Mitragyna speciosa

Mitragyna speciosa is a tropical evergreen tree of the Rubiaceae family native to Southeast Asia.<ref name= "GRIN">Template:GRIN</ref> It is indigenous to Cambodia, Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea,<ref name= "Rech2015">Template:Cite journal</ref> where its dark green, glossy leaves, known as kratom, have been used in herbal medicine since at least the 19th century.<ref name= "Hassan2013">Template:Cite journal</ref> They have also historically been consumed via chewing, smoking, and as a tea.<ref name= "Julien's Primer">Template:Cite book</ref> Kratom has opioid-like properties and some stimulant-like effects.<ref name= "FDA2018">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name= "Cin2015">Template:Cite journal</ref>

The efficacy and safety of kratom are unclear.<ref name="white">Template:Cite journal</ref> In 2019, the United States Food and Drug Administration (FDA) stated that there is no evidence that kratom is safe or effective for treating any condition.<ref name="fda4-3-19" /> Some people take it for managing chronic pain, for treating opioid withdrawal symptoms, or for recreational purposes.<ref name="Rech2015" /><ref name="warner">Template:Cite journal</ref> The onset of effects typically begins within five to ten minutes and lasts for two to five hours.<ref name= "Rech2015" /> Kratom contains over fifty alkaloids—primarily mitragynine and 7-hydroxymitragynine—which act as partial agonists at μ-opioid receptors with complex, receptor-specific effects and additional interactions across various neural pathways.

Anecdotal reports describe increased alertness, physical energy, talkativeness, sociability, sedation, changes in mood, and pain relief following kratom use at various doses.<ref name="warner" /> Common side effects include appetite loss, erectile dysfunction, nausea and constipation.<ref name=corkery/> More severe side-effects may include respiratory depression (decreased breathing), seizure, psychosis,<ref name=Rech2015/><ref name=FDA2018/><ref name="usdea">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name= Rosen>Template:Cite book</ref> elevated heart rate and blood pressure, trouble sleeping, and liver injury.<ref name=Rech2015/><ref name= "liverreview">Template:Cite journal</ref><ref name="livertox">Template:Cite journal</ref><ref name=cdc>Template:Cite journal</ref> Addiction is a possible risk with regular use: when use is stopped, withdrawal symptoms may occur.<ref name="Cin2015" /><ref name=warner/> A small number of deaths have been connected to the use of kratom, most commonly when mixed with other substances.<ref name=corkery/> Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.<ref name= Rech2015/><ref name= warner/>

As of 2018, kratom is a controlled substance in sixteen countries.<ref name= "FDA2018" /> Some countries, like Indonesia and Thailand, have recently moved toward regulated legal production for medical use. There is growing international concern about a possible threat to public health from kratom use.<ref name=FDA2018/><ref name=warner/><ref name= EMCDDA>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In some jurisdictions its sale and importation have been restricted, and several public health authorities have raised alerts.<ref name= warner/><ref name= EMCDDA/> Kratom is under preliminary research for possible antipsychotic and antidepressant properties.<ref name= "ReferenceA">Template:Cite journal</ref><ref name="Jack T 2019">Template:Cite journal</ref> Template:TOC limit

Description

Kratom has dark green oval-acuminate leaves and yellow globular flowers.

Kratom flowers and foliage

Mitragyna speciosa is an evergreen tree in the genus Mitragyna that can grow to a height of Template:Convert. Its trunk may grow to a Template:Convert diameter.<ref name="Eisenman" /> The trunk is generally straight, and the outer bark is smooth and grey.<ref name="Eisenman" /> The leaves, ovate-acuminate in shape and opposite in growth pattern, are dark green, glossy on their upper surfaces,<ref name="warner" /> and can grow to over Template:Convert long and Template:Convert wide. They have 12 to 17 pairs of veins.<ref name="Eisenman" /> The spherical inflorescences, which are deep yellow, grow in clusters of three at the ends of the branches.<ref>Template:Cite book</ref> The calyx-tube is Template:Convert long and has five lobes; the corolla-tube is Template:Convert long.<ref name="Eisenman">Template:Cite book</ref>

