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Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 968786, 11 pages http://dx.doi.org/10.1155/2015/968786

Research Article Following (the Roots) of Kratom ( speciosa): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in to a Recreational Psychoactive in Western Countries

Eduardo Cinosi,1,2 Giovanni Martinotti,1,2 Pierluigi Simonato,1 Darshan Singh,3 Zsolt Demetrovics,4 Andres Roman-Urrestarazu,5,6 Francesco Saverio Bersani,1,7 Balasingam Vicknasingam,3 Giulia Piazzon,1 Jih-Heng Li,8 Wen-Jing Yu,8 Máté Kapitány-Fövény,4,9,10 Judit Farkas,4,10 Massimo Di Giannantonio,2 and Ornella Corazza1,7

! Centre for Clinical & Health Research Services, School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hat"eld, Herts AL!# $AB, UK % Department of Neuroscience, Imaging and Clinical Sciences, Gabriele D’Annunzio University, Chieti, Italy & Centre for Drug Research, Universiti Sains, Penang, ' Institute of Psychology, Eotv¨ os¨ Lorand´ University, Budapest, Hungary ( London School of Economics and Political Science, LSE Health and Social Care, London, UK ) Department of Psychiatry, University of Cambridge, Cambridge, UK * Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy + School of Pharmacy and Ph.D. Program in Toxicology, Kaohsiung Medical University, Kaohsiung, Taiwan $ Faculty of Health Sciences, Semmelweis University, Budapest, Hungary !#Ny´ıro˝ Gyula Hospital, National Institute of Psychiatry and , Budapest, Hungary

Correspondence should be addressed to Ornella Corazza; [email protected]

Received !August "#$%; Revised$& October "#$%; Accepted$% October "#$%

Academic Editor: Yu-Ping Tang

Copyright © "#$% Eduardo Cinosi et al.' is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

'e use of substances to enhance human abilities is a constant and cross-cultural feature in the evolution of humanity. Although much has changed over time, the availability on the Internet, o(en supported by misleading marketing strategies, has made their use even more likely and risky. 'is paper will explore the case of Mitragyna speciosa Korth. (kratom), a tropical tree used traditionally to combat fatigue and improve work productivity among farm populations in Southeast Asia, which has recently become popular as novel psychoactive substance in Western countries. Speci)cally, it (i) reviews the state of the art on kratom pharmacology and identi)cation; (ii) provides a comprehensive overview of kratom use cross-culturally; (iii) explores the subjective experiences of users; (iv) identi)es potential risks and side-e*ects related to its consumption. Finally, it concludes that the use of kratom is not negligible, especially for self-medication, and more clinical, pharmacological, and socioanthropological studies as well as a better international collaboration are needed to tackle this marginally explored phenomenon.

1. Introduction certain regions of Southeast Asia, the chopped fresh or dried of the tree are chewed or made into tea by local manual Kratom (Mitragyna speciosa Korth., of the family) labourers to combat fatigue and improve work productivity is a +–$,-metre high tropical tree, indigenous to Southeast [$]. In addition, kratom preparations have also been used Asia, the Philippines, and New Guinea. Traditionally, in for centuries during socioreligious ceremonies and to treat " BioMed Research International

chemistry. 'is adds complexity of their pharmacological 15% e*ects, with a paucity of data relating to the toxicology of 2% 1% these materials, and even less regarding their interactions with conventional of abuse [!].'is is further compli- 9% cated by the possibility of adulteration processes [4].'e level of complexity, variability, and the unknown nature of these samples, coupled with the risks associated with taking psy- 7% 66% choactive materials, could o*er further risks of ill health by misadventure, with potentially life-threatening consequences [5]. In this scenario, predictions of novel trends in Western countries speci)cally suggest that kratom use will increase in the next years [$#]. (C23H30N2O4) 'e aim of the present study was to study this new Paynantheine (C23H28N2O4) phenomenon by (i) reviewing the state of the art on kratom Hydroxymitragynine (C23H30N2O5) pharmacology and identi)cation; (ii) providing a compre- Speciogynine (C23H30N2O4) hensive overview of kratom use cross-culturally, ranging Speciociliatine (C23H30N2O4) Other from its traditional use in native societies in Southeast Asia to its more recent di*usion as a NPS in Western countries; (iii) F-./01 $: An estimate of' ai kratom extract composition. 'e exploring the subjective experience of users; (iv) identifying phytochemicals isolated from various parts of the tree include risks and side-e*ects related to its consumption. overall +#structurally related as well as several 2avonoids, terpenoid , , and various glycosides. 2. Materials and Methods

