Kratom (Mitragyna speciosa) drug

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Chemistry
Physical form
Pharmacology
Origin
Mode of use
Other names
Analysis
Typical potency
Control status
Prevalence
Price
Medical use
Bibliography
Further reading

Mitragyna speciosa Korth. (of the Rubiaceae family) is a 4 to 16 metre high tropical
tree indigenous to South East Asia, the Philippines and New Guinea but now
cultivated elsewhere. In Thailand, the tree and leaf-preparations from it are called
kratom. Traditionally, fresh or dried kratom leaves are chewed or made into tea;
they are seldom smoked. At a low dose, kratom has stimulant effects and is used to
combat fatigue during long working hours. At high dosages, however, it can have
sedative-narcotic effects. It is also used in traditional medicine and as an opium
substitute. The phytochemicals isolated from various parts of the tree include over
40 structurally related alkaloids as well as several flavonoids, terpenoid saponins,
polyphenols, and various glycosides. The main psychoactive components in the
leaves are mitragynine and 7-hydroxymitragynine, both found only in Mitragyna
speciosa

Chemistry
Molecular structure: Mitragynine
Molecular formula: C23H30N2O4
Molecular weight: 398.50 g/mol
Mitragynine is the most abundant alkaloid in the leaves. It was first isolated in 1921
and its chemical structure was fully elucidated in 1964. The systematic (Chemical
Abstract) name is (E,2S,3S,12bS)-3-ethyl-1,2,3,4,6,7,12,12b-octahydro-8-methoxy-
-(methoxymethylene)-indolo[2,3-a]quinolizine-2-acetic acid methyl ester (CAS
Registry Number: 4098-40-2). Other names: (E)-16,17-didehydro-9,17-dimethoxy-
17,18-seco-20-yohimban-16-carboxylic acid methyl ester, 9-
methoxycorynantheidine, and SK&F 12711.

Mitragynine is insoluble in water but soluble in conventional organic solvents,

including acetone, acetic acid, alcohols, chloroform and diethyl ether providing
fluorescent solutions. Mitragynine distils at 230240 C at 5 mmHg. It forms white,
amorphous crystals that melt at 102106 C. The melting point of mitragynine
hydrochloric acid salt is 243C; the picrate melts at 223224 C and the acetate at
142 C.
Molecular structure: 7-hydroxymitragynine
Molecular formula: C23H30N2O5
Molecular weight: 414.50 g/mol
7-Hydroxymitragynine is present only in very small amounts in kratom leaves and
was identified in 1993. Its systematic (Chemical Abstract) name is
(E,2S,3S,7aS,12bS)-3-ethyl-1,2,3,4,6,7,7a,12b-octahydro-7a-hydroxy-8-methoxy--
(methoxymethylene)-indolo[2,3-a]quinolizine-2-acetic acid methyl ester (CAS
Registry Number: 174418-82-7).

The chemical total syntheses reported for several kratom alkaloids are too complex
to be used for economic production of any these compounds. However, mitragynine
can serve as a chemical precursor to the more potent 7-hydroxymitragynine.

Physical form
The leaves of the tree Mitragyna speciosa are oval or ovate-lanceolate and dark
green in colour and can grow to 180 mm long and 100 mm wide. The veins of the
leaves are either greenish-white or red the former is reputed to be more potent.
The average weight of a fresh and a dried leaf is about 1.7 and 0.43 g respectively.
The yellow and globular flowers of the tree bear up to 120 florets. The fruit is a
capsule containing numerous small flat seeds.
Kratom products are usually supplied as crushed or powdered dried leaves that are
light to dark green in colour. Powdery, greenish or beige-brown kratom preparations
fortified with extracts from other leaves are also available. Stable, paste-like
extracts and dark brown kratom resin can be made by partially or fully boiling down
the water from aqueous kratom leaf suspensions. Tinctures and capsules, filled with
powdered kratom, are also available.

