PE-22-28.
PE-22-28 is a synthetic seven-residue peptide corresponding to residues 22 to 28 of spadin, itself a fragment derived from the sortilin propeptide (also called neurotensin receptor-3).
PE-22-28 is a synthetic seven-residue peptide corresponding to residues 22 to 28 of spadin, itself a fragment derived from the sortilin propeptide (also called neurotensin receptor-3). PE-22-28 is research / preclinical, and PepCue grades its published evidence F tier (24/100). Also known as spadin analog. This is a research reference, not medical or dosing advice.
What it is
PE-22-28 is a synthetic seven-residue peptide corresponding to residues 22 to 28 of spadin, itself a fragment derived from the sortilin propeptide (also called neurotensin receptor-3). It was developed as a shortened, more stable analog of spadin intended to block the TREK-1 potassium channel. It has been studied as a fast-acting antidepressant candidate in rodent models. It is a preclinical research compound with no human data.
How it works
PE-22-28 acts by inhibiting the TREK-1 two-pore-domain potassium channel, which is implicated in mood regulation and in resistance to conventional antidepressants. By blocking TREK-1, it is proposed to increase serotonergic neurotransmission and promote hippocampal neurogenesis. Reported potency is high, with a sub-nanomolar IC50 and improved metabolic stability compared with spadin. These effects are characterized in cell and animal systems.
Mechanism pathways
Peptides that tune monoamine, GABA, opioid, ion-channel, and social-behaviour circuits.
Neuromodulation differs from neurotransmission. A neurotransmitter carries a discrete signal across a synapse; a neuromodulator adjusts how strongly and for how long many synapses respond, acting over a broader area and a longer timescale. Most of the compounds grouped here are neuromodulators, which is why their reported effects are described as shifts in tone rather than as switching a function on or off, and why their effects are often bidirectional depending on the starting state. Several routes are represented. One compound is a selective blocker of TREK-1, a two-pore-domain potassium channel. These channels set the resting membrane potential and therefore how easily a neuron fires. TREK-1 is expressed in mood-relevant regions and has been implicated in resistance to conventional antidepressants, and blocking it is proposed to increase serotonergic neurotransmission and support hippocampal neurogenesis. This is a well-defined molecular target, which distinguishes it from most of the group. Another is derived from an immune-active parent peptide and retains immunomodulatory activity while shifting toward central effects. Its proposed actions include modulation of serotonin, dopamine, and noradrenaline systems, interaction with GABAergic signalling, and inhibition of enkephalin-degrading enzymes, which prolongs the action of the body's own opioid peptides rather than adding an exogenous one. A third acts on the oxytocin receptor, a G-protein-coupled receptor. Peripherally this drives uterine contraction and the milk ejection reflex, which is the basis of its approved obstetric use. Centrally, oxytocin signalling in the amygdala, nucleus accumbens, and hypothalamus is associated with social salience, threat processing, and reward related to social interaction. Effects here are strongly context-dependent and are not reliably prosocial. A fourth has no confirmed receptor at all despite decades of study. Reported interactions are diffuse and concentration-dependent, spanning NMDA receptor modulation, stress-axis regulation, and several neuropeptide systems, and it has been framed as a homeostatic regulator with dose- and timing-dependent effects rather than as a sedative acting at a defined site. Honest assessment: one member is an approved medicine for a narrow peripheral indication, and its central effects remain an active research question rather than an established therapy. The others are unapproved research compounds whose mechanisms rest largely on rodent and in vitro work, with limited independent human evidence. Compounds affecting mood and arousal circuits also interact unpredictably with psychiatric medication.
