維生素B6可以幫助睡眠嗎？從活性型B6（PLP）與白天嗜睡、睡眠時間的研究談起

維生素B6可以幫助睡眠嗎？本文從活性型維生素B6（PLP）與白天嗜睡、睡眠時間的研究出發，解析B6與睡眠的可能關聯。

什麼是維生素B6？PLP又是什麼？

這篇研究在問什麼問題？

研究結果一：PLP濃度較高，白天嗜睡風險較低

研究結果二：男性的關聯較明顯，女性不一定顯著

從中醫與整合醫學角度看：睡眠不是單一營養素問題

日常飲食如何攝取維生素B6？

這篇研究給我們的三個提醒

結論：維生素B6與睡眠有關，但不是失眠萬靈丹

維生素B6可以幫助睡眠嗎？從活性型B6（PLP）與白天嗜睡、睡眠時間的研究談起

很多人睡不好時，第一個想到的是壓力太大、咖啡喝太多、手機滑太晚，或是身體太累。但如果把睡眠放到營養與代謝的角度來看，就會發現：睡眠不只是「大腦想不想睡」的問題，也和身體裡許多營養素、神經傳導物質、發炎狀態與日夜節律有關。

近年不少人開始注意到「維生素B群」與精神、疲勞、情緒、睡眠之間的關係。其中，維生素B6是一個特別值得討論的營養素。它不只是一般人印象中「幫助代謝」的維生素，也參與神經傳導物質的合成，和血清素、GABA、褪黑激素等與睡眠調節相關的系統有間接關聯。

不過，這不代表我們可以簡單地說：「睡不好就吃維生素B6。」更精確的說法應該是：有研究觀察到，血中活性型維生素B6，也就是 pyridoxal 5′-phosphate（PLP），和某些睡眠相關問題之間存在關聯，例如白天嗜睡、睡眠時間過短或過長等。但這類研究多屬於觀察性研究，仍不能直接推論補充維生素B6就能治療失眠。

這篇文章會從一篇發表於 Nutrients 的研究出發，整理維生素B6、PLP與睡眠之間可能的關係，並說明臨床與日常生活中應該怎麼理解這些結果。

什麼是維生素B6？PLP又是什麼？

維生素B6其實不是單一一種分子，而是一群相關化合物的總稱。常見的形式包括 pyridoxine、pyridoxal 和 pyridoxamine。一般保健食品標示中的「維生素B6」，很多時候指的是 pyridoxine；而在人體內真正參與許多酵素反應、被視為主要活性型的形式，則是 pyridoxal 5′-phosphate，也就是 PLP。

這篇研究也指出，PLP 是目前最常使用、較可靠且具代表性的維生素B6狀態生物標記。換句話說，如果想了解一個人體內維生素B6的狀態，測量血中 PLP 濃度會比只看飲食攝取量更接近生理上的實際情況。

這一點很重要。因為「吃進多少維生素B6」和「身體裡可用的活性型B6有多少」不一定完全相同。吸收、代謝、肝臟轉換、發炎狀態、生活型態與疾病狀況，都可能影響PLP濃度。因此，研究者選擇用血中PLP作為指標，比單純問受試者吃了多少B6，更能反映身體內部的營養狀態。

這篇研究在問什麼問題？

這篇研究的核心問題是：血中PLP濃度和睡眠相關問題之間，有沒有關聯？

研究者使用美國 NHANES，也就是 National Health and Nutrition Examination Survey 的資料進行分析。這是一個大型、具代表性的美國國民健康與營養調查資料庫。研究納入成人族群，並分析血中PLP濃度與睡眠品質、睡眠時間之間的關係。

研究中把睡眠相關問題分成兩大類：

第一類是睡眠品質相關問題，包括是否曾被醫師診斷為睡眠障礙、是否常常難以入睡、是否半夜醒來後難以再睡、是否白天過度嗜睡。

第二類是睡眠時間，也就是平常工作日或週間晚上睡多久。研究者把睡眠時間分成非常短睡眠、短睡眠、正常睡眠與長睡眠。正常睡眠定義為每晚7到小於9小時。

這樣的分類方式讓研究不只是看「失眠」這一件事，而是更細緻地觀察：PLP可能和入睡困難有關嗎？和半夜醒有關嗎？和白天嗜睡有關嗎？和睡太短或睡太長有關嗎？

這對臨床理解很重要。因為病人說「我睡不好」時，實際上可能代表很多不同狀況。有的人是睡不著，有的人是睡了會醒，有的人是睡很久還是累，有的人是白天嗜睡，有的人則是睡眠時間長期偏短。不同型態背後的原因並不一定相同。

研究結果一：PLP濃度較高，白天嗜睡風險較低

這篇研究最主要的發現之一，是血中PLP濃度和白天嗜睡之間呈現負相關。

研究者把PLP濃度分成四分位數來比較。結果發現，和PLP最低的一組相比，中間濃度組的白天嗜睡風險較低。經過年齡、性別、種族、教育程度、收入、婚姻狀態、BMI、運動、吸菸、咖啡因攝取、總熱量、飲酒、高血壓、糖尿病、憂鬱症狀與採樣季節等因素校正後，這個關聯仍然存在。

不過，這裡要特別注意兩件事。

第一，這不是說PLP越高越好。研究中提到，PLP與白天嗜睡風險之間呈現非線性關係，並不是單純「越高越有效」。研究者推測，在一定範圍內，PLP與白天嗜睡的風險下降有關，而大約在某個濃度附近可能出現最低風險，但這不代表追求超高劑量補充就是好的。