Pharmacology
Kratom preparations contain several phytochemicals in varying ratios rendering
their proper pharmacological evaluation difficult. Human clinical studies are scarce.
In general, the effects of kratom in humans are dose-dependent: small doses
produce cocaine-like stimulation while larger dosages cause morphine-like
sedative-narcotic effects.
After taking a few grams of dried leaves, the invigorating effects and euphoria are
felt within 10 minutes and last for one to one and a half hours. Kratom users report
increased work capacity, alertness, sociability and sometimes heightened sexual
desire. The pupils are usually normal or very slightly contracted; blushing may be
noted. In one of the few human clinical experiments, a 50 mg oral dose of
mitragynine produced motor excitement, followed by giddiness, loss of motor
coordination (positive Rombergs test), and tremors of the extremities and face. For
regular kratom users, loss of weight, tiredness, constipation, and hyperpigmentation
of the cheek may be notable side effects. The pharmacological mechanism
responsible for stimulant activity is unclear.
Kratom taken in large, sedating doses corresponding to 1025 g of dried leaves may
initially produce sweating, dizziness, nausea and dysphoria but these effects are
shortly superseded with calmness, euphoria and a dreamlike state that last for up to
six hours. Contracted pupils (miosis) are noted.
Mitragynine and 7-hydroxymitragynine, the two alkaloids mainly responsible for the
effects of kratom, are selective and full agonists of the -subtype opioid receptor
(MOR). The receptor agonist effect of kratom alkaloids is antagonised by the opioid
receptor antagonist naloxone. In addition, 5-HT2a and postsynaptic 2-adrenergic
receptors, as well as neuronal Ca2+ channels are also involved in the unique
pharmacological and behavioural activity of mitragynine.
In animal studies, the antinociceptive and cough-suppressant effects of mitragynine
were comparable to those of codeine. In mice, 7-hydroxymitragynine was several
times more potent analgesic than morphine even upon oral administration.
Kratom is slightly toxic to animals. Mice chronically treated with 7-
hydroxymitragynine developed tolerance, cross-tolerance to morphine and
withdrawal signs that could be precipitated by naloxone administration.
Regular kratom use may produce dependence. The withdrawal symptoms in
humans are relatively mild and typically diminish within a week. Craving, weakness
and lethargy, anxiety, restlessness, rhinorrhea, myalgia, nausea, sweating, muscle
pain, jerky movements of the limbs, tremor as well as sleep disturbances and
hallucination may occur. Treatment, if needed, may include dihydrocodeine-
lofexidine combination, non-steroidal antiinflammatory agents, antidepressants
and/or anxiolytics.
The metabolism of mitragynine in humans occurs via hydrolysis of the side-chain
ester, O-demethylation of the methoxy groups, oxidative and/or reductive
transformations, and the formation of glucuronide and sulfate conjugates. In a man
who fatally overdosed propylhexedrine and kratom, the postmortem mitragynine
concentrations ranged from 0.01 mg/kg to 1.20 mg/l.
The consumption of kratom concomitantly with other drugs can provoke serious
side effects. In fact, adverse drug interactions involving kratom tea taken with
carisoprodol, modafinil, propylhexedrine or Datura stramonium have been reported.
A fatal case in the United States involved a blend of kratom, fentanyl,
diphenhydramine, caffeine and morphine sold as a herbal drug.

Origin
Dried kratom leaves sold in head/smart/herbal shops and over the Internet are
thought to originate from Mitragyna speciosa cultivated in South East Asia, most
likely in Indonesia (Bali kratom) where the plant is not controlled.

