Kratom / Mitragyna speciosa

Kratom is de algemeen gangbare naam voor de Mitragyna speciosa Korthals, een boom die oorspronkelijk voorkomt in Zuidoost-Azië (Thailand, noordelijk Maleisisch schiereiland en Borneo). Het wordt het meest gekweekt in zuidelijke delen van Thailand 

De Mitragyna soort, behorend tot de klasse van Rubiaceae, komt voor in de (sub-)tropische regio's van Azië en Afrika. Aziatische Mitragyna's groeien vooral in het regenwoud, terwijl Afrikaanse soorten (die soms worden ondergebracht in een eigen klasse, Hallea) in moerassig gebied voorkomen. Sommige exemplaren reiken tot bijna 30 meter. De soort heeft zijn naam te danken aan de plantkundige Korthals: de stampers van eerste Mitragyna's die hij bestudeerde hadden de vorm van een bisschopsmijter. De bloemen van deze planten groeien in een bolvorm met elk zo'n 120 bloemetjes. In de gebieden waar zij van nature voorkomen, worden Mitragyna-soorten voor medicinale doeleinden, maar ook vanwege voor hun fijne hout gebruikt. De laatste tijd is de ondersoort Mitragyna speciosa steeds populairder geworden als recreatieve drug.

Mitragyna speciosa kan ongeveer 15 meter hoog worden met een wijdte van meer dan 4,5 meter. De stam is recht met zijtakken, de bloemen zijn geel. De bladeren verkleuren niet en zijn ovaal van vorm en glimmend, donkergroen van kleur. Kratom is groenblijvend. De plant laat voortdurend bladeren vallen, maar er is wel een soort seizoensgebonden bladverlies die samenhangt met een verandering in de omstandigheden. In het droge seizoen verliest de plant meer bladeren en in het natte seizoen is de groei van nieuwe bladeren sterker. Wanneer de plant buiten een tropisch klimaat wordt gekweekt, verliest hij zijn bladeren bij lage temperaturen (4° C).

Kweken
Kratom groeit bij voorkeur op een beschermde plek in natte, humusrijke aarde. De plant heeft veel voeding nodig en is gevoelig voor droogte en vorst. Voortplanting gebeurt door middel van verse zaden of stekjes. De succeskans is klein, omdat het bladvaatweefsel vaak wordt aangetast door een bepaalde schimmel.
Er is weinig bekend over het kweken van kratom. Zaden en stekjes zijn moeilijk te vinden. Kratomstekjes zijn bovendien nogal lastig om te kweken, hoewel de plant zelf, als deze eenmaal wortel heeft geschoten, redelijk stug is. Om deze reden experimenteren sommigen met het klonen van de plant. De twee grootste problemen met stekjes lijken te zijn dat ze of worden aangetast door een schimmel, of dat ze simpelweg nooit wortelen. Enkele suggesties om deze problemen te verminderen:

Het stekje bewaren in een laag water met een luchtpompje om het zuurstofniveau te verhogen;
Een klein beetje schimmelbestrijdingsmiddel aan het water toevoegen om schimmelvorming tegen te gaan;
Het water elke dag verschonen om schimmel geen kans te geven.
Volgens sommigen is de volgende methode succesvol: gebruik houtwol om het stekje vochtig te houden en er toch nog frisse lucht langs kan stromen, ververs het water elke dag en voeg voeding toe zodra de wortels beginnen te groeien.
kratom zaden
Er wordt gezegd dat de bladeren van de M. Speciosa het sterkst (hoogste concentratie alkaloiden) zijn in de late herfst, net voordat ze vallen. Planten die in een koud klimaat worden gekweekt zouden minder sterk zijn. Planten in een subtropisch klimaat zijn minder sterk in de late winter en in het voorjaar, en sterker in de late zomer, de herfst en begin winter. De meeste planten die in een kas worden gekweekt zijn ook minder sterk.

Pharmacology of Kratom

Chemistry and Pharmacognosy
As the use of kratom in the West has grown during the past 15 years,4,20,23,30 there have been increased efforts to identify and characterize the active pharmacologic agents that mediate the effects of kratom in the body. Thus far, more than 20 active compounds have been isolated from kratom, and considerable evidence shows that these compounds do, in fact, have major pharmacologic effects.30,31 Various aspects of the medicinal chemistry and pharmacognosy of kratom have recently been reviewed by Adkins et al.30 Accordingly, only a few key points regarding these topics will be considered in the present article. The Table shows the chemical structures and summarizes the major pharmacologic actions of some of the kratom-derived compounds that have been studied most extensively. The most extensively-characterized of kratom's active pharmacologic agents have been the mitragynine analogs.30 These agents contain an indole ring and are, in some respects, structurally similar to yohimbine.30 These agents have been shown to produce a wide variety of pharmacologic effects, both in vivo and in vitro.30 In the following sections, we will consider the importance of these compounds as they relate to the primary pharmacologic effects of kratom, particularly analgesia and the ability to suppress symptoms of opioid withdrawal.

