{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:58:30Z","timestamp":1789153110166,"version":"build-2803163510"},"reference-count":129,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:p>Kratom or <jats:italic>Mitragyna speciosa<\/jats:italic> (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits \u03b1<jats:sub>1<\/jats:sub>-adrenceptors preferentially over \u03b1<jats:sub>2<\/jats:sub>-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT<jats:sub>2A<\/jats:sub> receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.<\/jats:p>","DOI":"10.3389\/fpsyt.2021.640218","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T05:25:40Z","timestamp":1617168340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant"],"prefix":"10.3389","volume":"12","author":[{"given":"Alessandro E.","family":"Vento","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"de Persis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"De Filippis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Schifano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Napoletano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Corkery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios D.","family":"Kotzalidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,31]]},"reference":[{"key":"B1","first-page":"482","article-title":"Les alcalo\u00efdes du Mitragyna speciosa Korthals [The alkaloids of Mitragyna speciosa Korthals\u2013French]","volume":"8","author":"Raymond-Hamet","year":"1950","journal-title":"Ann Pharm Fr."},{"key":"B2","first-page":"594","article-title":"Les alcalo\u00efdes des Mitragyna [The alkaloids of Mitragyna]","volume":"11","author":"Ongley","year":"1953","journal-title":"Ann Pharm Fr."},{"key":"B3","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1055\/s-0028-1100122","article-title":"The Mitragyna species of Asia. V The anatomy of the leaves of Mitragyna speciosa","volume":"13","author":"Shellard","year":"1965","journal-title":"Korth Planta Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1111\/j.2042-7158.1965.tb07599.x","article-title":"Alkaloids from Mitragyna speciosa (Korth","volume":"17","author":"Beckett","year":"1965","journal-title":"J Pharm Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1055\/s-0028-1100055","article-title":"The Mitragyna species of Asia. VII Indole alkaloids from the leaves of Mitragyna speciosa Korth","volume":"14","author":"Beckett","year":"1966","journal-title":"Planta Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1055\/s-0028-1100054","article-title":"The Mitragyna species of Asia. VI. Oxindole alkaloids from the leaves of Mitragyna speciosa Korth","volume":"14","author":"Beckett","year":"1966","journal-title":"Planta Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.brainresbull.2016.05.004","article-title":"Traditional and non-traditional uses of Mitragynine (Kratom): a survey of the literature","volume":"126","author":"Singh","year":"2016","journal-title":"Brain Res Bull."},{"key":"B8","first-page":"1095","article-title":"Some medicinal products from the straits settlements","volume":"54","author":"Holmes","year":"1895","journal-title":"Pharm J."},{"key":"B9","first-page":"1480","volume-title":"A Dictionary of the Economic Products of the Malay Peninsula, Vol. II","author":"Burkill","year":"1935"},{"key":"B10","first-page":"453","article-title":"Notes on the anti-opium remedy","volume":"78","author":"Wray","year":"1907","journal-title":"Pharm J."},{"key":"B11","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.neubiorev.2012.11.012","article-title":"From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction","volume":"37","author":"Hassan","year":"2013","journal-title":"Neurosci Biobehav Rev."},{"key":"B12","first-page":"21","article-title":"A study of kratom eaters in Thailand","volume":"27","author":"Suwanlert","year":"1975","journal-title":"Bull Narc."},{"key":"B13","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1080\/02791072.1988.10472519","article-title":"Psychoactive properties of mitragynine (kratom)","volume":"20","author":"Jansen","year":"1988","journal-title":"J Psychoactive Drugs."},{"key":"B14","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/s0021-9673(01)80520-3","article-title":"The quantitative determination of some mitragyna oxindole alkaloids after separation by thin-layer chromatography. I Ultraviolet spectrophotometry","volume":"32","author":"Shellard","year":"1968","journal-title":"J Chromatogr."