Origin
Dried kratom leaves sold in head/smart/herbal shops and over the Internet are
thought to originate from Mitragyna speciosa cultivated in South East Asia, most
likely in Indonesia (Bali kratom) where the plant is not controlled.
Other names
The genus was given its Mitragyna name by the Dutch botanist Korthals because
the leaves and the stigmas of the flowers of the plant resemble the shape of a
bishops mitre. Other names of the plant are krathom, kakuam, ithang or thom
(Thailand), biak-biak or ketum (Malaysia), and mambog (Philippines).
Analysis
The alkaloid composition of botanical and forensic samples can be analysed by
regular chromatographic and spectroscopic methods. Phylogenetic characterisation
of kratom samples by specific DNA nucleotide sequences can complement the
phytochemical analyses.
Kratom alkaloids can be separated by thin layer chromatography on silica gel plates
with detection by UV (254 nm). Upon spraying with either modified Ehrlichs reagent
or ferric chloride-perchloric acid reagent, mitragynine gives purple or grey-to-brown
spots, respectively.
The UV spectrum of the methanol solution of mitragynine shows a maximum at 225
nm with shoulders at 247, 285 and 293 nm. The characteristic absorption bands in
the IR spectrum of mitragynine are at 3 365, 1 690 and 1 640 cm -1. Significant
fragments in the electron impact ionisation mass spectrum (m/z): 398(M+), 383,
366, 269, 214, 200 and 186.
The UV spectrum of the ethanol solution of 7-hydroxymitragynine shows a
maximum at 220 nm with shoulders at 245 and 305 nm. The characteristic
absorption bands in the IR spectrum of 7-hydroxymitragynine in CHCl3 are at 3 590,
2 850, 2 820, 2 750, 1 700, 1 645, 1 630, 1 600, 1 490, 1 465 and 1 440 cm -1.
Significant fragments in the electron impact ionisation mass spectrum (m/z):
414(M+), 397, 383 and 367.
The parent alkaloids and their metabolites can be quantified in the urine at >100
ng/ml by GC-MS, at >25 ng/ml by HPLC-UV, and at >0.02 ng/ml for HPLC-MS. For
example, the concentration of mitragynine in a forensic urine sample of a regular
kratom user was 167 ng/ml (HPLC-MS). In a poisoning case, the blood serum
concentration of mitragynine two weeks after cessation of regular oral ingestions of
large doses (1421 grams daily) of dried kratom leaves was 0.020 ng/ml (HPLC-MS).
No conventional immunological drug screening test is known that will detect kratom
alkaloids.
Typical potency
The chemical composition of kratom in commercial products is unspecified and
depends on several factors, such as the particular variety and age of the plant, the
environment, and the time of harvest. The total alkaloid concentration in dried
leaves ranges from 0.51.5 %. In Thai varieties, mitragynine is the most abundant
component (up to 66 % of total alkaloids) while 7-hydroxymitragynine is a minor
constituent (up to 2 % of total alkaloid content). In Malaysian kratom varieties,
mitragynine is present at lower concentration (12 % of total alkaloids). The typical
mitragynine and 7-hydroxymitragynine concentrations in dried leaf or powdered
kratom products available in Japan were 1221 mg/g and 0.110.39 mg/g,
respectively; kratom resins contained 35.662.6 mg/g of mitragynine and 0.120.37
mg/g of 7-hydroxymitragynine.
According to GC-MS analysis of freshly made Malaysian ketum drinks, prepared by
extended boiling of fresh leaves in water, one 250 ml glass of ketum contained
22.525 mg mitragynine. About three such drinks a day are said to be sufficient to
diminish opiate withdrawal symptoms.
In the early 2000s, some obscure products labelled kratom acetate or mitragynine
acetate did not actually contain mitragynine. In recent years, products sold in
Germany and Sweden under the name Krypton as enhanced kratom preparations
turned out to contain caffeine and synthetic O-desmethyltramadol (ODT) as
adulterants. ODT is a bioactive metabolite of the synthetic opioid analgesic
tramadol and was apparently added to the herbal preparations to mimic the
sedative-narcotic effects of kratom.
Control status
Neither Mitragyna speciosa nor mitragynine or other alkaloids from the plant are
listed in any of the Schedules of the United Nations Drug Conventions. Mitragyna
speciosa and/or mitragynine and/or 7-hydroxymitragynine are currently (September
2011) controlled in a number of EU Member States such as Denmark, Latvia,
Lithuania, Poland, Romania and Sweden.
Other countries that control kratom under their narcotic law are Australia, Malaysia,
Myanmar and Thailand. New Zealand controls Mitragyna speciosa and mitragynine
under its Medicines Amendment Regulations. In the USA, kratom is not controlled
though considered as a drug of concern.

Prevalence
Kratom appeared on the global drug market only recently, thus there is no
information on the extent of its use outside South East Asia.
In Thailand, the National Household Surveys provide information on drug use
prevalence in that country. The 2007 Survey (26 633 respondents aged 1265
years) indicated that the lifetime, past year and past 30 days prevalences for
kratom were 2.32 %, 0.81 % and 0.57 %, respectively. These figures, with the
exception of lifetime use, were significantly higher than those for cannabis making
kratom the most widely used illicit drug in the country. Also in Thailand, lifetime,
past year and past 30-days prevalence studies among 13- to 16-year-old high-
school students (n = 8 70812 148) in 2002, 2003 and 2004 showed an increase in
the lifetime use of kratom (from 3.97 % to 9.43 %) and cannabis (from 4.44 % to
6.75 %), while a slight decrease was noted for the use of amphetamines (2.79 % to
2.32 %). Past year and past 30-days prevalence use data followed similar trends.
A recent roadside survey involving 1 635 motor vehicle drivers in Thailand revealed
the use of kratom by 0.9 % of the drivers, a prevalence close to that of cannabis
(1.1 %) but much lower than that of amphetamines (1.8 %).Internet surveys
conducted by the EMCDDA in 2008 indicated that kratom was one of the most
widely offered legal highs in 44 % of the investigated 27 European online shops
along with Salvia divinorum (74 %), Hawaiian Baby Woodrose seeds (48 %), Spice
smoking mixtures (37 %), and stimulant-containing capsules (59 %). A more
extensive EMCDDA Internet survey in July 2011 showed that kratom was the most
widely offered product with 128 out of 631 (or 20 %) of online retailers shipping it to
the EU. An Internet snapshot carried out in the UK in April 2009 showed that among
the 346 unique products offered by 39 shops kratom (n = 30) was second only to
Salvia divinorum (n = 44).

