Nootropic Peptides | Best Peptides For Brain Function

Researchers working in the field of nootropic peptides may be wondering about the best compounds for brain function.

To that end, our expert team has reviewed the latest clinical research on this rapidly evolving field to create this comprehensive guide on nootropic peptides.

Nootropic peptides have been linked with numerous benefits, including:

• Enhanced memory
• Improved focus
• Increased mental energy
• Reduced anxiety
• Neuroprotective effects

In this detailed review, researchers will discover the most potent peptides for brain function and cognition, including their mechanisms of action and potential side effects.

Let's cut to the chase and start with the three most potent nootropic peptides for memory and cognition.

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Top 3 Nootropic Peptides

Here are the top three most potent nootropic research peptides based on their cognitive-enhancing properties, safety profiles, and the levels of scientific evidence supporting their use.

1. Semax

Semax (aka ACTH(4-7)Pro-Gly-Pro) is an analog of an adrenocorticotropic hormone fragment known as ACTH(4-10). Both ACTH(4-10) and Semax do not have any effects on the endocrine system [1].

Thanks to its design, Semax passes through the blood-brain barrier (BBB), where it interacts with multiple neurotrophic factors and neurotransmitters [2, 3, 4, 5, 6].

As a result, the peptide exerts potent neuroprotective and nootropic effects. This has led to its clinical use in Russia for cognitive disorders, stroke, optic nerve damage, encephalopathies, and other neurological indications [7].

Clinical studies show that a single intranasal application of Semax can exert stimulant-like effects and significantly improve cognitive performance in fatigued individuals. In addition to intranasal formulations, Semax is also available in injectable form for research into its systemic effects [8, 9].

2. Selank

Selank is a synthetic analog of the human tetrapeptide tuftsin, an immunomodulatory peptide (part of immunoglobulin G) found in the blood of different mammals. Similar to Semax, Selank has the addition of Pro-Gly-Pro at its C-terminus [7, 10, 11].

As a result, Selank is able to pass the BBB, where it exerts its effects on a variety of neurotransmitters and neurotrophic factors [4, 10, 11, 12, 13, 14].

Currently, intranasal Selank is clinically approved in Russia for therapy in generalized anxiety disorder and cognitive disorders [7].

Its nootropic effects have been demonstrated in elderly subjects with disorders of vascular origin, as Selank leads to improved reaction time, memory, and attention. In addition to intranasal formulations, the peptide is also available as Selank injections for research [7, 15].

3. P-21 Peptide

P-21 (P021) is a unique peptide mimetic of ciliary neurotrophic factor (CNTF) and modified via adamantylated glycine at the C-terminus to pass the BBB [16].

It has been reported to upregulate neurogenesis and neuroplasticity, potentially by inhibiting the leukemia inhibitory factor and by increasing the expression of other neurotrophic factors [17].

As a result, the peptide is under active investigation for its potential nootropic and neuroprotective effects in conditions related to cognitive impairment. Preliminary research in rodents suggests that it may help ameliorate cognitive aging and synaptic dysfunction [18, 19].

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What is Peptide Therapy?

Peptide therapy is the application of therapeutic peptides in clinical settings. Therapeutic peptides are a unique class of synthetic compounds with a wide variety of implications [20].

Similar to peptides in the human body, therapeutic peptides are made of amino acid chains, usually 2-50 amino acids long, which can be further modified via the addition of non-peptide structures [21].

Like their natural counterparts, peptide therapeutics can regulate various psychological processes, including brain function, muscle growth, metabolism, and recovery, or act as messengers, relay signals between cells and organs, and exert endocrine functions [20, 21].

Peptide therapy has a relatively recent history dating back 100 years, which started with the development of the first peptide therapeutic in 1922: insulin [20, 22].

Currently, there are over 60 approved peptide-based drugs and numerous research peptides with potential therapeutic effects. This makes peptide therapy one of the most rapidly developing areas in pharmacological research with exciting implications for human health [20, 23].

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How Do Peptides Work For Brain Function and Cognition?

Peptides work for brain function and cognition by interacting with various physiological processes that depend on their ability to cross the BBB. The BBB is a semi-permeable membrane separating the brain's blood vessels from the surrounding neural tissue.

Ultimately, the BBB protects the brain from harmful substances, but it can also be a hurdle for therapeutic agents like peptides [24].

Nootropic peptides are specifically designed to permeate this barrier effectively and exert their influence on the brain's neurochemistry [7, 16].

