Mitragyna speciosa

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
(Korth.) Havil.
Synonyms[1]
  • Nauclea korthalsii Steud. nom. inval.
  • Nauclea luzoniensis Blanco
  • Nauclea speciosa (Korth.) Miq.
  • Stephegyne speciosa Korth.

Mitragyna speciosa (commonly known as kratom[2]) 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,[3] where it has been used in herbal medicine since at least the nineteenth century.[4] Kratom has opioid properties and some stimulant-like effects.[5][6]

As of 2018, the efficacy and safety of kratom are unclear, and the drug was unapproved as a therapeutic agent due to the poor quality of the research.[7][8] 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.[9] Some people take it for managing chronic pain, for treating opioid withdrawal symptoms, or for recreational purposes.[3][7] The onset of effects typically begins within five to ten minutes and lasts for two to five hours.[3]

Anecdotal reports describe increased alertness, physical energy, talkativeness, sociability, sedation, changes in mood, and pain relief following kratom use at various doses.[7] Common side effects include appetite loss, erectile dysfunction, nausea and constipation.[10] More severe side effects may include respiratory depression (decreased breathing), seizure, addiction, and psychosis.[3][5][11][12] Other side effects may include high heart rate and blood pressure, trouble sleeping, and, rarely, liver toxicity.[3][13][14][15] When use is stopped, withdrawal symptoms may occur.[7][6] Deaths have occurred with kratom both by itself and mixed with other substances.[5][16] Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.[3][7]

Kratom is a controlled substance in 16 countries[5] and, in 2014, the FDA banned importing and manufacturing of kratom as a dietary supplement.[17] As of 2018, there is growing international concern about a possible threat to public health from kratom use.[5][7][18] In some jurisdictions, its sale and importation have been restricted, and several public health authorities have raised alerts.[7][18][19]

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.[20] The trunk is generally straight, and the outer bark is smooth and grey.[20] The leaves are dark green and glossy[7] and can grow to over 14–20 cm (5.5–7.9 in) long and 7–12 cm (2.8–4.7 in) wide when fully open, are ovate-acuminate in shape, and opposite in growth pattern, with 12–17 pairs of veins.[20] The flowers, which are deep yellow, grow in clusters of three at the ends of the branches.[21] 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.[20]

Mitragyna speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea.[3] 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.[20]: 59 

Uses

Kratom
Powder produced from unspecified tissues of the plant
Part(s) of plantLeaves
Geographic originSoutheast Asia[18]
Active ingredients
Main producers
Main consumersWorldwide (No. 1: Thailand)[18][4]
Retail price€6–15 per 10g (EU; as of 2011)[18]
Legal status
  • AU: S9[23]
  • CA: Not authorized for sale or use[24]
  • US: Drug of concern,[4] subject to import bans,[17] and sale for consumption is illegal[17][25][9]
  • EU: Illegal in Denmark, Republic of Ireland, Latvia, Lithuania, Poland, Romania and Sweden[18]
  • Illegal in Malaysia, Myanmar, and New Zealand[18][4]
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.[4] The U.S. Drug Enforcement Administration (DEA) said in 2013 that there is no legitimate medical use for kratom.[11] 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.[9]

Kratom leaves are commonly used by chewing, as a tea, powdered in capsules or pills, or extracted for use in liquids.[4] Kratom is rarely smoked.[18] Because some anecdotal reports claim that red vein varieties of kratom native to Bali tend to produce different effects than green and white vein varieties native to Malaysia, it has been speculated that different varieties of kratom contain different relative proportions of alkaloids.[7]

Traditional use

In cultures where the plant grows, kratom has been used in traditional medicine.[26] The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to khat and coca.[7] 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.[3][4][20] They are also used as intestinal deworming agents in Thailand.[27][18]

Kratom is often used by workers in laborious or monotonous professions to stave off exhaustion as well as a mood enhancer and painkiller.[20] In Thailand, kratom was "used as a snack to receive guests and was part of the ritual worship of ancestors and gods".[28] The herb is bitter and is generally combined with a sweetener.[22]

Opioid withdrawal

As of 2018, there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction.[5] Kratom is not approved for this or any other medical use.[18] However, because the withdrawal effects of kratom are often reported to be less severe than those associated with traditional opioids,[7] some people use kratom in the attempt to manage opioid use disorder.[29] While some literature reviews claim that kratom has less potential for dependence or overdose than traditional opioids,[30][31] other reviews note that kratom withdrawal itself can still be quite severe.[32]

Data on how often it is used worldwide are lacking, as it is not detected by typical drug-screening tests.[22] 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 use.[22]

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 nineteenth century.[4]

Recreational uses

At low doses, kratom produces euphoric effects comparable to coca.[33] At higher doses, kratom produces opioid-like effects.[33] The onset of effects typically begins within five to ten minutes and lasts for two to five hours.[3] Some anecdotal reports describe increased work capacity, alertness, talkativeness, sociability, increased sexual desire, positive mood, and euphoria following the consumption of kratom.[7]

