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Abstract
The main mechanisms of the chronopathological forms of magnesium depletion associate a low Mg intake with various dysregulating biorhythms. The differentiation between forms with hyperfunction and forms with hypofunction of the biological clock is seminal and the main marker is the production of melatonin (MT). The clinical forms of the various patterns of the chronopathological forms of Mg depletion may be central or peripheral. The clinical forms with hyperfunction of the biological clock (marker: increase in MT) may associate diverse expressions of nervous hypoexcitability: depression (i.e. Seasonal affective disease); cephalalgias nocturnal, without photophobia (i.e. cluster headaches); dyssomnia LASPS (advanced sleep phase syndrome) particularly]; asthenia and myalgias (i.e. fibromyalgia, chronic fatigue syndrome). The main comorbidity is found with depressive states. The therapy relies on classical bright light phototherapy, sometimes associated with psychoanaleptics. The clinical forms with hypofunction of biological clock (marker: decrease in MT) may associate various signs of nervous hyperexcitability (HEN): anxiety (from generalized anxiety to panic attacks); cephalalgias diurnal with photophobia (mainly migraine); dyssomnia [DSPS (delayed sleep phase syndrome) particularly, jet lag, night work disorders, age related insomnia, sometimes with inappropriate behaviour; photogenic epilepsia, generalized or focal; some clinical forms of chronic fatigue syndrome and fibromyalgia. The main comorbidity is between migraine and epilepsia. The treatment relies on the diverse forms of darkness therapy, possibly with the help of some psycholeptics: anxiolytics and anticonvulsants. The indications of chromatotherapy remain to be validated.
... The majority of headaches are idiopathic in origin. A clinical approach show a continuum ranging from mild to moderate then severe headache, with clinical symptoms, pathophysiological mechanisms and therapies similar in tension type headache and migraine [2][3][4]. Migraine may be accompanied by nausea, vomiting, diarrhoea, confusion. Sensitivity to light with photophobia-a clinical marker, noise and strong smells is also frequently reported during and between the algic attacks [3,4]. ...
... Migraine may be accompanied by nausea, vomiting, diarrhoea, confusion. Sensitivity to light with photophobia-a clinical marker, noise and strong smells is also frequently reported during and between the algic attacks [3,4]. The concept of hyperexcitability of the brain has arisen in the 15 last years, involving low cerebral magnesium levels, mitochondrial abnormalities, increased NO (nitric oxide) and calcium channelopathy [5][6][7][8]. ...
... The concept of hyperexcitability of the brain has arisen in the 15 last years, involving low cerebral magnesium levels, mitochondrial abnormalities, increased NO (nitric oxide) and calcium channelopathy [5][6][7][8]. In this regard, we showed two decades ago that the magnesium status and the Biological Clock (BC) function were strongly correlated and interacted between them [2,4,9]. One must distinguish between two types of magnesium deficit: Deficiency (a simple insufficient intake) and depletion (corresponding to a dysregulation of the magnesium status, due to the association of a reduced magnesium intake with various types of stress including BC dysrhythmias). ...
... Information for identifying chronotypes [26] was not obtained in this study. The output from SCN can perhaps affect cerebral excitability in general [27,28]. There is a striking parallel with the curve of day length in Tromsø ( Fig. 1) and the seasonal variation of migraine with aura, implying photoperiodism. ...
... An association between hypofunction of the biological clock (measured by a Figure 4 Seasonal variation in migraine with aura. decrease in melatonin secretion) has been associated with magnesium depletion, and has been postulated to cause nervous hyperexcitability which may cause dyssomnia (delayed sleep phase syndrome) and headaches with photophobia (migraine) [28]. ...
Seasonal rhythm of migraine attacks may support a role of the suprachiasmatic nucleus of the hypothalamus in the pathophysiology of migraine. The objective of this study was to provide evidence for seasonal variation in migraine. Eighty-nine female migraineurs volunteered to record every migraine attack in detail for 12 consecutive months. Attacks associated with sleep complaints were defined as insomnia-related. By using Edwards' model for recognition and estimation of cyclic trends, time-series analysis was made. Fifty-eight patients, of which 26 had migraine without aura (MO) and 32 had migraine with aura (MA), completed the study. A total of 1840 attacks were recorded. The mean age +/- SD was 36.9 +/- 6.0. Patients with a lifetime history of MA showed marked seasonal fluctuation with more attacks in the light season compared to the dark. Time of peak was May 21. Peak/low ratio was 1.30 (95% CI: 1.08-1.55). When insomnia-related attacks (n = 312) were removed the seasonal variation became insignificant. There is a seasonal trend with more migraine attacks in the light season compared to the dark season in females with MA, but not MO, living in an arctic area. This is caused by the seasonal variation of insomnia-related attacks in patients with MA.
... Magnesium is important in neuronal processes as evident by a high correlation of a higher concentration of magnesium in the forebrain with sleep duration in rats [50]. In addition, magnesium is also associated with the synthesis of melatonin, a key hormone involved in the regulation of sleep-wake cycles [51]. It has been reported that rats who were fed a magnesium-deficient diet have decreased melatonin levels [45]. ...
