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Mitragyna speciosa
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| Mitragyna speciosa | |
|---|---|
| Scientific classification | |
| Kingdom: | Plantae |
| Clade: | Tracheophytes |
| Clade: | Angiosperms |
| Clade: | Eudicots |
| Clade: | Asterids |
| Order: | Gentianales |
| Family: | Rubiaceae |
| Genus: | Mitragyna |
| Species: | M. speciosa
|
| Binomial name | |
| Mitragyna speciosa | |
| Synonyms[2] | |
| |
Mitragyna speciosa is a tropical evergreen tree of the Rubiaceae family (coffee family) native to Southeast Asia.[3] It is indigenous to Cambodia, Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea,[4] where its dark green, glossy leaves, known as kratom, have been used in herbal medicine since at least the 19th century.[5] They have also historically been consumed via chewing, smoking, and as a tea.[6] Kratom has opioid-like properties and some stimulant-like effects.[7][8]
The efficacy and safety of kratom are unclear.[9] In 2019, the US Food and Drug Administration (FDA) stated that there is no evidence that kratom is safe or effective for treating any condition.[10] Some people take it for managing chronic pain, for treating opioid withdrawal symptoms, or for recreational purposes.[4][11] The onset of effects typically begins within five to ten minutes and lasts for two to five hours.[4] 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.[11] Common side effects include appetite loss, erectile dysfunction, nausea and constipation.[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 liver injury.[4][15][16][17] Addiction is a possible risk with regular use: when use is stopped, withdrawal symptoms may occur.[8][11] A small number of deaths have been connected to the use of kratom, most commonly when mixed with other substances.[12] Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.[4][11]
As of 2018, kratom is a controlled substance in sixteen countries.[7] 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.[7][11][18] In some jurisdictions its sale and importation have been restricted, and several public health authorities have raised alerts.[11][18] Kratom is under preliminary research for possible antipsychotic and antidepressant properties.[19][20]
Description
[edit]
Mitragyna speciosa is an evergreen tree in the genus Mitragyna that can grow to a height of 25 m (82 ft). Its trunk may grow to a 0.9 m (3 ft) diameter.[21] The trunk is generally straight, and the outer bark is smooth and grey.[21] The leaves, ovate-acuminate in shape and opposite in growth pattern, are dark green, glossy on their upper surfaces,[11] and can grow to over 14–20 cm (5.5–7.9 in) long and 7–12 cm (2.8–4.7 in) wide. They have 12 to 17 pairs of veins.[21] The spherical inflorescences, which are deep yellow, grow in clusters of three at the ends of the branches.[22] The calyx-tube is 2 mm (0.08 in) long and has five lobes; the corolla-tube is 2.5–3 millimetres (0.098–0.12 in) long.[21]
Mitragyna speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea.[4] 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.[21]: 59
Uses of the leaves
[edit]| Kratom | |
|---|---|
Powder produced from unspecified tissues of the plant | |
| Part(s) of plant | Leaves |
| Geographic origin | Southeast Asia[18] |
| Active ingredients |
|
| Main producers | |
| Main consumers | Worldwide (No. 1: Thailand)[18][5] |
| Legal status | |

As of 2013[update], kratom has been studied in cells and in animals, but no clinical trials have been conducted in the United States.[5] The U.S. Drug Enforcement Administration (DEA) stated in 2013 that there is no legitimate medical use for kratom,[13] 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.[10]
Kratom is commonly ingested by chewing, as a tea, powdered in capsules or pills, or extracted for use in liquids.[5] Kratom is rarely smoked.[18] Different varieties of kratom contain different relative proportions of alkaloids such as mitragynine.[11]
Traditional use
[edit]In cultures where the plant grows, kratom has been used in traditional medicine.[8] The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to khat and coca.[11] 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.[4][5][21] They are also used as intestinal deworming agents in Thailand.[18][29]
Kratom is often used by workers in laborious or monotonous occupations to stave off exhaustion and as a mood-enhancer and painkiller.[21] In Thailand, kratom was "used as a snack to receive guests and was part of the ritual worship of ancestors and gods".[30] The herb is bitter and is generally combined with a sweetener.[23]
Opioid withdrawal
[edit]Because the withdrawal effects of kratom are often reported to be less severe than those associated with traditional opioids,[11] some people use kratom in the attempt to manage opioid use disorder,[31] though no clinical trials have been done supporting this use. As of 2018[update], there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction.[7] 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.[32] While some literature reviews claim that kratom has less potential for dependence or overdose than traditional opioids,[33][34] other reviews note that kratom withdrawal itself can still be quite severe.[35]
Data on how widely it is used worldwide are lacking, as it is not detected by typical drug screening tests.[23] 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.[23]
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.[5]
Recreational use
[edit]At low doses, kratom produces euphoric effects comparable to those of coca.[36] At higher doses, kratom produces opioid-like effects.[36] The onset of effects typically begins within five to ten minutes and lasts for two to five hours.[4] Some anecdotal reports describe increased work capacity, alertness, talkativeness, sociability, increased sexual desire, positive mood, and euphoria following the consumption of kratom.[11]
According to the U.S. DEA and a 2020 survey, kratom is used to alleviate pain, anxiety, depression, or opioid withdrawal.[13][37]
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,[18] and that kratom was the most widely used recreational drug in Thailand.[18]
Kratom may be mixed with other psychoactive drugs, such as caffeine and codeine.[8][38] 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.[39] As of 2012, use of the cocktail was a severe problem among youth in three provinces along the border of Malaysia and southern Thailand.[40]
In the U.S., as of 2015[update], 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.[11] In the United States, kratom use increased rapidly between 2011 and 2017.[41] By 2020, it was estimated that 15 million people worldwide use kratom.[42]
Adverse effects
[edit]Mitragyna speciosa may cause many adverse effects, and in November 2017 the FDA issued a public health advisory for the drug.[9] The side effects of kratom appear to be dose-dependent and are more common with doses that exceed 8 g.[34] 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%).[43][34] The study also reported two deaths and four cases of neonatal abstinence syndrome.[43] A different 2019 review listed as common side effects: decreased appetite, weight loss, erectile dysfunction, insomnia, sweating, hyperpigmentation, hair loss, tremor, and constipation.[12]
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.[44] 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.[4][11] 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.[11][14][45]
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] This may lead to resumption of use.[8][11][35]
Frequent use of high doses of kratom may cause tremors, anorexia, weight loss, seizures, psychosis and other mental health conditions.[11][46] Kratom use has a small but statistically significant association with externalizing mental health disorders.[47] Kratom use may worsen existing mental health conditions.[46] In case reports associating kratom use with psychosis, it remains unclear whether kratom use directly caused psychosis or simply unmasked the condition.[48] Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.[4][11] Herb–drug interactions may result when kratom is combined with alcohol, sedatives, benzodiazepines, opioids, caffeine, cocaine, yohimbine, or monoamine oxidase inhibitors (MAOIs).[45] Rhabdomyolysis is one of the rare and serious complications of this herb at high dosage.[49]
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.[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. For 173 (26.2%) exposure calls, no effects were reported, or poison center staff members were unable to follow up regarding effects.[17]
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.[41] 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.[41] 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.[41] 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.[50]
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.[4]
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.[51] 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.[51]
Addiction
[edit]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.[52] 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.[53] Kratom addiction carries a relapse risk as high as 78% to 89% at three months post-cessation.[54][55][56] In cases of severe addiction, an approach similar to the treatment of opioid addiction may be warranted.[57]
Respiratory depression
[edit]Respiratory depression is the leading cause of death from opioid use.[58] Although evidence is sparse, the risk of respiratory depression caused by taking kratom appears to be low, but, as of 2016[update], the Food and Drug Administration listed respiratory depression as a concern.[9][26] A 2018 review found that the alkaloids in kratom do not induce respiratory depression.[59]
Liver toxicity
[edit]Kratom use is thought to cause acute liver injury, with symptoms of abdominal discomfort, dark urine, itching and jaundice.[15][16] 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.[15] 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.[15]