},{"key":"B15","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/s0021-9673(01)80521-5","article-title":"The quantitative determination of some mitragyna oxindole alkaloids after separation by thin-layer chromatography. II Colorimetry, using the Vitali-Morin reaction","volume":"32","author":"Shellard","year":"1968","journal-title":"J Chromatogr."},{"key":"B16","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/s0021-9673(00)98661-8","article-title":"The quantitative determination of some mitragyna oxindole alkaloids after separation by thin layer chromatography. I. Ultraviolet spectrophotometry","volume":"33","author":"Shellard","year":"1968","journal-title":"J Chromatogr."},{"key":"B17","doi-asserted-by":"publisher","first-page":"5961","DOI":"10.1016\/s0040-4020(01)83103-3","article-title":"Some new mitragyna-type indoles and oxindoles the influence of stereochemistry on mass spectra","volume":"25","author":"Beckett","year":"1969","journal-title":"Tetrahedron."},{"key":"B18","first-page":"41","article-title":"The alkaloids of Mitragyna with special reference to those of Mitragyna speciosa, Korth","volume":"26","author":"Shellard","year":"1974","journal-title":"Bull Narc."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1248\/yakushi.20-00170","article-title":"\u6539\u826f PCR-RFLP \u6cd5\u306b\u3088\u308b Kratom \u54c1\u306e [Discrimination of kratom products by an improved PCR-RFLP method\u2013Japanese]","volume":"140","author":"Ogata","year":"2020","journal-title":"Yakugaku Zasshi."},{"key":"B20","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1139\/v58-147","article-title":"The structure of mitraphylline","volume":"36","author":"Seaton","year":"1958","journal-title":"Canad J Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1111\/adb.12661","article-title":"Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution: the missing link in pharmacodynamic studies","volume":"24","author":"Yusof","year":"2019","journal-title":"Addict Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1021\/acscentsci.9b00141","article-title":"7-Hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects","volume":"5","author":"Kruegel","year":"2019","journal-title":"ACS Cent Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1002\/jssc.201000008","article-title":"High-performance liquid chromatographic method for the quantification of Mitragyna inermis alkaloids in order to perform pharmacokinetic studies","volume":"33","author":"Sinou","year":"2010","journal-title":"J Sep Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1021\/acs.jnatprod.0c00257","article-title":"The chemistry of kratom [Mitragyna speciosa]: Updated characterization data and methods to elucidate indole and oxindole alkaloids","volume":"83","author":"Flores-Bocanegra","year":"2020","journal-title":"J Nat Prod."},{"key":"B25","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1007\/s12272-010-0410-3","article-title":"Rhynchophylline down-regulates NR2B expression in cortex and hippocampal CA1 area of amphetamine-induced conditioned place preference rat","volume":"33","author":"Zhou","year":"2010","journal-title":"Arch Pharm Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.neuroscience.2016.09.029","article-title":"Anticonvulsant effect of Rhynchophylline involved in the inhibition of persistent sodium current and NMDA receptor current in the pilocarpine rat model of temporal lobe epilepsy","volume":"337","author":"Shao","year":"2016","journal-title":"Neuroscience."},{"key":"B27","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.neuropharm.2018.03.007","article-title":"Rhynchophylline suppresses soluble A\u03b21-42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B-containing NMDA receptors","volume":"135","author":"Yang","year":"2018","journal-title":"Neuropharmacology."},{"key":"B28","first-page":"907","article-title":"Phytochemical characterization of the leaves of Mitragyna speciosa grown in U.S.A","volume":"4","author":"Le\u00f3n","year":"2009","journal-title":"Nat Prod Commun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/s0091-3057(96)00314-0","article-title":"Suppressive effect of mitragynine on the 5-methoxy-N,N-dimethyltryptamine-induced head-twitch response in mice","volume":"57","author":"Matsumoto","year":"1997","journal-title":"Pharmacol Biochem Behav."