AbstractThe major inhibitory neurotransmitter gamma-aminobutyric acid or GABA plays a pivotal role in mood and sleep. GABA exerts sedative and anxiolytic effects both within the central nervous system and through the gut-brain axis, which has generated interest in the potential for gut GABA to modulate mood and sleep. Several bacterial strains can produce GABA, yet their real-world impacts are poorly understood. We investigated the impact of 2 doses of the strain Lactiplantibacillus plantarum Lp815 on anxiety, sleep, mood, quality of life, cognition, heart rate variability and adverse events in adults with mild to moderate anxiety over a 6-week period. The trial was structured as a double-blinded, randomised, placebo-controlled trial with optional open label extension. Participants were blindly assigned to receive either a placebo, 1 billion colony-forming units (CFU), or 5 billion CFU of the oral capsule per day. Participants completed biweekly anxiety, insomnia and cognition measures, daily mood, sleep, and quality of life surveys, and collected wearable heart rate variability. 83 individuals were evaluated, aged 39 ± 13 years, 63% female and 64% Caucasian. Participants receiving 5 billion CFU exhibited significantly lower anxiety (GAD-7) scores at weeks 4 and 6 compared to placebo (Kruskal-Wallis ). This result was clinically meaningful, with 68% of participants in the 5 billion CFU cohort exhibiting improvement by more than one category in their GAD-7 scores at week 6, compared to 37% in the 1 billion CFU group and 26% in the placebo group (e.g. from moderate to no anxiety) (Fisher’s exact test for 5 billion CFU vs Placebo). No serious adverse events occurred. A daily capsule containing 5 billion CFU Lp815 significantly reduced anxiety in a diverse cohort of adults at 4 and 6 weeks following daily consumption. GABA-producing probiotics may offer a safe option for anxiety reduction in people with mild to moderate anxiety.Trial Registration. The trial was IRB approved and registered with ClinicalTrials.gov (NCT06466603).