Mitragyna speciosa

Mitragyna speciosa
Scientific classification
Kingdom: Plantae
(unranked): Angiosperms
(unranked): Eudicots
(unranked): Asterids
Order: Gentianales
Family: Rubiaceae
Subfamily: Cinchonoideae
Tribe: Naucleeae
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 also known as ketum or kratom,[2] is a tropical deciduous and evergreen tree in the coffee family (Rubiaceae) native to Southeast Asia in the Indochina and Malaysia floristic regions. M. speciosa is indigenous to Thailand where it has been used in traditional medicine.[3]

Its leaves are used for a variety of potential medicinal effects, but mainly to manage pain and/or anxiety and alcohol dependence. Though not an opiate itself, kratom is thought to behave similarly to an μ-opioid receptor agonist like morphine,[4] and thus is purported for managing chronic pain, as well as a recreational drug.[5] Kratom use is not detected by typical drug screening tests, but its metabolites can be detected by more specialized testing.[6][7] The pharmacological effects of kratom on humans, including its efficacy and safety, are not well-studied.[4]

Adverse effects may include palpitation, seizure, myalgia, insomnia, fatigue or chest discomfort.[8]

Taxonomy and etymology

Mitragyna speciosa was first formally described by the Dutch colonial botanist Pieter Korthals in 1839.[9] and in a 1897 publication by George Haviland.[10] The genus was named Mitragyna by Korthals because the stigmas in the first species he examined resembled the shape of a bishop's mitre. It is botanically related to the genera Corynanthe and Uncaria.

Description

Young M. speciosa tree

Mitragyna speciosa trees usually grow to a height of 12–30 ft (3.7–9.1 m) tall and 15 ft (4.6 m) wide, although some species can reach 40–70 ft (12–21 m) in height.[11] Mitragyna speciosa can be either evergreen or deciduous depending on the climate and environment in which it is grown. The stem is erect and branching. The leaves of the kratom tree are a dark green colour and can grow to over 7 inches (180 mm) long and 4 inches (100 mm) wide, are ovate-acuminate in shape, and opposite in growth pattern. The flowers are yellow and round and tend to grow in clusters at the end of the branches. The leaves of M. speciosa are elliptic and are smaller at the end of the branchlets and are pointed at the tip. The leaves have a round and heart-shape at the base with the petioles between 2 and 4 centimeters long. The flowers are crowded in a round terminal inflorescences that are three to five centimeters long. The calyx-tube is short and cup-shaped, with round lobes. The corolla-tube is five millimeters long with three millimiter long lobes and smooth and revolute in between.[12]

Chemistry

There are more than 40 compounds in M. speciosa leaves,[5] including many alkaloids such as mitragynine, mitraphylline, 7-hydroxymitragynine and mitragynine pseudoindoxyl.[13][14][15] Other active chemicals in M. speciosa include raubasine (best known from Rauwolfia serpentina) and yohimbe alkaloids such as corynantheidine.[16][17]

Mitragyna speciosa also contains at least one alkaloid (rhynchophylline) that is a calcium channel blocker, and reduces NMDA-induced current.[18][19] The amount of mitragynine within the leaves depends highly on many factors, one major factor is the location of the tree. When trees are grown in Southeast Asia, the levels tend to be higher but when grown elsewhere (even in greenhouses) the levels tend to be low or non-existent.[4] One analysis of products marketed as kratom leaf found, using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS), mitragynine at levels of 1–6% and 7-hydroxymirtrogynine at levels of 0.01–0.04%.[20] The chemical structure of mitragynines incorporate the nucleus of the tryptamine, and these may be responsible for the molecules observed in the serotonin and adrenergic systems. In mitragynine, the phenolic methyl ether is considered to be stronger in analgesic paradigms according to some studies. Moreover, the pharmacokinetics of M. speciosa in humans has not been well known.[21]

