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Family Rubiaceae
Mambog
Mitragyna speciosa Korth.
KRATOM

Scientific names Common names
Mitragyna speciosa Korth. Lugub (Mand.)
Nauclea speciosa Miq . Mambog (Tag.)
Nauclea luzoniensis Blanco. Polapupot (Ibn.)
Nauclea korthaisii Steud. Biak-biak (Malaysia)
Stephegyne speciosa Korth . Ketum (Thai.)
  Kratom (Thai., Engl.)

Street names
Thang, Kakuam, Thom, Ketum, Biak.

Botany
Mambog is a forest tree that grows to a height of 10 to 25 meters. Leaves are elliptic, 8.5 to 14 centimeters long, 5 to 10 centimeters wide, smaller at the ends of the branchlets, pointed at the tip, rounded or somewhat heart-shaped at the base, and hairy on the nerves beneath. Petioles are 2 to 4 centimeters long. Flowers are yellow, crowded in round, terminal inflorescences 3 to 5 centimeters long, the flowering heads consisting of up to 120 florets each. Calyx-tube is short and cup-shaped, with rounded lobes. Corolla tube is 5 millimeters long, smooth without and hairy within; the lobes 3 millimeters long, smooth and revolute in the margins. Fruit is oblong-ovoid and 5 to 7 millimeters long, with 10 ridges.

Distribution
- In forests at low altitudes in Cagayan Province in Luzon; in Mindoro and Mindanao.
- Indigenous to Thailand, Malaysia, Myanmar.
- Also occurs in Borneo and New Guinea.

Constituents
- Over 25 alkaloids have been isolated from kratom, and mitragynine is the primary active alkaloid in the plant.
- Mitragynine (C22H31O5N), an indole alkaloid, was first isolated from the leaves in 1907.

- Study of alkaloid constituents of young leaves have isolated mitragynine as the major constituent (66.2%), together with analogues, speciogynine (6.6%), speciociliatine (0.8%), and paynantheine (8.6%).
- Another indole, reported in the mid-90s, 7-hydroxymitragynine, C23H30,N2O5, is present in much lesser amounts, 2% of total alkaloids, but with the most potent opioid agonist and analgesic effect. On animal studies, the analgesic activity is reported to be 10x - 17x that of morphine. Other potency comparisons with morphine is from 6x, orally, with better oral absorption, and 2x, subcutaneously.
- Another analogue, 9-hydroxycorynantheidine, a 9-dimethyl analogue of mitragynine, showed a partial agonist effect on opioid receptors in guinea-pig ileum.

Properties
- Produces
both stimulant and sedative effects.
- Of the major alkaloids, mitragynine is a stimulant, and 7-hydroxymitragynine is sedative and analgesic acting primarily as an agonist at the u-opioid receptor.
- Mitragynine showed opioid-activity in animals. It inhibits electrically stimulated ileum and vas deferens smooth muscle contraction. Through action on centrally located opioid receptor, it inhibits gastric secretion and reduces pain response.
- At low doses, it produces increased alertness and energy, talkativeness and sociable behavior.
- At high dose, it causes sedative and euphoric effects and a narcotic analgesic (opium-like) effect.
- Long tern use causes anorexia, weight loss, insomnia, skin darkening, mouth dryness, frequent urination and constipation.
- A withdrawal syndrome may occur and manifest as emotional lability, hostility, aggression, aching muscles and bones, jerky movements of the limbs.
- CNS effects may include kratom psychosis, hallucinations, delusion, and confusion.
- Reported to possess morphine-like properties, antitussive, anesthetic, antinociceptive, analgesic.
- Kratom consumption can lead to addiction.

Parts used
Leaves.

