Biology:Mitragyna speciosa

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Short description: Plant species, recreational drug (kratom)

Mitragyna speciosa
Mitragyna speciosa111.JPG
Scientific classification edit
Kingdom: Plantae
Clade: Tracheophytes
Clade: Angiosperms
Clade: Eudicots
Clade: Asterids
Order: Gentianales
Family: Rubiaceae
Genus: Mitragyna
Species:
M. speciosa
Binomial name
Mitragyna speciosa
(Korth.) Havil.
Synonyms[2]
  • Nauclea korthalsii Steud. nom. inval.
  • Nauclea luzoniensis Blanco
  • Nauclea speciosa (Korth.) Miq.
  • Stephegyne speciosa Korth.

Mitragyna speciosa (commonly known as kratom, an herbal leaf from a tree of the Rubiaceae family[3][4]) is a tropical evergreen tree in the coffee family native to Southeast Asia. It is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea,[5] where it has been used in herbal medicine since at least the 19th century.[6] It has also historically been used for chewing, smoking, and tea.[7] Kratom has opiate properties and some stimulant-like effects.[8][9]

(As of 2018), the efficacy and safety of kratom are unclear. Although it was a federally legal dietary supplement, it was not approved as a therapeutic agent in the United States due to the poor quality of the research.[10][11] 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.[12] Some people take it for managing chronic pain, for treating opioid withdrawal symptoms, or for recreational purposes.[5][10] The onset of effects typically begins within five to ten minutes and lasts for two to five hours.[5]

Anecdotal reports describe increased alertness, physical energy, talkativeness, sociability, sedation, changes in mood, and pain relief following kratom use at various doses.[10] Common side effects include appetite loss, erectile dysfunction, nausea and constipation.[13] More severe side effects may include respiratory depression (decreased breathing), seizure, addiction, and psychosis.[5][8][14][15] Other side effects may include high heart rate and blood pressure, trouble sleeping, and, rarely, liver toxicity.[5][16][17][18] When use is stopped, withdrawal symptoms may occur.[10][9] A number of deaths have been attributed to the use of kratom, both by itself and mixed with other substances.[8] Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.[5][10]

In 2014, the FDA banned the import of the legal dietary supplement kratom into the U.S. due to lack of evidence for its safety.[19] (As of 2021) 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.[20]

As of 2018, kratom is a controlled substance in 16 countries.[8] (As of 2018), there is growing international concern about a possible threat to public health from kratom use, while others have argued that it could be a tool to help the opioid crisis.[21][8][10][22] In 2021, the World Health Organization's Executive Committee on Drug Dependency investigated the risks of kratom and declined to recommend a ban following a scientific review.[23][24] The committee, however, recommended kratom be kept "under surveillance."[25] In some jurisdictions, its sale and importation have been restricted, and several public health authorities have raised alerts.[10][22]

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 25 m (82 ft). Its trunk may grow to a 0.9 m (3 ft) diameter.[26] The trunk is generally straight, and the outer bark is smooth and grey.[26] The leaves, ovate-acuminate in shape and opposite in growth pattern, are dark green, glossy on their upper surfaces,[10] 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.[26] The spherical inflorescences, which are deep yellow, grow in clusters of three at the ends of the branches.[27] 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.[26]

Mitragyna speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea.[5] 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.[26]:59

Uses

Kratom
Powdered kratom.jpg
Powder produced from unspecified tissues of the plant
Part(s) of plantLeaves
Geographic originSoutheast Asia[22]
Active ingredients
Main producers
Main consumersWorldwide (No. 1: Thailand)[22][6]
Retail price
  • €6–15 per 10g (EU; (As of 2011))[22]
  • $0.70-5 per 10g (US; (As of 2022))
Legal status
Kratom leaves

(As of 2013), kratom has been studied in cells and in animals, but no clinical trials have been conducted in the United States.[6] The U.S. Drug Enforcement Administration (DEA) stated in 2013 that there is no legitimate medical use for kratom,[14] 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.[12]

Kratom is commonly ingested by chewing, drunk as a tea, powdered in capsules or pills, or extracted for use in liquids.[6] Kratom is rarely smoked.[22] Different varieties of kratom contain different relative proportions of alkaloids such as Mitragynine.[10]

Traditional use

In cultures where the plant grows, kratom has been used in traditional medicine.[9] The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to khat and coca.[10] 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.[5][6][26] They are also used as intestinal deworming agents in Thailand.[31][22]

