**10. Vitamins and minerals and sleep**

Management of sleep disturbances combines nonpharmacologic and pharmacologic ap‐ proaches individualized for the patient. According to the International Classification of Sleep Disorders (ICSD-2, 2005) [67] there are around 90 distinct sleep disorders. The cumulative effects of sleep loss and sleep disorders have been associated with a wide range of deleterious health consequences including an increased risk of hypertension, diabetes, obesity, depression, heart attack, stroke and nutritional status of an individual could play a major role on sleep quality. Observational studies have shown a link between sleep [68] and vitamins and minerals, whether taken in combination or individually, are the most frequently consumed dietary supplements among people today. Unlike other dietary supplement ingredients, vitamins and certain minerals are considered essential nutrients for which standards of adequacy are needed.

#### **10.1. Vitamins B**

B vitamins are essential micronutrients and have many important functions in the body. The B vitamins generally are coenzymes in the energy metabolism in the body. They are needed for the syntheses and release of certain neurotransmitters and neurohormones that are involved in the regulation of sleep and the circadian cycle. B vitamins have been advanced as a preventive for insomnia based on research that suggests deficiencies in vitamin B6 promote psychological distress and ensuing sleep disturbance [69]. Folic acid and vitamin B12 are both B vitamins. Folic acid is often used in combination with other B vitamins [70]. Although the direct link between vitamins and insomnia is unclear, there are studies that show an association between vitamins and sleep disorders.

vitamin D have been reported [82, 83, 84]. Further evidence suggest that low vitamin D levels increase the risk for autoimmune disease, chronic rhinitis, tonsillar hypertrophy, cardiovas‐ cular disease, and diabetes [85]. McCarty et al. [86] reported that persistent inadequacy of vitamin D may also increase the risk for obstructive sleep apnea via promotion of adenoton‐

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Vitamin A is the parent compound of retinoid, which regulate gene transcription by binding to nuclear retinoid receptors. It is involved in immune function, vision, reproduction, and cellular communication. Vitamin A is very important for the mucous membranes as it is needed for the proper production of mucopolysaccharides, which help to protect against infections. Barceló et al. [87], reported that patients with obstructive sleep apnoea syndrome have a decreased antioxidant capacity of vitamin A and E levels. Study of sleep in mouse models of ageing, Ransom et al [88] showed further clues as to the involvement of vitamin A in the regulation of delta oscillations. It has been suggested that retinoid signalling pathways are important for adult neural function in health and disease [89]. A definitive role for vitamin A signalling however is evident in the regulation of delta oscillations. This was first proposed by Maret et al. [90], who observed that the relative contribution of the delta wave to slow move sleep (SWS) is determined by the RA receptor RARb1. Moreover, vitamin A deficiency is

Vitamin C prevents some oxidative damage brought on by endurance exercise to the fat and muscle tissue. It is required for the transformation of dopamine into noradrenalin [92], and the function of this vitamin has been suggested to extend to neuromodulation of dopamine, regulation of acetylcholine and catecholamine release, and glutamate and GABA mediated neurotransmission [93]. Sleep symptoms are associated with weight gain and cardio metabolic disease. The potential role of diet including vitamin C that was associated independently with non-restorative sleep has been reported [82, 94], they suggest a novel associations between sleep symptoms and diet/metabolism, potentially explaining associations between sleep and cardiometabolic disease. Singh et al. [95], supplementing OSA patients with vitamins E and C concluded that that antioxidant treatment (oral vitamin E and C) reduced oxidative stress in OSA patients. Furthermore, decreased levels of antioxidants (superoxide dismutase, catalase, glutathione and homocysteine, as well as vitamins E, C, B11 and B12) and lower performance on the neuropsychological tasks were observed in patients with obstructive sleep apnea [96]. The authors suggest that an imbalance between antioxidants and pro-oxidants may contribute to neuropsychological alterations in this patient population. In restless leg syndrome (RLS), vitamins C and E and their combination are used as safe and effective treatments for reducing the severity of RLS in hemodialysis patients [97]. Ascorbic acid and sodium-dependent vitamin C transporters (SVCT) have been shown to have important functions in the peripheral nervous

sillar hypertrophy, airway muscle myopathy, and/or chronic rhinitis.

known to significantly reduce the power of the delta oscillation in mice [91].

