Skip to main content
SpringerLink
Log in

Kratom (Mitragyna Speciosa) Liver Injury: A Comprehensive Review

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Kratom (Mitragyna speciosa) leaves contain the mu opioid partial agonists mitragynine and 7-hydroxymitragynine. The US Drug Enforcement Agency considers it a ‘drug of concern’, and the US FDA is reviewing kratom, but there is a paucity of information regarding health effects. Liver injury is often cited as a potential health consequence, however the same few case reports are repeatedly referenced, without a broader context. Furthermore, reports have largely lacked standardized causality assessment methods. The objective is to evaluate causality in kratom liver injury, through a comprehensive scoping review of human cases, and by reviewing epidemiologic, animal, and mechanistic reports that relate to kratom liver injury. Hepatotoxicity causality was systematically examined using the Roussel Uclaf Causality Assessment Method (RUCAM) for case reports. Biopsy findings, potential pathophysiologic mechanisms, and management options are discussed. This review identified 26 case reports and abstracts, in addition to 7 cases reported from the Drug-Induced Liver Injury Network, 25 in FDA databases, and 27 in internet user forums. Latency periods to symptom onset had a median of 20.6 days and mean of 21 days (range 2–49). Common presenting signs and symptoms were abdominal discomfort, jaundice, pruritis, and dark urine. Histologic findings were predominantly cholestatic, although, biochemically, the condition was heterogenous or mixed; the median R ratio was 3.4 and the mean was 4.6 (range 0.24–10.4). Kratom likely causes liver injury based on the totality of low-quality human evidence, and, in the context of epidemiologic, animal, and mechanistic studies. It remains unclear which subgroups of users are at heightened risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kruegel AC, Madalee GM, Kapoor A, Váradi A, Majumdar S, Filizola M, et al. Synthetic and receptor signaling explorations of the mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulators. J Am Chem Soc. 2016;138(21):6754–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Warner ML, Kaufman NC, Grundmann O. The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Int J Legal Med. 2016;130(1):127–38.

    PubMed  Google Scholar 

  3. Smith KE, Lawson T. Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment program. Drug Alcohol Depend. 2017;180:340–8.

    PubMed  Google Scholar 

  4. Post S, Spiller HA, Chounthirath T, Smith GA. Kratom exposures reported to United States poison control centers: 2011–2017. Clin Toxicol. 2019;57(10):847–54.

    CAS  Google Scholar 

  5. Trakulsrichai S, Tongpo A, Sriapha C, Wongvisawakorn S, Rittilert P, Kaojarern S, et al. Kratom abuse in ramathibodi Poison Center, Thailand: a five-year experience. J Psychoact Drugs. 2013;45(5):404–8.

    Google Scholar 

  6. Griffin OH, Webb ME. The scheduling of kratom and selective use of data. J Psychoact Drugs. 2018;50(2):114–20.

    Google Scholar 

  7. US FDA. FDA and Kratom. https://www.fda.gov/news-events/public-health-focus/fda-and-kratom. Accessed 25 Apr 2019.

  8. US Drug Enforcement Administration. Kratom. https://www.dea.gov/factsheets/kratom. Accessed 1 Nov 2019.

  9. Mosedale M, Watkins PB. Drug-induced liver injury: advances in mechanistic understanding that will inform risk management. Clin Pharmacol Ther. 2017;101(4):469–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45.

    CAS  PubMed  Google Scholar 

  11. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26(3):664–9.

    CAS  PubMed  Google Scholar 

  12. Takikawa H, Takamori Y, Kumagi T, Onji M, Watanabe M, Shibuya A, et al. Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the International Consensus Meeting. Hepatol Res. 2003;27(3):192–5.

    PubMed  Google Scholar 

  13. Hayashi PH. Drug-induced liver injury network causality assessment: criteria and experience in the United States. Int J Mol Sci. 2016;17(2):201.

    PubMed  PubMed Central  Google Scholar 

  14. Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–30.

    CAS  PubMed  Google Scholar 

  15. Rockey DC, Seeff LB, Rochon J, Freston J, Chalasani N, Bonacini M, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method. Hepatology. 2010;51(6):2117–266.

    PubMed  PubMed Central  Google Scholar 

  16. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993;46(11):1331–6.