Acollaborativeandmultidisciplinarye*orttostudythe various medical conditions, such as dependence rapid di*usion of kratom was carried internationally by ten in 'ailand ["], and as substitute in Malaya ["]. It research centres: the School of Life and Medical Sciences, has been suggested that the genus was given the “Mitragyna” University of Hertfordshire (United Kingdom), Department name by the Dutch botanist Korthals because the leaves and of Neuroscience, Imaging and Clinical Sciences, Gabriele the stigmas of the 2owers of the resemble the shape D’Annunzio University, Chieti (Italy), Centre for Drug of a bishop’s mitre [&]. However, considering its variety of Research, Universiti Sains, Penang (Malaysia), Institute of uses, it could be speculated that the term derives from the Psychology, Eotv¨ os¨ Lorand´ University, Budapest (Hungary), “Mithraic cults,” seen as a source of spiritual transcendence London School of Economics and Political Science, LSE for thousands of years [+]. Health and Social Care, London (United Kingdom), Depart- Kratom preparations contain varying amounts of several ment of Psychiatry, University of Cambridge, Cambridge phytochemicals, making their pharmacological and toxi- (United Kingdom), Department of Neurology and Psychi- cological evaluation unique and di3cult (Figure $).'e atry, Sapienza University of Rome, Rome (Italy), School main psychoactive components in the leaves are alkaloids of Pharmacy and Ph.D. Program in Toxicology, Kaohsiung mitragynine and !-hydroxymitragynine both found only in Medical University, Kaohsiung (Taiwan), Faculty of Health Mitragyna speciosa, but other analogues have been identi)ed Sciences, Semmelweis University, Budapest (Hungary), and (e.g., speciogynine, paynantheine, and speciociliatine) [&, Ny´ıroGyulaHospitalNationalInstituteofPsychiatryand˝ +] (Figure $).'e e*ects of kratom in humans are dose- Addictions, Budapest (Hungary). A review of the literature dependent where small doses produce stimulatory e*ects ($5,!–"#$%) on kratom and its main components was per- resembling the e*ect of drugs such as or formed in three databases: PsycINFO, PubMed, and Med- , while larger dosages tend to be associated scape. Keywords used to carry out the database searches with - e*ects that resemble drugs such as included the following: “kratom”, “Mitragyna speciosa”, [%]. “mitragynine”, and “!-hydroxymitragynine”. Peer-review Imported to Western countries from Southeast Asia, data that emerged from the search were integrated with kratom has become in recent years a popular enhancer, an exploratory qualitative assessment of ""!websites, drug which could also be classi)ed as novel psychoactive substance fora, and other online resources (i.e., e-newsgroups, chat- (NPS) [&]. Beyond kratom, some of the most widely used rooms, mailing lists, e-newsletters, and bulletin boards). 'is psychoactive , largely not under international control, was carried out on a regular weekly basis (between January include ,(Catha edulis), Hawaiian baby "##4 and April "#$%) using the Google search engine in woodrose seeds (Argyreia nervosa),2y agaric (Amanita mus- three languages (English, Italian, and Hungarian). Once the caria), “Magic Mushrooms” (Psilocybe and related species), substance availability of information was identi)ed, further Peyote (Lophophora williamsii), Ayahuasca (Banisteriopsis speci)c searches were carried out for narratives focusing on caapi and Psychotria viridis), and “Genie” (a smoking mixture the following issues: (i) motivations behind its recreational containing multiple plant materials and of dubious phar- use and possible trends of misuse; (ii) the nature of its macognostical identity) [,]. Natural products o(en used e*ects on users, including adverse reactions and polydrug as enhancers are exceptionally complex in terms of their misuse/idiosyncratic combinations; (iii) any other relevant BioMed Research International & information. For the purpose of reporting the results in this constituent ("%) of M. speciosa,whenisolateddemonstrates paper, any data collected from online fora, such as usernames apotentantinociceptiveactivityinmice[$+].Itisnow and complete URLs for speci)c threads that were considered considered to be a major contributory factor for the personal identi)able, were anonymized. Additional searches properties of M. speciosa due to its selectivity for -and were conducted using the Global Public Health Intelligence - receptors [!].'e presence of a hydroxyl group Network (GPHIN), a secure Internet-based early warning at C-!increases the potency of !-hydroxymitragynine" to system developed by Health Canada and the World Health #be$&- and +,-fold higher than morphine and mitragynine, Organization (WHO), which monitors media reports in six respectively, both in vitro and in vivo [$",$%,$,].'is might languages, Arabic, Chinese, English, French, Russian, and be one of the main pharmacological markers of kratom Spanish. products’ qualityandpotency. Recent studiesfurther revealed Permission for the study was granted by the School of how complex is kratom’s pharmacology, involving a -opioid Pharmacy Ethics Committee, University of Hertfordshire, and dopamine D$receptors interaction in its various e*ects Hat)eld, United Kingdom (November "#$&; PHAEC/$#-+"). [$!]