--- title: "PE-22-28: Dosing & Vendor Prices | BodyHackGuide" url: https://www.bodyhackguide.co/compound/pe-22-28 description: "PE-22-28: dosing protocols, mechanism & side effects, 1 PubMed result. Compare 1 current vendor prices." lang: en --- Skip to content Compare notes on r/BodyHackGuide (https://reddit.com/r/bodyhackguide) Compare notes with other researchers. Join r/BodyHackGuide (https://reddit.com/r/bodyhackguide) # PE-22-28 Nootropics (https://www.bodyhackguide.co/wiki#cat-nootropics)Preclinical Also known as: PE2228 PE-22-28 is a synthetic seven-amino-acid peptide (sequence PAGASRLLLLTGEIDLP derivative, commonly truncated to PE-22-28 as shorthand for "position 22-28" within the parent humanin-family sequence) that was designed as an analog of Humanin with specific interest in activity at glutamate transporter regulation and cytoprotective signaling relevant to depression and neuroprotection. The peptide emerged from a research program characterizing short analogs of humanin that retain bioactivity while simplifying the structure for synthetic accessibility and potential therapeutic development. Image: Disguised Alpha logo (https://disguisedalpha.com/wp-content/themes/assets/logos/disguised-logo-2x.png) Lowest price per mg $5.50/mg $54.99 for 10mg at Disguised Alpha Buy at Disguised Alpha: https://disguisedalpha.com/product/pe-22-28-10mg/?coupon=reddit Half-life: Not characterized in humans MW: 773.9 g/mol 1 PubMed result (https://pubmed.ncbi.nlm.nih.gov/?term=PE-22-28%20peptide) Last reviewed: May 4, 2026 ## Overview ### At A Glance Mechanism PE-22-28 is a synthetic 7-amino-acid peptide (sequence GVSWGLR) and a shortened analog of spadin. Its proposed mechanism is inhibition of the TREK-1 (TWIK-related K+) channel, a two-pore-domain potassium channel (K2P2.1 / KCNK2) implicated in mood regulation. It is not related to… Half-Life Not characterized in humans. As a small 7-amino-acid peptide a short plasma half-life is expected; in mice the parent peptide spadin lost antidepressant activity by about 7 hours after a single dose, while modified analogs (e.g., G/A-PE 22-28) extended the behavioral effect to roughly 21-23 hours [PMID:28955242]. Dosing Once daily or every other day (research-chemical community protocols; no validated clinical dosing schedule). Dose Range 250-2000 mcg subcutaneous per dose (empirical research-chemical community range; no clinically validated human dose exists; effective preclinical rodent doses were far lower, ~3 mcg/kg). Potential Benefits Antidepressant-like effects in rodent models of depression (preclinical only) Potent, selective inhibition of the TREK-1 (K2P2.1) potassium channel (IC50 ~0.12 nM) Rapid-onset (~4-day) antidepressant profile in animals, unlike the multi-week lag of SSRIs Increased hippocampal neurogenesis in mice Increased cortical synaptogenesis (PSD-95) and BDNF expression in preclinical studies No human-validated benefits; not approved for any use (research use only) ### Overview PE-22-28 is a synthetic seven-amino-acid peptide (sequence PAGASRLLLLTGEIDLP derivative, commonly truncated to PE-22-28 as shorthand for "position 22-28" within the parent humanin-family sequence) that was designed as an analog of Humanin (https://www.bodyhackguide.co/compound/humanin) with specific interest in activity at glutamate transporter regulation and cytoprotective signaling relevant to depression and neuroprotection. The peptide emerged from a research program characterizing short analogs of humanin that retain bioactivity while simplifying the structure for synthetic accessibility and potential therapeutic development. PE-22-28 specifically attracted attention when preclinical work suggested antidepressant-like activity in rodent models of depression, with a proposed mechanism involving glial cell modulation and glutamate transporter 1 (GLT-1/EAAT2) regulation. The compound sits in the broader field of peptide-based neuropsychiatric therapeutics, alongside compounds like Selank (https://www.bodyhackguide.co/compound/selank) and Semax (https://www.bodyhackguide.co/compound/semax) that have been used in Russia for decades but remain investigational in Western markets. PE-22-28 is distinctive within this space because of its mechanistic grounding in humanin biology and glutamate homeostasis, which connects it to contemporary understanding of depression pathophysiology that emphasizes the role of glutamatergic signaling, astrocyte function, and neuroinflammation alongside the classical monoamine framework. The practical reality in April 2026 is that PE-22-28 remains a preclinical research peptide with limited published literature, no approved human use, no registered clinical trials, and a small but active self-experimentation community among biohackers interested in short peptide therapeutics for mood and cognitive applications. The compound is sold by research-chemical peptide vendors with the standard "for research purposes only" framing, and individual users have accumulated anecdotal experience with it in protocols typically involving daily or every-other-day subcutaneous dosing. The evidence base for PE-22-28 is substantially thinner than for