Psychedelic medicine (New Rochelle, N.Y.)Oct 22, 2026

How Psychedelic Drugs Affect the Brain's Serotonin Movement System

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 23, 2026

Abstract

Early studies revealed that LSD suppresses the firing of serotonergic neurons in the rat midbrain raphe.

Initial hypotheses linked serotonergic neurons to the acute hallucinogenic effects of psychedelics.
Over time, the focus shifted to understanding the relationship between neural activity and behavior.
More than 15 years of research explored the pharmacology and receptor mechanisms involved.
Current knowledge provides a framework for understanding how psychedelics interact with the brain's serotonergic circuits.

Simplified

Psychedelics rose to prominence in the 1960s, around the same time when neurobiologists identified the midbrain raphe as the brain's primary source of serotonin. It is therefore no surprise that early studies on classical psychedelics like d-lysergic acid diethylamide (LSD) focused on their effects within this brainstem nucleus. This review traces the arc of discovery: from the initial report in 1968 that LSD suppresses the firing of serotonergic neurons in the rat midbrain raphe, through more than 15 years of intensive work dissecting the pharmacology and receptor mechanisms. Early hypotheses erroneously suggested the serotonergic neurons as potential drivers of the acute hallucinogenic effects, but the conceptual framework gradually shifted after relating neural activity to behavior. We conclude this brief commentary by revisiting these early findings in light of current knowledge of the serotonergic circuits. Collectively, the pioneering studies laid the foundation for thinking about how psychedelics act on the brain through the lens of neurophysiology.

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How Psychedelic Drugs Affect the Brain's Serotonin Movement System

Abstract

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