Davunetide

NAP, AL-108 (intranasal formulation), AL-208 (intravenous formulation), NAPVSIPQ, ADNP-derived octapeptide

Cognitive & neuro

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Summary

Class: Synthetic octapeptide (8 amino acids: Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln), an exact fragment of the human protein ADNP (activity-dependent neuroprotective protein)
Mechanism: Stabilises microtubules inside neurons by interacting with microtubule end-binding proteins, which in cells and animals reduces tau tangling, protects synapses and improves survival under stress
Routes studied: Intranasal (human Phase 2 and 2/3 trials); intravenous (Phase 1); intraperitoneal, subcutaneous and intranasal (rodents)
Dose range reported: Human trials: 5 mg once daily or 15 mg twice daily intranasal (MCI, 12 weeks); 5 or 30 mg twice daily intranasal (schizophrenia, 12 weeks); 30 mg twice daily intranasal (PSP, 52 weeks). Rodents: nanogram-to-microgram doses, with activity reported at femtomolar concentrations in cells. Community-reported: rare; a handful of intranasal reports in the low-milligram range
Half-life: Short in plasma (minutes to about an hour in animals, with rapid distribution to brain after intranasal dosing); the pharmacodynamic effect outlasts measurable drug
Storage: Lyophilised: refrigerate, protect from light. Reconstituted: refrigerate; community practice is use within ~4 weeks
Regulatory status: Not approved anywhere. Held orphan-drug designations for progressive supranuclear palsy in the US and EU during development †

Doses are as reported in studies or by the community — never recommendations.

1What it is

Davunetide is an eight-amino-acid piece of a much larger human protein, ADNP, which is essential for brain development and is one of the most frequently mutated genes in autism-related syndromes. Illana Gozes's laboratory in Tel Aviv found in the late 1990s that this tiny fragment protected neurons in culture at extraordinarily low concentrations, and named it NAP after its first three letters (Bassan 1999). It was developed by Allon Therapeutics as AL-108 (nasal spray) and AL-208 (intravenous).

Its clinical story matters. A Phase 2 trial in amnestic mild cognitive impairment showed a signal on some memory tests; a Phase 2 in schizophrenia showed a signal on functional capacity but not cognition; and then a large Phase 2/3 in progressive supranuclear palsy (PSP), a tau-driven disease where the mechanism should have mattered most, was clearly negative in 2012–2014. Allon folded. The peptide has since re-emerged in academic work on ADNP syndrome (a rare neurodevelopmental disorder caused by ADNP mutations), and in retrospective analyses suggesting sex-dependent effects. It is a genuine, well-characterised research peptide with human trial data — and a cautionary example of a compelling mechanism not translating.

2How it's thought to work

Microtubule stabilisation. NAP binds tubulin and, more specifically, the microtubule end-binding proteins EB1 and EB3 through a short "SIP" motif, promoting microtubule growth and stability in neurons (Divinski 2004; Oz 2014). Microtubules are the cell's internal scaffolding and transport rails; their breakdown is an early event in Alzheimer's and other tauopathies.

Tau. By stabilising microtubules, NAP reduces tau hyperphosphorylation and aggregation in cell and mouse models, and protects against tau-related toxicity.

Synaptic protection and autophagy. Reported to protect dendritic spines, enhance axonal transport and support autophagy (cellular clean-up), with downstream reductions in cell death from oxidative stress, amyloid, glucose deprivation and other insults.

Potency. Activity at femtomolar concentrations in culture is a hallmark of the literature, and also a reason for scepticism about how such potency translates to dose-finding in people.

Proposed: an eight-amino-acid fragment of activity-dependent neuroprotective protein that binds tubulin and stabilises microtubules, keeping the transport a neuron depends on running. It reached phase III in progressive supranuclear palsy and did not meet its endpoints.Schematic — not to scale

3What the research shows

Graded A (small; mixed)

Amnestic mild cognitive impairment

A 12-week randomised, double-blind, placebo-controlled trial (n=144) of intranasal davunetide 5 mg once daily or 15 mg twice daily reported improvement on some memory measures (notably delayed match-to-sample) in the lower-dose group, with good tolerability; the overall cognitive battery was not uniformly positive (Morimoto 2013, Dement Geriatr Cogn Disord). It was a safety-and-signal study, not a pivotal trial. [5]

Graded A (negative on cognition)

Cognitive impairment in schizophrenia

A 12-week (n=63) found no improvement in the primary cognitive outcome but a signal on a functional-capacity measure (UPSA) (Javitt 2012, Schizophr Res). Small; not replicated. [6]

