EC Pharmacology And Toxicology

Use and misuse of kratom (Mitragyna speciosa), a Southeast Asian plant with both medicinal and psychoactive properties, has recently seen a significant rise in uncontrolled use. Due to the increased use and the abuse potential, this review provides a snapshot of the pharmacological properties and the dangers associated with kratom. Additionally, this review will help highlight a gap in our understanding of kratom use among pregnant women. The increase in opioid use in general has led to a growth in infants with neonatal opioid withdrawal syndrome (NOWS). However, only a handful of NOWS cases have been reported with kratom users. Currently, there is little to no evidence about the short- and long-term effects on neonates born with NOWS due to kratom abuse by mothers. In addition, very few animal models exist for the effects of kratom on adults and infants. This review suggests the need for further research and immediate interventions to safeguard the well-being of pregnant mothers and infants exposed to kratom in utero.

 Keywords: Kratom; Mitragynine; Neonatal; Abuse; Opioid; Withdrawal

1. Zhang M., et al. “Plant growth and phytoactive alkaloid synthesis in kratom [Mitragyna speciosa (Korth.)] in response to varying radiance". PLoS ONE4 (2022): e0259326.
2. Pohanka M. "Pharmacology and toxicology of kratom". Bratislava Medical Journal12 (2023): 896-902.
3. E Adkins J., et al. “Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity". Current Topics in Medicinal Chemistry9 (2011): 1165-1175.
4. Jansen KLR., et al. “Ethnopharmacology of kratom and the Mitragyna alkaloids". Journal of Ethnopharmacology1 (1988): 115-119.
5. Prozialeck WC., et al. “Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects". The Journal of the American Osteopathic Association 12 (2012): 792-799.
6. Suwanlert S. "A study of kratom eaters in Thailand". Bulletin on Narcotics3 (1975): 21-27.
7. Singh D., et al. “Traditional and non-traditional uses of Mitragynine (Kratom): A survey of the literature". Brain Research Bulletin1 (2016): 41-46.
8. Coe MA., et al. “Kratom as a substitute for opioids: Results from an online survey". Drug and Alcohol Dependence 202 (2019): 24-32.
9. Smith KE., et al. “Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment program". Drug and Alcohol Dependence 180 (2017): 340-348.
10. Grundmann O. "Patterns of Kratom use and health impact in the US—Results from an online survey". Drug and Alcohol Dependence 176 (2017): 63-70.
11. Vicknasingam B., et al. “Kratom and pain tolerance: A randomized, placebo-controlled, double-blind study". The Yale Journal of Biology and Medicine 2 (2020): 229-238.
12. Bowman J., et al. “Kratom use among pregnant and lactating individuals with substance use disorder". Journal of Addiction Medicine6 (2023): 722-724.
13. Garcia-Romeu A., et al. “Kratom (Mitragyna speciosa): User demographics, use patterns, and implications for the opioid epidemic". Drug and Alcohol Dependence 208 (2020): 107849.
14. Palamar JJ. "Past-year kratom use in the U.S.: Estimates from a nationally representative sample". American Journal of Preventive Medicine2 (2021): 240-245.
15. Singh D., et al. “Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users". Drug and Alcohol Dependence 139 (2014): 132-137.
16. Singh D., et al. “Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users". Journal of Ethnopharmacology 249 (2020): 112462.
17. Anwar M., et al. “Notes from the Field: Kratom (Mitragyna speciosa) exposures reported to poison centers - United States, 2010-2015". MMWR: Morbidity and Mortality Weekly Report29 (2016): 748-749.
18. Griffin OH., et al. “The scheduling of kratom and selective use of data". Journal of Psychoactive Drugs2 (2018): 114-120.
19. Covvey JR., et al. “Prevalence and characteristics of self-reported kratom use in a representative US general population sample". Journal of Addictive Diseases 4 (2020): 506-513.
20. Henningfield JE., et al. “We need better estimates of kratom use prevalence". American Journal of Preventive Medicine 1 (2022): 132-133.
21. Schimmel J., et al. “Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross‐sectional study". Addiction 1 (2021): 176-181.
22. Li X., et al. “An evaluation of adverse drug reactions and outcomes attributed to kratom in the <scp>US</scp> food and drug administration adverse event reporting system from January 2004 through September 2021". Clinical and Translational Science6 (2023): 1002-1011.
23. Pre-Review Report: Kratom (Mitragyna speciosa), mitragynine, and 7-hydroxymitragynine. Geneva (2024).
24. Wright ME., et al. “Outcomes of mothers and newborns to prenatal exposure to kratom: a systematic review". Journal of Perinatology6 (2021): 1236-1243.
25. Prozialeck WC., et al. “Kratom policy: The challenge of balancing therapeutic potential with public safety". International Journal of Drug Policy 70 (2019): 70-77.
