Dermatologists should not be in the dark about kratom

By Warren R. Heymann, MD, FAAD
Oct. 11, 2023
Vol. 5, No. 41

Dermatological sleuthing mandates an ever-expanding knowledge database. The correct diagnosis may prove elusive if you do not know the right questions to ask. Astute clinicians have a differential diagnosis of cutaneous and/or mucosal hyperpigmentation, including heavy metal exposure (gold, iron, silver), drugs (antibiotics, antimalarials, antineoplastic, anti-arrhythmic, psychotropic), and systemic diseases (Addison disease, Wilson disease, hemochromatosis). (1)

The landscape of substance abuse is ever-changing, and dermatologists must be mindful of these trends. DWI&I recently reviewed the devastating effects of xylazine (“tranq”). (2) This commentary focuses on kratom as a cause of photodistributed hyperpigmentation.

Kratom (pronounced krah-tm), a tree (Mitragyna speciose) native to Thailand, Malaysia, and Indonesia, has been used in Southeast Asia for hundreds of years as a cough suppressant, painkiller, antidiarrheal, and treatment for opium dependency. (3) The first documented use of kratom in the United States was around 2000; by 2020, an estimated 2.1 million U.S. residents used kratom. Kratom, and its two main pharmacologically active alkaloids, mitragynine and 7-hydroxymitragynine, are not controlled substances under UN international drug control treaties or the U.S. Controlled Substances Act. The DEA does not recognize kratom as a controlled substance. Kratom is unrestricted in the United States but listed as a “drug of concern” by the DEA. Kratom is illegal in six U.S. states (Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin) and several U.S. cities. (4,5,6)

The following is the FDA statement on kratom: (7)

The U.S. Food and Drug Administration is warning consumers not to use Mitragyna speciosa, commonly known as kratom, a plant which grows naturally in Thailand, Malaysia, Indonesia, and Papua New Guinea. FDA is concerned that kratom, which affects the same opioid brain receptors as morphine, appears to have properties that expose users to the risks of addiction, abuse, and dependence.

There are no FDA-approved uses for kratom, and the agency has received concerning reports about the safety of kratom. FDA is actively evaluating all available scientific information on this issue and continues to warn consumers not to use any products labeled as containing the botanical substance kratom or its psychoactive compounds, mitragynine and 7-hydroxymitragynine. FDA encourages more research to better understand kratom’s safety profile, including the use of kratom combined with other drugs.

The psychoactive properties of kratom are predominantly attributed to mitragynine and 7-hydroxymitragynine. Both compounds act through g-protein-coupled signaling with partial agonist effects on μ-opioid receptors and antagonist effects on the κ- and δ-opioid receptors. Mitragynine stimulates α2-adrenergic receptors presumably accentuating its sedative, hypnotic, and analgesic effects. Although mitragynine has additional effects on adenosine 2, dopamine, and 5-HT7 receptors, those effects remain to be fully characterized. (6)

According to Jentch and Pippin, “Multiple organ systems are at risk for potential injury due to kratom ingestion. Multiple case studies have found a range of toxicities and adverse events associated with kratom use, including hepatotoxicity, seizure and coma, lung injury, kidney injury, and cardiotoxicity. Pregnant patients who use kratom have an additional risk of their newborns developing neonatal abstinence syndrome.” Chronic kratom use may cause long-term cognitive impairment. In some cases, kratom toxicity may be fatal. (5)

Kratom came to my attention after reading the case presentation of a 54-year-old man by Powell et al, describing the slowly progressive, asymptomatic, hyperpigmented patches that developed in a photosensitive distribution on his face and arms over 18 months. He had been ingesting kratom for approximately five years to wean himself off prescription opioids for his degenerative osteoarthritis. A skin biopsy revealed clustered, refractile, nonpolarizable, intrahistiocytic, perivascular, and interstitial red-brown pigment ranging in size from 1-12 μm. The Fontana-Masson stain was positive for melanin; the Perl stain was negative for hemosiderin, and the colloidal iron stain demonstrated a normal amount of dermal mucin. Mass spectroscopy was not performed. The authors hypothesized “that this process or simple melanin-drug complex deposition may be responsible for hyperpigmentation and skin darkening in kratom users.” They concluded, “kratom-associated hyperpigmentation should be considered in the differential diagnosis when evaluating patients for other drug-associated pigmentary disorders, especially those found in a photodistributed pattern.” (8) Johnson et al reported a case of photodistributed hyperpigmentation in a 56-year-old woman who had been using kratom four-to-five times per day for seven years for chronic back pain. Her biopsy showed red-brown pigment within dermal histiocytes; both Fontana-Masson and Prussian blue stains were negative for melanin and iron, respectively. (9)