    CAS  PubMed  Google Scholar 

  17. Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016;17(1):14–46.

    Google Scholar 

  18. Danan G, Teschke R. Roussel uclaf causality assessment method for drug-induced liver injury: present and future. Front Pharmacol. 2019;10:853.

    PubMed  PubMed Central  Google Scholar 

  19. García-Cortés M, Stephens C, Lucena MI, Fernández-Castañer A, Andrade RJ. Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol. 2011;55(3):683–91.

    PubMed  Google Scholar 

  20. Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis. 2007;11(3):477–505.

    PubMed  Google Scholar 

  21. Rochon J, Protiva P, Seeff LB, Fontana RJ, Liangpunsakul S, Watkins PB, et al. Reliability of the Roussel Uclaf causality assessment method for assessing causality in drug-induced liver injury. Hepatology. 2008;48(4):1175–83.

    PubMed  PubMed Central  Google Scholar 

  22. Teschke R, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013;19(19):2864–82.

    PubMed  PubMed Central  Google Scholar 

  23. Suwanlert S. A study of kratom eaters in Thailand. Bull Narc. 1975;27(3):21–7.

    CAS  PubMed  Google Scholar 

  24. Ahmad K, Aziz Z. Mitragyna speciosa use in the northern states of Malaysia: a cross-sectional study. J Ethnopharmacol. 2012;141(1):446–50.

    PubMed  Google Scholar 

  25. Singh D, Müller CP, Murugaiyah V, Hamid SBS, Vicknasingam BK, Avery B, et al. Evaluating the hematological and clinical-chemistry parameters of kratom (Mitragyna speciosa) users in Malaysia. J Ethnopharmacol. 2018;214:197–206.

    CAS  PubMed  Google Scholar 

  26. Cumpston KL, Carter M, Wills BK. Clinical outcomes after Kratom exposures: a poison center case series. Am J Emerg Med. 2018;36(1):166–8.

    PubMed  Google Scholar 

  27. Kapp FG, Maurer HH, Auwärter V, Winkelmann M, Hermanns-Clausen M. Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J Med Toxicol. 2011;7(3):227–31.

    PubMed  PubMed Central  Google Scholar 

  28. Dorman C, Wong M, Khan A. Cholestatic hepatitis from prolonged kratom use: a case report. Hepatology. 2015;61(3):1086–7.

    PubMed  Google Scholar 

  29. Riverso M, Chang M, Soldevila-Pico C, Lai J, Liu X. Histologic characterization of kratom use-associated liver Injury. Gastroenterol Res. 2018;11(1):79–82.

    Google Scholar 

  30. Griffiths CL, Gandhi N, Olin JL. Possible kratom-induced hepatomegaly: a case report. J Am Pharm Assoc. 2018;58(5):561–3.

    Google Scholar 

  31. Mousa MS, Sephien A, Gutierrez J, OʼLeary C. N-Acetylcysteine for acute hepatitis induced by kratom herbal tea. Am J Ther. 2018;25(5): e550–e1.

    PubMed  Google Scholar 

  32. Antony A, Lee TP. Herb-induced liver injury with cholestasis and renal injury secondary to short-term use of kratom (Mitragyna speciosa). Am J Ther. 2019;26(4):e546–e547.

    PubMed  Google Scholar 

  33. Osborne CS, Overstreet AN, Rockey DC, Schreiner AD. Drug-induced liver injury caused by kratom use as an alternative pain treatment amid an ongoing opioid epidemic. J Investig Med High Impact Case Rep. 2019;7:1–5.

    Google Scholar 

  34. Fernandes CT, Iqbal U, Tighe SP, Ahmed A. Kratom-induced cholestatic liver injury and its conservative management. J Investig Med High Impact Case Rep. 2019;7:2324709619836138.

    PubMed  PubMed Central  Google Scholar 

  35. Aldyab M, Ells PF, Buib R, Chapmanc TD, Lee H. Kratom-induced cholestatic liver injury mimicking anti-mitochondrial antibody-negative primary biliary cholangitis: a case report and review of literature. Gastroenterol Res. 2019;12(4):211–5.

    Google Scholar 

  36. Tayabali K, Bolzon C, Foster P, Patel J, Kalim MO. Kratom: a dangerous player in the opioid crisis. J Commun Hosp Internal Med Perspect. 2018;8(3):107–10.

