Kratom

The fresh leaf is chewed, or brewed into a strong tea sweetened with honey or citrus. Dried leaves are sometimes smoked or powdered and drunk as tea ^{28Reference 28PuffPuff, C. (n.d.). Mitragyna speciosa (Korth.) Havil. — species description, distribution, ecology and uses — flora. In Flora of Thailand — Rubiaceae (online treatment), University of Vienna. https://web.archive.org/web/20191209001520/https://homepage.univie.ac.at/christian.puff/_FTH-RUB/FTH-RUB-Mitragyna_compl_WEB.htmView study →}.

Kratom is a working herb. Labourers across Thailand, Malaysia, Indonesia, Bali and Papua New Guinea took it to fight fatigue and work longer through long hot days, and some reports describe it being used to raise tolerance for working in the sun, easing the aches of hard physical labour. It was used much as coffee, a relative, or yerba maté are used.

Secondary traditional uses were for diarrhoea ^{28Reference 28PuffPuff, C. (n.d.). Mitragyna speciosa (Korth.) Havil. — species description, distribution, ecology and uses — flora. In Flora of Thailand — Rubiaceae (online treatment), University of Vienna. https://web.archive.org/web/20191209001520/https://homepage.univie.ac.at/christian.puff/_FTH-RUB/FTH-RUB-Mitragyna_compl_WEB.htmView study →}, intestinal infection and muscle pain.

Kratom also served as a substitute for opium ^{28Reference 28PuffPuff, C. (n.d.). Mitragyna speciosa (Korth.) Havil. — species description, distribution, ecology and uses — flora. In Flora of Thailand — Rubiaceae (online treatment), University of Vienna. https://web.archive.org/web/20191209001520/https://homepage.univie.ac.at/christian.puff/_FTH-RUB/FTH-RUB-Mitragyna_compl_WEB.htmView study →}. A botanist travelling through Malaysia in the 1800s recorded it in that role, and its use for opioid withdrawal became widespread in the West only in the last decade.

Kratom goes by many regional names, kakuam, ketum, biak-biak, ithang and thom among them.

A randomized, placebo-controlled, double-blind study (n=26 regular male users, single inpatient day) found that a kratom decoction significantly increased cold-pressor pain tolerance, from a mean 11.2 s before dosing to 24.9 s one hour after, with no change on placebo ^{1Reference 1Vicknasingam et al. · 2020RCTKratom and Pain Tolerance: A Randomized, Placebo-Controlled, Double-Blind Study — randomised controlled trialView study →}.

This aligns with the largest user survey (n=8049), in which self-treatment of pain was the leading reason for use (68%) ^{2Reference 2Grundmann · 2017ObservationalPatterns of Kratom use and health impact in the US — Results from an online survey — observationalView study →}, and with animal work: a methanolic leaf extract (100–200 mg/kg) produced dose-dependent antinociception across writhing, hot-plate and formalin tests in rodents ^{3Reference 3Shaik Mossadeq et al. · 2009AnimalAnti-inflammatory and antinociceptive effects of Mitragyna speciosa Korth methanolic extract — rat/mouse animal modelView study →}.

Mechanistically, mitragynine is a low-efficacy partial agonist at the µ-opioid receptor, and CYP3A-mediated conversion to 7-hydroxymitragynine — a much more potent µ-agonist — appears sufficient to explain most of the opioid-mediated analgesia in mice ^{4,6Reference 4Kruegel et al. · 2019In vitroKruegel, A. C., et al. (2019). 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects — in vitro / mouse. ACS Cent Sci. https://pubmed.ncbi.nlm.nih.gov/31263758/View study →Reference 6Hiranita et al. · 2022In vitroIn vitro and in vivo pharmacology of kratom — reviewView study →}.

In a chemotherapy-induced neuropathic-pain model, mitragynine’s benefit also depended partly on cannabinoid (CB1/CB2/TRPV1) mechanisms, suggesting more than one analgesic pathway ^{15Reference 15Farkas et al. · 2023AnimalCannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic pain — mouse animal modelView study →}.

Gap: The human evidence is a single small acute study in experienced users measuring experimental (not clinical) pain; there is no trial in pain patients, no standardized dose, and analgesic potency is inseparable from opioid-type risks.

Using kratom to manage opioid withdrawal is one of its most common Western uses, but the evidence is observational rather than experimental. Malaysian field surveys document that users take ketum specifically to reduce heroin intake and blunt withdrawal, describing it as cheaper and less stigmatizing than substitution therapy ^{8Reference 8Vicknasingam et al. · 2010ObservationalThe informal use of ketum (Mitragyna speciosa) for opioid withdrawal in northern peninsular Malaysia — observational surveyView study →}, and a US case series first flagged online self-treatment of opioid withdrawal in 2007 ^{9Reference 9Boyer et al. · 2007ObservationalSelf-treatment of opioid withdrawal with a dietary supplement, Kratom — observationalView study →}.

