Kratom

Animal models document hepatic, renal, pulmonary, and CNS toxicity at high dosessupported

In vivo: liver, kidney, lung, brain toxicity. j.jtumed.2024.12.002

Claim in safety — inconclusiveinconclusiveworking →

Kratom is a documented cause of drug-induced liver injury (DILI) with a predominantly cholestatic patternsupported

Predominantly cholestatic histology. RUCAM-assessed causality. Kratom likely causes liver injury based on totality of evidence. s40265-019-01242-6

A comprehensive review of 26 published 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 featurespartially supported

Scoping review of 26 case reports + 7 DILI Network cases + 25 FDA database + 27 internet cases. Latency 20.6 days (mean). s40265-019-01242-6

RUCAM causality assessment concluded that kratom "likely causes liver injury based on totality of evidence"supported

RUCAM-assessed causality. Kratom likely causes liver injury based on totality of evidence. s40265-019-01242-6

Individual cases have demonstrated cholestatic injury histologically mimicking primary biliary cholangitissupported

Severe cholestatic liver injury from kratom use histologically mimicking primary biliary cholangitis. wjh.v12.i10.863

Nine deaths in Sweden resulted from "Krypton" — kratom powder adulterated with 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 mu-opioid-receptor agonismsupported

9 fatal cases in Sweden. Krypton = powdered kratom + O-desmethyltramadol. ODT blood concentrations 0.4-4.3 μg/g. Mitragynine 0.02-0.18 μg/g. Deaths attributed to respiratory depression. pmid:21513619

A fatal case involving hydromorphone and kratom (femoral blood: 79 ng/mL hydromorphone, 560 ng/mL mitragynine) attributed death to hydromorphone toxicity with mitragynine as a contributing factorsupported

Fatal case: 79ng/mL hydromorphone, 560ng/mL mitragynine in femoral blood. Death attributed to hydromorphone toxicity with mitragynine contributing. 1556-4029.15394

The withdrawal syndrome was first systematically characterized in regular Malaysian kratom tea userssupported

First systematic study of kratom dependence, withdrawal, and craving in regular Malaysian users. j.drugalcdep.2014.03.017

A 26-year-old male died of cardiorespiratory failure following suspected kratom use, though pre-existing conditions and polydrug exposure were not fully excludedsupported

26-year-old in cardiorespiratory arrest after kratom use; died from cardiorespiratory failure and hypoxic brain damage. 1751143717712652

Claim in safety — inconclusiveinconclusiveworking →

Synthetic opioid adulterants: O-desmethyltramadol documented in "Krypton" products (9 fatalities); semi-synthetic 7-hydroxymitragynine enrichment in products marketed as botanical kratompartially supported

Krypton = powdered kratom + O-desmethyltramadol. Deaths attributed to respiratory depression. pmid:21513619

Synthetic opioid adulterants: O-desmethyltramadol documented in "Krypton" products (9 fatalities); semi-synthetic 7-hydroxymitragynine enrichment in products marketed as botanical kratompartially supported

7-OH is a potent mu-opioid receptor agonist occurring at trace levels in leaf material but enriched in US market semi-synthetic products. 13880209.2025.2590311

Labeling inaccuracy: Mitragynine content ranges 0.7–38.7% w/w across commercial products, a greater-than-50-fold differencesupported

Mitragynine 0.7-38.7% dta.2604

Higher doses and concentrated 7-hydroxymitragynine products are associated with anxiety, irritability, and — in rare documented cases — psychosissupported

Severe withdrawal from concentrated 7-OH mitragynine: opioid-like symptoms, agitation, psychosis, respiratory compromise requiring intubation. cureus.98386

Chronic kratom use may adversely affect cognitive performance through disruption of neuroplasticity via opioid, serotonergic, and adrenergic receptor interactionssupported

Kratom may adversely affect cognitive performances via disruption in synaptic plasticity and brain activity. Interaction with opioid, serotonergic, adrenergic receptors. j.bbr.2024.115387

Epigenetic mechanisms have been implicated in withdrawal-associated cognitive impairment in animal modelssupported

Epigenetic mechanism implicated in kratom withdrawal behavior and cognitive impairments. bph.16352

