Clinical Assistant Professor, Department of Family Medicine, University of Wisconsin; Clinical Assistant Professor of Medicine, Arizona Center for Integrative Medicine, University of Arizona, Tucson

Dr. Kiefer reports no financial relationships relevant to this field of study.

SYNOPSIS: Kratom, a plant that is banned in some countries, is available in the United States and has some safety concerns, mostly related to its opioid-like effects.

SOURCE: FDA Statement. Statement from FDA Commissioner Scott Gottlieb, M.D. on FDA advisory about deadly risks associated with kratom. Nov. 17, 2017. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584970.htm. Accessed Jan. 7, 2018.

This Abstract & Commentary is drawn from a U.S. Food and Drug Administration (FDA) press release, differing from the focus on randomized, controlled trials, as is more typical for Integrative Medicine Alert reviews. The primary reason for this is to highlight an important safety concern, and weave in some of the recent background research relevant to this natural product.

Kratom (Mitragyna speciosa, Family Rubiaceae) is a tree found in Southeast Asia and Africa, and its leaves are used medicinally, usually as a tea, for a variety of health conditions.¹ In the United States, it is marketed as a safe natural substance for the treatment of pain, anxiety, and depression. As per the FDA press release, there is the concern about the self-treatment of these serious conditions, but also the fact that kratom appears to have opioid-like effects and the expected issues of addiction, withdrawal, and death; 36 deaths have been reported. Outside of the supervision of a licensed healthcare provider, kratom also is being used to treat opioid withdrawal, another FDA concern. There has been a marked increase in calls made to U.S. poison control centers about the use of kratom-containing products.

At the end of the press release, the FDA director reminded the scientific community and the public at large about the process that exists for drug applications and the evaluation of dietary supplements, a path that he recommended for kratom or any other substance touted to be part of the solution to the opioid epidemic. The FDA considers kratom to be an unapproved drug and has “taken action against kratom-containing dietary supplements.” Officials are seizing the shipments and destroying the product, as the FDA continues the process of investigating the safety and efficacy of this botanical medicine.

COMMENTARY

Not all plants or natural products are safe. Kratom is one plant that may fall into this category, but the story is more complicated. Kratom contains more than 40 phytochemicals in the class of indole alkaloids, the primary one being mitragynine, although 7-hydroxymitragynine also is mentioned commonly in the literature.^1,2,3 The content of the alkaloids varies depending on geographic location, plant age, and numerous other factors, affecting the physiological effect of the plant. Storage also may play a role; mitragynine may be converted to 7-hydroxymitragynine upon exposure to air.³

An additional layer of complexity stems from the effect of kratom on opioid receptors. At the mu-opioid receptor, kratom extracts show both agonist (mitragynine) and antagonist (other alkaloids) activity.^1,2 Kratom extracts appear to be weak competitive antagonists at kappa-opioid receptors and weak antagonists at delta-opioid receptors, although extrapolating from some of this animal research to human effects is difficult and still needed.^1,3 Mitragynine also may bind to other central nervous system receptors, including alpha-2-adrenergic, adenosine, serotonin, and dopamine.¹ Much of the differential receptor binding is thought to be dose dependent, with opioid effects occurring at higher dose ranges. It is thought that the opioid effects of mitragynine are 13 times more potent than morphine, and those of 7-hydroxymitragynine are even more potent.⁴

Most people use kratom in a dose less than 8 grams per dose, delivering 120 to 180 milligrams of mitragynine.¹ It is thought that a stimulant effect may occur in doses of 1 to 5 grams, with more opioid-like effects occurring at or above 8 grams.^1,2,3 These latter effects are where kratom has been used for opioid withdrawal symptoms.

Adverse effects have been documented. Fatalities have occurred with the use of a product called Krypton, a blend of mitragynine and O-desmethyltramadol, although it is unknown which of the compounds ultimately caused the deaths.² Other adverse effects include hypertension, cognitive changes, dependency, and several cardiovascular and gastrointestinal system effects.⁴ Kratom overdose has been described and may be associated with seizures. A withdrawal phenomenon, not unlike opioid withdrawal, also is being seen.⁴

As some experts have mentioned, there is potential for kratom to play a role in the opioid epidemic, but there remains a lot of scientific work to be done to arrive at a consistent recommendation about safety and efficacy.³ More human clinical trials are necessary as are basic pharmacokinetics. Does basic science research on animals extrapolate to humans? Quality control and product labeling seem to be important given the phytochemical variations that have been documented, and they could affect the physiological effects of kratom significantly. This latter issue is not unlike challenges facing many other herbal products — one of the reasons for the development of such initiatives as the Botanical Adulterants Program through the American Botanical Council and the widespread use of third-party certification programs.

Is the FDA approach of product seizure and action against kratom-containing dietary supplements justified? Clinicians are comfortable with a “do no harm” approach to patient care, so perhaps for now, as some of the basic pharmacokinetics and clinical effects are clarified, a “use no kratom” strategy seems warranted.

REFERENCES

1. 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. Neuropharmacol 2017; Aug 19. pii: S0028-3908(17)30393-3. doi: 10.1016/j.neuropharm.2017.08.026. [Epub ahead of print].
2. Feng LY, Battulga A, Han E, et al. New psychoactive substances of natural origin: A brief review. J Food Drug Anal 2017;25:461-471.
3. Halpenny GM. Mitragyna speciosa: Balancing potential medical benefits and abuse. ACS Med Chem Lett 2017;8:897-899.
4. 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 2017; Oct 26. doi: 10.1213/XAA.0000000000000658. [Epub ahead of print].