than 50-fold across commercial products{{cite|pubmed=30997725|anchor=191ef671}}. Kratom carries clinically significant opioid-type '''dependence''' risk with prolonged use, producing a [[glossary:withdrawal]] characterized by myalgia, [[effect:insomnia]], [[effect:anxiety]], and [[effect:irritability]]{{cite|pubmed=24698080|anchor=275a7b0e}}. [[glossary:tolerance]] develops through μ-opioid receptor mechanisms, with documented [[glossary:cross-tolerance]] to classical opioids. '''Hepatotoxicity''' — predominantly cholestatic — has been reported at a median latency of approximately three weeks{{cite|pubmed=31919755|anchor=8c405a5a}}. The principal contemporary safety concern is the divergence between botanical leaf preparations and commercially enriched 7-hydroxymitragynine products, which carry substantially greater [[effect:respiratory-depression]] and [[glossary:dependence]] risk. No formal human [[glossary:dose-finding-study|dose-finding]] trials have published results, long-term safety data remain limited to observational studies and [[glossary:case-report|case reports]], and the commercial product landscape is unregulated at the US federal level.

===Traditional and historical use=== Kratom leaf chewing in southern Thailand and the Malay Peninsula dates to at least the mid-19th century{{cite|pubmed=26640804|anchor=367c742e}}{{cite|pubmed=31308789|anchor=66036945}}; Korthals formally described the plant in 1841{{cite|url=https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:756303-1|anchor=ded0d211}}. Farm laborers chewed fresh leaves daily to combat [[glossary:fatigue]] during manual work, functioning comparably to coca leaf use in South America{{cite|pubmed=26640804|anchor=399e1a07}}. As opium became restricted, kratom substituted as a cheaper remedy for pain, cough, and [[substance_class:psychoactive/opioid]] [[glossary:withdrawal]]{{cite|pubmed=23212430|anchor=58a623ee}}{{cite|pubmed=29273821|anchor=a5cbbdda}}; in some communities it was offered to guests as a social gesture, paralleling kava{{cite|pubmed=28544011|anchor=676bd3a9}}. ===Western discovery and modern era=== Kratom products entered Western markets around 2005–2010, marketed as a legal opioid alternative{{cite|pubmed=26640804|anchor=2c1432ac}}. The first comprehensive pharmacology review appeared in 2012{{cite|pubmed=23212430|anchor=ff3f3867}}, followed by a landmark neuropharmacology review in 2018 characterizing its G-protein-biased opioid agonism{{cite|pubmed=28830758|anchor=37cf6bd2}}. Thailand banned kratom in 1943 then legalized it again in August 2021{{cite|url=https://thediplomat.com/2021/08/thailand-legalizes-kratom-popular-plant-based-painkiller/|anchor=720c726e}}. In the United States, the [[glossary:drug-enforcement-administration|DEA]] proposed [[glossary:schedule-i]] classification in August 2016{{cite|url=https://www.federalregister.gov/documents/2016/08/31/2016-20803/schedules-of-controlled-substances-temporary-placement-of-mitragynine-and-7-hydroxymitragynine-into|anchor=3cdd1e8d}} then withdrew the notice after approximately 142,000 opposing public comments — the first such withdrawal in DEA history{{cite|url=https://www.federalregister.gov/documents/2016/10/13/2016-24659/withdrawal-of-notice-of-intent-to-temporarily-place-mitragynine-and-7-hydroxymitragynine-into|anchor=dba5405f}}. {{DiscoverMore|The Krypton Incident}} Between 2009 and 2011, a kratom-based product marketed as "Krypton" was linked to '''nine unintentional deaths in Sweden'''{{cite|pubmed=21513619|anchor=f7ae1524}}. Forensic analysis revealed the powder was adulterated with [[substance:o-desmethyltramadol]] — the [[glossary:active-metabolite]] of [[substance:tramadol]]. Deaths resulted from combined opioid [[glossary:receptor]] [[effect:stimulation]], not from kratom alkaloids alone. The incident remains the first documented mass-casualty kratom-associated event and underscores the critical distinction between botanical kratom and adulterated commercial products. {{/DiscoverMore}}

====Discovery and early record==== '''''Mitragyna speciosa''''' was first described by the Dutch botanist Pieter Willem Korthals in 1841 during botanical surveys of the Dutch East Indies (present-day Indonesia and surrounding territories){{cite|url=https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:756303-1|anchor=de7b53d4}}. Korthals named the genus ''Mitragyna'' for the resemblance of its stipules to a bishop's mitre; the species epithet ''speciosa'' refers to the plant's showy flower heads. Earlier European documentation of traditional leaf chewing in Peninsular Malaysia appears in the work of Low, dating to 1836{{cite|pubmed=26640804|anchor=d2572dca}}{{cite|pubmed=31308789|anchor=06270f2d}}. ====Traditional use in Southeast Asia==== Kratom — กระท่อม (''krathom'') in Thai, ''ketum'' in Malay — has been used in southern Thailand and the Malay Peninsula for centuries as a traditional work aid and folk medicine{{cite|pubmed=26640804|anchor=6b8cd12d}}{{cite|pubmed=28544011|anchor=d21b97e5}}. Farm and plantation workers chewed fresh leaves daily to combat [[glossary:fatigue]] and sustain energy during manual labor, functioning analogously to coca leaf use in South America{{cite|pubmed=26640804|anchor=e9aec04c}}. As opium became expensive or subject to regulatory control, kratom served as a less costly alternative in rural communities for managing pain, cough, and [[effect:diarrhea]]{{cite|pubmed=23212430|anchor=00da0707}}. By the mid-20th century, kratom was also used to manage [[substance_class:psychoactive/opioid]] [[glossary:withdrawal]] symptoms in traditional contexts{{cite|pubmed=29273821|anchor=b25b6e73}}. In some Thai and Malaysian communities, kratom tea was offered to guests as a social custom, analogous to kava hospitality in Pacific island cultures{{cite|pubmed=28544011|anchor=cf025fda}}. Traditional preparations included fresh leaf chewing (with the central vein removed), boiled aqueous decoction, and dried powdered leaf mixed into beverages. ====Western encounter and research==== Kratom products began appearing in Western retail outlets and online markets around 2005–2010, marketed both as a legal alternative to opioids and as a self-treatment for opioid withdrawal{{cite|pubmed=26640804|anchor=28725b37}}. Prozialeck, Jivan, and Andurkar published the first widely cited English-language pharmacology review in 2012{{cite|pubmed=23212430|anchor=0828bd06}}. A surge in research followed, driven by interest in kratom's potential for [[glossary:substance-use-disorder|opioid use disorder]] and chronic pain management in the context of the US opioid epidemic. Kruegel and Grundmann published a comprehensive neuropharmacology review in 2018 characterizing the G-protein-biased opioid agonism of kratom alkaloids{{cite|pubmed=28830758|anchor=52692700}}. By 2025, hundreds of peer-reviewed publications had addressed the plant's alkaloid pharmacology, [[glossary:pharmacokinetics]], [[glossary:toxicity]], and [[glossary:abuse-liability]]. ====Regulatory history and the Krypton event==== Thailand banned kratom in 1943 under the Kratom Act B.E. 2486 — paradoxically, while simultaneously profiting from opium taxation — and formally classified it as a Category 5 narcotic in 1979{{cite|url=https://thediplomat.com/2021/08/thailand-legalizes-kratom-popular-plant-based-painkiller/|anchor=63ca43f7}}. On August 24, 2021, Thailand reversed course, removing kratom from its narcotics list and legalizing traditional consumption{{cite|url=https://thediplomat.com/2021/08/thailand-legalizes-kratom-popular-plant-based-painkiller/|anchor=1f14a54a}}. Between 2009 and 2011, a kratom-based product marketed as "Krypton" was linked to '''nine unintentional deaths in Sweden'''{{cite|pubmed=21513619|anchor=5c2db309}}. Forensic analysis revealed the product was kratom leaf powder adulterated with [[substance:o-desmethyltramadol]], the [[glossary:active-metabolite]] of [[substance:tramadol]]. Deaths resulted from synergistic dual [[glossary:mu-opioid-receptor]] agonism, not from kratom alkaloids alone. This event remains historically significant as the first documented mass-casualty kratom-associated incident and underscores the critical importance of distinguishing botanical kratom from adulterated commercial products. In the United States, the [[glossary:drug-enforcement-administration]] published a notice of intent on August 31, 2016 to temporarily place [[substance:mitragynine]] and [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] into [[glossary:schedule-i]]{{cite|url=https://www.federalregister.gov/documents/2016/08/31/2016-20803/schedules-of-controlled-substances-temporary-placement-of-mitragynine-and-7-hydroxymitragynine-into|anchor=e4b09fb8}}. The agency withdrew the notice on October 13, 2016 — the first such withdrawal in DEA history — following approximately 142,000 public comments, the overwhelming majority opposing scheduling{{cite|url=https://www.federalregister.gov/documents/2016/10/13/2016-24659/withdrawal-of-notice-of-intent-to-temporarily-place-mitragynine-and-7-hydroxymitragynine-into|anchor=b0b7a9b9}}.

===Traditional and historical use=== '''''Mitragyna speciosa''''' was first described by the Dutch botanist Pieter Willem Korthals in 1841 during surveys of the Dutch East Indies{{cite|url=https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:756303-1|anchor=6dc27cfa}}. Korthals named the genus for the resemblance of its stipules to a bishop's mitre; earlier European accounts of leaf chewing in Peninsular Malaysia appear in the work of Low, dating to 1836{{cite|pubmed=26640804|anchor=4ec7e7f1}}{{cite|pubmed=31308789|anchor=2bc26f96}}. Kratom — กระท่อม (''krathom'') in Thai, ''ketum'' in Malay — has been used in southern Thailand and the Malay Peninsula for centuries as a traditional work aid and folk remedy{{cite|pubmed=26640804|anchor=5b9a7f8c}}{{cite|pubmed=28544011|anchor=c2b65ce6}}. Farm laborers chewed fresh leaves daily to combat [[glossary:fatigue]] during manual work, functioning analogously to coca leaf use in South America{{cite|pubmed=26640804|anchor=5707958a}}. As opium became expensive or restricted, kratom served as a cheaper substitute for managing pain, cough, [[effect:diarrhea]], and eventually [[substance_class:psychoactive/opioid]] [[glossary:withdrawal]]{{cite|pubmed=23212430|anchor=f7bf8cca}}{{cite|pubmed=29273821|anchor=09e3e581}}. In some communities, kratom tea was offered to guests as a social gesture, paralleling kava hospitality in Pacific island cultures{{cite|pubmed=28544011|anchor=692226b9}}. ===Western discovery and research=== Kratom products appeared in Western retail and online markets around 2005–2010, marketed as a legal opioid alternative and a self-treatment for opioid withdrawal{{cite|pubmed=26640804|anchor=e04bb08f}}. Prozialeck, Jivan, and Andurkar published the first widely cited English-language pharmacology review in 2012{{cite|pubmed=23212430|anchor=1ff59e20}}, and Kruegel and Grundmann followed in 2018 with a comprehensive neuropharmacology review characterizing the G-protein-biased opioid agonism of kratom alkaloids{{cite|pubmed=28830758|anchor=f060b32f}}. By 2025, hundreds of peer-reviewed publications had addressed the plant's pharmacology, [[glossary:toxicity]], and [[glossary:abuse-liability]]. ===Modern era=== Thailand banned kratom in 1943 under the Kratom Act B.E. 2486 — paradoxically, while simultaneously profiting from opium taxation — and classified it as a Category 5 narcotic in 1979{{cite|url=https://thediplomat.com/2021/08/thailand-legalizes-kratom-popular-plant-based-painkiller/|anchor=c27a759c}}. On August 24, 2021, Thailand reversed course, removing kratom from its narcotics list{{cite|url=https://thediplomat.com/2021/08/thailand-legalizes-kratom-popular-plant-based-painkiller/|anchor=aa57bb48}}. In the United States, the [[glossary:drug-enforcement-administration|DEA]] published a notice of intent on August 31, 2016 to temporarily place [[substance:mitragynine]] and [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] into [[glossary:schedule-i]]{{cite|url=https://www.federalregister.gov/documents/2016/08/31/2016-20803/schedules-of-controlled-substances-temporary-placement-of-mitragynine-and-7-hydroxymitragynine-into|anchor=cd5fb56a}}. The agency withdrew the notice on October 13, 2016 — the first such withdrawal in DEA history — following approximately 142,000 public comments opposing scheduling{{cite|url=https://www.federalregister.gov/documents/2016/10/13/2016-24659/withdrawal-of-notice-of-intent-to-temporarily-place-mitragynine-and-7-hydroxymitragynine-into|anchor=7cbdf705}}. {{DiscoverMore|The Krypton Incident}} Between 2009 and 2011, a kratom-based product marketed as "Krypton" was linked to '''nine unintentional deaths in Sweden'''{{cite|pubmed=21513619|anchor=bcfac8d2}}. Forensic analysis revealed the powder was adulterated with [[substance:o-desmethyltramadol]], the [[glossary:active-metabolite]] of [[substance:tramadol]] — deaths resulted from synergistic dual [[glossary:mu-opioid-receptor]] agonism, not from kratom alkaloids alone. The incident remains the first documented mass-casualty kratom-associated event and underscores the critical distinction between botanical kratom and adulterated commercial products. {{/DiscoverMore}}

''Mitragyna speciosa'' belongs to the Rubiaceae family — the coffee family — making it a distant relative of coffee (''Coffea'') and ''Psychotria viridis'', the [[substance:ayahuasca]] admixture plant. The genus ''Mitragyna'' contains roughly ten tree species across tropical Africa and Asia. ''M. speciosa'' is the only member widely used for its psychoactive properties. Kratom is native to a broad arc of tropical Southeast Asia — from southern Indochina through the Malay Peninsula, Sumatra, and Borneo{{cite|pubmed=26640804|anchor=c0395879}}. It thrives in lowland tropical forest with heavy rainfall and rich alluvial soil; wild populations grow along riverbanks and in swamp margins. Indonesia is today the dominant source for international commerce. The tree grows 15–25 meters tall with a straight trunk and broadly spreading crown. Leaves are large (up to 20 cm), glossy, and oval with prominent veining. '''Leaf vein color''' (red, green, or white) is widely used as a commercial cultivar marker, but the link between vein color and alkaloid profile is inconsistent and lacks peer-reviewed validation{{flag|citation-needed}}.

