Neurological Repair & Neurocognitive Support

A pig-brain-derived mixture of small peptides and amino acids, used in Russia, Eastern Europe and parts of Asia after stroke, with many trials but mixed, uncertain results.

Overview

Cerebrolysin is not a single molecule. It is a preparation made by breaking down purified pig brain protein into a mixture of small peptides and free amino acids. A 2019 mass spectrometry study identified more than 14,000 distinct peptide sequences in it, most only 5 to 9 amino acids long^[8]. It is given by infusion and is widely used for acute stroke in Russia, Eastern Europe, China and other Asian and post-Soviet countries^[1].

Unlike most compounds in this section, Cerebrolysin has been tested in many randomized trials. The results are mixed. A 2023 Cochrane review of seven stroke trials found it probably does not reduce deaths and may increase non-fatal serious adverse events^[1]. Smaller trials in stroke rehabilitation and brain injury reported functional benefits^[3,4], but several were supported by the manufacturer and some had a high risk of bias^[1].

Mechanism of Action

Because Cerebrolysin is a mixture, it has no single receptor target. The manufacturer and many researchers describe it as having "neurotrophic-like" activity, meaning it is proposed to imitate the support that natural growth factors such as BDNF and NGF give to nerve cells. That claim comes mostly from cell and animal work, not from direct measurement in patients. The proteomic analysis found that its light fraction is dominated by short fragments of more than 1,600 pig neuronal proteins^[8]. Which of these fragments survive in the blood, cross into the brain, and act on specific targets has not been worked out.

In controlled rat stroke studies, Cerebrolysin improved neurological scores when started within 48 hours, with larger amounts producing more benefit up to a plateau^[6,7]. One of those studies found no reduction in the size of the brain injury itself, which suggests that any effect is on recovery and rewiring rather than on saving tissue during the acute event^[7]. Both rodent studies included manufacturer-employed co-authors^[6,7]. How these effects would translate into human brains remains uncertain.

What the Research Shows

• Cochrane systematic review, acute ischemic stroke, 2023 (7 RCTs, 1,773 participants, plus one Cortexin trial): no clear effect on all-cause death (RR 0.96, 95% CI 0.65 to 1.41; moderate certainty). Non-fatal serious adverse events were higher with Cerebrolysin (RR 2.39, 95% CI 1.10 to 5.23; 3 trials, 1,335 participants). Total adverse events did not differ (RR 1.03). Many trials had unclear or high risk of bias, and the manufacturer supported three^[1].
• CASTA RCT, Stroke 2012 (n=1,070 in Asia, started within 12 hours, 90 days): the primary combined outcome (Rankin, Barthel and NIHSS scores) showed no significant difference. In a post hoc subgroup with severe stroke (NIHSS above 12), 90-day mortality was 10.5% vs 20.2% on placebo, a trend the authors said needs confirmation^[2].
• CARS RCT, Stroke 2016 (n=208, started 24 to 72 hours after stroke with 21 days of rehabilitation): arm motor function at day 90 favored Cerebrolysin (Mann-Whitney estimator 0.71, 95% CI 0.63 to 0.79, P<0.0001). The authors called the study exploratory and asked for a large confirmatory trial^[3].
• Safety meta-analysis, 2021 (12 RCTs, 2,202 stroke patients): no significant difference in serious adverse events, and mortality of 4.1% vs 5.0% on placebo (RR 0.83, P=0.36)^[9].
• CAPTAIN prospective meta-analysis, traumatic brain injury, 2021 (2 RCTs, n=185, moderate to severe TBI): a small-to-medium benefit on a combined functional and cognitive outcome at day 90 (odds ratio 1.77, P=0.015). Safety was similar to placebo^[4].
• Cochrane review, vascular dementia, 2019 (6 RCTs, 597 participants): cognition improved modestly (SMD 0.36) and global response was more likely (RR 2.69), but certainty was very low because of high risk of bias and heterogeneity, and the benefit may be too small to matter clinically^[5].

• Rats, embolic stroke, dose-response study: neurological outcome improved significantly at the three higher levels tested (P<0.001), with no extra gain beyond that. Lesion volume fell at one level only (P=0.016). Mortality did not differ^[6].
• Rats, embolic stroke, timing study (n=100): benefit was significant when treatment began at 4, 24 or 48 hours but not at 72 hours. Infarct volume and mortality did not differ between groups^[7].

• Proteomic analysis of the product: mass spectrometry identified 14,635 peptide sequences from 1,643 pig neuronal proteins, with nearly 90% of peptides weighing about 400 to 600 daltons^[8].

Open Questions

• Which of the thousands of peptide fragments, if any, cause the reported effects, and whether they reach the brain intact.
• Whether the rehabilitation and brain injury benefits hold up in large, independent trials not supported by the manufacturer^[1,3,4].
• Why non-fatal serious adverse events appeared more often in pooled stroke trials, and which events were involved^[1].
• Whether batch-to-batch variation in a biologically derived mixture affects results.
• Any effect at all in healthy people or for general cognitive enhancement, which has not been studied in controlled trials.

