PE-22-28 vs Davunetide
Comprehensive side-by-side comparison of mechanisms, dosing, side effects, and research
Also: PE22-28, Spadin Analog
PE-22-28 is a seven-amino-acid peptide that blocks a potassium channel in the brain called TREK-1, the same target tied to depression. It is a shortened, more potent and more stable version of spadin, a natural fragment cut from the sortilin propeptide, and it was built to act like a fast antidepressant. All evidence is from rodents. There are no human clinical trials.
Also: NAP, AL-108
Davunetide (NAP) is an eight-amino-acid fragment (NAPVSIPQ) of activity-dependent neuroprotective protein (ADNP), discovered at Tel Aviv University and given as a nasal spray. It was meant to protect brain cells by stabilizing microtubules, the scaffolding that tau normally supports. Its big test, a phase 2/3 trial in progressive supranuclear palsy (PSP), failed cleanly in 2012, and development stalled. It has since been revived by its inventors, who argue it works in women and are pursuing ADNP syndrome, but those claims rest on reanalyses of old data, not a new successful trial.
Key Comparison Insights
- Both peptides belong to the Cognitive category, suggesting similar primary applications.
- Davunetide has stronger research evidence (Human Trials) compared to PE-22-28 (Animal Studies).
Detailed Comparison
| Attribute | PE-22-28 | Davunetide |
|---|---|---|
| Category | Cognitive | Cognitive |
| FDA Status | Not FDA Approved | Not FDA Approved |
| Clinical Status | Pre I II III IV FDA | Pre I II III IV FDA |
| Mechanism of Action | PE-22-28 inhibits TREK-1, a two-pore-domain potassium channel that normally lets potassium leak out of neurons and quiets them down. Block that leak and serotonin-producing neurons in mood-related regions become easier to fire, which is the proposed antidepressant mechanism. This is the same pathway implicated in why TREK-1 knockout mice show a depression-resistant phenotype. Compared to the parent peptide spadin, PE-22-28 binds TREK-1 far more tightly and survives much longer in the body, which is why it was developed. Whether TREK-1 blockade translates into a real antidepressant effect in people remains unproven. | NAP comes from ADNP, a protein essential for brain development. In cell and animal studies it interacts with microtubule end-binding proteins (EB1 and EB3), promoting microtubule stability and reducing tau phosphorylation, which is why it was aimed at tauopathies like PSP and Alzheimer's disease. Mutations in the ADNP gene itself cause ADNP syndrome (Helsmoortel-Van der Aa syndrome), and in ADNP-deficient mice NAP improved some behavioral and neural measures, the rationale for that newer program. The PSP trial did not include target-engagement measures, so it never showed the drug was actually doing this in human brains. |
| Common Dosing | 100-300 mcg Once daily | 30 mg intranasal twice daily (PSP trial dose) Once or twice daily |
| Administration | Intranasal or subcutaneous injection | Intranasal spray (an IV form, AL-208, was tested in cardiac surgery) |
| Typical Duration | Research protocols vary, often 2-4 weeks | 12 weeks to 52 weeks in trials |
| Best Time to Take | Morning | Twice daily (trial schedule) |
Possible Side Effects May vary by individual |
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| Research Summary | The core data come from a single 2017 paper by Djillani and colleagues in Frontiers in Pharmacology, which screened shortened spadin analogs and found PE-22-28 to be the standout: dramatically stronger TREK-1 inhibition, longer in vivo stability, and antidepressant-like behavior in mice using standard tests like the forced swim and novelty-suppressed feeding paradigms. The same line of work reported that short treatment courses increased hippocampal neurogenesis in rodents, which the authors framed as a possible mechanism for faster mood effects than conventional SSRIs. The broader TREK-1 and spadin story traces back to Mazella et al. in 2010, who first described spadin as a natural antidepressant-type TREK-1 blocker. Importantly, every result is preclinical and in animals. There are no completed or published human efficacy or safety trials of PE-22-28, and it is not an approved drug anywhere. Claims that it treats depression, anxiety, or cognitive decline in people go well beyond what the evidence supports. | The headline result is negative. In the phase 2/3 PSP trial (Boxer and colleagues, Lancet Neurology 2014), 313 patients got 30 mg intranasal davunetide twice daily or placebo for 52 weeks. Disease progression was identical in both groups on both primary measures (PSP Rating Scale and Schwab and England daily living scale), and the authors concluded davunetide is not an effective treatment for PSP. Earlier phase 2 work was mixed: a 12-week trial in 144 people with amnestic mild cognitive impairment hinted at working-memory benefits, and a schizophrenia trial missed one co-primary endpoint while hitting another. The original developer, Allon Therapeutics, stopped investing and was later absorbed by Paladin Labs. The revival comes from the inventor's group: post hoc reanalyses of the PSP data (Translational Psychiatry 2023, Molecular Psychiatry 2026) report that women declined faster than men and that davunetide slowed decline in women only. A similar sex-split reanalysis of the MCI trial was published in 2024. These findings are interesting but are subgroup analyses of trials that failed overall, done by researchers tied to the company now developing the drug (ExoNavis Therapeutics), so they need a new prospective trial to mean much. ExoNavis has said a phase 3 in children with ADNP syndrome began in 2024, but Alzforum could not find it in trial registries. Davunetide holds FDA orphan and rare pediatric disease designations and EMA orphan status for ADNP syndrome. |
Frequently Asked Questions: PE-22-28 vs Davunetide
What is the difference between PE-22-28 and Davunetide?
PE-22-28 is a cognitive peptide that pe-22-28 is a seven-amino-acid peptide that blocks a potassium channel in the brain called trek-1, the same target tied to depression. it is a shortened, more potent and more stable version of spadin, a natural fragment cut from the sortilin propeptide, and it was built to act like a fast antidepressant. all evidence is from rodents. there are no human clinical trials. Davunetide is a cognitive peptide that davunetide (nap) is an eight-amino-acid fragment (napvsipq) of activity-dependent neuroprotective protein (adnp), discovered at tel aviv university and given as a nasal spray. it was meant to protect brain cells by stabilizing microtubules, the scaffolding that tau normally supports. its big test, a phase 2/3 trial in progressive supranuclear palsy (psp), failed cleanly in 2012, and development stalled. it has since been revived by its inventors, who argue it works in women and are pursuing adnp syndrome, but those claims rest on reanalyses of old data, not a new successful trial. The main differences lie in their mechanisms of action and clinical applications.
Which is better, PE-22-28 or Davunetide?
Neither is universally "better" - the choice depends on your specific goals. PE-22-28 is typically used for cognitive purposes, while Davunetide is used for cognitive. Always consult with a healthcare provider to determine which may be appropriate for your situation.
Can PE-22-28 and Davunetide be used together?
Some peptide protocols combine multiple compounds for synergistic effects. However, using PE-22-28 and Davunetide together should only be considered under medical supervision, as both compounds have their own side effect profiles and potential interactions. Research on their combined use may be limited.