Kratom toxicity: Difference between revisions
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==Background==
==Background==
*Derived from ''Mitragyna speciosa,'' a plant native to Southeast Asia
[[File:Kratom leaves.jpg|thumb|Kratom flowers and foliage.]]
*Contains numerous chemicals acting on mu opioid, adrenergic, serotonin, and GABA receptors
[[File:Powdered kratom.jpg|thumb|Typical powdered Kratom for commercial use.]]
*Increasingly popular in US for attempted self-treatment of pain, opioid addiction/withdrawal, and depression
*Derived from ''Mitragyna speciosa,'' a tropical evergreen tree in the coffee family native to Southeast Asia
**Patients often perceive incorrectly as a "safe" alternative to opioids
*Leaves contain over 40 alkaloids; the two most clinically relevant are:
**Mitragynine (most abundant, up to 66% of total alkaloid content) — partial mu-opioid receptor agonist<ref name="kruegel">Kruegel AC, Grundmann O. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. ''Neuropharmacology''. 2018;134(Pt A):108-120.</ref>
**7-Hydroxymitragynine (7-OH) (minor constituent, <2% of alkaloid content) — approximately 5-fold greater mu-opioid affinity than mitragynine<ref name="kruegel"/>
*Both alkaloids exhibit G-protein biased agonism at mu-opioid receptors with limited beta-arrestin recruitment (theoretically less respiratory depression than classical opioids, though still reported)<ref name="kruegel"/>
*Additional receptor activity at alpha-1A, alpha-2A, 5-HT1A, 5-HT2A, D1, and D2 receptors contributes to mixed stimulant-opioid clinical picture<ref name="yusof">Yusof SR, Zakaria Z, Amir Rawa MS, et al. Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers. ''Front Pharmacol''. 2021;12:751656.</ref>
*Mitragynine is metabolized by CYP3A4 to 7-hydroxymitragynine (a more potent metabolite) and inhibits CYP2D6 and CYP3A4, creating significant potential for drug-drug interactions<ref name="tanna">Tanna RS, Tian DD, Cech NB, et al. Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations. ''J Pharmacol Exp Ther''. 2021;376(1):64-73.</ref>
*Available in the US as powder, capsules, tablets, extracts, and liquid "shots" sold at gas stations, smoke shops, and online
**Products are unregulated, with highly variable alkaloid content and potential for contamination (''[[Salmonella]]'', heavy metals including lead)<ref name="fda">U.S. Food and Drug Administration. FDA and Kratom. Updated February 2024. https://www.fda.gov/news-events/public-health-focus/fda-and-kratom</ref>
*Estimated 1.7 million Americans aged ≥12 used kratom in 2021<ref name="fda"/>
*Not FDA-approved for any indication; not a legal dietary supplement or food additive<ref name="fda"/>
*Federally unscheduled but banned in several states (Alabama, Arkansas, Indiana, Vermont, Wisconsin, Louisiana); regulated in many others<ref name="crs">Congressional Research Service. Kratom Regulation: Federal Status and State Approaches. LSB11082. 2024.</ref>
*Patients commonly use for self-treatment of [[chronic pain]], [[opioid withdrawal]], depression, and anxiety
**Approximately one-third of users co-ingest with other substances<ref name="wapc">Washington Poison Center. Kratom and 7-hydroxymitragynine poisoning. 2025. https://www.wapc.org/data/data-blogs/kratom-and-7-hydroxymitragynine-poisoning/</ref>


==Clinical Features==
==Clinical Features==
*Effects are dose dependent and may mimic those of both opioid and stimulant toxicity
*Effects are dose-dependent and may mimic both opioid and stimulant toxicity
*Stimulant effects typically predominate at low doses (<5 g) with sedating effects more prevalent at higher doses
*Onset of effects typically within 10-20 minutes of ingestion; duration 2-5 hours


