Kratom is a botanical product derived from the tropical tree Mitragyna speciosa, containing the psychoactive alkaloids mitragynine and 7-hydroxymitragynine, which act as partial mu-opioid receptor agonists with additional adrenergic, serotonergic, and dopaminergic activity. [1] The toxidrome is variable and dose-dependent — producing stimulant effects at low doses and opioid-like effects at higher doses — and is significantly worsened by polysubstance use. [2-3] Kratom-related poison center reports increased approximately 1,200% from 2015 to 2025. [3]
1. History
- Ask about form consumed (leaves, tea, powder, capsules, concentrated extracts — extracts carry higher alkaloid loads and toxicity risk) [4]
- Dose, frequency, and duration of use — higher frequency correlates more strongly with dependence and withdrawal than dose amount [5]
- Timing of last use and amount ingested
- Intent: self-treatment of pain, opioid withdrawal, mood enhancement, recreational "legal high" [6]
- Co-ingestants: critically important — 79% of kratom-associated deaths involved multiple substances; ask specifically about opioids, benzodiazepines, alcohol, stimulants, gabapentinoids [3]
- Onset and progression of symptoms: neurological symptoms dominate acutely; hepatotoxicity has a median latency of ~14–21 days [7-8]
- Prior kratom use and tolerance level
- Withdrawal symptoms if cessation is suspected: myalgia, anxiety, irritability, lacrimation, rhinorrhea, insomnia, diarrhea, tremors [9]
2. Alarm Features
- Respiratory depression (2.8% of single-substance exposures) [10]
- Seizures (6.1% of exposures) [10]
- Coma or unresponsive altered mental status (2.3%) [10]
- Cardiac or respiratory arrest (0.6%) [10]
- Jaundice developing 2–7 weeks after use onset (acute liver injury, predominantly cholestatic) [7-8]
- Ventricular arrhythmia or hemodynamic instability [11-12]
- Serotonin syndrome features: agitation, clonus, hyperthermia, diaphoresis [2]
- Polysubstance ingestion — dramatically increases risk of hospitalization (44–56% vs 24–29%) and serious outcomes (57–66% vs 41–49%) [3]
3. Medications
- Naloxone: may reverse opioid-like effects (respiratory depression, CNS depression) in some cases; response is variable — prompted response in 2/3 cases in one series. The APA recommends providing naloxone to kratom users, especially those co-using CNS depressants [2][13]
- Buprenorphine-naloxone (Suboxone): first-line for kratom use disorder/dependence and withdrawal management [9][14-15]
- Clonidine IV: alternative for inpatient detoxification [9]
- Benzodiazepines: for seizure management and agitation
- Avoid: additional opioids, sedatives, or QTc-prolonging agents in the acute setting
- Drug interactions: kratom inhibits CYP3A (time-dependent) and CYP2D6, potentially increasing levels of co-administered drugs metabolized by these enzymes (e.g., midazolam AUC increased ~1.4-fold even at a low 2 g dose). Caution with methadone, certain antidepressants, antipsychotics, and other CYP3A/2D6 substrates [16-17]
4. Diet
- No specific dietary triggers for acute toxicity
- Hydration is important, particularly with vomiting (11.2% of exposures) [10]
- Kratom is commonly consumed as brewed tea — inquire about preparation method and concentration
- Long-term users may have poor nutritional status due to appetite suppression
5. Review of Systems
- Neurological: level of consciousness, confusion, hallucinations, seizures, tremors
- Cardiovascular: palpitations, chest pain, syncope
- GI: nausea, vomiting, abdominal pain, jaundice, pruritus, dark urine (hepatotoxicity)
- Psychiatric: agitation, anxiety, depression, suicidal ideation
- Respiratory: dyspnea, respiratory rate
- Musculoskeletal: myalgia (especially in withdrawal)
- Autonomic: diaphoresis, lacrimation, rhinorrhea, piloerection
6. Collateral History and Family History
- Collateral from family/friends regarding duration and escalation of use, behavioral changes, and co-substance use
- Source of kratom (online, smoke shops, gas stations) — product quality and alkaloid content are highly variable and unregulated; contamination with heavy metals (lead) has been reported [13]
- History of opioid use disorder or other substance use disorders
- Family history of substance use disorders, psychiatric illness, or liver disease
7. Risk Factors
- Male sex (70.8% of exposures) [18]
- Age 20–39 years (most common), though 40–59 age group is rapidly increasing [3]
- Polysubstance use — the single most important risk factor for serious outcomes and death [3][19]
- History of opioid use disorder — kratom often used as self-treatment for withdrawal [6]
- High-dose and high-frequency use [5]
