Download Magnesium and depression

Magnesium Research 2016; 29 (3): 112-9
REVIEW
Magnesium and depression*
Anna Serefko, Aleksandra Szopa, Ewa Poleszak
Chair and Department of Applied Pharmacy, Medical University of Lublin, Chodźki 1,
PL 20-093 Lublin, Poland
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Correspondence: Anna Serefko, Chair and Department of Applied Pharmacy, Medical University of Lublin,
Chodźki 1, PL 20-093 Lublin, Poland
<[email protected]>
Abstract. Magnesium is one of the most important elements in the human
body and is involved in a number of biochemical processes crucial for the proper
functioning of the cardiovascular, alimentary, endocrine, and osteoarticular systems. It also plays a vital modulatory role in brain biochemistry, influencing
several neurotransmission pathways associated with the development of depression. Personality changes, including apathy, depression, agitation, confusion,
anxiety, and delirium are observed when there is a deficiency of this element.
Rodents receiving a diet deficient in magnesium displayed depressive behaviour
that was reversed by antidepressant drugs. Poor nutrition, gastrointestinal and
renal diseases, insulin resistance and/or type 2 diabetes, alcoholism, stress, and
certain medications may lead to magnesium deficiency. Since the extracellular concentration of magnesium ions may not reflect their intracellular level,
none of the current methods of evaluating magnesium status is regarded as satisfactory. The mood-improving potential of magnesium compounds have been
confirmed by the results of numerous pre-clinical and clinical studies. It seems
that magnesium supplementation is well-tolerated and enhances the efficacy
of conventional antidepressant treatments, and as such could be a valuable
addition to the standard treatments for depression, although differences in
bioavailability between inorganic and organic compounds should be taken into
consideration.
Key words: magnesium, depression, antidepressant therapy
∗
Presented at The XIV International Magnesium Symposium, Magnesium and Health, Rome, Italy, June
23-24, 2016.
acid (RNA), and glutathione, generation and
utilisation of adenosine triphosphate (ATP), neuromuscular transmission, bone mineralisation,
blood glucose control, and regulation of blood pressure. Magnesium metabolism is closely related to
that of calcium and potassium, since it is required
for the active transport of their ions through cell
membranes. In addition, magnesium plays a vital
modulatory role in the central nervous system
(CNS) [1].
Magnesium homeostasis depends on magnesium intake and its secretion via urine and
faeces. The Recommended Daily Allowance (RDA)
of magnesium ranges between 310 and 420 mg,
depending on age and sex [2]. Nuts, sunflower
seeds, green leafy vegetables, and whole grains
are all abundant sources of this element. Magnesium absorption via both facilitated transport and
passive diffusion mostly takes place in the small
112
To cite this article: Serefko A, Szopa A, Poleszak E. Magnesium and depression. Magnes Res 2016; 29(3): 112-9
doi:10.1684/mrh.2016.0407
doi:10.1684/mrh.2016.0407
Magnesium is one the most important elements
in the human body. It regulates a number of
biochemical processes and influences the functioning of the majority of organs. The adult
human body contains approximately 24-35 g of
magnesium, which is mainly deposited in bones
(≈ 60%), muscles (≈ 20%) and other soft tissues.
The extracellular fluid contains only 1% of the
total body magnesium. Magnesium is a co-factor
for hundreds of enzymes, it participates in the
cell cycle, metabolism of carbohydrates, proteins,
fats, nucleic acids, and is partially responsible
for cell membrane permeability, cell signalling
and migration, stability of nucleic acids, synthesis of deoxyribonucleic acid (DNA), ribonucleic
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Magnesium and depression
intestine (jejunum); large intestine absorption
is not so significant. Acid conditions, parathormone, insulin, a diet rich in animal protein or
unsaturated fat, sodium, lactose, vitamin B6, and
vitamin D improve absorption of magnesium. On
the other hand, supplementation with very high
doses of zinc (i.e., 142 mg/day) may inhibit magnesium absorption [3].
In the case of a low magnesium intake, the kidneys are able to partially counteract the decrease
in magnesium levels. However, a balanced is
crucial [4]. If not, an insufficient magnesium
concentration in the human body may occur.