According to the U.S. DEA and a 2020 survey, kratom is used in the public to alleviate pain, anxiety, depression, or opioid withdrawal.[11][34]

In Thailand, a 2007 survey found that the lifetime, past year, and past 30 days kratom usage rates were 2.32%, 0.81% and 0.57%, respectively, among respondents aged 12–65 years,[18] and was the most widely used drug in Thailand.[18]

Kratom may be mixed with other psychoactive drugs, such as caffeine and codeine.[6][35] 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.[36] As of 2012, use of the cocktail was a severe problem among youth in three provinces along the border of Malaysia and southern Thailand.[37]

In the U.S., as of 2015, kratom was available in head shops and over the Internet; the prevalence of its use was unknown at the time.[7] In the United States, kratom use increased rapidly between 2011 and 2017.[38] By 2020, it was estimated that 15 million people in the U.S. use kratom.[39]

Adverse effects

Mitragyna speciosa may cause many adverse effects and in November 2017 the FDA issued a public health advisory for the drug.[8] The side effects of kratom appear to be dose-dependent and are more common with doses that exceed 8 g.[31] 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%).[40][31] The study also reported two deaths and four cases of neonatal abstinence syndrome.[40] 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.[10]

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.[41] However, there is no standard dosing system as kratom products may vary greatly in potency. 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.[3][7] 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.[7][12][42]

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 pains, jerky movement, watery eyes, hot flushes, fever, diarrhea, restlessness, anger, and sadness.[6] This may lead to resumption of use.[6][7][32]

Frequent use of high doses of kratom may cause tremors, anorexia, weight loss, seizures, and psychosis.[7] However, in case reports associating kratom use with psychosis, it remains unclear whether kratom use directly caused psychosis or simply unmasked the condition.[43] Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.[3][7] Herb-drug interactions may result when kratom is combined with alcohol, sedatives, benzodiazepines, opioids, caffeine, cocaine, yohimbine, or monoamine oxidase inhibitors (MAOIs).[42] Rhabdomyolysis is one of the rare complications of this herb at high dosage.[44]

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.[15] 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.[15]

A 2019 report from the American Association of Poison Control Centers (AAPCC) stated that kratom use was increasing rapidly, with 1807 kratom exposures and a 52-fold increase occurring over the years 2011 to 2017.[38] 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.[38] Multiple-substance exposures were associated with a higher number of hospitalizations than single-substance exposures, and involved 11 deaths, including two due to kratom alone.[38] Postmortem toxicology testing detected multiple substances for almost all those who died, with fentanyl and fentanyl analogs being the most frequently identified co-occurring substances.[45]

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.[3]

From October 2017 to February 2018 in the United States, 28 people in 20 different states were infected with salmonella, an outbreak occurring from the consumption of contaminated pills, powder, tea or unidentified sources of kratom.[46] An analytical method using whole genome sequencing applied to samples from the infected people indicated that the salmonella outbreak likely had a common kratom source.[46]

Respiratory depression

Respiratory depression is the leading cause of death from opioid use.[47] Although evidence is sparse, the risk from respiratory depression caused by taking Mitragyna speciosa appears to be low, but as of 2016 the Food and Drug Administration listed respiratory depression as a concern.[8][17] A 2018 review found that the alkaloids in kratom do not induce respiratory depression.[48]

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.[14][13] 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.[13] 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.[13]

Death

Kratom overdose is a subject of concern in many countries because of the rising number of hospitalizations and deaths in which chronic kratom use is a contributing factor.[7][14] According to clinical reviews, a kratom overdose can cause liver toxicity, seizures, coma, and death,[14] especially when in combination with excessive alcohol use. Between 2011 and 2017, forty-four deaths were kratom-related.[5] However many cases could not be fully assessed because of limited information.[5] People who died from kratom use typically have taken it in combination with other substances, or have underlying health conditions.[10]

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.[49][50][51] Nine deaths occurred in Sweden during 2010–11 relating to use of Krypton, a mixture of kratom, caffeine and O-desmethyltramadol, a prescription opioid analgesic.[16][52]

Chemistry

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.[7] 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.[7][53] In addition, at least 40 other compounds have been isolated from M. speciosa leaves,[22] including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from Rauvolfia serpentina), corynantheidine (also found in Pausinystalia johimbe),[54] as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline.[55][56]

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.[57] 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.[42]

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.[52][58] 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.[52][59]

Pharmacology

Mitragyna speciosa alkaloids at opioid receptors
CompoundAffinities (Ki (nM))RatioRef
MORDORKORMOR:DOR:KOR
7-Hydroxymitragynine13.51551231:11:9[60]
Mitragynine7.2460.31,1001:8:152[60]
Mitragynine pseudoindoxyl0.0873.0279.41:35:913[60]

