Ketum, Kratom

Mitragyna speciosa

Flora

Ketum, Kratom

Mitragyna speciosa

Ketum or Kratom, Mitragyna speciosa, an herbal leaf from a tree of the Rubiaceae family, is a tropical evergreen tree in the coffee family native to Southeast Asia. It is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea, where it has been used in herbal medicine since at least the nineteenth century. Kratom has opioid properties and some stimulant-like effects.

As of 2018, kratom is a controlled substance in 16 countries and, in 2014, the FDA banned importing and manufacturing of kratom as a dietary supplement. As of 2018, there is growing international concern about a possible threat to public health from kratom use, while others, such as Dr. Christopher McCurdy, have argued that it could be a tool to help the opioid crisis. In 2021, the World Health Organization’s Executive Committee on Drug Dependency investigated the risks of kratom and declined to recommend a ban following a scientific review. The committee, however, recommended kratom be kept “under surveillance.” In some jurisdictions, its sale and importation have been restricted, and several public health authorities have raised alerts.
Mitragyna speciosa is an evergreen tree in the genus Mitragyna that can grow to a height of 25 m (82 ft). Its trunk may grow to a 0.9 m (3 ft) diameter. The trunk is generally straight, and the outer bark is smooth and grey. The leaves are dark green and glossy and can grow to over 14–20 cm (5.5–7.9 in) long and 7–12 cm (2.8–4.7 in) wide when fully open, are ovate-acuminate in shape, and opposite in growth pattern, with 12–17 pairs of veins. The flowers, which are deep yellow, grow in clusters of three at the ends of the branches. The calyx-tube is 2 mm (0.08 in) long and has five lobes; the corolla-tube is 2.5–3 millimetres (0.098–0.12 in) long.

Mitragyna speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea. It was first formally described by the Dutch colonial botanist Pieter Korthals in 1839, who named it Stephegyne speciosa; it was renamed and reclassified several times before George Darby Haviland provided the final name and classification in 1859.
Chemistry

Many of the key psychoactive compounds in M. speciosa are indole alkaloids related to mitragynine, which is a tetracyclic relative of the pentacyclic indole alkaloids, yohimbine and voacangine. In particular, mitragynine and 7-hydroxymitragynine (7-HMG) compose significant proportions of the natural products isolable from M. speciosa; e.g., in one study, mitragynine was 12% by weight from Malaysian leaf sources, versus 66% from Thai sources, and 7-hydroxymitragynine constituted ~2% by weight.

In addition, at least 40 other compounds have been isolated from M. speciosa leaves, including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from Rauvolfia serpentina), corynantheidine (also found in Pausinystalia johimbe), as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline.

In addition to alkaloids, M. speciosa produces many other secondary metabolites. These include various saponins, iridoids and other monoterpenoids, triterpenoids such as ursolic acid and oleanic acid, as well as various polyphenols including the flavonoids apigenin and quercetin. Although some of these compounds possess antinociceptive, anti-inflammatory, gastrointestinal, antidepressant, antioxidant, and antibacterial effects in cells and non-human animals, there is no sufficient evidence to support the clinical use of kratom in humans.

Detection in body fluids The plant’s active compounds and metabolites are not detected by a typical drug screening test, but can be detected by more specialized testing. Blood mitragynine concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally. Detection in body fluids is typically by liquid chromatography-mass spectrometry.


Pharmacology

Kratom contains at least 54 alkaloids. These include mitragynine, 7-hydroxymitragynine (7-HMG), speciociliatine, paynantheine, corynantheidine, speciogynine, mitraphylline, rhynchophylline, mitralactonal, raubasine, and mitragynaline. The alkaloids mitragynine and 7-hydroxymitragynine are responsible for many of the complex effects of kratom, but other alkaloids may also contribute synergistically.

Both mitragynine and 7-HMG are partial agonists of the μ-opioid receptor and competitive antagonists of the δ-opioid receptor with low affinity for the κ-opioid receptor. 7-HMG appears to have higher affinity at the μ-opioid receptor than mitragynine. These compounds display functional selectivity and do not activate the β-arrestin pathway partly responsible for the respiratory depression, constipation, and sedation associated with traditional opioids. Both mitragynine and 7-HMG readily cross the blood-brain barrier.