第二，這是關聯，不是因果。也就是說，我們可以說「PLP濃度較低的人，白天嗜睡問題可能比較多」，但不能直接說「補充維生素B6一定可以改善白天嗜睡」。因為白天嗜睡可能和睡眠呼吸中止症、慢性睡眠不足、憂鬱、藥物、輪班工作、內分泌問題、貧血、慢性發炎或其他疾病有關。PLP可能是其中一個相關指標，但不一定是唯一原因。

研究結果二：男性的關聯較明顯，女性不一定顯著

這篇研究另一個有趣的地方，是性別分層分析。

研究發現，PLP濃度和白天嗜睡之間的負相關，在男性中比較明顯；但在女性中，結果並沒有達到統計上的顯著關聯。研究者在討論中也提到，睡眠節律、荷爾蒙與年齡變化可能會造成性別差異。

這提醒我們，營養素和睡眠之間的關係，不太可能是一個「所有人都一樣」的公式。同樣是睡不好，男性、女性、年輕人、更年期前後女性、老年人、輪班工作者、慢性壓力族群，背後機制可能都不一樣。

以臨床或衛教角度來說，這代表我們不應該把維生素B6包裝成單一解方。比較合理的做法是：把它放在睡眠評估的一個面向裡，和飲食、作息、壓力、慢性疾病、藥物使用與身體狀態一起看。

研究結果三：PLP也和異常睡眠時間有關

除了白天嗜睡之外，這篇研究也分析PLP與睡眠時間的關係。

研究者把每晚7到小於9小時視為正常睡眠時間，並與非常短睡眠、短睡眠、長睡眠做比較。結果發現，和正常睡眠時間相比，血中PLP濃度較高者，出現非常短睡眠、短睡眠與長睡眠的風險較低。

這個結果很有意思，因為它不是單純說「B6和睡得久有關」，而是比較接近「PLP狀態較好的人，比較可能落在正常睡眠時間範圍內」。

換句話說，睡眠時間不是越長越好，也不是越短越有效率。長期睡太短可能和壓力、生活型態、失眠、工作型態或身體疾病有關；睡太長也可能和疲勞、發炎、憂鬱、睡眠品質差或慢性疾病有關。正常睡眠時間本身可能反映一個人整體生理狀態比較穩定，而PLP也可能是這個穩定狀態的一部分。

但同樣需要強調，這仍然不能推論「補充B6就能讓睡眠時間正常」。研究的結果比較適合解讀為：血中PLP濃度與睡眠時間型態之間存在關聯，值得未來進一步研究。

維生素B6為什麼可能和睡眠有關？

從生理機制來看，維生素B6與睡眠的關係並不是完全沒有根據。研究文章中整理了幾個可能機制。

第一，PLP參與色胺酸代謝與血清素生成。血清素是褪黑激素合成的前驅物之一，而褪黑激素和日夜節律、睡眠調節有關。因此，PLP可能透過影響血清素與褪黑激素相關路徑，間接影響睡眠。

第二，PLP參與神經傳導物質的合成，例如GABA。GABA是中樞神經系統中重要的抑制性神經傳導物質，和放鬆、入睡及睡眠穩定度有關。若B6狀態不足，理論上可能影響某些神經傳導物質的合成與平衡。

第三，PLP可能和發炎與氧化壓力有關。研究文章提到，發炎和睡眠之間有關聯，而維生素B6或PLP也被認為參與抗氧化與發炎反應相關路徑。當身體處於慢性發炎或氧化壓力較高的狀態時，睡眠品質可能受到影響，而PLP可能是這些代謝與免疫狀態中的一個相關因子。

這些機制提供了合理的生物學解釋，但仍然不能直接等同於臨床療效。也就是說，機制上「有可能相關」，不代表實際補充後「一定有效」。

維生素B6可以治療失眠嗎？

這是很多人最關心的問題。

根據這篇研究，答案應該是：目前不能這樣直接下結論。

這篇研究是橫斷面研究，也就是在同一個時間點觀察血中PLP濃度與睡眠狀態之間的關係。這種研究可以找出相關性，但不能確定因果關係。研究作者也明確指出，橫斷面設計無法推論因果，若要確認B6對睡眠問題是否有保護或改善效果，仍需要更多前瞻性研究或介入研究。

所以，若有人把這篇研究解讀成「維生素B6可以治療失眠」，那就過度延伸了。

比較正確的說法是：

血中活性型維生素B6濃度與部分睡眠相關問題有關，特別是白天嗜睡與異常睡眠時間。但目前證據仍不足以支持把維生素B6當成治療失眠的主要方法。

在臨床上，如果一個人長期睡不好，應該先釐清睡眠問題的型態。例如是入睡困難、容易醒、早醒、睡醒不清爽、白天嗜睡、打呼嚴重、半夜呼吸中止、焦慮緊繃、腸胃逆流、夜尿、疼痛，還是輪班導致的節律混亂。不同原因，處理方式完全不同。

營養狀態可以納入評估，但不應取代完整診斷。

哪些人可以特別注意維生素B6狀態？

雖然不能說睡不好就一定要補充B6，但從營養與健康管理角度來看，有些人確實可以注意自己是否有B群攝取不足或代謝需求增加的情況。

例如，飲食長期不均衡、蛋白質攝取不足、蔬果攝取很少、長期外食、過度節食、慢性壓力大、飲酒較多、腸胃吸收不佳，或有某些慢性疾病的人，都可能需要更完整地檢視營養狀態。