The evidence
Evidence for PE-22-28 is preclinical only. In the foundational study, shortened spadin analogs including PE-22-28 showed stronger TREK-1 inhibition, longer in-vivo stability and antidepressant-like activity in behavioral tests such as forced swim and novelty-suppressed feeding, along with induction of neurogenesis after a short treatment course (Djillani et al., Frontiers in Pharmacology 2017). A review of TREK-1 blockers situates spadin and its analogs within antidepressant drug discovery (Djillani et al., Pharmacology and Therapeutics 2019). Related work describes the sortilin/NTSR3 origin of spadin and its role in the membrane expression of TREK-1, which supplies the mechanistic rationale for the shortened analogs (Frontiers in Pharmacology, 2018). Separate mouse work using genetic and pharmacological inhibition of TREK-1 reported changes in depression-related behavior and hippocampal neuronal plasticity (CNS Neuroscience and Therapeutics, 2021); that work supports the target as biologically interesting but does not test this peptide. The design of the supporting studies limits the conclusions available. They are rodent experiments run in academic laboratories, largely the group that originated spadin, over short treatment courses. The behavioral readouts are screening assays rather than models of depression: forced swim, tail suspension and novelty-suppressed feeding are sensitive to known antidepressants, which makes them useful filters, but a long list of compounds that performed well in them has failed in human trials. The reports are not blinded multi-centre studies, are not pre-registered, and have not been replicated head to head by an independent group. No completed or registered human clinical trial exists for PE-22-28. There is consequently no Phase 1 safety or tolerability dataset, no human pharmacokinetic profile, no measured central nervous system exposure in people, and no published toxicology package. This is a weaker position than that of compounds it is informally compared with: approved rapid-acting antidepressants such as esketamine were established through randomized, placebo-controlled trials with standard depression rating scales before approval, and even TREK-1 or novel-mechanism candidates that ultimately failed generally reached Phase 1 and produced human exposure and tolerability data. Antidepressant-like signals in rodents do not establish human efficacy or safety.
The evidence, in brief
A seven-residue shortened analogue of spadin that inhibits the TREK-1 potassium channel, studied as a fast-acting antidepressant candidate. Reported effects are antidepressant-like behaviour and neurogenesis in rodents, with better stability than spadin. No human trials exist, so rodent behavioural signals are the entire basis for the claims made about it.
- Djillani A et al.: Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant ActivityFront Pharmacol, 2017 (PMID 28955242)
- Djillani A et al.: Fighting against depression with TREK-1 blockers: past and future. A focus on spadinPharmacol Ther, 2019 (PMID 30291907)
Evidence maturity
An evidence-only reading: approval status, human vs preclinical data, mechanism and safety. Popularity never raises it. Research file #048
Mostly preclinical or mechanistic; little human data.
Findings come mainly from animal models, not people.
Claim receipts
Popular claims about PE-22-28, checked against the state of the evidence. The verdict describes evidence maturity, never an invented study result.
Antidepressant-like activity was reported in rodent screening assays such as forced swim and novelty-suppressed feeding, which filter candidates rather than model depression, and many compounds that performed well in them later failed in humans.
Rapid-acting antidepressants it is compared against were established through randomized placebo-controlled trials with standard depression endpoints; this peptide has no completed or registered human trial to compare against.
Neurogenesis was reported after short treatment courses in rodents; nothing comparable has been measured in people.
TREK-1 is a credible target supported by separate genetic and pharmacological work, but that work supports the target rather than this specific peptide, which has no human pharmacology data.
There is no Phase 1 tolerability study, no human pharmacokinetics and no published toxicology package, and TREK-1 is expressed outside the brain, so systemic off-target effects cannot be excluded.
