Melatonin and Multivitamin Use in Sleep Disturbance Populations: Associations with Health Outcomes and Mortality from a National Cohort Study

Melatonin and Multivitamin Use in Sleep Disturbance Populations: Associations with Health Outcomes and Mortality from a National Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Melatonin and Multivitamin Use in Sleep Disturbance Populations: Associations with Health Outcomes and Mortality from a National Cohort Study Zerui You, Lutong Gan, Jiamin Wu, Simeng Feng, Jiyang Pan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6213720/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Comprehensive health benefits and risks of melatonin remain scarce. This study aims to evaluate the association between melatonin use and health outcomes, as well as its comparative effectiveness against multivitamins. Methods In total, 7,717 adults experiencing sleep disturbances with dietary supplements data were enrolled from the 2005–2018 National Health and Nutrition Examination Survey (NHANES). Multivariable Cox regression analysis was employed to investigate the associations of melatonin and multivitamin supplementation with all-cause and cardiovascular mortality. Results Melatonin and multivitamin users had longer sleep durations than non-users (melatonin: t = 2.68, P < 0.001; multivitamins: t = 5.44, P < 0.001). Only multivitamin users showed fewer depressive symptoms (t = -7.00, P < 0.001), while melatonin users did not. Melatonin users (odds ratio [OR], 0.44; 95% CI: 0.20–0.86; P = 0.024) and multivitamin users (OR, 0.79; 95% CI: 0.69–0.91; P = 0.001) had lower odds of short sleep. After adjustments, melatonin users faced a higher risk of cardiovascular mortality (hazard ratio [HR], 3.46; 95% CI, 1.01 to 11.82; P = 0.048), whereas multivitamin users had lower risks of all-cause mortality (HR, 0.84; 95% CI, 0.71 to 0.99; P = 0.040) and cardiovascular mortality (HR, 0.61; 95% CI, 0.39 to 0.95; P = 0.027). Conclusions Melatonin does not appear to be the sole selection for early-stage sleep disturbances; multivitamins might constitute a more judicious alternative, associated with better sleep duration and overall health outcomes. Further studies are required to confirm these findings. Melatonin Multivitamins Short sleep duration Mortality NHANES Figures Figure 1 Figure 2 INTRODUCTION More than one-third of adults experience sleep-related disturbances. The most prevalent disturbances include difficulties in falling asleep and maintaining sleep, commonly referred to as insomnia symptoms 1 . Such sleep disturbances can profoundly impact physiological processes, leading to prolonged sleep onset latency, frequent nocturnal awakenings, and reduced sleep efficiency, among others 2 . These challenges can significantly impact overall health and well-being, adversely affecting cognitive functioning, emotional stability, and quality of life 3 , 4 . Due to the manifestations associated with sleep disturbances, this pathological state is regarded as a significant public health issue and has become a physical and economic burdens 5 . Therefore, comprehensive investigations into sleep disturbances within the framework of population-based cohorts are warranted. Currently, available therapeutic agents for the treatment of insomnia include benzodiazepines, benzodiazepine receptor agonists, antidepressants, antipsychotics, and melatonin, along with other options. Among these, exogenous melatonin is marketed as a non-pharmacological sleep aid, often promoted for managing circadian rhythm disorders and transient sleep disruptions, primarily due to its perceived “natural” origin 6 and modest evidence supporting sleep quality improvements in specific populations 2 , 7 , 8 . While some preclinical studies hypothesize that melatonin might regulate circadian rhythms or exhibit anti-inflammatory and antioxidant properties 9 – 12 , clinical evidence supporting its efficacy for sleep disturbances is inconsistent, with overall low-quality evidence for its use 13 . Since melatonin products are classified as “natural health products” or “dietary supplements” in some countries, they are subject to insufficient regulation, leading to multiple safety concerns 14 . Some products exhibit dosage inaccuracies and may include additional compounds, such as serotonin, which might not comply with established standards 15 , 16 . The current situation is that the prevalence of melatonin supplement consumption has significantly increased among various populations 17 . This trend is accompanied by a growing demand for robust evidence regarding the long-term safety of melatonin supplementation. However, high-quality, large-scale studies on the long-term safety of melatonin are still scarce 18 . The absence of comprehensive data hinders the ability to draw conclusions regarding the safety of long-term melatonin use. Growing evidence links dietary and circulating micronutrients (including multivitamins) with sleep quality 19 . The study using nationwide survey data found that men with moderate-to-severe insomnia were associated with a higher prevalence of inadequate vitamin C, B6, and folate 20 . In a separate analysis of Japanese adults, significant associations were observed between self-reported nutrient intake and sleep duration, with positive correlations for vitamins B12 and D 21 . A systematic review of randomized controlled trials (RCTs) found that vitamin D supplementation significantly reduced the Pittsburgh Sleep Quality Index (PSQI), suggesting that vitamin D supplementation may be effective in improving sleep quality 22 . Similar to melatonin, multivitamins have demonstrated the potential to alleviate depressive symptoms, particularly through components such as vitamin D 23 , vitamin C 24 , and vitamin B 25 . Nevertheless, evidence on dietary supplements for improving sleep is constrained by methodological limitations and inconsistent findings. Chan et al. noted that heterogeneity and wide confidence intervals undermine the reliability of the potential benefits of vitamin D and melatonin 26 . The efficacy of melatonin remains debated due to conflicting trial results, and evidence regarding other supplements remains inconclusive 27 . Additionally, direct comparisons between melatonin and multivitamins—two commonly used supplementations—are lacking in the existing literature. Therefore, we aim to investigate their impacts on sleep duration and depressive symptoms and their association with mortality in large cohorts, which may provide further insights into their clinical implications and risks. To the best of our knowledge, this is the first study based on the US National Health and Nutrition Examination Survey (NHANES) data to assess the effects and risks of melatonin and multivitamin supplements in individuals with sleep disturbance. In this study, we aimed to identify: (i) the effect of melatonin and multivitamins on health outcomes, including sleep duration and depressive symptoms, in individuals with sleep disturbance; (ii) whether melatonin and multivitamins confer any survival benefits, particularly in terms of reducing all-cause and cardiovascular mortality; and (iii) which dietary supplements were the most suitable choices. Of particular note, our research focused extensively on exploring the similarities and differences between melatonin and multivitamins in the context of sleep disturbance. We hypothesized that melatonin offers an advantage in enhancing sleep quality, alleviating depressive symptoms, and reducing all-cause mortality, demonstrating superior clinical effectiveness compared to multivitamins. By comparing their effects, we aimed to provide valuable insights into which dietary supplements offer a more favorable risk-benefit profile for addressing sleep disturbance. METHODS Study population This cross-sectional analysis utilized data from the NHANES conducted from 2005 to 2018 by the Centers for Disease Control and Prevention (CDC) to assess the health and nutritional conditions of the U.S. population. The protocols for NHANES received approval from the National Center for Health Statistics Research Ethics Review Board, aligning with the revised Declaration of Helsinki. Informed consent was obtained in writing from all participants. For further information regarding the NHANES initiative, please refer to the CDC website (Centers for Disease Control and Prevention (CDC), 2022). The inclusion and exclusion process for all eligible participants is shown in Fig. 1 . Assessment of sleep disturbance and duration Sleep disturbance and duration were assessed using the NHANES questionnaire. Participants reported their typical weekday sleep duration in hours, and their response to the question, “Have you ever told a doctor or other health professional that you have trouble sleeping?” was used to evaluate self-reported sleep disturbance. The response categories for this question included “Yes,” “No,” “Refused,” and “Do not know.” Responses from participants who selected 'Do not know' or 'Refused' were classified as missing values. Self-reported sleep duration was evaluated by posing the inquiry: “How much sleep do you usually get at night on weekdays or workdays?” Sleep hours were documented in whole numbers. Sleep duration was characterized as short sleep duration ( 8 hours) referenced to normal sleep (7–8 hours) 28 , 29 . Dietary supplement use The NHANES participants were asked whether they used any vitamins, minerals, or other dietary supplements during an in-house interview If the answer was yes, they were asked to show the containers to the interviewers. Each supplement includes a comprehensive description of its primary ingredients (e.g., vitamin C, vitamin D), and more than 75% of production information is recorded based on information from the container. Participants were also asked for the product name, dietary supplement contains, details regarding the frequency (e.g., number of times per day), serving form (e.g., capsules, tablets, or other formats), daily dosage (amount of ingredients per serving), duration, and so on. Any participant who consumes a dietary supplement that includes melatonin is categorized as a melatonin user. This classification applies regardless of the specific type of supplement as long as melatonin is one of its active ingredients. Vitamins, including 14 specific vitamins (Supplementary Table 1), and multivitamin mineral (MVM) supplements were assessed respectively. The classification of MVM supplements was defined as consuming products containing more than three kinds of vitamins, with or without additional minerals 30 . Participants who did not use any supplements were classified as non-users and served as the control group. Some participants used both melatonin and multivitamins; these individuals were excluded from the main analysis in each group and subsequently included in the sensitivity analysis. Mortality outcomes of the study Mortality data were extracted from the National Death Index (NDI), a database operated by the Centers for Disease Control and Prevention (CDC) ( https://www.cdc.gov/nchs/data-linkage/mortality-public.htm ). Each participant's follow-up period was determined from their enrollment date up to either their date of death or December 31, 2019, which is the most recent update available from the NDI. The study outcomes included cardiovascular mortality and all-cause mortality. Data pertaining to the fundamental causes of mortality were employed for case definition in accordance with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) 31 . Cardiovascular mortality was defined as death resulting from heart disease (ICD-10 codes I00-I09, I11, I13, I20-I51) or cerebrovascular disease (ICD-10 codes I60-I69). Covariates In our study, we included clinically significant covariates such as age at the time of the interview, sex, body mass index (BMI) group (underweight/normal/overweight/ obese), income level, race/ethnicity, education attainment, marital status, smoking status (never/former/current), drinking status (yes/no), physical activity (inactive/insufficiently active/sufficiently active), the presence of depressive symptoms (none/mild/moderate to severe), calorie intake (kcal), cardiovascular disease (CVD) history (yes/no), stroke history (yes/no) and diabetes status (yes/no). BMI was calculated as body weight (kg)/height 2 (m 2 ). BMI group was utilized to assess participants' weight status, categorizing them as underweight (< 18.5 kg/m 2 ), normal (18.5–24.9 kg/m 2 ), overweight (25–29.9 kg/m 2 ), or obese (≥ 30 kg/m 2 ). Income level of participants was evaluated using the ratio of household income to the poverty threshold (PIR). Educational attainment was stratified into five groups: less than 9th grade, 9th to 11th grade, high school diploma recipient, college or Associate of Arts (AA) degree holder, and those with a college degree or higher. Marital status was classified as single (widowed, divorced, or separated) or non-single (married or living with a partner), determined by their living situation. Smoking status was classified into three categories: never smoked (smoked < 100 cigarettes), formerly smoked (not currently smoking but smoked ≥ 100 cigarettes), and currently smoked (≥ 100 cigarettes and currently smoking every day or on some days). Alcohol use was classified into two categories: never drinking and ever or current drinking. Physical activity, as reported weekly by participants, predominantly during leisure periods, was obtained through individual interviews conducted with the Global Physical Activity Questionnaire. Total physical activity time was calculated by adding minutes of moderate-intensity activities to twice the minutes of vigorous-intensity activities. Physical activity was categorized into three groups: inactive (without any physical activity), insufficiently active (1-150 min/week), and sufficiently active (≥ 150 min/week) 32 . Depression severity was categorized using Patient Health Questionnaire-9 (PHQ-9) score (points): none (0–4), mild (5–9), and moderate to severe depression (≥ 10). The PHQ-9 score of 10 or more indicates the presence of significant depressive symptoms 33 . Total calorie intake was calculated based on the average value of two days of self-reported daily calorie intake assessments. CVD history, stroke history, and diabetes mellitus were determined based on self-reported diagnoses provided by medical professionals or if participants were instructed to take prescribed medications for these conditions. Those who gave a definite reply were considered to have the history or diagnosis, while the rest were regarded as not having any. Statistical Analysis Descriptive statistics were conducted to analyze the baseline characteristics of participants using various dietary supplements compared to those not utilizing any supplements. Continuous variables were expressed as the mean and standard deviation (SD) or as the median with interquartile range (IQR), while categorical variables were presented as frequencies and proportions. The characteristics were compared using the independent Student's t-test, Mann-Whitney U test, or Chi-squared test as appropriate. Cross-sectional binary logistic models were performed to compare sleep duration and depressive symptoms (yes/no) between participants with different dietary supplements, in comparison to those not utilizing any supplements and participants without dietary supplements. Survival analysis was performed using Cox proportional hazards models to investigate the association between dietary supplements and the risks of all-cause mortality as well as cardiovascular mortality. The influence of dietary supplements on overall mortality was evaluated through sequential adjustments of covariates across multiple modeling frameworks. Crude model represented a univariate analysis. Model I was adjusted for all demographic covariates, while Model II included modifications for demographic variables in conjunction with the history of calorie intake, CVD, stroke, and the existence of diabetes to evaluate the robustness of the results. Statistical analysis was conducted with the “survey” package (version 4.0.4) in R software. All analyses and models were conducted using R (version 4.4.1). The significance level was set at p < 0.05. RESULTS Population characteristics Table 1 presents the demographic characteristics of 7,717 individuals from NHANES 2005–2018. The participants had an average age of 52.6 years, reported an average sleep duration of 6.7 hours per day, and 41.8% were male. Among participants (Fig. 2 A), 5,020 (65.0%) used dietary supplements: 72 (0.9%) used melatonin only, 2,651 (34.3%) used multivitamin-mineral supplements (MVM) only, 63 (0.8%) used both, and 2,234 (28.9%) used other types. Melatonin use prevalence in this study (1.75% [135/7717]) matches prior national estimates in U.S. adults 17 . Participants with dietary supplements were more likely to be female, college graduates, white, not smoking, and exhibiting no depressive symptoms. Usual doses of melatonin range from 1 mg/d to 5 mg/d, with 3 mg/d being the most common (Fig. 2 B). To rule out the confounding effect of mixed-use dietary supplements and better statistical estimates, we analyzed participants who only used melatonin or MVM, in which the reference group included all participants who did not use dietary supplements in the subsequent main analysis. Additionally, apart from education level and diabetes status, no significant differences were observed between melatonin- and MVM-only users (Supplementary Table 2). Table 1 Characteristics of the study population with various groups. Variables Total ( N = 7717) Without dietary supplement ( n = 2697) With any dietary supplements ( n = 5020) Statistics p Age (years) 53.0 (40.0–65.0) 48.0 (36.0–60.0) 56.0 (43.0–67.0) <0.001 Gender, n (%) <0.001 Male 3222 (41.8%) 1266 (46.9%) 1956 (39.0%) Female 4495 (58.2%) 1431 (53.1%) 3064 (61.0%) BMI (kg/m2) 29.4 (25.2–34.7) 29.8 (25.2–35.4) 29.2 (25.2–34.4) 0.005 Calorie intake (kcal) 1858.0 (1413.5–2414.0) 1872.0 (1407.0–2450.0) 1852.2 (1415.8–2398.6) 0.573 Education, n (%) <0.001 Less Than 9th Grade 591 (7.7%) 256 (9.5%) 335 (6.7%) 9-11th Grade 1015 (13.2%) 489 (18.1%) 526 (10.5%) High School Grad/GED 1845 (23.9%) 719 (26.7%) 1126 (22.4%) Some College or AA degree 2567 (33.3%) 826 (30.6%) 1741 (34.7%) College Graduate or above 1699 (22.0%) 407 (15.1%) 1292 (25.7%) Marry status, n (%) 0.001 Marry/Living with partner 4288 (55.6%) 1429 (53.0%) 2859 (57.0%) Widowed/Divorced/Separated/Never married 3429 (44.4%) 1268 (47.0%) 2161 (43.0%) Race, n (%) <0.001 Non-Hispanic White 4147 (53.7%) 1221 (45.3%) 2926 (58.3%) Non-Hispanic Black 1553 (20.1%) 695 (25.8%) 858 (17.1%) Mexican American 797 (10.3%) 318 (11.8%) 479 (9.5%) Other Hispanic 626 (8.1%) 257 (9.5%) 369 (7.4%) Other Race/multiracial 594 (7.7%) 206 (7.6%) 388 (7.7%) PIR 2.1 (1.1–4.1) 1.6 (0.9–3.3) 2.4 (1.2–4.6) <0.001 Drinking status, n (%) 0.479 Yes 5950 (77.1%) 2067 (76.6%) 3883 (77.4%) No 1767 (22.9%) 630 (23.4%) 1137 (22.6%) Smoking status, n (%) <0.001 Never smoker 3528 (45.7%) 1131 (41.9%) 2397 (47.7%) Former smoker 2247 (29.1%) 642 (23.8%) 1605 (32.0%) Current smoker 1942 (25.2%) 924 (34.3%) 1018 (20.3%) Depressive symptom, n (%) <0.001 None 4249 (55.1%) 1370 (50.8%) 2879 (57.4%) Mild 1958 (25.4%) 731 (27.1%) 1227 (24.4%) Moderate to severe 1510 (19.6%) 596 (22.1%) 914 (18.2%) Physical activity, n (%) 0.960 Inactive 4700 (60.9%) 1639 (60.8%) 3061 (61.0%) Insufficiently active 1047 (13.6%) 370 (13.7%) 677 (13.5%) Sufficiently active 1970 (25.5%) 688 (25.5%) 1282 (25.5%) CVD history, n (%) 0.136 Yes 475 (6.2%) 151 (5.6%) 324 (6.5%) No 7242 (93.8%) 2546 (94.4%) 4696 (93.5%) Stroke history, n (%) 0.661 Yes 471 (6.1%) 169 (6.3%) 302 (6.0%) No 7246 (93.9%) 2528 (93.7%) 4718 (94.0%) Diabetes mellitus, n (%) 0.548 Yes 1437 (18.6%) 512 (19.0%) 925 (18.4%) No 6280 (81.4%) 2185 (81.0%) 4095 (81.6%) Continuous variables are expressed as Median with Interquartile Range (IQR). The categorical variables were presented as numbers and percentages. Abbreviations: BMI, body mass index; PIR, family poverty income ratio; CVD, cardiovascular disease. Bold p-values denote statistical significance at the p < 0.05 level. Observational associations between dietary supplements, sleep duration, and depressive symptoms. As expected, total sleep duration was significantly longer in dietary supplement users, including melatonin or MVM only, compared to non-users (melatonin: t = 2.68, P < 0.001; MVM: t = 5.44, P < 0.001; Fig. 2 C & Supplementary Table 3). The two groups had no difference in sleep duration (t = 1.42, P = 0.159). Additionally, only the MVM users exhibited fewer depressive symptoms (t = -7.00, P < 0.001; Fig. 2 C & Supplementary Table 4), whereas the melatonin users did not (t = 0.02, P = 0.988). Participants who took any dietary supplement containing the specified vitamins, such as vitamin A or C, also experienced significantly longer sleep durations and fewer depressive symptoms (Supplementary Table 3–4). Multivariate regression analysis revealed a significant relationship between dietary supplements and the risk of short sleep (Table 2 ). After adjusting for socio-demographic variables, participants with any dietary supplements (odds ratio [OR], 0.80; 95% CI: 0.71–0.90; P < 0.001), melatonin only (OR, 0.44; 95% CI: 0.20–0.86; P = 0.024), or MVM supplements only (OR, 0.79; 95% CI: 0.69–0.91; P = 0.001) had significantly lower odds of short sleep compared to non-users. However, there was no significant association between dietary supplements, long sleep, and depressive symptoms. Participants who took any dietary supplement containing the specified vitamin also had significantly lower odds of short sleep (Supplementary Table 5). Table 2 Logistic regression analyses of the associations between dietary supplements, sleep duration, and depressive symptoms. Group Short sleep duration Long sleep duration Depressive symptom OR (95% CI) P- value OR (95% CI) P- value OR (95% CI) P- value Without dietary supplement 1[Ref.] - 1[Ref.] - 1[Ref.] - With any dietary supplements 0.80 (0.71–0.90) < 0.001 1.06 (0.91–1.22) 0.466 1.12 (0.99–1.28) 0.078 Melatonin only 0.44 (0.20–0.86) 0.024 1.66 (0.87–3.00) 0.105 1.44 (0.78–2.54) 0.227 Multivitamin mineral supplements only 0.79 (0.69–0.91) 0.001 0.98 (0.82–1.17) 0.847 1.07 (0.91–1.25) 0.400 Model was adjusted for age, sex, race, BMI group, poverty income ratio, education, smoking status, drinking status, marital status, physical activity, stroke history, calorie intake, CVD history and diabetes status and with or without depressive symptom. Bold p-values denote statistical significance at the p < 0.05 level. Abbreviation: OR, odds ratio; CI, confidence interval; BMI: Body mass index; CVD, cardiovascular disease. Relationships of dietary supplements with mortality During an average of 86.8 months of follow-up, there were 941 all-cause deaths and 141 CVD-related deaths. In the unadjusted model, the hazard ratio (HR) for all-cause mortality was 2.11 (95% CI, 1.12 to 3.97; P = 0.020) for melatonin users compared to participants without any dietary supplement (Table 3 and Fig. 2 C). After adjusting for socio-demographic variables, this estimate was slightly attenuated and remained significant (HR: 1.97; 95% CI, 1.03 to 3.77; P = 0.040). The adjusted HR for MVM users showed a lower risk of all-cause mortality (HR, 0.84; 95% CI, 0.71 to 0.99; P = 0.040). Additionally, melatonin users showed a higher risk of cardiovascular mortality (HR, 3.46; 95% CI, 1.01 to 11.82; P = 0.048), while MVM users still showed a lower risk of cardiovascular mortality (HRs, 0.61; 95% CI, 0.39 to 0.95; P = 0.027). Adjusted HR for all-cause mortality in participants who took any dietary supplement containing some