Mitragyna speciosa

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Mitragyna speciosa
Mitragyna speciosa111.JPG
Scientific classification
Kingdom: Plantae
Division: Magnoliophyta
Class: Magnoliopsida
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 (ketum,[2] kratom or kratum,[3] Thai: กระท่อม) is a tropical deciduous and evergreen tree in the coffee family (Rubiaceae) native to Southeast Asia in the Indochina and Malesia floristic regions. Its leaves are used for medicinal properties. It is psychoactive, and leaves are chewed to uplift mood and to treat health problems.[4] M. speciosa is indigenous to Thailand and, despite growing naturally in the country, has been outlawed for 70 years and was originally banned because it was reducing the Thai government's tax revenue from opium distribution.[4]

Kratom behaves as a μ-opioid receptor agonist like morphine[5] and is used in the management of chronic pain, as well as recreationally.[6] Kratom use is not detected by typical drug screening tests, but its metabolites can be detected by more specialized testing.[7][8] The pharmacological effects of kratom on humans, including its efficacy and safety, are not well-studied.[5] Most side effects of kratom are thought to be mild, although isolated serious adverse effects such as psychosis, convulsions, hallucinations, and confusion have been reported rarely.[4] There has been a reported case in which chronic use of M. speciosa was associated with bowel obstruction, as well as anecdotal reports stating that the plant carries the potential for addiction and can lead to withdrawal symptoms.[4] There have been case reports that document deaths involving individuals who have combined kratom with other drugs or substances, but kratom itself has not been identified to be cause of death in any of these cases.[9][10][11]

Taxonomy and etymology[edit]

It was first formally described by the Dutch colonial botanist Pieter Korthals. 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 and shares some similar biochemistry.

Description[edit]

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 40–100 ft (12–30 m) in height[citation needed]. 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 to 4 centimeters long. The flowers are crowded in a round terminal inflorescences which 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[edit]

There are more than 40 compounds in M. speciosa leaves,[6] including many alkaloids such as mitragynine (once thought to be the primary active constituent), mitraphylline, and 7-hydroxymitragynine (which is currently the most likely candidate for the primary active chemical in the plant), and mitragynine pseudoindoxyl.[13][14] Other active chemicals in M. speciosa include raubasine (best known from Rauwolfia serpentina) and some yohimbe alkaloids such as corynantheidine.[15]

Mitragyna speciosa also contains at least one alkaloid (rhynchophylline) that is a calcium channel blocker, and reduces NMDA-induced current.[16][17] 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.[5] 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%.[18] The chemical structure of mitragynines incorporate the nucleus of the tryptamine, and these may be responsible for the molecules which are 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, studies concerning the pharmacokinetics of M. speciosa in humans has not been well studied and various aspects such as the half-life, protein binding properties and other properties such as the elimination or metabolism is not known.[19]

Use and Safety[edit]

Kratom leaves

Kratom has been traditionally chewed, in raw leaf form, by people in Thailand and especially in the southern peninsula. Kratom is also used in neighboring countries in Southeast Asia where it grows naturally.[4] As traditionally used, kratom is not seen as a drug and there is no stigma associated with kratom use or discrimination against kratom users.[4] In southern Thailand, kratom has been a part of traditional culture for thousands of years and is common in traditional cultural performances and in agriculture.[20] In southern Thailand, kratom chewers generally start at around the age of 25 and many continue to chew the leaves for the rest of their lives. A fresh leaf weighs on average 2 grams. The average number of leaves consumed is between 10 and 60 leaves per day, but even more than this is common. In southern Thailand, upwards of 70% of the male population uses kratom on a daily basis in some areas.[citation needed]

Kratom has seen therapeutic use in Thai ethnomedicine as an antidiarrhoeal, as a treatment for opioid dependence, and rarely to increase the duration of coitus.[21][22][23]

Kratom and its derivatives have been used as substitutes for opium as well as 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.[6] Kratom metabolites can be detected by specialized mass spectrometry tests.[8] 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.[6] As of 2011, there have been no formal clinical trials performed to study the efficacy or safety of kratom to treat opioid addiction.[5]

The pharmacological effects of kratom on humans are not well studied. Its metabolic half-life, protein binding, and elimination characteristics are all unknown.[5] Kratom behaves as a μ-opioid receptor agonist, similar to opiates like morphine, although its effects differ significantly from those of opiates.[5] Kratom does not appear to have significant adverse effects, and in particular appears not to cause the hypoventilation typical of other opioids.[5] Compulsive use has been reported among drug users who inject opioids, and those who use opioids to manage pain without direction from medical professionals.[5]

