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Receptor Selectivity and Therapeutic Potential of Kratom in Substance Use Disorders

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Abstract

Purpose of Review

Kratom (Mitragyna speciosa Korth) contains several alkaloids, some interacting with opioid receptors and attracting recreational use in the western world. Human self-report has consistently documented the use of kratom for treating pain, mood elevation, and substance use disorders (SUDs). These anecdotal uses are also supported by preclinical findings. According to preclinical research, kratom may induce these positive effects without any respiratory suppression, unlike traditional opioids. This review summarizes kratom as a potential substitution for opioids and compiles all the latest inventions to determine if this natural product or its active alkaloids could offer a better alternative compared to the current treatment of opioid use disorder (OUD) and other SUDs.

Recent Findings

According to recent reports, kratom has been found to be very efficient for managing dependence, including attenuating opioid withdrawal. There are encouraging findings in pre-clinical paradigms of kratom as a feasible, safe, and efficient treatment for OUD.

Summary

Presently, kratom administration at low-moderate doses appears, based on preclinical work and self-report to have therapeutic potential for treating OUD irrespective of the etiology. Kratom leaf extracts and especially the purified, major alkaloid mitragynine, appear to have legitimate potential for being developed as treatments for pain, substance use disorders, and opioid withdrawal. These therapeutic uses have been hypothesized to be a result of biased signaling at opioid receptors and the poly-pharmacology of the alkaloids at opioid and adrenergic receptors, with little to no addiction potential demonstrated in pre-clinical studies. Thus, the present review highlights the most recent findings on receptor binding and preclinical evidence to explore the use of kratom and its alkaloids as potentially effective pharmacotherapies for OUD and possible other SUDs.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. McLellan AT. Substance misuse and substance use disorders: why do they matter in healthcare? Trans Am Clin Climatol Assoc. 2017;128:112–30.

    PubMed  PubMed Central  Google Scholar 

  2. Esang M, Ahmed S. A closer look at substance use and suicide. Am J Psychiatry. 2018;13(6):6–8. https://doi.org/10.1176/appi.ajp-rj.2018.130603.

    Article  Google Scholar 

  3. Degenhardt L, Stockings E, Patton G, Hall WD, Lynskey M. The increasing global health priority of substance use in young people. Lancet Psychiat. 2016;3(3):251–64. https://doi.org/10.1016/S2215-0366(15)00508-8.

    Article  Google Scholar 

  4. Rehm J, Taylor B, Room R. Global burden of disease from alcohol, illicit drugs and tobacco. Drug Alcohol Rev. 2006;25(6):503–13. https://doi.org/10.1080/09595230600944453.

    Article  PubMed  Google Scholar 

  5. Hser YI, Mooney LJ, Saxon AJ, Miotto K, Bell DS, Zhu Y, et al. High mortality among patients with opioid use disorder in a large healthcare system. J Addict Med. 2017;11(4):315–9. https://doi.org/10.1097/adm.0000000000000312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Witkiewitz K, Vowles KE. Alcohol and opioid use, co-use, and chronic pain in the context of the opioid epidemic: a critical review. Alcohol Clin Exp Res. 2018;42(3):478–88. https://doi.org/10.1111/acer.13594.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Truong EI, Kishawi SK, Ho VP, Tadi RS, Warner DF, Claridge JA, et al. Opioids and injury deaths: a population-based analysis of the United States from 2006 to 2017. Injury. 2021;52(8):2194–8. https://doi.org/10.1016/j.injury.2021.03.018.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gomes T, Tadrous M, Mamdani MM, Paterson JM, Juurlink DN. The burden of opioid-related mortality in the United States. JAMA Network Open. 2018;1(2):e180217-e. https://doi.org/10.1001/jamanetworkopen.2018.0217.

  9. Hood LE, Leyrer-Jackson JM, Olive MF. Pharmacotherapeutic management of co-morbid alcohol and opioid use. Expert Opin Pharmacother. 2020;21(7):823–39. https://doi.org/10.1080/14656566.2020.1732349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Blanco-Gandía MC, Rodríguez-Arias M. Pharmacological treatments for opiate and alcohol addiction: a historical perspective of the last 50 years. Eur J Pharmacol. 2018;836:89–101. https://doi.org/10.1016/j.ejphar.2018.08.007.

    Article  CAS  PubMed  Google Scholar 

  11. Bart G. Maintenance medication for opiate addiction: the foundation of recovery. J Addict Dis. 2012;31(3):207–25. https://doi.org/10.1080/10550887.2012.694598.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Smith KE, Rogers JM, Strickland JC. Associations of lifetime nonmedical opioid, methamphetamine, and kratom use within a nationally representative US sample. J Psychoact Drugs. 2022;54(5):429–39. https://doi.org/10.1080/02791072.2021.2006374.