BPC-157 (https://www.bodyhackguide.co/compound/bpc-157), Selank (https://www.bodyhackguide.co/compound/selank), or Semax (https://www.bodyhackguide.co/compound/semax) in terms of published animal studies and translational groundwork; the peptide's profile rests on specific rodent behavioral studies and mechanistic biology inferred from its relationship to humanin and its proposed interactions with glutamate transporter regulation. This entry covers what is published about the peptide, the mechanistic rationale connecting it to humanin biology and glutamate homeostasis, the specific preclinical behavioral data that sparked interest in depression applications, realistic interpretation of that data in the context of the replication crisis in preclinical depression research, the theoretical and practical concerns with self-administration of a minimally characterized peptide, how PE-22-28 fits into the peptide stacking landscape alongside other cytoprotective and neuropsychiatric peptides, and what conservative thinking about this molecule looks like for someone considering it seriously rather than as a novelty. ## Chemical Information IUPAC Name Not yet available CAS Number Not yet available Molecular Formula C141H237N43O40S Molecular Mass 773.9 g/mol (average; molecular formula C35H55N11O9) Amino Acid Sequence GVSWGLR (Gly-Val-Ser-Trp-Gly-Leu-Arg) - an unmodified 7-residue peptide corresponding to residues 22-28 of the 44-amino-acid sortilin/neurotensin receptor-3 (NTSR3) propeptide. It is the C-terminal fragment of spadin (spadin = PE 12-28). ## Dosing & Protocols ### Unlock the dosing protocols Enter your email to keep reading. It is free, and it opens these tabs on every compound page in this browser. - Dose, how often and how long - Beginner, intermediate and advanced protocols - Reconstitution and handling notes - Stacking notes You also get the free peptide cheat sheet by email. Unsubscribe anytime. Have an account? Sign in (https://www.bodyhackguide.co/auth) ## Research ### Unlock the research summary - A summary of the key research - Safety and side effects - A link to the PubMed results ## Interactions ### Interaction Matrix ### Contraindications PE-22-28 has no human safety data and is not an approved medicine, so every "contraindication" below is precautionary and framed around its proposed target (the TREK-1 potassium channel) and the reality that it is used without medical supervision. Clinical depression is the central caution. Moderate-to-severe depression - especially with any suicidal ideation - is a serious medical condition that should be managed with evidence-based care (psychotherapy, approved antidepressants) under a clinician, not self-treated with a research-chemical peptide. PE-22-28 should never be used as a substitute for prescribed treatment or professional care, and anyone whose mood worsens should stop and seek help. Bipolar-spectrum and psychotic-spectrum disorders warrant particular caution: any agent that shifts mood or neuronal excitability carries a theoretical risk of destabilization (mania/hypomania, mood cycling, or unpredictable effects in psychosis), and PE-22-28 has no data in these populations. Pregnancy and breastfeeding should be treated as absolute contraindications given the complete absence of developmental safety data, and it should not be used by children or adolescents. Drug-interaction concerns are uncharacterized but plausible. Because the peptide's rationale involves TREK-1 blockade with downstream serotonergic and neurogenic effects, combining it with prescribed antidepressants (SSRIs, SNRIs, tricyclics, MAOIs) or with other centrally acting psychiatric drugs (lithium and other mood stabilizers, ketamine, memantine) could produce additive or unpredictable effects and should not be done without physician oversight. TREK-1 also has roles in pain, seizure threshold and cardiovascular tone, so people with epilepsy, significant cardiovascular disease, or recent stroke/head injury should avoid unsupervised use. Known hypersensitivity to peptide products or to any excipient (for example the bacteriostatic water used for reconstitution) is a contraindication. Finally, the practical contraindication is using PE-22-28 for a psychiatric indication without any clinical infrastructure to monitor progress or escalate care. Research Disclaimer This interaction data is compiled from published research and community reports. It may not be exhaustive. Always consult a healthcare professional before combining compounds. Best Price $54.99 Best $/mg $5.4990 Vendors 1 Listings 1 vial Form Sort | Vendor | Product | Form | Qty | Price | $/mg | Coupon | | | --- | --- | --- | --- | --- | --- | --- | --- | | Image: Disguised Alpha logo (https://disguisedalpha.com/wp-content/themes/assets/logos/disguised-logo-2x.png) Disguised Alpha (https://www.bodyhackguide.co/vendors/disguised-alpha) 50: https://www.bodyhackguide.co/vendor-trust-scorecard 🇺🇸 US 🇪🇺 EU 🇬🇧 UK | PE-22-28 10 mg | vial | 1 vial ● In Stock | $54.99 BEST | $5.50 | — | Buy: https://disguisedalpha.com/product/pe-22-28-10mg/?coupon=reddit | ### Sign in to leave a review Reviews on BodyHackGuide are tied to