LSD molecule wedged in a serotonin receptor's pocket.
Image credit: Annie Spikes, UNC School of Medicine
According to the National Institute on Drug Abuse, around 1 in 10 people in the United States have taken LSD at some point during their lifetime.
Users of LSD often report altered sensory experiences or visual effects, called a "trip," that include intensified colors, movement of stationary objects, distortion to shapes and sounds, and changes in the sense of time.
The drug's effects usually begin within 30 minutes and, depending on the dose taken, can last for 12 hours.
Brian Roth, Ph.D., a professor of pharmacology at the University of North Carolina (UNC) and senior co-author of the study, first developed an interest in the lasting effects of LSD at rock concerts when he was younger.
"A lot of people took LSD and similar drugs during concerts, and it would be interesting to be in the parking lot hearing people wondering when their LSD experience was going to end," says Roth. "A lot of people who take the drug are not aware of just how long it lasts."
LSD molecule becomes wedged, sealed in serotonin receptor
Most doses of LSD are small - an average of 100 micrograms - yet acid trips tend to be ongoing for the majority of a day. Molecules from LSD are removed from the bloodstream in a matter of hours, which has confused scientists as to why LSD effects linger for such a long time.
"There are different levels of understanding for how drugs like LSD work," advises Roth. "The most fundamental level is to find out how the drug binds to a receptor on a cell. The only way to do that is to solve the structure. And to do that, you need X-ray crystallography, the gold standard."
Postdoctoral researchers Daniel Wacker, Ph.D., and Sheng Wang, Ph.D., led experiments to capture crystallography images of an LSD molecule bound to a human brain's serotonin receptor - a method that creates images capable of displaying how a molecule's atoms are arranged.
The results of the study are published in the journal Cell.
The researchers discovered that the LSD molecule was wedged into the serotonin receptor's binding pocket at an unexpected angle. Furthermore, UNC postdoctoral researcher John McCorvy, Ph.D., found that part of the serotonin receptor had folded over the LSD molecule "like a lid," which sealed the drug inside. This action explains why the effects of LSD can take hours to disappear.
"Once LSD gets in the receptor, a lid comes over the LSD, so it's basically trapped in the receptor and can't get out," explains Roth. "LSD takes a really long time to get on the receptor, and then once it gets on, it doesn't get off," he adds.
Eventually, the lid moves around and frees some of the LSD molecules from the receptors. The brain cells will, sooner or later, respond to the remaining LSD molecules by drawing the receptors and LSD inside the cells, where they are broken down. This moment is suggested to be the point at which the acid trip ends.
Further understanding may pave way for new psychiatric drugs
Previous research has reported that LSD "washes out" of the serotonin receptors - located within the membrane of brain cells - within 4 hours. The new research shows that this is not the case and details how LSD can spark such a dramatic reaction in the brain.
During the 1950s and 1960s, there was experimentation with LSD to help people with mental health problems recall repressed thoughts and feelings. There has recently been renewed interest in the potential of using LSD treatment for medical conditions such as substance abuse, cluster headaches, and anxiety associated with life-threatening conditions.
LSD is also a semisynthetic member of a larger class of chemical compounds that are recognized as therapeutics for conditions including migraine headaches, postpartum hemorrhage, and Parkinson's disease.
The researchers point out that understanding the mechanism that drives LSD's potent and long-lasting actions in the body may assist drug developers with designing psychiatric drugs that are more effective and with fewer side effects.
Increasingly, people are said to be taking LSD at doses small enough to not cause hallucinations with the aim of amplifying creativity or reducing depression. While microdosing LSD has not yet been fully explored, scientists have been dubious in the past that such a small amount of the drug would trigger any detectable effect.
Now, the UNC group have found that when live cells in a Petri dish are exposed to microdose-sized quantities of LSD, the brain's serotonin receptor's signaling was affected - although it is currently unknown how the signaling changes will have an impact on a person's perception or mood.
Modifying receptors alters binding, attachment time of LSD
The action of the LSD molecule wedging in the receptor and the lid closing over the top depends on specific chemical structures of both the drug and the receptor. McCorvy and collaborators created mutant receptors with lids that had a "floppier" build. As a result, LSD both bound to and exited the receptor quicker. When compared with the longer binding events, these shorter binding events produced completely different signaling patterns.
"I think it's important for the pharmaceutical industry to understand that even if you modify just one tiny aspect of any compound, you may affect the way the entire compound sits in the receptor, and that affects the compound's performance."
Daniel Wacker, Ph.D.
"We do not advocate using LSD; it is potentially very dangerous. But, it could have potential medicinal uses, some of which were reported in the medical literature decades ago," says Roth. "Now that we've solved the structure of LSD bound to a receptor, we are learning what makes it so potent," he concludes.