Anxiety: treatment and what peptide research shows

What is anxiety and how many people does it affect?

Pathological anxiety is a group of disorders in which fear or worry is disproportionate, persistent and interferes with daily life: generalized anxiety disorder, panic disorder, phobias, social anxiety and separation anxiety, among others⁵⁶. ICD-10 groups them under code F41 (other anxiety disorders) and neighbouring categories.

The burden is enormous. WHO reports that 470 million people were living with an anxiety disorder in 2023, about 5.8% of the world population, and that only about 1 in 4 people who need treatment (27.6%) receive any¹. A systematic review of 87 studies in 44 countries estimated a global current prevalence of 7.3% (interval 4.8 to 10.9%), varying by culture, age, sex and armed conflict³. The Global Burden of Disease Study 2019 attributed 4.9% of the world's disability-adjusted life-years to mental disorders, 125.3 million in total, and found no reduction in burden since 1990².

Symptoms and how anxiety is diagnosed

Diagnosis is clinical. In generalized anxiety disorder, the central criterion is excessive, hard-to-control worry on most days for at least 6 months, with symptoms such as restlessness, fatigue, difficulty concentrating, irritability, muscle tension and disturbed sleep⁵. Panic disorder is recognized by sudden attacks of intense fear with physical symptoms, and social anxiety by marked fear of being judged in social situations⁶.

The physician must rule out organic causes (for example, medical conditions or effects of drugs, caffeine or substances), review alcohol and other substance use, and look for depression and other disorders that often accompany anxiety⁵. To measure symptom change, trials often use the Hamilton Anxiety Rating Scale (HAM-A)⁷.

Standard treatment of anxiety today

The World Federation of Societies of Biological Psychiatry (WFSBP, version 3, 2023) guidelines were prepared by 33 experts from 22 countries after evaluating 1,007 randomized trials. They conclude that selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the first-line medications and that cognitive behavioural therapy is the first-line psychotherapy⁶. WHO agrees: psychological interventions based on cognitive behavioural therapy, including exposure, are essential treatments, and antidepressants such as SSRIs can be useful in adults¹.

A network meta-analysis of 89 randomized trials with 25,441 patients and 22 active drugs compared treatments in generalized anxiety disorder. Versus placebo, duloxetine (mean difference −3.13 HAM-A points), pregabalin (−2.79), venlafaxine (−2.69) and escitalopram (−2.45) were more efficacious with relatively good acceptability; quetiapine had the largest effect (−3.60) but was poorly tolerated, and paroxetine and benzodiazepines were effective but less well tolerated⁷.

Benzodiazepines deserve a separate warning. In September 2020 the FDA required the boxed warning for the whole class to be updated to include the risks of abuse, misuse, addiction, physical dependence and withdrawal reactions⁸. WHO states that they are generally not recommended for anxiety disorders because of the risk of dependence and limited long-term effectiveness¹. This is the context in which alternatives, including peptide ones, are sought.

What peptide research has shown: Selank

Selank is a synthetic heptapeptide (Thr-Lys-Pro-Arg-Pro-Gly-Pro), an analogue of tuftsin, developed in Russia¹¹¹²²⁷. Its status differs from that of a drug approved in the United States or Europe: no FDA or EMA approval was found, and the claim that it is registered as a drug in Russia comes from secondary sources that could not be checked against the official Russian register in this review.

The best human evidence is two studies published in Russian. In the first, 62 patients with generalized anxiety disorder and neurasthenia received Selank (30 patients) or medazepam (32 patients); the anxiolytic effects of both were similar, with additional antiasthenic and psychostimulant effects with Selank, and the serum half-life of leu-enkephalin, which was reduced in patients, increased during Selank treatment⁹. In the second, 70 patients with anxiety disorders received phenazepam alone (30) or phenazepam with Selank (40): the effect of phenazepam appeared earlier and the tranquilizer's adverse effects were lower with the combination¹⁰. Neither abstract describes placebo, randomization or masking, and no independent replication outside Russia is known.

On mechanism, a radioligand-binding study showed that Selank acts as a positive allosteric modulator of GABA binding to brain membranes¹¹. In the frontal cortex of rats, Selank altered the expression of 45 neurotransmission genes one hour after administration¹²; in human neuroblastoma cells, by contrast, no changes were seen in the GABAergic genes studied¹³. In rats under unpredictable chronic mild stress, the combination of diazepam and Selank returned anxiety indices to their pre-stress values¹⁴. These are preclinical data that generate hypotheses; they do not prove efficacy in people.

