Skip to main content
Top
Published in: Drugs 3/2020

01-02-2020 | Review Article

Kratom (Mitragyna Speciosa) Liver Injury: A Comprehensive Review

Authors: Jonathan Schimmel, Richard C. Dart

Published in: Drugs | Issue 3/2020

Login to get access

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.
Literature
1.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
2.
go back to reference 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 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
3.
go back to reference 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 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
4.
go back to reference 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. 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.
5.
go back to reference 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. 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.
6.
go back to reference Griffin OH, Webb ME. The scheduling of kratom and selective use of data. J Psychoact Drugs. 2018;50(2):114–20. Griffin OH, Webb ME. The scheduling of kratom and selective use of data. J Psychoact Drugs. 2018;50(2):114–20.
9.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
10.
go back to reference 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.PubMed 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.PubMed
11.
go back to reference Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26(3):664–9.PubMed Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26(3):664–9.PubMed
12.
go back to reference 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 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
13.
go back to reference Hayashi PH. Drug-induced liver injury network causality assessment: criteria and experience in the United States. Int J Mol Sci. 2016;17(2):201.PubMedPubMedCentral Hayashi PH. Drug-induced liver injury network causality assessment: criteria and experience in the United States. Int J Mol Sci. 2016;17(2):201.PubMedPubMedCentral
14.
go back to reference 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.PubMed 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.PubMed
15.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
16.
go back to reference 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.PubMed 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.PubMed
17.
go back to reference Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016;17(1):14–46. Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016;17(1):14–46.
18.
go back to reference Danan G, Teschke R. Roussel uclaf causality assessment method for drug-induced liver injury: present and future. Front Pharmacol. 2019;10:853.PubMedPubMedCentral Danan G, Teschke R. Roussel uclaf causality assessment method for drug-induced liver injury: present and future. Front Pharmacol. 2019;10:853.PubMedPubMedCentral
19.
go back to reference 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 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
20.
go back to reference Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis. 2007;11(3):477–505.PubMed Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis. 2007;11(3):477–505.PubMed
21.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
22.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
23.
go back to reference Suwanlert S. A study of kratom eaters in Thailand. Bull Narc. 1975;27(3):21–7.PubMed Suwanlert S. A study of kratom eaters in Thailand. Bull Narc. 1975;27(3):21–7.PubMed
24.
go back to reference 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 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
25.
go back to reference 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.PubMed 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.PubMed
26.
go back to reference 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 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
27.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
28.
go back to reference Dorman C, Wong M, Khan A. Cholestatic hepatitis from prolonged kratom use: a case report. Hepatology. 2015;61(3):1086–7.PubMed Dorman C, Wong M, Khan A. Cholestatic hepatitis from prolonged kratom use: a case report. Hepatology. 2015;61(3):1086–7.PubMed
29.
go back to reference 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. 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.
30.
go back to reference Griffiths CL, Gandhi N, Olin JL. Possible kratom-induced hepatomegaly: a case report. J Am Pharm Assoc. 2018;58(5):561–3. Griffiths CL, Gandhi N, Olin JL. Possible kratom-induced hepatomegaly: a case report. J Am Pharm Assoc. 2018;58(5):561–3.
31.
go back to reference 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 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
32.
go back to reference 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 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
33.
go back to reference 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. 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.
34.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
35.
go back to reference 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. 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.
36.
go back to reference 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. 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.
38.
go back to reference Kupferschmidt H. Toxic hepatitis after Kratom (Mitragyna sp.) consumption. Clin Toxicol. 2011;49(6):532. Kupferschmidt H. Toxic hepatitis after Kratom (Mitragyna sp.) consumption. Clin Toxicol. 2011;49(6):532.
39.
go back to reference 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. 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.
40.
go back to reference 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. 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.
41.
go back to reference Shah SR, Basit SA, Orlando FL. Kratom-induced severe intrahepatic cholestasis: a case report. Am J Gastroenterol. 2017;112:S1190. Shah SR, Basit SA, Orlando FL. Kratom-induced severe intrahepatic cholestasis: a case report. Am J Gastroenterol. 2017;112:S1190.
42.
go back to reference Ricardo J, Conte J, Alkayali T, Salem AI, Gastroenterology S. Mo1466-Kratom induced cholestatic hepatitis. Gastroenterology. 2019;156(6):S1316. Ricardo J, Conte J, Alkayali T, Salem AI, Gastroenterology S. Mo1466-Kratom induced cholestatic hepatitis. Gastroenterology. 2019;156(6):S1316.
43.