Death
[edit]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.[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. Between 2011 and 2017, 44 U.S. deaths were kratom-related.[7] However, many cases could not be fully assessed, due to limited information.[7] People who die from kratom use typically have taken it in combination with other substances, or have underlying health conditions.[12]
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.[50][60][61] 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.[62][63]
Pharmacology
[edit]| Compound | Affinities (Ki (nM)) | Ratio | Ref | ||
|---|---|---|---|---|---|
| MOR | DOR | KOR | MOR:DOR:KOR | ||
| 7-Hydroxymitragynine | 13.5 | 155 | 123 | 1:11:9 | [64] |
| Mitragynine | 7.24 | 60.3 | 1,100 | 1:8:152 | [64] |
| Mitragynine pseudoindoxyl | 0.087 | 3.02 | 79.4 | 1:35:913 | [64] |
Kratom contains at least 54 alkaloids.[65][66][67] These include mitragynine, 7-hydroxymitragynine (7-HMG), speciociliatine, paynantheine, corynantheidine, speciogynine, mitraphylline, rhynchophylline, mitralactonal, raubasine, and mitragynaline.[9][11][34] The alkaloids mitragynine and 7-hydroxymitragynine are responsible for many of the complex effects of kratom,[9][11] but other alkaloids may also contribute synergistically.[34]
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.[34][45] 7-HMG appears to have higher affinity at the μ-opioid receptor than mitragynine.[9][59] 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.[34][68] Both mitragynine and 7-HMG readily cross the blood-brain barrier.[45][69]
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.[34] 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.[9] Kratom also contains rhynchophylline, a non-competitive NMDA receptor antagonist.[11][70]
Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resulting metabolites excreted in urine.[11] In in vitro experiments, kratom extracts inhibited CYP3A4, CYP2D6, and CYP1A2 enzymes, which results in significant potential for drug interactions.[11]
| Kratom (Mitragynine, 7-Hydroxy-Mitragynine, Speciogynine, Paynantheine, Speciociliatine, Corynantheidine, Corynoxeine, Corynoxine B, Speciofoline) | |
| Bioavailability: | PO estimated at 30%[71] |
| Onset: | PO: 30 minutes |
| Peak plasma time: | 1-4.5 hrs [71] |
| Duration: | 3 or more hours[71] |
| Half-life: | 12–45 hours[71] |
| Receptors: | Kappa: competitive antagonist
Delta: competitive antagonist Mu: partial agonist α2 adrenergic Adenosine A2a Dopamine D2 Serotonin receptors 5-HT2C and 5-HT7[71] |
| 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.[71] |
| Metabolism: | Cytochrome P-450, inhibitor of CYP2D6 and CYP3A[71] |
| Excretion: | Renally |
Chemistry
[edit]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.[11] 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.[11][72] At least 40 other compounds have been isolated from M. speciosa leaves,[23] including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from Rauvolfia serpentina), corynantheidine (also found in Corynanthe johimbe),[64] as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline.[73][74]
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.[75] 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.[45]
Detection in body fluids
[edit]The plant's active compounds and metabolites are not detected by a typical drug screening test but can be detected by more specialized testing.[63][76] 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.[63][77]
Regulation
[edit]
As of January 2018[update], neither the plant nor its alkaloids were listed in any of the Schedules of the United Nations Drug Conventions.[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. The committee, however, recommended kratom be kept "under surveillance."[78]
ASEAN
[edit]As of 2013[update], 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.[79]
Australia and New Zealand
[edit]As of January 2015[update], kratom was controlled as a narcotic in Australia and under Medicines Regulations 1985 (Amended August 6, 2015)[80] in New Zealand.[18]
Canada
[edit]As of October 2020[update], Health Canada disallowed marketing of kratom for any use by ingestion[81] and has taken action against companies marketing it for such purposes.[82][83] Kratom can be marketed for other uses, such as incense.[84]
Europe
[edit]As of 2011[update], the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania, and Sweden.[18]
In Bulgaria and Norway, kratom is a controlled substance.[85][86]
In the Czech Republic, regulated sales of kratom and kratom extracts became legal starting in July 2025.[87]
In Finland, scheduled in the "government decree on psychoactive substances banned from the consumer market".[88]
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.[89]
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".[90][91]
South America
[edit]Chile banned Kratom in 2021.[92]
Argentina banned Kratom in 2017.[93]
Brazil listed kratom as a New Psychoactive Substance (NPS) in 2020. However, it remains legal until it is included among prohibited substances.[94][95]
Indonesia
[edit]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.[96] However, in 2024, a revision to a regulation by Ministry of Trade legalized production and export of kratom leaves.[97] Later in September 2024, Indonesia's Ministry of Cooperatives and Small Medium Business stated that Indonesia will start building downstream industries for kratom exports.[98][99] These developments made kratom legal to export and manufacture in Indonesia.[97][99]
Malaysia
[edit]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.[100] 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.[101] 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.[102]
Thailand
[edit]Possession of kratom was illegal in Thailand until 2018.[103] The Thai government had passed the Kratom Act 2486, effective 3 August 1943, which made planting the tree illegal,[13] 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.[11] In 1979, the government placed kratom, along with cannabis, in Category V of a five-category classification of narcotics.[13] Kratom accounted for less than two percent of arrests for narcotics between 1987 and 1992.[104]
The Thai government has considered legalizing kratom for recreational use in 2004, 2009, 2013, and 2020.[105][106] In 2018, Thailand became the first Southeast Asian country to legalize kratom for medical purposes.[103] 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.[107][108]
United States
[edit]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.[26] As of 2021[update], 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.[109] There was consideration in late 2017 to make kratom a Schedule I drug.[110] In 2019, the FDA warned consumers that kratom remains unapproved for interstate commerce for use as a drug,[111] may be unsafe in commercially available products, and is on an import alert, which can lead to confiscation of imported supplies.[10] Efforts to schedule kratom generated significant controversy, both among the general public and the scientific community, and were ultimately unsuccessful.[31][112][113]
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.[114][115]
FDA assessment
[edit]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.[10] On April 4, 2018, the FDA issued the first mandatory recall in its history over concerns of salmonella contamination of several kratom-containing products.[116] 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.[117] 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.[116] Consumers were advised to immediately discard any such products to prevent serious health risks.[117]
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.[7] 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.[118] 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.[27]
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.[9][11] 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."[119]
DEA scheduling
[edit]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.[120] This drew strong protests among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol.[121] 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.[122][123]
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."[124] In October 2016, the DEA withdrew its notice of intent while inviting public comments over a review period ending on December 1, 2016.[125][126] As of July 2016, Alabama, Arkansas, Indiana, Vermont, and Wisconsin had made kratom illegal,[127] and the US Army had forbidden soldiers from using it.[128] 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.[129]
Public response
[edit]The FDA's arguments for the federal prohibition of kratom have drawn both criticism and support.[130][131][132] 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."[131] 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."[132] The FDA's position on kratom has also been criticized by the American Kratom Association and researchers including Walter Prozialeck.[130][131][133] 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.[132]
Research directions
[edit]Kratom is under preliminary research for possible antipsychotic and antidepressant properties, as well as pain management, withdrawal management, and dependence reduction.[19][20][134]
Kratom use has not been shown to affect positive mental health and shows a very small association with negative indicators (mainly externalizing disorders).[47]
See also
[edit]References
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Young people feel the need to drink 4x100 in hidden settings due to fears of arrest by law enforcement. In one district, 21 of 39 villages reported the presence of 4x100 users in their community. Compared to traditional use, 4x100 users are subject to some measure of community discrimination, though community perceptions are far milder than for yaba or heroin users.