- Use of concentrated extract products vs. whole-leaf preparations [3]
- Pre-existing liver disease — may increase susceptibility to hepatotoxicity
- Psychiatric comorbidities: depression, anxiety, PTSD [1]
8. Differential Diagnosis
- Opioid overdose (traditional opioids, fentanyl) — miosis, respiratory depression; typically more consistent naloxone response
- Sympathomimetic toxidrome (amphetamines, cocaine) — tachycardia, hypertension, agitation, mydriasis
- Serotonin syndrome (SSRIs, MAOIs, tramadol) — clonus, hyperthermia, hyperreflexia; kratom itself can contribute via serotonergic activity [2]
- Anticholinergic toxidrome — mydriasis, dry skin, urinary retention, delirium
- Mixed/polysubstance overdose — most common real-world scenario
- Hepatotoxicity mimics: viral hepatitis, acetaminophen toxicity, primary biliary cholangitis (kratom liver injury can histologically mimic PBC), alcoholic hepatitis [20]
- Withdrawal syndromes (opioid, alcohol, benzodiazepine)
9. Past Medical History
- Prior opioid use disorder or substance use history
- Previous kratom use and any prior toxicity episodes
- Liver disease (increases hepatotoxicity risk)
- Cardiac history — arrhythmias, QTc-prolonging conditions
- Psychiatric history — depression, anxiety, PTSD (common reasons for kratom self-medication)
- Chronic pain conditions
- Current medication list — critical for drug interaction assessment
10. Physical Exam
- Vital signs: tachycardia (16.9–21.4%), hypertension, or conversely bradycardia; monitor for hypothermia or hyperthermia [10][18]
- Neurological: GCS/level of consciousness (altered in ~90% of poisoning cases), pupil size (variable — miosis or mydriasis), clonus, hyperreflexia [2]
- Cardiovascular: rate, rhythm, murmurs
- Respiratory: rate, depth, oxygen saturation — assess for respiratory depression
- Abdominal: hepatomegaly, RUQ tenderness, jaundice, scleral icterus
- Skin: diaphoresis, track marks (co-substance use), jaundice
- Psychiatric: agitation (18.6%), hallucinations (4.8%), orientation [10]
11. Lab Studies
- Comprehensive metabolic panel: LFTs (AST, ALT, ALP, bilirubin — kratom hepatotoxicity is predominantly cholestatic with mixed biochemical pattern, median R ratio 3.4) [7]
- CBC
- Lactate if hemodynamically unstable
- Urine drug screen — standard immunoassays do not detect mitragynine; specialized testing (LC-MS/MS) is required [19]
- Comprehensive toxicology panel including synthetic opioids, fentanyl
- Acetaminophen and salicylate levels (rule out co-ingestion)
- Ethanol level
- Coagulation studies (INR/PT) if hepatotoxicity suspected
- BMP including glucose, creatinine (renal injury reported in some cases) [19]
- CK if prolonged immobilization or seizures
- Blood gas if respiratory depression present
12. Imaging
- Chest X-ray: if respiratory depression, aspiration concern, or pulmonary symptoms
- CT head: if altered mental status with unclear etiology, seizures, or focal neurological findings
- RUQ ultrasound: if hepatotoxicity suspected (evaluate for biliary obstruction, hepatomegaly)
- Imaging is not routinely necessary in straightforward kratom toxicity with clear history and improving clinical trajectory
13. Special Tests
- Mitragynine blood levels via LC-MS/MS — not widely available or rapid; living patients have shown levels of 5–340 ng/mL, deceased patients 3.5–7,500 ng/mL [19]
- RUCAM score (Roussel Uclaf Causality Assessment Method) for suspected kratom-induced liver injury [7]
- Liver biopsy: may be considered in unclear hepatotoxicity — findings are predominantly cholestatic, can mimic primary biliary cholangitis [20]
- Poison Control Center consultation — recommended for all significant exposures
14. ECG
- Obtain ECG in all symptomatic kratom exposures
- Sinus tachycardia: most common finding (OR 8.61 vs controls) [21]
- QTc prolongation: dose-dependent; in vitro hERG channel inhibition raises concern for torsades de pointes, though clinical cases remain rare [12][22-23]
- Ventricular arrhythmias: reported in case reports, particularly with polysubstance use [11][22]
- Continuous cardiac monitoring for patients with significant ingestion, QTc prolongation, or hemodynamic instability
- Mitragynine's arrhythmia mechanism may not solely involve QTc prolongation — sodium channel blockade (similar to propoxyphene) has been hypothesized [22]
15. Assessment
Kratom toxicity presents as a variable, mixed toxidrome combining features of opioid overdose (CNS/respiratory depression, miosis), sympathetic overactivation (tachycardia, hypertension, agitation, mydriasis), and serotonin-like syndrome. [2] The clinical picture depends on dose, product formulation, and co-ingestants.