Kratom use patterns meeting DSM-5 substance use disorder criteria have been documented, with dose frequency showing a stronger association with dependence severity than dose amount.supported

Study of how dosing amounts/frequencies relate to kratom SUD and physical dependence outcomes. j.drugalcdep.2024.111329

tolerance develops with prolonged and repeated use through μ-opioid receptor mechanisms. Cross-tolerance with classical opioids is documented; buprenorphine can precipitate withdrawal in kratom-dependent patients, confirming clinically significant opioid cross-tolerancepartially supported

Severe withdrawal from concentrated 7-OH mitragynine: opioid-like symptoms, agitation, psychosis, respiratory compromise requiring intubation. cureus.98386

The mitragynine pharmacokinetic half-life is approximately 23 hours; specific tolerance recovery timelines have not been validated in published clinical studies.supported

terminal half-life 23.24 +/- 16.07 h dddt.s79658

Physical dependence liability is highsupported

First systematic study of kratom dependence, withdrawal, and craving in regular Malaysian users. j.drugalcdep.2014.03.017

In studies of 150–170 regular users, cessation produced mild anxiety (70%), mild depression (81%), moderate pain intensity (84%), moderate pain interference (70%), and sleep problems (46%)partially supported

150 regular kratom users in Malaysia: 70% mild anxiety, 81% mild depression on cessation 02791072.2018.1511879

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Withdrawal was characterized as "relatively mild" compared to classical opioid analgesic withdrawal in these studiessupported

effects milder than opioid analgesics 02791072.2018.1443234

Severe withdrawal from concentrated 7-hydroxymitragynine products — including psychosis and respiratory compromise requiring intubation — has been documented in case reports.supported

Severe withdrawal from concentrated 7-OH mitragynine: opioid-like symptoms, agitation, psychosis, respiratory compromise requiring intubation. cureus.98386

{{Recovery}}Withdrawal from botanical kratom leaf at moderate doses is generally manageable without medical interventionsupported

effects milder than opioid analgesics 02791072.2018.1443234

Low-dose sublingual buprenorphine has achieved complete kratom abstinence within 3 weeks in documented casessupported

Low-dose sublingual buprenorphine led to complete abstinence from kratom (containing 7-HMG) within 3 weeks. bcr-2025-265834

Frequency reduction — rather than dose reduction alone — may be a key harm reduction strategy, given that use frequency shows a stronger association with dependence severity than dose amount.{{/Recovery}}supported

Study of how dosing amounts/frequencies relate to kratom SUD and physical dependence outcomes. j.drugalcdep.2024.111329

CYP3A4 inhibition is the best-characterized mechanism: a single 2 g dose of kratom tea increased midazolam (CYP3A probe) AUC by 1.39× (90% CI: 1.23–1.57) and Cmax by 1.50× in 12 healthy adults, consistent with intestinal CYP3A inhibitionsupported

2g kratom tea + midazolam (CYP3A probe): AUC increased 1.39x, Cmax 1.50x. Primarily intestinal CYP3A inhibition. cpt.2891

Physiologically based pharmacokinetic (PBPK) modeling predicts mitragynine increases midazolam exposure 2.2–2.7× with co-administrationsupported

midazolam exposure increases 2.2-2.7x acsptsci.5c00718

CYP2D6 inhibition is demonstrated in vitro (IC₅₀ 0.636 µg/mL) but was not clinically significant at a 2 g kratom dosepartially supported

CYP2D6 (IC50 0.636 ug/mL) molecules16097344

CYP2D6 inhibition is demonstrated in vitro (IC₅₀ 0.636 µg/mL) but was not clinically significant at a 2 g kratom dosepartially supported

No effect on dextromethorphan (CYP2D6). cpt.2891

PXR-mediated enzyme induction with repeated kratom use (CYP3A4, CYP1A2, P-glycoprotein; 3–6-fold activation) creates a paradoxical combination of acute CYP inhibition and chronic CYP inductionsupported

Kratom alkaloids activated PXR 3-6 fold and induced CYP3A4, CYP1A2, P-gp mRNA expression. ptr.5942

Fatal outcomes have been documented with kratom and hydromorphone and kratom products adulterated with O-desmethyltramadolpartially supported

