Beyond the toad's kiss: Mapping acute 5-MeO-DMT effects on brain connectivity across sex and dose using awake rat neuroimaging

Mar 9, 2026Neuropharmacology

Immediate effects of 5-MeO-DMT on brain network connections in awake rats vary by sex and dose

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Abstract

Females showed markedly enhanced sensitivity to low-dose 5-MeO-DMT (0.1 mg/kg) compared to males.

Extensive negative brain responses were observed in females at the 0.1 mg/kg dose, while males exhibited minimal responses.
The 1.0 mg/kg dose produced widespread negative brain responses in both sexes during the first 10 minutes post-injection.
Global functional connectivity decreased significantly across all doses, indicating potential widespread effects in brain networks.
Specific reductions in brain connectivity were noted in hypothalamic and cerebellar networks.
Peak neurobiological effects were recorded within the first 10 minutes, aligning with the rapid action of 5-MeO-DMT.

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BACKGROUND: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent serotonergic psychedelic with rapid therapeutic potential for depression and anxiety disorders. Despite growing clinical interest, the neurobiological mechanisms underlying 5-MeO-DMT's acute brain effects remain poorly understood, and potential sex differences in response have not been investigated. We conducted the first functional MRI study of 5-MeO-DMT in awake, drug-naïve rats using BOLD imaging.

METHODS: Male (n = 24) and female (n = 24) rats received I.P. injections of vehicle or 5-MeO-DMT (0.01, 0.1, or 1.0 mg/kg) during scanning sessions. BOLD signal changes and resting-state functional connectivity were assessed across 169 brain regions. Negative and positive BOLD volume activations were quantified during acute (1-10 min) and sustained (11-20 min) time windows post-injection, with sex-stratified analyses performed.

RESULTS: Females demonstrated markedly enhanced sensitivity to low-dose 5-MeO-DMT (0.1 mg/kg), exhibiting extensive negative BOLD responses that were largely absent in males at the same dose. The 1.0 mg/kg dose induced widespread negative BOLD responses across multiple brain regions in both sexes during the acute window (1-10 min post-injection), with effects substantially diminishing thereafter. Global functional connectivity was significantly reduced across all doses (p < 0.0001), with regional specificity observed in hypothalamic and cerebellar networks. Temporal analysis revealed peak neurobiological effects within the first 10 min, consistent with 5-MeO-DMT's known rapid pharmacokinetics.

CONCLUSION: To our knowledge, this is the first fMRI characterization of 5-MeO-DMT in any species, and it reveals a previously unreported sex difference in psychedelic response. The rapid onset and brief duration of peak effects align with 5-MeO-DMT's unique pharmacological profile and clinical reports.