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{{Short description|Plant species, recreational drug (kratom)}}
{{Taxobox
{{Pp-pc}}
{{Cs1 config|name-list-style=vanc}}
{{Speciesbox
| image = Mitragyna speciosa111.JPG | image = Mitragyna speciosa111.JPG
| regnum = ]ae | status = LC
| status_system = IUCN3.1
| divisio = ]
| status_ref = <ref>{{Cite iucn|title=''Mitragyna speciosa''|page=e.T192376330A192376332|last=IUCN SSC Global Tree Specialist Group & Botanic Gardens Conservation International (BGCI). 2021|year=2021|access-date=6 March 2022|doi=10.2305/IUCN.UK.2021-1.RLTS.T192376330A192376332.en}}</ref>
| classis = ]
| genus = Mitragyna
| ordo = ]
| species = speciosa
| familia = ]
| authority = (]) ]
| genus = '']''
| synonyms = * ''Nauclea korthalsii'' Steud. nom. inval.
| species = '''''M. speciosa'''''
| binomial = ''Mitragyna speciosa''
| binomial_authority = (]) ]
| synonyms =
* ''Nauclea korthalsii'' Steud. nom. inval.
* ''Nauclea luzoniensis'' Blanco * ''Nauclea luzoniensis'' Blanco
* ''Nauclea speciosa'' (Korth.) Miq. * ''Nauclea speciosa'' (Korth.) Miq.
* ''Stephegyne speciosa'' Korth. * ''Stephegyne speciosa'' Korth.
|synonyms_ref = <ref>{{cite web|url=http://www.theplantlist.org/tpl/record/kew-128805|title=The Plant List: A Working List of All Plant Species}}</ref> | synonyms_ref = <ref>. Theplantlist.org. Retrieved 2013-12-26.</ref>
}} }}
'''''Mitragyna speciosa''''' commonly called '''kratom''', '''kratum''', or '''krathom''' (]: กระท่อม)<ref name="GRIN">{{cite web|url=http://www.ars-grin.gov/cgi-bin/npgs/html/taxon.pl?417532|title=USDA GRIN Taxonomy}}</ref> is a ] ] and ] tree in the coffee family (]) native to ] in the ] and ] ]. The leaf of the tree has been traditionally used for its ] properties. ''Mitragyna speciosa'' is a ] tree,<ref name="idpc">{{cite journal | title = Kratom in Thailand: Decriminalization and Community Control? | journal = Series on Legislative reform of Drug Policies | date = April 2011 | first = Pascal | last = Tanguay | coauthors = | volume = 13 | issue = | pages = | url = http://www.tni.org/sites/www.tni.org/files/download/kratom-briefing-dlr13.pdf | format = PDF | accessdate = 2013-03-07}}</ref> and the leaves of the tree have been chewed to uplift mood{{citation needed}} as well as to treat a large number of health problems. M. Speciosa is indigenous to Thailand and, despite growing naturally in the country, has been outlawed for 70 years due largely to the properties of kratom curing opium addicts and reducing the Thai government's tax revenue from opium distribution. {{citation needed|date=May 2013}}


<!-- Definition and description -->
''Mitragyna speciosa'' is frequently the subject of media reports which assert that kratom causes a variety of side effects, though reviews of the scientific literature and population reports show these claims to be inaccurate or unfounded.{{citation needed}} No reported overdose of Kratom has ever been reported in medical literature,<ref name="Legislative Reform of Drug Policies"/> and Kratom is frequently used as a natural alternative to treat ], ], ], ], ] and ]. The leaf has also been proposed{{by whom?}} as a means of treating ] and ].{{citation needed}}
'''''Mitragyna speciosa''''' is a tropical ] tree of the ] family (coffee family) native to ].<ref name="GRIN">{{GRIN | access-date = 2013-12-26}}</ref> It is indigenous to ], ], ], ], ], and ],<ref name=Rech2015>{{cite journal|last1=Rech|first1=MA|last2=Donahey|first2=E|last3=Cappiello Dziedzic|first3=JM|last4=Oh|first4=L|last5=Greenhalgh|first5=E|title=New drugs of abuse|journal=Pharmacotherapy|date=February 2015|volume=35|issue=2|pages=189–97|pmid=25471045|doi=10.1002/phar.1522|s2cid=206358469|doi-access=free}}</ref> where its leaves, known as "kratom" have been used in ] since at least the 19th century.<ref name="Hassan2013">{{cite journal | last1=Hassan | first1=Z | last2=Muzaimi | first2=M | last3=Navaratnam | first3=V | last4=Yusoff | first4=NHM | last5=Suhaimi | first5=FW | last6=Vadivelu | first6=R | last7=Vicknasingam | first7=BK | last8=Amato | first8=D | last9=von Hörsten | first9=S | last10=Ismail | first10=NIW | last11=Jayabalan | first11=N | last12=Hazim | first12=AI| last13=Mansor | first13=SM | last14=Müller|first14=CP|year=2013|title=From Kratom to mitragynine and its derivatives: Physiological and behavioural effects related to use, abuse, and addiction|journal=Neurosci Biobehav Rev | volume=37 | issue=2 | pages=138–151 | doi=10.1016/j.neubiorev.2012.11.012 | issn=0149-7634 | pmid=23206666 | s2cid=8463133 }}</ref> They have also historically been consumed via chewing, smoking, and as a tea.<ref name="Julien's Primer">{{cite book |last1=Advokat |first1=Claire D. |last2=Comaty |first2=Joseph E. |last3=Julien |first3=Robert M. |title=Julien's Primer of Drug Action: a comprehensive guide to the actions, uses, and side effects of psychoactive drugs |date=2019 |publisher=Worth Publishers |location=New York |isbn=978-1-319-20054-1 |page=570 |edition=14th}}</ref> Kratom has ]-like properties and some ]-like effects.<ref name=FDA2018>{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm595622.htm|title=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|author=Gottlieb, Scott|date=6 February 2018|publisher=US Food and Drug Administration|access-date=6 February 2018}}</ref><ref name=Cin2015>{{cite journal|pmc=4657101|year=2015|last1=Cinosi|first1=E|title=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|journal=BioMed Research International|volume=2015|pages=1–11|last2=Martinotti|first2=G|last3=Simonato|first3=P|last4=Singh|first4=D|last5=Demetrovics|first5=Z|last6=Roman-Urrestarazu|first6=A|last7=Bersani|first7=F. S|last8=Vicknasingam|first8=B|last9=Piazzon|first9=G|last10=Li|first10=J. H|last11=Yu|first11=W. J|last12=Kapitány-Fövény|first12=M|last13=Farkas|first13=J|last14=Di Giannantonio|first14=M|last15=Corazza|first15=O|doi=10.1155/2015/968786|pmid=26640804|doi-access=free}}</ref>
<!-- Uses -->
{{As of|2018}}, the efficacy and safety of kratom are unclear.<ref name="white">{{cite journal|vauthors=White CM|year=2018|title=Pharmacologic and clinical assessment of kratom|journal=Am J Health Syst Pharm|type=Review|volume=75|issue=5|pages=261–267|doi=10.2146/ajhp161035|pmid=29255059}}</ref> In 2019, the United States ] (FDA) stated that there is no evidence that kratom is safe or effective for treating any condition.<ref name="fda4-3-19" /> Some people take it for managing ], for treating ] symptoms, or for ].<ref name=Rech2015/><ref name="warner">{{cite journal |vauthors=Warner ML, Kaufman NC, Grundmann O |year=2016 |title=The pharmacology and toxicology of kratom: from traditional herb to drug of abuse |journal=Int. J. Legal Med. |type=Review |volume=130 |issue=1 |pages=127–38 |doi=10.1007/s00414-015-1279-y |pmid=26511390 |s2cid=2009878}}</ref> The onset of effects typically begins within five to ten minutes and lasts for two to five hours.<ref name="Rech2015" />


<!-- Side effects -->
== Taxonomy & Description ==
] describe increased alertness, physical energy, talkativeness, sociability, sedation, changes in mood, and pain relief following kratom use at various doses.<ref name="warner" /> Common ]s include appetite loss, ], ] and ].<ref name=corkery/> More severe side-effects may include ] (decreased breathing), ], ],<ref name=Rech2015/><ref name=FDA2018/><ref name="usdea">{{cite web|url=http://www.deadiversion.usdoj.gov/drug_chem_info/kratom.pdf|title=Kratom (''Mitragyna speciosa'' Korth)|date=January 2013|publisher=U.S. Drug Enforcement Administration|archive-url=https://web.archive.org/web/20160611063419/http://www.deadiversion.usdoj.gov/drug_chem_info/kratom.pdf|archive-date=11 June 2016}}</ref><ref name=Rosen>{{cite book|author1=Marx, John|author2=Walls, Ron|author3=Hockberger, Robert|title=Rosen's emergency medicine : concepts and clinical practice|date=2014|publisher=Elsevier Health Sciences|location=London|isbn=978-1-4557-4987-4|pages=2015–23|edition=Eighth|chapter=Chapter 156: Hallucinogens|chapter-url=https://books.google.com/books?id=uggC0i_jXAsC&pg=RA2022}}</ref> elevated heart rate and blood pressure, trouble sleeping, and, rarely, ].<ref name=Rech2015/><ref name=liverreview/><ref name="livertox">{{cite web|title=Kratom|url=https://livertox.nih.gov/Kratom.htm|publisher=LiverTox, National Library of Medicine, US National Institutes of Health|access-date=29 March 2017|date=9 March 2017|pmid=31643176 }}</ref><ref name=cdc>{{Cite journal|last1=Anwar|first1=Mehruba|last2=Law|first2=Royal|last3=Schier|first3=Josh|date=2016-01-01|title=Notes from the Field: Kratom (''Mitragyna speciosa'') Exposures Reported to Poison Centers – United States, 2010–2015|journal=MMWR. Morbidity and Mortality Weekly Report|volume=65|issue=29|pages=748–49|doi=10.15585/mmwr.mm6529a4|issn=0149-2195|pmid=27466822|doi-access=free}}</ref> Addiction is a possible risk with regular use: when use is stopped, ] symptoms may occur.<ref name=warner/><ref name=Cin2015/> A number of deaths have been attributed to the use of kratom, both by itself and mixed with other substances.<ref name=FDA2018/> Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.<ref name=Rech2015/><ref name=warner/>
It was first formally described by the ] botanist ]. The genus was given the name ''Mitragyna'' by Korthals because the stigmas in the first species he examined resembled the shape of a bishop's ]. It is botanically related to the ] '']'' and '']'' and shares some similar biochemistry.
]
''Mitragyna speciosa'' trees usually grow to a height of {{convert|12|-|30|ft|m|abbr=on}} tall and {{convert|15|ft|m|abbr=on}} wide, although under the right conditions, certain species can reach up to {{convert|40|–|100|ft|m|abbr=on}} in height. ''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 {{convert|7|in|mm}} long and {{convert|4|in|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 ] and are pointed at the tip. The leaves have a round and heart-shape at the base with the ] between 2 to 4 centimeters long. The flowers are crowded in a round terminal ] which are 3 to 5 centimeters long. The ]-tube is fairly short and has a cup-shape to it, with round lobes. The corolla-tube is about 5 millimeters long with 3 millimiter long lobes and smooth and revolute in between.<ref name="bpi">Philippine Department of Agriculture - Bureau of Plant Industry: )</ref>


<!-- Society and culture -->
== Chemistry ==
As of 2018, kratom is a ] in 16 countries.<ref name="FDA2018" />
There is growing international concern about a possible threat to public health from kratom use.<ref name=FDA2018/><ref name=warner/><ref name=EMCDDA>{{cite web|title=Kratom profile (chemistry, effects, other names, origin, mode of use, other names, medical use, control status)|url=http://www.emcdda.europa.eu/publications/drug-profiles/kratom#control|publisher=European Monitoring Centre for Drugs and Drug Addiction|access-date=12 September 2016|date=8 January 2015}}</ref> In some jurisdictions its sale and importation have been restricted, and several public health authorities have raised alerts.<ref name=warner/><ref name=EMCDDA/>
{{TOC limit}}

== Description ==
]
''Mitragyna speciosa'' is an evergreen tree in the genus '']'' that can grow to a height of {{convert|25|m|ft|abbr=on}}. Its trunk may grow to a {{convert|3|ft|m|abbr=on|1|order=flip}} diameter.<ref name="Eisenman" /> The trunk is generally straight, and the outer bark is smooth and grey.<ref name="Eisenman" /> The leaves, ovate-acuminate in shape and opposite in growth pattern, are dark green, glossy on their upper surfaces,<ref name="warner" /> and can grow to over {{convert|14|-|20|cm|in|abbr=on}} long and {{convert|7|-|12|cm|in|abbr=on}} wide. They have 12 to 17 pairs of veins.<ref name="Eisenman" /> The spherical inflorescences, which are deep yellow, grow in clusters of three at the ends of the branches.<ref>{{Cite book|last=Rahman|first=Atta-ur|url=https://books.google.com/books?id=d7cCEAAAQBAJ&pg=PA195|title=Studies in Natural Products Chemistry|date=2021-04-16|publisher=Elsevier|isbn=978-0-323-89815-7|language=en}}</ref> The ]-tube is {{convert|2|mm|in|abbr=on |sigfig=1}} long and has five lobes; the corolla-tube is {{convert|2.5|-|3|mm|sigfig=2}} long.<ref name="Eisenman">{{cite book|last= Eisenman | first= Sasha W.|editor1-last=Raffa|editor1-first=Robert B.|title=Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium|date=2014|publisher=CRC Press|isbn= 978-1-4822-2519-8| pages= 57–76|chapter= Chapter 5. The Botany of ''Mitragyna speciosa'' (Korth.) Havil. and Related Species}}</ref>

