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Best Peptides for Anxiety & Stress

Anxiety disorders affect over 300 million people worldwide, making them the most common mental health condition on the planet.

Anxiety disorders affect over 300 million people worldwide, making them the most common mental health condition on the planet. Standard treatments --- SSRIs, benzodiazepines, therapy --- help many people but leave a significant portion either undertreated or dealing with side effects like sexual dysfunction, weight gain, cognitive blunting, or dependence.

This gap has pushed researchers to look at peptides: short chains of amino acids that act as signaling molecules in the brain and nervous system. Some modulate the same GABA system that benzodiazepines target but without the addiction risk. Others work through brain-derived neurotrophic factor (BDNF), serotonin, dopamine, or the stress hormone cortisol.

None of these peptides are FDA-approved for anxiety or depression. Most of the research is preclinical. But the mechanisms are real, the early data is promising, and the science is worth understanding.

Table of Contents

How Peptides Affect Anxiety and Stress

Your brain runs on neuropeptides. These small protein fragments act as neurotransmitters, neuromodulators, and hormones. They regulate everything from mood and fear processing to the hypothalamic-pituitary-adrenal (HPA) axis --- the system that controls your cortisol response to stress.

Peptides studied for anxiety and stress work through several distinct pathways:

  • GABAergic modulation --- amplifying the brain's primary inhibitory neurotransmitter, GABA, which calms neural activity
  • BDNF upregulation --- increasing brain-derived neurotrophic factor, which helps neurons form new connections and repair existing ones, particularly in areas that process fear and regulate emotion
  • HPA axis regulation --- modulating the cortisol response, reducing the hormonal cascade that drives chronic stress
  • Serotonin and dopamine modulation --- adjusting levels of neurotransmitters directly linked to mood, motivation, and emotional regulation
  • Ion channel activity --- blocking specific potassium channels (like TREK-1) that are overexpressed in depression

Different peptides work through different combinations of these pathways. That is part of what makes this research interesting --- it is not a single-target approach.

Selank: The GABAergic Anxiolytic

Selank is a synthetic heptapeptide developed at the Institute of Molecular Genetics of the Russian Academy of Sciences. It is built on a fragment of the human immunoglobulin G heavy chain (tuftsin: Thr-Lys-Pro-Arg) with an added Pro-Gly-Pro tripeptide tail for metabolic stability.

Mechanism of Action

Selank modulates GABA-A receptors in a way that resembles benzodiazepines but without the downsides. The similarity of its physiological effects to classical benzodiazepines like diazepam initially suggested a shared mechanism, and subsequent research confirmed the connection.

A gene expression study found that Selank and GABA affect many of the same neurotransmission genes. When researchers analyzed 84 genes involved in neurotransmission in rat frontal cortex, they found significant changes in 45 genes within one hour of either Selank or GABA administration. The correlation between the two was positive --- Selank was hitting the same pathways as the brain's main inhibitory system [1].

Selank also suppresses IL-6 gene expression, linking its anxiolytic effects to anti-inflammatory actions in the brain [2].

Clinical Evidence

This is where Selank stands out from most peptides on this list: it has actual human clinical trial data.

In a study of 62 patients with generalized anxiety disorder (GAD) and neurasthenia, Selank's anxiolytic effects were comparable to medazepam (a benzodiazepine). But Selank also showed antiasthenic and psychostimulant effects that the benzodiazepine lacked --- meaning patients felt less anxious and more mentally alert, rather than sedated [3].

Combined with diazepam, Selank amplified the anxiolytic effect, suggesting it may increase benzodiazepine receptor affinity [4].

Safety Profile

Clinical studies showed no amnesia, withdrawal symptoms, or dependence --- the three main problems with long-term benzodiazepine use [2]. However, most published research comes from Russian institutions, and international validation remains limited. Selank is approved in Russia for anxiety treatment but is not FDA-approved.

Semax: BDNF and the Stress Response

Semax is a synthetic analog of ACTH(4-10), the fragment of adrenocorticotropic hormone responsible for its cognitive effects without its hormonal activity. Like Selank, it was developed in Russia and is approved there as a prescription medication.

Mechanism of Action

Semax works primarily through BDNF. A single intranasal dose (50 micrograms per kilogram) produces:

  • A 1.4-fold increase in BDNF protein levels in the hippocampus
  • A 1.6-fold increase in TrkB receptor phosphorylation (the receptor BDNF acts through)
  • A 3-fold increase in exon III BDNF mRNA levels
  • A 2-fold increase in TrkB mRNA levels [5]

These are not trivial changes. BDNF is the most important growth factor for the neural circuits that process anxiety and fear. Low BDNF levels are consistently found in people with depression and anxiety disorders. Every effective antidepressant --- SSRIs, SNRIs, exercise --- raises BDNF. Semax appears to do it directly and quickly.

