The experimental peptide davunetide has been investigated as a potential treatment for several neurodegenerative and neuropsychiatric disorders, including progressive supranuclear palsy (PSP), mild cognitive impairment, and schizophrenia. Although a large Phase 2/3 trial in PSP failed to show an overall benefit, later analyses imply that the drug may have affected men and women differently.
A team led by Illana Gozes at Tel Aviv University now reports that uptake of intranasally administered davunetide in mice varies by stage of the estrous cycle, suggesting that hormone-dependent differences in drug exposure may have contributed to those earlier findings (Genomic Psychiatry 2026, DOI: 10.61373/gp026r.0039).
To explore whether biological sex influences drug delivery, the researchers tracked fluorescently labeled davunetide after intranasal administration in mice. Female mice in proestrus and estrus—phases associated with peak estrogen levels—showed significantly greater uptake of davunetide in the head region than males. As estrogen levels declined, the differences largely disappeared.
Reanalysis of an earlier clinical study also found sex-related differences in drug exposure, with women reaching roughly twice the peak concentrations observed in men and men retaining the drug longer.
The researchers speculate that estrogen’s effects on blood vessels and the blood-brain barrier may help explain the differences. But some of the mouse experiments compared just two or three females with a single male, and the human analysis included only eight participants.
“The findings could extend beyond davunetide and may apply more broadly to intranasal therapies designed to reach the brain,” Gozes says.
If so, sex and hormonal status may need to be considered more carefully when designing animal studies, clinical trials, and dosing strategies for brain-directed therapies.
