Kratom / Mitragyna speciosa / Kaim (Hindi)

General features: The botanical name of this tropical plant is Mitragyna speciosa (MS), commonly known as Kratom [1]. In India it is popularly called Kaim in Hindi. The plant belongs to Rubiaceae or coffee family of Mitragyna genus [2]. The genus, Mitragyna has been named by the Dutch botanist, Pieter Willem Korthals (1807 – 1892) who discovered Kratom during his service in Dutch East India Company (1831 – 1836) in Indonesia besides his other discoveries regarding the medicinal plants. He named the genus owing to the similarities between leaves and stigmas with bishop’s mitre (traditional headgear of bishop during ceremony) [3]. MS synthesizes plentiful phytochemicals that include loads of bioactive alkaloids. In addition to alkaloids, it produces flavonoids, saponins, terpenes, polyphenols, and glycosides [4]. A section of the alkaloids behaves like opiates. However, they also act as stimulants. But the behavior is largely dosedependent. Kratom / MS is an evergreen plant that grows in the tropical climate of Southeast Asian nations like Thailand, Philippine, Myanmar, Malaysia, Indonesia, Papua New Guinea, some parts of Africa, and Southern states of India. In many Southeast Asian countries, it is a precious herbal medicine providing relief from the musculoskeletal pain, enhancing appetite and energy also fortifying the sexual desire [5]. It helps heal wounds by subsequently acting as local anesthetics [6]. The leaves are used to treat coughs, diarrhea, or infections of the intestine. It can remove intestinal worms [7]. The leaf extract tastes bitter therefore sugars are often added before the use. The herb is majorly used by the Southeast Asian laborers to get rid of pain or to repel exhaustion and simultaneous boosting of the energy level [8]. In Thailand it is also used in some snacks as a part of the ritual while receiving guests or during praying for the ancestors in heaven or Gods. The plant grows about 50 ft high having large glossy dark green oval shaped leaves which are 7.0 inches in length and 1.5 inches wide. The flowers are deep yellow spherical clusters. The tree prefers to grow in wet and humid soil under the full sunlight. The dried leaves, including its stems, are normally harvested for consumption. Kratom is traditionally used for easing opoid withdrawal dating back to 1940s in Thailand [8]. The event of drug withdrawal usually produces unpleasant physical sensation generating sweating, cravings, and trembling of the body. In Asian countries Kratom is employed to ease the withdrawal symptoms while evoking feeling of euphoria and providing energetic sensation, reducing anxiety, pain, and depression [8]. In many countries, governments are not confident about the safety of Kratom use. It is new in the Western world and South American countries, but the popularity is soaring. In recent days, its growing misuse / abuse has become a concernable factor to the drug enforcement authorities (DEA). In US it is viewed as “drug of concern” but not enlisted yet to be a controlled substance although its import has been banned by the FDA, but the plantation is not regulated. Because of not being fully regarded as a controlled substance, the regular use of kratom leads to addiction which is often serious. Since, its troubled withdrawal symptoms are clearly noticed. Further research is needed to reveal the exact facts about the nature of kratom addiction. At present it is easy to purchase in any herbal shop. It is advertised as a legal psychoactive, sedative and a stimulant herbal component [8]. On the other hand, Kratom is a controlled substance in many Southeast nations.

Effects	Low dose (1-5g)	High dose (5-15g)
Stimulant	Increase of alertness, energy, talkativeness, and cheerful behavior.	Tachycardia
Opioid / sedative	Losing muscle coordination	Dizziness, Hypotension, Constipation, Sweating and Dry mouth
Adverse			Itching, Nausea, Appetite loss, Increase of urination.

Phytochemistry: Loads of phytochemicals of versatile nature are isolated but the notable ones are alkaloids, flavonoids, polyphenolics, and terpenoids. The alkaloids with indole moiety having tetra or penta cyclic rings are highly predominant among the phyto-ingredients. Kratom is famously known for those alkaloids particularly for its pharmacological role.  

