GABAvsMelatonin

GABA binds to GABA-A receptors (ligand-gated Cl- channels with alpha1-6, beta1-3, gamma1-3 subunits) and GABA-B receptors (G-protein coupled, Gi/o mediated), reducing neuronal excitability through hyperpolarization. However, supplemental GABA has limited blood-brain barrier penetration due to absence of a dedicated transporter and rapid metabolism by GABA-transaminase and succinate semialdehyde dehydrogenase in periphery. The calming effects may be mediated through: (1) GABA-A and GABA-B receptors in the enteric nervous system (gut-brain axis) — vagal afferents project to the nucleus tractus solitarius and influence limbic regions; (2) small amounts crossing the BBB via paracellular leakage or in individuals with compromised barrier integrity; (3) peripheral effects reducing systemic stress markers (cortisol, heart rate variability). PharmaGABA (Lactobacillus fermentation product) may have better absorption via peptide-like transport or different pharmacokinetics.

Melatonin binds to G-protein-coupled MT1 and MT2 receptors, which are densely expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus—the brain's master circadian pacemaker. MT1 activation couples to Gi/o proteins, inhibiting adenylyl cyclase and reducing cAMP, which suppresses SCN neuronal firing and promotes sleepiness. MT2 activation modulates cGMP signaling and phase-shifts the circadian rhythm (useful for jet lag and shift work). Melatonin also has direct antioxidant properties, scavenging hydroxyl and peroxyl radicals in mitochondria and upregulating antioxidant enzymes like glutathione peroxidase. It supports immune function through modulation of T-cell cytokine production and may act at MT3 (quinone reductase 2) binding sites. Low doses are often more effective because they mimic physiological nighttime levels.