Vitamin D and Sleep

    Vitamin D is a pro-hormone belonging to the category of the fat-soluble group of vitamins. In humans, vitamin D is obtained more from solar exposure and in smaller quantities through dietary intake. Vitamin D has traditionally been shown to be involved in calcium homeostasis and bone health, recent studies have found a positive association between vitamin D and sleep. Clinical studies in humans indicate that low levels of vitamin D are correlated with poor quality and short sleep duration. The mechanism by which this association is explained is still unclear. However, vitamin D receptors have been found in the brain regions involved in sleep regulation, and vitamin D appears to be involved in regulating the sleep-wake cycle (1).

    A meta-analysis with the goal of clarifying the association between vitamin D and sleep disorder risk included a total of nine studies (6 cross-sectional, 2 case-control, and 1 cohort studies) involving 9397 participants. By comparing the lowest versus highest levels of serum vitamin D, participants with vitamin D deficiency had a significantly increased risk of sleep disorders (OR: 1.50, 95% CI: 1.31, 1.72). Subgroup analysis showed that vitamin D deficiency also was associated with poor sleep quality (OR: 1.59, 95% CI: 1.23, 2.05), short sleep duration (OR: 1.74, 95% CI: 1.30, 2.32), and sleepiness (OR: 1.36, 95% CI: 1.12, 1.65). This meta-analysis suggested that vitamin D deficiency was associated with a higher risk of sleep disorders, and that serum 25(OH)D <20 ng/mL could significantly increase the risk of unhealthy sleep (2).

    A double-blind, clinical trial was performed on 89 people (20-50 year-old) with sleep disorders based on Petersburg's Sleep Index. Patient samples were divided randomly into two groups: intervention (n=44) and placebo (n=45). The intervention group received a 50 000-unit vitamin D supplement, once every 2 weeks for 8 weeks while the placebo group received a placebo (3).

    At the end of the study, sleep scores were reduced significantly in vitamin recipients as compared with placebo recipients (p < 0.05). This difference was significant even after modifying confounding variables (p < 0.05). This study showed that the use of vitamin D supplements improved sleep quality, reduced sleep latency, raised sleep duration, and improved subjective sleep quality in people 20-50 years old with sleep disorders (3).

    Vitamin D deficiency may be associated with some complications including nonspecific musculoskeletal pain and periodontal disease in maintenance methadone treatment (MMT) patients. A randomized, double-blind, placebo-controlled, clinical trial was carried out among 68 MMT patients to determine the effect of vitamin D supplementation on psychological symptoms and metabolic profiles. Participants were randomly allocated to receive either 50,000IU vitamin D supplements (n=34) or placebo (n=34) every 2 weeks for 12 weeks (4).

    After the 12-week intervention, serum 25(OH) vitamin D levels significantly increased in the intervention group compared with the placebo group (+8.1±4.9 vs. -0.4±3.0, p<0.001). Vitamin D supplementation significantly improved the Pittsburgh Sleep Quality Index (-1.5±2.2 vs. -0.2±2.3, p=0.02) and Beck Depression Inventory (-4.8±7.3 vs. -1.5±6.1, p=0.04) compared with the placebo. Patients who received vitamin D supplements had significantly decreased fasting plasma glucose (-7.5±10.6 vs. +0.3±10.7mg/dL, p=0.004), serum insulin levels (-3.6±5.3 vs. -0.9±3.5 μIU/mL, p=0.01), homeostasis model of assessment-insulin resistance (-1.0±1.3 vs. -0.2±0.7, p=0.003), serum triglycerides (-9.6±30.8 vs. +15.6±30.2mg/dL, p=0.001), total- (-8.7±20.9 vs. +11.0±27.4mg/dL, p=0.001) and LDL-cholesterol (-11.1±17.9 vs. +5.9±27.5mg/dL, p=0.004) compared with the placebo. Additionally, vitamin D intake resulted in a significant decrease in serum high sensitivity C-reactive protein (-2.2±4.2 vs. +2.0±3.7mg/L, p<0.001), and significant increases in plasma total antioxidant capacity (+26.2±99.8 vs. -86.3±127.5mmol/L, p<0.001) and glutathione levels (+292.3±172.4 vs. +48.9±208.9μmol/L, p<0.001) compared with the placebo. There was no significant effect of vitamin D supplementation on serum HDL-cholesterol, and other markers of insulin metabolism, inflammation, and oxidative stress (4).

    One study was conducted to assess the effect of hypovitaminosis D on the symptoms and quality of life of patients with fibromyalgia.  A total of 74 patients with hypovitaminosis D were randomly assigned into group A (Trazodone 25 mg at bedtime + vitamin D 50 000 IU weekly) and group B (Trazodone 25 mg at bedtime + placebo). Serum vitamin D level, Widespread Pain Index (WPI), Fibromyalgia Impact Questionnaire (FIQ), Pittsburgh Sleep Quality Index (PSQI), and Short Form Health Survey (SF-36) were used at the beginning, and after 4 and 8 weeks (5).