''Mitragyna speciosa'' is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea.<ref name="Rech2015" /> It was first formally described by the ] botanist ] in 1839, who named it ''Stephegyne speciosa''; it was renamed and reclassified several times before ] provided the final name and classification in 1859.<ref name="Eisenman" />{{rp|59}}

==Uses of the leaves==
{{main|Mitragynine#Uses}}
{{Infobox botanical product
|image = Powdered kratom.jpg
|caption = Powder produced from unspecified tissues of the plant
|title = Kratom
|product =
|plant =
|part = ]
|origin = ]<ref name=EMCDDA />
|active = {{flatlist|
* ]<ref name=warner/>
* ]<ref name=warner/>
* ]<ref name=warner/>
* ]<ref name=warner/>
* and more than 40 other compounds<ref name="Adkins 2011-05-01" />
}}
|producers = {{hlist|]<ref name=EMCDDA />|]<ref name=Hassan2013 />}}
|consumers = Worldwide (No. 1: Thailand)<ref name=EMCDDA /><ref name=Hassan2013 />
|wholesale =
|retail =
|legal_AU = S8<ref>{{cite conference |url=https://www.tga.gov.au/sites/default/files/ndpsc-record-40.pdf |title=National Drugs and Poisons Schedule Committee |author=Department of Health and Aging Therapeutic Goods Administration |author-link1=Therapeutic Goods Administration |date=26 February 2004 |publisher=Government of Australia |pages=103–105 |conference=40th meeting}}</ref>
|legal_BR = E
|legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-09-15 |title=RDC Nº 816 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 816 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-816-de-15-de-setembro-de-2023-510390164 |url-status=live |archive-url=https://web.archive.org/web/20231019120956/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-816-de-15-de-setembro-de-2023-510390164 |archive-date=2023-10-19 |access-date=2023-10-19 |publisher=] |language=pt-BR |publication-date=2023-09-18}}</ref>
|legal_CA = Unscheduled (Not authorized for sale or use), legal for religious use, such as incense <ref>{{cite web |title=Unauthorized "Sāj" kratom products seized from two Edmonton stores may pose serious health risks |url=http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2018/66710a-eng.php |website=Health Canada |publisher=Canada |access-date=8 August 2018 |date=4 May 2018}}</ref>
<ref name=EMCDDA />
|legal_US = Unscheduled (Drug of concern),<ref name=Hassan2013 /> subject to import bans<ref name=FDAImportAlert /><ref name=Tave>{{cite web|url=https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofFoods/CFSAN/CFSANFOIAElectronicReadingRoom/UCM598251.pdf|title=FDA warning letter to Industrial Chemicals, LLC, and INI Botanicals|publisher=Office of Dietary Supplement Programs, Center for Food Safety and Applied Nutrition, US Food and Drug Administration| last=Tave |first=Steven J.|date=26 February 2018|access-date=7 March 2018}}</ref><ref name="fda4-3-19">{{cite web |title=FDA and kratom |url=https://www.fda.gov/news-events/public-health-focus/fda-and-kratom |publisher=US Food and Drug Administration |access-date=8 August 2019 |date=3 April 2019}}</ref>
|legal_UN = Unscheduled
|legal_status = Illegal in ], ], ] and ]<ref name=EMCDDA /><ref name=Hassan2013 />
}}
] ]
{{As of|2013}}, kratom has been studied in cells and in animals, but no ] have been conducted in the United States.<ref name="Hassan2013" /> The U.S. ] (DEA) stated in 2013 that there is no legitimate medical use for kratom,<ref name="usdea" /> and in 2019, the U.S. ] (FDA) said that there is no evidence that kratom is safe or effective for treating any condition, and that there are no ] for kratom.<ref name="fda4-3-19" />
]


Kratom is commonly ingested by chewing, as a tea, powdered in ], or ]ed for use in liquids.<ref name="Hassan2013"/> Kratom is rarely smoked.<ref name="EMCDDA" /> Different varieties of kratom contain different relative proportions of ]s such as ].<ref name="warner" />
40 unique compounds had been discovered in M. Speciosa leaves,<ref name="Adkins 2011-05-01">{{cite journal | title = Mitragyna speciosa, a psychoactive tree from Southeast Asia with opioid activity. | journal = Current Topics in Medicinal Chemistry | date = 2011-05-01 | first = Jessica E. | last = Adkins | coauthors = Edward W. Boyer, Christopher R. McCurdy | volume = 11 | issue = 9 | pages = 1165–1175 | id = | doi = 10.2174/156802611795371305 | accessdate = 2012-10-26 | pmid=21050173}}</ref> including many ]s including ] (once thought to be the primary active constituent), ], and ] (which is currently the most likely candidate for the primary active chemical in the plant).<ref name="ChittrakarnMorphine">{{cite journal |last1=Chittrakarn|first1=S|last2=Keawpradub|first2=N|last3=Sawangjaroen|first3=K|last4=Kansenalak|first4=S|last5=Janchawee|first5=B |title=The neuromuscular blockade produced by pure alkaloid, mitragynine and methanol extract of kratom leaves (Mitragyna speciosa Korth.) |journal=Journal of Ethnopharmacology |volume=129|issue=3|pages=344–349|year=2010 |pmid=20371282 |doi=10.1016/j.jep.2010.03.035}}</ref><ref name="Pharmacology">{{Cite journal|url=http://www.ncbi.nlm.nih.gov/pubmed/23212430 |last1=Prozialeck|first1=WC|last2=Jivan|first2=JK|last3=Andurkar|first3=SV|title=Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic, and opioid-like effects|journal=The Journal of the American Osteopathic Association |volume=112|issue=12|pages=792–799|year=2012 |pmid=23212430 |doi=}}</ref> Other active chemicals in M. Speciosa include ] (best known from '']'') and some ] alkaloids such as ].<ref>{{cite journal| author=Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D et al.| title=Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands | journal=J Med Chem | year=2002 | volume=45 | issue=9 | pages=1949–1956 | pmid=11960505 | doi=10.1021/jm010576e }}</ref>


===Traditional use===
Mitragyna Speciosa also contains at least one alkaloid (]) that is a calcium channel blocker, and reduces NMDA-induced current.<ref name="justice"></ref><ref name="hend">Hendrickson, JB, Sims JJ. Mitragyna alkaloids - The structure of stipulatine. Tetrahedron Letters 1963;14:959-963.</ref> There is considerable research as to the role of NMDA receptor activity in the formation of dependence, and the symptoms of withdrawal. In 2005, Inturrisi demonstrated that co-administration of d-methadone (the isomer that lacks opioid activity, but is an NMDA antagonist) in small doses with morphine prevented the development of morphine tolerance in rats.<ref>Inturrisi, CE. Minerva Anestesiology 71, 435-437. 2005.</ref> The presence of mitragynine can be detected in urine by non-conventional immunological screenings.<ref name="KratomKrypton">{{citation |title=Kratom alkaloids and O-desmethyltramadol in urine of a "Krypton" herbal mixture consumer | pmid=21112167 | doi=10.1016/j.forsciint.2010.10.025}}</ref>
In cultures where the plant grows, kratom has been used in ].<ref name=Cin2015 /> The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to ] and ].<ref name= warner/> 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.<ref name=Rech2015/><ref name="Hassan2013" /><ref name=Eisenman/> They are also used as intestinal deworming agents in Thailand.<ref>{{Cite journal|last1=Singh|first1=Darshan|last2=Narayanan|first2=Suresh|last3=Vicknasingam|first3=Balasingam|last4=Corazza|first4=Ornella|last5=Santacroce|first5=Rita|last6=Roman-Urrestarazu|first6=Andres|date=2017|title=Changing trends in the use of kratom (''Mitragyna speciosa'') in Southeast Asia|journal=Human Psychopharmacology: Clinical and Experimental|language=en|volume=32|issue=3|pages=e2582|doi=10.1002/hup.2582|pmid=28544011|issn=1099-1077|doi-access=free|hdl=2299/18790|hdl-access=free}}</ref><ref name=EMCDDA />


Kratom is often used by workers in laborious or monotonous occupations to stave off exhaustion and as a mood-enhancer and painkiller.<ref name="Eisenman" /> In Thailand, kratom was "used as a snack to receive guests and was part of the ritual worship of ancestors and gods".<ref>{{cite journal|last1=Singh|first1= Darshan|last2=Narayanan|first2= Suresh| last3=Vicknasingam|first3= Balasingam| title= Traditional and non-traditional uses of Mitragynine (Kratom): A survey of the literature|journal=Brain Research Bulletin|date=September 2016|volume=126|issue=Pt 1|pages=41–46|doi=10.1016/j.brainresbull.2016.05.004|pmid=27178014|s2cid= 3952688}}</ref> The herb is bitter and is generally combined with a sweetener.<ref name="Adkins 2011-05-01">{{cite journal |last=Adkins |first=Jessica E. |author2=Edward W. Boyer |author3=Christopher R. McCurdy |date=2011-05-01 |title=''Mitragyna speciosa'', a psychoactive tree from Southeast Asia with opioid activity |journal=Current Topics in Medicinal Chemistry |volume=11 |issue=9 |pages=1165–75 |doi=10.2174/156802611795371305 |pmid=21050173}}</ref>
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. 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 adrnergic 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.<ref>{{Cite pmid|22133323}}</ref>


===Opioid withdrawal===
==Traditional use==
Because the withdrawal effects of kratom are often reported to be less severe than those associated with traditional opioids,<ref name="warner" /> some people use kratom in the attempt to manage ],<ref name=":2">{{Cite journal|last1=Swogger|first1=Marc T.|last2=Walsh|first2=Zach|date=2018-02-01|title=Kratom use and mental health: A systematic review|url=https://pubmed.ncbi.nlm.nih.gov/29248691/|journal=Drug and Alcohol Dependence|volume=183|pages=134–140|doi=10.1016/j.drugalcdep.2017.10.012|issn=1879-0046|pmid=29248691}}</ref> though no clinical trials have been done supporting this use. {{As of|2018}}, there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction.<ref name="FDA2018" /> Kratom is not approved for this or any other medical use.<ref name="EMCDDA" /> Stanciu et al. conducted a review of all literature and found insufficient evidence for any conclusions concerning whether kratom is harmful or whether can serve as harm reduction for those with opioid addiction.<ref>{{Cite journal |last1=Stanciu |first1=Cornel |last2=Ahmed |first2=Saeed |last3=Gnanasegaram |first3=Samantha |last4=Gibson |first4=Stephen |last5=Penders |first5=Thomas |last6=Grundmann |first6=Oliver |last7=McCurdy |first7=Christopher |date=2022-09-03 |title=Kratom as an opioid alternative: harm, or harm reduction? A systematic review of literature |url=https://pubmed.ncbi.nlm.nih.gov/36001875/ |journal=The American Journal of Drug and Alcohol Abuse |volume=48 |issue=5 |pages=509–528 |doi=10.1080/00952990.2022.2111685 |issn=1097-9891 |pmid=36001875|s2cid=251810402 }}</ref> While some ]s claim that kratom has less potential for ] or ] than traditional opioids,<ref>{{Cite journal|last1=Henningfield|first1=Jack E.|last2=Fant|first2=Reginald V.|last3=Wang|first3=Daniel W.|date=2018|title=The abuse potential of kratom according the 8 factors of the controlled substances act: implications for regulation and research|journal=Psychopharmacology|volume=235|issue=2|pages=573–589|doi=10.1007/s00213-017-4813-4|issn=1432-2072|pmc=5813050|pmid=29273821}}</ref><ref name=":3">{{Cite journal|last1=Eastlack|first1=Steven C.|last2=Cornett|first2=Elyse M.|last3=Kaye|first3=Alan D.|date=2020|title=Kratom—Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review|journal=Pain and Therapy|volume=9|issue=1|pages=55–69|doi=10.1007/s40122-020-00151-x|issn=2193-8237|pmc=7203303|pmid=31994019}}</ref> other reviews note that kratom withdrawal itself can still be quite severe.<ref name="Stan2019" />
Kratom has been traditionally chewed, in raw leaf form, by people in ] and especially in the southern peninsula. Kratom is also used in neighboring countries in ] where it grows naturally.<ref name =idpc/> As traditionally used, kratom is not seen as a ] and there is no stigma associated with kratom use or discrimination against kratom eaters.<ref name=idpc/> In ], kratom has been a part of traditional culture for thousands of years and is common in traditional cultural performances and in agriculture.<ref name="asna">{{cite journal | title = Kratom Plant in Thai society; culture, behavior. | journal = Health Science Laws | year = 2005 | first = S | last = Asnangkornchai | coauthors = Siriwong, A | volume = | issue = | pages = | url = | format = | accessdate = 2013-03-07}}</ref> 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. The average number of leaves consumed is between 10 and 60 leaves consumed daily, 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. Traditional use of kratom is considered equivalent to drinking coffee.<ref name=idpc/>
]
As with any substance that is ingested, ] or contamination is also a risk. One product, ''Krypton'' that contained a mix of several different substances rather than natural kratom was linked to the deaths of nine people in Sweden during 2010-2011.<ref>{{Cite journal |authors=Nelsen JL, Lapoint J, Hodgman MJ, Aldous KM |year=2010 |title=Seizure and coma following Kratom (''Mitragynina speciosa'' Korth) exposure |journal=Journal of Medical Toxicology |volume=6 |pages=424–426 |pmid=20411370 |doi=10.1007/s13181-010-0079-5 |issue=4}}</ref><ref>{{Cite journal |authors=Arndt T, Claussen U, Güssregen B, Schröfel S, Stürzer B, Werle A, Wolf G |year=2011 |title=Kratom alkaloids and O-desmethyltramadol in urine of a "Krypton" herbal mixture consumer |journal=Forensic Science International |volume=208 |pages=47–52 |pmid=21112167 |doi=10.1016/j.forsciint.2010.10.025 |issue=1-3}}</ref><ref>{{Cite journal |authors=Bäckstrom BG, Classon G, Löwenhielm P, Thelander G |year=2010 |title=Krypton—new, deadly Internet drug |language=Swedish |journal=Lakartidningen |volume=107 |pages=3196–3197 |pmid=21294331 |issue=50}}</ref><ref>{{Cite journal |authors=Kronstrand R, Roman M, Thelander G, Eriksson A |year=2011 |title=Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton, which is altered kratom and should not be confused with kratom |journal=Journal of Analytical Toxicology |volume=35 |pages=242–247 |pmid=21513619 |issue=4}}</ref><ref>{{Cite journal |authors=Kapp FG, Maurer HH, Auwärter V, Winkelmann M, Hermanns-Clausen M |year=2011 |title=Intrahepatic cholestasis following abuse of powdered kratom (''Mitragyna speciosa'') |journal=Journal of Medicinal Toxicology |volume=7 |pages=227–231 |pmid=21528385 |doi=10.1007/s13181-011-0155-5 |issue=3}}</ref><ref>{{Cite journal |authors=Adkins JE, Boyer EW, McCurdy CR |year=2011 |title=''Mitragyna speciosa'', a psychoactive tree from Southeast Asia with opioid activity |journal=Current Topics in Medicinal Chemistry |volume=11|pages=1165–1175 |pmid=21050173 |doi=10.2174/156802611795371305}}</ref> ''Krypton'' contained ] which is the active metabolite in ].<ref name="Pharmacology"/> ] is a considerably more potent μ-opioid agonist than ], its parent compound.<ref name="Pharmacology of tramadol">{{cite journal | title=Pharmacology of tramadol | author=Dayer, P; Desmeules, J; Collart, L | journal=Drugs | year=1997 | volume=53 | issue=Suppl 2 | pages=18–24 | doi=10.2165/00003495-199700532-00006 | pmid=9190321}}</ref> Since it is possible to overdose on Tramadol alone,<ref name="Fatality due to ingestion of tramadol alone">{{cite journal | url=http://www.fsijournal.org/article/S0379-0738(00)00374-1/abstract | title=Fatality due to ingestion of tramadol alone | author=Musshoff, F., and B. Madea. | journal=Forensic Science International | year=2001 | month=February | volume=116 | issue=6 | pages=197–199}}</ref> it can be assumed its more potent active metabolite, O-desmethyltramadol, causes fatalities as well.


