Significance of Events and Serotonin 2A

Peter Forster Basic Science, Psychobiology

Significance of Events and Serotonin 2AMaking sense of the constant bombardment of information and sensory experience that all of us face requires the ability to determine the significance of events, and an elegant study suggests that the serotonin 2A receptor plays a critical role in determining significance.

Many psychiatric conditions and human experiences are associated with the misattribution of meaning to events. For example, delusional disorder often involves the belief that events have a personal significance which they don’t in fact possess. I remember interviewing a woman with a paranoid delusional disorder on the inpatient unit many years ago. She looked at the tie that I was wearing and somehow in her mind that tie was tagged with “meaningfulness.” Then she connected that to a memory she had of a hostile interaction with a male friend that took place years before in Los Angeles. The starting point for this delusional connection was the belief that there was meaning in the color of the tie.

The study involved giving the participants LSD, a drug that is known to be associated with changes in awareness and the attribution of significance and that has broad stimulatory effects on serotonin and dopamine receptors, or placebo. Subjects were then exposed to a stimulus (music) which either did or did not have personal meaning and were asked to rate the meaning of the stimulus. During the exposure functional MRI was performed to compare brain responses to stimuli that were or were not meaningful. Finally a drug, ketanserin, that specifically acts to block serotonin 2A receptors was administered and the effects on attribution of meaning and brain activation were compared.

Subjects exposed to LSD without ketanserin rated the meaningless stimulus as if it possessed significance, and their brain activation was the same as those subjects given placebo and exposed to a meaningful stimulus. This was blocked when they received ketanserin.

The study found that the attribution of meaning was associated with a pattern of brain activation in a number of areas of the prefrontal cortex.

In agreement with the behavioral ratings and with previous studies, listening to personally meaningful music in the Pla treatment condition was associated with greater BOLD signal in the supplemental motor area (SMA), putamen, middle occipital gyrus, ventrolateral prefrontal cortex (vlPFC), and cerebellum than listening to neutral and personally meaningless music. Furthermore, comparing the neutral and meaningless music conditions revealed significant clusters of activity in the dmPFC, dorsolateral prefrontal cortex, insula, precentral gyrus, superior and middle temporal gyrus, and angular gyrus. Activity in these brain areas has been associated with listening to autobiographically salient and chill-inducing music, the ascription of subjective value, the appraisal of external stimuli, and the processing of self-relevant stimuli.”

The study raises some intriguing questions. For example the reason why the supplementary motor cortex was activated by meaningfulness is unclear, although the exact functions of this area of the brain remain to be worked out. It would also seem that ketanserin might play a role in the treatment of psychotic disorders but I could find no evidence of it having been studied for this purpose. It is approved for use in this country, but only for treatment of hypertension. It’s primary you seems to be in research studies such as this because it preferentially binds to serotonin 2A rather than serotonin 2C receptors.


Preller, Katrin H. et al. The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation. Current Biology , Volume 0 , Issue 0 , 2017