Price
Prices vary between countries and depend on the type and amount of the product
purchased. According to the EMCDDA Internet surveys conducted in 2008, the
prices of Kratom 15X extracts ranged from EUR 2.1 to 10.3 per gram in the
sampled European countries. In 2011, a follow-up EMCDDA snapshot of 314 online
shops found that prices ranged from EUR 6 to 15 per 10 gram of dried kratom and
EUR 7 to 8 per gram of Kratom 15X extract.

Medical use
Six Asian and four African Mitragyna species are known to be used in traditional
medicine but the stimulant/sedative-narcotic/psychoactive effects are characteristic
only for Mitragyna speciosa. In South East Asia, kratom is used as an antidiarrheal, a
cough suppressant, an antidiabetic, an intestinal deworming agent and wound
poultice as well as to wean addicts off heroin. Outside Asia, anecdotal use of kratom
preparations for the self-treatment of chronic pain and opioid withdrawal symptoms
and as a replacement for opioid analgesics have been reported. There is, however,
no approved use of kratom or its alkaloids in modern medicine. It has been
suggested that the therapeutic potential of kratom or its purified ingredients for the
treatment of pain, depression and drug withdrawal symptoms should be explored.
Bibliography
Adkins, J. E., Boyer, E. W., and McCurdy, C. R. (2011), Mitragyna speciosa, a
psychoactive tree from Southeast Asia with opioid activity, Current Topics in
Medicinal Chemistry, Volume 11, pp. 11651175.
Arndt, T., Claussen, U., Gssregen, B. et al. (2011), Kratom alkaloids and O-
desmethyltramadol in urine of a "Krypton" herbal mixture consumer, Forensic
Science International, Volume 208, pp. 4752.
Assanangkornchai, S., Muekthong, A., Sam-angsri, N., and Pattanasattayawong, U.
(2007), The use of Mitragynine [sic] speciosa ("Krathom"), an addictive plant, in
Thailand, Substance Use & Misuse, Volume 42, pp. 21452157.
Assanangkornchai, S., Pattanasattayawong, U., Samangsri, N., and Mukthong, A.
(2007), Substance use among high-school students in southern Thailand: Trends
over 3 years (20022004), Drug and Alcohol Dependence, Volume 86, pp. 167174.
Assanangkornchai, S., Aramrattana, A., Perngparn, U. et al. (2008), Current
situation of substance-related problems in Thailand, Journal of the Psychiatric
Association of Thailand, Volume 53 (Supplement 1), pp.24S36S.
Azizi, J., Ismail, S., Mordi, M. N. et al. (2010), In vitro and in vivo effects of three
different Mitragyna speciosa Korth leaf extracts on Phase II drug metabolizing
enzymesGlutathione transferases (GSTs), Molecules, Volume 15, pp. 432441.
Bckstrm, B., Classon, G., Lwenhielm, P., and Thelander, G. (2010), Krypton ny,
ddlig Internetdrog. Sedan oktober 2009 har nio unga personer dtt i Sverige
[Krypton, a deadly Internet drug. Nine dead in Sweden], Lkartidningen, Volume
107, pp. 31963197.
Beckett, A. H., Shellard, E. J., Phillipson, J. D., and Lee, C. M. (1966), The Mitragyna
species of Asia. Part. VII. Indole alkaloids from the leaves of Mitragyna speciosa
Korth, Planta Medica, Volume 14, pp. 277288.
Beckett, A. H., Dwuma-Badu, D., and Haddock, R. E. (1969), Some new mitragyna-
type indoles and oxindoles; The influence of stereochemistry on mass spectra,
Tetrahedron, Volume 25, pp. 59615969.
Botpiboon, O., Prutipanlai, S., Janchawee, B., and Thainchaiwattana, S. (2009),
Effect of caffeine and codeine on antinociceptive activity of alkaloid extract from
leaves of kratom (Mitragyna speciosa Korth.), Paper presented at The 35th
Congress on Science and Technology of Thailand, October 1517, 2009. The Tide
Resort (Bangsaen Beach) Chonburi, Thailand.
Boyer, E. W., Babu, K. M., Adkins, J. E., McCurdy, C. R., and Halpern, J. H. (2008),
Self-treatment of opioid withdrawal using kratom (Mitragyna speciosa korth),
Addiction, Volume 103, pp. 10481050.
Boyer, E. W., McCurdy, C. R., and Adkins, J. E. (2010), Methods for treating
withdrawal from addictive compounds, US Patent No. 2010/0209452 (Aug. 19,
2010).
Chan, K. B., Pakiam, C., and Rahim, R. A. (2005), Psychoactive plant abuse: the
identification of mitragynine in ketum and in ketum preparations, Bulletin of
Narcotics, Volume 57 (12), pp. 249256.
Chittrakarn, S., Penchumruth, P., and Krewpradub, N. (2009), Analysis of active