Kratom contains at least 54 alkaloids.[61][62][63] These include mitragynine, 7-hydroxymitragynine (7-HMG), speciociliatine, corynantheidine, speciogynine, paynantheine, mitraphylline, rhynchophylline, mitralactonal, raubasine, and mitragynaline.[31][7][8] The alkaloids mitragynine and 7-hydroxymitragynine are responsible for many of the complex effects of kratom,[7][8] but other alkaloids may also contribute synergistically.[31]

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.[31][42] 7-HMG appears to have higher affinity at the μ-opioid receptor than mitragynine.[64][65] 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.[31][66] Both mitragynine and 7-HMG readily cross the blood-brain barrier.[42][67]

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.[31] 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.[65] Kratom also contains rhynchophylline, a non-competitive NMDA receptor antagonist.[7][68]

Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resulting metabolites excreted in urine.[7] In in vitro experiments, kratom extracts inhibited CYP3A4, CYP2D6, and CYP1A2 enzymes, which results in significant potential for drug interactions.[7]

Regulation

As of January 2018, neither the plant nor its alkaloids were listed in any of the Schedules of the United Nations Drug Conventions.[18]

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.[69]

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)[70] in New Zealand.[18]

Canada

As of October 2020, Health Canada disallowed marketing of kratom for any use by ingestion,[71] and has taken action against companies marketing it for such purposes.[72][73] Kratom could be marketed for other uses, such as incense.[74]

Europe

As of 2011, the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania and Sweden.[18] In the UK, since 2016, the sale, import, and export of kratom are prohibited under the Psychoactive Substances Act.[75]

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.[76]

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.[77] This pending ban has been in place since 2019; the date of the ban going into effect was pushed out to 2024 to give Kratom farmers time to switch to other crops. Notably, this ban would likely devastate the Kratom supply in the United States, since almost all of America's Kratom is supplied via Indonesian exports.

Malaysia

The use of kratom leaves, known locally as ketum, is prohibited in Malaysia under Section 30 (3) Poisons Act 1952.[78] Although prohibited by statute, the use of kratom remains widely spread because the tree grows natively and tea decoctions are readily available in local communities.[79] 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.[80]

Thailand

Possession of kratom leaves (Thai: ต้นกระท่อม, RTGS: ton krathom) was illegal in Thailand until 2018.[81] The Thai government had passed the Kratom Act 2486, effective 3 August 1943, which made planting the tree illegal,[11] 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.[7] In 1979, the Thai government placed kratom, along with marijuana, in Category V of a five category classification of narcotics.[11] Kratom accounted for less than two percent of arrests for narcotics between 1987 and 1992.[82]

The Thai government has considered legalizing kratom for recreational use in 2004, 2009, 2013, and 2020.[83][84] In 2018, Thailand became the first Southeast Asian country to legalize kratom for medical purposes.[81] 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.[85][86]

United States

In the United States, there is consideration to make kratom a Schedule I drug.[87] In 2019, the FDA warned consumers that kratom remains unapproved for interstate commerce,[88] may be unsafe in commercially available products, and is on an import alert which can lead to confiscation of imported supplies.[9] Efforts to schedule kratom have generated significant controversy both among the general public and scientific community.[89][90][29]

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.[9] On April 4, 2018, the FDA issued the first mandatory recall in its history over concerns of salmonella contamination of several kratom-containing products.[91] 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.[92] 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.[91] Consumers were advised to immediately discard any such products to prevent serious health risks.[92]

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.[5] 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.[93] 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.[25]

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."[94]

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.[19] This drew strong protests among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol.[95] 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.[96][97] 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."[98] In October 2016, the DEA withdrew its notice of intent while inviting public comments over a review period ending on December 1, 2016.[99][100] As of July 2016, Alabama, Arkansas, Indiana, Vermont, and Wisconsin had made kratom illegal,[101] and the US Army had forbidden soldiers from using it.[102] 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.[103]

Public response

The FDA's arguments for the federal prohibition of kratom have drawn both criticism and support.[104][105][106] 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."[105] 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."[106] The FDA's position on kratom has also been criticized by the American Kratom Association and researchers including Walter Prozialeck.[104][105][107] 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.[106]

Research

Kratom is under preliminary research for its possible antipsychotic and antidepressant properties.[108][109] 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 and depression.[34][110][29] Kratom is also being studied in order to design novel drugs for treating pain, opioid use disorder, and alcohol use disorder.[111] There is no scientific evidence that kratom is safe or effective for any medical condition, as of 2021, and concerns remain about its safety.[112][113]