Analgesic and Opioid-Like Effects
In Southeast Asia, kratom has long been used for the management of pain and opium withdrawal.6,9-11,14 In the West, kratom is increasingly being used by individuals for the self-management of pain or withdrawal from opioid drugs such as heroin and prescription pain relievers.20,27 It is these aspects of kratom pharmacology that have received the most scientific attention. Although to our knowledge, no well-controlled clinical studies on the effects of kratom on humans have been published, there is evidence30-38 that kratom, kratom extracts, and molecules isolated from kratom can alleviate various forms of pain in animal models. Studies have used a variety of methods including hot plate,35,37,39 tail flick,32,39 writhing,37,38 and pressure/inflammation35,38 tests in mice32,35,38,39 and rats,35,37 as well as more elaborate tests in dogs and cats.35 In addition, a variety of chemical compounds have been isolated from kratom and shown to exhibit opioid-like activity on smooth muscle systems31,33,34 and in ligand-binding studies.39,40 Most notably, many of the central nervous system and peripheral effects of these kratom-derived substances are sensitive to inhibition by opioid antagonists.31-34,39-41

Most of the opioid-like activity of kratom has been attributed to the presence of the indole alkaloids, mitragynine and 7-hydroxymitragynine. Both compounds have been shown to have analgesic and antinociceptive effects in animals, although 7-hydroxymitragynime is more potent.30,32,40 These agents also produce opioid-like effects on organs such as the intestines and male internal genitalia.33,34 Moreover, when they are given to animals for 5 days or longer, both compounds produce a state of physical dependence, with withdrawal symptoms that resemble those of opioid withdrawal.31,32,41 In addition, ligand-binding studies and those using opioid antagonists indicate that these effects are largely mediated by means of actions on μ- and δ-type opioid receptors.30,31,33 Along with these various central nervous system effects, kratom also appears to have anti-inflammatory activity.38 Utar et al42 recently found that mitragynine can inhibit lipopolysaccharide-stimulated cyclooxygenase-2 expression and prostaglandin E2 production. In addition to direct mediation by means of opioid receptors, the antinociceptive effects of mitragynine appear to involve the activation of descending noradrenergic and serotonergic pathways in the spinal cord.43 Additionally, animal studies have shown that mitragynine may stimulate postsynaptic α2-adrenergic receptors and possibly even block 5-hydroxytryptamine2A receptors.33 Although kratom contains lower levels of 7-hydroxymitragynine than mitragynine, it has been suggested that 7-hydroxymitragynine is more potent and has better oral bioavailability and blood brain-barrier penetration than mitragynine,30,40 making it the predominant mediator of analgesic effects of kratom in the body.

Other compounds that have been isolated from kratom and implicated in some of its effects include speciociliatine, speciogynine, and paynatheine.30,40 These compounds have been shown to modulate intestinal smooth muscle function and behavioral response in animals.33,34,40,44 However, these effects were not inhibited by the opioid receptor antagonist naloxone, suggesting that they involve opioid-independent mechanisms.40,44 It remains to be determined how these compounds may contribute to the overall actions of kratom in vivo.

Subjective Effects
In spite of the fact that kratom has been widely touted and used as a “legal opioid,”23,31 few scientific studies have addressed the psychoactive properties of kratom.6,9,11,12 Most of the available information is based on anecdotal reports and patient experiences. The general subjective effects of kratom have been summarized in various reviews.6,9,12,30 In addition, many individuals have posted descriptions of their personal kratom experiences on Web sites such as Erowid, Sagewisdom, and WebMD.24-26 As noted previously, kratom produces an unusual combination of stimulant- and opioid-like effects. These effects are highly dependent on the dose of kratom and can vary markedly from one individual to another. Low to moderate doses (1-5 g of raw leaves) usually produce a mild stimulant effect that most individuals perceive as pleasant but not as intense as those of amphetamine-like drugs.24,25 Some individuals, however, report that these low-dose effects are mainly characterized by an unpleasant sense of anxiety and internal agitation.24-26 It is noteworthy that those who have used kratom products for pain management tend to view the stimulant effects of kratom as being more desirable than the sedative effects of traditional opioids.24-26

Opioid-like effects, such as analgesia, constipation, euphoria, and sedation are typically associated with the use of moderate-high doses of kratom (5-15 g). As with the lower-dose effects, the higher-dose effects may be either euphoric or dysphoric, depending on the individual. Of note, the euphoric effects of kratom generally tend to be less intense than those of opium and opioid drugs.6,10,11,25 Nevertheless, kratom is still sought by drug users.



