View source for Biology:Mitragyna speciosa

{{Short description|Plant species, recreational drug (kratom)}}
{{Speciesbox
| image = Mitragyna speciosa111.JPG
| status = LC
| status_system = IUCN3.1
| 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>
| genus = Mitragyna
| species = speciosa
| authority = (Korth.) Havil.
| synonyms = * ''Nauclea korthalsii'' Steud. nom. inval.
* ''Nauclea luzoniensis'' Blanco
* ''Nauclea speciosa'' (Korth.) Miq.
* ''Stephegyne speciosa'' Korth.
| synonyms_ref = <ref>[http://www.theplantlist.org/tpl/record/kew-128805 ''Mitragyna speciosa'' (Korth.) Havil. is an accepted name ]. Theplantlist.org. Retrieved 2013-12-26.</ref>
}}

<!-- Definition and description -->
'''''Mitragyna speciosa''''' (commonly known as '''kratom''', an herbal leaf from a tree of the [[Biology:Rubiaceae|Rubiaceae]] family<ref>{{cite web|url=https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/rubiaceae |title=Rubiaceae - an overview &#124; ScienceDirect Topics |publisher=Sciencedirect.com |date=2016-01-01 |accessdate=2022-08-25}}</ref><ref name="GRIN">{{GRIN | access-date = 2013-12-26}}</ref>) is a tropical [[Biology:Evergreen|evergreen]] tree in the [[Biology:Rubiaceae|coffee family]] native to [[Place:Southeast Asia|Southeast Asia]]. It is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea,<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 it has been used in [[Medicine:Herbal medicine|herbal medicine]] 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> It has also historically been used for chewing, smoking, and 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 opiate properties and some [[Chemistry:Stimulant|stimulant]]-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. Although it was a federally legal dietary supplement, it was not approved as a [[Medicine:Prescription drug|therapeutic agent]] in the United States due to the poor quality of the research.<ref name=warner>{{cite journal |vauthors=Warner ML, Kaufman NC, Grundmann O |title=The pharmacology and toxicology of kratom: from traditional herb to drug of abuse |journal=Int. J. Legal Med. |volume=130 |issue=1 |pages=127–38 |year=2016 |pmid=26511390 |doi=10.1007/s00414-015-1279-y |s2cid=2009878 |type=Review}}</ref><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 [[Organization:Food and Drug Administration|Food and Drug Administration]] (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 [[Medicine:Chronic pain|chronic pain]], for treating [[Chemistry:Opioid withdrawal|opioid withdrawal]] symptoms, or for recreational purposes.<ref name=Rech2015/><ref name=warner/> The onset of effects typically begins within five to ten minutes and lasts for two to five hours.<ref name="Rech2015" />

<!-- Side effects -->
[[Anecdotal evidence|Anecdotal reports]] describe increased alertness, physical energy, talkativeness, sociability, sedation, changes in mood, and pain relief following kratom use at various doses.<ref name="warner" /> Common side effects include appetite loss, [[Medicine:Erectile dysfunction|erectile dysfunction]], nausea and [[Medicine:Constipation|constipation]].<ref name=corkery/> More severe side effects may include respiratory depression (decreased breathing), seizure, [[Medicine:Addiction|addiction]], and [[Medicine:Psychosis|psychosis]].<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=9781455749874|pages=2015–23|edition=Eighth|chapter=Chapter 156: Hallucinogens|chapter-url=https://books.google.com/books?id=uggC0i_jXAsC&pg=RA2022}}</ref> Other side effects may include high heart rate and blood pressure, trouble sleeping, and, rarely, [[Medicine:Hepatotoxicity|liver toxicity]].<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}}</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> When use is stopped, [[Medicine:Drug withdrawal|withdrawal]] 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/>