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- ^ "FDA issues warnings to companies selling illegal, unapproved kratom drug products marketed for opioid cessation, pain treatment and other medical uses". US Food and Drug Administration. 25 June 2019. Retrieved 16 January 2020.[dead link]
- ^ MD PG (2019-08-07). "Kratom: Fear-worthy foliage or beneficial botanical?". Harvard Health. Retrieved 2021-06-21.
- ^ "Kratom ban will hinder studies of the plant as a treatment". Stat. 2016-09-08. Retrieved 2021-06-21.
- ^ "Attorney General James Uthmeier Files Emergency Rule; Immediately Removing Dangerous 7-OH from Store Shelves | My Florida Legal".
- ^ "Florida AG announces ban on "7-OH" products".
- ^ a b Chappell B (4 April 2018). "FDA Orders An Unprecedented Recall After Kratom Company Ignored Its Requests". NPR. Retrieved 5 April 2018.
- ^ a b FDA News Release. "FDA orders mandatory recall for kratom products due to risk of salmonella". Press Announcements. United States Food and Drug Administration. Archived from the original on April 5, 2018. Retrieved 5 April 2018.
- ^ "FDA oversees destruction and recall of kratom products; and reiterates its concerns on risks associated with this opioid". U.S. Food and Drug Administration. 21 February 2018. Archived from the original on February 22, 2018. Retrieved 7 March 2018.
The FDA recommends that consumers not use these or any kratom products and dispose of any products currently in their possession. While the FDA is not aware of recent reports of illness specifically associated with the use of Divinity Products Distribution's kratom-containing products, the agency asks healthcare professionals and consumers to report adverse events or quality problems associated with the use of Divinity Products Distribution's products or any kratom product to the agency's online Safety Reporting Portal
- ^ "Statement from FDA Commissioner Scott Gottlieb, M.D. on FDA advisory about deadly risks associated with kratom". U.S. Food and Drug Administration. 14 November 2017. Archived from the original on November 14, 2017. Retrieved 14 November 2017.
Patients addicted to opioids are using kratom without dependable instructions for use and more importantly, without consultation with a licensed health care provider about the product's dangers, potential side effects or interactions with other drugs. There's clear data on the increasing harms associated with kratom. Calls to U.S. poison control centers regarding kratom have increased 10-fold from 2010 to 2015, with hundreds of calls made each year. The FDA is aware of reports of 36 deaths associated with the use of kratom-containing products. There have been reports of kratom being laced with other opioids like hydrocodone. The use of kratom is also associated with serious side effects like seizures, liver damage, and withdrawal symptoms
- ^ "DEA Announces Intent to Schedule Kratom: SE Asian drug is imminent hazard to public safety". US Drug Enforcement Administration. 30 August 2016. Archived from the original on 15 September 2016. Retrieved 31 August 2016.
- ^ Silverman L (12 September 2016). "Kratom Advocates Speak Out Against Proposed Government Ban". NPR. Retrieved 12 September 2016.
- ^ Ingraham C (September 30, 2016). "DEA defies senators' appeal to reconsider 'unprecedented' kratom ban". The Washington Post.
- ^ Stapleton C (September 29, 2016). "Congress members ask DEA not to ban kratom: opioid research needed". Palm Beach Post. Archived from the original on November 3, 2016. Retrieved October 2, 2016.
- ^ Nelson S (September 30, 2016). "Kratom Will Remain Legal for Days, Possibly Longer". U.S. News & World Report.
- ^ "Kratom Gets Reprieve From Drug Enforcement Administration". NPR.org. Retrieved 2016-10-12.
- ^ "Withdrawal of Notice of Intent to Temporarily Place Mitragynine and 7-Hydroxymitragynine Into Schedule I: A Proposed Rule by the Drug Enforcement Administration on 10/13/2016". Federal Register. Drug Enforcement Administration. 2016-10-13. Retrieved 2016-10-18.
- ^ Brown M (May 20, 2016). "States ban kratom supplement over abuse worries". Associated Press via US News & World Report.
- ^ Schwarz A (2 January 2016). "Kratom, an Addict's Alternative, Is Found to Be Addictive Itself". The New York Times.
- ^ Smith PA (2019-02-19). "The Herbal Supplement That Might Be a Deadly Drug". Outside Online. Retrieved 2019-02-20.
- ^ a b "The U.S. May Ban Kratom. But Are its Effects Deadly or Lifesaving?". Discover Magazine. Retrieved 2021-06-22.
- ^ a b c Garber-Paul E, Garber-Paul E (2018-08-15). "Kratom Association Calls FDA Review of Drug 'Junk Science' in Scathing Report". Rolling Stone. Retrieved 2021-06-22.
- ^ a b c Marlan D (2021-06-08). "A Sensible, Evidence-Based Proposal for Kratom Reform". Bill of Health. Retrieved 2021-06-22.
- ^ Prozialeck WC, Avery BA, Boyer EW, Grundmann O, Henningfield JE, Kruegel AC, McMahon LR, McCurdy CR, Swogger MT, Veltri CA, Singh D (2019). "Kratom policy: The challenge of balancing therapeutic potential with public safety". The International Journal on Drug Policy. 70: 70–77. doi:10.1016/j.drugpo.2019.05.003. ISSN 1873-4758. PMC 7881941. PMID 31103778.
- ^ Prevete E, Kuypers KP, Theunissen EL, Corazza O, Bersani G, Ramaekers JG (2022). "A systematic review of (pre)clinical studies on the therapeutic potential and safety profile of kratom in humans". Human Psychopharmacology: Clinical and Experimental. 37 (1) e2805. doi:10.1002/hup.2805. ISSN 1099-1077. PMC 9285932. PMID 34309900.
External links
[edit]- "Kratom". European Union Drugs Agency (EUDA).