Unfortunately, regular drug screens do not detect kratom. Patient disclosure is the foundation of screening for kratom misuse. (5) Until more research determines if kratom should be a controlled substance, the likelihood is that it will remain a “drug of concern.” I concur with Sloan, who, in his editorial about the article by Powell et al, opined, “It is estimated that millions of people engage in kratom use each year and the level of use is rising, and should be considered in the differential diagnosis of a patient presenting with photodistributed hyperpigmentation.” (10) Recognizing this adverse reaction of kratom could help direct patients toward the multidisciplinary care (social, psychiatric, medical) necessary for their well-being.

Point to Remember: Kratom use has been dramatically increasing in the United States. Dermatologists may be the first to recognize it because of a photodistributed hyperpigmentation. Diagnostic confirmation is by history, not laboratory analysis. Rendering the diagnosis allows dermatologists to refer patients for appropriate social, psychiatric, and medical care.

Our expert’s viewpoint

David A. Gorelick, MD, PhD, DLFAPA, FASAM
Professor of Psychiatry
University of Maryland School of Medicine

Kratom is the common term for the tropical tree Mitragyna speciosa and products derived from it. (4) This plant grows in Southeast Asia and has been used by the indigenous population for centuries for its stimulant properties and as a treatment for a variety of psychological and physical conditions. Its two major pharmacologically active constituents are the alkaloids mitragynine and 7-hydroxymytragine, which act as agonists at opioid receptors.

Kratom use has grown increasingly popular in the U.S. over the past two decades. An estimated 1.7 million U.S. residents used kratom in 2021, representing 0.6% of the population 12 years and older. (11) Part of this popularity is due to kratom’s legal status compared to other psychoactive substances. Kratom is not a controlled substance at the federal government level, although it is considered a “drug of concern” by the Drug Enforcement Administration. Kratom is illegal in six states and several cities. Several other states ban its sale to minors. Kratom use is more common among men and young adults 18-25 years old. Kratom is taken orally in the form of dried, powdered leaves (loose or in capsules) or as a liquid (tea or decoction). (4)

There are very few controlled studies of kratom’s effects. Almost all information comes from large, anonymous online surveys of self-reported kratom users. The majority of users in the U.S. report using kratom as self-medication for pain, opioid use disorder, opioid withdrawal, depression, anxiety, or post-traumatic stress disorder (PTSD). (4,12)

Two types of skin abnormalities are associated with long-term kratom use. Darkened skin, especially on the cheeks, is reported as common among long-term kratom users in Southeast Asia and is self-reported by small numbers of U.S. kratom users on YouTube. (13,14) Itching or rash is mentioned in 3-6% of U.S. social media posts (Reddit, Twitter) mentioning kratom. (15,16,17) Neither itching, rash, nor darkened skin are mentioned in large, online surveys of U.S. kratom users or kratom-related calls to U.S. poison control centers. (12,18)

The true prevalence of skin abnormalities among kratom users remains unknown. The association of kratom use with hyperpigmentation has been confirmed by published observations; the association with itching and rash has not been so confirmed. A study of 35 Thai adults with daily kratom use for at least one year found that some (number not reported) had darkened skin, especially on the face. (13) Two recently published case reports from the U.S. documented photodistributed hyperpigmentation in adults using kratom at high doses for several years. (9,8) Other causes of hyperpigmentation were ruled out. Skin biopsies of affected areas showed histiocytes with red-brown pigment within the superficial dermis but no other abnormalities. In particular, there was no evidence of inflammation and melanocytes were normal. (Stimulation of melanocytes by mitragynine has been suggested as the mechanism for darkened skin, although there is no published evidence for this hypothesis.) (19) Topical treatments provided no benefit.

Dermatologists evaluating a patient with itching, rash, or hyperpigmentation should keep in mind the possibility of a kratom-associated condition. Kratom use must be identified by self-report, as kratom alkaloids do not appear on standard drug toxicology tests. (4) The prevalence and pathophysiology of kratom-associated skin conditions remain unknown, so the diagnosis should be one of exclusion, made only after other potential causes are ruled out. There are no known treatments, and we are not aware of any evidence that cessation of kratom use leads to resolution of the skin condition. Regardless, it seems prudent to advise the patient to stop kratom use. This may be difficult for patients with a kratom use disorder. An estimated 10-20% of daily kratom users have a kratom use disorder. (4) Kratom use disorder should be suspected if the patient is using kratom frequently or in high doses despite experiencing significant adverse consequences. Such patients should be referred to an addiction specialist for further evaluation and possible treatment.