- Single-substance exposures: generally self-limited, resolving within 24–48 hours; serious outcomes occur in 41–49% [3]
- Polysubstance exposures: significantly higher morbidity and mortality; account for 79% of kratom-associated deaths [3]
- Hepatotoxicity: subacute presentation (median latency ~14–21 days), predominantly cholestatic, generally reversible [7-8]
- Dependence: up to 20% of regular users may meet DSM-5 criteria for kratom use disorder [6]
16. Treatment Plan
Acute Stabilization
- ABCs — airway management if GCS depressed; intubation if refractory respiratory depression
- Naloxone 0.4–2 mg IV/IM/IN — trial warranted for opioid-like features (respiratory depression, CNS depression); may avoid intubation in some cases; repeat dosing may be needed [2][13]
- Benzodiazepines for seizures or severe agitation
- IV fluids for dehydration, hemodynamic support
- Activated charcoal: consider if presentation within 1–2 hours of ingestion and airway is protected
- Continuous cardiac monitoring and serial ECGs if QTc prolonged
Hepatotoxicity Management
- Supportive care — most cases resolve spontaneously [8]
- N-acetylcysteine may be considered empirically if acetaminophen co-ingestion cannot be excluded
- Hepatology consultation for acute liver failure
Withdrawal/Dependence
- Buprenorphine-naloxone: first-line for kratom use disorder; home induction via telehealth has been reported successfully [9][14-15]
- Clonidine: adjunct for autonomic withdrawal symptoms [9]
- Supportive measures: hydration, antiemetics, NSAIDs for myalgia
17. Disposition
Admit if
- Persistent altered mental status or respiratory depression requiring naloxone
- Seizures
- Hemodynamic instability or arrhythmia
- Significant polysubstance ingestion
- Evidence of hepatotoxicity (elevated LFTs, jaundice)
- Suicidal intent
Observe (4–6 hours minimum) if
- Mild-moderate symptoms with improving trajectory
- Single-substance exposure with stable vitals
Discharge if
- Asymptomatic or symptoms fully resolved after observation
- Normal vital signs, mental status, and ECG
- Reliable follow-up and safe disposition plan
- No concern for hepatotoxicity (may not manifest acutely)
Consult
- Toxicology/Poison Control for significant exposures
- Hepatology for acute liver injury
- Psychiatry/Addiction Medicine for kratom use disorder or co-occurring substance use disorders
- Cardiology if significant arrhythmia or QTc prolongation
18. Follow Up / Return Precautions
- Return immediately for: recurrent altered mental status, difficulty breathing, seizures, chest pain/palpitations, jaundice, dark urine, severe abdominal pain, or worsening symptoms
- Follow-up LFTs in 1–2 weeks if any baseline elevation, or sooner if symptomatic — hepatotoxicity may present with delayed onset (median ~14–21 days) [7]
- Substance use counseling and referral to addiction medicine; discuss buprenorphine-naloxone if dependence is identified [13-14]
- Narcan prescription/distribution for patients who continue kratom use, particularly those co-using CNS depressants [13]
- Patient counseling: kratom is not FDA-approved, products are unregulated with variable potency and potential contamination, and polysubstance use dramatically increases risk of death [3]
- Expected recovery: effects of acute intoxication typically resolve within 24–48 hours; withdrawal symptoms may persist for days to weeks [2][9]
References
1. Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna Speciosa). — Hartley C, Bulloch M, Penzak SR. Journal of Clinical Pharmacology. 2022.
2. Mitragyna Speciosa (Kratom) Poisoning: Findings From Ten Cases. — Peran D, Stern M, Cernohorsky P, et al. Toxicon : Official Journal of the International Society on Toxinology. 2023.