The relationship between sleep and micronutrients, including magnesium, is implicated in its regulation. The effects of low magnesium and other micronutrients on sleep disruption and telomere loss are not well understood. The present study was carried out in 172 healthy elderly subjects from South Australia. Plasma micronutrients including magnesium were measured. Each participant provided information about their sleep hours (<7 h or ≥7 h). Lymphocyte telomere length (TL) was measured by real-time qPCR assay. Plasma magnesium level was significantly low in subjects who sleep less than 7 h (p = 0.0002). TL was significantly shorter in people who are low in magnesium and sleep less than 7 h (p = 0.01). Plasma homocysteine (Hcy) is negatively associated with magnesium (r = −0.299; p < 0.0001). There is a significant interaction effect of magnesium and Hcy on sleep duration (p = 0.04) and TL (p = 0.003). Our results suggest that inadequate magnesium levels have an adverse impact on sleep and telomere attrition rate in cognitively normal elderly people, and this may be exacerbated by low levels of vitamin B12 and folate that elevate Hcy concentration.
... In patients with MS, increased disease activity occurs during spring and summer. This fact is associated with temperature changes [43][44][45]. Disease relapses were less frequent in patients with less severity of sensory discrimination. This hypothesis requires further, more detailed research. ...
Sensory integration disorder (SID) is also called, interchangeably, sensory processing disorder (SPD). Multiple sclerosis (MS) is an autoimmune, chronic, neurological disease of the central nervous system. Sensorimotor function disorders are present in both multiple sclerosis and SID. The study aimed to assess the SID among patients with MS and included 141 patients with relapse-remitting MS and 72 participants in the control group. To assess SID in both groups, a questionnaire prepared by Daniel Travis was used. Additionally, participants answered questions regarding their age, gender, handedness and in the study group about the duration of the disease, relapses in the past year and the advancement of the disease using EDSS. The occurrence of sensory seeking was significantly more frequent in the MS patients with relapses in the past year. Patients with MS had more often general disorders of sensory integration in the past. However, healthy subjects significantly more often showed the severity of social and emotional disorders in the past. Currently, the group of MS patients has a greater intensity of sensor-based motor abilities. The study revealed more severe SID in MS patients than in the control group. Still, more research is needed in this field.
... Increased AANAT activity was also reported in rats with Mg supplementation (10). Biological clock and magnesium status are also reported to be linked (17,18). On the other hand, independently of melatonin, magnesium has function on muscle contraction/relaxation, neurotransmitter release, neuromuscular impulse conduction and its deficiency cause irritability, sleep disorders, and muscle spasm (14). ...
... 9 Measurement of ionised Mg is possible although susceptible to false results without very well-defined sample handling, and probably has little value in addition to se total Mg levels. [16][17][18][19][20][21] RBC Mg does not correlate well with total body Mg or other measures of Mg status. 22 Lymphocyte Mg may be a better reflection of skeletal and muscle Mg stores; however, the measurement is technically difficult and has high intra-individual variation. ...
Hypomagnesaemia is common in pregnancy, particularly in developing countries and low-income communities. Despite the frequent therapeutic use of magnesium in pregnancy, and the evidence regarding the association of hypomagnesaemia with adverse pregnancy outcomes in animal studies, it remains unclear whether hypomagnesaemia is associated with complications in human pregnancy. Three case reports of pregnancies complicated by moderate–severe hypomagnesaemia are presented and magnesium physiology in pregnancy is discussed. The evidence as to whether hypomagnesaemia may represent a direct cause, a consequence of other disease processes or an epiphenomenon in adverse pregnancies outcomes is reviewed.
... Patient studies have also indicated excessive light sensitivity (Söderlund et al. 2000). This is in contrast to other studies, where reduced sensitivity towards sunny, dry, and long days compared to controls can be found (García-Borreguero et al. 1998), and which suggested a disturbance of the biological clock (Durlach et al. 2002). ...
Within the context of the promotion of wide-spread use of energy saving lamps, such as
compact fluorescent lamps (CFLs), and the possible phase-out of incandescent lamps, it
has been claimed that the symptoms of several diseases may be aggravated in the
presence of energy saving lamps (mainly CFLs).
SCENIHR did not find suitable direct scientific data on the relationship between energy
saving lamps and the symptoms in patients with various conditions (i.e xeroderma
pigmentosum, lupus, migraine, epilepsy, myalgic encephalomyelitis, Irlen-Meares
syndrome, fibromyalgia, electrosensitivity, AIDS/HIV, dyspraxia, and autism). Therefore,
SCENIHR examined whether three lamp characteristics (flicker, electromagnetic fields,
and UV/blue light emission) could act as triggers for disease symptoms. Due to lack of
data on CFLs, existing data on traditional fluorescent tubes were extrapolated to
situations when compact fluorescent lamps may be used.
While for some conditions either flicker and/or UV/blue light could exacerbate symptoms,
there is no reliable evidence that the use of fluorescent tubes was a significant
contributor. Of all compact fluorescent lamps properties, only UV/blue light radiation was
identified as a potential risk factor for the aggravation of the light-sensitive symptoms in
some patients with such diseases as chronic actinic dermatitis and solar urticaria.
The committee wishes to draw attention of the Commission Services to the fact that it
has been observed that some single-envelope CFLs emit UVB and traces of UVC
radiation. Under extreme conditions (i.e. prolonged exposures at distances <20 cm)
these CFLs may lead to UV exposures approaching the current workplace limit set to
protect workers from skin and retinal damage.