Uses

Opioid withdrawal

Kratom and its derivatives have been used for the management of opium withdrawal. Data on the incidence and prevalence of its use are lacking, as physicians are generally unfamiliar with it, and its use is not detected by typical drug screening tests.[5] Kratom metabolites can be detected by specialized mass spectrometry tests.[7] Incidence 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.[5] As of 2011, there have been no formal clinical trials performed to study the efficacy or safety of kratom to treat opioid addiction.[4]

The pharmacological effects of kratom on humans are not well studied. Its metabolic half-life, protein binding, and elimination characteristics are all unknown.[4] Kratom behaves as a μ-opioid receptor agonist, similar to opiates like morphine, although its effects differ significantly from those of opiates.[4]

It has also been used to manage opioid withdrawal symptoms by chronic opioid users.[11]

Traditional use

Kratom leaves

Kratom has been traditionally chewed, in raw leaf form, by people in Thailand and especially in the southern peninsula.[3] Kratom is often used by workers in laborious or monotonous professions to stave off exhaustion as well as a mood enhancer and/or painkiller. Kratom is also used in neighboring countries in Southeast Asia where it grows naturally.[3] Kratom has been used in Thailand as a form of traditional medicine as an antidiarrhoeal, as a treatment for opioid dependence as well as premature ejaculation during coitus.[22][23] As traditionally used, kratom is not seen as a drug and there is often no stigma associated with kratom use or discrimination against kratom users.[3] In southern Thailand, kratom has been a part of traditional culture and is common in cultural performances and agriculture.[24][25] A fresh leaf weighs on average 2 grams which may contain as much as 79 mg of mitragynine,[26] with the average number of leaves consumed daily between 10 and 60 leaves. In some areas of southern Thailand, kratom is often referred to by the street name P̄hī or 'Goblin'. Kratom leaves may also be used to make tea.

Side effects

Side effects associated with chronic kratom use include loss of appetite and weight loss, delayed ejaculation, constipation, and darkening of the skin color of the face and bowel obstruction.[5][27] Chronic users have also reported withdrawal symptoms including irritability, runny nose and diarrhea.[7] One other study on chronic Malaysian users of krakom (more than 6 months, estimated 276 mg of mitragynine daily) showed severe symptoms of muscle spasms and pain, sleeping difficulty, fever, decreased appetite and psychological withdrawal.[26]

Withdrawal is generally short-lived and mild, and it may be effectively treated with dihydrocodeine and loperamide.[28] Three case reports document deaths involving kratom. Other drugs were used in all cases, and Kratom was not found to be the cause in each case.[29][30][31] Several deaths in Sweden did occur from the use of a product that was at first believed to consist solely of kratom, called "Krypton Kratom", which was later found to contain O-Desmethyltramadol, the active metabolite of the prescription drug tramadol.[31]

Detection in body fluids

Blood concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally.[31][32]

Regulation

Thailand

Prohibition

Possession of kratom leaves is illegal in Thailand.[3] The Thai government passed the Kratom Act 2486, effective August 3, 1943, which made planting the tree illegal and required existing trees to be cut down. This law was not found effective, since the tree is indigenous to the country. A large aspect of Thai culture supports kratom; indeed, kratom leaves have been used for medicinal purposes by nomadic tribes throughout history.[33][34] However, despite this fact the Thai government had initiated a program of destroying kratom trees by burning forests or chopping large sections of kratom forests down. Eradication campaigns often destroy not only the trees but also other trees and wildlife in these areas, which are often untouched rainforests with sensitive ecosystems.[35] A general consensus exists in southern Thailand among leaders, public health officials, academics and policymakers that kratom use causes few health risks and may reduce dependence on imported morphine.[3][25]

Proposed decriminalization

In 2010, the Thai Office of the Narcotics Control Board proposed decriminalizing kratom and affirmed its use as an integral part of Thai culture.[3] The ONCB concluded that decades of non-problematic use, and an absence of health and social harm, make prohibiting the leaf unnecessary and counterproductive. According to the ONCB's report, kratom was in fact banned for economic reasons, not for health or social concerns. The Transnational Institute stated:

