Evidence-Based Reviews

Kratom: What we know, what to tell your patients

Current Psychiatry. 2020 March;19(3):37-42

References

1. Henningfield JE, Fant RV, Wang DW. The abuse potential of kratom according the 8 factors of the controlled substances act: implications for regulation and research. Psychopharmacology (Berl). 2018;235(2):573-589.
2. Chang-Chien GC, Odonkor CA, Amorapanth P, et al. Is kratom the new ‘legal high’ on the block?: the case of an emerging opioid receptor agonist with substance abuse potential. Pain Physician. 2017;20(1):E195-E198.
3. Penders T, Jones WB. Kratom, a substance of increasing concern [PCSS webinar]. Providers Clinical Support System. November 28, 2018. https://pcssnow.org/event/kratom-a-substance-of-increasing-concern. Accessed January 29, 2020.
4. Grundmann O. Patterns of kratom use and health impact in the US-results from an online survey. Drug Alcohol Depend. 2017;176:63-70.
5. US Drug Enforcement Administration. Drugs of concern. https://www.dea.gov/sites/default/files/sites/getsmartaboutdrugs.com/files/publications/DoA_2017Ed_Updated_6.16.17.pdf#page=84. Updated June 16, 2017. Accessed January 29, 2020.
6. Matsumoto K, Horie S, Ishikawa H, et al. Antinociceptive effect of 7-hydroxymitragynine in mice: discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life Sciences. 2004;74(17):2143-2155.
7. Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo). 2004;52(8):916-928.
8. Suhaimi FW, Yusoff NH, Hassan R, et al. Neurobiology of kratom and its main alkaloid mitragynine. Brain Res Bull. 2016;126(pt 1):29-40.
9. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. 2012;112(12):792-799.
10. Kruegel AC, Uprety R, Grinnell SG, et al. 7-hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects. ACS Cent Sci. 2019;5(6):992-1001.
11. Trakulsrichai S, Sathirakul K, Auparakkitanon S, et al. Pharmacokinetics of mitragynine in man. Drug Des Devel Ther. 2015:9:2421-2429.
12. Warner ML, Kaufman NC, Grundmann O, et al. The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Intl J Legal Med. 2016;130(1):127-138.
13. Stanciu CN, Gnanasegaram SA, Ahmed S, et al. Kratom withdrawal: a systematic review with case series. J Psychoactive Drugs. 2019;51(1):12-18.
14. Kamble SH, Sharma A, King TI, et al. Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom). Xenobiotica. 2019;49(11):1279-1288.
15. Smith LC, Lin L, Hwang CS, et al. Lateral flow assessment and unanticipated toxicity of kratom. Chem Res Toxicol. 2019;32(1):113-121.
16. Saingam D, Assanangkornchai S, Geater AF, et al. Factor analytical investigation of Krathom (Mitragyna speciosa Korth.) withdrawal syndrome in Thailand. J Psychoactive Drugs. 2016;48(2):76-85.
17. Vicknasingam B, Narayanan S, Beng GT, et al. The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int J Drug Policy. 2010;21(4):283-288.
18. Saingam D, Assanangkornchai S, Geater AF, et al. Pattern and consequences of krathom (Mitragyna speciosa Korth.) use among male villagers in southern Thailand: a qualitative study. Int J Drug Policy. 2013;24(4):351-358.
19. Fernandes CT, Iqbal U, Tighe SP, et al. Kratom-induced cholestatic liver injury and its conservative management. J Investig Med High Impact Case Rep. 2019;7:2324709619836138. doi: 10.1177/2324709619836138.
20. Dorman C, Wong M, Khan A. Cholestatic hepatitis from prolonged kratom use: a case report. Hepatology. 2015;61(3):1086-1087.
21. Osborne CS, Overstreet AN, Rockey DC, et al. 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;7:2324709619826167. doi: 10.1177/2324709619826167.
22. Mousa MS, Sephien A, Gutierrez J, et al. N-acetylcysteine for acute hepatitis induced by kratom herbal tea. Am J Ther. 2018;25(5):e550-e551.
23. Riverso M, Chang M, Soldevila-Pico C, et al. Histologic characterization of kratom use-associated liver injury. Gastroenterology Res. 2018;11(1):79-82.
24. Kapp FG, Maurer HH, Auwärter V, et al. Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J Med Toxicol. 2011;7(3):227-231.
25. 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.
26. Palasamudram Shekar S, Rojas EE, D’Angelo CC, et al. Legally lethal kratom: a herbal supplement with overdose potential. J Psychoactive Drugs. 2019;51(1):28-30.
27. Aldyab M, Ells PF, Bui R, et al. Kratom-induced cholestatic liver injury mimicking anti-mitochondrial antibody-negative primary biliary cholangitis: a case report and review of literature. Gastroenterology Res. 2019;12(4):211-215.