    Significant improvements were observed in WPI, FIQ, and PSQI scores in both groups. A combination of vitamin D and Trazodone resulted in significant improvement of SF-36 scores compared to Trazodone therapy. Improvement in pain-related indices including the WPI and the physical component score (PCS) fraction of SF-36 was more noticeable in vitamin D/Trazodone combination therapy. This study suggested that vitamin D supplementation had significant therapeutic benefits in the management of FMS, especially in pain reduction of patients with fibromyalgia. According to these results, a combination of vitamin D supplements and a conventional antidepressant, when given to vitamin D-deficient fibromyalgia patients, could significantly improve both physical and psychological symptoms (5).

    Enzymes that synthesize and metabolize vitamin D are magnesium dependent, thus magnesium intake may significantly interact with vitamin D in relation to vitamin D status. According to the US National Health and Nutrition Examination Survey, 79% of US adults do not meet their Recommended Dietary Allowance of magnesium (6).

    One study tested the hypothesis that magnesium supplementation differentially affects vitamin D metabolism dependent on baseline 25-hydroxyvitamin D [25(OH)D] concentration. This study included 180 participants aged 40-85 years old. This was a double-blind 2 × 2 factorial randomized controlled trial. Doses for both magnesium and placebo were customized based on baseline dietary intakes. Subjects were randomly assigned to treatments using a permuted-block randomization algorithm. Changes in plasma 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2 [25(OH)D2], 1,25-dihydroxy vitamin D3, 1,25-dihydroxy vitamin D2, and 24,25-dihydroxy vitamin D3 [24,25(OH)2D3] were measured by liquid chromatography-mass spectrometry (6).

    The relations between magnesium treatment and plasma concentrations of 25(OH)D3, 25(OH)D2, and 24,25(OH)2D3 were significantly different depending on the baseline concentrations of 25(OH)D. Magnesium supplementation increased the 25(OH)D3 concentration when baseline 25(OH)D concentrations were close to 30 ng/mL, but decreased it when baseline 25(OH)D was higher (from ∼30 to 50 ng/mL). Magnesium treatment significantly affected 24,25(OH)2D3 concentration when baseline 25(OH)D concentration was 50 ng/mL but not 30 ng/mL. On the other hand, magnesium treatment increased 25(OH)D2 as baseline 25(OH)D increased. These findings suggested that optimal magnesium status might be important for optimizing 25(OH)D status (6). Magnesium affects sleep, see a previous blog on Magnesium and Sleep.

    A comprehensive review to evaluate the efficacy of different dietary supplements on the market for improving sleep quality included 31 randomized controlled studies. Subjective sleep quality was significantly improved by supplementation of vitamin D (MD -1.63, 95% CI -3.15 to -0.10; I2=85%) (7).

    As indicated by these studies, sleep quality may be directly related to vitamin D levels. People with lower vitamin D levels may experience a lower sleep quality. Vitamin D supplementation could improve sleep score and quality in people with sleep disorders.

References:

1. Muscogiuri G, Barrea L, Scannapieco M, Di Somma C, Scacchi M, Aimaretti G, Savastano S, Colao A, Marzullo P. The lullaby of the sun: the role of vitamin D in sleep disturbance. Sleep Med. 2019 Feb;54:262-265. doi: 10.1016/j.sleep.2018.10.033. Epub 2018 Nov 24. PMID: 30660070.

2. Q, Kou T, Zhuang B, Ren Y, Dong X, Wang Q. The Association between Vitamin D Deficiency and Sleep Disorders: A Systematic Review and Meta-Analysis. Nutrients. 2018 Oct 1;10(10):1395. doi: 10.3390/nu10101395. PMID: 30275418; PMCID: PMC6213953.

3. Majid MS, Ahmad HS, Bizhan H, Hosein HZM, Mohammad A. The effect of vitamin D supplement on the score and quality of sleep in 20-50 year-old people with sleep disorders compared with control group. Nutr Neurosci. 2018 Sep;21(7):511-519. doi: 10.1080/1028415X.2017.1317395. Epub 2017 May 5. PMID: 28475473.

4. Ghaderi A, Banafshe HR, Motmaen M, Rasouli-Azad M, Bahmani F, Asemi Z. Clinical trial of the effects of vitamin D supplementation on psychological symptoms and metabolic profiles in maintenance methadone treatment patients. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):84-89. doi: 10.1016/j.pnpbp.2017.06.016. Epub 2017 Jun 19. PMID: 28642082.

5. Mirzaei A, Zabihiyeganeh M, Jahed SA, Khiabani E, Nojomi M, Ghaffari S. Effects of vitamin D optimization on quality of life of patients with fibromyalgia: A randomized controlled trial. Med J Islam Repub Iran. 2018 Apr 5;32:29. doi: 10.14196/mjiri.32.29. PMID: 30159280; PMCID: PMC6108287.

6. Dai Q, Zhu X, Manson JE, Song Y, Li X, Franke AA, Costello RB, Rosanoff A, Nian H, Fan L, Murff H, Ness RM, Seidner DL, Yu C, Shrubsole MJ. Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial. Am J Clin Nutr. 2018 Dec 1;108(6):1249-1258. doi: 10.1093/ajcn/nqy274. PMID: 30541089; PMCID: PMC6693398.

7. Chan V, Lo K. Efficacy of dietary supplements on improving sleep quality: a systematic review and meta-analysis. Postgrad Med J. 2022 Apr;98(1158):285-293. doi: 10.1136/postgradmedj-2020-139319. Epub 2021 Jan 13. PMID: 33441476.