Side effects associated with chronic kratom use include loss of appetite and weight loss, constipation, and darkening of the skin color of the face. Chronic use has been associated with bowel obstruction.[6][24] Chronic users have also reported withdrawal symptoms including irritability, runny nose and diarrhea.[8] Withdrawal is generally short-lived and mild, and it may be effectively treated with dihydrocodeine and lofexidine.[25] Three case reports document deaths involving kratom. Other drugs were used in all cases, and in one, kratom was speculated to possibly be the primary cause of death.[9][10][11] Several deaths in Sweden did occur from the use of a product which 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.[26] In 1975, there was an isolated report of serious adverse effects such as psychosis, convulsions, hallucinations, and confusion, among five individuals who had used kratom daily for 10–35 years.[4]

Media attention[edit]

Kratom is frequently a concern of politicians, journalists and regulatory officials.[27][28]

Regulation[edit]

Thailand[edit]

Prohibition

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 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, 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. A general consensus exists in southern Thailand, where the use of kratom is endemic, among leaders, public health officials, academics and policymakers that kratom use and dependence causes little, if any, health risks.[4]

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. The ONCB concluded that decades of unproblematic 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. In a snippet from a book written by Cassandra Hoffman:

"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."[4]

As of October 2, 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.[29]

Malaysia[edit]

The use of kratom leaves (locally known as 'ketum' which roughly translates as 'Goblin') 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.[30] 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.[31]

United States[edit]

Kratom itself is not regulated by the United States federal government. However, the Drug Enforcement Administration includes it in a list titled "Drugs and Chemicals of Concern".[32]

On February 28, 2014 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.[33]

Indiana House of Representatives HB1196, sponsored by Edward DeLaney, Steve Davisson, Terri Austin, Vernon G. Smith, and David Yarde during the 2012 regular session as a response to increasing synthetic drug use, made Indiana the first and only state to ban chemicals in kratom, although indirectly.[34] The text of the bill added kratom's two active alkaloids—mitragynine and 7-hydroxymitragynine—to the state's list of controlled substances, though kratom itself is not synthetic and was not specifically addressed by the authors of the bill. Due to kratom not being on the banned plants list nor being a synthetic, kratom is still legal in Indiana.[citation needed]

Iowa legislators grouped Mitragyna speciosa as a synthetic cannabinoid when a bill was proposed that would reclassify nearly all controlled substances in their state.[35][36] 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.[37] 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.[38]

Advocacy[edit]

The Transnational Institute has argued that while continued research is needed, the criminalization of kratom is unfounded and is based on economic control and disinformation. This group has argued that few records are available showing negative health or social consequences from kratom consumption, but despite this fact kratom is becoming increasingly subject to actions of law enforcement in numerous countries. The criminalization of kratom has created numerous barriers for research. In Thailand, the eradication campaigns have made it especially difficult for academics and researchers to adequately research the medicinal benefits of kratom. This group has concluded that the criminalization of kratom is unnecessary, problematic and counter-productive, and has summarily recommended that kratom be decriminalized. It also concluded that the evidence showing the health benefits of kratom, especially in treating drug and alcohol dependence, should serve as an important point to consider.[4]

References[edit]