substances in kratom (Mitragyna speciosa Korth.) cocktail.
Chittrakarn, S., Sawangjaroen, K., Prasettho, S., Janchawee, B., and Keawpradub, N.
(2008), Inhibitory effects of kratom leaf extract (Mitragyna speciosa Korth.) on the
rat gastrointestinal tract, Journal of Ethnopharmacology, Volume 116, pp. 173178.
DEA (U.S. Drug Enforcement Administration) (2005), Herbal drug update: Kratom,
Microgram Bulletin, Volume 38(7), pp. 114115.
de Moraes, N. V., Corra Moretti, R. A., Furr, E. B., III, McCurdy, C. R., and Lanchote,
V. L. (2009), Determination of mitragynine in rat plasma by LC-MS/MS: Application
to pharmacokinetics, Journal of Chromatography B, Volume 877, pp. 25932597.
Dresen, S., Ferreirs, N., Ptz, M., Westphal, F., Zimmermann, R., and Auwrter, V.
(2010), Monitoring of herbal mixtures potentially containing synthetic cannabinoids
as psychoactive compounds, Journal of Mass Spectrometry, Volume 45, pp. 1186
1194.
Farah Idayu, N., Taufik Hidayat, M., Moklas, M. A. M., Sharida, F., Nurul Raudzah, A. R.
et al. (2011), Antidepressant-like effect of mitragynine isolated from Mitragyna
speciosa Korth in mice model of depression, Phytomedicine, Volume 18, pp. 402
407.
Field, E. (1921), Mitragynine and mitraversine, two new alkaloids from species of
Mitragyne, Journal of the Chemical Society. Transactions, Volume 119, pp. 887891.
Grewal, K. S. (1932), The effect of mitragynine on man, British Journal of Medical
Psychology, Volume 12, pp. 4158.
Hanapi, N. A., Azizi, J., Ismail, S., and Mansor, S. M. (2010), Evaluation of selected
Malaysian medicinal plants on Phase I drug metabolizing enzymes, CYP2C9, CYP2D6
and CYP3A4 activities in vitro, International Journal of Pharmacology, Volume 6, pp.
490495.
Hanna, J. (2003), Bogus Kratom market exposed, The Entheogen Review, Volume
12(1), pp. 2628.
Harizal, S. N., Mansor, S. M., Hasnan, J., Tharakan, J. K. J., and Abdullah, J. (2010),
Acute toxicity study of the standardized methanolic extract of Mitragyna speciosa
Korth in rodent, Journal of Ethnopharmacology, Volume 131, pp. 404409.
Havemann-Reinecke, U. (2011), Kratom and alcohol dependence: Clinical
symptoms, withdrawal treatment and pharmacological mechanisms A case
report, European Psychiatry, Volume 26 (Supplement 1), p. 50.
Hillebrand, J., Olszewski, D., and Sedefov, R. (2010), Legal highs on the Internet,
Substance Use & Misuse, Volume 45, pp. 330340.
Holler, J. M., Vorce, S. P., McDonough-Bender, P. C. et al. (2011), A drug toxicity
death involving propylhexedrine and mitragynine, Journal of Analytical Toxicology,
Volume 35, pp. 5459.
Houghton, P. and Shellard, E. (2006), Kratom chemistry, New Scientist, Volume 192
(4 November 2006), p. 25.
Ing, H. R., and Raison, C. G. (1939), The alkaloids of Mitragyne speciosa. Part I.
Mitragynine, Journal of the Chemical Society, pp. 986990.
Ingsathit, A., Woratanarat, P., Anukarahanonta, T. et al. (2009), Prevalence of
psychoactive drug use among drivers in Thailand: A roadside survey, Accident
Analysis and Prevention, Volume 41, pp. 474478.
Ishikawa, H., Takayama, H., and Aimi, N. (2002), Dimerization of indole derivatives
with hipervalent iodines(III): a new entry for the concise total synthesis of rac- and
meso-chimonantines, Tetrahedron Letters, Volume 43, pp. 56375639.
Jansen, K. L. R. and Prast, C. J. (1988), Ethnopharmacology of kratom and the
Mitragyna alkaloids, Journal of Ethnopharmacology, Volume 23, pp. 115119.
Joshi, B., Raymond-Hamet, and Taylor, W. I. (1963), Structure of mitragynine (9-
methoxycorynantheidine), Chemistry and Industry, (Issue 14), p. 573.
Kaewklum, S., Kaewklum, M., Pootrakronchai, R. et al. (2005), Detection of
mitragynine and its metabolite in urine following ingestion of leaves of Mitragyna
speciosa Korth, in Schnzer,W., Geyer, H., Gotzmann, A. and Mareck, U. (eds.),
Recent Advances in Doping Analysis (13). Sport und Buch Strau, Kln. pp. 403406.
Kapp, F. G., Maurer, H. H., Auwrter, V., Winkelman, M., and Hermanns-Clausen, M.
(2011), Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna
speciosa), Journal of Medical Toxicology, (in print) doi 10.1007/s13181-011-0155-5.
Kikura-Hanajiri, R., Kawamura, M., Maruyama, T. et al. (2009), Simultaneous
analysis of mitragynine, 7-hydroxymitragynine, and other alkaloids in the