Data on how widely it is used worldwide are lacking, as it is not detected by typical drug screening tests.<ref name="Adkins 2011-05-01"/> 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 opioid use.<ref name="Adkins 2011-05-01"/>
However, there has never been a single documented lethal case of kratom overdose.<ref name="Legislative Reform of Drug Policies">{{cite journal | url=http://papers.ssrn.com/sol3/papers.cfm?abstract_id=1908849 | title=Kratom in Thailand Decriminalisation and Community Control? | author=Tanguay, Pascal; International Drug Policy Consortium | journal=Series on Legislative Reform of Drug Policies | year=2011 | month=April | doi=10.2139/ssrn.1908849}}</ref>


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 19th century.<ref name="Hassan2013" />
==Medicinal uses==
Kratom has seen therapeutic use in Thai ] as an ], as a treatment for ], and rarely to increase the duration of ].<ref name="Suwanlert 1975">{{cite journal | title = A Study of Kratom Eaters in Thailand | journal = Bulletin on Narcotics | year = 1975 | first = Sangun | last = Suwanlert | volume = 27 | issue = 3 | pages = 21–27 | accessdate = 2012-10-26}}</ref><ref name="Jansen 1988-01-04">{{cite journal | title = Ethnopharmacology of Kratom and the Mitragyna Alkaloids | journal = Journal of Ethnophamacology | date = 1988-01-04 | first = Karl L.R. | last = Jansen | coauthors = Colin J. Prast | volume = 23 | issue = 1 | pages = 115–119 | pmid = 3419199 | issn = 0378-8741| accessdate = 2012-10-26}}</ref><ref name="Reanmongkol 2007">{{cite journal | title = Effects of the extracts from Mitragyna speciosa Korth. leaves on analgesic and behavioral activities in experimental animals | journal = Songklanakarin Journal of Science and Technology | date = March 2007 | first = Wantana | last = Reanmongkol | coauthors = Niwat Keawpradub, Kitja Sawangjaroen | volume = 29 | issue = 1 | pages = 39–48 | url = http://www.thaiscience.info/journals/Article/Effects%20of%20the%20extracts%20from%20mitragyna%20speciosa%20korth%2E%20leaves%20on%20analgesic%20and%20behavioral%20activities%20in%20experimental%20animals.pdf | format = PDF | accessdate = 2012-10-26}}</ref> It is also a substance of interest in the treatment of ].<ref name="Purintrapiban 2008-10-10">{{cite journal | title = Study on glucose transport in muscle cells by extracts from Mitragyna speciosa (Korth) and mitragynine | journal = Natural Product Research | date = 2008-10-10 | first = Juntipa | last = Purintrapiban | coauthors = Niwat Keawpradub, Supaporn Kansenalak, Somsmorn Chittrakarn, Benjamas Janchawee, Kitja Sawangjaroen | volume = 25 | issue = 15 | pages = 1379–1387 | id = | doi = 10.1080/14786410802267627 | accessdate = 2012-10-30 | pmid=18846471}}</ref> A general consensus exists in Thailand among leaders, public health officials, academics and policymakers that kratom use and dependence causes little, if any, health risks.<ref name="Legislative Reform of Drug Policies" /> Many chronic pain patients report that kratom has greatly improved the quality of their lives.<ref name="Kratom Association">{{cite web | url=http://www.kratomassociation.org/kratom-testimonials | title=Kratom Association: Kratom Testimonials | publisher=Kratom Association | accessdate=December 2, 2012}}</ref>


===Recreational uses===
A derivative of mitragynine has also been shown to trigger a strong anti-nociceptive effect while, at the same time, having less side effects than conventional painkillers.<ref>{{Cite pmid|18550129}}</ref>
At low doses, kratom produces ] effects comparable to those of ].<ref name=":0">{{Cite journal|last1=Babu|first1=Kavita M.|last2=McCurdy|first2=Christopher R.|last3=Boyer|first3=Edward W.|date=2008|title=Opioid receptors and legal highs: ''Salvia divinorum'' and Kratom|journal=Clinical Toxicology|volume=46|issue=2|pages=146–152: 149|doi=10.1080/15563650701241795|pmid=18259963|s2cid=32501470|issn=1556-3650}}</ref> At higher doses, kratom produces opioid-like effects.<ref name=":0" /> The onset of effects typically begins within five to ten minutes and lasts for two to five hours.<ref name="Rech2015" /> Some anecdotal reports describe increased work capacity, alertness, talkativeness, ], increased ], ], and ] following the consumption of kratom.<ref name="warner" />


According to the U.S. DEA and a 2020 survey, kratom is used to alleviate pain, anxiety, depression, or ].<ref name=usdea/><ref name=":1">{{Cite journal|last1=Garcia-Romeu|first1=Albert|last2=Cox|first2=David J.|last3=Smith|first3=Kirsten E.|last4=Dunn|first4=Kelly E.|last5=Griffiths|first5=Roland R.|date=2020|title=Kratom (''Mitragyna speciosa''): User demographics, use patterns, and implications for the opioid epidemic|journal=Drug and Alcohol Dependence|volume=208|page=107849|doi=10.1016/j.drugalcdep.2020.107849|pmid=32029298|pmc=7423016|issn=0376-8716}}</ref>
===Treating addiction===
Since one of the main pharmacological target of Mitragyna alkaloids is the endogenous opioid system, kratom preparations have been shown to be effective in treating opioid withdrawal and chronic pain.<ref name="boyer2008">{{Cite pmid|18482427}}</ref> While kratom itself is mildly addictive, the withdrawal symptoms from cessation of kratom have been shown to be very weak and may include mild joint pain or sleeplessness.


In Thailand, a 2007 survey found that the lifetime, past year, and past 30 days kratom consumption rates were 2.32%, 0.81% and 0.57%, respectively, among respondents aged 12–65 years,<ref name="EMCDDA" /> and that kratom was the most widely used recreational drug in Thailand.<ref name="EMCDDA" />
===Anti-depressant effects===


Kratom may be mixed with other ]s, such as ] and ].<ref name="Cin2015" /><ref>{{cite book|url=https://books.google.com/books?id=M9KYCgAAQBAJ&pg=PA528|title=Karch's Pathology of Drug Abuse|last1=Karch|first1=Steven B.|last2=Drummer|first2=Olaf|date=2015|publisher=CRC Press|isbn=978-1-4398-6147-9|edition=Fifth|page=528}}</ref> 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, ], ] 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 ].<ref>{{cite web| last1=Tanguay|first1=Pascal|title=Kratom in Thailand: Decriminalisation and Community Control?|url=https://www.tni.org/files/download/kratom-briefing-dlr13.pdf|publisher= Transnational Institute|date= April 2011|quote= 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 ] or heroin users.}}</ref> {{As of|2012}}, use of the cocktail was a severe problem among youth in three provinces along the border of Malaysia and southern Thailand.<ref>{{cite news|last1= Fuller|first1= Thomas|title=A Fading Thai Drug Finds Its Resurgence in a Cocktail|url=https://query.nytimes.com/gst/fullpage.html?res=9E05EFDC103EF930A15754C0A9649D8B63| work= The New York Times| date=23 July 2012}}</ref>
Kratom is commonly used for its anti-depressants effects and studies have shown that ] has antidepressant-like effects. A study was done from isolated mitragynine, which was isolated from ''Mitragyna speciosa'', that attempted to investigate the antidepressant effects of adding mitragynine. The study concluded that there are significant anti-depressant effects to be gained from mitragynine.<ref>{{Cite pmid|20869223}}</ref>


In the U.S., {{as of|2015|lc=y}}, kratom was available in outlets such as ]s and over the Internet; the prevalence of its U.S. use was unknown at the time.<ref name= warner/> In the United States, kratom use increased rapidly between 2011 and 2017.<ref name="Post">{{cite journal|last1=Post|first1=Sara|last2=Spiller|first2=Henry A.|last3=Chounthirath|first3=Thitphalak|last4=Smith|first4=Gary A.|date=20 February 2019|title=Kratom exposures reported to United States poison control centers: 2011–2017|journal=Clinical Toxicology|volume=57|issue=10|pages=847–854|doi=10.1080/15563650.2019.1569236|issn=1556-3650|pmid=30786220|s2cid=73507086}}</ref> By 2020, it was estimated that 15 million people in the U.S. use kratom.<ref>{{Cite journal|last1=Ramanathan|first1=Surash|last2=McCurdy|first2=Christopher R.|date=2020|title=Kratom (''Mitragyna speciosa''): worldwide issues|url=https://pubmed.ncbi.nlm.nih.gov/32452943/|journal=Current Opinion in Psychiatry|volume=33|issue=4|pages=312–318|doi=10.1097/YCO.0000000000000621|issn=1473-6578|pmid=32452943|s2cid=218893286}}</ref>
===Antioxidant effects===
One of the active constituents in ''M. speciosa'' is ],<ref name="Phytochemical">{{Cite journal|url=http://www.ncbi.nlm.nih.gov/pubmed/?term=Epicatechin+kratom |last1=Leon|first1=F|last2=Habib|first2=E|last3=Adkins|first3=Je|title=Phytochemical characterization of the leaves of Mitragyna speciosa grown in U.S.A.|journal=Nat Prod Commun|volume=112|issue=7|pages=907–910|year=2009|pmid=19731590
|doi=}}</ref> and has been linked to numerous health benefits. In humans, there is a 2-3 hour time window for treatment of strokes to be effective and epicatechin appeared to limit neuronal damage when given to the mice even as long as 3.5 hours after the stroke.<ref name="pmid3002885">{{cite journal |author=Zanetti NC, Solursh M |title=Epithelial effects on limb chondrogenesis involve extracellular matrix and cell shape |journal=Dev. Biol. |volume=113 |issue=1 |pages=110–8 |year=1986 |month=January |pmid=3002885 |doi= 10.1016/0012-1606(86)90113-2|pmc=3002885}}</ref>


==Adverse effects==
===Improving high blood-pressure===
Kratom has also been suggested as a use by some users as an effective treatment in high blood pressure, or ]. While hypertension can cause life-threatening effects, some have suggested that kratom use has assisted in lowering blood-pressure. Kratom has also been suggested as an effective treatment in people who suffer from borderline personality disorder.<ref name="Hoffman">{{cite news | first = Cassandra |last = Hoffman| title = Kratom: Possible Natural Treatment of High Blood Pressure | date = 2009-03-12 | url = http://voices.yahoo.com/kratom-possible-natural-treatment-high-blood-pressure-2827229.html?cat=68 | work = Yahoo |accessdate = 2013-03-05}}</ref> One active alkaloid in ''M. speciosa'' is ], which is also known as "raubasine" or "δ-yohimbine" and is used as an ] ] used in the treatment of high ].<ref name="isbn0-306-45465-3">{{cite book | author = Wink, Michael; Roberts, M. W. | title = Alkaloids: biochemistry, ecology, and medicinal applications | publisher = Plenum Press | location = New York | year = 1998 | pages = | isbn = 0-306-45465-3 | oclc = | doi = | url = http://books.google.com/books?id=bMCzyrAtrvYC&lpg=PA450&dq=ajmalicine&as_brr=3&pg=PA451#v=onepage&q=&f=false}}</ref>


