Brain peptides! Which ones can help the brain?

Neuropeptides for cognition are having a moment. Specifically, there are six neuropeptides that are part of the general discussion: Cerebrolysin, Semax, Selank, Dihexa, P21, and FGL. Three questions determine whether any of these peptides are clinically useful: does it reach the target, has it been documented to produce desired effect once it gets there, and what is the regulatory status.

Some important housekeeping notes: Semax was just preliminarily approved by the PCAC Committee a couple days ago to be added to the 503A bulk list. Dihexa is being considered for addition in the upcoming February 2027 PCAC meeting.

Delivery of therapeutic peptides to the brain is the first hurdle as the blood-brain barrier is a notoriously tough barrier for targeted therapies. Formed by tight junctions between the endothelial cells lining cerebral capillaries, this barrier exists to protect the brain and disallow movement of many large molecules. Passive diffusion through the barrier is only available for lipid soluble molecules under 400–500 Daltons. By that standard, more than 98% of small-molecule drugs and effectively 100% of biologics fail to enter the brain in pharmacologically meaningful amounts. Sometimes molecule modifications can be made to allow for better BBB permeability and permit oral or IV dosage forms.

With large peptides that do not have the ability to passively diffuse through the barrier, intranasal dosage forms are used. Intranasal administration allows these larger molecules to have direct access to the central nervous system (CNS) through olfactory neurons and the trigeminal pathway. This delivery system is very useful but if administered incorrectly can be ineffective where the dose droplets are swallowed through the throat. Standard technique can be demonstrated by a physician: tilt head back slightly, exhale, insert applicator into nostril, spray during gentle inhalation, hold breath briefly, repeat in the other nostril. Patients who spray into the lower nasal cavity or inhale too deeply, dose the wrong tissue and get minimal CNS effect.

Cerebrolysin

Summary

• A mix of low-molecular-weight peptide fragments and free amino acids derived from porcine brain protein

• Administered intravenously (IV) or intramuscularly (IM)

Uses

• Acute ischemic stroke and post-stroke rehabilitation

• Traumatic brain injury

• Vascular dementia

• Alzheimer’s disease

Cerebrolysin was first developed in 1949 by Australian professor Gerhart Harrer. In the 1970s researchers in Austria began studying the effects of peptides on the brain.

In animal models of Alzheimer’s disease, Cerebrolysin promoted the growth of new neurons in the hippocampus and increased synapse formation, and modulates the Sonic Hedgehog (Shh) signaling pathway, which is involved in stem cell differentiation and tissue repair.

It was approved for use in the late 1990s and early 2000s in several countries including Austria, Germany, Russia, China, Czech Republic, Slovakia and Ukraine. It is currently approved in 45 different countries - just not the United States. Formal clinical studies began in 1973 and continued throughout the 1980s and 1990s.

Cerebrolysin is a naturally derived therapeutic isolated from porcine brain protein. The preparation contains fragments with neurotrophic activity resembling NGF, BDNF, CNTF, and GDNF, along with enkephalin and orexin fragments. Documented effects include protection against glutamate excitotoxicity and oxidative stress, reduced beta-amyloid deposition, decreased tau hyperphosphorylation, reduced perivascular microgliosis and astrogliosis, and increased GluR1 density in hippocampal formations. It addresses the cellular biology of neurodegeneration across several routes at once rather than targeting a single pathway.

For acute ischemic stroke, the 2023 Cochrane review pooled seven randomized controlled trials totaling 1,773 participants. Moderate-certainty evidence indicated no benefit on all-cause death, no benefit on the total number of patients with serious adverse events, and a potential increase in non-fatal serious adverse events. That is a negative review from the most methodologically conservative body in the field, and it has now been the conclusion across multiple update cycles.

For stroke rehabilitation, the picture is more favorable. The CARS trial randomized patients to 30 mL Cerebrolysin daily for 21 days alongside standardized rehabilitation, and reported a large effect on upper limb motor function at day 90 (Action Research Arm Test; Mann-Whitney estimator 0.71, 95% CI 0.63–0.79, P<0.0001). The authors themselves flagged the study as exploratory and small, requiring confirmation.

For traumatic brain injury (concussions), the CAPTAIN trial series used a multidimensional outcome ensemble analyzed by the Wei-Lachin procedure. CAPTAIN I missed statistical significance on the primary ITT endpoint; the prospective meta-analysis of the series (185 patients) reported benefit at days 30 and 90.

