Solved: The Psychedelic Experience of LSD

Following a mind-bending discovery, scientists now understand how psychedelics bind to specific brain cell receptors in humans to produce mind-altering effects, opening the door to the discovery of new kinds of antidepressants, anti-anxiety drugs, and treatments for substance use disorders.

Published by University of North Carolina Health Care, for the first time, scientists have solved how psychedelic drugs such as LSD, psilocybin, and mescaline cause severe and often long-lasting hallucinations. Using X-Rays, scientists now understand how psychedelics like LSD binds to serotonin receptors in the brain, specifically 5-HT2A receptors. Discovering the existence of a single amino acid that is critical in the hallucinogenic process.

Resulting from thirty-years of work in the field of psychedelics, lead author of the paper Bryan Roth, told Inverse, "we know how psychedelic drugs work – finally!" "Now we can use this information to, hopefully, discover better medications for many psychiatric diseases."

Setting the stage for discovering new kinds of antidepressants, anti-anxiety drugs, and treatments for substance use disorders, scientists have solved the high-resolution structure of psychedelic compounds when they are actively bound to the 5-HT2A serotonin receptor (HTR2A) on the surface of brain cells.

That's a lot of science, so what does it all mean for the millions of people that use these drugs recreationally? Essentially research has revealed a "first glimpse of how [psychedelics] act at the molecular level is really important, a key to understanding how they work." This activation of the HTR2A is essential to understanding the effects of hallucinogenic drugs. "When activated, the receptors cause neurons to fire in an asynchronous and disorganized fashion, putting noise into the brain's system," said Roth who believes this is the reason "these drugs cause a psychedelic experience."

Using a technique called X-ray crystallography researchers examined how LSD binds to a protein on the HTR2A serotonin receptors. Seeing for the first time "LSD bound to the protein in the brain which mediates the psychedelic actions of LSD," Roth said researchers "actually found a single amino acid was essential for the actions of LSD and is found in only this particular receptor." The LSD then settles into the receptors "pocket" setting off the mind-altering effects. "In a sense, we have a picture of the initial psychedelic event at the molecular level," added Roth.

Gaining this first glimpse of how they act at the molecular level is really important, a key to understanding how they work. Given the remarkable efficacy of psilocybin for depression (in Phase II trials), we are confident our findings will accelerate the discovery of fast-acting antidepressants and potentially new drugs to treat other conditions, such as severe anxiety and substance use disorder.University of North Carolina Health Care

The next step in this process, as was pointed out by the Beckley Foundation, is removing the trip. The "ultimate goal" for Roth, and other researchers in his field, "is to see if we can discover medications which are effective, like psilocybin, for depression but do not have the intense psychedelic actions". Figuring out a dose level which is "not expected to produce profound mind-altering effects" while still demonstrating medicinal benefits across a myriad of applications will be no easy feat.

With Roth and colleagues now applying their findings for the formulation of new therapeutics, this work among many others will continue to provide more pieces to the psychedelic puzzle.

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Elliot Nash
Elliot Nash

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