See also

  • Pausinystalia johimbe

References

  1. ↑ Mitragyna speciosa (Korth.) Havil. is an accepted name . Theplantlist.org. Retrieved 2013-12-26.
  2. ↑ "Mitragyna speciosa". Germplasm Resources Information Network (GRIN). Agricultural Research Service (ARS), United States Department of Agriculture (USDA). Retrieved 2013-12-26.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 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. S2CID 206358469.
  4. 1 2 3 4 5 6 7 8 9 Hassan, Z; Muzaimi, M; Navaratnam, V; Yusoff, NHM; Suhaimi, FW; Vadivelu, R; Vicknasingam, BK; Amato, D; von Hörsten, S; Ismail, NIW; Jayabalan, N; Hazim, AI; Mansor, SM; Müller, CP (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. S2CID 8463133.
  5. 1 2 3 4 5 6 7 8 9 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. Retrieved 6 February 2018.
  6. 1 2 3 4 5 Cinosi, E; Martinotti, G; Simonato, P; Singh, D; Demetrovics, Z; Roman-Urrestarazu, A; Bersani, F. S; Vicknasingam, B; Piazzon, G; Li, J. H; Yu, W. J; Kapitány-Fövény, M; Farkas, J; Di Giannantonio, M; Corazza, O (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. PMC 4657101. PMID 26640804.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Warner ML, Kaufman NC, Grundmann O (2016). "The pharmacology and toxicology of kratom: from traditional herb to drug of abuse". Int. J. Legal Med. (Review). 130 (1): 127–38. doi:10.1007/s00414-015-1279-y. PMID 26511390. S2CID 2009878.
  8. 1 2 3 4 5 White CM (2018). "Pharmacologic and clinical assessment of kratom". Am J Health Syst Pharm (Review). 75 (5): 261–267. doi:10.2146/ajhp161035. PMID 29255059.
  9. 1 2 3 4 5 "FDA and kratom". US Food and Drug Administration. 3 April 2019. Retrieved 8 August 2019.
  10. 1 2 3 Corkery JM, Streete P, Claridge H, Goodair C, Papanti D, Orsolini L, Schifano F, Sikka K, Körber S, Hendricks A (2019). "Characteristics of deaths associated with kratom use". J. Psychopharmacol. (Oxford) (Review). 33 (9): 1102–1123. doi:10.1177/0269881119862530. hdl:2299/21622. PMID 31429622. S2CID 201095094.
  11. 1 2 3 4 5 "Kratom (Mitragyna speciosa korth)" (PDF). U.S. Drug Enforcement Administration. January 2013. Archived from the original (PDF) on 11 June 2016.
  12. 1 2 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.
  13. 1 2 3 4 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. S2CID 210088143.
  14. 1 2 3 4 "Kratom". LiverTox, National Library of Medicine, US National Institutes of Health. 9 March 2017. Retrieved 29 March 2017.
  15. 1 2 3 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.
  16. 1 2 "Mitragynine". Toxnet, National Library of Medicine, US National Institutes of Health. 14 February 2012. Retrieved 15 February 2018.
  17. 1 2 3 4 "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. Retrieved 7 March 2018.
  18. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Kratom profile (chemistry, effects, other names, origin, mode of use, other names, medical use, control status)". Page last updated 8 January 2015: European Monitoring Centre for Drugs and Drug Addiction. Retrieved 12 September 2016.{{cite web}}: CS1 maint: location (link)
  19. 1 2 "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.
  20. 1 2 3 4 5 6 7 Eisenman, Sasha W. (2014). "Chapter 5. The Botany of Mitragyna speciosa (Korth.) Havil. and Related Species". In Raffa, Robert B. (ed.). 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.
  21. ↑ Rahman, Atta-ur (2021-04-16). Studies in Natural Products Chemistry. Elsevier. ISBN 978-0-323-89815-7.
  22. 1 2 3 4 5 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.
  23. ↑ Department of Health and Aging Therapeutic Goods Administration (26 February 2004). National Drugs and Poisons Schedule Committee (PDF). 40th meeting. Government of Australia. pp. 103–105.
  24. ↑ "Unauthorized "Sāj" kratom products seized from two Edmonton stores may pose serious health risks". Health Canada. Canada. 4 May 2018. Retrieved 8 August 2018.
  25. 1 2 Tave, Steven J. (26 February 2018). "FDA warning letter to Industrial Chemicals, LLC, and INI Botanicals" (PDF). Office of Dietary Supplement Programs, Center for Food Safety and Applied Nutrition, US Food and Drug Administration. Retrieved 7 March 2018.