Mitragyna speciosa
View on GrokipediaMitragyna speciosa, commonly known as kratom, is an evergreen tree in the genus Mitragyna of the Rubiaceae family, native to tropical regions of Southeast Asia including Thailand, Malaysia, Indonesia, Borneo, the Philippines, and Papua New Guinea.[1][2] The plant typically reaches heights of 4 to 16 meters and thrives in swampy or riverine forests, producing glossy, dark green, oval-acuminate leaves and small yellow globular flowers.[3][4] The leaves of M. speciosa contain over 40 alkaloids, with mitragynine and 7-hydroxymitragynine as the primary active compounds responsible for its pharmacological effects; these alkaloids act as partial agonists at mu-opioid receptors while also influencing adrenergic and serotonin systems, yielding dose-dependent stimulant effects at low intakes (e.g., increased energy and alertness) and opioid-like analgesia, sedation, and euphoria at higher doses.[5][6][7] Traditionally, Southeast Asian laborers have chewed fresh leaves or consumed them as tea to mitigate fatigue, enhance productivity, and treat ailments such as pain, diarrhea, and opioid withdrawal symptoms.[8][9] In contemporary contexts, particularly in Western countries, kratom products—often in powdered, capsule, or extract forms—are used by millions for self-management of chronic pain, anxiety, and opioid dependence, with user reports and limited observational studies indicating potential harm reduction in opioid cessation; however, empirical evidence also documents risks of dependence, withdrawal, hepatotoxicity, and seizures, frequently in association with polysubstance use or adulterated products.[5][10][7] Legal status remains contested, federally unregulated in the United States as a botanical but subject to state-level bans and FDA advisories citing safety concerns and lack of approved therapeutic claims, amid ongoing debates over its abuse potential versus therapeutic utility informed by preclinical pharmacology rather than large-scale clinical trials.[2][11][12]
Botanical Characteristics
Taxonomy and Morphology
Mitragyna speciosa, commonly known as kratom, is classified in the kingdom Plantae, phylum Tracheophyta, class Magnoliopsida, order Gentianales, family Rubiaceae, genus Mitragyna, and species speciosa.[13] The species was first described by Pieter Willem Korthals in 1839, with the binomial name later formalized as Mitragyna speciosa (Korth.) Havil.[14] It belongs to the Rubiaceae family, which includes about 13,000 species worldwide, characterized by features such as opposite leaves and interpetiolar stipules.[15] Morphologically, Mitragyna speciosa is a tropical evergreen tree that typically reaches heights of 4 to 9 meters, though specimens can grow up to 15 to 30 meters under optimal conditions.[15] The trunk forms a bole 60 to 100 cm in diameter, with erect, branching stems supported by a taproot system featuring numerous lateral roots.[16] Leaves are elliptic to ovate-acuminate, measuring 8.5 to 14 cm in length and 4 to 10 cm in width, with a glossy dark green surface and prominent venation; they are opposite and borne on petioles with mitriform stipules at the base.[16] [17] Flowers are small, yellow, and arranged in globular clusters, forming dense inflorescences.[1] The fruit consists of paired cylindrical follicles approximately 12 cm long, containing numerous seeds with a 2 cm coma.[18]
These morphological traits align with the Rubiaceae family's general characteristics, including axillary cymes and capsular fruits in related genera, facilitating adaptation to humid, lowland tropical environments.[19] Variations in leaf size and shape occur across populations, influenced by environmental factors, but the core features remain consistent for taxonomic identification.[20]
Habitat and Cultivation
Mitragyna speciosa, commonly known as kratom, is native to Southeast Asia, including central and southern Thailand, peninsular Malaysia, Sumatra, Borneo, the Philippines, and New Guinea.[1] It thrives in tropical lowland habitats such as open savannas, secondary forests, and swampy areas at low elevations, often near water sources where soil remains consistently moist or waterlogged.[4][1] The plant favors humid, coastal, and peninsular topographies with high rainfall, exhibiting adaptations to periodic flooding and nutrient-poor, acidic soils typical of these regions.[17] In natural settings, M. speciosa grows as an evergreen or briefly deciduous tree reaching 10–30 meters in height, with a straight trunk up to 1 meter in diameter and smooth gray bark.[4] Its distribution correlates with warm temperatures averaging 25–30°C (77–86°F), high humidity exceeding 80%, and annual precipitation of 1,500–2,500 mm, conditions that support robust leaf production and alkaloid synthesis influenced by local air and soil variations.[17][21] Cultivation mirrors these native conditions, requiring tropical climates with temperatures between 24–30°C (75–85°F), relative humidity of 70–90%, and well-drained yet moisture-retentive soils with pH 5.5–6.5 and high organic content.[1][22] Growth diminishes rapidly under drought, while excessive dryness or poor drainage can stunt development; supplemental irrigation and shading are often necessary in non-native settings to replicate swamp-edge environments.[1][23] Propagation primarily occurs via seeds, which a single mature tree can produce in thousands annually, though germination rates are low due to dormancy and viability issues; stem cuttings succeed under aeroponic or high-humidity conditions, with rooting enhanced by photoperiods of 14–24 hours and hormones like indole-3-butyric acid.[1][24] In vitro methods offer alternatives for clonal propagation, while greenhouse trials demonstrate 93–114% height increases under controlled lighting compared to full sun, optimizing alkaloid yields.[25] Commercial cultivation, as in Indonesia and Thailand, emphasizes mature trees for leaf harvest, with fertilizer applications boosting growth but varying alkaloid profiles based on rates.[26] Challenges include low propagation success (under 50% for cuttings) and sensitivity to frost or temperatures below 15°C, limiting outdoor growth to USDA zones 10–11.[27][28]Chemical Composition
Major Alkaloids
Mitragyna speciosa leaves harbor over 40 structurally related indole alkaloids, with compositional profiles exhibiting significant variability attributable to genetic strains (chemotypes), geographical origin, harvest timing, and post-harvest processing.[29][30] Mitragynine, the predominant alkaloid and a partial agonist at mu-opioid receptors, typically comprises 1-6% of dry leaf weight in commercial samples and up to 66% of the total alkaloid fraction in Thai varieties.[29][3] In mitragynine-dominant strains such as Green Maeng Da (K49), it exceeds 450 mg per analyzed sample, far surpassing secondary alkaloids like speciociliatine, speciogynine, and paynantheine (each around 20 mg).[30] 7-Hydroxymitragynine, an oxidized derivative and more potent mu-opioid agonist than mitragynine, occurs at trace levels in native leaves, ranging from 0.01-0.04% of dry weight or below 0.001% detection limits, though it accumulates as a metabolite following ingestion.[29][31] It constitutes up to 2% of total alkaloids in some varieties.[3] Other notable alkaloids include paynantheine (an oxidoreductase inhibitor, ~9-15 mg in dominant samples), speciogynine (a stereoisomer of mitragynine, ~20 mg), speciociliatine (the 7-epimer of mitragynine), and speciofoline, which can predominate (>55 mg) in alternative chemotypes like White Jongkong (K52) alongside oxindoles such as corynoxine A and B (38-52 mg).[30][29] These minor constituents contribute to the plant's overall pharmacological diversity but are present at 5-10% or less of total alkaloid content relative to mitragynine in standard profiles.[30] Kratom extracts represent a concentrated form of alkaloids derived from the leaves through processing to enhance alkaloid content. In these extracts, mitragynine comprises 60-70% of the total alkaloids, with 7-hydroxymitragynine present at less than 2%. Available as powders, liquids, or tablets, extracts deliver stronger effects than plain leaf material while preserving a broad-spectrum alkaloid profile.[3]Methods of Detection