===Low-Dose Effects (<5 g)===
*Stimulant effects predominate
*Increased alertness and energy
*[[Tachycardia]], [[hypertension]]
*Agitation, jitteriness
*Decreased appetite
===High-Dose Effects (>5 g)===
*Opioid-like sedation predominates
*[[Miosis]]
*[[Respiratory depression]] (especially with co-ingestions or concentrated extracts)
*Drowsiness, [[altered mental status]]
*Nausea, [[vomiting]]
*Constipation
===Severe/Complicated Presentations===
*[[Seizures]]<ref name="statpearls">Eastlack SC, Cornett EM, Kaye AD. Kratom—Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review. ''Pain Ther''. 2020;9(1):55-69.</ref>
*[[Respiratory failure]] requiring [[intubation]]
*[[Rhabdomyolysis]] and [[acute kidney injury]]<ref name="auctores">Narrative Review of Kratom in the Emergency Department. ''Auctores''. 2025.</ref>
*'''Hepatotoxicity''' — typically cholestatic pattern, onset 1-8 weeks of regular use; can be severe (bilirubin >20 mg/dL); usually reversible with cessation<ref name="livertox">LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Kratom. National Institute of Diabetes and Digestive and Kidney Diseases; 2020.</ref>
*Cardiac arrest (rare, primarily in polydrug exposure)<ref name="poison">Poison Control. What is kratom? https://www.poison.org/articles/kratom</ref>
*[[QT prolongation]] (theoretical and case-reported)
===Kratom Withdrawal===
*Occurs with chronic use; onset typically within 12-24 hours of last dose<ref name="auctores"/>
*Resembles mild-moderate [[opioid withdrawal]]: myalgias, rhinorrhea, diaphoresis, insomnia, irritability, nausea, diarrhea
*Generally less severe than traditional opioid withdrawal
*Can be scored using the [[Clinical Opiate Withdrawal Scale]] (COWS)


==Differential Diagnosis==
==Differential Diagnosis==
*[[Opioid overdose]]
*[[Opioid toxicity]]
*[[Opioid withdrawal]]
*[[Opioid withdrawal]]
*[[Sympathomimetic overdose]]
*[[Sympathomimetic toxicity]]
*[[Anticholinergic toxicity]]
*[[Anticholinergic toxicity]]
*[[Serotonin syndrome]] (due to serotonergic activity)
*[[Tianeptine toxicity]] (similar presentation, also sold at gas stations)
*[[Xylazine toxicity]]
*[[Phenibut toxicity]]
{{Drugs of abuse types}}


==Evaluation==
==Evaluation==
*Clinical diagnosis
*Primarily a '''clinical diagnosis''' — ask specifically about kratom, herbal supplements, and "gas station" products
*Labs not routinely required unless severe vomiting, seizure, or unclear diagnosis
*'''Kratom does NOT appear on standard urine drug screens'''<ref name="statpearls"/>
**May cause false-negative opioid screen despite opioid-like presentation
**Specialized testing for mitragynine exists but is not widely available and generally not clinically useful in the acute setting
*Consider early consultation with [[Poison control]] (1-800-222-1222)


===Labs===
*Not routinely required for mild presentations
*For moderate-severe presentations, consider:
**[[CBC]], [[BMP]]/[[CMP]]
**[[LFTs]] — particularly if chronic use or concern for hepatotoxicity
**[[CK]] if agitated, seizing, or prolonged immobilization ([[rhabdomyolysis]])
**[[Lactate]], [[VBG]]
**[[Acetaminophen]] and [[salicylate]] levels, [[ethanol]] level to rule out co-ingestion
**[[Urine drug screen]] — will be negative for kratom, but useful to evaluate for co-ingestions
**[[Coagulation studies]] if hepatotoxicity suspected
===ECG===
*Obtain [[EKG]] in moderate-severe presentations
*Evaluate for [[tachycardia]], [[QT prolongation]]


==Management==
==Management==
*Management should be tailored to primary symptoms
*Focus on ABCs and symptom-directed treatment
**Naloxone for respiratory depression  
*Consider early [[Poison control]] consultation (1-800-222-1222)
**Benzodiazepines for hyperarousal, tachycardia, hypertension, and seizures
 