Fatal case: 79ng/mL hydromorphone, 560ng/mL mitragynine in femoral blood. Death attributed to hydromorphone toxicity with mitragynine contributing. 1556-4029.15394

Fatal outcomes have been documented with kratom and hydromorphone and kratom products adulterated with O-desmethyltramadolpartially supported

9 fatal cases in Sweden. Krypton = powdered kratom + O-desmethyltramadol. Deaths attributed to respiratory depression. pmid:21513619

Claim in safety — inconclusiveinconclusiveworking →

Evidence is limited to case reports, but the opioid-like mechanism warrants avoidance during pregnancy and lactation.supported

limited evidence, a few case reports. Opioid-like but not classified as opioid. jmwh.13558

Kratom is a documented cause of drug-induced liver injury and may worsen pre-existing hepatic conditions.supported

Kratom likely causes liver injury based on totality of evidence. s40265-019-01242-6

Additive μ-opioid receptor agonism with documented fatal outcomes in polydrug contexts.supported

Fatal case: 79ng/mL hydromorphone, 560ng/mL mitragynine. Death attributed to hydromorphone toxicity with mitragynine contributing. 1556-4029.15394

Additive μ-opioid receptor agonism with documented fatal outcomes in polydrug contexts.supported

Krypton = powdered kratom + O-desmethyltramadol. Deaths attributed to respiratory depression. pmid:21513619

Kratom inhibits intestinal CYP3A at typical oral doses, potentially elevating co-administered drug plasma concentrations to toxic levels.supported

2g kratom tea + midazolam (CYP3A probe): AUC increased 1.39x, Cmax 1.50x. Primarily intestinal CYP3A inhibition. cpt.2891

Psychiatric history (psychosis): Relative contraindication for concentrated 7-hydroxymitragynine products, which have been associated with psychotic symptoms during withdrawal.supported

Severe withdrawal from concentrated 7-OH mitragynine: opioid-like symptoms, agitation, psychosis, respiratory compromise requiring intubation. cureus.98386

Claim in safety — inconclusiveinconclusiveworking →

Renal impairment was present as a contributing factor in a documented fatal kratom-polydrug case; the large volume of distribution (38 L/kg) suggests altered accumulation dynamics with impaired clearance.partially supported

Vd 38.04 +/- 24.32 L/kg dddt.s79658

Kratom alkaloids additionally interact with serotonergic, dopaminergic, and noradrenergic systems. serotonin release appears to contribute to both analgesia and withdrawal symptomatologysupported

opioid, noradrenergic, serotonergic, dopaminergic modulation j.pnpbp.2024.111215

Kratom alkaloids additionally interact with serotonergic, dopaminergic, and noradrenergic systems. serotonin release appears to contribute to both analgesia and withdrawal symptomatologysupported

Kratom alleviates pain by activating mu-opioid receptors triggering serotonin release. Serotonin also interferes with drug abuse effects. s12906-025-04947-2

Mitragynine is metabolized primarily by CYP3A4 to 7-hydroxymitragynine and also by cyp2d6. In vitro, kratom extract inhibits cyp3a4 (IC₅₀ 0.78 µg/mL) and CYP2D6 (IC₅₀ 0.636 µg/mL), with moderate CYP1A2 inhibitionpartially supported

7-HMG is a potent full MOR agonist produced from mitragynine by CYP3A. s13318-021-00684-2

Mitragynine is metabolized primarily by CYP3A4 to 7-hydroxymitragynine and also by cyp2d6. In vitro, kratom extract inhibits cyp3a4 (IC₅₀ 0.78 µg/mL) and CYP2D6 (IC₅₀ 0.636 µg/mL), with moderate CYP1A2 inhibitionsupported

MSE inhibited CYP3A4 (IC50 0.78 ug/mL) and CYP2D6 (IC50 0.636 ug/mL) most potently; moderate CYP1A2 inhibition. molecules16097344

The pharmacology of kratom is mediated primarily through opioid and adrenergic receptor systems. mitragynine functions as a partial agonist at the μ-opioid receptor (MOR) with G-protein-biased signaling — it does not significantly recruit β-arrestin-2supported

discusses biased agonism hypothesis and abuse potential of 7-HMG j.neuropharm.2017.08.026