Safety profile
No human safety data exist for PE-22-28; all information comes from short-term rodent studies. There is no published Phase 1 tolerability study, no human pharmacokinetic or elimination data, no immunogenicity assessment, and no repeat-dose or reproductive toxicology package in the public literature. Because TREK-1 is expressed in tissues outside the brain, including cardiovascular, smooth muscle and immune-related tissues, systemic and off-target effects are theoretically possible; the channel also contributes to cellular responses to mechanical and thermal stimuli, so blocking it chronically could have consequences that short rodent behavioral experiments were never designed to detect. Effects on mood-related circuitry are themselves a caution: psychoactive compounds acting on serotonergic signaling and neurogenesis can produce agitation, sleep disruption or worsening mood, and no monitored human exposure exists to characterize any of this. Purity, identity and long-term toxicology of material sold as a research chemical are not controlled. Such products are made outside pharmaceutical good manufacturing practice, carry no verified certificate of analysis for peptide content, impurity profile or endotoxin, and are labeled for laboratory use only. Buyers cannot confirm what the vial holds or whether a reconstituted solution is sterile. The lack of reported adverse events reflects the lack of supervised human use rather than a safety record. With no clinical trials, no pharmacovigilance reporting and no registry, harms occurring in unsupervised use would not be captured. It is not a medicine and is not intended for human use.
Compound notes
- PE-22-28 is a synthetic seven-residue peptide corresponding to residues 22 to 28 of spadin, itself a fragment derived from the sortilin propeptide (also called neurotensin receptor-3).
- It acts by inhibiting the TREK-1 two-pore-domain potassium channel, which is implicated in mood regulation and in resistance to conventional antidepressants.
- Blocking TREK-1 is proposed to increase serotonergic neurotransmission and promote hippocampal neurogenesis.
- Antidepressant-like activity has been shown in rodent behavioral tests such as forced swim and novelty-suppressed feeding; there are no human trials.
PE-22-28 is the shortened analog: reported sub-nanomolar TREK-1 inhibition and greater in-vivo stability than the parent spadin fragment.
- No human safety data exist; all information comes from short-term rodent studies.
- TREK-1 is expressed in tissues outside the brain, so systemic and off-target effects are theoretically possible.
- Not approved anywhere; distributed only as a research chemical and not intended for human use.
Regulatory status
PE-22-28 is not approved by the FDA or any other regulator and has no approved medical use. It exists only as a preclinical research compound. This summary is educational and includes no dosing guidance.
Sold research-use-only; human evidence is limited or preclinical.
By the numbers
- 01Seven-residue synthetic peptide from residues 22 to 28 of spadin.
- 02Selective inhibitor of the TREK-1 potassium channel.
- 03Reported sub-nanomolar potency and greater stability than spadin.
- 04Antidepressant-like effects and neurogenesis shown in rodent tests.
- 05Evidence is preclinical only, with no human trials.
- 06Not approved anywhere; distributed only as a research chemical.
PE-22-28: research formats
Choose the format you are researching to see route-specific notes.
Preclinical only. Antidepressant-like effects were shown in rodents, never in people.
PE-22-28 is a seven-residue synthetic peptide derived from spadin that selectively inhibits the TREK-1 potassium channel. Its reported antidepressant-like effects and neurogenesis findings come from rodent behavioral tests. There are no human trials, so no route, schedule, or human safety profile has been established and this page presents no example amounts.
Rodent antidepressant models are screening tools, not proof of a human effect, and they say nothing about how the compound would be administered to a person.
PE-22-28 is not approved by any regulator and is distributed only as a research chemical.
Sources
Every factual claim above resolves to a real, published source.
- Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant ActivityDjillani A et al. Front Pharmacol, 2017 (PMID 28955242)
- Fighting against depression with TREK-1 blockers: Past and future. A focus on spadinDjillani A et al. Pharmacol Ther, 2019 (PMID 30291907)
- The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1Djillani A, et al. Front Pharmacol, 2018 (PMID 30670975)
- Genetic and pharmacological inhibition of two-pore domain potassium channel TREK-1 alters depression-related behaviors and neuronal plasticity in the hippocampus in miceCNS Neurosci Ther, 2021 (PMID 32864894); target validation, not this peptide
- ClinicalTrials.gov: spadin and PE-22-28 registrationsRegistry search, used to confirm the absence of human trials
Cite this page
PepCue. “PE-22-28: the evidence.” PepCue, reviewed June 1, 2026. https://www.pepcue.app/p/pe-22-28.
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