Graded A (negative)

Progressive supranuclear palsy

The pivotal Phase 2/3 trial randomised 313 patients to intranasal davunetide 30 mg twice daily or placebo for 52 weeks. There was no difference on either co-primary endpoint (PSP Rating Scale and a functional activities scale) or any secondary measure (Boxer 2014, Lancet Neurol). This is the largest and best-controlled data set and it is firmly null. Later post-hoc analyses have explored sex differences (Gozes and colleagues), but these are hypothesis-generating only. [7]

Alzheimer's, tauopathy and injury models

Robust and repeated: improved cognition and reduced tau pathology in transgenic tauopathy mice, protection in models of traumatic brain injury, stroke, ischaemia and fetal alcohol exposure, across many papers from the Gozes group and collaborators.

Graded C/—

ADNP syndrome

Preclinical work in ADNP-deficient mice and a push toward clinical evaluation in children with ADNP mutations; no published efficacy trial as of review date †.

Community use

Rare. Where reported, intranasal, with no consistent claims. This is not a mainstream community peptide.

4Reported side effects and interactions

Literature-reported

The best-characterised safety profile of any peptide on this site that is not an approved medicine. Across trials totalling several hundred people, intranasal davunetide was well tolerated; adverse events were mostly nasal (irritation, rhinorrhoea, epistaxis) and comparable to placebo for serious events. No dose-limiting toxicity in Phase 1 IV dosing.

Community-reported

too few reports to summarise honestly.

Theoretical. microtubule-active agents in oncology (taxanes) work by over-stabilising microtubules in dividing cells; NAP is not that kind of agent and no proliferative or anti-proliferative signal appeared in trials, but the question is reasonable for a microtubule-acting molecule used long term.

Interactions. none identified in trials.

Markers researchers commonly monitor

No compound-specific markers are established. The trials used clinical scales, not biomarkers, as endpoints. Reasonable choices:

Marker	Why it's watched
A standardised cognitive battery (e.g. a computerised memory task or MoCA) at baseline and follow-up	the only outcome the human trials measured with any signal.
Plasma p-tau217 or p-tau181	now commercially available in some countries; the mechanism is tau-directed, so a baseline is scientifically interesting even though no trial has shown davunetide moves it.
CBC and CMP	general baseline for a non-approved compound.
Nasal symptoms	the main side-effect category in trials; worth noting in a log.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Supplied as powder. For intranasal use the powder is with sterile or and dispensed from a metered spray; the clinical formulation was a buffered nasal solution. Human trial doses were in milligrams per day, far higher than the rodent doses that generated the "femtomolar" reputation, so expect vial sizes of several milligrams. Refrigerate; protect from light.

Open in calculator, pre-loaded →

6Commonly studied alongside

Rarely combined in practice. Mechanistically it is discussed next to other microtubule or tau-directed strategies and alongside Cerebrolysin, Dihexa and P21 in "neurotrophic" community conversations, without any combined data. ADNP-related research also references VIP (vasoactive intestinal peptide), from which the ADNP story originated.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not FDA-approved. Investigational; received orphan-drug designation for PSP and fast-track status during development †. Not a compounding substance
European Union	Not authorised; EMA orphan designation for PSP was granted during development †
United Kingdom	Not licensed
Australia	Not approved
South Africa	Not registered
Sport (WADA)	Not specifically listed; as a non-approved substance it falls under S0 †

8Open questions

Why did a mechanism this clean fail in PSP? Dose, brain delivery, disease stage and choice of indication have all been proposed.
Is there a real sex-dependent effect, as post-hoc analyses suggest, or is this noise?
Does NAP have a role in ADNP syndrome, the one condition where its parent protein is directly deficient?
Pharmacokinetics of intranasal delivery in humans — brain concentrations were never directly measured.

9References

1Bassan M et al. (1999). Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem. PubMed · DOI
2Divinski I, Mittelman L, Gozes I (2004). A femtomolar acting octapeptide interacts with tubulin and protects astrocytes against zinc intoxication. J Biol Chem. PubMed · DOI
3Oz S et al. (2014). The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins. Mol Psychiatry. PubMed · DOI
4Gozes I et al. (2005). NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP). CNS Drug Rev. PubMed · DOI
5Morimoto BH et al. (2013). A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. Dement Geriatr Cogn Disord. PubMed · DOI
6Javitt DC et al. (2012). Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia. Schizophr Res. PubMed · DOI
7Boxer AL et al. (2014). Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. PubMed · DOI

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

26 Oct 2026Profile published — awaiting medical review

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