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Mitragyna speciosa

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Mitragyna speciosa
Mitragyna speciosa111.JPG
Scientific classification e
Kingdom: Plantae
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] also ketum) is a tropical evergreen tree in the coffee family native to Southeast Asia. M. speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea,[3] where it has been used in traditional medicine since at least the 19th century.[4] Kratom has opioid properties and some stimulant-like effects.[5][6][7]

As of 2018, little is known of kratom's worth or safety as a therapeutic agent, since research into its use has been of poor quality.[8][9] In February 2018, the Food and Drug Administration (FDA) stated that there is no evidence kratom is safe or effective for treating any condition.[6] Some people take it for managing chronic pain, for treating opioid withdrawal symptoms, or – more recently – for recreational purposes.[3][9] Onset of effects typically begins within 5 to 10 minutes and lasts 2 to 5 hours.[3]

Common minor side effects may include nausea, vomiting, and constipation.[3] More severe side effects may include respiratory depression (decreased breathing), seizure, addiction, and psychosis.[3][6][10][11] Other side effects may include high heart rate and blood pressure, trouble sleeping, and, rarely, liver toxicity.[3][12][13] When use is stopped, withdrawal symptoms may occur.[7][9] Deaths have occurred with kratom both by itself and mixed with other substances.[6][14] Between 2011 and 2017, 44 kratom-related deaths occurred, with one involving kratom alone.[6] Nine kratom-related deaths occurred in Sweden in 2011 and 2012, all involving a mixture of kratom with other opioids.[14]

As of 2018, there is growing international concern about a possible threat to public health from kratom use.[6][9][15] In some jurisdictions, its sale and importation have been restricted, and several public health authorities have raised alerts.[9][15][16] Kratom is a controlled substance in 16 countries,[6] and in 2014, the FDA banned imports and manufacturing of kratom as a dietary supplement.[17] Sometimes, the finished product is mixed into cocktails with other psychoactive drugs, such as caffeine and codeine.[7][18]

Description

Young M. speciosa tree

Mitragyna speciosa is an evergreen tree that can grow to a height of 25 m (82 ft) tall and the trunk may grow to a 0.9 m (3 ft) diameter.[19] The trunk is generally straight and the outer bark is smooth and grey.[19] The leaves are dark green and glossy,[9] 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.[19] The flowers grow in clusters of three at the ends of the branches. The calyx-tube is 2 mm (0.079 in) long and has 5 lobes; the corolla-tube is 2.5–3 millimetres (0.098–0.118 in) long.[19]

M. speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea.[3]

Mitragyna speciosa was first formally described by the Dutch colonial botanist Pieter Korthals in 1839, who named it as such; it was renamed and reclassified several times before George Darby Haviland provided the final name and classification in 1859.[19]:59

Uses

The United States Drug Enforcement Administration stated in 2013: "There is no legitimate medical use for kratom".[10] Kratom has become popular as a recreational drug and has been promoted with claims that it can improve mood, relieve pain and help with opiate addiction.[16] As of 2013, kratom and key extracts have been studied in cells and in animals, but no clinical trials have been conducted in the United States.[4]

Opioid withdrawal

In 1836, kratom was reported to be used as an opium substitute in Malaysia. Kratom was also used as an opium substitute in Thailand in the 19th century.[4]

Data on how often it is used worldwide are lacking as it is not detected by typical drug screening tests.[20] Rates of kratom use appears 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.[20] As of 2018, there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction.[6]

Traditional use

Kratom leaves

In cultures where the plant grows, it has been used in traditional medicine. The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to khat and coca.[9] 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][19] Kratom is often used by workers in laborious or monotonous professions to stave off exhaustion as well as a mood enhancer and/or painkiller.[19] In Thailand, kratom was "used as a snack to receive guests and was part of the ritual worship of ancestors and gods."[21] The herb is very bitter and is generally combined with a sweetener.[20]