Due to the lack of relevant data, the number of all light-sensitive patients in the
European Union, who might be at risk from the increased levels of UV/blue light radiation
generated by CFL is difficult to estimate. However, a preliminary rough estimation of the
worst-case scenario yields a number of around 250,000 individuals (0.05% of the
population) in the EU.
The committee notes that the use of double-envelope energy saving bulbs or similar
technology would largely or entirely mitigate both the risk of approaching workplace
limits on UV emissions in extreme conditions and the risk of aggravating the symptoms
of light-sensitive individuals.
... Deficiency of dietary Mg has been related to depressive disorders (Rasmussen et al, 1989;Hashizume and Mori, 1990). The pathological signs of Mg--deficiency and possible reasons for its development have been reviewed earlier (Morris, 1992;Durlach, 1984;Durlach et al, 1995;Durlach et al, 1997;Durlach, 2002). A recent study confirmed the epidemiological relationship between low dietary Mg intake and the risk of developing depression (Jacka et al, 2009). ...
The treatment of major depression is still a major unmet medical need in the majority of patients. Sixty percent of cases of MD are treatment-resistant depression (TRD), showing that classical treatments for MD are poorly effective to non-effective. Magnesium has been largely removed from processed foods, especially refined grains, in the Western world harming the brain and causing mood disorders. Magnesium deficiency causes N-methyl-D-aspartate (NMDA) coupled calcium channels to be biased towards opening which causes neuronal injury and neurological dysfunction, which we believe results in MD. Oral administration of Mg to animals produced antidepressant-like effects that were comparable to those of antidepressant drugs. Cerebral spinal fluid (CSF) Mg has been found low in suicidal TRD. The first report of Mg treatment for agitated depression was published in 1921 showing success in 220 out of 250 cases. One 2008 randomized clinical trial showed that Mg was as effective as the tricyclic antidepressant imipramine in treating MD. Intravenous and oral Mg protocols have been reported to rapidly terminate MD safely and without side effects. Brain Mg deficiency reduces serotonin levels, and antidepressant drugs have been shown to have the action of raising brain Mg. Excessive calcium, glutamate and aspartate intake can greatly worsen MD. We believe that – when taken together – there is more than sufficient evidence to implicate inadequate dietary Mg as contributing to the cause of MD, and we suggest that physicians prescribe Mg for its prevention and treatment.
... [30] In general, studies show that magnesium deficiency affects circadian cycle, melatonin reduction, and sleep disorders. [56,57] Morton and James suggested that the N-acetyltransferase (NAT) activity in rat is increased after magnesium injection. Moreover, magnesium increases NAT activity in pineal gland in vitro, suggesting that the pineal gland, not another place of the body, is the affect site. ...
Nearly 50% of older adults have insomnia, with difficulty in getting to sleep, early awakening, or feeling unrefreshed on waking. With aging, several changes occur that can place one at risk for insomnia, including age-related changes in various circadian rhythms, environmental and lifestyle changes, and decreased nutrients intake, absorption, retention, and utilization. The natural N-methyl-D-aspartic acid (NMDA) antagonist and GABA agonist, Mg(2+), seems to play a key role in the regulation of sleep. The objective of this study was to determine the efficacy of magnesium supplementation to improve insomnia in elderly.
A double-blind randomized clinical trial was conducted in 46 elderly subjects, randomly allocated into the magnesium or the placebo group and received 500 mg magnesium or placebo daily for 8 weeks. Questionnaires of insomnia severity index (ISI), physical activity, and sleep log were completed at baseline and after the intervention period. Anthropometric confounding factors, daily intake of magnesium, calcium, potassium, caffeine, calories form carbohydrates, and total calorie intake, were obtained using 24-h recall for 3 days. Blood samples were taken at baseline and after the intervention period for analysis of serum magnesium, renin, melatonin, and cortisol. Statistical analyses were performed using SPSS19 and P values < 0.05 were considered as statistically significant.
No significant differences were observed in assessed variables between the two groups at the baseline. As compared to the placebo group, in the experimental group, dietary magnesium supplementation brought about statistically significant increases in sleep time (P = 0.002), sleep efficiency (P = 0.03), concentration of serum renin (P < 0.001), and melatonin (P = 0.007), and also resulted in significant decrease of ISI score (P = 0.006), sleep onset latency (P = 0.02) and serum cortisol concentration (P = 0.008). Supplementation also resulted in marginally between-group significant reduction in early morning awakening (P = 0.08) and serum magnesium concentration (P = 0.06). Although total sleep time (P = 0.37) did not show any significant between-group differences.
Supplementation of magnesium appears to improve subjective measures of insomnia such as ISI score, sleep efficiency, sleep time and sleep onset latency, early morning awakening, and likewise, insomnia objective measures such as concentration of serum renin, melatonin, and serum cortisol, in elderly people.
... cluster headaches); advanced sleep phase syndrome; asthenia and myalgias (i.e. fibromyalgia, chronic fatigue syndrome) with the main comorbidity found in depressive states; or alternatingly, with hypofunction of the biological clock (marker: decrease in MT) resulting in various signs of nervous hyperexcitability: anxiety (from generalized anxiety to panic attacks); cephalalgias diurnal with photophobia (mainly migraine); dyssomnia (delayed sleep phase syndrome) particularly, jet lag, night work disorders, age related insomnia, sometimes with inappropriate behavior; photogenic epilepsy, generalized or focal; some clinical forms of chronic fatigue syndrome and fibromyalgia with the main comorbidity being found in migraine and/or epilepsy [69]. Anxiety due to magnesium-deficiency was suggested to be caused by increased production of epinephrine, and that magnesium and taurine were antidotes [70] . ...