High-performance liquid chromatography (HPLC) coupled with photodiode array detection (PDA) or diode array detection (DAD) serves as a primary method for quantifying mitragynine and 7-hydroxymitragynine in Mitragyna speciosa leaves and raw materials, involving methanol extraction followed by separation on a C18 column with a mobile phase of acetonitrile and aqueous buffers.[32] [33] Validation of such HPLC-PDA methods demonstrates linearity over 1–200 μg/mL for mitragynine, with limits of detection around 0.5 μg/mL and recovery rates exceeding 95% from plant matrices.[32] Liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides superior sensitivity for detecting multiple kratom alkaloids, including mitragynine, speciogynine, and speciociliatine, in leaf extracts, often using electrospray ionization in positive mode and multiple reaction monitoring for quantification down to nanogram-per-milliliter levels.[34] [35] This technique achieves baseline separation of isomers like mitragynine (retention time ~3.4 min) and enables simultaneous analysis of up to ten alkaloids in under 23 minutes per sample, with validated linearity from 1–200 ng/mL.[35] [36] Gas chromatography-mass spectrometry (GC-MS) is applied for both qualitative identification and quantification of mitragynine in kratom products after derivatization to enhance volatility, though it is less common than LC-based methods due to potential thermal degradation of alkaloids.[37] [38] Complementary techniques include direct analysis in real-time high-resolution mass spectrometry (DART-HRMS) for rapid presumptive screening of mitragynine in plant material without extensive preparation, achieving quantification limits of approximately 0.1% w/w.[39] Quantitative nuclear magnetic resonance (qNMR) offers a reference-standard approach for precise alkaloid measurement in extracts, independent of chromatographic separation.[40]Pharmacology
Receptor Binding and Mechanisms
Mitragynine, the predominant alkaloid in Mitragyna speciosa comprising up to 66% of total alkaloid content, binds to mu-opioid receptors (MOR) with moderate affinity (Ki approximately 200-500 nM in rodent models, varying by assay), functioning primarily as a partial agonist that preferentially activates G-protein signaling over β-arrestin pathways, which may contribute to reduced respiratory depression compared to full agonists like morphine.[41][6] Its metabolite, 7-hydroxymitragynine (7-HMG), formed via cytochrome P450-mediated hydroxylation, exhibits 7- to 28-fold higher binding affinity at MOR (Ki approximately 10-20 nM), κ-opioid receptors (KOR), and δ-opioid receptors (DOR), acting as a more potent partial agonist at MOR responsible for much of the plant's analgesic potency despite its lower concentration (typically <0.02% in leaves).[42][41][6] Both alkaloids show weaker interactions at non-opioid receptors, including adrenergic α2 receptors, where mitragynine demonstrates postsynaptic activation akin to yohimbine, potentially underlying stimulant effects at low doses, though with lower affinity than at opioid sites.[5][43] Serotonergic modulation occurs via binding to 5-HT1A receptors (Ki values of 0.54-5.8 μM for speciogynine, mitragynine, and related congeners), contributing to anxiolytic-like activity partly mediated through dopamine D1 and D2 receptors, where mitragynine acts as a moderate agonist.[44][45] These polypharmacological interactions, including inhibitory effects on cytochrome P450 enzymes like CYP3A and CYP2D6, suggest potential for downstream signaling crosstalk, such as enhanced antinociception via combined MOR and α2-adrenergic activation, though in vitro efficacy varies with receptor subtype and species.[46][47]| Alkaloid | MOR Affinity (Ki, nM) | Primary Mechanism at MOR | Other Key Interactions |
|---|---|---|---|
| Mitragynine | ~200-500 (rodent/human assays) | Partial agonist, G-protein biased | α2-adrenergic agonist; 5-HT1A partial agonist; D1/D2 dopamine agonist[41][45] |
| 7-Hydroxymitragynine | ~10-20 (9-fold > mitragynine) | Partial agonist | Weaker at α2-adrenergic; KOR/DOR binding[42][41] |
Physiological and Psychological Effects
The primary physiological effects of Mitragyna speciosa are dose-dependent and biphasic, with low doses (typically 1-5 g of leaf material, equivalent to approximately 10-50 mg mitragynine) eliciting stimulant-like responses such as increased energy, alertness, and enhanced physical performance, mediated in part by adrenergic and serotonergic receptor interactions.[48] Higher doses (above 5 g, or roughly 50-100 mg mitragynine) shift toward sedative and analgesic outcomes, primarily through partial agonism at mu-opioid receptors by the alkaloid 7-hydroxymitragynine, which exhibits about fivefold greater affinity for these receptors than mitragynine itself.[29] [42] Analgesic effects have been demonstrated in animal models via hot-plate and tail-flick tests, where mitragynine and its metabolites reduce nociception comparably to low-dose opioids but with reduced respiratory depression.[49] Autonomic physiological responses include potential cardiovascular changes such as tachycardia (reported in 22.5% of U.S. poison control cases from 2011-2017) and elevated blood pressure, particularly with polysubstance use or higher intakes (mean 434 mg/day mitragynine associated with 8.6-fold increased odds of sinus tachycardia in a 2021 study).[50] Gastrointestinal effects commonly involve constipation, nausea (14.7% prevalence in user surveys), and vomiting (12.9%), attributable to opioid receptor modulation slowing gut motility.[50] Neurological impacts range from mild headaches and disorientation at moderate doses to rare seizures or coma in overdose scenarios, often confounded by adulterants or co-ingestants.[50] Psychologically, M. speciosa consumption is associated with mood elevation, reduced anxiety, and euphoria, particularly among users employing it for self-medication, as evidenced by observational data where daily users report improved productivity and opioid substitution benefits.[51] A 2024 multilevel meta-analysis of 36 studies found no significant correlation with positive mental health indicators (r = -0.031, 95% CI [-0.149, 0.087]) but a small positive association with negative indicators overall (r = 0.092, 95% CI [0.020, 0.164]), driven largely by externalizing disorders like substance use (r = 0.201, 95% CI [0.107, 0.300]).[52] Cognitive effects in humans appear limited; a 2018 study of frequent users (intakes >3 glasses/day, equating to 72.5-74.9 mg mitragynine) showed no deficits in motor function, memory, attention, or executive performance despite high consumption.[49] However, acute high doses (e.g., 40 mg mitragynine) may induce subjective amnesia and mild distress, while animal data suggest potential impairments in object recognition or working memory with chronic exposure.[53] [49] Antidepressant-like effects have been observed in rodent models via GABA_B receptor activation, though human evidence remains anecdotal or correlational.[49]Historical Context
Traditional Uses in Southeast Asia
Mitragyna speciosa, indigenous to countries including Thailand, Malaysia, Indonesia, and Myanmar, has been utilized traditionally by rural laborers for its stimulant effects to boost endurance and mitigate fatigue during demanding physical work such as farming, rubber tapping, and fishing. In Thailand, workers typically chewed 1-3 fresh leaves multiple times daily, often mixed with sugar to counteract bitterness, to enhance productivity and provide mild euphoria.[54] [55] Similar practices prevailed in Malaysia, where the plant, known as ketum or biak, was consumed to support prolonged manual labor without significant social stigma, particularly among men fulfilling familial obligations.[54] [56] Beyond stamina enhancement, the leaves served medicinal purposes in folk remedies across these regions, addressing conditions like pain, diarrhea, fever, cough, hypertension, diabetes, and wounds through preparation as teas from fresh or dried leaves or as topical poultices.[56] [55] In areas with historical opium consumption, Mitragyna speciosa acted as an accessible substitute, aiding in withdrawal management or replacing unavailable opium supplies, with reports of its use for deworming, appetite suppression, and even as an aphrodisiac in Malaysian traditions.[57] [56] Culturally, consumption extended to social and ritual contexts, functioning as an evening beverage in male gatherings—preferred over alcohol by some Muslim communities—and as an offering in village religious ceremonies in Thailand.[56] Ethnopharmacological documentation traces these applications back centuries, with Western reports emerging around 1836, though oral traditions suggest millennia of integration into Southeast Asian ethnobotany; regulatory responses included Thailand's 1943 ban and Malaysia's 1952 classification under the Poisons Act amid concerns over dependency.[54] [55]Introduction to Western Markets
