Anna Serefko1, Aleksandra Szopa1, Piotr WlaŸ2, Gabriel Nowak3,4,Maria Radziwoñ-Zaleska5, Micha³ Skalski5, Ewa Poleszak1
Chair and Department of Applied Pharmacy, Medical University of Lublin, ChodŸki 1, PL 20-093 Lublin, Poland Department of Animal Physiology, Faculty of Biology and Biotechnology, Maria Curie-Sk³odowska University,Akademicka 19, PL 20-033 Lublin, Poland
!Department of Neurobiology, Institute of Pharmacology, Polish Academy of Science, Smêtna 12,PL 31-343 Kraków, Poland
"Department of Cytobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland#Department of Psychiatry, Medical University of Warsaw, Nowowiejska 27, PL 00-665 Warszawa, Poland
Correspondence: Ewa Poleszak, e-mail: [email protected] and Micha³ Skalski, Abstract: Magnesium is one of the most essential mineral in the human body, connected with brain biochemistry and the fluidity of neuronal membrane. A variety of neuromuscular and psychiatric symptoms, including different types of depression, was observed in magne- sium deficiency. Plasma/serum magnesium levels do not seem to be the appropriate indicators of depressive disorders, since ambigu- ous outcomes, depending on the study, were obtained. The emergence of a new approach to magnesium compounds in medical practice has been seen. Apart from being administered as components of dietary supplements, they are also perceived as the effective agents in treatment of migraine, alcoholism, asthma, heart diseases, arrhythmias, renal calcium stones, premenstrual tension syn- drome etc. Magnesium preparations have an essential place in homeopathy as a remedy for a range of mental health problems. Mechanisms of antidepressant action of magnesium are not fully understood yet. Most probably, magnesium influences several sys- tems associated with development of depression. The first information on the beneficial effect of magnesium sulfate given hypoder- mically to patients with agitated depression was published almost 100 years ago. Numerous pre-clinical and clinical studies confirmed the initial observations as well as demonstrated the beneficial safety profile of magnesium supplementation. Thus, mag- nesium preparations seem to be a valuable addition to the pharmacological armamentarium for management of depression. Key words: magnesium, depression, antidepressant-like effect, antidepressant therapy Introduction
is localized in bones while the rest is found in soft tis-sues and plasma/serum . According to literature
Magnesium, one of the most essential minerals in the
[20, 64] magnesium is widely connected with brain
human body, a co-factor of many enzymatic reactions
biochemistry as well as the fluidity of neuronal mem-
[43, 54], is known to be involved in proper function-
brane. Thus, a variety of neuromuscular and psychiat-
ing of cardiovascular, alimentary, endocrine and os-
ric symptoms (i.e., hyperexcitability, agitation, tetany,
teoarticular systems. An adult contains about 24
headaches, seizures, ataxia, vertigo, muscular weak-
grams of magnesium, of which more than 50 percent
ness, tremors, irritability, anxiety, insomnia, nervous
Pharmacological Reports, 2013, 65, 547554
fits, lipothymias, fatigue, confusion, hallucinations,
erythrocyte magnesium concentration and the clinical
depression) was observed in magnesium deficiency.
progress of this disorder was also noted [60, 89]. In
All of them were reversible by restoration of normal
contrast, Nechifor et al.  showed a decrease of
brain magnesium level [66, 84]. Experimentally in-
erythrocyte magnesium in patients with severe and
duced magnesium deficiency resulted in depression-
medium major depression. Magnesium decrease was
like behavior in rodents [57, 78, 80, 88], which was
positively correlated with the severity of clinical
effectively managed by antidepressants [78, 88].
symptoms measured by Hamilton scale. The same
The diet of depressed people appears to be impov-
author  observed lower erythrocyte magnesium
erished in magnesium . Jacka et al.  found an
level (versus the control group) in adult patients with
inverse relationship between magnesium intake and
major depression who had received antidepressant
depressive symptoms in community-dwelling adults.