Sixty percent of cases of clinical depression are considered to be treatment-resistant depression (TRD). Magnesium-deficiency causes N-methyl-d-aspartate (NMDA) coupled calcium channels to be biased towards opening, causing neuronal injury and neurological dysfunction, which may appear to humans as major depression. Oral administration of magnesium to animals led to anti-depressant-like effects that were comparable to those of strong anti-depressant drugs. Cerebral spinal fluid (CSF) magnesium has been found low in treatment-resistant suicidal depression and in patients that have attempted suicide. Brain magnesium has been found low in TRD using phosphorous nuclear magnetic resonance spectroscopy, an accurate means for measuring brain magnesium. Blood and CSF magnesium do not appear well correlated with major depression. Although the first report of magnesium treatment for agitated depression was published in 1921 showing success in 220 out of 250 cases, and there are modern case reports showing rapid terminating of TRD, only a few modern clinical trials were found. A 2008 randomized clinical trial showed that magnesium was as effective as the tricyclic anti-depressant imipramine in treating depression in diabetics and without any of the side effects of imipramine. Intravenous and oral magnesium in specific protocols have been reported to rapidly terminate TRD safely and without side effects. Magnesium has been largely removed from processed foods, potentially harming the brain. Calcium, glutamate and aspartate are common food additives that may worsen affective disorders. We hypothesize that - when taken together - there is more than sufficient evidence to implicate inadequate dietary magnesium as the main cause of TRD, and that physicians should prescribe magnesium for TRD. Since inadequate brain magnesium appears to reduce serotonin levels, and since anti-depressants have been shown to have the action of raising brain magnesium, we further hypothesize that magnesium treatment will be found beneficial for nearly all depressives, not only TRD.
Применение препаратов магния в медицине имеет давнюю историю. По некоторым данным, первые попытки употребления человеком магний- и кальцийсодержащих минералов внутрь, предположительно в лечебных целях, могли иметь место ещё в доисторические времена.
Также к доисторическим временам относятся первые попытки применения природных магниево-кальциевых щелочных материалов для повышения биодоступности алкалоидов некоторых психоактивных растений, таких, как бетель, табак и кока.
Позднее рядом античных авторов, в частности, Гиппократом II, Клавдием Галеном и Сораном Эфесским, были описаны слабительный эффект морской соли и измельчённого доломита, а также положительное воздействие на психику питья, приёма ванн и ректального введения минеральных вод из источников, которые, как было установлено современными исследованиями, были очень богаты солями магния, лития и брома.
Слабительный эффект минеральных вод из некоторых источников, богатых магния сульфатом, или выпаренных из них солей – например, «Седлицкой соли» и «соли из Эгры» был хорошо известен в Средние века. В соответствии с доминировавшей тогда теорией о том, что слабительный эффект равнозначен
«очищению организма» и полезен для «восстановления баланса хуморов», эти соли широко применялись для лечения самых разных заболеваний. Позднее Парацельс обнаружил, что эти соли могут быть полезными вовсе не только как слабительное, но и как успокаивающее и средство от нервных тиков и мышечных подёргиваний.
В 1707 г. Массимилиано Валентини впервые получил оксид магния, который сразу же стал применяться в качестве антацидного средства, мягкого слабительного и присыпки. А в 1926 г. Жаком Лероем была впервые доказана жизненная важность магния для организма животных.
В данной статье мы подробно освещаем историю применения препаратов магния и исследований его биологической роли с древности до наших дней.
Ключевые слова: магний, кальций, литий, бром, история медицины, тетания, эпилепсия, спазмофилия, гуморальная теория
Для цитирования: Беккер Р.А., Быков Ю.В., Шкурат А.О., Воронина А.С. Препараты магния в психиатрии, наркологии, неврологии и общей медицине. Часть I. Историческая. Acta biomedica scientifica. 2019; 4(3): 63-80. doi: 10.29413/ABS.2019-4.3.9
The use of magnesium preparations in medicine has a long history. According to some sources, first attempts by humans to consume magnesium- and calcium-rich minerals orally, presumably for medicinal purposes, could have occurred even in prehistoric times. First attempts to use natural magnesium-calcium alkaline materials to increase the bioavailability of the alkaloids of some psychoactive plants, such as betel, tobacco, and coca, also date back to prehistoric times.
Later, several ancient authors, in particular, Hippocrates II, Claudius Galen and Soran of Ephesus, have described the profound laxative effect of sea salt and of crushed dolomite, as well as a positive effect on the psyche of drinking mineral waters from sources that were found by modern scientists to be rich in magnesium, lithium and bromine.
The laxative effect of mineral waters from some sources rich in magnesium, or of salts that were extracted from such sources was known in the Middle Ages. Later, Paracelsus discovered that these salts could be useful not only as a laxative, but also as a sedative.