psychotropic plant "kratom" (Mitragyna speciosa) by LC-ESI-MS, Forensic
Toxicology, Volume 27, pp. 6774.
Kronstrand, R., Roman, M., Thelander, G., and Eriksson, A. (2011), Unintentional
fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend
Krypton, Journal of Analytical Toxicology, Volume 35, pp. 242247.
Kumarnsit, E., Keawpradub, N., and Nuankaew, W. (2007), Effect of Mitragyna
speciosa aqueous extract on ethanol withdrawal symptoms in mice. Fitoterapia,
Volume 78, pp. 182185.
Kumarnsit, E., Vongvatcharanon, U., Keawpradub, N. and Intasaro, P. (2007), Fos-
like immunoreactivity in rat dorsal raphe nuclei induced by alkaloid extract of
Mitragyna speciosa, Neuroscience Letters, Volume 416, pp. 128132.
Len, F., Habib, E., Adkins, J. E. et al. (2009), Phytochemical characterization of the
leaves of Mitragyna speciosa grown in USA, Natural Products Communications,
Volume 4, pp. 907910.
Lu, S., Tran, B. N., Nelsen, J. L., and Aldous, K. M. (2009), Quantitative analysis of
mitragynine in human urine by high performance liquid chromatography-tandem
mass spectrometry, Journal of Chromatography B, Volume 877, pp. 24992505.
Ma, J., Yin, W., Zhou, H., Liao, X., and Cook, J. M. (2009), General approach to the
total synthesis of 9-methoxy-substituted indole alkaloids: synthesis of mitragynine,
as well as 9-methoxygeissoschizol and 9-methoxy-Nb-methylgeissoschizol, Journal
of Organic Chemistry, Volume 74, pp. 264273.
Macko, E., Weisbach, J. A., and Douglas, B. (1972), Some observations on the
pharmacology of mitragynine, Archives Internationales de Pharmacodynamie et de
Thrapie, Volume 198, pp. 145161.
Maruyama, T., Kawamura, M., Kikura-Hanajiri, R. et al. (2009), The botanical origin
of kratom (Mitragyna speciosa; Rubiaceae) available as abused drugs in the
Japanase markets, Journal of Natural Medicine, Volume 63, p. 340344.
Matsumoto, K., Mizowaki, M., Suchitra, T. et al. (1996), Central antinociceptive
effects of mitragynine in mice: contribution of descending noradrenergic and
serotonergic systems, European Journal of Pharmacology, Volume 317, pp. 7581.
Matsumoto, K., Mizowaki, M., Takayama, H. et al. (1997), Suppressive effect of
mitragynine on the 5-methoxy-N,N-dimethyltryptamine-induced head-twitch
response in mice, Pharmacology, Biochemistry and Behavior, Volume 57, pp. 319
323.
Matsumoto, K., Horie, S., Ishikawa, H. et al. (2004), Antinociceptive effect of 7-
hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the
Thai medicinal herb Mitragyna speciosa, Life Sciences, Volume 74, pp. 21432155.
Matsumoto, K., Horie, S., Takayama, H. et al. (2005), Antinociception, tolerance and
withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai
medicinal herb Mitragyna speciosa, Life Sciences, Volume 78, pp. 27.
Matsumoto, K., Yamamoto, L. T., Watanabe, K. et al. (2005), Inhibitory effect of
mitragynine, an analgesic alkaloid from Thai herbal medicine, on neurogenic
contraction of the vas deferens, Life Sciences, Volume 78, pp. 187194.
Matsumoto, K., Hatori, Y., Murayama, T. et al. (2006), Involvement of -opioid
receptors in antinociception and inhibition of gastrointestinal transit induced by 7-
hydroxymitragynine, isolated from Thai herbal medicine Mitragyna speciosa,
European Journal of Pharmacology, Volume 549, pp. 6370.
Matsumoto, K., Takayama, H., Ishikawa, H. et al. (2006), Partial agonistic effect of
9-hydroxycorynantheidine on -opioid receptor in the guinea-pig ileum, Life
Sciences, Volume 78, pp. 22652271.
Matsumoto, K., Takayama, H., Narita, M. et al. (2008), MGM-9 [(E)-methyl 2-(3-
ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-
methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate], a derivative of the indole
alkaloid mitragynine: A novel dual acting - and -opioid agonist with potent
antinociceptive and weak rewarding effects in mice, Neuropharmacology, Volume
55, pp. 154165.
McWhirter, L., and Morris, S. (2010), A case report of inpatient detoxification after
kratom (Mitragyna speciosa) dependence, European Addiction Research, Volume
16, pp. 229231.
Nelsen, J. L., Lapoint, J., Hodgman, M. J., and Aldous, K. M. (2010), Seizure and
coma following kratom (Mitragyna speciosa) exposure, Journal of Medical
Toxicology, Volume 6, pp. 424426.
Parthasarathy, S., Ramanathan, S., Ismail, S. et al. (2010), Determination of