verified user accounts and moderated before publishing. Sign in (free, no spam) to share your experience with PE-22-28. Current low $54.99 current listings 7-day low — not enough history yet 30-day low — not enough history yet 30-day change — not enough history yet Tracking since Sep 5, 2026 · 1 data point ### Vendors Selling PE-22-28 #### Disguised Alpha 1 listing · from $54.99 https://www.bodyhackguide.co/vendors/disguised-alpha How we score these vendors Every supplier above is graded 0 to 100 on COA verification, payment transparency, shipping, reviews, and active listings. Methodology published, no pay-to-rank. View Scorecard (https://www.bodyhackguide.co/vendors/scorecard) ### Related Compounds View All (https://www.bodyhackguide.co/wiki) ### 9-Me-BC (9-Methyl-β-carboline) Nootropics Preclinical 9-Methyl--carboline (9-Me-BC) is a synthetic -carboline alkaloid that has drawn nootropic-community interest for a preclinical property that is genuinely unusual among -carbolines: in rodent and cell-culture studies it appears to stimulate the dopaminergic phenotype - raising tyrosine hydroxylase, the number of differentiated dopamine neurons and dopamine content - while also showing neuroprotective, neurorestorative and anti-inflammatory effects, plus in-vitro MAO-A/MAO-B inhibition [PMID:17913302, PMID:20374418, PMID:32285253]. t½ Not characterized in humans (no pharmacokinetic data). Community/anecdotal only: ~5-25 mg per day, oral. No validated or approved human dose exists. 6 PubMed View Profile https://www.bodyhackguide.co/compound/9-mbc ### Aniracetam Nootropics Approved (Italy) Aniracetam is a pyrrolidinone in the racetam family, developed by Hoffmann-La Roche under the code Ro 13-5057. t½ About half an hour for the parent drug in humans. Plasma elimination half-life was 0.47 to 0.49 hours after a single 400 mg oral dose in 20 healthy male volunteers (PMID: 19025058). Aniracetam is extensively metabolized to N-anisoyl-GABA and anisic acid; in six elderly hospitalized patients with cerebrovascular disease and reduced creatinine clearance, metabolite half-life was 4 to 7 times longer than in young volunteers (PMID: 9062694). Preclinical View Profile https://www.bodyhackguide.co/compound/aniracetam ### Bemethyl (bemitil) Nootropics Approved (Russia) Bemethyl, known in the Russian literature as bemitil and sold in the region under names including Metaprot, Bemactor and Antihot, is 2-ethylthiobenzimidazole, normally handled as the hydrobromide salt. t½ Not established in humans; in healthy volunteers given a single 250 mg oral dose of the Metaprot capsule form, peak serum ethylthiobenzimidazole averaged 0.91 microg/mL at about 1.06 h, and no terminal half-life was reported (PMID: 21870773) Preclinical View Profile https://www.bodyhackguide.co/compound/bemethyl ### Bromantane Nootropics Russia Approved Bromantane is an atypical psychostimulant and anxiolytic developed in the 1980s at the Zakusov Institute of Pharmacology of the Russian Academy of Medical Sciences, originally created as an adaptogen for Soviet military and elite athletic use and later approved in Russia for the treatment of neurasthenic and asthenic disorders under the trade name Ladasten. 34 PubMed View Profile https://www.bodyhackguide.co/compound/bromantane ### Cyclazodone Nootropics Preclinical Cyclazodone is the N-cyclopropyl derivative of pemoline, a 4-oxazolidinone stimulant. Preclinical View Profile https://www.bodyhackguide.co/compound/cyclazodone ### Dihexa Nootropics Preclinical Dihexa is a synthetic peptide analogue of the angiotensin IV metabolite LVV-hemorphin-7, developed at Washington State University. t½ Not characterized in humans. Dihexa was engineered for metabolic stability (resistant to plasma and enzymatic degradation) and blood-brain-barrier penetration; in preclinical work its central procognitive effects appear to outlast its plasma presence. 5 to 40 mg oral per day (anecdotal range; no established human dose) 1 PubMed View Profile https://www.bodyhackguide.co/compound/dihexa View Full Dosage Guide → Protocols, calculator & safety for PE-22-28 https://www.bodyhackguide.co/guides/dosage/pe-22-28 ### Lowest Price per mg Disguised Alpha $54.99($5.50/mg) 1 vendor · 1 listing ### Research Score 30 1 PubMed result ### Quality Indicators Data Completeness 100% Description Mechanism of Action Chemical Data Dosing Protocols Safety Profile PubMed Results Interactions Vendor Listings Research Volume 1 PubMed results Limited research available ### Quick Facts Half-Life Molecular Weight Trial Phase Preclinical 0 Research Disclaimer This information is for educational and research purposes only. Not intended as medical advice. Consult a healthcare professional before use. ## Frequently Asked Questions What is PE-22-28 and how is it related to spadin? PE-22-28 is a synthetic 7-amino-acid peptide (sequence GVSWGLR) and a shortened analog of spadin. Spadin (PE 12-28) is a natural 17-amino-acid fragment released when the receptor sortilin (neurotensin receptor-3) is processed, and it blocks the TREK-1 potassium channel. Researchers found PE-22-28 among spadin's breakdown fragments and showed it is the shortest piece that