with 32% of the incidents requiring admission to a health care facility and half of the admissions as a serious medical condition. multiple-substance exposures were associated with a higher number of hospitalizations than kratom-only exposures, and involved 11 deaths, including two due to kratom alone. post-mortem toxicology testing detected multiple substances for almost all those who died, with fentanyl and fentanyl analogs being the most frequently identified co-occurring substances. overdoses of kratom are managed similarly to opioid overdoses, and naloxone can be considered to treat an overdose that results in a reduced impulse to breathe, despite mixed results for its utility, based on animal models. from october 2017 to february 2018 in the united states, 28 people in 20 different states were infected with salmonella, an outbreak linked to the consumption of contaminated pills, powder, tea or unidentified sources of kratom. 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. addiction kratom is a botanical with a known addiction liability and, in vulnerable individuals, dependence may develop rather quickly with tolerance noted at 3 months and 4- to 10-fold dose escalations required within the first few weeks. kratom addiction carries a relapse risk as high as 78% to 89% at 3 months post-cessation. in cases of severe addiction, a similar approach to treatment of opioid addiction may be warranted. respiratory depression respiratory depression is the leading cause of death from opioid use. although evidence is sparse, the risk of respiratory depression caused by taking mitragyna speciosa appears to be low, but as of 2016 the food and drug administration listed respiratory depression as a concern. confusingly, a 2018 review found that the alkaloids in kratom do not induce respiratory depression. liver toxicity 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. liver injury has been reported with a latency (time from first use to onset of symptoms) of median 20.6 days. reported liver biopsies tend to show cholestasis; however, blood biomarkers can show a range of cholestatic, mixed, or hepatocellular injury pattern. the majority of users do not seem to develop liver injury, and it is unclear which users are at heightened risk. the mechanism by which kratom causes liver damage in some people is unknown and poorly studied, but a model has been proposed. death kratom overdose is a subject of concern in many countries because of the associated rising number of hospitalizations and deaths in which chronic kratom use is a contributing factor. according to clinical reviews, a kratom overdose can cause liver toxicity, seizures, coma, and death, especially in combination with excessive alcohol use. between 2011 and 2017, 44 u.s. deaths were kratom-related. however, many cases could not be fully assessed, due to limited information. people who die from kratom use typically have taken it in combination with other substances, or have underlying health conditions. over 18 months in 2016 and 2017, 152 overdose deaths involving kratom were reported in the united states, with kratom as the primary overdose agent in 91 of the deaths, and 7 with kratom being the only agent detected. nine deaths occurred in sweden during 2010–11 relating to use of krypton, a mixture of kratom, caffeine and o-desmethyltramadol, a prescription opioid analgesic. pharmacology mitragyna speciosa alkaloids at opioid receptors compoundaffinities (ki (nm))ratioref mordorkormor:dor:kor 7-hydroxymitragynine13.51551231:11:9 mitragynine7.2460.31,1001:8:152 mitragynine pseudoindoxyl0.0873.0279.41:35:913 kratom contains at least 54 alkaloids. these include mitragynine, 7-hydroxymitragynine (7-hmg), speciociliatine, paynantheine, corynantheidine, speciogynine, mitraphylline, rhynchophylline, mitralactonal, raubasine, and mitragynaline. the alkaloids mitragynine and 7-hydroxymitragynine are responsible for many of the complex effects of kratom, but other alkaloids may also contribute synergistically. both mitragynine and 7-hmg are partial agonists of the μ-opioid receptor and competitive antagonists of the δ-opioid receptor with low affinity for the κ-opioid receptor. 7-hmg appears to have higher affinity at the μ-opioid receptor than mitragynine. 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. both mitragynine and 7-hmg readily cross the blood-brain barrier. mitragynine also appears to inhibit cox-2, block l-type and t-type calcium channels, and interact with other receptors in the brain including 5-ht2c and 5-ht7 serotonin receptors, d2 dopamine receptors, and a2a adenosine receptors. 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. this activity might explain why kratom can be dangerous when used in combination with other sedatives. kratom also contains rhynchophylline, a non-competitive nmda receptor antagonist. mitragynine is metabolized in humans via phase i and phase ii mechanisms with the resulting metabolites excreted in urine. in in vitro experiments, kratom extracts inhibited cyp3a4, cyp2d6, and cyp1a2 enzymes, which results in significant potential for drug interactions. chemistry main article: mitragynine 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. in particular, mitragynine and 7-hydroxymitragynine (7-hmg) compose significant proportions of the natural products isolable from m. speciosa; e.g., in one study, mitragynine was 12% by weight from malaysian leaf sources, versus 66% from thai sources, and 7-hydroxymitragynine constituted ~2% by weight. in addition, at least 40 other compounds have been isolated from m. speciosa leaves, including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from rauvolfia serpentina), corynantheidine (also found in pausinystalia johimbe), as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline. in addition to alkaloids, m. speciosa produces many other secondary metabolites. these include various saponins, iridoids and other monoterpenoids, triterpenoids such as ursolic acid and oleanic acid, as well as various polyphenols including the flavonoids apigenin and quercetin. 