Mitragynine
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Mitragynine is a naturally-occurring opioid of the indole alkaloid class. It is the primary psychoactive compound in kratom, a tree native to Southeast Asia. It activates opioid receptors, but depends on a liver-generated metabolite to produce most of its pain-relieving effects.[1]
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Kratom has been used in Southeast Asia for centuries — leaves chewed or brewed as tea for fatigue, pain, and opium substitution.[2] Scientific interest grew when researchers found mitragynine activates opioid receptors without triggering the respiratory depression seen with conventional opioids.[3] It remains unscheduled at the US federal level and is under active investigation as an opioid use disorder treatment.
Subjective effects include stimulation, heightened focus, pain suppression, warm mood elevation, and sedation. Low doses feel like strong coffee with added warmth; higher doses shift into opioid sedation and heavy-limbed calm. Nausea, constipation, and mental fog are characteristic unwanted effects.
Physical dependence develops with regular use; stopping brings withdrawal — muscle aches, insomnia, anxiety, and low mood.[4] The dominant danger is combination: 87% of kratom-associated deaths involved other substances,[5] and mixing with opioids or benzodiazepines multiplies respiratory failure risk. Human clinical data remain limited — no lethal dose has been established, and toxicity thresholds are not yet known.
History[edit]
Discovery
Mitragyna speciosa was described botanically by Pieter Willem Korthals in 1839. Traditional use — leaves chewed or brewed as tea for fatigue, pain, and opium substitution — was documented across Southeast Asia.[2] Mitragynine was isolated as a discrete compound in 1921 by Ellen Field, with its structure established in 1965.[6]
Scientific significance
The decisive finding: mitragynine activates opioid receptors without triggering the respiratory depression that kills people in overdose.[7][3] Researchers also discovered the liver converts mitragynine into 7-hydroxymitragynine — a more potent compound that drives most of the opioid effect.[1]
Regulation and modern use
The DEA attempted emergency scheduling in 2016 but withdrew after 51 members of Congress objected and over 23,000 public comments were filed.[8] Thailand — which had controlled kratom since 1943 — legalized it in 2021; the WHO declined to recommend international scheduling the same year.[8] An estimated 1.9 million Americans have used kratom, and the first clinical study of pure mitragynine is underway.[9]
The name Mitragyna was given by Korthals, who noted the plant's stipules resembled a bishop's mitre. In Southeast Asian labor culture, kratom occupied a niche like betel nut and tea — a work-enhancing plant integrated into daily routine, not consumed recreationally. In Western markets, kratom arrived through online vendors in the 2000s and became closely associated with self-managed opioid withdrawal.
Chemistry[edit]
Structural class
Mitragynine belongs to the Corynanthe-type indole alkaloid family — the same core structure found in related kratom alkaloids speciogynine, speciociliatine, and paynantheine.[10] A methoxy group on the indole ring and a distinctive side chain help distinguish it from these closely related compounds.[11]
Molecular properties
| Molecular formula | C₂₃H₃₀N₂O₄ |
| Molecular weight | 398.5 g/mol |
Natural occurrence
Mitragynine is the dominant alkaloid in kratom leaves, typically comprising 40–66% of total alkaloid content.[10] Three naturally occurring diastereomers also appear in the plant — speciogynine, speciociliatine, and mitraciliatine — with differing absorption rates and duration in the body.[12][11] Over 40 related indole alkaloids have been identified in kratom.[2]
Pharmacology[edit]
Mechanism of action
Mitragynine is a partial agonist at the µ-opioid receptor[13] — it activates the receptor but reaches a lower ceiling than full opioids like morphine. The liver converts it to 7-hydroxymitragynine (7-HMG), a much more potent compound that drives most of the pain-relieving activity.[1]
Both mitragynine and 7-HMG activate opioid receptors through a pathway that does not trigger the signaling behind respiratory depression, constipation, and rapid tolerance seen with conventional opioids.[3][7] Mitragynine also blocks opioid receptor types associated with dysphoria,[14] and its stimulant-like effects at low doses likely stem from epinephrine receptor activity.[15][16]
Pharmacokinetics
After oral ingestion, mitragynine reaches peak blood levels within about one hour.[17][12] Its half-life is unusually long — roughly 23 hours after a single dose, extending to 44–68 hours with repeated daily use.[18] It inhibits CYP3A, the liver enzyme that processes many medications, meaning its drug interaction potential grows with continued use.[19]
Neuroscience[edit]
Where it acts
Opioid receptor activation in the brain's mesolimbic pathway releases dopamine, producing the mood-elevating and reinforcement.[20] As a partial agonist, mitragynine produces less dopamine release than full opioids — consistent with milder euphoria. Blocking opioid receptor types associated with dysphoria may further contribute to positive mood.[14]
Pain relief works through opioid receptors in the brainstem, which suppress pain signals traveling up from the spinal cord. This effect depends on the liver converting mitragynine to 7-HMG,[1] so individual differences in liver metabolism produce variable analgesic responses.
