Pinealon (EDR): Evidence Review & Dose Reality Check

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.

Commonly reported community range

1-2 mg once daily subcutaneously (a minority report 5-10 mg/day); oral capsules approximately 1-20 mg/day in the Khavinson consumer line. These figures come from vendor and community convention, not from any dose-finding study. Scaled by body weight, they sit roughly 70 to 570 times above the rodent behavioural doses — two orders of magnitude at the conservative end and approaching three at the wide end. The dosage section sets out the full calculation.

Routes reported

Subcutaneous injection after reconstitution (the dominant US research-use-only format, in 10 mg and 20 mg lyophilised vials); intranasal spray; and oral capsules, which is the format used in the small Russian human observations.

Reported frequency and cycle

Once daily for 10-20 days (sometimes extended to 28), repeated every 2-3 months or 2-4 times yearly. No pharmacokinetic basis exists for daily dosing — the schedule is conventional, not derived from exposure data.

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.

Reported ranges from research/community — examples, not recommendations.

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.

Dosage — reported ranges (overview)

There is no established human dose for Pinealon by any route. That sentence is the most important one in this section, and everything below describes what has been published or reported — it is not a recommendation, a protocol, or a statement that any of these amounts is effective or safe. The doses that produced the published cognitive and neuroprotective effects were tiny. The rodent behavioural work (Karantysh et al., Neurochemical Journal, 2020;14(3):314-320) used 50, 100 and 200 ng per kilogram of body weight. Some other rodent protocols are reported at roughly 10-100 mcg per animal, and that figure needs handling carefully: it is a per-animal amount, not per-kilogram, and for a ~250 g rat it works out to roughly 40-400 mcg/kg — far above the ng/kg behavioural doses and, on a body-weight basis, above the ~14 mcg/kg that a 1 mg dose represents in a 70 kg human. Mouse work in the same tradition has used intraperitoneal administration in the hundreds of mcg/kg range. The published rodent range is therefore very wide, and any comparison between rodent and human amounts is meaningless unless both are normalised to body weight. The dose-gap argument that follows concerns specifically the ng/kg behavioural work, which is the source of the cognition and neuroprotection claims that drive interest in this compound. What the RUO and community world actually does looks nothing like those ng/kg figures. The most commonly reported injection practice is 1-2 mg once daily subcutaneously, taken in the morning or early afternoon, for a 10-20 day cycle (sometimes extended to 28 days), repeated every 2-3 months or 2-4 times per year. Some protocol sites publish a titration example of 1.0 mg on days 1-5, 1.5 mg on days 6-14 and 2.0 mg on days 15-20. A minority of community sources report 5-10 mg/day. Intranasal dosing is also reported, usually at lower per-dose amounts. The oral Khavinson capsule line — the format actually used in the Russian human observations — runs approximately 1-20 mg/day across 10-30 day courses, repeated 2-4 times yearly. The calculation that most sources skip runs as follows. Scaling the rodent behavioural doses to a 70 kg human on a straight body-weight basis: 50 ng/kg x 70 kg = 3,500 ng = 3.5 mcg; 200 ng/kg x 70 kg = 14,000 ng = 14 mcg. So the entire body-weight-scaled range is roughly 3.5 to 14 micrograms. Community injection protocols use 1-2 mg, which is 1,000-2,000 micrograms. The gap is therefore about 71-fold (1 mg versus 14 mcg) at the conservative end and about 571-fold (2 mg versus 3.5 mcg) at the wide end — two orders of magnitude at the conservative end and approaching three at the wide end. Applying conventional rat-to-human allometric correction (dividing the rat mg/kg dose by approximately 6.2 to obtain a human equivalent dose) shrinks the scaled range further, to roughly 0.6-2.3 mcg, and widens the gap to somewhere between about 440-fold and about 3,500-fold — that is, up to roughly three and a half orders of magnitude at the most extreme defensible comparison, and closer to two on the like-for-like one. Being precise about this matters, because the surrounding category is not. A claim that circulates widely across this category holds that the gap is "four orders of magnitude" or "10,000-fold". That figure is wrong. The only way to reach it is to compare an absolute rodent dose (roughly 50 nanograms delivered to a 250 g rat) against an absolute 1 mg human dose without normalising for body weight at all — an invalid cross-species comparison. The correct answer is smaller and still striking: nothing in the published literature justifies 1-2 mg per day, and the community figures sit roughly one hundred to several hundred times above the body-weight-equivalent of the doses that generated the published effects. Those figures originate in vendor and community convention. They were not derived from a dose-finding study, because no dose-finding study for Pinealon exists in animals or humans. For that reason the reconstitution table below gives working numbers for two reference doses one order of magnitude apart: 100 mcg and 1 mg. The 1 mg figure is the order of magnitude community injection protocols report. The 100 mcg figure is a low-end reference point, and it should not be mistaken for the animal-literature equivalent — the body-weight-scaled rodent behavioural dose is 3.5-14 mcg, roughly seven to thirty times lower than 100 mcg. The reason the table starts at 100 mcg rather than at the scaled figure is purely practical: at the concentrations produced by a 10 or 20 mg vial and 1-4 mL of water, 14 mcg is 0.14 to 0.28 units on a U-100 syringe, which cannot be measured. Reaching that range would require serial dilution well beyond what these vial sizes accommodate, a fact worth stating plainly in its own right — the doses the literature actually studied are not readily deliverable from the product format the market sells. The dosing frequency is equally conventional. As covered in the half-life section, no pharmacokinetic data exist for this compound in any species, so once-daily administration cannot be justified on exposure grounds. It is a habit inherited from the rest of the bioregulator category. All of the above is educational information about reported practice under research-use-only framing.

The full step-by-step protocol examples, titration schedule, and a printable protocol sheet with a dosing and injection log are included in the paid Protocol Playbook for this guide.