此外，若一個人同時有疲倦、精神不濟、白天嗜睡、皮膚狀況不穩定、口角炎、情緒低落、手腳麻木等狀況，也可以在醫師或營養專業人員評估下，考慮是否需要檢查或調整飲食。

但要注意的是，B群補充不等於越多越好。維生素B6雖然是水溶性維生素，但長期高劑量補充仍可能有風險，特別是神經相關副作用。因此，不建議自行長期大量補充高劑量B6。

從中醫與整合醫學角度看：睡眠不是單一營養素問題

如果把這篇研究放到診間看，最有價值的地方不在於「推薦大家吃B6」，而是在提醒我們：睡眠與身體內在狀態密切相關。

中醫在看睡眠時，也不會只問「睡幾小時」，而會進一步問：是難入睡，還是容易醒？是半夜三點醒，還是清晨早醒？是睡醒疲倦，還是白天昏沉？有沒有心悸、胃脹、口乾、夜尿、怕冷、潮熱、焦慮、痰多、鼻塞、咳嗽、皮膚癢？

這些細節會指向不同體質與病機。有人是壓力鬱結、肝氣不舒；有人是心脾兩虛、氣血不足；有人是陰虛火旺、夜間煩熱；有人是痰濕內阻、身體沉重；有人是胃氣不和，躺下後逆流、咳嗽或胸口悶，導致睡眠被打斷。

從這個角度看，維生素B6或PLP可以被視為現代營養代謝中的一個觀察點，但不能取代整體辨證與生活型態評估。真正穩定的睡眠，往往需要同時處理作息、壓力、飲食、腸胃、鼻咽呼吸、疼痛、荷爾蒙與慢性發炎等多個層面。

日常飲食如何攝取維生素B6？

若想從生活中支持維生素B6狀態，最基本的方式仍然是均衡飲食，而不是一開始就依賴高劑量補充品。

維生素B6廣泛存在於多種食物中，例如魚類、雞肉、豬肉、蛋、豆類、全穀類、堅果、香蕉、馬鈴薯與深綠色蔬菜等。若日常飲食中蛋白質來源足夠、蔬菜與全穀類攝取穩定，通常比單一補充品更能支持整體代謝。

對睡眠不穩定的人來說，晚餐也不宜過度油膩、過飽或太晚吃。因為即使營養素充足，如果腸胃負擔太重、胃食道逆流、夜間腹脹或血糖波動明顯，也可能干擾睡眠。

換句話說，與其只問「要不要吃B6」，不如先問：「我的飲食型態是否穩定？蛋白質是否足夠？晚餐是否太晚太油？咖啡因是否過量？身體是否長期處於壓力與發炎狀態？」

這樣才比較接近真正有用的睡眠管理。

這篇研究給我們的三個提醒

第一，睡眠問題可能和營養代謝有關。血中PLP濃度與白天嗜睡、睡眠時間異常之間的關聯，提醒我們睡眠不是單純意志力問題，也不是只靠放鬆就一定能改善。

第二，B6不是越多越好。研究顯示的是非線性關係，不是單純濃度越高越好。這也提醒我們，營養素的重點在於平衡，而不是追求高劑量。

第三，不能把觀察性研究解讀成治療建議。這篇研究的價值在於提供線索，而不是給出「失眠就補B6」的結論。若長期睡不好，仍應該回到完整評估。

結論：維生素B6與睡眠有關，但不是失眠萬靈丹

總結來說，這篇研究指出，血中活性型維生素B6，也就是PLP，和部分睡眠相關問題存在關聯。PLP濃度較低者，可能較容易出現白天嗜睡，並且較可能落在過短或過長的睡眠時間範圍。研究也提出可能機制，包括PLP參與血清素、褪黑激素、GABA、發炎與氧化壓力相關路徑。

但這篇研究不能證明補充維生素B6可以治療失眠，也不能取代醫療評估。睡眠是一個牽涉神經、內分泌、免疫、腸胃、呼吸、情緒與生活型態的複雜問題。維生素B6值得被納入討論，但不應被過度神化。

如果你長期有入睡困難、半夜醒來、早醒、白天嗜睡、睡很久仍疲倦，或伴隨打呼、胃食道逆流、焦慮、心悸、夜尿、咳嗽、鼻塞等問題，建議不要只靠自行補充保健品，而是進一步找出睡眠被干擾的真正原因。

營養素可以是睡眠健康的一部分，但真正好的睡眠，通常來自整體身體狀態的重新穩定。

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Nutrients. 2022 Aug 26;14(17):3516. doi: 10.3390/nu14173516

Association of Pyridoxal 5′-Phosphate with Sleep-Related Problems in a General Population

, Jia Luo

Editor: Justyna Godos

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PMCID: PMC9460331 PMID: 36079774

Abstract

The evidence on the relationship of pyridoxal 5′-phosphate (PLP) with sleep-related problems is limited and controversial. Notably, there is a lack of studies on the general population and studies of the dose–response relationship. Therefore, we conducted a cross-sectional study to examine the associations between serum PLP concentration and sleep-related problems (sleep quality and sleep duration) in adults, using the data of the National Health and Nutrition Examination Survey 2005–2010. High-performance liquid chromatography (HPLC) was used to test PLP in blood samples. Sleep quality and sleep duration were based on self-reported data, with sleep quality categorized as sleep disorder, trouble falling asleep, waking up during the night, and daytime sleepiness. The primary analyses utilized logistic regression models and restricted cubic spline. Compared with the first quartile (Q1), the odds ratios (ORs) and 95% confidence intervals (CIs) of daytime sleepiness for the Q2 and Q3 of serum PLP concentrations were 0.76 (0.59–0.99) and 0.78 (0.62–0.98), respectively. The relationship was only significant for males. Furthermore, a non-linear dose–response relationship was observed between serum PLP concentration and the risk of daytime sleepiness. Compared with the normal sleep duration group, serum PLP concentrations were negatively associated with the risks of very short, short, and long sleep duration, with relative risk ratios (RRRs) of 0.58 (0.43–0.81) (Q4), 0.71 (0.61–0.83) (Q4) and 0.62 (0.34–0.94) (Q3), respectively. The average serum PLP concentrations were higher in people with normal sleep duration, suggesting a non-linear dose–response relationship. Our study indicated that serum PLP concentrations were negatively associated with daytime sleepiness, and this association may only exist in males. Moreover, it was also inversely related to abnormal sleep duration (very short, short, long) compared to normal sleep duration.

