Effect of saffron extract supplementation on mood in healthy adults with subclinical symptoms of depression: a randomized, double-blind placebo-controlled study

Abstract

Background: Subclinical depressive symptoms, including low mood, fatigue and anxiety, refer to clinically relevant depressive manifestations that do not meet the criteria for major depressive disorder. These symptoms affect quality of life and can lead to chronic mental health issues. Nutritional interventions, such as saffron extract supplementation, may help modulate mood and inflammation, potentially alleviating these symptoms.

Objectives: This study evaluated the efficacy of a 6-wk saffron extract supplementation on mood in healthy individuals with subclinical neuropsychiatric symptoms and explored the underlying mechanisms.

Methods: This randomized, double-blind, placebo-controlled study involved 51 adult healthy individuals who received oral administration of either saffron extract or a placebo for 6 wk. The primary outcome was a composite z-score averaging standardized scores of depression (Beck Depression Inventory-II), anxiety (State-Trait Anxiety Inventory-YA), and fatigue (Multidimensional Fatigue Inventory 20). Secondary outcomes included neuropsychiatric scores, quality of life, inflammatory markers, and hypothalamic-pituitary-adrenal axis reactivity. Amino acid derivatives were analyzed in blood samples.

Results: Saffron extract did not significantly affect the primary outcome of combined depressive, anxiety, and fatigue symptoms (z-score) nor individual symptoms. However, it improved autoperceived mental health, as reflected in increased mental health scores over time on the Medical Outcome Study Short-Form 12 questionnaire, compared with placebo (mean at 6 wk: 53.8 ± 12.7 vs 44.6 ± 11.4 for placebo and saffron group, respectively; time × treatment, P = 0.04). There were no significant effects on inflammatory parameters or hypothalamic-pituitary-adrenal axis reactivity. Metabolomic analysis revealed that saffron extract significantly modulated N-acetyl-phenylalanine.

Conclusions: Saffron extract supplementation do not affect subclinical depressive symptoms, either as a composite score or individual symptom categories. A potential effect on improved mental health outcomes cannot be excluded but requires further replication in future well-powered trials. This trial (Saffromfood study) is registered at clinicaltrial.gov as NCT05690126 (https://clinicaltrials.gov/study/NCT05690126?term=NCT05690126&rank=1).

Keywords: dietary supplement; hypothalamic-pituitary-adrenal axis reactivity; inflammation; metabolomic; mood alteration; quality of life; saffron; subclinical depressive symptoms.