    Google Scholar 

  37. Drago JZ, Lane B, Kochav J, Chabner B. The harm in kratom. Oncologist. 2017;22(8):1010–1.

    PubMed  PubMed Central  Google Scholar 

  38. Kupferschmidt H. Toxic hepatitis after Kratom (Mitragyna sp.) consumption. Clin Toxicol. 2011;49(6):532.

    Google Scholar 

  39. Kesar V, Michel A, Weisberg I. Mitragyna Speciosa (Kratom)-induced cholestatic hepatitis in abstracts Submitted for the 78th Annual Scientific Meeting of the American College of Gastroenterology. Am J Gastroenterol. 2013;108:S106–S161161.

    Google Scholar 

  40. Bernier M, Allaire M, Lelong-Boulouard V, Rouillon C, Boisselier R. Inserm. Kratom (Mitragyna speciosa) “phyto-toxicomania": about a case of acute hepatitis. Fundam Clin Pharmacol. 2017;31:19–211.

    Google Scholar 

  41. Shah SR, Basit SA, Orlando FL. Kratom-induced severe intrahepatic cholestasis: a case report. Am J Gastroenterol. 2017;112:S1190.

    Google Scholar 

  42. Ricardo J, Conte J, Alkayali T, Salem AI, Gastroenterology S. Mo1466-Kratom induced cholestatic hepatitis. Gastroenterology. 2019;156(6):S1316.

    Google Scholar 

  43. Bøgevig S, Breindal T, Christensen MB, Nielsen T, Hoegberg LCG. Severe liver injury caused by recommended doses of the food supplement kratom. Clin Toxicol. 2019;57(6):527.

    Google Scholar 

  44. Rivera R, Sharma R, Shah A. Liver toxicity following abuse of kratom (Mitragyna speciosa): 753. Am J Gastroenterol. 2011;106:S284.

    Google Scholar 

  45. Pronesti V, Sial M, Talwar A, Aoun E. Cholestatic liver injury caused by kratom ingestion: 2426. Am J Gastroenterol. 2019;114:S1344.

    Google Scholar 

  46. Kaur R, Siedlecki C, Jafri SM. A case of kratom induced cholestasis. J Gen Intern Med. 2019;34(2):S425–S426426.

    Google Scholar 

  47. Desai P, Ramachandra K, Shah M. Kratom induced hepatotoxicity and the role of N-acetyl cysteine. Abstract from conference: Southern Regional Meeting 2019. J Investig Med High Impact Case Rep. 2019;67(2):606.

    Google Scholar 

  48. Arens A, Gerona R, Meier K, Smollin C. Acute cholecystitis associated with Kratom abuse. Clin Toxicol. 2015;53(7):661.

    Google Scholar 

  49. Mackenzie C, Thompson M. Salmonella contaminated Kratom ingestion associated with fulminant hepatic failure requiring liver transplantation. Clin Toxicol. 2018;56(19):947.

    Google Scholar 

  50. De Francesco E, Lougheed C, Mackenzie C. Kratom-induced acute liver failure. Can J Hosp Pharm. 2019;72(1):69.

    Google Scholar 

  51. Sullivan SN. Acute cholestatic hepatitis due to kratom. Unpublished manuscript. 10.13140/RG.2.1.3651.7366. 2016.

  52. LiverTox, NIH. Summary of case 6972. https://livertox.niddk.nih.gov/Home/ReferenceCases/kratom/6972. Accessed 25 Apr 2019.

  53. LiverTox, NIH. Summary of case 8332. https://livertox.niddk.nih.gov/Home/ReferenceCases/kratom/8332. Accessed 25 Apr 2019.

  54. Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806–15.

    CAS  PubMed  Google Scholar 

  55. Navarro VJ, Odin J, Ahmad J, Hayashi PH, Fontana RJ, Conjeevaram HS, et al. Increasing episodes of hepatotoxicity in the drug induced liver injury network associated with kratom, a botanical product with opioid-like activity. Hepatology. 2019;70(1):138A.

    Google Scholar 

  56. CFSAN Adverse Event Reporting System (CAERS). Data files, January 2004–June 2018. https://www.fda.gov/food/complianceenforcement/ucm494015.htm. Accessed 25 Apr 2019.