therapy before hospital admittance. On the other
However, the authors wonder if the poor quality of
hand, antidepressant therapy with amitriptyline or ser-
depressives’ diet was a causative factor or a conse-
traline increased concentration of erythrocyte magne-
quence of their mental disorder. Apart from malnutri-
sium level . Data of another trial showed that sig-
tion, low magnesium level in the body may occur due
nificantly lower erythrocyte magnesium level in
to defects in its absorption or as a result of its renal
patients with major depression was associated with
loss (for example in case of diabetes, alcoholism,
diminished magnesium plasmatic level as well as
treatment with antidiuretics, aminoglycosides, fluoro-
increased plasmatic concentration of copper .
quinolones, cisplatin, digoxin, cyclosporine, ampho-
A positive correlation between serum level of magne-
tericin B) . Acute emotional stress and stressful
sium and thyroid hormone T4  along with the in-
activities increase magnesium excretion as well .
volvement of an imbalance in the serum magne-
It has also been proposed that the transfer of large
sium/copper ratio have been found in depressed
amounts of this element from mother’s blood to fetus
patients . Opposing results were obtained by
with other nutrients may contribute to occurrence of
Hasey et al. , who noticed an inverse correlation
postpartum depression . Some authors try to asso-
between serum magnesium concentration and T3 and
ciate a long-term insufficient intake of magnesium
T4 levels. No relationship was demonstrated between
with development of systemic inflammation, which in
zinc and magnesium or/and copper concentrations or
turn is likely to aggravate the symptoms of depression
[23, 49, 50, 67, 86]. Major and suicidal depression
Plasma/serum magnesium levels do not seem to be
particularly seems to be related with magnesium in-
appropriate indicators of depressive disorders, since
sufficiency. Literature data indicate that cerebrospinal
ambiguous outcomes, depending on the study, were
fluid magnesium concentration was low in patients
obtained. There are several reports on higher concen-
with history of suicidal behavior [4, 5] while serum
tration of magnesium in depressed patients [8, 37, 48]
and cerebrospinal fluid calcium to magnesium ratios
and more than a few on the lower magnesium level [6,
were usually elevated in acutely depressed individuals
38, 75, 96]; some authors claim that there is no differ-
when compared to the healthy subjects . As pointed
ence in the serum/plasma concentrations of magne-
out by Eby and Eby , this connection is not so obvi-
sium ion or calcium/magnesium ratios between the af-
ous for “melancholy”, depression developed as a re-
fected subjects and the control group [46, 93]. Levine
sult of hormonal imbalance, low cholesterol, food al-
et al.  compiled data from multiple researches on
lergy, Wilson’s disease and other ailments or depres-
plasma/serum levels of magnesium and calcium in de-
sion being an adverse reaction to drugs.
pressives. Similar non-consistency of results wasnoted in relation to magnesium plasma/serum levelsafter initiation of antidepressant drug therapy – Frizelet al.  showed a significant increase of magne-
Magnesium levels in depression
sium concentration while Naylor et al.  found nodifferences. Most probably, all these divergences oc-
There is evidence of rise in erythrocyte magnesium
curred because of the influence of distinct factors and
levels in severely and moderately depressed people
methodology of clinical trials on the obtained results
versus the slightly depressed ones and healthy indi-
[46, 60]. One of them might have been the imple-
viduals [28, 89–91]. Positive correlation between
mented therapy – for example, some studies demon-
Pharmacological Reports, 2013, 65, 547554
Magnesium in depression
strated that neuroleptics [2, 40], antidepressants [5,
dietary supplements but also they are perceived as the
90] and lithium treatments promote alterations in
effective agents in treatment of migraine, alcoholism,
plasma/serum levels of magnesium . These diver-
asthma, heart diseases, arrhythmias, renal calcium
gent results have made recognition of depression as
stones, premenstrual tension syndrome and many
being caused by magnesium deficiency nearly impos-
others [3, 17, 19, 27, 44, 52, 77, 94, 95]. The role of
sible to the clinician and have very greatly retarded
magnesium preparations in management of a range of
research. Eby et al.  suggested that tissue magne-
mental disorders as well as emotional problems [20,
sium level is a much better indicator than magnesium
55] cannot be neglected. For many decades magne-
plasma/serum concentration. Iosifescu et al.  and
sium has had its essential place in homeopathy as
Nowak et al.  reported the link between reduced
a remedy for a range of mental health problems,
content of magnesium in brain and depression. Phos-
including depression . Promising preclinical and
phorus magnetic resonance spectroscopy seems to be
clinical reports support therapeutic potential of
currently the best tool for in vivo assessing magne-
diverse magnesium compositions in different kind of
sium level in the human brain . It has a potential
depression (Tab. 1). Antidepressant activity of mag-
to become a reliable method that could help in diag-
nesium was observed after both short-term and
nosis of different pathological conditions associated
chronic administration [69, 81, 82].