Mitragyna speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea.<ref name="Rech2015" /> It was first formally described by the Dutch colonial botanist Pieter Korthals in 1839, who named it Stephegyne speciosa; it was renamed and reclassified several times before George Darby Haviland provided the final name and classification in 1859.<ref name="Eisenman" />Template:Rp

Uses of the leaves

File:Kratom leafes.jpg

Kratom leaves

Template:As of, kratom has been studied in cells and in animals, but no clinical trials have been conducted in the United States.<ref name="Hassan2013" /> The U.S. Drug Enforcement Administration (DEA) stated in 2013 that there is no legitimate medical use for kratom,<ref name="usdea" /> and in 2019, the U.S. Food and Drug Administration (FDA) said that there is no evidence that kratom is safe or effective for treating any condition, and that there are no approved clinical uses for kratom.<ref name="fda4-3-19" />

Kratom is commonly ingested by chewing, as a tea, powdered in capsules or pills, or extracted for use in liquids.<ref name="Hassan2013"/> Kratom is rarely smoked.<ref name="EMCDDA" /> Different varieties of kratom contain different relative proportions of alkaloids such as mitragynine.<ref name="warner" />

Traditional use

In cultures where the plant grows, kratom has been used in traditional medicine.<ref name=Cin2015 /> The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to khat and coca.<ref name= warner/> The leaves, or extracts from them, are used to heal wounds and as a local anesthetic. Extracts and leaves have been used to treat coughs, diarrhea, and intestinal infections.<ref name=Rech2015/><ref name="Hassan2013" /><ref name=Eisenman/> They are also used as intestinal deworming agents in Thailand.<ref name="EMCDDA" /><ref>Template:Cite journal</ref>

Kratom is often used by workers in laborious or monotonous occupations to stave off exhaustion and as a mood-enhancer and painkiller.<ref name="Eisenman" /> In Thailand, kratom was "used as a snack to receive guests and was part of the ritual worship of ancestors and gods".<ref>Template:Cite journal</ref> The herb is bitter and is generally combined with a sweetener.<ref name="Adkins 2011-05-01">Template:Cite journal</ref>

Opioid withdrawal

Because the withdrawal effects of kratom are often reported to be less severe than those associated with traditional opioids,<ref name="warner" /> some people use kratom in the attempt to manage opioid use disorder,<ref name=":2">Template:Cite journal</ref> though no clinical trials have been done supporting this use. Template:As of, there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction.<ref name="FDA2018" /> Stanciu et al. conducted a review of all literature and found insufficient evidence for any conclusions concerning whether kratom is harmful or whether can serve as harm reduction for those with opioid addiction.<ref>Template:Cite journal</ref> While some literature reviews claim that kratom has less potential for dependence or overdose than traditional opioids,<ref>Template:Cite journal</ref><ref name=":3">Template:Cite journal</ref> other reviews note that kratom withdrawal itself can still be quite severe.<ref name="Stan2019" />

Data on how widely it is used worldwide are lacking, as it is not detected by typical drug screening tests.<ref name="Adkins 2011-05-01"/> Rates of kratom use appear to be increasing among those who have been self-managing chronic pain with opioids purchased without a prescription and are cycling (but not quitting) their opioid use.<ref name="Adkins 2011-05-01"/>

In 1836, kratom was reported to have been used as an opium substitute in Malaysia. Kratom was also used as an opium substitute in Thailand in the 19th century.<ref name="Hassan2013" />

Recreational use

At low doses, kratom produces euphoric effects comparable to those of coca.<ref name=":0">Template:Cite journal</ref> At higher doses, kratom produces opioid-like effects.<ref name=":0" /> The onset of effects typically begins within five to ten minutes and lasts for two to five hours.<ref name="Rech2015" /> Some anecdotal reports describe increased work capacity, alertness, talkativeness, sociability, increased sexual desire, positive mood, and euphoria following the consumption of kratom.<ref name="warner" />