In 1707, Massimiliano Valentini first obtained magnesium oxide, which immediately found its use in medicine, as an antacid, as a mild laxative and skin powder. In 1926, Jacques Leroy was the first to prove the vital importance of magnesium for the physiology of animals.
In this article, we thoroughly review the history of the medicinal use of magnesium preparations and the history of studies of biological role of magnesium, from antiquity to modern times.
Keywords: magnesium, calcium, lithium, bromide, history of medicine, tetany, epilepsy, spasmophilia, humoral theory
For citation: Bekker R.A., Bykov Yu.V., Shkurat A.O., Voronina A.S. Magnesium preparations in psychiatry, addiction medicine,neurology and general medicine (Part I. History). Acta biomedica scientifica. 2019; 4(3): 63-80. doi: 10.29413/ABS.2019-4.3.9
Animals, human beings among them, can adapt their behavior to (predictable) temporal fluctuations in the environment (such as day and night alternation, food and water availability, or social contact) by learning and memory processes interacting with an endogenous circadian clock. Behavioral, physiological, and biochemical circadian rhythms are crucial for the good mental health of an individual and rely on the integrity and functioning of the circadian system. The master clock in the suprachiasmatic nucleus synchronizes independent circadian peripheral clocks, localized in other brain areas, organs, and tissues to the appropriate phases by neural and humoral signals. Thus, circadian clocks orchestrate interactions between the organism’s internal processes and the environment in healthy, but also in pathological, conditions. This chapter focuses on the main components of the circadian system; the temporal organization of cognitive functions at the molecular, biochemical, and behavioural levels and their clock-mediated regulation; as well as on factors that could disrupt the normal functioning of the circadian system and thus, contribute to the etiology of cognitive disorders.
Comorbidity is defined as the co-occurrence of 2 medical conditions more frequently than would be expected by chance alone. Migraine and epilepsy are highly comorbid and share clinical features that suggest overlapping pathophysiology. The Epilepsy Family Study of Columbia University demonstrates the comorbidity of migraine and epilepsy; this relationship cannot be explained by a unidirectional causality (ie, that one disorder causes the other), shared genetic risk factors, or shared environmental risk factors. Analysis of epidemiologic and biological data suggests that brain hyperexcitability due either to environmental or genetic risk factors may account for the co-occurrence of migraine and epilepsy. However, our current understanding of hyperexcitability is not yet clear. Comorbidity is critical because it affects diagnosis as well as treatment. When conditions are comorbid, it is a mistake to make a single diagnosis. When epilepsy is diagnosed, it is more likely, not less likely, that the patient also has migraine. The presence of comorbid disorders presents both therapeutic opportunities and limitations. In some cases, a single medication can be used to treat both disorders; in other cases, medication to treat one disorder may be contraindicated for the other disorder.
The clinical forms of magnesium depletion due to dysregulation biorhythms may result from the association of a low magnesium intake with a dysregulated biorhythm: either hyperfunction or hypofunction of the biological clock. Their main biological marker is the production of melatonin.1 The biological dysfunction of the biological clock may be primary (e.g., impaired maturation of photoneuroendocrine system in clinical forms of sudden infant death due to magnesium depletion by hypofunction of the biological clock) 2,3 or secondary to light hypersensitivity. The organism responds to the pathogenic effect of this hypersensitivity with a protective reactive photophobia whose mechanism is still unclear.1,4-6
The lore of magnesium in medicine, starting as far back as the 17th century up to the first quarter of the 20th century, covers a large span of the chemical and pharmacological fields of knowledge.
Magnesium status is highly associated with stress levels, with both stress and hypomagnesemia potentiating each other’s negative effects. Indeed, hypomagnesemia has been associated with stressful conditions such as photosensitive headache, fibromyalgia, chronic fatigue syndrome, audiogenic stress, cold stress, and physical stress, amongst others. The role of magnesium in these conditions is unclear, although a number of potential mechanisms for magnesium’s action have been identified including via the glutamatergic, serotonergic, and adrenergic neurotransmitter systems, as well as via several neurohormones. The current review examines the link between magnesium deficiency and stress, focusing on the association between magnesium and various stress pathologies, magnesium’s potential interaction with stress pathways, and magnesium’s effects on the brain.
Photic hypersensitivity may induce various signs of nervous hypersensitivity, including diurnal cephalalgias, anxiety, dyssomnia, seizures, fatigue and/or myalgias. The patients usually present both dishabituation and generalization in response to repetitive light stimuli instead of habituation as in normal subjects. These clinical manifestations appear when light intensity is maximum (daytime; spring and summer) in magnesium-depleted patients with hypofunction of the biological clock. The best photic hypersensitivity management involves darkness therapy, either darkness per se or darkness-mimicking agents. To detect efficiently the best drugs that may be used in the treatment of disorders due to photosensitive magnesium depletion, we are proposing a simple and reproducible actimetry-based test in a murine photosensitive magnesium depletion model. Photostimulation using a stroboscope (100 J, 50 Hz) was performed on magnesium-deficient and control mice. It led to habituation with a decreased activity in response to intermittent light stimulation in control mice, whereas it induced in magnesium-deficient mice both sensitization (or potentiation), with nervous hyperexcitability, and generalization, involving sound hypersensitivity, after visual stimulation. In preclinical evaluation, this test provides a valuable animal model to study the neuroprotective effect of drugs in photosensitive syndromes, which often associate sensitization and generalization to various stimuli.