go back to reference 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. 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.
44.
go back to reference Rivera R, Sharma R, Shah A. Liver toxicity following abuse of kratom (Mitragyna speciosa): 753. Am J Gastroenterol. 2011;106:S284. Rivera R, Sharma R, Shah A. Liver toxicity following abuse of kratom (Mitragyna speciosa): 753. Am J Gastroenterol. 2011;106:S284.
45.
go back to reference Pronesti V, Sial M, Talwar A, Aoun E. Cholestatic liver injury caused by kratom ingestion: 2426. Am J Gastroenterol. 2019;114:S1344. Pronesti V, Sial M, Talwar A, Aoun E. Cholestatic liver injury caused by kratom ingestion: 2426. Am J Gastroenterol. 2019;114:S1344.
46.
go back to reference Kaur R, Siedlecki C, Jafri SM. A case of kratom induced cholestasis. J Gen Intern Med. 2019;34(2):S425–S426426. Kaur R, Siedlecki C, Jafri SM. A case of kratom induced cholestasis. J Gen Intern Med. 2019;34(2):S425–S426426.
47.
go back to reference 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. 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.
48.
go back to reference Arens A, Gerona R, Meier K, Smollin C. Acute cholecystitis associated with Kratom abuse. Clin Toxicol. 2015;53(7):661. Arens A, Gerona R, Meier K, Smollin C. Acute cholecystitis associated with Kratom abuse. Clin Toxicol. 2015;53(7):661.
49.
go back to reference Mackenzie C, Thompson M. Salmonella contaminated Kratom ingestion associated with fulminant hepatic failure requiring liver transplantation. Clin Toxicol. 2018;56(19):947. Mackenzie C, Thompson M. Salmonella contaminated Kratom ingestion associated with fulminant hepatic failure requiring liver transplantation. Clin Toxicol. 2018;56(19):947.
50.
go back to reference De Francesco E, Lougheed C, Mackenzie C. Kratom-induced acute liver failure. Can J Hosp Pharm. 2019;72(1):69. De Francesco E, Lougheed C, Mackenzie C. Kratom-induced acute liver failure. Can J Hosp Pharm. 2019;72(1):69.
51.
go back to reference Sullivan SN. Acute cholestatic hepatitis due to kratom. Unpublished manuscript. 10.13140/RG.2.1.3651.7366. 2016. Sullivan SN. Acute cholestatic hepatitis due to kratom. Unpublished manuscript. 10.13140/RG.2.1.3651.7366. 2016.
54.
go back to reference 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.PubMed 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.PubMed
55.
go back to reference 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. 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.
60.
go back to reference Macko E, Weisbach JA, Douglas B. Some observations on the pharmacology of mitragynine. Arch Int Pharmacodyn Ther. 1972;198(1):145–61.PubMed Macko E, Weisbach JA, Douglas B. Some observations on the pharmacology of mitragynine. Arch Int Pharmacodyn Ther. 1972;198(1):145–61.PubMed
61.
go back to reference 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.PubMed 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.PubMed
62.
go back to reference 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. 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.
63.
go back to reference 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.PubMed 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.PubMed
64.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
65.
go back to reference 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. 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.
66.
go back to reference 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. 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.
67.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
68.
go back to reference 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. 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.
69.
go back to reference 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. 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.
70.
go back to reference 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.PubMed 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.PubMed
71.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
72.
go back to reference 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.PubMed 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.PubMed
73.
go back to reference 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. 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.
74.
go back to reference 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. 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.
75.
go back to reference 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. 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.
76.
go back to reference 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. 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.
77.
go back to reference 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.PubMed 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.PubMed
78.
go back to reference 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. 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.
79.
go back to reference 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. 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.
80.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
81.
go back to reference 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. 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.
82.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
83.
go back to reference 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. 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.
84.
go back to reference Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003;60(1):6–20.PubMed Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003;60(1):6–20.PubMed
85.
go back to reference Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–31.PubMed Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–31.PubMed
86.
go back to reference 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.PubMed 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.PubMed
87.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
Metadata
Title
Kratom (Mitragyna Speciosa) Liver Injury: A Comprehensive Review
Authors
Jonathan Schimmel
Richard C. Dart
Publication date
01-02-2020
Publisher
Springer International Publishing
Published in
Drugs / Issue 3/2020
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-019-01242-6

Other articles of this Issue 3/2020

Drugs 3/2020 Go to the issue

AdisInsight Report

Ubrogepant: First Approval

AdisInsight Report

Givosiran: First Approval