However, complete absence of respiratory depression has not been established — the risk is reduced, not eliminated, particularly with concentrated 7-hydroxymitragynine preparations.supported

mitragynine partial agonist at MOR without beta-arrestin-2 signaling; reduced respiratory depression. s00213-022-06244-z

Mitragynine also acts as an α₂-adrenergic receptor agonist, confirmed by binding assays and isobolographic synergy studies, and functions as a competitive antagonist at κ- and delta-opioid-receptor receptors. 7-Hydroxymitragynine binds mu-opioid-receptor only — with no significant α₂-adrenergic activity — and acts as a potent full MOR agonist with approximately 13-fold greater activity than mitragynine.partially supported

7-HMG displays only MOR binding affinity (not alpha-2). jpet.122.001192

Mitragynine also acts as an α₂-adrenergic receptor agonist, confirmed by binding assays and isobolographic synergy studies, and functions as a competitive antagonist at κ- and delta-opioid-receptor receptors. 7-Hydroxymitragynine binds mu-opioid-receptor only — with no significant α₂-adrenergic activity — and acts as a potent full MOR agonist with approximately 13-fold greater activity than mitragynine.supported

Comprehensive review of kratom medicinal chemistry and neuropharmacology; discusses biased agonism hypothesis and abuse potential of 7-HMG. j.neuropharm.2017.08.026

Claim in neuroscience — inconclusiveinconclusiveworking →

Cognitive effects are attributed to disruption of neuroplasticity via opioid, serotonergic, and adrenergic receptor interactions.supported

Kratom may adversely affect cognitive performances via disruption in synaptic plasticity and brain activity. Interaction with opioid, serotonergic, adrenergic receptors. j.bbr.2024.115387

The first human pharmacokinetic study of mitragynine was conducted in 10 chronic kratom tea users in Thailand, using a two-compartment oral modelsupported

First human PK study in 10 chronic kratom users. Two-compartment model. dddt.s79658

With repeated daily administration over 15 days, mitragynine, speciogynine, and speciociliatine accumulate in plasma — consistent with the approximately 23-hour half-lifepartially supported

Mitragynine accumulated after 15-day dosing. Clinical trial samples showed mitragynine, 7-OH-mitragynine, speciogynine, speciociliatine, paynantheine quantifiable. s00216-024-05689-9

Mitragynine is also a time-dependent CYP3A inhibitor (Ki ~4 µM, kinact ~0.07 min⁻¹)supported

Mitragynine is time-dependent CYP3A inhibitor: KI ~4 uM, kinact ~0.07 min-1. cpt.2891

Concurrently, kratom alkaloids activate the pregnane X receptor (PXR) 3–6-fold, inducing CYP3A4, CYP1A2, and P-glycoprotein mRNA expression with repeated exposuresupported

Kratom alkaloids activated PXR 3-6 fold and induced CYP3A4, CYP1A2, P-gp mRNA expression. ptr.5942

Claim in history — inconclusiveinconclusiveworking →

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 withdrawalsupported

Evolution of an Enhancer from a Traditional Use... to a Recreational Psychoactive Drug in Western Countries 968786

Claim in history — inconclusiveinconclusiveworking →

Claim in history — not_supportednot supportedworking →

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 medicinesupported

Traditional enhancer in SE Asia to Western recreational drug. 968786

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 medicinesupported

traditional use as stimulant; changing patterns toward recreational and youth use hup.2582

Claim in history — inconclusiveinconclusiveworking →

Claim in history — inconclusiveinconclusiveworking →

Claim in history — inconclusiveinconclusiveworking →

Kruegel and Grundmann published a comprehensive neuropharmacology review in 2018 characterizing the G-protein-biased opioid agonism of kratom alkaloidssupported

Comprehensive review of kratom medicinal chemistry and neuropharmacology; discusses biased agonism hypothesis j.neuropharm.2017.08.026

