Kisspeptin Administration Stimulates Reproductive Hormones but Does Not Affect Anxiety in Humans
Mills EG, Comninos AN, Dhillo WS
Journal of Clinical Endocrinology & Metabolism (2025) · n=95
A biologically active dose of kisspeptin-54 to 95 men and women produced no measurable effect on behavioral, biochemical, or physiological anxiety measures — a primary-negative result that disambiguates the limbic-circuit mood findings from a generalized anxiolytic claim.
This is the Imperial College London reproductive endocrinology group's prespecified test of whether kisspeptin-54 — established as the principal hypothalamic activator of the gonadotropin-releasing-hormone axis and shown in the same group's earlier fMRI work to modulate limbic-circuit responses to sexual and bonding stimuli — exerts effects on human anxiety at the behavioral, biochemical, and physiological level. The rodent literature had run in three directions: anxiolytic effects in some paradigms, neutral in others, and anxiogenic in a smaller body of work, with the implication that the human translational signal could not be predicted from the preclinical record alone.
Investigators enrolled 95 healthy adult participants (63 male, 32 female, mean age 30.9 ± 0.9 years) in a double-blind, randomized, placebo-controlled, two-way crossover protocol. Each participant attended two visits separated by at least seven days, receiving on one visit kisspeptin-54 at 1 nmol/kg/h via 75-minute intravenous infusion and on the other visit equivalent-volume vehicle. The prespecified primary endpoints were state anxiety on standardized inventories, plasma cortisol, heart rate, and systolic and diastolic blood pressure. Luteinizing-hormone response confirmed pharmacologic engagement of the reproductive axis on the active-treatment day.
The result was uniformly negative across the prespecified anxiety endpoints. State anxiety scores did not differ between kisspeptin and placebo conditions (p = 0.13); cortisol was unchanged (p = 0.73); heart rate (p = 0.52), systolic blood pressure (p = 0.74), and diastolic blood pressure (p = 0.90) all unaffected. Luteinizing hormone increased robustly on kisspeptin administration, confirming the dose was biologically active. The authors frame the result as the first prospective human evidence that biologically active kisspeptin does not measurably affect anxiety endpoints in men or women, with the implication that the molecule's translational profile for reproductive and psychosexual indications is not complicated by an anxiogenic safety signal — and that the previously observed mood-modulation findings from the Comninos et al. 2017 fMRI study reflect stimulus-specific limbic-circuit modulation rather than a generalized anxiolytic or anxiogenic action.
Cross-link to the kisspeptin peptide page for the broader pharmacology and to the antecedent Abbara et al. 2017 IVF Phase 2 and Comninos et al. 2017 fMRI work for the reproductive-and-affective context.
The trial population is healthy adults without psychiatric diagnosis; generalizability to populations with clinical anxiety disorders is open and would require a separate trial design. The acute single-infusion protocol does not address chronic-administration effects; the molecule's pharmacokinetics and the typical kisspeptin-54 use case in reproductive medicine make chronic dosing an unusual scenario, but the question is not closed by an acute-design paper. The crossover design at 95 participants is adequately powered for the prespecified primary endpoints, but subtle subgroup effects — sex-stratified, baseline-anxiety-stratified, or dose-stratified — are not the focus of this paper and are likely under-powered for definitive resolution. The trial is single-center (Hammersmith Hospital / Imperial College London) and conducted by the same investigator group that produced the antecedent fMRI mood-effect work — high methodological continuity, with both the advantage of consistent kisspeptin-54 handling and the limitation of single-group dominance of the human kisspeptin-CNS literature. Industry independence is high; the trial was funded through UK academic-grant channels (NIHR, MRC). The negative-result framing is the most important translational signal: kisspeptin-54 as an investigational reproductive-axis agent does not appear to carry an anxiety signal that would constrain its clinical-translation profile, and the affective-circuit findings from the 2017 fMRI work should be read as stimulus-conditioned limbic modulation rather than a generalized mood drug.
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