Gen info

Genus name Mitragyna was given by the Dutch botanist Korthais because the leaves and stigmas of the flowers resemble the shape of the bishop's mitre. (25) 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. Different strains of kratom are grouped by leaf morphology: green veim (Yakyai), white vein (Tang gua), and red veins (Kan daeng). Maeng Da is a genetically enhanced form of Thai Kratom thought to be most potent. 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. The three most abundant indole alkaloids are mitragynine, paynanthine and speciogynine. 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.

- The two alkaloids, mitragynine and 7-hydroxymitragynine, are mainly responsible for the effects of kratom. They are selective and full agonists of the µ-subtype opioid receptor MOR. The receptor agonist effects are antagonized by the opioid receptor antagonist naloxone.

- Chemical synthesis for several kratom alkaloids are too complex for economic production. However, mitragine can be used as chemical precursor to the more potent 7-hydroxymitragynine. (25)

- 7-hydroxymitragynine is considered 40 times more potent than MG at the mu opioid receptor level.

- 7α-hydroxy-7H-mitragynine (7-OH MG) is a minor constituent (2.0% based on the crude base (Ponglux et al. 1994)) of the leaves. The antinociceptive activity of 7-OH-MG is approximately 40-fold more potent than mitragynine and approximately 10-fold more potent than morphine (Matsumoto et al. 2004). (38)

- Another analogue, 9-hydroxycorynantheidine, a 9-dimethyl analogue of mitragynine, showed a partial agonist effect on opioid receptors in guinea-pig ileum.

- Study of Thai kratom extract composition from various parts of the tree yielded 40 structurally related alkaloids viz. mitragynine 66% (primary active alkaloids), paynantheine, speciogynine, hydroxymitragynine, speciocilitine, and others, as well as several flavonoids, terpenoid saponins, polyphenols and various glycosides. (Biomed Res. Int. 2015: 2015) (26)

- Studies have yielded varying alkaloid contents and concentrations: almalicine (Raubasine), akuammgine, ciliaphylline <1%, corynantheidine <1%, corynoxeine <1%, corynoxine A and B <1%, epicatechin, 9-hydroxycorynantheidine, 7-hydroxymitragynine ±2%, isomitraphylline <1%, isomitrafoline <1%, isopteropodine, isorhynchophylline <1%, isospeciofoline <1%, mitracillatine <1%, mitragynine 66%, mitragynine oxindole B <1%, mitrafoline <1%, mitraphylline <1%, mitraversine, paynantheine 8.6% to 9%, rhynchophylline <1%, speciocillatine 0.8% to 1%, speciofoline, speciogynine 6.6%-7%, speciophylline <1%, stipulatine, and tetrahydroalstonine. (45)



Properties

- Alkaloidal extracts of leaves have showed very potent anti-inflammatory, analgesic and opioid properties.

- At low doses, kratom has stimulant effects; at high doses, sedative-narcotic 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, about 10 to 25 g of dried leaves, it causes sedative and euphoric effects and a narcotic analgesic (opium-like) effect. Early symptoms are sweating, dizziness, nausea, and dysphoria followed by euphoria and a dreamlike state that may last up to six hours.

- 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.

- Studies have suggested analgesic, sedative, antidiabetic, hypoglycemic, anti-inflammatory, antidepressant, antioxidant, antipyretic, antiproliferative properties.



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.

- When making tea, lemon juice is often added to facilitate extraction of plant alkaloids; sugar or honey is added to mask the bitter taste of the brew. (25)

- In preparing tea, some suggest prolonged boling of leaves.

Folkloric

- No reported folkloric use in the Philippines.

- 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.

- Leaves heated with those of Blumea balsamifera, Morinda citrifolia and Oroxylum indicum are applied warm to enlarged spleen. (55)

- 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.

- In Malaysia, used for treatment of diarrhea, worm infestation, and as analgesic and antipyretic.

- Leaves used for fever, coughs, malaria, diarrhea and as tonic.

- Leaves used to treat diarrhea, intestinal infections by amoeba and protozoa.

Abuse / Opioid Substitute / Recreational Use

- Kratom use is quite high in Southeast Asia, In Thailand alone, there is more than 1 million regular adult users. Globally fewer than 100 SAEs, primarily from Southeast Asia, have been reported—most cases were associated with co-administration or use of other chemical substances or drugs. (38)

- 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 in times of opium scarcity.