specified vitamin was also significantly lower (Supplementary Table 6–7 and Fig. 2 D). Table 3 Multivariate Cox regression analysis examining the impact of dietary supplements on mortality. Group Number of deaths Crude Model Model 1 Model 2 HR (95% CI) P -value HR (95% CI) P -value HR (95% CI) P -value All-cause mortality Without dietary supplement 313 1[Ref.] - 1[Ref.] - 1[Ref.] - With any dietary supplements 628 1.14 (1.00–1.31) 0.055 0.90 (0.78–1.04) 0.153 0.92 (0.80–1.06) 0.271 Melatonin only 10 2.11 (1.12–3.97) 0.020 1.93 (1.01–3.70) 0.046 1.97 (1.03–3.77) 0.040 Multivitamin mineral supplements only 320 1.02 (0.87–1.19) 0.786 0.81 (0.69–0.96) 0.017 0.84 (0.71–0.99) 0.040 Cardiovascular mortality Without dietary supplement 52 1[Ref.] - 1[Ref.] - 1[Ref.] - With any dietary supplements 89 0.97 (0.69–1.37) 0.879 0.74 (0.52–1.06) 0.101 0.76 (0.53–1.09) 0.135 Melatonin only 3 4.29 (1.33–13.85) 0.015 3.38 (0.99–11.49) 0.052 3.46 (1.01–11.82) 0.048 Multivitamin mineral supplements only 43 0.83 (0.55–1.24) 0.352 0.60 (0.39–0.93) 0.023 0.61 (0.39–0.95) 0.027 Cox proportional hazard models were performed for all-cause mortality. Competing risk analyses of cause-specific mortality were performed. The crude model did not adjust for any covariates. Model 1 was adjusted for age, sex, race, BMI group, poverty income ratio, education, smoking status, drinking status, marital status, physical activity, and depressive symptoms. Model 2 was adjusted for calorie intake, CVD history, stroke history, and diabetes status in addition to Model 1. Bold p-values denote statistical significance at the p < 0.05 level. Abbreviation: HR, Hazard Ratio; CI, confidence interval; BMI: Body mass index; CVD, cardiovascular disease. Sensitivity analysis In the sensitivity analysis, melatonin users were identified as who as long as used melatonin (135 participants), while MVM users were identified as who as long as used MVM (2,714 participants). The sensitivity analyses were similar to the main analyses (Supplementary Table 8–9). Melatonin users continued to exhibit a higher risk of cardiovascular mortality (HR, 3.82; 95% CI, 1.54 to 9.46; P = 0.004; Supplementary Table 8). Additionally, after containing those who use both melatonin and MVM, the protective association in MVM consumption on all-cause mortality remained statistically significant (HR, 0.86; 95% CI, 0.75 to 0.99; P = 0.031), while the association with cardiovascular mortality was no longer statistically significant (HR, 0.77; 95% CI, 0.53 to 1.11; P = 0.167). DISCUSSION The objective of this study was to investigate the effects and risks of melatonin in individuals with sleep disturbances, in contrast to multivitamins, using a large-scale national dataset. The study confirmed that dietary supplements, notably melatonin and multivitamins, enhance sleep duration in individuals experiencing sleep disturbances. Moreover, the data indicate that intake of multivitamins, along with any dietary supplements containing the specified vitamins, but not melatonin, was associated with fewer depressive symptoms among the participants. Contrary to our initial expectations, the utilization of melatonin was connected to an increased risk of cardiovascular mortality, while multivitamins demonstrated correlations with lower all-cause and cardiovascular mortality. This suggests that while melatonin is linked to improved sleep quality, it must be used with caution, especially for long-term use. Based on our findings, multivitamin supplements might be a better option for individuals with sleep disturbances. Our investigation aligns with earlier discoveries, indicating that melatonin could prolong sleep duration and reduce the risk of short sleep. It achieves these without increasing the probability of long sleep, which may adversely affect health 34 – 36 . Mechanistically, melatonin modulates sleep-wake patterns through MT1/MT2 receptor-mediated, regulating various sleep aspects including the circadian rhythm, and sleep architecture 37 . Additionally, melatonin also demonstrates antidepressant-like effects by suppressing inflammatory responses through both immune and non-immune mechanisms 9 , 10 , which in turn affect neuroinflammation and neurotoxicity in brain regions associated with depression. However, the large-scale clinical data in this study indicated that depressive symptoms in participants treated with melatonin were similar to those in the control group; thereby, the linkage between melatonin use and the alleviation of depressive symptoms remains unclear. This evidence suggests that while melatonin acts as an effective agent to augment sleep duration, its utility in managing mood disorders requires further scrutiny. In a population-based cohort study, Nagata and his colleagues found that melatonin is linked to lower overall and cardiovascular mortality 38 . Our observations are at odds with this view. Such discrepancies may stem from the limited sample size, the modest number of events, and the definition of melatonin intake in our study. Given the complex interplay between sleep duration, sleep quality, and cardiovascular health 39 , further research is warranted to clarify the relationship between melatonin and cardiovascular risk. Research findings indicate that taking multivitamin supplements has the potential to improve emotional states. For example, a study conducted with older adults experiencing mild cognitive impairment revealed that multivitamin interventions not only augmented cognitive abilities but also significantly alleviated depressive symptoms 40 . Similarly, it has been shown in a double-blind, randomized controlled trial to significantly mitigate depressive symptoms among individuals undergoing methadone maintenance therapy 41 . Moreover, vitamin levels are correlated with the quality of sleep. The serum levels of vitamin D demonstrate a positive correlation with self-reported daily sleep duration among elderly individuals 42 . Concurrent supplementation of poly-γ-glutamic acid and vitamin B6 has been shown to enhance sleep duration 43 . In this study, the results showed that multivitamin supplementation demonstrated associations with prolonged sleep duration, attenuated depressive symptom scores, and lower all-cause mortality. These findings align with existing literature highlighting the positive effects of multivitamins on both mental and physical health 44 . Taken together, these findings contribute to the growing body of evidence suggesting that multivitamin intake is essential for improving overall health, particularly among populations with sleep disturbances. In parallel, these emphasize that melatonin may not be the exclusive intervention in the initial stages of sleep disturbance, as the incorporation of multivitamin intake and sleep hygiene practices may also yield benefits and offer long-term safety. The predominant strength of our study lies in its design as a prospective cohort study, employing the NHANES database—an authoritative and representative dataset—that provides reliable estimates of melatonin use across racial/ethnic groups. We leveraged the dataset to investigate the unverified effects and long-term safety of melatonin and multivitamin supplementation in sleep disturbance, adjusting for confounders to bolster the rigor and dependability of our findings. Notwithstanding, the present study should be considered with caution in light of some study limitations. First, the sample size of patients using only melatonin is relatively small compared to the overall cohort, potentially limiting the detection of clinically meaningful relationships and elevating the risk of Type II errors. Additionally, the inability to precisely determine the time frame during which dietary supplements are used or not used hinders the analysis of time-dependent effects. Although the supplement containers were authenticated for nearly all participants, notable discrepancies exist in dosage and compositional inconsistency among marketed melatonin supplements. Finally, this article focuses solely on the consumption of exogenous supplements for melatonin and vitamins, while omitting considerations of dietary food intake. CONCLUSION In summary, our results indicated while melatonin use was associated with sleep quality, its long-term safety was linked to an increased risk of cardiovascular mortality. Additionally, multivitamins demonstrated correlations with fewer depressive symptoms and decreased all-cause mortality. These findings suggest that melatonin does not appear to be the sole selection for early-stage sleep disturbances, while multivitamins, associated with prolonged sleep duration and improved health outcomes, emerge as a more suitable alternative. Given the scant investigations regarding the impact of melatonin on sleep disturbances and its long-term safety, further studies are needed to validate these results. Declarations Declaration of Interest Statement The authors have no actual or potential conflicts of interest to declare. Funding This work was funded by National Key R&D Program of China (Grant No.: 2022YFC2503902), and Guangzhou Key Laboratory for Germ-free animals and Microbiota Application (Grant No.: 202201020381). Ethics and approval The study protocol (Protocol Number: Protocol #2011–17 and Protocol #2018–01) was approved by the NCHS Research Ethics Review Board (ERB) and all participants provided written informed consent prior to participation. (https://www.cdc.gov/nchs/nhanes/irba98.htm). A uthorship contribution statement Zerui You: Conceptualization, Methodology, Data extraction, Statistical analysis, Writing-original draft, Writing-review & editing. Lutong Gan, Jiamin Wu, Simeng Feng: Conceptualization, Methodology. Jiyang Pan: Conceptualization, Funding acquisition, Investigation, Supervision, Project administration. All authors have read and agreed to the published version of the manuscript. Data Availability Statement All relevant data are described within the paper. The NHANES data underpinning the findings of this research are accessible to the public at https://www.cdc.gov/nchs/nhanes/index.htm. Acknowledgments No. References Hisler, G. C., Muranovic, D. & Krizan, Z. Changes in sleep difficulties among the U.S. population from 2013 to 2017: results from the National Health Interview Survey. Sleep Health 5 , 615–620 (2019). Golombek, D. A., Pandi-Perumal, S. R., Brown, G. M. & Cardinali, D. P. Some implications of melatonin use in chronopharmacology of insomnia. Eur. J. Pharmacol. 762 , 42–48 (2015). Ohayon, M. M. & Reynolds, C. F. Epidemiological and clinical relevance of insomnia diagnosis algorithms according to the DSM-IV and the International Classification of Sleep Disorders (ICSD). Sleep Med. 10 , 952–960 (2009). Hillman, D. R. & Lack, L. C. Public health implications of sleep loss: the community burden. Med. J. Aust. 199 , S7-10 (2013). Morin, C. M. & Jarrin, D. C. Epidemiology of Insomnia: Prevalence, Course, Risk Factors, and Public Health Burden. Sleep Med. Clin. 17 , 173–191 (2022). Waldron, A. Y., Spark, M. J. & Dennis, C. M. The Use of Melatonin by Children: Parents’ Perspectives. J. Clin. Sleep Med. JCSM Off. Publ. Am. Acad. Sleep Med. 12 , 1395–1401 (2016). Ferracioli-Oda, E., Qawasmi, A. & Bloch, M. H. Meta-analysis: melatonin for the treatment of primary sleep disorders. PloS One 8 , e63773 (2013). F, C.-S. et al. Optimizing the Time and Dose of Melatonin as a Sleep-Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose-Response Meta-Analysis. J. Pineal Res. 76 , (2024). Won, E., Na, K. S. & Kim, Y. K. Associations between Melatonin, Neuroinflammation, and Brain Alterations in Depression. Int J Mol Sci 23 , (2021). Ali, T. et al. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation. J. Pineal Res. 69 , e12667 (2020). Rj, R. et al. 