What peptide research has shown: intranasal oxytocin

Oxytocin is a hypothalamic nonapeptide involved in social behaviour, stress and fear learning²¹. As a medicine, injectable oxytocin is FDA-approved (Pitocin) to initiate or improve uterine contractions and to produce contractions in the third stage of labour; the label has no psychiatric indication²². Its intranasal use in anxiety is a research hypothesis.

The physiological basis comes from a functional magnetic resonance imaging study in 15 healthy men with a double-blind crossover design: compared with placebo, intranasal oxytocin markedly reduced amygdala activation to fear-inducing stimuli and its coupling with brainstem regions¹⁵. In rhesus macaques, labelled oxytocin given intranasally (not intravenously) was detected in brain regions lying along the trajectories of the olfactory and trigeminal nerves²³.

Clinical trials are less favourable. In a randomized, double-blind, placebo-controlled trial of 25 people with social anxiety, oxytocin alongside exposure therapy improved positive evaluations of appearance and speech performance but did not improve the overall treatment outcome¹⁶. A systematic review of 15 randomized trials (7 in social anxiety, 1 in arachnophobia, 3 in major depression and 4 in postnatal depression), mostly with single administrations, found no significant effects on core symptoms and concluded that the evidence is still inconclusive¹⁷. A later systematic review of 16 imaging trials (11 in post-traumatic stress disorder and 5 in social anxiety) described oxytocin changing amygdala–cortex connectivity, while noting that clinical efficacy remains mixed¹⁸.

In post-traumatic stress disorder the data are preliminary. A pilot trial with 17 participants, which added intranasal oxytocin to prolonged exposure therapy, found lower symptoms in the oxytocin group that did not reach statistical significance¹⁹. A trial with 107 analysed emergency-department patients found no difference in CAPS score at 1.5 months (primary outcome), although scores were lower in the subgroup with high baseline symptoms²⁰. More context on the fragility of this literature is in Intranasal oxytocin: anatomy of a replication crisis.

Safety and contraindications

For Selank, safety data come only from small, short studies published in Russia; the second study described fewer adverse effects with the combination than with phenazepam alone¹⁰, but no long-term or special-population safety data come from controlled trials. For the wider picture of nootropic peptides, see Semax, Selank and DSIP: what is behind the nootropic peptides and the guide to sleep and cognition peptides.

For intranasal oxytocin, the post-traumatic stress trials reported few adverse events: in the 17-person pilot there was one adverse event, in the placebo group, and three dropouts¹⁹. Critics also point to a methodological problem: a statistical analysis warned that the intranasal oxytocin literature has small samples and a risk of false-positive findings²⁵. And the substance named on a label cannot be assumed equivalent to a pharmaceutical-grade drug, because how much reaches the brain from the nose is uncertain and debated²³²⁴.

In practice, this means a physician evaluating a patient with anxiety today has options backed by dozens of randomized trials, while the peptides described here remain in the research domain. To interpret any new result it helps to ask four questions: was there a placebo group, was the trial masked, how many participants were analysed, and did an independent group replicate it¹⁶¹⁷²⁵. A positive result in an uncontrolled study, in animals or in cells, however well described, answers none of those four questions.

Summary by agent

Frequently asked questions

Is any peptide approved to treat anxiety? Not according to the sources reviewed: no FDA or EMA approval was found for Selank or for oxytocin in anxiety, and international guidelines recommend SSRIs, SNRIs and cognitive behavioural therapy⁶²².

Does Selank work better than a benzodiazepine? There is no evidence of that. In a Russian study of 62 patients the anxiolytic effects were similar to those of medazepam, but the abstract does not describe placebo or masking and there is no independent replication⁹.

Does intranasal oxytocin reduce social anxiety? Results are mixed. It reduced amygdala activation in healthy volunteers¹⁵, but in a trial of 25 people with social anxiety it did not improve the overall result of exposure therapy¹⁶, and the systematic review concluded the evidence is inconclusive¹⁷.

Why are benzodiazepines not a first choice? Because the FDA requires a boxed warning for risks of abuse, misuse, addiction, physical dependence and withdrawal, and WHO notes their long-term effectiveness is limited¹⁸.

Which treatment has the best evidence in generalized anxiety? Cognitive behavioural therapy and SSRIs or SNRIs are first-line⁶; in a network meta-analysis of 89 trials, duloxetine, pregabalin, venlafaxine and escitalopram beat placebo with good acceptability⁷.