Library / Peptides / Cognitive & Neuro / PE-22-28

No human data · Grade D

PE-22-28

PE-22-28 (Spadin Analogue)

Evidence

No Human Data

Route

Subcutaneous injection or Intranasal

Frequency

Once daily

Mechanism.

PE-22-28 is a synthetic peptide derived from spadin, a natural peptide that inhibits the TREK-1 potassium channel. TREK-1 inhibition has been identified as a novel mechanism for antidepressant and cognitive-enhancing effects. PE-22-28 was designed to be more stable and potent than its parent compound spadin. Research is limited to animal models, where it has demonstrated antidepressant-like and pro-cognitive effects.

TREK-1 channels act like brakes on certain brain circuits involved in mood and cognition. PE-22-28 releases those brakes, allowing neurons in mood and memory centers to fire more readily. It is like loosening an overly tight parking brake that was holding your brain's mood and learning systems back.

Mechanism · technical

PE-22-28 selectively blocks TREK-1 (TWIK-related potassium channel 1), a two-pore domain potassium channel expressed in the brain. TREK-1 knockout mice display a depression-resistant phenotype, and TREK-1 blockade increases serotonergic neuron firing in the dorsal raphe nucleus. By inhibiting TREK-1, PE-22-28 enhances neuronal excitability and promotes BDNF (brain-derived neurotrophic factor) signaling, which supports neuroplasticity and hippocampal neurogenesis.

Part 02 · Dosing & administration

How it's taken.

Values below describe how PE-22-28 has been administered in published trials and labeling. Provided for educational purposes only — this is not medical advice and not instructions for self-administration. Consult your healthcare provider before making any health decision.

Standard dose

200-500 mcg

Subcutaneous injection or Intranasal · Once daily

Duration

4-6 weeks typical cycle

Spadin analogue targeting TREK-1 potassium channels. Potential antidepressant mechanism. No human clinical data. Research compound only.

Need help with reconstitution?

Use the free peptide calculator for dilution, unit conversion, and injection volume.

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Part 03 · Safety

Side effects, rare serious events, who shouldn't.

Reported side effects

No human safety data exists. Animal studies have shown relatively favorable tolerability. Theoretical concerns include effects on cardiac TREK-1 channels, which play a role in cardiac protection during ischemia. The absence of human data means the side effect profile is unknown.

Absolute · do not use

Pregnancy or breastfeeding

Children under 18

Known hypersensitivity to PE-22-28, spadin, or any component

Bipolar disorder or mania (may have antidepressant-like effects that could trigger mania)

Concurrent use of MAOIs

Interactions

SSRIs (fluoxetine, sertraline)

PE-22-28 blocks TREK-1 potassium channels (same target as some antidepressant mechanisms); additive antidepressant-like effects

Moderate

MAOIs

Combined antidepressant mechanisms may increase risk of serotonin-related adverse effects

Major

Benzodiazepines

Theoretical interaction through shared effects on neuronal excitability; may alter anxiolytic response

Minor

Lithium

Both affect neuronal ion channel function; monitor for additive CNS effects

Moderate

Labs to monitor

CMP (Comprehensive Metabolic Panel)

Baseline and every 3 months

Liver and kidney function

CBC with Differential

Baseline and every 3 months

General safety monitoring

Sodium and Potassium

Baseline and monthly

TREK-1 channel modulation can affect electrolyte handling

Part 04 · Research log

Every study we cite.

Each study with its published finding and a plain-language note on limitations or funding.

2010

Spadin, a TREK-1 channel blocker, with antidepressant-like activity

Spadin (parent compound) blocked TREK-1 channels and showed antidepressant effects in mice within 4 days vs 21 days for SSRIs

Preclinical; discovery paper; Bhatt lab

PMID 20890290 ↗

2017

PE-22-28 as optimized spadin analogue

PE-22-28 had improved stability and maintained antidepressant-like effects in rodent models

Preclinical; same research group

Part 05 · Cost & access

Where you can get it.

Regulatory status

PE-22-28 is not FDA-approved and has no regulatory approval anywhere. It is available only as a research chemical. No clinical trials have been registered.

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Part 06 · Your appointment

Questions to bring.

Is there any human safety or efficacy data for PE-22-28?

How does TREK-1 inhibition compare to established antidepressant mechanisms?

What are the risks of using a compound with no human pharmacokinetic data?

Are there better-studied options for cognitive enhancement or mood support?