Mitragynine also appears to inhibit COX-2, block L-type and T-type calcium channels, and interact with other receptors in the brain including 5-HT2C and 5-HT7 serotonin receptors, D2 dopamine receptors, and A2A adenosine receptors. Mitragynine stimulates α2-adrenergic receptors, inhibiting the release of norepinephrine (noradrenaline); other compounds in this class include dexmedetomidine, which is used for sedation, and clonidine, which is used to manage anxiety and some symptoms of opioid withdrawal. This activity might explain why kratom can be dangerous when used in combination with other sedatives. Kratom also contains rhynchophylline, a non-competitive NMDA receptor antagonist.

Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resulting metabolites excreted in urine. In in vitro experiments, kratom extracts inhibited CYP3A4, CYP2D6, and CYP1A2 enzymes, which results in significant potential for drug interactions.

Ketum, Kratom - Mitragyna speciosa

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Indonesia
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Philippines
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Thailand
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Malaysia

Uses

As of 2013, kratom has been studied in cells and in animals, but no clinical trials have been conducted in the United States.[6] The U.S. Drug Enforcement Administration (DEA) said in 2013 that there is no legitimate medical use for kratom.[13] and in 2019, the U.S. Food and Drug Administration (FDA) said that there is no evidence that kratom is safe or effective for treating any condition, and that there are no approved clinical uses for kratom.[11] Kratom leaves are commonly used by chewing, as a tea, powdered in capsules or pills, or extracted for use in liquids.[6] Kratom is rarely smoked.[21] Different varieties of kratom contain different relative proportions of alkaloids such as Mitragynine.

While many Nepenthes species are generalists in what they capture, at least one, N. albomarginata, has specialised and almost exclusively traps termites and produces nearly no nectar. Nepenthes albomarginata gains its name from the ring of white trichomes directly beneath the peristome. These trichomes—or “hairs”—are palatable to termites and will attract them to the pitcher. In the course of collecting the edible trichomes, hundreds or thousands of termites will fall into the pitcher.   Symbioses N. bicalcarata provides space in the hollow tendrils of its upper pitchers for the carpenter ant Camponotus schmitzi to build nests. The ants take larger prey from the pitchers, which may benefit N. bicalcarata by reducing the amount of putrefaction of collected organic matter that could harm the natural community of infaunal species that aid the plant’s digestion. N. lowii has also formed a dependent relationship, but with vertebrates instead of insects. The pitchers of N. lowii provide a sugary exudate reward on the reflexed pitcher lid (operculum) and a perch for tree shrew species, which have been found eating the exudate and defecating into the pitcher. A 2009 study, which coined the term “tree shrew lavatories”, determined between 57 and 100% of the plant’s foliar nitrogen uptake comes from the faeces of tree shrews. Another study showed the shape and size of the pitcher orifice of N. lowii exactly match the dimensions of a typical tree shrew (Tupaia montana). A similar adaptation was found in N. macrophylla, N. rajah, N. ampullaria, and is also likely to be present in N. ephippiata. Similarly, N. hemsleyana, which is native to Borneo, has a symbiotic partnership with Hardwicke’s woolly bat. During the day, a bat may roost above the digestive fluid inside the pitcher. While a bat is inside, it may defaecate, and the plant can get nitrogen from the droppings.   Antimicrobial properties Nepenthes digestive fluids are sterile before pitchers open and contain secondary metabolites and proteins that act as bactericides and fungicides after the pitcher opens. While the digestive fluid is being produced, the pitcher is not yet open, so there is no chance of microbial contamination. During pitcher development, at least 29 digestive proteins including proteases, chitinases, pathogenesis-related proteins and thaumatin-like proteins are produced in the pitcher fluid. In addition to breaking down prey, these can act as antimicrobial agents. When the pitchers open, the fluid is exposed to bacteria, fungal spores, insects and rain. Often pitchers have a lid that covers the trap, excepting a few (e.g. N. lowii, N. attenboroughii and N. jamban), preventing rain water from entering. The lid inhibits rainwater from diluting the digestive fluid. Once the bacteria and fungi enter the fluid, secondary metabolites are produced in addition to antimicrobial proteins. Naphthoquinones, a class of secondary metabolite, are commonly produced, and these either kill or inhibit the growth and reproduction of bacteria and fungi. This adaptation could have evolved since Nepenthes plants that could produce secondary metabolites and antimicrobial proteins to kill bacteria and fungi were most likely more fit. Plants that produced antimicrobial compounds could prevent loss of valuable nutrients gained from insects within the pitcher. Since Nepenthes cannot digest certain bacteria and fungi, the bactericides and fungicides allow plants to maximize nutrient uptake.  
Chemistry