**10.4. Vitamin A**

**10.5. Vitamin C**

system (PNS) [98].

#### **10.2. Vitamin B12, B6 and Folic Acid**

Vitamin B12 deficiency has been linked to various neuropsychiatric disorders including slow cerebration; confusion; memory changes; delirium, with or without hallucinations and/or delusions; depression; acute psychotic states; sleep, and reversible manic and schizophreni‐ form states affective illness [71, 72]. It has been shown that depressed subjects have low serum vitamin B12 levels [73]. It has been reported that high levels of vitamin B12 are associated with good treatment outcome in patients with MDD [74]. However, others did not found any association [75]. It has been reported that both folate and vitamin B12 are essential in several metabolic pathways in the central nervous system, and their metabolism is intimately con‐ nected [76]. A deficiency of either vitamin causes impaired methylation in the central nervous system and may result in neurological and psychiatric disease that becomes irreversible if not treated properly [71]. Furthermore, vitamin B12 has been shown to modulate human melatonin secretion [77]. Vitamin B6 is involved in the same metabolic pathways in the central nervous system as vitamin B12 and folate. Earlier studies found a low level of plasma vitamin B6 associated with symptoms of depression [78]. Other reported that vitamin B6 supplementation has positive effects on memory performance, but not on mood [79].

#### **10.3. Vitamin D**

Vitamin D is a group of fat-soluble prohormones synthesised in response to sunlight. The major source of vitamin D in humans is exposure to UV radiation. The active form of vitamin D in the body is 1,25-dihydroxyvitamin D, or calcitriol. Vitamin D has received a great deal of attention recently. It has long been recognized as primarily a regulator of calcium and phosphorus, helping to protect bone density. In recent years, however, our understanding of the functions of Vitamin D in the body has expanded with numerous health outcomes. Vitamin D is now understood to play an important role in metabolic and immune system functions. Vitamin D deficiency has been linked to a number of illnesses and chronic conditions, including high blood pressure, diabetes; metabolic syndrome, pulmonary disease, and chronic pain. Vitamin D supplementation during winter improve mood in healthy volunteers [80]. One possible mechanism of action is that serum 1,25-dihydroxyvitamin D levels affect the levels of serotonin in the hypothalamus [81] and thereby enhance the synthesis and transmission of serotonin, leading to improvement in mood. Novel associations between sleep symptoms and vitamin D have been reported [82, 83, 84]. Further evidence suggest that low vitamin D levels increase the risk for autoimmune disease, chronic rhinitis, tonsillar hypertrophy, cardiovas‐ cular disease, and diabetes [85]. McCarty et al. [86] reported that persistent inadequacy of vitamin D may also increase the risk for obstructive sleep apnea via promotion of adenoton‐ sillar hypertrophy, airway muscle myopathy, and/or chronic rhinitis.

#### **10.4. Vitamin A**

**10.1. Vitamins B**

**10.3. Vitamin D**

between vitamins and sleep disorders.

198 Pharmacology and Nutritional Intervention in the Treatment of Disease

**10.2. Vitamin B12, B6 and Folic Acid**

B vitamins are essential micronutrients and have many important functions in the body. The B vitamins generally are coenzymes in the energy metabolism in the body. They are needed for the syntheses and release of certain neurotransmitters and neurohormones that are involved in the regulation of sleep and the circadian cycle. B vitamins have been advanced as a preventive for insomnia based on research that suggests deficiencies in vitamin B6 promote psychological distress and ensuing sleep disturbance [69]. Folic acid and vitamin B12 are both B vitamins. Folic acid is often used in combination with other B vitamins [70]. Although the direct link between vitamins and insomnia is unclear, there are studies that show an association