Kratom is often used by workers in laborious or monotonous professions to stave off exhaustion, and as a mood-enhancer and painkiller.[26] In Thailand, kratom was "used as a snack to receive guests and was part of the ritual worship of ancestors and gods".[32] The herb is bitter and is generally combined with a sweetener.[28]

Opioid withdrawal

(As of 2018), there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction.[8] Kratom is not approved for this or any other medical use.[22] However, because the withdrawal effects of kratom are often reported to be less severe than those associated with traditional opioids,[10] some people use kratom in the attempt to manage opioid use disorder.[33] 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. [34] While some literature reviews claim that kratom has less potential for dependence or overdose than traditional opioids,[35][36] other reviews note that kratom withdrawal itself can still be quite severe.[37]

Data on how widely it is used worldwide are lacking, as it is not detected by typical drug-screening tests.[28] 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.[28]

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.[6]

Recreational uses

At low doses, kratom produces euphoric effects comparable to coca.[38] At higher doses, kratom produces opioid-like effects.[38] The onset of effects typically begins within five to ten minutes and lasts for two to five hours.[5] Some anecdotal reports describe increased work capacity, alertness, talkativeness, sociability, increased sexual desire, positive mood, and euphoria following the consumption of kratom.[10]

According to the U.S. DEA and a 2020 survey, kratom is used to alleviate pain, anxiety, depression, or opioid withdrawal.[14][39]

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,[22] and that kratom was the most widely used recreational drug in Thailand.[22]

Kratom may be mixed with other psychoactive drugs, such as caffeine and codeine.[9][40] 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.[41] (As of 2012), use of the cocktail was a severe problem among youth in three provinces along the border of Malaysia and southern Thailand.[42]

In the U.S., (As of 2015), 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.[10] In the United States, kratom use increased rapidly between 2011 and 2017.[43] By 2020, it was estimated that 15 million people in the U.S. use kratom.[44]

Adverse effects

Mitragyna speciosa may cause many adverse effects, and in November 2017 the FDA issued a public health advisory for the drug.[11] The side effects of kratom appear to be dose-dependent and are more common with doses that exceed 8 g.[36] 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%), seizure (6.1%), withdrawal (6.1%), hallucinations (4.8%), respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%).[45][36] The study also reported two deaths and four cases of neonatal abstinence syndrome.[45] A different 2019 review listed as common side effects: decreased appetite, anorexia, weight loss, temporary erectile dysfunction, insomnia, sweating, hyperpigmentation, hair loss, tremor, and constipation.[13]

Kratom products in the U.S. are commonly used in doses ranging from 2–6 g of dried leaf per dose, and doses exceeding 8 g are relatively uncommon.[46] 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 like itching, nausea, loss of appetite, and increased urination begin to appear.[5][10] 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.[10][15][47]

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 sexual drive, trouble sleeping, muscle spasms, muscle and bone pain, myoclonus, watery eyes, hot flushes, fever, diarrhea, restlessness, anger, and sadness.[9] This may lead to resumption of use.[9][10][37]

Frequent use of high doses of kratom may cause tremors, anorexia, weight loss, seizures, and psychosis.[10] However, 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.[5][10] Herb-drug interactions may result when kratom is combined with alcohol, sedatives, benzodiazepines, opioids, caffeine, cocaine, yohimbine, or monoamine oxidase inhibitors (MAOIs).[47] 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.[18] 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.[citation needed] For 173 (26.2%) exposure calls, no effects were reported, or poison center staff members were unable to follow up regarding effects.[18]

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.[43] 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.[43] 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.[43] 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.[5]

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

Kratom is a botanical with a known addiction liability and, in vulnerable individuals, dependence may develop rather quickly with tolerance noted at 3 months and 4- to 10-fold dose escalations required within the first few weeks. [52] Kratom addiction carries a relapse risk as high as 78% to 89% at 3 months post-cessation. [53] [54] [55] In cases of severe addiction, a similar approach to treatment of opioid addiction may be warranted. [56]

Respiratory depression

Respiratory depression is the leading cause of death from opioid use.[57] Although evidence is sparse, the risk of respiratory depression caused by taking kratom appears to be low, but (As of 2016) the Food and Drug Administration listed respiratory depression as a concern.[11][19] Confusingly, a 2018 review found that the alkaloids in kratom do not induce respiratory depression.[58]