Why it matters
The low-dose stimulant effects — alertness, energy, focus — likely reflect epinephrine receptor activity rather than opioid mechanisms.[16][15] This dual pharmacology explains kratom's unusual bimodal dose-response. Preclinical evidence suggests kratom alkaloids produce less withdrawal than morphine at equivalent doses.[21]
No neuroimaging studies of mitragynine's effects in humans have been published — how the bimodal dose-response maps onto brain activity remains unknown. Whether people with low liver enzyme activity experience predominantly stimulant effects with attenuated opioid activity has not been studied. The compound's long-term effects on brain structure and synaptic function are unknown.
Subjective Effects[edit]
Mitragynine delivers a bimodal experience unlike any classical opioid. Low doses feel activating — clear-headed energy, heightened focus, sociable warmth. As the dose rises, the opioid dimension takes over: sedation deepens, pain dissolves, and the body settles into a heavy, weighted calm. Where this crossover happens varies considerably between individuals.
Compared to classical opioids like morphine or oxycodone, low doses are far more stimulant-inflected and less sedating, with a partial-agonist ceiling keeping euphoria well below full opioid levels. Compared to buprenorphine — another partial µ-opioid agonist — mitragynine's adrenergic activity gives it a distinct activating quality that buprenorphine lacks.
Effect Grid
Common doses (15–40 mg mitragynine) represent the transition zone between stimulant-dominant and opioid-dominant effects. Analgesia begins to emerge alongside continued mood elevation. Cognitive euphoria becomes more pronounced, and anxiety suppression is frequently reported. Sociability may persist or begin yielding to a more inward, relaxed state.
Physical effects shift noticeably: warmth and body high develop, muscle relaxation appears, and some users experience nausea at the upper end of this range. Pupil constriction becomes detectable. Appetite suppression typically persists. Mild dizziness is possible.
This range corresponds to approximately 2–5 grams of dried leaf. The balance between stimulation and sedation is strongly influenced by individual CYP3A metabolizer status, which determines the rate of conversion to the more potent opioid metabolite 7-hydroxymitragynine.
Modeled from the effect's dose-dependence curve — not per-substance measurements.
Vestibular distortion · Visual acuity suppression · Tinnitus
Constipation · Muscle relaxation · Nausea · Sedation · Stimulation · Bodily heaviness · Diarrhea · Dizziness · Wakefulness · Appetite suppression · Breathing alteration · Dry mouth · Excessive sweating · Insomnia · Muscle tension · Physical fatigue · Restlessness · Tactile euphoria · Trembling · Vomiting · Yawning · Brain zaps · Headache · Heart rate perception changes · Sexual arousal suppression · Watery eyes · Nystagmus (eye wobbles) · Pain enhancement
Stimulation · Bodily heaviness · Diarrhea · Dizziness · Wakefulness · Appetite suppression · Breathing alteration · Dry mouth · Excessive sweating · Insomnia · Muscle tension · Physical fatigue · Restlessness · Tactile euphoria · Trembling · Vomiting · Yawning · Brain zaps · Headache · Heart rate perception changes · Sexual arousal suppression · Watery eyes · Nystagmus (eye wobbles) · Pain enhancement
Cognitive fatigue · Cognitive impairment · Focus suppression · Information processing enhancement · Information processing suppression · Thought deceleration · Confusion · Motivation suppression
Information processing suppression · Thought deceleration · Confusion · Motivation suppression
Emotional suppression · Anhedonia · Dysphoria
Timeline
Initial awareness of effects — subtle stimulation, mild alertness shift, or faint warmth depending on dose. Sub-threshold at the lowest doses.
Effects build steadily. Low doses develop stimulant clarity and sociability; higher doses begin to introduce opioid warmth and emerging analgesia. Mild nausea possible at upper dose ranges.
