Pinealon Guide: Evidence, Sourcing & Protocol Sheet

Pinealon at a glance

What it is

Synthetic tripeptide H-Glu-Asp-Arg-OH (EDR), CAS 175175-23-2, C15H26N6O8, average MW 418.40 Da. A "short peptide bioregulator" from Vladimir Khavinson's St. Petersburg group. The originating tradition describes EDR as an active fragment derived from Cortexin, a Russian cerebral-cortex preparation; that attribution is repeated throughout the vendor and review literature, but no independent fragment-isolation paper establishing it appears to be available in English, so it is best read as an attribution of the originating group rather than a documented finding.

Name correction

Not a pineal or melatonin peptide despite the "Pineal-" prefix. The pineal compounds in this tradition are Epithalamin, Epitalon/Epithalon (AEDG) and Endoluten. Pinealon's entire published pharmacology is cortical and CNS-focused.

Researched for

Reduction of reactive oxygen species in neuronal and immune cell models, resistance to hypoxic stress, learning and memory endpoints in rodent water-maze work, and dendritic-spine preservation in in-vitro Alzheimer's models.

Doses actually studied

The rodent behavioural work used 50, 100 and 200 ng per kilogram of body weight (Karantysh et al., Neurochemical Journal 2020;14(3):314-320). Other rodent protocols are reported at roughly 10-100 mcg per animal — a per-animal figure rather than a per-kilogram one, which for a ~250 g rat corresponds to roughly 40-400 mcg/kg, far above the ng/kg behavioural doses. Mouse work in the same tradition has used intraperitoneal doses in the hundreds of mcg/kg range. The published rodent range is therefore extremely wide, and the figures are not comparable across studies without normalising for body weight.

Evidence status

Animal and in-vitro work, plus a small body of uncontrolled Russian human observation — a 32-patient geroprotection series and a 72-patient traumatic-brain-injury series cited second-hand — generated almost entirely by one research tradition. No randomised controlled trial has been published, no registration was located on ClinicalTrials.gov or the WHO ICTRP, and no independent Western laboratory appears to have replicated the core mechanistic claim.

Regulatory status

Not approved by FDA for any indication, and not approved as a drug in any major regulated market. Not marketed as a dietary supplement in the US, and peptides of this type are generally not accepted by FDA as lawful dietary-supplement ingredients. Not a controlled substance under the CSA. Not eligible for lawful compounding under section 503A; US policy on peptide compounding has been revised repeatedly, and the current position is best checked against FDA's own published guidance. Sold in the US under research-use-only labelling. Not named on WADA's Prohibited List, but the Section S0 (Non-Approved Substances) definition appears to capture it, so the prudent reading for tested athletes is that it is prohibited, with status confirmed through the relevant anti-doping organisation.

Educational reference. This page does not publish dose ranges or reconstitution arithmetic.