According to the U.S. DEA and a 2020 survey, kratom is used to alleviate pain, anxiety, depression, or opioid withdrawal.<ref name=usdea/><ref name=":1">Template:Cite journal</ref>

In Thailand, a 2007 survey found that the lifetime, past year, and past 30 days kratom consumption rates were 2.32%, 0.81% and 0.57%, respectively, among respondents aged 12–65 years,<ref name="EMCDDA" /> and that kratom was the most widely used recreational drug in Thailand.<ref name="EMCDDA" />

Kratom may be mixed with other psychoactive drugs, such as caffeine and codeine.<ref name="Cin2015" /><ref>Template:Cite book</ref> Starting in the 2010s, a tea-based cocktail known as "4×100" became popular among some young people across Southeast Asia and especially in Thailand. It is a mix of kratom leaves, cough syrup, Coca-Cola, and ice. Around 2011, people who consumed the cocktail were often viewed more negatively than users of traditional kratom, but not as negatively as users of heroin.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> As of 2012, use of the cocktail was a severe problem among youth in three provinces along the border of Malaysia and southern Thailand.<ref>Template:Cite news</ref>

In the U.S., Template:As of, kratom was available in outlets such as head shops and over the Internet; the prevalence of its U.S. use was unknown at the time.<ref name= warner/> In the United States, kratom use increased rapidly between 2011 and 2017.<ref name="Post">Template:Cite journal</ref> By 2020, it was estimated that 15 million people worldwide use kratom.<ref>Template:Cite journal</ref>

Adverse effects

Mitragyna speciosa may cause many adverse effects, and in November 2017 the FDA issued a public health advisory for the drug.<ref name=white/> The side effects of kratom appear to be dose-dependent and are more common with doses that exceed 8 g.<ref name=":3" /> While the incidence of adverse effects in people who use kratom is unknown, a 2019 review of 935 kratom exposures reported to U.S. poison control centers over a seven-year period listed the following signs and symptoms: agitation (18.6%), tachycardia (16.9%), drowsiness (13.6%), vomiting (11.2%), confusion (8.1%), seizures (6.1%), withdrawal symptoms (6.1%), hallucinations (4.8%), respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%).<ref name=":5">Template:Cite journal</ref><ref name=":3" /> The study also reported two deaths and four cases of neonatal abstinence syndrome.<ref name=":5" /> A different 2019 review listed as common side effects: decreased appetite, weight loss, erectile dysfunction, insomnia, sweating, hyperpigmentation, hair loss, tremor, and constipation.<ref name=corkery/>

Kratom products in the U.S. are commonly used in doses of 2–6 g of dried leaf, and doses exceeding 8 g are relatively uncommon.<ref>Template:Cite journal</ref> Given that kratom products may vary greatly in potency, there is no standard dosing system. At relatively low doses (1–5 g of raw leaves), at which there are mostly stimulant effects, side effects include contracted pupils and blushing; adverse effects related to stimulation include anxiety and agitation, and opioid-related effects such as itching, nausea, loss of appetite, and increased urination begin to appear.<ref name=Rech2015/><ref name=warner/> At moderate to high doses (5–15 g of raw leaves), at which opioid effects generally appear, additional adverse effects include tachycardia (an increased stimulant effect) as well as the opioid side effects of constipation, dizziness, hypotension, dry mouth, and sweating.<ref name="warner" /><ref name="Rosen" /><ref name=":4">Template:Cite journal</ref>

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.<ref name=Cin2015/> This may lead to resumption of use.<ref name=Cin2015/><ref name=warner/><ref name=Stan2019>Template:Cite journal</ref>

