The Effects of a Multi-Strain Probiotic Formulation Containing Saffron Extract and Fructooligosaccharides on Anxiety, Depressive Symptoms, Inflammatory Markers, and BDNF: A Double-Blind, Randomized, Placebo-Controlled Pilot Study

Depression and anxiety are highly prevalent mental health conditions, with growing evidence implicating the gut–brain–immune axis in their pathophysiology. Probiotic supplementation has emerged as a potential psychobiotic intervention, although clinical findings remain inconsistent. This double-blind, randomized, placebo-controlled pilot study assessed the feasibility of a three-month trial and generated preliminary effect estimates for a fixed multi-component formulation. Nineteen psychotropic-naïve adults with a Hospital Anxiety and Depression Scale (HADS) score ≥ 8 on the anxiety and/or depression subscale were randomized to the formulation (n = 9) or matched placebo (n = 10) once daily for three months. The formulation contained Lacticaseibacillus rhamnosus, Bifidobacterium animalis subsp. lactis, Bifidobacterium breve and Bifidobacterium longum (≥1 × 109 CFU total), 28 mg saffron (Crocus sativus) extract, 100 mg fructooligosaccharides, and 75 mg magnesium—the placebo contained identical excipients and none of the active ingredients. HADS-A, HADS-D, IL-6, TNF-α, CRP, and BDNF were measured at baseline and three months. The cohort was anxiety-predominant (baseline median HADS-A 10.0 [IQR 8.0–11.5] placebo, 11.0 [10.0–12.0] intervention), with baseline HADS-D imbalanced between arms (7.5 [6.25–9.5] vs. 3.0 [2.5–8.0]). Within the intervention arm, BDNF increased over three months (median change +0.27 ng/mL [IQR 0.09–0.84]; Z = −2.429, p = 0.015), and HADS-A fell by a median of 1.0 point [IQR −2.0 to 0.5] (p = 0.121); within the placebo arm, TNF-α fell (p = 0.047), as it also did non-significantly in the intervention arm (p = 0.086). No between-group difference in change scores reached significance for any outcome, including BDNF (+0.27 vs. +0.07 ng/mL, p = 0.142), HADS-A (−1.0 vs. −0.5 points, p = 0.407) and TNF-α (−1.24 vs. −1.08 pg/mL, p = 0.838); 21 uncorrected tests were performed. Since the randomized between-group comparison—the only comparison that licenses causal inference—was null throughout, these data support no conclusion about efficacy. Because saffron extract at the dose used has independent antidepressant and anxiolytic activity, no effect can be attributed to the probiotic strains. The study’s usable output are feasibility data and variance estimates for the design of an adequately powered, component-controlled trial.