Kratom

• How It Works

  Kratom is an herbal supplement that has properties similar to other opioids. It is not recommended as a treatment for pain at this time due to lack of research, harmful side effects, and product contamination.

  Kratom is an herbal supplement known to have both stimulant and calming effects. It may also have pain-relieving properties similar to opioids. However, kratom cannot be used as a substitution for prescription pain medications, because studies on its safety or usefulness in humans have not been conducted. Its use is banned in some countries and US states due to potential for abuse. Moreover, some kratom products were recalled due to contamination.

• Purported Uses

  In general there are very limited data on effects in humans for all uses. More research is needed to determine the safety and effectiveness of this herbal supplement.

  Anxiety
  Although animal studies suggest kratom may relieve anxiety, it may also cause anxiety in humans during withdrawal.

  Insomnia
  Kratom appears to have sedative effects at higher doses.

  Pain relief
  Kratom appears to have pain-relieving effects at higher doses.

  Stimulant
  Lower doses of kratom have been traditionally used for its stimulating effects. It may also cause appetite suppression.

• Patient Warnings
  • The FDA recently recalled powdered kratom supplements for salmonella contamination and issued a public health advisory against kratom. It also issued warnings of addiction and overdose risks similar to that of other opioids.
  • The Drug Enforcement Administration includes kratom on its Drugs of Concern list. These substances are not currently regulated by the Controlled Substances Act, but pose risks to persons who abuse them. In addition, the National Institute of Drug Abuse identified kratom as an emerging drug of abuse.
• Do Not Take If
  • You have heart problems: Laboratory studies and case reports suggest kratom could worsen heart problems.
  • You are taking CYP450 or UGT substrate drugs: Kratom may affect the clearance of these drugs.
  • You are taking P-glycoprotein substrate drugs: When taken with psychoactive drugs that are P-gp substrates, mitragynine may cause significant toxicity.
• Side Effects

  Withdrawal symptoms: Flu-like symptoms such as nausea, vomiting, chills, sweats, muscle spasms and pain, decreased appetite, or diarrhea; anxiety, irritability, depressed mood, hot flashes, sleeping difficulty. Symptoms are more likely with heavier use.

  Case reports

  • Addiction and severe opioid-like withdrawal: In a middle-aged woman who had to be medically treated.
  • Overdose and withdrawal: In a young man with no evidence of other drug use.
  • Liver damage: From prolonged kratom use.
  • Heart attack: In a 26-year-old man. Considered to be caused by kratom as no other cause was identified.
  • Cardiac arrest: In a 35-year-old man following kratom use.
  • Other fatalities/cardiotoxicities: Involving kratom and mitragynine.
  • Deaths: Associated with kratom-containing products or use of multiple drugs in which kratom may have contributed. However, conclusions about which specific drugs caused the deaths could not be determined.
• Special Point
  • Several countries and US states have banned kratom.
• Scientific Name

  Mitragyna speciosa

• Clinical Summary

  Mitragyna speciosa, commonly known as kratom, is indigenous to Southeast Asia. The leaves have been used in traditional medicine to treat pain, fatigue, fever, diarrhea, and wounds ⁽¹⁾, while its extracts are known for their psychoactive properties, especially morphine-like effects ⁽²⁾. Kratom has gained popularity as a supplement to improve mood, and decrease anxiety and pain. It has also been a source of significant controversy. The FDA has issued numerous statements against kratom, citing adverse events, potentially related deaths, risk of addiction or overdose, and incidences of contaminated supplements ^{(3) (4) (5)}.

  Kratom has both stimulant and sedative properties ⁽⁶⁾. The main psychoactive constituents are mitragynine and 7-hydroxymitragynine ⁽⁷⁾. In vivo studies of derivative compounds and analogs from kratom demonstrate antinociceptive effects ⁽⁸⁾. Animal models suggest that kratom has muscle relaxant ⁽⁹⁾, anti-inflammatory ⁽¹⁰⁾, analgesic ⁽¹¹⁾, and anorectic ⁽¹²⁾ properties. Mitragynine has also shown antioxidant and antiproliferative effects in a few cancer cell lines ⁽¹³⁾.

  Data on the use and safety of kratom in humans are very limited. Stimulant effects occur at lower doses, while sedative and pain-relieving effects occur at higher doses ⁽¹⁴⁾. Kratom users may develop physiological dependence and experience withdrawal ⁽¹⁵⁾, but this risk has not yet been adequately quantified ⁽¹⁶⁾. More research on the therapeutic uses for kratom and its constituents, as well as its toxic effects and abuse potential is needed.