Liver toxicity

In rare cases, though with a dangerous delay, kratom use has been linked to acute liver injury, with symptoms of abdominal discomfort, dark urine, itching and jaundice.[17][16] Liver injury has been reported with a latency (time from first use to onset of symptoms) of median 20.6 days. Reported liver biopsies tend to show cholestasis; however, blood biomarkers can show a range of cholestatic, mixed, or hepatocellular injury pattern.[16] The majority of users do not seem to develop liver injury, and it is unclear which users are at heightened risk. The mechanism by which kratom causes liver damage in some people is unknown and poorly studied, but a model has been proposed.[16]

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.[10][17] According to clinical reviews, a kratom overdose can cause liver toxicity, seizures, coma, and death,[17] especially in combination with excessive alcohol use. Between 2011 and 2017, 44 U.S. deaths were kratom-related.[8] However, many cases could not be fully assessed, due to limited information.[8] People who die from kratom use typically have taken it in combination with other substances, or have underlying health conditions.[13]

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][59][60] 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.[61][62]

Pharmacology

Mitragyna speciosa alkaloids at opioid receptors
Compound Affinities (Ki (nM)) Ratio Ref
MOR DOR KOR MOR:DOR:KOR
7-Hydroxymitragynine 13.5 155 123 1:11:9 [63]
Mitragynine 7.24 60.3 1,100 1:8:152 [63]
Mitragynine pseudoindoxyl 0.087 3.02 79.4 1:35:913 [63]

Kratom contains at least 54 alkaloids.[64][65][66] These include mitragynine, 7-hydroxymitragynine (7-HMG), speciociliatine, paynantheine, corynantheidine, speciogynine, mitraphylline, rhynchophylline, mitralactonal, raubasine, and mitragynaline.[36][10][11] The alkaloids mitragynine and 7-hydroxymitragynine are responsible for many of the complex effects of kratom,[10][11] but other alkaloids may also contribute synergistically.[36]

Both mitragynine and 7-HMG are partial agonists of the μ-opioid receptor and competitive antagonists of the δ-opioid receptor with low affinity for the κ-opioid receptor.[36][47] 7-HMG appears to have higher affinity at the μ-opioid receptor than mitragynine.[58][11] 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.[36][67] Both mitragynine and 7-HMG readily cross the blood-brain barrier.[47][68]

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.[36] 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.[11] Kratom also contains rhynchophylline, a non-competitive NMDA receptor antagonist.[10][69]

Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resulting metabolites excreted in urine.[10] In in vitro experiments, kratom extracts inhibited CYP3A4, CYP2D6, and CYP1A2 enzymes, which results in significant potential for drug interactions.[10]

Chemistry

Main page: Chemistry:Mitragynine

Many of the key psychoactive compounds in M. speciosa are indole alkaloids related to mitragynine, which is a tetracyclic relative of the pentacyclic indole alkaloids, yohimbine and voacangine.[10] 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.[10][70] In addition, at least 40 other compounds have been isolated from M. speciosa leaves,[28] including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from Rauvolfia serpentina), corynantheidine (also found in Corynanthe johimbe),[63] as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline.[71][72]

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.[73] 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.[47]

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.[62][74] 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.[62][75]

Regulation

(As of January 2018), neither the plant nor its alkaloids were listed in any of the Schedules of the United Nations Drug Conventions.[22]

ASEAN

(As of 2013), kratom was listed by ASEAN in its annex of products that cannot be included in traditional medicines and health supplements that are traded across ASEAN nations.[76]

Australia and New Zealand

(As of January 2015), kratom was controlled as a narcotic in Australia and under Medicines Regulations 1985 (Amended August 6, 2015)[77] in New Zealand.[22]

Canada

(As of October 2020), Health Canada disallowed marketing of kratom for any use by ingestion,[78] and has taken action against companies marketing it for such purposes.[79][80] Kratom could be marketed for other uses, such as incense.[81]

Europe

(As of 2011), the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania and Sweden.[22]

Kratom is a controlled substance in Bulgaria. [82]

The sale, import, and export of kratom have been prohibited in the UK since 2016 under the Psychoactive Substances Act.[83]

In 2017, kratom was designated a Schedule 1 illegal drug (the highest level) in the Republic of Ireland, under the names 7-hydroxymitragynine and mitragynine.[84]

Indonesia

Kratom is scheduled to become an illegal substance in Indonesia in 2024 once new regulations from the Indonesian National Narcotics Agency (BNN) go into effect.[85] This pending ban has been in place since 2019; the date of the ban going into effect was pushed out to 2024 to give Kratom farmers time to switch to other crops. Notably, this ban would likely devastate the Kratom supply in the United States, since almost all of America's Kratom is supplied via Indonesian exports.[citation needed]

