INTRODUCTION: Cyclic vomiting syndrome (CVS) is a disorder of gut-brain interaction often triggered by stress. Interventions such as meditation may improve psychological outcomes and health-related quality of life (HRQoL), but their efficacy and the underlying mechanism are unknown. METHODS: We conducted a 6-week single-arm pilot study to assess the effects of heartfulness meditation (HFM) in CVS using a custom-designed meditation app. Primary outcomes included state and trait anxiety and mood state changes pre vs post-meditation, and secondary outcomes were psychological distress, coping, sleep quality, and HRQoL at baseline and at weeks 3 and 6. Serum concentrations of endocannabinoids N -arachidonylethanolamine and 2-arachidonoylglycerol and related lipids were measured pre- and post-HFM at baseline and week 6. RESULTS: In 30 treatment completers, there was a significant improvement in state anxiety ( P < 0.001), total mood disturbance ( P < 0.001), and other mood states (all P values < 0.05) across the 3 time points. Trait anxiety was also improved at week 6. There was a significant improvement in psychological distress (Global Severity Index), sleep quality (daytime dysfunction), coping (using religion/spirituality), and HRQoL (mental and physical) across the 3 time points (all P < 0.05). Significant increases in N -arachidonylethanolamine and related lipids N -oleoylethanolamine and palmitoylethanolamide post vs pre-HFM were observed at week 6 ( P < 0.001, 0.002, 0.003, respectively). No adverse effects were noted. DISCUSSION: App-delivered HFM is feasible, safe, and effective and improves psychological outcomes and augments endocannabinoids. This provides insight into the mechanism underlying HFM and has potential for widespread use as a digital therapeutic in CVS and other disorder of gut-brain interaction.