Regulatory Status

Not approved by the FDA or the EMA, though it is registered and widely used in Russia, Eastern Europe, China and other Asian countries^[1]. It does not appear on FDA's 503A compounding lists, so it has no legal pathway for US compounding. It is not named on the WADA 2026 Prohibited List; because it holds national approvals, the S0 catch-all for unapproved substances does not clearly apply^[10].

Related Compounds

A small lab-made molecule derived from an angiotensin fragment, reported to boost brain-cell connections in rodents, with no human studies and a key supporting paper now retracted.

Overview

Dihexa is a small modified molecule built from a fragment of angiotensin IV, a breakdown product of the blood pressure hormone angiotensin. Researchers at Washington State University chemically reworked the active three-amino-acid piece so it would resist breakdown and cross into the brain, producing a compound they described as orally active and brain-penetrant^[1,4]. It is often grouped with peptides, but it is better described as a small peptide-like molecule.

In rat studies from the developing lab, dihexa reversed drug-induced memory deficits and helped aged rats in maze tests^[1]. An independent Chinese group later reported memory improvement in an Alzheimer's mouse model^[5]. However, the 2013 founding paper carries a 2021 expression of concern, and the 2014 paper linking dihexa to the HGF/c-Met growth factor system was retracted in 2025^[1,2,3]. No human trial has ever been published.

Mechanism of Action

The developers started from norleucine-angiotensin IV, an experimental peptide with memory effects in rodents, and found that its first three amino acids carried most of the activity. They then capped both ends and made the molecule more fat-soluble and less prone to hydrogen bonding, which made it stable in the body and able to cross the blood-brain barrier^[1]. The result, dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide), increased the formation of new connections between hippocampal neurons in culture and in rats^[1,4].

The proposed explanation is that dihexa binds HGF and helps it activate its receptor, c-Met, which drives cell growth, branching and protection from injury^[4]. The main experimental evidence for this link was published in 2014 and retracted in 2025, after a 2021 expression of concern^[2,3]. Supporting signals come from a zebrafish study in which blocking HGF reduced dihexa's protective effect^[6] and from a mouse study pointing to the PI3K/AKT survival pathway^[5]. Its human pharmacology has never been measured.

What the Research Shows

• No human studies published. No clinical trial, case series or pharmacokinetic study of dihexa in people appears in the literature.
• Related compound, phase 2/3 RCT, 2025 (n=287, mild-to-moderate Alzheimer's disease, 26 weeks): fosgonimeton, a separate drug that also targets the HGF/MET system, missed its primary and secondary endpoints (cognition difference P=0.35, daily function P=0.61). Discontinuation due to adverse events was 14.2% vs 4.6% on placebo. This is not dihexa, but it is the closest human test of the same strategy^[8].

• Rats, scopolamine-induced amnesia and aged rats: dihexa reversed memory deficits in the Morris water maze and increased hippocampal synapse formation. This paper has carried an expression of concern since 2021^[1].
• APP/PS1 Alzheimer's model mice (n=6 to 12 per group, 3 months of treatment): improved water maze performance, more surviving neurons, more synaptophysin, and lower inflammatory markers (IL-1β, TNF-α). Blocking PI3K reversed the anti-inflammatory effects. No effect sizes were reported^[5].
• Rats, sciatic nerve cut and repair (6 to 8 per group, 16 weeks): dihexa combined with stem cells, injected into the calf muscle, improved motor function (P<0.05) and reduced contractures. Dihexa was not clearly effective alone^[7].
• Larval zebrafish, antibiotic-induced hair cell damage: dihexa protected sensory hair cells from neomycin and gentamicin, and an HGF blocker reduced the protection. Two authors had financial ties to a company developing HGF mimetics^[6].

• Rat hippocampal neurons: dihexa and related analogs increased dendritic spine and synapse formation in culture^[1,4].

Open Questions

• Whether dihexa actually works through HGF/c-Met, now that the central mechanistic paper has been retracted^[2,3].
• Whether the rodent memory results replicate outside the originating lab beyond a single mouse study^[1,5].
• Absorption, brain levels, half-life and safety in humans, none of which have been measured.
• Cancer risk from long-term stimulation of a growth factor pathway.
• Why a related HGF/MET drug failed in Alzheimer's patients, and what that implies for dihexa^[8].

Regulatory Status

Not approved anywhere. A nomination of dihexa acetate for FDA's 503A compounding bulks list was withdrawn, so it is not on any list that permits compounding, and FDA notes no human exposure data^[9]. It is not named on the WADA 2026 Prohibited List, but as a proposed growth factor modulator with no regulatory approval it would be covered by class S2.3 or the S0 catch-all, both prohibited at all times^[10].

Related Compounds

A short synthetic peptide built from a fragment of the stress hormone ACTH, registered in Russia as a nasal drop for stroke and brain disorders, with thin and uncontrolled human evidence.