In Depth: Botany and Pharmacology of Kratom

Kratom grows in swamps and damp valley areas that are rich with humus, and forms “dense stands in the new alluvial substrate of ox-bow lakes and low muddy river banks that are frequently inundated.”9 The species is said to be a common riverside pioneer (i.e., a species that is the first to colonize previously disrupted or damaged ecosystems).

According to one source, the tree can grow to 4-16 meters (13-52 feet) tall with a spread of more than 15 feet.6,45 According to Kratom and Other Mitragynines, it can grow to 25 meters (82 feet) in height and two to three feet in diameter. The trunk is usually straight. The outer bark is smooth and gray, and the inner bark is pinkish.9 The leaves are oval or ovate-lanceolate and dark green.6 They are 14-20 centimeters long and 7-12 centimeters wide.9 The veins of the leaves are either greenish-white or red. Leaves with greenish-white veins are said to be more potent. The average weight of a fresh leaf is about 1.7 grams, while the average weight of a dried leaf is about 0.43 grams. The tree produces yellow and globular flowers that can bear up to 120 florets. The fruit is a capsule that contains several small, flat seeds.6

Alkaloid Chemistry and Composition
The tree contains more than 40 structurally related alkaloids, in addition to several flavonoids, saponins, polyphenols, and glycosides. Kratom is the only species known to produce the indole alkaloids MG and 7-OH-MG, two of the main psychoactive components in the plant.6 At least three other alkaloids found in kratom (speciogynine, paynantheine, and speciociliatine) have been shown to have some opioid receptor affinity.46

The chemical profile of kratom varies depending on several factors: the variety and age of the plant, the environment, and the time of harvest. The total alkaloid concentration in dried leaves typically ranges from 0.5% to 1.5%.6

MG is structurally similar to yohimbine (a compound derived from the African tree yohimbe [Pausinystalia johimbe, Rubiaceae]),10 and it is typically the most abundant alkaloid in the leaves,9 although it has also reportedly been found in the fruits and stembark of kratom.47 MG was first isolated in 1921, and its structure was determined in 1965.9

The amount of MG that kratom yields depends on geography and the maturity of the leaves.9 For example, MG accounted for 66% of the crude base of alkaloids extracted from young leaves of a specimen from Thailand, while the compound accounted for only 12% of the alkaloids extracted from mature leaves of a specimen from Malaysia.47 It is possible that, in this case, geography, not leaf maturity, accounted for the difference, since, according to Kratom and Other Mitragynines, MG is typically much more abundant in older plants than younger ones, and much more abundant in Thai plants than Malaysian ones. Interestingly, the predominant alkaloid found in a kratom specimen grown at the University of Mississippi was the oxindole-type mitraphylline (at 45% of the total alkaloids), not MG.9 Mitraphylline is also found in the bark of cat’s claw (Uncaria tomentosa, Rubiaceae).48

7-OH-MG is a minor alkaloidal constituent of kratom. It accounted for just 2% of the crude base of alkaloids extracted from young leaves of a specimen from Thailand. A 2004 study using guinea pigs showed that 7-OH-MG was almost 50-fold more potent than MG and more than 10-fold more potent than morphine.47 Another study using guinea pigs, however, showed that 7-OH-MG was 30-fold more potent than MG and 17-fold more potent than morphine.46 It is thought that 7-OH-MG is more potent than morphine because it is more lipophilic (i.e., able to combine with or dissolve in fats) than morphine and distributes more quickly across the blood-brain barrier, a diffusion barrier that impedes the influx of most compounds from the blood into the brain.9,49 However, 7-OH-MG is less lipophilic than MG, and it is thought that it is more potent than MG because of tighter receptor binding to the mu-opioid receptors (MORs), which is associated with 7-OH-MG’s hydroxyl group (-OH) at the C7 position, a structural feature not present in MG.9,40

MG and mitraphylline have also been shown to be able to diffuse across the blood-brain barrier in vitro. In addition, MG and 7-OH-MG were found by one study to be unstable in simulated gastric fluid (which could account for why some of the 7-OH-MG [23%] was converted to MG), but both were found to be stable in simulated intestinal fluid.48 MG is not soluble in water, but it is soluble in conventional organic solvents (i.e., solvents that contain carbon atoms).6