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.[86] 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.[87] 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.[88]

Thailand

Possession of kratom leaves (Thai: ต้นกระท่อม, RTGS: ton krathom) was illegal in Thailand until 2018.[89] The Thai government had passed the Kratom Act 2486, effective 3 August 1943, which made planting the tree illegal,[14] in response to a rise in its use when opium became very expensive in Thailand and the Thai government was attempting to gain control of the opium market.[10] In 1979, the Thai government placed kratom, along with marijuana, in Category V of a five category classification of narcotics.[14] Kratom accounted for less than two percent of arrests for narcotics between 1987 and 1992.[90]

The Thai government has considered legalizing kratom for recreational use in 2004, 2009, 2013, and 2020.[91][92] In 2018, Thailand became the first Southeast Asian country to legalize kratom for medical purposes.[89] 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.[93][94]

United States

In the United States, there was consideration in late 2017 to make kratom a Schedule I drug.[95] In 2019, the FDA warned consumers that kratom remains unapproved for interstate commerce for use as a drug,[96] may be unsafe in commercially available products, and is on an import alert which can lead to confiscation of imported supplies.[12] Efforts to schedule kratom generated significant controversy both among the general public and scientific community, and were ultimately unsuccessful.[97][98][33]

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.[12] On April 4, 2018, the FDA issued the first mandatory recall in its history over concerns of salmonella contamination of several kratom-containing products.[99] 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.[100] 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.[99] Consumers were advised to immediately discard any such products to prevent serious health risks.[100]

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.[8] 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.[101] 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.[30]

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."[102]

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.[103] This drew strong protests among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol.[104] 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.[105][106] 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."[107] In October 2016, the DEA withdrew its notice of intent while inviting public comments over a review period ending on December 1, 2016.[108][109] As of July 2016, Alabama, Arkansas, Indiana, Vermont, and Wisconsin had made kratom illegal,[110] and the US Army had forbidden soldiers from using it.[111] 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.[112]

Public response

The FDA's arguments for the federal prohibition of kratom have drawn both criticism and support.[113][114][115] 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."[114] 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."[115] The FDA's position on kratom has also been criticized by the American Kratom Association and researchers including Walter Prozialeck.[113][114][116] 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.[115]

Research

Kratom is under preliminary research for its possible antipsychotic and antidepressant properties.[117][118] A study has shown that high doses of Kratom have antipsychotic-effects similar to that of haloperidol,[119] however it should be noted Kratom affects everyone differently. Survey studies found that some people use kratom as a self-treatment strategy for conditions such as opioid use disorder, acute pain, chronic pain, and various mental health conditions, including anxiety, ADHD and depression.[39][120][33] Kratom is also being studied in order to design novel drugs for treating pain, opioid use disorder, and alcohol use disorder.[121] Further clinical research is necessary to corroborate anecdotal reports of kratom as an effective treatment for chronic pain, and to determine whether it is a safe or effective treatment for illness.[122][123]