Vitamin B12 deficiency has been linked to various neuropsychiatric disorders including slow cerebration; confusion; memory changes; delirium, with or without hallucinations and/or delusions; depression; acute psychotic states; sleep, and reversible manic and schizophreni‐ form states affective illness [71, 72]. It has been shown that depressed subjects have low serum vitamin B12 levels [73]. It has been reported that high levels of vitamin B12 are associated with good treatment outcome in patients with MDD [74]. However, others did not found any association [75]. It has been reported that both folate and vitamin B12 are essential in several metabolic pathways in the central nervous system, and their metabolism is intimately con‐ nected [76]. A deficiency of either vitamin causes impaired methylation in the central nervous system and may result in neurological and psychiatric disease that becomes irreversible if not treated properly [71]. Furthermore, vitamin B12 has been shown to modulate human melatonin secretion [77]. Vitamin B6 is involved in the same metabolic pathways in the central nervous system as vitamin B12 and folate. Earlier studies found a low level of plasma vitamin B6 associated with symptoms of depression [78]. Other reported that vitamin B6 supplementation

Vitamin D is a group of fat-soluble prohormones synthesised in response to sunlight. The major source of vitamin D in humans is exposure to UV radiation. The active form of vitamin D in the body is 1,25-dihydroxyvitamin D, or calcitriol. Vitamin D has received a great deal of attention recently. It has long been recognized as primarily a regulator of calcium and phosphorus, helping to protect bone density. In recent years, however, our understanding of the functions of Vitamin D in the body has expanded with numerous health outcomes. Vitamin D is now understood to play an important role in metabolic and immune system functions. Vitamin D deficiency has been linked to a number of illnesses and chronic conditions, including high blood pressure, diabetes; metabolic syndrome, pulmonary disease, and chronic pain. Vitamin D supplementation during winter improve mood in healthy volunteers [80]. One possible mechanism of action is that serum 1,25-dihydroxyvitamin D levels affect the levels of serotonin in the hypothalamus [81] and thereby enhance the synthesis and transmission of serotonin, leading to improvement in mood. Novel associations between sleep symptoms and

has positive effects on memory performance, but not on mood [79].

Vitamin A is the parent compound of retinoid, which regulate gene transcription by binding to nuclear retinoid receptors. It is involved in immune function, vision, reproduction, and cellular communication. Vitamin A is very important for the mucous membranes as it is needed for the proper production of mucopolysaccharides, which help to protect against infections. Barceló et al. [87], reported that patients with obstructive sleep apnoea syndrome have a decreased antioxidant capacity of vitamin A and E levels. Study of sleep in mouse models of ageing, Ransom et al [88] showed further clues as to the involvement of vitamin A in the regulation of delta oscillations. It has been suggested that retinoid signalling pathways are important for adult neural function in health and disease [89]. A definitive role for vitamin A signalling however is evident in the regulation of delta oscillations. This was first proposed by Maret et al. [90], who observed that the relative contribution of the delta wave to slow move sleep (SWS) is determined by the RA receptor RARb1. Moreover, vitamin A deficiency is known to significantly reduce the power of the delta oscillation in mice [91].

#### **10.5. Vitamin C**

Vitamin C prevents some oxidative damage brought on by endurance exercise to the fat and muscle tissue. It is required for the transformation of dopamine into noradrenalin [92], and the function of this vitamin has been suggested to extend to neuromodulation of dopamine, regulation of acetylcholine and catecholamine release, and glutamate and GABA mediated neurotransmission [93]. Sleep symptoms are associated with weight gain and cardio metabolic disease. The potential role of diet including vitamin C that was associated independently with non-restorative sleep has been reported [82, 94], they suggest a novel associations between sleep symptoms and diet/metabolism, potentially explaining associations between sleep and cardiometabolic disease. Singh et al. [95], supplementing OSA patients with vitamins E and C concluded that that antioxidant treatment (oral vitamin E and C) reduced oxidative stress in OSA patients. Furthermore, decreased levels of antioxidants (superoxide dismutase, catalase, glutathione and homocysteine, as well as vitamins E, C, B11 and B12) and lower performance on the neuropsychological tasks were observed in patients with obstructive sleep apnea [96]. The authors suggest that an imbalance between antioxidants and pro-oxidants may contribute to neuropsychological alterations in this patient population. In restless leg syndrome (RLS), vitamins C and E and their combination are used as safe and effective treatments for reducing the severity of RLS in hemodialysis patients [97]. Ascorbic acid and sodium-dependent vitamin C transporters (SVCT) have been shown to have important functions in the peripheral nervous system (PNS) [98].