. Serotonergic and adrenergic pathways have also# been involved in the e*ects of mitragynine, mostly due to its broad 3. Results a3nity to di*erent receptors [$4]. Indeed, the pharmacologi- cal mechanisms responsible for stimulant activity are yet to be $$& studies emerged from the literature review and were clearly established [$5]. Another confounding factor might be critically analysed. Among these, $4results were considered the action of some other isolated compounds (speciociliatine, not relevant (resulting duplicated, botanical studies, or stud- speciogynine, and paynantheine), for example, whose e*ects ies focusing mainly on other selected chemical compounds) were not inhibited by in animal studies [$",$%]. and therefore excluded. 'e remaining 5% articles were It is possible that mitragynine is relatively safe at lower further qualitatively analysed and thematically divided in subchronic dose but exhibits toxicity at a highest dose three main areas of interest related to Mitragyna speciosa ["#]. However, the erratic pharmacology of kratom makes and its main constituents: ($) in vitro and preclinical data it di3cult to de)ne a speci)c dose threshold. According to on pharmacology and behavioral e*ects ( ), (") online reports and traditional experiences, subjective e*ects laboratoristic techniques for identi)cation/characterization of kratom depend on the dosage: at low to moderate dose ( ), and (&) epidemiological/toxicological!=51 reports on ($–%g) it has a mild pleasant stimulant e*ect; at moderate- humans ( ). Data on kratom that emerged from the high dose (%–$% g) the compound has opioid-like analgesia online!=26 searches were identi)ed, monitored, and registered and sedation ["#,"$]. No studies have been conducted so into %categories:!=18 epidemiology and motivation of use; far to determine the blood concentration in patients, and legal status, methods of purchase, and typical price; forms future approach should consider this point in order to prevent of kratom use; (1) subjective pleasurable e*ects, adverse(2) overdose, considering the possible risk of no response to e*ects, and fatal intoxications related to kratom; pattern(3) of naloxone ["","&].'e standard half-life of mitragynine is polyabuse. 'e results(4) from the review of scienti)c literature &.4% $hr,dependingupontheindividualsnaturallevels and online sources were comprehensively integrated(5) and of and other factors ["+,"%].!-Hydroxymitragynine summarized in the following three main subsections: (i) has quite±∼ a bit shorter duration, with an average half-life of preclinical data about pharmacology and identi)cation of ".% #.!hours ["+,"%]. Recent evidences suggest that the kratom constituents; (ii) kratom use in humans in Southeast hydrophobicity, poor water solubility, high variability of drug Asia; (iii) kratom use in humans in Western countries. release± in simulated biological 2uids, and acid degradable characteristics of mitragynine probably further in2uence the &.!. Pharmacology and Identi"cation of Kratom Constituents. large variability of its pharmacological responses reported Kratom has both opioid- and psychostimulant-like subjective in the literature ["+]. 'is was con)rmed by liver, kidney, e*ects [$$].'e phytochemicals isolated from various parts and brain histopathological changes, as well as hematological of the kratom tree include over +# structurally related and biochemical changes in mice ["#]. Mitragynine, !- alkaloids [!] of which mitragynine (Figure$ ) is the most hydroxymitragynine, and mitraphylline exhibit high plasma important with up to ,,% purity in the extract of leaves protein binding ( 5#%) determined by equilibrium dialysis from 'ailand, and only $"% in kratom leaves from Malaysia. ["%]. 'e of kratom is mainly hepatic. While 'is is the one responsible for analgesic activity it seems that kratom> is unlikely to have any signi)cant that has been linked to kratom use mostly due to its potent clinical e*ects on CYP&A+activity, on the other hand opioid agonist property [$"]. Although mitragynine can act mitragynine might inhibit other cytochrome P+%# on the mu ( ), kappa ( ), and delta ( )opioidreceptors,it activities, speci)cally CYP"D,[",,"!].'ese data indicate is structurally di*erent from morphine and other compo- the possibility of a if mitragynine and !- nents from" the opioid# family; the reason$ why it has been hydroxymitragynine are coadministered with drugs that are suggested is that it might also present with a more broad P-glycoprotein substrates ["!]. receptor binding activity [$&]. Mitragynine and its analogues Current preclinical information on kratom suggests that in kratom (including speciogynine (!%), paynantheine (5%), this ethnodrug, containing several di*erent active alkaloids, and speciociliatine ($%) (Figure $)) are indole alkaloids of the has a harmful toxicological pro)le and must be studied in Corynanthe-type, possessing a () moiety detail in order to better de)ne its potential as therapeutic [$"]. Di*erently, !-hydroxymitragynine (Figure $), a minor drug ["4]. Acute administration of mitragynine produces + BioMed Research International anxiolytic-like e*ects attributed to the interactions among as an opium substitute in Malaya during opium scarcity [+!]. receptor systems ["5]. Other authors attempted It is still popularly consumed in Asian communities during to reveal a possible link with the stress-related corticotropin social gatherings in the village [+!]