See also

References

  1. ↑ IUCN SSC Global Tree Specialist Group & Botanic Gardens Conservation International (BGCI). 2021 (2021). "Mitragyna speciosa". IUCN Red List of Threatened Species 2021: e.T192376330A192376332. doi:10.2305/IUCN.UK.2021-1.RLTS.T192376330A192376332.en. https://www.iucnredlist.org/species/192376330/192376332. Retrieved 6 March 2022. 
  2. ↑ Mitragyna speciosa (Korth.) Havil. is an accepted name . Theplantlist.org. Retrieved 2013-12-26.
  3. ↑ "Rubiaceae - an overview | ScienceDirect Topics". Sciencedirect.com. 2016-01-01. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/rubiaceae. Retrieved 2022-08-25. 
  4. ↑ {{citation | mode = cs1 | title = Mitragyna speciosa | work = Germplasm Resources Information Network (GRIN) | url = | publisher = [[Organization:Agricultural Research ServAgricultural Research Service (ARS), United States Department of Agriculture (USDA) | access-date = 2013-12-26 }}
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 Rech, MA; Donahey, E; Cappiello Dziedzic, JM; Oh, L; Greenhalgh, E (February 2015). "New drugs of abuse". Pharmacotherapy 35 (2): 189–97. doi:10.1002/phar.1522. PMID 25471045. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Hassan, Z; Muzaimi, M; Navaratnam, V; Yusoff, NHM; Suhaimi, FW; Vadivelu, R; Vicknasingam, BK; Amato, D et al. (2013). "From Kratom to mitragynine and its derivatives: Physiological and behavioural effects related to use, abuse, and addiction". Neurosci Biobehav Rev 37 (2): 138–151. doi:10.1016/j.neubiorev.2012.11.012. ISSN 0149-7634. PMID 23206666. 
  7. ↑ Advokat, Claire D.; Comaty, Joseph E.; Julien, Robert M. (2019). Julien's Primer of Drug Action: a comprehensive guide to the actions, uses, and side effects of psychoactive drugs (14th ed.). New York: Worth Publishers. p. 570. ISBN 978-1-319-20054-1. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 Gottlieb, Scott (6 February 2018). "Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency's scientific evidence on the presence of opioid compounds in kratom, underscoring its potential for abuse". US Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm595622.htm. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Cinosi, E; Martinotti, G; Simonato, P; Singh, D; Demetrovics, Z; Roman-Urrestarazu, A; Bersani, F. S; Vicknasingam, B et al. (2015). "Following "the Roots" of Kratom (Mitragyna speciosa): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries". BioMed Research International 2015: 1–11. doi:10.1155/2015/968786. PMID 26640804. 
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17 10.18 10.19 10.20 10.21 10.22 10.23 10.24 10.25 10.26 10.27 10.28 10.29 10.30 "The pharmacology and toxicology of kratom: from traditional herb to drug of abuse". Int. J. Legal Med. 130 (1): 127–38. 2016. doi:10.1007/s00414-015-1279-y. PMID 26511390. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 "Pharmacologic and clinical assessment of kratom". Am J Health Syst Pharm 75 (5): 261–267. 2018. doi:10.2146/ajhp161035. PMID 29255059. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "FDA and kratom". US Food and Drug Administration. 3 April 2019. https://www.fda.gov/news-events/public-health-focus/fda-and-kratom. 
  13. ↑ 13.0 13.1 13.2 "Characteristics of deaths associated with kratom use". J. Psychopharmacol. (Oxford) 33 (9): 1102–1123. 2019. doi:10.1177/0269881119862530. PMID 31429622. http://openaccess.sgul.ac.uk/111141/15/Characteristics%20of%20deaths%20associated%20with%20kratom%20use%20-%20JP%20-%20final%20version%20accepted%2017%20June%202019.docx. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 "Kratom (Mitragyna speciosa Korth)". U.S. Drug Enforcement Administration. January 2013. http://www.deadiversion.usdoj.gov/drug_chem_info/kratom.pdf. 
  15. ↑ 15.0 15.1 Marx, John; Walls, Ron; Hockberger, Robert (2014). "Chapter 156: Hallucinogens". Rosen's emergency medicine : concepts and clinical practice (Eighth ed.). London: Elsevier Health Sciences. pp. 2015–23. ISBN 9781455749874. https://books.google.com/books?id=uggC0i_jXAsC&pg=RA2022. 
  16. ↑ 16.0 16.1 16.2 16.3 Schimmel, Jonathan; Dart, Richard C. (Feb 2020). "Kratom (Mitragyna speciosa) Liver Injury: A Comprehensive Review". Drugs 80 (3): 263–283. doi:10.1007/s40265-019-01242-6. PMID 31919755. 