For vascular dementia, the Cochrane review found improvement in cognition and global function with no adverse signal, but concluded the evidence was insufficient to recommend routine use — six trials, 597 participants, most industry-supported, substantial heterogeneity.

Semax

Summary

• Based on natural ACTH (adrenocorticotropic hormone)

• MW 813.9 g/mol

• Heptapeptide; sequence Met-Glu-His-Phe-Pro-Gly-Pro

Uses

• Stroke recovery (acute and post-acute phases)

• Transient ischemic attack (TIA)

• TBI and post-concussion syndrome cognitive symptoms

• Memory and cognitive disorders

• Anxiety and depression

• ADHD-like symptoms in some clinical contexts

• Neuroprotection against hypoxia and glutamate excitotoxicity

• Optic nerve support

• Peptic ulcer disease (peripheral effect)

• Cognitive optimization in healthy patients

Semax was developed in Russia in the 1980s as a synthetic analog of ACTH designed for stroke recovery. Throughout the years, it has since accumulated clinical use across cognitive support, anxiolytic applications, and neuroprotection. Russian clinical literature describing Semax exists but is underutilized in Western medicine in large part due to the language barrier and difference in study design.

A notable randomized, double-blind, placebo-controlled stroke trial reported reduced 30-day mortality and improved neurological recovery. Data has also been published to show measurable increases in plasma BDNF alongside Barthel index and motor scale improvement in post-stroke cohorts and chronic cerebrovascular insufficiency.

Mechanistically, the peptide works through neurotrophin upregulation. Additional reported mechanisms include dopaminergic and serotonergic modulation. In rat studies, a single dose of Semax produced up to a 1.4-fold increase in hippocampal BDNF protein, a 1.6-fold increase in TrkB tyrosine phosphorylation, and threefold and twofold increases in exon III BDNF and TrkB mRNA respectively, alongside improved conditioned avoidance performance. In permanent middle cerebral artery occlusion models, Semax activates transcription of neurotrophins and their receptors in cortex, and genome-wide analysis shows effects on immune and vascular system gene expression after focal ischemia.

Just this past week, Semax was just preliminarily approved by the PCAC Committee a couple days ago to be added to the 503A bulk list. That means that there is a very good chance by the end of 2026, or early 2027, Semax will be available to be safely and legally compounded by pharmacies in the United States.

Semax is one of the few neuropeptides that produces noticeable subjective cognitive effects in the short term. Patients often report mental clarity, reduced anxiety, and improved focus within days of beginning intranasal Semax therapy. This rapid feedback distinguishes Semax from compounds where effects emerge over weeks and reinforces patient compliance during the longer-term protocol.

Some of my patients really love Semax.

Selank (or TP-7)

Summary

• Synthetic analog of human tuftsin (IgG fragment)

• MW = 751.89 g/mol

• 7 amino acid sequence: Thr-Lys-Pro-Arg-Pro-Gly-Pro

Uses

• Generalized anxiety disorder

• Depression with anxiety component

• Asthenia (chronic fatigue with cognitive component)

• Sleep balance regulation (without sedation)

• Memory and cognitive function support

• Antiviral activity in some clinical contexts

• Inflammation regulation

• Adjunct in stress-related conditions

• Cognitive optimization in healthy patients with anxiety component

Selank is another Russian peptide, in use since the 1990s. It is based on tuftsin, a naturally occurring immune tetrapeptide cleaved from IgG. It has full approval in Russia for use as an intranasal prescription.

The primary clinical study cited compares Selank against medazepam in patients with generalized anxiety disorder and neurasthenia. Selank matched the benzodiazepine in calming anxiety without the sedative effect, dependency, or cognitive impairment associated with benzodiazepines. Its mechanisms include: modulation of interleukin-6; balanced T cell cytokine effects; elevated BDNF in the hippocampus; influence on monoamine neurotransmitters; reduced breakdown of enkephalins; increased inhibitory action of GABA; regulation of BCL6 protein (an important transcriptional regulator of the immune system).

I’ve prescribed Selank many times, and it doesn’t get quite the same positive response that Semax does. Some patients will choose to alternate the two, with a common protocol using Semax (Monday, Wednesday) and Selank (Tuesday, Thursday).

