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.
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 (αE,2S,3S,12bS)-3-ethyl-1,2,3,4,6,7,12,12b-octahydro-8-methoxy-α-(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-20α-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 230–240 °C at 5 mmHg. It forms white, amorphous crystals that melt at 102–106 °C. The melting point of mitragynine hydrochloric acid salt is 243°C; the picrate melts at 223–224 °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 (αE,2S,3S,7aS,12bS)-3-ethyl-1,2,3,4,6,7,7a,12b-octahydro-7a-hydroxy-8-methoxy-α-(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.
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.
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 Romberg’s 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 10–25 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 μ-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 α2-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.
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.
Traditionally, the fresh or dried leaves of kratom are chewed or brewed into tea. When making tea, lemon juice is often added to facilitate the extraction of plant alkaloids; before drinking, sugar or honey may be added to mask the bitter taste of the brew. The dried leaves are occasionally smoked.
To experience vigour and euphoria, traditional ‘kratom eaters’ chew one to three fresh leaves at a time. The veins are usually removed from the leaves before eating and sometimes salt is added ‘to prevent constipation’. Only the masticated material is swallowed. Consumption is followed by drinking warm water or coffee, tea or palm sugar syrup. Regular and addicted users chew 3 to 10 times a day. When kratom is not available, the leaves of Mitragyna javanica (other name Mitragyna parvifolia) are used as substitute.
In southern Thailand, in recent years homemade ice-cold cocktails, called ‘4x100’, have become popular for their alleged alcohol-mimicking effect among young Muslim people. The cocktails are made from kratom leaves, a caffeine-containing soft drink, and codeine- or diphenhydramine-containing cough syrup as the three basic ingredients to which ice cubes, an anxiolytic, an antidepressant or an analgesic drug is added.
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 bishop’s mitre. Other names of the plant are krathom, kakuam, ithang or thom (Thailand), biak-biak or ketum (Malaysia), and mambog (Philippines).
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 Ehrlich’s 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 (14–21 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.
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 0.5–1.5 %. 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 12–21 mg/g and 0.11–0.39 mg/g, respectively; kratom resins contained 35.6–62.6 mg/g of mitragynine and 0.12–0.37 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 22.5–25 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.
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’.
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 12–65 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 = 8 708–12 148) 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).
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.
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.
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