Consumption of excessive amount of fat, calcium, phosphates, fibre, coffee, and strong tea
either reduces absorption of magnesium ions from
the alimentary tract or enhances their elimination. There are also several groups of people
at risk of magnesium deficiency, including the
elderly, patients with gastrointestinal or renal
diseases, patients with insulin resistance and/or
type 2 diabetes, alcoholics, individuals treated
with loop and thiazide diuretics, antibiotics, hypnotics, sedatives, psychotropic, or cytostatic drugs,
and those who have used proton pump inhibitors
(esomeprazole, lansoprazole) for a long time. A
long-term crash diet, stress, or oral contraceptives may also lead to magnesium deficiency.
Magnesium requirements increase in pregnancy,
breast-feeding, during periods of intensive growth
and strenuous physical exercise [5-8].
An adequate magnesium level in the human
body is important for the normal functioning
of the CNS. A variety of neuromuscular and
psychiatric symptoms have been observed in
magnesium deficiency, and there are several
pathways by which this ion might contribute
to their development [9]. Alhough higher consumption of magnesium (total intake or with
diet) most probably does not protect against the
occurrence of depressive disorder, a very low
magnesium intake may be a cause of increased
depression risk [10]. Reduced magnesium intake
with an everyday diet resulted in depressionand anxiety-like behaviour in animals [11].
Mice with low magnesium levels displayed more
aggressive behaviour, higher rectal temperature,
and increased brain and urine concentrations of
noradrenalin as compared to animals with a high
magnesium status [12]. There are also reports on
the development of depression in a Norwegian
community population as a consequence of poor
dietary intake of magnesium [13]. Tarleton and
Littenberg [14] found that a relationship between
very low magnesium intake and depression is
particularly evident in the case of younger adults.
Magnesium levels in depressed people
In spite of the fact that there are several
methods for evaluating magnesium status (i.e.,
measurement in blood, plasma/serum, erythrocytes, cerebrospinal fluid, saliva, urine levels),
none of them is regarded as satisfactory. It
should be remembered that the extracellular
concentration of this element may not reflect
its intracellular level. According to literature
data, an adequate magnesium concentration in
serum is 0.62-1.02 mmol/L [15] and when serum
magnesium levels drop below 0.75 mmol/L, hypomagnesaemia is diagnosed [16]. Cerebrospinal
fluid (CSF) magnesium levels are higher than
those observed in plasma (i.e., 1.2 mmol/L) [17].
As anticipated, studies on magnesium levels in
serum/plasma and the CSF of depressed patients
have not demonstrated reproducible results. Several authors did not find any differences between
healthy and depressed groups in relation to the
CSF concentration of magnesium [18, 19]. According to the results from a clinical trial carried out by
Levine et al. [20], the calcium:magnesium ratio in
the CSF of subjects with depression was increased
when compared to controls, although neither the
CSF magnesium level nor its calcium:magnesium
ratio turned out to be indices of depression
severity. On the other hand, Sowa-Kućma et al.
[21] reported an association between a reduced
content of magnesium in brain and depression. An
obvious link between serum/plasma magnesium
levels and the presence of symptoms of depression was demonstrated in quite a few studies
(e.g., [22-25]), although other scientists have not
found similar correlations [26]. Moreover, in some
cases a positive relationship was recorded (i.e.,
depressed patients presented high magnesium
levels) (e.g., [23, 25]), while in others – an inverse
one (i.e., subjects with depression showed lower
magnesium concentrations) (e.g., [27, 28]). A similar discrepancy was observed in studies focused
on correlations between magnesium status and
severity of symptoms of depression. Sometimes,
an association was observed for specific groups
of patients (i.e. with chronic depression) [23] or
was sex-dependent [24, 25]. It should not be
surprising that symptoms, such as depression,
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A. SEREFKO, ET AL.