Frequent use of high doses of kratom may cause tremors, anorexia, weight loss, seizures, psychosis and other mental health conditions.<ref name="warner" /><ref name=bachu>Template:Cite journal</ref> Kratom use has a small but statistically significant association with externalizing mental health disorders.<ref name=":12">Template:Cite journal</ref> Kratom use may worsen existing mental health conditions.<ref name=bachu/> In case reports associating kratom use with psychosis, it remains unclear whether kratom use directly caused psychosis or simply unmasked the condition.<ref>Template:Cite book</ref> Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.<ref name=Rech2015/><ref name=warner/> Herb–drug interactions may result when kratom is combined with alcohol, sedatives, benzodiazepines, opioids, caffeine, cocaine, yohimbine, or monoamine oxidase inhibitors (MAOIs).<ref name=":4" /> Rhabdomyolysis is one of the rare and serious complications of this herb at high dosage.<ref name="pmid34430176">Template:Cite journal</ref>

In July 2016, the Centers for Disease Control issued a report stating that between 2010 and 2015, US poison control centers received 660 reports of exposure to kratom. Medical outcomes associated with kratom exposure were reported as minor (minimal signs or symptoms, which resolved rapidly with no residual disability) for 162 (24.5%) exposures, moderate (non-life-threatening, with no residual disability, but requiring some form of treatment) for 275 (41.7%) exposures, and major (life-threatening signs or symptoms, with some residual disability) for 49 (7.4%) exposures. Overall, 92.6% of outcomes were resolved with no residual disability.<ref name=cdc/> 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. For 173 (26.2%) exposure calls, no effects were reported, or poison center staff members were unable to follow up regarding effects.<ref name=cdc/>

A 2019 report from the American Association of Poison Control Centers (AAPCC) noted that kratom use was increasing rapidly, with 1807 kratom exposures and a 52-fold increase occurring over the years 2011 to 2017.<ref name=Post/> Most exposures occurred intentionally by adult males in their homes, with 32% of the incidents requiring admission to a health care facility and half of the admissions as a serious medical condition.<ref name=Post/> 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.<ref name=Post/> 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.<ref name="cdc2019" />

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.<ref name= Rech2015/>

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.<ref name="cdc18">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name= cdc18/>

Addiction

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.<ref>Alsarraf E, Myers J, Culbreth S, Fanikos J. Kratom from head to toe—case reviews of adverse events and toxicities. Curr Emerg Hosp Med Rep. 2019;7(4):141-168. doi:10.1007/s40138-019-00194-1</ref> 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.<ref>Hill K, Grundmann O, Smith KE, Stanciu CN. Prevalence of Kratom Use Disorder Among Kratom Consumers. J Addict Med. 2024 May-Jun 01;18(3):306-312. doi: 10.1097/ADM.0000000000001290.</ref> Kratom addiction carries a relapse risk as high as 78% to 89% at three months post-cessation.<ref>Vicknasingam B, Narayanan S, Beng GT, Mansor SM. The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int J Drug Policy.2010;21(4):283-288. doi:10.1016/j.drugpo.2009.12.003</ref><ref>Singh D, Müller CP, Vicknasingam BK. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms, and craving in regular users. Drug Alcohol Depend. 2014;139:132-137. doi:10.1016/j.drugalcdep.2014.03.017</ref><ref>Singh D, Müller CP, Vicknasingam BK, Mansor SM. Social functioning of kratom (Mitragyna speciosa) users in Malaysia. J Psychoactive Drugs. 2015;47(2):125-131. doi:10.1080/02791072.2015.1012610</ref> In cases of severe addiction, an approach similar to the treatment of opioid addiction may be warranted.<ref>Stanciu C, Ahmed S, Hybki B, Penders T, Galbis-Reig D. Pharmacotherapy for Management of 'Kratom Use Disorder': A Systematic Literature Review With Survey of Experts. WMJ. 2021;120(1)</ref>

Respiratory depression

Respiratory depression is the leading cause of death from opioid use.<ref name= Beckett2014>Template:Cite book</ref> Although evidence is sparse, the risk of respiratory depression caused by taking kratom appears to be low, but, Template:As of, the Food and Drug Administration listed respiratory depression as a concern.<ref name=white/><ref name="FDAImportAlert">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A 2018 review found that the alkaloids in kratom do not induce respiratory depression.<ref name="Kruegel">Template:Cite journal</ref>