  The biological activities of kratom in humans are still poorly characterized ⁽¹⁷⁾. Because of its potential interactions with other drugs ^(18) (19) and possible side effects ⁽²⁰⁾, kratom should not be used as a substitution for prescription pain medications. Several countries and US states have banned the use of kratom due to its potential for abuse ^(21) (22).

• Purported Uses
  • Anxiety
  • Insomnia
  • Pain relief
  • Stimulant
• Mechanism of Action

  The main active alkaloids in kratom are mitragynine; and 7-hydroxymitragynine (7-HMG), which is thought to have analgesic effects comparable to morphine ^(11) (23). Through monoaminergic and opioid receptors, both compounds produce a range of CNS stimulant and depressant effects ^{(23) (24) (25)}.

  Although structurally different ⁽²⁶⁾, mitragynine administration causes cognitive impairment and addiction profiles that closely resemble those of morphine ⁽²⁷⁾. Other research also suggests these compounds share classic opioid characteristics—affinity for opioid receptors, analgesic cross-tolerance, and competitive interaction with naloxone–while possessing other novel attributes ⁽²⁸⁾.

  In animal models, anxiolytic-like effects are attributed to opioidergic, GABAergic, and dopaminergic interactions in brain regions ⁽²⁹⁾. Mitragynine may also obstruct neuronal calcium channels ⁽³⁰⁾.

• Warnings
  • The FDA recently recalled powdered kratom supplements for salmonella contamination ⁽⁵⁾ and issued a public health advisory against kratom ⁽³⁾, with warnings of addiction and overdose risks similar to that of other opioids ⁽⁴⁾.
  • The Drug Enforcement Administration includes kratom on its Drugs of Concern list. These substances are not currently regulated by the Controlled Substances Act, but pose risks to persons who abuse them. In addition, the National Institute of Drug Abuse identified kratom as an emerging drug of abuse ⁽³¹⁾.
  • Herbal mixtures that contain synthetic compounds and kratom have been linked to altered behavior ⁽³²⁾, hemorrhagic stroke ⁽⁴⁵⁾ and multiple deaths ⁽³³⁾.
• Contraindications
  • Patients with tachycardia should avoid using kratom as laboratory studies suggest the potential for cardiotoxicity or exacerbation of Torsade de Pointes ⁽³⁴⁾.
• Adverse Reactions

  Withdrawal symptoms: Flu-like symptoms such as nausea, vomiting, chills, sweats, muscle spasms and pain, decreased appetite, or diarrhea; anxiety, irritability, depressed mood, hot flashes, sleeping difficulty; symptoms are more likely with heavier use ^{(15) (16) (35)}.

  Case reports
  Addiction and severe opioid-like withdrawal syndrome: In a 37-year-old woman who was treated with clonidine and hydroxyzine ⁽³⁶⁾.
  Overdose and withdrawal: In a young man with negative toxicology screens ⁽¹⁴⁾.
  Liver injury: From prolonged kratom use ^{(37) (50) (51)}.
  Cardio-respiratory arrest: In a 26-year-old man and considered a direct result of kratom ingestion in the absence of other identified causes ⁽³⁸⁾.
  Cardiac arrest: In a 35-year-old man following kratom use ⁽⁴⁹⁾.
  Other fatalities/cardiotoxicities: Involving kratom and mitragynine ⁽³⁴⁾ .
  Deaths: Associated with the use of kratom-containing products or polydrug use in which kratom was suspected to have possibly contributed ^{(3) (39) (40) (33) (41) (31) (46) (47) (48)}. The multi-drug circumstances confound conclusive interpretation ⁽⁴²⁾.

• Herb-Drug Interactions
  • Cytochrome P450 (CYP 450) substrates: Increased clearance of drugs metabolized by CYP450s ^(18) (19) . Kratom may also inhibit CYP2D6 ⁽⁴³⁾, and induce CYP1A2 ⁽⁴⁴⁾.
  • UGT (Uridine 5’-diphospho-glucuronosyltransferase) substrates: Increased clearance of drugs metabolized by UGT1A6 with kratom use ⁽¹⁸⁾.
  • P-glycoprotein substrates: Mitragynine inhibits P-gp in vitro, and concurrent administration with psychoactive drugs that are P-gp substrates may cause significant toxicity ⁽⁵²⁾.
• References

  1. Hassan Z, Muzaimi M, Navaratnam V, et al. From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction. Neurosci Biobehav Rev. Feb 2013;37(2):138-151.