Maximum intensity plateau. Low-dose peak: focused stimulation, mood elevation, wakefulness. High-dose peak: sedation, strong analgesia, opioid-type euphoria, bodily heaviness, pupil constriction.
Gradual diminution of primary effects. Residual warmth, relaxation, or mild stimulation persists. Nausea typically resolves.
Mild residual effects — lingering mood elevation, subtle fatigue, or gentle relaxation. Pharmacological activity persists well beyond subjective experience due to the 23–67 hour elimination half-life.
⚠ Do not drive or operate heavy machinery for several hours after subjective effects resolve, as motor coordination may remain subtly impaired due to mitragynine's long elimination half-life.
Safety[edit]
- Acute toxicity
- Moderate
- Chronic toxicity
- Moderate
- Withdrawal
- Moderate
- Tolerance buildup
- moderate
- Tolerance reset
- 21 days
- Physical
- Moderate
- Psychological
- Moderate
- Compulsive redosing
- Moderate
- Dose escalation
- Moderate
- Cross-tol.
- morphine · oxycodone · heroin
Toxicity
No human lethal dose for mitragynine has been established. The largest mortality analysis — 156 kratom-associated deaths — found 87% involved co-exposure to other substances.[5] Only 23% of cases identified mitragynine as the sole intoxicant.
Liver injury
Mitragynine can damage the liver. Multiple case reports document a cholestatic pattern — bile flow disruption — typically appearing within 2–49 days of use, with symptoms including abdominal discomfort, yellowing of the skin, itching, and dark urine.[22][23] The mechanism is unclear — direct toxicity, immune-mediated injury, and contaminant effects are all under investigation.[24]
Heart and circulation
Case reports link kratom use to blood pressure instability, heart muscle damage, and abnormal heart rhythms.[25] Surgical patients with kratom use history present specific clinical concerns around blood pressure and agitation.[9]
Respiratory effects
Mitragynine's signaling profile predicts less breathing suppression than classical opioids, and animal data confirm significantly less respiratory depression than morphine at equivalent pain-relieving doses.[26] Fatal respiratory depression has nonetheless been reported, primarily alongside other sedating substances.
Seizures
Seizures have been reported in association with kratom use, including a documented case involving kratom combined with modafinil.[14] Multiple reviews cite seizures as a recognized adverse event.[27]
Neonatal effects
Kratom use during pregnancy can produce neonatal abstinence syndrome. Three published case reports document withdrawal symptoms in newborns born to mothers using kratom, including oral intolerance, restlessness, irritability, and vomiting.[28][29][30] Perceived safety as a "natural" herb does not confer safety in pregnancy.[31]
Kidney injury
Acute kidney injury has been documented in severe overdose complicated by muscle breakdown.[25] No data on chronic kidney effects are available.
Psychological risks
In the only controlled human study, 40 mg mitragynine produced increased ratings of memory suppression and mild psychological symptoms.[32] User surveys describe anxiety, irritability, and depressed mood as dose-dependent or withdrawal-related phenomena.[33] Chronic heavy use has been linked to cognitive complaints in observational studies, though controlled evaluations are lacking.citation needed
Tolerance & dependence
Tolerance to mitragynine's opioid effects develops with repeated use, and cross-tolerance to morphine has been documented.[34] Physical dependence occurs with regular use — consumption exceeding approximately 4 glasses of kratom tea per day (76–115 mg/day mitragynine) is associated with higher withdrawal severity.[4]
Withdrawal symptoms include muscle aches, watery eyes, insomnia, diarrhea, feverish sensations, appetite suppression, tremors, and nausea.[4] Psychological symptoms include depressed mood (81% report mild depression), anxiety (70% report mild anxiety), restlessness, and irritability.[33] Severity is rated milder than classical opioid withdrawal,[4][21] and treatment most commonly uses buprenorphine-naloxone (Suboxone).[34]
Drug interactions
Mitragynine's interaction risk arises from three converging mechanisms: liver enzyme inhibition, transport protein inhibition, and additive effects with other sedating drugs.