1. Eichenfield DZ, Cohen PR. Amitriptyline-induced cutaneous hyperpigmentation: case report and review of psychotropic drug-associated mucocutaneous hyperpigmentation. Dermatol Online J. 2016 Feb 17;22(2):13030/qt3455571b. PMID: 27267189.

2. www.aad.org/dw/dw-insights-and-inquiries/archive/2022/xylazine-potential-for-loss-of-life-and-limb

3. Phoong SW, Phoong SY, Yeoh YJ. Kratom: A Bibliometric Analysis of Scientific Publications. J Psychoactive Drugs. 2022 Dec 22:1-9. doi: 10.1080/02791072.2022.2159591. Epub ahead of print. PMID: 36560854.

4. Gorelick DA. Kratom: Substance of Abuse or Therapeutic Plant? Psychiatr Clin North Am. 2022 Sep;45(3):415-430. doi: 10.1016/j.psc.2022.04.002. Epub 2022 Jul 31. PMID: 36055730.

5. Jentsch MJ, Pippin MM. Kratom. 2022 Aug 31. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 36256767.

6. Sethi R, Hoang N, Ravishankar DA, McCracken M, Manzardo AM. Kratom (Mitragyna speciosa): Friend or Foe? Prim Care Companion CNS Disord. 2020 Jan 30;22(1):19nr02507. doi: 10.4088/PCC.19nr02507. PMID: 31999896.

7. www.fda.gov/news-events/public-health-focus/fda-and-kratom. Accessed February 2, 2023.

8. Powell LR, Ryser TJ, Morey GE, Cole R. Kratom as a novel cause of photodistributed hyperpigmentation. JAAD Case Rep. 2022 Aug 9;28:145-148. doi: 10.1016/j.jdcr.2022.07.033. PMID: 36187435; PMCID: PMC9523091.

9. Johnson KM, Lause M, Chung C, Massick S. Kratom ingestion associated with photodistributed hyperpigmentation. Int J Dermatol. 2023 Mar 21. doi: 10.1111/ijd.16650. Epub ahead of print. PMID: 36942835.

10. Sloan B. This Month in JAAD Case Reports: January 2023: Kratom hyperpigmentation. J Am Acad Dermatol. 2023 Jan;88(1):25. doi: 10.1016/j.jaad.2022.10.048. Epub 2022 Oct 29. PMID: 36404453.

11. Center for Behavioral Health Statistics and Quality. (2022). Results from the 2021 National Survey on Drug Use and Health: Detailed tables. Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/report/2021-nsduh-detailed-tables (accessed 27 Feb. 2023).

12. Grundmann O. Patterns of kratom use and health impact in the US—Results from an online survey. Drug Alcohol Depend 2017;176:63-70.

13. Suwanlert MDS. A study of kratom eaters in Thailand. Bull Narcotics. 1975;27(3):21-27.

14. Prevete E, Hupli A, Marrinan S, et al. Exploring the use of Kratom (Mitragyna speciosa ) via the YouTube data tool: A novel netnographic analysis. Emerging Trends Drugs, Addictions, Health. 2021;1:100007.

15. Smith KE, Rogers JM, Schriefer D, et al. Therapeutic benefit with caveats?: Analyzing social media data to understand the complexities of kratom use. Drug Alcohol Depend 2021;226:108879.

16. M. T. Swogger, Hart E, Erowid F, et al., Experiences of kratom users: a qualitative analysis. J Psychoactive Drugs. 2015;47:360-367.

17. Wahbeh A, Nasralah T, El-Gayar O, et a. Adverse Health Effects of Kratom: An Analysis of Social Media Data. Proceedings of the 54th Hawaii International Conference on System Sciences, 2021. file:///E:/kratom%20(Dermatology%20World)/KratomEffectsSocialMedia(WahbehA%2054th%20Hawaii%20Int%20Conf%20SystemSci2021).pdf (accessed 18 May 2023).

18. Post S, Spiller HA, Chounthirath T, Smith GA. Kratom exposures reported to United States poison control centers: 2011-2017. Clin Toxicol. 2019;57(10):847-854.

19. 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. https://doi.org/10.1155/2015/968786.

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