In Thailand, kratom was first scheduled for control in 1943 under the Kratom Act. At the time, the government was levying taxes from users and shops involved in the opium trade. Because of the increasing opium costs, many users were switching to kratom to manage their withdrawal symptoms. However, the launch of the Greater East Asia War in 1942 and declining revenues from the opium trade pushed the Thai government into action to curb and suppress competition in the opium market by making kratom illegal.[3]

As of October, 2013, the justice ministry of Thailand suggested removal of kratom from the narcotic drug list relating to Category 5 of the Narcotic Drug Law of 1979, though still recommended regulating kratom in other ways due to its effects on the nervous system. This recommendation will be made to the Ministry of Public Health, which can move forward with the removal from the list or not.[25]

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 penalized with a maximum compound of MYR 10,000 (USD 3,150) or up to 4 years imprisonment.[36] 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.[37]

United States

The U.S. Drug Enforcement Administration has issued a "Drugs of Abuse Resource Guide", which states "Kratom is not controlled under the Federal Controlled Substances Act; however, there may be some State regulations or prohibitions against the possession and use of kratom... In addition, DEA has listed kratom as a Drug and Chemical of Concern."[38] There is no FDA-approved medical use for kratom in the United States.

On June 9, 2015, the Food and Drug Administration (FDA) announced an import alert for kratom, issuing guidance that shipments are to be seized without physical examination from several vendors listed due to concerns that there is no evidence that Kratom does not pose an unnecessary risk of illness or injury, further stating that "[C]onsumption of kratom can lead to a number of health impacts, including respiratory depression, nervousness, agitation, aggression, sleeplessness, hallucinations, delusions, tremors, loss of libido, constipation, skin hyperpigmentation, nausea, vomiting, and severe withdrawal signs and symptoms."[39]

Some U.S. states have considered making kratom or its psychoactive constituents illegal. In response to increasing synthetic drug use, in 2012 the Indiana House of Representatives HB1196 made Indiana the first and only state to ban chemicals in kratom.[40] Also in 2012, Iowa legislators grouped Mitragyna speciosa as a synthetic cannabinoid when a bill was proposed that would reclassify nearly all controlled substances in their state.[41][42] The Louisiana legislature proposed an age limit of 18 to be able to legally purchase, possess and consume kratom. Violators would have been assessed a penalty of no more than $500 or sentenced to six months in jail, or both.[43] Massachusetts Representative Daniel K. Webster sponsored legislation in 2011 that would have included compounds of Mitragyna speciosa in the state's controlled substance classification list.[44] In 2016, New Hampshire State Senator Martha Fuller Clark (D-Portsmouth) sponsored SB540 - prohibiting the possession, use, or sale of kratom by anyone under the age of 18.[45]