Recreational use

Across Southeast Asia, and especially in Thailand in the 2010s, a tea-based cocktail known as 4×100 became popular among some younger people. It is a mix of kratom leaves, cough syrup, Coca-Cola, and ice; as of 2011, people who consumed this were often viewed more negatively than users of traditional kratom, but not as negatively as users of heroin.[22] As of 2012, use of the cocktail was a severe problem among youth in three provinces along the border with Malaysia.[23]

In the US, as of 2015, kratom was available in head shops and over the internet; prevalence of use was unknown as of that time.[9]

Adverse effects

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][9] At moderate (5 to 15 g of raw leaves) doses and higher, at which opioid effects generally appear, additional adverse effects include tachycardia (increased stimulant effect) as well as the opioid side effects of constipation, dizziness, hypotension, dry mouth, and sweating.[9][11] Frequent use of high doses of kratom may cause tremor, anorexia, weight loss, seizures, and psychosis.[9] If heavy users try to stop using kratom, they may experience withdrawal symptoms including irritability, feelings of distress, nausea, hypertension, insomnia, runny nose, muscle and joint pain, and diarrhea.[9][7]

Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.[3][9]

In July 2016, the Centers for Disease Control (CDC) issued a report stating that between 2010 and 2015, US Poison 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.[13] 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 again regarding effects.[13]

Overdose of kratom is managed similar to opioid overdose, 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 consumption of contaminated pills, powder, tea or unidentified sources of kratom.[24] 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.[24]

Respiratory depression

Respiratory depression is a major risk with opioids, especially those that have activity at the mu-opioid receptor. This is the leading cause of death from opioid use.[25]:196 In animal studies at very high doses, mitragynine caused respiratory depression, but less than morphine or codeine.[25]:196[20] The respiratory effects of kratom and its main bioactive components have not been studied in people.[4][25]:196

A 2016 CDC report on kratom exposures did not list respiratory depression as a risk of kratom,[13] nor did a 2013 DEA report.[10] In 2016, the Food and Drug Administration did list respiratory depression as one of the concerns.[17] Some literature review articles do not list respiratory depression;[4][9] however other literature reviews and some medical textbooks do name respiratory depression as a risk.[3][26][11][27]:15

Liver toxicity

In rare cases, chronic use of kratom has been linked to acute liver injury with associated symptoms of fatigue, nausea, itching and jaundice.[12][28] Liver injury is associated with cholestasis and may involve acute renal failure.[12] As of 2016, the mechanism by which kratom causes liver damage in some people was poorly understood.[28]

Death

Kratom overdose is a subject of concern in many countries because of the rising number of hospitalizations and deaths from chronic kratom abuse.[5][9][12] According to clinical reviews, kratom overdose can cause liver toxicity, seizures, coma and death,[12] especially when in combination with alcohol abuse.[5] Between 2011 and 2017, forty four deaths were kratom-related.[6] In one autopsy, substantial levels of mitragynine and the psychostimulant, propylhexedrine, were found in the blood sample.[14] In an additional autopsy were high levels of mitragynine and signs of opioid toxicity.[9] 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.[14][26]

Chemistry

The key psychoactive compounds in M. speciosa are mitragynine and 7-hydroxymitragynine (7-HMG),[9] but there are more than 40 compounds in M. speciosa leaves,[20] including about 25 alkaloids other than mitragynine and 7-hydroxymitragynine including ajmalicine, mitraphylline, mitragynine pseudoindoxyl, and Rhynchophylline.[29][30] Other active chemicals in M. speciosa include raubasine (best known from Rauvolfia serpentina) and Pausinystalia johimbe alkaloids such as corynantheidine.[31]

Mitragynine is about 60% of alkaloid extractions, while 7-hydroxymitragynine is about 2%.[9] Mitragynine is structurally similar to yohimbine and voacangine.[9]

Pharmacology

As of 2017, much of the pharmacology of kratom was not well understood, having stimulant effects at low doses, an opioid-like effect at higher doses, as well as sedative and sensory-suppressive effects.[5][8][9]