What it is / mechanism

Pinealon is about as small as a bioactive peptide gets: three residues — glutamic acid, aspartic acid, arginine — with an average molecular weight of 418.40 Da (C15H26N6O8, CAS 175175-23-2). It comes from the research programme Vladimir Khavinson's group ran at the St. Petersburg Institute of Bioregulation and Gerontology, which set out to synthesise ultrashort (2-4 residue) peptides that would reproduce the activity of organ-derived peptide extracts. EDR is described in that tradition as an active fragment derived from Cortexin, a cerebral-cortex preparation used clinically in Russia. That attribution is worth flagging as an attribution: it is repeated consistently across the review and vendor literature, but a primary fragment-isolation paper demonstrating it does not appear to be available in English, and other cortex-associated short peptides exist in the same line (Cortagen, Ala-Glu-Asp-Pro). It should be read as the originating group's account rather than an independently documented identification. Before anything else, the naming needs clearing up, because it drives a large share of the search traffic for this compound: Pinealon is not the pineal peptide. The pineal members of this family are Epithalamin (the natural extract), Epitalon/Epithalon (the AEDG tetrapeptide) and the Endoluten capsule. Pinealon's published pharmacology is cortical and neuroprotective from end to end. Nothing in it concerns melatonin synthesis or circadian timing. The proposed mechanism — and it should be read as a hypothesis advanced by one research tradition, not as established pharmacology — is that a peptide this small can cross both the plasma membrane and the nuclear envelope without a dedicated transporter, bind sequence-selectively to promoter-region DNA and/or to histone proteins, and thereby de-repress transcription of genes supporting neuronal function, antioxidant defence and synaptic maintenance. The supporting work is largely internal to the same tradition. Silanteva and colleagues (J Phys Chem B, 2019) published molecular-dynamics simulations of Glu-Asp-Arg interacting with DNA, including the role of mono- and divalent ions in that binding. Fedoreyeva and colleagues (Biochemistry (Moscow), 2011) reported fluorescence-labelled short peptides entering HeLa cell nuclei with what they described as sequence-specific interaction. Khavinson's group also published computational modelling of cellular uptake for 26 ultrashort peptides via the PEPT and LAT transporter families (Biomolecules, 2023) — that paper is in silico only, with no wet-lab transport confirmation for EDR specifically. The downstream effects that have actually been measured are more concrete, and mostly sit in cell culture and rodents. The foundational paper (Khavinson et al., Rejuvenation Research, 2011;14(5):535-41) reported dose-dependent restriction of ROS accumulation in rat cerebellar granule cells, zymosan-activated neutrophils and PC12 pheochromocytoma cells, with reduced necrotic death on propidium-iodide assay, alongside a delayed time-course of ERK1/2 activation and modification of cell-cycle progression. The authors built a specific argument out of a dissociation in that data: the ROS and mortality effects saturated at low concentrations while the cell-cycle effects continued to change at higher concentrations, which they read as evidence of a direct genomic action rather than simple radical-scavenging chemistry. Other reported findings include increased superoxide dismutase 2 and glutathione peroxidase 1 activity in hypoxia-sensitive rats — reportedly rising toward the levels seen natively in hypoxia-resistant animals — reduced brain caspase-3 activity and modulated serum cytokines in aged rats under acute hypoxic hypoxia, restoration of dendritic-spine number in an in-vitro Alzheimer's model (Kraskovskaya et al., Bull Exp Biol Med, 2017), prevention of dendritic-spine loss in 5xFAD transgenic mice alongside a second tripeptide (Khavinson et al., Pharmaceuticals, 2021;14(6):515), protection of fibroblast-derived induced neurons from age-related changes (Kraskovskaya et al., Int J Mol Sci, 2024), and altered hippocampal NMDA-receptor subunit gene expression in experimentally diabetic rats (Karantysh et al., Neurochemical Journal, 2020;14(3):314-320). The honest caveat has to be stated plainly, because almost no commercial page states it. The model in which a free, unmodified tripeptide survives plasma aminopeptidases, crosses the blood-brain barrier, enters the nucleus and produces sequence-selective gene regulation at nanogram-per-kilogram doses is regarded by mainstream pharmacology as highly implausible on first principles, and no independent Western laboratory appears to have replicated the core claim. There is a related mechanistic problem with the oral capsule format used in the Russian human reports: an unprotected tripeptide should be very largely destroyed by gastric and brush-border peptidases before absorption. That is not a resolved question in the literature — it is an open one, and it should be understood as open. To be equally precise in the other direction: no retraction or expression of concern was identified in connection with the Pinealon literature or with Khavinson's Pinealon papers, and no formal misconduct finding was identified. One ordinary post-publication figure correction was issued for the 2021 transgenic-mouse paper, which the authors state does not affect its conclusions; that is a routine correction, not an integrity finding. The criticism here concerns study design, source independence and prior plausibility. It is not an allegation of fraud.

