LSD blurs boundaries between the experience of self and other

March 19, 2018

Science Daily/University of Zurich

LSD reduces the borders between the experience of our own self and others, and thereby affects social interactions. Researchers at the University of Zurich have now found that the serotonin 2A receptor in the human brain is critically involved in these intertwined psychological mechanisms. This knowledge could help develop new therapies for psychiatric disorders such as schizophrenia or depression.

Virtually all mental health disorders come with difficulties in interpersonal relations that in the long run negatively affect the progression of the disease. The associated health and social restrictions can only be marginally improved by current forms of therapy. One of the reasons for this is that there has been very little research into the basic neurobiological principles and in particular the neurochemical mechanisms of these kinds of disorders. A further symptom of various psychiatric disorders is distortions of self-experience. People suffering from mental disorders often show either an inflated or weakened sense of self.

Researchers at the University Hospital of Psychiatry Zurich have now investigated the links between changes in the sense of self and changes in social interaction, and the pharmacological mechanisms that play a role in these processes.

LSD impacts self-boundaries

"LSD blurs the boundaries between one's own self and others during a social interactions ," explains Katrin Preller. She led the research team of the Neuropsychology and Brain Imaging group together with Prof. Franz Vollenweider and cooperated with the Max Planck Institute of Psychiatry in Munich on the study. While lying in an MRI scanner, study participants communicated with a virtual avatar by means of eye movements after having been administered a placebo, LSD, or LSD in combination with ketanserin.

Changes in social interaction

"This allowed us to show that brain regions which are important for distinguishing between self and others were less active under the influence of LSD," says Preller. "And this also changed social interactions." The researchers were also able to show that the LSD-induced changes were blocked by ketanserin indicating that the serotonin 2A receptor (5-HT2A receptor) plays a critical role in this mechanism.

Approaches for new drugs

These findings demonstrate that self-experience and social interaction are closely linked. Varying impairments of these intertwined processes could be the result of an impaired transfer of information mediated by the 5-HT2A receptor system. This could be important for the development of new pharmacological therapies. For example, blocking this receptor in patients suffering from an incoherent sense of self such as schizophrenia could improve their symptoms as well as their social abilities. On the other hand, stimulating this receptor could help patients who suffer from an increased self-focus, as is the case with depression, for example.

https://www.sciencedaily.com/releases/2018/03/180319155948.htm

Structure of LSD and its receptor explains its potency

January 26, 2017

Science Daily/Cell Press

Lysergic acid diethylamide -- more commonly known as "LSD" or simply "acid" -- is one of the longest lasting and most potent hallucinogens, but researchers have never understood why LSD's effects linger for 12 hours or more. The key to the drug's psychedelic longevity lies in how it fits into receptors in the brain, as reported in a study appearing January 26 in Cell.

"When I was younger, and The Grateful Dead was still around, I would occasionally go to Grateful Dead concerts. 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 Bryan Roth, a professor of pharmacology at University of North Carolina and a senior co-author on the study. "A lot of people who take the drug are not aware of just how long it lasts."

Scientists from Roth's lab at UNC captured crystallography images (images showing how a molecule's atoms are arranged) of an LSD molecule bound to a human serotonin receptor and discovered that the LSD molecule was wedged into the receptor's binding pocket at an angle no one had expected. On top of that, part of the receptor protein had folded in over the LSD like a lid, sealing the drug inside.

"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," says Roth. "LSD takes a really long time to get on the receptor, and then once it gets on, it doesn't get off," he added.

This finding explains why LSD trips last for a full day, even though LSD doses are extremely small -- the average dose is 100 or so micrograms -- and LSD molecules are cleared from the bloodstream in a couple of hours. Given that there has been a tentative resurgence in testing LSD for some medical conditions, understanding the mechanism of its potent and long-lasting actions may help drug developers design more effective psychiatric drugs with fewer side effects, the researchers say.

While speculative, the study's results may help researchers think about how LSD micro-dosing could work. About 1 in 10 Americans have taken LSD at some point in their life, but increasingly, people are taking LSD at doses too small to cause hallucinations with the goal of boosting their creativity and countering depression. LSD micro-dosing has never been clinically tested, and many scientists have doubted that taking such small amounts of the drug would have any detectable effect. But when Roth's group exposed live cells in a Petri dish to micro-dose-sized amounts of LSD, those tiny doses of LSD affected the receptors' signaling. It's as yet unknown how this signaling would translate into an effect on a person's mood or perception, although the studies demonstrate LSD's remarkably potent actions on cellular signaling.

LSD's ability to fit in and let the receptor's "lid" close over it depends on the specific chemical structures of both the drug and the receptor. When the team exposed cells with mutant receptors that had floppier lids to LSD, the LSD bound more quickly and also exited the receptor much faster. Those short LSD binding events produced very different signaling patterns than the longer binding events.

"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," says study first author Daniel Wacker, a postdoctoral fellow at UNC.

The researchers stressed that they do not advocate LSD use, as it is an illegal and potentially dangerous drug. However, its potential medical applications, and its enormous impact on pop culture, warrant an understanding of its modes of action and ways in which they can be modified.

A separate study on LSD, published January 26 in Current Biology, found that one of the receptors the team tested plays a role in peoples' experience of music while on LSD.

This research was supported by the National Institutes of Health, the National Institute of Mental Health, a Terman Faculty Fellowship, and the Michael Hooker Distinguished Chair of Pharmacology.

https://www.sciencedaily.com/releases/2017/01/170126132541.htm