Uses

Edibility
- Thai and Malaysian natives traditionally consume the leaves by chewing, smoking, or drinking it as tea, mainly for its euphoric and stimulant effect.
Folkloric
- In Perak, pounded leaves applied to wounds.
- Whole heated leaves applied over enlarged spleens.
- Poultice of leaves applied to upper abdomen used for expulsion of worms in children.
- Long used in tropical areas for its opium- and coca-like effects.
- In Thailand and Malaysia, reported use as stimulant, to combat fatigue and enhance physical endurance.
- Leaves used for fever, coughs, malaria, diarrhea and as tonic.
- Leaves used to treat diarrhea, intestinal infections by amoeba and protozoa.
Opioid substitute
- In Malaya, leaves are chewed, prepared as tea or infusion from leaves, or smoked as dried leaves or kratom resin. Opium smokers use it as a substitute for opium when the latter is not procurable.
- As a drug, leaves are swallowed in a cup of cold water or infused with hot water and drunk as tea.
- Syrup may be smoked, in the manner of opium, in a pipe.
- Used to wean addicts off morphine.
- It is controlled in Thailand, Malaysia and Myanmar. In Australia, kratom and mitragynine were designated a 'most restricted' Schedule 9.
- In the United Kingdom, kratom is promoted as a "herbal speedball."


Studies

Opioid Withdrawal Use: (1) Kratom has been reported as a traditional alternative to manage drug withdrawal symptoms in Malaysia. Report described it as affordable and easily available with no serious side effects despite prolonged use, and allows self-treatment that avoids stigmatization as a drug dependent. The claims merit further and serious scientific investigation, with the potential as a low-cost alternative therapy, especially in developing countries. (2) In a cross-sectional study in Malaysia (see below), 87% reported they were not able to stop using MS.
Analgesic / Behavioral Activities: Study on analgesic and behavioral activities of the methanol and alkaloid extracts of Mitragyna speciosa showed it possessed analgesic activity which partly acted at opioid receptors in the supraspinal opioid system. It produced no significant prolongation of latency in nociceptive response.
Sedating Effects: Study results suggest that mitragynine possess sedative properties acting on the CNS of rats. The methanol and alkaloid extracts produced no significant changes in locomotor activity.
Urine Alkaloid Markers: Study reports a simple urine extraction procedure for routine GC-MS analysis and suggests two major alkaloids in urine samples as markers of kratom consumption: mitragynine and speciogynine.

Effect on Drug Metabolizing Enzyme Glutathione Transferases (GSTs): Data showed concentration-dependent inhibition of cytosolic GSTs when MS extract was added to the reaction mixture. Only MS aqueous extract at dosage of 100 mg/kg showed significant results. GSTs are dimeric enzymes involved in the detoxification of toxic and carcinogenic compounds in the cells. GSTs also act as antioxidant enzymes due to their selenium-independent GSH peroxidase activity.
Anti-Diarrheal: Study showed methanolic extracts of leaves caused a dose-dependent protection against castor-oil induced diarrhea in rats and also inhibited intestinal transit. The anti-diarrheal effect was not antagonized by naloxone. The effect may occur via pathways in addition to the action on opioid receptors.
Memory / Cognitive Behavioral Effects: Study suggests that the chronic administration of mitragynine can alter cognitive behavioral function in mice.
Antinociceptive / Anti-Inflammatory: (1) Study in rodents suggests the presence of potent antinociceptive and anti-inflammatory principles in the methanol extract, with significant dose-dependent activity in all nociceptive models and dose dependent suppression of carrageenan-induced paw edema.
(2) Study showed the antinociceptive effect of mitragynine was less potent than the crude extract of Mitragyna speciosa, suggesting that one or more minor constituents of MS may have a very potent antinociceptive effect.
Neuromuscular Blockade: Study investigated the effects of mitragynine and a methanolic extract of kratom leaves on neuromuscular junction and compound nerve action potential. The ME and mitragynine blocked nerve conduction, amplitude and duration of compound nerve action potential. Muscle contraction was greater with with extract. The dominant effect of the K extract was at the neuromuscular junction and not at the skeletal muscle or somatic nerve.
Alcohol Withdrawal Benefit / Antidepressant Effect: Administration of the aqueous extract of MS at dose of 300 mg/K significantly inhibited ethanol-induced withdrawal behaviors such as rearing, displacement and head weaving. It also showed antidepressant activity without affecting spontaneous motor activity.
Acute Toxicity Study: Oral administration of methanolic extract in rats resulted in increased blood pressure. The highest extract dose also induced acute severe hepatotoxicity and mild nephrotoxicity.
Mitragynine / Glucose Muscle Transport Effect: Study evaluated various leaf extracts and major constituent mitragynine for enhancement of glucose transport. Results showed significant increase in rate of glucose intake, associated with increase in GLUT1 protein content. Increase glucose transport was associated with increases in activities of key enzymes dependent on the insulin-stimulated glucose transport for its acute action.
Cytochrome P450 Toxicity Study: Study on alkaloid extract showed most potent inhibitory effect on CYP3A4 and CYP2D6
Hepatotoxicity: Case report from Germany describes a 25-year old man who developed intrahepatic cholestasis after taking an overdose of kratom power.
Cross-Sectional Study / Malaysia: Of 562 respondents, 88% reported daily use. The main mode of use was drinking of extract as tea, 90%. Mean age was 28.3. Reasons for use: social and recreational needs, stamina and physical endurance, pain relief and improvement of sexual performance. As for use in weaning off opiate addiction, 87% they were not able to stop using MS.