''Mitragyna speciosa'' may cause many adverse effects, and in November 2017 the FDA issued a public health advisory for the drug.<ref name=white/> The side effects of kratom appear to be ] and are more common with doses that exceed 8 g.<ref name=":3" /> While the ] of adverse effects in people who use kratom is unknown, a 2019 review of 935 kratom exposures reported to U.S. ]s over a seven-year period listed the following signs and symptoms: agitation (18.6%), ] (16.9%), ] (13.6%), ] (11.2%), ] (8.1%), ] (6.1%), ] (6.1%), ]s (4.8%), ] (2.8%), ] (2.3%), and ] or ] (0.6%).<ref name=":5">{{Cite journal|last1=Eggleston|first1=William|last2=Stoppacher|first2=Robert|last3=Suen|first3=Kyle|last4=Marraffa|first4=Jeanna M.|last5=Nelson|first5=Lewis S.|date=2019|title=Kratom Use and Toxicities in the United States|url=https://pubmed.ncbi.nlm.nih.gov/31099038/|journal=Pharmacotherapy|volume=39|issue=7|pages=775–777|doi=10.1002/phar.2280|issn=1875-9114|pmid=31099038|s2cid=157058636}}</ref><ref name=":3" /> The study also reported two deaths and four cases of ].<ref name=":5" /> A different 2019 review listed as common side effects: ], ], ], ], ], ], ], ], and ].<ref name=corkery/>
==Media attention==

Kratom, like several other natural ], is frequently a concern ], ] and regulatory officials.<ref name='Groov'/><ref name="saunders">{{cite news | first = Hannah| last = Saunders| title = Enhanced Kratom: The next big drug | date = 2013-04-04 | url = http://www.wzzm13.com/news/article/245297/2/Investigation-The-Next-Big-Drug---Preview | work = WZZM13| accessdate = 2013-03-05}}</ref> Some journalists make assertions that kratom causes a litany of side effects including hallucinations, addiction, anger, psychosis and many other claims.<ref name="Groov">{{cite news | first = last = Staff | title = 'Groovy new drug' Kratom gaining in popularity - and perfectly legal | date = 2013-03-06 | url = http://www.kboi2.com/news/local/Kratom-Drug-News-Idaho-195690741.html | work = KBOI | accessdate = 2013-03-06}}</ref> A recent incident involving a 27 year old woman from ] was blamed on kratom consumption. The woman was arrested after being caught naked running in the street with a hammer. According to reports she had smoked marijuana laced with chemicals prior to this incident in addition to consuming kratom.<ref name="Lystra">{{cite news | first = Tonylast = Lystra| title = Kelso police restrain naked woman carrying an infant, swinging a hammer | date = 2013-04-03 | url = http://tdn.com/news/local/kelso-police-restrain-naked-woman-carrying-an-infant-swinging-a/article_35cd0c22-848e-11e2-ba66-001a4bcf887a.html | work = TDN| accessdate = 2013-03-05}}</ref><ref name="cassuto">{{cite news | first = Dan | last = Cassuto| title = 100% natural, 100% potent, 110% party' but possibly dangerous | date = 2013-04-04 | url = http://www.katu.com/news/local/Kratom-100-natural-100-potent-110-party-but-possibly-dangerous-195202071.html | work = KATU | accessdate = 2013-03-05}}</ref>
Kratom products in the U.S. are commonly used in doses of 2–6 g of dried leaf, and doses exceeding 8 g are relatively uncommon.<ref>{{Cite journal|last=Grundmann|first=Oliver|date=2017-07-01|title=Patterns of Kratom use and health impact in the US-Results from an online survey|url=https://pubmed.ncbi.nlm.nih.gov/28521200/|journal=Drug and Alcohol Dependence|volume=176|pages=63–70|doi=10.1016/j.drugalcdep.2017.03.007|issn=1879-0046|pmid=28521200}}</ref> Given that kratom products may vary greatly in potency, there is no standard dosing system. 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 such as itching, nausea, loss of appetite, and increased urination begin to appear.<ref name=Rech2015/><ref name=warner/> At moderate to high doses (5–15 g of raw leaves), at which opioid effects generally appear, additional adverse effects include ] (an increased stimulant effect) as well as the opioid side effects of constipation, dizziness, hypotension, dry mouth, and sweating.<ref name="warner" /><ref name="Rosen" /><ref name=":4">{{Cite journal|last1=Meireles|first1=Vânia|last2=Rosado|first2=Tiago|last3=Barroso|first3=Mário|last4=Soares|first4=Sofia|last5=Gonçalves|first5=Joana|last6=Luís|first6=Ângelo|last7=Caramelo|first7=Débora|last8=Simão|first8=Ana Y.|last9=Fernández|first9=Nicolás|last10=Duarte|first10=Ana Paula|last11=Gallardo|first11=Eugenia|date=2019-03-04|title=''Mitragyna speciosa'': Clinical, Toxicological Aspects and Analysis in Biological and Non-Biological Samples|journal=Medicines|volume=6|issue=1|page=35|doi=10.3390/medicines6010035|issn=2305-6320|pmc=6473843|pmid=30836609|doi-access=free}}</ref>

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 ], insomnia, muscle spasms, muscle and bone pain, ], ], ], ], ], restlessness, anger, and sadness.<ref name=Cin2015/> This may lead to resumption of use.<ref name=Cin2015/><ref name=warner/><ref name=Stan2019>{{Cite journal|last1=Stanciu|first1=Cornel N.|last2=Gnanasegaram|first2=Samantha A.|last3=Ahmed|first3=Saeed|last4=Penders|first4=Thomas|date=January 2019|title=Kratom Withdrawal: A Systematic Review with Case Series|journal=Journal of Psychoactive Drugs|volume=51|issue=1|pages=12–18|doi=10.1080/02791072.2018.1562133|issn=2159-9777|pmid=30614408|s2cid=58643707}}</ref>

Frequent use of high doses of kratom may cause tremors, anorexia, weight loss, ]s, psychosis and other mental health conditions.<ref name=bachu>{{cite journal |vauthors=Bachu AK, Singal P, Griffin B, Harbaugh L, Prasad S, Jain L, Mohiuddin S, Papudesi BN, Nagi T, Youssef NA, Chopra A, Ahmed S |title=Kratom use and mental health: A systematic literature review and case example |journal=J Addict Dis |volume= 42|issue= 4|pages=301–312 |date=November 2023 |pmid=37942896 |doi=10.1080/10550887.2023.2273192 |s2cid=265064749 |url=}}</ref><ref name=warner/> Kratom use may worsen existing mental health conditions.<ref name=bachu/> In case reports associating kratom use with psychosis, it remains unclear whether kratom use directly caused psychosis or simply unmasked the condition.<ref>{{Cite book|last1=Dye|first1=Leslie R.|url=https://books.google.com/books?id=cEFEDwAAQBAJ&q=kratom+psychosis&pg=PA238|title=Case Studies in Medical Toxicology: From the American College of Medical Toxicology|last2=Murphy|first2=Christine|last3=Calello|first3=Diane P.|last4=Levine|first4=Michael D.|last5=Skolnik|first5=Aaron|date=2017-12-22|publisher=Springer|isbn=978-3-319-56449-4|language=en}}</ref> Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.<ref name=Rech2015/><ref name=warner/> ] may result when kratom is combined with ], ]s, ]s, ]s, ], ], ], or ]s (MAOIs).<ref name=":4" /> ] is one of the rare and serious complications of this herb at high dosage.<ref name="pmid34430176">{{cite journal |vauthors=Patel P, Aknouk M, Keating S, Richard I, Kata P, Ali RY, Cheriyath P |title=Cheating Death: A Rare Case Presentation of Kratom Toxicity |journal=] |volume=13 |issue=7 |pages=e16582 |date=July 2021 |pmid=34430176 |pmc=8378318 |doi=10.7759/cureus.16582 |doi-access=free |url= |issn=}}</ref>

In July 2016, the ] issued a report stating that between 2010 and 2015, US ]s 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.<ref name=cdc/> One death was reported in a person who was exposed to the medications ] (an ]) and ] (an ] and ]) in addition to kratom.{{citation needed|date=January 2023}} For 173 (26.2%) exposure calls, no effects were reported, or poison center staff members were unable to follow up regarding effects.<ref name=cdc/>

A 2019 report from the American Association of Poison Control Centers ] noted that kratom use was increasing rapidly, with 1807 kratom exposures and a 52-fold increase occurring over the years 2011 to 2017.<ref name=Post/> 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.<ref name=Post/> Multiple-substance exposures were associated with a higher number of hospitalizations than kratom-only exposures and involved 11 deaths, including two due to kratom alone.<ref name=Post/> Post-mortem toxicology testing detected multiple substances for almost all those who died, with ] and ] being the most frequently identified co-occurring substances.<ref name="cdc2019" />

Overdoses of kratom are managed similarly to ]s, and ] 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.<ref name= Rech2015/>

From October 2017 to February 2018 in the United States, 28 people in 20 different states were infected with ], an ] linked to the consumption of contaminated pills, powder, tea, or unidentified sources of kratom.<ref name="cdc18">{{cite web|title=Multistate Outbreak of Salmonella I 4,,12:b:- Infections Linked to Kratom Products {{!}} February 2018 {{!}} Salmonella |url= https://www.cdc.gov/salmonella/kratom-02-18/index.html|website= cdc.gov| publisher= Centers for Disease Control| access-date=22 February 2018|date=20 February 2018}}</ref> An analytical method using ] applied to samples from the infected users indicated that the salmonella outbreak likely had a common kratom source.<ref name= cdc18/>

===Addiction===
Kratom is a botanical with a known addiction liability and, in vulnerable individuals, dependence may develop rather quickly with tolerance noted at three months and four- to ten-fold dose escalations required within the first few weeks.<ref>Alsarraf E, Myers J, Culbreth S, Fanikos J. Kratom from head to toe—case reviews of adverse events and toxicities. Curr Emerg Hosp Med Rep. 2019;7(4):141-168. doi:10.1007/s40138-019-00194-1</ref>
A survey by Stanciu et al. of kratom consumers found that 25.5% of respondents reported symptoms consistent with a substance use disorder diagnosis based on the Diagnostic and Statistical Manual's criteria. After controlling for variables such as age, gender, daily kratom use frequency, and a history of substance use disorders or mental health conditions, individuals with a concurrent diagnosis of another SUD had 2.83 times the odds of meeting criteria for kratom addiction compared to those without a concurrent substance use disorder diagnosis. <ref>Hill K, Grundmann O, Smith KE, Stanciu CN. Prevalence of Kratom Use Disorder Among Kratom Consumers. J Addict Med. 2024 May-Jun 01;18(3):306-312. doi: 10.1097/ADM.0000000000001290.</ref>
Kratom addiction carries a relapse risk as high as 78% to 89% at three months post-cessation.<ref>Vicknasingam B, Narayanan S, Beng GT, Mansor SM. The informal use of ketum (''Mitragyna speciosa'') for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int J Drug Policy.2010;21(4):283-288. doi:10.1016/j.drugpo.2009.12.003</ref><ref>Singh D, Müller CP, Vicknasingam BK. Kratom (''Mitragyna speciosa'') dependence, withdrawal symptoms, and craving in regular users. Drug Alcohol Depend. 2014;139:132-137. doi:10.1016/j.drugalcdep.2014.03.017</ref><ref>Singh D, Müller CP, Vicknasingam BK, Mansor SM. Social functioning of kratom (''Mitragyna speciosa'') users in Malaysia. J Psychoactive Drugs. 2015;47(2):125-131. doi:10.1080/02791072.2015.1012610</ref> In cases of severe addiction, an approach similar to the treatment of opioid addiction may be warranted.<ref>Stanciu C, Ahmed S, Hybki B, Penders T, Galbis-Reig D. Pharmacotherapy for Management of ‘Kratom Use Disorder': A Systematic Literature Review With Survey of Experts. WMJ. 2021;120(1)</ref>

===Respiratory depression===
] is the leading cause of death from opioid use.<ref name= Beckett2014>{{cite book| first= Jaclyn R. | last= Beckett|editor1-last=Raffa|editor1-first= Robert B.|title=Kratom and other mitragynines: the chemistry & pharmacology of opioids from|date= 2014| publisher= CRC Press|isbn= 978-1-4822-2518-1|pages= 195–204|chapter= Non-Analgesic CNS Effects}}</ref> Although evidence is sparse, the risk of respiratory depression caused by taking kratom appears to be low, but, {{as of|lc=yes|2016}}, the Food and Drug Administration listed respiratory depression as a concern.<ref name=white/><ref name="FDAImportAlert">{{cite web |date=20 December 2016 |title=Import Alert 54-15; Detention without physical examination of dietary supplements and bulk dietary ingredients that are or contain ''Mitragyna speciosa'' or kratom |url=http://www.accessdata.fda.gov/cms_ia/importalert_1137.html |access-date=7 March 2018 |publisher=U.S. Food and Drug Administration}}</ref> Confusingly, a 2018 review found that the alkaloids in kratom do not induce respiratory depression.<ref name="Kruegel">{{Cite journal|last1=Kruegel|first1=Andrew C.|last2=Grundmann|first2=Oliver|date=2018|title=The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse|url=http://dx.doi.org/10.1016/j.neuropharm.2017.08.026|journal=Neuropharmacology|volume=134|issue=Pt A|pages=108–120|doi=10.1016/j.neuropharm.2017.08.026|pmid=28830758|s2cid=24009429|issn=0028-3908}}</ref>

