Benefits
Memory scores in older adults taking a nobiletin-containing formula
In a 16-week placebo-controlled trial in healthy Japanese adults aged 65 and over (108 analyzed), a capsule formula of shiikuwasa peel extract with black ginger root and Peucedanum japonicum leaf raised the general memory index of a standard memory test more than placebo. Other cognitive tests showed no difference, and the multi-ingredient design means the effect cannot be credited to nobiletin alone.
Cognitive scores with perilla oil plus ponkan peel powder
In a 12-month randomized trial in 49 healthy older Japanese adults, perilla seed oil plus nobiletin-rich ponkan peel powder (2.91 mg nobiletin a day) gave higher cognitive index scores than perilla oil alone, alongside rises in serum BDNF. There was no placebo-only group, and two authors listed a company affiliation.
Nighttime bathroom trips in older adults
In a 6-week crossover trial in 40 adults aged 50 or older with nocturia (frequent night urination), a citrus extract giving 30 mg nobiletin and 15 mg tangeretin after dinner did not change night bladder capacity, the main outcome, but cut night voids by about 0.5 per night more than placebo. The extract maker supplied the product and part of the funding.
Thigh muscle composition during rehabilitation
In a 12-week pilot trial in 40 patients recovering from a recent stroke, 200 mg a day of shiikuwasa fruit extract (12 mg nobiletin) did not change total thigh muscle area versus placebo. The non-affected thigh had more normal-density muscle in the extract group. The trial was small, funded by the supplier, and needs confirmation.
Cholesterol with a citrus flavone and tocotrienol blend
In a 12-week placebo-controlled trial in 240 adults with raised LDL cholesterol, a blend of citrus peel polymethoxylated flavones (the family that includes nobiletin) with palm tocotrienols lowered LDL no more than placebo, and inflammation marker hsCRP did not change.
Circadian clock and metabolism in laboratory mice
In cell screens nobiletin increased the strength of daily clock gene rhythms, and in obese and aging mice it counteracted metabolic problems, raised energy expenditure and improved muscle mitochondria; in obese mice these benefits largely depended on a working Clock gene. These are cell and animal findings; no human trial cited here measured circadian rhythm.
Mechanism of action
Boosts the amplitude of the body clock
In cell and mouse studies nobiletin bound the ROR receptors, nuclear proteins that drive core clock genes, which increased the strength of daily clock rhythms. The metabolic effects in mice were largely absent in mice with a defective Clock gene, tying them to the clock.
Supports mitochondrial respiration in muscle
In aging mice fed a high-fat diet, nobiletin switched on genes for the mitochondrial respiratory chain in skeletal muscle, raising energy (ATP) production while lowering reactive oxygen species. These findings come from mice only.
Poorly absorbed and processed by liver enzymes
Nobiletin has poor oral bioavailability, which reviewers cite as a main barrier to human use. In rats it reached the liver after a dose of shiikuwasa peel, and in lab tests it inhibited several cytochrome P450 drug-metabolizing enzymes.
Clinical trials
Multicenter, randomized, double-blind, placebo-controlled trial of Nobilex, a capsule of shiikuwasa (Citrus depressa) peel extract combined with Kaempferia parviflora (black ginger) root powder and Peucedanum japonicum leaf powder, partly funded by its maker Okinawa Research Center, with which two authors were affiliated (the paper declares no conflicts of interest). (Yamada et al. 2021, Food Sci Nutr)
122 healthy Japanese adults aged 65 and over with MMSE scores of 24 to 30 and memory lapses were randomized; 108 were analyzed per protocol. The paper lists 10.0 mg nobiletin and 5.8 mg tangeretin per capsule, taken as three capsules once a day for 16 weeks.
The general memory index of the Wechsler Memory Scale-Revised rose more with the formula than with placebo (total score change 9.0 vs 5.9). The visual memory index also rose more, while the verbal memory and attention indices and several other cognitive and mood tests showed no difference between groups. No adverse events were reported. Results are per-protocol, and the placebo lacked all three plant ingredients, so nobiletin's own contribution is unknown.
Randomized, double-blind, parallel trial comparing perilla seed oil alone with perilla seed oil plus air-dried immature ponkan peel powder; two authors list Sankyo Holdings as their affiliation. (Hashimoto et al. 2022, Food Funct)
49 healthy elderly Japanese adults; daily capsules of 1.47 mL perilla oil (0.88 g alpha-linolenic acid) alone or with 1.12 g ponkan powder (2.91 mg nobiletin) for 12 months.
After 12 months the perilla oil plus ponkan group had higher cognitive index scores than the perilla oil group, accompanied by increases in serum BDNF, antioxidant potential and red blood cell omega-3 levels. Both groups received an active product, so the trial cannot show an effect against placebo.
Randomized, placebo-controlled, double-blind crossover trial of a Citrus depressa polymethoxylated flavone extract taken after dinner; the extract maker Okinawa Research Center supplied the products and part of the funding. (Ito et al. 2023, J Clin Med)
40 patients aged 50 or older with nocturia recorded more than twice a night on a frequency-volume chart (mean age 73.5, 13 women); 36 completed. Each took 50 mg of extract (30 mg nobiletin, 15 mg tangeretin) or placebo once daily for 6 weeks, with a washout of at least 2 weeks.
The primary outcome, nocturnal bladder capacity, changed little versus placebo. Night voids fell by 0.5 per night more than with placebo (p = 0.040), a secondary outcome, and the nocturnal polyuria index fell 2.8% from baseline. No adverse events were linked to the extract.
Double-blind, randomized, placebo-controlled pilot trial during rehabilitation, funded by Morinaga Milk Industry, whose employees were co-authors. (Honaga et al. 2022, J Integr Complement Med)
40 subacute stroke patients with moderate-to-severe one-sided weakness; 200 mg/day of shiikuwasa fruit extract (two capsules, each with 6.0 mg nobiletin and 2.6 mg tangeretin) or placebo for 12 weeks.
Total thigh muscle area, measured by CT, did not differ between groups. Normal-density muscle area on the non-affected side was higher with the extract at 12 weeks, and serum CRP, an exploratory outcome, was lower. No adverse events related to the extract were seen. The authors call it a pilot needing a larger trial.
Double-blind, placebo-controlled trial of two doses of a palm tocotrienol and citrus peel polymethoxylated flavone combination. (Schuchardt et al. 2015, Eur J Clin Nutr)
240 adults with LDL cholesterol of 3.36 mmol/L or higher and hsCRP of 1 mg/L or higher; 204 analyzed per protocol. Groups took 103 mg flavones with 12 mg tocotrienols, 32 mg flavones with 27 mg tocotrienols, or placebo daily.
After 12 weeks LDL cholesterol, the primary outcome, did not differ between groups; it fell about 4 to 5% in every group, including placebo. Total cholesterol and hsCRP did not change significantly. The authors concluded the supplements had no effect beyond placebo.