Kratom: Overview

This article addresses the most general questions about kratom, briefly examines the pharmacology of the plant, presents the structures of the most well-known alkaloids of the plant, etc. The information is provided for informational purposes only. I would like to briefly raise the topic of kratom and, of course, entheo-shops where it is sold in Ukraine and Russia. But it is clear that, first and foremost, I would like to touch on the subject of kratom as a psycho- and biologically active phenomenon, as there are many "legends" where there is not a grain of truth about the true pharmacology of this entheogen. In Ukraine, and in many countries of the world, this plant has "survived" the times of sales of extracts of "Diviner's Sage" and a whole range of other entheogens, which can now be easily found in the "lists of narcotic and potent psychotropic substances, their precursors, etc.", along with heroin, cocaine, and many other genuine and well-known drugs. I have been studying kratom since approximately 2004, and the first thing I noticed was the suspicious absence on the internet of diverse scientific studies of even the main active substances of kratom, which have been known for over 100 years. That is, the pharmacology of kratom is still poorly covered in scientific and popular science literature: open sources only provide the most general information about the most well-known alkaloids of the plant, which were previously considered the main active substances of the entheogen. Today, more than 30 alkaloids have been identified in the leaves of kratom, and dozens of structures of biologically active substances (BAS) of this plant are known. This involuntarily arouses surprise. Kratom is not a fly agaric, which is characterized by significant fluctuations in the content of a whole range of psychoactive substances (PAS) and BAS, where, depending on the variety and growing conditions, drying, storage, etc., the differences in the content of various substances in plant material are so significant that some substances may be present in large amounts in one specimen, while in another, from another region, or collected under different conditions, etc., they may be virtually undetectable. And besides that, it is well known to many that the fly agaric as an entheogen can have quite low toxicity at high activity, and this will depend heavily on the specifics of the heat treatment of the cap of this mushroom, during which ibotenic acid is transformed into the more active muscimol. Kratom, however, is a very "predictable" and well-known plant in Southeast Asia, Africa, and even in some Middle Eastern countries, not to mention the mysterious flora of South America, and although their percentage of different alkaloids, etc. may vary from variety to variety, these are still well-known alkaloids, the sum of which can be easily obtained in laboratory conditions. It so happened that the "main" active ingredients of kratom are considered the alkaloids mitragynine and 7-hydroxymitragynine, although the effects of these alkaloids in experiments do not fully correspond to the effects of natural kratom leaves. Also well-known alkaloids of kratom are paynantheine, speciogynine, speciociliatine, and corynantheidine.

 

Main Alkaloids of Kratom

In the russian-language Wikipedia, mitragynine is cited as the "basic" alkaloid of Kratom, which, as is known at this time, is not the main active substance of the plant, but has already been included in the "opioid" group, and in Russia, it is indeed quite difficult to buy this relatively safe entheogen. It is known that cancer patients and people with other serious health problems are actively requesting all who care to leave active forms from Kratom leaves as a definitely effective and definitely much safer alternative to powerful opioid analgesics such as morphine, its derivatives, and synthetic analogs.

So why is it that online information about even the simple pharmacology of well-known active substances of the plant is very fragmentary and superficial, but it is loudly stated that mitragynine is an "opioid analgesic", considered an "analogue of morphine", in tests some alkaloids demonstrate the effectiveness of mu-opioid receptor agonists and "in terms of potency" are many times stronger than morphine? And a recently extracted brand new Kratom alkaloid - mitragynine pseudoindoxyl - is compared in activity to enkephalin (that is, it is approximately 50 times more active than morphine).

However, although the plant is available to many who wish, in various forms, you will not often come across cases of "narcotic addiction to Kratom", even in the regions where it grows, where you can almost see groves of this plant, as well as the use of stems of adult specimens for building huts, houses, etc. Thus, we have some kind of absurdity: there is an available "opioid, many times more active than morphine at least", but there is no clear description of even the simplest pharmacology, and there are no "hundreds of thousands of addiction clinics where they treat Kratom addiction", and in general this topic is not very clear to an ordinary person, who just stumbled upon all this by chance on the Internet, or even on various social networks. Perhaps, taking all this into account, it is worth delving into this phenomenon a bit? Based on known facts, etc.

