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bioRxiv · 10.64898/2026.08.06.743248

Preclinical Comparison of DMT and 5-MeO-DMT Reveals Behavioral Dissociation, Distinct TrkB Activation and Differential Plasticity Profiles

Shahar, O.·Botvinnik, A.·Chaykin, M.·Shwartz, A.·Lerer, E.·Golding, P.·Ben Ari, M.·Shalev, O.·Lifschytz, T.·Lerer, B.
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Abstract

N, N-dimethyltryptamine (DMT) and 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) are structurally related tryptamine psychedelics with emerging therapeutic potential, yet their comparative acute pharmacology and longer-term neuroplastic effects remain incompletely defined. Here we show that DMT produces a bell-shaped dose-response curve in the mouse head-twitch response (HTR) assay, whereas 5-MeO-DMT elicits a monotonic increase. Selective antagonism at 5-HT2A or 5-HT1D receptors, or agonism at 5-HT1A, robustly attenuates HTR for both compounds without abolishing their ability to reduce marble burying, a screening assay for OCD-like behavior. Acutely, both agents elevate TrkB phosphorylation in a region-specific manner, with broader engagement by DMT across default-mode-network and hippocampal territories. Twelve days after a single dose, both compounds increase synaptic proteins (PSD-95, synaptophysin; SV2A for DMT), while DMT uniquely lowers hippocampal BDNF and reprograms frontal-cortex glutathione and energy metabolism. These findings demonstrate that acute hallucinogenic-like activity and selected therapeutic-like behavioral and plasticity outcomes can be pharmacologically dissociated, informing the rational design of more tolerable, scalable psychedelic-based treatments.

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Shahar, O., Botvinnik, A., Chaykin, M., Shwartz, A., Lerer, E., Golding, P., Ben Ari, M., Shalev, O., Lifschytz, T., Lerer, B.. 2026-08-12. Preclinical Comparison of DMT and 5-MeO-DMT Reveals Behavioral Dissociation, Distinct TrkB Activation and Differential Plasticity Profiles. https://doi.org/10.64898/2026.08.06.743248

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