Once in the brain, many of these peptides either stimulate or mimic the function of neurotrophic factors such as Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF), and Ciliary Neurotrophic Factor (CNTF) [5, 11, 16, 17].

These neurotrophic factors are proteins that support the growth, survival, and differentiation of both developing and mature neurons. They play a pivotal role in brain plasticity, which is crucial for learning, memory, and cognitive function [25].

In addition to neurotrophic factors, peptides can also interact with other molecules like neurotransmitters, hormones, or cellular receptors. They may modulate the function or expression of these entities, thereby impacting cognitive processes.

For example, some peptides might boost the levels of neurotransmitters such as dopamine, serotonin, and enkephalins, known for their roles in mood regulation, motivation, and reward [4, 14].

Others might interact with the receptors of growth factors like hepatocyte growth factor (HGF), influencing neurogenesis or mimic proteins such as Neural Cell Adhesion Molecule (NCAM), a cell surface protein involved in neuron-neuron adhesion, synaptic plasticity, and learning memory [26, 27, 28].

Regardless of the mechanism of action, nootropic peptides are promising compounds with potent benefits for brain function and cognition, as shown in both preclinical and clinical research [8, 18, 19, 29, 30, 31, 32, 33].

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Do Nootropic Peptides Actually Work?

The effectiveness of nootropic peptides has been the subject of intense research in both preclinical and clinical settings.

While many research peptides lack data from human trials, several other compounds have been tested and approved for human use in countries like Russia, Germany, and South Korea [7, 34].

The peptides Selank and Semax are already approved in Russia and Ukraine for a wide variety of neurological indications, ranging from stroke and dementia to optic nerve damage and anxiety disorders [7].

Further, a blend of nootropic peptides known as Cerebrolysin has earned endorsement from numerous European and Asian nations as a treatment for vascular dementia, Alzheimer's, acute ischemic stroke, and other neurological disorders [31, 34, 35].

In addition, an independent meta-analysis of six randomized controlled trials with a total of 597 participants reported that courses of intravenous Cerebrolysin improved cognition and general function in test subjects suffering from vascular dementia [31].

Therefore, there is a substantial amount of evidence for several nootropic peptides to indicate that they may induce cognitive benefits in test subjects.

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Best Peptides For Brain Function and Cognition

Nootropic peptides are among the most actively researched compounds in the peptide space. Below, we will cover the most notable and promising nootropics, including their mechanisms and potential benefits.

Semax

Semax is a synthetic analog of the ACTH(4-10) fragment that appears to possess potent neuroprotective and nootropic effects and is approved in Russia and Ukraine as an intranasal formulation [7].

Thanks to its design, the peptide can pass through the BBB barrier within 1-2 minutes after administration as either Semax injections or intranasal Semax. Once in the brain, it regulates levels of the neurotrophic growth factors Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) [2, 5, 6, 36].

Via the activation of BDNF and NGF, Semax is thought to reduce inflammation, increase neuroplasticity, and enhance brain cell tolerance to negative conditions such as hypoxia that occur in brain stroke [37, 38]. In addition, the peptide also appears to regulate levels of serotonin, dopamine, and enkephalins in brain tissue [3, 4]

Based on these numerous interactions and its potent neuroprotective effects in various neurological conditions such as stroke, the peptide has also been investigated as a potential nootropic agent in healthy individuals [7, 8, 39].

For example, one study showed that a single intranasal dose of 1000mcg Semax (about 16mcg/kg) improved memory test accuracy for 24 hours by 71% in fatigued study volunteers post an 8-hour work shift, compared to 41% accuracy in the control group [8].

In addition, Semax is also available as an acetylated and amidated version called N-Acetyl Semax Amidate. This chemical transformation is reported to modify its interactions with copper ions and redox agents, thus improving its overall stability [40, 41].

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Selank

Selank can also effectively pass through the BBB, regardless of whether it is applied via injection or intranasally [15]. Inside brain tissue, the peptide appears to interact with a variety of brain neurotransmitters, including GABA, enkephalins, dopamine, serotonin, and norepinephrine [4, 10, 12, 13, 14].

Notably, the peptide appears to inhibit the degradation of enkephalins, which are the natural ligands of the opioid receptors, and their regulation plays a role in mood, desire, and nociception [4, 12]. The peptide also upregulates GABA and serotonergic signaling, which are known to have relaxant, anxiolytic and antidepressant effects [10, 13].