26. Prevete E., et al. “A preliminary inventory of kratom (Mitragyna speciosa) products and vendors on the darknet and cryptomarkets". Journal of Psychoactive Drugs4 (2024): 485-495.
27. Smith KE., et al. “Therapeutic benefit with caveats?: Analyzing social media data to understand the complexities of kratom use". Drug and Alcohol Dependence 226 (2021): 108879.
28. Hill K., et al. “Evaluating health information provided to kratom consumers by good manufacturing practice-qualified vendors". Substance Abuse Treatment, Prevention, and Policy1 (2023): 21.
29. Raffa RB., et al. “Nature’s first ‘atypical opioids’: Kratom and mitragynines". Journal of Clinical Pharmacy and Therapeutics3 (2018): 437-441.
30. Chear NJY., et al. “Exploring the chemistry of alkaloids from Malaysian Mitragyna speciosa (Kratom) and the role of oxindoles on human opioid receptors". Journal of Natural Products4 (2021): 1034-1043.
31. Obeng S., et al. “Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloids". Journal of Medicinal Chemistry1 (2020): 433-439.
32. Laforest LC., et al. “Metabolite and molecular characterization of Mitragyna speciosa identifies developmental and genotypic effects on monoterpene indole and oxindole alkaloid composition". Journal of Natural Products4 (2023): 1042-1052.
33. Flores-Bocanegra L., et al. “The chemistry of kratom [Mitragyna speciosa]: Updated characterization data and methods to elucidate indole and oxindole alkaloids". Journal of Natural Products7 (2020): 2165-2177.
34. Gorelick DA. "Kratom: Substance of abuse or therapeutic plant?". Psychiatric Clinics of North America3 (2022): 415-430.
35. Cinosi E., et al. “Following ‘the roots’ of kratom (Mitragyna speciosa): The evolution of an enhancer from a traditional use to increase work and productivity in southeast Asia to a recreational psychoactive drug in western countries". BioMed Research International (2015): 968786.
36. Hassan Z., et al. “From Kratom to mitragynine and its derivatives: Physiological and behavioural effects related to use, abuse, and addiction". Neuroscience and Biobehavioral Reviews2 (2013): 138-151.
37. Kamble SH., et al. “Pharmacokinetics of eleven kratom alkaloids following an oral dose of either traditional or commercial kratom products in rats". Journal of Natural Products4 (2021): 1104-1112.
38. Kruegel AC., et al. “The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse". Neuropharmacology 134 (2018): 108-120.
39. Sharma A., et al. “Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra‐performance liquid chromatography−tandem mass spectrometry". Drug Testing and Analysis8 (2019): 1162-1171.
40. Obeng S., et al. “Pharmacological comparison of mitragynine and 7-hydroxymitragynine: In vitro affinity and efficacy for μ-opioid receptor and opioid-like behavioral effects in rats". Journal of Pharmacology and Experimental Therapeutics3 (2021): 410-427.
41. Smith KE., et al. “Searching for a signal: Self-reported kratom dose-effect relationships among a sample of US adults with regular kratom use histories". Frontiers in Pharmacology 13 (2022): 765917.
42. Todd DA., et al. “Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions". Scientific Reports1 (2020): 19158.
43. Zhou Y., et al. “Predicted mode of binding to and allosteric modulation of the μ-opioid receptor by kratom’s alkaloids with reported antinociception in vivo". Biochemistry18 (2021): 1420-1429.
44. Smith KE., et al. “Kratom alkaloids: A blueprint?". ACS Chemical Neuroscience2 (2023): 195-197.
45. Stolt AC., et al. “Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract". Psychopharmacology 1 (2014): 13-25.
46. Giovannitti JA., et al. “Alpha-2 adrenergic receptor agonists: A review of current clinical applications". Anesthesia Progress1 (2015): 31-38.
47. Suhaimi FW., et al. “Neurobiology of Kratom and its main alkaloid mitragynine". Brain Research Bulletin1 (2016): 29-40.
48. Ulbricht C., et al. “An evidence-based systematic review of kratom (Mitragyna speciosa) by the natural standard research collaboration". Journal of Dietary Supplements2 (2013): 152-170.
49. Michael White C. "Pharmacologic and clinical assessment of kratom". American Journal of Health-System Pharmacy 5 (2018): 261-267.
50. Boyer EW., et al. “Self‐treatment of opioid withdrawal using kratom (Mitragyna speciosa korth)". Addiction 6 (2008): 1048-1050.
51. Buresh M. "Treatment of kratom dependence with buprenorphine-naloxone maintenance". Journal of Addiction Medicine6 (2018): 481-483.
52. Khazaeli A., et al. “Treatment of kratom withdrawal and addiction with buprenorphine". Journal of Addiction Medicine 6 (2018): 493-495.