Reconstitution — bac-water math

Pinealon ships as a lyophilised (freeze-dried) powder, most commonly in 10 mg and 20 mg vials, and is reconstituted before subcutaneous use. The only variable in the process is the volume of bacteriostatic water added: that sets the concentration, and the concentration sets how many units are drawn on a U-100 insulin syringe. Adding more or less water does not change the total amount of peptide in the vial; it changes only how finely a dose can be measured. Because the two reference doses tabulated below are one order of magnitude apart — 100 mcg and 1 mg — draw volumes are given for both at each dilution, so the arithmetic is available either way. On a U-100 syringe, 100 units = 1.0 mL, so 1 unit = 0.01 mL. Medibact sells USP-grade bacteriostatic water (0.9% benzyl alcohol preserved) and digital educational guides; it does not sell peptides, and this arithmetic is provided for educational purposes only. The two dose columns below are reference points only: 100 mcg sits at the low end of what is discussed, and 1 mg reflects the order of magnitude reported in community injection protocols. Neither corresponds to the body-weight-scaled equivalent of the animal literature, which works out to roughly 3.5-14 mcg for a 70 kg adult.

This is concentration math, not a dose recommendation.

Injection / administration basics

Reconstitution handling for Pinealon is the same as for any lyophilised research peptide, and it matters more than is often assumed: these molecules are physically fragile and the powder cake is easily disturbed. The sequence described in laboratory handling references and reported in research settings runs as follows. The vial stopper and the bacteriostatic water stopper are wiped with a fresh alcohol swab and allowed to dry. The intended volume of bacteriostatic water is drawn, and the needle is introduced at an angle so that the stream runs down the inner wall of the vial rather than jetting directly onto the powder, with the vial's vacuum drawing it in slowly. Shaking is avoided. The vial is swirled gently or rolled between the fingers until the solution is clear, which for a 10 or 20 mg cake is typically a minute or two. A solution that remains cloudy or shows particulates after full dissolution time is generally treated as a reason to stop and question the material rather than to proceed. Reconstituted vials are refrigerated. The route reported for the RUO powder format is subcutaneous injection using an insulin syringe — typically 29-31 gauge, 5/16 to 1/2 inch — into subcutaneous fat, with sites described as the abdomen well away from the navel, the flank, or the outer thigh, rotated between administrations. Reported administration involves swabbing of the site, lifting of a fold of tissue, insertion at 45-90 degrees depending on tissue depth, slow depression of the plunger, withdrawal, and brief pressure afterwards. The draw volumes are small, and they follow directly from the table: at the 1 mg figure reported in community protocols, the draw is 10 units at 10 mg/mL, 15 units at 6.67 mg/mL and 20 units at 5 mg/mL, while at the 100 mcg reference point it is 1 unit at 10 mg/mL, 1.5 units at 6.67 mg/mL and 2 units at 5 mg/mL. That contrast is what makes the more dilute preparations worth understanding at the low end: a one-unit measurement error is the whole of a 100 mcg dose at 10 mg/mL and half of it at 5 mg/mL, whereas the same one-unit error against a 1 mg dose is a tenth of it at 10 mg/mL and a twentieth at 5 mg/mL. At the low end of the reported range, a larger reconstitution volume buys measurement resolution, at the cost of a shorter in-use window per vial relative to the amount of peptide it contains. Two route-specific points are worth separating out. Intranasal preparations are a secondary reported route and were used in some rodent work; per-dose amounts reported for nasal use are generally lower, and no comparative bioavailability data exist between nasal and subcutaneous delivery for this compound — it has not been measured. Oral capsules are the format used in the Russian human observations, which is mechanistically odd given that an unprotected tripeptide should be substantially degraded by gastric and brush-border peptidases; the literature does not resolve this, and no bioavailability figure for oral EDR has been published. Everything above is a description of reported research practice under research-use-only framing. It is not instruction for human use, and Medibact does not sell peptides.

Half-life & frequency rationale

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.

Stacking — overview

No combination involving Pinealon has been studied in a controlled setting — not with another bioregulator, not with a nootropic, not with anything. Every stack described below is a description of what is discussed in research and community settings, set out so the landscape is legible, not offered as a protocol. The general principle applies with more force than usual here: combining a compound with no human pharmacokinetics, no dose-response data and no toxicology alongside other compounds in the same position multiplies uncertainty rather than distributing it, and makes it impossible to attribute either a benefit or an adverse effect to any single input. The stacking logic discussed around Pinealon usually falls into one of three patterns. The first is the traditional Khavinson course, running several short bioregulators together or in sequence on the theory that different tripeptides address different tissues — this is how the compounds were designed to be used in the originating tradition, and it is also where the shared evidence caveat applies most broadly, since the entire family rests on the same single-tradition literature. The second is a cognition-focused pairing with the Russian nootropic peptides, where a distinction is worth drawing: Semax and Selank have a materially larger Russian clinical literature than Pinealon does, and Semax has featured in US peptide-compounding policy discussion in a way Pinealon has not. That difference is one of regulatory attention rather than of approval, and it says nothing about whether combining the two does anything. The third pattern is a longevity or mitochondrial-support grouping, which is speculative in every direction. One pairing is worth flagging specifically because of the naming confusion: people who come to Pinealon looking for sleep benefits are almost always describing what Epithalon (AEDG, the actual pineal peptide) and DSIP are discussed for. Pinealon has no direct published evidence of a sleep or circadian effect, so a "Pinealon for sleep" stack is built on a misunderstanding of what the compound is. The Epithalon guide covers the pineal side of this family.

For how combinations are grouped by research context, the named blends, and why a pre-mixed blend vial cannot be calculated from its total milligrams, see the peptide stacks guide.

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.

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