DEA Info
Kratom / Drugs and Chemicals of Concern: Kratom has been used by natives of Thailand and other Southeast Asian regions as a herbal drug for decades, traditionally leaf-chewing as a herbal stimulant to overcome the fatigue associated with hard work. It has also been used as an opium substitute. and also to manage opium withdrawal symptoms in chronic opioid users. In 1943, Thailand passed Kratom Act 2486 that made the planting of the tree illegal. In 1979, the Thai government enacted Narcotics Act B.E. 2522, placing Kratom with marijuana in Category V of narcotics. It continues to be a popular drug in Thailand, rating in December 2006, as the third most popular drug in southern Thailand, after methamphetamine and marijuana.
4X100: The 4x100 is a concoction reported used by Thai militants - a mixture of boiled kratom leaves, mosquito coils, and cola or a mixture of boiled cough syrup, kratom leaves and cola served with ice. The concoction is reported to to induce or increase "boldness" and "fearlessness."
Addiction: Consumption can lead to addiction. Long-term use can cause anorexia, weight loss, insomnia, skin darkening, dry mouth, frequent urination, and constipation.
Withdrawal: Symptoms consist of hostility, aggression, emotional lability, wet nose, achy muscles and bones, jerky extremity movements. Kratom psychoses has been observed, with hallucinations, delusions, and confusion.

Mutagenicity Study: With its potential for use in opioid withdrawal management, study was done to investigate any potential mutagenic effect. Studies have suggested indole alkaloids to possess antimicrobial activity. Results showed high dose mitragynine and total alkaloid extract of M. speciosa inhibited the growth of revertant colonies, suggesting mitragyine and total alkaloids of MS were non- mutagenic with antimicrobial activities.

Availability
Wild-crafted.
Leaves, powders, extracts, encapsulated powder and extract resin "pies" in the cybermarket.
Seeds and trees reportedly sold by web vendors.

Last Update August 2012

IMAGE SOURCE: Large Mitragyna speciosa leaf / File:Mitragyna speciosa Leaf.JPG / Uomo Vitruviano / Creative Commons Attribution / Wikimedia Commons
OTHER IMAGE SOURCE: Mitragyna speciosa leaves / File:Mitragyna speciosa111.JPG / Uomo Vitruviano / GNU Free Documentation License / Wikimedia Commons
OTHER IMAGE SOURCE: Mitragyna speciosa / Flower and leaf / AllProHerbs