},{"key":"B30","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1111\/j.1476-5381.1982.tb09317.x","article-title":"alpha-Adrenoceptor blocking properties of raubasine in pithed rats","volume":"77","author":"Demichel","year":"1982","journal-title":"Br J Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/0014-2999(84)90698-8","article-title":"Inhibition of the alpha 1 and alpha 2-adrenoceptor-mediated pressor response in pithed rats by raubasine, tetrahydroalstonine and akuammigine","volume":"106","author":"Roquebert","year":"1984","journal-title":"Eur J Pharmacol."},{"key":"B32","first-page":"252","article-title":"Selectivity of raubasine stereoisomers for alpha 1- and alpha 2-adrenoceptors in the rat","volume":"282","author":"Roquebert","year":"1986","journal-title":"Arch Int Pharmacodyn Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1021\/acs.jmedchem.9b01465","article-title":"Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloids","volume":"63","author":"Obeng","year":"2020","journal-title":"J Med Chem."},{"key":"B34","doi-asserted-by":"crossref","first-page":"E195","DOI":"10.36076\/ppj.2017.1.E195","article-title":"Is kratom the new 'legal high' on the block?: the case of an emerging opioid receptor agonist with substance abuse potential","volume":"20","author":"Chang-Chien","year":"2017","journal-title":"Pain Physician."},{"key":"B35","first-page":"283","article-title":"The potential for kratom as an antidepressant and antipsychotic","volume":"93","author":"Johnson","year":"2020","journal-title":"Yale J Biol Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"8381","DOI":"10.1021\/acs.jmedchem.6b00748","article-title":"Mitragynine\/Corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit \u03b2-arrestin-2","volume":"59","author":"V\u00e1radi","year":"2016","journal-title":"J Med Chem."},{"key":"B37","first-page":"31","article-title":"Malay plant names","volume":"30","author":"Ridley","year":"1897","journal-title":"J Straits Branch of the Royal Asiatic Society."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1126\/science.179.4077.1011","article-title":"Opiate receptor: demonstration in nervous tissue","volume":"179","author":"Pert","year":"1973","journal-title":"Science."},{"key":"B39","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1111\/j.1600-0773.1973.tb01477.x","article-title":"Stereospecific interaction between narcotic analgesics and a synaptic plasm a membrane fraction of rat cerebral cortex","volume":"32","author":"Terenius","year":"1973","journal-title":"Acta Pharmacol Toxicol."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.0c00658","article-title":"Predicted mode of binding to and allosteric modulation of the \u03bc-opioid receptor by kratom's alkaloids with reported antinociception in vivo","author":"Zhou","year":"2020","journal-title":"Biochemistry"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1016\/0024-3205(96)00432-8","article-title":"Antinociceptive action of mitragynine in mice: evidence for the involvement of supraspinal opioid receptors","volume":"59","author":"Matsumoto","year":"1996","journal-title":"Life Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/s0014-2999(96)00714-5","article-title":"Central antinociceptive effects of mitragynine in mice: contribution of descending noradrenergic and serotonergic systems","volume":"317","author":"Matsumoto","year":"1996","journal-title":"Eur J Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/s0306-3623(98)00265-1","article-title":"Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa","volume":"33","author":"Yamamoto","year":"1999","journal-title":"Gen Pharmacol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1021\/jm010576e","article-title":"Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands","volume":"45","author":"Takayama","year":"2002","journal-title":"J Med Chem."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1016\/s0024-3205(98)00075-7","article-title":"Identification of opioid receptor subtypes in antinociceptive actions of supraspinally-administered mitragynine in mice","volume":"62","author":"Thongpradichote","year":"1998","journal-title":"Life Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/s00414-015-1279-y","article-title":"The pharmacology and toxicology of kratom: from traditional herb to drug of abuse","volume":"130","author":"Warner","year":"2016","journal-title":"Int J Legal Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"108310","DOI":"10.1016\/j.drugalcdep.2020.108310","article-title":"Lyophilized kratom tea as a therapeutic option for opioid dependence","volume":"216","author":"Wilson","year":"2020","journal-title":"Drug Alcohol Depend."