Anxiety and depression affect several signaling systems in the brain. While most treatments target neurotransmitters such as serotonin or norepinephrine, researchers have also studied peptides and neuropeptides that regulate stress, fear, mood, sleep, and emotional resilience.
Neuropeptides are short chains of amino acids used by neurons to communicate. Some also act as hormones elsewhere in the body. Neuropeptide Y, oxytocin, and thyrotropin-releasing hormone occur naturally in humans, while Selank and nemifitide are synthetic peptides developed to influence related biological pathways.
Human studies have found promising results with several peptides for anxiety and depression. The evidence is still limited, and none of these findings proves that an experimental peptide is an established treatment. However, the clinical results show that peptide signaling can influence depression, generalized anxiety, social anxiety, and trauma-related symptoms.
Important: This article reviews clinical research. It does not provide a dosing protocol or recommend using unapproved peptide products to treat a mental health condition.
Neuropeptide Y Improved Depression and Trauma-Related Anxiety
Neuropeptide Y, or NPY, is a naturally occurring neuropeptide made from 36 amino acids. It is widely distributed throughout the brain and nervous system.
NPY helps regulate fear, appetite, sleep, stress responses, and emotional resilience. Researchers are especially interested in its ability to reduce the biological effects of severe stress. Lower NPY activity has been observed in some people with depression and trauma-related disorders, suggesting that weakened NPY signaling may make it harder for the brain to recover from prolonged stress.
A randomized controlled trial tested intranasal NPY in 30 people with major depressive disorder. Participants remained on stable antidepressant treatment and received either a single NPY administration or a placebo.
Depression scores improved more after NPY at five hours and 24 hours. The 24-hour difference represented a moderate treatment effect. However, the difference was no longer statistically significant at 48 hours, which was the study’s primary endpoint.
These results suggest that the neuropeptide produced a rapid but temporary antidepressant signal. The study did not show that one administration could provide lasting relief. It did show that directly increasing NPY activity could affect depressive symptoms within one day.
The original publication was A Randomized Controlled Trial of Intranasal Neuropeptide Y in Patients With Major Depressive Disorder. PMID: 33009815.
NPY was also studied in 26 people with post-traumatic stress disorder. Participants received intranasal NPY and placebo on separate treatment days. Researchers then exposed them to personalized trauma-related scripts and measured their anxiety responses.
Higher NPY doses were associated with a greater reduction in anxiety on the Beck Anxiety Inventory. The State-Trait Anxiety Inventory did not show the same significant dose-related result. NPY was reported as well tolerated through the highest dose tested.
The PTSD study was titled A Randomized Dose-Ranging Study of Neuropeptide Y in Patients With Posttraumatic Stress Disorder. PMID: 29186416.
Together, the depression and PTSD trials show that NPY can influence human mood and trauma-related anxiety. The benefits were limited to certain measurements and short periods, but both studies produced a measurable clinical signal.
Selank Reduced Anxiety and Fatigue
Selank is a synthetic heptapeptide made from seven amino acids. Its sequence was developed from tuftsin, a naturally occurring peptide involved in immune regulation.
Although Selank is frequently marketed as a nootropic, its most relevant clinical research involves anxiety disorders. It was developed primarily for its possible anxiolytic, or anxiety-reducing, properties.
A human study examined 62 people diagnosed with generalized anxiety disorder or neurasthenia. Thirty participants received Selank, while 32 received medazepam, a benzodiazepine-class anti-anxiety medication used in some countries.
Researchers reported that Selank reduced anxiety and produced anti-fatigue effects. These findings were especially relevant because chronic anxiety can cause exhaustion, poor concentration, reduced motivation, and persistent physical tension.
The researchers also examined Selank’s relationship with enkephalins. Enkephalins are naturally occurring opioid peptides that help regulate pain, stress, and emotional responses.
Selank may reduce the breakdown of enkephalins, allowing these natural regulatory peptides to remain active longer. A separate investigation found that Selank inhibited enzymes involved in enkephalin degradation, offering one possible explanation for its anxiety-reducing effects.