See also

References

  1. ↑ Mitragyna speciosa (Korth.) Havil. is an accepted name . Theplantlist.org. Retrieved 2013-12-26.
  2. ↑ Mitragyna speciosa information from NPGS/GRIN. Ars-grin.gov. Retrieved 2013-12-26.
  3. 1 2 3 4 5 6 7 8 Tanguay, Pascal; Drug Policy Consortium, International (April 2011). "Kratom in Thailand: Decriminalization and Community Control?". Series on Legislative reform of Drug Policies 13. doi:10.2139/ssrn.1908849. Retrieved 2013-03-07.
  4. 1 2 3 4 5 6 Ward J, Rosenbaum C, Hernon C, McCurdy CR, Boyer EW; Rosenbaum; Hernon; McCurdy; Boyer (December 2011). "Herbal medicines for the management of opioid addiction: safe and effective alternatives to conventional pharmacotherapy?". CNS Drugs 25 (12): 999–1007. doi:10.2165/11596830-000000000-00000. PMID 22133323.
  5. 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): 1165–1175. doi:10.2174/156802611795371305. PMID 21050173.
  6. ↑ Le D, Goggin MM, Janis GC; Goggin; Janis (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.
  7. 1 2 3 Rosenbaum CD, Carreiro SP, Babu KM; Carreiro; Babu (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.
  8. ↑ Trakulsrichai S, Tongpo A, Sriapha C, Wongvisawakorn S, Rittilert P, Kaojarern S, Wananukul W (2013). "Kratom abuse in Ramathibodi Poison Center, Thailand: a five-year experience". J Psychoactive Drugs 45 (5): 404–8. PMID 24592666.
  9. ↑ Pieter Willem Korthals, "Observasions de Nauclais Indicis"; Bonnea; 1839; p. 20.
  10. ↑ George Darby Haviland, "A Revision of the Tribe Naucleeae (Nat. Ord. Rubiaceae)"; Journal of Linnean Society; p. 65-69; Linnean Society of London, Feb. 4 1897. A Revision of the Tribe Naucleeae (Nat. Ord. Rubicae)
  11. 1 2 "KRATOM (Mitragyna speciosa korth)" (PDF). U.S. Drug Enforcement Administration. Retrieved 1 March 2015.
  12. ↑ Philippine Department of Agriculture – Bureau of Plant Industry: Eintrag Mambog)
  13. ↑ 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. doi:10.1016/j.brainresbull.2016.03.015. PMID 27018165.
  14. ↑ Chittrakarn, S; Keawpradub, N; Sawangjaroen, K; Kansenalak, S; Janchawee, B (2010). "The neuromuscular blockade produced by pure alkaloid, mitragynine and methanol extract of kratom leaves (Mitragyna speciosa Korth.)". Journal of Ethnopharmacology 129 (3): 344–349. doi:10.1016/j.jep.2010.03.035. PMID 20371282.
  15. ↑ 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): 792–799. PMID 23212430.
  16. ↑ Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D; 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): 1949–1956. doi:10.1021/jm010576e. PMID 11960505.
  17. ↑ "Chemistry of Kratom -Mitragyna speciosa". Microblog - Kratom Emporium.
  18. ↑ "Kratom Mitragyna speciosa" (PDF). Microgram Bulletin – Department of Justice. XXXIX (3): 30. March 2006.
  19. ↑ Hendrickson, James B.; Sims, James J. (1963). "Mitragyna alkaloids: The structure of stipulatine". Tetrahedron Letters 4 (14): 929–935. doi:10.1016/S0040-4039(01)90746-4.
  20. ↑ Kikura-Hanajiri, Ruri; Kawamura, Maiko; Maruyama,Takuro; Kitajima, Mariko; Takayama, Hiromitsu; Goda, Yukihiro (1 July 2009). "Simultaneous analysis of mitragynine, 7-hydroxymitragynine, and other alkaloids in the psychotropic plant "kratom" (Mitragyna speciosa) by LC-ESI-MS". Forensic Toxicology 27 (2): 67–74. doi:10.1007/s11419-009-0070-5. Retrieved 23 June 2013.
  21. ↑ Ward, J.; Rosenbaum, C.; Hernon, C.; McCurdy, C. R.; Boyer, E. W. (2011). "Herbal Medicines for the Management of Opioid Addiction". CNS Drugs 25 (12): 999–1007. doi:10.2165/11596830-000000000-00000. PMID 22133323.