3. Increases in Kratom-Related Reports to Poison Centers - National Poison Data System, United States, 2015-2025. — Towers EB, Thomas YT, Holstege CP, Farah R. MMWR. Morbidity and Mortality Weekly Report. 2026.
4. Beneficial and Adverse Health Effects of Kratom (Mitragyna Speciosa): A Critical Review of the Literature. — Heywood J, Smallets S, Paustenbach D. Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association. 2024.
5. Kratom Addiction Per DSM-5 SUD Criteria, and Kratom Physical Dependence: Insights From Dosing Amount Versus Frequency. — Rogers JM, Weiss ST, Epstein DH, et al. Drug and Alcohol Dependence. 2024.
6. Kratom: Substance of Abuse or Therapeutic Plant?. — Gorelick DA. The Psychiatric Clinics of North America. 2022.
7. Kratom (Mitragyna Speciosa) Liver Injury: A Comprehensive Review. — Schimmel J, Dart RC. Drugs. 2020.
8. Liver Injury Associated With Kratom, a Popular Opioid-Like Product: Experience From the U.S. Drug Induced Liver Injury Network and a Review of the Literature. — Ahmad J, Odin JA, Hayashi PH, et al. Drug and Alcohol Dependence. 2021.
9. Kratom Dependence and Treatment Options: A Comprehensive Review of the Literature. — Bin Abdullah MFIL. Current Drug Targets. 2020.
10. Kratom Use and Toxicities in the United States. — Eggleston W, Stoppacher R, Suen K, Marraffa JM, Nelson LS. Pharmacotherapy. 2019.
11. Cardiovascular Health in Kratom Users; A Narrative Review. — Chichagi F, Alikhani R, Beigi Harchegani A. Journal of Addictive Diseases. 2024.
12. The Adverse Cardiovascular Effects and Cardiotoxicity of Kratom ( Korth.): A Comprehensive Review. — Leong Bin Abdullah MFI, Singh D. Frontiers in Pharmacology. 2021.
13. Resource Document on Harm Reduction. — Lief Fenno MD PHD, Nancy Shenoi MD, Kenn Ashley MD, et al American Psychiatric Association (2024). 2024.
14. Controversies in Assessment, Diagnosis, and Treatment of Kratom Use Disorder. — Smith KE, Epstein DH, Weiss ST. Current Psychiatry Reports. 2024.
15. Kratom Use Disorder: Case Reports on Successful Treatment With Home Induction of Buprenorphine-Naloxone. — Kiyokawa M, Kwon AK, Cape MC, Streltzer JM. Family Practice. 2023.
16. Translating Kratom-Drug Interactions: From Bedside to Bench and Back. — Tanna RS, Cech NB, Oberlies NH, et al. Drug Metabolism and Disposition: The Biological Fate of Chemicals. 2023.
17. Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. — Tanna RS, Nguyen JT, Hadi DL, et al. Clinical Pharmacology and Therapeutics. 2023.
18. Kratom Exposures Reported to United States Poison Control Centers: 2011-2017. — Post S, Spiller HA, Chounthirath T, Smith GA. Clinical Toxicology. 2019.
19. The Acute Adverse Health Effects of Kratom: An Evaluation of Case Reports. — Smallets S, Litvin S, Abele G, Kirsh S, Paustenbach D. Frontiers in Pharmacology. 2025.
20. Kratom Induced Severe Cholestatic Liver Injury Histologically Mimicking Primary Biliary Cholangitis: A Case Report. — Gandhi D, Ahuja K, Quade A, Batts KP, Patel L. World Journal of Hepatology. 2020.
21. Is Kratom ( Korth.) Use Associated With ECG Abnormalities? Electrocardiogram Comparisons Between Regular Kratom Users and Controls. — Leong Abdullah MFI, Tan KL, Narayanan S, et al. Clinical Toxicology. 2021.
22. Ventricular Arrhythmias Associated With Over-the-Counter and Recreational Opioids. — Krantz MJ, Rudo TJ, Haigney MCP, et al. Journal of the American College of Cardiology. 2023.
23. Assessment of Cardiovascular Functioning Among Regular Kratom ( Korth) Users: A Case Series. — Leong Bin Abdullah MFI, Singh D. Frontiers in Pharmacology. 2021.