Scientists uncover the molecular origins of an LSD trip

The psychedelic experience of LSD, lysergic acid diethylamide, is so expansive it encompasses our entire experience of consciousness. But it begins with a tiny invisible process: LSD binding to a receptor in the brain.

After some "fair amount of trial and error" scientists now know how that binding happens and what it actually looks like, findings that help explain how the whole mind-altering process starts.

Previously, scientists suspected that LSD creates a powerful psychedelic experience by binding to serotonin receptors in the brain, specifically 5-HT2A receptors. When receptors at a specific layer in the cortex are activated they fire in an unorganized way, and become unable to take inputs from the outside world.

But scientists were still unsure of how LSD actually activates these receptors. Now, a research team shows that there's actually a single amino acid (a building block) that's unique to the receptor protein. When LSD binds to that protein, the trip begins.

This finding was published Thursday in the journal Cell.

Bryan Roth is the paper's lead author and a pharmacologist and psychiatrist at The University of North Carolina School of Medicine. He says the paper caps off 30 years of work in the field of psychedelics.

"Now we know how psychedelic drugs work – finally!" he tells Inverse. "Now we can use this information to, hopefully, discover better medications for many psychiatric diseases."

How LSD binds to the brain – LSD has a crystal structure, which means that scientists can track the way that x-ray beams reflect off of that structure to get a better sense of its shape. For instance, Roth's previous research demonstrated that LSD has a "lid," which makes it particularly sticky when it binds to a serotonin receptor. That's perhaps one reason, he suggested in 2017, that a trip can last hours.

In this study, Roth and colleagues used a technique called X-ray crystallography to examine how LSD binds to a protein on those serotonin receptors called Gαq, and even more specifically to one amino acid (a building block of that protein).

"This is the first time we see LSD bound to the protein in the brain which mediates the psychedelic actions of LSD," he says. "We actually found a single amino acid was essential for the actions of LSD and is found in only this particular receptor."

Ultimately, LSD settles into a "pocket" on the receptor and the looping helix shape of the protein begins to shift outwards (see the red arrows below).

To figure out what happens in greater detail, the team also investigated how a designer psychedelic called 25CN-NBOH binds to serotonin receptors as well. Technically, LSD is only a partial agonist, which means it binds to the receptor but only partially activates it. That designer drug, 25CN-NBOH is a full agonist, which means it activates the receptor to its fullest extent.

In that designer drug's case, the team suggests that this pocket actually expands slightly (seen in green below), compared to when LSD is bound (seen in purple).

Eventually, those serotonin receptors end up activated, setting firing patterns in motion that block out the outside world, in the case of a trip.

"In a sense, we have a picture of the initial psychedelic event at the molecular level," Roth adds.

How can we use this information – After a drought of psychedelic research that began in the 1970s, there's a renewed interest in the potential therapeutic effects of hallucinogens, including LSD. Recent studies suggest that LSD has the potential to decrease the sensation of physical pain or the severity of conditions like a cluster headache.

Some research suggests it can also help reset neurons, and ease the experience of anxiety or depression. For example, clinical trials have shown that it can alleviate anxiety related to terminal diseases.

That said, an LSD trip isn't for everyone. There are significant risks to tripping on LSD, even if it's not traditionally considered addictive. LSD can raise heart rate and blood pressure during the experience, both potentially problematic for people with heart problems. And there's still the risk of having an unpleasant "bad" trip, though adverse effects are usually short-lived.

"Our ultimate goal is to see if we can discover medications which are effective, like psilocybin, for depression but do not have the intense psychedelic actions," he says.

The key is figuring out how to separate the psychedelic or hallucinogenic effects of these drugs might be separated from the psychedelic therapeutic ones – if they can be separated at all. Roth adds that by taking apart them signaling processes involved with an LSD experience piece by piece, we might be able to switch some effects on while keeping others off.

Abstract: Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions— both therapeutic and hallucinogenic—are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state struc- ture of HTR2A bound to 25-CN-NBOH—a prototypical hallucinogen—in complex with an engineered Gaq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gaq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.