Kratom: What we know, what to tell your patients Educate patients about the risks of this increasingly popular but unregulated substance itragyna speciosa, better known as kratom, is a tropi- cal evergreen tree that is native to Southeast Asia. MBotanically, it is a member of the Rubiaceae family, as is the coffee plant, and physical laborers among indigenous pop- ulations have historically chewed the leaves or brewed them as a tea to improve endurance and reduce fatigue.1 Kratom is psy- choactive; small amounts (up to 5 g of plant material) possess stimulant properties, while larger doses (>5 g) produce opioid- like, sedative, euphoric, and antinociceptive effects.2 In recent years, kratom has gained popularity in Western parts of the world due to its unique properties and perceived safety as a botanical product. Individuals may use kratom to boost their energy, relieve pain, or treat a wide range of physi- M. SOMCHAI/SHUTTERSTOCK cal or mood problems. Increasingly, kratom is being used by people who abuse opioids to self-manage opioid withdrawal, Cornel N. Stanciu, MD, MRO, FASAM, FAPA or for its euphoric effects. But kratom carries several impor- Assistant Professor tant risks, including addiction, serious adverse effects, and Dartmouth’s Geisel School of Medicine Hanover, New Hampshire possibly death. In this article, we review the epidemiology Director of Addiction Services and pharmacology of kratom, and provide some guidance for New Hampshire Hospital educating patients about this substance. Concord, New Hampshire Bryan G. Hybki, MD PGY-4 Psychiatry Resident Dartmouth-Hitchcock Medical Center Widely used but not FDA approved Lebanon, New Hampshire Although kratom is not regulated or approved by the FDA, 3 Thomas M. Penders, MS, MD 3 to 5 million Americans use it regularly. According to an Affiliate Professor East Carolina University Brody School of Medicine Acknowledgment Attending Psychiatrist The authors would like to acknowledge the contribution of Karen Goodman, MSLIS, MA, Medical Librarian at the Dorothy M. Breene Memorial Library, New Hampshire Hospital, who assisted with Walter B. Jones Alcohol and Drug Abuse Treatment Center the literature search and procuration of the studies needed for this article. Greenville, North Carolina Disclosures The authors report no financial relationships with any companies whose products are mentioned Current Psychiatry in this article, or with manufacturers of competing products. Vol. 19, No. 3 37 Box alkaloids of significant interest are mitrag- The legal status of kratom ynine (Figure 1, page 39) and 7-hydroxymi- tragynine (Figure 2, page 39), both of which he use and sale of kratom is illegal in are unique to M. speciosa and have opioid- several countries, including Australia, T like properties. Administering these alka- Poland, Denmark, Sweden, Malaysia, and Vietnam. In the United States, kratom was loids to morphine-dependent rats resulted legal to grow and purchase in all 50 states in cross-tolerance and precipitated with- Teaching patients until 2015, when the Drug Enforcement drawal when the rats were given nalox- Administration (DEA) identified kratom as 7 about kratom a “substance of concern.” In August one. The potency of kratom at the mu 2016, the DEA submitted a notice opioid receptor has been found to exceed of intent to place mitragynine and that of morphine. 7-hydroxymitragynine, 2 alkaloids of kratom that have opioid-like properties, into Competitive binding studies that exam- Schedule I of the Controlled Substance Act; ined the affinity of mitragynine and however, due to significant public pressure, 7-hydroxymitragynine at the various opi- the DEA withdrew the request in October oid receptor subtypes found a preference 2016. As of February 2020, kratom was illegal to for the kappa receptors (antagonism), Clinical Point buy, sell, or use in Wisconsin, Rhode Island, followed by mu (partial agonism), and Vermont, Indiana, Arkansas, Alabama, specific lastly delta. This profile of mitragynine Chronic kratom use counties of some states, and the District of 8 Columbia. Legislation was pending in New is very similar to that of buprenorphine. can result in weight York, Missouri, and Louisiana. The affinity of 7-hydroxymitragynine loss, insomnia, Source: Reference 5 for the mu receptor (agonism) is signifi- constipation, cantly greater than that of mitragynine.9 dehydration, skin Mitragynine also interacts with norad- renergic and serotonergic pathways by hyperpigmentation, stimulating postsynaptic alpha-2 adrener- and extreme fatigue internet survey, kratom users are mostly gic receptors and inhibiting 5-HT2A recep- college-educated, employed white men, age tors.9 These properties are responsible for 31 to 50, who take the substance to manage kratom’s