Keywords: sleep quality, sleep duration, pyridoxal 5′-phosphate, vitamin B6, dose–response relationship, cross-sectional study

1. Introduction

Healthy sleep is essential for maintaining mental and physical functions [1,2,3,4,5]. However, millions of people around the world suffer from sleep-related problems, especially with the COVID-19 pandemic bringing many new challenges to sleep problems [6,7]. Inappropriate sleep duration and sleep disorders have been linked to numerous negative effects on the body, including digestive system problems [8], cardiovascular disease [9,10], diabetes [11], cancer [12], depression symptoms [13], and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s [14,15]. Currently, factors that influence sleep are being explored, including genetics [16], environment [17], hormones [18], and various diseases [19,20,21]. However, much attention has been drawn to dietary factors that are self-selectable and modifiable. According to relevant reviews and studies, overall diet quality and some nutrients are associated with sleep [22,23,24,25,26].

Vitamin B6, mainly including pyridoxine, pyridoxal, and pyridoxamine, is a water-soluble vitamin with a wide range of sources. Notably, its antioxidant properties have attracted extensive attention [27,28]. Vitamin B6 deficiency can lead to dermatitis [29], neuropsychiatric symptoms [30], impaired immune function [31], and epilepsy [32,33]. The most widely used direct biomarker of vitamin B6 is pyridoxal 5′-phosphate (PLP), which is more reliable and representative [34]. As a coenzyme, PLP promotes the conversion of tryptophan to 5-hydroxytryptamine (5-HT) [35,36], which is considered to be a precursor of melatonin synthesis [37,38], suggesting that PLP may affect sleep.

Several studies have been conducted to explore the relationship between vitamin B6 and sleep. An observational study of older adults in Taiwan showed that people with poor sleep quality consumed less vitamin B6 than those with good sleep quality [39]. Another study suggested that vitamin B6, combined with other substances, was effective in treating mild to moderate insomnia [40]. However, a randomized controlled trial, using a vitamin B6-containing complex, found no significant difference in sleep quality between the complex and placebo [41]. Furthermore, an intervention study showed that vitamin B6 supplements did not significantly affect sleep in volunteers [42]. The participants of the above studies were mainly the elderly, patients, and volunteers, rather than the general population. Meanwhile, there are few studies on the relationship between serum PLP and sleep. More importantly, there was no clear dose–response relationship between serum PLP and sleep. Therefore, given these inconsistencies, differences, and unknown quantitative relationships, we conducted this cross-sectional study to examine the relationships between serum PLP concentrations and sleep-related problems, including sleep quality and sleep duration.

2. Materials and Methods

2.1. Participants

The National Health and Nutrition Examination Survey (NHANES) is a program of the National Center for Health Statistics to assess the health and nutritional status of the non-institutionalized civilian population in the United States. NHANES has been an ongoing survey since 1999. The survey conducts a sample survey of about 5000 nationally representative people every year, with a biennial release cycle. All participants provided informed consent. More information about NHANES can be found elsewhere [43].

NHANES began to conduct sleep questionnaires in 2005–2006, and the sleep-related items were incomplete in 2009–2010. In addition, the measurement of serum PLP was up to 2019–2010, and the detection method was consistent between 2005 and 2010. Thus, in this study, two cycles of data (NHANES 2005–2006, and 2007–2008) and three cycles of data (NHANES 2005–2006, 2007–2008, and 2009–2010) were selected to explore sleep quality (n = 9710) and sleep duration (n = 15,206), respectively. We excluded participants <18 years old and those who did not have serum PLP data. Participants with extreme energy intake (500 kcal/day for both males and females, >8000 kcal/day for males, and >5000 kcal/day for females), females who were pregnant and lactating, and subjects using sedative-hypnotics were further excluded. Finally, 9710 people were included to study sleep quality and 15,206 were included to study sleep duration. The specific process is shown in Figure 1.

Figure 1.

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Flowchart of the screening process for the selection of eligible participants.

2.2. Sleep-Related Problems

We divided sleep-related problems into two dimensions: sleep quality and sleep duration. Sleep quality was categorized as sleep disorders, trouble falling asleep, waking up during the night, and daytime sleepiness in detail. The detailed definitions were as follows.

Sleep quality: Sleep disorders were defined as those diagnosed by a doctor or health professional [44]. Trouble falling asleep was defined as having trouble falling asleep more than five times in the past month—self-reported “often” or “almost always” (≥5 times a month) [45]. Wake up during the night was defined as self-reported “often” or “almost always” (≥5 times a month) waking up during the night and having trouble getting back to sleep in the past month [45]. Daytime sleepiness was defined as “often” or “almost always” (≥5 times a month) feeling excessively or overly sleepy (self-reported) during the day five or more times in the past month [46,47].

Sleep duration: The question was, “How much sleep do you usually get at night on weekdays or workdays?” According to the answers, sleep duration was classified into very short sleep (<5 h), short sleep (5–<7 h), normal sleep (7–<9 h), or long sleep (≥9 h) [26,48].

2.3. Serum Pyridoxal 5′-Phosphate Measurement

Blood samples were collected at the Mobile Examination Center (MEC). Serum PLP, which was the main active form and a reliable biomarker of vitamin B6 [34], was analyzed by high-performance liquid chromatography (HPLC) [49].

