PE-22-28 — Research, Dosing & Price Guide

PE-22-28 is a synthetic peptide derived from the spadin family that acts as a blocker of the TREK-1 potassium channel. TREK-1 inhibition produces rapid antidepressant and cognitive-enhancing effects, making PE-22-28 a novel nootropic with mood-elevating properties. It represents a fundamentally different approach to cognitive enhancement and mood regulation compared to traditional monoamine-targeting compounds.

PE-22-28 is a 7-amino-acid peptide that selectively blocks the TREK-1 (TWIK-related potassium channel-1), a two-pore-domain potassium channel highly expressed in the hippocampus, prefrontal cortex, and amygdala. TREK-1 normally acts as a 'leak' potassium channel that stabilizes resting membrane potential, and blocking it increases neuronal excitability in mood- and cognition-relevant brain regions. This produces effects analogous to SSRIs but through an entirely different mechanism and with a much faster onset. TREK-1 blockade increases serotonergic neurotransmission in the dorsal raphe nucleus, enhances hippocampal neurogenesis, and increases BDNF expression. The rapid onset (within hours vs. weeks for SSRIs) is attributed to direct modulation of neuronal excitability rather than slow reuptake transporter adaptations.

• Moha Ou Maati et al. (2012) in PLoS ONE demonstrated that spadin (the parent compound) produced antidepressant effects in mice within 4 days vs. 21 days for SSRIs
• Research showed TREK-1 knockout mice exhibit a depression-resistant phenotype, validating the target (Nature Neuroscience, 2006)
• Studies demonstrated PE-22-28 increased hippocampal neurogenesis and BDNF expression in rodent models
• Preclinical data showed PE-22-28 improved performance in the forced swim test and tail suspension test (standard depression models)
• Research in the European Journal of Pharmacology confirmed PE-22-28's selectivity for TREK-1 over other potassium channels

• Intranasal: 50–200 mcg per dose, 1–2 times daily
• Subcutaneous: 100–500 mcg once daily
• Start with 50 mcg intranasally to assess response
• Cycle: 2–4 weeks on, 1–2 weeks off
• Morning dosing preferred for cognitive enhancement; evening dosing may benefit mood and next-day resilience
• Effects may be noticeable within hours due to the fast-onset mechanism

Known Side Effects

• Headache — reported in some users, generally mild
• Overstimulation — potential for restlessness or anxiety at higher doses, particularly in anxiety-prone individuals
• Insomnia — if dosed too late in the day
• Very limited human safety data — almost all evidence is preclinical
• Nasal irritation with intranasal administration

Safety Profile

PE-22-28 is a research compound with no human clinical trial data. Its safety profile is extrapolated from preclinical studies and the broader spadin literature. TREK-1 is widely expressed in the brain, and modulating its activity could have effects beyond mood and cognition. The compound has not been assessed for genotoxicity, carcinogenicity, or reproductive toxicity. Users should treat it as an experimental compound with appropriate caution. Individuals on SSRIs, SNRIs, or other antidepressants should exercise caution due to potential serotonergic interactions.

Within hours: Some users report subtle mood elevation and improved motivation within the first day, consistent with the rapid-onset mechanism demonstrated in preclinical studies. Days 1–3: Improved mood stability and cognitive clarity. Tasks feel less effortful and motivation increases. Weeks 1–2: Cumulative neurogenic effects emerge. Users report improved emotional resilience, better stress management, and enhanced cognitive flexibility. Weeks 3–4: Peak effects. Mood is notably improved and stable, cognitive performance is enhanced, and overall sense of well-being is elevated. After cessation, effects taper over 1–2 weeks.

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