  2. Sabetghadam A, Ramanathan S, Sasidharan S, et al. Subchronic exposure to mitragynine, the principal alkaloid of Mitragyna speciosa, in rats. J Ethnopharmacol. Apr 19 2013;146(3):815-823.

  3. U.S. Food and 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. February 6, 2018.

  4. U.S. Food and Drug Administration. FDA oversees destruction and recall of kratom products; and reiterates its concerns on risks associated with this opioid. February 21, 2018.

  5. U.S. Food and Drug Administration. FDA orders mandatory recall for kratom products due to risk of salmonella. April 3, 2018.

  6. Fluyau D, Revadigar N. Biochemical Benefits, Diagnosis, and Clinical Risks Evaluation of Kratom. Front Psychiatry. 2017;8:62.

  7. Griffin OH, 3rd, Daniels JA, Gardner EA. Do You Get What You Paid For? An Examination of Products Advertised as Kratom. J Psychoactive Drugs. Nov-Dec 2016;48(5):330-335.

  8. Varadi A, Marrone GF, Palmer TC, et al. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit beta-Arrestin-2. J Med Chem. Sep 22 2016;59(18):8381-8397.

  9. Chittrakarn S, Keawpradub N, Sawangjaroen K, et al. The neuromuscular blockade produced by pure alkaloid, mitragynine and methanol extract of kratom leaves (Mitragyna speciosa Korth.). J Ethnopharmacol. Jun 16 2010;129(3):344-349.

  10. Shaik Mossadeq WM, Sulaiman MR, Tengku Mohamad TA, et al. Anti-inflammatory and antinociceptive effects of Mitragyna speciosa Korth methanolic extract. Med Princ Pract. 2009;18(5):378-384.

  11. Takayama H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo). Aug 2004;52(8):916-928.

  12. Kumarnsit E, Keawpradub N, Nuankaew W. Acute and long-term effects of alkaloid extract of Mitragyna speciosa on food and water intake and body weight in rats. Fitoterapia. Jul 2006;77(5):339-345.

  13. Goh TB, Koh RY, Mordi MN, et al. Antioxidant value and antiproliferative efficacy of mitragynine and a silane reduced analogue. Asian Pac J Cancer Prev. 2014;15(14):5659-5665.

  14. Diep J, Chin DT, Gupta S, et al. Kratom, an Emerging Drug of Abuse: A Case Report of Overdose and Management of Withdrawal. A A Case Rep. Oct 26 2017.

  15. Singh D, Muller CP, Vicknasingam BK. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend. Jun 1 2014;139:132-137.

  16. Swogger MT, Walsh Z. Kratom use and mental health: A systematic review. Drug Alcohol Depend. Feb 1 2018;183:134-140.

  17. 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. Aug 19 2017:Aug 19. [Epub ahead of print].

  18. 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 Metabol Drug Interact. 2013;28(2):95-105.

  19. Maurer HH. Chemistry, pharmacology, and metabolism of emerging drugs of abuse. Ther Drug Monit. Oct 2010;32(5):544-549.

  20. Lydecker AG, Sharma A, McCurdy CR, et al. Suspected Adulteration of Commercial Kratom Products with 7-Hydroxymitragynine. J Med Toxicol. Dec 2016;12(4):341-349.

  21. 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). Feb 2018;235(2):573-589.

  22. Adkins JE, Boyer EW, McCurdy CR. Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity. Curr Top Med Chem. 2011;11(9):1165-1175.

  23. Warner ML, Kaufman NC, Grundmann O. The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Int J Legal Med. Jan 2016;130(1):127-138.

  24. Rech MA, Donahey E, Cappiello Dziedzic JM, et al. New drugs of abuse. Pharmacotherapy. Feb 2015;35(2):189-197.

  25. Suhaimi FW, Yusoff NH, Hassan R, et al. Neurobiology of Kratom and its main alkaloid mitragynine. Brain Res Bull. Sep 2016;126(Pt 1):29-40.

  26. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. Dec 2012;112(12):792-799.

  27. Yusoff NH, Suhaimi FW, Vadivelu RK, et al. Abuse potential and adverse cognitive effects of mitragynine (kratom). Addict Biol. Jan 2016;21(1):98-110.