Additional Sources and Suggested Readings
(1)
The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy / Balasingam Vicknasigam et al / The International Journal of Drug Policy,
Volume 21, Issue 4, Pages 283-288 (July 2010)
(2)
Effects of the extracts from Mitragyna speciosa Korth. leaves on analgesic and behavioral activities in experimental animals / Wantana Reanmongkol et al / Songklanakarin J. Sci. Technol., Vol.29 (Suppl. 1), March 2007 : Thai Herbs II
(3)
Analysis of Mitragyna speciosa (kratom) alkaloids in human urine as a marker of chronic kratom abuse: Preliminary results / Charoendee Pingsuthiwong et al / Bureau of Drug and Narcotics, Department of Medical Sciences, Ministry of Public Health, Nonthaburi 11000, Thailand.
(4)
In Vitro and in Vivo Effects of Three Different Mitragyna speciosa Korth Leaf Extracts on Phase II Drug Metabolizing Enzymes—Glutathione Transferases (GSTs)
/ Juzaili Azizi et al / Molecules 2010, 15, 432-441; doi:10.3390/molecules15010432
(5)
Inhibitory effects of kratom leaf extract (Mitragyna speciosa Korth.) on the rat gastrointestinal tract / Somsmorn Chittrakarn et al / doi:10.1016/j.jep.2007.11.032
(6)
Study on glucose transport in muscle cells by extracts from Mitragyna speciosa (Korth) and mitragynine / Juntipa Purintrapiban et al / Natural Product Research, 10 October 2008 / DOI: 10.1080/14786410802267627
(7)
Effects of mitragynine from Mitragyna speciosa Korth leaves on working memory / Evhy Apryani, M Taufik Hidayat, M A A Moklas, S Fakurazi and N Farah Idayu /
Journal of Ethnopharmacology, Vol 129, Issue 3, 16 June 2010, Pages 357-360 / doi:10.1016/j.jep.2010.03.036
(8
Anti-Inflammatory and Antinociceptive Effects of Mitragyna speciosa Korth Methanolic Extract / W.M. Shaik Mossadeq, M R Sulaiman et al / Med Princ Pract 2009;18:378-384 (DOI: 10.1159/000226292)
(9)
The neuromuscular blockade produced by pure alkaloid, mitragynine and methanol extract of kratom leaves (Mitragyna speciosa Korth.) / Chittrakarn S, Keawpradub N et al / J Ethnopharmacol. 2010 Jun 16;129(3):344-9. Epub 2010 Apr 3.
(10)
Pharmacological Studies on 7-Hydroxymitragynine, Isolated from the Thai Herbal Medicine Mitragyna speciosa: Discovery of an Orally Active Opioid Analgesic / Kenjiro Matsumoto / 2006
(11)
Effect of Mitragyna speciosa aqueous extract on ethanol withdrawal symptoms in mice / Ekkasit Kumarnsit et al / Fitoterapia, Volume 78, Issue 3, April 2007, Pages 182-185 / doi:10.1016/j.fitote.2006.11.01
(12)
Acute toxicity study of the standardized methanolic extract of Mitragyna speciosa Korth in rodent. / Harizal SN, Mansor SM, Hasnan J, Tharakan JK, Abdullah J. / J Ethnopharmacol. 2010 Sep 15;131(2):404-9. Epub 2010 Jul 17.
(13)
Study on glucose transport in muscle cells by extracts from Mitragyna speciosa (Korth) and mitragynine. / Purintrapiban J, Keawpradub N, Kansenalak S, Chittrakarn S, Janchawee B, Sawangjaroen K. / Nat Prod Res. 2011 Sep;25(15):1379-87. Epub 2011 Jul 8.
(14)
KRATOM (Mitragyna speciosa korth) / US DEA, Office of Diversion Control
(15)
Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay / Wai Mun Kong, Zamri Chik, Murali Ramachandra, Umarani Subramaniam, Raja Elina Raja Aziddin and Zahurin Mohamed / Molecules 2011, 16, 7344-7356; doi:10.3390/molecules16097344
(16)
Intrahepatic Cholestasis Following Abuse of Powdered Kratom (Mitragyna speciosa) / Kapp FG et al. / J Med Toxicol 2011 April 29.
(17)
KRATOM (Mitragyna speciosa korth) / Drugs and Chemicals of Concern / DEA -Office of Diversion Control
(18)
MUTAGENICITY STUDIES OF MITRAGYNINE AND TOTAL ALKALOID OF MITRAGYNA SPECIOSA / MOHAMAD YUSUF BIN MAT ABDULLAH / Dissertation/ November 2010 / UNIVERSITI TEKNOLOGI MARA
(19)
Mitragyna speciosa use in the northern states of Malaysia: a cross-sectional study.
/ Ahmad K, Aziz Z. / J Ethnopharmacol. 2012 May 7;141(1):446-50. Epub 2012 Mar 14.


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