Melatonin is taken nightly by millions of adults who regard it as essentially harmless — a natural sleep aid with a strong antioxidant profile. That assumption may deserve scrutiny. A hypothesis paper now proposes a biologically plausible, if speculative, mechanism by which chronic melatonin supplementation could, under certain conditions, elevate cardiovascular risk through an intermediate hormonal pathway involving prolactin.
The paper centers on a not-yet-peer-reviewed conference abstract reporting a statistically significant increase in new-onset heart failure, heart-failure-related hospitalization, and all-cause mortality among adults with insomnia who used melatonin for one year or longer. Rather than accepting or dismissing this signal, the authors construct a mechanistic hypothesis: exogenous melatonin may modulate hypothalamic dopaminergic neurons in a way that raises prolactin secretion. Sustained hyperprolactinemia becomes the proposed intermediate step. The critical link to cardiac risk draws on established peripartum cardiomyopathy biology, where cathepsin D cleaves full-length prolactin into a 16-kDa fragment that is directly cardiotoxic, impairing endothelial function and promoting cardiomyocyte apoptosis. The authors speculate that chronically elevated prolactin from long-term melatonin use could activate a similar fragmenting pathway outside pregnancy.
Several layers of uncertainty deserve emphasis. The foundational epidemiological signal comes from a single, unpublished, non-peer-reviewed abstract — a critically weak evidentiary base. The melatonin-to-prolactin elevation itself is documented in acute settings but whether it persists with long-term supplementation is unresolved. The jump from transient prolactinemia to the cardiotoxic 16-kDa cleavage product in non-pregnant adults is entirely hypothetical at this stage. This paper is hypothesis generation, not hypothesis confirmation. That said, peripartum cardiomyopathy research has repeatedly validated the 16-kDa prolactin-cardiac axis, giving the mechanism genuine biological plausibility. The editorial value here is that it frames testable questions — does chronic melatonin raise prolactin sustainably, and does prolactin fragment in non-pregnant cardiac tissue? Until prospective trials address these gaps, the finding is intriguing but far from actionable.