. pathway [&#]. Other evidences show that mitragynine exerts Traditionally, the fresh or dried leaves of kratom are an e*ect in animal behavioral model inter- chewed or brewed into tea or smoked [+5]. Ketum is bitter acting with neuroendocrine HPA axis systems [&$]. Among and sugar or sweet beverages are commonly added to mask its potential bene)ts, in addition to analgesic activity [$&, its taste [+5]. To experience vigour and , traditional &"], mitragynine seems to be also a key component for “kratom eaters” chew one to three fresh leaves at a time the anti-in2ammatory properties of kratom by suppressing [$,"]. Regular and addicted users chew &–$#times a day [$]. prostaglandin E"(PGE-") production in the cyclooxygenase Amattayakul [%#] reported that an average green weighs "(COX-") pathway [$,]. Moreover, some authors claim about $.!g and a dry leaf about #.+& g and twenty kratom that kratom might be promising and anticancer leaves contain about $!mg of mitragynine; no information or chemopreventive compounds [&&]. Kratom extracts and is available on other active compounds of the plant. Ketum mitragynine have been shown to possess cytotoxicity to some is currently widely available in many Asian countries (e.g., in human cancer cell lines, namely, SH-SY%Y cells (neuronal Malaysia) where it can be easily bought from ketum traders cells), [&+] and avoid the tolerance and dependence on in the community [$]. Consumers can be classi)ed into two chronic morphine treatment in mice as well as in human main groups: the )rst includes those who solely use ketum to neuroblastoma SK-N-SH cell [&%,&,]. Other interesting prop- improve physical tolerance to laborious work and the second erties of the compound might be the capability to modulate polydrug users who attempt to manage muscle neurogenic contraction [&!–&5] and gastric secretion symptoms or reduce the intake of other opiates like [+#]. [%$]. A recent study showed that out-of-treatment users While kratom could have the potential to be in Malaysia o(en use ketum to reduce their dependence developed as new therapeutic agents, there are also possible on illicit opiate as well as to ameliorate opiate withdrawal serious adverse e*ects of these materials under investigation. symptoms [%$]. 'ere have been di*erent studies showing serious conditions At present, there is no systematic data on the prevalence a(er repeated administration as elevated blood pressure, of ketum use in all the native countries, but it seems to nephrotoxic e*ects [+$], impaired cognition and behaviour be considerable in Malaysia and 'ailand. A survey per- [+",+&], dependence potential [+"], and hepatic failure [+$, formed in "##! investigating kratom use in 'ailand (",,,&& ++].' e onset of liver injury is described to occur within respondents aged $"–,% years) indicated that the lifetime, "to4weeksofstartingregularuseofkratompowderor past year, and past &#days prevalences for kratom were tablets, with symptoms of fatigue, nausea, pruritus, and dark ".&"%,#.4$%, and #.%!%, respectively [&].'ese) gures, with urine followed by [+$,++].'e pattern of liver injury the exception of lifetime use, were signi)cantly higher than seems to be typically cholestatic and can be severe with those for making kratom the most widely used illicit serum bilirubin levels rising above "# mg/dL [++]. Kratom drug in 'ailand. Again in 'ailand past &#-day prevalence constituents were also identi)ed to be potentially cardiotoxic, studies among $&–$,-year-old students – ideally potentiating Torsade de Pointes through inhibition in "##","##&, and "##+ showed an increase in the lifetime of rapid delayed recti)er potassium current (IKr) in human use of kratom (from &.5!% to 5.+&%)( [&&].= Another 8 708 12 study 148) cardiomyocytes [+%]. in 'ailand in "##,showed a prevalence of psychoactive At present, kratom constituents are not detected by drugs in $,,&% motor vehicle drivers: #.5% were positive to conventional drug screening tests: advanced tests like liq- mitragynine [%"]. Overall, reported linked to kratom uid chromatography-tandem or ion-mass spectrometry are quintupled in 'ailand from "##% to "#$$, far higher than required [!]. those reported for any other drug [,]. Kratom reported seizures in Malaysia and also reached record levels &.%. Kratom Use in Southeast Asia in "#$$, at roughly one ton each [,]. Conversely, in Taiwan, heroin, , and some new drugs such as syn- &.%.!. Di,usion and Modalities of Consumption. Mitragyna thetic cathinones (methylone, , and MDPV) and speciosa (Rubiaceae) is an indigenous plant of Southeast Asia. (K") have been identi)ed since "###s 'is herbal plant is also known as “kratom,” as “ketum” according to the Monitoring and Reporting or “biak” (Malaysia), or as “krathom” ('ailand, “thom” Systems (SAMRS), which is a national data collection system in Southern 'ailand) and has been used for millennia (a) for substance abuse [%&]. However, use of kratom and its as a stimulant; (b) as a remedy in ; major alkaloid mitragynine has not been detected via the and (c) in social context [+,,+!]. Historically, manual collected information from the SAMRS [%&].'erefore, it labourers (e.g., )sherman, farmers, and rubber-tappers) in could be suggested that kratom may not yet be a drug of northern Malaysia and southern 'ailand commonly used choice in Taiwan and might still be considered a rather ketum leaves to improve their work productivity under the culture-bounded phenomenon in Asian countries. sweltering sun and to relieve fatigue [$]. Rural folk have 'e possession of kratom leaves has been illegal in traditionally ingested ketum leaves to self-treat common 'ailand since $5+&[ +5]. Kratom is also controlled in a few medical problems (e.g., diabetes, diarrhoea, fever, and ) other countries in the region (Malaysia and Myanmar) and and used it as a wound poultice [+,,+4]. Ketum was also used elsewhere (Australia, Bhutan) [,]. In parallel, kratom-related BioMed Research International %