2.4. Covariates

Several demographic characteristics, lifestyles, dietary factors, and diseases were included as covariates to control potential confounding effects based on previous literature [18,26]: age, sex, races/ethnicities, the ratio of income to poverty, educational level, marital status, body mass index, physical activity, caffeine intake, energy intake, smoking status, drinking, hypertension, diabetes, depressive symptoms, and sampling seasons. Table S1 shows the detailed classification of covariates.

2.5. Statistical Analysis

To account for the complex sampling design of NHANES and make the results more representative, all statistical analyses were weighted in this study. Qualitative and non-normal quantitative data were described using numbers (weighted percentage) and median (quartile range), respectively. Participants were divided into quartiles based on their PLP levels. Chi-square test and Kruskal–Wallis test were used to test the difference among quartiles of PLP levels.

Serum PLP concentrations were divided into quartiles, with quartile 1 (Q1) as the reference. Binary logistic regression and multinomial logistic regression were used to assess the relationship between serum PLP and sleep-related problems, along with calculating the ES (effect size, OR, and RRR) and 95% confidence intervals (CIs). Only sex and age were adjusted in Model 1. Model 2 further adjusted for races/ethnicities, the ratio of income to poverty, educational level, marital status, body mass index, physical activity, caffeine intake, energy intake, smoking status, drinking, hypertension, diabetes, depressive symptoms, and sampling seasons. In the analysis of sleep duration by multinomial logistic regression, normal sleep duration (7–<9 h) was used as the reference. In addition, taking into account sex and age differences in sleep [50,51], we performed stratified analyses based on these two factors. Finally, the dose–response relationship between serum PLP concentration and risk of sleep quality problems was explored using restricted cubic spline with three knots at the 5th, 50th, and 95th percentiles, and the dose–response relationship between serum PLP concentrations and sleep duration. p < 0.05 (two-sided) was considered statistically significant using Stata 15.0.

3. Results

Table 1 lists the characteristics of each serum PLP concentrations quartile for participants. Except for the sampling season, significant differences were seen in the distribution of participants in other characteristics across quintiles of serum PLP concentrations. Compared with participants with lower serum PLP concentrations, participants in the higher PLP group were more likely to be male and married/cohabiting, had higher levels of education, and did higher intensity physical activity. In addition, participants in the lowest quartile of serum PLP concentrations were more likely to be poor, obese, have diabetes, and have depressive symptoms. Participants in the highest quartile of serum PLP concentrations were more likely to drink alcohol and less likely to smoke.

Table 1.

Baseline characteristics of participants by quartile of pyridoxal 5′-phosphate (PLP) (NHANES 2005–2008).

Characteristics

Quartiles Plasma Pyridoxal 5′-Phosphate (PLP) (nmol/L)

p-Value

Q1 (<26.4)

Q2 (26.4–43.4)

Q3 (43.4–74.8)

Q4 (≥74.8)

n = 3804

n = 3815

n = 3790

n = 3797

Gender (%)

Male

1533 (37.63)

1891 (48.66)

2209 (57.24)

2120 (53.65)

<0.001

Female

2271 (62.37)

1924 (51.33)

1581 (42.76)

1677 (46.35)

Age (%)

18–39 years

1125 (31.83)

1579 (42.66)

1630 (43.01)

1351 (37.15)

<0.001

40–59 years

1222 (40.39)

1212 (38.60)

1157 (37.70)

1103 (36.62)

≥60 year

1457 (27.76)

1024 (18.74)

1003 (19.28)

1343 (26.23)

Race/ethnicity (%)

Mexican American

610 (7.22)

828 (10.00)

836 (9.87)

598 (6.43)

Other Hispanic

286 (3.83)

372 (5.45)

349 (4.98)

294 (3.91)

Non-Hispanic White

1724 (67.54)

1610 (65.17)

1723 (69.11)

2115 (76.13)

<0.001

Non-Hispanic Black

1058 (16.83)

817 (12.33)

683 (9.53)

602 (7.45)

Other races

126 (4.58)

188 (7.05)

199 (6.51)

188 (6.08)

Educational level (%)

<high school

1379 (25.26)

1254 (22.43)

1075 (18.57)

814 (13.05)

<0.001

High school

1031 (29.87)

932 (24.94)

914 (24.18)

816 (20.76)

>high school

1386 (44.87)

1627 (52.63)

1796 (57.26)

2163 (66.19)

Ratio of income to poverty (%)

959 (18.21)

808 (14.15)

695 (11.92)

503 (7.86)

<0.001

≥1

2845 (81.79)

3007 (85.84)

3095 (88.08)

3294 (92.14)

Marital status (%)

Married/Cohabiting

1983 (58.91)

2158 (63.91

2218 (66.19)

2263 (66.23)

<0.001

Windowed/Living alone

1741 (41.09)

1514 (36.09)

1394 (33.81)

1410 (33.77)

Body mass index (%)

<25 kg/m

971 (26.81)

1098 (30.02)

1204 (32.93)

1371 (38.88)

<0.001

25 to <30 kg/m

1026 (25.37)

1218 (31.40)

1372 (35.88)

1430 (37.37)

≥30 kg/m

1807 (47.81)

1499 (38.58)

1214 (31.20)

996 (23.75)

Physical activity (%)

Vigorous

882 (26.80)

1284 (37.29)

1536 (44.33)

1588 (45.78)

<0.001

Moderate

1142 (32.22)

1080 (29.83)

1086 (30.72)

1197 (32.61)

Other

1780 (40.98)

1450 (32.88)

1168 (24.95)

1012 (21.61)

Depressive symptoms (%)

397 (10.95)

279 (6.68)

201 (4.85)

179 (3.50)

<0.001

Diabetes (%)

861 (18.52)

616 (11.78)

505 (10.20)

492 (9.21)

<0.001

Hypertension (%)

2194 (53.96)

1786 (44.11)