Overview

Semax is a seven-amino-acid peptide (Met-Glu-His-Phe-Pro-Gly-Pro). Its first four amino acids come from ACTH, the pituitary hormone that tells the adrenal glands to make cortisol, and the last three (Pro-Gly-Pro) were added to slow its breakdown. Unlike ACTH, it has no hormonal activity^[1]. It was developed in Russia, where it is registered and sold as 0.1% and 1% nasal drops^[1].

Most human studies come from a single Russian research group and test Semax in stroke and chronic cerebrovascular disease, reporting faster recovery than in untreated patients^[3,4,5]. None of these abstracts describes randomization or blinding. In July 2026, an FDA advisory committee voted narrowly to recommend Semax for the compounding bulks list despite FDA staff concluding that the evidence weighed against it^[1,2].

Mechanism of Action

Fragments of ACTH were studied for decades because they affected attention and learning in animals without acting as hormones. Semax extends the ACTH(4-7) fragment with Pro-Gly-Pro, a tripeptide that resists enzymes^[1]. In rats it is broken down quickly in blood and brain, with Pro-Gly-Pro as the main product, and only a small fraction of a dose reaches the brain, more after nasal than intravenous delivery^[1]. No human pharmacokinetic study has been found, so its half-life in people is unknown^[1].

In rat brain tissue, labeled Semax binds specific sites with high affinity (KD 2.4 nM), and nasal Semax raised levels of BDNF, a growth factor that supports nerve cells, in the basal forebrain within 3 hours^[7]. After experimental stroke in rats, it shifted the activity of hundreds of genes, mostly immune and blood vessel genes^[8]. Lab work also shows it can slow enzymes that break down enkephalins, the body's own opioid-like peptides^[9]. FDA described its mechanisms as poorly understood^[1].

What the Research Shows

• Controlled clinical study, acute ischemic stroke, 1997 (n=30 on Semax vs 80 conventionally treated controls): neurological, especially motor, recovery appeared faster with Semax. The abstract describes no randomization, placebo or blinding^[3].
• Comparative study, chronic cerebrovascular insufficiency, 2005 (n=187): the authors reported clinical improvement, slower progression and fewer strokes and transient ischemic attacks, with few side effects. The abstract gives no numerical outcomes or design details^[4].
• Clinical study, stroke rehabilitation, 2018 (n=110, roughly 3 to 7 months after stroke): Semax-treated subgroups had higher plasma BDNF and faster gains in daily-living scores than untreated subgroups. Randomization and blinding were not described^[5].
• Placebo-controlled fMRI study, healthy adults, 2018 (n=24; 14 Semax, 10 placebo): a single nasal application changed resting brain network activity within 20 minutes. This shows a brain effect, not a clinical benefit^[6].
• FDA review of English-language evidence, 2026: beyond a meeting abstract, the only clinical data were an uncontrolled 1996 study of 37 people with migraine or facial nerve pain given one dose; 4 of 12 migraine patients reported their headache stopped, and the authors concluded Semax had no analgesic effect in trigeminal neuralgia^[1].

• Rats, BDNF: nasal Semax raised BDNF protein in the basal forebrain after 3 hours but not in the cerebellum^[7].
• Rats, permanent stroke model: genome-wide analysis found Semax mostly altered immune-response genes (over 50% of affected genes) and 24 vascular genes at 3 hours^[8].
• Rats, cerebral ischemia models: Semax reduced ischemic damage in several studies, though FDA noted fixed dosing and no exposure-response data^[1].
• Mice and rats, other findings: Semax increased amphetamine-triggered dopamine release in mice and showed anticoagulant effects in stressed rats, which FDA flagged as possible abuse and bleeding concerns^[1].

• Human serum enzymes: Semax inhibited enkephalin-degrading enzymes with an IC50 of 10 µM^[9].

Open Questions

• Whether any benefit holds up in a large, randomized, placebo-controlled, blinded trial outside Russia.
• Basic human pharmacology: how much reaches the brain, and how long it lasts^[1].
• Long-term safety, including bleeding risk and abuse potential^[1].
• Whether FDA will accept the 2026 advisory committee's recommendation, given its own staff's negative assessment^[1,2].

Regulatory Status

Not FDA-approved. On July 24, 2026, FDA's Pharmacy Compounding Advisory Committee voted narrowly to recommend semax for the 503A bulks list against FDA staff's recommendation; it cannot be legally compounded unless FDA accepts this and completes rulemaking^[1,2]. Registered in Russia^[1]. It is not named on the WADA 2026 Prohibited List, and its Russian approval means the S0 catch-all may not apply^[10].

Related Compounds

A short synthetic peptide based on the immune fragment tuftsin, developed in Russia as an anti-anxiety drug, with small, low-rigor human trials and mostly animal research behind it.

Overview

Selank is a seven-amino-acid peptide (Thr-Lys-Pro-Arg-Pro-Gly-Pro)^[1]. Its first four amino acids are tuftsin, a natural fragment of an antibody molecule that stimulates immune cells, and the last three are the same enzyme-resistant Pro-Gly-Pro tail used in Semax. It was developed in Russia, and Western reviewers have described it as a poorly studied Russian drug sold online to US consumers as a supplement^[8].