still blocks TREK-1 - and is actually more potent and more selective than spadin. It has been studied only in cells and mice as a fast-acting antidepressant candidate. It is not related to humanin. [PMID:28955242] Has PE-22-28 been tested in humans? No. As of 2026 there are no published human trials of PE-22-28, no ClinicalTrials.gov registrations, and no human pharmacokinetic, safety or efficacy data. All evidence is preclinical (cell lines and mice), and all human use is self-experimentation with research-chemical vendor material. [PMID:28955242] How does PE-22-28 work for depression? Its proposed mechanism is blockade of the TREK-1 (K2P2.1) potassium channel. In mice, removing TREK-1 produces a depression-resistant, pro-serotonergic phenotype, so blocking the channel pharmacologically is thought to be antidepressant. PE-22-28 inhibits TREK-1 with an IC50 near 0.12 nM (more potent than spadin), and in rodents a few days of dosing increases hippocampal neurogenesis, cortical synaptogenesis and BDNF - a rapid-onset pattern unlike the multi-week lag of SSRIs. This is a plausible, preclinically supported mechanism, but human efficacy has not been demonstrated. [PMID:28955242][PMID:20405001] What dose of PE-22-28 is typically used? There is no clinically validated dose. Effective rodent doses were very low (around 3 micrograms per kilogram, injected). Research-chemical community protocols instead use fixed doses in the range of roughly 250-2000 micrograms per injection, subcutaneously, once daily or every other day - figures that are empirical and not derived from human studies. Because no human pharmacokinetic data exist, all of these numbers should be treated as unvalidated. [PMID:28955242] How long before PE-22-28 effects are noticeable? In rodents, the antidepressant-type effects and the neurogenesis that accompanies them developed over about 4 days of dosing rather than after a single dose, and the parent peptide's behavioral effect was relatively short-lived per dose. Community self-reports vary widely - some describe changes within days, others none at all. Any human onset timing is anecdotal, since there are no controlled human data. [PMID:28955242] Is PE-22-28 safe for long-term use? Unknown. There are no long-term safety data in humans and no extended toxicology studies. The preclinical appeal is that PE-22-28 was selective for TREK-1 and did not affect the cardiac hERG channel or several related potassium channels, and spadin analogs showed no obvious effects on pain, seizures or heart function in short rodent studies - but chronic TREK-1 blockade in humans has never been evaluated. Conservative community practice is to cycle rather than dose continuously. [PMID:28955242] Can I combine PE-22-28 with my antidepressant medication? Not without talking to the prescriber first. PE-22-28's proposed mechanism (TREK-1 blockade with downstream serotonergic and neurogenic effects) overlaps conceptually with how antidepressants act, so combining it with SSRIs, SNRIs, tricyclics, MAOIs, lithium, or ketamine could have additive or unpredictable effects that have never been studied. Do not stop or replace a prescribed medication with PE-22-28, and keep regular psychiatric follow-up. [PMID:28955242] What are the main side effects of PE-22-28? No side effects are documented in humans because no trials have been done. In practice the most concrete risks are those of any injected research peptide: injection-site reactions and flu-like symptoms from endotoxin/pyrogen contamination or from impure or mislabeled material. Paradoxical worsening of mood or anxiety is possible with any centrally acting compound, especially in people with bipolar or psychotic vulnerability. [PMID:28955242] Can PE-22-28 be used for anxiety, not just depression? It has only been studied as an antidepressant candidate in rodents; there are no controlled data for anxiety. TREK-1 does have roles in mood and neuronal excitability, so an effect on anxiety is conceivable, but community reports are mixed and unverified. Significant anxiety disorders should be treated with evidence-based care rather than an unvalidated peptide. [PMID:28955242] Is PE-22-28 worth trying given the limited evidence? That is a personal risk decision, and the honest answer is that the evidence is thin: promising, mechanistically coherent rodent data from a single research group, no human trials, and an unregulated supply chain of variable quality. For anyone with more than mild, subclinical mood complaints - and certainly for moderate-to-severe or unstable depression - established care (therapy, approved medication, sleep, exercise) is the appropriate path, and PE-22-28 is not a substitute. Anyone who does experiment should use tested material, keep expectations realistic, and be prepared to conclude it does nothing. [PMID:28955242] ## Research Tools ### Peptide Calculator Reconstitution & syringe units https://www.bodyhackguide.co/tools/reconstitution ### Reconstitution Guide How to mix, step by step https://www.bodyhackguide.co/guides/how-to-reconstitute-peptides ### Nasal Spray Calc mL per actuation https://www.bodyhackguide.co/tools/intranasal ### Half-Life Visualizer Decay curves https://www.bodyhackguide.co/tools/halflife ## Related Compounds ### 9-Me-BC (9-Methyl-β-carboline) Nootropics Preclinical ### Aniracetam Nootropics Approved (Italy) ### Bemethyl (bemitil) Nootropics Approved (Russia) ### Bromantane Nootropics Russia Approved ### Cyclazodone Nootropics Preclinical ### Dihexa Nootropics Preclinical Free 2026 Peptide Cheat Sheet (PDF) 38 compounds and blends: vial sizes, BAC water volumes, dosing ranges and bloodwork markers. Download Free (https://www.bodyhackguide.co/guides/peptide-cheat-sheet-download) ### Need bloodwork before starting? 