===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, ] and ].<ref name=livertox/><ref name=liverreview>{{cite journal |last1=Schimmel |first1=Jonathan |last2=Dart |first2=Richard C. |title=Kratom (''Mitragyna speciosa'') Liver Injury: A Comprehensive Review |journal=Drugs |date=Feb 2020 |volume=80 |issue=3 |pages=263–283 |doi=10.1007/s40265-019-01242-6 |pmid=31919755 |s2cid=210088143 }}</ref> Liver injury has been reported with a latency (time from first use to the onset of symptoms) of median 20.6 days. Reported liver biopsies tend to show ]; however, blood biomarkers can show a range of cholestatic, mixed, or hepatocellular injury patterns.<ref name=liverreview/> 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.<ref name=liverreview/>

===Death===
Kratom overdose is a subject of concern in many countries because of the associated rising number of hospitalizations and deaths in which chronic kratom use is a contributing factor.<ref name=warner/><ref name=livertox/> According to clinical reviews, a kratom overdose can cause ], ]s, ], and death,<ref name=livertox/> especially in combination with excessive alcohol use. Between 2011 and 2017, 44 U.S. deaths were kratom-related.<ref name=FDA2018/> However, many cases could not be fully assessed, due to limited information.<ref name=FDA2018/> People who die from kratom use typically have taken it in combination with other substances, or have underlying health conditions.<ref name=corkery>{{cite journal |vauthors=Corkery JM, Streete P, Claridge H, Goodair C, Papanti D, Orsolini L, Schifano F, Sikka K, Körber S, Hendricks A |title=Characteristics of deaths associated with kratom use |journal=J. Psychopharmacol. (Oxford) |volume=33 |issue=9 |pages=1102–1123 |year=2019 |pmid=31429622 |doi=10.1177/0269881119862530 |hdl=2299/21622 |s2cid=201095094 |url=http://openaccess.sgul.ac.uk/111141/15/Characteristics%20of%20deaths%20associated%20with%20kratom%20use%20-%20JP%20-%20final%20version%20accepted%2017%20June%202019.docx |type=Review|hdl-access=free }}</ref>

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.<ref name="cdc2019">{{cite journal|vauthors=Olsen EO, O'Donnell J, Mattson CL, Schier JG, Wilson N|title=Notes from the Field: Unintentional Drug Overdose Deaths with Kratom Detected — 27 States, July 2016 – December 2017|journal= MMWR. Morbidity and Mortality Weekly Report|date=12 April 2019|volume=68|issue=14|pages=326–327|doi=10.15585/mmwr.mm6814a2|pmid=30973850|pmc=6459583}}</ref><ref>{{cite news| title=CDC: Kratom linked to 91 U.S. overdose deaths |author=Mari A. Schaefer | agency=The Philadelphia Inquirer | publisher=Lodi News-Sentinel |page=16 |date=April 13, 2019}}</ref><ref>{{cite web|title=Kratom Caused 91 Overdose Deaths During 18-Month Period: CDC – Partnership News Service from the Partnership for Drug-Free Kids|url=https://drugfree.org/drug-and-alcohol-news/kratom-caused-91-overdose-deaths-during-18-month-period-cdc/|access-date=2020-08-05|website=Partnership to End Addiction {{!}} Where Families Find Answers|language=en-US}}</ref> Nine deaths occurred in Sweden during 2010–11 relating to use of ''Krypton'', a mixture of kratom, caffeine and ], a metabolite of the opioid analgesic ].<ref name="toxnet12">{{cite web|title=Mitragynine|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+7901|publisher=Toxnet, National Library of Medicine, US National Institutes of Health|access-date=15 February 2018|date=14 February 2012}}</ref><ref name="rosenbaum_2012">{{cite journal |vauthors=Rosenbaum CD, Carreiro SP, Babu KM |year=2012 |title=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=Journal of Medical Toxicology |volume=8 |issue=1 |pages=15–32 |doi=10.1007/s13181-011-0202-2 |pmc=3550220 |pmid=22271566}}</ref>

==Pharmacology==
{| class="wikitable floatright" style="text-align: center;"
|+ ''Mitragyna speciosa'' alkaloids at opioid receptors
|-
! rowspan="2" | Compound || colspan="3" | ] ({{abbrlink|K<sub>i</sub> (nM)|Inhibitor constant}}) || Ratio || rowspan="2" | Ref
|-
! {{abbrlink|MOR|μ-Opioid receptor}} !! {{abbrlink|DOR|δ-Opioid receptor}} !! {{abbrlink|KOR|κ-Opioid receptor}} !! MOR:DOR:KOR
|-
| ] || 13.5 || 155 || 123 || 1:11:9 || <ref name="pmid11960505">{{cite journal | vauthors = 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 | title = Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands | journal = J. Med. Chem. | volume = 45 | issue = 9 | pages = 1949–56 | year = 2002 | pmid = 11960505 | doi = 10.1021/jm010576e}}</ref>
|-
| ] || 7.24 || 60.3 || 1,100 || 1:8:152 || <ref name="pmid11960505" />
|-
| ] || 0.087 || 3.02 || 79.4 || 1:35:913 || <ref name="pmid11960505" />
|}

Kratom contains at least 54 ]s.<ref>{{Cite journal|last1=Kerrigan|first1=Sarah|last2=Basiliere|first2=Stephanie|title=Kratom: A systematic review of toxicological issues|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/wfs2.1420|journal=WIREs Forensic Science|year=2021|volume=4|language=en|pages=e1420|doi=10.1002/wfs2.1420|s2cid=236630556|issn=2573-9468}}</ref><ref>{{Cite journal|last1=Chakraborty|first1=Soumen|last2=Uprety|first2=Rajendra|last3=Daibani|first3=Amal E.|last4=Rouzic|first4=Valerie L.|last5=Hunkele|first5=Amanda|last6=Appourchaux|first6=Kevin|last7=Eans|first7=Shainnel O.|last8=Nuthikattu|first8=Nitin|last9=Jilakara|first9=Rahul|last10=Thammavong|first10=Lisa|last11=Pasternak|first11=Gavril W.|date=2021-07-21|title=Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom|journal=ACS Chemical Neuroscience|volume=12|issue=14|pages=2661–2678|doi=10.1021/acschemneuro.1c00149|issn=1948-7193|pmc=8328003|pmid=34213886}}</ref><ref>{{Cite journal|last1=Flores-Bocanegra|first1=Laura|last2=Raja|first2=Huzefa A.|last3=Graf|first3=Tyler N.|last4=Augustinović|first4=Mario|last5=Wallace|first5=E. Diane|last6=Hematian|first6=Shabnam|last7=Kellogg|first7=Joshua J.|last8=Todd|first8=Daniel A.|last9=Cech|first9=Nadja B.|last10=Oberlies|first10=Nicholas H.|date=2020-07-24|title=The Chemistry of Kratom : Updated Characterization Data and Methods to Elucidate Indole and Oxindole Alkaloids|url=https://doi.org/10.1021/acs.jnatprod.0c00257|journal=Journal of Natural Products|volume=83|issue=7|pages=2165–2177|doi=10.1021/acs.jnatprod.0c00257|issn=0163-3864|pmc=7718854|pmid=32597657}}</ref> These include ], ] (7-HMG), ], paynantheine, corynantheidine, speciogynine, ], ], mitralactonal, ], and mitragynaline.<ref name=":3" /><ref name="warner" /><ref name="white" /> The alkaloids mitragynine and 7-hydroxymitragynine are responsible for many of the complex effects of kratom,<ref name="warner" /><ref name="white" /> but other alkaloids may also contribute ].<ref name=":3" />

The effects of both mitragynine and 7-HMG remain disputed despite substantial study. Both are ]s of the ]. While most data indicates agonism at all three opioid receptors, other data suggests the alkaloids are ] of the ] with low affinity for the ].<ref name=":3" /><ref name=":4" /> 7-HMG appears to have higher ] at the μ-opioid receptor than mitragynine.<ref name="Kruegel" /><ref name="white" /> These compounds display ] and do not activate the ] pathway partly responsible for the respiratory depression, constipation, and sedation associated with traditional ]s.<ref name=":3" /><ref>{{Cite journal|last1=Ya|first1=Kimheang|last2=Tangamornsuksan|first2=Wimonchat|last3=Scholfield|first3=C. Norman|last4=Methaneethorn|first4=Janthima|last5=Lohitnavy|first5=Manupat|date=2019|title=Pharmacokinetics of mitragynine, a major analgesic alkaloid in kratom (''Mitragyna speciosa''): A systematic review|url=http://dx.doi.org/10.1016/j.ajp.2019.05.016|journal=Asian Journal of Psychiatry|volume=43|pages=73–82|doi=10.1016/j.ajp.2019.05.016|pmid=31100603|s2cid=157067698|issn=1876-2018}}</ref> Both mitragynine and 7-HMG readily cross the ].<ref name=":4" /><ref>{{Cite journal|last1=Gonçalves|first1=Joana|last2=Luís|first2=Ângelo|last3=Gallardo|first3=Eugenia|last4=Duarte|first4=Ana Paula|date=2021-03-05|title=Psychoactive Substances of Natural Origin: Toxicological Aspects, Therapeutic Properties and Analysis in Biological Samples|journal=Molecules|volume=26|issue=5|page=1397|doi=10.3390/molecules26051397|issn=1420-3049|pmc=7961374|pmid=33807728|doi-access=free}}</ref>

Mitragynine also appears to ], block ] and ] ], and interact with other receptors in the brain including ] and ] ], ] ]s, and ] ]s.<ref name=":3" /> Mitragynine stimulates ]s, inhibiting the release of ] (noradrenaline); other compounds in this class include ], which is used for sedation, and ], 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.<ref name="white" /> Kratom also contains ], a non-competitive ].<ref name="warner" /><ref>{{Cite journal|last1=Brown|first1=Paula N.|last2=Lund|first2=Jensen A.|last3=Murch|first3=Susan J.|date=2017-04-18|title=A botanical, phytochemical and ethnomedicinal review of the genus ''Mitragyna'' korth: Implications for products sold as kratom|url=https://pubmed.ncbi.nlm.nih.gov/28330725/|journal=Journal of Ethnopharmacology|volume=202|pages=302–325|doi=10.1016/j.jep.2017.03.020|issn=1872-7573|pmid=28330725}}</ref>

Mitragynine is ] in humans via ] and ] mechanisms with the resulting ]s excreted in ].<ref name="warner" /> In '']'' experiments, kratom extracts ]ed ], ], and ] ]s, which results in significant potential for ]s.<ref name="warner" />

== Chemistry ==
{{main|Mitragynine}}

Many of the key psychoactive compounds in ''M. speciosa'' are ]s related to ], which is a tetracyclic relative of the pentacyclic indole alkaloids, ] and ].<ref name="warner" /> In particular, mitragynine and ] (7-HMG) compose significant proportions of the ]s 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.<ref name="warner" /><ref>{{cite book |last1=Gibbons |first1=Simon |title=Novel Psychoactive Substances: Classification, Pharmacology and Toxicology |last2=Arunotayanun |first2=Warunya |date=2013 |publisher=Academic Press |isbn=978-0-12-415816-0 |pages=345–362 |chapter=Chapter 14. Natural Product (Fungal and Herbal): Novel Psychoactive Substances |doi=10.1016/B978-0-12-415816-0.00014-6 |access-date=January 24, 2020 |chapter-url=https://www.sciencedirect.com/science/article/pii/B9780124158160000146}}{{full citation needed|date=January 2020}}</ref> At least 40 other compounds have been isolated from ''M. speciosa'' leaves,<ref name="Adkins 2011-05-01" /> including ~25 additional ]s, including ] (originally isolated from '']''), corynantheidine (also found in '']''),<ref name="pmid11960505" /> as well as ], ], and ].<ref>{{cite journal |vauthors=Suhaimi FW, Yusoff NH, Hassan R, Mansor SM, Navaratnam V, Müller CP, Hassan Z |year=2016 |title=Neurobiology of Kratom and its main alkaloid mitragynine |journal=Brain Res Bull |volume=Mar 25 |issue=Pt 1 |pages=29–40 |doi=10.1016/j.brainresbull.2016.03.015 |pmid=27018165 |s2cid=3952200}}</ref><ref name="Pharmacology">{{Cite journal |last1=Prozialeck |first1=WC |last2=Jivan |first2=JK |last3=Andurkar |first3=SV |year=2012 |title=Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic, and opioid-like effects |journal=The Journal of the American Osteopathic Association |volume=112 |issue=12 |pages=792–99 |pmid=23212430}}</ref>

In addition to ]s, ''M. speciosa'' produces many other ]s. These include various ]s, ]s and other ], ] such as ] and ], as well as various ]s including the ]s ] and ].<ref>{{Cite journal |last1=Ramanathan |first1=Surash |last2=León |first2=Francisco |last3=Chear |first3=Nelson J.Y. |last4=Yusof |first4=Siti R. |last5=Murugaiyah |first5=Vikneswaran |last6=McMahon |first6=Lance R. |last7=McCurdy |first7=Christopher R. |date=2021-01-01 |title=Kratom (''Mitragyna speciosa'' Korth.): A description on the ethnobotany, alkaloid chemistry, and neuropharmacology |url=https://www.sciencedirect.com/science/article/pii/B9780128194874000033 |journal=Studies in Natural Products Chemistry |language=en |volume=69 |pages=195–225 |doi=10.1016/B978-0-12-819487-4.00003-3 |isbn=978-0-12-819487-4 |issn=1572-5995 |s2cid=234947828}}</ref> Although some of these compounds possess ], ], ], ], ], and ] effects in cells and non-human animals, there is no sufficient evidence to support the clinical use of kratom in humans.<ref name=":4" />

=== 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.<ref name="rosenbaum_2012" /><ref>{{cite journal |vauthors=Le D, Goggin MM, Janis GC |year=2012 |title=Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom |journal=Journal of Analytical Toxicology |volume=36 |issue=9 |pages=616–25 |doi=10.1093/jat/bks073 |pmid=23024321 |doi-access=free}}</ref> 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.<ref name="rosenbaum_2012" /><ref>{{cite book |author=Baselt RC |title=Disposition of toxic drugs and chemicals in man |publisher=Biomedical Publications |year=2014 |isbn=978-0-9626523-9-4 |location=Seal Beach, Calif. |page=1382}}</ref>