  57. FDA Adverse Event Reporting System (FAERS). Public dashboard. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/adversedrugeffects/ucm070093.htm. Accessed 25 Apr 2019.

  58. Erowid Experience Vaults: Kratom Reports (also Mitragyna speciosa). https://www.erowid.org/experiences/subs/exp_Kratom.shtml. Accessed 1 Apr 2019.

  59. Bluelight Forum. https://www.bluelight.org/xf/forums. Accessed 1 Apr 2019.

  60. Macko E, Weisbach JA, Douglas B. Some observations on the pharmacology of mitragynine. Arch Int Pharmacodyn Ther. 1972;198(1):145–61.

    CAS  PubMed  Google Scholar 

  61. Harizal SN, Mansor SM, Hasnan J, Tharakan JKJ, Abdullah J. Acute toxicity study of the standardized methanolic extract of Mitragyna speciosa Korth in rodent. J Ethnopharmacol. 2010;131(2):404–9.

    CAS  PubMed  Google Scholar 

  62. Kamal MS, Ghazali AR, Yahya NA. Acute toxicity study of standardized Mitragyna speciosa korth aqueous extract in Sprague dawley rats. J Plant Stud. 2012;1:2.

    Google Scholar 

  63. Sabetghadam A, Ramanathan S, Sasidharan S, Mansor SM. Subchronic exposure to mitragynine, the principal alkaloid of Mitragyna speciosa, in rats. J Ethnopharmacol. 2013;146(3):815–23.

    CAS  PubMed  Google Scholar 

  64. Fakurazi S, Rahman SA, Hidayat MT, Ithnin H, Moklas MAM, Arulselvan P. The combination of mitragynine and morphine prevents the development of morphine tolerance in mice. Molecules. 2013;18(1):666–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sakaran R, Othman F, Jantan I, Thent ZC, Das S. Effect of subacute dose of Mitragyna speciosa Korth crude extract in female sprague dawley rats. J Med Bioeng. 2014;3:2.

    Google Scholar 

  66. Ali SRE, Moklas MAM, Taib CNM. DREAM and C-fos proteins expression after treatment with malaysian Mitragyna speciosa. Res J Pharm Biol Chem Sci. 2014;5(5):32.

    Google Scholar 

  67. Ilmie MU, Jaafar H, Mansor SM, Abdullah JM. Subchronic toxicity study of standardized methanolic extract of Mitragyna speciosa Korth in Sprague-Dawley Rats. Front Neurosci. 2015;9:189.

    PubMed  PubMed Central  Google Scholar 

  68. Haslan H, Suhaimi FH, Das S. Mitragyna speciosa-induced hepatotoxicity-treated effectively by piper betle: scope as a future antidote. Asian J Pharm Clin Res. 2018;11(3):43–6.

    Google Scholar 

  69. Guenther E, Musick M, Davis T. Faseb. Reversal of hepatomegaly following cessation of Kratom Consumption in C57BL/6 male and female mice. FASEB J. 2019;33(Suppl 1):765–8.

    Google Scholar 

  70. Manda VK, Avula B, Dale OR, Ali Z, Khan IA, Walker LA, et al. PXR mediated induction of CYP3A4, CYP1A2, and P-gp by Mitragyna speciosa and its alkaloids. Phytother Res. 2017;31(12):1935–45.

    CAS  PubMed  Google Scholar 

  71. Wang YM, Chai SC, Brewer CT, Chen T. Pregnane X receptor and drug-induced liver injury. Expert Opin Drug Metab Toxicol. 2014;10(11):1521–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology. 2010;51(2):615–20.

    CAS  PubMed  Google Scholar 

  73. Trakulsrichai S, Sathirakul K, Auparakkitanon S, Krongvorakul J, Sueajai J, Noumjad N, et al. Pharmacokinetics of mitragynine in man. Drug Des Dev Ther. 2015;9:2421–9.

    CAS  Google Scholar 

  74. Ya K, Tangamornsuksan W, Scholfield CN, Methaneethorn J, Lohitnavy M. Pharmacokinetics of mitragynine, a major analgesic alkaloid in kratom (Mitragyna speciosa): a systematic review. Asian J Psychiatry. 2019;43:73–82.