''Mitragyna speciosa'' Korth. is a medium to large tropical tree reaching up to 25 m in height with a trunk diameter of up to 0.9 m{{cite|pubmed=23212430|anchor=c558bda5}}. Leaves are dark green, glossy, and ovate-elliptical, measuring 15–45 cm in length. Flowers are yellow, globular, and borne in terminal panicles; fruit is a capsule containing small, winged seeds. The plant belongs to the family Rubiaceae, sharing its family with coffee (''Coffea'' spp.) and quinine (''Cinchona'' spp.){{cite|pubmed=29456604|anchor=d946b48b}}. The genus ''Mitragyna'' contains approximately 8 species. Four synonyms for ''M. speciosa'' are confirmed by Plants of the World Online: ''Nauclea speciosa'' (Korth.) Miq. (homotypic), ''Stephegyne speciosa'' (Korth.) Korth. (homotypic), ''Nauclea korthalsii'' Steud. (heterotypic), and ''Nauclea luzoniensis'' Blanco (heterotypic){{cite|url=https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:756303-1|anchor=b96a5087}}. The native range spans southern Indochina to New Guinea, with documented populations in Borneo, Cambodia, peninsular Malaysia, Myanmar, the Philippines, Sumatra, Thailand, and Vietnam{{cite|url=https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:756303-1|anchor=0eab5ab5}}. The plant grows in the wet tropical biome, preferring lowland riverine areas and seasonally waterlogged soils. Commercial cultivation is concentrated in Indonesian Borneo (Kalimantan), the primary source of global kratom exports. Wild populations persist throughout the native range. No formal CITES listing exists for the species. No published reports of toxic look-alike species have been identified in the reviewed literature. ''Mitragyna'' species are morphologically distinct trees in their native range, and botanical [[effect:confusion]] risk in Southeast Asian traditional contexts is low. For dried powder preparations sold in Western markets, the primary identification risk is mislabeling and [[glossary:adulterant|adulteration]] rather than botanical [[glossary:misidentification]]. Commercially, kratom products are often classified by "vein color" — red, green, and white — a system widely used in retail marketing. No peer-reviewed phytochemical studies have validated vein color as a reliable indicator of alkaloid chemotype or predictable pharmacological differences{{flag|citation-needed}}. This classification should be treated as a commercial marketing convention until published pharmacognosy data confirm systematic compositional distinctions.

''Mitragyna speciosa'' Korth. belongs to the family Rubiaceae — the coffee family — making it a distant botanical relative of ''Coffea'' (coffee) and ''Psychotria'' (the genus containing the [[substance:ayahuasca]] admixture ''Psychotria viridis''). The genus ''Mitragyna'' contains roughly ten species of trees distributed across tropical Africa and Asia; ''M. speciosa'' is the only member widely used for its psychoactive properties. Kratom is native to a broad swath of tropical Southeast Asia, from southern Indochina through the Malay Peninsula, Sumatra, Borneo, and as far east as New Guinea{{cite|pubmed=26640804|anchor=78eb43cd}}. It thrives in lowland tropical forest with heavy rainfall, rich alluvial soils, and partial to full sun. Wild populations grow along riverbanks and in swamp margins. Today it is widely cultivated in Thailand, Indonesia, and Malaysia, with Indonesia the dominant source for international commerce. The tree reaches 15–25 meters at maturity with a straight trunk and broadly spreading crown. Leaves are the pharmacologically relevant organ: large (up to 20 cm long), glossy, ovate, with prominent pinnate venation. '''Leaf vein color''' — red, green, or white — is the primary commercial cultivar marker, though the relationship between vein color and alkaloid profile is inconsistent and poorly validated in peer-reviewed literature{{flag|citation-needed}}. Flowers are deep yellow, globular, and clustered in heads, giving rise to the genus name (''mitra'' = mitre, for the shape of the stipules). For psychoactive use, leaves are harvested at maturity when alkaloid content is highest. Traditional preparation involves chewing fresh leaves with the tough central vein removed. For commercial sale, leaves are dried, powdered, and sometimes further extracted. Drying method, leaf maturity, and post-harvest processing all influence final alkaloid concentration.

Kratom leaf contains over 40 identified [[substance_class:chemical/indole-alkaloid|indole alkaloids]], but its pharmacology is dominated by two: [[substance:mitragynine]] and its hepatic [[glossary:metabolite]] [[substance:7-hydroxymitragynine]]. Mitragynine constitutes approximately 66% of total alkaloid content{{cite|doi=10.1021/acs.jnatprod.6b00838|anchor=19a510c8}} and typically represents 0.5–1.5% of dry leaf weight. It acts as a [[glossary:partial-agonist]] at [[glossary:mu-opioid-receptor|μ-opioid receptors]] with G-protein-biased signaling and simultaneously engages α₂-adrenergic [[glossary:receptor|receptors]]{{cite|pubmed=28830758|anchor=9ef25aa1}}. This [[glossary:dual-mechanism]] is proposed to explain the [[substance_class:psychoactive/stimulant]] character at low doses (adrenergic dominance) and [[substance_class:psychoactive/opioid]]-like [[effect:sedation]] at higher doses (μ-opioid dominance). 7-Hydroxymitragynine occurs at trace levels in unprocessed leaf but is also produced ''in vivo'' through hepatic [[glossary:cyp3a4]] [[glossary:metabolism]] of mitragynine{{cite|pubmed=33847897|anchor=12e4a300}}. It binds μ-opioid receptors with roughly 13-fold greater [[glossary:potency]] than mitragynine and acts as a [[glossary:full-agonist]] without significant α₂-adrenergic activity{{cite|pubmed=36153006|anchor=81b71ed1}}{{cite|pubmed=15304982|anchor=cefe8b3c}}. Commercially enriched extracts contain dramatically higher 7-hydroxymitragynine concentrations than botanical leaf, producing a fundamentally different pharmacological and risk profile{{cite|pubmed=41275505|anchor=d8f95cfb}}. Minor alkaloids include '''speciogynine''' and '''speciociliatine''' (both diastereomers of mitragynine, each approximately 6–7% of total alkaloid content) and '''paynantheine''' (roughly 9%). These accumulate in [[glossary:plasma]] with repeated daily dosing{{cite|pubmed=39644381|anchor=e3027daa}} but their individual contributions to [[index:effects|subjective effects]] remain poorly characterized — most evidence is ''in vitro''. Alkaloid concentrations vary enormously across commercial products. A survey of retail kratom found mitragynine content ranging from 0.7% to 38.7% w/w — a greater-than-50-fold difference{{cite|pubmed=30997725|anchor=969e1fc8}}. Growing conditions, leaf maturity at harvest, drying method, and post-harvest extraction all contribute to this variability. Vein color (red, green, white) is marketed as a reliable potency indicator but lacks consistent peer-reviewed validation{{flag|citation-needed}}.

Kratom leaf contains over 40 identified alkaloids, but two dominate its pharmacology. [[substance:mitragynine]] makes up roughly 66% of total alkaloid content{{cite|doi=10.1021/acs.jnatprod.6b00838|anchor=0095310b}} — typically 0.5–1.5% of dry leaf weight. It activates [[substance_class:psychoactive/opioid]] [[glossary:receptor|receptors]] in the brain while simultaneously engaging adrenergic ([[substance_class:psychoactive/stimulant]]) pathways{{cite|pubmed=28830758|anchor=7842e04d}}. This dual action is what produces kratom's characteristic dose-dependent shift: [[effect:stimulation]] at low doses, [[effect:sedation]] and [[effect:pain-suppression|analgesia]] at higher doses. [[substance:7-hydroxymitragynine]] forms in the body as mitragynine is processed by the liver{{cite|pubmed=33847897|anchor=3e9f0886}}. It binds opioid receptors with roughly 13 times the [[glossary:potency]] of mitragynine and acts as a full opioid [[glossary:agonist]] — not partial{{cite|pubmed=36153006|anchor=41090c6f}}{{cite|pubmed=15304982|anchor=91ded454}}. Commercial extracts can contain dramatically enriched 7-hydroxymitragynine concentrations, fundamentally changing both the experience and the risk profile compared to plain leaf{{cite|pubmed=41275505|anchor=23f12186}}. Minor alkaloids — speciogynine, speciociliatine (each roughly 6–7% of total alkaloids), and paynantheine (roughly 9%) — accumulate in the body with repeated daily dosing{{cite|pubmed=39644381|anchor=973f74b3}}. Their individual contributions to [[index:effects|subjective effects]] are poorly understood; most evidence is from laboratory studies. Mitragynine content across commercial products ranges from 0.7% to 38.7% by weight — a greater than 50-fold difference{{cite|pubmed=30997725|anchor=e3910051}}.

The alkaloid profile of kratom has been systematically characterized by ultra-performance liquid chromatography-tandem [[glossary:mass-spectrometry]] (UPLC-MS/MS), with ten key alkaloids quantified across leaf extracts and commercial products{{cite|pubmed=30997725|anchor=e3c393d8}}. All are [[substance_class:chemical/indole]] or oxindole monoterpenoid alkaloids of the Corynanthe type{{cite|pubmed=15304982|anchor=c2c66e5d}}. ====Dominant alkaloid: mitragynine==== [[substance:mitragynine]] (C₂₃H₃₀N₂O₄, MW 398.5 g/mol) is the dominant alkaloid in ''M. speciosa'' leaf, constituting 0.7–38.7% of commercial product weight (w/w){{cite|pubmed=30997725|anchor=6b483da4}}. This greater-than-50-fold concentration range reflects variation in geographic origin, harvest timing, drying method, extraction process, and intentional enrichment or [[glossary:adulterant|adulteration]]. Mitragynine functions as a partial [[glossary:mu-opioid-receptor]] [[glossary:agonist]] with G-protein-biased signaling and concurrent α₂-adrenergic [[glossary:receptor]] activity; detailed receptor pharmacology is covered on the mitragynine compound page. ====7-Hydroxymitragynine==== [[substance:7-hydroxymitragynine]] (C₂₃H₃₀N₂O₅, MW 414.5 g/mol) occurs at trace levels (<1% w/w) in natural leaf material but is produced from mitragynine by hepatic and intestinal [[glossary:cyp3a4]] [[glossary:metabolism]]{{cite|pubmed=33847897|anchor=ee13abf4}}. Despite its low natural abundance, 7-hydroxymitragynine is the more pharmacologically potent alkaloid — a full μ-opioid receptor agonist approximately 46-fold more potent than [[substance:morphine]] in some [[glossary:assay|assays]]{{cite|pubmed=15304982|anchor=0829bb16}}. The US market increasingly offers chemically enriched or [[glossary:semi-synthetic]] 7-hydroxymitragynine products marketed as "kratom" that are pharmacologically and toxicologically distinct from botanical preparations{{cite|pubmed=41275505|anchor=215959fc}}{{cite|pubmed=40762659|anchor=0be054e4}}. This distinction is critical for dose, [[glossary:dependence]], and safety characterization. ====Minor alkaloids==== Three additional alkaloids are present at pharmacologically relevant concentrations{{cite|pubmed=30997725|anchor=dfe0e2ec}}: * '''Paynantheine''' (0.3–12.8% w/w): the second most abundant alkaloid; demonstrates weak [[substance_class:psychoactive/opioid]] receptor activity * '''Speciociliatine''' (0.4–12.3% w/w): a diastereomer of mitragynine at C-12b; largely inactive at the μ-opioid receptor * '''Speciogynine''' (0.1–5.3% w/w): minor opioid activity Additional minor alkaloids — corynantheidine, corynoxine, corynoxine B, and isocorynantheidine — have been quantified at 0.01–2.8% w/w. Mitraphylline was below the lower limit of quantification in all analyzed products{{cite|pubmed=30997725|anchor=08e34dd6}}. ====Preparation effects on alkaloid ratios==== Dried leaf powder and capsules retain the native alkaloid ratio, with mitragynine dominant and 7-hydroxymitragynine at trace levels. Aqueous decoctions (traditional tea) preferentially extract water-soluble alkaloids, yielding a ratio similar to raw leaf but with per-dose mitragynine dependent on leaf quantity and brew time. Ethanolic extracts achieve more complete alkaloid extraction, delivering higher mitragynine per dose. Concentrated "full-spectrum" extracts further enrich mitragynine while maintaining relatively low 7-hydroxymitragynine. Enriched 7-hydroxymitragynine products represent a pharmacologically distinct category with dramatically different [[glossary:receptor-binding]] profiles and risk characteristics{{cite|pubmed=41275505|anchor=9a81472b}}.