3000 arrests more than doubled between "##!and"#$$ in both Myanmar and 'ailand [,]. To control its widespread abuse, ketum was banned in Malaysia and regulated under the 2500 Poisons Act $5%" [+5].' ose caught for possessing or pro- cessing ketum leaves can be )ned for approximately RM ",###(US +%#) or imprisoned if found guilty [+5].'e 2000 Malaysian government is in the midst of regulating ketum under the Dangerous Drugs Act $5%", which will consider the substances as harmful as opiates and amphetamines [+5]. 1500

&.%.%. Stigma and Side-E,ects. Among rural folk, the believe that kratom is a better alternative to illicit drugs, such 1000 as heroin and methamphetamine, is still di*use and it is mainly used for its invigorating-like e*ects [%+,%%]. Five 500 to ten minutes a(er kratom consumption users describe themselves as feeling happy, strong, and active, especially among those working in the agricultural sector [$].'ey 0 claim that “their mind is calm” a(er the consumption of 2007 2008 2009 2010 2011 the drug [$]. Overall, there is no real social stigma towards ketum users and being dependent on ketum is not seen as Kratom-related treatment admissions in !ailand amajorproblemortabooinMalaysia,atleastformen. F-./01 ": Kratom-related treatment admissions in 'ailand almost Apparently, society accepts male addicts who work to support tripled between "##! and "#$$. Source: United Nations O3ce on their family but do not accept female addicts [$]. Moreover, it Drugs and Crime, Patterns and Trends of -Type and Other Drugs: Asia and the Paci)c—"#$" (Bangkok, seems that ketum dependents are not neglecting their family "#$"). and the impairment of their social functioning is still under debate [%,]. A recent cross-sectional survey in three northern states of Peninsular Malaysia investigated "5& regular kratom psychotic symptoms such as mental , delusion, and consumers [%+]. Findings showed that regular kratom users [$]. do not seem to experience major impairments in their Regarding polydrug abuse, in Asia, patterns of com- social functioning, despite being dependent on kratom for plex cointaking involving kratom are also reported. Beyond prolonged periods [%+]. Furthermore, ketum use does not “classic” substances and many NPS as synthetic phenylethy- imply risky behaviours such as , common in lamines and cathinones, peculiarly there have been cases heroin dependents [%!]. On the other hand, evidence shows where is added into kratom drinks to obtain a that kratom can generate problems and lead to better “high” or euphoria. In southern 'ailand, in recent other social issues [%+]. Considering how kratom use is years, homemade ice-cold cocktails, called “+ $##,” have consistent, )gures for treatment admissions for its use appear become popular for their alleged -mimicking e*ect rather low, accounting for, for example, "percent of all among young Muslim people [&]. 'e cocktails× are made drug treatment admissions in 'ailand in "#$$(Figure "). from kratom leaves, a ca*eine-containing so(drink, and However, they are declared to be considerably on the rise [,]. codeine- or diphenhydramine-containing cough syrup as the Kratom-related treatment admissions almost tripled between three basic ingredients to which ice cubes, an anxiolytic, an "##!and"#$$ (Figure" )[,].'is could be also partially due antidepressant, or an analgesic drug is added [&,%5]. to a more strict antidrug policy, where individuals caught So far, there have not been any mortality or toxicity with kratom are obliged to engage in treatment programs. incidents directly related to ketum use reported in Asian Surely, )ndings show that regular kratom use is associated countries. One possibility is that ketum users in Asia nor- with drug dependency, development of withdrawal symp- mally buy fresh ketum juice, from a local known supplier toms, and craving [%+]. Many regular users declare their in the rural area, unlikely to be an adulterated preparation. di3culty to abstain from kratom use and experiencing Traditionally, ketum in Asia has been used for its stimulant sharp unpleasant symptoms during abstinence periods [%4]. e*ects and the dose consumed might be lower than the Physical withdrawal symptoms include anorexia, weight loss, one consumed for recreational purposes [$5]. But it is also decreased sexual drive, insomnia, muscle spasms and pain, possible that local health care providers in Asia, perceiving aching in the muscles and bones, jerky movement of the ketum as a safe traditional herbal drink, might not attribute limbs, watery eyes/nose, hot 2ushes, fever, decreased appetite, some of the medical problems reported by users to ketum use; and diarrhoea [+4,%+]. Psychological withdrawal symptoms this factor may indeed contribute to the underreporting of commonly reported are nervousness, restlessness, tension, adverse e*ects among ketum users in Southeast Asia. anger, hostility, aggression, and sadness [$,%+]. Long-term addicts are described to become thin and have skin pigmen- &.&. Kratom Use in Western Countries tation on their cheeks, due to the capacity of mitragynine to increase the production of melanocytes-stimulating sub- &.&.!. Di,usion, Modalities, and Reasons of Consumption. In stance [$,+,]. Regular ketum use is also reported to cause recent years kratom has become popular in the EU, US, , BioMed Research International and other countries (e.g., Japan) as a recreational novel pills and smoked in pipes (“madatin”) [",]. Small pellets of compound [&,,,,#]. A variety of Mitragyna speciosa related this extract can be ingested, or again the compound can be products are easily accessible from local smart shops and dissolved in hot water and consumed alone or mixed with increasingly available for sale on the Internet, in particular on other ordinary herbal teas to make it more palatable (the so- web based “legal highs” pharmacies, but their exact content is called toss and wash) ["!,,+,,5]. Other users prefer alcoholic not always veri)ed [,$,,"]. Many di*erent formulations are beverages or to ingest it with food, mixing it with yoghurt or available, including raw leaves, capsules, tablets, powder, and preparing cookies, in order to contrast the bitterness of the concentrated extracts [+5]. Prices vary between countries, compound [!