Liver toxicity

Kratom use is thought to cause acute liver injury, with symptoms of abdominal discomfort, dark urine, itching and jaundice.<ref name="liverreview" /><ref name=livertox/> Liver injury has been reported with a latency (time from first use to the 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 patterns.<ref name=liverreview/> Although cases are likely underreported, many 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.<ref name=liverreview/>

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.<ref name=warner/><ref name=livertox/> According to clinical reviews, a kratom overdose can cause liver toxicity, seizures, coma, and death,<ref name=livertox/> especially in combination with excessive alcohol use. Between 2011 and 2017, 44 U.S. deaths were kratom-related.<ref name=FDA2018/> However, many cases could not be fully assessed, due to limited information.<ref name=FDA2018/> People who die from kratom use typically have taken it in combination with other substances, or have underlying health conditions.<ref name=corkery>Template:Cite journal</ref>

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.<ref name="cdc2019">Template:Cite journal</ref><ref>Template:Cite news</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="toxnet12">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="rosenbaum_2012">Template:Cite journal</ref>

Pharmacology

Mitragyna speciosa alkaloids at opioid receptors

Compound	Affinities (Template:Abbrlink)			Ratio	Ref
	Template:Abbrlink	Template:Abbrlink	Template:Abbrlink	MOR:DOR:KOR
7-Hydroxymitragynine	13.5	155	123	1:11:9	<ref name="pmid11960505">Template:Cite journal</ref>
Mitragynine	7.24	60.3	1,100	1:8:152	<ref name="pmid11960505" />
Mitragynine pseudoindoxyl	0.087	3.02	79.4	1:35:913	<ref name="pmid11960505" />

Kratom contains at least 54 alkaloids.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> These include mitragynine, 7-hydroxymitragynine (7-HMG), speciociliatine, paynantheine, corynantheidine, speciogynine, mitraphylline, rhynchophylline, mitralactonal, raubasine, and mitragynaline.<ref name="white" /><ref name="warner" /><ref name=":3" /> The alkaloids mitragynine and 7-hydroxymitragynine are responsible for many of the complex effects of kratom,<ref name="white" /><ref name="warner" /> but other alkaloids may also contribute synergistically.<ref name=":3" />

The effects of both mitragynine and 7-HMG remain disputed despite substantial study. Both are partial agonists of the μ-opioid receptor. While most data indicates agonism at all three opioid receptors, other data suggests the alkaloids are antagonists of the δ-opioid receptor with low affinity for the κ-opioid receptor.<ref name=":3" /><ref name=":4" /> 7-HMG appears to have higher affinity at the μ-opioid receptor than mitragynine.<ref name="white" /><ref name="Kruegel" /> 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.<ref name=":3" /><ref>Template:Cite journal</ref> Both mitragynine and 7-HMG readily cross the blood-brain barrier.<ref name=":4" /><ref>Template:Cite journal</ref>

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-HT_2C and 5-HT₇ serotonin receptors, D₂ dopamine receptors, and A_2A adenosine receptors.<ref name=":3" /> 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.<ref name="white" /> Kratom also contains rhynchophylline, a non-competitive NMDA receptor antagonist.<ref name="warner" /><ref>Template:Cite journal</ref>

Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resulting metabolites excreted in urine.<ref name="warner" /> In in vitro experiments, kratom extracts inhibited CYP3A4, CYP2D6, and CYP1A2 enzymes, which results in significant potential for drug interactions.<ref name="warner" />

Table 1: Pharmaceutical profile of Kratom

Kratom (Mitragynine, 7-Hydroxy-Mitragynine, Speciogynine, Paynantheine, Speciociliatine, Corynantheidine, Corynoxeine, Corynoxine B, Speciofoline)
Bioavailability:	PO estimated at 30%<ref name=":11">Template:Cite journal</ref>
Onset:	PO: 30 minutes
Peak plasma time:	1-4.5 hrs <ref name=":11" />
Duration:	3 or more hours<ref name=":11" />
Half-life:	12–45 hours<ref name=":11" />
Receptors:	Template:Unbulleted list
Mechanism of action:	Competitive antagonist at Kappa opioid receptors with stronger affinity compared to other receptors, competitive antagonist at Delta opioid receptors. Partial agonist at Mu opioid receptors. Causes G-protein linked second messenger activation, and calcium channel blocker.<ref name=":11" />
Metabolism:	Cytochrome P-450, inhibitor of CYP2D6 and CYP3A<ref name=":11" />
Excretion:	Renally