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. detection in body fluids the plant's active compounds and metabolites are not detected by a typical drug screening test, but can be detected by more specialized testing. blood mitragynine concentrations are expected to be in a range of 10–50 μg/l in persons using the drug recreationally. detection in body fluids is typically by liquid chromatography-mass spectrometry. regulation as of january 2018, neither the plant nor its alkaloids were listed in any of the schedules of the united nations drug conventions. asean as of 2013, kratom was listed by asean in its annex of products that cannot be included in traditional medicines and health supplements that are traded across asean nations. australia and new zealand as of january 2015, kratom was controlled as a narcotic in australia and under medicines regulations 1985 (amended august 6, 2015) in new zealand. canada as of october 2020, health canada disallowed marketing of kratom for any use by ingestion, and has taken action against companies marketing it for such purposes. kratom could be marketed for other uses, such as incense. europe as of 2011, the plant was controlled in denmark, latvia, lithuania, poland, romania and sweden. in the uk, since 2016, the sale, import, and export of kratom are prohibited under the psychoactive substances act. in 2017, kratom was designated a schedule 1 illegal drug (the highest level) in the republic of ireland, under the names 7-hydroxymitragynine and mitragynine. indonesia kratom is scheduled to become an illegal substance in indonesia in 2024 once new regulations from the indonesian national narcotics agency (bnn) go into effect. this pending ban has been in place since 2019; the date of the ban going into effect was pushed out to 2024 to give kratom farmers time to switch to other crops. notably, this ban would likely devastate the kratom supply in the united states, since almost all of america's kratom is supplied via indonesian exports. malaysia 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), act. 366 poisons act 1952 and will be punished by imprisonment or fine or both. 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. certain parties have urged the government to penalize the use of kratom under the dangerous drugs act instead of the poisons act, which would carry heavier penalties. thailand possession of kratom leaves (thai: ต้นกระท่อม, rtgs: ton krathom) was illegal in thailand until 2018. the thai government had passed the kratom act 2486, effective 3 august 1943, which made planting the tree illegal, in response to a rise in its use when opium became very expensive in thailand and the thai government was attempting to gain control of the opium market. in 1979, the thai government placed kratom, along with marijuana, in category v of a five category classification of narcotics. kratom accounted for less than two percent of arrests for narcotics between 1987 and 1992. the thai government has considered legalizing kratom for recreational use in 2004, 2009, 2013, and 2020. in 2018, thailand became the first southeast asian country to legalize kratom for medical purposes. in 2021, thailand fully legalized kratom and removed it from the list of category v narcotics, and more than 12,000 people who had been convicted for kratom-related offences when it was still considered a narcotic were granted an amnesty. united states in the united states, there is consideration to make kratom a schedule i drug. in 2019, the fda warned consumers that kratom remains unapproved for interstate commerce, may be unsafe in commercially available products, and is on an import alert which can lead to confiscation of imported supplies. efforts to schedule kratom have generated significant controversy both among the general public and scientific community. fda assessment in april 2019, the fda issued a statement declaring that kratom was not approved for any medical use, was potentially unsafe in commercial products available in the united states, and remained on an import alert where imported supplies would be confiscated. on april 4, 2018, the fda issued the first mandatory recall in its history over concerns of salmonella contamination of several kratom-containing products. samples of the products, manufactured by triangle pharmanaturals, and marketed under the brand name 'raw form organics', tested positive for contamination and the manufacturer did not comply with federal requests for voluntary recall. 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. consumers were advised to immediately discard any such products to prevent serious health risks. 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. also in 2018, the fda supervised the voluntary destruction of kratom dietary supplements by a nationwide distributor in missouri, and encouraged all companies involved in kratom commerce to remove their products from the market. on february 26, the fda warned a california manufacturer of a kratom product called "mitrasafe" that the supplement was not confirmed as safe, was not approved as a dietary supplement or drug, and was illegal for interstate commerce. in november 2017, the fda cited serious concerns over the marketing and effects (including death) associated with the use of kratom in the united states, stating that "there is no reliable evidence to support the use of kratom as a treatment for opioid use disorder; there are currently no fda-approved therapeutic uses of kratom... and the fda has evidence to show that there are significant safety issues associated with its use." dea scheduling on august 30, 2016, the drug enforcement administration (dea) announced its intention to place the active materials in the kratom plant into schedule i of the controlled substances act as a warning about an imminent hazard to public safety, citing over 600 calls to poison control centers between 2010 and 2015 and 15 kratom-related deaths between 2014