<!-- Society and culture -->
In 2014, the FDA banned the import of the legal dietary supplement kratom into the U.S. due to lack of evidence for its safety.<ref name="FDAImportAlert">{{cite web|url=http://www.accessdata.fda.gov/cms_ia/importalert_1137.html|title=Import Alert 54-15; Detention without physical examination of dietary supplements and bulk dietary ingredients that are or contain ''Mitragyna speciosa'' or kratom|date=20 December 2016|publisher=U.S. Food and Drug Administration|access-date=7 March 2018}}</ref> {{asof|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|url= https://health.clevelandclinic.org/what-is-kratom/|title= What is Kratom?|date= June 30, 2021|website= Cleveland Clinic|access-date= July 8, 2023}}</ref> 

As of 2018, kratom is a [[Chemistry:Controlled substance|controlled substance]] in 16 countries.<ref name="FDA2018" /> 
{{As of|2018}}, there is growing international concern about a possible threat to public health from kratom use, while others have argued that it could be a tool to help the opioid crisis.<ref>{{cite web | url=https://www.nccih.nih.gov/research/blog/april-25-lecture-to-explore-kratoms-therapeutic-potential-in-opioid-addiction | title=April 25 Lecture to Explore Kratom's Therapeutic Potential in Opioid Addiction }}</ref><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 2021, the [[Organization:World Health Organization|World Health Organization]]'s Executive Committee on Drug Dependency investigated the risks of kratom and declined to recommend a ban following a scientific review.<ref>{{cite web | url=https://filtermag.org/who-kratom-ban/ | title=World Health Organization Decides Not to Call for Global Kratom Ban | date=8 December 2021 }}</ref><ref>{{cite web | url=https://www.marijuanamoment.net/united-nations-panel-rejects-international-kratom-ban/ | title=United Nations Panel Rejects International Kratom Ban | date=7 December 2021 }}</ref> 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> In some jurisdictions, its sale and importation have been restricted, and several public health authorities have raised alerts.<ref name=warner/><ref name=EMCDDA/>

== Description ==
[[File:Kratom leaves.jpg|alt=Kratom has dark green oval-acuminate leaves and yellow globular flowers.|thumb|Kratom flowers and foliage]]
''Mitragyna speciosa'' is an evergreen tree in the genus ''[[Biology:Mitragyna|Mitragyna]]'' 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 [[Biology:Sepal|calyx]]-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 [[Place:Dutch Empire|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.<ref name="Eisenman" />{{rp|59}}

==Uses==
{{Infobox botanical product
|image         = Powdered kratom.jpg
|caption       = Powder produced from unspecified tissues of the plant
|title         = Kratom
|product       =
|plant         = 
|part          = Leaves
|origin        = [[Place:Southeast Asia|Southeast Asia]]<ref name=EMCDDA />
|active        = {{flatlist|
* [[Chemistry:Mitragynine|Mitragynine]]<ref name=warner/>
* 7-hydroxymitragynine<ref name=warner/>
* Other alkaloids<ref name=warner/>
* Raubasine<ref name=warner/>
* and more than 40 other compounds<ref name="Adkins 2011-05-01" />
}}
|producers     = {{hlist|Indonesia<ref name=EMCDDA />|Thailand<ref name=Hassan2013 />}}
|consumers     = Worldwide (No. 1: Thailand)<ref name=EMCDDA /><ref name=Hassan2013 />
|wholesale     = 
|retail        =  {{ubl
|€6–15 per 10g  (EU; {{As of|2011|lc=y}})<ref name=EMCDDA />
|$0.70-5 per 10g  (US; {{As of|2022|lc=y}})
}}
|legal_BR = E
|legal_CA      = Not authorized for sale or use<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>
|legal_EU      = Illegal in {{wipe|Denmark}}, Republic of Ireland, Latvia, Lithuania, {{wipe|Poland}}, Romania and Sweden<ref name=EMCDDA />
|legal_US      = Drug of concern,<ref name=Hassan2013 /> subject to import bans,<ref name=FDAImportAlert /> and sale for consumption is illegal<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      = 
|legal_status  = Illegal in Malaysia, Myanmar, and [[Earth:New Zealand|New Zealand]]<ref name=EMCDDA /><ref name=Hassan2013 />
}}
[[Image:Kratom leafes.jpg|thumb|right|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.<ref name="Hassan2013" /> The U.S. [[Organization:Drug Enforcement Administration|Drug Enforcement Administration]] (DEA) stated in 2013 that there is no legitimate medical use for kratom,<ref name="usdea" /> and in 2019, the U.S. [[Organization:Food and Drug Administration|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 [[Medicine:Approved drug|approved clinical uses]] for kratom.<ref name="fda4-3-19" />

