Kratom – structure, effect, pharmacology

CHEMICAL FORMULA OF THE ALKALOID MITRAGYNINE AND

WHERE/HOW IT EFFECTS THE BODY

Strukturformel Mitragynin
Mitragynin

Mitragynine is an indole alkaloid. Chemically seen mitragynine is a 9-methoxy-coryantheidine of the formula C23H30N2O4, and a molecular weight of 398.49. It is a white powder with a boiling point of 102-106 degree Celsius (215.6 to 222.8 degree Fahrenheit). Mitragynine can be dissolved in alcohol, chloroform and acetic acid.

Figure 1. The chemical formula of the structure of mitragynine. Mitragynine is the main component of the alkaloid fractionation from the leaves of the tree Mitragyna speciosa Korth.

After taking kratom an increase in the irritability of the parasympathetic and sympathetic part of the autonomic nervous system is observed, in addition to the increase in the irritability of the Medulla oblongata (syn. extended spinal cord), the center for the control of circulation, breathing and for the sneezing-, coughing-,  swallowing-, and sucking-reflexes as well as the vomiting-reflex. The motor systems of the central nervous systems are likewise stimulated. This fact makes the effect absolutely paradox; it stimulates on the one hand like cocaine and calms on the other hand like opium. Mitragynine shows in vitro activity at the supra spinal (above the vertebral column; e.g. brain) opioid - and - receptors. All opioids interact with endogenous opioid-receptor systems which include four different subtypes and receptors (Dhawan et al., 1996). These are marked with the letters , , , and ORL-1. One can find these receptors almost everywhere in the system of mammals, they occur also in all vertebrae. A high density of these receptors is found in the brain and spinal cord; but they are also found in the stomach/intestinal tract and in the cells of the immune system. The three main opioid receptors, the -, -, and -receptors provide freedom from pain, while the -opioid-receptor is mainly responsible for freedom of pain after taking opiates.

The pharmacology of Mitragyna speciosa and mitragynine was the first time researched by the scientist Grewal (1932) at the University of Cambridge. After a series of experiments with animal tissues and a group of 5 volunteers he found, that mitragynine stimulates the central nervous system and causes effects similar to the application of cocaine. Macko et al. (1972) reported that mitragynine has an analgesic (anti-nociceptive) and a coughing alleviating effect in mice, similar to the effect of codeine. They also found, that mitragynine differently from opioid pain-relievers did not show undesirable side effects when taken at the same dosage. Mitragynine is said to be similarly involved in the descending noradrenergic (mainly responsible for the bodily concomitant symptoms of anxiety) and serotonergic systems of the spinal cord. There are different pain modulating systems in the central nervous system, where the noradrenergic and serotonergic systems play an important role in the transmission of nociceptive information from sensory neurons (primary afferent neurons in the dorsal horn of the vertebrae), that pass information of their dendritic receptors of sensory organs or other organs  of the body on to the brain. The dorsal horn receives these different sensory informations of the body (Proudfit, 1988). Matsumoto et al. (1996b) have found in their studies, that mitragynine releases analgesic activity (reduces the sensitivity to pain causing stimuli) depending on the dosage. He has proven this with the “tail-pinch test” and the “hot-plate test” (where mice were placed on a heating plate with a temperature of 55°C (131° F), and were observed for nociceptive reactions as e. g. jumping

and licking of the paws. He found that the supra spinal opioid-system is also partially involved in the effect of mitragynine. He arrived at this conclusion, because the effect of mitragynine was annihilated through naloxone, an opium receptor antagonist. 1966a Matsumoto et al. found in a further study, that mitragynine causes directly or indirectly the release of endogenous noradrenaline and 5-HT at the nerve endings of aminergic neurons, which use monoamines as neurotransmitters, leading to the blockage of nociceptive informations. But presently no proof exists for the affinity of mitragynine for these special receptors. Nevertheless the similarity of kratom alkaloids to other biologically active components allows the conclusion, that mitragynine and its congeners are taking part in the activation or inhibition of other receptor systems (Babu et al. 2008).

