Non-nutritive sweeteners (NNS) were developed and aggressively commercialized as a panacea for the global obesity and diabetes epidemics, offering the hedonic reward of sweet taste without the corresponding caloric payload [cite: 1, 4]. However, decades of clinical, biochemical, and epidemiological data reveal a highly complex and often detrimental physiological response to chronic NNS consumption [cite: 3]. This comprehensive research treatise maps the molecular topologies of major artificial sweeteners (Saccharin, Aspartame, Acesulfame-K, and Neotame) to their interaction with the T1R2/T1R3 heterodimeric sweet taste receptors [cite: 1]. Furthermore, it deeply explores the systemic health disadvantages of NNS, specifically analyzing gut microbiome dysbiosis, the uncoupling of cephalic phase insulin responses (CPIR), neurobiological satiety disruptions, and the induction of metabolic syndrome [cite: 1, 5]. By integrating structural chemistry with epidemiological hazard models, this paper provides a definitive framework for evaluating the safety profiles of artificial sweeteners [cite: 2, 3].