Evidence-Based Reviews

Kratom: What we know, what to tell your patients

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Educate patients about the risks of this increasingly popular but unregulated substance.



Mitragyna speciosa, better known as kratom, is a tropical evergreen tree that is native to Southeast Asia. Botanically, it is a member of the Rubiaceae family, as is the coffee plant, and physical laborers among indigenous populations have historically chewed the leaves or brewed them as a tea to improve endurance and reduce fatigue.1 Kratom is psychoactive; 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 physical or mood problems. Increasingly, kratom is being used by people who abuse opioids to self-manage opioid withdrawal, or for its euphoric effects. But kratom carries several important risks, including addiction, serious adverse effects, and possibly death. In this article, we review the epidemiology and pharmacology of kratom, and provide some guidance for educating patients about this substance.

Widely used but not FDA approved

Although kratom is not regulated or approved by the FDA, 3 to 5 million Americans use it regularly.3 According to an internet survey, kratom users are mostly college-educated, employed white men, age 31 to 50, who take the substance to manage pain or to treat general anxiety and mood disorders.4 Some individuals use kratom as an opioid substitute to reduce symptoms of opioid withdrawal.4

Kratom is available from a wide range of manufacturers in various formulations, including powders, tablets, liquids, and gum. It is sometimes sold in combination with other agents as a single product. Low-cost, over-the-counter kratom products are available as “dietary supplements” in retail stores or online. Although the product packaging sometimes recommends a specific dose, the amount of active ingredients (as well as other agents) is unknown. Kratom is illegal in several states (Box5).


The legal status of kratom

The use and sale of kratom is illegal in several countries, including Australia, Poland, Denmark, Sweden, Malaysia, and Vietnam. In the United States, kratom was legal to grow and purchase in all 50 states until 2015, when the Drug Enforcement Administration (DEA) identified kratom as a “substance of concern.” In August 2016, the DEA submitted a notice of intent to place mitragynine and 7-hydroxymitragynine, 2 alkaloids of kratom that have opioid-like properties, into Schedule I of the Controlled Substance Act; however, due to significant public pressure, the DEA withdrew the request in October 2016.

As of February 2020, kratom was illegal to buy, sell, or use in Wisconsin, Rhode Island, Vermont, Indiana, Arkansas, Alabama, specific counties of some states, and the District of Columbia. Legislation was pending in New York, Missouri, and Louisiana.

Source: Reference 5

The 2 alkaloids of interest

More than 40 alkaloids have been isolated from kratom leaves. The proportions of these alkaloids vary significantly depending on the environment in which the plant is grown, the breeding and harvesting techniques, and the age of the plant.6 Two alkaloids of significant interest are mitragynine (Figure 1) and 7-hydroxymitragynine (Figure 2), both of which are unique to M. speciosa and have opioid-like properties. Administering these alkaloids to morphine-dependent rats resulted in cross-tolerance and precipitated withdrawal when the rats were given naloxone.7 The potency of kratom at the mu opioid receptor has been found to exceed that of morphine.

Chemical structure of mitragynine

Competitive binding studies that examined the affinity of mitragynine and 7-hydroxymitragynine at the various opioid receptor subtypes found a preference for the kappa receptors (antagonism), followed by mu (partial agonism), and lastly delta. This profile of mitragynine is very similar to that of buprenorphine.8 The affinity of 7-hydroxymitragynine for the mu receptor (agonism) is significantly greater than that of mitragynine.9 Mitragynine also interacts with noradrenergic and serotonergic pathways by stimulating postsynaptic alpha-2 adrenergic receptors and inhibiting 5-HT2A receptors.9 These properties are responsible for kratom’s ability to manage opioid withdrawal symptoms, which are generally attributed to a hyperactive noradrenergic system. There also is evidence that the hepatic metabolite 7-hydroxymitragynine is important in mediating the analgesic component of mitragynine.10

Chemical structure of 7-hydroxymitragynine

The initial effects of kratom typically begin within 10 to 20 minutes of consumption, and the full effects are experienced in 30 to 60 minutes.1 The half-life of mitragynine in humans has not yet been determined, but is believed to be relatively short.11 In rats, the half-life of mitragynine is 2 to 3 hours.12 Individuals who use kratom to prevent opioid withdrawal have reported taking it as often as every 6 to 12 hours.13

Continue to: Metabolism of mitragynine...


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