Flavonoids, triterpenoids, and polyphenolics – The leaf extract shows the presence of flavonoids like apigenin and its glycosides at a significant level. The presence of quercitin, and its glycosides, quercitrin, rutin, isoquercitrin, hyperoside, quercitin-3galactoside-7-rhamnoside, kaempferol, its glucosides, and epicatechin. Regarding polyphenolics the existence of caffeic and chlorogenic acid at considering levels are identified along with the few others. Normally, flavonoids and their glycosides exhibit antioxidant, antiinflammatory, and antiatherosclerosis effects. Similar effects are also noticed within polyphenolics like caffeic and chlorogenic acids and their other derivatives. The presence of triterpenoids and triterpenoid saponins are also identified in leaf, bark, and root extract [4].

Pentacyclic triterpenes and their glycosides or saponins exhibit numerous pharmacological effects. The most prominent ones are the dominant anticancer role. They can inhibit tumor growth by exerting cytotoxicity, apoptosis or retarding the cell divisions. Uniquely, they do not affect the normal cells. The major intracellular pathways frequently targeted are NF-κβ and STAT – 3. It is also claimed that triterpenes can prevent intracellular switching mechanism during transformation from normal to tumor cells by deactivating proto-oncogenes or activating tumor suppressor genes like p53 or others if administered previously [9].

Kratom alkaloids – action, addiction, and pharmacology: Kratom is widely known for its addictive nature. Before discussing the Kratom addiction, it is better to understand a few scientific facts about the process of addiction. What is an addiction? Addiction is considered as a brain disorder oriented toward compulsive use of addictive drugs despite having the knowledge about its adverse consequences. It is a brain disorder which creates functional changes inside the neuronal circuits which are involved in stress, self-control, or reward events. Eventually, that changes reflect into the abnormal behavior compelling to seek for the drugs in order to get relief, which is commonly viewed as an addictive behavior. Those substances / drugs despite its medicinal roles are always assessed as addictive compounds, in a street sense termed as “drugs.” Like the other diseases or disorders, addiction interrupts normal functioning of brain, or the organs directly influenced by nervous systems. As a result, the situations often bring serious physical and mental problems that even lead to fatality. Judging from various perspectives, the phenomenon of addiction has been accepted by the medical communities as being treatable and preventable like other diseases or disorders. Although the social contribution during the treatment phase could not be ignored. If left untreated that might lead to severe unfortunate consequences [10]. Kratom / MS is declared illegal only in the four Southeast Asian nations, especially in Thailand.  It is widely available in the US and not counted to be an illegal item. It has been recorded that kratom exhibits addictive behavior because if stopped abruptly after the long-term regular use, causes pain, sleeping trouble, fever, nervousness, tension, tremor, anger, or sadness [11]. Thus, opoid abstinence syndrome is noticed among the regular kratom users. In addition, development of hyperpigmentation on the cheeks is visible among the long-term consumers. Uniquely, the extract produces both stimulant and opoid actions. However, the actions are highly dosedependent. Stimulant effects occur at lower doses whereas opiate effects appear mostly at the higher concentrations. Identical observations are verified within animal models also. But in humans, doses to produce stimulant action, analgesia, toxicity, or anything else are not well defined. Mitragynine is the major indole alkaloid identified in the leaf / bark extract which exerts the foremost biological actions. Structurally, the compound bears uncanny similarity to Yohimbine which is a potent α₂ – adrenergic receptor α_2A, α_2B, and α_{2C antagonist} (K_i ~ 1.05 – 1.19 nM) [15]. On the other hand, Mitragynine exerts opioid effects by acting on the µ, δ, and κ receptors. Some of the effects of Mitragynine are identical to Codeine like, producing anorexia, weight loss, psychosis, nausea, vomiting, and hyperpigmentation. The compound also acts as antitussive and antinociceptive agents. Another similar alkaloid 7-hydroxy-mitragynine displays much higher affinity toward the opoid receptors. It also exerts analgesic and antinociceptive effects in both animals and humans. Both compounds exert opiate effects on intestine and male genitalia [1].