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Vitamin D Supplementation and Sleep: A Systematic Review and Meta-Analysis of Intervention Studies. Nutrients 14 , 1076 (2022). Casseb, G. A. S., Kaster, M. P. & Rodrigues, A. L. S. Potential Role of Vitamin D for the Management of Depression and Anxiety. CNS Drugs 33 , 619–637 (2019). Yosaee, S. et al. The effect of vitamin C supplementation on mood status in adults: a systematic review and meta-analysis of randomized controlled clinical trials. Gen. Hosp. Psychiatry 71 , 36–42 (2021). Jahan-Mihan, A. et al. The Role of Water-Soluble Vitamins and Vitamin D in Prevention and Treatment of Depression and Seasonal Affective Disorder in Adults. Nutrients 16 , 1902 (2024). Chan, V. & Lo, K. Efficacy of dietary supplements on improving sleep quality: a systematic review and meta-analysis. Postgrad. Med. J. 98 , 285–293 (2022). Esquivel, M. K. & Ghosn, B. Current Evidence on Common Dietary Supplements for Sleep Quality. Am. J. Lifestyle Med. 18 , 323–327 (2024). Park, S. et al. Short or Long Sleep Duration and CKD: A Mendelian Randomization Study. J. Am. Soc. Nephrol. JASN 31 , 2937–2947 (2020). Y, L. et al. Sleep duration and risk of fatal and nonfatal stroke: a prospective study and meta-analysis. Neurology 84 , (2015). Chen, F. et al. Association Among Dietary Supplement Use, Nutrient Intake, and Mortality Among U.S. Adults: A Cohort Study. Ann. Intern. Med. 170 , 604–613 (2019). Brämer, G. R. International statistical classification of diseases and related health problems. Tenth revision. World Health Stat. Q. Rapp. Trimest. Stat. Sanit. Mond. 41 , 32–36 (1988). J, L. et al. Association of daily sitting time and leisure-time physical activity with body fat among U.S. adults. J. Sport Health Sci. 13 , (2024). Smolderen, K. G. et al. Health care insurance, financial concerns in accessing care, and delays to hospital presentation in acute myocardial infarction. JAMA 303 , 1392–1400 (2010). Ai, S. et al. Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK Biobank. Eur. Heart J. 42 , 3349–3357 (2021). Shan, Z. et al. Sleep duration and risk of type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care 38 , 529–537 (2015). Chen, J.-C. et al. Sleep duration, cognitive decline, and dementia risk in older women. Alzheimers Dement. J. Alzheimers Assoc. 12 , 21–33 (2016). Comai, S. & Gobbi, G. Melatonin, Melatonin Receptors and Sleep: Moving Beyond Traditional Views. J. Pineal Res. 76 , e13011 (2024). Nagata, C. et al. Associations Between Dietary Melatonin Intake and Total and Cause-Specific Mortality Among Japanese Adults in the Takayama Study. Am. J. Epidemiol. 190 , 2639–2646 (2021). Kobayashi, D., Kuriyama, N., Osugi, Y., Arioka, H. & Takahashi, O. Longitudinal relationships between cardiovascular events, risk factors, and time-dependent sleep duration. Cardiol. J. 25 , 229–235 (2018). Lee, H. K., Kim, S. Y. & Sok, S. R. Effects of Multivitamin Supplements on Cognitive Function, Serum Homocysteine Level, and Depression of Korean Older Adults With Mild Cognitive Impairment in Care Facilities. J. Nurs. Scholarsh. Off. Publ. Sigma Theta Tau Int. Honor Soc. Nurs. 48 , 223–231 (2016). N, L., A, B., R, G. & N, T. The effect of multivitamins on anxiety and depression in patients undergoing methadone maintenance treatment: A double-blind randomized controlled trial. Int. J. Psychiatry Med. 58 , (2023). Kim, J. H., Chang, J. H., Kim, D. Y. & Kang, J. W. Association between self-reported sleep duration and serum vitamin D level in elderly Korean adults. J. Am. Geriatr. Soc. 62 , 2327–2332 (2014). García-García, C. & Baik, I. Effects of poly-gamma-glutamic acid and vitamin B6 supplements on sleep status: a randomized intervention study. Nutr. Res. Pract. 15 , 309–318 (2021). Sarris, J., Mehta, B., Óvári, V. & Ferreres Giménez, I. Potential mental and physical benefits of supplementation with a high-dose, B-complex multivitamin/mineral supplement: What is the evidence? Nutr. Hosp. 38 , 1277–1286 (2021). Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6213720","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":455679975,"identity":"a8a759a0-ff44-47f8-bcd8-5c990a4fb0fb","order_by":0,"name":"Zerui You","email":"","orcid":"","institution":"First Affiliated Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Zerui","middleName":"","lastName":"You","suffix":""},{"id":455679976,"identity":"9c5383c9-a4dd-4c61-ad64-13eae14b57c8","order_by":1,"name":"Lutong Gan","email":"","orcid":"","institution":"First Affiliated Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Lutong","middleName":"","lastName":"Gan","suffix":""},{"id":455679977,"identity":"19082d3c-de2c-4f52-b7a8-f219464e0aa7","order_by":2,"name":"Jiamin Wu","email":"","orcid":"","institution":"The Eighth Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiamin","middleName":"","lastName":"Wu","suffix":""},{"id":455679978,"identity":"e70b9949-4be2-4250-9bb2-c8f9c6058f48","order_by":3,"name":"Simeng Feng","email":"","orcid":"","institution":"First Affiliated Hospital of Jinan University","correspondingAuthor":false,"prefix":"","firstName":"Simeng","middleName":"","lastName":"Feng","suffix":""},{"id":455679979,"identity":"381a8073-aa92-4ede-8f7e-ae52ec00482e","order_by":4,"name":"Jiyang Pan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAp0lEQVRIiWNgGAWjYBACxmYwZcPDz99AmpY0GckZB0iz7LCNQUMCkWqZ23nMHvzccZ7HgOEA44ePOUQ5jMfcsPfMbR5z5gZmyZnbiNNiJsHbdpvHsuEAGzMvsVok/7ad4zE4kECCFmnetgMkaWErN5ZtS+aRnHGwmTi/GPYf3vbwbZudPT9/88EPH4nS0sBhBrOwgQj1QCDPwP6MOJWjYBSMglEwcgEA3OIyN6L7pXUAAAAASUVORK5CYII=","orcid":"","institution":"First Affiliated Hospital of Jinan University","correspondingAuthor":true,"prefix":"","firstName":"Jiyang","middleName":"","lastName":"Pan","suffix":""}],"badges":[],"createdAt":"2025-03-12 16:23:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6213720/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6213720/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82705955,"identity":"0a2793e9-40d3-4ec7-9692-0727ea45eec0","added_by":"auto","created_at":"2025-05-14 10:28:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4767805,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of participants included in this study.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviation: NHANES, National Health and Nutrition Examination Survey; PIR, family poverty income ratio; BMI, body mass index; CVD, cardiovascular disease.\u003c/p\u003e","description":"","filename":"Fig1flowchart.png","url":"https://assets-eu.researchsquare.com/files/rs-6213720/v1/c676011de606be81c2c5765e.png"},{"id":82705969,"identity":"8a9d525e-5023-447c-8d40-1ed49518f6f3","added_by":"auto","created_at":"2025-05-14 10:28:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":17632985,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDifference in different dietary supplement groups and association between dietary supplements and mortality.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA \u003c/strong\u003eThe proportion of participants using dietary supplements. \u003cstrong\u003eB\u003c/strong\u003eMelatonin daily dosage histogram. \u003cstrong\u003eC \u003c/strong\u003eComparison of sleep duration and depressive symptoms among dietary supplement groups. Depressive symptoms were assessed by the PHQ-9 scores. Melatonin group consists of participants who used only melatonin (72 participants), while MVM group includes those who used only multivitamin-mineral supplements (2651 participants). Non-users are those who didn’t use any dietary supplement (2697 participants). \u003cstrong\u003eD \u003c/strong\u003eAssociation of dietary supplement with all-cause and cardiovascular mortality. Coefficients are presented with 95%CI using the multivariable Cox regression models. All estimated models were adjusted for age, sex, race, BMI, poverty income ratio, education, smoking status, drinking status, physical activity, depressive symptoms, calorie intake, CVD history, stroke history, and diabetes status. Abbreviation: PHQ-9, Patient Health Questionnaire; BMI: Body mass index; CVD, cardiovascular disease; HR, hazard ratio; CI, confidence interval; MVM, multivitamin mineral supplements. ***: P \u0026lt; 0.001; **: P \u0026lt; 0.01; *: P \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-6213720/v1/afe7b2d836909e8c742c8b71.png"},{"id":106959444,"identity":"564ae66c-f9b3-4387-8c43-39c0c12ae883","added_by":"auto","created_at":"2026-04-15 09:09:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":19496774,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6213720/v1/7df9e5cf-556c-4a48-aab8-df3c5657c554.pdf"},{"id":82705954,"identity":"5a0e23ba-9e8c-42b9-b966-a2629025f543","added_by":"auto","created_at":"2025-05-14 10:28:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":67640,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6213720/v1/783c27cd6878123da819e5e1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Melatonin and Multivitamin Use in Sleep Disturbance Populations: Associations with Health Outcomes and Mortality from a National Cohort Study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eMore than one-third of adults experience sleep-related disturbances. The most prevalent disturbances include difficulties in falling asleep and maintaining sleep, commonly referred to as insomnia symptoms\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Such sleep disturbances can profoundly impact physiological processes, leading to prolonged sleep onset latency, frequent nocturnal awakenings, and reduced sleep efficiency, among others\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. These challenges can significantly impact overall health and well-being, adversely affecting cognitive functioning, emotional stability, and quality of life\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Due to the manifestations associated with sleep disturbances, this pathological state is regarded as a significant public health issue and has become a physical and economic burdens\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Therefore, comprehensive investigations into sleep disturbances within the framework of population-based cohorts are warranted.\u003c/p\u003e \u003cp\u003eCurrently, available therapeutic agents for the treatment of insomnia include benzodiazepines, benzodiazepine receptor agonists, antidepressants, antipsychotics, and melatonin, along with other options. Among these, exogenous melatonin is marketed as a non-pharmacological sleep aid, often promoted for managing circadian rhythm disorders and transient sleep disruptions, primarily due to its perceived \u0026ldquo;natural\u0026rdquo; origin\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e and modest evidence supporting sleep quality improvements in specific populations\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. While some preclinical studies hypothesize that melatonin might regulate circadian rhythms or exhibit anti-inflammatory and antioxidant properties\u003csup\u003e\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, clinical evidence supporting its efficacy for sleep disturbances is inconsistent, with overall low-quality evidence for its use\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Since melatonin products are classified as \u0026ldquo;natural health products\u0026rdquo; or \u0026ldquo;dietary supplements\u0026rdquo; in some countries, they are subject to insufficient regulation, leading to multiple safety concerns\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Some products exhibit dosage inaccuracies and may include additional compounds, such as serotonin, which might not comply with established standards\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. The current situation is that the prevalence of melatonin supplement consumption has significantly increased among various populations\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. This trend is accompanied by a growing demand for robust evidence regarding the long-term safety of melatonin supplementation. However, high-quality, large-scale studies on the long-term safety of melatonin are still scarce\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The absence of comprehensive data hinders the ability to draw conclusions regarding the safety of long-term melatonin use.