Survey data likewise list withdrawal relief among primary motivations ^{2Reference 2Grundmann · 2017ObservationalPatterns of Kratom use and health impact in the US — Results from an online survey — observationalView study →}.

Preclinically, combined kratom alkaloid extract and mitragynine produced significantly fewer naloxone-precipitated withdrawal signs than morphine and eased withdrawal in morphine-dependent mice ^{10Reference 10Wilson et al. · 2021AnimalKratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal — mouse animal modelView study →}, and mitragynine reduced heroin — but not methamphetamine — self-administration in rats while itself failing to maintain self-administration, indicating low intrinsic abuse liability ^{11,12Reference 11Yue et al. · 2018AnimalAbuse liability of mitragynine assessed with a self-administration procedure in rats — animal modelView study →Reference 12Hemby et al. · 2019AnimalAbuse liability and therapeutic potential of the Mitragyna speciosa alkaloids mitragynine and 7-hydroxymitragynine — rat self-administrationView study →}.

Kratom itself causes dependence: a survey of 293 regular users found more than half met criteria for severe dependence, with a recognizable withdrawal syndrome (muscle pain, insomnia, watery eyes, irritability) ^{7Reference 7Singh et al. · 2014ObservationalKratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users — observational cohortView study →}.

Gap: No controlled trial has tested whether kratom actually relieves opioid withdrawal in humans; the signal is entirely self-report and animal data, and kratom has documented dependence and withdrawal of its own.

Stimulation is dose-dependent, with low doses energizing and higher doses becoming sedative ^{16Reference 16Parthasarathy et al. · 2009In vitroEvaluation of antioxidant and antibacterial activities of aqueous, methanolic and alkaloid extracts from Mitragyna speciosa leaves — in vitroView study →}.

Several alkaloids act on adrenergic receptors, a catecholamine-like mechanism for increased alertness ^{6Reference 6Hiranita et al. · 2022In vitroIn vitro and in vivo pharmacology of kratom — reviewView study →}.

Human data are supportive but uncontrolled: energy and mood enhancement rank among the top self-reported effects in large surveys ^{2Reference 2Grundmann · 2017ObservationalPatterns of Kratom use and health impact in the US — Results from an online survey — observationalView study →}, and a placebo-controlled abuse-potential study in 116 healthy adults recorded modest, dose-related subjective drug effects that decreased on repeated dosing ^{13Reference 13Coe et al. · 2026RCTAssessment of Abuse Potential-Related Effects of Oral Dried Kratom Leaf Powder in Healthy Normal Participants Following Single and Multiple Daily Doses — randomised placebo-controlled trialView study →}.

No trial has isolated an ergogenic or alertness endpoint under controlled conditions.

Gap: There is no objective, controlled measure of energy, endurance or vigilance.

Anti-inflammatory activity is documented preclinically. The same rodent study that showed antinociception also found that a methanolic leaf extract (100–200 mg/kg) suppressed carrageenan-induced paw edema and, at the higher dose, granuloma formation, with the authors attributing the effect to lipoxygenase and cyclooxygenase inhibition ^{3Reference 3Shaik Mossadeq et al. · 2009AnimalAnti-inflammatory and antinociceptive effects of Mitragyna speciosa Korth methanolic extract — rat/mouse animal modelView study →}.

More recent in-vitro work is mechanistically specific: a kratom alkaloid extract (~46% mitragynine) produced dual inhibition of COX-2 and 5-LOX in LPS-stimulated macrophages at low concentrations, cutting ROS, nitric oxide, TNF-α and IL-6, whereas a crude leaf extract with ~5% mitragynine was inactive — implicating the concentrated alkaloid fraction specifically ^{14Reference 14Rahmawati et al. · 2024In vitroDual anti-inflammatory activities of COX-2/5-LOX driven by kratom alkaloid extracts in LPS-induced RAW 264.7 cells — in vitroView study →}.

All of it is animal or cell-based, and the active concentrations sit close to cytotoxic levels in vitro.

Mood improvement is a frequently self-reported reason for kratom use ^{2Reference 2Grundmann · 2017ObservationalPatterns of Kratom use and health impact in the US — Results from an online survey — observationalView study →}, but controlled support is preclinical. In a diabetic-rat model, a hydro-alcoholic leaf extract (50 and 200 mg/kg for 5 weeks) reduced depression- and anxiety-like behavior in forced-swim, open-field and elevated-plus-maze tests while lowering brain oxidative stress and pro-inflammatory cytokines ^{18Reference 18Chen et al. · 2022AnimalAnxiolytic and Antidepressant-like Effects of Mitragyna speciosa Extract in Diabetic Rats — rat animal modelView study →}. The underlying pharmacology is consistent with mood effects — mitragynine has serotonergic (5-HT2A) activity alongside its opioid and adrenergic actions ^{6Reference 6Hiranita et al. · 2022In vitroIn vitro and in vivo pharmacology of kratom — reviewView study →} — but the support is mechanistic and animal-level.