1726 (44.24)

1847 (45.17)

<0.001

Caffeine intake (mg/d)

103 (212)

94 (172)

86 (152)

96.5 (173)

<0.001

Total energy (kcal/day)

1772.5 (180.5)

1891.5 (166)

2591 (164)

1977 (188)

<0.001

Smoke at least 100 cigarettes in life (%)

2020 (56.11)

1677 (48.63)

1513 (44.21)

1485 (40.02)

<0.001

Had at least 12 alcohol drinks a year (%)

2133 (68.03)

2261 (75.85)

2387 (78.23)

2539 (79.51)

<0.001

Sampling season (%)

November to April

1825 (42.90)

1824 (40.04)

1697 (39.29)

1595 (37.30)

0.081

May to October

1979 (57.10)

1991 (59.96)

2093 (60.71)

2202 (62.70)

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Data are represented the number of subjects (weighted percentage) or median (interquartile range).

Chi-square test was used to compare the percentages between participants in different quartiles of serum PLP concentrations.

Kruskal–Wallis test were used to compare the medians between participants in different quartiles of serum PLP concentrations.

The relationships between serum PLP concentrations and sleep quality are shown in Table 2. In Model 2, the OR values between serum PLP concentrations and sleep disorders, trouble falling asleep, and waking up during the night were not statistically significant. However, compared with Q1, the ORs for daytime sleepiness of serum PLP concentrations in the Q2 and Q3 were 0.76 (0.59–0.99) and 0.78 (0.62–0.98), respectively. In the analysis stratified by sex, serum PLP concentrations were negatively associated with daytime sleepiness in males, with the OR (95% CI) of 0.65 (0.45–0.93) in Q4, whereas no significant association was found in females (Table 3). In different age groups, an inverse association of serum PLP concentration with daytime sleepiness was only observed in participants aged 40–59 years (OR = 0.62, 95% CI: 0.43–0.90) (Table S2). The results of other sleep quality-related problems in Model 2 are not statistically significant by either sex or age stratification (Tables S3 and S4), except for trouble falling asleep, which is negatively associated with serum PLP concentrations in older adults (≥60 years old) with the ORs of 0.68 (0.48–0.97) in Q2 and 0.69 (0.49–0.96) in Q3 (Table 4).

Table 2.

Weighted odds ratios (95% confidence intervals) for sleep disorders across quartiles of pyridoxal 5′-phosphate (PLP) concentrations (NHANES 2005–2008).

Cases/

Participants

Crude

Model 1

Model 2

Sleep disorders

Q1 (<27.3)

195/2428

1.00 (ref)

Q2 (27.3 to <44.0)

153/2430

0.74 (0.54–1.03)

0.77 (0.55–1.07)

0.78 (0.53–1.16)

Q3 (44.0 to <76.3)

141/2425

0.67 (0.49–0.90) **

0.67 (0.49–0.93) **

0.88 (0.61–1.28)

Q4 (≥76.3)

150/2427

0.75 (0.55–1.03)

0.74 (0.53–1.03)

1.02 (0.66–1.58)

Trouble falling asleep

Q1 (<27.3)

447/2428

1.00 (ref)

Q2 (27.3 to <44.0)

385/2430

0.77 (0.66–0.90) **

0.81 (0.69–0.96) *

0.93 (0.76–1.14)

Q3 (44.0 to <76.3)

334/2425

0.66 (0.54–0.79) **

0.72 (0.58–0.89) **

0.93 (0.72–1.19)

Q4 (≥76.3)

342/2427

0.70 (0.58–0.84) **

0.76 (0.63–0.93) **

1.09 (0.87–1.36)

Wake up during the night

Q1 (<27.3)

541/2428

1.00 (ref)

Q2 (27.3 to <44.0)

429/2430

0.72 (0.57–0.90) **

0.79 (0.63–0.98) **

0.92 (0.69–1.22)

Q3 (44.0 to <76.3)

424/2425

0.68 (0.59–0.80) **

0.77 (0.66–0.90) **

0.98 (0.79–1.22)

Q4 (≥76.3)

404/2427

0.63 (0.53–0.75) **

0.69 (0.58–0.82) **

0.89 (0.73–1.10)

Daytime sleepiness

Q1 (<27.3)

503/2428

1.00 (ref)

Q2 (27.3 to <44.0)

382/2430

0.66 (0.55–0.79) **

0.67 (0.55–0.80) **

0.76 (0.59–0.99) *

Q3 (44.0 to <76.3)

368/2425

0.62 (0.51–0.75) **

0.64 (0.53–0.77) **

0.78 (0.62–0.98) *

Q4 (≥76.3)

373/2427

0.59 (0.51–0.69) **

0.63 (0.54–0.72) **

0.80 (0.64–1.00)

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Calculated using binary logistic regression models.

Model 1 adjusted for age and sex.

Model 2 adjusted for age, sex, race/ethnicity, education level, household poverty ratio, marital status, body mass index, physical activity, smoking status, caffeine intake, energy, alcohol consumption, hypertension, diabetes, depressive symptoms, and sampling season. * p < 0.05; ** p < 0.01.

Table 3.

Weighted odds ratios (95% confidence intervals) for daytime sleepiness across quartiles of pyridoxal 5′-phosphate (PLP) concentrations stratified by gender (NHANES 2005–2008).

Model 2

Males

Females

Q1 (<27.3)

1.00 (ref)

Q2 (27.3 to <44.0)

0.68 (0.46–1.02)

0.81 (0.58–1.13)

Q3 (44.0 to <76.3)

0.72 (0.53–0.97) *

0.82 (0.58–1.16)

Q4 (≥76.3)

0.65 (0.45–0.93) *

0.95 (0.70–1.30)

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Calculated using binary logistic regression models.