Many of the key psychoactive compounds in M. speciosa are indole alkaloids related to mitragynine, which is a tetracyclic relative of the pentacyclic indole alkaloids, yohimbine and voacangine. In particular, mitragynine and 7-hydroxymitragynine (7-HMG) compose significant proportions of the natural products isolable from M. speciosa; e.g., in one study, mitragynine was 12% by weight from Malaysian leaf sources, versus 66% from Thai sources, and 7-hydroxymitragynine constituted ~2% by weight.

In addition, at least 40 other compounds have been isolated from M. speciosa leaves, including ~25 additional alkaloids, including raubasine/ajmalicine (originally isolated from Rauvolfia serpentina), corynantheidine (also found in Pausinystalia johimbe), as well as mitraphylline, mitragynine pseudoindoxyl, and rhynchophylline.

In addition to alkaloids, M. speciosa produces many other secondary metabolites. These include various saponins, iridoids and other monoterpenoids, triterpenoids such as ursolic acid and oleanic acid, as well as various polyphenols including the flavonoids apigenin and quercetin. Although some of these compounds possess antinociceptive, anti-inflammatory, gastrointestinal, antidepressant, antioxidant, and antibacterial effects in cells and non-human animals, there is no sufficient evidence to support the clinical use of kratom in humans.

Detection in body fluids The plant’s active compounds and metabolites are not detected by a typical drug screening test, but can be detected by more specialized testing. Blood mitragynine concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally. Detection in body fluids is typically by liquid chromatography-mass spectrometry.


Pharmacology

Kratom contains at least 54 alkaloids. These include mitragynine, 7-hydroxymitragynine (7-HMG), speciociliatine, paynantheine, corynantheidine, speciogynine, mitraphylline, rhynchophylline, mitralactonal, raubasine, and mitragynaline. The alkaloids mitragynine and 7-hydroxymitragynine are responsible for many of the complex effects of kratom, but other alkaloids may also contribute synergistically.

Both mitragynine and 7-HMG are partial agonists of the μ-opioid receptor and competitive antagonists of the δ-opioid receptor with low affinity for the κ-opioid receptor. 7-HMG appears to have higher affinity at the μ-opioid receptor than mitragynine. These compounds display functional selectivity and do not activate the β-arrestin pathway partly responsible for the respiratory depression, constipation, and sedation associated with traditional opioids. Both mitragynine and 7-HMG readily cross the blood-brain barrier.

Mitragynine also appears to inhibit COX-2, block L-type and T-type calcium channels, and interact with other receptors in the brain including 5-HT2C and 5-HT7 serotonin receptors, D2 dopamine receptors, and A2A adenosine receptors. Mitragynine stimulates α2-adrenergic receptors, inhibiting the release of norepinephrine (noradrenaline); other compounds in this class include dexmedetomidine, which is used for sedation, and clonidine, which is used to manage anxiety and some symptoms of opioid withdrawal. This activity might explain why kratom can be dangerous when used in combination with other sedatives. Kratom also contains rhynchophylline, a non-competitive NMDA receptor antagonist.

Mitragynine is metabolized in humans via phase I and phase II mechanisms with the resulting metabolites excreted in urine. In in vitro experiments, kratom extracts inhibited CYP3A4, CYP2D6, and CYP1A2 enzymes, which results in significant potential for drug interactions.