### **10.6. Vitamin E**

Vitamin E has active ingredients of tocopherols and tocotrienols. It exists in eight different natural forms, all of which have antioxidant properties When supplemented it may reduce damage to cell DNA and cell and it has neuroprotective effect on the brain. Vitamin E may stabilize peripheral blood circulation, suppressing abrupt deformation of vessels [99], accel‐ eration of blood flow in vessels would increase the pressure of blood on the vessel walls, and subtle changes in vessel tension or shape might stimulate nerve fibres that are in anatomical proximity to the vessels [99]. Vitamin E normalized chronic sleep deprivation-induced reduction in the hippocampus GSH/GSSG ratio, and activity of catalase, super oxide dismutase (SOD), and glutathione peroxidase (GPx) [100]. Decreased levels of antioxidants and lower performance on the neuropsychological tasks were observed in patients with obstructive sleep apnea [10]1 . This study suggests that an imbalance between antioxidants and pro-oxidants may contribute to neuropsychological alterations in this patient population.During eight-year follow-up study to investigate the link between vitamin E, namely α-tocopherol, and memory disorders, it was found that higher total serum levels of vitamin E, and higher levels of γtocopherol, β-tocotrienol and total tocotrienols in particular, seemed to protect against memory disorders [102]. Their results show that the entire vitamin E family plays a role in memory processes. Accordingly, measuring the levels of vitamin E from serum is the most reliable way to determine whether they are sufficiently high. Limited research indicates that supplemental vitamin E may reduce symptom occurrence in restless leg syndrome [103].

supplementation compared with placebo [114]. Although narcolepsy is a rather rare disorder, daytime sleepiness is not. It is possible that low levels of carnitine could be a cause of fatigue and daytime sleepiness. For example, low serum carnitine levels have been observed in patients with chronic fatigue syndrome (CFS) – a clinically defined condition characterized by severe disabling fatigue and a combination of symptoms, such as musculoskeletal pain,

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L-carnitine supplementation also increased serum carnitine levels and reduced serum triglycerides concentration indicating improvement in the burning of fat as energy. Other researchers found that ALC treatment reduced symptoms of depression in older people [116]. It also improved dysthymia, a milder form of depression, about as well as a common medi‐ cation. Several studies show that ALC may help improve certain behaviours in boys with fragile X syndrome (FXS), such as their social skills and hyperactivity. The study has linked ALC with less pain or less-intense pain in people with nerve problems from these causes. ALC is a compound of great interest in various neurological disorders such as in treating Alzheim‐ er's dementia, HIV-infection, diabetic neuropathies and aging [117,118,119,120]. A decrease of sleep disorders, a muscle discomfort, and of the prolonged fatigue after exercise has also been shown [121]. Carnitine supplementation could be helpful in mitochondrial disorders as the sleep problems are commonly reported in patients with mitochondrial myopathies [122,123].

