Kratom, mitragynine, 7-hydroxymitragynine

Alternative names
Mitragyna speciosa, mitragynine and 7-hydroxymitragynine

methyl (2S)-2-[[1-(4-fluorobutyl)indole-3-carbonyl]amino]-3,3-dimethylbutanoate

Current Scheduling Status
Year(s) and type of review / ECDD meetings
Drug Class

Recommendation (from TRS)

Substance identification
Kratom is the common term for Mitragyna speciosa, a tree native to South-East Asia. Kratom is used almost exclusively orally, typically by chewing the leaves, ingesting powdered leaf, drinking an infusion or decoction or by ingesting powdered leaf as a capsule or pill or dissolved in a beverage. Other forms such as extracts and resins are also used.

Several alkaloids have been detected in kratom plants. The main known psychoactive components are mitragynine and 7-hydroxymitragynine, both of which are found in the leaves of M. speciosa. Mitragynine is the most abundant alkaloid in kratom. While 7-hydroxymitragynine is a minor alkaloid, it is also a metabolite of mitragynine.

WHO review history
Kratom has been under ECDD surveillance since 2020, when a national report indicated the potential for abuse, dependence and harm to public health from mitragynine and 7-hydroxymitragynine, and a report from an international organization documented fatalities associated with kratom use. A pre-review on kratom, mitragynine and 7-hydroxymitragynine was initiated after consideration of those reports.

Similarity to known substances and effects on the central nervous system
Mitragynine and 7-hydroxymitragynine are partial agonists at the µ-opioid receptor. The analgesic effects of kratom have been demonstrated in humans, while kratom extract, mitragynine and 7-hydroxymitragynine have been shown to be antinociceptive in animal models. The antinociceptive effects are reversed by an opioid antagonist.

Mitragynine also binds to adrenergic, serotonergic and dopamine receptors. Although there is limited information on its effects at these receptors, kratom extracts and mitragynine have been reported to have a variety of non-opioid-like behavioural effects in animals, including antidepressant and antipsychotic effects.

Reported adverse effects after kratom intoxication have included neuropsychiatric (agitation, confusion, sedation, hallucinations, tremor, seizure, coma), cardiovascular (tachycardia, hypertension), gastrointestinal (abdominal pain, nausea, vomiting) and respiratory (respiratory depression) symptoms. A number of cases of kratom-associated liver toxicity have been documented.

Dependence potential
In animal models, repeated dosing with mitragynine produced dependence, evidenced by naloxone-precipitated withdrawal. The withdrawal syndrome from kratom appeared to be less severe than that from morphine.

In humans, opioid-like withdrawal symptoms have been reported after cessation of kratom use. Limited epidemiological evidence indicates that withdrawal is usually mild. A few cases of neonatal opioid withdrawal symptoms have been reported in neonates born to mothers who used kratom regularly.

Actual abuse and/or evidence of likelihood of abuse
Kratom extracts did not show abuse liability in one animal model. Mitragynine and 7-hydroxymitragynine had effects indicative of abuse liability in some animal models but not in others. Mitragynine is not self-administered by animals, while 7-hydroxymitragynine has been shown to be self-administered, supporting likely abuse liability.

Kratom can produce serious toxicity in people who use high doses, but the number of cases is probably low as a proportion of the total number of people who use kratom. Although mitragynine has been analytically confirmed in a number of deaths, almost all involved use of other substances, and the contribution of kratom use to the fatalities is unclear.

Kratom and mitragynine have been associated with cases of DUID, but their role in driving impairment could not be established in most instances.

Multiple countries across various regions report nonmedical use of kratom. Seizures of kratom and related products have been reported in several countries.

Therapeutic usefulness
People report using kratom to self-medicate for a variety of disorders and conditions, including pain, opioid withdrawal, opioid use disorder, anxiety and depression. Kratom is used in traditional medicine in some countries.

Research is under way to determine the basic pharmacology and potential therapeutic value of kratom, mitragynine and 7-hydroxymitragynine.

Kratom contains multiple alkaloids. The two main known psychoactive alkaloids, mitragynine and 7-hydroxymitragynine, have at least some effects similar to those of opioids under international control. Mitragynine, the most abundant of these alkaloids, also has non-opioid activity, the significance of which is unclear. There is mixed evidence on the abuse liability of mitragynine in animal models. Kratom is used for self-medication for a variety of disorders but there is limited evidence of abuse liability in humans. Cessation of regular use of kratom may lead to withdrawal symptoms.

The Committee considered information on traditional use and investigation into possible medical applications of kratom.

The Committee concluded that there is insufficient evidence to recommend a critical review of kratom. With respect to mitragynine and 7-hydroxymitragynine, the Committee, except for one member, also concluded that there is insufficient evidence to recommend a critical review at this time.

Recommendation: The Committee recommended that kratom, mitragynine and 7-hydroxymitragynine be kept under surveillance by the WHO secretariat.

ECDD Recommendation

Added to surveillance list by 8th WG meeting (2020)

Mitragynine and 7-OH-mitragynine are substances with opioid activity that are found in the plant Mitragyna speciosa (kratom). The kratom plant is native to South-East Asia and has been used as a traditional medicine in a number of countries in that region. Opioid effects can be produced by consumption of the plant, extracts of the plant or by the purified substances. Use of mitragynine and 7-OH-mitragynine has increased significantly in recent years and there are reports of use from many countries across different regions. There are reports of dependence on these substances and of fatal and non-fatal overdoses in which consumption of mitragynine and/or 7-OH-mitragynine played a significant role. At the 44th ECDD meeting in 2021, it was recommended that, due to insufficient evidence to recommend a critical review of kratom, mitragynine and 7-OH-mitragynine, these substances should be kept under surveillance.