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-020-01034-7","article-title":"Kratom alkaloids, natural and semi-synthetic, show less physical dependence and ameliorate opioid withdrawal","author":"Wilson","year":"2021","journal-title":"Cell Mol Neurobiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"23","DOI":"10.2147\/SAR.S164261","article-title":"Current perspectives on the impact of Kratom use","volume":"10","author":"Veltri","year":"2019","journal-title":"Subst Abuse Rehabil."},{"key":"B50","volume-title":"The Psychoactive Substances Bill 2015","author":"Barber","year":"2015"},{"key":"B51","year":"2018"},{"key":"B52","unstructured":"Indonesian Kratom Ban Has Been Moved Up From 2024 To 2022, And This Would Cut Off The Entire Supply Of Kratom In The United States, But There Is Some Hope\n            KratomHerald\n          2021"},{"key":"B53","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.drugpo.2019.05.003","article-title":"Kratom policy: the challenge of balancing therapeutic potential with public safety","volume":"70","author":"Prozialeck","year":"2019","journal-title":"Int J Drug Policy."},{"key":"B54","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.drugalcdep.2017.10.012","article-title":"Kratom use and mental health: a systematic review","volume":"183","author":"Swogger","year":"2018","journal-title":"Drug Alcohol Depend."},{"key":"B55","doi-asserted-by":"publisher","first-page":"e20181839","DOI":"10.1542\/peds.2018-1839","article-title":"Neonatal abstinence syndrome due to maternal kratom use","volume":"142","author":"Eldridge","year":"2018","journal-title":"Pediatrics."},{"key":"B56","first-page":"121","article-title":"Novel case of maternal and neonatal kratom dependence and withdrawal","volume":"64","author":"Mackay","year":"2018","journal-title":"Can Fam Physician."},{"key":"B57","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.siny.2019.01.010","article-title":"Effects of unconventional recreational drug use in pregnancy","volume":"24","author":"Chomchai","year":"2019","journal-title":"Semin Fetal Neonatal Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"109","DOI":"10.3233\/NPM-1863","article-title":"Natural drugs, not so natural effects: Neonatal abstinence syndrome secondary to 'kratom'","volume":"12","author":"Davidson","year":"2019","journal-title":"J Neonatal Perinatal Med."},{"key":"B59","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1093\/pch\/pxy084","article-title":"An unusual cause for neonatal abstinence syndrome","volume":"24","author":"Murthy","year":"2019","journal-title":"Paediatr Child Health."},{"key":"B60","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1093\/ajhp\/zxz221","article-title":"Pharmacologic and clinical assessment of kratom: An update","volume":"76","author":"White","year":"2019","journal-title":"Am J Health Syst Pharm."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.2174\/1389450121666200719011653","article-title":"Kratom dependence and treatment options: a comprehensive review of the literature","volume":"21","year":"2020","journal-title":"Curr Drug Targets."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1002\/dta.1970","article-title":"Mitragynine (Kratom) - monitoring in sports drug testing","volume":"8","author":"Guddat","year":"2016","journal-title":"Drug Test Anal."},{"key":"B63","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/s13181-019-00741-y","article-title":"Kratom adulterated with phenylethylamine and associated intracerebral hemorrhage: Linking toxicologists and public health officials to identify dangerous adulterants","volume":"16","author":"Nacca","year":"2020","journal-title":"J Med Toxicol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/00952990.2020.1836185","article-title":"A comparative analysis of kratom exposure cases in Thailand and the United States from 2010-2017","volume":"24","author":"Davidson","year":"2020","journal-title":"Am J Drug Alcohol Abuse."},{"key":"B65","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1080\/15563650701241795","article-title":"Opioid receptors and legal highs: Salvia divinorum and Kratom","volume":"46","author":"Babu","year":"2008","journal-title":"Clin Toxicol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"505","DOI":"10.4321\/s1137-66272013000300015","article-title":"Drogas emergentes (III): plantas y hongos alucin\u00f3genos [Emergent drugs (III): hallucinogenic plants and mushrooms\u2013Spanish]","volume":"36","author":"Burillo-Putze","year":"2013","journal-title":"An Sist Sanit Navar."