
Sleep is a vital natural process for restoring the body, enhancing health, preserving memory, and optimizing performance. Sleep deprivation is associated with increased health risks, reduced quality of life, and adverse socioeconomic impacts. While behavioral strategies like improving sleep hygiene are often the first line of treatment, pharmaceutical drugs are commonly used as supplements. However, these drugs are often prohibitively expensive and pose risks of severe side effects and dependency with prolonged use. Consequently, many individuals seek safe and effective alternatives derived from natural sources.
Some natural products on the market have scientific support for improving sleep and mood. Among them, UP165, a corn leaf extract standardized for 6-methoxybenzoxazolinone (6-MBOA), has shown sleep—and mood-enhancing effects in various studies. 6-methoxybenzoxazolinone (6-MBOA) is a natural substance similar in structure to melatonin. 6-MBOA has been shown to have several biological effects, including boosting reproductive function, fighting fungi and viruses, and stimulating melatonin production. It also acts as a weak β-adrenergic agonist and may interact with melatonin receptors. Since serotonin is a precursor to melatonin and 6-MBOA shares similarities with melatonin, it is speculated that 6-MBOA may have mood-enhancing effects.
This standardized corn leaf extract was evaluated for its effect on sleep quality and overall well-being in a double-blind, placebo-controlled clinical trial, administered orally at 250 and 500 mg/day. Participants (n = 45) (age range 19-73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks. Measurements included daily sleep quality, as monitored by a fitness tracker; the Pittsburgh Sleep Quality Index (PSQI) for sleep quality and efficiency; salivary cortisol levels for stress; and Profile of Mood States (POMS) to assess general well-being (1).
Participants who received the corn leaf extract showed a statistically significant and dose-correlated reduction in salivary cortisol (up to 36%), an increase in deep sleep time (up to 30 minutes), increased total sleep time (up to 10%), an improvement in sleep quality (up to 49%), and an enhanced POMS (36-58%). Participants in the UP165 group showed a sevenfold increase in deep sleep time and a 10-fold increase in PSQI sleep quality improvement compared to placebo. Collectively, UP165 is a safe nutritional supplement clinically proven to support better quality and efficiency of sleep at night and an improved mood state and overall well-being during the day (1).
The Pittsburgh Sleep Quality Index (PSQI), a self-rated questionnaire measuring sleep quality and disturbances over four weeks, showed significant improvements in participants supplemented with the corn leaf extract. Improvements in sleep quality were observed as early as week 1 (p ≤ 0.05) and sustained throughout the 4-week study (1).
During this period, sleep quality improved by up to 48.9% for the 500 mg/day group and 35.1% for the 250 mg/day group, compared to baseline. In contrast, the placebo group showed an initial 31.6% improvement in week 1, which diminished for the rest of the study. By week 4, the placebo group showed only a 3.7% improvement, while the corn leaf extract groups maintained significant improvements of 35.1% (250 mg/day) and 36.2% (500 mg/day). These results were statistically significant (p = .041 for 250 mg/day vs. placebo; p = .037 for 500 mg/day vs. placebo), confirming that corn leaf extract supplementation significantly enhances sleep quality and efficiency (1).
Cortisol levels decreased by 11.0%, 21.8%, 20.2%, and 27.5% in the 250 mg/day corn leaf extract group and by 15.0%, 18.2%, 29.5%, and 36.3% in the 500 mg/day group over weeks 1–4. In contrast, the placebo group showed increases of 6.2%, 9.8%, 1.7%, and 3.4% during the same period. These cortisol reductions align with the improved deep sleep observed, confirming the positive impact of corn leaf extract on sleep quality and efficiency (1).
S-adenosyl-methionine (SAM-e) is one of the most studied and widely used natural compounds that can help with depression and anxiety. Corn leaf extract was found to be as effective as S-adenosyl-methionine (SAMe) to treat depression and anxiety (2).
One study aimed to compare the effectiveness of corn leaf extract with S-adenosyl-methionine (SAM-e). Subjects with mild depression or anxiety were given the Beck Depression Inventory Second Edition (BDI-II), the Beck Anxiety Inventory (BAI), and the Schwartz Outcome Scale (SOS-10). Forty-two subjects (21-65 years old) were randomized to eight weeks of supplementation with corn leaf extract (250 mg/day) or SAM-e (400 mg/day), with questionnaires being administered at randomization, week four and eight (2).
Those receiving corn leaf extract achieved significant reductions from baseline for the BDI-II at weeks four and eight, respectively. There was also a trend for reductions in BAI at week four and significance at week eight. There was a trend for improvement on the SOS at week four and significance at week eight. SAM-e demonstrated a trend for improvement on the BDI-II by week eight over the corn leaf extract, with no differences between the two for the BAI or the SOS (2).
As the primary objective of the study was to determine the effects of intervention with corn leaf extract on mood states, intervention with corn leaf extract was shown to reduce the BDI-II by greater than 50% from baseline to week four (17.2 ± 4.2 to 10.2 ± 7.2; p < 0.001), and this reduction remained significant at week eight (17.2 ± 4.2 to 11.8 ± 8.4; p < 0.012). The corn leaf extract was found to have a significant effect on anxiety at the four-week mark (12.8 ± 5.4 to 6.7 ± 5.6; p < 0.001), which remained significant at week eight (12.8 ± 5.4 to 8.1 ± 7.4; p = 0.01) (2).