Receptor Activity and Mechanisms of Action
According to the study conducted by researchers at Columbia University, both MG and 7-OH-MG are partial agonists of the MORs, and MG was shown to have about 34% of the maximal effect of a full agonist. This study was conducted using human kidney cells that had been genetically modified to express the human versions of each opioid receptor subtype. MORs are located in the brain, spinal cord, and gastrointestinal tract, and MOR agonists (like morphine) are the “gold standard” of pain therapy. But, in addition to producing analgesia, MOR activation can produce serious adverse side effects, including constipation, sedation, nausea, itching, and, as previously mentioned, respiratory depression. In addition, the euphoria produced by MOR agonists makes them widely subject to misuse.40

Kroll proposed three explanations for why MG and 7-OH-MG cause less-to-no respiratory depression, compared with other MOR agonists. “First, they are partial agonists at the MORs, meaning that the maximal effect is lower than the maximal effect of a full agonist like morphine,” he wrote. “What this means is that no matter how much MG or 7-OH-MG you put in the system, you’ll never get to the same effect as the maximum effect of morphine.”

“Second, the Mitragyna speciosa alkaloids all appear to be ‘biased’ toward the G-protein signaling pathway and away from the beta-arrestin-2 pathway,” Kroll continued. “This is a relatively new and often confusing concept, even to some pharmacologists. When a receptor sitting on the cell surface is bound by a drug, it can either do nothing (as with a blocker, or antagonist), or it can transduce a signal to the inside of the cell that triggers a cascade of events. MORs can signal through a so-called G-protein and/or the beta-arrestin-2 protein. Beta-arrestin-2 seems, at least in part, to mediate respiratory depression (as well as tolerance, accounting for why patients and addicts all require progressively more opioids over time to produce the same effect).”

According to Kroll, a possible third reason “is that MG and 7-OH-MG are both antagonists at kappa-opioid receptors [KORs], albeit with less potency than as partial MOR agonists. The overall effect is that you can get painkilling approaching that of morphine with much less respiratory depression.”

KOR antagonists, such as MG and 7-OH-MG, have shown the potential to help promote stress resilience, which may help treat certain types of anxiety, depression, and addiction disorders, all of which are exacerbated by hypersensitivity to stress.50 The Columbia University study also showed that MG and 7-OH-MG are antagonists of the delta-opioid receptors (DORs).40 Animal studies suggest that DORs control rewarding or addictive properties of drugs that act on the MORs or other non-opioid receptor sites. Therefore, DOR antagonists may have the ability to block morphine reward and tolerance.51

Interestingly, the Thai strain of kratom used by the Columbia University researchers yielded only trace quantities of 7-OH-MG that were too small to isolate. “Therefore,” the researchers wrote, “it is doubtful that this alkaloid is a universal constituent of all Mitragyna speciosa preparations and is unlikely to generally account for the psychoactive properties of this plant.” They were, however, able to prepare 7-OH-MG through photochemical oxidation of MG, which, according to Kroll, indicates that “growing and storage conditions may dramatically affect the overall potency of the botanical material.”40

In addition, the study found that paynantheine, speciogynine, and speciociliatine (which, together, accounted for a percentage of the total extracted alkaloids that was approximately equal to the percentage accounted for by MG) all exhibited antagonist activity at the MORs that competed with the agonist activity of MG. The researchers, therefore, concluded that “the gross psychoactive effects of crude plant material are likely to represent a complex interplay of competing agonist and antagonist effects at the opioid receptors.”40

Kratom’s unusual and paradoxical stimulant/sedative effects are not fully understood. “Some opioids have a paradoxical stimulating effect in some patients, particularly in elderly folks,” Kroll wrote. “But the Mitragyna speciosa alkaloids have some other receptor effects (e.g., alpha-2-adrenergic) that may or may not be relevant for the amounts of kratom people consume. From anecdotes, the [stimulating] effect does sound like it’s real but it hasn’t been systematically studied in humans or attributed to a specific compound or neuroreceptor system.”

One guinea pig study showed that MG may produce analgesic effects through the blockade of neuronal calcium ion (Ca2+) channels.52 And another source suggests that MG’s analgesic effects may involve the activation of serotonergic and noradrenergic pathways that descend down the spinal cord. In addition, kratom seems to have anti-inflammatory properties.10

Conclusion
Kratom is a complicated plant that is not fully understood, either by the scientific community or by the global community. It is likely that language has played a part in shaping perceptions about kratom, with some sources referring to it as an opium “substitute” and other sources referring to it as an opium “remedy.”9 Different perceptions of the plant have led some to celebrate it for its medicinal potential and others to malign it for its abuse potential.