Semax also activates both dopaminergic and serotonergic brain systems [6], which explains its combined cognitive-enhancing and mood-stabilizing effects.

Anxiety and Stress Research

Chronic Semax administration (0.05 mg/kg daily for 10 to 14 days) produced both anxiolytic and antidepressant effects in rats without affecting exploratory activity in non-stressful environments [7]. This is a useful distinction: it reduced anxiety without sedation or behavioral suppression.

The researchers attributed these effects to activation of the serotonergic system combined with increased hippocampal BDNF expression.

Current Status

Semax is approved in Russia for stroke treatment and cognitive enhancement. It is not FDA-approved and is primarily sold as a research compound outside of Russia and some Eastern European countries. Most published research is preclinical, though human studies for cognitive and neuroprotective applications exist.

BPC-157: The Gut-Brain Connection

BPC-157 is best known for tissue healing (see our guide on Best Peptides for Wound Healing), but its effects on the gut-brain axis make it relevant to anxiety and stress research.

The Gut-Brain Axis

BPC-157 is a gastric peptide --- it is derived from a protective protein naturally present in human stomach acid. The gut-brain axis refers to the bidirectional communication between the gastrointestinal tract and the central nervous system. Disruptions in this axis are increasingly linked to anxiety, depression, and stress disorders.

A comprehensive review in Current Pharmaceutical Design outlined how BPC-157 may bridge gut and brain function. From the gut side, it reduces serotonin release in the enteric nervous system and increases enteric neuron survival. From the brain side, it modulates both serotonin and dopamine systems in specific brain regions [8].

Dopamine and Serotonin Modulation

BPC-157 interacts extensively with the dopamine system. In animal models, it counteracts behavioral disturbances --- tremors, akinesia, catalepsy, and stereotypies --- that result from either too little or too much dopamine activity. Rather than simply raising or lowering neurotransmitter levels, BPC-157 appears to restore homeostatic balance [9].

For serotonin, even a single dose significantly alters the regional rate of serotonin synthesis in brain areas including the hypothalamus, hippocampus, substantia nigra, and dorsal raphe nucleus [8].

Anxiolytic Evidence

In behavioral studies, BPC-157 showed direct anxiolytic effects in the shock probe/burying test and the light/dark test --- standard animal models for measuring anxiety [10]. It also attenuated benzodiazepine tolerance and physical dependence, which suggests it could have a role in managing the withdrawal effects of anti-anxiety medications.

BPC-157 counteracted depression symptoms in Porsolt's forced swim test and the chronic unpredictable stress model, and it fully reversed serotonin syndrome manifestations in rats [8].

Practical Relevance

BPC-157's gut-healing properties may be independently relevant to anxiety. Conditions like irritable bowel syndrome (IBS) and inflammatory bowel disease have high comorbidity with anxiety disorders. A peptide that improves gut integrity while also modulating brain neurotransmitters could address both sides of the gut-brain connection. See also our guide on Best Peptides for Gut Health.

DSIP: Delta Sleep-Inducing Peptide and Cortisol

DSIP (Delta Sleep-Inducing Peptide) is a nine-amino-acid neuropeptide first isolated in 1974 from the cerebral venous blood of sleeping rabbits. Its name suggests a sleep-specific function, but its relationship to anxiety and stress runs deeper than sleep alone.

HPA Axis and Cortisol Regulation

DSIP decreases basal corticotropin (ACTH) levels and blocks its release, acting as what researchers have called a "stress-limiting factor." In depressive patients, both basal DSIP and cortisol concentrations were elevated compared to healthy controls, and they were highly correlated --- suggesting DSIP rises as part of the body's attempt to counteract excessive cortisol [11].

Low plasma DSIP has been found in patients with Cushing's syndrome, a condition defined by chronic cortisol excess.

Stress Tolerance

In controlled double-blind studies, DSIP normalized disturbed sleep and improved waking performance, but it also improved stress tolerance and coping behavior [12]. Sudakov et al. specifically studied DSIP's role in resistance to emotional stress, finding it had measurable effects on stress coping in animal models.

Limitations

DSIP research is mixed. Some studies show clear stress-modulating effects; others find no significant impact on ACTH and cortisol secretion. The primary receptor for DSIP has not been definitively identified, and effects appear to be dose-dependent and model-dependent. Long-term safety data is lacking.