Chemistry

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

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.<ref name="warner" /> 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.<ref name="warner" /><ref>Template:Cite bookTemplate:Full citation needed</ref> At least 40 other compounds have been isolated from M. speciosa leaves,<ref name="Adkins 2011-05-01" /> including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from Rauvolfia serpentina), corynantheidine (also found in Corynanthe johimbe),<ref name="pmid11960505" /> as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline.<ref>Template:Cite journal</ref><ref name="Pharmacology">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> 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.<ref name=":4" />

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.<ref name="rosenbaum_2012" /><ref>Template:Cite journal</ref> 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.<ref name="rosenbaum_2012" /><ref>Template:Cite book</ref>

Regulation

File:Kratom laws.png

Kratom status by country Template:Legend-col

Template:As of, neither the plant nor its alkaloids were listed in any of the Schedules of the United Nations Drug Conventions.<ref name=EMCDDA/>

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. The committee, however, recommended kratom be kept "under surveillance."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

ASEAN

Template:As of, 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Australia and New Zealand

Template:As of, kratom was controlled as a narcotic in Australia and under Medicines Regulations 1985 (Amended August 6, 2015)<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> in New Zealand.<ref name=EMCDDA/>

Canada

Template:As of, Health Canada disallowed marketing of kratom for any use by ingestion<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and has taken action against companies marketing it for such purposes.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite news</ref> Kratom can be marketed for other uses, such as incense.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Europe

Template:As of, the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania, and Sweden.<ref name=EMCDDA/>

In Bulgaria and Norway, kratom is a controlled substance.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In the Czech Republic, regulated sales of kratom and kratom extracts became legal starting in July 2025.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In Finland, scheduled in the "government decree on psychoactive substances banned from the consumer market".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In the Republic of Ireland in 2017, kratom was designated a Schedule 1 illegal drug (the highest level), under the names 7-hydroxymitragynine and mitragynine.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In the UK, the sale, import, and export of kratom is prohibited under the Psychoactive Substances Act 2016, which broadly bans any substance that "produces a psychoactive effect".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite news</ref>

South America

Chile banned Kratom in 2021.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Argentina banned Kratom in 2017.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Brazil listed kratom as a New Psychoactive Substance (NPS) in 2020. However, it remains legal until it is included among prohibited substances.<ref>Kratom Legality by Country 2025</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Indonesia

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> However, in 2024, a revision to a regulation by Ministry of Trade legalized production and export of kratom leaves.<ref name=":9">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Later in September 2024, Indonesia's Ministry of Cooperatives and Small Medium Business stated that Indonesia will start building downstream industries for kratom exports.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":10">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> These developments made kratom legal to export and manufacture in Indonesia.<ref name=":9" /><ref name=":10" />

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) of the Poisons Act 1952, and will be punished by imprisonment or fine or both.<ref name=Utusan>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Veltri C, Grundmann O. Current perspectives on the impact of Kratom use. Subst Abuse Rehabil. 2019;10:23–31. Published 2019 Jul 1. doi:10.2147/SAR.S164261</ref> 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.<ref name="TMI">Pengasih wants abuse of kratom leaves penalised under Dangerous Drugs Act. The Malaysian Insider. October 28, 2012.</ref>

Thailand

Possession of kratom was illegal in Thailand until 2018.<ref name=AJ-20181226>Template:Cite news</ref> The Thai government had passed the Kratom Act 2486, effective 3 August 1943, which made planting the tree illegal,<ref name=usdea/> in response to a rise in its use when opium became very expensive in Thailand and the government was attempting to gain control of the opium market.<ref name=warner/> In 1979, the government placed kratom, along with cannabis, in Category V of a five-category classification of narcotics.<ref name=usdea/> Kratom accounted for less than two percent of arrests for narcotics between 1987 and 1992.<ref>Template:Cite journal</ref>