The primary clinical paper was titled Efficacy and Possible Mechanisms of Action of a New Peptide Anxiolytic Selank in the Therapy of Generalized Anxiety Disorders and Neurasthenia. PMID: 18454096.
Another comparative study examined Selank against phenazepam in 60 people with phobic-anxiety, generalized anxiety, or somatoform disorders. The researchers reported therapeutic anxiety reduction with Selank, providing additional human evidence beyond the original generalized anxiety study. PMID: 25176261.
Selank therefore has direct human evidence involving diagnosed anxiety conditions. Its research base remains relatively small and is largely concentrated among Russian investigators, but the published studies reported improvement in anxiety symptoms rather than only changes in laboratory markers or animal behavior.
MIF-1 and Nemifitide Produced Antidepressant Responses
MIF-1 is a naturally occurring tripeptide made from three amino acids: proline, leucine, and glycine. Its full sequence is Pro-Leu-Gly-NH₂.
MIF-1 should not be confused with macrophage migration inhibitory factor. That is an unrelated immune protein that uses the same abbreviation.
MIF-1 has been investigated as a neuropeptide with possible antidepressant effects. Early researchers were especially interested in how quickly some participants appeared to respond.
In a double-blind pilot study, 20 people with major depression received either subcutaneous MIF-1 or placebo for five consecutive days.
By the end of the first week, eight of the nine participants initially given MIF-1 showed marked improvement. Only two of the 11 participants initially given placebo experienced the same level of improvement.
The study then crossed the treatment groups. Participants who initially received placebo began receiving MIF-1, and substantial improvement was again reported after the peptide was introduced.
The study was titled Improvement in Major Depression After Low Subcutaneous Doses of MIF-1. PMID: 7989637.
An earlier clinical investigation also reported rapid responses to MIF-1 in people with major depressive illness. That study used several depression-rating tools to evaluate changes after treatment. PMID: 6138756.
Nemifitide was later developed from the MIF-1 research program. It is a synthetic pentapeptide made from five amino acids and was previously identified as INN 00835.
A double-blind, placebo-controlled pilot study enrolled 52 people with major depression. Participants received either nemifitide or placebo for five consecutive days and were then followed for four weeks.
Participants who reached adequate blood concentrations of nemifitide showed greater improvement than the placebo group. The results also suggested a relationship between blood exposure and antidepressant response. Some benefits continued during follow-up after the five-day treatment period had ended.
The study was titled A Double-Blind, Placebo-Controlled, Efficacy, Safety, and Pharmacokinetic Study of INN 00835 in the Treatment of Major Depression. PMID: 11099750.
A later multicenter study included 81 people with major depressive disorder. Participants received either 30 milligrams of nemifitide, 45 milligrams, or placebo.
The 45-milligram group showed a statistically significant advantage over placebo at the point of greatest effect, which occurred one week after treatment ended. Participants who started with more severe depression appeared to experience stronger benefits.
The multicenter study was titled Efficacy and Safety of 30 mg/d and 45 mg/d Nemifitide Compared to Placebo in Major Depressive Disorder. PMID: 16259645.
MIF-1 and nemifitide are closely related parts of the same peptide research program. Both produced antidepressant signals in human studies, and some improvements appeared after relatively short treatment periods.
The trials were small, and the results were not equally strong across every dose or participant group. Still, the repeated findings show that these peptide compounds affected depressive symptoms in controlled clinical research.
Oxytocin Supported Certain Effects of Therapy
Oxytocin is a naturally occurring neuropeptide and hormone made from nine amino acids. It is involved in childbirth, lactation, bonding, social recognition, emotional processing, and stress regulation.
It is often called the “love hormone,” but that description is too simple. Oxytocin can increase attention to social information without always making that information feel positive.
Its effects may change based on trauma history, biological sex, baseline anxiety, and the emotional context of an interaction. Researchers have therefore studied oxytocin as a possible addition to psychotherapy rather than assuming it works as a direct stand-alone anxiety treatment.
A randomized controlled trial examined 25 people receiving exposure therapy for social anxiety disorder. Participants received either intranasal oxytocin or placebo alongside the therapy.