  17. ↑ 17.0 17.1 17.2 17.3 "Kratom". LiverTox, National Library of Medicine, US National Institutes of Health. 9 March 2017. https://livertox.nih.gov/Kratom.htm. 
  18. ↑ 18.0 18.1 18.2 Anwar, Mehruba; Law, Royal; Schier, Josh (2016-01-01). "Notes from the Field: Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers – United States, 2010–2015". MMWR. Morbidity and Mortality Weekly Report 65 (29): 748–49. doi:10.15585/mmwr.mm6529a4. ISSN 0149-2195. PMID 27466822. 
  19. ↑ 19.0 19.1 19.2 19.3 "Import Alert 54-15; Detention without physical examination of dietary supplements and bulk dietary ingredients that are or contain Mitragyna speciosa or kratom". U.S. Food and Drug Administration. 20 December 2016. http://www.accessdata.fda.gov/cms_ia/importalert_1137.html. 
  20. ↑ "What is Kratom?". June 30, 2021. https://health.clevelandclinic.org/what-is-kratom/. 
  21. ↑ "April 25 Lecture to Explore Kratom's Therapeutic Potential in Opioid Addiction". https://www.nccih.nih.gov/research/blog/april-25-lecture-to-explore-kratoms-therapeutic-potential-in-opioid-addiction. 
  22. ↑ 22.00 22.01 22.02 22.03 22.04 22.05 22.06 22.07 22.08 22.09 22.10 22.11 22.12 22.13 22.14 22.15 "Kratom profile (chemistry, effects, other names, origin, mode of use, other names, medical use, control status)". European Monitoring Centre for Drugs and Drug Addiction. 8 January 2015. http://www.emcdda.europa.eu/publications/drug-profiles/kratom#control. 
  23. ↑ "World Health Organization Decides Not to Call for Global Kratom Ban". 8 December 2021. https://filtermag.org/who-kratom-ban/. 
  24. ↑ "United Nations Panel Rejects International Kratom Ban". 7 December 2021. https://www.marijuanamoment.net/united-nations-panel-rejects-international-kratom-ban/. 
  25. ↑ "Summary of assessments, findings and recommendations of the 44th World Health Organization's (WHO) Expert Committee on Drug Dependence (ECDD)". October 2021. https://s3.documentcloud.org/documents/21150126/ecdd-report-dec-2021.pdf. 
  26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 26.6 Eisenman, Sasha W. (2014). "Chapter 5. The Botany of Mitragyna speciosa (Korth.) Havil. and Related Species". in Raffa, Robert B.. Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium. CRC Press. pp. 57–76. ISBN 978-1-4822-2519-8. 
  27. ↑ Rahman, Atta-ur (2021-04-16) (in en). Studies in Natural Products Chemistry. Elsevier. ISBN 978-0-323-89815-7. https://books.google.com/books?id=d7cCEAAAQBAJ&pg=PA195. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Adkins, Jessica E.; Edward W. Boyer; Christopher R. McCurdy (2011-05-01). "Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity". Current Topics in Medicinal Chemistry 11 (9): 1165–75. doi:10.2174/156802611795371305. PMID 21050173. 
  29. ↑ "Unauthorized "Sāj" kratom products seized from two Edmonton stores may pose serious health risks". Canada. 4 May 2018. http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2018/66710a-eng.php. 
  30. ↑ 30.0 30.1 Tave, Steven J. (26 February 2018). "FDA warning letter to Industrial Chemicals, LLC, and INI Botanicals". Office of Dietary Supplement Programs, Center for Food Safety and Applied Nutrition, US Food and Drug Administration. https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofFoods/CFSAN/CFSANFOIAElectronicReadingRoom/UCM598251.pdf. 
  31. ↑ Singh, Darshan; Narayanan, Suresh; Vicknasingam, Balasingam; Corazza, Ornella; Santacroce, Rita; Roman-Urrestarazu, Andres (2017). "Changing trends in the use of kratom (Mitragyna speciosa) in Southeast Asia" (in en). Human Psychopharmacology: Clinical and Experimental 32 (3): e2582. doi:10.1002/hup.2582. ISSN 1099-1077. PMID 28544011. 
  32. ↑ Singh, Darshan; Narayanan, Suresh; Vicknasingam, Balasingam (September 2016). "Traditional and non-traditional uses of Mitragynine (Kratom): A survey of the literature". Brain Research Bulletin 126 (Pt 1): 41–46. doi:10.1016/j.brainresbull.2016.05.004. PMID 27178014. 
  33. ↑ 33.0 33.1 33.2 Swogger, Marc T.; Walsh, Zach (2018-02-01). "Kratom use and mental health: A systematic review". Drug and Alcohol Dependence 183: 134–140. doi:10.1016/j.drugalcdep.2017.10.012. ISSN 1879-0046. PMID 29248691. https://pubmed.ncbi.nlm.nih.gov/29248691/. 