53. Schmid P., et al. “Eine ambulante Entzugsbehandlung von Kratom bei sozialer Phobie: psychotherapeutische Praxis trifft suchtpsychiatrische Institutsambulanz". Psychiatrische Praxis04 (2022): 217-220.
54. Trakulsrichai S., et al. “Kratom abuse in Ramathibodi poison center, Thailand: A five-year experience". Journal of Psychoactive Drugs 5 (2013): 404-408.
55. Dorman C., et al. “Cholestatic hepatitis from prolonged kratom use: A case report". Hepatology3 (2015): 1086-1087.
56. Griffiths CL., et al. “Possible kratom-induced hepatomegaly: A case report". Journal of the American Pharmacists Association5 (2018): 561-563.
57. Kapp FG., et al. “Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa)". Journal of Medical Toxicology3 (2011): 227-231.
58. Bowe A., et al. “A complex case of kratom dependence, depression, and chronic pain in opioid use disorder: Effects of buprenorphine in clinical management". Journal of Psychoactive Drugs5 (2020): 447-452.
59. Smith KE., et al. “Non-prescribed buprenorphine use mediates the relationship between heroin use and kratom use among a sample of polysubstance users". Journal of Psychoactive Drugs4 (2019): 311-322.
60. O’Neill-Dee C., et al. “Natural psychoactive substance-related exposures reported to United States poison control centers, 2000-2017". Clinical Toxicology8 (2020): 813-820.
61. Olsen EO., et al. “Notes from the Field: Unintentional drug overdose deaths with kratom detected - 27 states, July 2016-December 2017". MMWR: Morbidity and Mortality Weekly Report 14 (2019): 326-327.
62. Stevens S., et al. “Opioid withdrawal behavior in spiny mice: A novel preclinical model of neonatal opioid withdrawal syndrome (NOWS)". Heliyon4 (2021): e06694.
63. Haight SC., et al. “Opioid use disorder documented at delivery hospitalization - united states, 1999-2014". MMWR: Morbidity and Mortality Weekly Report 31 (2018): 845-849.
64. Ko JY., et al. “Vital signs: Prescription opioid pain reliever use during pregnancy - 34 U.S. Jurisdictions, 2019". MMWR: Morbidity and Mortality Weekly Report28 (2020): 897-903.
65. Hirai AH., et al. “Neonatal abstinence syndrome and maternal opioid-related diagnoses in the US, 2010-2017". JAMA2 (2021): 146-155.
66. Saref A., et al. “Self-reported prevalence and severity of opioid and kratom (Mitragyna speciosa) side effects". Journal of Ethnopharmacology 238 (2019): 111876.
67. Davidson L., et al. “Natural drugs, not so natural effects: Neonatal abstinence syndrome secondary to ‘kratom’". Journal of Neonatal-Perinatal Medicine1 (2019): 109-112.
68. Eldridge WB., et al. “Neonatal abstinence syndrome due to maternal kratom use". Pediatrics6 (2018).
69. Mackay L., et al. “Novel case of maternal and neonatal kratom dependence and withdrawal". Canadian Family Physician Medecin de Famille Canadien2 (2018): 121-122.
70. Murthy P., et al. “An unusual cause for neonatal abstinence syndrome". Paediatrics and Child Health1 (2019): 12-14.
71. Leferink TM., et al. “[Neonatal abstinence syndrome due to kratom]". Nederlands Tijdschrift Voor Geneeskunde 167 (2023): D7541.
72. Damodaran T., et al. “Comparative toxicity assessment of kratom decoction, mitragynine and speciociliatine versus morphine on zebrafish (Danio rerio) embryos". Frontiers in Pharmacology 12 (2021).
73. Azadfard M., et al. “Opioid Addiction (Archived)". In StatPearls. StatPearls Publishing (2021).
74. Chang HY., et al. “Healthcare costs and utilization associated with high-risk prescription opioid use: a retrospective cohort study". BMC Medicine1 (2018): 69.
75. Schedules of controlled substances: Temporary placement of mitragynine and 7-hydroxymitragynine into schedule I. Federal Register (2016).
76. Quinn TA., et al. “The feto-placental unit, and potential roles of dehydroepiandrosterone (DHEA) in prenatal and postnatal brain development: A re-examination using the spiny mouse". The Journal of Steroid Biochemistry and Molecular Biology 160 (2016): 204-213.
77. Bath R., et al. “Self-reported health diagnoses and demographic correlates with kratom use: Results from an online survey". Journal of Addiction Medicine3 (2020): 244-252.
78. García Pardo MP., et al. “Modelos animales de adicción a las drogas". Adicciones 4 (2017): 278.
79. Váradi A., et al. “Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with Mu agonism and delta antagonism, which do not recruit β-arrestin-2". Journal of Medicinal Chemistry18 (2016): 8381-8397.