Mitragyna speciosa, known as kratom, gained initial Western botanical recognition in 1831 when Dutch botanist Pieter Willem Korthals documented the plant during expeditions in Southeast Asia.[58] Commercial availability in the United States emerged in the mid-1990s through smoke shops and herbal stores, often adulterated initially to enhance appeal, with broader online sales developing by the early 2000s.[59] Early adoption included Southeast Asian immigrants and Vietnam War veterans familiar with traditional preparations, though documented self-treatment cases for opioid withdrawal and pain surfaced prominently in the early 2000s.[60] In Europe, kratom products, including extracts like "kratom acetate," appeared in head shops and online markets around the same early 2000s period, sourced primarily from Southeast Asian cultivation.[61] Consumption patterns shifted toward recreational and self-medicative uses in the 2010s, coinciding with the U.S. opioid crisis, as users reported kratom's alkaloids providing opioid-like effects without pharmaceutical prescriptions.[62] U.S. use increased rapidly from 2011 to 2017, with the first kratom-serving kava bars opening in Florida in 2002 and expanding thereafter, facilitating social consumption.[63] National surveys indicate past-year kratom use among approximately 0.7% of U.S. adults by the early 2020s, equating to roughly 1.8 million individuals, predominantly White middle-class males in certain regions.[64][65] Market growth persisted despite limited regulation, with kratom ranking among the top 25 functional ingredients in mainstream sales by 2024, driven by powder and leaf products imported mainly from Indonesia.[66] Regulatory responses shaped market dynamics from the outset. The U.S. Food and Drug Administration issued its initial import alert for kratom-containing products in 2012, escalating to broader detentions in 2014 amid concerns over contamination and adulteration, though enforcement focused on imports rather than domestic sales.[67] State-level prohibitions began with Alabama in 2016, followed by others like Arkansas and Indiana, creating a patchwork of legality that influenced distribution but failed to curb overall availability or user estimates of 2 to 15 million daily U.S. consumers.[68] In Europe, status varied by nation, with some countries like the UK classifying mitragynine as controlled by 2016, yet online and gray-market sales continued amid calls for harmonized oversight.[69] This regulatory tension, often highlighting risks from mainstream health authorities, contrasted with user-driven demand, sustaining an unregulated industry valued in billions globally by the mid-2020s.[70]Potential Benefits and Uses
Analgesic and Anti-Inflammatory Effects
Mitragynine, the primary alkaloid in Mitragyna speciosa, and its metabolite 7-hydroxymitragynine act as partial agonists at mu-opioid receptors (MOR), contributing to analgesic effects through biased agonism that favors G-protein signaling over β-arrestin-2 recruitment, potentially reducing certain adverse outcomes associated with full opioid agonists.[42][6] Preclinical rodent models have demonstrated dose-dependent antinociception from mitragynine, with efficacy comparable to or exceeding morphine in some assays, mediated partly by MOR but also involving non-opioid pathways such as serotonin release and adrenergic modulation.[71][72] A randomized, placebo-controlled, double-blind trial conducted in 2020 involving healthy volunteers tested oral kratom decoction (equivalent to 0.71 mg/kg mitragynine) and found a statistically significant increase in pain tolerance threshold during cold pressor testing, with effects peaking at 2 hours post-ingestion and lasting up to 5 hours, though subjective pain intensity reductions were not significant.[73] User surveys and observational data indicate that chronic pain is prevalent among kratom consumers, with many reporting substantial self-managed relief from conditions like back pain or arthritis, often at doses of 3-5 grams of leaf powder multiple times daily, though these accounts are subject to self-report bias and confounding by concurrent substance use.[74] Regarding anti-inflammatory effects, methanolic and ethanolic extracts of M. speciosa leaves have shown inhibition of pro-inflammatory mediators in carrageenan-induced paw edema models in rats, reducing edema volume by up to 50% at doses of 100-200 mg/kg, comparable to indomethacin.[75][76] Mitragynine specifically suppresses cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) pathways in vitro, decreasing prostaglandin E2 production and vascular permeability in lipopolysaccharide-stimulated macrophages, while also modulating nitric oxide and reactive oxygen species in wound healing models.[77][78] These findings align with traditional use for inflammatory conditions, but human clinical data remain sparse, limited primarily to anecdotal reports and preclinical extrapolations, necessitating caution against overgeneralization due to inter-species pharmacokinetic differences.[79]Role in Opioid Use Disorder Management
Mitragyna speciosa, known as kratom, is utilized by some individuals to self-manage opioid use disorder (OUD), primarily for alleviating withdrawal symptoms such as anxiety, muscle aches, and cravings, as well as reducing overall opioid consumption. In a 2019 online survey of 2,361 kratom users who substituted it for opioids, 91% reported it helped relieve withdrawal, 86% noted decreased opioid use, and 67% experienced reduced pain without opioids.[80] Similarly, a 2021 analysis of national survey data found kratom use more prevalent among those with opioid misuse histories, with self-reports indicating its role in mitigating dependence symptoms.[81] These patterns align with broader observational evidence from 2021 reviews, where kratom emerged as a self-treatment option amid the U.S. opioid crisis, often preferred for its partial opioid agonist effects via alkaloids like mitragynine and 7-hydroxymitragynine.[82] Preclinical research provides mechanistic support for these applications, showing kratom extracts and mitragynine attenuate opioid withdrawal in animal models. For example, in a 2020 study, lyophilized kratom tea administered repeatedly to morphine-dependent rats significantly decreased naloxone-precipitated withdrawal behaviors without inducing physical dependence in non-dependent animals.[83] Mitragynine demonstrates lower abuse liability than classic opioids in rodent self-administration assays, with precipitated withdrawal being less severe and shorter-lasting, attributed to its atypical partial agonism at mu-opioid receptors and additional non-opioid pathways.[84] A 2022 mini-review of preclinical data further highlighted mitragynine's potential therapeutic value, noting reduced adverse effects like respiratory depression compared to morphine.[85] Human clinical evidence, however, is sparse and largely anecdotal or observational, lacking large-scale randomized controlled trials to establish efficacy or safety for OUD management. A 2024 review positioned kratom as a potential harm reduction agent, citing user reports of alleviated cravings and lower overdose risk—estimated at over 1,000 times less than opioids based on toxicity data—but emphasized the need for controlled studies amid variable product potency.[86][84] The U.S. Food and Drug Administration has not approved kratom for any medical use, including OUD, due to insufficient evidence and reports of adverse events, though it acknowledges self-treatment patterns.[11] Dependence risks persist, with surveys identifying kratom use disorder in up to 11% of regular users, featuring withdrawal symptoms treatable via opioid protocols like buprenorphine, though milder than full opioid withdrawal in severity.[87] Ongoing trials, such as a 2023 protocol assessing kratom withdrawal with Clinical Opiate Withdrawal Scale monitoring, underscore the parallels to opioid dependence while exploring management strategies.[88]Other Reported Applications