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  35. ↑ Henningfield, Jack E.; Fant, Reginald V.; Wang, Daniel W. (2018). "The abuse potential of kratom according the 8 factors of the controlled substances act: implications for regulation and research". Psychopharmacology 235 (2): 573–589. doi:10.1007/s00213-017-4813-4. ISSN 1432-2072. PMID 29273821. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 36.6 36.7 Eastlack, Steven C.; Cornett, Elyse M.; Kaye, Alan D. (2020). "Kratom—Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review". Pain and Therapy 9 (1): 55–69. doi:10.1007/s40122-020-00151-x. ISSN 2193-8237. PMID 31994019. 
  37. ↑ 37.0 37.1 Stanciu, Cornel N.; Gnanasegaram, Samantha A.; Ahmed, Saeed; Penders, Thomas (January 2019). "Kratom Withdrawal: A Systematic Review with Case Series". Journal of Psychoactive Drugs 51 (1): 12–18. doi:10.1080/02791072.2018.1562133. ISSN 2159-9777. PMID 30614408. 
  38. ↑ 38.0 38.1 Babu, Kavita M.; McCurdy, Christopher R.; Boyer, Edward W. (2008). "Opioid receptors and legal highs: Salvia divinorum and Kratom". Clinical Toxicology 46 (2): 146–152: 149. doi:10.1080/15563650701241795. ISSN 1556-3650. PMID 18259963. 
  39. ↑ 39.0 39.1 Garcia-Romeu, Albert; Cox, David J.; Smith, Kirsten E.; Dunn, Kelly E.; Griffiths, Roland R. (2020). "Kratom (Mitragyna speciosa): User demographics, use patterns, and implications for the opioid epidemic". Drug and Alcohol Dependence 208: 107849. doi:10.1016/j.drugalcdep.2020.107849. ISSN 0376-8716. PMID 32029298. 
  40. ↑ Karch, Steven B.; Drummer, Olaf (2015). Karch's Pathology of Drug Abuse (Fifth ed.). CRC Press. p. 528. ISBN 9781439861479. https://books.google.com/books?id=M9KYCgAAQBAJ&pg=PA528. 
  41. ↑ Tanguay, Pascal (April 2011). "Kratom in Thailand: Decriminalisation and Community Control?". Transnational Institute. https://www.tni.org/files/download/kratom-briefing-dlr13.pdf. "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." 
  42. ↑ Fuller, Thomas (23 July 2012). "A Fading Thai Drug Finds Its Resurgence in a Cocktail". The New York Times. https://query.nytimes.com/gst/fullpage.html?res=9E05EFDC103EF930A15754C0A9649D8B63. 
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  91. ↑ "Leafy highs: Kratom personal use push under way". Bangkok Post. 5 February 2020. https://www.bangkokpost.com/thailand/general/1850589/leafy-highs-kratom-personal-use-push-under-way. 
  92. ↑ Prasert, Poungchompoo (4 October 2013). "Decision yet to be reached on making 'kratom' legal". The Nation. http://www.nationmultimedia.com/national/Decision-yet-to-be-reached-on-making-kratom-legal-30216276.html. 
  93. ↑ "Parliament votes to remove kratom from narcotics list". Bangkok Post. https://www.bangkokpost.com/thailand/general/2058139/parliament-votes-to-remove-kratom-from-narcotics-list. 
  94. ↑ Laohong, King-oua (2021-08-23). "Kratom now listed as legal herb". Bangkok Post. https://www.bangkokpost.com/thailand/general/2169411/kratom-now-listed-as-legal-herb. 
  95. ↑ "HHS recommended that the DEA ban kratom, documents show – STAT". 9 November 2018. https://www.statnews.com/2018/11/09/hhs-recommended-dea-ban-kratom-documents-show/. 
  96. ↑ "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. https://www.fda.gov/news-events/press-announcements/fda-issues-warnings-companies-selling-illegal-unapproved-kratom-drug-products-marketed-opioid. 
  97. ↑ MD, Peter Grinspoon (2019-08-07). "Kratom: Fear-worthy foliage or beneficial botanical?" (in en). https://www.health.harvard.edu/blog/kratom-fear-worthy-foliage-or-beneficial-botanical-2019080717466. 
  98. ↑ "Kratom ban will hinder studies of the plant as a treatment" (in en-US). 2016-09-08. https://www.statnews.com/2016/09/08/kratom-ban-hinders-research/. 
  99. ↑ 99.0 99.1 Chappell, Bill (4 April 2018). "FDA Orders An Unprecedented Recall After Kratom Company Ignored Its Requests". NPR. https://www.npr.org/sections/thetwo-way/2018/04/04/599443476/fda-orders-an-unprecedented-recall-after-kratom-company-ignored-its-requests. 
  100. ↑ 100.0 100.1 FDA News Release. "FDA orders mandatory recall for kratom products due to risk of salmonella". United States Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm603517.htm. 