Small Russian trials in generalized anxiety and related disorders reported anxiety relief similar to benzodiazepines such as medazepam and phenazepam, with fewer sedative side effects^[2,3,4]. None used a placebo group, and the abstracts do not describe how patients were randomized or whether raters were blinded. Most mechanism work comes from rodents and a small number of Russian laboratories.

Mechanism of Action

In binding studies on rat brain membranes, Selank acted as a positive allosteric modulator of GABA binding, meaning it changed how the GABA-A receptor responds to the brain's main calming chemical rather than activating the receptor directly. It also interfered with the binding effects of diazepam and olanzapine, suggesting partly overlapping sites^[1]. In rats, a single dose changed the expression of 45 of 84 neurotransmission genes in the frontal cortex within an hour, with a pattern that correlated with GABA's own effects^[5].

A second proposed route is protecting the body's own calming peptides. In human serum, Selank inhibited enzymes that degrade enkephalins (natural opioid-like peptides) with an IC50 of 20 µM^[6], and in an anxiety trial, a measure of enkephalin stability rose during treatment^[2]. It also shifts immune signaling: it altered cytokine balance in patients and immune gene expression in mouse spleen^[7,9]. How these pieces fit together, and which matter at the concentrations reached in humans, is unclear.

What the Research Shows

• Active-comparator trial, generalized anxiety and neurasthenia, 2008 (n=62; 30 Selank, 32 medazepam): both drugs reduced anxiety to a similar degree, and Selank also showed anti-fatigue and mildly stimulating effects. Serum enkephalin stability rose during Selank treatment. No placebo group; randomization and blinding not described^[2].
• Comparative trial, anxiety and somatoform disorders, 2014 (n=60, Selank vs phenazepam): Selank showed anti-anxiety and mild nootropic effects lasting about a week after stopping. Group sizes and blinding were not reported^[3].
• Add-on trial, anxiety disorders, 2015 (n=70; phenazepam alone vs phenazepam plus Selank): adding Selank sped the anti-anxiety response and reduced several phenazepam side effects, including sedation and memory problems. Randomization method and blinding not described^[4].
• Immune study, anxiety-asthenic disorders, 2008 (patients treated for 14 days, no control group described): Selank shifted the blood Th1/Th2 cytokine balance^[7].
• Placebo-controlled fMRI study, healthy adults, 2020 (n=52, Selank, Semax or placebo): Selank altered resting connectivity between the right amygdala and temporal cortex within 20 minutes. This shows a brain effect, not a clinical benefit^[10].

• Rats, chronic mild stress: Selank reduced anxiety in the elevated plus maze and enhanced diazepam's anti-anxiety effect under stress; no numerical results were given in the abstract^[11].
• Rats, frontal cortex gene expression: 45 of 84 neurotransmission-related genes changed at 1 hour and 22 at 3 hours after dosing^[5].
• Mice, spleen immune genes: a single dose cut complement C3 mRNA about 3-fold at 30 minutes, an effect shared by its Gly-Pro fragment^[9].

• Rat brain membranes: Selank positively modulated tritium-labeled GABA binding in a subtype-selective, concentration-dependent way^[1].
• Human serum enzymes: Selank inhibited enkephalin-degrading enzymes with an IC50 of 20 µM^[6].

Open Questions

• Whether Selank beats placebo in a properly randomized, blinded trial.
• Human pharmacokinetics, including how much reaches the brain after nasal use.
• Dependence, withdrawal and interaction risks, especially with benzodiazepines, alcohol or other sedatives^[8,11].
• Long-term safety beyond the 2 to 4 weeks studied.

Regulatory Status

Not FDA-approved. A nomination of selank acetate for FDA's 503A compounding bulks list was withdrawn, so it is not on any list that permits compounding^[12]. It was developed and studied clinically in Russia^[2,8]. It is not named on the WADA 2026 Prohibited List; whether the S0 catch-all applies depends on whether it holds a national approval^[13].

Related Compounds

A pairing of two Russian-developed nasal peptides, Semax (studied for brain injury and cognition) and Selank (studied for anxiety); each has small studies of its own, but the combination has never been tested.

Overview

Semax + Selank is a market product category, not a studied treatment. Both are short synthetic peptides developed in Russia. Semax is an analog of a fragment of ACTH, a pituitary hormone, and in rats it raised levels of BDNF, a growth factor for nerve cells^[2]. Selank, developed at the Institute of Molecular Genetics of the Russian Academy of Sciences, is a modified version of tuftsin, a small immune peptide, and is studied for anxiety, with animal data pointing toward the brain's GABA calming system^[3].

The pairing rests on the idea that one peptide sharpens and the other calms. No published study has given the two together. Researchers have compared them side by side, finding both shared and distinct effects on brain connectivity after a single administration^[1], but that tells us nothing about combining them.

Mechanism of Action

Semax combines a fragment of ACTH with a short proline-glycine-proline tail that slows its breakdown. In rats, a single administration raised hippocampal BDNF protein about 1.4-fold and activation of its receptor, TrkB, about 1.6-fold, with a threefold rise in one form of BDNF messenger RNA^[2]. These changes are proposed to underlie its studied effects on memory and recovery after brain injury, but the human data supporting those effects are limited.