Researched effects

What the published work reports, ordered by how well it is supported: the most reproducible findings are cellular. Pinealon restricted ROS accumulation and necrotic death in cultured neurons, neutrophils and PC12 cells in a dose-dependent way, and in the same experiments altered ERK1/2 signalling kinetics and cell-cycle progression. In rodents, the recurring theme is stress tolerance rather than baseline enhancement: animals given Pinealon before or during hypoxic, hypothermic or hyperhomocysteinemic challenge performed better on behavioural endpoints and showed better antioxidant-enzyme profiles than untreated controls. The Morris water maze work at 50, 100 and 200 ng/kg (Karantysh et al., Neurochemical Journal, 2020;14(3):314-320) reported dose-dependent effects on acquisition and retention of a learned skill, with 100 ng/kg described as most favourable for skill retention after streptozotocin-induced diabetes and associated with the smallest shifts in hippocampal NMDA-receptor subunit expression. Related work from the same Rostov group examined aged rats under acute hypoxic hypoxia and hypothermia. In the prenatal hyperhomocysteinemia model (Arutjunyan, Kozina et al., Int J Clin Exp Med, 2012;5(2):179-85), maternal methionine loading impaired offspring spatial orientation and learning, and Pinealon administration improved those outcomes while reducing ROS accumulation and necrotic cell counts in isolated cerebellar neurons. What users report is a different category of information entirely and should be treated as such. In research and biohacking communities, the commonly described subjective effects are improved mental clarity or reduced brain fog, better focus and working memory during demanding cognitive work, subjectively faster recovery from sleep deprivation or stress, and a general calm alertness. None of these has been measured under blinded conditions in humans. There is no placebo-controlled data on Pinealon, and any subjective effect at these dose levels, on a compound with no measured pharmacokinetics, is an unusually good candidate for expectancy effects. A specific point worth being direct about: a large share of consumer interest in Pinealon is sleep-related, and there is no direct evidence for a sleep or circadian effect. That search interest appears to rest on confusion with Epitalon, which is the pineal peptide in this family. Where the underlying interest is sleep, Pinealon is not the compound the literature points toward. On evidence quality, the classification for this compound is preclinical — animal and in-vitro — with a small body of uncontrolled human observation attached to it, and that human material needs to be described accurately rather than upgraded. No randomised controlled trial of Pinealon has been published in any population, no registration was located on ClinicalTrials.gov or the WHO ICTRP, and nothing appears in a major Western clinical journal. What exists is a small body of low-grade, mostly uncontrolled reports in Advances in Gerontology, a Russian gerontology journal, plus a 72-patient series of traumatic brain injury sequelae and cerebrasthenia treated with oral Pinealon — reporting improved memory, shorter and less intense headaches, better emotional balance and an increased EEG alpha index — which is cited second-hand inside the Khavinson hypothesis review and whose Russian-language primary source could not be independently verified in English. That series is an uncontrolled clinical observation. It is routinely presented by vendors as if it were a trial result. It is not one, and this guide does not present it as one.

Half-life & pharmacokinetics

No published pharmacokinetic data exist for Pinealon in any species. There is no measured plasma half-life, no bioavailability figure, no Cmax or Tmax, no volume of distribution, and no direct measurement of blood-brain-barrier penetration. The Khavinson group's own EDR mechanism review (Molecules 2021;26(1):159), the most detailed mechanistic paper on this peptide, provides none of these. Any specific half-life number appearing on a vendor page or a "peptide database" site — whether the commonly quoted 20-30 minutes or the occasional claim of "over 24 hours" — is unsourced. Those numbers were not measured. What can be said honestly is general pharmacology rather than compound-specific data. Unmodified linear tripeptides circulating in plasma are substrates for aminopeptidases and carboxypeptidases and are typically cleared within single-digit to low-double-digit minutes. The Khavinson group's own position is consistent with that: they hold that the parent peptide's plasma residence is brief and that any effects are downstream of a transcriptional event and therefore outlast the molecule. That claim is internally coherent with their epigenetic hypothesis, but it has not been directly demonstrated for EDR. Tritium-labelling methodology for tracking short-peptide biodegradation does exist in the Russian literature — it has been applied to Selank and to PGP — but it does not appear to have been published for Pinealon. The practical implication is worth stating explicitly: half-life cannot be used to justify any dosing frequency for this compound, because there is no half-life on record. The once-daily convention is inherited from the category, not derived from exposure data. Claims that Pinealon must be dosed daily because of its short half-life rest on a number that does not exist in the published literature.

