Kratom

Background

Kratom is a name for preparations made from the Mitragyna speciosa, a tree native to Southeast Asia.1 The leaves of this tree have long been smoked, chewed, or used to make a tea to improve work stamina, and as an opioid substitute.1 Kratom preparations are also used traditionally in social and religious gatherings.1 Recently, kratom preparations have become available in Western countries in shops that sell items of interest to people looking for a “legal high,” and on the internet.1,2 Kratom is promoted as an opioid replacement substitute, an analgesic, and an anxiolytic.1 People also use it for cough, depression, diabetes, diarrhea, hypertension, and sexual performance enhancement.3 The U.S. Centers for Disease Control and Prevention (CDC) notes that calls to Poison Control Centers involving kratom have increased tenfold since 2010.4 This professional resource covers kratom’s mechanism of action, side effects, and potential drug interactions.

How Supplied

Kratom is commonly taken in capsule form in the U.S.5 It is also available in leaf, powder, tablet, extract, gum/resin, and patch forms.1,6 Kratom is bitter, so the powder is often mixed in a beverage (e.g., tea, alcohol) or food (e.g., added to yogurt, baked into cookies).1 Examples of strains advertised online include Bali, red vein kali, and maeng da.

Mechanism of Action

Kratom consists of over 40 alkaloids, flavonoids, terpenoid saponins, polyphenols, and glycosides.1 The main psychoactive and analgesic constituents of kratom, mitragynine and 7-hydroxymitragynine, bind to opioid receptors, but are structurally different from prescription opioids.1 Mitragynine binds to mu receptors, and to delta and kappa receptors to a lesser extent.7 Its affinity for mu receptors is less than that of morphine.7 Mitragynine also has serotonergic, dopaminergic, and adrenergic effects.1

Subjective Effects

Kratom’s effects are dose-dependent, with stimulant effects at lower doses and sedative/opioid effects at higher doses.1,5,8 Users describe effects similar to those produced by an opioid or marijuana, plus psychostimulant effects.1 Some users may perceive the stimulant effect as unpleasant (e.g., anxiety, agitation).2 Users may also note a warm sensation, calmness, a dreamlike state, and analgesia.1

In addition to dose, the strain of kratom influences the predominant effects users experience. This is due to differences in phytochemical composition among strains. For example, the red vein strain from Bali is noted for its analgesic effect, while the white vein strain from Malaysia tends to be stimulating. Both the green and white vein strains are known for their mood-enhancing effects.8

Regulation

Kratom is on the U.S. Drug Enforcement Administration’s (DEA) list of drugs and chemicals of concern.4 Possession is prohibited in some states, but it is not a controlled substance on a federal level.1 The FDA has issued an import alert, and over 55,000 kilograms were seized at U.S. borders between February 2014 and July 2016.6 The DEA wants to classify kratom as a Schedule I controlled substance, but some members of Congress have called for more time for public comment before scheduling occurs.4,6 There is concern that such scheduling will hamper research efforts into potential therapeutic uses for kratom, such as opioid replacement therapy.4 Others fear that banning kratom will harm patients who use it to stay off of controlled substances, or who prefer it to prescription medications.4,9 (At this time, kratom has not been authorized for sale as a Natural Health Product [NHP] in Canada.)15

Side Effects

Many kratom side effects appear dose-dependent.8 However, because kratom products are not standardized,6 what constitutes a “high” or “low” dose of a particular product is hard to say. Characterization of kratom’s toxicities is also complicated by the concomitant use of other substances, and product contamination.

Opioid-like side effects (e.g., nausea, constipation, sedation, dizziness, hypotension, sweating) are particularly prominent at doses over 5 g of raw leaves.8 Tachycardia is also seen at these doses.8 Long-term users in Southeast Asia have experienced anorexia, weight loss, tremor, hyperpigmentation of the cheeks, psychosis, and constipation.1,2,10 Tolerance, and cross-tolerance to opioids, has been reported by kratom users.1 Its addiction potential relative to prescription opioids is unclear.2

Kratom has been associated with hypothyroidism, adult respiratory distress syndrome, and seizures in case reports.2,11 Two cases of intrahepatic cholestasis following short-term use of kratom powder have been described.3,12 However, whether these toxicities were due to kratom, a contaminant, an underlying medical condition, or an interaction is unclear. Kratom constituents may have the potential to cause torsades de pointes.1

Epidemiologic data suggest that people with psychiatric disorders or alcohol use disorder who use kratom have a higher risk of suicide than people who use kratom but do not have these disorders.3

Cessation of kratom following habitual ingestion has been associated with a mild withdrawal syndrome with symptoms similar to those seen with opioid withdrawal: irritability, anxiety, insomnia, muscle pain and spasms, nausea, vomiting, diarrhea, runny nose, and shakiness.1,3,8