Similar to Semax, Selank can also increase neuroplasticity by promoting the expression of the neurotrophic factor BDNF [11].

Overall, these benefits result in potent anxiolytic and nootropic effects. Studies in older subjects with cerebral perfusion disorders reveal improvement in reaction time, memory, and attention [7].

Further, research in test subjects with anxiety-phobic, hypochondriac, and somatoform disorders report that Selank may minimize the side effects of benzodiazepines on cognition, such as attention and memory impairment [29].

The peptide can also be modified via acetylation and amidation, resulting in a derivative known as N-Acetyl Selank Amidate, which may possess improved stability.

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P-21 Peptide

P-21 stands out as a nootropic and neuroprotective compound that actively passes through the BBB and interacts with neurotrophic factors in the brain [17].

It was developed in the 2000s via epitope mapping of antibodies to the endogenous neurotrophic factor CNTF, which helped locate the most active regions of the CNTF sequence [16].

The peptide appears to work by inhibiting the leukemia inhibitory factor (LIF) signaling pathway and by enhancing the transcription and expression of BDNF. The peptide may also upregulate the expressions of pCREB, which is associated with long-term memory formation [42, 43].

Unfortunately, clinical research on P-21 is lacking. Yet, studies on rats show that the peptide may prevent the age-related decline in cognition, learning, and memory [18, 19].

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Dihexa

Dihexa (aka PNB-0408, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a first-in-class synthetic peptide that is under research for its potential in the treatment of neurodegenerative diseases [30].

It is derived from the molecule of angiotensin IV, based on the available research regarding the potential nootropic properties of angiotensins [44].

Dihexa has undergone N- and C-terminal modifications, which allow it to actively pass through the BBB to exert its effects on the brain [30].

Dihexa has a strong affinity for the brain's hepatocyte growth factor (HGF)/c-Met receptor system. Studies suggest that the activation of the c-Met receptor in later stages of life can spur neurogenesis and offer protection against tissue damage in a variety of cell types, including brain cells [26, 27].

At present, no clinical trials on Dihexa have been conducted or initiated. However, existing rat studies suggest that Dihexa could enhance cognitive function, as demonstrated by the Morris water maze test, and in vitro rat brain cell experiments show that a five-day course of Dihexa nearly triples the count of dendritic spines [30]

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Cerebrolysin

Cerebrolysin, also known as FPF-1070, is a compound composed of 80% low-molecular-weight peptides and 20% free amino acids derived from pig brain [45, 46].

It reportedly exhibits neuroprotective and neurotrophic effects akin to endogenous growth factors like NGF and BDNF, and potentially enhances cognitive performance, including memory, through upregulation of NGF expression [47].

A total of 638 unique peptides have been reported in Cerebrolysin, although none directly correspond to known trophic factors or precursors. It is theorized that these active peptides might be part of proteins harboring concealed functional peptide sequences [48].

Numerous clinical trials have explored the effects of intravenously administered Cerebrolysin in individuals with neurological conditions such as ischemic stroke and vascular dementia.

A 2019 Cochrane review indicates that available data suggest a potential for enhanced cognition, memory, and overall function in vascular dementia patients, without associated adverse effects. However, no notable benefits in stroke patients have been reported [31, 35].

As of writing, Cerebrolysin is approved for human use in Austria, China, Germany, Russia, and South Korea but not in the United States [34].

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FGL

FGL, aka FG loop peptide, is a neurotrophic pentadecapeptide known for its ability to mimic neural cell adhesion molecule (NCAM) activity. The peptide has a 15-amino acid sequence in the second fibronectin type III module of NCAM, which is a binding site for the fibroblast growth factor receptor (FGFR) [28].

Preliminary research suggests that FGL may improve cognitive performance, reduce anxiety-like behavior, and have neuroprotective effects in rat models of aging and neurodegenerative conditions [32, 49, 50].

Clinical research regarding the peptide is scarce, and as of writing, there is only one clinical trial published. According to the authors, the peptide was administered intranasally and showed an excellent safety profile with no side effects, but the investigators did not report data on its nootropic effects [51].

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PE-22-28

PE-22-28 is a 7 amino acid peptide that was developed from studying spadin's degradation products in the blood [33].

Spadin is a peptide derived from another protein called sortilin, and it has therapeutic potential for treating depression due to its ability to block the TREK-1 potassium ion channel in the brain. TREK-1 inhibition has been linked to potential therapeutic effects in treating depression by promoting neuronal activity and mood regulation [52].