Storage & handling

• Lyophilised (unreconstituted) vials are stored refrigerated at 2-8°C, or frozen at -20°C for long-term storage, protected from light. Sealed lyophilised peptide powder is generally described as tolerating several days at ambient temperature without meaningful degradation, which is the reason vials in this category are commonly shipped without cold packs. That is a general property of freeze-dried peptides rather than an assurance about any particular vendor's material, whose handling and condition on arrival cannot be verified from the outside.
• After reconstitution with bacteriostatic water, vials are refrigerated at 2-8°C and kept there. The benzyl alcohol preservative in USP-grade bacteriostatic water supports multi-dose use for up to 28 days from first puncture per USP and manufacturer labelling, which is the practical in-use window for a reconstituted vial.
• Reconstituted solution is not frozen and is not shaken at any point. Freeze-thaw cycling and mechanical agitation both denature peptides in solution; gentle swirling is the only agitation described as appropriate.
• Reconstituted vials are protected from light — commonly kept in the original box or a dark container on a refrigerator shelf rather than in the door, where temperature swings with every opening.
• Standard laboratory practice is to label each vial with the reconstitution date, the volume of water added and the resulting concentration in mg/mL at the time of mixing. At 5-10 mg/mL with single-digit-unit draws, an unlabelled vial is a dosing error waiting to happen, and no visual inspection can establish the concentration afterwards.

Evidence File

The Pinealon Evidence File: Twenty-Two Records, Six Human Reports, and Every Circulating Figure Traced

The free guide states that Pinealon's human evidence is small, uncontrolled and Russian. This file is that evidence, enumerated. Every record indexed under the compound name is listed and classified, the human reports are inventoried one by one with their designs and their own internal arithmetic checked, and each figure that circulates as clinical proof is followed back through its citation chain to the document it actually came from. The registry searches, the full-text term scans and the indexing checks that establish what has never been studied are named individually, so every absence in this file can be re-run rather than taken on trust.

• 22 records make up the entire PubMed literature indexed under the term Pinealon
• Six Russian-language human reports, none randomised, blinded or placebo-controlled
• One published human dose regimen exists in the whole corpus
• No interventional registration on ClinicalTrials.gov under any name, sequence or CAS

Sourcing File

The Pinealon Sourcing File: Six Sequences That Weigh the Same, a UNII That Does Not Exist, and the Salt-Mass Gap

A Pinealon certificate can carry the right CAS number, the right molecular formula, a purity figure above 98 percent and a molecular ion in exactly the right place, and still describe material that is not Pinealon. This file works out why, from identity numbers fetched directly from PubChem: which mass an instrument should actually report and which one it should not, which related molecules are indistinguishable by mass and which are trivially separable, what a label mass means once a counterion is present, and which single registry field should never appear on this compound's paperwork at all. It closes with a line-by-line read of a specimen document.

• 419.19 is the [M+H]+ mass an ESI trace should show, not the 418.40 catalogue average
• All six orderings of Glu, Asp and Arg share one monoisotopic mass to eight decimals
• No UNII exists: the FDA GSRS registry holds no Pinealon substance record
• A TFA salt label can mean 21 to 35 percent less peptide than the stated mass

Benefit & Outcome Review

The Pinealon Benefit and Outcome Review: Seven Head-to-Heads, Four Losses, and the Sentences the Authors Wrote About Their Own Mechanism

Pinealon has been tested directly against another named compound far more often than its marketing suggests, and the results are not uniform. This review scores every circulating claim against the published record at the tier where evidence actually exists, keeping human separate from animal, animal separate from cell culture, and cell culture separate from computer modelling. It reports the effect sizes and p-values where the authors published them, the nulls they published alongside them, and the sentences in which the originating group qualifies its own central mechanism. It closes by comparing the three dose regimens that appear anywhere in print.

• Seven head-to-head comparisons against a named compound, and Pinealon lost four
• No study in any species has measured melatonin, sleep or a circadian endpoint
• In the 5xFAD mouse the mushroom-spine endpoint did not move, at p = 0.053
• The two published in-vivo regimens sit a thousandfold apart once scaled to human

Guide FAQ

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