$,!"]. Regarding desired/recreational e*ects of depending on the type and amount of the purchased product, kratom, users report that at low doses it is rather stimulant, for example, ranging from "to$# per gram for “kratom mind is “more alert,” physical energy and sometimes sexual $%X” extracts,, to $% euros per $# gram for dried kratom [+5], arousal are increased, and ability to do physical work may or sometimes even for lower prices (from less than $ per be improved and they also described “entactogenic” e*ects, gram for “kratom power”) ["$,,&–,%]. like empathy and euphoria (Box $) [,4,!#,!$]. Some people Mitragyna speciosa and/or mitragynine and/or !-hydrox- )nd this level edgy rather than pleasant [,4,,5]. At higher ymitragynine are currently controlled only in a small number doses, experiences describe it as more sedative and analgesic; of EU Member States, such as , , , users prefer to be less sensitive to physical or emotional , , and [&]. Kratom is also largely pain, to feel and look calm, and to have a general feeling of uncontrolled in the US at a federal level while at the state comfortable pleasure [,4,!#]. Others report an increase of level there are some exceptions such as Indiana, Iowa, empathy feelings (Box $)[,4]. Louisiana, and Massachusetts. 'is means all parts of the plant and its extracts are legal to cultivate, buy, possess, and &.&.&. Side-E,ects. Avarietyoflessexploredside-e*ects distribute without a license or prescription, and, when sold experienced by users also emerged from our work (Table $). as a supplement, sales must conform to US supplement laws 'ese frequently include nausea, , sleep prob- [,,]. Recently, in February "#$+, the Food and Drug Admin- lems, temporary , itching, and sweating istration (FDA) issued “Import Alert %+-$%” that seems to and also hyperpigmentation and tremor and anorexia and provide customs and border agents broad authority to seize weight loss in long term [,+,,4–!"]. Some users describe kratom products from a number of suppliers outside the US , probably related to a regular (daily) use of kratom [,,]. [,5]. Withdrawal symptoms are also common, including As kratom is o(en not monitored in national drug abuse muscle aches, irritability, mood disturbances, runny nose, surveys, there is still little information on prevalence of its diarrhoea, and muscle jerking (Table $)[!#]. Users describe use. An initial warning about this phenomenon has been tolerance (requiring the consumption of higher doses to launched by the Drug Enforcement Administration (DEA) achieve the same e*ects) and also a “cross-tolerance” to as early as "##%[ ,!]. Internet surveys conducted by the both kratom and opiates a(er repeated intake [,+,,4–!"]. EMCDDA in "##4 indicated that kratom was one of the most Moreover, kratom is increasingly purchased from Internet widely o*ered “legal highs” in ++% of the investigated "! sources for self-medication [&,,$], especially by individuals online shops across the EU [&]. A more extensive EMCDDA with to self-manage [,$,,5] Internet survey in July "#$$showed that kratom was the or heroin, , or suboxone withdrawal symptoms most widely o*ered product with $"4 out of ,&$ (or"# %) of [,4], or for its anxiolytic and antidepressant e*ects [!&]. online retailers shipping it to the EU. A further online study For this reason, it is o(en advertised online as a cheaper identi)ed&$+ online shops selling NPS that would dispatch alternative to traditional opioid replacement therapies with products to at least one EU Member State (United Kingdom no need of medical prescription ["4].'is could pose a appeared to be the most common) [+5]. Kratom and Salvia serious problem for doctors prescribing pain medication or divinorum were the most frequently o*ered NPS, available opioid substitution therapy to someone who is a regular in 5" and!" online shops, respectively [&]. In "#$"the term kratom user. Adverse e*ects and intoxications cases across “kratom” was found in more than two million results. Of the various countries have also been reported, including liver )rst $##websites listed in the search results, !4were primarily toxicity, , and [,#,!+–!,], reports of patients focused on the sale of kratom, while ""were focused on su*ering from intrahepatic a(er two weeks of disseminating information about kratom through the use of kratom use [++], Adult Respiratory Distress Syndrome [!!], discussion boards [%]. and hypothyroidism [!4] (Table $). Evidence also suggests that kratom might be a deadly substance when mixed with &.&.%. Subjective Experience: Online Reports. Since "##$, an other compounds (Table $). Fatalities resulting from the use exponential growing number of kratom’s subjective experi- of a kratom-based product known as “Krypton” have also ences have been posted online by users (Box $)[,+,,4–!"]. been reported [!5] with 5documented cases in Sweden Kratom can be smoked, but according to users this has no [""]. Subsequent forensic studies revealed that Krypton advantage over chewing or making a tea: the amount of leaves contained high amounts of the exogenous pharmaceutical that constitutes a typical dose is too much to be smoked agent O-desmethyltramadol, an opioid analgesic and the easily [!$,!"]. A paste-like extract can be prepared by lengthy main active of , and it had been added boiling of fresh or dried leaves and the syrup produced can to the plant material. 'e presence of this contaminant be mixed with )nely chopped leaves of the palm, made into in some online products is well documented [4,"",!5]. BioMed Research International !

