Green shows the expansion of the pocket that the scientist believe may be caused by the designer drug. LSD’s position in the pocket is shown in purple. Cell
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.