==Regulation== ==Regulation==
{{As of|2018|January}}, neither the plant nor its alkaloids were listed in any of the Schedules of the United Nations Drug Conventions.<ref name=EMCDDA/>
]
===Thailand===
;Prohibition
Possession of kratom leaves is illegal in Thailand, despite the tree being native to the country. The Thai government passed the ''Kratom Act 2486'' which went into effect on August 3, 1943. This law makes planting the tree illegal and requires existing trees to be cut down. This law was not found effective, since the tree is indigenous to the country. Today, kratom is scheduled in category 5 of the Narcotics Acts (1979), in the same category as cannabis and magic mushrooms (the least punitive category). A large aspect of Thai culture supports kratom, however despite this fact the Thai government has 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.<ref name=idpc/>


In 2021, the ]'s Executive Committee on Drug Dependency investigated the risks of kratom and declined to recommend a critical review of it. The committee, however, recommended kratom be kept "under surveillance."<ref>{{cite web|url=https://s3.documentcloud.org/documents/21150126/ecdd-report-dec-2021.pdf|title=Summary of assessments, findings and recommendations of the 44th World Health Organization's (WHO) Expert Committee on Drug Dependence (ECDD)|date=October 2021|website=SD3.documentcloud.org|access-date=24 June 2022}}</ref>
;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:


===ASEAN===
{{quote|''"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."''<ref name="Decriminalization and Community Control?">{{citation |url=http://www.tni.org/sites/www.tni.org/files/download/kratom-briefing-dlr13.pdf |title=Kratom in Thailand: Decriminalization and Community Control? Proposal by the Thai Office of the Narcotics Control Board}}</ref>}}
{{As of|2013}}, kratom was listed by ] in its annex of products that cannot be included in traditional medicines and health supplements that are traded across ASEAN nations.<ref>{{cite web|publisher=Association of South East Asian Nations (ASEAN)|url=http://www.fda.gov.ph/attachments/article/218035/ANNEX%20I%20ASEAN%20GP%20for%20the%20Negative%20List%20Ver%203.0%20(14Nov14).pdf|title=Annex I: ASEAN Guiding Principles For Inclusion into or Exclusion from the Negative List of Substances for Traditional Medicines and Health Supplements|date=June 28, 2014|access-date=September 12, 2016|archive-url=https://web.archive.org/web/20161026164939/http://www.fda.gov.ph/attachments/article/218035/ANNEX%20I%20ASEAN%20GP%20for%20the%20Negative%20List%20Ver%203.0%20(14Nov14).pdf|archive-date=October 26, 2016|url-status=dead}}</ref>


===Australia and New Zealand===
While additional research is needed<ref name=idpc/> kratom proponents argue that the criminalization of kratom is unfounded and is based on economic control and misinformation. The criminalization of kratom has made research more difficult, especially in Thailand. It has been recommended by the Transnational Institute that kratom be decriminalized and that the criminalization of kratom to be unnecessary, problematic and counter-productive. The Institute also argues that the evidence showing the health benefits of kratom, particularly in treating drug and ], are worth exploring further.<ref name=idpc/>
{{As of|2015|January}}, kratom was controlled as a narcotic in Australia and under Medicines Regulations 1985 (Amended August 6, 2015)<ref>{{cite web|title=Medicines Regulations 1984|url=http://www.legislation.govt.nz/regulation/public/1984/0143/latest/DLM95668.html|website=New Zealand Legislation|access-date=31 May 2017}}</ref> in New Zealand.<ref name=EMCDDA/>

===Canada===
{{As of|2020|October}}, ] disallowed marketing of kratom for any use by ingestion<ref>{{cite web |title=Unauthorized products may pose serious health risks (kratom) |url=https://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/74169a-eng.php |publisher=Health Canada |access-date=18 January 2021 |date=21 October 2020}}</ref> and has taken action against companies marketing it for such purposes.<ref>{{cite web|title=Health Product Advertising Complaints|date=26 March 2015 |url=http://www.hc-sc.gc.ca/dhp-mps/advert-publicit/complaint-plaintes/index-eng.php|publisher=Health Canada, Health Products and Food Branch|archive-url=https://web.archive.org/web/20170214220337/http://www.hc-sc.gc.ca/dhp-mps/advert-publicit/complaint-plaintes/index-eng.php|archive-date=14 February 2017}}</ref><ref>{{cite news|url=https://globalnews.ca/news/3561227/kratom-a-controversial-herbal-product-seized-from-2-edmonton-stores-health-canada/|title=Kratom, a controversial herbal product, seized from 2 Edmonton stores: Health Canada|author=Phil Heidenreich|date=27 June 2017|newspaper=Global News}}</ref> Kratom can be marketed for other uses, such as incense.<ref>{{cite web|url=https://ca.news.yahoo.com/after-us-delayed-decision-on-kratom-a-look-at-213934868.html|title=After U.S. delayed decision on kratom, a look at Canada's laws on the {{sic|psych|adelic|hide=y}} plant|publisher=Yahoo News Canada|date=14 October 2016|author=Coles, Terri}}</ref>

===Europe===
{{As of|2011}}, the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania, and Sweden.<ref name=EMCDDA/>

Kratom is a controlled substance in Bulgaria.<ref>{{Cite web |title=Какво е кратом? |url=https://www.drugsinfo-bg.org/azbuka-na-narkoticite/kratom/kakvo-e-kratom/ |access-date=2023-11-28 |website=Национална информационна линия за наркотиците, алкохола и хазарта}}</ref>

The sale, import, and export of kratom have been prohibited in the UK since 2016 under the ].<ref>{{cite web |url=http://www.legislation.gov.uk/ukpga/2016/2/contents |title=Psychoactive Substances Act 2016 |publisher=The National Archives, HM Government Publishing |date=9 September 2016}}</ref>

In 2017, kratom was designated a Schedule 1 illegal drug (the highest level) in the ], under the names ] and ].<ref>{{cite web|url=https://health.gov.ie/wp-content/uploads/2017/05/si174.pdf|title=MISUSE OF DRUGS (DESIGNATION) ORDER 2017|date=2017|website=STATUTORY INSTRUMENTS, S.I. No. 174 of 2017. Stationery Office, Dublin}}</ref>

=== Indonesia ===
Kratom was previously scheduled to become an illegal substance in Indonesia in 2024 once new regulations from the Indonesian National Narcotics Agency (BNN) go into effect.<ref>{{cite web|date=December 22, 2020|title=Mulai 2024, Pemerintah Larang Penggunaan dan Ekspor Kratom|url=https://www.beritasatu.com/nasional/811035/mulai-2024-pemerintah-larang-penggunaan-dan-ekspor-kratom|access-date=2022-06-12|website=beritasatu.com|language=id}}</ref> However, in 2024, a revision to a regulation by ] legalized production and export of kratom leaves.<ref name=":9">{{Cite web |last=adminkalbaronline |date=2024-09-04 |title=Bupati Kapuas Hulu: Sudah Terbit Permendag RI Nomor 21 Tahun 2024 Tentang Ekspor Komoditi Kratom - KalbarOnline.Com |url=https://kalbaronline.com/2024/09/04/bupati-kapuas-hulusudah-terbit-permendag-ri-nomor-21-tahun-2024-tentang-ekspor-komoditi-kratom/ |access-date=2024-09-04 |website=kalbaronline.com/ |language=en-US}}</ref> Later in September 2024, Indonesia's Ministry of Cooperatives and Small Medium Business stated that Indonesia will start building downstream industries for kratom exports.<ref>{{Cite web |title=Teten Masduki Akan Wariskan Program Hilirisasi Kratom untuk Prabowo |url=https://kumparan.com/kumparanbisnis/teten-masduki-akan-wariskan-program-hilirisasi-kratom-untuk-prabowo-23XfQMRRM7n |access-date=2024-09-18 |website=kumparan |language=id-ID}}</ref><ref name=":10">{{Cite web |title=Menkop Teten Dorong Hilirisasi Produk Kratom, Bisa Dijual Rp90 Juta per Kilogram |url=https://www.merdeka.com/uang/menkop-teten-dorong-hilirisasi-produk-kratom-bisa-dijual-rp90-juta-per-kilogram-198673-mvk.html |access-date=2024-09-18 |website=merdeka.com |language=en}}</ref> These developments made kratom legal to export and manufacture in Indonesia.<ref name=":9" /><ref name=":10" />

===Malaysia===
The use of kratom leaves, known locally as ''ketum or Biak'' is prohibited to use, import, export, manufacture, compound, mix, dispense, sell, supply, administer or possess in Malaysia under Section 30(3) of the Poisons Act 1952, and will be punished by imprisonment or fine or both.<ref name=Utusan>{{cite web|title=Amend the Act leaves the density of the Dangerous Drugs Act|url=https://translate.google.com/translate?hl=en&sl=auto&tl=en&prev=_dd&u=http%3A%2F%2Fwww.utusan.com.my%2Futusan%2FParlimen%2F20121213%2Fpa_02%2FPinda-akta-daun-ketum-kepada-Akta-Dadah-Berbahaya|access-date=18 April 2014|date=13 December 2012}}</ref> Although prohibited by statute, the use of kratom remains widely spread especially in Northern and East Coast region of Malaysia's Peninsula because the tree grows natively and tea decoctions are readily available in local communities.<ref>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</ref> 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.<ref name="TMI">. The Malaysian Insider. October 28, 2012.</ref>

===Thailand===
Possession of kratom leaves ({{langx|th|ต้นกระท่อม}}, {{RTGS|''ton krathom''}}) was illegal in Thailand until 2018.<ref name=AJ-20181226>{{cite news |title=Thailand legislature legalises medical cannabis and kratom |url=https://www.aljazeera.com/news/2018/12/thailand-legislature-legalises-medical-cannabis-kratom-181226010249208.html |access-date=26 December 2018 |work=Aljazeera English |date=26 December 2018}}</ref> The Thai government had passed the Kratom Act 2486, effective 3 August 1943, which made planting the tree illegal,<ref name=usdea/> 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.<ref name=warner/> In 1979, the Thai government placed kratom, along with marijuana, in Category V of a five-category classification of narcotics.<ref name=usdea/> Kratom accounted for less than two percent of arrests for narcotics between 1987 and 1992.<ref>{{cite journal |last1=Cheurprakobkit |first1=Sutham |title=The drug situation in Thailand: the role of government and the police |journal=Drug and Alcohol Review |volume=19 |issue=1 |year=2000 |pages=17–26 |doi=10.1080/09595230096101 }}</ref>

The Thai government has considered legalizing kratom for recreational use in 2004, 2009, 2013, and 2020.<ref>{{cite news |title=Leafy highs: Kratom personal use push under way |url=https://www.bangkokpost.com/thailand/general/1850589/leafy-highs-kratom-personal-use-push-under-way |access-date=5 February 2020 |work=Bangkok Post |date=5 February 2020}}</ref><ref>{{cite news|last1=Prasert|first1=Poungchompoo|title=Decision yet to be reached on making 'kratom' legal|url=http://www.nationmultimedia.com/national/Decision-yet-to-be-reached-on-making-kratom-legal-30216276.html|work=The Nation|date=4 October 2013|access-date=13 September 2016|archive-date=16 May 2019|archive-url=https://web.archive.org/web/20190516113645/http://www.nationmultimedia.com/national/Decision-yet-to-be-reached-on-making-kratom-legal-30216276.html|url-status=dead}}</ref> In 2018, Thailand became the first Southeast Asian country to legalize kratom for medical purposes.<ref name=AJ-20181226 /> 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.<ref>{{Cite news|title=Parliament votes to remove kratom from narcotics list|work=Bangkok Post|date=27 January 2021 |url=https://www.bangkokpost.com/thailand/general/2058139/parliament-votes-to-remove-kratom-from-narcotics-list|access-date=2021-06-22 | vauthors = Sattaburuth A }}</ref><ref>{{cite news |last=Laohong |first=King-oua |date=2021-08-23 |title=Kratom now listed as legal herb |url=https://www.bangkokpost.com/thailand/general/2169411/kratom-now-listed-as-legal-herb |work=Bangkok Post |access-date=2021-08-24}}</ref>


===United States=== ===United States===
In 2014, the United States ] (FDA) banned the import of kratom into the U.S. due to a lack of evidence for its safety.<ref name="FDAImportAlert" /> {{as of|2021}}, kratom is illegal in six states: Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin, and it may be outlawed by local ordinance in other states.<ref name="C-Clinic">{{cite web |date=June 30, 2021 |title=What is Kratom? |url=https://health.clevelandclinic.org/what-is-kratom/ |access-date=July 8, 2023 |website=Cleveland Clinic}}</ref> There was consideration in late 2017 to make kratom a ] drug.<ref>{{cite web|url=https://www.statnews.com/2018/11/09/hhs-recommended-dea-ban-kratom-documents-show/|title=HHS recommended that the DEA ban kratom, documents show – STAT|date=9 November 2018|website=STAT|access-date=15 November 2018}}</ref> In 2019, the FDA warned consumers that kratom remains unapproved for interstate commerce for use as a drug,<ref name="fda6-19">{{cite web |title=FDA issues warnings to companies selling illegal, unapproved kratom drug products marketed for opioid cessation, pain treatment and other medical uses |url=https://www.fda.gov/news-events/press-announcements/fda-issues-warnings-companies-selling-illegal-unapproved-kratom-drug-products-marketed-opioid |publisher=US Food and Drug Administration |access-date=16 January 2020 |date=25 June 2019}}</ref> may be unsafe in commercially available products, and is on an import alert, which can lead to confiscation of imported supplies.<ref name="fda4-3-19" /> Efforts to schedule kratom generated significant controversy, both among the general public and the scientific community, and were ultimately unsuccessful.<ref>{{cite web|last=MD|first=Peter Grinspoon|date=2019-08-07|title=Kratom: Fear-worthy foliage or beneficial botanical?|url=https://www.health.harvard.edu/blog/kratom-fear-worthy-foliage-or-beneficial-botanical-2019080717466|access-date=2021-06-21|website=Harvard Health}}</ref><ref>{{cite web|date=2016-09-08|title=Kratom ban will hinder studies of the plant as a treatment|url=https://www.statnews.com/2016/09/08/kratom-ban-hinders-research/|access-date=2021-06-21|website=Stat}}</ref><ref name=":2" />
Kratom itself is not regulated by the ], though the ] includes the tree in its "Drug and Chemical of Concern" list.<ref name="Kratom as a Drug and Chemical of Concern">{{citation |url=http://www.deadiversion.usdoj.gov/drugs_concern/index.html |title=Kratom as a Drug and Chemical of Concern}}</ref>