- A GC-MS analysis of freshly made Malaysian 'ketum' drinks, prepared from extended boiling of fresh leaves in water, a 250 ml glass yielded 22.5-25 mg of mitragynine. Three drinks a day is considered sufficient to diminish opiate withdrawal symptoms. (25)

- Often, one to three fresh leaves are chewed for the vigor and euphoria effects. The masticated material is swallowed, followed by drinking warm water, tea, or coffee.

- Leaves are also infused with hot or cold 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."

- When kratom is not available, leaves of Mitragyna parviflora (kaim) are used as substitute. (25)

- In southern Thailand, an ice-cold cocktail, "4x100", has become popular for its alcohol-mimicking effect. The cocktail is a mixture of three basic ingredient: kratom leaves, a caffeine-containing soft drink, and a codeine- or diphenhydramine-containing cough syrup, to which is added an anxiolytic, an antidepressant, or an analgesic. (25)

- Products are sold under the guise of Kratom. In the early 2000s, products labeled as 'kratom acetate' or mitragynine acetate' contained no mitragynine. In Germany and Sweden, a product called 'Krypton' was found to be a concoction of caffeine and synthetic O-desmethyltramadol (ODT), the latter a bioactive metabolite of synthetic opioid analgesic tramadol mimics the sedative-narcotic effects of kratom. (25)

- Kratom is often used in combination with other recreational drugs e.g., alcohol, marihuana, benzodiazepines, methadone, cocaine, amphetamines and halllucinogenic mushrooms and other NPS (novel psychoactive substances) like kava, mephedrone, synthetic cathinones, tryptamines, etc. (26)



Studies

• Opioid Withdrawal Use: 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. (1)

• 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. (2)

• 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. (3)

• 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. (4)

• 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. (5)

• Memory / Cognitive Behavioral Effects: Study suggests that the chronic administration of mitragynine can alter cognitive behavioral function in mice. (7)

• Antinociceptive / Anti-Inflammatory: 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. (8) Study evaluated the aqueous leaf extracts of Mitragyna speciosa and Erythroxylum cuneatum for anti-inflammatory and antinociceptive activities. Both extracts showed anti-inflammatory activity in a carrageenan-induced rat paw edema model and decreased acetic-acid induced writhing in mice models. (47)

• Antinociceptive: 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. • Study evaluated the antinociceptive activity of various concentrations of alkaloids and extracts of M. speciosa leaves administered orally to nine groups of rats. Morphine and aspirin were used as control. Results showed oral administration of the alkaloid (20mg), methanolic and aqueous extracts significantly prolonged the latency of nociceptive response in both hot plate and tail flick tests (p<0.05). The antinociceptive effect was significantly blocked by naloxone. The effect varied according to type of solvents used for extraction. (53)

• 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. (9)

• 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. (11)

• Acute Toxicity Study: Study evaluated the acute toxicity of M. speciosa standardized methanolic extract in vivo in 4-week old Sprague-Dawley rats using single doses of 100, 500, and 1000 mg/kg. No mortality was noted after 14 days of treatment. Results showed increased blood pressure after an hour of the test doses. The highest extract dose (1000 mg/kbw) also induced acute severe hepatotoxicity and mild nephrotoxicity. (12)

• Mitragynine / Glucose Muscle Transport Effect / GLUT1: Study evaluated various leaf extracts and major constituent mitragynine for enhancement of glucose transport. Protein levels of glucose transporters (GLUTs) were measured by Western blotting. 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, and increases in the GLUT1 content for its long term effect. (6)

• Cytochrome P450 Toxicity Study / Potential Herb Drug Interaction: Study evaluated the effects of M. speciosa alkaloid extract on human recombinant cytochrome P450 (CYP) enzyme activities. Results showed MSE has a most potent inhibitory effect on CYP3A4 and CYP2D6 . MSE may contribute to an herb-drug interaction is administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6, and CYP1A2. (15)

• Hepatotoxicity: Case report from Germany describes a 25-year old man who developed intrahepatic cholestasis after taking an overdose of kratom powder. (16)

• Cross-Sectional Study / Malaysia: Of 562 respondents, 88% reported dail y 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% said they were not able to stop using MS. (19)

• Simulation Study on Rat Hippocampus Pyramidal Neuron Effect: Study evaluated the ability of Ketum alkaloid to block L-type Ca channel in rat's brain. Previous studies showed Mitragyna speciosa could block long lasting calcium channel currents in N1E-115 neuroblastoma cells. (21)