Kratom has been reported for anxiolytic and mood-enhancing effects, with users citing reductions in anxiety symptoms and improvements in overall mood.[89] [52] A systematic review of user experiences indicated that 67% employed kratom for anxiety and 42% for depression, often as self-medication.[90] Preclinical studies attribute these effects to mitragynine's interactions with adrenergic and serotonin receptors, suggesting antidepressant and anxiolytic potential, though human clinical trials remain limited.[48] [91] At lower doses, kratom exhibits stimulant properties, with reports of increased energy, alertness, and fatigue mitigation among laborers and users seeking cognitive enhancement.[92] Traditional Southeast Asian use includes boosting stamina for manual work, supported by anecdotal evidence of enhanced productivity without the crash associated with caffeine.[93] [94] Emerging reports link kratom to metabolic benefits, including blood glucose regulation and potential antidiabetic effects. Thai research identified kratom compounds that lower blood sugar levels, synergizing with insulin or antidiabetic drugs in preliminary models.[79] A 2025 meta-analysis found associations between regular kratom use and reduced metabolic syndrome risks, such as lower BMI and improved lipid profiles, though causality requires further validation.[95] Traditional applications also encompass cough suppression and diarrhea management, attributed to mitragynine's antitussive and antidiarrheal actions in ethnomedicinal contexts.[93] [94] These uses stem largely from self-reports and observational data, with preclinical evidence but scant randomized controlled trials confirming efficacy or safety.[91]Risks and Adverse Outcomes
Dependence Formation and Withdrawal
Dependence on Mitragyna speciosa develops through repeated exposure to its primary alkaloids, mitragynine and 7-hydroxymitragynine, which act as partial agonists at mu- and delta-opioid receptors, inducing neuroadaptations including tolerance and downregulation of endogenous opioid systems.[7] This partial agonism, characterized by G-protein biased signaling that minimizes beta-arrestin recruitment, results in dependence formation that is mechanistically similar to but less intense than that of full opioid agonists like morphine, as evidenced by lower reinforcement in animal self-administration models.[96] Chronic use, particularly at doses exceeding 5 grams of leaf equivalent daily (yielding approximately 200-300 mg mitragynine), elevates risk, with tolerance manifesting as escalating intake to achieve desired effects.[97] Empirical data indicate high dependence rates among heavy users but low overall incidence. In a 2012 survey of 293 Malaysian males with regular kratom consumption averaging 3.5 glasses daily (equivalent to 276 mg mitragynine), over 50% met criteria for severe dependence after more than six months of use, with odds increasing at higher doses.[97] Among U.S. daily or near-daily users, 66.7% fulfilled DSM-5 criteria for kratom use disorder in a 2024 analysis, correlating with dose frequency and withdrawal endorsement.[98] Conversely, fewer than 10% of broader U.S. kratom users report clinically significant withdrawal, suggesting dependence primarily affects chronic, high-dose consumers rather than occasional ones.[99] Withdrawal symptoms onset 12-48 hours post-cessation, peak within 1-3 days, and subside over 3-10 days, driven by abrupt discontinuation of opioid receptor stimulation alongside disruptions in adrenergic, serotonergic, and dopaminergic pathways.[99] Physical manifestations include rhinorrhea, myalgias, diarrhea, insomnia, diaphoresis, and anorexia, while psychological features comprise anxiety, irritability, restlessness, depressed mood, tension, anger, and intense cravings.[97][99] These are typically moderate in severity and self-limiting, contrasting with the more profound autonomic hyperactivity and protracted course of classic opioid withdrawal.[99] Treatment emphasizes supportive care and tapering; most cases resolve without intervention, though adjuncts like clonidine for autonomic symptoms or lofexidine for alpha-2 agonism may alleviate discomfort.[99] Users commonly report using supplements to manage symptoms, including magnesium glycinate (200–400 mg daily for reducing muscle tension, anxiety, restlessness, and supporting sleep); vitamin C (500–2000 mg daily, divided doses, for antioxidant support and detoxification); B-complex vitamins (for addressing nutrient depletion, supporting energy levels, and promoting mood stability); agmatine sulfate (for modulating tolerance and mood support); and omega-3 fatty acids (EPA/DHA for anti-inflammatory effects and mood improvement). Other options such as passionflower for anxiety and insomnia or DL-phenylalanine for mood support are also reported, though evidence for their efficacy is limited. Buprenorphine or methadone is effective for severe presentations, particularly with comorbid opioid use disorder, but carries risks of precipitating withdrawal if mismatched to kratom's partial agonism profile.[100] Neonatal withdrawal has been documented in infants exposed in utero, presenting with irritability, tremors, and feeding difficulties treatable via standard opioid protocols.[7]Acute and Chronic Toxicity
Acute toxicity from Mitragyna speciosa typically arises at doses exceeding 8 grams, producing symptoms such as nausea, vomiting, dizziness, constipation, agitation, tachycardia, hypertension, and confusion, with rarer instances of seizures, coma, or respiratory depression mimicking an opioid toxidrome.[7][101] Combining kratom with alcohol, medications, or other substances should be avoided due to increased risks of interactions and exacerbated adverse effects. In animal studies, oral administration of kratom extracts up to 2000 mg/kg body weight in rats resulted in no mortality, though elevated liver enzymes and mild hepatic congestion were observed, suggesting a high acute safety margin relative to typical human doses of 1-5 grams.[102] Human case series of presumed overdoses report similar acute effects, including loss of consciousness and seizures in survivors, but postmortem analyses of 35 kratom-associated deaths revealed polysubstance involvement—such as opioids, benzodiazepines, or stimulants—in 91% of cases, with mitragynine blood levels ranging from 3.5 to 7500 ng/mL often not exceeding therapeutic ranges in isolation.[103] No verified fatalities attributable solely to kratom have been identified, as confounding factors like adulterants or co-ingestants consistently complicate causal attribution in toxicology reports.[103] Chronic toxicity primarily involves hepatotoxicity, with at least 24 documented cases of drug-induced liver injury linked to regular use, manifesting as cholestatic or mixed patterns with jaundice, pruritus, fatigue, and peak bilirubin levels exceeding 20 mg/dL in severe instances, typically emerging 1-8 weeks after initiation, alongside potential blood pressure problems from prolonged use.[104][101] These cases often resolve spontaneously upon cessation, though prolonged cholestasis may occur, and management with N-acetylcysteine has been attempted without established efficacy; predisposing factors include higher doses or underlying liver conditions, but incidence remains low relative to widespread use.[104] Subchronic animal studies at 100-500 mg/kg over 28 days showed liver hypertrophy, sinusoid dilation, and renal tubular damage without lethality, alongside human reports of rare cardiotoxicity like arrhythmias, underscoring potential organ risks from prolonged exposure but highlighting the paucity of large-scale longitudinal data.[102] Overall, empirical evidence indicates chronic effects are infrequent and reversible in most instances, though variability in product alkaloid content—due to unregulated sourcing—may elevate risks beyond standardized extracts.[102]Associated Mortality and Case Reviews