28. Post S, Spiller HA, Chounthirath T. Kratom exposures reported to United States poison control centers: 2011-2017. Clinical Toxicol (Phila). 2019;57(10):847-854.
29. Eggleston W, Stoppacher R, Suen K, et al. Kratom use and toxicities in the United States. Pharmacotherapy. 2019;39(7):775-777.
30. US Food & Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency’s scientific evidence on the presence of opioid compounds in kratom , underscoring its potential for abuse. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-scientific-evidence-presence-opioid-compounds. Published February 6, 2019. Accessed January 29, 2020.
31. Gershman K, Timm K, Frank M, et al. Deaths in Colorado attributed to kratom. N Engl J Med. 2019;380(1):97-98.
32. Kronstrand R, Roman M, Thelander G, et al. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend krypton. J Anal Toxicol. 2011;35(4):242-247.
33. Hughes RL. Fatal combination of mitragynine and quetiapine - a case report with discussion of a potential herb-drug interaction. Forensic Sci Med Pathol. 2019;15(1):110-113.
34. Abdullah HMA, Haq I, Lamfers R. Cardiac arrest in a young healthy male patient secondary to kratom ingestion: is this ‘legal high’ substance more dangerous than initially thought? BMJ Case Rep. 2019;12(7):pii: e229778. doi: 10.1136/bcr-2019-229778.
35. Laboratory analysis of kratom products for heavy metals. US FDA. https://www.fda.gov/news-events/public-health-focus/laboratory-analysis-kratom-products-heavy-metals. Updated April 3, 2019. Accessed January 29, 2020.
36. FDA investigated multistate outbreak of salmonella infections linked to products reported to contain kratom. US FDA. https://www.fda.gov/food/outbreaks-foodborne-illness/fda-investigated-multistate-outbreak-salmonella-infections-linked-products-reported-contain-kratom. Updated June 29, 2018. Accessed January 14, 2020.
37. Aggarwal G, Robertson E, McKinlay J, et a., Death from kratom toxicity and the possible role of intralipid. J Intensive Care Soc. 2018;19(1):61-63.
38. Drug Facts. Kratom. Confirm Biosciences. https://www.confirmbiosciences.com/knowledge/drug-facts/kratom/. Accessed January 14, 2020.
39. Grinspoon P. How long does kratom stay in the system? Addiction Resource. https://addictionresource.com/drugs/kratom/how-long-kratom-stay-in-your-system/. Updated December 18, 2019. Accessed January 29, 2020.
40. Kaewklum D, Kaewklum M, Pootrakronchai R, et al. Detection of mitragynine and its metaboilite in urine following ingestion of leaves of Mitragyna speciosa korth. Recent Advances in Doping Analysis (13). Proceedings of the Manfred Donike Workshop, 23rd Cologne Workshop on Dope Analysis. 2005:403-406.
41. Lu S, Tran BN, Nelsen JL, et al. Quantitative analysis of mitragynine in human urine by high performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(24):2499-2505.
42. Philipp AA, Wissenbach DK, Zoerntlein SW, et al. 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):1249-1261.
43. Manda VK, Bharathi A, Ali Z, et al. Evaluation of in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline. Planta Med. 2014;80(7):568-576.
44. Davidson L, Rawat M, Stojanovski S, et al. Natural drugs, not so natural effects: neonatal abstinence syndrome secondary to ‘kratom‘. J Neonatal Perinatal Med. 2019;12(1):109-112.
45. Mackay L, Abrahams R. Novel case of maternal and neonatal kratom dependence and withdrawal. Can Fam Physician. 2018;64(2):121-122.
46. McWhirter L, Morris S. A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence. Eur Addict Res. 2010;16(4):229-231.
47. Galbis-Reig David. A case report of kratom addiction and withdrawal. WMJ. 2016;115(1):49-52; quiz 53.
48. Singh D, Müller CP, Vicknasingam BK. Kratom (Mitragyna speciose) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend. 2014;139:132-137.
49. Singh D, Müller CP, Vicknasingam, et al. Social functioning of kratom (Mitragyna speciosa) users in Malaysia. J Psychoactive Drugs. 2015;47(2):125-131.
50. Khazaeli A, Jerry JM, Vazirian M. Treatment of kratom withdrawal and addiction with buprenorphine. J Addict Med. 2018;12(6):493-495.
51. Buresh M. Treatment of kratom dependence with buprenorphine-naloxone maintenance. J Addict Med. 2018;12(6):481-483.
52. Overbeek DL, Abraham J, Munzer BW. Kratom (mitragynine) ingestion requiring naloxone reversal. Clin Pract Cases Emerg Med. 2019;3(1):24-26.