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occur no matter whether the serum magnesium
level is elevated or within normal ranges, since
magnesium ions can be redistributed between
pools via compensatory mechanisms (blood, tissues, organs). However, Camardese et al. [26]
found that plasma magnesium levels correlated
with a patient’s response to antidepressant treatment. The literature data demonstrated higher
erythrocyte magnesium levels in the depressed
population (e.g., [22, 24, 25]), although this feature was not observed in each trial [29], and may
be influenced by other factors [22, 24]. According
to the outcomes of some studies [20, 30], a higher
serum calcium:magnesium ratio may be associated with both depression and risk of development
of this disease. However, this association was not
observed by Young et al. [31].
Biological pathways involved in the
antidepressant action of magnesium
Literature data have indicated both the contribution of magnesium deficiency to the pathophysiology of mood disorders and the antidepressant/anxiolytic potential of magnesium ions.
Several pathways are responsible for these effects.
Magnesium ions act as natural antagonists of
calcium. They block the NMDA receptor channel in a voltage-dependent manner, preventing
the flow of calcium ions through it. In addition to that, magnesium ions enhance expression
of the GluN2B subunit belonging to the NMDA
receptor complex. Low magnesium levels in the
hippocampus, plus high levels of both calcium
and glutamate, may result in altered functioning of synapses in the human brain that leads to
development of mood disorders, including depression [32]. That the magnesium-induced effects
in the forced swim test (FST) can be reversed
by administration of NMDA receptor agonists
(NMDA or D-serine) supports the involvement of
the glutamatergic system in the mechanism of
action of magnesium [33]. Literature data also
indicate the participation of serotonergic neurotransmission in the antidepressant effect of
magnesium, since p-chlorophenylalanine-induced
serotonergic lesions, as well as 5-HT1A and 5HT2A/C receptor antagonists, reduced its activity
in the forced swim test (FST) [34, 35]. In addition, the research team led by Cardoso et al. [35]
confirmed the involvement of both noradrenergic and dopaminergic systems in the mechanism
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of action of magnesium. Concurrent administration of ␣1-, ␣2-, D1-, or D2-receptor inhibitors
diminished the anti-immobility effects of magnesium in the Porsolt test. Pochwat et al. [36]
suggest a potential relationship between magnesium antidepressant activity and the ␣-amino-3hydroxy-5 methyl-4-isoxazolepropionic acid/brain
derived neurotrophic factor (AMPA/BDNF) pathway. Magnesium potentiates phosphorylation of
the cAMP response element-binding protein
(CREB), increases expression of BDNF in the prefrontal cortex (PFC), and enhances activation of
calcium/calmodulin-dependent protein kinase II
(CaMKII) [32]. Both BDNF and CaMKII expression turned out to be reduced in certain brain
areas of patients suffering from different types of
depression [37]. By influencing CaMKII function,
magnesium ions indirectly increase AMPAergic
activity. Additionally, magnesium interacts with
other factors that are relevant in the pathophysiology of depression: it suppresses hippocampal
kindling, modulates the protein kinase C (PKC)
pathway as well as nitric oxide (NO) release
in the PFC [32]. Based on the available data,
magnesium is a potent inhibitor of the GSK3 enzyme, and affects mechanisms/systems that
play an important role in the stress response
(i.e., limbic-hypothalamus-pituitary-adrenal axis,
release of adrenocorticotropic hormone, benzodiazepine/GABAA receptors). Most probably, it acts
on the access of corticosteroids to the brain via
an influence on P-glycoprotein [38]. It is also
possible that the anti-inflammatory effects of magnesium contribute to its anti-depressant activity,
since systemic inflammation and cell-mediated
immune activation are present in major depression. An inverse relationship between magnesium
intake and systemic inflammation was observed
by King et al. [39]. Pre-clinical studies demonstrated development of sleep disturbances evoked
by inadequate magnesium intake [40]. The same
research team proved magnesium normalises
sleep organisation and related brain bioelectrical activity. Disorders of the sleep/wake cycle are
linked with the pathophysiology of depression.