\u003c/p\u003e \u003cp\u003eGrowing evidence links dietary and circulating micronutrients (including multivitamins) with sleep quality\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. The study using nationwide survey data found that men with moderate-to-severe insomnia were associated with a higher prevalence of inadequate vitamin C, B6, and folate\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In a separate analysis of Japanese adults, significant associations were observed between self-reported nutrient intake and sleep duration, with positive correlations for vitamins B12 and D\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. A systematic review of randomized controlled trials (RCTs) found that vitamin D supplementation significantly reduced the Pittsburgh Sleep Quality Index (PSQI), suggesting that vitamin D supplementation may be effective in improving sleep quality\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Similar to melatonin, multivitamins have demonstrated the potential to alleviate depressive symptoms, particularly through components such as vitamin D\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, vitamin C\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, and vitamin B\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Nevertheless, evidence on dietary supplements for improving sleep is constrained by methodological limitations and inconsistent findings. Chan et al. noted that heterogeneity and wide confidence intervals undermine the reliability of the potential benefits of vitamin D and melatonin\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. The efficacy of melatonin remains debated due to conflicting trial results, and evidence regarding other supplements remains inconclusive\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Additionally, direct comparisons between melatonin and multivitamins\u0026mdash;two commonly used supplementations\u0026mdash;are lacking in the existing literature. Therefore, we aim to investigate their impacts on sleep duration and depressive symptoms and their association with mortality in large cohorts, which may provide further insights into their clinical implications and risks.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first study based on the US National Health and Nutrition Examination Survey (NHANES) data to assess the effects and risks of melatonin and multivitamin supplements in individuals with sleep disturbance. In this study, we aimed to identify: (i) the effect of melatonin and multivitamins on health outcomes, including sleep duration and depressive symptoms, in individuals with sleep disturbance; (ii) whether melatonin and multivitamins confer any survival benefits, particularly in terms of reducing all-cause and cardiovascular mortality; and (iii) which dietary supplements were the most suitable choices. Of particular note, our research focused extensively on exploring the similarities and differences between melatonin and multivitamins in the context of sleep disturbance. We hypothesized that melatonin offers an advantage in enhancing sleep quality, alleviating depressive symptoms, and reducing all-cause mortality, demonstrating superior clinical effectiveness compared to multivitamins. By comparing their effects, we aimed to provide valuable insights into which dietary supplements offer a more favorable risk-benefit profile for addressing sleep disturbance.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis cross-sectional analysis utilized data from the NHANES conducted from 2005 to 2018 by the Centers for Disease Control and Prevention (CDC) to assess the health and nutritional conditions of the U.S. population. The protocols for NHANES received approval from the National Center for Health Statistics Research Ethics Review Board, aligning with the revised Declaration of Helsinki. Informed consent was obtained in writing from all participants. For further information regarding the NHANES initiative, please refer to the CDC website (Centers for Disease Control and Prevention (CDC), 2022). The inclusion and exclusion process for all eligible participants is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAssessment of sleep disturbance and duration\u003c/h3\u003e\n\u003cp\u003eSleep disturbance and duration were assessed using the NHANES questionnaire. Participants reported their typical weekday sleep duration in hours, and their response to the question, \u0026ldquo;Have you ever told a doctor or other health professional that you have trouble sleeping?\u0026rdquo; was used to evaluate self-reported sleep disturbance. The response categories for this question included \u0026ldquo;Yes,\u0026rdquo; \u0026ldquo;No,\u0026rdquo; \u0026ldquo;Refused,\u0026rdquo; and \u0026ldquo;Do not know.\u0026rdquo; Responses from participants who selected 'Do not know' or 'Refused' were classified as missing values. Self-reported sleep duration was evaluated by posing the inquiry: \u0026ldquo;How much sleep do you usually get at night on weekdays or workdays?\u0026rdquo; Sleep hours were documented in whole numbers. Sleep duration was characterized as short sleep duration (\u0026lt;\u0026thinsp;6 hours) and long sleep duration (\u0026gt;\u0026thinsp;8 hours) referenced to normal sleep (7\u0026ndash;8 hours)\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eDietary supplement use\u003c/h3\u003e\n\u003cp\u003e The NHANES participants were asked whether they used any vitamins, minerals, or other dietary supplements during an in-house interview If the answer was yes, they were asked to show the containers to the interviewers. Each supplement includes a comprehensive description of its primary ingredients (e.g., vitamin C, vitamin D), and more than 75% of production information is recorded based on information from the container. Participants were also asked for the product name, dietary supplement contains, details regarding the frequency (e.g., number of times per day), serving form (e.g., capsules, tablets, or other formats), daily dosage (amount of ingredients per serving), duration, and so on.\u003c/p\u003e \u003cp\u003eAny participant who consumes a dietary supplement that includes melatonin is categorized as a melatonin user. This classification applies regardless of the specific type of supplement as long as melatonin is one of its active ingredients. Vitamins, including 14 specific vitamins (Supplementary Table\u0026nbsp;1), and multivitamin mineral (MVM) supplements were assessed respectively. The classification of MVM supplements was defined as consuming products containing more than three kinds of vitamins, with or without additional minerals\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Participants who did not use any supplements were classified as non-users and served as the control group. Some participants used both melatonin and multivitamins; these individuals were excluded from the main analysis in each group and subsequently included in the sensitivity analysis.\u003c/p\u003e\n\u003ch3\u003eMortality outcomes of the study\u003c/h3\u003e\n\u003cp\u003eMortality data were extracted from the National Death Index (NDI), a database operated by the Centers for Disease Control and Prevention (CDC) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/nchs/data-linkage/mortality-public.htm\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/nchs/data-linkage/mortality-public.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Each participant's follow-up period was determined from their enrollment date up to either their date of death or December 31, 2019, which is the most recent update available from the NDI. The study outcomes included cardiovascular mortality and all-cause mortality.\u003c/p\u003e \u003cp\u003eData pertaining to the fundamental causes of mortality were employed for case definition in accordance with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10)\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Cardiovascular mortality was defined as death resulting from heart disease (ICD-10 codes I00-I09, I11, I13, I20-I51) or cerebrovascular disease (ICD-10 codes I60-I69).\u003c/p\u003e\n\u003ch3\u003eCovariates\u003c/h3\u003e\n\u003cp\u003eIn our study, we included clinically significant covariates such as age at the time of the interview, sex, body mass index (BMI) group (underweight/normal/overweight/ obese), income level, race/ethnicity, education attainment, marital status, smoking status (never/former/current), drinking status (yes/no), physical activity (inactive/insufficiently active/sufficiently active), the presence of depressive symptoms (none/mild/moderate to severe), calorie intake (kcal), cardiovascular disease (CVD) history (yes/no), stroke history (yes/no) and diabetes status (yes/no).\u003c/p\u003e \u003cp\u003eBMI was calculated as body weight (kg)/height\u003csup\u003e2\u003c/sup\u003e (m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e). BMI group was utilized to assess participants' weight status, categorizing them as underweight (\u0026lt;\u0026thinsp;18.5 kg/m\u003csup\u003e2\u003c/sup\u003e), normal (18.5\u0026ndash;24.9 kg/m\u003csup\u003e2\u003c/sup\u003e), overweight (25\u0026ndash;29.9 kg/m\u003csup\u003e2\u003c/sup\u003e), or obese (\u0026ge;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e). Income level of participants was evaluated using the ratio of household income to the poverty threshold (PIR). Educational attainment was stratified into five groups: less than 9th grade, 9th to 11th grade, high school diploma recipient, college or Associate of Arts (AA) degree holder, and those with a college degree or higher. Marital status was classified as single (widowed, divorced, or separated) or non-single (married or living with a partner), determined by their living situation. Smoking status was classified into three categories: never smoked (smoked\u0026thinsp;\u0026lt;\u0026thinsp;100 cigarettes), formerly smoked (not currently smoking but smoked\u0026thinsp;\u0026ge;\u0026thinsp;100 cigarettes), and currently smoked (\u0026ge;\u0026thinsp;100 cigarettes and currently smoking every day or on some days). Alcohol use was classified into two categories: never drinking and ever or current drinking. Physical activity, as reported weekly by participants, predominantly during leisure periods, was obtained through individual interviews conducted with the Global Physical Activity Questionnaire. Total physical activity time was calculated by adding minutes of moderate-intensity activities to twice the minutes of vigorous-intensity activities. Physical activity was categorized into three groups: inactive (without any physical activity), insufficiently active (1-150 min/week), and sufficiently active (\u0026ge;\u0026thinsp;150 min/week)\u003csup\u003e32\u003c/sup\u003e. Depression severity was categorized using Patient Health Questionnaire-9 (PHQ-9) score (points): none (0\u0026ndash;4), mild (5\u0026ndash;9), and moderate to severe depression (\u0026ge;\u0026thinsp;10). The PHQ-9 score of 10 or more indicates the presence of significant depressive symptoms\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Total calorie intake was calculated based on the average value of two days of self-reported daily calorie intake assessments. CVD history, stroke history, and diabetes mellitus were determined based on self-reported diagnoses provided by medical professionals or if participants were instructed to take prescribed medications for these conditions. Those who gave a definite reply were considered to have the history or diagnosis, while the rest were regarded as not having any.