},{"key":"B67","doi-asserted-by":"publisher","first-page":"863","DOI":"10.4254\/wjh.v12.i10.863","article-title":"Kratom induced severe cholestatic liver injury histologically mimicking primary biliary cholangitis: A case report","volume":"12","author":"Gandhi","year":"2020","journal-title":"World J Hepatol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1080\/10826084.2019.1645178","article-title":"Effects of kratom (Mitragyna speciosa Korth.) use in regular users","volume":"54","author":"Singh","year":"2019","journal-title":"Subst Use Misuse."},{"key":"B69","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1111\/j.1360-0443.2008.02209.x","article-title":"Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa Korth)","volume":"103","author":"Boyer","year":"2008","journal-title":"Addiction."},{"key":"B70","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.drugalcdep.2017.08.034","article-title":"Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment program","volume":"180","author":"Smith","year":"2017","journal-title":"Drug Alcohol Depend."},{"key":"B71","doi-asserted-by":"publisher","first-page":"166","DOI":"10.2174\/1389450118666170425154120","article-title":"Kratom and future treatment for the opioid addiction and chronic pain: Periculo beneficium?","volume":"20","author":"Ismail","year":"2019","journal-title":"Curr Drug Targets."},{"key":"B72","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1080\/02791072.2018.1511879","article-title":"Severity of kratom (Mitragyna speciosa Korth.) psychological withdrawal symptoms","volume":"50","author":"Singh","year":"2018","journal-title":"J Psychoactive Drugs."},{"key":"B73","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1080\/02791072.2018.1443234","article-title":"Severity of pain and sleep problems during Kratom (Mitragyna speciosa Korth.) cessation among regular kratom users","volume":"50","author":"Singh","year":"2018","journal-title":"J Psychoactive Drugs."},{"key":"B74","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1021\/acsmedchemlett.7b00298","article-title":"Mitragyna speciosa: Balancing potential medical benefits and abuse","volume":"8","author":"Halpenny","year":"2017","journal-title":"ACS Med Chem Lett."},{"key":"B75","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1080\/02791072.2016.1156791","article-title":"Factor analytical investigation of Krathom (Mitragyna speciosa Korth.) withdrawal syndrome in Thailand","volume":"48","author":"Saingam","year":"2016","journal-title":"J Psychoactive Drugs."},{"key":"B76","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1007\/s13181-010-0079-5","article-title":"Seizure and coma following Kratom (Mitragynina speciosa Korth) exposure","volume":"6","author":"Nelsen","year":"2010","journal-title":"J Med Toxicol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.ebcr.2018.04.002","article-title":"Recurrent seizures from chronic kratom use, an atypical herbal opioid","volume":"10","author":"Tatum","year":"2018","journal-title":"Epilepsy Behav Case Rep."},{"key":"B78","doi-asserted-by":"publisher","first-page":"e6588","DOI":"10.7759\/cureus.6588","article-title":"A case of kratom-induced seizures","volume":"12","author":"Afzal","year":"2020","journal-title":"Cureus."},{"key":"B79","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1080\/02791072.2018.1562591","article-title":"Legally lethal kratom: a herbal supplement with overdose potential","volume":"51","author":"Palasamudram Shekar","year":"2019","journal-title":"J Psychoactive Drugs."},{"key":"B80","doi-asserted-by":"publisher","first-page":"24","DOI":"10.5811\/cpcem.2018.11.40588","article-title":"Kratom (Mitragynine) ingestion requiring naloxone reversal","volume":"3","author":"Overbeek","year":"2019","journal-title":"Clin Pract Cases Emerg Med."},{"key":"B81","doi-asserted-by":"publisher","first-page":"239","DOI":"10.5005\/jp-journals-10071-23170","article-title":"Undifferentiated shock and extreme elevation of procalcitonin related to kratom use","volume":"23","author":"Zuberi","year":"2019","journal-title":"Indian J Crit Care Med."},{"key":"B82","doi-asserted-by":"publisher","first-page":"e229778","DOI":"10.1136\/bcr-2019-229778","article-title":"Cardiac arrest in a young healthy male patient secondary to kratom ingestion: is this 'legal high' substance more dangerous than initially thought?","volume":"12","author":"Abdullah","year":"2019","journal-title":"BMJ Case Rep."