===Where it acts=== Kratom's mixed pharmacology explains its unusual dose-dependent character. [[substance:mitragynine]] partially activates [[glossary:mu-opioid-receptor|μ-opioid receptors]] with G-protein-biased signaling — meaning it does not significantly recruit β-arrestin-2 — and simultaneously agonizes α₂-adrenergic [[glossary:receptor|receptors]]{{cite|pubmed=28830758|anchor=8354f582}}{{cite|pubmed=27556704|anchor=95066a64}}. At lower doses, adrenergic [[effect:stimulation]] predominates, producing alertness and energy; at higher doses, [[substance_class:psychoactive/opioid]] [[glossary:receptor-binding|receptor engagement]] overtakes it, producing [[effect:sedation]] and [[effect:pain-suppression|analgesia]]. Kratom alkaloids additionally interact with serotonergic, dopaminergic, and noradrenergic systems, contributing to mood [[glossary:elevation]] and, during [[glossary:withdrawal]], affective [[glossary:disturbance]]{{cite|pubmed=39662722|anchor=488cdfd3}}{{cite|pubmed=40483515|anchor=e6b9a962}}. ===What it changes=== The G-protein-biased agonism of mitragynine is proposed to preserve analgesic [[glossary:efficacy]] while reducing β-arrestin-2-mediated [[glossary:adverse-effects]] such as [[effect:respiratory-depression]] and rapid [[glossary:tolerance]]{{cite|pubmed=27556704|anchor=7b3b4f39}}. However, respiratory depression risk is reduced rather than eliminated, particularly with concentrated [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] preparations{{cite|pubmed=36308562|anchor=c416a0ef}}. [[glossary:chronic-use]] leads to opioid-receptor adaptation and tolerance, with documented [[glossary:cross-tolerance]] to classical opioids{{cite|pubmed=41487756|anchor=3537eb86}}. Cognitive effects with sustained use are attributed to [[glossary:disruption]] of [[glossary:neuroplasticity]] across opioid, serotonergic, and adrenergic systems{{cite|pubmed=39643045|anchor=68e8648b}}. {{DiscoverMore|Open Questions}} The relative contribution of α₂-adrenergic versus μ-opioid agonism to the [[substance_class:psychoactive/stimulant]]-to-sedative dose shift has not been resolved. Preparation-specific [[glossary:pharmacokinetics]] for extracts and enriched 7-hydroxymitragynine products remain uncharacterized in controlled human studies. No neuroimaging studies using kratom preparations in human subjects have been published. {{/DiscoverMore}}

===Where it acts=== [[substance:mitragynine]] partially activates [[substance_class:psychoactive/opioid]] [[glossary:receptor|receptors]] while simultaneously engaging adrenergic ([[substance_class:psychoactive/stimulant]]) receptors{{cite|pubmed=28830758|anchor=e61c528e}}{{cite|pubmed=27556704|anchor=71348ba7}}. At lower doses, adrenergic [[effect:stimulation]] dominates — producing alertness and energy. At higher doses, opioid [[glossary:receptor-binding|receptor engagement]] takes over, producing [[effect:sedation]], [[effect:pain-suppression|analgesia]], and [[glossary:warmth]]. Kratom alkaloids also interact with [[glossary:serotonin]] and [[substance_class:pharmacological/dopamine-system|dopamine systems]], contributing to mood [[glossary:elevation]] and — during [[glossary:withdrawal]] — emotional [[glossary:disruption]]{{cite|pubmed=39662722|anchor=868f2cf1}}{{cite|pubmed=40483515|anchor=534fd745}}. ===What it changes=== With [[glossary:chronic-use]], the brain's opioid receptors adapt and [[glossary:tolerance]] builds — [[glossary:cross-tolerance]] with classical opioids is documented{{cite|pubmed=41487756|anchor=187e4256}}. The partial opioid agonism of mitragynine is thought to produce less [[effect:respiratory-depression]] than a full opioid [[glossary:agonist]], though this protection diminishes substantially with concentrated extract products{{cite|pubmed=27556704|anchor=4dd2fb0d}}{{cite|pubmed=36308562|anchor=c715dfc6}}. Sustained use may disrupt [[glossary:neuroplasticity]] across opioid, serotonin, and adrenergic systems, impairing cognition{{cite|pubmed=39643045|anchor=3ed30b7c}}. {{DiscoverMore|Open Questions}} The relative contribution of adrenergic versus opioid signaling to the stimulant-to-sedative dose shift has not been resolved. [[glossary:pharmacokinetics]] for extracts and enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] products remain uncharacterized in controlled human studies. No neuroimaging studies using kratom preparations in human subjects have been published. {{/DiscoverMore}}

Kratom preparations span a spectrum from minimally processed botanical material to chemically enriched isolates, with clinically significant differences in alkaloid content, onset, and risk profile. [[glossary:potency]] variability is a defining feature of the commercial kratom landscape: alkaloid content varies more than 50-fold across vendors and batches{{cite|pubmed=30997725|anchor=3e2441cc}}. The Dose · by preparation card presents [[glossary:dose-range|dose ranges]] in structured format; the narrative below contextualizes each preparation. ====Dried leaf powder (oral)==== The most common Western commercial form. Dried leaves are ground to a fine powder and consumed in capsules, mixed into beverages, or taken directly. This preparation retains the native alkaloid ratio, with [[substance:mitragynine]] dominant and [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] at trace levels. '''Dried leaf powder (oral):''' Threshold approximately 1–3 g; common 3–8 g; heavy >8–15 g{{cite|pubmed=28521200|anchor=586fc04d}}{{cite|pubmed=35300296|anchor=2bc7c591}}. Onset: 15–30 minutes. [[glossary:peak]]: 1–2 hours. Total duration: 2–5 hours. Effects at lower doses (1–3 g) are predominantly [[substance_class:psychoactive/stimulant]]; [[substance_class:psychoactive/opioid]]-like [[effect:pain-suppression|analgesia]] and [[effect:sedation]] emerge above approximately 5 g{{cite|pubmed=35300296|anchor=edc70dba}}. {{flag|safety-citation-needed}} ''All dose ranges for dried leaf powder are derived from survey studies and traditional use accounts, not controlled dose-finding trials.'' ====Traditional tea / decoction (oral)==== The traditional Southeast Asian preparation. Fresh or dried leaves are boiled in water for 15–45 minutes, with the central vein typically removed. One glass of traditional kratom tea contains approximately 19–29 mg mitragynine, derived from a study of heavy users consuming 76–115 mg mitragynine across 4 glasses daily{{cite|pubmed=29558272|anchor=d4107fd7}}. Users in Malaysian studies consumed 1–8+ glasses daily{{cite|pubmed=29558272|anchor=4f014b5e}}. '''Traditional tea (oral):''' Onset: 15–45 minutes. Duration: 3–6 hours. Aqueous extraction preferentially captures water-soluble alkaloids; the overall alkaloid ratio is similar to leaf powder. ====Concentrated extracts==== Ethanolic or aqueous extracts concentrate mitragynine relative to raw leaf material. Commercial products marketed as "full-spectrum" extracts and liquid "kratom shots" may contain substantially higher mitragynine per dose than an equivalent weight of leaf powder. Tinctures ([[glossary:sublingual]] or oral) may have faster onset than powder. No published controlled human dose data exist for these preparations. The product landscape is characterized by inconsistent labeling and minimal quality assurance{{cite|pubmed=40762659|anchor=95a20e82}}. ====7-Hydroxymitragynine enriched products==== {{Warning}}Products containing chemically enriched or [[glossary:semi-synthetic]] 7-hydroxymitragynine are '''pharmacologically distinct''' from botanical kratom preparations{{cite|pubmed=41275505|anchor=e931ec07}}{{cite|pubmed=40762659|anchor=a1a45a79}}. Natural kratom leaf contains only trace 7-hydroxymitragynine; enriched products may contain orders of magnitude more. These products exhibit potent full [[glossary:mu-opioid-receptor]] agonism, carry substantially greater [[effect:respiratory-depression]] risk, and produce more severe [[glossary:dependence]] and [[glossary:withdrawal]]{{cite|pubmed=41487756|anchor=fef60bee}}. No published controlled human dose data exist. The US [[glossary:fda]] has issued specific warning letters targeting 7-hydroxymitragynine enriched products{{cite|url=https://www.fda.gov/news-events/public-health-focus/fda-and-kratom|anchor=5d0fcee6}}.{{/Warning}} ====Capsules==== Commercial kratom capsules contain dried leaf powder, typically 0.5–1 g per capsule. Pharmacokinetically equivalent to loose dried leaf powder; capsule dissolution may slightly delay onset compared to direct powder [[glossary:ingestion]]. Dose ranges and duration are identical to those for dried leaf powder above.

Kratom's character is defined by a dose-dependent shift. At low doses, the experience is warm, sociable [[effect:stimulation]] — mood lifts, focus sharpens, energy builds. At higher doses, [[substance_class:psychoactive/opioid]]-like qualities emerge: pain fades, the body feels heavy, thinking slows. Preparation type shapes the arc: leaf powder tea produces a gradual curve, while concentrated extracts compress onset and amplify the peak. At low doses the profile resembles coca leaf — functional energy with an underpinning of mood lift. At higher doses it approaches mild opioid [[effect:pain-suppression|analgesia]], comparable in [[glossary:warmth]] and body feeling to a low dose of [[substance:codeine]], but with a [[substance_class:psychoactive/stimulant]] quality that conventional opioids lack. Enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] extract products produce a qualitatively different experience dominated by full opioid character — closer to a classical opioid than to traditional leaf.

Kratom's experiential character is defined by a dose-dependent inversion: at lower doses, a warm, sociable [[effect:stimulation]] with mood [[glossary:elevation]] and enhanced focus; at higher doses, [[substance_class:psychoactive/opioid]]-like [[effect:pain-suppression|analgesia]], [[effect:bodily-heaviness]], and cognitive slowing. The [[substance_class:psychoactive/stimulant]] range carries a quality distinct from [[substance:caffeine]] — attributed to concurrent adrenergic and partial opioid [[glossary:receptor]] activity — while the sedative range approaches the analgesic [[glossary:warmth]] of [[substance:codeine]]. Preparation type is the primary modifier: leaf powder tea produces a gentler arc than concentrated extracts, which compress onset and amplify peak [[glossary:intensity]]. Set, setting, and individual opioid [[glossary:tolerance]] strongly shape the experience. Pharmacologically, kratom occupies a position between stimulant plants and classical opioids. Its low-dose profile resembles coca leaf — functional energy with mood lift — while its higher-dose profile approaches mild opioid analgesia, distinguished by reduced [[effect:respiratory-depression]] risk and a dual adrenergic-opioid quality absent from conventional opioids. Enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] products produce a qualitatively different experience dominated by full [[glossary:mu-opioid-receptor]] agonism, closer to classical opioid character than to traditional leaf preparations.