Table 4.

Weighted odds ratios (95% confidence intervals) for having trouble falling asleep across quartiles of pyridoxal 5′-phosphate (PLP) concentrations stratified by age (NHANES 2005–2008).

Model 2

18 ≤ Age < 40 Years

40 ≤ Age < 60 Years

Age ≥ 60 Years

Q1 (<27.3)

1.00 (ref)

Q2 (27.3 to <44.0)

1.03 (0.64–1.64)

0.93 (0.62–1.40)

0.68 (0.48–0.97) *

Q3 (44.0 to <76.3)

0.95 (0.66–1.37)

1.01 (0.69–1.49)

0.69 (0.49–0.96) *

Q4 (≥76.3)

0.82 (0.52–1.30)

1.56 (0.97–2.50)

0.75 (0.51–1.10)

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Calculated using binary logistic regression models.

There was a non-linear relationship between serum PLP concentrations and the risk of daytime sleepiness (P

for-nonlinearity

= 0.019) (Figure 2a). We speculated that when the serum PLP concentration was within about 220 nmol/L, the negative correlation was statistically significant. To further explore the dose–response relationship in males, the result was prepared as Figure 2b (P

for-nonlinearity

= 0.015). Within a certain range, for both males and females, PLP was negatively associated with daytime sleepiness, and we speculated that the OR value was the lowest when the serum PLP concentration was about 75 nmol/L.

Figure 2.

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Restricted cubic spline model of the odds ratios (ORs) of day sleepiness with pyridoxal 5′-phosphate (PLP) concentration for the overall population (a) and males (b). The solid line and dashed lines represent the estimated ORs and the 95% confidence intervals.

The relationship between serum PLP concentrations and sleep duration is shown in Table 5. Compared with normal sleep duration (7–<9 h/night), serum PLP concentrations were negatively associated with the risks of very short sleep, short sleep, and long sleep duration. In Model 2, the relative risk ratios (RRRs) with the corresponding 95%CI were 0.58 (0.43–0.81) for very short sleep duration (Q4), 0.71 (0.61–0.83) for short sleep duration (Q4), and 0.62 (0.34–0.94) for long sleep duration (Q3). Table S5 lists the differences between the sexes. Serum PLP concentrations were only negatively associated with very short sleep (RRR = 0.66, 95% CI: 0.45–0.97) and short sleep duration (RRR = 0.68, 95% CI: 0.52–0.89) in males. In the age stratification analyses, serum PLP concentrations were related to very short and short sleep duration (0.41 CI: 0.21–0.79, 0.74 CI: 0.59–0.93) among participants older than 60 years old, and only negatively related to short sleep (0.61 CI: 0.46–0.81) among participants 18–39 years old (Table S6).

Table 5.

Weighted relative risk ratios (95% CIs) for sleep duration (reference, 7–<9 h/night) across quartiles of pyridoxal 5′-phosphate (PLP) concentrations (NHANES 2005–2010).

Pyridoxal 5′-Phosphate (PLP) (nmol/L)

Model 2

Very Short Sleep

(<5 h/Night)

Short Sleep

(5–<7 h/Night)

Long Sleep

(≥9 h/Night)

Q1 (<26.4)

1.00 (ref)

Q2 (26.4 to <43.4)

0.73 (0.54–1.00)

0.79 (0.68–0.92) **

0.83 (0.53–1.30)

Q3 (43.4 to <74.8)

0.58 (0.45–0.76) **

0.74 (0.65–0.85) **

0.62 (0.34–0.94) *

Q4 (≥74.8)

0.58 (0.43–0.81) **

0.71 (0.61–0.83) **

0.67 (0.40–1.02)

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Calculated using multinomial logistic regression models.

The dose–response relationship between serum PLP concentrations and sleep duration is shown in Figure 3a, presenting an inverted U-shape trend. We found similar relationships for both sexes (Figure 3b,c). Average serum PLP concentrations were highest in both males and females with normal sleep duration (7–<9 h).

Figure 3.

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Dose–response relationships between sleep duration and pyridoxal 5′-phosphate (PLP) based on restricted cubic spline models for the overall population (a), males (b), and females (c). The red line and blue area represent the average concentration of PLP and the 95% confidence interval.

4. Discussion

To the best of our knowledge, this was the first study to examine the relationships between serum PLP concentration and sleep-related problems (sleep quality and sleep duration) in the general population. Our study manifested that serum PLP concentration is nonlinearly and negatively associated with sleep quality problems, mainly daytime sleepiness. An interesting finding was that this relationship was significant only in males, but not in females. With age stratification, serum PLP concentrations were negatively related with daytime sleepiness only in middle-aged people, and with difficulty falling asleep in elderly adults. In terms of sleep duration, serum PLP concentration was negatively associated with very short sleep, short sleep, and long sleep duration risks. Moreover, participants with normal sleep duration had the highest average serum PLP concentrations. This negative relationship was found in all three sleep durations mentioned above in females, but only in very short and short sleep durations in males. Serum PLP concentration was negatively associated with very short sleep and short sleep risk in older adults (≥60 years) with age stratification, whereas this relationship was only significant for short sleep duration in younger adults (18–39 years).

A previous observational study has found that vitamin B6 intake was lower in people with poor sleep quality than in people with good sleep quality [39]. Moreover, vitamin B6 supplements with melatonin have been demonstrated to help treat insomnia in a prospective pilot study [40]. In addition, a randomized controlled trial suggested that the combination of vitamin B6 and γ-glutamate can improve sleep quality [52]. These studies indirectly support our findings. In contrast, one study found no significant difference in sleep quality in the vitamin B6 group compared to the placebo group [42]. The results of another intervention study also showed that the vitamin B6-containing complex did not significantly improve sleep compared with the control group [41]. Furthermore, a study suggested that taking pyridoxine had no effect on melatonin secretion in men [53]. The reason for the inconsistent results may be the different target populations and sample sizes of the studies. In addition, differences in how the studies measured sleep performance, such as sleep quality, using a simple question or different questionnaires, also contributed to the inconsistency.