PE-22-28: The TREK-1 Blocker

PE-22-28 (also called Mini-Spadin) is a synthetic heptapeptide that represents a different approach to anxiety and depression: blocking a specific potassium channel linked to depressive states.

The TREK-1 Connection

TREK-1 is a two-pore potassium channel expressed in the dorsal raphe nucleus --- the brain region where serotonergic neurons originate. When TREK-1 is overactive, it hyperpolarizes serotonergic neurons, reducing serotonin output. Genetic knockout of TREK-1 in mice produces an antidepressant phenotype [13].

PE-22-28 blocks TREK-1 with an IC50 of 0.12 nM --- roughly 300 to 500 times more potent than its parent compound spadin. By blocking TREK-1 in the dorsal raphe nucleus, PE-22-28 activates serotonergic neurons, increasing serotonin transmission in a manner similar to SSRIs [13].

Speed of Action

This is PE-22-28's most striking feature. Classical antidepressants (fluoxetine, sertraline) require 3 to 4 weeks to take effect. Spadin, the parent peptide, showed antidepressant activity within 4 days. PE-22-28 appears to match or improve on that timeline in animal models [13].

Neurogenesis

PE-22-28 stimulates neurogenesis and synaptogenesis in the hippocampus --- the growth of new neurons and new synaptic connections. This is significant because impaired hippocampal neurogenesis is considered a core feature of depression, and every effective antidepressant eventually promotes neurogenesis. PE-22-28 appears to trigger this process within days rather than weeks.

Current Status

All evidence is preclinical. No human trials have been conducted. PE-22-28 is selective for TREK-1 and does not affect the hERG cardiac channel, which is important for cardiac safety. But it remains an early-stage research compound.

Oxytocin: Social Stress and the Bonding Peptide

Oxytocin is a nine-amino-acid peptide hormone produced in the hypothalamus. It is often called the "love hormone" or "bonding peptide" for its roles in social attachment, trust, and maternal behavior. Its relationship to anxiety is real but complicated.

Anxiolytic Effects

Oxytocin has been described as a "profound anxiolytic and antistress factor of the brain" with effects on the amygdala --- the brain region that processes fear and threat. Intranasal oxytocin reduces amygdala reactivity to threatening stimuli [14].

In a clinical paradigm combining social stress with oxytocin administration, participants who received both social support and intranasal oxytocin showed the lowest levels of anxiety, cortisol, and autonomic nervous system activation [15].

Clinical trials in social anxiety disorder (SAD) have shown mixed but generally positive results. One randomized, double-blind trial found that six weeks of daily intranasal oxytocin significantly reduced social anxiety symptoms compared to placebo.

The Complication

Oxytocin is not purely anxiolytic. A Northwestern Medicine study found that oxytocin strengthens social memories --- and if those memories are stressful, the hormone can actually intensify fear and anxiety in response to future similar situations [16]. It increases stress sensitivity in negative social contexts while reducing it in positive ones.

Gender differences also emerge. Men given oxytocin reported less negative affect and showed greater vagal rebound after social stress, while women showed more anger and better task performance. The effects depend heavily on context, genetics, gender, and individual oxytocin receptor profiles.

Practical Takeaway

Oxytocin is not a straightforward anti-anxiety peptide. It amplifies social-emotional processing in both directions. In supportive environments, it reduces stress. In hostile or threatening environments, it may worsen it.

Neuropeptide Y: The Resilience Factor

Neuropeptide Y (NPY) is a 36-amino-acid peptide and the most abundant neuropeptide in the human brain. It is not available as an exogenous peptide therapy in the same way as the others on this list, but the research around NPY and stress resilience is too important to omit.

NPY and Military Stress Resilience

Some of the most striking NPY research comes from military studies. During survival training exercises (which simulate extreme combat stress), Special Forces soldiers showed significantly greater increases in plasma NPY compared to non-Special Forces soldiers. Their NPY levels also returned to baseline faster after the stress ended [17].

In combat veterans, those with PTSD had lower NPY levels than combat-exposed veterans without PTSD. Among veterans who recovered from PTSD, NPY levels were higher than in those who did not recover. The correlation is consistent: more NPY equals better stress coping [18].

Genetic Component

A functional polymorphism in the NPY gene promoter (rs16147) accounts for more than half of the variation in plasma NPY levels. The T allele is associated with resilience under conditions of high cumulative traumatic stress, particularly resilience against intrusion symptoms of PTSD [19].