There is a lack of quality control of commercially available kratom preparations. The FDA has found kratom products that exceeded the level of safe exposure to nickel and lead.³⁵ There have also been reports of Salmonella outbreaks associated with kratom products.³⁶

Detecting kratom use

Mitragynine is a lipophilic alkaloid that is poorly soluble in water³⁷ and eliminated primarily in urine.¹² Based on data from treatment center admissions, kratom can be detected in urine samples for 5 to 6 days after use.^24,38,39 However, kratom is not detectable by a standard urine toxicology screen; therefore, a high degree of suspicion and special confirmatory testing are necessary. The breakdown products of mitragynine can be detected through gas chromatography coupled with mass spectrometry (GC/MS), liquid chromatography with linear ion trap mass spectrometry, or electrospray tandem mass spectrometry.^40-42

A familiar withdrawal syndrome

Abrupt discontinuation of high-dose, long-term kratom use can produce withdrawal symptoms.¹³ Symptoms of kratom withdrawal resemble those of opioid withdrawal. These include physiological symptoms (mydriasis, nausea, sweating and chills, muscle and body aches, tremors and twitches, diarrhea, rhinorrhea, and lacrimation) and psychological symptoms (insomnia, restlessness, irritability/hostility, fatigue, anxiety, mood disturbances, and hallucinations).¹³ Symptoms are first noted starting 12 hours after the last use of kratom, and can last up to 7 days.⁴³ Withdrawal intensity has been positively correlated with the daily amount of kratom consumed, as well as the duration and frequency of use.^13,16

In 2 case reports, the newborns of women who used kratom during pregnancy experienced neonatal abstinence syndrome.^44,45 In these 2 reports, symptoms such as jitteriness, irritability, feeding intolerance, and vomiting emerged on postpartum Day 2. The newborns were admitted to a neonatal ICU and started on a standard opioid protocol with IV morphine and subsequently tapered with an oral formulation over 5 days.^44,45

Helping patients who use kratom

The best approach to treating a patient who is experiencing kratom withdrawal is symptomatic management, as would be appropriate for a patient experiencing opioid withdrawal.¹³ However, the use of agents such as methadone or buprenorphine for patients undergoing kratom withdrawal has not been thoroughly evaluated; very few reports have been published.^46,47

Continue to: Similarly, while the standard of care...

Kratom: What we know, what to tell your patients

References

Detecting kratom use

A familiar withdrawal syndrome

Helping patients who use kratom

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