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Image: BodyHackGuide (https://www.bodyhackguide.co/assets/bodyhackguide-logo-DOzZNUyh.webp) ### BodyHackGuide Your biohacking research hub: compound pricing, brain health protocols, dosing tools, and vendor reviews. support@bodyhackguide.co Join our Discord: https://discord.gg/Mhq5UdRYBA r/BodyHackGuide on Reddit: https://reddit.com/r/BodyHackGuide #### Explore - Compare prices: https://www.bodyhackguide.co/compare - Vendors: https://www.bodyhackguide.co/vendors - Deals: https://www.bodyhackguide.co/deals - Coupons: https://www.bodyhackguide.co/coupons - Nootropics: https://www.bodyhackguide.co/nootropics - Brain health: https://www.bodyhackguide.co/brain-health - Blog: https://www.bodyhackguide.co/blog - Guides: https://www.bodyhackguide.co/guides #### Tools - Reconstitution: https://www.bodyhackguide.co/tools/reconstitution - Half-life visualizer: https://www.bodyhackguide.co/tools/halflife - COA reader: https://www.bodyhackguide.co/tools/coa - Cost calculator: https://www.bodyhackguide.co/tools/cost-calculator - Stack builder: https://www.bodyhackguide.co/stack-builder - All tools: https://www.bodyhackguide.co/tools #### Trust & vendors - Vendor directory: https://www.bodyhackguide.co/vendors - Trust scorecard: https://www.bodyhackguide.co/vendors/scorecard - Vendor trust badge: https://www.bodyhackguide.co/vendors/get-vetted - Scoring methodology: https://www.bodyhackguide.co/vendors/methodology - Peptide cheat sheet: https://www.bodyhackguide.co/guides/peptide-cheat-sheet-download #### Company - About: https://www.bodyhackguide.co/about - Affiliate disclosure: https://www.bodyhackguide.co/affiliate-disclosure - Editorial standards: https://www.bodyhackguide.co/editorial-standards - Creators: https://www.bodyhackguide.co/creators - Coaches: https://www.bodyhackguide.co/coaches - 1-on-1 coaching: https://www.bodyhackguide.co/coaching - Privacy: https://www.bodyhackguide.co/privacy - Terms: https://www.bodyhackguide.co/terms - Full site directory: https://www.bodyhackguide.co/site-directory **Affiliate Disclosure:** We rank every vendor on the same public, reproducible methodology (https://www.bodyhackguide.co/vendors/methodology), and we earn a commission from purchases made through some of our links at no extra cost to you. 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All rights reserved. · Terms (https://www.bodyhackguide.co/terms) · Privacy (https://www.bodyhackguide.co/privacy) ## Structured data ```json [ { "@context": "https://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": 1, "name": "Home", "item": "https://www.bodyhackguide.co/" }, { "@type": "ListItem", "position": 2, "name": "Compounds", "item": "https://www.bodyhackguide.co/compare" }, { "@type": "ListItem", "position": 3, "name": "PE-22-28" } ] }, { "@context": "https://schema.org", "@type": "Product", "name": "PE-22-28", "description": "PE-22-28 is a synthetic seven-amino-acid peptide (sequence PAGASRLLLLTGEIDLP derivative, commonly truncated to PE-22-28 as shorthand for \"position 22-28\" within the parent humanin-family sequence) that was designed as an analog of Humanin with specific interest in activity at glutamate transporter regulation and cytoprotective signaling relevant to depression and neuroprotection. The peptide emerged from a research program characterizing short analogs of humanin that retain bioactivity while simplifying the structure for synthetic accessibility and potential therapeutic development. PE-22-28 specifically attracted attention when preclinical work suggested antidepressant-like activity in rodent models of depression, with a proposed mechanism involving glial cell modulation and glutamate transporter 1 (GLT-1/EAAT2) regulation. The compound sits in the broader field of peptide-based neuropsychiatric therapeutics, alongside compounds like Selank and Semax that have been used in Russia for decades but remain investigational in Western markets. PE-22-28 is distinctive within this space because of its mechanistic grounding in humanin biology and glutamate homeostasis, which connects it to contemporary understanding of depression pathophysiology that emphasizes the role of glutamatergic signaling, astrocyte function, and neuroinflammation alongside the classical monoamine framework. The practical reality in April 2026 is that PE-22-28 remains a preclinical research peptide with limited published literature, no approved human use, no registered clinical trials, and a small but active self-experimentation community among biohackers interested in short peptide therapeutics for mood and cognitive applications. The compound is sold by research-chemical peptide vendors with the standard \"for research purposes only\" framing, and individual users have accumulated anecdotal experience with it in protocols typically involving daily or every-other-day subcutaneous dosing. 