Chronic primary Mg deficiency is frequent. Around 20% of the population consumes less than two-thirds of the RDA for Mg, in both genders and in women particularly: for example, in France, 23% of women and 18% of men. Primary Mg deficiency may occur in fertile women. Gestational Mg deficiency is able to induce maternal, fetal, and pediatric consequences which might last throughout life. Experimental studies of gestational Mg deficiency show that Mg deficiency during pregnancy may have marked effects on the processes of parturition and of postuterine involution. It may interfere with fetal growth and development from teratogenic effects to morbidity: i.e. hematological effects and disturbances in temperature regulation. Clinical studies on the consequences of maternal primary Mg deficiency in women have been insufficiently investigated. To check the validity of the role of this frequent gestational Mg deficiency, the protocol of a long term multicentric placebo controlled prospective study on the effects of maternal nutritional Mg supplementation on lethality and morbidity in fetus, neonates, infants, children and adults should be carried out not only during pregnancy and the first year of life, but throughout life. Two clinical forms of chronic gestational Mg deficiency in women have been stressed: Premature labor when chronic maternal Mg deficiency is involved in uterine hyperexcitability, Sudden Infant Death Syndrome (SIDS) when it is caused by either simple Mg deficiency or various forms of Mg depletion. Nutritional Mg treatment of premature labor. If gestational Mg deficiency is the only cause for uterine overactivity, nutritional Mg supplementation constitutes the etiopathogenic atoxic tocolytic treatment. But although it is an adjuvant factor in premature labor, it is only a useful accessory treatment, devoid of toxicity but which increases the effectiveness and safety of the associated tocolytic drugs such as beta-2 mimetics. SIDS due to gestational Mg deficit: Mg deficiency or various forms of Mg depletion. SIDS may be caused by the fetal consequences of maternal Mg deficiency through an impaired control of Brown Adipose Tissue (BAT) thermoregulation, mechanisms leading to a modified temperature set point. SIDS may result from dysthermias: hypo- or hyperthermic forms. A possible prevention could rest on simple maternal nutritional Mg supplementation. Various stresses in pregnant women or in the infant may transform a simple Mg deficiency into Mg depletion: stress in baby care such as bedding in prone position, environmental factors such as parental smoking, but the role of chronopathological stress particularly appears to be too often neglected as it constitutes a clinical form of primary hypofunction of the biological clock [with its anatomical and clinical stigma such as reduced production of melatonin (MT) and of its urinary metabolite: 6 Sulfatoxy-Melatonin (6 SMT)]. SIDS might be linked to an impaired maturation of both the photoneuroendocrine system and BAT. A preventive treatment of this form of SIDS should associate atoxic nutritional Mg therapy for pregnant women with total light deprivation at night for the infant. The place of Mg therapy for the infant and of MT, L Tryptophan and taurine is uncertain for the moment.
Chronic primary Mg deficiency is frequent. About 20% of the population consumes less than two-thirds of the RDA for Mg. Women, particularly, have low intakes. For example, in France, 23% of women and 18% of men have inadequate intakes. Mg deficiency during pregnancy can induce maternal, fetal, and pediatric consequences that might last throughout life. Studies of gestational Mg deficiency in animals show that Mg deficiency may have marked effects on parturition and postuterine involution. It has interfered with fetal growth and development, and caused morbidity from hematological effects and disturbances in temperature regulation, to teratogenic effects. Emphasis, here, is on effects of chronic clinical gestational Mg deficiency as it affects the infant. Premature labor, contributed to by uterine hyperexcitability caused by chronic maternal Mg deficiency, that can be intensified by stress, gives rise to preterm birth. If the only cause of uterine overactivity is Mg deficiency, its supplementation constitutes nontoxic tocolytic treatment, as an adjuvant treatment, that is devoid of toxicity and enhances efficacy and safety of tocolytic drugs such as beta-2 mimetics. Evidence is considered that Mg deficiency or Mg depletion can contribute to the Sudden Infant Death Syndrome (SIDS). SIDS may be a fetal consequence of maternal Mg deficiency through impaired control of Brown Adipose Tissue (BAT) thermoregulation mechanisms leading to a modified temperature set point. SIDS can result from dysthermias: hypo- or hyperthermic forms. Possibly, simple nutritional Mg supplements might be preventive. Various stresses in an infant can transform simple Mg deficiency into Mg depletion. For example, lying prone can be stressful for the baby, as can parental smoking. The role of chronopathological stress appears to be often neglected, as it constitutes a clinical form of primary hypofunction of the biological clock [with its anatomical and clinical stigma such as reduced production of melatonin (MT) and of its urinary metabolite: 6 Sulfatoxy-Melatonin (6 SMT)]. SIDS might be linked to impaired maturation of both the photoneuroendocrine system and BAT. Prophylaxis of this form of SIDS should include atoxic nutritional Mg therapy for pregnant women with total light deprivation at night for the infant. Consequences of maternal primary Mg deficiency have been inadequately studied. To determine ultimate outcomes of gestational Mg deficiency in infants, a long-term multicenter placebo-controlled prospective study should undertaken on effects of maternal nutritional Mg supplementation on lethality/morbidity in fetus, neonates, infants, children and adults, not only during pregnancy and the baby's first year, but throughout life.