    Article  CAS  Google Scholar 

  13. Vosburg SK, Faraone SV, Newcorn JH, Rostain AL, Findling RL, Butler SF, et al. Prescription stimulant nonmedical use among adolescents evaluated for substance use disorder treatment (CHAT™). J Atten Disord. 2020;25(13):1859–70. https://doi.org/10.1177/1087054720943283.

    Article  PubMed  Google Scholar 

  14. Smith KE, Dunn KE, Rogers JM, Grundmann O, McCurdy CR, Garcia-Romeu A, et al. Kratom use as more than a “self-treatment.” Am J Drug Alcohol Abuse. 2022;48(6):684–94. https://doi.org/10.1080/00952990.2022.2083967.

    Article  PubMed  Google Scholar 

  15. Smith KE, Rogers JM, Dunn KE, Grundmann O, McCurdy CR, Schriefer D et al. Searching for a signal: self-reported kratom dose-effect relationships among a sample of US adults with regular kratom use histories. Front Pharmacol. 2022;13. https://doi.org/10.3389/fphar.2022.765917.

  16. Demick DS, Lee TT, Summers AT, El-Mallakh RS. Kratom: a growing substance of abuse in the United States. Ann Clin Psychiatry. 2020;32(4):275–80. https://doi.org/10.12788/acp.0012.

    Article  PubMed  Google Scholar 

  17. Ahmad I, Prabowo WC, Arifuddin M, Fadraersada J, Indriyanti N, Herman H et al. Mitragyna species as pharmacological agents: from abuse to promising pharmaceutical products. Life. 2022;12(2). https://doi.org/10.3390/life12020193.

  18. Adkins JE, Boyer EW, McCurdy CR. Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity. Curr Top Med Chem. 2011;11(9):1165–75. https://doi.org/10.2174/156802611795371305.

    Article  CAS  PubMed  Google Scholar 

  19. Suhaimi FW, Yusoff NHM, Hassan R, Mansor SM, Navaratnam V, Muller CP, et al. Neurobiology of kratom and its main alkaloid mitragynine. Brain Res Bull. 2016;126:29–40. https://doi.org/10.1016/j.brainresbull.2016.03.015.

    Article  CAS  PubMed  Google Scholar 

  20. Jansen KLR, Prast CJ. Ethnopharmacology of kratom and the Mitragyna alkaloids. J Ethnopharmacol. 1988;23(1):115–9. https://doi.org/10.1016/0378-8741(88)90121-3.

    Article  CAS  PubMed  Google Scholar 

  21. Takayama H, Kurihara M, Kitajima M, Said IM, Aimi N. New indole alkaloids from the leaves of Malaysian Mitragyna speciosa. Tetrahedron. 1998;54(29):8433–40. https://doi.org/10.1016/S0040-4020(98)00464-5.

    Article  CAS  Google Scholar 

  22. Singh D, Narayanan S, Vicknasingam B. Traditional and non-traditional uses of Mitragynine (kratom): a survey of the literature. Brain Res Bull. 2016;126:41–6. https://doi.org/10.1016/j.brainresbull.2016.05.004.

    Article  CAS  PubMed  Google Scholar 

  23. Vicknasingam B, Narayanan S, Beng GT, Mansor SM. 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):283–8. https://doi.org/10.1016/j.drugpo.2009.12.003.

    Article  PubMed  Google Scholar 

  24. Singh D, Narayanan S, Vicknasingam B, Corazza O, Santacroce R, Roman-Urrestarazu A. Changing trends in the use of kratom (Mitragyna speciosa) in Southeast Asia. Hum Psychopharmacol. 2017;32(3):e2582. https://doi.org/10.1002/hup.2582.

    Article  Google Scholar 

  25. Singh D, Yeou Chear NJ, Narayanan S, Leon F, Sharma A, McCurdy CR, et al. Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users. J Ethnopharmacol. 2020;249:112462. https://doi.org/10.1016/j.jep.2019.112462.

    Article  CAS  PubMed  Google Scholar 

  26. Brown PN, Lund JA, Murch SJ. A botanical, phytochemical and ethnomedicinal review of the genus Mitragyna Korth: implications for products sold as kratom. J Ethnopharmacol. 2017;202:302–25. https://doi.org/10.1016/j.jep.2017.03.020.

    Article  CAS  PubMed  Google Scholar 

  27. 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. 2018;235(2):573–89. https://doi.org/10.1007/s00213-017-4813-4.