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The evidence base for PE-22-28 is substantially thinner than for BPC-157, Selank, or Semax in terms of published animal studies and translational groundwork; the peptide's profile rests on specific rodent behavioral studies and mechanistic biology inferred from its relationship to humanin and its proposed interactions with glutamate transporter regulation. This entry covers what is published about the peptide, the mechanistic rationale connecting it to humanin biology and glutamate homeostasis, the specific preclinical behavioral data that sparked interest in depression applications, realistic interpretation of that data in the context of the replication crisis in preclinical depression research, the theoretical and practical concerns with self-administration of a minimally characterized peptide, how PE-22-28 fits into the peptide stacking landscape alongside other cytoprotective and neuropsychiatric peptides, and what conservative thinking about this molecule looks like for someone considering it seriously rather than as a novelty.", "lastReviewed": "2026-05-04T11:35:45.136+00:00", "url": "https://www.bodyhackguide.co/compound/pe-22-28", "author": { "@type": "Person", "name": "BioChonch", "url": "https://www.bodyhackguide.co/about", "jobTitle": "Founder & Lead Researcher", "sameAs": [ "https://reddit.com/r/BodyHackGuide", "https://reddit.com/r/BrainHackGuide", "https://reddit.com/r/Biohackingher" ], "worksFor": { "@type": "Organization", "name": "BodyHackGuide", "url": "https://www.bodyhackguide.co" } }, "reviewedBy": { "@type": "Person", "name": "BioChonch", "url": "https://www.bodyhackguide.co/about", "jobTitle": "Founder & Lead Researcher", "sameAs": [ "https://reddit.com/r/BodyHackGuide", "https://reddit.com/r/BrainHackGuide", "https://reddit.com/r/Biohackingher" ], "worksFor": { "@type": "Organization", "name": "BodyHackGuide", "url": "https://www.bodyhackguide.co" } }, "publisher": { "@type": "Organization", "name": "BodyHackGuide", "url": "https://www.bodyhackguide.co" }, "mainContentOfPage": { "@type": "WebPageElement", "cssSelector": "main" }, "about": { "@type": "Drug", "name": "PE-22-28", "alternateName": [ "PE2228" ], "description": "PE-22-28 is a synthetic seven-amino-acid peptide (sequence PAGASRLLLLTGEIDLP derivative, commonly truncated to PE-22-28 as shorthand for \"position 22-28\" within the parent humanin-family sequence) that was designed as an analog of Humanin with specific interest in activity at glutamate transporter regulation and cytoprotective signaling relevant to depression and neuroprotection. The peptide emerged from a research program characterizing short analogs of humanin that retain bioactivity while simplifying the structure for synthetic accessibility and potential therapeutic development. PE-22-28 specifically attracted attention when preclinical work suggested antidepressant-like activity in rodent models of depression, with a proposed mechanism involving glial cell modulation and glutamate transporter 1 (GLT-1/EAAT2) regulation. The compound sits in the broader field of peptide-based neuropsychiatric therapeutics, alongside compounds like Selank and Semax that have been used in Russia for decades but remain investigational in Western markets. PE-22-28 is distinctive within this space because of its mechanistic grounding in humanin biology and glutamate homeostasis, which connects it to contemporary understanding of depression pathophysiology that emphasizes the role of glutamatergic signaling, astrocyte function, and neuroinflammation alongside the classical monoamine framework. The practical reality in April 2026 is that PE-22-28 remains a preclinical research peptide with limited published literature, no approved human use, no registered clinical trials, and a small but active self-experimentation community among biohackers interested in short peptide therapeutics for mood and cognitive applications. The compound is sold by research-chemical peptide vendors with the standard \"for research purposes only\" framing, and individual users have accumulated anecdotal experience with it in protocols typically involving daily or every-other-day subcutaneous dosing. The evidence base for PE-22-28 is substantially thinner than for BPC-157, Selank, or Semax in terms of published animal studies and translational groundwork; the peptide's profile rests on specific rodent behavioral studies and mechanistic biology inferred from its relationship to humanin and its proposed interactions with glutamate transporter regulation. This entry covers what is published about the peptide, the mechanistic rationale connecting it to humanin biology and glutamate homeostasis, the specific preclinical behavioral data that sparked interest in depression applications, realistic interpretation of