  26. ↑ Cinosi, Eduardo; Martinotti, Giovanni; Simonato, Pierluigi; Singh, Darshan; Demetrovics, Zsolt; Roman-Urrestarazu, Andres; Bersani, Francesco Saverio; Vicknasingam, Balasingam; Piazzon, Giulia; Li, Jih-Heng; Yu, Wen-Jing (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: 968786. doi:10.1155/2015/968786. ISSN 2314-6133. PMC 4657101. PMID 26640804.
  27. ↑ 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". Human Psychopharmacology: Clinical and Experimental. 32 (3): e2582. doi:10.1002/hup.2582. ISSN 1099-1077. PMID 28544011.
  28. ↑ 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. S2CID 3952688.
  29. 1 2 3 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.
  30. ↑ 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. PMC 5813050. PMID 29273821.
  31. 1 2 3 4 5 6 7 8 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. PMC 7203303. PMID 31994019.
  32. 1 2 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. S2CID 58643707.
  33. 1 2 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. S2CID 32501470.
  34. 1 2 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. PMC 7423016. PMID 32029298.
  35. ↑ Karch, Steven B.; Drummer, Olaf (2015). Karch's Pathology of Drug Abuse (Fifth ed.). CRC Press. p. 528. ISBN 9781439861479.
  36. ↑ Tanguay, Pascal (April 2011). "Kratom in Thailand: Decriminalisation and Community Control?" (PDF). Transnational Institute. 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.
  37. ↑ Fuller, Thomas (23 July 2012). "A Fading Thai Drug Finds Its Resurgence in a Cocktail". The New York Times.
  38. 1 2 3 4 Post, Sara; Spiller, Henry A.; Chounthirath, Thitphalak; Smith, Gary A. (20 February 2019). "Kratom exposures reported to United States poison control centers: 2011–2017". Clinical Toxicology. 57 (10): 847–854. doi:10.1080/15563650.2019.1569236. ISSN 1556-3650. PMID 30786220. S2CID 73507086.
  39. ↑ Ramanathan, Surash; McCurdy, Christopher R. (2020). "Kratom (Mitragyna speciosa): worldwide issues". Current Opinion in Psychiatry. 33 (4): 312–318. doi:10.1097/YCO.0000000000000621. ISSN 1473-6578. PMID 32452943. S2CID 218893286.
  40. 1 2 Eggleston, William; Stoppacher, Robert; Suen, Kyle; Marraffa, Jeanna M.; Nelson, Lewis S. (2019). "Kratom Use and Toxicities in the United States". Pharmacotherapy. 39 (7): 775–777. doi:10.1002/phar.2280. ISSN 1875-9114. PMID 31099038. S2CID 157058636.
  41. ↑ Grundmann, Oliver (2017-07-01). "Patterns of Kratom use and health impact in the US-Results from an online survey". Drug and Alcohol Dependence. 176: 63–70. doi:10.1016/j.drugalcdep.2017.03.007. ISSN 1879-0046. PMID 28521200.
  42. 1 2 3 4 5 Meireles, Vânia; Rosado, Tiago; Barroso, Mário; Soares, Sofia; Gonçalves, Joana; Luís, Ângelo; Caramelo, Débora; Simão, Ana Y.; Fernández, Nicolás; Duarte, Ana Paula; Gallardo, Eugenia (2019-03-04). "Mitragyna speciosa: Clinical, Toxicological Aspects and Analysis in Biological and Non-Biological Samples". Medicines. 6 (1): 35. doi:10.3390/medicines6010035. ISSN 2305-6320. PMC 6473843. PMID 30836609.
  43. ↑ Dye, Leslie R.; Murphy, Christine; Calello, Diane P.; Levine, Michael D.; Skolnik, Aaron (2017-12-22). Case Studies in Medical Toxicology: From the American College of Medical Toxicology. Springer. ISBN 978-3-319-56449-4.
  44. ↑ Patel P, Aknouk M, Keating S, Richard I, Kata P, Ali RY, Cheriyath P (July 2021). "Cheating Death: A Rare Case Presentation of Kratom Toxicity". Cureus. 13 (7): e16582. doi:10.7759/cureus.16582. PMC 8378318. PMID 34430176.
  45. ↑ Olsen, Emily O’Malley; O’Donnell, Julie; Mattson, Christine L.; Schier, Joshua G.; Wilson, Nana (12 April 2019). "Unintentional Drug Overdose Deaths with Kratom Detected — 27 States, July 2016 – December 2017". MMWR. Morbidity and Mortality Weekly Report. 68 (14): 326–327. doi:10.15585/mmwr.mm6814a2. PMC 6459583. PMID 30973850.
  46. 1 2 "Multistate Outbreak of Salmonella I 4,[5],12:b:- Infections Linked to Kratom Products | February 2018 | Salmonella". cdc.gov. Centers for Disease Control. 20 February 2018. Retrieved 22 February 2018.
  47. ↑ Beckett, Jaclyn R. (2014). "Non-Analgesic CNS Effects". In Raffa, Robert B. (ed.). Kratom and other mitragynines : the chemistry & pharmacology of opioids from. CRC Press. pp. 195–204. ISBN 9781482225181.