},{"key":"B83","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s12245-020-00301-0","article-title":"Intractable nausea and vomiting in na\u00efve ingestion of kratom for analgesia","volume":"13","author":"Singh","year":"2020","journal-title":"Int J Emerg Med."},{"key":"B84","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1093\/anatox\/35.1.54","article-title":"A drug toxicity death involving propylhexedrine and mitragynine","volume":"35","author":"Holler","year":"2011","journal-title":"J Anal Toxicol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1093\/anatox\/35.4.242","article-title":"Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton","volume":"35","author":"Kronstrand","year":"2011","journal-title":"J Anal Toxicol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"S278","DOI":"10.1111\/1556-4029.12009","article-title":"A drug fatality involving Kratom","volume":"58","author":"Neerman","year":"2013","journal-title":"J Forensic Sci."},{"key":"B87","doi-asserted-by":"publisher","first-page":"e29","DOI":"10.1016\/j.forsciint.2014.10.025","article-title":"An accidental poisoning with mitragynine","volume":"245","author":"Karinen","year":"2014","journal-title":"Forensic Sci Int."},{"key":"B88","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1093\/jat\/bku137","article-title":"Mitragynine 'Kratom' related fatality: a case report with postmortem concentrations","volume":"39","author":"McIntyre","year":"2015","journal-title":"J Anal Toxicol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.forsciint.2016.12.020","article-title":"Mitragynine concentrations in two fatalities","volume":"271","author":"Domingo","year":"2017","journal-title":"Forensic Sci Int."},{"key":"B90","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1093\/jat\/bkx048","article-title":"Two fatal intoxications involving 3-methoxyphencyclidine","volume":"41","author":"Mitchell-Mata","year":"2017","journal-title":"J Anal Toxicol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1177\/1751143717712652","article-title":"Death from Kratom toxicity and the possible role of intralipid","volume":"19","author":"Aggarwal","year":"2018","journal-title":"J Intensive Care Soc."},{"key":"B92","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1177\/1925362118782076","article-title":"Fatal mitragynine-associated toxicity in Canada: A case report and review of the literature","volume":"8","author":"Wang","year":"2018","journal-title":"Acad Forensic Pathol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1111\/1556-4029.14082","article-title":"Fatality of 33-year-old man involving kratom toxicity","volume":"64","author":"Matson","year":"2019","journal-title":"J Forensic Sci."},{"key":"B94","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1080\/02791072.2018.1562133","article-title":"Kratom withdrawal: A systematic review with case series","volume":"51","author":"Stanciu","year":"2019","journal-title":"J Psychoactive Drugs."},{"key":"B95","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1159\/000320288","article-title":"A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence","volume":"16","author":"McWhirter","year":"2010","journal-title":"Eur Addict Res."},{"key":"B96","first-page":"49","article-title":"A case report of kratom addiction and withdrawal","volume":"115","author":"Galbis-Reig","year":"2016","journal-title":"WMJ."},{"key":"B97","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1213\/XAA.0000000000000658","article-title":"Kratom, an emerging drug of abuse: a case report of overdose and management of withdrawal","volume":"10","author":"Diep","year":"2018","journal-title":"A A Pract."},{"key":"B98","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1097\/ADM.0000000000000428","article-title":"Treatment of kratom dependence with buprenorphine-naloxone maintenance","volume":"12","author":"Buresh","year":"2018","journal-title":"J Addict Med."},{"key":"B99","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1080\/08897077.2019.1671945","article-title":"Home induction and outpatient treatment of kratom use disorder with buprenorphine-naloxone: A case report in a young adult","volume":"41","author":"Schmuhl","year":"2020","journal-title":"Subst Abus."},{"key":"B100","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/02791072.2020.1773586","article-title":"A complex case of kratom dependence, depression, and chronic pain in opioid use disorder: effects of buprenorphine in clinical management","volume":"17","author":"Bowe","year":"2020","journal-title":"J Psychoactive Drugs."