A 2019 analysis by the Centers for Disease Control and Prevention (CDC) of U.S. national vital records identified 152 unintentional overdose deaths involving kratom detection between July 2016 and December 2017, spanning 27 states; however, every case included concurrent detection of other substances, with opioids present in 89.6% (136 cases), benzodiazepines in 60.5% (92 cases), and stimulants in 18.4% (28 cases).[105] Medical examiners or coroners attributed kratom as a contributing cause in 91 (59.9%) of these deaths, based on factors such as positive toxicology and absence of trauma, though no fatalities were linked exclusively to kratom.[105] This pattern aligns with earlier poison center data from 2011–2015, where kratom exposures rarely resulted in death (one reported case involving co-ingestants paroxetine and lamotrigine).[106] Reviews of state-level data reinforce polysubstance confounding. In Colorado, examination of death certificates from 1999 to 2017 revealed 15 kratom-associated fatalities, all involving combinations with fentanyl, heroin, methamphetamine, or other depressants, with no isolated kratom attributions.[107] A 2025 systematic evaluation of 95 kratom-related acute adverse events (including hospital and autopsy data) confirmed mitragynine in 55 cases, 35 of which were fatal; yet, benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), opioids, and antipsychotics co-occurred frequently, complicating direct causality.[103] Toxicology literature notes that while high-dose mitragynine can induce respiratory depression or seizures in animal models, human case reports of pure kratom lethality remain absent, with documented overdoses typically exceeding 15 grams of leaf equivalent and involving adulterants or synergists.[102] Comparative risk assessments estimate kratom's overdose mortality rate at over 1,000 times lower than prescription or illicit opioids, based on exposure-adjusted incidence from user surveys and death registries.[86] Rare exceptions involve adulterated products, such as those laced with synthetic analogs like 7-hydroxymitragynine, which contributed to multiple fatalities in Los Angeles County in 2025 among otherwise healthy individuals, absent other substantive contributors.[108] Case series from poison centers and emergency departments highlight non-fatal outcomes like agitation, tachycardia, and coma in 80–90% of symptomatic exposures, often resolving with supportive care, underscoring kratom's narrow therapeutic window only in polypharmacy contexts.[109] Federal agencies like the FDA have cited kratom in over 40 deaths as of 2017, but these reports derive from voluntary adverse event submissions without mandatory toxicology adjudication, limiting their evidentiary weight relative to coroner-verified data.[110]Patterns of Modern Consumption
Recreational and Self-Medicative Use
Surveys of kratom users in the United States reveal that self-medicative use predominates, with recreational consumption forming a smaller subset, often overlapping with therapeutic intentions such as mood enhancement or productivity boosts. In a 2020 online survey of 2,798 primarily American users (mean age 40 years, 90% White, 61% female), 91.3% reported using kratom for pain relief, 67% for anxiety or depression, and 65.6% for opioid withdrawal management, while 37.1% endorsed it for increasing energy or alertness, indicative of recreational stimulant-seeking.[111] Similarly, a 2022 analysis of self-reported motivations among kratom consumers found 73% using it to self-treat pain and 42.2% for emotional or mental health conditions without medical oversight, with daily use common for sustained symptom management.[112] These patterns align with ecological momentary assessments showing most users dose daily to alleviate pain, elevate mood, or substitute for opioids, though some report acute recreational effects like euphoria or sociability at low doses (1-5 grams).[51] Recreational use typically involves lower doses for mitragynine's stimulant properties, mimicking caffeine-like effects including increased focus and mild euphoria, contrasting with higher-dose (5-15 grams) sedation akin to opioids due to 7-hydroxymitragynine.[113] In Southeast Asia, traditional patterns blend labor enhancement with occasional intoxication, but Western adoption emphasizes self-medication for chronic conditions, with 68.9% of surveyed substance users citing reduction of opioid dependence as a key driver.[114] Prevalence data from the 2019 National Survey on Drug Use and Health estimate past-year kratom use at 0.7% nationally, concentrated among middle-aged, educated individuals seeking alternatives to prescription drugs.[81] User demographics skew toward those with prior substance use histories, where kratom serves as a perceived lower-risk option for managing withdrawal or cravings, though self-reports may underrepresent purely recreational initiators due to survey recruitment via pro-kratom communities.[113][111] Divergent motivations highlight kratom's dual profile: therapeutic applications outnumber recreational ones in U.S. data, with over 40 endorsed reasons including fatigue mitigation and psychiatric symptom control, yet field studies note recreational escalation risks in non-medical contexts.[115] Convenience sampling in these studies introduces potential selection bias favoring positive outcomes, as participants are often advocates, contrasting with regulatory concerns over unmonitored escalation from self-medication to dependence.[116] Nonetheless, cross-study consistency underscores self-medicative primacy, with recreational elements more evident in acute, low-dose scenarios or among younger users experimenting for social or performance enhancement.[51][117]Dosage and Product Forms
Mitragyna speciosa, commonly known as kratom, is available in several product forms, primarily derived from its dried leaves. The most prevalent forms include powdered leaf, which is ground from dried foliage and consumed directly or mixed into beverages; encapsulated powder for convenient oral ingestion; and brewed teas prepared by steeping leaves or powder in hot water.[7][2] Extracts, which concentrate alkaloids like mitragynine through processes such as solvent evaporation, are also marketed in liquid, resin, or enhanced powder variants, though these vary widely in potency due to inconsistent standardization.[3] Less common forms encompass whole dried leaves for chewing or fresh leaves in traditional Southeast Asian contexts, and innovative preparations like tinctures or gummies in modern markets.[5] Consumption methods emphasize oral administration to facilitate absorption of active alkaloids. Powder is often ingested via "toss and wash," where it is placed on the tongue and swallowed with liquid, or incorporated into food and drinks to mask its bitter taste; capsules provide measured doses without direct tasting; and teas allow for decoction-based extraction, sometimes enhanced with citrus for alkaloid solubility.[111] In user surveys, powder ingestion accounts for approximately 44% of use, followed by prepared beverages at around 30%.[111] These forms lack regulatory oversight, leading to variability in alkaloid content—typically 1-2% mitragynine in leaf material—which influences effective dosing.[30] Dosage recommendations derive from self-reported user data rather than clinical standardization, with effects dose-dependent: low doses (1-5 grams of dried leaf equivalent) commonly elicit stimulant properties such as increased energy and sociability, while moderate to high doses (5-15 grams) produce opioid-like sedation, analgesia, and euphoria.[118] A survey of regular U.S. users indicated typical single doses ranging from under 1 gram (8.6%) to over 7 grams (8.9%), with 3-5 grams being the most frequent (about 41% of administrations).[119][118] Beginners are advised to start at 1-2 grams to assess tolerance, as individual factors like body weight, strain potency, and prior opioid exposure modulate responses; exceeding 15 grams risks nausea, dizziness, or dysphoria.[3] Daily consumption patterns among habitual users often involve multiple doses totaling 5-20 grams, though chronic high intake correlates with dependence risks.[119] Equivalent mitragynine doses approximate 12-50 milligrams, underscoring the need for strain-specific alkaloid testing absent in unregulated products.[120]