    Article  CAS  PubMed  Google Scholar 

  28. Grundmann O. Patterns of Kratom use and health impact in the US-results from an online survey. Drug Alcohol Depend. 2017;176:63–70. https://doi.org/10.1016/j.drugalcdep.2017.03.007.

    Article  PubMed  Google Scholar 

  29. León F, Habib E, Adkins JE, Furr EB, McCurdy CR, Cutler SJ. Phytochemical characterization of the leaves of Mitragyna speciosa grown in U.S.A. Nat Prod Commun. 2009;4(7):907–10.

    PubMed  PubMed Central  Google Scholar 

  30. Schimmel J, Amioka E, Rockhill K, Haynes CM, Black JC, Dart RC, et al. Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross-sectional study. Addiction. 2021;116(1):176–81. https://doi.org/10.1111/add.15082.

    Article  PubMed  Google Scholar 

  31. 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. https://doi.org/10.1080/15563650.2019.1569236.

    Article  CAS  Google Scholar 

  32. Gutridge AM, Robins MT, Cassell RJ, Uprety R, Mores KL, Ko MJ, et al. G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder. Br J Pharmacol. 2020;177(7):1497–513. https://doi.org/10.1111/bph.14913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Flores-Bocanegra L, Raja HA, Graf TN, Augustinović M, Wallace ED, Hematian S, et al. The chemistry of kratom [Mitragyna speciosa]: updated characterization data and methods to elucidate indole and oxindole alkaloids. J Nat Prod. 2020;83(7):2165–77. https://doi.org/10.1021/acs.jnatprod.0c00257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant. Mitragyna speciosa Chem Pharm Bull. 2004;52(8):916–28. https://doi.org/10.1248/cpb.52.916.

    Article  CAS  Google Scholar 

  35. Karunakaran T, Ngew KZ, Zailan AAD, Mian Jong VY, Abu Bakar MH. The chemical and pharmacological properties of mitragynine and its diastereomers: an insight review. Front Pharmacol. 2022;13:805986. https://doi.org/10.3389/fphar.2022.805986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sharma A, Kamble SH, León F, Chear NJ, King TI, Berthold EC, 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 Test Anal. 2019;11(8):1162–71. https://doi.org/10.1002/dta.2604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sharma A, McCurdy CR. Assessing the therapeutic potential and toxicity of Mitragyna speciosa in opioid use disorder. Expert Opin Drug Metab Toxicol. 2021;17(3):255–7. https://doi.org/10.1080/17425255.2021.1853706.

    Article  CAS  PubMed  Google Scholar 

  38. • Chear NJ, Leon F, Sharma A, Kanumuri SRR, Zwolinski G, Abboud KA et al. Exploring the chemistry of alkaloids from Malaysian Mitragyna speciosa (kratom) and the role of oxindoles on human opioid receptors. J Nat Prod. 2021;84(4):1034–43. https://doi.org/10.1021/acs.jnatprod.0c01055. This paper highlights the details of receptor selectivity of various oxindole-based kratom alkaloids towards opioid receptors.

  39. Kruegel AC, Uprety R, Grinnell SG, Langreck C, Pekarskaya EA, Le Rouzic V, 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. https://doi.org/10.1021/acscentsci.9b00141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pearson BJ, Campbell SM, Avery B, McCurdy C, Francisco J, Sharma A et al., editors. Preliminary examination of mitragynine and 7-hydroxymitragynine synthesis in response to production environment and postharvest techniques of Mitragyna speciosa. Acta Hortic. 2020;1274:89–96 https://doi.org/10.17660/ActaHortic.2020.1274.10.

  41. • Zhang M, Sharma A, León F, Avery B, Kjelgren R, McCurdy CR et al. Plant growth and phytoactive alkaloid synthesis in kratom [Mitragyna speciosa (Korth.)] in response to varying radiance. Plos One. 2022;17(4):e0259326. https://doi.org/10.1371/journal.pone.0259326. This paper highlights the effect of environment and growing conditions towards the impact of kratom plant production and percentage of alkaloids contains. The plants are grown in this study in three different sun lighting conditions: full sun in the field, greenhouse unshaded, and greenhouse shaded.

  42. 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;134:108–20. https://doi.org/10.1016/j.neuropharm.2017.08.026.

    Article  CAS  PubMed  Google Scholar 

  43. Stolt AC, Schröder H, Neurath H, Grecksch G, Höllt V, Meyer MR, et al. Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract. Psychopharmacology. 2014;231(1):13–25. https://doi.org/10.1007/s00213-013-3201-y.