mitragynine in plasma with solid-phase extraction and rapid HPLCUV analysis, and
its application to a pharmacokinetic study in rat, Analytical and Bioanalytical
Chemistry, Volume 397, pp. 20232030.
Philipp, A. A., Wissenbach, D. K., Zoerntlein, S. W. et al. (2009), Studies on the
metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and
human urine using liquid chromatography-linear ion trap mass spectrometry,
Journal of Mass Spectrometry, Volume 44, pp. 12491261.
Philipp, A. A., Meyer, M. R., Wissenbach, D. K. et al. (2011), Monitoring of kratom or
Krypton intake in urine using GC-MS in clinical and forensic toxicology, Analytical
and Bioanalytical Chemistry, Volume 400, pp. 127135.
Philipp, A. A., Wissenbach, D. K., Weber, A. A., Zapp, J., and Maurer, H. H. (2011),
Metabolism studies of the Kratom alkaloids mitraciliatine and isopaynantheine,
diastereomers of the main alkaloids mitragynine and paynantheine, in rat and
human urine using liquid chromatographylinear ion trap-mass spectrometry,
Journal of Chromatography B, Volume 879, pp. 10491055.
Phillipson, J. D., and Hemingway, S. R. (1975), Chromatographic and spectroscopic
methods for the identification of alkaloids from herbarium samples of the genus
Uncaria, Journal of Chromatography, Volume 105, pp. 163178.
Ponglux, M., Wongseripipatana, S., Takayama, H. et al. (1994), A new indole
alkaloid, 7-hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand, Planta
Medica, Volume 60, pp. 580581.
Posch, T., Ptz, M., and Huhn, C. (2011), Forensic analysis of biogenic recreational
drugs by non-aqueous capillary electrophoresis mass spectrometry, Toxichem
Krimtech, Volume 78(2), p. 120.
Reanmongkol, W., Keawpradub, N., and Sawangjaroen, K. (2007), Effects of the
extracts from Mitragyna speciosa Korth. leaves on analgesic and behavioral
activities in experimental animals, Songklanakarin Journal of Science & Technology,
Volume 29 (Supplement 1), pp. 3948.
Roche, K. M., Hart, K., Sangalli, B., Lefberg, J., and Bayer, M. (2008), Kratom: A case
of a legal high, Clinical Toxicology, Volume 46(7), p. 598.
Sabetghadam, A., Ramanathan, S., and Mansor, S. M. (2010), The evaluation of
antinociceptive activity of alkaloid, methanolic, and aqueous extracts of Mitragyna
speciosa Korth leaves in rats, Pharmacognosy Research, Volume 2(3), pp. 181185.
Schmidt, M. M., Sharma, A., Schifano, F., and Feinmann, C. (2011), "Legal highs" on
the netEvaluation of UK-based Websites, products and product information,
Forensic Science International, Volume 206, pp. 9297.
Shellard, E. J. (1974), The alkaloids of Mitragyna with special reference to those of
Mitragyna speciosa, Korth, Bulletin on Narcotics, Volume 26(2), pp. 4155.
Shellard, E. J., and Lees, M. D. (1965), The Mitragyna species of Asia. Part V. The
anatomy of the leaves of Mitragyna speciosa Korth, Planta Medica, Volume 13, pp.
280290.
Solberg, U. (2011), EMCDDA Internet monitoring, Presentation at the 11th Annual
meeting of the Reitox Early-warning system network, 11 May, 2011. Lisbon,
Portugal.
Sukrong, S., Zhu, S., Ruangrungsi, N. et al. (2007), Molecular analysis of the genus
Mitragyna existing in Thailand based on rDNA ITS sequences and its application to
identify a narcotic species: Mitragyna speciosa, Biological and Pharmaceutical
Bulletin, Volume 30, pp. 12841288.
Suwanlert, S. (1975), A study of kratom eaters in Thailand, Bulletin of Narcotics,
Volume 27(3), pp. 2127.
Takayama, H. (2004), Chemistry and pharmacology of analgesic indole alkaloids
from the rubiaceous plant, Mitragyna speciosa, Chemical and Pharmaceutical
Bulletin, Volume 52, pp. 916928.
Takayama, H., Maeda, M., Ohbayashi, S. et al.(1995), The first total synthesis of (-)-
mitragynine, an analgesic indole alkaloid in Mitragyna speciosa, Tetrahedron
Letters, Volume 36, pp. 93379340.
Takayama, H., Ishikawa, H., Kurihara, M. et al. (2002), Studies on the synthesis and
opioid agonistic activities of mitragynine-related indole alkaloids: Discovery of
opioid agonists structurally different from other opioid ligands, Journal of Medicinal
Chemistry, Volume 45, pp. 19491956.
Tanguay, P. (2011), Kratom in Thailand, (Series on Legislative Reform of Drug
Policies No. 13): Transnational Institute International Drug Policy Consortium.
Amsterdam and London.