====Toxicity==== No human [[glossary:lethal-dose]] has been established. [[glossary:acute-toxicity]] from traditional leaf doses is low; [[glossary:chronic-toxicity]] data are limited but raise concerns for liver and cognitive function{{cite|pubmed=39802218|anchor=3f529ffb}}. Kratom is a documented cause of '''drug-induced liver injury''' with a predominantly cholestatic pattern — meaning bile flow from the liver becomes blocked{{cite|pubmed=31919755|anchor=3d81cf66}}. Jaundice, itching, and dark urine are common early signs, appearing at a median of about 20 days from first use (range 2–49 days){{cite|pubmed=31919755|anchor=00dd8d02}}. Some cases have mimicked primary biliary cholangitis — a chronic autoimmune liver condition{{cite|pubmed=33200023|anchor=cdbf0957}}. Published kratom-associated fatalities nearly all involve [[glossary:polydrug]] exposure. Nine deaths in Sweden resulted from kratom powder adulterated with [[substance:o-desmethyltramadol]] — not from kratom alkaloids alone{{cite|pubmed=21513619|anchor=e7e9e8c8}}. One documented death involved kratom combined with [[substance:hydromorphone]]; another involved a 26-year-old male where polydrug exposure was not fully excluded{{cite|pubmed=37753815|anchor=a58c533f}}{{cite|pubmed=29456604|anchor=a1a1fa50}}. No deaths attributed solely to botanical kratom appear in Southeast Asian published literature{{cite|pubmed=31308789|anchor=c7b638e4}}. Commercial kratom products carry additional [[glossary:contamination|contaminant]] risks: * '''Synthetic opioid adulterants:''' O-desmethyltramadol documented in "Krypton" products (9 fatalities){{cite|pubmed=21513619|anchor=c1ecb4bb}}; enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] in products marketed as botanical kratom{{cite|pubmed=41275505|anchor=b3fc80a0}} * '''Microbial contamination:''' Salmonella contamination cited by [[glossary:fda]] as basis for import detentions{{cite|url=https://www.fda.gov/news-events/public-health-focus/fda-and-kratom|anchor=ba345ac4}}{{flag|citation-needed}} * '''Heavy metals:''' Lead and cadmium contamination is a theoretical concern for dried botanical products{{flag|citation-needed}} * '''Labeling inaccuracy:''' [[substance:mitragynine]] content ranges 0.7–38.7% w/w across commercial products{{cite|pubmed=30997725|anchor=30587fb2}} No federally mandated testing program exists for commercial kratom in the United States. ====Psychological Risks==== Higher doses and concentrated extract products are associated with [[effect:anxiety]], [[effect:irritability]], and — in rare documented cases — [[glossary:psychosis]]{{cite|pubmed=41487756|anchor=31440347}}. [[glossary:chronic-use]] may impair cognition by disrupting [[glossary:neuroplasticity]] across [[substance_class:psychoactive/opioid]], [[glossary:serotonin]], and adrenergic systems{{cite|pubmed=39643045|anchor=fed84658}}{{cite|pubmed=38523471|anchor=8eafeb7a}}. Patterns of use meeting diagnostic criteria for [[glossary:substance-use-disorder]] have been documented, with dosing frequency a stronger predictor of [[glossary:dependence]] [[glossary:severity]] than dose size{{cite|pubmed=38788532|anchor=f33dff69}}. ====Tolerance & Dependence==== [[glossary:tolerance]] develops with prolonged use through opioid [[glossary:receptor]] adaptation. [[substance:buprenorphine]] can precipitate [[glossary:withdrawal]] in kratom-dependent individuals, confirming clinically significant [[glossary:cross-tolerance]] with conventional opioids{{cite|pubmed=41487756|anchor=9bcad4ee}}. Mitragynine has a [[glossary:half-life]] of approximately 23 hours{{cite|pubmed=25995615|anchor=a7bf1c7e}}. [[glossary:physical-dependence]] risk is '''high'''{{cite|pubmed=24698080|anchor=5b18f50c}}. Studies of 150–170 regular Malaysian kratom tea users found that stopping produced mild anxiety (70%), mild [[effect:depression]] (81%), moderate pain (84%), and sleep problems (46%){{cite|pubmed=30152738|anchor=a39480b9}}{{cite|pubmed=29558272|anchor=3ff0723b}}. Users consuming four or more glasses daily had higher rates of depression, pain, and [[glossary:sleep-disruption|sleep disturbance]]{{cite|pubmed=29558272|anchor=d8340320}}. Withdrawal was described as milder than classical opioid withdrawal in these studies{{cite|pubmed=29558272|anchor=d4dc1c29}}. Severe withdrawal from concentrated 7-hydroxymitragynine products — including psychosis and breathing failure requiring intubation — has been documented{{cite|pubmed=41487756|anchor=c302e1a9}}. {{Recovery}}Withdrawal from botanical kratom leaf at moderate doses is generally manageable without medical intervention{{cite|pubmed=29558272|anchor=cdbe2334}}. Low-dose [[glossary:sublingual]] buprenorphine has achieved complete kratom [[glossary:abstinence]] within 3 weeks in documented cases{{cite|pubmed=40518266|anchor=ca7ac9e3}}. Reducing use frequency — rather than dose size alone — may be more effective, given that frequency shows a stronger link to dependence severity{{cite|pubmed=38788532|anchor=c9c6d260}}.{{/Recovery}} ====Drug Interactions==== The highest-risk combination is opioids. Adding kratom to an opioid amplifies opioid receptor activity; fatal outcomes have been documented{{cite|pubmed=37753815|anchor=94f5e4d9}}{{cite|pubmed=21513619|anchor=1afc7c14}}. [[substance_class:chemical/benzodiazepine|Benzodiazepines]], [[substance:alcohol]], [[substance:ghb]], and [[substance:ketamine]] carry plausible risk of additive [[effect:sedation]] and breathing depression{{flag|safety-citation-needed}}. Kratom inhibits [[glossary:cyp3a4]] — a liver [[glossary:enzyme]] that clears many common drugs. A [[glossary:clinical-study]] found a 2 g kratom dose raised [[substance:midazolam]] blood levels by 1.39× (90% CI: 1.23–1.57){{cite|pubmed=36924284|anchor=9aa940fa}}; pharmacokinetic modeling predicts a 2.2–2.7× increase with direct co-administration{{cite|pubmed=41743842|anchor=0c6acd99}}. Opioids, benzodiazepines, immunosuppressants, and statins may reach toxic blood levels when combined with kratom. [[glossary:cyp2d6]] [[glossary:inhibition]] is seen in laboratory studies{{cite|pubmed=21876481|anchor=99beb59d}} but was not clinically significant at a 2 g dose{{cite|pubmed=36924284|anchor=d4582ef9}}. With repeated use, kratom activates a regulatory pathway that increases CYP3A4, [[glossary:cyp1a2]], and P-glycoprotein activity 3–6-fold{{cite|pubmed=29071751|anchor=478d5e08}} — potentially reducing the [[glossary:efficacy]] of co-administered drugs over time. ====Contraindications==== '''Pregnancy:''' Contraindicated. Neonatal withdrawal syndrome has been documented with kratom use during [[glossary:pregnancy]]{{cite|pubmed=30744980|anchor=caf529bc}}; teratogenicity is unknown, and the opioid-like mechanism warrants avoidance during pregnancy and lactation{{cite|pubmed=37679866|anchor=8fcb0169}}. '''Liver disease:''' Contraindicated. Kratom is a documented cause of drug-induced liver injury and may worsen existing hepatic conditions{{cite|pubmed=31919755|anchor=ed281754}}. '''Concurrent opioid use:''' Contraindicated. Additive opioid receptor [[effect:stimulation]] with documented fatal outcomes{{cite|pubmed=37753815|anchor=f42c554c}}{{cite|pubmed=21513619|anchor=5b49d993}}. '''Drugs with a narrow therapeutic index (e.g., cyclosporine, fentanyl, alprazolam):''' Relative [[glossary:contraindication]]. Kratom inhibits CYP3A4 at typical oral doses and can raise co-administered drug concentrations to toxic levels{{cite|pubmed=36924284|anchor=c23b898f}}. '''Personal or family history of psychosis:''' Relative contraindication for concentrated extract products, which are associated with psychotic symptoms during withdrawal{{cite|pubmed=41487756|anchor=d264ac45}}. '''Kidney impairment:''' Relative contraindication. Renal [[glossary:impairment]] was a contributing factor in a documented fatal polydrug case; kratom's large [[glossary:volume-of-distribution]] (38 L/kg) suggests altered [[glossary:accumulation]] with impaired [[glossary:clearance]]{{cite|pubmed=37753815|anchor=70ac3e05}}{{cite|pubmed=25995615|anchor=3058afd6}}.