    Article  CAS  PubMed  Google Scholar 

  44. White CM. Pharmacologic and clinical assessment of kratom. Am J Health Syst Pharm. 2018;75(5):261–7. https://doi.org/10.2146/ajhp161035.

    Article  CAS  PubMed  Google Scholar 

  45. Zhou Y, Ramsey S, Provasi D, El Daibani A, Appourchaux K, Chakraborty S, et al. Predicted mode of binding to and allosteric modulation of the μ-opioid receptor by kratom’s alkaloids with reported antinociception in vivo. Biochemistry. 2021;60(18):1420–9. https://doi.org/10.1021/acs.biochem.0c00658.

    Article  CAS  PubMed  Google Scholar 

  46. Singh D, Müller CP, Vicknasingam BK. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug and Alcohol Depend. 2014;139:132–7. https://doi.org/10.1016/j.drugalcdep.2014.03.017.

    Article  Google Scholar 

  47. Hassan Z, Muzaimi M, Navaratnam V, Yusoff NHM, Suhaimi FW, Vadivelu R, et al. From kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction. Neurosci Biobehav Rev. 2013;37(2):138–51. https://doi.org/10.1016/j.neubiorev.2012.11.012.

    Article  CAS  PubMed  Google Scholar 

  48. Hanapi NA, Chear NJ-Y, Azizi J, Yusof SR. Kratom alkaloids: interactions with enzymes, receptors, and cellular barriers. Front Pharmacol. 2021;12. https://doi.org/10.3389/fphar.2021.751656.

  49. Striley CW, Hoeflich CC, Viegas AT, Berkowitz LA, Matthews EG, Akin LP, et al. Health effects associated with kratom (Mitragyna speciosa) and polysubstance use: a narrative review. Subst Abuse. 2022;16:11782218221095872. https://doi.org/10.1177/11782218221095873.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Xu KY, Hartz SM, Borodovsky JT, Bierut LJ, Grucza RA. Association between benzodiazepine use with or without opioid use and all-cause mortality in the United States, 1999–2015. JAMA Network Open. 2020;3(12):e2028557-e. https://doi.org/10.1001/jamanetworkopen.2020.28557.

  51. • Ismail I, Wahab S, Sidi H, Das S, Lin LJ, Razali R. Kratom and future treatment for the opioid addiction and chronic pain: periculo beneficium? Curr Drug Targets. 2019;20(2):166–72. https://doi.org/10.2174/1389450118666170425154120. This review highlights the potential use of kratom as a alternate treatment for chronic pain and opioid addiction and the underlying mechanism of actions of drug addiction.

  52. • Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D et al. Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands. J Med Chem. 2002;45(9):1949–56. https://doi.org/10.1021/jm010576e. This is the first reported interaction of mitragynine and its related indole alkaloids with MOR, DOR, and KOR receptors derived from guinea pig brain by radioligand displacement assay.

  53. Boyer EW, Babu KM, Adkins JE, McCurdy CR, Halpern JH. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa Korth). Addiction. 2008;103(6):1048–50. https://doi.org/10.1111/j.1360-0443.2008.02209.x.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Kruegel AC, Gassaway MM, Kapoor A, Varadi 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. https://doi.org/10.1021/jacs.6b00360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ellis CR, Racz R, Kruhlak NL, Kim MT, Zakharov AV, Southall N, et al. Evaluating kratom alkaloids using PHASE. Plos One. 2020;15(3):e0229646. https://doi.org/10.1371/journal.pone.0229646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. • Obeng S, Kamble SH, Reeves ME, Restrepo LF, Patel A, Behnke M 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. J Med Chem. 2020;63(1):433–9. https://doi.org/10.1021/acs.jmedchem.9b01465. This paper is important because indole-based kratom alkaloids are studied against various subtypes of adrenergic receptor and their binding mode are described. This paper also demonstrate mitragynine has higher affinity at opioid receptors than at adrenergic receptors, while for corynantheidine, its is vice versa.

  57. Matsumoto K, Mizowaki M, Suchitra T, Murakami Y, Takayama H, Sakai S, et al. Central antinociceptive effects of mitragynine in mice: contribution of descending noradrenergic and serotonergic systems. Eur J Pharmacol. 1996;317(1):75–81. https://doi.org/10.1016/s0014-2999(96)00714-5.

    Article  CAS  PubMed  Google Scholar 

  58. Matsumoto K, Mizowaki M, Suchitra T, Takayama H, Sakai S, Aimi N, et al. Antinociceptive action of mitragynine in mice: evidence for the involvement of supraspinal opioid receptors. Life Sci. 1996;59(14):1149–55. https://doi.org/10.1016/0024-3205(96)00432-8.