At a time when the United States needs safer alternatives to opioids more than ever, the DEA’s placement of the kratom alkaloids in Schedule I would force those who were successfully using the plant for pain management, opioid withdrawal, and other therapeutic purposes to become criminals, seek alternatives that may be more dangerous, or simply do without. Detractors point to the fact that kratom users may become addicted to, dependent on, and tolerant of kratom over time. Proponents emphasize that the kratom alkaloids produce less constipation and, more importantly, less-to-no respiratory depression, compared to other common opioids.

However, proponents, and even some detractors, agree that more research is needed, on both the potential benefits and the potential dangers of kratom. DEA scheduling would make this research more difficult.

“I think that the best kratom researchers should get together and write a couple of clinical trial protocols to the National Center for Complementary and Integrative Health (NCCIH) to investigate a well-characterized, analytical and GMP[good manufacturing practice]-verified kratom product to investigate pharmacokinetics of each compound and metabolite, and efficacy in pain and substance dependence recovery, while also assessing adverse effects, including dependence on the kratom itself,” Kroll wrote.

As far as the individual compounds, Kroll believes that MG, 7-OH-MG, the fermentation product mitragynine pseudoindoxyl, and semisynthetic analogs of each should be investigated as single-entity drugs. “But the semisynthetic analogs will likely be required, not just for intellectual property purposes, but for improved half-life and dosage formulation,” Kroll wrote. “Users have told me they need to dose with kratom tea up to four or five times in a day, and there is some published data that MG’s half-life [i.e., the time it takes for half of the administered amount to be eliminated from the bloodstream] is on the order of an hour.”

Though according to some it is not legally realistic to expect kratom to remain unregulated, there is interest within the scientific community about the potential for new therapeutics derived from the plant (either single compounds or whole-plant preparations) to become safer and better pain-relievers and opioid recovery aids. “At a time when the opioid dependence issue is at its greatest national awareness,” Kroll wrote, “I think we need any tool — pharmacological, psychological, [mindful] meditation, yoga, etc. — that can relieve people of the burden, pain, and potential lethality of substance dependence.”

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Kratom is a complicated plant that is not fully understood, either by the scientific community or by the global community. It is likely that language has played a part in shaping perceptions about kratom, with some sources referring to it as an opium “substitute” and other sources referring to it as an opium “remedy.”9 Different perceptions of the plant have led some to celebrate it for its medicinal potential and others to malign it for its abuse potential.

At a time when the United States needs safer alternatives to opioids more than ever, the DEA’s placement of the kratom alkaloids in Schedule I would force those who were successfully using the plant for pain management, opioid withdrawal, and other therapeutic purposes to become criminals, seek alternatives that may be more dangerous, or simply do without. Detractors point to the fact that kratom users may become addicted to, dependent on, and tolerant of kratom over time. Proponents emphasize that the kratom alkaloids produce less constipation and, more importantly, less-to-no respiratory depression, compared to other common opioids.

However, proponents, and even some detractors, agree that more research is needed, on both the potential benefits and the potential dangers of kratom. DEA scheduling would make this research more difficult.

“I think that the best kratom researchers should get together and write a couple of clinical trial protocols to the National Center for Complementary and Integrative Health (NCCIH) to investigate a well-characterized, analytical and GMP[good manufacturing practice]-verified kratom product to investigate pharmacokinetics of each compound and metabolite, and efficacy in pain and substance dependence recovery, while also assessing adverse effects, including dependence on the kratom itself,” Kroll wrote.

As far as the individual compounds, Kroll believes that MG, 7-OH-MG, the fermentation product mitragynine pseudoindoxyl, and semisynthetic analogs of each should be investigated as single-entity drugs. “But the semisynthetic analogs will likely be required, not just for intellectual property purposes, but for improved half-life and dosage formulation,” Kroll wrote. “Users have told me they need to dose with kratom tea up to four or five times in a day, and there is some published data that MG’s half-life [i.e., the time it takes for half of the administered amount to be eliminated from the bloodstream] is on the order of an hour.”

Though according to some it is not legally realistic to expect kratom to remain unregulated, there is interest within the scientific community about the potential for new therapeutics derived from the plant (either single compounds or whole-plant preparations) to become safer and better pain-relievers and opioid recovery aids. “At a time when the opioid dependence issue is at its greatest national awareness,” Kroll wrote, “I think we need any tool — pharmacological, psychological, [mindful] meditation, yoga, etc. — that can relieve people of the burden, pain, and potential lethality of substance dependence.”

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