• Acute Toxicity Study / Leaves: Study investigated the acute toxicity of a standardized leaf aqueous extract on Sprague Dawley rats at 175, 500 and 2000 mg/kg body weight. The standardized MS aqueous extract did not cause lethality and only two symptoms at the highest dose, with no significant changes in body weight, food and water consumption. (also see: 11) (27)

• Subchronic Toxicity Testing: Study investigated the subchronic toxicity of methanolic extract of ketum in Sprague Dawley rats at doses of 100,, 200 and 500 mg/kg for 28 days. Biochemistry findings showed abnormalities in liver and renal parameters (ADT, creatinine, globulin, glucose, total protein, urea. Results showed M. speciosa is toxic to rat upon subchronic exposure of 28 days. (29)

• Dependence, Withdrawal and Craving in Regular Users: A cross-sectional Malaysian survey of 293 regular Kratom users showed that more than half of the regular users (>6 months of use) developed severe Kratom dependence problems, while 45% showed moderate Kratom dependence. Common physical withdrawal symptoms included muscle spasms and pain, sleeping difficulty, watery eyes/nose, hot flashes, fever, decreased appetite and diarrhea. Phychological withdrawal symptoms were restlessness, tension, anger, sadness, and nervousness. Average dose of mitragynine in a single dose of Kratom drink was 79 mg, suggesting an average intake of 276.5 mg daily. Regular users of more than 3 drinks a day were more likely to develop dependence, withdrawal and craving. (31)

• Antioxidant / Antiproliferative / Mitragynine: Study investigated the antioxidant value and anticancer functions of mitragynine (MTG) and its silane-reduced analogues (SRM) in vitro. SRM and MTG demonstrated moderate antioxidant value with ABTS assay (Trolox equivalent antioxidant capacity/TEAC): 2.25±0.02 mmol trolox/ mmol and 1.96±o.04 mmol trolox / mmol, respectively. Both showed concentration-dependent cytotoxicity effects and exerted profound antiproliferative efficacy at >100 µM concentration towards HCT 116 and K562 cancer cell lines, comparable to BA and 5-FY. (32)

• Comparative Study of MS and Mitragynine on Thermal Nociception in Rats: Study in Sprague-Dawley rats compared the effects of M. speciosa and mitragynine against effects of classic, well-known and commonly abused opioids, morphine and oxycodone, on thermal nociception in rats. Mitragynine showed analgesic effects similar to oxycodone when administered orally and IP, while M. speciosa exhibited a trend towards antinociceptive effects when administered orally and IP. Study results suggest properties like oxycodone that raises the possibility of abuse liability which might warrant restrictions for the botanical in the consumer marketplace. (33)

• Effect of Adolescent Chronic Exposure to Kratom on Leaning and Memory in Adulthood: Study on chronic exposure to alkaloids present in legally available Kratom during adolescence is capable of producing a variety of subtle but lasting changes affecting spatial and working memory performance in adulthood, well after the exposure to Kratom has ended. (34)

• In-Utero Effects on Neural Tube Formation / Leaves: Study investigated the effects of in-utero administration of crude ethanolic extract of leaves of M. speciosa on neural tube formation in pregnant Sprague-Dawley rats. Study showed the crude extract of leaves of MS is capable of selective neurotoxicity and producing spina bifida like NTD (neural tube defect) as characterized by altered brain size and neural tube formation, a finding with important implication in the dependence liability associated with its use. (35)

• Abuse Potential / Adverse Cognitive Effects of Mitragynine: Studies on rodent models clearly suggest that mitragynine, the main alkaloids of the psychoactive herb, kratom, has significant abuse and addiction potential which can cause profound emotional and cognitive impairments resembling that of opiate and psychostimulant drugs. (36)

• Toxicity Studies: • Toxicity in animal studies are claimed to be relatively low. Animal studies with doses as high as 920 mg/kg administered to dogs reported no toxicity in measures of tremors or convulsions. • Another study reported lethal toxicity with oral dose of 200 mg of pure mitragynine to rats. • Mitragynine and 7-hydroxymitragynine given to animals five days or longer produced physical dependence and withdrawal symptoms similar to opioid withdrawal. • In humans, toxicity reports of seizures associated with kratom overdose. One toxicological report reported a mitragynine concentration of 167 ± 15 ng/mL. • There have been toxicity reports and deaths attributed to krypton, a very potent form of kratom sold in Sweden. The interaction between mitragynine and O-desmethyltramadol in krypton was speculated as the cause of deaths. • A U.S. case of human toxicity was attributed to the use of mitragynine, 7-hydroxymitragynine and propylexedrine use. • Increased toxicity concerns are raised with the hazardous potential of mixing highly concentrated mitragynine and 7-hydroxymitragynine with other psychoactive drugs such as alcohol, sedatives, and cannabinoids. (37)

