A study published June 16 in Genomic Psychiatry by researchers at Tel Aviv University demonstrates that the amount of drug reaching the brain can vary dramatically depending on where a woman is in her menstrual cycle, and that this variability may have been masking real drug efficacy for decades.
The researchers, led by Jason Blatt and Illana Gozes, tracked the intranasal bioavailability of davunetide, a microtubule-stabilizing peptide derived from the Activity-Dependent Neuroprotective Protein (ADNP), across the oestrous cycle in female mice. Using fluorescently labeled davunetide and live IVIS imaging over 2.5 hours, they found that drug uptake in the brain was strongly dependent on cycle phase. In proestrus, when oestrogen is at its highest, head bioavailability in females was strongly higher than in males (p = 4.253 × 10⁻⁶). In estrus, the difference was less pronounced but still significant (p = 0.03). In metestrus, when oestrogen drops to its minimum, the sex difference disappeared entirely (p = 0.1265). In elderly mice, where cycling oestrogen has ceased, sex differences diminished with age.
A failed trial, re-examined
The study was motivated by a puzzling result from a Phase 2/3 trial of davunetide for progressive supranuclear palsy (PSP), a fatal 4R tauopathy. The trial, enrolling 313 patients, failed to show efficacy when the data from men and women were pooled, and the drug was shelved.
But a re-analysis by Gozes and colleagues, published in Translational Psychiatry in 2023, split the data by sex and found a different story. Women deteriorated faster than men on the PSP rating scale (p = 0.04), but davunetide provided significant benefit in women at week 52 across multiple measures: activities of daily living (p = 0.003), bulbar function (speaking and swallowing, p = 0.01), and limb motor function (p = 0.03). The drug slowed deterioration by roughly 10 to 20 percent in women. In men, there was no benefit, and possibly overdosing. Ventricular volume analysis showed that davunetide completely blocked the testosterone-driven ventricular enlargement seen in placebo females.
Why the blood-brain barrier is not the same in everyone
The mechanism involves multiple factors working together. Oestrogen affects P-glycoprotein (P-gp), an efflux transporter at the blood-brain barrier that pumps drugs out of the brain. P-gp function decreases with age in men but is maintained in women until menopause. Oestrogen also increases cerebral blood flow, enhances microtubule dynamics (which affects intracellular drug transit), and regulates ADNP itself, creating a bidirectional feedback loop between the peptide and the hormone that controls its delivery.
What this means for clinical trials
The implications extend far beyond davunetide. Current clinical trial design pools results from men and women, typically ignores menstrual cycle phase, and assumes that a given dose produces equivalent brain exposure across sexes. The data show this assumption is false.
As Jens Pahnke of the University of Oslo told New Scientist: “It’s very common that brain disease is regulated by steroid hormones and that’s not taken into consideration very often, which is a massive, massive problem.”
The authors call for a paradigm shift toward sex-specific brain medicine, in which hormonal status is measured and reported alongside sex, and dose optimization accounts for cycle phase. Alzheimer’s disease, which affects women at roughly twice the rate of men, is cited as an area where this oversight may have been particularly consequential. Gozes now plans to run sex-stratified trials for davunetide in ADNP syndrome, PSP, and other indications.
Source: Blatt, J., Guz, L.S., Shabat, D., Gozes, I. Intranasal bioavailability is estrous-cycle regulated: Davunetide as a case study. Genomic Psychiatry (2026). DOI: 10.61373/gp026r.0039