There is a growing consensus that omega-3 fatty acids are essential nutrients for humans. Much of the evidence is based on physiological measurements such as neurological development and visual acuity. To better understand why this class of polyunsaturated fatty acids is required, we must determine the biochemical basis for the essentiality. Of the eight fatty acids that comprise the omega-3 metabolic pathway, the two that are most likely to have essential biochemical functions are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

EPA can be converted to prostaglandins, thromboxanes and lipoxygenase products [124]. However, no essential role for these EPA-metabolites has been reported, and it seems unlikely that the formation of these products is the reason that omega-3 fatty acids are essential. When elevated amounts of EPA are available, the incorporation of arachidonic acid (AA) into cell phospholipids and its conversion to eicosanoid mediators is reduced. Thus, EPA acts as a competitive inhibitor of AA, and this probably accounts for some of the beneficial effects of omega-3 fatty acids in the treatment of cardiovascular and inflammatory diseases. While the possibility that EPA is essential in order to modulate the effects of AA cannot be ruled out, the amounts ordinarily present in the plasma and tissues probably are too low to competitively inhibit the actions of AA. Therefore, modulation of AA metabolism is more likely to be a pharmacological effect of omega-3 fatty acid supplements rather than an essential physiolog‐

The basis for considering DHA as the biochemically essential omega-3 component is much more compelling. DHA is the most abundant omega-3 fatty acid in most tissues, and it is

difficulty in concentration and sleep disturbances.

**11. Fatty acids**

ical function.

#### **10.7. L-carnitine and Sleep**

Acetyl-L-carnitine (ALC) is a naturally occurring compound that facilitates the transport of fatty acids into mitochondria for β-oxidation [104]. Acetyl-L-carnitine can enter the brain, and the acetyl group helps form acetylcholine, an important neurotransmitter. L-carnitine enhan‐ ces resistance to oxidative stress by reducing DNA damage in Ataxia telangiectasia cells [105]. Positive results were seen in carnitine supplementation in depression, dysthymia, mental and physical energy, with less fatigue, muscle pain, and sleep problems [106,107,108]. Muscle weakness and hepatic dysfunction can also been noted [109]. Supplementation of carnitine has also been shown to be a mood elevator in the elderly [110]. Acetyl L-Carnitine helps the brain form acetylcholine, a neurotransmitter needed for memory and thinking [111].

Evidence for the effectiveness of L-carnitine in attention deficit and hyperactivity disorder (ADHD) has been studied [112]. Other studies in animals and human have shown that a combination of acetyl-L-carnitine and alpha-lipoic acid reversed many of the signs of aging and restored both physical and mental vigor. Low levels of carnitine are associated with a higher frequency of fragmented wakefulness [113].

L-Carnitine has been demonstrated to be therapeutic for individuals with narcolepsy. A recent study investigated the contribution of a gene polymorphism found in narcolepsy called CPT1B, which is important in fatty acid oxidation [114]. They found that individuals with narcolepsy had very low levels of serum acylcarnitine [115]. L-carnitine was given (510 mg/ day) to patients with narcolepsy it was revealed that total time for dozing off during daytime in narcolepsy patients, the primary endpoint, was significantly decreased by L-carnitine supplementation compared with placebo [114]. Although narcolepsy is a rather rare disorder, daytime sleepiness is not. It is possible that low levels of carnitine could be a cause of fatigue and daytime sleepiness. For example, low serum carnitine levels have been observed in patients with chronic fatigue syndrome (CFS) – a clinically defined condition characterized by severe disabling fatigue and a combination of symptoms, such as musculoskeletal pain, difficulty in concentration and sleep disturbances.

L-carnitine supplementation also increased serum carnitine levels and reduced serum triglycerides concentration indicating improvement in the burning of fat as energy. Other researchers found that ALC treatment reduced symptoms of depression in older people [116]. It also improved dysthymia, a milder form of depression, about as well as a common medi‐ cation. Several studies show that ALC may help improve certain behaviours in boys with fragile X syndrome (FXS), such as their social skills and hyperactivity. The study has linked ALC with less pain or less-intense pain in people with nerve problems from these causes. ALC is a compound of great interest in various neurological disorders such as in treating Alzheim‐ er's dementia, HIV-infection, diabetic neuropathies and aging [117,118,119,120]. A decrease of sleep disorders, a muscle discomfort, and of the prolonged fatigue after exercise has also been shown [121]. Carnitine supplementation could be helpful in mitochondrial disorders as the sleep problems are commonly reported in patients with mitochondrial myopathies [122,123].