CYP3A substrates
Mitragynine inhibits CYP3A, the liver enzyme that processes many medications.[19] This raises blood levels of drugs like midazolam, triazolam, certain immunosuppressants (tacrolimus, cyclosporine), and some antiretrovirals — with midazolam exposure predicted to increase 2.2–2.7 times.[35] A fatal case possibly attributable to CYP-mediated potentiation of quetiapine has been reported.[36]
CYP3A inhibitors like azole antifungals, macrolide antibiotics, and ritonavir reduce 7-HMG formation, potentially attenuating opioid effects while increasing parent compound exposure.[35]
CNS depressants
Combining with opioids, benzodiazepines, alcohol, or sedating antihistamines poses the highest acute fatality risk. The majority of kratom-associated deaths involved concurrent sedating substances.[5][37][38][39]
P-glycoprotein substrates
Mitragynine inhibits P-glycoprotein,[40] a transport protein that controls how much of some drugs enters the bloodstream and brain. Affected drugs include digoxin, dabigatran, and certain chemotherapy agents.
CYP2D6 substrates
Mitragynine inhibits CYP2D6 in laboratory studies, though clinical effects at typical kratom doses appear minimal.[19] Higher doses or sensitive substrates may present risk.[40]
Serotonergic drugs
Mitragynine interacts with serotonin pathways, creating a theoretical risk of serotonin syndrome — a potentially life-threatening overheating and seizure response — when combined with SSRIs, SNRIs, or MAOIs. No published case reports of this combination have been identified.safety citation needed
Other interactions
A seizure case has been reported with kratom combined with modafinil.[14] Standard opioid urine drug screens do not reliably detect mitragynine or 7-HMG; specific laboratory methods are required.[41]
Contraindications
Pregnancy: Mitragynine crosses the placenta. Neonatal abstinence syndrome has been documented.[28][29][30]
Liver disease: Pre-existing liver conditions increase risk of drug-induced liver injury and impair clearance of both mitragynine and its metabolite.[22]
Concurrent sedating substances: Combining with opioids, benzodiazepines, alcohol, or gabapentinoids risks additive respiratory depression. Most kratom-associated fatalities involve poly-substance exposure.[5]
CYP3A-metabolized medications with narrow safety margins: Mitragynine's enzyme inhibition can raise co-administered drug levels to toxic concentrations.[19]
Kidney disease: Acute kidney injury has been documented in severe overdose.[25] No safety data exist for pre-existing kidney disease.
Surgery: Patients with kratom use history require specific clinical attention due to risks of blood pressure instability, agitation, pain management difficulty, and withdrawal.[9]
Harm Reduction[edit]
Forms & Identification
Kratom's alkaloid content varies considerably between vendors, batches, and geographic sources. Even plain leaf powder sold as the same "strain" can produce substantially different effects at the same weight. Extract products concentrate mitragynine and may contain elevated 7-hydroxymitragynine, making dosing unpredictable without tested potency information.
Products marketed as "enhanced" or "7-OH" contain semi-synthetic 7-hydroxymitragynine — a pharmacologically distinct substance, closer to a full opioid than to plain leaf. Treat any 7-HMG product as a different substance class from plain leaf.
Guidelines
- Start with low doses of any new batch or product, as alkaloid content varies considerably between sources
- Measure doses by weight rather than volume — a kitchen scale accurate to 0.1 g is sufficient for powder
- Allow at least 45–60 minutes before redosing, as peak effects can be delayed
- Avoid daily use to reduce dependence risk — even short tolerance breaks of 2–3 days help
- Stay hydrated; kratom can produce dry mouth and reduced thirst awareness
- Inform medical providers of kratom use before surgery or when prescribed new medications, particularly CYP3A-metabolized drugs
Set & Setting
Mitragynine's bimodal dose-response means context matters most at the boundary between stimulant and sedating doses. Low doses are compatible with work and social settings. Higher sedating doses are best taken where rest is available — avoid driving or operating machinery at any dose above the stimulant range.
Aftercare & integration. Mitragynine's long half-life (up to 24–68 hours depending on use pattern[18]) means residual effects and drug interactions may persist well beyond the subjective experience. Avoid other sedating substances for at least 24 hours after a high dose.
After regular use, even brief cessation may produce mild withdrawal symptoms including muscle aches, sleep disruption, and low mood. These typically peak 2–3 days after the last dose and resolve within a week. Maintaining hydration, light exercise, and consistent sleep schedules supports recovery during this period.
Recovery & Support
Physical dependence on kratom develops with regular use and is a physiological adaptation, not a moral failure. Withdrawal is milder than classical opioid withdrawal but nonetheless uncomfortable, and medical support can substantially ease the process.