Kratom is commonly ingested by chewing, drunk as a tea, powdered in [[Medicine:Capsule (pharmacy)|capsules or pills]], or [[Chemistry:Extract|extract]]ed for use in liquids.<ref name="Hassan2013"/> Kratom is rarely smoked.<ref name="EMCDDA" /> Different varieties of kratom contain different relative proportions of [[Chemistry:Alkaloid|alkaloid]]s such as [[Chemistry:Mitragynine|Mitragynine]].<ref name="warner" />

===Traditional use===
In cultures where the plant grows, kratom has been used in [[Medicine:Traditional medicine|traditional medicine]].<ref name=Cin2015 /> The leaves are chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire in ways similar to [[Biology:Khat|khat]] and [[Chemistry:Coca|coca]].<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 professions 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>

===Opioid withdrawal===
{{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" /> However, 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 [[Medicine:Opioid use disorder|opioid use disorder]].<ref name=":2" /> 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 [[Literature review|literature review]]s claim that kratom has less potential for [[Medicine:Substance dependence|dependence]] or [[Medicine:Drug overdose|overdose]] 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" />

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"/>

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" />

===Recreational uses===
At low doses, kratom produces [[Chemistry:Euphoria|euphoric]] effects comparable to [[Chemistry:Coca|coca]].<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, [[Social:Social behavior|sociability]], increased sexual desire, positive mood, and [[Chemistry:Euphoria|euphoria]] 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 [[Chemistry:Opioid withdrawal|opioid withdrawal]].<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>

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" />

Kratom may be mixed with other psychoactive drugs, such as [[Biology:Caffeine|caffeine]] and [[Chemistry:Codeine|codeine]].<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=9781439861479|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, cough syrup, [[Engineering:Coca-Cola|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 [[Chemistry:Heroin|heroin]].<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 yaba 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>

In the U.S., {{as of|2015|lc=y}}, 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.<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>

==Adverse effects==

''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 [[Chemistry:Dose–response relationship|dose-dependent]] and are more common with doses that exceed 8 g.<ref name=":3" /> While the [[Medicine:Incidence (epidemiology)|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%), [[Medicine:Tachycardia|tachycardia]] (16.9%), [[Medicine:Somnolence|drowsiness]] (13.6%), [[Medicine:Vomiting|vomiting]] (11.2%), [[Medicine:Confusion|confusion]] (8.1%), [[Medicine:Seizure|seizure]] (6.1%), [[Medicine:Drug withdrawal|withdrawal]] (6.1%), [[Unsolved:Hallucination|hallucination]]s (4.8%), respiratory depression (2.8%), [[Medicine:Coma|coma]] (2.3%), and [[Medicine:Cardiac arrest|cardiac]] or [[Medicine:Respiratory arrest|respiratory arrest]] (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 neonatal abstinence syndrome.<ref name=":5" /> A different 2019 review listed as common side effects: decreased appetite, anorexia, weight loss, temporary erectile dysfunction, insomnia, sweating, hyperpigmentation, hair loss, tremor, and constipation.<ref name=corkery/>