    Google Scholar 

  75. Saidin NA, Randall T, Takayama H. Malaysian Kratom, a phyto-pharmaceutical of abuse: studies on the mechanism of its cytotoxicity. Toxicology. 2008;1(253):19–20.

    Google Scholar 

  76. Oliveira AS, Fraga S, Carvalho F. Chemical characterization and in vitro cyto-and genotoxicity of ‘legal high’ products containing Kratom (Mitragyna speciosa). Forensic Toxicol. 2016;34(2):213–26.

    CAS  Google Scholar 

  77. Philipp AA, Wissenbach DK, Zoerntlein SW, Klein ON, Kanogsunthornrat J, Maurer HH. Studies on the metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and human urine using liquid chromatography-linear ion trap mass spectrometry. J Mass Spectrom. 2009;44(8):1249–61.

    CAS  PubMed  Google Scholar 

  78. Azizi J, Ismail S, Mansor SM. Mitragyna speciosa Korth leaves extracts induced the CYP450 catalyzed aminopyrine-N-demethylase (APND) and UDP-glucuronosyl transferase (UGT) activities in male Sprague-Dawley rat livers. Drug Metab Drug Interact. 2013;28(2):95–105.

    CAS  Google Scholar 

  79. Haron M, Ismail S. Effects of mitragynine and 7-hydroxymitragynine (the alkaloids of Mitragyna speciosa Korth) on 4-methylumbelliferone glucuronidation in rat and human liver microsomes and recombinant human uridine 5’-diphospho-glucuronosyltransferase isoforms. Pharmacogn Res. 2015;7:4.

    Google Scholar 

  80. Azizi J, Ismail S, Mordi MN, Ramanathan S, Said MIM, Mansor SM. In vitro and in vivo effects of three different Mitragyna speciosa korth leaf extracts on phase II drug metabolizing enzymes—glutathione transferases (GSTs). Molecules. 2010;15(1):432–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Rusli N, Amanah A, Kaur G, Adenan MI, Sulaiman SF, Wahab HA, et al. The inhibitory effects of mitragynine on P-glycoprotein in vitro. Naunyn Schmiedeberg's Arch Pharmacol. 2019;392(4):481–96.

    CAS  Google Scholar 

  82. Kotsampasakou E, Ecker GF. Predicting drug-induced cholestasis with the help of hepatic transporters-an in silico modeling approach. J Chem Inf Model. 2017;57(3):608–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Gijbels E, Vinken M. Mechanisms of drug-induced cholestasis. In: M Vinken (ed) Experimental cholestasis research. methods in molecular biology. New York: Humana Press; 2019.

    Google Scholar 

  84. Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003;60(1):6–20.

    CAS  PubMed  Google Scholar 

  85. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–31.

    CAS  PubMed  Google Scholar 

  86. Dalton HR, Fellows HJ, Stableforth W, Joseph M, Thurairajah PH, Warshow U, et al. The role of hepatitis E virus testing in drug-induced liver injury. Aliment Pharmacol Ther. 2007;26(10):1429–35.

    CAS  PubMed  Google Scholar 

  87. Davern TJ, Chalasani N, Fontana RJ, Hayashi PH, Protiva P, Kleiner DE, et al. Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology. 2011;141(5):1665–72.e1.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Laurie Halmo, MD, for contributions to the manuscript.

Funding

This report did not receive any specific funding.

Author information

Authors and Affiliations

  1. Department of Emergency Medicine, Division of Medical Toxicology, Mount Sinai Hospital Icahn School of Medicine, New York, NY, USA

    Jonathan Schimmel

  2. Rocky Mountain Poison and Drug Safety, Denver Health and Hospital Authority, Denver, CO, USA

    Richard C. Dart

Authors
  1. Jonathan Schimmel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard C. Dart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan Schimmel.

Ethics declarations

Conflict of interest

Jonathan Schimmel and Richard C. Dart declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schimmel, J., Dart, R.C. Kratom (Mitragyna Speciosa) Liver Injury: A Comprehensive Review. Drugs 80, 263–283 (2020). https://doi.org/10.1007/s40265-019-01242-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-019-01242-6

Search

Navigation