• Analytical Study: Study reports on a GC-MS method for the analysis of small kratom samples. The method successfully detected mitragynine, paynantheine, and/or 3-isopaynantheine. These are alkaloids specific to M. speciosa, which will allow identification of the test samples as kratom. (37)

• Factors Related to the Relative Abuse Potential of Mitragyna Speciosa (Kratom) and Mitragynine in the form of VivaZen: This is a written summary of oral testimony for the State of Wisconsin Controlled Substances Board commenting on the pharmacology of United Naturals marketed dietary supplement, VivaZen and its regulation. (38)

• Cerebellum and Endocannabinoid Receptors / Neurobiological Link for Mitragynine Abuse Liability: Mitragynine's potential as a psychoactive plant and opium substitute has emerged with abuse liability. Targets within the brain-reward circuitry are implicated in drug-induced synaptic plasticity of addiction. Given mitragynine's opioid agonism, study postulates that the ubiquitous and abundant endocannabinoid CB1R within the cerebellum may represent the novel neurochemical basis of mitragynine/Ketum abuse liabilities. Authors suggest further research is warranted to ascertain the role of CB1R as potential candidate within the cerebellum and its connection with brain rewards circuitry. (40)

• Cardiotoxicity of Mitragynine and Analogues: Study evaluated the cardiotoxicity of mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMS). Data showed that mitragynine and its analogues, at concentrations close to plasma levels reported in lethal cases, exert significant cardiotoxicity by inhibiting hERG current, prolonging APD, and inducing arrhythmia. Results showed mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr (rapid delayed rectifier potassium current) in human cardiomyocytes. (41)

• Inpatient Detoxification After Kratom Dependence: Study reports on detoxification and drug treatment of kratom dependence. Observations support the idea that kratom dependence syndrome is due to short-acting opioid receptor agonist activity, and suggest that dihydrocodeine and lofexidine are effective in supporting detoxification. (42)

• Effect on Social Functioning: Malaysian study evaluated the kratom effect on social functioning of 293 regular users using the Addiction Severity Index in a snowball sampling technique. Results suggest that regular kratom users do not experience major impairments in their social functioning, despite being dependent on kratom for prolonged periods. (43)

• Synthetic and Receptor Signaling Study / Mitragynine as Molecular Framework for Opioid Receptor Modulators: Study describes the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-. and delta-opioid receptors. Results show that mitragynine and the oxidized analogue 70hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. Study suggests the mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. (44)

• Variations in Alkaloid Content: Report lists 28 different alkaloids from the Kratom plant. Alkaloid content varies quantitatively by geographical location, month to month, and leaf harvest time, with geographical variants within the same species. Mitragynine was once the focus of almost all chemical studies on kratom. Recent studies identify 7-hydroxymitragynine as the principal psychoactive alkaloids. (45)

• Oral Testimony Relating to Abuse Potential of Kratom and Mitragynine in the form of VivaZen: Testimony reviews studies on abuse potential and toxicity of kratom and the alkaloids mitragynine and 7-hydroxymitragynine. The pharmacological basis for the effects of concern is due to partial mu opioid agonist activity of MG and 7-OHMG. VivaZen is a dietary supplement whose formula is based on the specific traditional use of M. speciosa: energizing and pain relief. The more potent alkaloid, 7-OHMG in not present in VivaZen at detectable levels, and is therefore not a safety concern. The other alkaloid, MG, which makes up as much as 2/3 of the alkaloid content of kratom leaf, is 40 times less potent than 7-OHMG at the mu opioid receptor, and appears in VivaZen at a dose of 45 mg/serving (one bottle/ a two-ounce liquid dietary supplement). The analysis for serious adverse effects (SAEs) demonstrate a very strong safety profile. The testimony compares the product with other consumer products and dietary substances for at least mild potential for dependence and abuse. Author suggests no precautionary scheduling for kratom products. (45)