Experiments have established that five days or longer administration of Mitragynine or 7-hydroxymitragynine produces physical dependency in addition to withdrawal symptom that resembles the actual opiate withdrawal. Ligand binding studies using opiate antagonists points out that the effects are mediated via the µ- and δ- receptors [12]. Besides influencing the nervous system, Mitragynine also inhibits lipopolysaccharide (LPS) induced cyclooxygenase – 2 (COX-2) expression and subsequent generation of PGE-2 that might provide antiinflammatory effects. Further aside from the direct actions on opiate receptors, its antinociceptive role is seen due to the activation of descending noradrenergic and serotonergic pathways in spinal cord [6]. Mitragynine stimulates postsynaptic α₂-adrenergic receptors, also blocks the 5HT_2A receptors [12]. Along with Mitragynine, 7-hydroxymitragynine is synthesized at exceptionally low levels but it shows more bioavailability as well as the permeation ability through the blood-brain barrier enabling it to make it a dominant analgesic agent. Some other alkaloids of this family are speciociliatine, speciogynine, and paynatheine. They exert effects on intestinal smooth function and subsequently create behavioral responses [19]. But the effects are not inhibited by the opiate antagonist Naloxone. So as per the speculation, they may work in an independent way not related to the opiate receptors waiting to be identified [13].

Functions of µ-, δ – and κ- receptors – The widely known common opiate receptors are µ-, δ-, and κ- subtypes which are distributed throughout the body. µ- receptors are located on central nervous system (CNS) that includes brain, spinal cord, peripheral sensory nerves, and gastrointestinal system. The major perceptive actions are analgesia, dependence, euphoria, respiratory depression, and constipation. These occur via µ_{2 –} activation whereas µ₃ – causes vasodilation. The endogenous ligands are endorphin and endomorphin. δ- receptors produce analgesia. It is located on the brain and peripheral nervous systems. The endogenous ligand is Enkephalin. κ- receptors exist in central (CNS) and peripheral nervous system. It produces analgesia, diuresis, and dysphoria. The endogenous ligand is dynorphin [13].

The highlighted functional sites of each molecule shown above are responsible for interacting with the receptors. Four major sites are noticed to be important for high affinity binding, especially of 7-hydroxymitragynine. The C-7 position, C-9 position, β- methoxy-acrylate, and N_b lone pair. C-7 is important for high affinity, C-9 for intrinsic activity, β- methoxy-acrylate is important for the opiate action, and N_b lone pair is crucial for docking to the receptor [41]. Further any changes within the Mitragynine moiety can alter the binding and subsequent biological activity as well, for example: A – any change at this position by substituting with long ether, or taking a way – CH₃, – OH or acetylation will reduce the activity. B – adding – OH group at this position will enhance the activity and binding affinity, C- oxidation at this position / N-oxidation eliminates the activity, D – presence of double bond (=) will lower the activity, E- changing of stereochemistry eliminates the activity, F – replacing with – NH group eliminates the activity, G – activity is reduced if ester is hydrolyzed [4].  

Actions of the major alkaloids –

Mitragynine – it acts on µ-, δ-, and κ- opiate receptors. The major actions are oriented toward the µ- receptors (K_i = 238 ± 28 nM) exerting analgesic effects also causing physical dependency. It activates descending noradrenergic and serotonergic pathways in spinal cord. Binding to the κ- opiate receptors (K_i = 482 ± 29 nM) also exerts analgesia slowing down the pain sensation. In addition, it may produce anti-depressive effects. It is somewhat inactive toward δ- receptors. Mitragynine stimulates postsynaptic α₂– adrenergic receptors along with blocking of stimulating action on 5-HT_2A receptors [14].

7- hydroxy Mitragynine – The compound is extremely potent (13 – 46 times) than either morphine or Mitragynine. The binding affinity toward µ- receptor is 16 ± 1 nM and for κ- receptor 113 ± 37 nM whereas for the δ – 137 ± 21 nM.  Factually, the presence of – OH group at C7 position is liable for this high affinity effect. The compound shows significant antinociceptive action which is noticed to be dosedependent [14].

Speciociliatine – It is a C3 stereoisomer of Mitragynine. It inhibits twitch contraction independent of Naloxone way also inhibits the release of acetylcholine from presynaptic nerve endings other than opiate receptor stimulation [14].