====Toxicity==== No human [[glossary:lethal-dose]] has been established for [[substance:mitragynine]] or any kratom preparation. [[glossary:animal-model|Animal studies]] document hepatic, renal, pulmonary, and [[glossary:central-nervous-system|CNS]] [[glossary:toxicity]] at high doses{{cite|pubmed=39802218|anchor=fcaa0529}}. [[glossary:acute-toxicity]] from traditional leaf doses is considered low; chronic toxicity data are limited but raise concerns for liver and cognitive function{{cite|pubmed=39802218|anchor=e22c6328}}. Kratom is a documented cause of '''drug-induced liver injury (DILI)''' with a predominantly cholestatic pattern{{cite|pubmed=31919755|anchor=1ea6f883}}. A comprehensive review found a median latency of 20.6 days from first use to symptom onset (range 2–49 days), with jaundice, pruritus, and dark urine as common presenting features{{cite|pubmed=31919755|anchor=ebcb2235}}. Causality assessment concluded that kratom "likely causes liver injury based on totality of evidence"{{cite|pubmed=31919755|anchor=68543566}}. Individual cases have demonstrated cholestatic injury mimicking primary biliary cholangitis{{cite|pubmed=33200023|anchor=594d90b2}}. Published fatalities attributed in whole or part to kratom involve [[glossary:polydrug]] exposures in nearly all cases. Nine deaths in Sweden resulted from "Krypton" — kratom powder adulterated with [[substance:o-desmethyltramadol]]{{cite|pubmed=21513619|anchor=470b7ba5}}. A fatal case involving [[substance:hydromorphone]] and kratom attributed death to hydromorphone toxicity with mitragynine as a contributing factor{{cite|pubmed=37753815|anchor=508af445}}. A 26-year-old male died of cardiorespiratory failure following suspected kratom use, though polydrug exposure was not fully excluded{{cite|pubmed=29456604|anchor=20220e22}}. No deaths attributed solely to botanical kratom appear in published Southeast Asian literature{{cite|pubmed=31308789|anchor=9f4d42a3}}. '''Contaminant and adulterant risk''' is a distinct safety concern for commercial kratom products: * '''Synthetic opioid adulterants:''' O-desmethyltramadol was documented in "Krypton" products (9 fatalities){{cite|pubmed=21513619|anchor=dbab8a09}}; semi-synthetic [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] enrichment appears in products marketed as botanical kratom{{cite|pubmed=41275505|anchor=ef39de25}} * '''Microbial contamination:''' FDA Import Alert 54-15 cites Salmonella contamination risk as a basis for detaining imported products{{cite|url=https://www.fda.gov/news-events/public-health-focus/fda-and-kratom|anchor=f3e62a87}}{{flag|citation-needed}} * '''Heavy metals:''' Lead, cadmium, and other heavy metal contamination is a theoretical concern for dried botanical products; no published validated surveys specific to kratom products were identified{{flag|citation-needed}} * '''Labeling inaccuracy:''' Mitragynine content ranges 0.7–38.7% w/w across commercial products{{cite|pubmed=30997725|anchor=78350341}} No ISO/IEC-accredited mandatory federal testing program exists for commercial kratom products in the United States. Some US states implementing Kratom Consumer Protection Act (KCPA) frameworks require testing and labeling standards. ====Psychological Risks==== Higher doses and concentrated 7-hydroxymitragynine products are associated with [[effect:anxiety]], [[effect:irritability]], and — in rare documented cases — [[glossary:psychosis]]{{cite|pubmed=41487756|anchor=8ac11edb}}. Chronic kratom use may adversely affect cognitive performance through [[glossary:disruption]] of [[glossary:neuroplasticity]] via [[substance_class:psychoactive/opioid]], serotonergic, and adrenergic [[glossary:receptor-binding|receptor interactions]]{{cite|pubmed=39643045|anchor=8f449c0c}}. Epigenetic mechanisms have been implicated in [[glossary:withdrawal]]-associated [[effect:cognitive-impairment]] in animal models{{cite|pubmed=38523471|anchor=183d5d75}}. Kratom use patterns meeting DSM-5 substance use disorder criteria have been documented, with dose frequency showing a stronger association with [[glossary:dependence]] [[glossary:severity]] than dose amount{{cite|pubmed=38788532|anchor=5970c82c}}. ====Tolerance & Dependence==== [[glossary:tolerance]] develops with prolonged use through μ-opioid mechanisms. [[glossary:cross-tolerance]] with classical opioids is documented; [[substance:buprenorphine]] can precipitate withdrawal in kratom-dependent individuals, confirming clinically significant opioid cross-tolerance{{cite|pubmed=41487756|anchor=e8adb505}}. The mitragynine [[glossary:half-life]] is approximately 23 hours{{cite|pubmed=25995615|anchor=a509b0a1}}; specific tolerance recovery timelines have not been validated in published studies. Physical dependence [[glossary:liability]] is '''high'''{{cite|pubmed=24698080|anchor=88110606}}. In studies of 150–170 regular Malaysian kratom tea users, cessation produced mild anxiety (70%), mild [[effect:depression]] (81%), moderate pain intensity (84%), moderate pain interference (70%), and sleep problems (46%){{cite|pubmed=30152738|anchor=604f9489}}{{cite|pubmed=29558272|anchor=5ef41565}}. Severity was dose-dependent — users consuming ≥4 glasses daily had higher odds of more severe depression, pain interference, and sleep problems{{cite|pubmed=29558272|anchor=b4163046}}. Withdrawal was characterized as "relatively mild" compared to classical opioid analgesic withdrawal in these studies{{cite|pubmed=29558272|anchor=4e152aac}}. Severe withdrawal from concentrated 7-hydroxymitragynine products — including psychosis and respiratory compromise requiring intubation — has been documented in [[glossary:case-report|case reports]]{{cite|pubmed=41487756|anchor=46c8d7fd}}. {{Recovery}}Withdrawal from botanical kratom leaf at moderate doses is generally manageable without medical intervention{{cite|pubmed=29558272|anchor=d1bc9355}}. Low-dose sublingual buprenorphine has achieved complete kratom abstinence within 3 weeks in documented cases{{cite|pubmed=40518266|anchor=db6d5535}}. Reducing use frequency — rather than dose alone — may be a key [[index:harm-reduction|harm reduction]] strategy, given that frequency shows a stronger association with dependence severity than dose amount{{cite|pubmed=38788532|anchor=4714c1c2}}.{{/Recovery}} ====Drug Interactions==== Kratom is both a [[glossary:cytochrome-p450|CYP enzyme]] [[glossary:substrate]] and [[glossary:inhibitor]]/inducer, creating complex herb–[[glossary:drug-interaction]] liability. '''CYP3A4 inhibition''' is the best-characterized mechanism: a single 2 g dose of kratom tea increased [[substance:midazolam]] AUC by 1.39× (90% CI: 1.23–1.57) and C''max'' by 1.50× in 12 healthy adults{{cite|pubmed=36924284|anchor=525c4f79}}. PBPK modeling predicts mitragynine increases midazolam exposure 2.2–2.7× with co-administration{{cite|pubmed=41743842|anchor=66b9ae2b}}. Drugs extensively metabolized by [[glossary:cyp3a4]] — including many opioids ([[substance:oxycodone]], [[substance:fentanyl]]), [[substance_class:chemical/benzodiazepine|benzodiazepines]] (midazolam, [[substance:alprazolam]]), immunosuppressants (cyclosporine, tacrolimus), and statins — may reach toxic levels with concurrent kratom use. '''CYP2D6 inhibition''' is demonstrated ''in vitro''{{cite|pubmed=21876481|anchor=1f2a305d}} but was not clinically significant at a 2 g kratom dose{{cite|pubmed=36924284|anchor=788e4b75}}. Significance at higher doses remains uncharacterized. '''PXR-mediated enzyme induction''' with repeated kratom use (CYP3A4, CYP1A2, P-glycoprotein; 3–6-fold [[glossary:activation]]){{cite|pubmed=29071751|anchor=f53a6582}} creates a paradoxical combination of acute CYP [[glossary:inhibition]] and chronic CYP induction, potentially reducing [[glossary:efficacy]] of co-administered drugs during sustained use. '''Pharmacodynamic synergy with opioids and CNS depressants''' is the highest-risk interaction class. Fatal outcomes have been documented with kratom and hydromorphone{{cite|pubmed=37753815|anchor=6559cf4b}} and kratom products adulterated with O-desmethyltramadol{{cite|pubmed=21513619|anchor=4e0c4b57}}. Combinations with [[substance:alcohol]], [[substance:ghb]]/[[substance:gbl]], benzodiazepines, or [[substance:ketamine]] carry pharmacodynamically plausible risk of additive CNS and [[effect:respiratory-depression]]{{flag|safety-citation-needed}}. ====Contraindications==== '''Pregnancy:''' Contraindicated. Neonatal abstinence syndrome has been documented with kratom use during [[glossary:pregnancy]]{{cite|pubmed=30744980|anchor=21515c04}}; teratogenicity is unknown. The opioid-like mechanism warrants avoidance during pregnancy and lactation{{cite|pubmed=37679866|anchor=fb053d29}}. '''Hepatic impairment:''' Contraindicated. Kratom is a documented cause of drug-induced liver injury and may worsen pre-existing hepatic conditions{{cite|pubmed=31919755|anchor=2f35577d}}. '''Concurrent opioid use:''' Contraindicated. Additive μ-opioid receptor agonism with documented fatal outcomes in polydrug contexts{{cite|pubmed=37753815|anchor=395785c8}}{{cite|pubmed=21513619|anchor=07cda29a}}. '''Concurrent CYP3A4 substrates with narrow therapeutic index:''' Relative [[glossary:contraindication]]. Kratom inhibits intestinal CYP3A at typical oral doses, potentially elevating co-administered drug concentrations to toxic levels{{cite|pubmed=36924284|anchor=820abf17}}. '''Psychiatric history (psychosis):''' Relative contraindication for concentrated 7-hydroxymitragynine products, which have been associated with psychotic symptoms during withdrawal{{cite|pubmed=41487756|anchor=a4cc755b}}. '''Renal impairment:''' Relative contraindication. Renal [[glossary:impairment]] was present as a contributing factor in a documented fatal kratom-polydrug case{{cite|pubmed=37753815|anchor=cdbaca9d}}; the large [[glossary:volume-of-distribution]] (38 L/kg) suggests altered [[glossary:accumulation]] with impaired [[glossary:clearance]]{{cite|pubmed=25995615|anchor=84c3d926}}.

====Fresh leaf (chewed)==== '''Fresh leaf''' is the traditional Southeast Asian preparation. Leaves are plucked, the tough central vein is removed, and the remaining lamina is chewed and held in the cheek. Onset occurs within 5–10 minutes; effects last 1–2 hours. Typical traditional use involves 1–3 leaves per session{{cite|pubmed=26640804|anchor=eecc73e6}}. Fresh leaf is rarely available outside cultivation regions. ====Dried leaf powder (oral — toss-and-wash or mixed)==== '''Dried leaf powder''' is the most common commercial preparation worldwide. Users swallow measured powder directly with water ("toss and wash") or mix it into juice, yogurt, or a smoothie. Onset is 20–40 minutes; total duration 3–5 hours{{cite|pubmed=35300296|anchor=e1adb281}}. [[glossary:dose-range|Dose ranges]] are preparation-specific: * Threshold: 1–2 g * Common ([[substance_class:psychoactive/stimulant]] range): 2–4 g * Common (sedative range): 4–6 g * Strong: 6–8 g Alkaloid content varies more than 50-fold across commercial products{{cite|pubmed=30997725|anchor=bb501dd3}}, making batch-specific dose calibration essential. ====Tea (oral, aqueous decoction)==== '''Kratom tea''' is prepared by simmering dried leaf powder or crushed leaf in water for 15–30 minutes and straining the [[glossary:plant-material]]. Onset is slightly faster than powder (15–30 minutes) due to pre-extraction of alkaloids into solution; duration is comparable at 3–5 hours. Dose ranges parallel dried powder by weight of starting material. Tea produces a somewhat smoother onset curve with less gastrointestinal irritation than raw powder, as insoluble plant fiber is removed. ====Capsules (oral)==== '''Capsules''' contain pre-measured dried leaf powder, typically 0.5–1 g per capsule. Onset is delayed (30–60 minutes) due to capsule dissolution. Duration and dose ranges are equivalent to powder. Capsules reduce taste aversion but make dose titration less flexible. ====Extracts and concentrated products==== '''Extracts''' — sold as resins, tinctures, and liquid "shots" — concentrate kratom alkaloids well beyond natural leaf levels. These products carry the highest risk of any kratom preparation. Commercial extracts marketed as botanical kratom may contain dramatically enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] concentrations, producing a fundamentally different pharmacological profile from leaf{{cite|pubmed=41275505|anchor=89be7cf0}}. Onset is rapid (10–20 minutes for liquid extracts); duration varies by concentration. Dose equivalence between extracts and leaf powder is unreliable — labeling is frequently inaccurate, and no standardized [[glossary:potency]] system exists. '''Start at half or less of the dose a user would take in powder form and titrate cautiously.''' Per-preparation dose tiers, timelines, and [[glossary:bioavailability]] data are in the Dose · by preparation card on this page.

====Fresh leaf (chewed)==== The traditional Southeast Asian preparation. Leaves are plucked fresh, the central vein is removed, and the remaining leaf is chewed and held in the cheek{{cite|pubmed=26640804|anchor=4566ee50}}. Onset: 5–10 minutes. Duration: 1–2 hours. Fresh leaf is rarely available outside cultivation regions. ====Dried leaf powder (oral)==== The most common commercial preparation worldwide. Powder is swallowed directly with water (“toss and wash”) or mixed into juice, yogurt, or a smoothie. Onset: 20–40 minutes. Duration: 3–5 hours{{cite|pubmed=35300296|anchor=89d33235}}. [[glossary:dose-range|Dose ranges]] (dried leaf powder, oral): * Threshold: 1–2 g * Common ([[substance_class:psychoactive/stimulant]] range): 2–4 g * Common (sedative range): 4–6 g * Strong: 6–8 g Alkaloid content varies more than 50-fold across commercial products{{cite|pubmed=30997725|anchor=3a54816b}} — batch-specific dose calibration is essential. ====Tea (aqueous decoction)==== Dried powder or crushed leaf is simmered in water for 15–30 minutes, then strained. Onset is slightly faster than powder — 15–30 minutes — because alkaloids are pre-extracted into solution. Duration: 3–5 hours. Less gastrointestinal irritation than raw powder, as insoluble plant fiber is removed. ====Capsules (oral)==== Pre-measured dried leaf powder, typically 0.5–1 g per capsule. Onset is delayed (30–60 minutes) due to capsule dissolution. Duration and dose ranges are equivalent to dried powder. Capsules reduce taste aversion but make flexible [[glossary:dose-adjustment]] harder. ====Extracts and concentrated products==== Sold as resins, tinctures, and liquid shots. These carry the highest risk of any kratom preparation{{cite|pubmed=41275505|anchor=245af1fb}}. Commercial extracts may contain enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] at concentrations far exceeding natural leaf levels, producing a fundamentally different pharmacological and risk profile. Onset is rapid (10–20 minutes for liquid forms). No standardized [[glossary:potency]] system exists — labeling is frequently inaccurate. Start at half or less of an equivalent powder dose and titrate cautiously. Per-preparation dose tiers, timelines, and [[glossary:bioavailability]] data are in the Dose · by preparation card on this page.