In many Ukrainian entheoshops you can easily read a series of articles on the fact that the use of Kratom as a medicine in Southeast Asia has a millennia-long history, as well as what exactly the plant was used for: as an analgesic, but without a number of pronounced, inherent to "classical opioid" analgesics, dangerous side effects such as respiratory depression, bradycardia, and especially - the formation of harmful addiction, with strong tolerance to the active substances of the plant, and then - severe physical and psychological dependence. And most importantly - it is definitely known that no "extracts", not to mention pure Kratom alkaloids, are not used parenterally in medicine and cannot be taken in this way by drug addicts. That is, the most terrible thing in "opium addiction" is missing - intravenous administration of something based on Kratom. There are examples that such studies were conducted, quite a long time ago, and very unpleasant and dangerous examples are described when even pure plant alkaloids are consumed orally. This is primarily a visual impairment in the form of severe "double vision" (not due to the narcotic effect as from vodka, for example, it is the direct pharmacological activity of some alkaloids of Kratom in relation to certain formations of the CNS: it is important to understand clearly what is being discussed), problems with the cardiovascular system (severe hemodynamic disturbances are possible), and much else happens when introducing such a "frightening opioid" mitragynine parenterally or even in pure form inside. Of course, there is no talk of classic opiate "euphoria," nor the potential for such "recreational use" of the plant. If we compare figuratively, then some of these unsuccessful experiments are somewhat reminiscent of experiments on pure nicotine from tobacco, where subjects were actually threatened with death.

So, we have: neither "IV drug addiction" with a well-known moment of "onset" even to laymen (the fundamental moment in heroin abuse is precisely IV), nor anything even remotely similar; no addiction clinics with a sign "kratom addiction," no Kratom "on the streets" along with basic drugs, etc., etc. But we also clearly see that Kratom alkaloids indeed have properties of agonists, primarily of mu-opioid receptors, and the sale and purchase of Kratom in "understandable" stores do take place, as does the illegality of Kratom in Thailand and much else. So what are we talking about? After all, some entheo-shops, one of which I gave as an example, provide only Kratom, and everywhere it is clearly stated that it is "not for human consumption" and - "for research and collections." However, as strange as it may sound, many people do indeed purchase this entheogen for research purposes.

The chemical nature of the "main" alkaloids of Kratom is well known: it is, surprisingly, indole derivatives, very close in this respect to a number of alkaloids of Yohimbe, Rauwolfia, and even "Cat's Claw" - a well-known vine with proven activity in terms of immune activation. The only thing that is truly striking is the presence of a methoxy group in a known position, from a chemical point of view, of "psychedelic tryptamines" such as psilocybin and LSD, as it is known that the presence of hydroxyl and other groups in this position in "classic" tryptamine psychedelics (in general, psilocybin in the body undergoes hydrolysis and ultimately, as in mitragynine and in the case of other basic Kratom alkaloids, such alkaloids in the human body are metabolized by means of "detaching" a methyl (or other) fragment with a hydroxyl group); if we talk about LSD, then it is generally a tetracyclic psychedelic complex alkaloid, but there is also a substitution in this fragment of the indole "foundation".

 

If we were to transfer the hydroxyl group in psilocin to the 5th position, we would get the simplest positional isomer of psilocin (i.e., the same structure but with a different location of the hydroxyl group) – and we would have bufotenin, which, although it exhibits psychedelic activity in high doses, is not comparable in both "quality" and duration to the effects of psilocin, and is a completely different, quite dangerous psychoactive substance, often present in the skin of some toads and in a variety of higher and lower plants. It is also clear that mitragynine and its analogs in Kratom are closer to the so-called "condensed indole derivatives - beta-carbolines like harmine and its analogs, but these substances are simpler, and are well known for their toxicity (they are irreversible MAOIs), although this group of substances gave a "push" for the creation of quite effective, well-known antidepressant MAO-A drugs in psychiatry, usually with stimulating and even nootropic activity, such as pyrazidol, inkazan, tetrindol, and some others. It should be noted that the structures of these drugs resemble only one "part" of the molecules of Kratom's alkaloids, like mitragynine (indole), and in terms of pharmacological properties, these are completely different substances. On the other hand, if we consider only the "indole" part of the mitragynine molecule and its derivatives, we can see (a rough conditional comparison) the substitution "in the 4th position" (if mitragynine was a simple tryptamine like psilocybin). Put simply, these Kratom alkaloids should have been substances with pronounced psychedelic properties, but here we have a phenomenon: mitragynine and other Kratom substances are not MAOIs, but also do not exhibit pronounced psychedelic properties, typical of simple tryptamine derivatives like psilocin.

So, it is evident that Kratom's alkaloids, while indole derivatives and having substitution in the typical location for simpler "tryptamine psychedelics," do not remotely exhibit the properties inherent to both simple "tryptamine psychedelics" like psilocybin and more complex ones, like harmine derivatives, not to mention the specific properties of the aforementioned examples of MAOI antidepressants.

The most accurate information about Kratom, in terms of botany, is this excerpt, found on Wikipedia and other sources:

"Kratom (Mitragyna speciosa) is a large tree native to Southeast Asia, belonging to the Rubiaceae family, first described by Dutch colonial explorer Korthals. This species is botanically related to such plants as Corynanthe, Cinchona, and Uncaria and is similar to them in a biochemical sense. Kratom is in the same family as the Coffee tree and the psychoactive plant Psychotria viridis."

