Now it's time to write about the most popular and most famous neurotransmitter - serotonin. The most interesting thing is that for several decades various strata of society have been raving about him - from housewives and humanitarians, with their myths about the "hormone of happiness", to mother's psychonauts, who once threw themselves off on a stamp with DOB and are now ready to tell every passer-by about the delights of an "altered state of consciousness".
Initially it was believed that serotonin affects only the tone of blood vessels and smooth muscles, its direct presence in the central nervous system was discovered only in 1953 by Irwin Page and Betty Tverog, information about their discovery they published in The American Journal of Physiology - "Serotonin content of some mammalian tissues and urine and a method for its determination."
In each of these situations, history treats science in the same way: any insufficiently well-researched area begins to grow overgrown with speculation, or really important and serious experiments and publications are lost in the general noise. The explosions of shells and the whistle of bullets during World War II drowned out Albert Hoffman's LSD experience, and songs of universal love in the 60s were more engaging than the works of Shulgin and Nichols. I think that one should not hide the fact that 90% of the world's "psychedelic culture" is tied to substances that in one way or another affect serotoninergic neurons in the central nervous system.
So the story about serotonin should start not with Hoffman, Shulgin or Tverog, but with a short narration about the history of altered states of consciousness.
Let us start the story about altered states of consciousness with a story about the evolution of the brain. In 2009, in the "Trinity Variant" geneticist Mikhail Gelfand published a wonderful article entitled "Schizophrenia as a consequence of the evolution of the brain." The main conclusion of which I will allow myself to formulate more succinctly than it was in the source - a person got acquainted with madness at the time of becoming a person. In this case, the word "moment" in the context of evolutionary neurobiology can be safely taken for several tens of thousands of years. Scientists analyzed a sample of candidate genes, mutations in which are most often found in people with schizophrenia, and compared them with genes of healthy people and the genes of our closest relatives - chimpanzees and rhesus monkeys.
As a result, it turned out that most of the candidate genes influenced the level of metabolism of nerve cells and, accordingly, in the case of humans, was one of the most rapidly evolving groups of genes. So schizophrenia in the context of this particular study can be considered a "childhood disease" in the evolutionary path of man.
At this moment, some people acquired the ability from birth to perceive the world a little differently, which was not the case with chimpanzees. But this was not enough for the man - he demanded the continuation of the banquet! Here, another evolutionary acquisition helped - the enzyme ADH (alcohol dehydrogenase), which made it possible to eat fermented fruits and, a little later - since the invention of ceramics, drink spoiled fruit juice.
What to do with a hangover? Of course! Look for all kinds of roots and try - what if it helps?
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In such a simple way, ancient mankind discovered the first medicines, dyes and poisons. Among accidentally consumed plants with a high degree of probability, since the ancestral home of mankind was in Africa, there was iboga. This small shrub is a cult plant for the Mitsogo people, whose religious cult "Bwiti" may be a descendant of the most ancient practices of directed consciousness change, a living relic of psychedelics. Interestingly, ibogaine contained in ibog and its metabolite, noribogaine, are both ligands of opioid and sertonin (5-HT3, ionotropic subtype) receptors.
In many ancient cultures, where the ritual use of plants containing mind-altering substances was widespread, these same substances often affected precisely serotonergic neurotransmission. You can also remember the mythical drink of the gods of ancient India - amrita, which, according to legend, was prepared from ephedra and mushrooms. Also, ayahuasca from South America can be cited as a more fully documented example. Interestingly, the ancient Indians somehow managed to come up with a mixture that contains both DMT (dimethyltryptamine, a strong serotoninergic psychedelic) and MAOIs (monoamine oxidase inhibitors) of plant origin. Under normal conditions, DMT is inactive when taken orally, but it is activated when mixed with MAOIs, which slow down its breakdown in the gastrointestinal tract.
In Russia, our ancestors also sometimes caught homespun and bast parishes, baked right in the village oven. This business was called "drunk bread" - that is, bread baked from the flour of cereal plants affected by the fungus. Interestingly, this concept meant just two types of fungus - Fusarium graminearum, containing vomitoxin, and Claviceps purpurea (ergot), containing ergotamine derivatives.
And if vomitoxin poisoning proceeded relatively easily, ergot poisoning even got its name - ergotism. With ergotism, in addition to acute psychosis, the tone of the blood vessels is disturbed. This can lead to limb necrosis or gangrene.
With the advent of modern times and the smooth transition of alchemy to chemistry, it became possible to isolate active substances from plant sources. Initially, any extract contained just an alcoholic solution of the sum of alkaloids - nitrogen-containing substances, which, to put it simply, could be isolated by standard acid-base extraction. Then people learned to isolate individual substances from the total extract. This made it possible to observe the "pure" pharmacological effect of individual chemicals on the body.
In this respect, the serotoninergic system is average: despite the fact that the first reports of a "substance that affects muscle tone" date back to the 19th century, pure serotonin was isolated only in 1935 by Vittorio Erspamer. Later, this substance was found in many tissues and organs, incl. and in the nervous system (see above). However, the first information about serotonin receptors dates back only to 1957: J. Gaddum discovered that the ability of serotonin to contract smooth muscles can be blocked by LSD (D-lysergic acid diethylamide, in the domestic literature the contraction of DLK was also used), and morphine can prevent the excitation of autonomic ganglia which occurs with direct exposure to serotonin. Thus,up to the 90s of the twentieth century, serotonin receptors were divided only into 2 classes - D- and M-receptors. Now, thanks to the methods of molecular biology, 7 classes of serotonin receptors have been discovered, and many of them have several subclasses (subtypes).
It is also worth mentioning that serotonin is not only a neurotropic hormone whose functions are limited only to the limits of the nervous system. For example, it participates in the processes of blood clotting and digestion. Moreover, in 2003 the term "serotonylation" was introduced, describing the direct effect of serotonin on intracellular proteins. This process has been described in relation to a trigger mechanism that determines the release of signaling substances from the beta cells of the pancreas and the activation of platelets.
Surely I could tell a respected reader about the fascinating visions and perceptual deceptions that the human brain generates when poisoned with LSD or mescaline. However, according to modern ideas about the nature of hallucinations, their content does not depend on the source of their cause. Of course, in the discussion of this article, people will certainly appear who will argue that red elves come to them under 25N-nBOMe, and green elves come to them under 25I-nBOMe, but this will only be a subjective experience, not related to a wide sample, and, most likely, depending on the setting of the trip. In placebo-controlled randomized multicenter studies, it was found that the aforementioned 25N-nBOMe gives completely different results in different people in different settings: someone talks about liberal reforms with a portrait of Parfyonov, someone catches fish,and someone is looking for Aztec patterns on the walls.
No kidding. Many psychoactive substances that are used in medicine to treat various diseases are not the product of any complex SAR calculations, it just happened that the stars formed - attentive clinicians began to pay attention to the condition of patients after the administration of anti-inflammatory, vasoconstrictor or antihistamines. Now, in order to develop a new cure for depression or a formidable hardcore psychedelic that knocks DOB veterans off their feet, you do not need to stand behind flasks and test tubes for several years - it is enough to have data on the three-dimensional structure of the receptor and binding sites, a head on your shoulders and a little imagination.
I hope that this article will come out a little earlier on April 19 - a landmark for all psychopharmacology and neurophysiology, when Albert Hoffman experienced the effects of LSD. It was on April 19 that the world was shown that 100 micrograms of a substance, which are difficult to see even with the naked eye, can change the course of thought of one person and the course of history for millions.