Mg depletion is a type of Mg deficit due to a dysregulation of the Mg status. It cannot be corrected through nutritional supplementation only, but requires the most specific correction of the dysregulating mechanism. Among those, Biological Clock (BC) dysrhythmias are to be considered. The aim of this study is to analyze the clinical forms of Mg depletion with hypofunction of the Biological Clock (hBC). hBC may be due to either Primary disorders of BC [Suprachiasmatic Nuclei (SCN) and pineal gland (PG)] or Secondary with homeostatic response [reactive Photophobia (Pphi] to light neurostimulating effects [Nervous Hyper Excitability (NHE)]. The symptomatology is mainly diurnal and observed during fair weather (Spring,Summer). The elective marker of hBC is represented by a decrease in melatonin and in its metabolites in various fluids. The clinical forms of NHE due to Mg depletion with hBC are central and peripheral. The central forms associate anxiety, headaches and dyssomnia. The peripheral manifestations are neuromuscular: photosensitive epilepsia mainly. Three chronopathological forms of Mg depletion with hBC have been highlighted: 1. Headaches with Pphi: mainly migraine; 2. Sudden Infant Death Syndrome (SIDS); 3. Multiple Sclerosis (MS).- Headaches with Pphi, migraine particularly. These cephalalgias are diurnal with Pphi and are aggravated during the fair seasons (particularly during midnight sun-summer). Migraine is their typical form with its dishabituation to visual stimuli and its occipital cortex hyperexcitability. Comorbidity with anxiety is frequent. In 2/3 of the cases, it appears first.- SIDS might be linked to an impaired maturation of both photoendocrine system and brown adipose tissue. MS may be associated with primary disorders of BC Clinical forms of Mg depletion with hBC in MS present diurnal exacerbations and relapses during fair seasons. They have been underestimated because they disagree with the dogma of the < latitude gradient >, presently questioned. Comorbidities with anxiety and migraine are frequent.hBC may be treated by using darkness therapy with a balanced Mg status. Absolute light deprivation should only be used only in acute indications and is time-limited. Partial substitutive therapy and chromatotherapy have not been validated yet and are still uncertain.
Asthma is a chronic, inflammatory disorder of the airways leading to airflow limitation. Its worldwide rise, mainly in developed countries, is a matter of concern. Nocturnal asthma (NA) frequently occurs and concerns two thirds of asthmatics. But, it remains controversial whether NA is a distinct entity or is a manifestation of more severe asthma. Generally, it is considered as an exacerbation of the underlying pathology. The pathological mechanisms most likely involve endogenous circadian rhythms with pathological consequences on both respiratory inflammation and hyperresponsiveness. A decrease in blood and tissue magnesium levels is frequently reported in asthma and often testifies to a true magnesium depletion. The link with magnesium status and chronobiology are well established. The quality of magnesium status directly influences the Biological Clock (BC) function, represented by the suprachiasmatic nuclei and the pineal gland. Conversely, BC dysrythmias influence the magnesium status. Two types of magnesium deficits must be clearly distinguished: deficiency corresponding to an insufficient intake which can be corrected through mere nutritional Mg supplementation and depletion due to a dysregulation of the magnesium status which cannot be corrected through nutritional supplementation only, but requires the more or less specific correction of the dysregulation mechanisms. Both in clinical and in animal experiments, the dysregulation mechanisms of magnesium depletion associate a reduced magnesium intake with various types of stress including biological clock dysrhythmias. The differenciation between Mg depletion forms with hyperfunction of BC (HBC) and forms with hypofunction of BC (hBC) is seminal and the main biological marker is melatonin (MT) production alteration. We hypothesize that magnesium depletion with HBC or hBC may be involved in chronopathological forms of asthma. Nocturnal asthma would be linked to HBC, represented by an increase in MT levels. The corresponding clinical forms associate diverse expressions of nervous hypoexcitability such as depression, cluster headaches, dyssomnia, mainly advanced sleep phase syndrome, some clinical forms of chronic fatigue syndrome and of fibromyalgia. The main comorbidities are depression and/or asthenia. They take place during the night or the "bad" seasons (autumn and winter) when sunshine is at a minimum. The corresponding chronopathological therapy relies on bright light phototherapy sometimes with additional psychoanaleptics. Conversely, asthma forms linked to hBC are less frequently studied as a whole and present a decrease in MT levels. They associate various signs of nervous hyperexcitability such as anxiety, diurnal cephalalgia (mainly migraine), dyssomnia, mainly delayed sleep phase syndrome, and some clinical forms of chronic fatigue syndrome and of fibromyalgia. The treatment relies on diverse forms of "darkness therapy", possibly with the help of some psycholeptics. Finally, the treatment of asthma involves the maintenance of a standard dosing schedule of anti-asthma drugs, a balanced magnesium intake and the appropriate treatment of the chronopathological disorders.