  48. ↑ Kruegel, Andrew C.; Grundmann, Oliver (2018). "The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse". Neuropharmacology. 134 (Pt A): 108–120. doi:10.1016/j.neuropharm.2017.08.026. ISSN 0028-3908. PMID 28830758. S2CID 24009429.
  49. ↑ Olsen EO, O’Donnell J, Mattson CL, Schier JG, Wilson N (12 April 2019). "Notes from the Field: Unintentional Drug Overdose Deaths with Kratom Detected — 27 States, July 2016 – December 2017". MMWR. Morbidity and Mortality Weekly Report. 68 (14): 326–327. doi:10.15585/mmwr.mm6814a2. PMC 6459583. PMID 30973850.{{cite journal}}: CS1 maint: uses authors parameter (link)
  50. ↑ Mari A. Schaefer (April 13, 2019). "CDC: Kratom linked to 91 U.S. overdose deaths". Lodi News-Sentinel. The Philadelphia Inquirer. p. 16.
  51. ↑ "Kratom Caused 91 Overdose Deaths During 18-Month Period: CDC – Partnership News Service from the Partnership for Drug-Free Kids". Partnership to End Addiction | Where Families Find Answers. Retrieved 2020-08-05.
  52. 1 2 3 Rosenbaum CD, Carreiro SP, Babu KM (2012). "Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines". Journal of Medical Toxicology. 8 (1): 15–32. doi:10.1007/s13181-011-0202-2. PMC 3550220. PMID 22271566.
  53. ↑ Gibbons, Simon & Arunotayanun, Warunya (2013). "Chapter 14. Natural Product (Fungal and Herbal): Novel Psychoactive Substances". Novel Psychoactive Substances: Classification, Pharmacology and Toxicology. pp. 345–362. doi:10.1016/B978-0-12-415816-0.00014-6. Retrieved January 24, 2020.{{cite book}}: CS1 maint: multiple names: authors list (link)
  54. ↑ Takayama, Hiromitsu; et al. (2002). "Studies on the Synthesis and Opioid Agonistic Activities of Mitragynine-Related Indole Alkaloids: Discovery of Opioid Agonists Structurally Different from Other Opioid Ligands". Journal of Medicinal Chemistry. 45 (9): 1949–56. doi:10.1021/jm010576e. PMID 11960505.
  55. ↑ Suhaimi FW, Yusoff NH, Hassan R, Mansor SM, Navaratnam V, Müller CP, Hassan Z (2016). "Neurobiology of Kratom and its main alkaloid mitragynine". Brain Res Bull. Mar 25 (Pt 1): 29–40. doi:10.1016/j.brainresbull.2016.03.015. PMID 27018165. S2CID 3952200.
  56. ↑ Prozialeck, WC; Jivan, JK; Andurkar, SV (2012). "Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic, and opioid-like effects". The Journal of the American Osteopathic Association. 112 (12): 792–99. PMID 23212430.
  57. ↑ Ramanathan, Surash; León, Francisco; Chear, Nelson J.Y.; Yusof, Siti R.; Murugaiyah, Vikneswaran; McMahon, Lance R.; McCurdy, Christopher R. (2021-01-01). "Kratom (Mitragyna speciosa Korth.): A description on the ethnobotany, alkaloid chemistry, and neuropharmacology". Studies in Natural Products Chemistry. 69: 195–225. doi:10.1016/B978-0-12-819487-4.00003-3. ISBN 9780128194874. ISSN 1572-5995. S2CID 234947828.
  58. ↑ Le D, Goggin MM, Janis GC (2012). "Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom". Journal of Analytical Toxicology. 36 (9): 616–25. doi:10.1093/jat/bks073. PMID 23024321.
  59. ↑ Baselt RC (2014). Disposition of toxic drugs and chemicals in man. Seal Beach, Calif.: Biomedical Publications. p. 1382. ISBN 978-0-9626523-9-4.
  60. 1 2 3 Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, Koyama F, Matsumoto K, Moriyama T, Yamamoto LT, Watanabe K, Murayama T, Horie S (2002). "Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands". J. Med. Chem. 45 (9): 1949–56. doi:10.1021/jm010576e. PMID 11960505.
  61. ↑ Kerrigan, Sarah; Basiliere, Stephanie (2021). "Kratom: A systematic review of toxicological issues". WIREs Forensic Science. 4: e1420. doi:10.1002/wfs2.1420. ISSN 2573-9468. S2CID 236630556.
  62. ↑ Chakraborty, Soumen; Uprety, Rajendra; Daibani, Amal E.; Rouzic, Valerie L.; Hunkele, Amanda; Appourchaux, Kevin; Eans, Shainnel O.; Nuthikattu, Nitin; Jilakara, Rahul; Thammavong, Lisa; Pasternak, Gavril W. (2021-07-21). "Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom". ACS Chemical Neuroscience. 12 (14): 2661–2678. doi:10.1021/acschemneuro.1c00149. ISSN 1948-7193. PMC 8328003. PMID 34213886.
  63. ↑ Flores-Bocanegra, Laura; Raja, Huzefa A.; Graf, Tyler N.; Augustinović, Mario; Wallace, E. Diane; Hematian, Shabnam; Kellogg, Joshua J.; Todd, Daniel A.; Cech, Nadja B.; Oberlies, Nicholas H. (2020-07-24). "The Chemistry of Kratom [Mitragyna speciosa]: Updated Characterization Data and Methods to Elucidate Indole and Oxindole Alkaloids". Journal of Natural Products. 83 (7): 2165–2177. doi:10.1021/acs.jnatprod.0c00257. ISSN 0163-3864. PMC 7718854. PMID 32597657.