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were conducted to analyze the baseline characteristics of participants using various dietary supplements compared to those not utilizing any supplements. Continuous variables were expressed as the mean and standard deviation (SD) or as the median with interquartile range (IQR), while categorical variables were presented as frequencies and proportions. The characteristics were compared using the independent Student's t-test, Mann-Whitney U test, or Chi-squared test as appropriate. Cross-sectional binary logistic models were performed to compare sleep duration and depressive symptoms (yes/no) between participants with different dietary supplements, in comparison to those not utilizing any supplements and participants without dietary supplements. Survival analysis was performed using Cox proportional hazards models to investigate the association between dietary supplements and the risks of all-cause mortality as well as cardiovascular mortality. The influence of dietary supplements on overall mortality was evaluated through sequential adjustments of covariates across multiple modeling frameworks. Crude model represented a univariate analysis. Model I was adjusted for all demographic covariates, while Model II included modifications for demographic variables in conjunction with the history of calorie intake, CVD, stroke, and the existence of diabetes to evaluate the robustness of the results. Statistical analysis was conducted with the \u0026ldquo;survey\u0026rdquo; package (version 4.0.4) in R software. All analyses and models were conducted using R (version 4.4.1). The significance level was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePopulation characteristics\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the demographic characteristics of 7,717 individuals from NHANES 2005\u0026ndash;2018. The participants had an average age of 52.6 years, reported an average sleep duration of 6.7 hours per day, and 41.8% were male. Among participants (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), 5,020 (65.0%) used dietary supplements: 72 (0.9%) used melatonin only, 2,651 (34.3%) used multivitamin-mineral supplements (MVM) only, 63 (0.8%) used both, and 2,234 (28.9%) used other types. Melatonin use prevalence in this study (1.75% [135/7717]) matches prior national estimates in U.S. adults\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Participants with dietary supplements were more likely to be female, college graduates, white, not smoking, and exhibiting no depressive symptoms. Usual doses of melatonin range from 1 mg/d to 5 mg/d, with 3 mg/d being the most common (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). To rule out the confounding effect of mixed-use dietary supplements and better statistical estimates, we analyzed participants who only used melatonin or MVM, in which the reference group included all participants who did not use dietary supplements in the subsequent main analysis. Additionally, apart from education level and diabetes status, no significant differences were observed between melatonin- and MVM-only users (Supplementary Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the study population with various groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7717)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWithout dietary supplement\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2697)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWith any dietary supplements\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5020)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStatistics\u003c/p\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53.0 (40.0\u0026ndash;65.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.0 (36.0\u0026ndash;60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56.0 (43.0\u0026ndash;67.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3222 (41.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1266 (46.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1956 (39.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4495 (58.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1431 (53.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3064 (61.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29.4 (25.2\u0026ndash;34.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29.8 (25.2\u0026ndash;35.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.2 (25.2\u0026ndash;34.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalorie intake (kcal)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1858.0 (1413.5\u0026ndash;2414.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1872.0 (1407.0\u0026ndash;2450.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1852.2 (1415.8\u0026ndash;2398.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLess Than 9th Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e591 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e256 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e335 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9-11th Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1015 (13.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e489 (18.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e526 (10.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh School Grad/GED\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1845 (23.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e719 (26.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1126 (22.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSome College or AA degree\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2567 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e826 (30.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1741 (34.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCollege Graduate or above\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1699 (22.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e407 (15.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1292 (25.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarry status, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarry/Living with partner\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4288 (55.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1429 (53.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2859 (57.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWidowed/Divorced/Separated/Never married\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3429 (44.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1268 (47.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2161 (43.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-Hispanic White\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4147 (53.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1221 (45.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2926 (58.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-Hispanic Black\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1553 (20.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e695 (25.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e858 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMexican American\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e797 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e318 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e479 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Hispanic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e626 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e257 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e369 (7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Race/multiracial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e594 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e206 (7.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e388 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePIR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.1 (1.1\u0026ndash;4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.6 (0.9\u0026ndash;3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.4 (1.2\u0026ndash;4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrinking status, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.479\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5950 (77.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2067 (76.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3883 (77.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1767 (22.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e630 (23.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1137 (22.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking status, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3528 (45.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1131 (41.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2397 (47.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2247 (29.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e642 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1605 (32.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1942 (25.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e924 (34.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1018 (20.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepressive symptom, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4249 (55.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1370 (50.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2879 (57.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1958 (25.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e731 (27.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1227 (24.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate to severe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1510 (19.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e596 (22.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e914 (18.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical activity, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.960\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInactive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4700 (60.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1639 (60.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3061 (61.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsufficiently active\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1047 (13.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e370 (13.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e677 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSufficiently active\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1970 (25.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e688 (25.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1282 (25.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCVD history, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.136\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e475 (6.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e151 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e324 (6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7242 (93.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2546 (94.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4696 (93.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke history, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.661\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e471 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e169 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e302 (6.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7246 (93.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2528 (93.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4718 (94.