Selank (threonine-lysine-proline-arginine-proline-glycine-proline) uses the same stabilizing tail on tuftsin. In rats, one intranasal administration shifted expression of genes tied to GABA signaling in the frontal cortex, in a pattern partly resembling GABA itself, leading the authors to propose that it modulates the GABA system indirectly^[3]. In healthy adults, each peptide altered connectivity between the right amygdala, a fear-processing region, and the temporal cortex, with both common and peptide-specific effects^[1]. Whether these signals add up, cancel or interfere when combined is untested.

What the Research Shows

• fMRI study, 2020 (n=52 healthy adults, single administration, scans before and at 5 and 20 minutes): Semax and Selank, given to separate groups versus placebo, each changed resting connectivity between the right amygdala and right temporal cortex, with both general and peptide-specific effects. No combination arm was included^[1].
• No published human study has given Semax and Selank together.

• Rats, hippocampus (Semax alone): BDNF protein rose up to 1.4-fold and TrkB phosphorylation 1.6-fold after a single administration^[2].
• Rats, frontal cortex (Selank alone, n=30): 17 of 77 GABA-related genes changed expression at 3 hours, including large rises in some GABA receptor subunit genes^[3].

Open Questions

• Whether the two peptides interact, for example whether Selank's proposed calming effects offset or amplify Semax's proposed effects on alertness and memory.
• Whether the shared proline-glycine-proline tail means the peptides compete for the same breakdown enzymes or targets.
• Whether short-term changes in brain connectivity translate into any measurable benefit in people.
• How much of the evidence for either peptide has been independently replicated outside the developing laboratories.

Regulatory Status

Neither peptide is FDA approved; nominations for both were withdrawn from FDA's Category 2 compounding safety-risk list^[4]. In July 2026 an FDA advisory committee voted 8-5 to recommend Semax for the 503A bulks list against FDA staff advice, and FDA has not yet acted; Selank was not reviewed^[6,7]. Neither is named on the 2026 WADA list, though WADA's S0 class covers unapproved substances not listed elsewhere^[5].

Related Compounds

A seven-amino-acid fragment of the natural peptide spadin that blocks a brain potassium channel and showed fast antidepressant-like effects in mice, with no human data.

Overview

PE-22-28 is a shortened version of spadin, a peptide released when the brain processes a receptor protein called sortilin. Spadin blocks TREK-1, a potassium channel that acts as a brake on nerve cell firing. Mice lacking TREK-1 resist depression-like behavior, which made blocking it an appealing antidepressant idea^[1]. In 2017, researchers designed PE-22-28 from a breakdown fragment of spadin found in blood^[2].

In mice, PE-22-28 blocked TREK-1 far more potently than spadin, lasted longer, and reduced depression-like behavior after only 4 days, compared with the several weeks typical of standard antidepressants^[2]. All published work comes from a single French group, uses mice or cultured cells, and relies on behavioral tests that only approximate human depression. No human trial has been reported.

Mechanism of Action

TREK-1 is a two-pore-domain potassium channel. When open, it lets potassium out of neurons and dampens their activity. The parent peptide spadin, a 17-amino-acid fragment (PE 12-28) of the sortilin propeptide, binds TREK-1 with about 10 nM affinity and blocks it in hippocampal neurons. In mice, spadin increased the firing of serotonin neurons in the dorsal raphe, raised hippocampal CREB activation and boosted the birth of new neurons within 4 days^[1]. Its effect lasted only about 7 hours^[2].

PE-22-28 keeps just the last seven amino acids of spadin. In human TREK-1 expressed in cells, it blocked the channel with an IC50 of 0.12 nM, several hundred times more potent than spadin (40 to 60 nM), and did not affect related channels (TREK-2, TRAAK, TRESK, TASK-1) or the hERG heart channel at the concentration tested^[2]. In mouse neurons it raised PSD-95, a marker of new synapses. The authors cite earlier spadin work for faster BDNF increases, but BDNF was not measured for PE-22-28 itself^[2].

What the Research Shows

• No human studies published. No clinical trial, case report or pharmacokinetic study of PE-22-28 or spadin in people appears in the literature.

• Mice, depression-like behavior (n=10 per group): PE-22-28 and its analogs reduced immobility in the forced swim test. After 4 days of treatment, it shortened the time to eat in the novelty suppressed feeding test, a model sensitive to chronic antidepressants. New neuron formation increased within 4 days. Action lasted about 23 hours vs about 7 hours for spadin^[2].
• Mice, parent peptide spadin: resistance to depression-like behavior in five behavioral tests and a strong effect after a 4-day course, with increased hippocampal neurogenesis^[1].
• Mice, stroke and post-stroke depression: mini-spadin, another shortened spadin analog from the same group, improved motor and cognitive deficits and prevented depression-like behavior after focal brain ischemia. Low amounts activated TREK-1 while higher amounts blocked it, an unusual two-way effect^[3].

