Advancing precision sleep medicine through dual-pathway integration: a systematic review of circadian and GABAergic interactions in therapeutic optimization

Current sleep pharmacotherapies often target single neurotransmitter systems, yielding limited efficacy and high non-response rates. We propose a dual-pathway integration framework, combining circadian (melatonin-mediated) and GABAergic (botanical) modulation, as a hypothesis-generating model for precision sleep medicine. Grounded in foundational work (e.g. SCN as circadian pacemaker; Borbély’s two-process model), this review assessed evidence from five databases per PRISMA 2020 guidelines. Among GABAergic botanicals, Passiflora incarnata was selected for its clinical relevance and mechanistic data. Putative convergence is hypothesized at molecular nodes (e.g. cAMP/PKC pathways) and neuroanatomical sites (e.g. GABAergic SCN neurons). However, no studies have formally tested pharmacodynamic synergy between melatonin and Passiflora. Clinical evidence is limited to monotherapy trials, with one uncontrolled pilot (N = 43) showing subjective improvement. Meta-analyses of some phytotherapeutics (e.g. multi-ingredient or poorly standardized formulations) report extreme heterogeneity (I2 > 95%) due to variability in composition and study populations. The 2023 European Insomnia Guidelines conclude that evidence for herbal medicines (e.g. valerian, chamomile and passionflower) is insufficient to support recommendations for routine clinical use. Most data come from European-ancestry cohorts, despite known pharmacogenetic differences (e.g. CYP1A2, GABRA2 variants). We conclude that dual-pathway therapy remains hypothetical and requires empirical validation via biomarker-stratified, randomized trials in diverse populations before clinical use.