Gap: No human trial for anxiety or depression exists; the animal model is confounded by diabetes, and forced-swim-type assays are themselves of debated predictive value.

Antioxidant activity in vitro is modest and preparation-dependent. Leaf extracts scavenge DPPH radicals in proportion to their phenolic content, with the methanolic extract (rich in flavonoids, IC50 ≈ 37 µg/mL) outperforming aqueous and alkaloid extracts ^{16Reference 16Parthasarathy et al. · 2009In vitroEvaluation of antioxidant and antibacterial activities of aqueous, methanolic and alkaloid extracts from Mitragyna speciosa leaves — in vitroView study →}.

Isolated mitragynine shows only moderate radical-scavenging capacity (ABTS and DPPH assays) ^{17Reference 17Goh et al. · 2014In vitroAntioxidant value and antiproliferative efficacy of mitragynine and a silane reduced analogue — in vitroView study →}.

The leaf’s antioxidant capacity tracks its epicatechin and other flavonoid content rather than its alkaloids. All of it is in vitro and extract-specific.

In-vitro screens show measurable but weak antibacterial activity. Aqueous, methanolic and alkaloid leaf extracts inhibited Salmonella typhi and Bacillus subtilis with minimum inhibitory concentrations of roughly 3–6 mg/mL — high concentrations — with the alkaloid extract the most active ^{16Reference 16Parthasarathy et al. · 2009In vitroEvaluation of antioxidant and antibacterial activities of aqueous, methanolic and alkaloid extracts from Mitragyna speciosa leaves — in vitroView study →}.

Fermented leaf preparations (with Lactobacillus rhamnosus) later showed antibacterial and antibiofilm activity against Staphylococcus aureus, MRSA and E. coli alongside antioxidant and anti-inflammatory readouts ^{21Reference 21Sornsenee et al. · 2025In vitroAntibacterial, Antibiofilm, Antioxidant and Anti-Inflammatory Activities of Kratom Leaf Fermentation Supernatant — in vitroView study →}.

Activity appears only at high in-vitro concentrations, with no in-vivo confirmation and nothing to suggest oral kratom reaches antimicrobial exposures.

Evidence is limited to cell-line antiproliferation. Mitragynine and a silane-reduced analogue inhibited K562 leukemia and HCT116 colorectal cancer cells with IC50 values comparable to reference cytotoxics, and showed some selectivity for cancer over normal cells ^{17Reference 17Goh et al. · 2014In vitroAntioxidant value and antiproliferative efficacy of mitragynine and a silane reduced analogue — in vitroView study →}.

These are cytotoxicity screens at high micromolar concentrations, not disease models. There are no animal tumour models and no human data.

Traditional use for “sugar” and modern in-vitro work suggest a glucose-handling angle, but the strongest supporting study has been retracted. In vitro, mitragynine and kratom ethanol extracts inhibit α-glucosidase (more potently than acarbose in one assay) and, less strongly, pancreatic lipase — enzyme-level mechanisms relevant to post-meal glucose ^{19Reference 19Limcharoen et al. · 2022In vitroInhibition of α-Glucosidase and Pancreatic Lipase Properties of Mitragyna speciosa Leaves — in vitroView study →}. However, the only in-vivo study, an antidiabetic/antioxidant experiment in type-2 diabetic rats, was retracted by the journal in 2026 and cannot be relied upon ^{20Reference 20Zhang et al. · 2026AnimalRetraction notice to “Antidiabetic and antioxidant activities of Mitragyna speciosa leaf extract in type 2 diabetic rats” — retraction of a rat studyView study →}.

Gap: After the retraction, the evidence is in-vitro enzyme inhibition plus traditional use only — there is no trustworthy in-vivo or human data supporting a glucose-lowering effect.

Several of these alkaloids are better characterised in Uncaria (cat’s claw) than in kratom, and much of the per-compound data is preliminary or in vitro.

