The Effects of Combined Scutellaria and Saffron Supplementation on Mood Regulation in Participants with Mild-to-Moderate Depressive Symptoms: A Randomized, Double-Blind, Placebo-Controlled Study

<b>Background/Objectives:</b> The global prevalence of mental health disorders, particularly anxiety and depression, has increased significantly, with rates further elevated by the COVID-19 pandemic. Conventional pharmacological treatments, while effective, often lead to side effects that can impact patient adherence and quality of life. This has driven interest in safer, natural adjunctive therapies. <i>Crocus sativus</i> L. (<i>Iridaceae</i>) (saffron) and <i>Scutellaria baicalensis Georgi</i> (<i>Lamiaceae</i>) (scutellaria) have individually shown potential, in humans and animals, respectively, as mood regulators, with bioactive compounds that modulate neurotransmitter systems and possess anti-inflammatory and anxiolytic effects. This study aimed (1) to explore the efficacy and safety of scutellaria extracts in humans and (2) to test a possible synergistic effect when combining scutellaria and saffron on mood regulation in individuals experiencing mild-to-moderate depressive symptoms. <b>Methods:</b> In a randomized, double-blind, placebo-controlled trial, 180 participants with mild-to-moderate depressive symptoms were assigned to receive either scutellaria extract alone (SCUTELL'UP^®), saffron extract alone (SAFFR'ACTIV^®), a combination of scutellaria and saffron extracts (SAFFR'UP^®), or a placebo for six weeks. The primary outcome was assessed using a standardized depression scale (Beck Depression Inventory). The secondary outcomes, including anxiety, emotional state, well-being level, and sleep quality, were all assessed using validated questionnaires. Safety and tolerability were evaluated throughout the study period. <b>Results:</b> The results confirmed the beneficial effects of saffron extract on depressive and anxious symptoms, as well as its role in improving sleep quality. For the first time in humans, scutellaria extract demonstrated a positive effect on mood regulation. Furthermore, a synergistic effect of the combination of these two extracts was identified, leading to enhanced improvements in depressive and anxious symptoms and emotional well-being among individuals with mild-to-moderate depression, compared to the placebo group. Minimal adverse effects were reported across all treatment groups. <b>Conclusions:</b> This natural adjunctive nutritional strategy offers a promising alternative for individuals seeking safer options for mental health support. Further research is warranted to exclude potential long-term side effects and to explore potential mechanisms of this combined supplementation.