The LSD receptor
The unusual power of LSD was explained by a receptor "trap"
Oleg Lischuk, N+1, based on Nature News: First look at LSD in action reveals acid-trip biochemistry
Two independent research teams from the USA and Switzerland have obtained new data on the receptor action of LSD and the role of receptors in the realization of its psychedelic effects. One of the papers was published in the journal Cell (Wacker et al., Crystal Structure of an LSD-Bound Human Serotonin Receptor), the other appeared in the journal Current Biology (The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation).
LSD (lysergic acid diethylamide) – a semi-synthetic derivative of ergoline alkaloids of ergot (Claviceps purpurea). It was first synthesized in 1938 by the Swiss pharmacologist Albert Hoffman, who also accidentally discovered the psychoactive effects of the substance in 1943. LSD has become the prototype of psychedelic hallucinogens and is the most powerful of the known psychoactive substances, effective in doses of less than 100 micrograms. It has been shown that it acts on various G-protein-bound receptors for amine neurotransmitters (in particular, serotonin, dopamine and norepinephrine), and activates both the "canonical" G–protein signaling pathway and the alternative beta-arrestin pathway. However, its exact interaction with the active center of the receptors was not known.
Employees of the Universities of North Carolina, Stanford and California conducted an X-ray crystallographic analysis of the serotonin 5-HT 2B receptor complex with LSD.
It turned out that when interacting with LSD, the main (orthosteric) active center of the receptor undergoes conformational changes in order to "accept" the substance molecule. This explains the selectivity of the stereoisomer (+)-D-LSD against serotonin receptors – other isomers are pharmacologically inactive.
Molecular dynamics modeling has shown that when LSD binds to 5-HT 2B and the 5-HT 2A receptor homologous to it, one of the extracellular loops of the receptor molecule forms a kind of lid that "seals" the substance molecule in the active center of the receptor. Scientists attribute to this the duration of LSD action (from 6 to 15 hours, depending on the dose) and its effectiveness in unusually small doses. In their opinion, this also testifies to the validity of numerous consumer statements that ultra-small doses of LSD (about one tenth of the minimum hallucinogenic) produce a certain effect, which is expressed in a slight increase in the productivity of mental and creative work.
"The fact that LSD falls into a 'trap' provides an explanation for why extremely small amounts of the substance can produce an effect," explained the lead author of the work, Bryan Roth (Bryan Roth).
The researchers also found that a point mutation of the serotonin receptor, which increases the mobility of the "lid", significantly accelerates the dissociation of the LSD molecule with it and selectively blocks the activation of the beta-arrestin signaling pathway, which indicates the importance of this "trap" for the realization of the action of the substance.
Interaction of LSD with the serotonin 5-HT 2B receptor and structural similarity
serotonin, LSD and ergotamine, one of the ergot alkaloids (from an article in Cell).
The work of a research team from the University Hospitals of Zurich and Basel is devoted to the receptor mechanisms of the psychedelic effects of LSD, in particular, its effect on the subjective sense of meaning. To do this, the scientists invited 22 students to participate in the experiment. All of them were asked to list songs that are of great importance to them personally. After that, participants were randomly given a placebo, LSD, or a combination of LSD with the serotonin 5-HT 2A receptor blocker ketanserin. After a while, they were given to listen to the named compositions, works similar to them, as well as music in the style of free jazz, which did not have much significance for the volunteers. During the listening, participants were given an fMRI of the brain, after which they were asked to evaluate the meaningfulness and pleasantness of each composition and a sense of personal connection with it.
It turned out that free jazz caused a subjective emotional response and gained significance only for participants who took pure LSD. Also, only they showed other psychedelic effects of the substance, such as feelings of unity with the world, mystical revelation, separation from the body and various synesthesia. In addition, when listening to previously insignificant music, taking LSD caused significant activation of the cortical structures of the median line of the brain responsible for processing meaningful stimuli. Ketanserin blocked all these effects, which indicates the need to activate 5-HT 2A receptors for their implementation.
Katrin Preller, the head of the study, expressed the hope that the results obtained will help to develop drugs for the treatment of symptoms of schizophrenia associated with a distorted perception of meaning (for example, paranoia, in which neutral objects or people seem hostile).
In recent years, the interest of researchers in psychedelics, such as LSD, psilocybin and others, and their potential use in medicine has begun to resume. This has led to a number of publications on various aspects of their operation. So, the human brain under the influence of LSD was first examined on fMRI, and also studied the effect of this substance on the tongue. Scientists have also confirmed that psilocybin (the main active ingredient of hallucinogenic mushrooms) is effective in severe depression. The sum of the conducted studies of methylenedioxymethamphetamine (MDMA, MDMA, "ecstasy") It became the reason for the resolution of large-scale clinical trials of this substance in the USA.
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30.01.2017