Mind-altering effects of LSD point to serotonin 2A receptor as a therapeutic target in mental illness

By inducing measurable changes in the brain regions involved in differentiating self from others, LSD may have helped pinpoint the serotonin 2A (5-HT_2A) receptor as a potential treatment target in mental illnesses such as depression and schizophrenia, which are characterized by dysfunctional social cognition and distortions of self, according to results published in the Journal of Neuroscience.

“Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment approaches,” wrote these authors, led by Katrin H. Preller, PhD, University of Zurich, Switzerland.

In this double-blind, randomized, counterbalanced, crossover imaging study, researchers assessed the role of the serotonin 2A receptor in social interaction. They enrolled 24 healthy subjects (18 male) who were given either LSD (100 µg) plus placebo, ketanserin (a serotonin 2A receptor antagonist; 40 mg) plus LSD (100 µg), or placebo plus placebo at three different times.

Subjects took part in a gaze-following game with a virtual human character. Using functional magnetic resonance imaging and eye tracking, researchers observed that LSD interfered with the ability to coordinate attention with the virtual character on a particular object on the screen.

“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,” said Dr. Preller. “And this also changed social interactions.”

LSD reduced activity in the areas of the brain that are vital in establishing a sense of self. Patients who took LSD experienced confusion in whether they or the virtual character took the lead in directing attention.

Ketanserin, on the other hand, blocked these LSD-induced effects. This finding suggests that the effects of LSD are attributable to stimulation of the serotonin 2A receptors.

The results also suggest that this receptor system may play an important role in social interaction, and be a potential target for the treatment of social impairment in mental disorders that are characterized by an increased self-focus or an incoherent sense of self, due to depression or schizophrenia.

“The administration of lysergic acid diethylamide (LSD) in combination with functional magnetic resonance imaging and real-time eye-tracking offers the unique opportunity to study alterations in self-experience, their relation to social cognition, and the underlying neuropharmacology. Results demonstrate that LSD alters self-experience as well as basic social cognition processing in areas of the ‘social brain'. Furthermore, these alterations are attributable to 5-HT_2A receptor stimulation, thereby pinpointing towards this receptor system in the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders,” concluded researchers.

This study was supported by grants from the Heffter Research Institute, the Swiss Neuromatrix Foundation, the Usona Institute, and the Swiss National Science Foundation.