This description allows for the study of Kratom's biochemistry by comparing the structures of its alkaloids to the structures of alkaloids in "related plants." In this regard, the Yohimbe tree is the most "similar" to Kratom.

I initially explained that I am providing the most general information about Kratom, and it is quite possible that in the very near future, it will be possible to become more deeply acquainted with this plant. Why is all this necessary? At least because if you rely only on available (open) information about this truly amazing plant, you can, of course, fear the emergence of not only terms such as "opioid" but also topics like "cocaine-like stimulant." It is also important how different forms of Kratom are taken internally and for what purposes, as the pharmacological effects can vary greatly in this case.

I am bringing up the topic of Kratom also because it is an entheogen that, in terms of efficacy and minimal toxicity, is comparable to medical cannabis and other Hemp products, which are finding increasingly wide and successful use in developed countries, primarily in the treatment of the most sinister diseases where malignant oncology is far from "everything," but rather something like the "tip of the iceberg." The most important aspect of the issue, in my opinion, is that in reality, a very small percentage of people use cannabis exclusively as a PLS (psychoactive substance), and it is quite obvious that behind the name "Medical Marijuana," one can only guess what is actually hidden, as this, as they say, is a "silk purse" for many, and today, the recreational use of cannabis is already a problem, but this topic deserves separate careful analysis.

If we talk about the "strongest" strains of Kratom, or about powerful "water extracts," or about a "balanced mix" of the most active PAV (psychoactive substances) of the plant (standardized sum of alkaloids), then although we read that something is "50 times stronger than morphine," in practice, we have something entirely different. The level of purely "opioid" effect of Kratom, even in the case of extracts, is usually compared to the effects of either codeine, tramadol, or hydrocodone, and other opioid and mixed central analgesics, but no one has yet described the effect of Kratom as "comparable to the effect of heroin/morphine." In addition to this, one should not forget about the atypical structures of the main alkaloids of Kratom that exhibit properties of mu-opioid receptor agonists; in chemical terms, the closest analogue for these alkaloids among opioid analgesics, to some extent, is such a PLS as etonitazene and its derivatives, but even this comparison will be very conditional.

In my humble opinion, comparing the structure of mitragynine or 7-Hydroxymitragynine (as of today, it is the main candidate for the primary active alkaloid of Kratom, before that, it was believed that mitragynine was responsible for the main effects) with the structure of beta-prodine, one of the first fully synthetic opioid analgesics used in medical practice, is at least incorrect, though quite symbolic: after the full synthesis of morphine and its active research, scientists unexpectedly discovered morphine-like properties in pethidine acid and its derivatives. Psychopharmacologists are well aware of the so-called "Shauman morphine transcription" and the "Morphine Rule" concept.

O. Shauman immediately linked the activity of pethidine to the structural similarity with morphine, drawing the formula of the latter in a favorable transcription for this purpose, and this comparison gave a powerful impetus to the search for new, fully synthetic opioid analgesics. The main elements of similarity between these completely different molecules are clearly visible in the provided "figure," and this is what led to the concept of the "Morphine Rule," which imposes structural requirements on this kind of psychoactive substance. Let me remind you of these requirements:

The presence of a benzene ring (element a), directly connected to a tetrasubstituted carbon atom (element b), and a tertiary nitrogen atom (element c), removed from element b at a distance of two carbon atoms. The first effective synthetic analgesics were synthesized based on these structural requirements, but later more powerful drugs were discovered, the structures of which did not correspond to the "Morphine Rule", where the classic example is the fentanyls, surpassing morphine by hundreds and hundreds of times in analgesic activity. To date, hundreds of active opioid analgesics can be cited, the structures of which either fully or partially meet the requirements of the "Morphine Rule", as well as hundreds of others that do not meet these requirements. As for mitragynine and its analogs, in these cases drawing parallels with the "Morphine Rule" may be more symbolic if applicable at all, but nonetheless.

But that's not the point. In 3D, the difference between the molecules of classic opioid analgesics and mitragynine is simply colossal, but the direct pharmacological effects of these substances are even more different. Basic Kratom alkaloids are incapable of inducing full-blown opioid euphoria, and even at high doses, Kratom remains more stimulating than relaxing, as well-known to active users of plant-based preparations. In addition, recent studies provide grounds for a global reconsideration of the pharmacology of Kratom alkaloids. At this point, the structure and properties of a completely atypical alkaloid of this plant, known as mitragynine pseudoindoxyl, have been established, and it has a structure different not only from classic opioids but also from the "main alkaloids" of Kratom itself.