===Forms & Identification=== Lab testing matters more for kratom than for most botanicals because alkaloid content varies more than 50-fold across commercial products{{cite|pubmed=30997725|anchor=32903007}}. Some products marketed as botanical kratom contain enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] at concentrations far exceeding natural leaf levels{{cite|pubmed=41275505|anchor=5fc034a6}}. A Certificate of Analysis (COA) from an ISO-accredited laboratory confirms [[substance:mitragynine]] and 7-hydroxymitragynine concentrations, screens for [[glossary:contamination|contaminants]], and verifies absence of [[glossary:synthetic]] [[glossary:adulterant|adulterants]]. Products without a COA should be treated as unverified. In US states with Kratom Consumer Protection Act (KCPA) frameworks, testing and labeling are mandatory — KCPA-regulated vendors carry greater reliability than unregulated sources. ===Set & Setting=== Kratom's [[substance_class:psychoactive/opioid]]-class pharmacology makes context important. [[glossary:daily-use]] at higher doses carries [[glossary:impairment]] risk — [[effect:sedation]], cognitive slowing, and reduced reaction time are dose-dependent effects. The line between [[substance_class:psychoactive/stimulant]] and sedative dosing is narrow and varies by batch. Driving or operating machinery after higher doses carries risk comparable to mild opioid impairment. {{Guideline}} ===Guidelines=== * '''Start low, go slow.''' Begin with 1–2 g of dried leaf powder and wait at least 60 minutes before [[glossary:redose|redosing]]. For extracts, start at half or less of an equivalent powder dose and titrate cautiously. * '''Use lab-tested products.''' Purchase from vendors providing a current COA from an ISO-accredited laboratory. Verify that 7-hydroxymitragynine content is consistent with botanical leaf (typically <0.1% of dry weight) — substantially higher concentrations indicate enrichment. * '''Track dose and frequency.''' Dose frequency is a stronger predictor of [[glossary:dependence]] [[glossary:severity]] than dose amount{{cite|pubmed=38788532|anchor=6c535c4f}}. Limit use to 2–3 days per week when possible to reduce dependence risk. * '''Avoid combinations.''' Never combine kratom with opioids, [[substance_class:chemical/benzodiazepine|benzodiazepines]], [[substance:alcohol]], or other [[glossary:cns-depressants]] — additive [[effect:respiratory-depression]] risk is the highest-severity interaction class{{cite|pubmed=37753815|anchor=50d7266e}}{{cite|pubmed=21513619|anchor=e84de9a2}}. * '''Hydrate and eat.''' Kratom suppresses appetite and can cause [[glossary:dehydration]]. Maintain fluid and food intake, especially with daily use. * '''Store securely.''' Keep all kratom products away from children and pets. Label stored powder and extracts clearly. {{/Guideline}} {{Emergency}} ===Emergency Response=== '''Recognizing an emergency:''' Slow or stopped breathing, blue or gray lips, unresponsiveness, pinpoint pupils, or [[glossary:seizure|seizures]] after kratom use — especially with concentrated extracts or in combination with other substances — constitute a medical emergency. Treat suspected kratom [[glossary:overdose]] as an [[glossary:opioid-overdose]]. '''Immediate steps:''' * '''1.''' Call emergency services immediately (911 in the US). * '''2.''' If the person is not breathing or breathing very slowly, administer '''naloxone''' if available — kratom's opioid agonism is [[substance:naloxone]]-reversible. * '''3.''' Place the person in the [[glossary:recovery-position]] (on their side) to prevent [[glossary:aspiration]]. * '''4.''' Stay with the person until emergency responders arrive. * '''5.''' Do not induce [[effect:vomiting]]. '''What to tell the dispatcher:''' Name the substance (kratom — specify if extract or powder), approximate amount and time of last dose, any other substances taken, and current symptoms. [[glossary:good-samaritan-law|Good Samaritan laws]] in many US jurisdictions provide legal protection for individuals reporting overdoses. '''Naloxone:''' Naloxone reverses opioid agonism from both mitragynine and 7-hydroxymitragynine. It is available over the counter in the United States. Anyone using kratom extracts regularly should keep naloxone accessible. {{/Emergency}} {{Aftercare}} ===Aftercare & Integration=== After higher-dose kratom use, expect a period of low energy and mild mood dip lasting several hours as effects recede — a normal pharmacological [[glossary:rebound-effect]], not a medical concern. Hydrate thoroughly; kratom is mildly diuretic and appetite-suppressing, so fluid and electrolyte replenishment supports recovery. If using kratom daily, monitor for [[effect:constipation]] — a common opioid-class side effect — and maintain dietary fiber intake. {{/Aftercare}} {{Recovery}} ===Recovery & Support=== Kratom dependence is an opioid-class [[glossary:physical-dependence]]. For users wanting to reduce or stop use: * '''Gradual taper''' is the first-line approach. Reduce dose by 0.5 g every 2–3 days, or reduce frequency by one session per week. Frequency reduction may be more effective than [[glossary:dose-reduction]] alone{{cite|pubmed=38788532|anchor=7be1434a}}. * '''Medical support:''' Low-dose [[glossary:sublingual]] [[substance:buprenorphine]] has achieved complete kratom [[glossary:abstinence]] within 3 weeks in documented cases{{cite|pubmed=40518266|anchor=32a72109}}. Consult a physician experienced in [[glossary:substance-use-disorder|opioid use disorder]] treatment. * '''Withdrawal management:''' Botanical kratom [[glossary:withdrawal]] is generally mild compared to classical opioid withdrawal — muscle aches, [[effect:insomnia]], [[effect:anxiety]], and [[effect:irritability]] are common symptoms{{cite|pubmed=24698080|anchor=b6afc929}}{{cite|pubmed=29558272|anchor=6ff75324}}. Withdrawal from concentrated 7-hydroxymitragynine products can be significantly more severe{{cite|pubmed=41487756|anchor=88bf7cfd}}. * '''SAMHSA National Helpline:''' 1-800-662-4357 (free, confidential, 24/7). Provides [[glossary:referral|referrals]] to local treatment facilities, support groups, and community-based organizations. * '''Support communities:''' Online peer-support forums provide lived-experience guidance, though advice should be verified against clinical sources. {{/Recovery}}

===Forms & Identification=== Lab testing matters more for kratom than for most botanical preparations because alkaloid content varies more than 50-fold across commercial products{{cite|pubmed=30997725|anchor=5bf11661}} and because some products marketed as botanical kratom contain enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] at concentrations far exceeding natural leaf levels{{cite|pubmed=41275505|anchor=2867971b}}. A Certificate of Analysis (COA) from an ISO-accredited laboratory confirms [[substance:mitragynine]] and 7-hydroxymitragynine concentrations, screens for heavy metals and microbial [[glossary:contamination|contaminants]], and verifies absence of [[glossary:synthetic]] [[glossary:adulterant|adulterants]]. Products sold without a COA should be treated as unverified. In US states that have enacted Kratom Consumer Protection Act (KCPA) frameworks, testing and labeling are mandatory — products from KCPA-regulated vendors carry greater reliability than unregulated sources. ===Set & Setting=== Kratom's [[substance_class:psychoactive/opioid]]-class pharmacology makes context especially important. [[glossary:daily-use]] in workplace settings carries [[glossary:impairment]] risk at higher doses — [[effect:sedation]], cognitive slowing, and impaired reaction time are dose-dependent effects. Users who take kratom for functional [[effect:stimulation]] should be aware that the line between [[substance_class:psychoactive/stimulant]] and sedative dosing is narrow and varies by batch. Driving or operating machinery after higher doses carries risk comparable to mild opioid impairment. Social or solitary use at sedating doses should occur in a safe, stable environment. {{Guideline}} ===Guidelines=== * '''Start low, go slow.''' Begin with 1–2 g of dried leaf powder and wait at least 60 minutes before [[glossary:redose|redosing]]. For extracts, start at half or less of an equivalent powder dose and titrate cautiously. * '''Use lab-tested products.''' Purchase from vendors who provide a current COA from an ISO-accredited laboratory. Verify that 7-hydroxymitragynine content is consistent with botanical leaf (typically <0.1% of dry weight) — substantially higher concentrations indicate enrichment. * '''Track dose and frequency.''' Dose frequency is a stronger predictor of [[glossary:dependence]] [[glossary:severity]] than dose amount{{cite|pubmed=38788532|anchor=fd52fb29}}. Limit use to 2–3 days per week when possible to reduce dependence risk. * '''Avoid combinations.''' Never combine kratom with opioids, [[substance_class:chemical/benzodiazepine|benzodiazepines]], [[substance:alcohol]], or other [[glossary:cns-depressants]] — additive [[effect:respiratory-depression]] risk is the highest-severity interaction class{{cite|pubmed=37753815|anchor=eb6e3666}}{{cite|pubmed=21513619|anchor=b32399e8}}. * '''Hydrate and eat.''' Kratom suppresses appetite and can cause [[glossary:dehydration]]. Maintain fluid and food intake, especially with daily use. * '''Store securely.''' Keep all kratom products away from children and pets. Label stored powder and extracts clearly. {{/Guideline}} {{Emergency}} ===Emergency Response=== '''Recognizing an emergency:''' Slow or stopped breathing, blue or gray lips, unresponsiveness, pinpoint pupils, or [[glossary:seizure|seizures]] after kratom use — especially with concentrated extracts or in combination with other substances — constitute a medical emergency. Treat suspected kratom [[glossary:overdose]] as an [[glossary:opioid-overdose]]. '''Immediate steps:''' * '''1.''' Call emergency services immediately (911 in the US). * '''2.''' If the person is not breathing or breathing very slowly, administer '''naloxone''' if available — kratom's [[glossary:mu-opioid-receptor]] agonism is [[substance:naloxone]]-reversible. * '''3.''' Place the person in the [[glossary:recovery-position]] (on their side) to prevent [[glossary:aspiration]]. * '''4.''' Stay with the person until emergency responders arrive. * '''5.''' Do not induce [[effect:vomiting]]. '''What to tell the dispatcher:''' Name the substance (kratom — specify if extract or powder), approximate amount and time of last dose, any other substances taken, and current symptoms. [[glossary:good-samaritan-law|Good Samaritan laws]] in many US jurisdictions provide legal protection for individuals reporting overdoses. '''Naloxone:''' Naloxone reverses μ-opioid agonism from both mitragynine and 7-hydroxymitragynine. It is available over the counter in the United States. Anyone using kratom extracts regularly should keep naloxone accessible. {{/Emergency}} {{Aftercare}} ===Aftercare & Integration=== After higher-dose kratom use, expect a period of low energy and mild mood dip lasting several hours as effects recede — this is a normal pharmacological [[glossary:rebound-effect]], not a medical concern. Hydrate thoroughly; kratom is mildly diuretic and appetite-suppressing, so fluid and electrolyte replenishment (water, broth, potassium-rich foods) supports recovery. If using kratom daily, monitor for [[effect:constipation]] — a common opioid-class side effect — and maintain dietary fiber intake. Next-day grogginess is more likely with evening dosing of sedating doses; plan accordingly. {{/Aftercare}} {{Recovery}} ===Recovery & Support=== Kratom dependence is an opioid-class [[glossary:physical-dependence]]. For users wanting to reduce or stop use: * '''Gradual taper''' is the first-line approach. Reduce dose by 0.5 g every 2–3 days, or reduce frequency by one session per week. Frequency reduction may be more effective than [[glossary:dose-reduction]] alone{{cite|pubmed=38788532|anchor=2fe1fcbc}}. * '''Medical support:''' Low-dose [[glossary:sublingual]] [[substance:buprenorphine]] has achieved complete kratom [[glossary:abstinence]] within 3 weeks in documented cases{{cite|pubmed=40518266|anchor=b4ef1a39}}. Consult a physician experienced in [[glossary:substance-use-disorder|opioid use disorder]] treatment. * '''Withdrawal management:''' Botanical kratom [[glossary:withdrawal]] is generally mild compared to classical opioid withdrawal — myalgia, [[effect:insomnia]], [[effect:anxiety]], and [[effect:irritability]] are common symptoms{{cite|pubmed=24698080|anchor=7d535418}}{{cite|pubmed=29558272|anchor=2004b254}}. Withdrawal from concentrated 7-hydroxymitragynine products can be significantly more severe{{cite|pubmed=41487756|anchor=22533803}}. * '''SAMHSA National Helpline:''' 1-800-662-4357 (free, confidential, 24/7). Provides [[glossary:referral|referrals]] to local treatment facilities, support groups, and community-based organizations. * '''Support communities:''' Online peer-support forums provide lived-experience guidance, though advice should be verified against clinical sources. {{/Recovery}}

