A signaling signature distinguishes hallucinogenic from non-hallucinogenic psychedelics

The study identified a distinct intracellular signalling signature that differentiated hallucinogenic psychedelics from closely related non-hallucinogenic compounds..

This 2026 Translational Psychiatry study used quantitative phosphoproteomics in neural cells to compare hallucinogenic psychedelics with closely related non-hallucinogenic compounds. The researchers identified a distinct 73-phosphosite signalling signature that differentiated the hallucinogenic compounds, with FOXK2 phosphorylation emerging as a prominent feature.

The hallucinogenic compounds also increased lactate accumulation, pointing to differences in cellular metabolic signalling. The findings suggest that hallucinogenic and non-hallucinogenic serotonergic compounds engage distinct intracellular signalling architectures, providing potential molecular markers and pathways for further investigation into how these compounds produce different biological effects. However, this was an in-vitro mechanistic study, so it does not establish that these signalling changes cause hallucinations or mediate therapeutic effects in humans.

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 signaling, and how hallucinogenic drugs diverge from related non-hallucinogenic forms, is poorly understood.

A central question is whether hallucinogenic serotonergic compounds are associated with intracellular signaling features that distinguish them from closely related non-hallucinogenic analogues. Here, we show that chemically diverse serotonergic psychedelics trigger a coordinated reorganization of phosphorylation patterns across many proteins in neural cells, and that this global response contains a distinct signature that separates hallucinogenic compounds from non-hallucinogenic counterparts of similar structure.

We use phosphorylation of the glycolysis-regulating transcription factor FOXK2 as an example of biological follow-up from this signature and show that hallucinogenic compounds, but not their non-hallucinogenic analogues, enhance lactate accumulation.

These findings indicate that hallucinogenic and non-hallucinogenic serotonergic compounds engage separable intracellular signalling architectures under defined in vitro conditions. The dataset is provided as a community resource to enable hypothesis generation and targeted mechanistic validation.

Martin-Guerrero, S.M., Taddei-Tardon, M., Maltman, J.L. et al. A signaling signature distinguishes hallucinogenic from non-hallucinogenic psychedelics. Transl Psychiatry (2026). Read Paper

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