  22. ↑ Suwanlert, Sangun (1975). "A Study of Kratom Eaters in Thailand". Bulletin on Narcotics 27 (3): 21–27. PMID 1041694.
  23. ↑ Jansen, Karl L.R.; Colin J. Prast (1988-01-04). "Ethnopharmacology of Kratom and the Mitragyna Alkaloids". Journal of Ethnophamacology 23 (1): 115–119. doi:10.1016/0378-8741(88)90121-3. ISSN 0378-8741. PMID 3419199.
  24. ↑ Asnangkornchai, S; Siriwong, A (2005). "Kratom Plant in Thai society; culture, behavior". Health Science Laws.
  25. 1 2 3 Jeerapong Prasertpolkrung (29 August 2013). "Kratom may be taken off narcotics list". The Nation (Bangkok, Thailand). Retrieved 6 May 2016.
  26. 1 2 Singh D, Müller CP, Vicknasingam BK (2014). "Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users". Drug Alcohol Depend 139: 132–7. doi:10.1016/j.drugalcdep.2014.03.017. PMID 24698080.
  27. ↑ Hassan Z, Muzaimi M, Navaratnam V, Yusoff NH, Suhaimi FW, Vadivelu R; et al. (2013). "From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction". Neuroscience & Biobehavioral Reviews 37 (2): 138–51. doi:10.1016/j.neubiorev.2012.11.012. PMID 23206666.
  28. ↑ McWhirter L, Morris S; Morris (2010). "A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence". European Addiction Research 16 (4): 229–31. doi:10.1159/000320288. PMID 20798544.
  29. ↑ Neerman MF, Frost RE, Deking J; Frost; Deking (2013). "A drug fatality involving Kratom". Journal of Forensic Sciences. 58 Suppl 1: S278–9. doi:10.1111/1556-4029.12009. PMID 23082895.
  30. ↑ Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J, Solomon CJ, Levine B; Vorce; McDonough-Bender; Magluilo Jr; Solomon; Levine (2011). "A drug toxicity death involving propylhexedrine and mitragynine". Journal of Analytical Toxicology 35 (1): 54–9. doi:10.1093/anatox/35.1.54. PMID 21219704.
  31. 1 2 3 Kronstrand R, Roman M, Thelander G, Eriksson A; Roman; Thelander; Eriksson (2011). "Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton". Journal of Analytical Toxicology 35 (4): 242–7. doi:10.1093/anatox/35.4.242. PMID 21513619.
  32. ↑ Baselt RC (2014). Disposition of toxic drugs and chemicals in man. Seal Beach, Calif.: Biomedical Publications. p. 1382. ISBN 978-0-9626523-9-4.
  33. ↑ Suwanwela, C. (1983). "Thailand: Traditional and urban patterns of opium use". Drug Use and Misuse: cultural perspectives: 50–57.
  34. ↑ "A Culture Born on Kratom: Thailand's Prohibition Symposium". Kratomystic. Retrieved 4 June 2015.
  35. ↑ 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. Retrieved 4 June 2015.
  36. ↑ "Amend the Act leaves the density of the Dangerous Drugs Act". 13 December 2012. Retrieved 18 April 2014.
  37. ↑ Pengasih wants abuse of kratom leaves penalised under Dangerous Drugs Act. The Malaysian Insider. October 28, 2012.
  38. ↑ . US DEA.
  39. ↑ "Import Alert 54-15". FDA. 28 February 2014. Retrieved 18 April 2014.
  40. ↑ Bill Text: IN HB1196 | 2012 | Regular Session | Enrolled. LegiScan. Retrieved 2013-12-26.
  41. ↑ Bill Text: IA SF2341 | 2011–2012 | 84th General Assembly | Introduced. LegiScan. Retrieved 2013-12-26.
  42. ↑ Kiley, Brendan (2012-04-10). "The Rush to Prohibit Kratom". The Stranger. Retrieved 2012-10-30.
  43. ↑ Bill Text: LA SB130 | 2012 | Regular Session | Chaptered. LegiScan. Retrieved 2013-12-26.
  44. ↑ Bill Text: MA H526 | 2011–2012 | 187th General Court | Introduced. LegiScan. Retrieved 2013-12-26.
  45. ↑ Bill Text: NH SB540 | 2015-2016 | Introduced. Retrieved 2016-02-02.

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