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.548\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1437 (18.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e512 (19.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e925 (18.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6280 (81.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2185 (81.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4095 (81.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eContinuous variables are expressed as Median with Interquartile Range (IQR). The categorical variables were presented as numbers and percentages. Abbreviations: BMI, body mass index; PIR, family poverty income ratio; CVD, cardiovascular disease. Bold p-values denote statistical significance at the p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 level.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eObservational associations between dietary supplements, sleep duration, and depressive symptoms.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAs expected, total sleep duration was significantly longer in dietary supplement users, including melatonin or MVM only, compared to non-users (melatonin: t\u0026thinsp;=\u0026thinsp;2.68, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; MVM: t\u0026thinsp;=\u0026thinsp;5.44, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC \u0026amp; Supplementary Table\u0026nbsp;3). The two groups had no difference in sleep duration (t\u0026thinsp;=\u0026thinsp;1.42, P\u0026thinsp;=\u0026thinsp;0.159). Additionally, only the MVM users exhibited fewer depressive symptoms (t = -7.00, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC \u0026amp; Supplementary Table\u0026nbsp;4), whereas the melatonin users did not (t\u0026thinsp;=\u0026thinsp;0.02, P\u0026thinsp;=\u0026thinsp;0.988). Participants who took any dietary supplement containing the specified vitamins, such as vitamin A or C, also experienced significantly longer sleep durations and fewer depressive symptoms (Supplementary Table\u0026nbsp;3\u0026ndash;4).\u003c/p\u003e \u003cp\u003eMultivariate regression analysis revealed a significant relationship between dietary supplements and the risk of short sleep (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). After adjusting for socio-demographic variables, participants with any dietary supplements (odds ratio [OR], 0.80; 95% CI: 0.71\u0026ndash;0.90; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), melatonin only (OR, 0.44; 95% CI: 0.20\u0026ndash;0.86; P\u0026thinsp;=\u0026thinsp;0.024), or MVM supplements only (OR, 0.79; 95% CI: 0.69\u0026ndash;0.91; P\u0026thinsp;=\u0026thinsp;0.001) had significantly lower odds of short sleep compared to non-users. However, there was no significant association between dietary supplements, long sleep, and depressive symptoms. Participants who took any dietary supplement containing the specified vitamin also had significantly lower odds of short sleep (Supplementary Table\u0026nbsp;5).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLogistic regression analyses of the associations between dietary supplements, sleep duration, and depressive symptoms.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eShort sleep duration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eLong sleep duration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eDepressive symptom\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWithout dietary supplement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWith any dietary supplements\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.80 (0.71\u0026ndash;0.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.06 (0.91\u0026ndash;1.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.12 (0.99\u0026ndash;1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMelatonin only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.44 (0.20\u0026ndash;0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.024\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.66 (0.87\u0026ndash;3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.44 (0.78\u0026ndash;2.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.227\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultivitamin mineral supplements only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.79 (0.69\u0026ndash;0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98 (0.82\u0026ndash;1.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.847\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.07 (0.91\u0026ndash;1.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.400\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eModel was adjusted for age, sex, race, BMI group, poverty income ratio, education, smoking status, drinking status, marital status, physical activity, stroke history, calorie intake, CVD history and diabetes status and with or without depressive symptom. Bold p-values denote statistical significance at the p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 level. Abbreviation: OR, odds ratio; CI, confidence interval; BMI: Body mass index; CVD, cardiovascular disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRelationships of dietary supplements with mortality\u003c/h2\u003e \u003cp\u003eDuring an average of 86.8 months of follow-up, there were 941 all-cause deaths and 141 CVD-related deaths. In the unadjusted model, the hazard ratio (HR) for all-cause mortality was 2.11 (95% CI, 1.12 to 3.97; P\u0026thinsp;=\u0026thinsp;0.020) for melatonin users compared to participants without any dietary supplement (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). After adjusting for socio-demographic variables, this estimate was slightly attenuated and remained significant (HR: 1.97; 95% CI, 1.03 to 3.77; P\u0026thinsp;=\u0026thinsp;0.040). The adjusted HR for MVM users showed a lower risk of all-cause mortality (HR, 0.84; 95% CI, 0.71 to 0.99; P\u0026thinsp;=\u0026thinsp;0.040). Additionally, melatonin users showed a higher risk of cardiovascular mortality (HR, 3.46; 95% CI, 1.01 to 11.82; P\u0026thinsp;=\u0026thinsp;0.048), while MVM users still showed a lower risk of cardiovascular mortality (HRs, 0.61; 95% CI, 0.39 to 0.95; P\u0026thinsp;=\u0026thinsp;0.027). Adjusted HR for all-cause mortality in participants who took any dietary supplement containing some specified vitamin was also significantly lower (Supplementary Table\u0026nbsp;6\u0026ndash;7 and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate Cox regression analysis examining the impact of dietary supplements on mortality.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNumber of deaths\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eCrude Model\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eModel 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eModel 2\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eAll-cause mortality\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWithout dietary supplement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e313\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWith any dietary supplements\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e628\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.14 (1.00\u0026ndash;1.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.90 (0.78\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.92 (0.80\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.271\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMelatonin only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.11 (1.12\u0026ndash;3.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.93 (1.01\u0026ndash;3.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.046\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.97 (1.03\u0026ndash;3.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.040\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultivitamin mineral supplements only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e320\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.02 (0.87\u0026ndash;1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.786\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81 (0.69\u0026ndash;0.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.84 (0.71\u0026ndash;0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.040\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCardiovascular mortality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWithout dietary supplement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1[Ref.]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWith any dietary supplements\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.97 (0.69\u0026ndash;1.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.879\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.74 (0.52\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.76 (0.53\u0026ndash;1.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMelatonin only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.29 (1.33\u0026ndash;13.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.38 (0.99\u0026ndash;11.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.052\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.46 (1.01\u0026ndash;11.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.048\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultivitamin mineral supplements only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.83 (0.55\u0026ndash;1.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.352\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.60 (0.39\u0026ndash;0.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.61 (0.39\u0026ndash;0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.027\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eCox proportional hazard models were performed for all-cause mortality. Competing risk analyses of cause-specific mortality were performed. The crude model did not adjust for any covariates. Model 1 was adjusted for age, sex, race, BMI group, poverty income ratio, education, smoking status, drinking status, marital status, physical activity, and depressive symptoms. Model 2 was adjusted for calorie intake, CVD history, stroke history, and diabetes status in addition to Model 1. Bold p-values denote statistical significance at the p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 level.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eAbbreviation: HR, Hazard Ratio; CI, confidence interval; BMI: Body mass index; CVD, cardiovascular disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eIn the sensitivity analysis, melatonin users were identified as who as long as used melatonin (135 participants), while MVM users were identified as who as long as used MVM (2,714 participants). The sensitivity analyses were similar to the main analyses (Supplementary Table\u0026nbsp;8\u0026ndash;9). Melatonin users continued to exhibit a higher risk of cardiovascular mortality (HR, 3.82; 95% CI, 1.54 to 9.46; P\u0026thinsp;=\u0026thinsp;0.004; Supplementary Table\u0026nbsp;8). Additionally, after containing those who use both melatonin and MVM, the protective association in MVM consumption on all-cause mortality remained statistically significant (HR, 0.86; 95% CI, 0.75 to 0.99; P\u0026thinsp;=\u0026thinsp;0.031), while the association with cardiovascular mortality was no longer statistically significant (HR, 0.77; 95% CI, 0.53 to 1.11; P\u0026thinsp;=\u0026thinsp;0.167).