• HEK cells expressing human TREK-1: IC50 of 0.12 nM for PE-22-28 vs 40 to 60 nM for spadin, with no effect on hERG currents at 10 µM^[2].
• Mouse cortical neurons: PE-22-28 and derivatives increased expression of PSD-95, a synaptic protein^[2].

Open Questions

• Whether the mouse antidepressant effects translate to humans at all.
• Whether long-term TREK-1 blockade carries risks, given the channel's roles in pain, neuroprotection and other tissues^[3].
• Human absorption, stability and brain penetration, none of which have been measured.
• Independent replication outside the originating laboratory.
• Whether it raises BDNF, which has been claimed but not measured for PE-22-28^[2].

Regulatory Status

Not approved anywhere and not listed in any FDA compounding category or nomination^[5]. It is not named on the WADA 2026 Prohibited List, but as a substance with no regulatory approval it falls under the S0 catch-all, prohibited at all times^[6].

Related Compounds

A three-amino-acid synthetic peptide from a St. Petersburg research group, studied mostly in cells and rodents as a possible brain-protecting agent, with only thin, unverified human reports.

Overview

Pinealon is the tripeptide Glu-Asp-Arg (EDR), one of the short "peptide bioregulators" developed by Vladimir Khavinson's group in St. Petersburg^[1,8]. The group proposes that peptides this small can enter cells, reach the nucleus and nudge gene activity. Its research covers oxidative stress, nerve-cell survival and models of Alzheimer's disease^[1,2]. Nearly all of this work comes from one research network and its collaborators, and much of it appeared in Russian journals such as Advances in Gerontology and Bulletin of Experimental Biology and Medicine^[1,8].

In cell cultures, pinealon reduced free-radical build-up and helped cells survive chemical stress^[2]. In rodents, it improved maze learning in rat pups exposed to high homocysteine before birth^[3] and modestly preserved dendritic spines in an Alzheimer's mouse model^[5]. A 2021 review by the developers describes Russian clinical reports in brain-injury patients and older adults, but these were small and not randomized^[1]. No independent replication outside this network has been found, including in 2025.

Mechanism of Action

The proposed mechanism is epigenetic, meaning it would change which genes are switched on rather than acting on a classic receptor. In test-tube and modeling work, EDR bound double-stranded DNA in the major groove and docking studies predicted binding sites in the promoters of genes such as PPARA, PPARG, SOD2, GPX1 and the serotonin-making enzyme TPH^[1,7,8]. In cultured rat brain-cortex cells, EDR roughly doubled serotonin staining in young cultures (1.20% to 2.32% of area) but had no significant effect in aged cultures^[7]. These binding sites come mostly from computer modeling, not from direct measurement in living cells^[1].

A second line of work focuses on oxidative stress. In rat cerebellar neurons, pinealon blocked the rise in reactive oxygen species caused by homocysteine (a 92% increase) and ouabain, delayed ERK1/2 signaling by about 20 minutes, and increased survival of PC12 cells exposed to hydrogen peroxide^[2]. The developers link these findings to lower caspase-3 activity and better-preserved synapses in rodent models^[1,5]. How a three-residue peptide given by mouth or injection reaches the brain intact has not been established in published pharmacokinetic studies.

What the Research Shows

• Clinical reports summarized in a developer review, 2021 (n=72 patients with after-effects of traumatic brain injury, pinealon by mouth added to standard therapy): reported better memory, shorter and milder headaches and better emotional balance. The review gives no control-group or randomization details, and the source reports are Russian-language papers and a patent^[1].
• Older adults, same review: improved memory, attention and processing speed were described in elderly patients, but without sample sizes or design details^[1].
• No randomized controlled trial of pinealon has been published, and no human data from groups outside the developers' network were found.

• Rats, prenatal high homocysteine: pups of mothers given methionine plus pinealon found the water-maze platform faster (137 vs 170 seconds on the first day-2 trial; controls 112 seconds). Their brain cells showed less oxidative stress (ROS 108.6 vs 158.7) and fewer dead cells after peroxide (7.0% vs 17.7%). Pinealon did not lower homocysteine itself. Some measures used only 4-5 animals per group^[3].
• Mice, 5xFAD Alzheimer's model: EDR increased CA1 dendritic spine density by 11% (P=0.039) but did not significantly change long-term potentiation, a measure of synaptic plasticity. No memory or behavioral results were reported^[5].
• Rats, hypoxia and ischemia models: the developers report reduced caspase-3 activity and better maze learning in young and old rats, mostly in Russian-language papers^[1].

• Mouse hippocampal neurons, amyloid toxicity: EDR increased mature "mushroom" spines by 71%, back to normal levels^[4].
• Neurons converted from skin cells of three women aged 61-68: EDR increased total dendrite length by 46% (P=0.033). Its reduction in oxidative DNA damage (23%) narrowly missed significance, and markers of mitochondrial health, lysosomes and p16 did not change^[6].