The Thai government has considered legalizing kratom for recreational use in 2004, 2009, 2013, and 2020.<ref>Template:Cite news</ref><ref>Template:Cite news</ref> In 2018, Thailand became the first Southeast Asian country to legalize kratom for medical purposes.<ref name=AJ-20181226 /> 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.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>

United States

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.<ref name="FDAImportAlert" /> Template:As of, kratom is illegal in six states: Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin, and it may be outlawed by local ordinance in other states.<ref name="C-Clinic">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> There was consideration in late 2017 to make kratom a Schedule I drug.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2019, the FDA warned consumers that kratom remains unapproved for interstate commerce for use as a drug,<ref name="fda6-19">{{#invoke:citation/CS1|citation |CitationClass=web }}Template:Dead linkTemplate:Cbignore</ref> may be unsafe in commercially available products, and is on an import alert, which can lead to confiscation of imported supplies.<ref name="fda4-3-19" /> Efforts to schedule kratom generated significant controversy, both among the general public and the scientific community, and were ultimately unsuccessful.<ref name=":2" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

On August 13, 2025, Florida attorney general James Uthmeier announced an emergency rule placing 7-hydroxymitragynine into Schedule I status under Florida state law, without any mention of a carve out or any exclusions for Mitragyna speciosa which contains low amounts of 7OH, effectively making kratom illegal in Florida.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="fda4-3-19" /> On April 4, 2018, the FDA issued the first mandatory recall in its history over concerns of salmonella contamination of several kratom-containing products.<ref name="Chappell">Template:Cite news</ref> 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.<ref name="FDArecall">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Chappell" /> Consumers were advised to immediately discard any such products to prevent serious health risks.<ref name="FDArecall" />

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.<ref name=FDA2018/> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=Tave />

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.<ref name="white" /><ref name="warner" /> 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."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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 and 2016.<ref name=dea>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This drew strong protests among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A group of 51 members of the U.S. House of Representatives and a group of nine Senators each sent letters to acting DEA administrator Chuck Rosenberg protesting the listing and around 140,000 people signed an online White House Petition protesting it.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>

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. We have to rely upon science."<ref>Template:Cite news</ref> In October 2016, the DEA withdrew its notice of intent while inviting public comments over a review period ending on December 1, 2016.<ref>Template:Cite news</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> As of July 2016, Alabama, Arkansas, Indiana, Vermont, and Wisconsin had made kratom illegal,<ref>Template:Cite news</ref> and the US Army had forbidden soldiers from using it.<ref>Template:Cite news</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Public response

The FDA's arguments for the federal prohibition of kratom have drawn both criticism and support.<ref name=":8">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":6">Template:Cite magazine</ref><ref name=":7">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> FDA commissioner Gottlieb responded to criticism in 2018 by stating that "The FDA has done an exhaustive review of adverse event reports, clinical literature and other sources of information related to kratom."<ref name=":6" /> 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."<ref name=":7" /> The FDA's position on kratom has also been criticized by the American Kratom Association and researchers including Walter Prozialeck.<ref name=":8" /><ref name=":6" /><ref>Template:Cite journal</ref> Former commissioner Gottlieb continued to defend the agency's position in 2021, stating that he was convinced that kratom was fueling the U.S. opioid epidemic, though Gottlieb's partiality has been called into question as he has since gone on to become a member of the board of directors of Pfizer Inc., a company that has been heavily criticized for its sale and marketing of opioid drugs.<ref name=":7" />

Research directions

Kratom is under preliminary research for possible antipsychotic and antidepressant properties, as well as pain management, withdrawal management, and dependence reduction.<ref name="ReferenceA"/><ref name="Jack T 2019"/><ref>Template:Cite journal</ref>

Kratom use has not been shown to affect positive mental health and shows a very small association with negative indicators (mainly externalizing disorders).<ref name=":12" />

See also

• Deumitragynine
• Pausinystalia johimbe

External links

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