  64. ↑ Kruegel AC, Grundmann O (2017). "The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse". Neuropharmacology. 134 (A): 108–20. doi:10.1016/j.neuropharm.2017.08.026. PMID 28830758. S2CID 24009429.
  65. 1 2 White, CM (1 March 2018). "Pharmacologic and clinical assessment of kratom". American Journal of Health-System Pharmacy. 75 (5): 261–267. doi:10.2146/ajhp161035. PMID 29255059.
  66. ↑ Ya, Kimheang; Tangamornsuksan, Wimonchat; Scholfield, C. Norman; Methaneethorn, Janthima; Lohitnavy, Manupat (2019). "Pharmacokinetics of mitragynine, a major analgesic alkaloid in kratom (Mitragyna speciosa): A systematic review". Asian Journal of Psychiatry. 43: 73–82. doi:10.1016/j.ajp.2019.05.016. ISSN 1876-2018. PMID 31100603. S2CID 157067698.
  67. ↑ Gonçalves, Joana; Luís, Ângelo; Gallardo, Eugenia; Duarte, Ana Paula (2021-03-05). "Psychoactive Substances of Natural Origin: Toxicological Aspects, Therapeutic Properties and Analysis in Biological Samples". Molecules. 26 (5): 1397. doi:10.3390/molecules26051397. ISSN 1420-3049. PMC 7961374. PMID 33807728.
  68. ↑ Brown, Paula N.; Lund, Jensen A.; Murch, Susan J. (2017-04-18). "A botanical, phytochemical and ethnomedicinal review of the genus Mitragyna korth: Implications for products sold as kratom". Journal of Ethnopharmacology. 202: 302–325. doi:10.1016/j.jep.2017.03.020. ISSN 1872-7573. PMID 28330725.
  69. ↑ "Annex I: ASEAN Guiding Principles For Inclusion into or Exclusion from the Negative List of Substances for Traditional Medicines and Health Supplements" (PDF). Association of South East Asian Nations (ASEAN). June 28, 2014. Archived from the original (PDF) on October 26, 2016. Retrieved September 12, 2016.
  70. ↑ "Medicines Regulations 1984". New Zealand Legislation. Retrieved 31 May 2017.
  71. ↑ "Unauthorized products may pose serious health risks (kratom)". Health Canada. 21 October 2020. Retrieved 18 January 2021.
  72. ↑ "Health Product Advertising Complaints". Health Canada, Health Products and Food Branch. Archived from the original on 14 February 2017.
  73. ↑ Phil Heidenreich (27 June 2017). "Kratom, a controversial herbal product, seized from 2 Edmonton stores: Health Canada". Global News.
  74. ↑ Coles, Terri (14 October 2016). "After U.S. delayed decision on kratom, a look at Canada's laws on the psychadelic plant". Yahoo News Canada.
  75. ↑ "Psychoactive Substances Act 2016". The National Archives, HM Government Publishing. 9 September 2016.
  76. ↑ "MISUSE OF DRUGS (DESIGNATION) ORDER 2017" (PDF). STATUTORY INSTRUMENTS, S.I. No. 174 of 2017. Stationery Office, Dublin. 2017.
  77. ↑ "Mulai 2024, Pemerintah Larang Penggunaan dan Ekspor Kratom". beritasatu.com (in Indonesian). December 22, 2020. Retrieved 2021-09-02-29. {{cite web}}: Check date values in: |access-date= (help)
  78. ↑ "Amend the Act leaves the density of the Dangerous Drugs Act". 13 December 2012. Retrieved 18 April 2014.
  79. ↑ Veltri C, Grundmann O. Current perspectives on the impact of Kratom use. Subst Abuse Rehabil. 2019;10:23–31. Published 2019 Jul 1. doi:10.2147/SAR.S164261
  80. ↑ Pengasih wants abuse of kratom leaves penalised under Dangerous Drugs Act. The Malaysian Insider. October 28, 2012.
  81. 1 2 "Thailand legislature legalises medical cannabis and kratom". Aljazeera English. 26 December 2018. Retrieved 26 December 2018.
  82. ↑ Cheurprakobkit, Sutham (2000). "The drug situation in Thailand: the role of government and the police". Drug and Alcohol Review. 19 (1): 17–26. doi:10.1080/09595230096101.
  83. ↑ "Leafy highs: Kratom personal use push under way". Bangkok Post. 5 February 2020. Retrieved 5 February 2020.
  84. ↑ Prasert, Poungchompoo (4 October 2013). "Decision yet to be reached on making 'kratom' legal". The Nation.
  85. ↑ Limited, Bangkok Post Public Company. "Parliament votes to remove kratom from narcotics list". Bangkok Post. Retrieved 2021-06-22.
  86. ↑ Laohong, King-oua (2021-08-23). "Kratom now listed as legal herb". Bangkok Post. Retrieved 2021-08-24.
  87. ↑ "HHS recommended that the DEA ban kratom, documents show – STAT". STAT. 9 November 2018. Retrieved 15 November 2018.
  88. ↑ "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.