},{"key":"B101","doi-asserted-by":"publisher","first-page":"e04507","DOI":"10.1016\/j.heliyon.2020.e04507","article-title":"Kratom instrumentalization for severe pain self-treatment resulting in addiction - A case report of acute and chronic subjective effects","volume":"6","author":"M\u00fcller","year":"2020","journal-title":"Heliyon."},{"key":"B102","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/10550887.2020.1813357","article-title":"The diagnosis of severe obsessions in the setting of kratom withdrawal and treatment with lorazepam: case report","volume":"12","author":"Sablaban","year":"2020","journal-title":"J Addict Dis."},{"key":"B103","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1007\/s13181-011-0155-5","article-title":"Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa)","volume":"7","author":"Kapp","year":"2011","journal-title":"J Med Toxicol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1002\/hep.27612","article-title":"Cholestatic hepatitis from prolonged kratom use: a case report","volume":"61","author":"Dorman","year":"2015","journal-title":"Hepatology."},{"key":"B105","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1634\/theoncologist.2017-0279","article-title":"The harm in kratom","volume":"22","author":"Drago","year":"2017","journal-title":"Oncologist."},{"key":"B106","doi-asserted-by":"publisher","first-page":"79","DOI":"10.14740\/gr990e","article-title":"Histologic characterization of kratom use-associated liver injury","volume":"11","author":"Riverso","year":"2018","journal-title":"Gastroenterology Res."},{"key":"B107","doi-asserted-by":"publisher","first-page":"2324709619826167","DOI":"10.1177\/2324709619826167","article-title":"Drug-induced liver injury caused by kratom use as an alternative pain treatment amid an ongoing opioid epidemic","volume":"7","author":"Osborne","year":"2019","journal-title":"J Investig Med High Impact Case Rep."},{"key":"B108","doi-asserted-by":"publisher","first-page":"2324709619836138","DOI":"10.1177\/2324709619836138","article-title":"Kratom-induced cholestatic liver injury and its conservative management","volume":"7","author":"Fernandes","year":"2019","journal-title":"J Investig Med High Impact Case Rep."},{"key":"B109","doi-asserted-by":"publisher","first-page":"211","DOI":"10.14740\/gr1204","article-title":"Kratom-induced cholestatic liver injury mimicking anti-mitochondrial antibody-negative primary biliary cholangitis: a case report and review of literature","volume":"12","author":"Aldyab","year":"2019","journal-title":"Gastroenterology Res."},{"key":"B110","doi-asserted-by":"publisher","first-page":"e546","DOI":"10.1097\/MJT.0000000000000802","article-title":"Herb-induced liver injury with cholestasis and renal injury secondary to short-term use of kratom (Mitragyna speciosa)","volume":"26","author":"Antony","year":"2019","journal-title":"Am J Ther."},{"key":"B111","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.japh.2018.05.006","article-title":"Possible kratom-induced hepatomegaly: a case report","volume":"58","author":"Griffiths","year":"2018","journal-title":"J Am Pharm Assoc"},{"key":"B112","doi-asserted-by":"publisher","first-page":"e550","DOI":"10.1097\/MJT.0000000000000631","article-title":"N-acetylcysteine for acute hepatitis induced by kratom herbal tea","volume":"25","author":"Mousa","year":"2018","journal-title":"Am J Ther."},{"key":"B113","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1124\/jpet.120.000270","article-title":"Refined prediction of pharmacokinetic kratom-drug interactions: time-dependent inhibition considerations","volume":"376","author":"Tanna","year":"2020","journal-title":"J Pharmacol Exp Ther."},{"key":"B114","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.toxlet.2019.11.005","article-title":"Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids","volume":"319","author":"Kamble","year":"2020","journal-title":"Toxicol Lett."},{"key":"B115","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1007\/s12024-018-0049-9","article-title":"Fatal combination of mitragynine and quetiapine - a case report with discussion of a potential herb-drug interaction","volume":"15","author":"Hughes","year":"2019","journal-title":"Forensic Sci Med Pathol."},{"key":"B116","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1007\/s40265-019-01242-6","article-title":"Kratom (Mitragyna Speciosa) liver injury: a comprehensive review","volume":"80","author":"Schimmel","year":"2020","journal-title":"Drugs."