that data in the context of the replication crisis in preclinical depression research, the theoretical and practical concerns with self-administration of a minimally characterized peptide, how PE-22-28 fits into the peptide stacking landscape alongside other cytoprotective and neuropsychiatric peptides, and what conservative thinking about this molecule looks like for someone considering it seriously rather than as a novelty.", "activeIngredient": "PE-22-28", "mechanismOfAction": "PE-22-28 is a synthetic 7-amino-acid peptide (sequence GVSWGLR) and a shortened analog of spadin. Its proposed mechanism is inhibition of the TREK-1 (TWIK-related K+) channel, a two-pore-domain potassium channel (K2P2.1 / KCNK2) implicated in mood regulation. It is not related to humanin and is not a mitochondrial-derived peptide. Spadin itself (PE 12-28, a 17-amino-acid peptide) is a natural fragment released when sortilin - also called neurotensin receptor-3 (NTSR3) - is cleaved by furin to its mature form, liberating a 44-amino-acid propeptide (PE); spadin corresponds to residues 12-28 of that propeptide and blocks TREK-1 PMID:20405001. Working from spadin's blood-degradation products, Djillani and colleagues identified PE 22-28 (residues 22-28) as the shortest fragment that still blocks TREK-1, and found it is actually more potent and more selective than spadin, with an IC50 near 0.12 nM versus roughly 40-60 nM for spadin [PMID:28955242]. TREK-1 is a background (\"leak\") potassium channel that helps set and stabilize the resting membrane potential of neurons. In mice, genetic deletion of the TREK-1 gene produces a depression-resistant phenotype with enhanced serotonergic neurotransmission and increased hippocampal neurogenesis, which is the rationale for treating depression by pharmacologically blocking TREK-1 PMID:28955242. By inhibiting TREK-1, PE-22-28 is proposed to increase the firing of serotonergic neurons (spadin raised 5-HT firing in the dorsal raphe) and, over a few days, to drive hippocampal neurogenesis, cortical synaptogenesis (increased PSD-95), and a rapid rise in BDNF expression - the same downstream markers linked to spadin's fast-onset antidepressant action PMID:28955242. Importantly, in patch-clamp screens PE-22-28 was selective for TREK-1: it did not inhibit the related K2P channels TREK-2, TRAAK, TRESK or TASK-1, and it had no effect on the cardiac hERG channel, which the authors argue should limit off-target and cardiac liability [PMID:28955242]. All of this mechanistic evidence is preclinical (cell lines and mice); PE-22-28's targets, tissue distribution and blood-brain-barrier penetration have not been characterized in humans, so \"proposed mechanism\" remains a weaker claim than \"demonstrated mechanism.\"", "dosageForm": "vial", "legalStatus": "Not approved for human use (research chemical)", "warning": "For research purposes only. Not for human consumption." } }, { "@context": "https://schema.org", "@type": "FAQPage", "mainEntity": [ { "@type": "Question", "name": "What is PE-22-28 and how is it related to spadin?", "acceptedAnswer": { "@type": "Answer", "text": "PE-22-28 is a synthetic 7-amino-acid peptide (sequence GVSWGLR) and a shortened analog of spadin. Spadin (PE 12-28) is a natural 17-amino-acid fragment released when the receptor sortilin (neurotensin receptor-3) is processed, and it blocks the TREK-1 potassium channel. Researchers found PE-22-28 among spadin's breakdown fragments and showed it is the shortest piece that still blocks TREK-1 - and is actually more potent and more selective than spadin. It has been studied only in cells and mice as a fast-acting antidepressant candidate. It is not related to humanin. [PMID:28955242]" } }, { "@type": "Question", "name": "Has PE-22-28 been tested in humans?", "acceptedAnswer": { "@type": "Answer", "text": "No. As of 2026 there are no published human trials of PE-22-28, no ClinicalTrials.gov registrations, and no human pharmacokinetic, safety or efficacy data. All evidence is preclinical (cell lines and mice), and all human use is self-experimentation with research-chemical vendor material. [PMID:28955242]" } }, { "@type": "Question", "name": "How does PE-22-28 work for depression?", "acceptedAnswer": { "@type": "Answer", "text": "Its proposed mechanism is blockade of the TREK-1 (K2P2.1) potassium channel. In mice, removing TREK-1 produces a depression-resistant, pro-serotonergic phenotype, so blocking the channel pharmacologically is thought to be antidepressant. PE-22-28 inhibits TREK-1 with an IC50 near 0.12 nM (more potent than spadin), and in rodents a few days of dosing increases hippocampal neurogenesis, cortical synaptogenesis and BDNF - a rapid-onset pattern unlike the multi-week lag of SSRIs. This is a plausible, preclinically supported mechanism, but human efficacy has not been demonstrated. PMID:28955242" } }, { "@type": "Question", "name": "What dose of PE-22-28 is typically used?", "acceptedAnswer": { "@type": "Answer", "text": "There is no clinically validated dose. Effective rodent doses were very low (around 3 micrograms per kilogram, injected). Research-chemical community protocols instead use fixed doses in