Therapeutic Development

Intranasal NPY delivery has been tested in a Phase Ib double-blind, randomized, placebo-controlled trial in PTSD patients. High doses were associated with reduced anxiety on some measures and were well tolerated at all tested doses [20]. In animal models, intranasal NPY administered before or shortly after trauma exposure "has a pronounced resilient effect and ameliorates development of PTSD-like symptoms."

This provides proof of concept for prophylactic use in populations likely to experience traumatic stress --- first responders, military personnel.

Peptide Comparison Table

PeptidePrimary MechanismEvidence LevelKey AdvantageKey Limitation
SelankGABA-A modulation, IL-6 suppressionClinical trial (GAD patients)Benzodiazepine-like effects without dependenceMost research from Russian institutions
SemaxBDNF upregulation, serotonin/dopaminePreclinical + limited humanRapid, direct BDNF increaseNot FDA-approved; limited Western research
BPC-157Gut-brain axis, serotonin/dopamine balanceStrong preclinicalAddresses gut and brain simultaneouslyNo human trials for psychiatric applications
DSIPHPA axis, cortisol modulationMixed preclinical + limited clinicalStress-limiting factor, sleep improvementInconsistent findings; receptor unknown
PE-22-28TREK-1 blockade, serotonin activationPreclinical onlyRapid onset (days vs. weeks); neurogenesisNo human data; very early stage
OxytocinAmygdala modulation, social bondingMultiple human trialsStrong clinical evidence baseContext-dependent; can worsen anxiety
Neuropeptide YStress resilience, fear modulationMilitary studies + Phase Ib trialStrongest resilience biomarker dataDelivery challenges (BBB crossing)

What About Peptide Combinations?

Combining peptides for anxiety and stress is less established than stacking for physical healing (see our Peptide Stacking Guide). However, some researchers have noted potentially complementary pairings:

Selank + Semax --- These two Russian-developed peptides work through different mechanisms (GABA modulation versus BDNF upregulation) and are sometimes discussed together in nootropic research circles. Both are administered intranasally.

BPC-157 + Selank --- BPC-157's gut-brain axis effects combined with Selank's direct GABAergic anxiolytic action could theoretically address anxiety from both peripheral and central routes.

These are mechanistic hypotheses, not clinically validated protocols. No controlled studies have compared peptide stacks to individual peptides for anxiety outcomes.

Frequently Asked Questions

Which peptide has the best evidence for anxiety? Selank has the strongest clinical evidence, with a human trial showing effects comparable to a benzodiazepine in patients with generalized anxiety disorder. Oxytocin also has multiple human trials but with more variable results.

Can peptides replace anti-anxiety medication? No. Peptides for anxiety are not FDA-approved, and the evidence base does not support using them as replacements for established medications. They are research compounds that may eventually inform new therapeutic approaches. If you are currently taking anxiety medication, do not stop without consulting your doctor.

Are peptides for anxiety safe? Safety data varies by peptide. Selank showed no dependence or withdrawal in clinical studies. BPC-157 has no identified toxic dose in animal studies. But long-term human safety data is limited for all peptides on this list. The absence of known side effects is not the same as proven safety.

How quickly do anxiety peptides work? In animal models, Selank shows anxiolytic effects within hours of administration. Semax produced antidepressant effects within 10 to 14 days of chronic dosing. PE-22-28 showed antidepressant activity within days. Clinical timelines in humans may differ.

What about the gut-brain connection and anxiety? Growing evidence links gut health to mental health through the gut-brain axis. BPC-157's dual action on gut integrity and brain neurotransmitter systems makes it a particularly interesting candidate for people whose anxiety coexists with digestive issues.

Is neuropeptide Y available as a supplement? Not as a direct exogenous supplement in the way other peptides are. Research has focused on intranasal delivery, which is still experimental. Some lifestyle factors --- exercise, social connection, adequate sleep --- are associated with higher endogenous NPY levels.

The Bottom Line

Peptide research for anxiety and stress is in an earlier phase than many people realize. Selank stands out as the only peptide on this list with clinical trial data directly for generalized anxiety disorder. Semax has strong preclinical evidence for BDNF-mediated mood effects. BPC-157 offers a unique angle through the gut-brain axis. PE-22-28 represents a novel mechanism (TREK-1 blockade) with promising speed of action. And the neuropeptide Y research from military populations provides some of the most compelling evidence linking a specific peptide system to real-world stress resilience.