This compound is compared in potency to enkephalin, an endogenous ligand for opioid receptors, surpassing morphine by about 50 times. It should be noted that about three dozen active alkaloids have been found in Kratom leaves.

However, people familiar with the effects of morphine and its analogs, as well as the effects of Kratom, unanimously claim that, qualitatively, these effects differ radically. As mentioned above, even the most potent extracts of the entheogen can be compared in terms of analgesic quality at most with hydrocodone, and the duration of effects lasts only a few hours, peaking at one hour. Moreover, the most dangerous side effects of opioids are not observed, which is crucial when evaluating the pharmacological properties of Kratom alkaloids or Kratom as such (I remind you that isolated plant alkaloids do not offer significant prospects for medicine or recreational purposes due to a whole bouquet of acute side effects, and there is no such phenomenon as a "rush," which is also important, as intravenous or intramuscular administration of isolated Kratom alkaloids is by no means advisable, and such non-targeted use of Kratom is not just unlikely but rather unrealistic).

Thus, we can see again and again that positioning Kratom or its individual alkaloids as "powerful opioid analgesics" is purely formal: these plant alkaloids do indeed exhibit the properties of agonists of opioid receptors of the mu-, delta-, and other types, but this is a very specific type of interaction and is qualitatively incomparable to that of genuine classic opioids. This is a separate topic requiring basic knowledge in biochemistry, etc. For this reason, I am omitting these aspects for now, but that doesn't mean they can be ignored, quite the opposite.

The most appropriate comparison of the effects of Kratom remains with the effects of codeine - a rather atypical alkaloid of opium, as codeine does not particularly exhibit pronounced narcotic or analgesic properties within the range of therapeutic doses. Furthermore, codeine does not have the hypnotic effect characteristic of morphine and its pharmaceutical analogs. Based on the above, Kratom should not be dismissively classified as an "opioid" in the narrow sense, comparing it to the infamous heroin and similar drugs, with an emphasis on their recreational potential, as seen in public sources. The above review is indeed something like a "prologue" regarding the analysis of the pharmacology of Kratom and/or its individual active substances. It is quite clear that Kratom, as an "everyday narcotic drug," is hard to imagine, especially considering its "taste qualities" and numerous other pharmacological effects that I have not even mentioned yet, as well as the cost of the most popular forms of this entheogen. It is also obvious that the information available about the plant on Wikipedia and in some other sources cannot be considered "exhaustive" and, moreover, this information often raises more questions about Kratom than it answers, often leading to a range of misconceptions about this entheogen among interested researchers and its popularizers. On the other hand, taking into account the pronounced psychotropic effects when using the plant, the side effects of short-term, episodic, long-term use for various purposes, considering the specific features of different varieties, individual characteristics of consumers, etc., it is impermissible to ignore the "other side of the coin" about which not much has been written, although there is a great deal of experience among Kratom consumers today, as well as a number of observations and private studies of the plant.

The main danger of Kratom alkaloids is their potential use as active ingredients in the notorious "smoking blends." This is the main reason for Kratom's inclusion in certain "lists," along with a number of other completely safe plants. Drug traffickers today will stop at nothing, and individual Kratom alkaloids have been found in some "smoking blends," along with other powerful synthetic active substances. In these cases, it is easy to understand the governments of countries where Kratom or its individual alkaloids are illegal. Some unscrupulous Kratom sellers may also add synthetic opioid analgesics to the leaf powder, such as O-Desmethyltramadol, etc. These are rare but factual occurrences. For these and other reasons, public awareness of this issue is extremely important, and we will do everything to ensure that buyers have the opportunity to purchase only natural, tested, Indonesian Kratom of various sorts, and not its substitutes and the like.

So, analyzing all the pharmacological effects of all available forms of all varieties of Kratom is a very complex and relevant topic, and various side effects, risks, etc. when using Kratom are even more relevant. In light of this, I would like to emphasize once again that this article is a very superficial overview of this entheogen, but I decided to provide even this small amount of information in this form because, as many are well aware, even simple Blue Water Lily can quickly end up on the same lists as heavy synthetic drugs, due to mere assumptions about its potential "dangers." Kratom, however, is a fairly well-known powerful psychoactive plant, and all these tendencies in terms of "defining" this entheogen as a "legal opioid drug," coupled with comparing its alkaloids to the most dangerous narcotic substances, are certainly alarming if one has information closer to reality.

The potential of Kratom as a natural drug is hard to overestimate, but the information available to ordinary people, as one can see, leaves much to be desired, to put it very mildly. The problems associated with non-targeted use or simply side effects when consuming Kratom remain unanswered, and this adds fuel to the fire, so to speak.

But there are adequate answers to all these questions, and we are ready to provide them at the earliest opportunity.