**NSAIDs, antiemetics, fluids, etc. for opioid withdrawal symptoms
===Respiratory Depression===
***Medication-assisted treatment with buprenorphine or methadone
*Supplemental oxygen, [[BVM]] ventilation as needed
*[[Naloxone]] — effective for kratom-induced respiratory depression due to mu-opioid agonism<ref name="greatimitator">Mikkelsen A, Van Roekel C, Grande EJ, et al. The Great Imitator: A Case of Accidental Kratom Overdose. ''Cureus''. 2023;15(7):e42497.</ref>
**Standard dosing as per [[opioid toxicity]] protocols
**Be aware of potential for rebound respiratory depression within 24 hours per poison control center reports<ref name="greatimitator"/>
 
===Agitation / Sympathomimetic Features===
*[[Benzodiazepines]] for hyperarousal, agitation, [[tachycardia]], [[hypertension]], and [[seizures]]
*IV fluids
*Avoid [[haloperidol]] if concern for [[QT prolongation]]
 
===Seizures===
*[[Benzodiazepines]] are first-line
*Standard [[seizure]] management algorithm
 
===Kratom Withdrawal===
*Symptom-directed treatment similar to [[opioid withdrawal]]:
**[[NSAIDs]] for myalgias
**[[Antiemetics]] (e.g., [[ondansetron]]) for nausea/vomiting
**[[Loperamide]] for diarrhea
**[[Clonidine]] for autonomic symptoms
**IV fluids for dehydration
*Medication-assisted treatment for opioid use disorder:
**[[Buprenorphine]] — most commonly reported for kratom withdrawal/dependence; can be initiated in the ED per standard protocols<ref name="wapc"/>
**[[Methadone]] — alternative for patients not candidates for buprenorphine


===Hepatotoxicity===
*Discontinue kratom
*Supportive care; most cases resolve spontaneously<ref name="livertox"/>
*GI consultation for severe hepatic injury (bilirubin >20 mg/dL, coagulopathy, or signs of [[acute liver failure]])
*Corticosteroids and [[NAC]] have been used in case reports but efficacy is unproven<ref name="livertox"/>


===Drug Interactions===
*Be aware that mitragynine inhibits CYP3A4 and CYP2D6<ref name="tanna"/>
*Potential to increase levels of co-ingested medications metabolized by these pathways (e.g., [[benzodiazepines]], [[methadone]], certain [[antipsychotics]], [[SSRIs]])
*Polydrug exposure is common and may significantly increase morbidity and mortality


==Disposition==
==Disposition==
*Discharge unless presenting with severe/intractable symptoms
*Discharge if:
 
**Mild symptoms (nausea, mild stimulant effects) that resolve with observation and supportive care
**Normal vital signs and mental status at time of disposition
**Able to tolerate PO
*Observation / Admission if:
**Required naloxone for respiratory depression (observe ≥24 hours given risk of rebound respiratory depression)<ref name="greatimitator"/>
**Persistent [[altered mental status]]
**[[Seizure]]
**Concern for [[rhabdomyolysis]] or [[acute kidney injury]]
**Elevated [[LFTs]] or signs of hepatotoxicity
**Hemodynamic instability
**Significant co-ingestion
*ICU admission for:
**Respiratory failure / need for [[intubation]]
**Refractory [[seizures]]
**[[Acute liver failure]]
**Hemodynamic instability requiring vasopressors
*For all patients: provide counseling on risks of kratom, advise cessation, and consider referral to addiction medicine if regular use or dependence is identified
*Provide [[naloxone]] prescription at discharge if ongoing use is anticipated


==See Also==
==See Also==
 
*[[Opioids]]
*[[Opioid toxicity]]
*[[Opioid withdrawal]]
*[[Buprenorphine]]
*[[Tianeptine toxicity]]