    Article  CAS  PubMed  Google Scholar 

  59. Matsumoto K, Mizowaki M, Takayama H, Sakai S, Aimi N, Watanabe H. Suppressive effect of mitragynine on the 5-methoxy-N, N-dimethyltryptamine-induced head-twitch response in mice. Pharmacol Biochem Behav. 1997;57(1–2):319–23. https://doi.org/10.1016/s0091-3057(96)00314-0.

    Article  CAS  PubMed  Google Scholar 

  60. Hazim AI, Ramanathan S, Parthasarathy S, Muzaimi M, Mansor SM. Anxiolytic-like effects of mitragynine in the open-field and elevated plus-maze tests in rats. J Physiol Sci. 2014;64(3):161–9. https://doi.org/10.1007/s12576-014-0304-0.

    Article  CAS  PubMed  Google Scholar 

  61. Vijeepallam K, Pandy V, Kunasegaran T, Murugan DD, Naidu M. Mitragyna speciosa leaf extract exhibits antipsychotic-like effect with the potential to alleviate positive and negative symptoms of psychosis in mice. Front Pharmacol. 2016;7:464. https://doi.org/10.3389/fphar.2016.00464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Foss JD, Nayak SU, Tallarida CS, Farkas DJ, Ward SJ, Rawls SM. Mitragynine, bioactive alkaloid of kratom, reduces chemotherapy-induced neuropathic pain in rats through alpha-adrenoceptor mechanism. Drug Alcohol Depend. 2020;209:107946. https://doi.org/10.1016/j.drugalcdep.2020.107946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chakraborty S, DiBerto JF, Faouzi A, Bernhard SM, Gutridge AM, Ramsey S, et al. A novel mitragynine analog with low-efficacy mu opioid receptor agonism displays antinociception with attenuated adverse effects. J Med Chem. 2021;64(18):13873–92. https://doi.org/10.1021/acs.jmedchem.1c01273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Matsumoto K, Yamamoto LT, Watanabe K, Yano S, Shan J, Pang PKT, et al. Inhibitory effect of mitragynine, an analgesic alkaloid from Thai herbal medicine, on neurogenic contraction of the vas deferens. Life Sci. 2005;78(2):187–94. https://doi.org/10.1016/j.lfs.2005.04.042.

    Article  CAS  PubMed  Google Scholar 

  65. Hiranita T, Obeng S, Sharma A, Wilkerson JL, McCurdy CR, McMahon LR. In vitro and in vivo pharmacology of kratom. Adv Pharmacol. 2022;93:35–76. https://doi.org/10.1016/bs.apha.2021.10.001.

    Article  CAS  PubMed  Google Scholar 

  66. Kudla L, Przewlocki R. Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors. Pharmacol Rep. 2021;73(4):1033–51. https://doi.org/10.1007/s43440-021-00251-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Conibear AE, Kelly E. A biased view of μ-opioid receptors? Mol Pharmacol. 2019;96(5):542–9. https://doi.org/10.1124/mol.119.115956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Váradi A, Marrone GF, Palmer TC, Narayan A, Szabó MR, Le Rouzic V, et al. Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with Mu agonism and delta antagonism, which do not recruit β-arrestin-2. J Med Chem. 2016;59(18):8381–97. https://doi.org/10.1021/acs.jmedchem.6b00748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kamble SH, Sharma A, King TI, León F, McCurdy CR, Avery BA. Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom). Xenobiotica. 2019;49(11):1279–88. https://doi.org/10.1080/00498254.2018.1552819.

    Article  CAS  PubMed  Google Scholar 

  70. Kamble SH, León F, King TI, Berthold EC, Lopera-Londoño C, Siva Rama Raju K et al. Metabolism of a kratom alkaloid metabolite in human plasma increases its opioid potency and efficacy. ACS Pharmacol Transl Sci. 2020;3(6):1063–8. https://doi.org/10.1021/acsptsci.0c00075.

  71. Yusof SR, Mohd Uzid M, Teh EH, Hanapi NA, Mohideen M, Mohamad Arshad AS, et al. Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution: the missing link in pharmacodynamic studies. Addict Biol. 2019;24(5):935–45. https://doi.org/10.1111/adb.12661.

    Article  CAS  PubMed  Google Scholar 

  72. Chabot-Doré AJ, Schuster DJ, Stone LS, Wilcox GL. Analgesic synergy between opioid and α2 -adrenoceptors. Br J Pharmacol. 2015;172(2):388–402. https://doi.org/10.1111/bph.12695.

