Dorsal Raphe Revisited: A Systems Neuroscience Lens on Psychedelic Drug Action
Psychedelic Medicine April 9, 2026 DOI: 10.1177/28314425261429232 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | LSD Mescaline Serotonin |
| Keywords | Midbrain Dorsal raphe nucleus Hallucinogen Brainstem Raphe nuclei Action physics Locus coeruleus Dorsum |
| Key findings | Early hypotheses that serotonergic neurons in the midbrain raphe drive hallucinogenic effects were incorrect, and the conceptual framework shifted after relating neural activity to behavior. |
Abstract
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.
Comparable studies
Other narrative reviews on mescaline, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Study of a New Schizophrenomimetic Drug—Sernyl | 1959 | Review | |
| Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways | 2017 | Review | |
| Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine | 2020 | Review | |
| Legal highs: staying on top of the flood of novel psychoactive substances | 2015 | Review | |
| Psychedelic Drugs in Biomedicine | 2017 | Review |
Citations in the library
Cites 23
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Journal of Neuroscience April 15, 1997
and 18 more in the library