Clinical and paraclinical data (visual stress tests, electroencephalographic and cerebrovascular photic driving, visual evoked potentials) demonstrate that the concept of photosensitive headache is fully justified. The interictal hallmark of photosensitive cephalalgic patients is potentiation (or sensitization) instead of habituation. The aetiopathogenic mechanisms of photosensitive headache associate hypofunction of the biological clock and magnesium depletion. The new concept of headache due to photosensitive magnesium depletion seems justified. It appears logical to add the treatments of magnesium depletion and of photosensitivity to classical treatment of headache. Prophylactic magnesium treatment relies on atoxic nutritional magnesium supplementation in case of primary magnesium deficiency. Pharmacological doses of parenteral magnesium may be used but may induce toxicity. Therefore it is necessary to know the therapeutic index of magnesium compound used: the larger its value, the greater the safety margin. Treatment of photosensitivity uses various types of : darkness therapy through physiologic, psychotherapic, physiotherapic, pharmacologic stimulating techniques and substitutive darkness therapy through palliative treatment. Melatonin is only a partial substitutive treatment of photosensitivity. A new model of photosensitive magnesium depletion with potentiation should be a useful tool for discriminating the most efficient gent.
Stress and anxiety of university science students (Chemistry) was evaluated in basal conditions and during exams using validated stress and anxiety questionnaires. The relations between the data obtained and various biochemical markers were established. Results showed that the evaluated students did not experience stress increase as a consequence of exams but suffered a significant increase in anxiety. The psychological findings agree with the urinary biomarkers studied. It is known that anxiety is related to partial magnesium reduction associated with a urinary magnesium excretion increase, as observed in the present data. Nevertheless, stress also correlates with a urinary calcium increase which was not detected in the present study.
It has been postulated that Mg depletion is associated with decreased melatonin. Exogenous magnesium (Mg) has been found to increase the activity of serotonin N-acetyltransferase, an enzyme in the pathway for melatonin synthesis; but no data have been found on the effect of Mg deficiency on plasma melatonin. This pilot study examined the effect of a dietary Mg deficiency on plasma melatonin in male, Sprague-Dawley rats. Weanling rats were placed on a Mg-deficient (150 ppm) or a Mg-adequate (1000 ppm) diets for four weeks, after which they were sacrificed 4, 5 or 7 hours into the dark cycle. Plasma was assayed for melatonin concentrations. A significant decrease (p = 0.0101) occurred in mean (+/- SEM) plasma melatonin levels of the Mg-deficient animals (50 +/- 6.4 pg/mL) when compared to the Mg-adequate animals (75 +/- 6.6 pg/mL). There was no obvious phase shift in the melatonin profile of the Mg-deficient animals when compared to the Mg-adequate animals.
Magnesium deficiency has been implicated as a possible contributing factor to some symptoms of premenstrual syndrome (PMS) and several studies have reported a lower intracellular magnesium concentration in women with PMS. Thus, it has been suggested that magnesium supplementation may improve certain symptoms in women with PMS.
This open-label study assessed the efficacy and safety of a patented modified-release magnesium 250 mg tablet for improving symptoms in women affected by PMS.
After a 3-month observational period, women aged 18-45 years with a regular menstrual cycle (from 25-35 days) who were affected by PMS (determined by a score of > or =25 points on a PMS questionnaire) [n = 41] were given the modified-release magnesium tablet over three menstrual cycles, beginning 20 days after the start of their last menstrual period and continuing until the start of their next menstrual period.
PMS symptoms improved during magnesium treatment. After 3 months, the mean total PMS score (primary endpoint), as assessed by the investigator using Moos' Modified Menstrual Distress Questionnaire, was significantly lower than before therapy (p < 0.0001). During the same period, the mean PMS scores, as recorded in patients' diaries (secondary efficacy variables), also showed significant improvements (p < 0.0001 for all subscales). The relative decreases in total PMS scores, as assessed by investigator and patient, were 35.1% and 33.5%, respectively. The magnesium tablet was well tolerated, with vertigo the only treatment-related adverse event reported (one patient).
We concluded that modified-release magnesium was effective in reducing premenstrual symptoms in women with PMS in this preliminary study.
Chronic fatigue syndrome (CFS) is characterized by profound, debilitating fatigue and a combination of several other symptoms resulting in substantial reduction in occupational, personal, social, and educational status. CFS is often misdiagnosed as depression. The objective of this study was to evaluate and discuss different etiologies, approaches, and management strategies of CFS and to present ways to differentiate it from the fatigue symptom of depression.
A MEDLINE search was conducted to identify existing information about CFS and depression using the headings chronic fatigue syndrome AND depression. The alternative terms major depressive disorder and mood disorder were also searched in conjunction with the term chronic fatigue syndrome. Additionally, MEDLINE was searched using the term chronic fatigue. All searches were limited to articles published within the last 10 years, in English. A total of 302 articles were identified by these searches. Also, the term chronic fatigue syndrome was searched by itself. This search was limited to articles published within the last 5 years, in English, and resulted in an additional 460 articles. Additional publications were identified by manually searching the reference lists of the articles from both searches.
CFS definitions, etiologies, differential diagnoses (especially depression) and management strategies were extracted, reviewed, and summarized to meet the objectives of this article.
CFS is underdiagnosed in more than 80% of the people who have it; at the same time, it is often misdiagnosed as depression. Genetic, immunologic, infectious, metabolic, and neurologic etiologies were suggested to explain CFS. A biopsychosocial model was suggested for evaluating, managing, and differentiating CFS from depression.
Evaluating and managing chronic fatigue is a challenging situation for physicians, as it is a challenging and difficult condition for patients. A biopsychosocial approach in the evaluation and management is recommended. More studies about CFS manifestations, evaluation, and management are needed.
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