==== FDA assessment ====
] HB1196, sponsored by ], Steve Davisson, ], ], and David Yarde during the 2012 regular session as a response to increasing synthetic drug use, made ] the first and only state to ban kratom, although indirectly.<ref name="HB1196">{{citation |url=http://legiscan.com/gaits/text/603106 |title=Indiana HB1196}}</ref> 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. Petitioners on ] subsequently sought delisting of kratom's alkaloids by raising the issue with ] ].<ref> ].</ref>
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.<ref name="fda4-3-19" />
On April 4, 2018, the FDA issued the first mandatory recall in its history over concerns of ] contamination of several kratom-containing products.<ref name="Chappell">{{cite news|last1=Chappell|first1=Bill|title=FDA Orders An Unprecedented Recall After Kratom Company Ignored Its Requests|url=https://www.npr.org/sections/thetwo-way/2018/04/04/599443476/fda-orders-an-unprecedented-recall-after-kratom-company-ignored-its-requests|access-date=5 April 2018|work=NPR|date=4 April 2018}}</ref> 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.<ref name="FDArecall">{{cite web|last1=FDA News Release|title=FDA orders mandatory recall for kratom products due to risk of salmonella|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm603517.htm|website=Press Announcements|publisher=United States Food and Drug Administration|access-date=5 April 2018}}</ref> 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.<ref name="Chappell" /> Consumers were advised to immediately discard any such products to prevent serious health risks.<ref name="FDArecall" />


In February 2018, the ], ], 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.<ref name=FDA2018/> 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.<ref>{{cite web|title=FDA oversees destruction and recall of kratom products; and reiterates its concerns on risks associated with this opioid| url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm597649.htm|publisher=U.S. Food and Drug Administration|access-date=7 March 2018|date=21 February 2018|quote=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 healthcare 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}}</ref> 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.<ref name=Tave />
Iowa legislators grouped ''Mitragyna speciosa'' as a ] when a bill was proposed that would reclassify nearly all controlled substances in their state.<ref name="SF2341">{{citation |url=http://legiscan.com/gaits/text/635604 |title=Iowa SF2341}}</ref><ref name="Kiley 2012-04-10">{{cite news | first = Brendan | last = Kiley | title = The Rush to Prohibit Kratom | date = 2012-04-10 | url = http://www.thestranger.com/seattle/the-rush-to-prohibit-kratom/Content?oid=13321119 | work = The Stranger | accessdate = 2012-10-30}}</ref> 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.<ref name="SB130">{{citation |url=http://legiscan.com/gaits/text/651753 |title=Louisiana SB130}}</ref> ] ] sponsored legislation in 2011 that would have included compounds of ''Mitragyna speciosa'' in the state's controlled substance classification list.<ref name="H526">{{citation |url=http://legiscan.com/gaits/text/166358 |title=Massachusetts H526}}</ref>

Although it was a federally legal ], kratom was not approved as a ] in the United States due to the poor quality of the research.<ref name="warner" /><ref name="white" /> 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 ]; 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."<ref>{{cite web|title=Statement from FDA Commissioner Scott Gottlieb, M.D. on FDA advisory about deadly risks associated with kratom| url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584970.htm|publisher=U.S. Food and Drug Administration|access-date=14 November 2017|date=14 November 2017|quote=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}}</ref>

==== DEA scheduling ====
On August 30, 2016, the ] (DEA) announced its intention to place the active materials in the kratom plant into Schedule I of the ] 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.<ref name=dea>{{cite web | url=https://www.dea.gov/divisions/hq/2016/hq083016.shtml | title=DEA Announces Intent to Schedule Kratom: SE Asian drug is imminent hazard to public safety | publisher=US Drug Enforcement Administration | date=30 August 2016 | access-date=31 August 2016 | archive-url=https://web.archive.org/web/20160915180244/https://www.dea.gov/divisions/hq/2016/hq083016.shtml | archive-date=15 September 2016 | url-status=dead }}</ref> This drew strong protests among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol.<ref>{{cite web|last1=Silverman|first1=Lauren|title=Kratom Advocates Speak Out Against Proposed Government Ban|url=https://www.npr.org/sections/health-shots/2016/09/12/493295493/kratom-advocates-speak-out-against-proposed-government-ban|website=NPR|access-date=12 September 2016|date=12 September 2016}}</ref> 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 ] protesting the listing and around 140,000 people signed an online White House Petition protesting it.<ref>{{cite news|last1=Ingraham|first1=Christopher|title=DEA defies senators' appeal to reconsider 'unprecedented' kratom ban |url=https://www.washingtonpost.com/news/wonk/wp/2016/09/30/dea-defies-senators-appeal-to-reconsider-unprecedented-kratom-ban/ |newspaper=]|date=September 30, 2016}}</ref><ref>{{cite news|last1=Stapleton|first1=Christine|title=Congress members ask DEA not to ban kratom: opioid research needed|url=http://www.mypalmbeachpost.com/news/news/national-govt-politics/kratom-ban-starts-friday-frankel-among-lawmakers-t/nshQ6/|work=Palm Beach Post|date=September 29, 2016|access-date=October 2, 2016|archive-date=November 3, 2016|archive-url=https://web.archive.org/web/20161103190439/http://www.mypalmbeachpost.com/news/news/national-govt-politics/kratom-ban-starts-friday-frankel-among-lawmakers-t/nshQ6/|url-status=dead}}</ref>

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."<ref>{{cite news|last1=Nelson|first1=Steven|title=Kratom Will Remain Legal for Days, Possibly Longer|url=https://www.usnews.com/news/articles/2016-09-30/kratom-will-remain-legal-for-days-possibly-longer|work=U.S. News & World Report|date=September 30, 2016}}</ref> In October 2016, the DEA withdrew its notice of intent while inviting public comments over a review period ending on December 1, 2016.<ref>{{Cite news|url=https://www.npr.org/sections/health-shots/2016/10/12/497697627/kratom-gets-reprieve-from-drug-enforcement-administration|title=Kratom Gets Reprieve From Drug Enforcement Administration|newspaper=NPR.org|access-date=2016-10-12}}</ref><ref>{{cite web|url=https://www.federalregister.gov/documents/2016/10/13/2016-24659/withdrawal-of-notice-of-intent-to-temporarily-place-mitragynine-and-7-hydroxymitragynine-into|title=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|date=2016-10-13|website=Federal Register|publisher=Drug Enforcement Administration|access-date=2016-10-18}}</ref> As of July 2016, Alabama, Arkansas, Indiana, Vermont, and Wisconsin had made kratom illegal,<ref>{{cite news|last1=Brown|first1=Melissa|title=States ban kratom supplement over abuse worries|url=https://www.usnews.com/news/us/articles/2016-05-20/states-ban-kratom-supplement-over-abuse-worries|work=Associated Press via US News & World Report|date=May 20, 2016}}</ref> and the US Army had forbidden soldiers from using it.<ref>{{cite news|last1=Schwarz|first1=Alan|title=Kratom, an Addict's Alternative, Is Found to Be Addictive Itself|url=https://www.nytimes.com/2016/01/03/us/kratom-an-addicts-alternative-is-found-to-be-addictive-itself.html|work=The New York Times|date=2 January 2016}}</ref> 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 ].<ref>{{cite web|url=https://www.outsideonline.com/2387546/kratom-safety|title=The Herbal Supplement That Might Be a Deadly Drug|last=Smith|first=Peter Andrey|date=2019-02-19|website=Outside Online|access-date=2019-02-20}}</ref>

==== Public response ====
The FDA's arguments for the federal ] of kratom have drawn both criticism and support.<ref name=":8">{{cite web|title=The U.S. May Ban Kratom. But Are its Effects Deadly or Lifesaving?|url=https://www.discovermagazine.com/health/the-us-may-ban-kratom-but-are-its-effects-deadly-or-lifesaving|access-date=2021-06-22|website=Discover Magazine|language=en}}</ref><ref name=":6">{{Cite magazine|last1=Garber-Paul|first1=Elisabeth|last2=Garber-Paul|first2=Elisabeth|date=2018-08-15|title=Kratom Association Calls FDA Review of Drug 'Junk Science' in Scathing Report|url=https://www.rollingstone.com/culture/culture-news/kratom-drug-industry-fda-opioid-711169/|access-date=2021-06-22|magazine=Rolling Stone|language=en-US}}</ref><ref name=":7">{{cite web|last=Marlan|first=Dustin|date=2021-06-08|title=A Sensible, Evidence-Based Proposal for Kratom Reform|url=https://blog.petrieflom.law.harvard.edu/2021/06/08/a-sensible-evidence-based-proposal-for-kratom-reform/|access-date=2021-06-22|website=Bill of Health|language=en-US}}</ref> 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."<ref name=":6" /> However, in 2021, former Acting ] ] claimed that the FDA's recommendation to schedule kratom was rejected because of "embarrassingly poor evidence data."<ref name=":7" /> The FDA's position on kratom has also been criticized by the ] and researchers including ].<ref name=":8" /><ref name=":6" /><ref>{{Cite journal|last1=Prozialeck|first1=Walter C.|last2=Avery|first2=Bonnie A.|last3=Boyer|first3=Edward W.|last4=Grundmann|first4=Oliver|last5=Henningfield|first5=Jack E.|last6=Kruegel|first6=Andrew C.|last7=McMahon|first7=Lance R.|last8=McCurdy|first8=Christopher R.|last9=Swogger|first9=Marc T.|last10=Veltri|first10=Charles A.|last11=Singh|first11=Darshan|date=2019|title=Kratom policy: The challenge of balancing therapeutic potential with public safety|journal=The International Journal on Drug Policy|volume=70|pages=70–77|doi=10.1016/j.drugpo.2019.05.003|issn=1873-4758|pmc=7881941|pmid=31103778}}</ref> Former commissioner Gottlieb continued to defend the agency's position in 2021, stating that he was convinced that kratom was fueling the U.S. ], though Gottlieb's partiality has been called into question as he has since gone on to become a member of the board of directors of ], a company that has been heavily criticized for its sale and marketing of opioid drugs.<ref name=":7" />

== Research directions==
Kratom is under preliminary research for possible ] and ] properties.<ref>{{Cite journal|last1=Johnson|first1=Lindsay E.|last2=Balyan|first2=Lilian|last3=Magdalany|first3=Amy|last4=Saeed|first4=Fizza|last5=Salinas|first5=Robert|last6=Wallace|first6=Starla|last7=Veltri|first7=Charles A.|last8=Swogger|first8=Marc T.|last9=Walsh|first9=Zach|last10=Grundmann|first10=Oliver|date=2020-06-29|title=The Potential for Kratom as an Antidepressant and Antipsychotic|journal=The Yale Journal of Biology and Medicine|volume=93|issue=2|pages=283–289|issn=0044-0086|pmc=7309668|pmid=32607089}}</ref><ref>{{Cite journal|last1=Taylor Levine|first1=M.|last2=Gao|first2=Jin|last3=Satyanarayanan|first3=Senthil Kumaran|last4=Berman|first4=Sarah|last5=Rogers|first5=Jack T.|last6=Mischoulon|first6=David|date=2020|title=S-adenosyl-l-methionine (SAMe), cannabidiol (CBD), and kratom in psychiatric disorders: Clinical and mechanistic considerations|journal=Brain, Behavior, and Immunity|volume=85|pages=152–161|doi=10.1016/j.bbi.2019.07.013|issn=1090-2139|pmid=31301401|s2cid=195848995}}</ref>


== See also == == See also ==
{{Portal|Medicine}}
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== References == == References ==
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== Further reading == == External links ==
{{refbegin}} {{Scholia|topic}}
* {{Commons category inline}}
*
*K. M. Babu, Ch. R. McCurdy, E.W. Boyer: Opioid receptors and legal highs: Salvia divinorum and Kratom, Clinical Toxicology * 46, 146-152
*E.W. Boyer, K. M. Babu, G. E. Macalino, W. Compton, Self-Treatment of Opioid With-drawal with a Dietary Supplement, Kratom, The American Journal on Addictions, 16: 352-356, 2007
*E.W. Boyer, K. M. Babu, J. E. Adkins, Ch. R. McCurdy, J. H. Halpern, Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth), Addiction, 103 *. 1048-1050, 2008
*{{Cite journal |last1=European Monitoring Centre for Drugs and Drug Addiction |title=Kratom (''Mitragyna speciosa'') |url=http://www.emcdda.europa.eu/publications/drug-profiles/kratom |accessdate=2013-03-08}}
*K. S. Grewal, Observations on the pharmacology of mitragynine, J Pharmacology and Experimental Therapeutics 1932, 46:251-71 und K. S. Grewal, The Effect of Mitragynine on Man, British Journal of Medical Psychology 1932, 12: 41-58
*http://www.usdoj.gov/dea/programs/forensicsci/microgram/mg0306/mg0306.pdf
*S. Suwanlert, A study of kratom eaters in Thailand, UNODC – Bulletin on Narcotics Vol. 27*: 21-27, 1975
*Jansen, Prast Psychoactive properties of mitragynine (kratom), ] 1988, 20*-457
*Hiromitsu Takayama: Chemistry and Pharmacology of Analgetic Indole Alkaloids from the Rubiaceous Plant, Mitragyna speciosa; Review; Chem. Pharm. Bull. 52* 916-928 *
*Suchitra Thongpradichote, et al.: Identification of opioid receptor subtypes in antino-ciceptive actions of supraspinally-administered mitragynine in mice; Life Sciences, Vol. 62, No. 16, Seite 1371-1378, 1998
*UNITED NATIONS OFFICE ON DRUGS AND CRIME, Vienna, BULLETIN ON NARCOTICS, Volume LVII, Nos. 1 and 2, 2005, S. 249-256, UNITED NATIONS New York, 2007
*Aekajit Chaiyawong: "Drugs Situation and the Drugs Information System in Thailand", Global Workshop on Drug Information Systems: Activities, Methods and Future Oppor-tunities, Wien, 3.-5. Dezember 2001, unterstützt durch das "United Nations International Drug Control Programme under the Global Assessment Programme on Drug Abuse" (GAP). United Nations, New York, 2002, Weitere Informationen sind auf der GAP Inter-netseite www.undcp.org zu finden.

