Quantitative phosphoproteomics uncovers the signalling dynamics of hallucinogenic psychedelics

Abstract Psychedelic drugs can induce intense changes in perception and thought, and some also promote long-lasting adaptations in brain circuits that are being explored for treatment of mood and anxiety disorders. How these compounds differ at the level of intracellular signalling, and how hallucinogenic drugs diverge from related non-hallucinogenic forms, is poorly understood. A central question is whether a shared molecular fingerprint distinguishes hallucinogenic psychedelic action from other forms of receptor activation in neurons. Here, we show that chemically diverse psychedelics trigger a coordinated reorganisation of phosphorylation patterns across many proteins in neural cells, and that this global signalling response contains a distinct signature that separates hallucinogenic compounds from non-hallucinogenic counterparts of similar structure. We use a glycolysis-regulating transcription factor as an example of the signature’s functional relevance to show that hallucinogenic psychedelics, but not their non-hallucinogenic analogues, enhance markers of glycolytic metabolism. These findings reveal that hallucinogenic and non-hallucinogenic psychedelics engage separable intracellular architectures, and establish a framework for understanding how different psychoactive compounds couple receptor activation to specific cellular states. More broadly, this work opens a path to using signalling fingerprints to guide the design of psychedelic-inspired therapeutics with tailored behavioural and metabolic profiles. Competing Interest Statement The authors have declared no competing interest.