with low brain magnesium, e.g., major depression
Mode of action of antidepressant-like effect of
magnesium is not fully understood yet . There isstrong evidence that magnesium influences severalsystems associated with development of depression. This cation is known to modulate the activity ofNMDA and GABA receptors, play an important role
Mechanism of antidepressant action
in suppression of hippocampal kindling and release ofadrenocorticotropic hormone and interact with the
The emergence of a new approach to magnesium
limbic-hypothalamus-pituitary-adrenal (HPA) axis,
compounds in medical practice has been seen. Not
frequently dysregulated in depressives . Besides,
only are they administered as components of ordinary
it probably affects access of corticosteroids to the
Tab. 1. Preclinical and clinical reports supporting the involvement of magnesium in treatment of depression Magnesium deficiency and depression-like behavior in rodents
Antidepressant activity of magnesium
after short-term and chronic administration
in post-traumatic depression (decreased incidence and severity)
Effect of joint administration of magnesium and other agents
enhancement of the antidepressant-like activity of magnesium by NMDA antagonists
inhibition of the antidepressant-like activity of magnesium by NMDA agonists
synergistic antidepressant-like effect of magnesium and fluoxetine, imipramine, citalopram, tianeptine, bupropion
Efficacy of magnesium treatment/supplementation
in reducing depressive symptoms in chronic fatigue syndrome
in reducing depressive symptoms in women with premenstrual syndrome
in elderly depressives with hypomagnesaemia and type 2 diabetes
Pharmacological Reports, 2013, 65, 547554
brain via influence on P-glycoprotein, participates in
ago . Administration of magnesium sulfate to rats
inactivation of protein kinase C neurotransmission
subjected to traumatic brain injury significantly de-
and stimulates activity of Na+/K+ATPase [1, 31, 35,
creased both incidence of post-traumatic depression
55, 76, 92]. Depletion of magnesium, a physiological
and its severity . Decollogne et al.  and
voltage-dependent blocker of NMDA receptor ion
Poleszak et al. [69, 72–74] observed that the immobil-
channel, allows calcium and sodium ions to enter the
ity time in forced swimming test in mouse and rat
postsynaptic neuron and to exit potassium ions [21,
models was significantly reduced by magnesium ions.
51, 53]. Increased influx of calcium ions leads to pro-
The obtained results were comparable to those re-
duction of toxic reactive oxygen species and toxic
corded for imipramine and MK-801 . Moreover,
amount of nitric oxide radicals as well as neuronal
the ineffective doses of NMDA antagonists (MK-801,
swelling and neuronal death [9, 21, 51]. Neuronal
CGP 37849, L-701,324, D-cycloserine) given jointly
dysfunction and depression as a consequence of an
with a low and also subactive dose of magnesium hy-
excessive leak of calcium into cells triggering the syn-
droaspartate shortened the immobility time in the FST
aptic release of glutamate, depolarization of neurons
. On the other hand, the agonists of different bind-
and further increase of calcium ions is also observed
ing sites of the NMDA receptor complex (i.e., NMDA
in ATP insufficiency in neurons. Magnesium ions are
and D-serine) abolished the magnesium-induced
known to take part in a proper formation and utilisa-
antidepressant-like effect [70, 71]. Co-treatment of
tion of ATP [12, 21]. Some authors confirmed that the
magnesium salts and antidepressants from different
shortage of magnesium ions along with the excess of
classes (i.e., fluoxetine, imipramine and bupropion)
calcium ions and glutamate are the cause of brain cell
results in the synergistic antidepressant-like effect,
synaptic dysfunction leading to mood and behavioral
measured by the standard broadly accepted FST, used
disorders, including depression . Although the an-
in behavioral experiments [10, 74]. Similar outcomes
tidepressant activity of magnesium is predominantly
were also observed by Poleszak  for combination
attributed to the blockade of NMDA receptor [14, 63],
of magnesium ions and citalopram or tianeptine.