People who received oxytocin developed more positive evaluations of their appearance and speaking performance during treatment. However, oxytocin did not produce greater overall improvement in anxiety severity, dysfunctional thoughts, or daily functioning compared with placebo.
The study was titled A Randomized Controlled Trial of Intranasal Oxytocin as an Adjunct to Exposure Therapy for Social Anxiety Disorder. PMID: 19246160.
The results suggest that oxytocin affected a specific part of the therapeutic process. Participants viewed their social performance more positively, even though their overall social anxiety outcomes were not significantly better.
Oxytocin has also been examined in depressive disorders. A 2025 systematic review evaluated randomized trials of intranasal oxytocin across major depression, treatment-resistant depression, and postpartum depression.
The review found evidence that oxytocin may improve outcomes when added to psychotherapy or medication for major depressive disorder and treatment-resistant depression. In postpartum depression, it improved some maternal perceptions and responses toward infants, but mood improvements were inconsistent.
The review was titled Effects of Intranasal Oxytocin Across Various Depressive Disorders. PMID: 40798888.
Oxytocin’s strongest potential may be as an adjunctive neuropeptide. Rather than acting like a conventional antidepressant, it may influence emotional learning, social interpretation, and engagement with therapy.
Thyrotropin-Releasing Hormone Acted Within Hours
Thyrotropin-releasing hormone, or TRH, is a naturally occurring tripeptide. Its synthetic form is called protirelin.
TRH is produced in the hypothalamus and is best known for stimulating the release of thyroid-stimulating hormone. It also acts as a neuropeptide within the brain and can influence mood and behavior independently of its thyroid-related effects.
A placebo-controlled study included 42 women with major depression. Twenty-six received intravenous protirelin, while 16 received placebo.
Participants completed measurements of emotional state and anxiety before treatment and again two hours later. The TRH group showed significant improvement, and protirelin performed better than placebo on the State-Trait Anxiety Inventory.
The behavioral improvement was not significantly connected to changes in thyroid hormone or thyroid-stimulating hormone. This suggests that TRH may have affected mood-related brain pathways directly rather than simply changing thyroid function.
The study was titled Short-Lasting Behavioural Effects of Thyrotropin-Releasing Hormone in Depressed Women: Results of a Placebo-Controlled Study. PMID: 8416053.
Another randomized, double-blind study examined TRH in 20 people experiencing a major depressive episode associated with bipolar I or bipolar II disorder.
Ten participants received intravenous TRH at midnight, while ten received saline.
Within 24 hours, 60% of the TRH group experienced at least a 50% reduction in depression scores. Only 10% of the saline group reached that response. Average depression scores fell by 52% after TRH and 12% after saline.
The antidepressant effect lasted for up to 48 hours. Researchers observed a modest increase in mania-rating scores, but no participant developed a manic or hypomanic episode during the study.
The study was titled Rapid Antidepressant Response After Nocturnal TRH Administration in Patients With Bipolar Type I and Bipolar Type II Major Depression. PMID: 16012274.
TRH produced some of the fastest improvements reported in peptide-based depression research. Its effects appeared within hours, but they were temporary and required intravenous administration.
Bottom Line
Human studies show that several peptides and neuropeptides can influence symptoms of anxiety and depression.
The naturally occurring neuropeptide NPY improved depression scores within 24 hours and reduced one measure of trauma-related anxiety. The synthetic peptide Selank reduced anxiety and fatigue in people with generalized anxiety disorder and related conditions.
The tripeptide MIF-1 produced marked antidepressant responses in small clinical studies. Nemifitide, a synthetic pentapeptide developed from that research, also produced positive results in placebo-controlled depression trials.
Oxytocin improved certain social and emotional outcomes when added to therapy and showed potential as an adjunct in some depressive disorders. TRH produced rapid antidepressant effects within hours, although those effects lasted only a short time.
These findings are important because they show that peptide and neuropeptide pathways can directly influence human mood, anxiety, trauma responses, and emotional processing. The studies remain limited, but the reported clinical effects support continued research into peptide-based approaches for anxiety and depression.