• Mitragynine — the dominant alkaloid (~66% of the alkaloid fraction) and the most studied. A partial mu-opioid agonist with adrenergic and 5-HT2A serotonergic activity; antitussive, antidiarrheal, analgesic, and both stimulant and sedative depending on dose.
• 7-Hydroxymitragynine — a minor but far more potent mu-opioid agonist, formed partly by the body’s own metabolism of mitragynine. It drives much of the opioid effect and carries the clearest abuse liability, which is why concentrated “7-OH” products differ from the leaf.
• Paynantheine — second most abundant, at roughly 8% of the alkaloids, with weak opioid activity.
• Speciogynine — third most abundant; a close relative of mitragynine with muscle-relaxant properties.
• 9-Hydroxycorynantheidine — a partial opioid agonist thought to modulate the effects of the stronger agonists.
• Corynantheidine — a low-efficacy mu-opioid partial agonist which, because it is weak, functionally opposes the stronger agonists alongside it. It binds alpha-1D adrenergic receptors far more tightly than mitragynine does.
• Ajmalicine — also found in yohimbe and Rauwolfia; an α-adrenergic antagonist used pharmaceutically for blood pressure, and a mild smooth-muscle relaxant and sedative.
• Mitraphylline, rhynchophylline and isorhynchophylline — oxindole alkaloids with reported vasodilating, blood-pressure-lowering and calcium-channel effects, mostly from Uncaria research.
• Isomitraphylline and isopteropodine — oxindole alkaloids reported as immunostimulant in older work.
• Speciophylline — shared with cat’s claw; early cell-line work suggests antileukemic activity.

Dependence and withdrawal. Kratom acts through the µ-opioid system, and regular use causes tolerance, dependence and withdrawal. In a survey of 293 long-term users, the majority met criteria for severe dependence, with muscle pain, insomnia, watery eyes, irritability and restlessness on stopping ^{7Reference 7Singh et al. · 2014ObservationalKratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users — observational cohortView study →}. Daily, heavy or long-term use is the pattern that leads to dependence; occasional, low-dose use is much less likely to. Kratom dependence is generally milder than dependence on pharmaceutical opioids, while concentrated 7-hydroxymitragynine products behave more like classical opioids ^{12Reference 12Hemby et al. · 2019AnimalAbuse liability and therapeutic potential of the Mitragyna speciosa alkaloids mitragynine and 7-hydroxymitragynine — rat self-administrationView study →}. People with a history of addiction, especially to opioids, should talk to a doctor before using kratom.

Drug interactions. Kratom is a clinically confirmed CYP3A inhibitor. A single 2 g dose of kratom tea raised exposure to the drug midazolam by about 40% ^{23Reference 23Tanna et al. · 2023RCTClinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom — randomised clinical pharmacokinetic studyView study →}. Combining it with medications heavily metabolised by CYP3A, or with other opioids, sedatives or alcohol, can cause serious interactions. Anyone taking medication or with a medical condition should check with their doctor first.

Liver injury. Cholestatic liver injury is uncommon but established, with biopsy-confirmed case reports and a prospective US cohort of 11 attributed cases that recovered after stopping ^{24,25Reference 24Ahmad et al. · 2021ObservationalLiver injury associated with kratom: Experience from the U.SView study →Reference 25Fernandes et al. · 2019Case reportKratom-Induced Cholestatic Liver Injury and Its Conservative Management — case reportView study →}.

Product quality. Serious harms and deaths cluster in high-concentration Western extracts, adulterated products and use alongside other drugs, rather than in traditional leaf. Commercial kratom has documented heavy-metal and microbial contamination and several-fold batch-to-batch variability in alkaloid content ^{26Reference 26Sengnon et al. · 2023Seasonal and Geographic Variation in Alkaloid Content of Kratom (Mitragyna speciosa) from Thailand — analyticalView study →}.

Whole leaf. Taken on its own at ordinary doses, whole leaf has a fairly wide margin. An old (1972) study found no deaths in animals even at very high doses of mitragynine, and the wobble tends to stop people well before they can take a dangerous amount of leaf. That margin does not extend to extracts or to combinations with other drugs.

Kratom Side Effects

Most side effects are dose-related. Because the plant works through both adrenergic and opioid receptors, they come in two groups.

Adrenergic (stimulant-type):

• Nausea
• Dizziness
• Anxiety
• Stimulation
• Insomnia
• Dry mouth
• Headaches
• Irritability
• Sweating
• Diarrhea
• Increased urination
• Rapid heartbeat

Opioid (sedative-type):

• Sedation
• Lethargy
• Nausea or vomiting
• Dizziness
• Itchy nose
• Euphoria
• Constipation
• Increased urination

What Is the “Kratom Wobble”?

The kratom wobble is the most common side effect of high doses. It brings dizziness and loss of coordination and can make people feel quite unwell.

Kratom wobble has three main symptoms:

1. Blurry vision
2. Dizziness
3. Nausea / vomiting

It is more common with some strains than others. The effects usually pass within a few minutes but can last a few hours, and sitting or lying somewhere comfortable helps; many people find ginger tea or warm water settles it. Wobble means the dose was past the limit for that strain.