==External Links==
==External Links==
*[https://www.fda.gov/news-events/public-health-focus/fda-and-kratom FDA and Kratom]
*[https://www.ncbi.nlm.nih.gov/books/NBK548231/ LiverTox — Kratom]
*[https://www.ncbi.nlm.nih.gov/books/NBK585120/ StatPearls — Kratom Toxicity]
*[https://www.poison.org/articles/kratom National Poison Control — Kratom]


==References==
{{reflist|2}}


==References==
[[Category:Toxicology]]
<references/>
*Swogger M, Walsh D. Kratom use and mental health: A systematic review. Drug and Alcohol Dependence. 2017;183:134-140.
*Vestal C. Kratom Concerns. State Legislatures Magazine. 2018; 44(4)
*Killelea E. Kratom: Why Did the FDA Declare the Herbal Supplement an Opiate? Rolling Stone Magazine. March 2018.
*Gottlieb, S. Statement from FDA Commissioner Scott Gottlieb, M.D., on new warning letters FDA is issuing to companies marketing kratom with unproven medical claims; and the agency’s ongoing concerns about kratom [press release]. Sep 11, 2018.

Latest revision as of 09:30, 22 March 2026

Background

Kratom flowers and foliage.
Typical powdered Kratom for commercial use.
  • Derived from Mitragyna speciosa, a tropical evergreen tree in the coffee family native to Southeast Asia
  • Leaves contain over 40 alkaloids; the two most clinically relevant are:
    • Mitragynine (most abundant, up to 66% of total alkaloid content) — partial mu-opioid receptor agonist[1]
    • 7-Hydroxymitragynine (7-OH) (minor constituent, <2% of alkaloid content) — approximately 5-fold greater mu-opioid affinity than mitragynine[1]
  • Both alkaloids exhibit G-protein biased agonism at mu-opioid receptors with limited beta-arrestin recruitment (theoretically less respiratory depression than classical opioids, though still reported)[1]
  • Additional receptor activity at alpha-1A, alpha-2A, 5-HT1A, 5-HT2A, D1, and D2 receptors contributes to mixed stimulant-opioid clinical picture[2]
  • Mitragynine is metabolized by CYP3A4 to 7-hydroxymitragynine (a more potent metabolite) and inhibits CYP2D6 and CYP3A4, creating significant potential for drug-drug interactions[3]
  • Available in the US as powder, capsules, tablets, extracts, and liquid "shots" sold at gas stations, smoke shops, and online
    • Products are unregulated, with highly variable alkaloid content and potential for contamination (Salmonella, heavy metals including lead)[4]
  • Estimated 1.7 million Americans aged ≥12 used kratom in 2021[4]
  • Not FDA-approved for any indication; not a legal dietary supplement or food additive[4]
  • Federally unscheduled but banned in several states (Alabama, Arkansas, Indiana, Vermont, Wisconsin, Louisiana); regulated in many others[5]
  • Patients commonly use for self-treatment of chronic pain, opioid withdrawal, depression, and anxiety
    • Approximately one-third of users co-ingest with other substances[6]

Clinical Features

  • Effects are dose-dependent and may mimic both opioid and stimulant toxicity
  • Onset of effects typically within 10-20 minutes of ingestion; duration 2-5 hours

Low-Dose Effects (<5 g)

  • Stimulant effects predominate
  • Increased alertness and energy
  • Tachycardia, hypertension
  • Agitation, jitteriness
  • Decreased appetite

High-Dose Effects (>5 g)

Severe/Complicated Presentations

Kratom Withdrawal

  • Occurs with chronic use; onset typically within 12-24 hours of last dose[8]
  • Resembles mild-moderate opioid withdrawal: myalgias, rhinorrhea, diaphoresis, insomnia, irritability, nausea, diarrhea
  • Generally less severe than traditional opioid withdrawal
  • Can be scored using the Clinical Opiate Withdrawal Scale (COWS)