Based on animal research, kratom can cause respiratory depression.3 Kratom does not show up on drug screens.1 If kratom exposure results in respiratory depression, consider naloxone in addition to airway management.13 Not all effects of kratom would be expected to be reversed by naloxone.1

Interactions

In vitro data suggest that kratom extract might inhibit CYP1A2, CYP2C19, CYP2D6, and CYP3A4.3

Kratom is often used with other psychoactive substances such as marijuana, alcohol, benzodiazepines, opioids, cocaine, amphetamines, hallucinogens, and kava.1 Ingesting kratom with other central nervous system depressants could theoretically increase the risk of respiratory depression.3 Fatalities have been reported in patients who ingested kratom laced with O-desmethyltramadol, the active metabolite of tramadol.1,3 This product is sometimes called krypton.1 Fatalities have also involved the use of kratom with venlafaxine, diphenhydramine, and mirtazapine; zopiclone, citalopram, and lamotrigine; paroxetine and lamotrigine; acetaminophen, promethazine, morphine, and propylhexedrine (a decongestant); and temazepam, diphenhydramine, and dextromethorphan.1,8,14 One recent review found no reports of fatalities where kratom alone was the sole ingestant.8

A case of generalized tonic-clonic seizure was reported in a man who used kratom plus modafinil as a self-treatment for opioid withdrawal. In another case, seizure and coma was described in a habitual kratom user following ingestion of a tea containing kratom and jimson weed, an anticholinergic. Seizure and coma have been reported with jimson weed.3

Among calls to U.S. poison control centers from 2010 to 2015 involving kratom exposure, kratom was used with other substances in 35.2% of cases. The most common co-ingestants were alcohol, botanicals, benzodiazepines, opioids, and acetaminophen.14 Most exposed persons were male, with a median age of 28 years.14 Signs and symptoms reported included tachycardia, agitation, irritability, drowsiness, nausea, and hypertension.14

Conclusion

Kratom use appears to be increasing. Characterization of its effects, and emergency management, are complicated by the frequent concomitant use of other substances and unknown product potency and purity. Help patients self-medicating with kratom find appropriate alternatives, such as treatment for opioid dependence, if applicable.

Project Leader in preparation of this professional resource: Melanie Cupp, Pharm.D., BCPS

References

  1. Cinosi E, Martinotti G, Simonato P, 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 Res Int 2015;2015:968786.
  2. 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;112:792-9.
  3. Jellin JM, Gregory PJ, et al. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. (Accessed October 3, 2016).
  4. Ault A. Congress members call for halt on DEA kratom ban. http://www.medscape.com/viewarticle/869402. (Accessed October 3, 2016).
  5. U.S. Department of Justice. Drug Enforcement Administration. Drugs of Abuse. A DEA resource guide. 2015 edition. https://www.dea.gov/pr/multimedia-library/publications/drug_of_abuse.pdf#page=84. (Accessed October 4, 2016).
  6. U.S. Drug Enforcement Administration. DEA announces intent to schedule kratom. SE Asian drug is imminent hazard to public safety. August 30, 2016. https://www.dea.gov/divisions/hq/2016/hq083016.shtml. (Accessed October 4, 2016).
  7. Scott GN. Kratom: therapy or threat? October 22, 2015. http://www.medscape.com/viewarticle/852866. October 4, 2016.
  8. 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;127-38.
  9. DiSalvo D. What the DEA’s plan to schedule 1 kratom will mean for millions. September 13, 2016. http://www.forbes.com/sites/daviddisalvo/2016/09/13/what-the-deas-plan-to-schedule-1-kratom-will-mean-for-millions/#44892ca872a9. (Accessed October 6, 2016).
  10. Ujvary I. Psychoactive natural products: overview of recent developments. Ann Ist Super Sanita 2014;50:12-27.
  11. Nelsen JL, Lapoint J, Hodgman MJ, Aldous KM. Seizure and coma following kratom (Mitragynina speciosa Korth) exposure. J Med Toxicol 2010;6:424-6.
  12. Dorman C, Wong M, Khan A. Cholestatic hepatitis from prolonged kratom use: a case report. Hepatology 2015;61:1086-7.
  13. Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol 2012;8:15-32.
  14. Anwar M, Law R, Schier J. Notes from the field: Kratom (Mitragyna speciosa) exposures reported to poison centers-United States, 2010-2015. MMWR Morbid Mortal Wkly Rep 2016;65:748-9.
  15. Personal communication (written). E. Morrissette. Media Relations Health Canada. October 14, 2016.

Cite this document as follows: Professional Resource, Kratom. Pharmacist’s Letter/Prescriber’s Letter. November 2016.

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