Both mitragynine and 7-HMG are selective full agonists of the μ-opioid receptor; 7-HMG appears to have higher affinity.[9] The stimulant effects appear to be mediated via prevention of activation of serotonin 5-HT2A receptors and postsynaptic α2-adrenergic receptors.[9] Rhynchophylline is a non-competitive NMDA antagonist found in kratom.[9]

Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resulting metabolites excreted in urine.[9] In in vitro experiments, kratom extracts inhibited CYP3A4, CYP2D6, and CYP1A2 enzymes, which results in significant potential for drug interactions.[9]

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.[32][26] 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.[26][33]

Regulation

As of January 2018, neither the plant nor its alkaloids were listed in any of the Schedules of the United Nations Drug Conventions.[15]

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.[34]

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)[35] of New Zealand.[15]

Canada

As of October 2016, it was not legal to market kratom for any use in which it was ingested, but could be marketed for other uses, such as incense.[36] Health Canada has taken action against companies marketing it for ingestion.[37][38]

Europe

In Europe, as of 2011, the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania and Sweden.[15] In the UK, since 2016, the sale, import, and export of kratom are prohibited under the Psychoactive Substances Act.[39]

Malaysia

The use of kratom leaves, known locally as 'ketum', is prohibited in Malaysia under Section 30 (3) Poisons Act 1952 and the user may be fined with a maximum amount of MYR 10,000 (USD 3,150) or up to 4 years imprisonment.[40] Certain parties have urged the government to penalize the use of kratom under the Dangerous Drugs Act instead of the Poisons Act, which will carry heavier penalties.[41]

Thailand

Possession of kratom leaves is illegal in Thailand. The Thai government passed the Kratom Act 2486, effective August 3, 1943, which made planting the tree illegal,[10] in response to a rise in its use when opium became very expensive in Thailand and the Thai government was attempting to gain control in the opium market.[9] In 1979, the Thai government placed kratom, along with marijuana, in Category V of a five category classification of narcotics.[10] Kratom accounted for less than 2% of arrests for narcotics between 1987 and 1992.[42]

The government considered legalizing kratom in 2004, 2009, and 2013.[43]

United States

Over the period 2010 to 2015, kratom-related reports of poisoning in the United States increased by 10-fold.[13] Because kratom was being marketed as a dietary supplement in 2014 – but had never been commonly used in the United States or confirmed to be safe – the FDA coordinated with other US agencies to seize imported shipments.[17][44] As of March 2018, Alabama, Arkansas, Indiana, Tennessee, Vermont, and Wisconsin had made kratom illegal,[45] and the US Army had forbidden soldiers from using it.[46]

On 30 August 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.[16] This drew strong protests among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol.[47] A group of 51 members of the US House of Representatives and a group of 9 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.[48][49] 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."[50] In October 2016, the DEA withdrew its notice of intent while inviting public comments over a review period ending 1 December 2016.[51][52]

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."[53]

In February 2018, the Commissioner of the FDA, Dr. Scott Gottlieb, released a statement describing further opioid-like properties of kratom and that it should not be used for any medical treatment or recreational use.[6] 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.[54] 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.[55]

On April 4, 2018, the FDA issued the first mandatory recall in its history over concerns of salmonella contamination of several kratom-containing products.[56] Samples of the products, manufactured by Triangle Pharmanaturals and marketed under the brand name of Raw Form Organics, tested positive for contamination and the manufacturer did not comply with federal requests for voluntary recall.[57] FDA Commissioner Gottleib 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.[56] Consumers were advised to immediately discard any such products to prevent serious health risks.[57]

See also

References

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  52. ^ "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. 
  53. ^ "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 
  54. ^ "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 
  55. ^ Steven J. Tave (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. 
  56. ^ a b Chappell, Bill (4 April 2018). "FDA Orders An Unprecedented Recall After Kratom Company Ignored Its Requests". NPR. Retrieved 5 April 2018. 
  57. ^ a b FDA News Release. "FDA orders mandatory recall for kratom products due to risk of salmonella". Press Announcements. United States Food and Drug Administration. Retrieved 5 April 2018. 

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