“About twenty minutes a(er ingesting the Kratom, I began to feel a nice, pleasant euphoria identical to that of an opiate I did notice the simultaneous stimulant/ e*ect like I notice in or ” https://www.erowid.org/experiences/exp.php?ID=... %&%&&

“I start to feel this intense warmth come over my entire body, it feels like a combination of my )rst MDMA high with a nice OxyContin like twist, along with the social aspect of Cocaine” https://www.erowid.org/experiences/exp.php?ID=,#%!+

“I felt my insides become so(and pliable like the onset of most trippy drugs” https://www.erowid.org/experiences/exp.php?ID=4%$,+

“I felt relaxed, sedated, and free of my normal back and thumb pain in my right hand which Ithoughtwouldneverbepossible.IalsofeltanicefuzzyfeelingalloverwhichIgetfrom smoking pot sometimes” https://www.erowid.org/experiences/exp.php?ID=,5,!!

“I began 2oating in and out of waking dreams, the ‘nod’, whatever you want to call it, where you’re not really asleep but you still see dreamlets and dream fragments 2oating before your eyes. 'is goes on for quite some time”. https://drugs-forum.com/forum/showthread.php?t=5+%$

“I lost track of time at this point, as I was completely lost in the music and my own thoughts. I wasn’t really feeling euphoria or a ‘high,’ like when using marijuana. I did feel very ‘stoned’ though, and I guess I would refer to my state as being high because of my total relaxation and contentment”. https://www.erowid.org/experiences/exp.php?ID=5&"#$

“When I’m at the peak, I feel a very pleasant body buzz, kind of like being wrapped around a warm, so(blanket all day long. On the comedown, I feel relaxed but scatterbrained and my concentration takes a hit, and I can easily enter ‘waking dreams’ where I’m not sleeping but dreaming while being unaware of either state of consciousness, which o(en causes me to jolt awake and open my eyes” https://www.erowid.org/experiences/exp.php?ID=$#$4$+

B67 $: Qualitative analysis of kratom users’ experiences.

Even though mitragynine was also detected in the products, tryptamines, and phenylethylamines such as "C-E, AL-LAD, it was not determined how the two substances may have and +-HO-MiPT) [,4]. interacted to cause death. Other “deadly cases” are available: an article described a fatal reaction that appeared to be asso- 4. Discussion and Conclusions ciated with mixing with propylhexedrine (an -agonist and amphetamine-like stimulant, used as decongestant inhalers); Indeed, the use of substances to enhance human abilities another case indicated that a mix of kratom, over-the-counter( is a constant and cross-cultural feature in the evolution of cold medications, and was responsible for humanity. Opium, leaves, mescaline, and various other the death of a $!-year-old boy; a postmortem detection of natural substances have been used for millennia in various kratom together with venlafaxine, diphenhydramine, and cultures for therapeutic purposes, religious ceremonies, and was screened in a "+-year man found unrespon- improvement or modi)cation of the physical and mental sive in bed; a middle aged man in therapy with zopiclone, abilities. Although much has changed over time, the drive citalopram, and was found dead at home and for human enhancement has not diminished and drugs postmortem analysis of peripheral blood revealed high con- availability on the Internet, o(en supported by misleading centrations of mitragynine and !-hydroxymitragynine and marketing strategies, has made their use even more likely and therapeutic values of intake of the other compounds ["&,4#, risky [5]. In this context,the tropical tree Mitragyna speciosa 4$]. Korth. (kratom) has now planted its “roots” of use worldwide. It must also be noted that kratom is commonly taken Although the phenomenon has only been marginally studied, in combination with a variety of other recreational “classic an exponential number of kratom’s subjective experiences drugs” (e.g., alcohol, cannabis, benzodiazepines, methadone, have been posted online on drug fora by users in the EU cocaine, amphetamine, and hallucinogenic mushrooms) and and US and elsewhere. Kratom, still easily available in native NPS (e.g., , mephedrone, and other synthetic cathinones, countries, is now just “a click” away and potentially available 4 BioMed Research International