Paynantheine and Isopaynanthiene – It prevents twitch contraction in Naloxone insensitive manner also inhibits muscarinic receptors’ action in illeal smooth muscles by controlling the contraction. Isopaynanthiene acts as a κ- receptor agonist which regulates dopamine release and lowers the dopamine level in caudate putamen affecting movements, learning behavior, and emotion [14].

Speciogynine – The compound inhibits twitch contraction which is insensitive to Naloxone. It also inhibits muscarinic receptors in illeal smooth muscle [14].

Speciofoline, Corynoxine, and Mitragyninepseudoindoxyl –  Speciofoline is an orally active oxindole alkaloid isolated from the leaf and stem bark which shows analgetic and antitussive effects which means to act as pain-relieving and cough agent (Patent – GSK). The compound does not interact with any opiate receptors, κ-, µ-, or δ- subtypes [15]. It provides soothing effect during any discomfort with mild mood enhancement adding with slight euphoric sense. The level varies in plants which is about less than 1%. Kratom leaves and barks also synthesize a few other oxindole alkaloids which also show significant affinity toward opiate receptors including G-protein actions, β-arrestin – 2 signaling. Besides Speciofoline, the important ones are Corynoxine and Mitragyninepseudoindoxyl. Both Corynoxine and Mitragyninepseudoindoxyl are full µ – receptor agonist (K_i ~ 0.1 nM) blocking the pain [ 15].

The combination of stimulant and opoid like effects are unique for the kratom extract. Evidently, the effects are dosedependent and exhibit individual variations. About 1-5g of raw leaves which is considered as moderate doses produce stimulant effects, felt being pleasant but not to the extent of drugs like amphetamine. Users of pain management appreciate the effect since traditional opiates offer undesired sedative action. The opiate like effects creating analgesia, euphoria, constipation, and sedation is associated with higher doses, 5 – 15g of raw leaves.

Toxic effects: The noxious role of Kratom is due to its dual action wielded by stimulant as well as the opiate effects [16,17]. The stimulant actions induce anxiety, irritability, and aggressive behavior. On the other hand, the opiate effects demonstrate nausea, sedation, constipation, and itching. Uniquely, these effects occur dosedependently and vary from one individual to other. Chronic use of Kratom at high doses produces plenty of unpleasant outcomes which are hyperpigmentation on cheeks, anorexia, tremor, weight loss, and psychosis. Overdoses (>15g) create serious toxicity which often leads to severe seizures. It is further noticed that intrahepatic cholestasis is frequently noticed among the habitual Kratom users [12]. Additionally, the incident of cardiotoxicity is also documented in many cases, for example ventricular arrythmia, ventricular tachycardia, ventricular fibrillation, cardiomyopathy, coronary atherosclerosis, focal band necrosis in myocardium, myocardial infarction, hypertensive cardiovascular disease, left ventricular hypertrophy, myocardial ischemia, and myocarditis [18]. Surprisingly, the occurrences of cardiotoxicity have been reported only in the West, but not in Southeast Asian nations. Although intriguing many hold doubts that it could be due to lack of proper recording of the events. Studies using human induced pluripotent stem cell-derived cardiomyocytes showed that in the presence of Mitragynine, the psychoactive alkaloid of Kratom indicates prolonging of action potential duration of myocytes. The event intends to increase the risk of prolonged QTc interval and torsades de pointes (very fast heart rhythm / tachycardia). Malaysian studies on human subjects further indicate that the chronic users of kratom increases the risk of borderline QTc interval, 431 – 450 ms [19,20].

Short time use effect	Nausea, Constipation, Sleeping trouble, temporary erectile dysfunction, Itching and Sweating.
Long time use effect	Anorexia, Dry mouth, Problems in diuresis, Darkening of skin, and Hair loss
Withdrawal symptom	Hostility, Aggression, Muscle and bone aching, Tremor / Jerky limb movement, Anorexia, Weight loss, and Insomnia.
Infrequent effects	Seizures, Intrahepatic cholestasis, Psychosis, Adult respiratory distress syndrome, and Hypothyroidism.
Fatalities	Kratom when mixed other drugs: O-desmethyltramadol, Propylhexedrine. Over the counter cold medications: Benzodiazepines, Venlafaxine, Diphenhydramine, Mirtazapine, Zopiclone, Citalopram, and Lamotrigine.

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