Effectiveness and Safety of a Mixture of Nobiletin and Tangeretin in Nocturia Patients: A Randomized, Placebo-Controlled, Double-Blind, Crossover Study

Nobiletin and tangeretin (NoT) are flavonoids derived from the peel of Citrus depressa, and they have been found to modulate circadian rhythms. Because nocturia can be considered a circadian rhythm disorder, we investigated the efficacy of NoT for treating nocturia. A randomized, placebo-controlled, double-blind, crossover study was conducted. The trial was registered with the Japan Registry of Clinical Trials (jRCTs051180071). Nocturia patients aged ≥50 years who presented nocturia more than 2 times on a frequency–volume chart were recruited. Participants received NoT or a placebo (50 mg once daily for 6 weeks), followed by a washout period of ≥2 weeks. The placebo and NoT conditions were then switched. Changes in nocturnal bladder capacity (NBC) were the primary endpoint, and changes in nighttime frequency and nocturnal polyuria index (NPi) were secondary endpoints. Forty patients (13 women) with an average age of 73.5 years were recruited for the study. Thirty-six completed the study, while four withdrew. No adverse events directly related to NoT were observed. NoT had little effect on NBC compared with the placebo. In contrast, NoT significantly changed nighttime frequency by −0.5 voids compared with the placebo (p = 0.040). The change in NPi from baseline to the end of NoT was significant (−2.8%, p = 0.048). In conclusion, NoT showed little change in NBC but resulted in decreased nighttime frequency with a tendency toward reduced NPi.