FURTHER ALKALOIDS ISOLATED FROM KRATOM

7-hydroxymitragynine. Further alkaloids isolated from kratom, as e.g. 7-hydroxymitragynine, have as well analgesic effects and a high affinity for opioid-receptors, which were demonstrated in animal experiments. Studies have found indications, that the alkaloid 7-hydroxymitragynine is more effective than morphine, even after oral application. Matsumoto et al. (2004) in an earlier study have compared the effect of mitragynine with the effect of Mitragyna speciosa and found that the analgesic effect of mitragynine was less than that of Mitragyna speciosa. This means, that possibly other components existing in small concentrations in Mitrogyna speciosa have a strong analgesic effect. Ponglux et al. (1994) have isolated the alkaloid 7-hydroxymitragynine from Mitragyna speciosa which shows a stronger analgesic effect in guinea pigs than mitragynine. Takayama et al. (2002) have found, that 7-hydroxymitragynine has a considerable affinity for -opioid-receptors. Mastumoto et al. (2004) tested the effect of 7-hydroxymitragynine with the ileum (distal small intestine) of guinea pigs and found, that it acts on the nerve endings and thus blocks the release of neurotransmitters. In addition, 7-hydroxymitragynine is an agonist for the - and/or -opioid-receptors and shows a 13 time stronger effect than morphine in the ileum test.

Mitragynine pseudoindoxyl. The alkaloid mitragynine pseudindoxyl is an oxidative derivative of the alkaloid mitragynine. In 1974 the scientist Zarembo et al. produced it by using the fungus Helminthosporum sp. to transform mitragynine. He found that mitragynine pseudoindoxyl shows an up to 10 time stronger analgesic effect than mitragynine. The 2002 published study of Takayama et al. has reported that it has an up to 20 time stronger analgesic effect than morphine, if studied with the ileum test with guinea pigs, considering their weights, while the “pinch-tail-test” performed with mice only a small analgesic effect compared with morphine could be noticed.

(-)-Epicatechin. (-)-Epicatechin is a flavenol of the group flavenoids (secondary plant metabolites) and can be found among others in the cocoa bean. Bayard et al. (2007) have studied the cause of death between the population of the San Blas Islands (with possibly the richest flavonoids nourishment through the natural cocoa consumption) and the population of the bordering mainland of Panama and found, that on the mainland the main cause of death were heart/circulation diseases, and diabetes mellitus, while on the San Blas islands significantly fewer people died from these diseases. Hollerbach postulated that 4 of the 5 most frequent

diseases in the Western world (stroke, heart attack, cancer, and diabetes) can be reduced to 10 % through the use of epicatechin. Admittedly, this study is no final proof, that the reduction of these diseases is caused through the high epicatechin consumption by the population of the San Blas Islands, or that certain genetic characteristics, the young age of death (the risks of diseases like heart/circulation problems and tumors increases with age), or other factors played a role as well.

9-hydroxycorynantheidine und corynantheidine. Despite the fact that kratom finds so far no application in the conventional medicine, the alkaloids 9-hydroxycorynantheidine and corynantheidine are very promising for medical use, because the former is a partial -opioid-agonist and the last an -opioid-antagonist. Both alkaloids occur in the leaves of Mitragyna speciosa. The combination of a complete agonist (as e.g. 7-hydroxymitragynine and mitragynine) with an antagonist or a partial agonist is comparable with the use of a partial opioid-agonist to break an opium dependency. An example for such a partial agonist/antagonist is burprenorphine, which is accepted by the FDA and is also employed in dependency cases.

Table1. Active substances in Kratom and their effect (from http://www.murple.net/yachay/index.php/Kratom

The role of the secondary ingredients, which can be found in kratom, is not yet fully studied, but it looks as if kratom is much more than a simple anesthetic. Further studies are necessary to research the pharmacology of these ingredients, and to understand it, in order to make use of the optimal advantage of this plant in medicine.

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Mitragynine.
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