What are the main side effects of Davunetide (NAP/AL-108)?

Davunetide (NAP/AL-108) side effects and warning signals include Nasal irritation, Headache, Upper respiratory tract infection, Rhinorrhea, and Generally well-tolerated in clinical trials.

What evidence level is Davunetide (NAP/AL-108)?

Davunetide (NAP/AL-108) is rated Level C; the listed research status is Phase 2.

Cognitive & Nootropic / Level C / Phase 2 / Last reviewed 2026-04-04

Davunetide (NAP/AL-108) Evidence Guide

Davunetide (NAP) has Phase 2 data in schizophrenia and PSP, but the PSP Phase 2 trial failed to meet its primary endpoint, which is a significant setback. The schizophrenia data showed cognitive improvement signals in a small trial. The ADNP-derived mechanism is scientifically interesting but clinical development is stalled. Current evidence does not support a confident research protocol.

Our Take

Best for: ADNP-derived neuropeptide research, microtubule-stabilizing cognitive peptide mechanistic studies
Evidence grade: Level C
Confidence: Low
Starting point: Phase 2 doses: 5-30mg intranasal daily (schizophrenia context)

Benefits and Evidence

Microtubule Stabilization: Level B, mostly non-human evidence - Extensive preclinical evidence confirms davunetide stabilizes microtubules, enhances tau-tubulin interactions, and protects against colchicine and nocodazole-induced microtubule disruption.
Cognitive Function (MCI): Level C, includes human evidence - A Phase 2 trial in amnestic mild cognitive impairment showed improvements in specific memory subtests with intranasal davunetide, though the overall results were mixed.
PSP Disease Modification: Level C, includes human evidence - The Phase 2/3 trial in progressive supranuclear palsy did not meet its primary endpoint (PSP Rating Scale), though post-hoc analyses suggested possible benefits in some cognitive subdomains.
Neuroprotection in Animal Models: Level C, mostly non-human evidence - Davunetide demonstrates robust neuroprotection across diverse preclinical models including ischemia, traumatic brain injury, fetal alcohol exposure, and multiple tauopathy models.

Side Effects and Warnings

Nasal irritation
Headache
Upper respiratory tract infection
Rhinorrhea
Generally well-tolerated in clinical trials
Phase 2/3 PSP trial failed to meet primary endpoint, raising questions about clinical translatability
Development was discontinued by Allon Therapeutics/Paladin Labs after PSP trial results
Gap between robust preclinical and modest clinical results suggests challenges in human translation

Research Dosage References

<strong>Intranasal</strong> - 2-15 mg twice daily - Twice daily - Intranasal davunetide achieves brain concentrations through olfactory epithelium transport. Used in Phase 2 trials at 5-15 mg BID.
<strong>Intravenous</strong> - Variable (clinical trial dosing) - As studied in clinical protocols - IV route used in some clinical studies. Intranasal is preferred for chronic dosing due to convenience and direct CNS access.

Mechanism of Action

Davunetide binds to tubulin subunits and promotes microtubule polymerization and stability, similar to but distinct from taxol-like microtubule stabilizers. It enhances tau-microtubule binding by promoting tau's interaction with beta-tubulin at the taxol binding site region. Additional mechanisms include: (1) Protection of tubulin from oxidative damage; (2) Enhancement of autophagy-mediated clearance of misfolded proteins; (3) Modulation of the ADNP-associated SWI/SNF chromatin remodeling complex; (4) Reduction of GSK-3beta activity and tau hyperphosphorylation; (5) Promotion of dendritic spine integrity and synaptic function. Its intranasal bioavailability is a significant pharmacological advantage.

Legal Status

Investigational drug; clinical development paused after Phase 2/3; available as research compound.

Primary Sources

A Phase 2/3 randomized clinical trial of davunetide in progressive supranuclear palsy. JAMA Neurology, 2014.
NAP (davunetide): pharmacology and neuroprotection. CNS Drug Reviews, 2007.
Intranasal NAP administration in amnestic mild cognitive impairment: Phase 2 results. Alzheimer's & Dementia, 2012.