PE-22-28

A synthetic 7-amino-acid peptide derived from sortilin (parent compound spadin). 300–500x more potent than spadin. Investigated as a fast-acting antidepressant — works on a different mechanism than SSRIs. Hunter Williams (Apr 2026): may work in 4 days vs the 3–4 weeks SSRIs typically require.

Selectively blocks the TREK-1 potassium channel in serotonergic neurons. Without TREK-1 dampening neuron firing, serotonin signaling increases rapidly. Also strongly upregulates BDNF (brain-derived neurotrophic factor) — driving new neuronal connections within hours. Mechanism is independent of monoamine reuptake.

Animal data is robust for rapid antidepressant effect, BDNF elevation, and anxiolytic action. Zero human RCTs to date. What data exists is personal experimentation by clinicians (Hunter Williams) and biohacker community reports.

Sources: PubMed: spadin TREK-1

Range

250 mcg/day SubQ

Frequency

4–5 days on / 2–3 days off (Hunter Williams protocol)

Duration

Short cycles; no long-term safety data

Sources: PubMed

Common

• Limited data — Hunter Williams reports clean profile vs SSRIs
• No withdrawal effects reported
• No cardiovascular effects observed

Serious / theoretical

• Long-term safety unknown — no human RCT data
• Combining with SSRIs theoretically problematic (serotonin syndrome risk)
• Avoid in pregnancy

Sources: PubMed

Promising but unproven — Hunter Williams (Apr 2026) is the highest-profile clinician currently using it. The TREK-1 mechanism is genuinely novel for depression. If you're on SSRIs/SNRIs, this is NOT a swap — combining serotonergic agents risks serotonin syndrome. Treat as experimental.