Buprenorphine-naloxone (Suboxone) is the most commonly used treatment for kratom dependence.[34] Medical detoxification is advisable for anyone using high daily doses or experiencing significant withdrawal symptoms. Online communities — including kratom-specific recovery forums — provide peer support and practical guidance for tapering and cessation.
For anyone using kratom to manage opioid withdrawal independently, medical supervision is strongly recommended. Self-managed substitution carries risks of dose escalation and cross-dependence.
Recovery resources, crisis lines, and support pathways → View all
Emergency Response
Recognizing an emergency: Most kratom experiences, even uncomfortable ones, are not medical emergencies. Seek immediate help if any of the following occur: breathing becomes slow, shallow, or stops; lips or fingertips turn blue; the person becomes unresponsive or cannot be woken; seizure activity; severe chest pain; or yellowing of the skin or eyes (a sign of liver injury requiring urgent evaluation).
Immediate steps:
- 1. Call emergency services if breathing is compromised or the person is unresponsive
- 2. Place an unresponsive but breathing person in the recovery position (on their side, airway clear)
- 3. If opioid overdose is suspected and naloxone is available, administer it — naloxone reverses µ-opioid agonism from both mitragynine metabolites and any co-ingested opioids
- 4. Do not induce vomiting
- 5. Stay with the person until help arrives
What to tell the dispatcher: Name the substance (kratom / mitragynine), approximate amount, time of ingestion, and any other substances taken. Good Samaritan laws in many jurisdictions protect people who call for help during a drug emergency.
Reversal agent: Naloxone is effective against the µ-opioid component of mitragynine's effects. Keep naloxone accessible whenever using kratom alongside other opioids or at high doses.
Legal Status[edit]
Mitragynine is not scheduled under any UN international drug convention — the WHO found insufficient evidence to recommend scheduling in 2021.[8] It remains unscheduled at the US federal level after the DEA's 2016 emergency scheduling attempt was withdrawn following congressional and public opposition.[8] Status ranges from commercially available to outright prohibition depending on jurisdiction.
Legal status for mitragynine and kratom is evolving rapidly across jurisdictions. The information below reflects status as of early 2026 and may not capture recent legislative changes.
| Jurisdiction | Classification | Key provisions |
|---|---|---|
| United States | Not federally scheduled | DEA "Drugs and Chemicals of Concern" list; FDA Import Alert 54-15; state-level bans in AL, AR, IN, RI, VT, WI; KCPA enacted in several states[8] |
| United Kingdom | Illegal | Banned under Psychoactive Substances Act 2016 |
| Australia | Schedule 9 (Prohibited Substance) | Complete ban on possession, sale, and use |
| Canada | Legal to possess | Sales for human consumption not permitted under Food and Drugs Act |
| Thailand | Decriminalized / legal for traditional use | Removed from narcotics list under Kratom Act 2021; commercial export regulations in development |
| Malaysia | Illegal | Controlled under Poisons Act 1952 |
| Ireland | Schedule 1 controlled drug | Scheduled since 2017 under Misuse of Drugs Act |
| France | Illegal | Banned since 2020 |
| Netherlands | Legal | Sold in smart shops; not scheduled |
| Denmark / Romania / Poland | Banned | Various national scheduling instruments |
references
- [1] ^abcdKruegel AC, Uprety R, Grinnell SG, Langreck C, Pekarskaya EA, et al. (2019) 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects — ACS Central Science doi:10.1021/acscentsci.9b00141
- [2] ^abcCinosi E, Martinotti G, Simonato P, Singh D, Demetrovics Z, et al. (2015) Following the Roots of Kratom (Mitragyna speciosa): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries — BioMed Research International doi:10.1155/2015/968786
- [3] ^abcTodd DA, Kellogg JJ, Wallace ED, Khin M, Flores-Bocanegra L, et al. (2020) Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions — Scientific Reports doi:10.1038/s41598-020-76119-w
- [4] ^abcdSingh D, Narayanan S, Vicknasingam BK, Prozialeck WC, et al. (2018) Severity of Pain and Sleep Problems during Kratom (Mitragyna speciosa Korth.) Cessation among Regular Kratom Users — Journal of Psychoactive Drugs doi:10.1080/02791072.2018.1443234
- [5] ^abcdCorkery J, Streete P, Claridge H, et al. (2019) Characteristics of deaths associated with kratom use — Journal of Psychopharmacology doi:10.1177/0269881119862530
- [6]