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe objective of this study was to investigate the effects and risks of melatonin in individuals with sleep disturbances, in contrast to multivitamins, using a large-scale national dataset. The study confirmed that dietary supplements, notably melatonin and multivitamins, enhance sleep duration in individuals experiencing sleep disturbances. Moreover, the data indicate that intake of multivitamins, along with any dietary supplements containing the specified vitamins, but not melatonin, was associated with fewer depressive symptoms among the participants. Contrary to our initial expectations, the utilization of melatonin was connected to an increased risk of cardiovascular mortality, while multivitamins demonstrated correlations with lower all-cause and cardiovascular mortality. This suggests that while melatonin is linked to improved sleep quality, it must be used with caution, especially for long-term use. Based on our findings, multivitamin supplements might be a better option for individuals with sleep disturbances.\u003c/p\u003e \u003cp\u003eOur investigation aligns with earlier discoveries, indicating that melatonin could prolong sleep duration and reduce the risk of short sleep. It achieves these without increasing the probability of long sleep, which may adversely affect health\u003csup\u003e\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Mechanistically, melatonin modulates sleep-wake patterns through MT1/MT2 receptor-mediated, regulating various sleep aspects including the circadian rhythm, and sleep architecture\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Additionally, melatonin also demonstrates antidepressant-like effects by suppressing inflammatory responses through both immune and non-immune mechanisms\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, which in turn affect neuroinflammation and neurotoxicity in brain regions associated with depression. However, the large-scale clinical data in this study indicated that depressive symptoms in participants treated with melatonin were similar to those in the control group; thereby, the linkage between melatonin use and the alleviation of depressive symptoms remains unclear. This evidence suggests that while melatonin acts as an effective agent to augment sleep duration, its utility in managing mood disorders requires further scrutiny. In a population-based cohort study, Nagata and his colleagues found that melatonin is linked to lower overall and cardiovascular mortality\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Our observations are at odds with this view. Such discrepancies may stem from the limited sample size, the modest number of events, and the definition of melatonin intake in our study. Given the complex interplay between sleep duration, sleep quality, and cardiovascular health\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, further research is warranted to clarify the relationship between melatonin and cardiovascular risk.\u003c/p\u003e \u003cp\u003eResearch findings indicate that taking multivitamin supplements has the potential to improve emotional states. For example, a study conducted with older adults experiencing mild cognitive impairment revealed that multivitamin interventions not only augmented cognitive abilities but also significantly alleviated depressive symptoms\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Similarly, it has been shown in a double-blind, randomized controlled trial to significantly mitigate depressive symptoms among individuals undergoing methadone maintenance therapy\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Moreover, vitamin levels are correlated with the quality of sleep. The serum levels of vitamin D demonstrate a positive correlation with self-reported daily sleep duration among elderly individuals\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Concurrent supplementation of poly-γ-glutamic acid and vitamin B6 has been shown to enhance sleep duration\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. In this study, the results showed that multivitamin supplementation demonstrated associations with prolonged sleep duration, attenuated depressive symptom scores, and lower all-cause mortality. These findings align with existing literature highlighting the positive effects of multivitamins on both mental and physical health\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Taken together, these findings contribute to the growing body of evidence suggesting that multivitamin intake is essential for improving overall health, particularly among populations with sleep disturbances. In parallel, these emphasize that melatonin may not be the exclusive intervention in the initial stages of sleep disturbance, as the incorporation of multivitamin intake and sleep hygiene practices may also yield benefits and offer long-term safety.\u003c/p\u003e \u003cp\u003eThe predominant strength of our study lies in its design as a prospective cohort study, employing the NHANES database\u0026mdash;an authoritative and representative dataset\u0026mdash;that provides reliable estimates of melatonin use across racial/ethnic groups. We leveraged the dataset to investigate the unverified effects and long-term safety of melatonin and multivitamin supplementation in sleep disturbance, adjusting for confounders to bolster the rigor and dependability of our findings. Notwithstanding, the present study should be considered with caution in light of some study limitations. First, the sample size of patients using only melatonin is relatively small compared to the overall cohort, potentially limiting the detection of clinically meaningful relationships and elevating the risk of Type II errors. Additionally, the inability to precisely determine the time frame during which dietary supplements are used or not used hinders the analysis of time-dependent effects. Although the supplement containers were authenticated for nearly all participants, notable discrepancies exist in dosage and compositional inconsistency among marketed melatonin supplements. Finally, this article focuses solely on the consumption of exogenous supplements for melatonin and vitamins, while omitting considerations of dietary food intake.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn summary, our results indicated while melatonin use was associated with sleep quality, its long-term safety was linked to an increased risk of cardiovascular mortality. Additionally, multivitamins demonstrated correlations with fewer depressive symptoms and decreased all-cause mortality. These findings suggest that melatonin does not appear to be the sole selection for early-stage sleep disturbances, while multivitamins, associated with prolonged sleep duration and improved health outcomes, emerge as a more suitable alternative. Given the scant investigations regarding the impact of melatonin on sleep disturbances and its long-term safety, further studies are needed to validate these results.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no actual or potential conflicts of interest to declare.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by National Key R\u0026amp;D Program of China (Grant No.: 2022YFC2503902), and Guangzhou Key Laboratory for Germ-free animals and Microbiota Application (Grant No.: 202201020381).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEthics and approval \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol (Protocol Number: Protocol #2011\u0026ndash;17 and Protocol #2018\u0026ndash;01) was approved by the NCHS Research Ethics Review Board (ERB) and all participants provided written informed consent prior to participation. (https://www.cdc.gov/nchs/nhanes/irba98.htm). \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003cstrong\u003euthorship contribution statement \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZerui You: Conceptualization, Methodology, Data extraction, Statistical analysis, Writing-original draft, Writing-review \u0026amp; editing. Lutong Gan, Jiamin Wu, Simeng Feng: Conceptualization, Methodology. Jiyang Pan: Conceptualization, Funding acquisition, Investigation, Supervision, Project administration. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant data are described within the paper. The NHANES data underpinning the findings of this research are accessible to the public at https://www.cdc.gov/nchs/nhanes/index.htm.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHisler, G. C., Muranovic, D. \u0026amp; Krizan, Z. Changes in sleep difficulties among the U.S. population from 2013 to 2017: results from the National Health Interview Survey. \u003cem\u003eSleep Health\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 615\u0026ndash;620 (2019).\u003c/li\u003e\n\u003cli\u003eGolombek, D. A., Pandi-Perumal, S. R., Brown, G. M. \u0026amp; Cardinali, D. P. Some implications of melatonin use in chronopharmacology of insomnia. \u003cem\u003eEur. J. Pharmacol.\u003c/em\u003e \u003cstrong\u003e762\u003c/strong\u003e, 42\u0026ndash;48 (2015).\u003c/li\u003e\n\u003cli\u003eOhayon, M. M. \u0026amp; Reynolds, C. F. 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Hosp.\u003c/em\u003e \u003cstrong\u003e38\u003c/strong\u003e, 1277\u0026ndash;1286 (2021).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Melatonin, Multivitamins, Short sleep duration, Mortality, NHANES","lastPublishedDoi":"10.21203/rs.3.rs-6213720/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6213720/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eComprehensive health benefits and risks of melatonin remain scarce. This study aims to evaluate the association between melatonin use and health outcomes, as well as its comparative effectiveness against multivitamins.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn total, 7,717 adults experiencing sleep disturbances with dietary supplements data were enrolled from the 2005\u0026ndash;2018 National Health and Nutrition Examination Survey (NHANES). Multivariable Cox regression analysis was employed to investigate the associations of melatonin and multivitamin supplementation with all-cause and cardiovascular mortality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMelatonin and multivitamin users had longer sleep durations than non-users (melatonin: t\u0026thinsp;=\u0026thinsp;2.68, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; multivitamins: t\u0026thinsp;=\u0026thinsp;5.44, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Only multivitamin users showed fewer depressive symptoms (t = -7.00, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while melatonin users did not. Melatonin users (odds ratio [OR], 0.44; 95% CI: 0.20\u0026ndash;0.86; P\u0026thinsp;=\u0026thinsp;0.024) and multivitamin users (OR, 0.79; 95% CI: 0.69\u0026ndash;0.91; P\u0026thinsp;=\u0026thinsp;0.001) had lower odds of short sleep. After adjustments, melatonin users faced a higher risk of cardiovascular mortality (hazard ratio [HR], 3.46; 95% CI, 1.01 to 11.82; P\u0026thinsp;=\u0026thinsp;0.048), whereas multivitamin users had lower risks of all-cause mortality (HR, 0.84; 95% CI, 0.71 to 0.99; P\u0026thinsp;=\u0026thinsp;0.040) and cardiovascular mortality (HR, 0.61; 95% CI, 0.39 to 0.95; P\u0026thinsp;=\u0026thinsp;0.027).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMelatonin does not appear to be the sole selection for early-stage sleep disturbances; multivitamins might constitute a more judicious alternative, associated with better sleep duration and overall health outcomes. Further studies are required to confirm these findings.\u003c/p\u003e","manuscriptTitle":"Melatonin and Multivitamin Use in Sleep Disturbance Populations: Associations with Health Outcomes and Mortality from a National Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-14 10:28:10","doi":"10.21203/rs.3.rs-6213720/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"28b18a23-5ef9-4cf2-b599-00b2dfd06691","owner":[],"postedDate":"May 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-01T07:44:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-14 10:28:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6213720","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6213720","identity":"rs-6213720","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}