====Primary receptor targets==== The pharmacology of kratom is mediated primarily through [[substance_class:psychoactive/opioid]] and adrenergic [[glossary:receptor-system|receptor systems]]. [[substance:mitragynine]] functions as a '''partial agonist at the μ-opioid receptor (MOR)''' with G-protein-biased signaling — it does not significantly recruit β-arrestin-2{{cite|pubmed=28830758|anchor=bfbbb029}}{{cite|pubmed=27556704|anchor=dc5824ab}}. This biased agonism is proposed to preserve analgesic [[glossary:efficacy]] while reducing β-arrestin-2-mediated [[glossary:adverse-effects]] including [[effect:respiratory-depression]], [[effect:constipation]], and rapid [[glossary:tolerance]] development{{cite|pubmed=27556704|anchor=e75e4ab2}}. However, complete absence of respiratory depression has not been established — the risk is reduced, not eliminated, particularly with concentrated [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] preparations{{cite|pubmed=36308562|anchor=1793d80c}}. Mitragynine also acts as an '''α₂-adrenergic receptor agonist''', confirmed by binding [[glossary:assay|assays]] and isobolographic [[glossary:potentiation|synergy]] studies, and functions as a competitive [[glossary:antagonist]] at κ- and [[glossary:delta-opioid-receptor]] [[glossary:receptor|receptors]]{{cite|pubmed=36153006|anchor=72e95584}}{{cite|pubmed=28830758|anchor=c4d92609}}. 7-Hydroxymitragynine binds [[glossary:mu-opioid-receptor]] only — with no significant α₂-adrenergic activity — and acts as a potent full MOR [[glossary:agonist]] with approximately 13-fold greater activity than mitragynine{{cite|pubmed=36153006|anchor=b74584b0}}{{cite|pubmed=15304982|anchor=b07120cc}}. Kratom alkaloids additionally interact with serotonergic, dopaminergic, and noradrenergic systems{{cite|pubmed=39662722|anchor=80d7e8de}}. [[glossary:serotonin-release]] appears to contribute to both [[effect:pain-suppression|analgesia]] and [[glossary:withdrawal]] symptomatology{{cite|pubmed=40483515|anchor=214126d4}}. Cognitive effects are attributed to [[glossary:disruption]] of [[glossary:neuroplasticity]] via opioid, serotonergic, and adrenergic [[glossary:receptor-binding|receptor interactions]]{{cite|pubmed=39643045|anchor=bf89287e}}. ====Pharmacokinetics==== The first human pharmacokinetic study of mitragynine was conducted in 10 chronic kratom tea users in Thailand, using a two-compartment oral model{{cite|pubmed=25995615|anchor=42ee15a0}}. Key parameters: T''max'' 0.83 ± 0.35 h (approximately 50 minutes); terminal [[glossary:half-life]] 23.24 ± 16.07 h; [[glossary:volume-of-distribution]] 38.04 ± 24.32 L/kg, indicating extensive tissue binding; urinary [[glossary:excretion]] of unchanged mitragynine 0.14%, confirming extensive [[glossary:metabolism|hepatic metabolism]]. [[glossary:pharmacokinetics]] were linear across the [[glossary:dose-range]] tested{{cite|pubmed=25995615|anchor=41a1131b}}. With repeated daily administration over 15 days, mitragynine, speciogynine, and speciociliatine accumulate in [[glossary:plasma]] — consistent with the approximately 23-hour half-life{{cite|pubmed=39644381|anchor=af84a1ae}}. Oral [[glossary:bioavailability]] (fraction absorbed) has not been directly measured in humans. ====CYP enzyme involvement==== Kratom is both a CYP [[glossary:substrate]] and a CYP [[glossary:inhibitor]]/[[glossary:inducer]], creating significant herb–[[glossary:drug-interaction]] [[glossary:liability]]. Mitragynine is metabolized primarily by '''CYP3A4''' to 7-hydroxymitragynine and also by [[glossary:cyp2d6]]{{cite|pubmed=33847897|anchor=8a02fc05}}. ''In vitro'', kratom extract inhibits [[glossary:cyp3a4]] (IC₅₀ 0.78 µg/mL) and CYP2D6 (IC₅₀ 0.636 µg/mL), with moderate [[glossary:cyp1a2]] [[glossary:inhibition]]{{cite|pubmed=21876481|anchor=3d5ba6c5}}. Mitragynine is also a time-dependent CYP3A inhibitor (K''i'' ~4 µM, k''inact'' ~0.07 min⁻¹){{cite|pubmed=36924284|anchor=744e740a}}. Concurrently, kratom alkaloids activate the pregnane X receptor (PXR) 3–6-fold, inducing CYP3A4, CYP1A2, and P-glycoprotein mRNA [[glossary:expression]] with repeated exposure{{cite|pubmed=29071751|anchor=3768af46}}. Phase II metabolism (UGT-mediated [[glossary:glucuronidation]]) of kratom alkaloids remains poorly characterized, representing a significant gap in drug interaction prediction{{cite|pubmed=39325152|anchor=ad65f51d}}. ====Open questions==== The preparation-specific pharmacokinetics of kratom extracts and enriched 7-hydroxymitragynine products have not been characterized in controlled human studies. The relative contribution of α₂-adrenergic agonism versus μ-opioid partial agonism to the dose-dependent [[substance_class:psychoactive/stimulant]]-to-sedative phenomenological shift remains unresolved. No neuroimaging studies (fMRI, PET, EEG) using kratom preparations in human subjects have been published.

Kratom is not listed under any UN [[glossary:drug-control]] treaty. In 2021 the WHO reviewed kratom and found insufficient evidence to recommend international scheduling{{cite|url=https://www.who.int/publications/i/item/9789240036468|anchor=faa9a7a4}}. In the United States, kratom is federally [[glossary:unscheduled]] but banned in several states — Alabama, Arkansas, Indiana, Vermont, and Wisconsin — while Rhode Island transitioned from a ban to a regulated framework in April 2026{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=ccf8d21e}}. The [[glossary:fda]] authorizes detention of imported kratom products under Import Alert 54-15{{cite|url=https://www.fda.gov/news-events/public-health-focus/fda-and-kratom|anchor=06974b1a}}. Thailand legalized kratom in 2021 after banning it since 1943{{cite|url=https://thediplomat.com/2021/08/thailand-legalizes-kratom-popular-plant-based-painkiller/|anchor=f56d096f}}. Malaysia prohibits it under the Poison Act 1952{{cite|pubmed=22440259|anchor=67ec44e1}}. Australia lists kratom as Schedule 9 (prohibited) since 2003{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=1446ef1b}}. The UK banned it in 2016 under the Psychoactive Substances Act{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=e8b85b01}}; France banned it in 2020{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=d7eeceb4}}; Sweden prohibited it in 2011{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=5801d458}}. Germany and the Netherlands remain unscheduled at the federal level{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=720412a6}}. Kratom alkaloids are '''not detected''' by standard immunoassay drug screening panels{{cite|pubmed=21112167|anchor=210c52b7}}. {{Warning}} Legal status changes frequently. This overview reflects the status as of May 2026 and is not legal advice. Verify current law in the relevant jurisdiction before acting on this information. {{/Warning}}

[[substance:mitragynine]] and [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] are not listed under any of the three major UN [[glossary:drug-control]] treaties. In 2021, the WHO Expert Committee on Drug Dependence reviewed kratom and found insufficient evidence to recommend international scheduling{{cite|url=https://www.who.int/publications/i/item/9789240036468|anchor=f82484c0}}. This absence of treaty-level control has produced a patchwork of national and subnational regulations. In the United States, kratom is federally [[glossary:unscheduled]] but banned in several states, while a growing number of states have adopted Kratom Consumer Protection Act (KCPA) frameworks that regulate rather than prohibit. {{Info}}Kratom legal status is evolving rapidly at the state and national level. The information below reflects the regulatory landscape as of May 2026 and should be verified against current legislation before reliance.{{/Info}}

Jurisdiction	Scheduling status	Notes
United States (federal)	Unscheduled	Not listed under the Controlled Substances Act. DEA proposed Schedule I placement August 31, 2016; withdrew October 13, 2016 following approximately 142,000 public comments{{cite|url=https://www.federalregister.gov/documents/2016/10/13/2016-24659/withdrawal-of-notice-of-intent-to-temporarily-place-mitragynine-and-7-hydroxymitragynine-into|anchor=bb3af507}}. FDA Import Alert 54-15 authorizes detention of imported kratom products; kratom is not lawfully marketed as a drug, dietary supplement, or food additive{{cite|url=https://www.fda.gov/news-events/public-health-focus/fda-and-kratom|anchor=db355c28}}.
US — Alabama	Schedule I (2016)	Mitragynine and 7-hydroxymitragynine listed as Schedule I{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=20f5b761}}
US — Arkansas	Schedule VI (2016)	Banned{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=90ae95c3}}
US — Indiana	Schedule I (2014)	Among the earliest US state bans{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=3e07bad0}}
US — Vermont	Banned	Sale and possession prohibited{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=7ea8eb78}}
US — Wisconsin	Schedule I	Banned{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=6773abe9}}
US — Rhode Island	KCPA regulated (April 2026)	Historically banned; signed Kratom Consumer Protection Act July 2025, effective April 1, 2026 — transitioning from ban to regulated framework with age restrictions, labeling, and testing requirements{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=3503c768}}
Thailand	Legal (2021)	Banned 1943 (Kratom Act B.E. 2486); Category 5 narcotic 1979. Legalized August 24, 2021{{cite|url=https://thediplomat.com/2021/08/thailand-legalizes-kratom-popular-plant-based-painkiller/|anchor=4c153aac}}
Malaysia	Illegal	Prohibited under Poison Act 1952{{cite|pubmed=22440259|anchor=b5face6b}}
Australia	Schedule 9 (Prohibited)	Listed under the Poisons Standard (SUSMP) since 2003{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=c9ae76c4}}
United Kingdom	Banned (2016)	Prohibited under Psychoactive Substances Act 2016{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=e08c40d7}}
Netherlands	Legal	Unscheduled; available through licensed retail outlets{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=71425aa7}}
Sweden	Banned (2011)	Prohibited{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=728745af}}
France	Banned (2020)	Prohibited{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=eb70c896}}
Germany	Unscheduled (federal)	No federal ban; individual state regulations may vary{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=d0e0c173}}

Several US states have enacted KCPA frameworks imposing age restrictions (typically 21+), labeling requirements, and testing standards rather than outright [[glossary:prohibition]]. This regulatory approach represents a middle path between federal inaction and state-level criminalization. ====Detection==== Kratom alkaloids are '''not detected''' by standard immunoassay drug screening panels, including standard [[substance_class:psychoactive/opioid]] immunoassays{{cite|pubmed=21112167|anchor=ea9ee3fd}}. [[glossary:detection]] requires specific LC-MS/MS or GC-MS [[glossary:analytical-method|analytical methods]]. No commercially available kratom-specific rapid test validated for point-of-care use has been identified in the published literature.

Kratom's experiential character is defined by a dose-dependent shift from functional [[effect:stimulation]] to [[substance_class:psychoactive/opioid]]-like [[effect:sedation]], with preparation type as the primary modifier. The [[substance_class:psychoactive/stimulant]] range carries a [[glossary:warmth]] and sociable energy qualitatively distinct from [[substance:caffeine]], attributed to concurrent α₂-adrenergic and partial [[glossary:mu-opioid-receptor]] activity. At higher doses, the opioid character predominates — analgesic warmth, cognitive slowing, and [[effect:bodily-heaviness]]. Enriched [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] products produce a qualitatively different experience from leaf preparations, dominated by full μ-opioid agonism. Kratom occupies a pharmacological position between stimulant plants and classical opioid analgesics. Its low-dose profile resembles coca leaf — functional stimulation with mood [[glossary:elevation]] — while its higher-dose profile approaches the analgesic warmth of [[substance:codeine]], distinguished by reduced [[effect:respiratory-depression]] risk and a dual adrenergic-opioid quality absent from conventional opioids.

