Vol. 10, Special Issue 1, Part D (2026)

High-intensity sweeteners (HIS) are widely used as sugar substitutes because they provide sweetness with little or no energy. They are commonly added to diet foods and beverages to support calorie reduction and glycaemic control. Over the past decades, regulatory authorities have evaluated these sweeteners and generally concluded that they are safe when consumed within established Acceptable Daily Intake (ADI) limits. Despite this, public concern and scientific debate about their long-term safety continue to grow. This review provides a critical and balanced overview of the safety, metabolic effects, and regulatory risk assessment of commonly used high-intensity sweeteners. It summarises their classification and key absorption, distribution, metabolism, and excretion (ADME) characteristics to clarify exposure pathways. Evidence from toxicological studies, animal experiments, human trials, and epidemiological research is reviewed in this paper. Particular attention is given to carcinogenicity, genotoxicity, reproductive and developmental effects, neurotoxicity, immunotoxicity, and gut microbiota-related metabolic outcomes. Most findings indicate that high-intensity sweeteners do not pose serious health risks when consumed within approved intake limits. However, emerging evidence suggests that some sweeteners may influence biological processes through indirect pathways. These effects are mainly linked to gut microbiota modulation and metabolic signalling. The review also highlights limitations of traditional ADI-based risk assessment frameworks. These include a focus on single compounds, reliance on overt toxicity endpoints, and limited consideration of cumulative exposure and population variability. Vulnerable groups such as children, pregnant women, and individuals with metabolic disorders are often underrepresented in long-term studies. Overall, current evidence supports the regulated use of high-intensity sweeteners within established limits. At the same time, continued research is needed. Long-term human studies, improved exposure assessment, and integration of emerging biological endpoints will be essential to strengthen future regulatory decisions and public health guidance.