Differential Diagnosis

Drugs of abuse

Evaluation

  • Primarily a clinical diagnosis — ask specifically about kratom, herbal supplements, and "gas station" products
  • Kratom does NOT appear on standard urine drug screens[7]
    • May cause false-negative opioid screen despite opioid-like presentation
    • Specialized testing for mitragynine exists but is not widely available and generally not clinically useful in the acute setting
  • Consider early consultation with Poison control (1-800-222-1222)

Labs

ECG

Management

  • Focus on ABCs and symptom-directed treatment
  • Consider early Poison control consultation (1-800-222-1222)

Respiratory Depression

  • Supplemental oxygen, BVM ventilation as needed
  • Naloxone — effective for kratom-induced respiratory depression due to mu-opioid agonism[11]
    • Standard dosing as per opioid toxicity protocols
    • Be aware of potential for rebound respiratory depression within 24 hours per poison control center reports[11]

Agitation / Sympathomimetic Features

Seizures

Kratom Withdrawal

  • Symptom-directed treatment similar to opioid withdrawal:
  • Medication-assisted treatment for opioid use disorder:
    • Buprenorphine — most commonly reported for kratom withdrawal/dependence; can be initiated in the ED per standard protocols[6]
    • Methadone — alternative for patients not candidates for buprenorphine

Hepatotoxicity

  • Discontinue kratom
  • Supportive care; most cases resolve spontaneously[9]
  • GI consultation for severe hepatic injury (bilirubin >20 mg/dL, coagulopathy, or signs of acute liver failure)
  • Corticosteroids and NAC have been used in case reports but efficacy is unproven[9]

Drug Interactions

  • Be aware that mitragynine inhibits CYP3A4 and CYP2D6[3]
  • Potential to increase levels of co-ingested medications metabolized by these pathways (e.g., benzodiazepines, methadone, certain antipsychotics, SSRIs)
  • Polydrug exposure is common and may significantly increase morbidity and mortality

Disposition

  • Discharge if:
    • Mild symptoms (nausea, mild stimulant effects) that resolve with observation and supportive care
    • Normal vital signs and mental status at time of disposition
    • Able to tolerate PO
  • Observation / Admission if:
  • ICU admission for:
  • For all patients: provide counseling on risks of kratom, advise cessation, and consider referral to addiction medicine if regular use or dependence is identified
  • Provide naloxone prescription at discharge if ongoing use is anticipated

See Also

External Links

References

  1. ↑ 1.0 1.1 1.2 Kruegel AC, Grundmann O. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology. 2018;134(Pt A):108-120.
  2. ↑ Yusof SR, Zakaria Z, Amir Rawa MS, et al. Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers. Front Pharmacol. 2021;12:751656.
  3. ↑ 3.0 3.1 Tanna RS, Tian DD, Cech NB, et al. Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations. J Pharmacol Exp Ther. 2021;376(1):64-73.
  4. ↑ 4.0 4.1 4.2 U.S. Food and Drug Administration. FDA and Kratom. Updated February 2024. https://www.fda.gov/news-events/public-health-focus/fda-and-kratom
  5. ↑ Congressional Research Service. Kratom Regulation: Federal Status and State Approaches. LSB11082. 2024.
  6. ↑ 6.0 6.1 Washington Poison Center. Kratom and 7-hydroxymitragynine poisoning. 2025. https://www.wapc.org/data/data-blogs/kratom-and-7-hydroxymitragynine-poisoning/
  7. ↑ 7.0 7.1 Eastlack SC, Cornett EM, Kaye AD. Kratom—Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review. Pain Ther. 2020;9(1):55-69.
  8. ↑ 8.0 8.1 Narrative Review of Kratom in the Emergency Department. Auctores. 2025.
  9. ↑ 9.0 9.1 9.2 LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Kratom. National Institute of Diabetes and Digestive and Kidney Diseases; 2020.
  10. ↑ Poison Control. What is kratom? https://www.poison.org/articles/kratom
  11. ↑ 11.0 11.1 11.2 Mikkelsen A, Van Roekel C, Grande EJ, et al. The Great Imitator: A Case of Accidental Kratom Overdose. Cureus. 2023;15(7):e42497.
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