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Mitragyna speciosa

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Mitragyna speciosa
Mitragyna speciosa111.JPG
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 Korth. (also known as ketum or kratom),[2] is a tropical evergreen tree in the coffee family (Rubiaceae) native to Southeast Asia in the Indochina and Malaysia phytochoria (botanical regions). M. speciosa is indigenous to Thailand, Indonesia, and Malaysia, Myanmar, and Papua New Guinea.[3]

Little research has been done on the health effects and it has no approved medical uses.[4][3] In cultures where the plant grows, it has been used in traditional medicine.[3] Some people use it for managing chronic pain, opioid withdrawal, or recreationally;[3] as of 2015 the recreational use was fairly recent.[4] Effects typically last 2 to 5 hours, with onset beginning 5 to 10 minutes after ingestion.[3] The plant's active compounds and metabolites are not detected by a typical drug screening test, but can be detected by more specialized testing.[5][6]

Minor side effects may include itchiness, vomiting, and constipation.[3] More severe side effects may include respiratory depression (decreased breathing), seizure, addiction, and psychosis.[3] Other side effects include high heart rate and blood pressure, liver toxicity, and trouble sleeping.[7][8] There is a risk of addiction.[3] In the United States between 2014 and 2016, 15 deaths have been associated with kratom use.[7] Though not an opiate itself, kratom is thought to behave similarly to an opiate like morphine.[9]

As of 2015 there was a growing international concern about a possible threat to public health from kratom use.[4][10] In some jurisdictions its sale and importation have been restricted, and a number of public health authorities have raised alerts.[4][7][10]

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 3 ft (0.91 m) diameter,[11] The trunk is generally straight and the outer bark is smooth and grey.[11] The leaves are dark green and glossy,[4] 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.[11] The flowers grow in clusters of three at the end 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[11]

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

Uses

As of 2013 the United States Drug Enforcement Administration stated, "There is no legitimate medical use for kratom".[12] 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.[7]

Opioid withdrawal

Informal use of kratom to aid in overcoming opioid withdrawal dates back to the early 1940s in Thailand, when a shortage of opium led addicts to turn to kratom.[4] Data on how often it is used are lacking as it is not detected by typical drug screening tests.[13] Kratom metabolites can be detected by specialized mass spectrometry tests.[6] 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.[13] As of 2011, there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction.[9]

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, increase energy, appetite, and sexual desire in ways similar to khat and coca,[4] and the leaves or extracts from them are used to heal wounds, and as a local anesthetic, and extracts have been used to treat coughs, diarrhea .[3][11] Kratom is often used by workers in laborious or monotonous professions to stave off exhaustion as well as a mood enhancer and/or painkiller.[11] The herb is very bitter and is generally combined with a sweetener.[13]

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 2015 people who consumed this were often viewed like methamphetamine and heroin addicts.[4] 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.[4]

Adverse effects

Kratom has become a subject of concern in many countries because of the rising number of hospital visits and reports of deaths associated with its users.[4] According to the DEA, 15 deaths in the United States between 2014 and 2016 were kratom-related.[7]

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.[8] 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.[8]

Adverse effects are similar to opioids and include hallucinations, psychosis, seizures, agitation, tachycardia, nausea, constipation, bowel obstruction, drowsiness, respiratory depression (normal breathing is reduced, which can lead to carbon dioxide poisoning and death), reduced appetite, itching, sweating, dry mouth, and increased urination.[3][7][13][14] Chronic users have also reported withdrawal symptoms including irritability, runny nose and diarrhea.[6] One other study on chronic Malaysian users of kratom (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.[15] Overdose of kratom is managed similar to the overdose of opioids, and naloxone can be considered to treat an overdose that results in a reduced effort to breathe despite mixed results for its utility in animal models.[3]

Withdrawal is generally short-lived and mild, and it may be effectively treated with dihydrocodeine and lofexidine.[16] Three case reports document deaths involving kratom. Other drugs were used in all cases, and Kratom was found not to be the cause in each case.[17][18][19] 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.[19]

Pharmacology

As of 2015, much of the pharmacology of kratom was not well understood.[4] As of that time, mitragynine was thought to have about 13 times the potency of morphine; 7-HMG appeared to be about 4 times more potent in its CNS stimulant and depressant effects than mitragynine.[4] Kratom may have a stimulant effect at lower doses and and opioid-like effect at higher doses; different varieties of kratom may have more powerful stimulant or opioid effects.[4]

Both mitragynine and 7-HMG are selective and full agonists of μ-opioid subtype receptors; 7-HMG appears to have higher affinity.[4] Stimulant activity appears to arise from blocking stimulation of serotonergic 5-HT2A receptors and blocking stimulation of postsynaptic alpha-2 adrenergic receptors.[4]

Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resuling metabolites excreted in urine.[4] In in vitro experiments kratom extracts inhibit CYP 3A4, 2D6, and 1A2 enzymes, which creates significant risks for interactions with prescription and over the counter drugs.[4]

Chemistry

The key psychoactive compounds in M. speciosa are mitragynine and 7-hydroxymitragynine,[4] but there are more than 40 compounds in M. speciosa leaves,[13] including about 25 alkaloids other than mitragynine and 7-hydroxymitragynine including mitraphylline, and mitragynine pseudoindoxyl.[20][21] Other active chemicals in M. speciosa include raubasine (best known from Rauvolfia serpentina) and Pausinystalia johimbe alkaloids such as corynantheidine.[22]