• Sedative / Anxiolytic / Cognitive Impairment: Study evaluated the effect of methanol and aqueous extracts of M. speciosa on cognitive behavior of rats and mice. Results showed all dosage treatment reduced locomotor and impaired cognitive performance significantly. M. speciosa also induced a sedative effect in a dose-dependent manner. It also increased time spent in open arm of plus maze indicating low anxiety level of the rodent. (48)

• Isolation and Purification Protocol for Isolation of Mitragynine from Leaves: Study reports on a simple, faster, and cost effective method for the isolation of mitragynine from M. speciosa leaves. Method obtained around 0.088% (w/w) pure mitragynine with a purity of 99.0% (w/w) based on GC-MS analysis. Recovery from the chloroform extract was also more than 95.0%. The method required less solvent, incurred less steps, and was more economical. (49)

• Kratom Side Effects: (1) Low dose side effects: At 1-5 g, stimulant effects predominate, occurring within 10 minutes and lasting for 60-90 minutes. Primary stimulant effects are amphetamine-like, although less intense: increased energy and alertness, decreased appetite, increased sociability, heightened libido. (2) Moderate to High Doses: At 5-15 g, primary effects are opioid-like and lasts for several hours, which include a "euphoric" high, less intense than other opioid drugs, which may be described by some as unpleasant or dysphoric. They include: pain reduction, drowsiness, calm and dreamlike mental state, cough suppression, and reduction in symptoms of opioid withdrawal. (3) Greater than 15 g effects are similar to high doses of opioids, including extreme sedation and, occasionally, loss of consciousness. (4) Side Effects which are dose dependent, range in severity from inconvenient to dangerous: pupillary constriction (tiny pupils), facial flushing, tremors or loss of coordination, constipation, sweating, dizziness, nausea and vomiting, and itching. Seizures, the most serious toxic reactions, are associated with high doses of kratom (>15g). (5) Long-term from chronic use may be: hyperpigmentation or darkening of the skin, anorexia and weight loss, and psychosis. (50)

• Effect on Prenane X Receptor Modulation / Potential for Drug Interactions: Pregnane X Receptor (PXR), a type of nuclear receptor, has been shown to transcriptionally regulate the expression of drug metabolizing enzymes and drug transporters. Study evaluated the effects of M. speciosa methanolic extract, alkaloid rich fraction, and its 6 alkaloid constituents on PXR activation. Results suggest chronic intake of M. speciosa may lead to potential drug interactions as a result of PXR activation and increased expression of target genes, thereby affecting pharmacokinetics and pharmacodynamics of conventional drugs that are substrates of CYPs and P-gp. (52)

• Effect on Brain Receptors (Mu-Opioid Receptors) Similar to Opioids: Study showed for the first time that kratom's primary constituent, mitragynine, and four related alkaloids bind to and partially activate human u-opioid receptors (MORs), primary targets of strong opioids in the brain, spinal cord and GIT. 7-OH mitragynine (7-hydroxymitragynine), a mitragynine oxidation product, is the most potent of the alkaloids, with an MOR potency 1/10 of morphine, compared to 1/100 with mitragynine. While mitragynine may not be a very potent alkaloid, the plant can provide almost two-thirds of the alkaloid extract from kratom leaves. Study suggested sunlight and oxidizing conditions can convert about half of the mitragynine in solution to 7-OH mitragynine, while sunlight alone can convert about 8% of the mitragynine. Study suggests storage conditions can affect potency by increasing the amount of oxidized alkaloid. Furthermore, study showed that activation of MORs by kratom alkaloids affect pathways independent of the ß-arrestin protein. ß-arrestin pathway has been shown to mediate many undesirable effects of traditional opioids. This finding suggests a potential for design of safer alternative opioid pain killer. (see source study: 56) (55)

• Mitragynine as Atypical Molecular Framework for Opioid Receptor Modulators: Mu-opioid receptor agonists are mainstays of pain management. Study describes the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. Study showed mitragynine and 7)H mitragynine are G-protein-biases agonists of the mu-opioid receptors, which do not recruit ß-arrestin following receptor activation. Molecular docking studies suggest Mitragyna alkaloids adopt a binding pose at mu-opioid receptor that is distinct from classical opioids. (56)

• Quantitative and Qualitative Analysis of Mitragynine in Kratom: Kratom leaves consist of two primary active alkaloids: mitragynine (66.2%) and 7-hydroxy-7H-mitragynine (2.0%), and three indole alkaloids: paynantheine (8.6%), speciogynine (6.6%) and speciociliatine (0.8%). Study reports on the methodology for qualitative identification and quantitation of Kratom in different types of products (powders, liquids, spent-leaf materials) using a quick methanolic based extraction procedure. (57)

• Study of Product Samples Advertised as Kratom: Study reports on testing of 15 samples of products either directly listed as kratom or listed on web search (no directly advertised as kratom). Testing showed all products advertised as kratom contained the active chemical mitragynine, but 7-hydroxymitragynine was not detected in any of the samples. Implications are discussed. (58) 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. (14)

• 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, rhinorrhea, achy muscles and bones, jerky extremity movements. Kratom psychoses has been observed, with hallucinations, delusions, and confusion. There have been reports of seizures following Kratom use.

