Abstract

Melatonin is not a conventional sedative but a timing signal that tells the brain night has begun, which makes delivery unusually important. Oral tablets undergo extensive first-pass metabolism (absolute bioavailability ~15%; range 9–33%) and reach peak plasma concentrations only after 40–90 minutes. Intranasal delivery bypasses the gastrointestinal tract: human studies show peak plasma concentrations within ~5–10 minutes at doses of 200–400 µg, with exposure comparable to a 2.5 mg oral tablet. The earliest intranasal spray dissolved melatonin in ethanol and caused painful nasal irritation; modern alcohol-free hydroxypropyl-β-cyclodextrin systems solve solubility without the same tolerability problem. Intranasal melatonin remains investigational.