Open Questions

• Whether pinealon reaches the brain intact after being swallowed or injected.
• Whether its proposed DNA binding actually happens in living cells and drives the observed effects^[1].
• Whether any result holds up in an independent laboratory; no 2025 or earlier replication outside the developers' network was found.
• Whether the human reports would survive a randomized, blinded, placebo-controlled trial.

Regulatory Status

Not approved by the FDA, the EMA or another major regulator for any use. The FDA's July 2026 Pharmacy Compounding Advisory Committee reviewed epitalon, a related Khavinson-group peptide, but not pinealon^[9]. Pinealon is not named individually on the WADA Prohibited List, which separately bars substances not approved for human therapeutic use.

Related Compounds

A four-amino-acid synthetic peptide linked to a Russian brain-tissue extract, studied in a handful of small animal and cell experiments on nerve repair and gene activity.

Overview

Cortagen is the tetrapeptide Ala-Glu-Asp-Pro (AEDP)^[2,5]. It was described as a synthetic peptide derived from Cortexin, a Russian drug made from animal brain cortex, and belongs to the Khavinson group's family of short "peptide bioregulators"^[2]. Its literature is small: a medical index entry dates its first indexed report to a 2000 rat nerve-repair study in Bulletin of Experimental Biology and Medicine^[1,5]. Nearly every paper comes from the same St. Petersburg research network.

In rats with a cut and repaired sciatic nerve, 10 days of cortagen injections were reported to speed nerve-fiber regrowth by 27% and raise conduction velocity by 40%^[1]. In mice, five days of cortagen changed activity in about 1.5% of 15,000 heart genes^[2]. In white blood cells from people aged 75 to 88, it loosened tightly packed chromatin in a lab dish^[3]. No human clinical trial has been published, and no independent replication was found, including in 2025.

Mechanism of Action

Like other Khavinson-group peptides, cortagen is proposed to act on gene regulation rather than on a single receptor. In lymphocytes taken from people aged 75 to 88, cortagen and four related peptides activated ribosomal genes and decondensed tightly packed chromatin, releasing genes that age-related condensation had silenced^[3]. The developers' 2021 systematic review lists AEDP among peptides reported to push stem cells toward skin, connective-tissue and nerve-cell fates^[4]. These findings come from cell cultures, and the exact molecular target of the peptide has not been identified.

The mouse microarray study gives the broadest look at cortagen's effects in a living animal. After five days of injections in 10 female mice (versus 10 saline controls), 234 transcripts in heart tissue changed, 208 up and 26 down, with the largest change about 5.4-fold. RT-PCR confirmed the direction of change for 9 of 12 genes tested^[2]. The authors described a pattern partly shared with other peptides (Vilon, Epitalon) and partly unique^[2]. A gene-expression shift is not the same as a health benefit, and the study did not measure heart function.

What the Research Shows

• No human clinical trials of cortagen have been published in peer-reviewed literature. A 2004 paper states it had earlier aided peripheral nerve recovery in humans, but gives no study details^[2].

• Rats, cut and sutured sciatic nerve: 10 days of intramuscular cortagen increased nerve-fiber growth rate by 27% and conduction velocity by 40%. Group sizes and control details are not in the available abstract^[1].
• Mice, heart gene expression: 5 days of cortagen in 6-month-old female mice (n=10 per group) changed 1.5% of about 15,000 transcripts, mostly upward^[2].

• Lymphocytes from people aged 75-88: cortagen activated ribosomal genes and decondensed chromatin, but, unlike Epithalon, Livagen and Prostamax, it was not reported to decondense the chromosome 1 region examined^[3].
• Stem cell cultures: AEDP is reported to steer differentiation toward skin, connective-tissue and nerve lineages^[4].

Open Questions

• Whether the 2000 nerve-repair result has ever been repeated, by the original group or anyone else^[1].
• What cortagen binds to inside cells, and whether its gene-expression changes are beneficial, harmful or neutral^[2,3].
• Whether it survives digestion or reaches nerve tissue in useful amounts.
• How it relates to the brain extract Cortexin, which contains many peptides.

Regulatory Status

Not approved by the FDA, the EMA or another major regulator for any use. It was not among the peptides reviewed at the FDA's July 2026 Pharmacy Compounding Advisory Committee meeting, which considered the related Khavinson-group peptide epitalon^[6]. Cortagen is not named individually on the WADA Prohibited List, which separately bars substances not approved for human therapeutic use.

Related Compounds

A trade-name product sold as a modified version of the Russian peptide Semax, with no published structure, no animal studies and no human trials behind the name.

Overview

ADAMAX is a market name, not a scientific one. Sellers describe it as a modified form of Semax, a Russian peptide drug built from a fragment of the stress hormone ACTH, and some descriptions say a bulky cage-shaped chemical group (adamantane) has been attached. We could not find a peer-reviewed paper, patent record or regulatory filing that confirms what the molecule actually is, who designed it, or how pure commercial material is.

Because of that, nothing reliable can be said about ADAMAX itself. Semax, the claimed parent, has been used clinically in Russia for stroke and other brain conditions and has a body of mostly Russian animal and clinical literature^[1,2]. Whether any of that applies to a chemically altered version is unknown, since even small structural changes can alter how a peptide behaves.