There are several potential mechanisms for the link between PLP and sleep. Firstly, PLP is a coenzyme that can participate in the synthesis of melatonin, which is generally considered an important hormone that affects sleep [54,55]. Specifically, PLP participates in the hydroxylation of tryptophan to generate 5-hydroxytryptophan (5-HTP) and decarboxylation to produce 5-HT, which is considered as a precursor for melatonin [56]. Secondly, PLP can affect the nervous system by participating in the synthesis of neurotransmitters [57], such as GABA, which may be involved in the regulation of sleep [58]. In addition, the anti-inflammatory and antioxidant effects of PLP are also possible mechanisms involved in sleep. Inflammation has been shown in studies to affect sleep [59,60], and some markers of inflammation also have a circadian rhythm [61]. During inflammation, PLP is mobilized to active inflammatory sites and regulates PLP-dependent enzymes and metabolic pathways, which play a role in the inflammatory response [62,63]. Furthermore, oxidative stress can disrupt sleep homeostasis through different mechanisms [64]. Vitamin B6, or PLP, is an antioxidant that protects against oxidative stress by directly scavenging free radicals or indirectly participating in the glutathione-dependent antioxidant system [34,57,65,66,67]. Furthermore, we observed sex and age differences in the association between serum PLP concentrations and the risk of sleep-related problems. The reason may be that there are differences in sleep rhythms and hormone levels among people of different genders and ages, which can affect sleep [51,68,69,70].

There are several advantages to this study. Firstly, this study used data from NHANES, a nationally representative database in the United States, and rigorous quality control was performed to ensure the authenticity and generalization of the results. Secondly, we used serum PLP, a biomarker of vitamin B6, which reflects biological effective exposure. Thirdly, we explored potential dose–response relationships between serum PLP and sleep-related problems. However, there are some potential limitations. The first is the disadvantage of the cross-sectional design, which cannot infer causality. The exact protective effect of B6 on sleep-related problems requires further prospective studies to determine. Secondly, sleep-related problems were self-reported, which may not reflect objective sleep conditions and lead to information bias. Finally, some residual confounding may influence the results, although as many influencing factors as possible were included in this study, including demographic characteristics, lifestyle, dietary factors, and some diseases.

5. Conclusions

Our study suggested that serum PLP concentrations were nonlinearly and negatively associated with the risk of daytime sleepiness, especially in males. In addition, serum PLP concentrations were negatively related to very short, short, and long sleep durations.

Acknowledgments

The authors would like to thank all participants and contributors of NHANES.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu14173516/s1. Table S1: The classifications of categorical covariates. Table S2: Weighted odds ratios (95% confidence intervals) for day sleepiness across quartiles of pyridoxal 5′-phosphate (PLP) concentrations stratified by age (NHANES 2005–2008). Table S3: Weighted odds ratios (95% confidence intervals) for other sleep quality problems across quartiles of pyridoxal 5′-phosphate (PLP) concentrations stratified by gender (NHANES 2005–2008). Table S4: Weighted odds ratios (95% confidence intervals) for other sleep quality problems across quartiles of pyridoxal 5′-phosphate (PLP) concentrations stratified by age (NHANES 2005–2008). Table S5: Weighted relative risk ratios (95% confidence intervals) for sleep duration (reference, 7 ≤ 9 h/night) across quartiles of pyridoxal 5′-phosphate (PLP) concentrations stratified by gender (NHANES 2005–2010). Table S6: Weighted relative risk ratios (95% confidence intervals) for sleep duration (reference, 7 ≤ 9 h/night) across quartiles of pyridoxal 5′-phosphate (PLP) concentrations stratified by age (NHANES 2005–2010).

Click here for additional data file.

(154.3KB, zip)

Author Contributions

Conceptualization, L.G. and D.Z.; methodology, L.G., J.L. and D.Z; data curation, L.G., L.Z. and X.K.; writing—original draft preparation, L.G.; writing—review and editing, D.Z. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the Research Ethics Review Board of the National Center for Health Statistics (protocol code #2005-06).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The datasets supporting the conclusions of this article are publicly available from the NHANES (https://www.cdc.gov/nchs/nhanes/index.htm (accessed on 19 April 2022)).

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This research received no external funding.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Click here for additional data file.

(154.3KB, zip)

Data Availability Statement

The datasets supporting the conclusions of this article are publicly available from the NHANES (https://www.cdc.gov/nchs/nhanes/index.htm (accessed on 19 April 2022)).

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維生素B6可以幫助睡眠嗎？從活性型B6（PLP）與白天嗜睡、睡眠時間的研究談起

維生素B6可以幫助睡眠嗎？從活性型B6（PLP）與白天嗜睡、睡眠時間的研究談起

什麼是維生素B6？PLP又是什麼？

這篇研究在問什麼問題？

研究結果一：PLP濃度較高，白天嗜睡風險較低

研究結果二：男性的關聯較明顯，女性不一定顯著

研究結果三：PLP也和異常睡眠時間有關

維生素B6為什麼可能和睡眠有關？

維生素B6可以治療失眠嗎？

哪些人可以特別注意維生素B6狀態？

從中醫與整合醫學角度看：睡眠不是單一營養素問題

日常飲食如何攝取維生素B6？

這篇研究給我們的三個提醒

結論：維生素B6與睡眠有關，但不是失眠萬靈丹

中醫艾灸：基本原理、補瀉、過敏與腸胃調理的應用