the range of roughly 250-2000 micrograms per injection, subcutaneously, once daily or every other day - figures that are empirical and not derived from human studies. Because no human pharmacokinetic data exist, all of these numbers should be treated as unvalidated. [PMID:28955242]" } }, { "@type": "Question", "name": "How long before PE-22-28 effects are noticeable?", "acceptedAnswer": { "@type": "Answer", "text": "In rodents, the antidepressant-type effects and the neurogenesis that accompanies them developed over about 4 days of dosing rather than after a single dose, and the parent peptide's behavioral effect was relatively short-lived per dose. Community self-reports vary widely - some describe changes within days, others none at all. Any human onset timing is anecdotal, since there are no controlled human data. [PMID:28955242]" } }, { "@type": "Question", "name": "Is PE-22-28 safe for long-term use?", "acceptedAnswer": { "@type": "Answer", "text": "Unknown. There are no long-term safety data in humans and no extended toxicology studies. The preclinical appeal is that PE-22-28 was selective for TREK-1 and did not affect the cardiac hERG channel or several related potassium channels, and spadin analogs showed no obvious effects on pain, seizures or heart function in short rodent studies - but chronic TREK-1 blockade in humans has never been evaluated. Conservative community practice is to cycle rather than dose continuously. [PMID:28955242]" } }, { "@type": "Question", "name": "Can I combine PE-22-28 with my antidepressant medication?", "acceptedAnswer": { "@type": "Answer", "text": "Not without talking to the prescriber first. PE-22-28's proposed mechanism (TREK-1 blockade with downstream serotonergic and neurogenic effects) overlaps conceptually with how antidepressants act, so combining it with SSRIs, SNRIs, tricyclics, MAOIs, lithium, or ketamine could have additive or unpredictable effects that have never been studied. Do not stop or replace a prescribed medication with PE-22-28, and keep regular psychiatric follow-up. [PMID:28955242]" } }, { "@type": "Question", "name": "What are the main side effects of PE-22-28?", "acceptedAnswer": { "@type": "Answer", "text": "No side effects are documented in humans because no trials have been done. In practice the most concrete risks are those of any injected research peptide: injection-site reactions and flu-like symptoms from endotoxin/pyrogen contamination or from impure or mislabeled material. Paradoxical worsening of mood or anxiety is possible with any centrally acting compound, especially in people with bipolar or psychotic vulnerability. [PMID:28955242]" } }, { "@type": "Question", "name": "Can PE-22-28 be used for anxiety, not just depression?", "acceptedAnswer": { "@type": "Answer", "text": "It has only been studied as an antidepressant candidate in rodents; there are no controlled data for anxiety. TREK-1 does have roles in mood and neuronal excitability, so an effect on anxiety is conceivable, but community reports are mixed and unverified. Significant anxiety disorders should be treated with evidence-based care rather than an unvalidated peptide. [PMID:28955242]" } }, { "@type": "Question", "name": "Is PE-22-28 worth trying given the limited evidence?", "acceptedAnswer": { "@type": "Answer", "text": "That is a personal risk decision, and the honest answer is that the evidence is thin: promising, mechanistically coherent rodent data from a single research group, no human trials, and an unregulated supply chain of variable quality. For anyone with more than mild, subclinical mood complaints - and certainly for moderate-to-severe or unstable depression - established care (therapy, approved medication, sleep, exercise) is the appropriate path, and PE-22-28 is not a substitute. Anyone who does experiment should use tested material, keep expectations realistic, and be prepared to conclude it does nothing. [PMID:28955242]" } } ] }, { "@context": "https://schema.org", "@type": "Organization", "@id": "https://www.bodyhackguide.co#organization", "name": "BodyHackGuide", "alternateName": "BHG", "url": "https://www.bodyhackguide.co", "logo": { "@type": "ImageObject", "url": "https://www.bodyhackguide.co/logo.png", "width": 512, "height": 512 }, "description": "Evidence-based research reference for peptides and nootropics. 124+ compound profiles, interactive dosing calculators, vendor price comparisons, and trust-scored vendor reviews scored on a public, reproducible methodology applied to every vendor. We earn a commission on purchases through some of our links.", "foundingDate": "2024", "founder": { "@id": "https://www.bodyhackguide.co/about#person" }, "sameAs": [ "https://reddit.com/r/BodyHackGuide", "https://reddit.com/r/BrainHackGuide", "https://reddit.com/r/Biohackingher", "https://discord.gg/Mhq5UdRYBA" ], "knowsAbout": [ "Peptide research", "Nootropic research", "Biohacking", "Compound dosing", "Vendor transparency" ], "publishingPrinciples": "https://www.bodyhackguide.co/editorial-standards", "ethicsPolicy": "https://www.bodyhackguide.co/editorial-standards", "diversityPolicy": "https://www.bodyhackguide.co/editorial-standards" } ] ```