Intervention with SAM-e also led to a significant reduction in the BDI-II scores at weeks four and eight, respectively (16.1 ± 3.5 to 9.0 ± 7.0; p = 0.001 and 16.1 ± 3.5 to 7.2 ± 7.4; p = 0.002). SAM-e also had significant effects as measured by the BAI at week eight (12.9 ± 6.4 to 6.9 ± 5.6; p = 0.026). Intervention with SAM-e produced significant changes in the SOS-10 score at week eight (37.1 ± 9.7 to 41.2 ± 13.7; p = 0.038). Overall, this study indicated that there may be a benefit to corn leaf extract for mood enhancement in those with mild depression or anxiety (2).
One study evaluated the effects of UP165, corn leaf extract standardized for 6-MBOA content, on sleep latency and sleep time in a pentobarbital‑induced mouse sleep model. The extract was orally administered at 250 mg/kg (low dose), 500 mg/kg (mid dose), and 1000 mg/kg (high dose) daily for 32 days. The immediate impact of the extract on sleep was also assessed (3).
Mice were given pentobarbital 15 minutes after their last dose of UP165 to evaluate its effect on sleep time. Results showed that mice treated with the high dose of UP165 experienced an increase of 11.6 ± 0.2 minutes (from 30.6 ± 9.4 to 42.2 ± 9.2, p = 0.008) in sleep time compared to the control group. Similarly, the 250 mg/kg and 500 mg/kg doses of UP165 increased sleep time by 10.2 ± 2.4 minutes (p = 0.022) and 10.5 ± 0.9 minutes (p = 0.017), respectively. For comparison, melatonin, the reference compound, increased sleep time by 12.0 ± 1.3 minutes (p = 0.003). Even at a low dose of 250 mg/kg, UP165 significantly extended sleep time in the pentobarbital-induced sleep model (3).
Sleep latency refers to the time it takes for mice to lose their righting reflex after receiving pentobarbital. The subthreshold dose of pentobarbital sodium was determined to be 26 mg/kg, where 80%–90% of mice retained the reflex. To test the effects of UP165 on sleep latency, this dose was given to each mouse 15 minutes after the final test material dose. After 30 minutes, the number of mice unable to turn over within 1 minute was recorded as the incidence of sleep (3).
Results showed that 10 out of 15 mice (67%) in the high-dose UP165 group and 12 out of 15 mice (80%) in the melatonin group had reduced sleep latency, statistically significant compared to the 20% in the control group. Positive effects were also observed in the low- and mid-dose UP165 groups, with 60% of mice showing reduced latency. UP165 showed no immediate drowsiness effect. The study concluded that UP165 could be used as an adjunct for a sleep disorder (3).
Another study examined how corn leaf extract (UP165) and its active compound, 6-MBOA, promote sleep in rodents. Researchers measured sleep duration in a pentobarbital-induced sleep model and assessed sleep quality using EEG analysis. They also studied sleep mechanisms by combining UP165 with receptor blockers (4).
UP165 and 6-MBOA significantly increased sleep duration—UP165 (100 mg/kg) tripled sleep time, while 6-MBOA (280 μg/kg) increased it by 2.3 times. UP165 also improved sleep in a caffeine-induced insomnia model, increasing sleep duration by 71.6%. This effect was linked to enhanced non-REM sleep, particularly increased δ-wave sleep (4).
Further analysis showed that UP165 and 6-MBOA work by binding to GABA type A receptors and melatonin receptors. After 4 weeks of UP165 use, GABAA, melatonin 1A, and melatonin 1B receptors increased. High doses of UP165 also reduced corticosterone (a stress hormone) and boosted brain levels of GABA, serotonin, and melatonin. These findings suggest that UP165 and 6-MBOA could be effective natural ingredients for improving sleep (4).
The content of 6-methoxybenzoxazolinone (6-MBOA) in corn can vary depending on the corn variety, growing conditions, and stage of development but generally ranges between 0.1% to 0.5% of the dry weight of the plant tissue, with the highest concentrations found in the leaves.
The standardized corn leaf extract (UP165) has been shown to improve sleep quality and efficiency. Studies in mice found that the corn leaf extract reduced the time needed to fall asleep and increased sleep duration. It significantly improved deep sleep, lowered stress hormone levels, and enhanced mood. It also helped with mild depression and anxiety. The main active compound, 6-MBOA, is structurally like melatonin and supports melatonin production. It also has antibacterial and antiviral properties and binds to melatonin receptors, suggesting potential sleep and mood benefits.
References:
1. Talbott SM, Talbott JA, Brownell L, Yimam M. UP165, A Standardized Corn Leaf Extract for Improving Sleep Quality and Mood State. J Med Food. 2023 Jan;26(1):59-67. doi: 10.1089/jmf.2021.0197. Epub 2022 Sep 30. PMID: 36179066; PMCID: PMC9889011.
2. Kalman DS, Feldman S, Vazquez RR, Krieger DR. A Prospective Randomized Double-Blind Study Evaluating UP165 and S-Adenosyl-l-Methionine on Depression, Anxiety and Psychological Well-Being. Foods. 2015 May 8;4(2):130-139. doi: 10.3390/foods4020130. PMID: 28231193; PMCID: PMC5302331.
3. Yimam, M., Jiao, P., Hong, M., Brownell, L., & Jia, Q. (2018). Effect of UP165, a Zea mays
leaf extract standardized for 6-methoxybenzoxazolinone, as sleep adjunct.
Pharmacognosy Research, 10(2), 156–160. https://doi.org/10.4103/pr.pr_148_17
4. Kim, H. J., Kim, H., Kim, Y. J., Do, S. G., Suh, H. J., Chang, Y. B., & Lee, H. (2024). UP165, standardized corn leaf extract and its active component 6-methoxybenzoxazolinone induce non-rapid eye movement sleep through melatonergic and GABAergic mechanisms. Food Bioscience, 61, 104584. https://doi.org/10.1016/j.fbio.2024.104584
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