ability to manage opioid with- pain or to treat general anxiety and mood drawal symptoms, which are generally disorders.4 Some individuals use kratom as attributed to a hyperactive noradrenergic an opioid substitute to reduce symptoms of system. There also is evidence that the opioid withdrawal.4 hepatic metabolite 7-hydroxymitragynine Kratom is available from a wide range is important in mediating the analgesic of manufacturers in various formulations, component of mitragynine.10 including powders, tablets, liquids, and The initial effects of kratom typically gum. It is sometimes sold in combination begin within 10 to 20 minutes of consump- with other agents as a single product. Low- tion, and the full effects are experienced in 30 cost, over-the-counter kratom products to 60 minutes.1 The half-life of mitragynine are available as “dietary supplements” in in humans has not yet been determined, but retail stores or online. Although the prod- is believed to be relatively short.11 In rats, uct packaging sometimes recommends a the half-life of mitragynine is 2 to 3 hours.12 specific dose, the amount of active ingredi- Individuals who use kratom to prevent opi- ents (as well as other agents) is unknown. oid withdrawal have reported taking it as Kratom is illegal in several states (Box5). often as every 6 to 12 hours.13 Metabolism of mitragynine is predomi- Discuss this article at nantly carried out through cytochrome www.facebook.com/ The 2 alkaloids of interest P450 (CYP) 3A4, with minor contributions MDedgePsychiatry More than 40 alkaloids have been isolated by 2D6 and 2C9. A total of 13 metabolites from kratom leaves. The proportions of are produced, including 7-hydroxymi- these alkaloids vary significantly depend- tragynine.14 Kratom’s constituents also ing on the environment in which the plant interact with the CYP system, inhibiting is grown, the breeding and harvesting 2C9, 2D6, and 3A4 isoenzymes, and to Current Psychiatry 38 March 2020 techniques, and the age of the plant.6 Two some extent, 1A2. Figure 1 Chemical structure of mitragynine MDedge.com/psychiatry H2C O N CH2 H O CH2 N H O Clinical Point As of February 2018, H2C O the FDA had received reports of 44 deaths Figure 2 associated with Chemical structure of 7-hydroxymitragynine kratom H3C O HO N CH3 O CH3 N H O H3C O Adverse effects can be fatal and creatinine levels from baseline were An animal study revealed that when observed. administered intravenously, mitragy- Chronic kratom use can result in weight nine and 7-hydroxymitragynine have a loss, insomnia, constipation, dehydration, similar toxicity profile to heroin.15 When skin hyperpigmentation, and extreme these alkaloids were administered in fatigue.16 There have also been reports of ascending doses, increases in blood pres- seizures, delusions, hallucinations, respira- Current Psychiatry sure and elevations in liver function tests tory depression, hepatotoxicity, coma, and Vol. 19, No. 3 39 death.17,18 An emerging concern is the poten- primarily in urine.12 Based on data from tial development of fatty liver infiltrates treatment center admissions, kratom can leading to cholestatic liver damage.19-25 One be detected in urine samples for 5 to 6 case report described a young man who days after use.24,38,39 However, kratom is developed a serum aspartate aminotrans- not detectable by a standard urine toxi- ferase level of 1,300 IU/L (reference range: cology screen; therefore, a high degree of 5 to 45 IU/L) and a serum alanine amino- suspicion and special confirmatory testing Teaching patients transaminase level of 3,700 IU/L (reference are necessary. The breakdown products of about kratom range: 5 to 60 IU/L) after he ingested a mitragynine can be detected through gas kratom product.26 Histologically, the pat- chromatography coupled with mass spec- tern of liver injury mimics primary biliary trometry (GC/MS), liquid chromatography cholangitis.27 with linear ion trap mass spectrometry, or In recent years, calls to poison control electrospray tandem mass spectrometry.40-42 centers in the United States related to kra- tom exposure have risen. Between 2011 and 2017, the number of calls increased from 1 A familiar withdrawal syndrome Clinical Point a month to 2 each day.28 The US National Abrupt discontinuation of high-dose, Abrupt discontinuation Poison Data System has also noted an long-term kratom use can produce with- increase in the number of calls in refer- drawal symptoms.13 Symptoms of kra- of high-dose, long- ence to kratom. It received 2,312 calls from tom withdrawal resemble those of opioid term kratom use can January 2011 through July 2018, with 18 withdrawal. These include physiological produce withdrawal calls occurring in 2011, and 357 within the symptoms (mydriasis, nausea, sweating symptoms