  1. ^ Mitragyna speciosa (Korth.) Havil. is an accepted name . Theplantlist.org. Retrieved 2013-12-26.
  2. ^ Erowid Kratom (Mitragyna speciosa) Vault. Erowid.org. Retrieved 2013-12-26.
  3. ^ Mitragyna speciosa information from NPGS/GRIN. Ars-grin.gov. Retrieved 2013-12-26.
  4. ^ a b c d e f g h i j Tanguay, Pascal; Drug Policy Consortium, International (April 2011). "Kratom in Thailand: Decriminalization and Community Control?" (PDF). Series on Legislative reform of Drug Policies 13. doi:10.2139/ssrn.1908849. Retrieved 2013-03-07. 
  5. ^ a b c d e f g h 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. 
  6. ^ a b c d e 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. 
  7. ^ 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". J Anal Toxicol 36 (9): 616–25. doi:10.1093/jat/bks073. PMID 23024321. 
  8. ^ a b c 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". J Med Toxicol 8 (1): 15–32. doi:10.1007/s13181-011-0202-2. PMC 3550220. PMID 22271566. 
  9. ^ a b Neerman MF, Frost RE, Deking J; Frost; Deking (2013). "A drug fatality involving Kratom". J Forensic Sci. 58 Suppl 1: S278–9. doi:10.1111/1556-4029.12009. PMID 23082895. 
  10. ^ a b 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". J Anal Toxicol 35 (1): 54–9. doi:10.1093/anatox/35.1.54. PMID 21219704. 
  11. ^ a b 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". J Anal Toxicol 35 (4): 242–7. doi:10.1093/anatox/35.4.242. PMID 21513619. 
  12. ^ Philippine Department of Agriculture – Bureau of Plant Industry: Eintrag Mambog)
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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". J Med Chem 45 (9): 1949–1956. doi:10.1021/jm010576e. PMID 11960505. 
  16. ^ "Kratom Mitragyna speciosa". Microgram Bulletin – Department of Justice. XXXIX (3): 30. March 2006. 
  17. ^ Hendrickson, James B.; Sims, James J. (1963). "Mitragyna alkaloids: The structure of stipulatine". Tetrahedron Letters 4 (14): 929. doi:10.1016/S0040-4039(01)90746-4. 
  18. ^ 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. 
  19. ^ 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.  edit
  20. ^ Asnangkornchai, S; Siriwong, A (2005). "Kratom Plant in Thai society; culture, behavior". Health Science Laws. 
  21. ^ Suwanlert, Sangun (1975). "A Study of Kratom Eaters in Thailand". Bulletin on Narcotics 27 (3): 21–27. PMID 1041694. 
  22. ^ 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. 
  23. ^ Reanmongkol, Wantana; Niwat Keawpradub; Kitja Sawangjaroen (March 2007). "Effects of the extracts from Mitragyna speciosa Korth. leaves on analgesic and behavioral activities in experimental animals" (PDF). Songklanakarin Journal of Science and Technology 29 (1): 39–48. Retrieved 2012-10-26. 
  24. ^ 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". Neurosci Biobehav Rev 37 (2): 138–51. doi:10.1016/j.neubiorev.2012.11.012. PMID 23206666. 
  25. ^ McWhirter L, Morris S; Morris (2010). "A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence". Eur Addict Res 16 (4): 229–31. doi:10.1159/000320288. PMID 20798544. 
  26. ^ Kronstrand, R., Roman, M., Thelander, G., & Eriksson, A. (2011). Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. Journal of analytical toxicology, 35(4), 242-247.
  27. ^ "'Groovy new drug' Kratom gaining in popularity – and perfectly legal". KBOI. 2013-03-06. Retrieved 2013-03-06.  |first1= missing |last1= in Authors list (help)
  28. ^ Saunders, Hannah (2013-04-04). "Enhanced Kratom: The next big drug". WZZM13. Retrieved 2013-03-05. 
  29. ^ สำนักข่่าวแห่งชาติ : Kratom to be removed from the narcotics list. Thainews.prd.go.th (2013-10-03). Retrieved 2013-12-26.
  30. ^ "Amend the Act leaves the density of the Dangerous Drugs Act". 13 December 2012. Retrieved 18 April 2014. 
  31. ^ Pengasih wants abuse of kratom leaves penalised under Dangerous Drugs Act. The Malaysian Insider. October 28, 2012.
  32. ^ DEA Diversion Control – Drugs and Chemicals of Concern. US DOJ.
  33. ^ "Import Alert 54-15". FDA. 28 February 2014. Retrieved 18 April 2014. 
  34. ^ Bill Text: IN HB1196 | 2012 | Regular Session | Enrolled. LegiScan. Retrieved 2013-12-26.
  35. ^ Bill Text: IA SF2341 | 2011–2012 | 84th General Assembly | Introduced. LegiScan. Retrieved 2013-12-26.
  36. ^ Kiley, Brendan (2012-04-10). "The Rush to Prohibit Kratom". The Stranger. Retrieved 2012-10-30. 
  37. ^ Bill Text: LA SB130 | 2012 | Regular Session | Chaptered. LegiScan. Retrieved 2013-12-26.
  38. ^ Bill Text: MA H526 | 2011–2012 | 187th General Court | Introduced. LegiScan. Retrieved 2013-12-26.

Further reading[edit]

  • Singh D, Müller CP, Vicknasingam BK; Müller; Vicknasingam (June 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. 

External links[edit]