===Toxicity=== No published human [[glossary:lethal-dose|LD₅₀]] exists for [[substance:mitragynine]] or any kratom preparation. [[glossary:animal-model|Animal models]] document hepatic, renal, pulmonary, and [[glossary:central-nervous-system|CNS]] [[glossary:toxicity]] at high doses{{cite|pubmed=39802218|anchor=a10e6803}}. [[glossary:acute-toxicity]] at typical traditional leaf doses is considered low; chronic toxicity data are limited but raise concerns for hepatic and cognitive function{{cite|pubmed=39802218|anchor=5b1c7250}}. Kratom is a documented cause of '''drug-induced liver injury (DILI)''' with a predominantly cholestatic pattern{{cite|pubmed=31919755|anchor=b6541cc9}}. A comprehensive review of 26 published [[glossary:case-report|case reports]], 7 DILI Network cases, and 25 FDA database cases found a median latency of 20.6 days from first use to symptom onset (range 2–49 days), with jaundice, pruritus, and dark urine as common presenting features{{cite|pubmed=31919755|anchor=f2874f90}}. Histological pattern is predominantly cholestatic (median R ratio 3.4). RUCAM causality assessment concluded that kratom "likely causes liver injury based on totality of evidence"{{cite|pubmed=31919755|anchor=654729d8}}. Individual cases have demonstrated cholestatic injury histologically mimicking primary biliary cholangitis{{cite|pubmed=33200023|anchor=f45100b1}}. At-risk subgroups have not been identified. Published fatalities attributed in whole or part to kratom involve [[glossary:polydrug]] exposures in nearly all cases. Nine deaths in Sweden resulted from "Krypton" — kratom powder adulterated with [[substance:o-desmethyltramadol]] — with blood levels of 0.02–0.18 µg/g mitragynine and 0.4–4.3 µg/g O-desmethyltramadol; deaths were attributed to synergistic dual μ-opioid agonism{{cite|pubmed=21513619|anchor=a1a099d3}}. A fatal case involving [[substance:hydromorphone]] and kratom (femoral blood: 79 ng/mL hydromorphone, 560 ng/mL mitragynine) attributed death to hydromorphone toxicity with mitragynine as a contributing factor{{cite|pubmed=37753815|anchor=a55e7fa8}}. A 26-year-old male died of cardiorespiratory failure following suspected kratom use, though pre-existing conditions and polydrug exposure were not fully excluded{{cite|pubmed=29456604|anchor=8b9ab004}}. No deaths attributed solely to botanical kratom have been documented in Southeast Asian published literature{{cite|pubmed=31308789|anchor=b3903cc8}}. ====Contaminant and adulterant risk==== Commercial kratom products carry '''significant contaminant and adulterant risk''': * '''Synthetic opioid adulterants:''' O-desmethyltramadol documented in "Krypton" products (9 fatalities){{cite|pubmed=21513619|anchor=f9e5e4e9}}; semi-synthetic [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] enrichment in products marketed as botanical kratom{{cite|pubmed=41275505|anchor=6cd74005}} * '''Microbial contamination:''' FDA Import Alert 54-15 cites Salmonella contamination risk as a basis for detaining imported products{{cite|url=https://www.fda.gov/news-events/public-health-focus/fda-and-kratom|anchor=a2f3185b}}; no peer-reviewed contamination surveys were identified in the literature reviewed{{flag|citation-needed}} * '''Heavy metals:''' Lead, cadmium, and other heavy metal contamination is a theoretical concern for dried botanical products; no published validated surveys specific to kratom products were identified{{flag|citation-needed}} * '''Labeling inaccuracy:''' Mitragynine content ranges 0.7–38.7% w/w across commercial products, a greater-than-50-fold difference{{cite|pubmed=30997725|anchor=1e0361bc}} No ISO/IEC-accredited mandatory federal testing program exists for commercial kratom products. Some US states implementing Kratom Consumer Protection Act (KCPA) frameworks require testing and labeling standards. ===Psychological risks=== Higher doses and concentrated 7-hydroxymitragynine products are associated with [[effect:anxiety]], [[effect:irritability]], and — in rare documented cases — [[glossary:psychosis]]{{cite|pubmed=41487756|anchor=0471543b}}. Chronic kratom use may adversely affect cognitive performance through [[glossary:disruption]] of [[glossary:neuroplasticity]] via [[substance_class:psychoactive/opioid]], serotonergic, and adrenergic [[glossary:receptor-binding|receptor interactions]]{{cite|pubmed=39643045|anchor=b5094553}}. Epigenetic mechanisms have been implicated in [[glossary:withdrawal]]-associated [[effect:cognitive-impairment]] in animal models{{cite|pubmed=38523471|anchor=337bd796}}. Kratom use patterns meeting DSM-5 substance use disorder criteria have been documented, with dose frequency showing a stronger association with [[glossary:dependence]] [[glossary:severity]] than dose amount{{cite|pubmed=38788532|anchor=239f371f}}. ===Tolerance & dependence=== [[glossary:tolerance]] develops with prolonged and repeated use through μ-opioid receptor mechanisms. Cross-tolerance with classical opioids is documented; [[substance:buprenorphine]] can precipitate withdrawal in kratom-dependent patients, confirming clinically significant opioid cross-tolerance{{cite|pubmed=41487756|anchor=1c04a022}}. The mitragynine pharmacokinetic [[glossary:half-life]] is approximately 23 hours{{cite|pubmed=25995615|anchor=04730b64}}; specific tolerance recovery timelines have not been validated in published clinical studies. Physical dependence [[glossary:liability]] is high{{cite|pubmed=24698080|anchor=8f2db7c1}}. The withdrawal syndrome was first systematically characterized in regular Malaysian kratom tea users{{cite|pubmed=24698080|anchor=1ad95348}}. In studies of 150–170 regular users, cessation produced mild anxiety (70%), mild [[effect:depression]] (81%), moderate pain intensity (84%), moderate pain interference (70%), and sleep problems (46%){{cite|pubmed=30152738|anchor=e7bc3a0e}}{{cite|pubmed=29558272|anchor=81ceafb9}}. Severity was dose-dependent — users consuming ≥4 glasses daily had higher odds of more severe depression, pain interference, and sleep problems{{cite|pubmed=29558272|anchor=5c18bbda}}. Withdrawal was characterized as "relatively mild" compared to classical opioid analgesic withdrawal in these studies{{cite|pubmed=29558272|anchor=4868a281}}. Severe withdrawal from concentrated 7-hydroxymitragynine products — including psychosis and respiratory compromise requiring intubation — has been documented in case reports{{cite|pubmed=41487756|anchor=5b9c0ac9}}. {{Recovery}}Withdrawal from botanical kratom leaf at moderate doses is generally manageable without medical intervention{{cite|pubmed=29558272|anchor=5d246711}}. Low-dose sublingual buprenorphine has achieved complete kratom abstinence within 3 weeks in documented cases{{cite|pubmed=40518266|anchor=ad0e237a}}. Frequency reduction — rather than dose reduction alone — may be a key [[index:harm-reduction|harm reduction]] strategy, given that use frequency shows a stronger association with dependence severity than dose amount{{cite|pubmed=38788532|anchor=9f293091}}.{{/Recovery}} ===Drug interactions=== Kratom's dual role as both a CYP [[glossary:substrate]] and CYP [[glossary:inhibitor]]/inducer creates complex herb–[[glossary:drug-interaction]] liability across multiple [[glossary:enzyme]] systems. '''CYP3A4 inhibition''' is the best-characterized mechanism: a single 2 g dose of kratom tea increased [[substance:midazolam]] (CYP3A probe) AUC by 1.39× (90% CI: 1.23–1.57) and C''max'' by 1.50× in 12 healthy adults, consistent with intestinal CYP3A [[glossary:inhibition]]{{cite|pubmed=36924284|anchor=ad2a3b1f}}. Physiologically based pharmacokinetic (PBPK) modeling predicts mitragynine increases midazolam exposure 2.2–2.7× with co-administration{{cite|pubmed=41743842|anchor=910a8d6c}}. Drugs extensively metabolized by [[glossary:cyp3a4]] — including many opioids ([[substance:oxycodone]], [[substance:fentanyl]]), [[substance_class:chemical/benzodiazepine|benzodiazepines]] (midazolam, [[substance:alprazolam]]), immunosuppressants (cyclosporine, tacrolimus), and statins — may reach supratherapeutic levels with concurrent kratom use. '''CYP2D6 inhibition''' is demonstrated ''in vitro'' (IC₅₀ 0.636 µg/mL){{cite|pubmed=21876481|anchor=f16ec13e}} but was not clinically significant at a 2 g kratom dose{{cite|pubmed=36924284|anchor=0809b5bc}}. Clinical significance at higher kratom doses remains uncharacterized. '''PXR-mediated enzyme induction''' with repeated kratom use (CYP3A4, CYP1A2, P-glycoprotein; 3–6-fold [[glossary:activation]]){{cite|pubmed=29071751|anchor=3b94cdfa}} creates a paradoxical combination of acute CYP inhibition and chronic CYP induction. This may reduce [[glossary:efficacy]] of co-administered drugs metabolized by these enzymes during sustained kratom use. '''Pharmacodynamic synergy with opioids and CNS depressants''' is the highest-risk interaction class. Fatal outcomes have been documented with kratom and hydromorphone{{cite|pubmed=37753815|anchor=43b88be7}} and kratom products adulterated with O-desmethyltramadol{{cite|pubmed=21513619|anchor=ef4a3ddc}}. Combinations with [[substance:alcohol]], [[substance:ghb]]/[[substance:gbl]], benzodiazepines, or [[substance:ketamine]] carry pharmacodynamically plausible risk of additive CNS and [[effect:respiratory-depression]]; published clinical case reports confirming fatalities from kratom in combination with alcohol, GHB/GBL, or ketamine specifically were not identified in the literature reviewed{{flag|safety-citation-needed}}. ===Contraindications=== '''Pregnancy:''' Contraindicated. Neonatal abstinence syndrome has been documented with kratom use during [[glossary:pregnancy]]{{cite|pubmed=30744980|anchor=1ff7bea2}}; teratogenicity is unknown. Evidence is limited to case reports, but the opioid-like mechanism warrants avoidance during pregnancy and lactation{{cite|pubmed=37679866|anchor=bdc51573}}. '''Hepatic impairment:''' Contraindicated. Kratom is a documented cause of drug-induced liver injury and may worsen pre-existing hepatic conditions{{cite|pubmed=31919755|anchor=81d076bd}}. '''Concurrent opioid use:''' Contraindicated. Additive μ-opioid receptor agonism with documented fatal outcomes in polydrug contexts{{cite|pubmed=37753815|anchor=56fe92ae}}{{cite|pubmed=21513619|anchor=cb1c73b6}}. '''Concurrent CYP3A4 substrates with narrow therapeutic index:''' Relative [[glossary:contraindication]]. Kratom inhibits intestinal CYP3A at typical oral doses, potentially elevating co-administered drug [[glossary:plasma-concentration|plasma concentrations]] to toxic levels{{cite|pubmed=36924284|anchor=caa8055a}}. '''Psychiatric history (psychosis):''' Relative contraindication for concentrated 7-hydroxymitragynine products, which have been associated with psychotic symptoms during withdrawal{{cite|pubmed=41487756|anchor=cf014070}}. '''Renal impairment:''' Relative contraindication. Renal [[glossary:impairment]] was present as a contributing factor in a documented fatal kratom-polydrug case{{cite|pubmed=37753815|anchor=6de33c58}}; the large [[glossary:volume-of-distribution]] (38 L/kg) suggests altered [[glossary:accumulation]] dynamics with impaired [[glossary:clearance]]{{cite|pubmed=25995615|anchor=69b4b628}}.

[[substance:mitragynine]] and [[substance:7-hydroxymitragynine|7-hydroxymitragynine]] — the primary kratom alkaloids — are not listed under any of the three major UN [[glossary:drug-control]] treaties (1961 Single Convention on Narcotic Drugs, 1971 [[glossary:convention-on-psychotropic-substances]], 1988 Convention Against Illicit Traffic). In 2021, the WHO Expert Committee on Drug Dependence conducted a critical review of kratom and found insufficient evidence to recommend international scheduling{{cite|url=https://www.who.int/publications/i/item/9789240036468|anchor=a2d0e988}}. This absence of treaty-level control accounts for the patchwork of national and subnational regulations described below. {{Info}}Kratom legal status is evolving rapidly at the state and national level. The information below reflects the regulatory landscape as of May 2026 and should be verified against current legislation before reliance.{{/Info}}

Jurisdiction	Classification	Key provisions
United States (federal)	Unscheduled	Not listed under the Controlled Substances Act. DEA proposed Schedule I placement August 31, 2016; withdrew October 13, 2016 following approximately 142,000 public comments{{cite|url=https://www.federalregister.gov/documents/2016/10/13/2016-24659/withdrawal-of-notice-of-intent-to-temporarily-place-mitragynine-and-7-hydroxymitragynine-into|anchor=0831201a}}. FDA Import Alert 54-15 authorizes detention of imported kratom products; kratom is not lawfully marketed as a drug, dietary supplement, or food additive{{cite|url=https://www.fda.gov/news-events/public-health-focus/fda-and-kratom|anchor=90375b08}}.
US — Alabama	Schedule I (2016)	Mitragynine and 7-hydroxymitragynine listed as Schedule I{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=a65b5d5d}}
US — Arkansas	Schedule VI (2016)	Banned{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=02f6ef27}}
US — Indiana	Schedule I (2014)	Among the earliest US state bans{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=b0c107ea}}
US — Vermont	Banned	Sale and possession prohibited{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=1a3f83a3}}
US — Wisconsin	Schedule I	Banned{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=2267f9a5}}
US — Rhode Island	KCPA regulated (April 2026)	Historically banned; signed Kratom Consumer Protection Act July 2025, effective April 1, 2026 — transitioning from ban to regulated framework with age restrictions, labeling, and testing requirements{{cite|url=https://www.congress.gov/crs-product/LSB11082|anchor=29436a67}}
Thailand	Legal (2021)	Banned 1943 (Kratom Act B.E. 2486); Category 5 narcotic 1979. Legalized August 24, 2021 under Narcotics Act Amendment No. 8{{cite|url=https://thediplomat.com/2021/08/thailand-legalizes-kratom-popular-plant-based-painkiller/|anchor=4be680de}}
Malaysia	Illegal	Prohibited under Poison Act 1952{{cite|pubmed=22440259|anchor=c6bad60b}}
Australia	Schedule 9 (Prohibited)	Listed under the Poisons Standard (SUSMP) since 2003; same scheduling category as heroin and MDMA{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=cf90ee16}}
United Kingdom	Banned (2016)	Prohibited under Psychoactive Substances Act 2016; importation, sale, and supply illegal{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=7f595302}}
Netherlands	Legal	Unscheduled; available through licensed retail outlets{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=bb8a28ac}}
Sweden	Banned (2011)	Prohibited{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=0d67a687}}
France	Banned (2020)	Prohibited{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=34ddebac}}
Germany	Unscheduled (federal)	No federal ban; individual state regulations may vary{{cite|url=https://worldpopulationreview.com/country-rankings/kratom-legality-by-country|anchor=5a85e836}}

Several US states have enacted Kratom Consumer Protection Act (KCPA) frameworks imposing age restrictions (typically 21+), labeling requirements, and testing standards rather than outright [[glossary:prohibition]]. This regulatory approach represents a middle path between federal inaction and state-level criminalization. ====Detection==== Kratom alkaloids are '''not detected''' by standard immunoassay drug screening panels, including standard [[substance_class:psychoactive/opioid]] immunoassays{{cite|pubmed=21112167|anchor=43a0b921}}. [[glossary:detection]] requires specific LC-MS/MS or GC-MS [[glossary:analytical-method|analytical methods]]. No commercially available kratom-specific rapid test validated for consumer or point-of-care use has been identified in the published literature.