Claim in preparations — inconclusiveinconclusiveworking →

Claim in preparations — inconclusiveinconclusiveworking →

Claim in preparations — inconclusiveinconclusiveworking →

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 dailysupported

76-115 mg mitragynine/day in 4+ glasses 02791072.2018.1443234

These products exhibit potent full mu-opioid-receptor agonism, carry substantially greater respiratory depression risk, and produce more severe dependence and withdrawalsupported

Severe withdrawal from concentrated 7-OH mitragynine: opioid-like symptoms, agitation, psychosis, respiratory compromise requiring intubation. cureus.98386

Potency variability is a defining feature of the commercial kratom landscape: alkaloid content varies more than 50-fold across vendors and batchessupported

Mitragynine 0.7-38.7% dta.2604

Claim in preparations — inconclusiveinconclusiveworking →

Claim in preparations — inconclusiveinconclusiveworking →

{{Warning}}Products containing chemically enriched or semi-synthetic 7-hydroxymitragynine are pharmacologically distinct from botanical kratom preparationssupported

7-OH is a potent mu-opioid receptor agonist occurring at trace levels in leaf material but enriched in US market semi-synthetic products. 13880209.2025.2590311

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)supported

Mitragynine 0.7-38.7% dta.2604

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 cyp3a4 metabolismpartially supported

7-HMG is a potent full MOR agonist produced from mitragynine by CYP3A. s13318-021-00684-2

The alkaloid profile of kratom has been systematically characterized by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), with ten key alkaloids quantified across leaf extracts and commercial productssupported

UPLC-MS/MS method for 10 alkaloids dta.2604

Claim in alkaloid-profile — inconclusiveinconclusiveworking →

Claim in alkaloid-profile — inconclusiveinconclusiveworking →

The US market increasingly offers chemically enriched or semi-synthetic 7-hydroxymitragynine products marketed as "kratom" that are pharmacologically and toxicologically distinct from botanical preparationssupported

Concentrated/isolated alkaloids cause substantially different and riskier symptom presentation. s11920-025-01631-7

Three additional alkaloids are present at pharmacologically relevant concentrations:supported

paynantheine 0.3-12.8%, speciociliatine 0.4-12.3%, speciogynine 0.1-5.3% w/w dta.2604

Claim in alkaloid-profile — inconclusiveinconclusiveworking →

Claim in summary — inconclusiveinconclusiveworking →

First described by the Dutch botanist Pieter Willem Korthals in 1841, kratom has been used as a traditional work aid and folk medicine in Thailand and the Malay Peninsula for centuriessupported

Traditional enhancer in SE Asia to Western recreational drug. 968786

Mitragynine acts as a G-protein-biased partial-agonist at the μ-opioid receptor that does not significantly recruit β-arrestin-2, and simultaneously binds α₂-adrenergic receptorssupported

discusses biased agonism hypothesis and abuse potential of 7-HMG j.neuropharm.2017.08.026

Its metabolite 7-hydroxymitragynine is a potent full μ-opioid 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.supported

7-OH is a potent mu-opioid receptor agonist occurring at trace levels in leaf material but enriched in US market semi-synthetic products. 13880209.2025.2590311

Effects and duration vary substantially by preparation method, and alkaloid content varies more than 50-fold across commercial products.supported

Mitragynine 0.7-38.7% dta.2604

Kratom carries clinically significant opioid-type dependence risk with prolonged use, producing a withdrawal characterized by myalgia, insomnia, anxiety, and irritability. tolerance develops through μ-opioid receptor mechanisms, with documented cross-tolerance to classical opioids. Hepatotoxicity — predominantly cholestatic — has been reported at a median latency of approximately three weekspartially supported

First systematic study of kratom dependence, withdrawal, and craving in regular Malaysian users. j.drugalcdep.2014.03.017

Kratom carries clinically significant opioid-type dependence risk with prolonged use, producing a withdrawal characterized by myalgia, insomnia, anxiety, and irritability. tolerance develops through μ-opioid receptor mechanisms, with documented cross-tolerance to classical opioids. Hepatotoxicity — predominantly cholestatic — has been reported at a median latency of approximately three weekspartially supported

Latency 20.6 days (mean). Predominantly cholestatic histology. s40265-019-01242-6

Claim in botanical-overview — inconclusiveinconclusiveworking →

Claim in botanical-overview — not_supportednot supportedworking →