Kratom products in the U.S. are commonly used in doses ranging from 2–6 g of dried leaf per dose, 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 like 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 [[Medicine:Tachycardia|tachycardia]] (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 sexual drive, trouble sleeping, muscle spasms, muscle and bone pain, [[Medicine:Myoclonus|myoclonus]], watery eyes, hot flushes, fever, diarrhea, 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, [[Medicine:Seizure|seizure]]s, and psychosis.<ref name=warner/> However, 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/> [[Medicine:Drug interaction|Herb-drug interactions]] may result when kratom is combined with [[Chemistry:Alcoholic drink|alcohol]], [[Chemistry:Sedative|sedative]]s, [[Chemistry:Benzodiazepine|benzodiazepine]]s, [[Chemistry:Opioid|opioid]]s, [[Biology:Caffeine|caffeine]], [[Biology:Cocaine|cocaine]], [[Chemistry:Yohimbine|yohimbine]], or [[Biology:Monoamine oxidase inhibitor|monoamine oxidase inhibitor]]s (MAOIs).<ref name=":4" /> [[Medicine:Rhabdomyolysis|Rhabdomyolysis]] 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=Cureus |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 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.<ref name=cdc/> One death was reported in a person who was exposed to the medications [[Chemistry:Paroxetine|paroxetine]] (an [[Chemistry:Antidepressant|antidepressant]]) and [[Chemistry:Lamotrigine|lamotrigine]] (an [[Chemistry:Anticonvulsant|anticonvulsant]] and mood stabilizer) in addition to kratom.{{fact|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 (AAPCC) 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 [[Chemistry:Fentanyl|fentanyl]] and [[Chemistry:List of fentanyl analogues|fentanyl analogs]] being the most frequently identified co-occurring substances.<ref name="cdc2019" />

Overdoses of kratom are managed similarly to [[Medicine:Opioid overdose|opioid overdose]]s, and [[Chemistry:Naloxone|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.<ref name= Rech2015/>

From October 2017 to February 2018 in the United States, 28 people in 20 different states were infected with [[Biology:Salmonella|salmonella]], an [[Medicine:Outbreak|outbreak]] 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,[5],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 [[Biology:Whole genome sequencing|whole genome sequencing]] 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 3 months and 4- to 10-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> Kratom addiction carries a relapse risk as high as 78% to 89% at 3 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, a similar approach to 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===
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= 9781482225181|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 {{asof|lc=yes|2016}} the Food and Drug Administration listed respiratory depression as a concern.<ref name=white/><ref name=FDAImportAlert/> 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, itching and [[Medicine:Jaundice|jaundice]].<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 onset of symptoms) of median 20.6 days. Reported liver biopsies tend to show [[Medicine:Cholestasis|cholestasis]]; however, blood biomarkers can show a range of cholestatic, mixed, or hepatocellular injury pattern.<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 [[Medicine:Hepatotoxicity|liver toxicity]], seizures, [[Medicine:Coma|coma]], 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 O-desmethyltramadol, a metabolite of the opioid analgesic [[Chemistry:Tramadol|tramadol]].<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" | Affinities ({{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
|-
| [[Chemistry:7-Hydroxymitragynine|7-Hydroxymitragynine]] || 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>
|-
| [[Chemistry:Mitragynine|Mitragynine]] || 7.24 || 60.3 || 1,100 || 1:8:152 || <ref name="pmid11960505" />
|-
| [[Chemistry:Mitragynine pseudoindoxyl|Mitragynine pseudoindoxyl]] || 0.087 || 3.02 || 79.4 || 1:35:913 || <ref name="pmid11960505" />
|}

Kratom contains at least 54 [[Chemistry:Alkaloid|alkaloid]]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 [''Mitragyna speciosa'']: 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 [[Chemistry:Mitragynine|mitragynine]], [[Chemistry:7-Hydroxymitragynine|7-hydroxymitragynine]] (7-HMG), [[Chemistry:Speciociliatine|speciociliatine]], paynantheine, corynantheidine, speciogynine, [[Chemistry:Mitraphylline|mitraphylline]], [[Chemistry:Rhynchophylline|rhynchophylline]], mitralactonal, [[Chemistry:Ajmalicine|raubasine]], 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 synergistically.<ref name=":3" />