In vitro studies demonstrated that PE 22-28 has a higher specificity and affinity for the TREK-1 channel than spadin. It also has a lower IC50 meaning that less of the compound is needed to achieve the desired effect [33].

In behavioral models of depression, such as the forced swimming test and the novelty-suppressed feeding test, PE 22-28 demonstrated potent antidepressant properties. The peptide also induced neurogenesis and enhanced synaptogenesis, indicating an increased formation of synapses between neurons and potential cognitive enhancing effects [33].

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Peptides For Brain Health | Side Effects and Safety

Nootropic peptides come with potential side effects and risks. The nature and severity of these side effects will differ from one peptide to the next and depend on the dosage and route of administration.

Therefore, no general conclusions can be made regarding the safety of nootropic peptides, and researchers should refer to individual peptide studies and guidelines for side effects and contraindications. Here is a brief rundown of select compounds:

• The nootropic peptides Semax and Selank have shown favorable safety profiles with minor risks of side effects. Unfortunately, the majority of trials do not mention specific side effects but state that they are mild and transient [7].
• Other clinically tested peptides like Cerebrolysin have not shown any notable side effects according to several meta-analyses encompassing the majority of human trials [31, 35, 53].
• Preliminary clinical research on FGL also shows a favorable safety profile and no adverse reactions following the intranasal administration in 24 healthy subjects [51].
• Researchers should be aware of the risk of unexpected side effects in test subjects when administering peptides that have little to no published clinical data. These include peptides such as P-21, Dihexa, and PE-22-28.

Scientists should also consider the risk of side effects associated with the route of administration. The majority of nootropic peptides can be administered either subcutaneously or intranasally, while Cerebrolysin is also often administered via intravenous infusion [53].

Subcutaneous administration carries a risk of local reactions at the injection site, including pain, swelling, bleeding, and redness. Intranasal administration can lead to irritation of the mucosal membranes in the nose and throat.

In general, most nootropic peptides have not been studied in conditions such as pregnancy and lactation. Therefore, researchers should exclude pregnant and breastfeeding subjects from nootropic peptide research.

Further, common contraindications for peptides in general, including nootropic compounds such as Cerebrolysin, are allergies to any of the ingredients and severe renal failure [53].

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Nootropic Peptides | FAQ

Below, our expert panel provides evidence-based answers to some of the most frequently asked questions by researchers delving into the field of nootropic peptides.

What is the best peptide for cognitive function?

The best nootropic peptide for cognitive function depends on factors like the research objective and targeted outcome. For example, the nootropic peptide Semax has demonstrated significant benefits for cognitive function in study volunteers suffering from acute stroke [39].

Another notable peptide, Selank, has demonstrated cognitive benefits for patients with anxiety-related disorders [29]. The peptide compound Cerebrolysin has also shown benefits in vascular dementia [31].

Are peptides good for the brain?

Several nootropic peptides have demonstrated clinically-significant benefits for brain health in study volunteers suffering from stroke, neurodegenerative, and other neurological disorders. Notable examples include Semax, Selank, and Cerebrolysin [7, 31, 35].

What is the best peptide for memory loss?

Both Selank and Semax have been shown to improve memory in both young and older adults with vascular dementia. In fact, Semax has been reported to improve memory test results after a single administration [7, 8].

The multi-peptide compound Cerebrolysin has shown potential efficacy in traumatic brain injury (TBI), a condition commonly associated with memory loss [53].

What are smart peptides?

“Smart peptides” is an informal term that may refer to nootropic peptides, or peptides that enhance cognitive functions like attention, memory, and learning capacity. Examples of nootropic or “smart” peptides include Semax, Selank, P-21, Dihexa, Cerebrolysin, FGL, and PE-22-28.

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Peptide Nootropics | Verdict

In summation, nootropic peptides have emerged as highly promising agents with the potential to revolutionize the medical and pharmaceutical arenas, piquing the interest of distinguished researchers across the globe.

Nootropic peptides that are available as reference materials for research include Semax, Selank, P-21, and PE-22-28. They offer a wide range of potential benefits for subjects with neurological conditions as well as for healthy test subjects.

Nootropic peptides should be studied strictly by trained lab experts and procured from a reputable source.

Qualified researchers may legally purchase high-purity nootropic peptides as reference materials from trusted vendors. We recommend Limitless Life Nootropics.

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