Mechanism of Action

No mechanism has been studied for ADAMAX. The claimed parent, Semax, is a seven-amino-acid peptide (Met-Glu-His-Phe-Pro-Gly-Pro) designed as an analog of the ACTH(4-10) fragment, developed at the Institute of Molecular Genetics of the Russian Academy of Sciences^[1]. Reviews of Semax describe reduced glutamate toxicity and oxidative stress, better mitochondrial energy production under low oxygen, and higher levels of growth factors for nerve cells in animal brain tissue^[2]. In rodents, Semax raised a marker of serotonin turnover in the striatum and strongly amplified amphetamine-triggered dopamine release, though it did not change dopamine on its own^[3].

Adding a bulky chemical group like adamantane could, in principle, change how a peptide dissolves, resists breakdown or crosses membranes. Whether that was done here, where the group sits, and whether it helps or harms activity have not been reported. Claims that ADAMAX is a stronger or longer-acting Semax are therefore untested. It is also possible that products sold under this name differ in content from one another, which cannot be checked without a published reference structure.

What the Research Shows

• No human studies of ADAMAX have been published. Semax itself has been used clinically in Russia for ischemic stroke and other neurological conditions, but the published reports are mostly Russian-language and give limited trial detail^[2].

• ADAMAX itself: no published animal studies were found.
• Parent compound Semax, rats: increased the serotonin metabolite 5-HIAA in the striatum by up to about 180% and markedly enhanced amphetamine-induced dopamine release and movement^[3].

Open Questions

• The actual chemical structure of products sold as ADAMAX.
• Whether it shares any of Semax's reported effects, and whether the modification changes potency, duration or toxicity.
• Whether it is stable, absorbed, or reaches the brain by any route.
• Short- and long-term safety, including interactions with stimulant or psychiatric medications.

Regulatory Status

Not approved by the FDA or any other regulator that we could identify, and not listed among bulk substances nominated for 503A compounding as of May 2026^[4]. Its claimed parent, Semax, was among the peptides scheduled for review at FDA's Pharmacy Compounding Advisory Committee meeting in July 2026^[5].

Related Compounds

A frog-skin opioid peptide many times stronger than morphine in animal tests, never approved as a medicine and best known today as an illegal doping agent in horse racing.

Overview

Dermorphin is a seven-amino-acid peptide first isolated from frog skin and characterized in 1981 as a new class of potent opioid peptides^[2]. It binds the mu-opioid receptor, the same target as morphine, fentanyl and oxycodone, and is classified by the U.S. National Library of Medicine as an opioid analgesic^[4]. Its potency has been described as 30 to 40 times that of morphine^[1].

Dermorphin was never developed into an approved medicine. Its main real-world footprint is in doping: its misuse went undetected in North American horse racing until 2011, which prompted laboratories to build sensitive tests to catch it in horse blood and urine^[1]. It should be understood as a potent opioid, with all the dangers that word carries.

Mechanism of Action

Dermorphin is an agonist at the mu-opioid receptor, the main receptor through which opioid drugs relieve pain and also produce euphoria, sedation and slowed breathing^[3,4]. Its sequence (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH₂) contains an alanine in the unusual mirror-image D-form^[3,4]. Early pharmacology studies in 1981 established it as an exceptionally potent opioid in animal tests^[2].

Studies in rats and mice exposed to dermorphins over time were reported to show greater pain-blocking potency than morphine and less tendency to produce tolerance and dependence^[3]. Those findings came from rodent experiments decades ago and have not been confirmed in people. Any drug that strongly activates the mu-opioid receptor carries the core risks of the opioid class, and nothing in the published record shows that dermorphin escapes them. In horses, the peptide remains stable in plasma at room temperature, which aids detection^[1].

What the Research Shows

• No published controlled human trials of dermorphin were identified for this entry. It has never been approved as a medicine in any country we could find.

• Laboratory animal pharmacology, 1981: the first pharmacological characterization described dermorphins as a new class of potent opioid peptides from amphibian skin^[2].
• Rats and mice, chronic exposure: a 1996 review reported higher pain-blocking potency and efficacy than morphine, with less tolerance, dependence and typical opioid side effects than morphine in these models^[3].
• Horses, doping-control research: after administration to research horses, dermorphin was measurable in plasma and urine with a test that detects as little as 10 pg/mL in plasma and 20 pg/mL in urine; the method was applied to official post-race samples^[1].

Open Questions

• Whether the reduced tolerance and dependence seen in old rodent studies has any relevance to humans; the claim is untested.
• Its toxicity, breathing effects and overdose threshold in people.
• How it is absorbed and how long it lasts by different routes in humans.
• How widely it is still misused in animal or human sport, since detection depends on labs actively testing for it.

Regulatory Status

Not approved by the FDA or any other regulator, and not nominated for 503A compounding as of May 2026^[5]. Misuse in North American horse racing was identified in 2011, and dedicated doping-control tests for horse plasma and urine have since been published^[1].

Related Compounds