Both mitragynine and 7-HMG are [[Chemistry:Partial agonist|partial agonist]]s of the [[Biology:Μ-opioid receptor|μ-opioid receptor]] and competitive [[Biology:Receptor antagonist|antagonists]] of the [[Biology:Δ-opioid receptor|δ-opioid receptor]] with low affinity for the [[Biology:Κ-opioid receptor|κ-opioid receptor]].<ref name=":3" /><ref name=":4" /> 7-HMG appears to have higher affinity at the μ-opioid receptor than mitragynine.<ref name="Kruegel" /><ref name="white" /> These compounds display [[Biology:Functional selectivity|functional selectivity]] and do not activate the [[Biology:Arrestin|β-arrestin]] pathway partly responsible for the respiratory depression, constipation, and sedation associated with traditional [[Chemistry:Opioid|opioid]]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 [[Biology:Blood–brain barrier|blood-brain barrier]].<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 [[Biology:COX-2 inhibitor|inhibit COX-2]], block [[Biology:L-type calcium channel|L-type]] and [[Biology:T-type calcium channel|T-type]] [[Biology:Voltage-gated calcium channel|calcium channels]], and interact with other receptors in the brain including [[Biology:5-HT2C receptor|5-HT<sub>2C</sub>]] and [[Biology:5-HT7 receptor|5-HT<sub>7</sub>]] [[Biology:5-HT receptor|serotonin receptors]], [[Biology:Dopamine receptor D2|D<sub>2</sub>]] [[Biology:Dopamine receptor|dopamine receptor]]s, and A<sub>2A</sub> [[Biology:Adenosine receptor|adenosine receptor]]s.<ref name=":3" /> Mitragynine stimulates [[Biology:Alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]]s, inhibiting the release of [[Biology:Norepinephrine|norepinephrine]] (noradrenaline); other compounds in this class include [[Chemistry:Dexmedetomidine|dexmedetomidine]], which is used for sedation, and [[Chemistry:Clonidine|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.<ref name="white" /> Kratom also contains [[Chemistry:Rhynchophylline|rhynchophylline]], a non-competitive [[Chemistry:NMDA receptor antagonist|NMDA receptor antagonist]].<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 [[Biology:Metabolism|metabolized]] in humans via phase I and phase II mechanisms with the resulting [[Biology:Metabolite|metabolite]]s excreted in [[Biology:Urine|urine]].<ref name="warner" /> In ''[[In vitro|in vitro]]'' experiments, kratom extracts [[Biology:Enzyme inhibitor|inhibit]]ed [[Biology:CYP3A4|CYP3A4]], [[Biology:CYP2D6|CYP2D6]], and [[Biology:CYP1A2|CYP1A2]] [[Biology:Enzyme|enzyme]]s, which results in significant potential for [[Medicine:Drug interaction|drug interaction]]s.<ref name="warner" />

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

Many of the key psychoactive compounds in ''M. speciosa'' are [[Chemistry:Indole alkaloid|indole alkaloid]]s related to [[Chemistry:Mitragynine|mitragynine]], which is a tetracyclic relative of the pentacyclic indole alkaloids, [[Chemistry:Yohimbine|yohimbine]] and [[Chemistry:Voacangine|voacangine]].<ref name="warner" /> In particular, mitragynine and 7-hydroxymitragynine (7-HMG) compose significant proportions of the [[Chemistry:Natural product|natural product]]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=9780124158160 |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> In addition, at least 40 other compounds have been isolated from ''M. speciosa'' leaves,<ref name="Adkins 2011-05-01" /> including ~25 additional [[Chemistry:Alkaloid|alkaloid]]s, including [[Chemistry:Ajmalicine|raubasine/ajmalicine]] (originally isolated from ''[[Biology:Rauvolfia serpentina|Rauvolfia serpentina]]''), corynantheidine (also found in ''[[Biology:Corynanthe johimbe|Corynanthe johimbe]]''),<ref name="pmid11960505" /> as well as [[Chemistry:Mitraphylline|mitraphylline]], [[Chemistry:Mitragynine pseudoindoxyl|mitragynine pseudoindoxyl]], and [[Chemistry:Rhynchophylline|rhynchophylline]].<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 [[Chemistry:Alkaloid|alkaloid]]s, ''M. speciosa'' produces many other [[Biology:Secondary metabolite|secondary metabolite]]s. These include various [[Chemistry:Saponin|saponin]]s, [[Chemistry:Iridoid|iridoid]]s and other [[Chemistry:Monoterpene|monoterpenoids]], [[Chemistry:Triterpene|triterpenoids]] such as [[Chemistry:Ursolic acid|ursolic acid]] and [[Chemistry:Oleanolic acid|oleanic acid]], as well as various [[Chemistry:Polyphenol|polyphenol]]s including the [[Chemistry:Flavonoid|flavonoid]]s [[Chemistry:Apigenin|apigenin]] and [[Chemistry:Quercetin|quercetin]].<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=9780128194874 |issn=1572-5995 |s2cid=234947828}}</ref> Although some of these compounds possess [[Biology:Analgesic|antinociceptive]], [[Chemistry:Anti-inflammatory|anti-inflammatory]], [[Biology:Gastrointestinal tract|gastrointestinal]], [[Chemistry:Antidepressant|antidepressant]], [[Biology:Antioxidant|antioxidant]], and [[Chemistry:Antibiotic|antibacterial]] 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==
{{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/>