There is a chance that Selank is under consideration to be discussed by the PCAC Committee in February 2027 to be added to the 503A bulk list, along with Dihexa.

Dihexa

[ATH-1017 (Fosgonimeton), and ATH-1105 (Brelgometon)]

Summary

• Targets the Hepatocyte Growth Factor (HGF) / c-Met

• Different modified dipeptide versions of sequence: Tyr-Ile

Proposed Uses

• TBI and post-concussion syndrome

• Post-stroke cognitive rehabilitation

• Memory disorders

• Parkinson’s disease (preclinical motor models)

• Age-related cognitive decline

• Amyotrophic lateral sclerosis (ALS)

Dihexa was designed in the 2010s at Washington State University as a metabolically stabilized angiotensin IV analog, engineered with a lipophilic modification specifically to cross the blood-brain barrier. Dihexa is a small enough molecule that testing has been performed on oral formulations. Dihexa did not make it past mouse studies as it lacked optimal pharmacokinetic properties for human delivery. The research team redesigned Dihexa using the same theoretical pathway into a differently modified peptide Fosgonimeton/ATH-1017 and now ATH-1105.

ATH-1017 progressed into human trials for Alzheimer’s disease with favorable Phase 1 safety profiles but the program was ultimately scrapped after Phase 3 trials failed to show slowing cognitive decline in the treatment group. ATH-1105 is currently under review with positive results from Phase 1 trials recently published. ATH-1105 is targeting approval for treatment of Amyotrophic lateral sclerosis (ALS). The company commercializing these therapies is M3 Biotechnology/Athira Pharmaceuticals/LeonaBio and they recently were in the news settling a whistleblower claim with the US government over the previous CEO’s past academic research misconduct.

P21

Summary

• Based on ciliary neurotrophic factor (CNTF)

• MW 578.3 g/mol

• Modified peptide with backbone sequence: Asp-Gly-Gly-Leu-Ala-Gly

Proposed Uses

• Alzheimer’s disease and related tauopathies

• TBI and post-concussion recovery

• Age-related cognitive decline

• Hippocampal neurogenesis support

P21 came out of a New York based research institute, first published in the 2010s. As a small peptide, the exact formulation is designed for better blood-brain barrier permeability and is dosed orally. The specific mechanism of action is similar to that of Cerebrolysin. Currently P21 has only been published in mouse models. P21 is also referred to as P021, and P21 adamantane in the literature.

FGL

Summary

• Based on the neural cell adhesion molecule (NCAM), FG loop region

• 15 amino acid sequence: EVYVVAENQQGKSKA

Uses

• Neuroprotection following ischemic injury

• Cognitive support in age-related decline

• Neuroinflammation modulation

• Synaptic and memory consolidation support

FGL was developed at the University of Copenhagen by Elisabeth Bock and Vladimir Berezin as part of a program mapping functional motifs within NCAM. NCAM mediates neuron-to-neuron adhesion and is central to synaptic plasticity and learning, but the full protein is not druggable. FGL reproduces the single functional motif that binds FGFR1, allowing that pharmacology to be accessed with a short peptide. It roughly doubles FGFR1 phosphorylation, activating downstream Ras-MAPK and PI3K-Akt signaling.

Preclinically, FGL induces neurite outgrowth, promotes synaptogenesis, and enhances presynaptic function. Administered to rats immediately after fear conditioning or water maze training, it produced long-lasting memory improvement. It also carries a distinct anti-inflammatory profile: in aged rats it attenuated microglial activation markers and the IL-1β increase while restoring long-term potentiation, and after middle cerebral artery occlusion it mobilized endogenous neural stem cells and induced remyelination. Phase 1 trials were published with positive human safety results in 2007, though Phase 2 and 3 efficacy data has yet to follow.

Recent Regulatory Updates

In 2023, FDA classified a large group of peptides onto the Category 2 list prohibiting 503A compounding. These affected peptides included Semax, Selank acetate (TP-7), and Dihexa acetate. Earlier this year, all three of these peptides were part of the list of substances that were then removed from the Category 2 classification.

This past week in the meeting of the Pharmacy Compounding Advisory Committee (PCAC) which advises on FDA policies, Semax was recommended to be considered for inclusion on the 503A Bulks List for cerebral ischemia, migraine, and trigeminal neuralgia. Selank and Dihexa were not on the list of molecules considered during the meeting, but will be considered at the upcoming meeting in February 2027.

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