T89:1 $: Report of adverse/toxicological e*ects of kratom. Kratom pharmacology itself is complex and requires future research: this compound in fact acts on opioid as well Nausea, constipation, sleep problems, as on dopaminergic, serotonergic, GABAergic, and adren- Short time use e*ects temporary erectile dysfunction, ergic systems [$!,$5]. 'erefore, subjective e*ects are very itching, or sweating peculiar ranging from psychostimulant to sedative-narcotic. Anorexia, dry mouth, problems in Long time use e*ects Pharmacological mechanisms responsible for several of its diuresis, darker skin, and hair loss alkaloids activity deserve yet to be clearly established in future Hostility, aggression, aching of muscles studies. Altogether, available data on kratom suggest caution: Withdrawal and bones, jerky movements of the this unregulated plant could exhibit a serious harmful poten- symptoms limbs, anorexia and weight loss, and insomnia tial, far beyond any “therapeutic” desired e*ect; in parallel, its anxiolytic, antidepressant, and analgesic properties need to be Seizures (individuals using high doses better explored by scienti)c research works, like, for example, of kratom, either alone or combined with other drugs), intrahepatic in large blind randomized controlled clinical trials ["4]. Infrequent e*ects cholestasis, psychotic symptoms, Adult Potential users who tend to self-medicate and health Respiratory Distress Syndrome, and professionals working with them should be clearly aware of hypothyroidism the risks associated with kratom consumption [5"]. As it Kratom mixed with other substances: emerged from this and other previous studies [5&], kratom O-desmethyltramadol; is advertised and sold online as “cheaper alternative” to propylhexedrine; traditional opioid replacement therapies, as a painkiller for over-the-counter cold medications and chronic pain, or as an anxiolytic remedy in psychiatric Fatalities benzodiazepines; population, with no need of medical prescription or supervi- venlafaxine, diphenhydramine, and sion. 'is encourages a tendency to self-medicate and could mirtazapine; become a serious problem for unaware doctors prescribing zopiclone, citalopram, and lamotrigine medication to a patient who is a regular kratom user or in case of acute intoxication related to the substance. Another issue of concern is the action of other isolated compounds (e.g., speciociliatine, speciogynine, and paynantheine) whose to wide range of new users, including vulnerable individuals. e*ects were not inhibited by naloxone in animal studies ["", As it emerged from our previous studies [5,4"–44], the web "&], meaning a potentially very di3cult management in case serves also as a repository of information for selected groups, of overdose. 'erefore, in this scenario, the risk of adverse who can share experiences and suggest new products or reactions or possible misdiagnosis might be very high. It novel modalities of intake via online fora, chat-rooms, blogs, might also be worth adding that kratom use is not detected videos, and others. by conventional drug screening tests as advanced tests, like Anthropologically, drug addiction history is the complex liquid chromatography-tandem or ion-mass spectrometry, history of human vicissitude and desire, as human being is a are required [!]. We also reiterate here the importance of desiring being, trying in every way to assuage su*erings, to focusing and asking direct questions on the nature and enhance feelings of pleasure, and to satisfy inexhaustible and patterns of drug intake, including medical products diversion incessant desires [45]. Even today, the line between socially and consumption of NPS, during clinical assessments [5+]. acceptable and unlawful use of a variety of psychoactive Giventhatnowadayspolydruguserepresentsthenormrather products seems to be culture-bound. Kratom is a plant with than the exception, especially in emergency settings [5#], the awell-establishedtraditionaluseinSouthAsiatoenhance simultaneous use of drugs should also be promptly iden- work abilities as well as support traditional medicine and ti)ed, investigated, and well discriminated. Future studies culture, even if o3cially banned. At the same time, its rapid should explicitly examine the e*ects of the combination in di*usion in Western societies, where it is o(en considered a complex patterns of polydrug intake, including kratom, to “natural” and thus safer option than illicit drugs or an alter- fully understand the synergistic e*ects and associated clinical native to opioid treatment, is not devoid of risks. According and toxicological implications. Attention should also be paid to preclinical data and case reports published in scienti)c to the motivations behind such behaviours, social norms, literature as well as anecdotal experiences posted online, stigma, availability, and other lifestyle factors. kratom is not a safe drug. Its consumption is associated Surely, a possible limitation of our analysis could be per se with drug dependency, development of withdrawal given by the fact that publicly available websites, fora, and symptoms, craving, serious adverse e*ects, and life-threating similar sources were also considered and included together e*ects, especially in a multidrug-intoxicating scenario ["&, with a systematic literature review. One could wonder about 4#,4$,5#]. Furthermore, the idea that legality can equate the limitations of carrying out a risk assessment of a drug with the safety of a product might still remain a common while taking into account also the online comments. It may insidious misbelief amongst drug users [5$]. On the other be inappropriate to trust information obtained from the hand, Suwanlert has pointed out in $5!% that “it is hoped Internet without independent veri)cation and we did not that drug education will be a more e*ective step towards have any possibility here to ascertain if the substance the kratom use control” [$], foreseeing the failure of the legislative online alleged drug users were taking was indeed kratom. On measures in South Asian countries. the other hand, online reports about kratom seem genuine BioMed Research International 5

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