    Article  CAS  PubMed  Google Scholar 

  73. Di Cesare ML, Micheli L, Crocetti L, Giovannoni MP, Vergelli C, Ghelardini C. α2 adrenoceptor: a target for neuropathic pain treatment. Mini Rev Med Chem. 2017;17(2):95–107. https://doi.org/10.2174/1389557516666160609065535.

    Article  CAS  Google Scholar 

  74. Carroll I, Mackey S, Gaeta R. The role of adrenergic receptors and pain: the good, the bad, and the unknown. Semin Anesth, Perioper Med Pain. 2007;26(1):17–21. https://doi.org/10.1053/j.sane.2006.11.005.

    Article  CAS  Google Scholar 

  75. Reeve ME, Obeng S, Oyola FL, Behnke M, Restrepo LF, Patel A et al. The adrenergic a2 receptor-mediated discriminative-stimulus effects of mitragynine, the primary alkaloid in kratom (Mitragyna Speciosa) in rats. FASEB J. 2020;34(S1):1-. https://doi.org/10.1096/fasebj.2020.34.s1.05233.

  76. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–66. https://doi.org/10.1146/annurev.med.60.042307.110802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Roth BL. Multiple serotonin receptors: clinical and experimental aspects. Ann Clin Psychiatry. 1994;6(2):67–78. https://doi.org/10.3109/10401239409148985.

    Article  CAS  PubMed  Google Scholar 

  78. Obeng S, León F, Patel A, Restrepo L, Gamez-Jimenez L, Zuarth Gonzalez J et al. Serotonin 5-HT1A receptor activity of kratom alkaloids mitragynine, paynantheine, and speciogynine. FASEB J. 2021;35(S1). https://doi.org/10.1096/fasebj.2021.35.S1.04764.

  79. • León F, Obeng S, Mottinelli M, Chen Y, King TI, Berthold EC et al. Activity of Mitragyna speciosa (“kratom”) alkaloids at serotonin receptors. J Med Chem. 2021;64(18):13510–23. https://doi.org/10.1021/acs.jmedchem.1c00726. This paper demonstrates the binding and behavior of kratom alkaloids towards seretonin receptors (5- HTRs) (in vitro and in vivo).

  80. Wilson LL, Chakraborty S, Eans SO, Cirino TJ, Stacy HM, Simons CA, et al. Kratom alkaloids, natural and semi-synthetic, show less physical dependence and ameliorate opioid withdrawal. Cell Mol Neurobiol. 2021;41(5):1131–43. https://doi.org/10.1007/s10571-020-01034-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wilson LL, Harris HM, Eans SO, Brice-Tutt AC, Cirino TJ, Stacy HM, et al. Lyophilized kratom tea as a therapeutic option for opioid dependence. Drug Alcohol Depend. 2020;216:108310. https://doi.org/10.1016/j.drugalcdep.2020.108310.

    Article  CAS  PubMed  Google Scholar 

  82. Cheaha D, Reakkamnuan C, Nukitram J, Chittrakarn S, Phukpattaranont P, Keawpradub N et al. Effects of alkaloid-rich extract from Mitragyna speciosa (Korth.) Havil. on naloxone-precipitated morphine withdrawal symptoms and local field potential in the nucleus accumbens of mice. J Ethnopharmacol. 2017;208:129–37. https://doi.org/10.1016/j.jep.2017.07.008.

  83. Volkow ND, Woodcock J, Compton WM, Throckmorton DC, Skolnick P, Hertz S et al. Medication development in opioid addiction: meaningful clinical end points. Sci Transl Med. 2018;10(434):eaan2595.https://doi.org/10.1126/scitranslmed.aan2595.

  84. Ahmad K, Aziz Z. Mitragyna speciosa use in the northern states of Malaysia: a cross-sectional study. J Ethnopharmacol. 2012;141(1):446–50. https://doi.org/10.1016/j.jep.2012.03.009.

    Article  PubMed  Google Scholar 

  85. Bowe A, Kerr PL. A complex case of kratom dependence, depression, and chronic pain in opioid use disorder: effects of buprenorphine in clinical management. J Psychoact Drugs. 2020;52(5):447–52. https://doi.org/10.1080/02791072.2020.1773586.

    Article  Google Scholar 

  86. Buresh M. Treatment of kratom dependence with buprenorphine-naloxone maintenance. J Addict Med. 2018;12(6).

  87. Diep J, Chin DT, Gupta S, Syed F, Xiong M, Cheng J. Kratom, an emerging drug of abuse: a case report of overdose and management of withdrawal. A&A Pract. 2018;10(8):192–4. https://doi.org/10.1213/xaa.0000000000000658.