Mitragynine is about 60% of alkaloid extractions, while 7-hydroxymitragynine is about 2%.[4]

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.[9] Mitragynine is structurally similar to yohimbine and voacangine.[4]

Detection in body fluids

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.[19][23]

Taxonomy and etymology

Mitragyna speciosa was first formally described by the Dutch colonial botanist Pieter Korthals in 1839.[24] and in a 1897 publication by George Haviland.[25] 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.[citation needed]

Regulation

As of January 2015 neither the plant nor its alkaloids were listed in any of the Schedules of the United Nations Drug Conventions.[10]

Europe

In Europe as of 2011 the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania and Sweden.[10]

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.[26]

Australia and New Zealand

As of January 2015 kratom was controlled as a narcotic in Australia and under the Medicines Amendment Regulations of New Zealand.[10]

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,[12] 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.[4] In 1979, the Thai government placed kratom along with marijuana in Category V of a five category classification of narcotics.[12] Kratom accounted for less than 2% of arrests for narcotics between 1987 and 1992.[27]

The government considered legalizing kratom in 2004, 2009, and 2013.[28]

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.[29] 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.[30]

United States

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.[7] This has caused concern among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol.[31]

According to the DEA press release, "Kratom is abused for its ability to produce opioid-like effects and is often marketed as a legal alternative to controlled substances. Law enforcement nationwide has seized more kratom in the first half of 2016 than any previous year and easily accounts for millions of dosages intended for the recreational market, according to DEA findings. In addition, kratom has a high potential for abuse, has no currently accepted medical use in treatment in the United States, and has a lack of accepted safety for use under medical supervision. These three factors constitute a Schedule I controlled substance according to the Controlled Substances Act passed by Congress in 1970."[7] DEA reported 15 kratom-related deaths between 2014 and 2016.[7]

On June 9, 2015, 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 kratom poses a risk of illness or injury, 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."[32]

See also

References

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  2. ^ Mitragyna speciosa information from NPGS/GRIN. Ars-grin.gov. Retrieved 2013-12-26.
  3. ^ a b c d e f g h i j k l 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. 
  4. ^ a b c d e f g h i j k l m n o p q r s t u 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. 
  5. ^ 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. 
  6. ^ 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". Journal of Medical Toxicology. 8 (1): 15–32. doi:10.1007/s13181-011-0202-2. PMC 3550220free to read. PMID 22271566. 
  7. ^ a b c d e f g h i "DEA Announces Intent to Schedule Kratom: SE Asian drug is imminent hazard to public safety". US Drug Enforcement Administration. 30 August 2016. Retrieved 31 August 2016. 
  8. ^ a b c 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): 748–749. doi:10.15585/mmwr.mm6529a4. ISSN 0149-2195. PMID 27466822. 
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  10. ^ a b c d e "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. 
  11. ^ a b c d e f Eisenman, Sasha W (2014). "Chapter 5. The Botany of Mitragyna speciosa (Korth.) Havil. and Related Species". In Raffa, Robert B. Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium. CRC Press. pp. 57–76. ISBN 978-1-4822-2519-8. 
  12. ^ a b c "KRATOM (Mitragyna speciosa korth)" (PDF). U.S. Drug Enforcement Administration. January 2013. Archived from the original (PDF) on 11 June 2016. 
  13. ^ 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. 
  14. ^ Hassan, Zurina; Muzaimi, Mustapha; Navaratnam, Visweswaran; Yusoff, Nurul H.M.; Suhaimi, Farah W.; Vadivelu, Rajakumar; Vicknasingam, Balasingam K.; Amato, Davide; von Hörsten, Stephan; Ismail, Nurul I.W.; Jayabalan, Nanthini; Hazim, Ammar I.; Mansor, Sharif M.; Müller, Christian P. (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. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ Neerman, Michael F.; Frost, Randall E.; Deking, Janine (2013). "A Drug Fatality Involving Kratom". Journal of Forensic Sciences. 58: S278–9. doi:10.1111/1556-4029.12009. PMID 23082895. 
  18. ^ Holler, J. M.; Vorce, S. P.; McDonough-Bender, P. C.; Magluilo, J.; Solomon, C. J.; Levine, B. (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. 
  19. ^ a b c 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): 242–7. doi:10.1093/anatox/35.4.242. PMID 21513619. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ Baselt RC (2014). Disposition of toxic drugs and chemicals in man. Seal Beach, Calif.: Biomedical Publications. p. 1382. ISBN 978-0-9626523-9-4. 
  24. ^ Pieter Willem Korthals, "Observasions de Nauclais Indicis"; Bonnea; 1839; p. 20.
  25. ^ 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)
  26. ^ "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. Retrieved September 12, 2016. 
  27. ^ 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. 
  28. ^ Prasert, Poungchompoo (October 4, 2013). "Decision yet to be reached on making 'kratom' legal". The Nation (Thailand). 
  29. ^ "Amend the Act leaves the density of the Dangerous Drugs Act". 13 December 2012. Retrieved 18 April 2014. 
  30. ^ Pengasih wants abuse of kratom leaves penalised under Dangerous Drugs Act. The Malaysian Insider. October 28, 2012.
  31. ^ Silverman, Lauren (12 September 2016). "Kratom Advocates Speak Out Against Proposed Government Ban". NPR. Retrieved 12 September 2016. 
  32. ^ "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. 28 February 2014. Retrieved 18 April 2014. 

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