Antidepressant activity of magnesium
in pre-clinical studies (table 1)
The results of pre-clinical studies have clearly
indicated an antidepressant activity of magnesium that was observed after both acute and
Magnesium and depression
Table 1. Pre-clinical studies confirming the anti-depressant potential of magnesium
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Antidepressant activity of magnesium
• the forced swim test/tail suspension test in rodents (after acute and long-term administration) [41, 42, 44]
• post-traumatic depression [43]
• the chronic mild stress model [36]
• the olfactory bulbectomy model [45]
Effect of concurrent administration of magnesium and other agents with antidepressant potential
• synergistic antidepressant effect with NMDA antagonists [33]
• antagonistic effect with NMDA agonists [33,46]
• synergistic antidepressant effect with conventional treatment [34, 35]
chronic administration, and this effect was accompanied by an increase in serum magnesium levels.
The antidepressant potential of magnesium in the
FST and the tail suspension test (TST) was comparable to that observed for conventional treatment,
and was not influenced by changes in spontaneous locomotor activity of the tested animals
[41, 42]. Administration of magnesium sulphate
was effective in post-traumatic depression/anxiety
in rats [43], whereas Haj-Mirzaian et al. [44]
confirmed the effectiveness of a single injection
of this compound in reversing depression symptoms induced by social isolation in adolescent
mice. The animals spent less time immobile after
placing them in water and presented intensified grooming behaviour in the splash test. The
antidepressant activity of magnesium aspartate
was also demonstrated in the chronic mild stress
(CMS) and olfactory bulbectomy (OB) models in
rats [36, 45]. Animals subjected to chronic treatment presented higher consumption of 1% sucrose
solution, reduced hyperactivity in the open field
test, as well as better outcomes in the passive avoidance test. Together with the improved
results in behavioural tests, normalisation of the
changes in the GluN1 and GluN2A subunits of
the NMDA receptor complex induced by the CMS
was observed. Moreover, chronic administration of
magnesium ions increased levels of the GluN2B
subunit, postsynaptic density protein 95 (PSD-95)
and/or BDNF in different brain areas of animals
subjected to the CMS. Decreased levels of GluN2B,
PSD-95, and BDNF were detected in the hippocampus of suicide victims [21, 37].
The outcomes obtained in our lab [33, 34] confirmed that magnesium potentiates activity of
antidepressant drugs, most probably via modulation of glutamate and serotonergic signalling.
A synergistic effect was observed for combinations of magnesium and fluoxetine, imipramine,
bupropion, citalopram, and tianeptine [34, 35].
Moreover, a significant reduction in immobility
time in the FST after concurrent administration of
sub-effective doses of both magnesium and several
other antagonists of the NMDA receptor complex
(i.e., CGP 37849, D-cycloserine, L- 701,324, MK801) was found [33, 46]. However, a similar effect
was not detected for ifenprodil, i.e., a selective
inhibitor of the GluN2B subunit [47]. No synergistic interaction was observed between magnesium
hydroaspartate and adenosine-receptor antagonists with antidepressant potential (i.e., caffeine)
in the FST in mice [48]. In addition to that, coadministration of a magnesium compound with
a phosphodiesterase type 5 inhibitor (i.e., sildenafil citrate) at a high dose largely reversed the
antidepressant properties of the former [49].
Depressive
behaviours
induced
by
a
magnesium-deficient diet were reversed by
treatment with either magnesium salts (with or
without vitamin B6) or agents with recognised
antidepressant potential (desipramine, hypericum extract) [11]. Nikseresht et al. [50] showed
that a single, concomitant administration of zinc,
magnesium, and vitamin B6 improved depressive
behaviour in female mice.
Antidepressant activity of magnesium
in clinical studies (table 2)
The reports from clinical trials on the antidepressant potential of magnesium compounds are
supportive. Initial data on the beneficial effects
of magnesium sulphate given hypodermically to
patients with agitated depression were available at the beginning of the last century [51].
These observations have been confirmed in later
years. In a pilot study by Chouinard et al.
[52], chronic administration of magnesium aspartate hydrochloride (40 mEq/day) was effective in
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A. SEREFKO, ET AL.
Table 2. Clinical studies confirming the anti-depressant potential of magnesium
Efficacy of magnesium treatment/supplementation
• mood stabilization in bipolar disorder [52]
• depressive symptoms in women with premenstrual syndrome [53, 61]
• depressive symptoms in chronic fatigue syndrome [55]
• depressive/anxiety states that accompany epilepsy [56]
• depressive states and paresthesia that accompany Gitelman’s syndrome [57]
• major depression [58]
• in elderly depressives with hypomagnesaemia and type 2 diabetes [59]
• depression and premenstrual dysphoric disorder [60]
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mood stabilization in 50% of manic-depressive
subjects. Fracchinetti et al. [53] demonstrated
that oral administration of magnesium pyrrolidone carboxylic acid (3 × 360 mg/day for at least
one month) relieved premenstrual mood changes.