    Article  Google Scholar 

  88. Giancola NB, Caplan JP, McKnight CA. “A kratom konundrum”: management of kratom withdrawal with gabapentin in a patient with a left ventricular assist device. J Acad Consult Liaison Psychiatry. 2021;62(3):368–9. https://doi.org/10.1016/j.psym.2020.10.004.

    Article  PubMed  Google Scholar 

  89. Kucharik M, Gupta A, Averkiou P, Luck GR, Ross AS. Complicated postoperative course secondary to kratom withdrawal: a case report. J Surg Case Rep. 2019;2019(11). https://doi.org/10.1093/jscr/rjz309.

  90. Lei J, Butz A, Valentino N. Management of kratom dependence with buprenorphine/naloxone in a veteran population. Subst Abus. 2021;42(4):497–502. https://doi.org/10.1080/08897077.2021.1878086.

    Article  CAS  PubMed  Google Scholar 

  91. McWhirter L, Morris S. A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence. Eur Addict Res. 2010;16(4):229–31. https://doi.org/10.1159/000320288.

    Article  PubMed  Google Scholar 

  92. Sablaban IM, Gautam M. The diagnosis of severe obsessions in the setting of kratom withdrawal and treatment with lorazepam: case report. J Addict Dis. 2020;39(1):138–9. https://doi.org/10.1080/10550887.2020.1813357.

    Article  PubMed  Google Scholar 

  93. Singh D, Narayanan S, Müller CP, Swogger MT, Rahim AA, Leong Bin Abdullah MFI et al. Severity of kratom (Mitragyna speciosa Korth.) psychological withdrawal symptoms. J Psychoact Drugs. 2018;50(5):445–50. https://doi.org/10.1080/02791072.2018.1511879.

  94. Singh D, Narayanan S, Vicknasingam BK, Prozialeck WC, Ramanathan S, Zainal H et al. Severity of pain and sleep problems during kratom (Mitragyna speciosa Korth.) cessation among regular kratom users. J Psychoact Drugs. 2018;50(3):266–74. https://doi.org/10.1080/02791072.2018.1443234.

  95. Swogger MT, Hart E, Erowid F, Erowid E, Trabold N, Yee K, et al. Experiences of kratom users: a qualitative analysis. J Psychoact Drugs. 2015;47(5):360–7. https://doi.org/10.1080/02791072.2015.1096434.

    Article  Google Scholar 

  96. Vento AE, de Persis S, De Filippis S, Schifano F, Napoletano F, Corkery JM et al. Case report: treatment of kratom use disorder with a classical tricyclic antidepressant. Front Psychiatry. 2021;12. https://doi.org/10.3389/fpsyt.2021.640218.

  97. Weiss ST, Douglas HE. Treatment of kratom withdrawal and dependence with buprenorphine/naloxone: a case series and systematic literature review. J Addict Med. 2021;15(2).

  98. Grundmann O, Hendrickson RG, Greenberg MI. Kratom: history, pharmacology, current user trends, adverse health effects and potential benefits. Dis Mon. 2022:101442. https://doi.org/10.1016/j.disamonth.2022.101442.

  99. Davidson L, Rawat M, Stojanovski S, Chandrasekharan P. Natural drugs, not so natural effects: neonatal abstinence syndrome secondary to ‘kratom.’ J Neonatal Perinatal Med. 2019;12:109–12. https://doi.org/10.3233/NPM-1863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wright ME, Ginsberg C, Parkison AM, Dubose M, Sherbondy M, Shores E. Outcomes of mothers and newborns to prenatal exposure to kratom: a systematic review. J Perinatol. 2021;41(6):1236–43. https://doi.org/10.1038/s41372-021-00952-8.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Perry CJ, Zbukvic I, Kim JH, Lawrence AJ. Role of cues and contexts on drug-seeking behaviour. Br J Pharmacol. 2014;171(20):4636–72. https://doi.org/10.1111/bph.12735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. McKendrick G, Graziane NM. Drug-induced conditioned place preference and its practical use in substance use disorder research. Front Behav Neurosci. 2020;14. https://doi.org/10.3389/fnbeh.2020.582147.

  103. Sufka KJ, Loria MJ, Lewellyn K, Zjawiony JK, Ali Z, Abe N, et al. The effect of Salvia divinorum and Mitragyna speciosa extracts, fraction and major constituents on place aversion and place preference in rats. J Ethnopharmacol. 2014;151(1):361–4. https://doi.org/10.1016/j.jep.2013.10.059.