===ASEAN===
{{As of|2013}}, kratom was listed by [[Organization:ASEAN|ASEAN]] 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===
{{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}}, [[Organization:Health Canada|Health Canada]] 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|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 could 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 |last=OnlineMarketing.bg |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 Psychoactive Substances Act.<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 Republic of Ireland, under the names 7-hydroxymitragynine and [[Chemistry:Mitragynine|mitragynine]].<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 is 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> This pending ban has been in place since 2019; the date of the ban going into effect was pushed out to 2024 to give Kratom farmers time to switch to other crops. Notably, this ban would likely devastate the Kratom supply in the United States, since almost all of America's Kratom is supplied via Indonesian exports.{{citation needed|date=September 2021}}

===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">[https://web.archive.org/web/20121029094717/http://www.themalaysianinsider.com/malaysia/article/pengasih-wants-abuse-of-kratom-leaves-penalised-under-dangerous-drugs-act/ Pengasih wants abuse of kratom leaves penalised under Dangerous Drugs Act]. The Malaysian Insider. October 28, 2012.</ref>

===Thailand===
Possession of kratom leaves ({{lang-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}}</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|last=<!--Check author names-->|first=|title=Parliament votes to remove kratom from narcotics list|work=Bangkok Post|url=https://www.bangkokpost.com/thailand/general/2058139/parliament-votes-to-remove-kratom-from-narcotics-list|access-date=2021-06-22}}</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===
In the United States, there was consideration in late 2017 to make kratom a Schedule I 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 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|language=en}}</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|language=en-US}}</ref><ref name=":2" />

==== 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.<ref name="fda4-3-19" />
On April 4, 2018, the FDA issued the first mandatory recall in its history over concerns of [[Biology:Salmonella|salmonella]] 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 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.<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 health care professionals and consumers to report adverse events or quality problems associated with the use of Divinity Products Distribution's products or any kratom product to the agency's online Safety Reporting Portal}}</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 />

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 [[Medicine:Opioid use disorder|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."<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 [[Organization:Drug Enforcement Administration|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.<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 Chuck Rosenberg 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={{wipe|The Washington Post}}|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}}</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 [[Organization:International Narcotics Control Board|International Narcotics Control Board]].<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 [[Medicine:Prohibition of drugs|prohibition]] 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 Commissioner of Food and Drugs Brett Giroir claimed that the FDA's recommendation to schedule kratom was rejected because of "embarrassingly poor evidence [and] data."<ref name=":7" /> The FDA's position on kratom has also been criticized by the American Kratom Association and researchers including Walter Prozialeck.<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. [[Chemistry:Opioid epidemic|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.<ref name=":7" />