But none of these peptides are approved for treating anxiety. The regulatory environment is uncertain. Most evidence comes from animal models or small studies. And the gap between "shows anxiolytic effects in rats" and "reliably treats anxiety in humans" is the same gap that has claimed countless drug candidates over the decades.

If you are struggling with anxiety, established treatments --- cognitive behavioral therapy, medication, exercise, sleep optimization --- remain the evidence-based first line. Peptide research is worth following for what it tells us about the biology of stress and resilience. It is not yet a substitute for the tools we already have.

For related reading, see our guides on Best Peptides for Inflammation and Best Peptides for Athletic Performance.

References

  1. Volkova A, Shadrina M, Kolomin T, et al. Selank administration affects the expression of some genes involved in GABAergic neurotransmission. Frontiers in Pharmacology. 2016;7:31. PMC

  2. Zozulya AA, Gabaeva MV, Sokolov OY, Surkina ID, Kost NV. Peptide-based anxiolytics: the molecular aspects of heptapeptide Selank biological activity. Protein and Peptide Letters. 2018;25(10):914-923. PubMed

  3. Zozulia AA, Neznamov GG, Siuniakov TS, et al. Efficacy and possible mechanisms of action of a new peptide anxiolytic Selank in the therapy of generalized anxiety disorders and neurasthenia. Zhurnal Nevrologii i Psikhiatrii. 2008;108(4):38-48. PubMed

  4. Kasian A, Kolomin T, Narkevich V, et al. Peptide Selank enhances the effect of diazepam in reducing anxiety in unpredictable chronic mild stress conditions in rats. Behavioural Neurology. 2017;2017:5091027. PMC

  5. Dolotov OV, Karpenko EA, Inozemtseva LS, et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research. 2006;1117(1):54-60. PubMed

  6. Eremin KO, Kudrin VS, Grivennikov IA, Myasoedov NF, Rayevsky KS. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochemical Research. 2005;30(12):1493-1500. PubMed

  7. Levitskaya NG, et al. Semax, synthetic ACTH(4-10) analogue, attenuates behavioural and neurochemical alterations following early-life fluvoxamine exposure in white rats. Neuropeptides. 2021;86:102114. PubMed

  8. Sikiric P, Rucman R, Turkovic B, et al. Brain-gut axis and pentadecapeptide BPC 157: theoretical and practical implications. Current Neuropharmacology. 2016;14(8):857-865. PMC

  9. Sikiric P, et al. Pentadecapeptide BPC 157 and the central nervous system. Neural Regeneration Research. 2022;17(3):482-487. PubMed

  10. Klicek R, Sever M, Radic B, et al. Anxiolytic effect of BPC-157, a gastric pentadecapeptide: shock probe/burying test and light/dark test. Behavioural Pharmacology. 2001. ResearchGate

  11. Fischman AJ, Kastin AJ, Graf MV, Moldow RL. Delta-sleep-inducing peptide response to human corticotropin-releasing hormone in major depressive disorder. Peptides. 1988;9(2):393-397. PubMed

  12. Schneider-Helmert D. Effects of delta sleep-inducing peptide on sleep of chronic insomniac patients: a double-blind study. Psychopharmacology. 1987;91(4):445-447. PubMed

  13. Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M. Shortened spadin analogs display better TREK-1 inhibition, in vivo stability and antidepressant activity. Frontiers in Pharmacology. 2017;8:643. PMC

  14. Neumann ID, Slattery DA. Oxytocin in general anxiety and social fear: a translational approach. Biological Psychiatry. 2016;79(3):213-221. PubMed

  15. Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biological Psychiatry. 2003;54(12):1389-1398. PMC

  16. Guzmán YF, Tronson NC, Jovasevic V, et al. Fear-enhancing effects of septal oxytocin receptors. Nature Neuroscience. 2013;16(9):1185-1187.

  17. Morgan CA, Wang S, Southwick SM, et al. Plasma neuropeptide-Y concentrations in humans exposed to military survival training. Biological Psychiatry. 2000;47(10):902-909.

  18. Yehuda R, Brand S, Yang RK. Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping. Biological Psychiatry. 2006;59(7):660-663. PubMed

  19. Donner J, Sipilä T, Ripatti S, et al. Association between functional polymorphism in neuropeptide Y gene promoter rs16147 and resilience to traumatic stress in US military veterans. Journal of Clinical Psychiatry. 2019.

  20. Sayed S, Van Dam NT, Horn SR, et al. Randomized dose-ranging study of neuropeptide Y in patients with posttraumatic stress disorder. International Journal of Neuropsychopharmacology. 2018;21(1):3-11. Oxford Academic