Kratom is a substance that has been gaining popularity in the U.S. over the last decade as an herbal supplement and a drug of abuse, as well as an alternative option for treatment of opioid-use disorders. It is touted by users to provide relief from pain, stress, and anxiety. Others seek its euphoric effects, as it possesses both stimulant and opioid-like activity. [1] Currently, Kratom is not scheduled by the DEA, and is easily purchased at gas stations and herbal shops throughout the U.S. However, Kratom sales are banned in six states, including Alabama, Arkansas, Indiana, Wisconsin, Vermont, and Rhode Island. [2] In Florida, individual counties, including Sarasota County, have imposed a ban on Kratom sales as well. Kratom is sold as an herbal supplement and is supplied in a variety of formulations including bulk powder, capsules, tinctures, and electronic cigarette liquid. Lack of regulation means these products may vary widely in content and potency, raising safety concerns for consumers.

Kratom (Mitragyna speciosa) is a tree in the coffee (Rubicaea) family that is native to Southeast Asia where it has a history of traditional use as an analgesic as well as a stimulant used by laborers and farmers. [3] The leaves are often chewed while working or made into a tea and consumed. Kratom contains dozens of unique indole alkaloids, including the primary active constituent, mitragynine. Mitragynine, which makes up about two-thirds of the alkaloid content of the plant leaves, is a partial agonist at the µ-opioid receptor and is responsible for Kratom’s opioid-like effects. [3] It has activity at post-synaptic α-2 receptors, which may contribute to Kratom’s antinociceptive effects. In addition, mitragynine has affinity for 5-HT2C and 5-HT7 serotonin receptors which may play a role in its stimulant-like effects. Despite agonist activity at the µ-opioid receptor, some evidence suggests that mitragynine and its metabolite, 7-hydroxymitragynine, induce limited recruitment of β-arrestin, which is believed to be responsible for many of the undesirable effects associated with opioid use, such as respiratory depression. [3,4] It was theorized that this may be why respiratory depression is not seen to the same extent in Kratom as with classic opioids. However, a recent study by Kliewer et al. that may disprove this theory has demonstrated that morphine is capable of inducing respiratory depression in mice independent of β-arrestin. [5]

Despite some promising characteristics, Kratom use is associated with a number of adverse effects. One retrospective review of cases reported to the National Poison Data System showed that the most common symptoms reported were agitation, tachycardia, drowsiness, and confusion. [6] Neurologic symptoms included seizures, hallucinations, and (rarely) coma. Kratom use has been linked to end-organ system dysfunction, with hepatic injury being the most common. Other case reports have attributed various renal, cardiac, and pulmonary complications to Kratom use. The National Institute of Health lists Kratom as an agent of concern on their LiverTox® database with regards to its potential for hepatic dysfunction. [7] Chronic use and discontinuation is associated with a withdrawal syndrome similar to that of opioid withdrawal. [3] Symptoms include nausea, vomiting, diarrhea, chills and sialorrhea with physical exam findings demonstrating restlessness, hypothermia, tremors, and diaphoresis. Tolerance to Kratom along with withdrawal on discontinuation may explain the development of habitual use.

Treatment of Kratom intoxication is largely supportive, including early airway support if needed. While opioid antagonists such as naloxone are effective in opioid overdoses, there are no controlled studies evaluating efficacy in Kratom cases. Limited anecdotal evidence from case reports suggests that the use of opioid antagonists may be beneficial. [8] Seizure activity should be managed with intravenous benzodiazepines. [9] Acute hepatitis may be managed similar to other cases of drug-induced hepatitis with N-acetylcysteine. [3] Management may be tailored to treat other symptoms as appropriate. Overall, the prognosis for Kratom overdose remains favorable and the majority of cases appear to resolve with simple supportive care. There are deaths linked to Kratom use, but many of the fatalities are clouded by the presence of other substances of abuse, making it difficult to attribute them solely to Kratom.

With its growing popularity and ease of availability, Kratom may become a more significant public health issue in the coming years. Due to the current opioid epidemic, the number of individuals seeking alternatives to conventional opioid therapy or treatment of their withdrawal may increase. The absence of regulation and increased popularity could lead to growth in the Kratom industry which causes additional concerns due to lack of quality control and potential for adulteration. Future studies may continue to elucidate the health effects of Kratom both with chronic use and in overdose. In the meantime, healthcare professionals should continue to familiarize themselves with the available literature to optimize patient care. ■

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. Veltri C, Grundmann O. Current perspectives on the impact of Kratom use. Subst Abuse Rehabil. 2019;10:23-31.
3. Eastlack SC, Cornett EM, Kaye AD. Kratom-Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review. Pain Ther. 2020
4. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ and Caron MG (2000) mu-Opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408(6813): 720-723
5. Kliewer A, Gillis A, Hill R, et al. Morphine-induced respiratory depression is independent of β-arrestin2 signalling. Br J Pharmacol. 2020
6. Eggleston W, Stoppacher R, Suen K, Marraffa JM, Nelson LS. Kratom Use and Toxicities in the United States. Pharmacotherapy. 2019;39(7):775-777.
7. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Kratom. [Updated 2018 Apr 10]. Available from: www.ncbi.nlm.nih.gov/books/NBK548231/
8. Overbeek DL, Abraham J, Munzer BW. Kratom (Mitragynine) Ingestion Requiring Naloxone Reversal. Clin Pract Cases Emerg Med. 2019;3(1):24-26.
9. Nelsen JL, Lapoint J, Hodgman MJ, Aldous KM. Seizure and coma following Kratom (Mitragynina speciosa Korth) exposure. J Med Toxicol. 2010;6(4):424-6.