• 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 mitragynine and total alkaloids of MS were non- mutagenic with antimicrobial activities.

• DEA status / News Update: Kratom remains legal, for now! On August 31, 2016, the Drug Enforcement Administration (DEA) published in the Federal Register a notice of intent to temporarily place mitragynine and 7-hydroxymitragynine, which are the main psychoactive constituents of the plant Mitragyna speciosa, also referred to as kratom, into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act. Since publishing that notice, DEA has received numerous comments from members of the public challenging the scheduling action and requesting that the agency consider those comments and accompanying information before taking further action. In addition, DEA will receive from the Food and Drug Administration (FDA) a scientific and medical evaluation and scheduling recommendation for these substances, which DEA previously requested. The DEA is therefore taking the following actions: DEA is withdrawing the August 31, 2016 notice of intent; and soliciting comments from the public regarding the scheduling of mitragynine and 7-hydroxymitragynine under the Controlled Substances Act. DATES: The notice of intent that was published on August 31, 2016 (81 FR 59929) is withdrawn. The comment period will be open until December 1, 2016. (30)

• Status in the USA: States Where Kratom is Legal (2017):Alaska, Arizona (LF:Legislation Failed), California, Colorado, Connecticut, DC, Deleware, Florida (except for Sarasota where it is banned), Georgia, Hawaii, Idaho, Iowa (FL), Kansas, Kentucky (FL), Louisiana, Maine, Maryland, Massachusetts, Minnesota, Mississippi, Missouri, Montana, Nebraska, New Hampshire, New Jersey (FL), Nevada, New Mexico, New York (Legislation pending), North Carolina, North Dakota, Ohio, Oklahoma (LF)

Oregon (Ongoing study), Pennsylvania, Rhode Islan, South Dakota, Texas, Virginia, Washington, West, Virginia, Utah (LF), Wyoming . States Where Kratom is Illegal: Alabama, Arkansas, Indiana, Tennessee, Vermont, Wisconsin.



Drug interactions

• Adverse drug interactions have been reported with the use of kratom with other drugs, i.e., carisoprodol, modafinil, propylhexedrine or herbal plant Datura stramonium.

• Fatal case reported in the U.S. involved a blend of kratom, fentanyl, diphenhydraine, caffeine and morphine sold as a herbal drug. (25) In the news

• Police officer's death linked to kratom use: A 27-year old police sergeant, Matt Dana, reportedly died after overdosing on Kratom, according to Associated Press. The coroner's report stated the death resulted from hemorrhagic pulmonary edema. The only unusual substance found in Dana's blood was a high level of kratom. . . The AP story said Dana was consuming the herb which he prepared himself by grinding it into a paste. . . (59) (read more). . . report revealed Dana had 3,500 nanograms per milliliter of mitragynine in his blood. . . that is nearly five times as much as in other people whose deaths involved kratom. The federal DEA reported last year that it is aware of 15 kratom-related deaths n the U.S. between 2014 and 2016. (60)

• Kratom group files demand for retraction of FDA head's warning on botanical: The AKA (American Kratom Association) has filed a formal demand for a retraction of FDA commissioner Scott Gottlieb/s warning about the botanical. However, reports on adverse events suggest new data available to the FDA may mean the agency has evidence to support the warning. Concerns have been raised about the lack of safety data on kratom. Calls to US poison control centers have increased 10-fold from 2010 to 2015, with hundreds of calls a year. There have been 36 deaths associated with the use of kratom-containing products. Its use is associated with serious side effects like seizures, liver damage, and withdrawal symptoms, according to Gottlieb. There have been reports of kratom laced with other opioids like hydrocodone. (61)



Availability

- Wild-crafted.

- Leaves, powders, extracts, encapsulated powder and extract resin "pies" in the cybermarket.

- Seeds and trees reportedly sold by web vendors.

