PE-22-28

The last seven amino acids of spadin, a natural peptide cut from the sortilin protein. French researchers (Mazella, Borsotto and colleagues, CNRS Nice) identified spadin as an antidepressant candidate and picked out PE-22-28 from its breakdown products in blood.

Blocks TREK-1, a 'leak' potassium channel that quiets neurons; mice lacking TREK-1 behave as if resistant to depression. In human TREK-1 cell assays it was more than 300-fold stronger than spadin, and it did not affect related channels or the hERG cardiac channel at tested levels. Treated mice showed more new-cell formation in the hippocampus.

In male mice, PE-22-28 reduced immobility in swim tests and improved other depression-model tests after four days, faster than standard antidepressants act in the same tests, with longer-lasting effects than spadin. It was also active after oral administration in one mouse test. No human study exists; human evidence for the target is only genetic (TREK-1 gene variants are linked to depression and SSRI response). Long-term toxicology, effects in females, and independent replication are missing.

Effects in humans are unknown. TREK-1 helps protect the brain during stroke and limits pain, and mice lacking it died more often after brain ischemia, so blocking it carries theoretical risks that have not been studied. Many SSRIs also act on TREK-1, and combined effects are unstudied.

Not FDA-approved, and no US trial was found. Not eligible for compounding. Not named on the 2026 WADA list; as an unapproved substance it would fall under S0.