  89. ↑ MD, Peter Grinspoon (2019-08-07). "Kratom: Fear-worthy foliage or beneficial botanical?". Harvard Health. Retrieved 2021-06-21.
  90. ↑ "Kratom ban will hinder studies of the plant as a treatment". Stat. 2016-09-08. Retrieved 2021-06-21.
  91. 1 2 Chappell, Bill (4 April 2018). "FDA Orders An Unprecedented Recall After Kratom Company Ignored Its Requests". NPR. Retrieved 5 April 2018.
  92. 1 2 FDA News Release. "FDA orders mandatory recall for kratom products due to risk of salmonella". Press Announcements. United States Food and Drug Administration. Retrieved 5 April 2018.
  93. ↑ "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. 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 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
  94. ↑ "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. 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
  95. ↑ Silverman, Lauren (12 September 2016). "Kratom Advocates Speak Out Against Proposed Government Ban". NPR. Retrieved 12 September 2016.
  96. ↑ Ingraham, Christopher (September 30, 2016). "DEA defies senators' appeal to reconsider 'unprecedented' kratom ban". The Washington Post.
  97. ↑ Stapleton, Christine (September 29, 2016). "Congress members ask DEA not to ban kratom: opioid research needed". Palm Beach Post.
  98. ↑ Nelson, Steven (September 30, 2016). "Kratom Will Remain Legal for Days, Possibly Longer". US News & World Report.
  99. ↑ "Kratom Gets Reprieve From Drug Enforcement Administration". NPR.org. Retrieved 2016-10-12.
  100. ↑ "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.
  101. ↑ Brown, Melissa (May 20, 2016). "States ban kratom supplement over abuse worries". Associated Press via US News & World Report.
  102. ↑ Schwarz, Alan (2 January 2016). "Kratom, an Addict's Alternative, Is Found to Be Addictive Itself". The New York Times.
  103. ↑ Smith, Peter Andrey (2019-02-19). "The Herbal Supplement That Might Be a Deadly Drug". Outside Online. Retrieved 2019-02-20.
  104. 1 2 "The U.S. May Ban Kratom. But Are its Effects Deadly or Lifesaving?". Discover Magazine. Retrieved 2021-06-22.
  105. 1 2 3 Garber-Paul, Elisabeth; Garber-Paul, Elisabeth (2018-08-15). "Kratom Association Calls FDA Review of Drug 'Junk Science' in Scathing Report". Rolling Stone. Retrieved 2021-06-22.
  106. 1 2 3 Marlan, Dustin (2021-06-08). "A Sensible, Evidence-Based Proposal for Kratom Reform". Bill of Health. Retrieved 2021-06-22.
  107. ↑ Prozialeck, Walter C.; Avery, Bonnie A.; Boyer, Edward W.; Grundmann, Oliver; Henningfield, Jack E.; Kruegel, Andrew C.; McMahon, Lance R.; McCurdy, Christopher R.; Swogger, Marc T.; Veltri, Charles A.; Singh, Darshan (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.
  108. ↑ Johnson, Lindsay E.; Balyan, Lilian; Magdalany, Amy; Saeed, Fizza; Salinas, Robert; Wallace, Starla; Veltri, Charles A.; Swogger, Marc T.; Walsh, Zach; Grundmann, Oliver (2020-06-29). "The Potential for Kratom as an Antidepressant and Antipsychotic". The Yale Journal of Biology and Medicine. 93 (2): 283–289. ISSN 0044-0086. PMC 7309668. PMID 32607089.
  109. ↑ Taylor Levine, M.; Gao, Jin; Satyanarayanan, Senthil Kumaran; Berman, Sarah; Rogers, Jack T.; Mischoulon, David (2020). "S-adenosyl-l-methionine (SAMe), cannabidiol (CBD), and kratom in psychiatric disorders: Clinical and mechanistic considerations". Brain, Behavior, and Immunity. 85: 152–161. doi:10.1016/j.bbi.2019.07.013. ISSN 1090-2139. PMID 31301401. S2CID 195848995.
  110. ↑ Covvey, Jordan R.; Vogel, Samantha M.; Peckham, Alyssa M.; Evoy, Kirk E. (2020). "Prevalence and characteristics of self-reported kratom use in a representative US general population sample". Journal of Addictive Diseases. 38 (4): 506–513. doi:10.1080/10550887.2020.1788914. ISSN 1545-0848. PMID 32657217. S2CID 220499407.
  111. ↑ Kudla, Lucja; Przewlocki, Ryszard (2021-04-09). "Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors". Pharmacological Reports: PR. 73 (4): 1033–1051. doi:10.1007/s43440-021-00251-1. ISSN 1734-1140. PMC 8413226. PMID 33835467.
  112. ↑ "Kratom DrugFacts". National Institute on Drug Abuse, US National Institutes of Health. 1 April 2019. Retrieved 17 June 2021.
  113. ↑ 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.
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