== Research ==
Kratom is under preliminary research for its possible [[Chemistry:Antipsychotic|antipsychotic]] and [[Chemistry:Antidepressant|antidepressant]] 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> A study has shown that high doses of Kratom have antipsychotic-effects similar to that of [[Chemistry:Haloperidol|haloperidol]],<ref>{{Cite journal |title=Mitragyna speciosa Leaf Extract Exhibits Antipsychotic-Like Effect with the Potential to Alleviate Positive and Negative Symptoms of Psychosis in Mice |date=2016 |pmc=5138496 |last1=Vijeepallam |first1=K. |last2=Pandy |first2=V. |last3=Kunasegaran |first3=T. |last4=Murugan |first4=D. D. |last5=Naidu |first5=M. |journal=Frontiers in Pharmacology |volume=7 |page=464 |doi=10.3389/fphar.2016.00464 |pmid=27999544 |doi-access=free }}</ref> however it should be noted Kratom affects everyone differently. Survey studies found that some people use kratom as a self-treatment strategy for conditions such as [[Medicine:Opioid use disorder|opioid use disorder]], [[Medicine:Pain|acute pain]], [[Medicine:Chronic pain|chronic pain]], and various mental health conditions, including [[Medicine:Anxiety|anxiety]], ADHD and [[Medicine:Depression (mood)|depression]].<ref name=":1" /><ref>{{Cite journal|last1=Covvey|first1=Jordan R.|last2=Vogel|first2=Samantha M.|last3=Peckham|first3=Alyssa M.|last4=Evoy|first4=Kirk E.|date=2020|title=Prevalence and characteristics of self-reported kratom use in a representative US general population sample|journal=Journal of Addictive Diseases|volume=38|issue=4|pages=506–513|doi=10.1080/10550887.2020.1788914|issn=1545-0848|pmid=32657217|s2cid=220499407}}</ref><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> Kratom is also being studied in order to [[Drug design|design]] novel drugs for treating [[Medicine:Pain|pain]], [[Medicine:Opioid use disorder|opioid use disorder]], and [[Medicine:Alcoholism|alcohol use disorder]].<ref>{{Cite journal|last1=Kudla|first1=Lucja|last2=Przewlocki|first2=Ryszard|date=2021-04-09|title=Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors|journal=Pharmacological Reports |volume=73|issue=4|pages=1033–1051|doi=10.1007/s43440-021-00251-1|issn=1734-1140|pmid=33835467|pmc=8413226|doi-access=free}}</ref> Further clinical research is necessary to corroborate anecdotal reports of kratom as an effective treatment for chronic pain, and to determine whether it is a safe or effective treatment for illness.<ref>{{cite web|publisher=National Institute on Drug Abuse, US National Institutes of Health|title=Kratom DrugFacts|url=https://www.drugabuse.gov/publications/drugfacts/kratom|access-date=17 June 2021|date=1 April 2019}}</ref><ref>{{Cite journal|last1=Prevete|first1=Elisabeth|last2=Kuypers|first2=Kim Paula Colette|last3=Theunissen|first3=Eef Lien|last4=Corazza|first4=Ornella|last5=Bersani|first5=Giuseppe|last6=Ramaekers|first6=Johannes Gerardus|date=2021-07-26|title=A systematic review of (pre)clinical studies on the therapeutic potential and safety profile of kratom in humans|journal=Human Psychopharmacology|volume=37|issue=1|pages=e2805|doi=10.1002/hup.2805|issn=1099-1077|pmid=34309900|pmc=9285932 |doi-access=free}}</ref>

== See also ==
* ''[[Biology:Pausinystalia johimbe|Pausinystalia johimbe]]''

== References ==
{{reflist|colwidth=30em}}

== External links ==

{{Opioidergics}}
{{Taxonbar|from=Q139698}}

[[Category:Anxiolytics]]
[[Category:Antidepressants]]
[[Category:Euphoriants]]
[[Category:Medicinal plants]]
[[Category:Opioids]]
[[Category:Naucleeae]]

{{Sourceattribution|Mitragyna speciosa}}