  28. Raffa RB, Beckett JR, Brahmbhatt VN, et al. Orally active opioid compounds from a non-poppy source. J Med Chem. Jun 27 2013;56(12):4840-4848.

  29. Hazim AI, Ramanathan S, Parthasarathy S, et al. Anxiolytic-like effects of mitragynine in the open-field and elevated plus-maze tests in rats. J Physiol Sci. May 2014;64(3):161-169.

  30. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Kratom (Mitragyna speciosa) drug profile. January 2015.

  31. Anwar M, Law R, Schier J. Notes from the Field: Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers – United States, 2010-2015. MMWR Morb Mortal Wkly Rep. Jul 29 2016;65(29):748-749.

  32. Arndt T, Claussen U, Gussregen B, et al. Forensic Sci Int. May 20 2011;208(1-3):47-52.

  33. Kronstrand R, Roman M, Thelander G, et al. J Anal Toxicol. May 2011;35(4):242-247.

  34. Lu J, Wei H, Wu J, et al. Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes. PLoS One. 2014;9(12):e115648.

  35. Grundmann O. Patterns of Kratom use and health impact in the US-Results from an online survey. Drug Alcohol Depend. Jul 1 2017;176:63-70.

  36. Galbis-Reig D. A Case Report of Kratom Addiction and Withdrawal. WMJ. Feb 2016;115(1):49-52; quiz 53.

  37. Dorman C, Wong M, Khan A. Cholestatic hepatitis from prolonged kratom use: A case report. Hepatology. Nov 22 2014.

  38. Aggarwal G, Robertson E, McKinlay J, et al. Death from Kratom toxicity and the possible role of intralipid. J Intensive Care Soc. Feb 2018;19(1):61-63.

  39. Neerman MF, Frost RE, Deking J. A drug fatality involving Kratom. J Forensic Sci. Jan 2013;58 Suppl 1:S278-279.

  40. Holler JM, Vorce SP, McDonough-Bender PC, et al. A drug toxicity death involving propylhexedrine and mitragynine. J Anal Toxicol. Jan 2011;35(1):54-59.

  41. Karinen R, Fosen JT, Rogde S, et al. An accidental poisoning with mitragynine. Forensic Sci Int. Oct 24 2014;245c:e29-e32.

  42. Domingo O, Roider G, Stover A, et al. Mitragynine concentrations in two fatalities. Forensic Sci Int. Feb 2017;271:e1-e7.

  43. Hanapi NA, Ismail S, Mansor SM. Inhibitory effect of mitragynine on human cytochrome P450 enzyme activities. Pharmacognosy Res. Oct 2013;5(4):241-246.

  44. Lim EL, Seah TC, Koe XF, et al. In vitro evaluation of cytochrome P450 induction and the inhibition potential of mitragynine, a stimulant alkaloid. Toxicol In Vitro. Mar 2013;27(2):812-824.

  45. Nacca N, Schult RF, Li L, et al. Kratom Adulterated with Phenylethylamine and Associated Intracerebral Hemorrhage: Linking Toxicologists and Public Health Officials to Identify Dangerous Adulterants. J Med Toxicol. 2019 Nov 11.

  46. Hughes RL. Fatal combination of mitragynine and quetiapine – a case report with discussion of a potential herb-drug interaction. Forensic Sci Med Pathol. 2019 Mar;15(1):110-113.

  47. Gershman K, Timm K, Frank M, et al. Deaths in Colorado Attributed to Kratom. N Engl J Med. 2019 Jan 3;380(1):97-98.

  48. Matson M, Schenk N. Fatality of 33-Year-Old Man Involving Kratom Toxicity. J Forensic Sci. 2019 Nov;64(6):1933-1935.

  49. 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 Jul 19;12(7). pii: e229778.

  50. Aldyab M, Ells PF, Bui R, Chapman TD, Lee H. Kratom-Induced Cholestatic Liver Injury Mimicking Anti-Mitochondrial Antibody-Negative Primary Biliary Cholangitis: A Case Report and Review of Literature. Gastroenterology Res. 2019 Aug;12(4):211-215.

  51. 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 Jan-Dec;7:2324709619826167.

  52. Rusli N, Amanah A, Kaur G, et al. The inhibitory effects of mitragynine on P-glycoprotein in vitro. Naunyn Schmiedebergs Arch Pharmacol. 2019 Apr;392(4):481-496.