  101. ↑ "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. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm597649.htm. "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 health care 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" 
  102. ↑ "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. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584970.htm. "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" 
  103. ↑ "DEA Announces Intent to Schedule Kratom: SE Asian drug is imminent hazard to public safety". US Drug Enforcement Administration. 30 August 2016. https://www.dea.gov/divisions/hq/2016/hq083016.shtml. 
  104. ↑ Silverman, Lauren (12 September 2016). "Kratom Advocates Speak Out Against Proposed Government Ban". https://www.npr.org/sections/health-shots/2016/09/12/493295493/kratom-advocates-speak-out-against-proposed-government-ban. 
  105. ↑ Ingraham, Christopher (September 30, 2016). "DEA defies senators' appeal to reconsider 'unprecedented' kratom ban". The Washington Post. https://www.washingtonpost.com/news/wonk/wp/2016/09/30/dea-defies-senators-appeal-to-reconsider-unprecedented-kratom-ban/. 
  106. ↑ Stapleton, Christine (September 29, 2016). "Congress members ask DEA not to ban kratom: opioid research needed". Palm Beach Post. http://www.mypalmbeachpost.com/news/news/national-govt-politics/kratom-ban-starts-friday-frankel-among-lawmakers-t/nshQ6/. 
  107. ↑ Nelson, Steven (September 30, 2016). "Kratom Will Remain Legal for Days, Possibly Longer". U.S. News & World Report. https://www.usnews.com/news/articles/2016-09-30/kratom-will-remain-legal-for-days-possibly-longer. 
  108. ↑ "Kratom Gets Reprieve From Drug Enforcement Administration". NPR.org. https://www.npr.org/sections/health-shots/2016/10/12/497697627/kratom-gets-reprieve-from-drug-enforcement-administration. 
  109. ↑ "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". Drug Enforcement Administration. 2016-10-13. https://www.federalregister.gov/documents/2016/10/13/2016-24659/withdrawal-of-notice-of-intent-to-temporarily-place-mitragynine-and-7-hydroxymitragynine-into. 
  110. ↑ Brown, Melissa (May 20, 2016). "States ban kratom supplement over abuse worries". Associated Press via US News & World Report. https://www.usnews.com/news/us/articles/2016-05-20/states-ban-kratom-supplement-over-abuse-worries. 
  111. ↑ Schwarz, Alan (2 January 2016). "Kratom, an Addict's Alternative, Is Found to Be Addictive Itself". The New York Times. https://www.nytimes.com/2016/01/03/us/kratom-an-addicts-alternative-is-found-to-be-addictive-itself.html. 
  112. ↑ Smith, Peter Andrey (2019-02-19). "The Herbal Supplement That Might Be a Deadly Drug". https://www.outsideonline.com/2387546/kratom-safety. 
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  114. ↑ 114.0 114.1 114.2 Garber-Paul, Elisabeth; Garber-Paul, Elisabeth (2018-08-15). "Kratom Association Calls FDA Review of Drug 'Junk Science' in Scathing Report" (in en-US). Rolling Stone. https://www.rollingstone.com/culture/culture-news/kratom-drug-industry-fda-opioid-711169/. Retrieved 2021-06-22. 
  115. ↑ 115.0 115.1 115.2 Marlan, Dustin (2021-06-08). "A Sensible, Evidence-Based Proposal for Kratom Reform" (in en-US). https://blog.petrieflom.law.harvard.edu/2021/06/08/a-sensible-evidence-based-proposal-for-kratom-reform/. 
  116. ↑ Prozialeck, Walter C.; Avery, Bonnie A.; Boyer, Edward W.; Grundmann, Oliver; Henningfield, Jack E.; Kruegel, Andrew C.; McMahon, Lance R.; McCurdy, Christopher R. et al. (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. PMID 31103778. 
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  122. ↑ "Kratom DrugFacts". National Institute on Drug Abuse, US National Institutes of Health. 1 April 2019. https://www.drugabuse.gov/publications/drugfacts/kratom. 
  123. ↑ Prevete, Elisabeth; Kuypers, Kim Paula Colette; Theunissen, Eef Lien; Corazza, Ornella; Bersani, Giuseppe; Ramaekers, Johannes Gerardus (2021-07-26). "A systematic review of (pre)clinical studies on the therapeutic potential and safety profile of kratom in humans". Human Psychopharmacology 37 (1): e2805. doi:10.1002/hup.2805. ISSN 1099-1077. PMID 34309900. 

External links

Wikidata ☰ Q139698 entry



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