},{"key":"B117","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/s00216-010-4464-3","article-title":"Monitoring of kratom or Krypton intake in urine using GC-MS in clinical and forensic toxicology","volume":"400","author":"Philipp","year":"2011","journal-title":"Anal Bioanal Chem."},{"key":"B118","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.forsciint.2013.01.014","article-title":"A simple HPLC-DAD method for the detection and quantification of psychotropic mitragynine in Mitragyna speciosa (ketum) and its products for the application in forensic investigation","volume":"226","author":"Parthasarathy","year":"2013","journal-title":"Forensic Sci Int."},{"key":"B119","doi-asserted-by":"publisher","first-page":"105851","DOI":"10.1016\/j.ypmed.2019.105851","article-title":"Risk of death associated with kratom use compared to opioids","volume":"128","author":"Henningfield","year":"2019","journal-title":"Prev Med."},{"key":"B120","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1111\/add.15082","article-title":"Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross-sectional study","volume":"116","author":"Schimmel","year":"2021","journal-title":"Addiction."},{"key":"B121","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1111\/add.15173","article-title":"Kratom use in the United States: a diverse and complex profile","volume":"116","author":"Grundmann","year":"2021","journal-title":"Addiction."},{"key":"B122","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1111\/add.15170","article-title":"Kratom use in the United States: Response to Grundmann et al","volume":"116","author":"Schimmel","year":"2021","journal-title":"Addiction."},{"key":"B123","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1002\/phar.2280","article-title":"Kratom use and toxicities in the United States","volume":"39","author":"Eggleston","year":"2019","journal-title":"Pharmacotherapy."},{"key":"B124","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/BF02089946","article-title":"Chronic administration of the antidepressants phenelzine, desipramine, clomipramine, or maprotiline decreases binding to 5-hydroxytryptamine2A receptors without affecting benzodiazepine binding sites in rat brain","volume":"15","author":"Todd","year":"1995","journal-title":"Cell Mol Neurobiol."},{"key":"B125","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/s0006-3223(98)00007-9","article-title":"The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine","volume":"45","author":"Attar-L\u00e9vy","year":"1999","journal-title":"Biol Psychiatry."},{"key":"B126","doi-asserted-by":"publisher","first-page":"69","DOI":"10.2478\/v10153-012-0008-2","article-title":"Antinociceptive effect of clomipramine through interaction with serotonin 5-HT2 and 5-HT3 receptor subtypes","volume":"54","author":"Kostadinov","year":"2012","journal-title":"Folia Med (Plovdiv)."},{"key":"B127","first-page":"419","article-title":"Les antid\u00e9presseurs tricycliques interagissent directement avec les sites de liaison opiac\u00e9s dans la m\u00e9dullosurr\u00e9nale bovine [Direct interaction of tricyclic antidepressants with opiate binding sites in the bovine adrenal medulla\u2013French]","volume":"302","author":"Carydakis","year":"1986","journal-title":"C R Acad Sci III."},{"key":"B128","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1111\/j.2042-7158.1989.tb06390.x","article-title":"Apparent down-regulation of rat brain mu- and kappa-opioid binding sites labelled with [3H]cycloFOXY following chronic administration of the potent 5-hydroxytryptamine reuptake blocker, clomipramine","volume":"41","author":"Benkelfat","year":"1989","journal-title":"J Pharm Pharmacol."},{"key":"B129","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/0165-0327(86)90060-1","article-title":"Opiate receptor sensitivity in depressed patients before and after clomipramine treatment","volume":"11","author":"Naber","year":"1986","journal-title":"J Affect Disord."}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2021.640218\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T05:25:53Z","timestamp":1617168353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2021.640218\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,31]]},"references-count":129,"alternative-id":["10.3389\/fpsyt.2021.640218"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2021.640218","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,31]]},"article-number":"640218"}}