However, Walker et al. [54] observed no alleviation
of depressive symptoms during the second month
of treatment, in women with premenstrual syndrome (PMS), who had been given 200 mg/day
of magnesium as magnesium oxide. A poor efficacy of magnesium oxide was also found by de
Souza et al. [61], who supplemented 44 women,
for one menstrual cycle with this compound (200
mg of magnesium/day). The authors noted that
mild, premenstrual anxiety-related syndromes
were slightly reduced by the combination of magnesium oxide with vitamin B6 (50 mg/day), but
the effect of monotherapy with magnesium oxide
was not significant. After six weeks of intramuscular administration of magnesium sulphate (one
injection/week), patients with chronic fatigue syndrome reported improved energy levels, a better
emotional state, and less pain [55]. A 28-day
treatment of epileptic subjects with magnesium
lactate and vitamin B6 (given in additional to
anticonvulsant medications) was beneficial in
terms of the patients’ mental (anxiety/depressive)
state [56]. Enya et al. [57] reported considerable
alleviation of depression symptoms and paresthesia in woman who suffered from Gitelman’s
syndrome, after intravenous administration of
magnesium sulphate. Eby and Eby [58] reported
several cases of patients with major depression
who were successfully treated with magnesium
compounds: 125-300 mg of magnesium (as glycinate and taurinate) was taken with each meal,
and before going to sleep. Basing on the outcomes
obtained by Barragan-Rodriguez et al. [59], 12week treatments with magnesium chloride (450
mg/day) or imipramine (50 mg/day) were comparably effective in newly diagnosed depression in
116
elderly diabetic patients with hypomagnesaemia.
Three-month magnesium supplementation (320
mg/day) reduced certain signs and symptoms
of depression (e.g., depressed mood, guilt feelings, insomnia, psychomotor retardation, anxiety,
somatic gastrointestinal symptoms) in female
patients diagnosed with clinical depression and
premenstrual dysphoric disorder [60].
Preparations of magnesium
There are a plethora of magnesium preparations available in the pharmaceutical and dietary
supplement markets. Bioavailability is the most
important feature that differentiates them. Since
magnesium absorption is poor (only 30-40% of
the consumed amount), the compound used as an
active ingredient is very important. The highly
soluble ones are better absorbed. Magnesium
aspartate, citrate, lactate, and chloride are more
bioavailable than magnesium oxide or sulphate.
When alimentary tracts function properly and the
patient does not suffer from hyper- or hypoacidity,
the organic magnesium compounds (i.e., citrate,
lactate, aspartate) are recommended, as these are
the ones whose chemical structure is more similar to magnesium compounds present in diet.
Addition of vitamin B6 improves magnesium
absorption as well as its transportation and intracellular storage. Moreover, the gastro-resistant or
enteric-coated oral dosage forms are preferred,
since magnesium is mainly absorbed in the lower
parts of the digestive system. The usual daily dose
of magnesium supplementation varies between
200 and 1000 mg, and the best effects are observed
after long-term administration [62, 63]. Oral magnesium preparations seem to be well tolerated and
safe, though some patients (particularly subjects
with an impaired renal function) can experience
Magnesium and depression
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adverse effects, including diarrhoea [1, 2]. The
tolerable upper intake level for supplemental
magnesium was assessed as 350 mg/day [2]. Since
magnesium treatment may reduce absorption
of several other drugs (i.e., digoxin, nitrofurantoin, anti-malarial medications, bisphosphonates), close monitoring of patients with
concomitant diseases is recommended. Moreover,
reduced efficacy of chlorpromazine, penicillamine,
oral anticoagulants, quinolones, and tetracyclines
was reported when co-administrated with preparations of magnesium [64].
Disclosure
Financial support: none. Conflict of interest: none.
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