Taufik Hidayat, M., Apryani, E., Nabishah, B. M. et al. (2010), Determination of

mitragynine bound opioid receptors, Advances in Medical and Dental Sciences,
Volume 3(3), pp. 6570.
The Irish Times (2011), Coroner warns on using herbal tea with other substances,
(June 9, 2011).
The United States Attorneys Office, District of Alaska (2011), Florida man pleads
guilty to manufacturing and sending synthetic drug to Alaska, Press Release. July
27, 2011.
Thongpradichote, S., Matsumoto, K., Tohda, M. et al. (1998), Identification of opioid
receptor subtypes in antinociceptive actions of supraspinally-administered
mitragynine in mice, Life Sciences, Volume 62, pp. 13711378.
Tungtananuwat, W., and Lawanprasert, S. (2010), Fatal 4x100: Home-made kratom
juice cocktail, Journal of Health Research, Volume 24, pp. 4347.
United Nations Office on Drugs and Crime (2010), Patterns and Trends of
Amphetamine-Type Stimulants and Other Drugs: Asia and the Pacific . United Nations
Office on Drugs and Crime, Vienna.
Verachai, V., and Nilbun, S. (2005), [Clinical symptoms of kratom dependence],
Bulletin of the Department of Medical Services, Volume 30(6), pp. 310313 (in Thai
with English summary).
Vicknasingam, B., Narayanan, S., Beng, G. T., and Mansor, S. M. (2010), The
informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern
states of peninsular Malaysia and implications for drug substitution therapy,
International Journal of Drug Policy, Volume 21, pp. 283288.
Yamamoto, L. T., Horie, S., Takayama, H. et al. (1999), Opioid receptor agonistic
characteristics of mitragynine pseudoindoxyl in comparison with mitragynine
derived from Thai medicinal plant Mitragyna speciosa, General Pharmacology,
Volume 33, pp. 7381.
Zacharias, D. E., Rosenstein, R. D., and Jeffrey, G. A. (1965), The structure of
mitragynine hydroiodide, Acta Crystallographica, Volume 18, pp. 10391043.
Zarembo, J. E., Douglas, B., Valenta, J., and Weisbach, J. A. (1974), Metabolites of
mitragynine, Journal of Pharmaceutical Sciences, Volume 63, pp. 14071415.
Further reading
http://www.murple.net/yachay/index.php/kratom
Rtsch, C. (2005), The Encyclopedia of Psychoactive Plants. Ethnopharmacology
and Its Applications, Park Street Press, Rochester, Vermont. ISBN: 0-89281-978-2.
Siebert, D. (2008), The Kratom Users Guide