Summary: A new study reveals how the brain’s perception of meaning shifts when a person is under the influence of LSD.
Source: University of Zurich.
Researchers at the University of Zurich have identified how LSD alters the brain’s assignment of personal meaning. The study shows that activation of the serotonin 2A (5-HT2A) receptor drives these changes in perception, a finding that could inform future pharmacological approaches for psychiatric conditions such as depression, addiction and phobias.
Everyday objects, sounds and experiences carry different weight for different people: a song can feel deeply meaningful to one person and merely pleasant to another. In psychiatric disorders, the attribution of personal significance to stimuli is often distorted. Addiction can make drug-related cues feel overwhelmingly important; phobias magnify the significance of feared objects or situations; and depression often involves an intensified negative evaluation of the self. Despite the clinical importance of these alterations, the neural and neurochemical mechanisms that shape how personal relevance is assigned have been poorly understood.
To investigate these mechanisms, a research team from the Department of Psychiatry, Psychotherapy and Psychosomatics at Zurich University Hospital used lysergic acid diethylamide (LSD) as a pharmacological probe. LSD is known to change subjective meaning and perception, and it interacts with multiple neurotransmitter receptors in the brain. The researchers focused on the serotonin 2A receptor (5-HT2A), one of the key serotonin receptor subtypes implicated in psychedelic effects.
In the study, participants first categorized 30 musical excerpts as either personally meaningful or lacking personal relevance. During subsequent experimental sessions, participants received LSD or a placebo while undergoing functional magnetic resonance imaging (fMRI). Under LSD, many of the musical pieces that subjects had originally rated as meaningless were reclassified as personally meaningful. “Pieces of music previously classified as meaningless suddenly became personally meaningful under the influence of LSD,” explains Katrin Preller, who led the study with Professor Franz Vollenweider and the Neuropsychopharmacology and Brain Imaging team.
LSD’s effects hinge on serotonin 2A receptor activation
The researchers further examined the role of the 5-HT2A receptor by administering a selective antagonist to block that receptor prior to LSD exposure. When the serotonin 2A receptor was pharmacologically blocked, the LSD-induced changes in meaning attribution were prevented, and the other psychological effects of LSD were also normalized. This result was unexpected to some extent because animal research has shown that LSD can also affect other receptor systems, such as dopamine D2 receptors, which were thought to contribute to euphoria and other aspects of the psychedelic state. The current human study indicates that activation of the serotonin 2A receptor is central both to the subjective change in experienced meaning and to the brain activity changes observed with fMRI.
Using fMRI, the team identified that changes in the attribution of personal relevance under LSD were associated with altered activity in cortical midline structures—brain regions implicated in self-referential processing and the construction of a coherent sense of self. A functioning cortical midline network appears critical to how we attribute meaning. LSD’s modulation of this network via the 5-HT2A receptor may explain why previously neutral stimuli can acquire profound personal significance during the psychedelic experience.
Implications for psychiatric treatment and psychopharmacology
These findings illuminate the neuropharmacology of how meaning is created, suggesting a division of labor among neurotransmitter systems: serotonin 2A receptor activation seems crucial for generating novel meaning, while the dopamine system may help regulate which stimuli are generally regarded as important or salient. Understanding these mechanisms opens possibilities for targeted pharmacotherapies that aim to correct maladaptive patterns of meaning attribution found in mental health disorders.
For example, interventions that modulate 5-HT2A receptor signaling could one day be used, in controlled therapeutic settings, to reshape overly rigid or maladaptive significance assigned to certain stimuli—an approach that might benefit people with depression, phobias or addiction. The research advances mechanistic understanding of how subjective meaning is constructed in the brain and highlights cortical midline regions and the 5-HT2A receptor as potential therapeutic targets.
Source: University of Zurich
Original research article: “The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation” by Katrin H. Preller, Marcus Herdener, Thomas Pokorny, Amanda Planzer, Rainer Kraehenmann, Philipp Stämpfli, Matthias E. Liechti, Erich Seifritz, and Franz X. Vollenweider. Published in Current Biology (online January 16, 2017).
Abstract
The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation
Highlights
- LSD-induced effects are blocked by the 5-HT2A receptor antagonist ketanserin.
- LSD increased the attribution of meaning to music that participants had previously rated as meaningless.
- Stimulation of the 5-HT2A receptor is crucial for generating new subjective meaning.
- Changes in personal meaning attribution are mediated by cortical midline structures.
Summary
Attributing personal relevance to everyday stimuli is a central feature of the human self and allows us to experience our environment as meaningful. Abnormalities in this process characterize several psychiatric disorders. Combining fMRI with administration of LSD—with and without pretreatment using a 5-HT2A antagonist—this study shows that LSD’s effects on personal relevance and subjective experience depend critically on 5-HT2A receptor activation and involve cortical midline brain regions. These findings enhance our mechanistic understanding of how the brain generates meaningful experiences and point to potential targets for treating psychiatric illnesses that involve altered attribution of personal relevance.