    Article  CAS  PubMed  Google Scholar 

  104. Henningfield JE, Wang DW, Huestis MA. Kratom abuse potential 2021: an updated eight factor analysis. Front Pharmacol. 2021;12:775073. https://doi.org/10.3389/fphar.2021.775073.

    Article  CAS  PubMed  Google Scholar 

  105. 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. https://doi.org/10.1007/s00414-015-1279-y.

    Article  PubMed  Google Scholar 

  106. Harun N, Johari IS, Mansor SM, Shoaib M. Assessing physiological dependence and withdrawal potential of mitragynine using schedule-controlled behaviour in rats. Psychopharmacology. 2020;237(3):855–67. https://doi.org/10.1007/s00213-019-05418-6.

    Article  CAS  PubMed  Google Scholar 

  107. Hassan R, Pike See C, Sreenivasan S, Mansor SM, Müller CP, Hassan Z. Mitragynine attenuates morphine withdrawal effects in rats-a comparison with methadone and buprenorphine. Front Psychiatry. 2020;11. https://doi.org/10.3389/fpsyt.2020.00411.

  108. Khor BS, Jamil MF, Adenan MI, Shu-Chien AC. Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish. Plos One. 2011;6(12):e28340. https://doi.org/10.1371/journal.pone.0028340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yue K, Katz JL, Shu X. Physiological dependence to mitragynine indicated by a rapid cross-dependence procedure with heroin-dependent mice. Psychopharmacology. 2022;239(3):897–908. https://doi.org/10.1007/s00213-022-06080-1.

    Article  CAS  PubMed  Google Scholar 

  110. Yue K, Kopajtic TA, Katz JL. Abuse liability of mitragynine assessed with a self-administration procedure in rats. Psychopharmacology. 2018;235(10):2823–9. https://doi.org/10.1007/s00213-018-4974-9.

    Article  CAS  PubMed  Google Scholar 

  111. Hassan R, Othman N, Mansor SM, Müller CP, Hassan Z. Proteomic analysis reveals brain Rab35 as a potential biomarker of mitragynine withdrawal in rats. Brain Res Bull. 2021;172:139–50. https://doi.org/10.1016/j.brainresbull.2021.04.018.

    Article  CAS  PubMed  Google Scholar 

  112. 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. https://doi.org/10.1016/j.jep.2013.02.008.

    Article  CAS  PubMed  Google Scholar 

  113. Yusoff NHM, Suhaimi FW, Vadivelu RK, Hassan Z, Rümler A, Rotter A, et al. Abuse potential and adverse cognitive effects of mitragynine (kratom). Addict Biol. 2016;21(1):98–110. https://doi.org/10.1111/adb.12185.

    Article  CAS  PubMed  Google Scholar 

  114. • Behnood-Rod A, Chellian R, Wilson R, Hiranita T, Sharma A, Leon F et al. Evaluation of the rewarding effects of mitragynine and 7‐hydroxymitragynine in an intracranial self-stimulation procedure in male and female rats. Drug Alcohol Depend. 2020;215:108235. https://doi.org/10.1016/j.drugalcdep.2020.108235. This paper concludes that mitragynine, 7-hydroxymitragynine, and morphine have effect on the brain reward thresholds and do not have abuse potential.

  115. Hemby SE, McIntosh S, Leon F, Cutler SJ, McCurdy CR. Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7-hydroxymitragynine. Addict Biol. 2019;24(5):874–85. https://doi.org/10.1111/adb.12639.

    Article  CAS  PubMed  Google Scholar 

  116. Obeng S, Wilkerson JL, León F, Reeves ME, Restrepo LF, Gamez-Jimenez LR, 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. J Pharmacol Exp Ther. 2021;376(3):410–27. https://doi.org/10.1124/jpet.120.000189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Matsumoto K, Horie S, Takayama H, Ishikawa H, Aimi N, Ponglux D, et al. Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa. Life Sci. 2005;78(1):2–7. https://doi.org/10.1016/j.lfs.2004.10.086.

    Article  CAS  PubMed  Google Scholar 

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Funding

A portion of this work was supported by UG3DA048353 and R01DA047855 grants from the National Institute on Drug Abuse.

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  1. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA

    Sushobhan Mukhopadhyay, Sampa Gupta & Christopher R. McCurdy

  2. Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA

    Jenny L. Wilkerson & Lance R. McMahon

  3. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA

    Abhisheak Sharma

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Mukhopadhyay, S., Gupta, S., Wilkerson, J.L. et al. Receptor Selectivity and Therapeutic Potential of Kratom in Substance Use Disorders. Curr Addict Rep 10, 304–316 (2023). https://doi.org/10.1007/s40429-023-00472-9

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