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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