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Mitragyna Speciosa}}
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Latest revision as of 20:53, 9 December 2024

Plant species, recreational drug (kratom)

Mitragyna speciosa
Conservation status

Least Concern  (IUCN 3.1)
Scientific classification Edit this 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
  • Nauclea korthalsii Steud. nom. inval.
  • Nauclea luzoniensis Blanco
  • Nauclea speciosa (Korth.) Miq.
  • Stephegyne speciosa Korth.

Mitragyna speciosa is a tropical evergreen tree of the Rubiaceae family (coffee family) native to Southeast Asia. It is indigenous to Cambodia, Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea, where its leaves, known as "kratom" have been used in herbal medicine since at least the 19th century. They have also historically been consumed via chewing, smoking, and as a tea. Kratom has opioid-like properties and some stimulant-like effects. As of 2018, the efficacy and safety of kratom are unclear. 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. Some people take it for managing chronic pain, for treating opioid withdrawal symptoms, or for recreational purposes. The onset of effects typically begins within five to ten minutes and lasts for two to five hours.

Anecdotal reports describe increased alertness, physical energy, talkativeness, sociability, sedation, changes in mood, and pain relief following kratom use at various doses. Common side-effects include appetite loss, erectile dysfunction, nausea and constipation. More severe side-effects may include respiratory depression (decreased breathing), seizure, psychosis, elevated heart rate and blood pressure, trouble sleeping, and, rarely, liver toxicity. Addiction is a possible risk with regular use: when use is stopped, withdrawal symptoms may occur. A number of deaths have been attributed to the use of kratom, both by itself and mixed with other substances. Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances.

As of 2018, kratom is a controlled substance in 16 countries. There is growing international concern about a possible threat to public health from kratom use. In some jurisdictions its sale and importation have been restricted, and several public health authorities have raised alerts.

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. The trunk is generally straight, and the outer bark is smooth and grey. The leaves, ovate-acuminate in shape and opposite in growth pattern, are dark green, glossy on their upper surfaces, and can grow to over 14–20 cm (5.5–7.9 in) long and 7–12 cm (2.8–4.7 in) wide. They have 12 to 17 pairs of veins. The spherical inflorescences, which are deep yellow, grow in clusters of three at the ends of the branches. 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.

Mitragyna speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea. 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.

Uses of the leaves

Main article: Mitragynine § Uses
Mitragyna speciosa
Powder produced from unspecified tissues of the plant
Part(s) of plantLeaves
Geographic originSoutheast Asia
Active ingredients
Main producers
Main consumersWorldwide (No. 1: Thailand)
Legal status
  • AU: S8
  • BR: Class E (Controlled plants)
  • CA: Unscheduled (Not authorized for sale or use), legal for religious use, such as incense

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. The U.S. Drug Enforcement Administration (DEA) stated in 2013 that there is no legitimate medical use for kratom, 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.

Kratom is commonly ingested by chewing, as a tea, powdered in capsules or pills, or extracted for use in liquids. Kratom is rarely smoked. Different varieties of kratom contain different relative proportions of alkaloids such as mitragynine.

Traditional use

In cultures where the plant grows, kratom 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. 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. They are also used as intestinal deworming agents in Thailand.

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

Opioid withdrawal

Because the withdrawal effects of kratom are often reported to be less severe than those associated with traditional opioids, some people use kratom in the attempt to manage opioid use disorder, though no clinical trials have been done supporting this use. As of 2018, there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction. Kratom is not approved for this or any other medical use. Stanciu et al. conducted a review of all literature and found insufficient evidence for any conclusions concerning whether kratom is harmful or whether can serve as harm reduction for those with opioid addiction. While some literature reviews claim that kratom has less potential for dependence or overdose than traditional opioids, other reviews note that kratom withdrawal itself can still be quite severe.

Data on how widely it is used worldwide are lacking, as it is not detected by typical drug screening tests. 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 opioid use.

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 19th century.

Recreational uses

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

According to the U.S. DEA and a 2020 survey, kratom is used to alleviate pain, anxiety, depression, or opioid withdrawal.

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

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

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

Adverse effects

Mitragyna speciosa may cause many adverse effects, and in November 2017 the FDA issued a public health advisory for the drug. The side effects of kratom appear to be dose-dependent and are more common with doses that exceed 8 g. 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%), seizures (6.1%), withdrawal symptoms (6.1%), hallucinations (4.8%), respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%). The study also reported two deaths and four cases of neonatal abstinence syndrome. A different 2019 review listed as common side effects: decreased appetite, weight loss, erectile dysfunction, insomnia, sweating, hyperpigmentation, hair loss, tremor, and constipation.

Kratom products in the U.S. are commonly used in doses of 2–6 g of dried leaf, and doses exceeding 8 g are relatively uncommon. Given that kratom products may vary greatly in potency, there is no standard dosing system. 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 such as itching, nausea, loss of appetite, and increased urination begin to appear. 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.

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 libido, insomnia, muscle spasms, muscle and bone pain, myoclonus, watery eyes, hot flashes, fever, diarrhea, restlessness, anger, and sadness. This may lead to resumption of use.

Frequent use of high doses of kratom may cause tremors, anorexia, weight loss, seizures, psychosis and other mental health conditions. Kratom use may worsen existing mental health conditions. In case reports associating kratom use with psychosis, it remains unclear whether kratom use directly caused psychosis or simply unmasked the condition. Serious toxicity is relatively rare and generally appears at high doses or when kratom is used with other substances. Herb–drug interactions may result when kratom is combined with alcohol, sedatives, benzodiazepines, opioids, caffeine, cocaine, yohimbine, or monoamine oxidase inhibitors (MAOIs). Rhabdomyolysis is one of the rare and serious complications of this herb at high dosage.

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. 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.

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

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.

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

Addiction

Kratom is a botanical with a known addiction liability and, in vulnerable individuals, dependence may develop rather quickly with tolerance noted at three months and four- to ten-fold dose escalations required within the first few weeks. A survey by Stanciu et al. of kratom consumers found that 25.5% of respondents reported symptoms consistent with a substance use disorder diagnosis based on the Diagnostic and Statistical Manual's criteria. After controlling for variables such as age, gender, daily kratom use frequency, and a history of substance use disorders or mental health conditions, individuals with a concurrent diagnosis of another SUD had 2.83 times the odds of meeting criteria for kratom addiction compared to those without a concurrent substance use disorder diagnosis. Kratom addiction carries a relapse risk as high as 78% to 89% at three months post-cessation. In cases of severe addiction, an approach similar to the treatment of opioid addiction may be warranted.

Respiratory depression

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

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. Liver injury has been reported with a latency (time from first use to the 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 patterns. 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.

Death

Kratom overdose is a subject of concern in many countries because of the associated rising number of hospitalizations and deaths in which chronic kratom use is a contributing factor. According to clinical reviews, a kratom overdose can cause liver toxicity, seizures, coma, and death, especially in combination with excessive alcohol use. Between 2011 and 2017, 44 U.S. deaths were kratom-related. However, many cases could not be fully assessed, due to limited information. People who die from kratom use typically have taken it in combination with other substances, or have underlying health conditions.

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. Nine deaths occurred in Sweden during 2010–11 relating to use of Krypton, a mixture of kratom, caffeine and O-desmethyltramadol, a metabolite of the opioid analgesic tramadol.

Pharmacology

Mitragyna speciosa alkaloids at opioid receptors
Compound Affinities (Ki (nM)Tooltip Inhibitor constant) Ratio Ref
MORTooltip μ-Opioid receptor DORTooltip δ-Opioid receptor KORTooltip κ-Opioid receptor MOR:DOR:KOR
7-Hydroxymitragynine 13.5 155 123 1:11:9
Mitragynine 7.24 60.3 1,100 1:8:152
Mitragynine pseudoindoxyl 0.087 3.02 79.4 1:35:913

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

The effects of both mitragynine and 7-HMG remain disputed despite substantial study. Both are partial agonists of the μ-opioid receptor. While most data indicates agonism at all three opioid receptors, other data suggests the alkaloids are antagonists of the δ-opioid receptor with low affinity for the κ-opioid receptor. 7-HMG appears to have higher affinity at the μ-opioid receptor than mitragynine. 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. Both mitragynine and 7-HMG readily cross the blood-brain barrier.

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. 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. Kratom also contains rhynchophylline, a non-competitive NMDA receptor antagonist.

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

Chemistry

Main article: Mitragynine

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. 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. At least 40 other compounds have been isolated from M. speciosa leaves, including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from Rauvolfia serpentina), corynantheidine (also found in Corynanthe johimbe), as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline.

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. 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.

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. 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.

Regulation

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

In 2021, the World Health Organization's Executive Committee on Drug Dependency investigated the risks of kratom and declined to recommend a critical review of it. The committee, however, recommended kratom be kept "under surveillance."

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.

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) in New Zealand.

Canada

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

Europe

As of 2011, the plant was controlled in Denmark, Latvia, Lithuania, Poland, Romania, and Sweden.

Kratom is a controlled substance in Bulgaria.

The sale, import, and export of kratom have been prohibited in the UK since 2016 under the Psychoactive Substances Act.

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.

Indonesia

Kratom was previously scheduled to become an illegal substance in Indonesia in 2024 once new regulations from the Indonesian National Narcotics Agency (BNN) go into effect. However, in 2024, a revision to a regulation by Ministry of Trade legalized production and export of kratom leaves. Later in September 2024, Indonesia's Ministry of Cooperatives and Small Medium Business stated that Indonesia will start building downstream industries for kratom exports. These developments made kratom legal to export and manufacture in Indonesia.

Malaysia

The use of kratom leaves, known locally as ketum or Biak is prohibited to use, import, export, manufacture, compound, mix, dispense, sell, supply, administer or possess in Malaysia under Section 30(3) of the Poisons Act 1952, and will be punished by imprisonment or fine or both. Although prohibited by statute, the use of kratom remains widely spread especially in Northern and East Coast region of Malaysia's Peninsula because the tree grows natively and tea decoctions are readily available in local communities. 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.

Thailand

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

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

United States

In 2014, the United States Food and Drug Administration (FDA) banned the import of kratom into the U.S. due to a lack of evidence for its safety. As of 2021, kratom is illegal in six states: Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin, and it may be outlawed by local ordinance in other states. There was consideration in late 2017 to make kratom a Schedule I drug. In 2019, the FDA warned consumers that kratom remains unapproved for interstate commerce for use as a drug, may be unsafe in commercially available products, and is on an import alert, which can lead to confiscation of imported supplies. Efforts to schedule kratom generated significant controversy, both among the general public and the scientific community, and were ultimately unsuccessful.

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

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. 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. 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.

Although it was a federally legal dietary supplement, kratom was not approved as a therapeutic agent in the United States due to the poor quality of the research. 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."

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. This drew strong protests among those using kratom to deal with chronic pain or wean themselves off opioids or alcohol. 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.

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." In October 2016, the DEA withdrew its notice of intent while inviting public comments over a review period ending on December 1, 2016. As of July 2016, Alabama, Arkansas, Indiana, Vermont, and Wisconsin had made kratom illegal, and the US Army had forbidden soldiers from using it. 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.

Public response

The FDA's arguments for the federal prohibition of kratom have drawn both criticism and support. 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." 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 data." The FDA's position on kratom has also been criticized by the American Kratom Association and researchers including Walter Prozialeck. 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, though Gottlieb's partiality has been called into question as he has since gone on to become a member of the board of directors of Pfizer Inc., a company that has been heavily criticized for its sale and marketing of opioid drugs.

Research directions

Kratom is under preliminary research for possible antipsychotic and antidepressant properties.

See also

References

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Scholia has a topic profile for Mitragyna speciosa.
Opioid receptor modulators
μ-opioid
(MOR)
Agonists
(abridged;
full list)
Antagonists
δ-opioid
(DOR)
Agonists
Antagonists
κ-opioid
(KOR)
Agonists
Antagonists
Nociceptin
(NOP)
Agonists
Antagonists
Others
  • Others: Kyotorphin (met-enkephalin releaser/degradation stabilizer)
Taxon identifiers
Mitragyna speciosa
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