[3] It is indigenous to Cambodia, Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea,[4] where its leaves, known as kratom, have been used in herbal medicine since at least the 19th century.

[4] Anecdotal reports describe increased alertness, physical energy, talkativeness, sociability, sedation, changes in mood, and pain relief following kratom use at various doses.

[12] More severe side-effects may include respiratory depression (decreased breathing), seizure, psychosis,[4][7][13][14] elevated heart rate and blood pressure, trouble sleeping, and, rarely, liver toxicity.

[8] The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to khat and coca.

[11][14][43] Long-term use of high doses of kratom may lead to development of tolerance, dependence, and withdrawal symptoms, including loss of appetite, weight loss, decreased libido, insomnia, muscle spasms, muscle and bone pain, increased yawning and/or sneezing, myoclonus, watery eyes, hot flashes, fever, diarrhea, restlessness, anger, and sadness.

[8][11][33] Frequent use of high doses of kratom may cause tremors, anorexia, weight loss, seizures, psychosis and other mental health conditions.

[4][11] Herb–drug interactions may result when kratom is combined with alcohol, sedatives, benzodiazepines, opioids, caffeine, cocaine, yohimbine, or monoamine oxidase inhibitors (MAOIs).

[17] One death was reported in a person who was exposed to the medications paroxetine (an antidepressant) and lamotrigine (an anticonvulsant and mood stabilizer) in addition to kratom.

[48] An analytical method using whole genome sequencing applied to samples from the infected users indicated that the salmonella outbreak likely had a common kratom source.

[48] Kratom is a botanical with a known addiction liability and, in vulnerable individuals, dependence may develop rather quickly with tolerance noted at three months and four- to ten-fold dose escalations required within the first few weeks.

[49] A survey by Stanciu et al. of kratom consumers found that 25.5% of respondents reported symptoms consistent with a substance use disorder diagnosis based on the Diagnostic and Statistical Manual's criteria.

After controlling for variables such as age, gender, daily kratom use frequency, and a history of substance use disorders or mental health conditions, individuals with a concurrent diagnosis of another SUD had 2.83 times the odds of meeting criteria for kratom addiction compared to those without a concurrent substance use disorder diagnosis.

[56] In rare cases, though with a dangerous delay, kratom use has been linked to acute liver injury, with symptoms of abdominal discomfort, dark urine, itching and jaundice.

[11][16] According to clinical reviews, a kratom overdose can cause liver toxicity, seizures, coma, and death,[16] especially in combination with excessive alcohol use.

[47][57][58] Nine deaths occurred in Sweden during 2010–11 relating to use of Krypton, a mixture of kratom, caffeine and O-desmethyltramadol, a metabolite of the opioid analgesic tramadol.

[56][9] These compounds display functional selectivity and do not activate the β-arrestin pathway partly responsible for the respiratory depression, constipation, and sedation associated with traditional opioids.

[32] Mitragynine stimulates α2-adrenergic receptors, inhibiting the release of norepinephrine (noradrenaline); other compounds in this class include dexmedetomidine, which is used for sedation, and clonidine, which is used to manage anxiety and some symptoms of opioid withdrawal.

[11] Table 1: Pharmaceutical profile of Kratom Delta: competitive antagonist Mu: partial agonist α2 adrenergic Adenosine A2a Dopamine D2 Serotonin receptors 5-HT2C and 5-HT7[68] Many of the key psychoactive compounds in M. speciosa are indole alkaloids related to mitragynine, which is a tetracyclic relative of the pentacyclic indole alkaloids, yohimbine and voacangine.

[72] Although some of these compounds possess antinociceptive, anti-inflammatory, gastrointestinal, antidepressant, antioxidant, and antibacterial effects in cells and non-human animals, there is no sufficient evidence to support the clinical use of kratom in humans.

[18] In 2021, the World Health Organization's Executive Committee on Drug Dependency investigated the risks of kratom and declined to recommend a critical review of it.

[86] Kratom was previously scheduled to become an illegal substance in Indonesia in 2024 once new regulations from the Indonesian National Narcotics Agency (BNN) go into effect.

[88][90] The use of kratom leaves, known locally as ketum or Biak is prohibited to use, import, export, manufacture, compound, mix, dispense, sell, supply, administer or possess in Malaysia under Section 30(3) of the Poisons Act 1952, and will be punished by imprisonment or fine or both.

[91] Although prohibited by statute, the use of kratom remains widely spread especially in Northern and East Coast region of Malaysia's Peninsula because the tree grows natively and tea decoctions are readily available in local communities.

[98][99] In 2014, the United States Food and Drug Administration (FDA) banned the import of kratom into the U.S. due to a lack of evidence for its safety.

[106] FDA Commissioner Gottlieb stated that the recall was, "...based on the imminent health risk posed by the contamination of this product with salmonella" and not related to other regulatory concerns.

[106] In February 2018, the commissioner of the FDA, Scott Gottlieb, released a statement describing further opioid-like properties of kratom and stating that it should not be used for any medical treatment or recreational use.

[25] Although it was a federally legal dietary supplement, kratom was not approved as a therapeutic agent in the United States due to the poor quality of the research.

[111][112] The DEA noted the responses but said that it intended to go forward with the listing; a spokesman said: "We can't rely upon public opinion and anecdotal evidence.

[117] Between February 2014 and July 2016, U.S. law-enforcement authorities "encountered 55 tons of kratom," or roughly "50 million individual doses," according to the International Narcotics Control Board.

"[120] However, in 2021, former Acting Commissioner of Food and Drugs Brett Giroir claimed that the FDA's recommendation to schedule kratom was rejected because of "embarrassingly poor evidence [and] data.