PE-22-28 vs Orforglipron
Side-by-side comparison of key properties, dosing, and research.
Cognitive Enhancement
PE-22-28GLP-1 / Weight Loss Agonists
Orforglipron- Summary
- PE-22-28 is a synthetic analog of spadin derived from sortilin, designed to block TREK-1 potassium channels with rapid-onset antidepressant and neurogenic effects. It shows fast-acting depression relief (within 24 hours) and promotes hippocampal neurogenesis.
- Orforglipron is an oral, once-daily small-molecule GLP-1 receptor agonist developed by Eli Lilly. Unlike injectable GLP-1 peptides, it is a non-peptide compound absorbed orally without food restrictions, representing a major convenience advancement. Phase 2 trials showed up to 9.4% weight loss at 36 weeks, and Phase 3 trials (ATTAIN program) are ongoing for obesity and type 2 diabetes.
- Half-Life
- Relatively short; CNS effects may persist due to neurogenic mechanisms
- ~12 hours (once-daily oral dosing)
- Admin Route
- SubQ, Intranasal
- Oral
- Research
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- Typical Dose
- 200–400 mcg
- 12 mg → 24 mg → 36 mg → 45 mg
- Frequency
- Once daily
- Once daily
- Key Benefits
- Rapid-onset antidepressant effects (within 24 hours)
- Promotes hippocampal neurogenesis
- Improves cognitive performance and memory
- Reduces anxiety and depressive behavior
- Novel mechanism — does not act on serotonin/dopamine/GABA receptors directly
- May help treatment-resistant depression
- Neuroprotective effects
- Oral pill — no injections required
- Once-daily dosing without food restrictions (unlike oral semaglutide)
- Up to 9.4% body weight reduction in Phase 2 at 36 weeks
- Significant HbA1c reduction in type 2 diabetes trials
- Small-molecule stability — no cold chain requirements
- Broadens access for injection-averse patients
- Potential class-defining convenience advantage over injectable GLP-1s
- Side Effects
- Generally well tolerated in animal models
- Limited human data available
- Possible mild headache or transient mood changes at initiation
- Injection site reactions (SC)
- Nausea (most common, dose-dependent)
- Vomiting
- Diarrhea
- Decreased appetite
- +2 more
- Stacks With
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