animal studies performed by Carsodo et al.  con-
Depression-like behavioral disturbances induced in
firmed that various receptors from several other sys-
rats by magnesium-deficient diet were reversed by
tems: serotonergic (5 HT1A-, 5 HT2A/2C-receptors),
treatment with Mg L-aspartate and magnesium chlo-
noradrenergic (a1-, a2-receptors) and dopaminergic
ride hexahydrate combined with vitamin B$ .
(D1-, D2-receptors) are relevant, as well. Involvement
Similar results were obtained after joint administra-
of serotoninergic system in anti-depressant action of
tion of magnesium and pyridoxine hydrochloride in
magnesium ions was also demonstrated by Poleszak
experiments carried out in animal model of chronic
 in the forced swimming test (FST) in mice – an
alcoholism . According to Singewald et al. ,
anti-immobility activity of magnesium was dimin-
chronic oral administration of desipramine or hype-
ished by pre-treatment with p-chlorophenylalanine, an
ricum extract as an addition to a 21-day magnesium-
inhibitor of serotonin synthesis. Since it was shown
deficient diet prevents development of depression-
that 15 mg/kg of magnesium moderately stimulates
like behavior disturbances. In experiments performed
the reward system in rats , there are some suppo-
by Nikseresht et al.  on female mice, a single joint
sitions that the brain reward system may contribute to
administration of zinc, magnesium and vitamin B
the antidepressant effect of magnesium [45, 60]. Sup-
3 days after delivery improved depressive behavior.
plementation of magnesium ions prolongs duration of
Co-administration of a high dose of sildenafil cit-
slow wave sleep which is decreased in the course of
rate (20 mg/kg) with magnesium hydroaspartate thor-
oughly inhibits the antidepressant properties of thelatter . Because of the sedative activity of magne-sium, caution is advised when anesthetic drugs andthis element are given together. Reduction in anes-
Pre-clinical and clinical studies
Eby and Eby  observed the efficacy of magne-
The first information on the beneficial effect of mag-
sium supplementation in patients with postpartum and
nesium sulfate given hypodermically to patients with
major depression. Magnesium treatment also im-
agitated depression was published almost 100 years
proved symptoms of depression in chronic fatigue
Pharmacological Reports, 2013, 65, 547554
Magnesium in depression
syndrome  and in women with premenstrual syn-
topical application of 25% magnesium chloride solu-
drome . Randomized clinical trial performed by
tion to the chest and back was proposed as well [20,
Barragan-Rodriguez et al.  demonstrated that 12-
83], since this route can result in increases in brain
week oral administration of 5% solution of magne-
sium chloride to elderly depressives with hypomagne-
Given that standard antidepressant therapies,
semia and type 2 diabetes exerts therapeutic effect
though varied but with numerous side effects, do not
similar to imipramine 50 mg daily. A recovery within
meet clinical expectations [15, 65] in about 60% of
less than 7 days from major depression after taking
patients , magnesium preparations with their
magnesium glycinate and magnesium taurinate with
overall beneficial safety profile seem to be a valuable
each meal and at bedtime, was reported for several
addition to the pharmacological armamentarium for
cases . However, some authors wonder to what
management of depression. As a prevention strategy,
degree magnesium given alone may decrease the in-
Eby et al.  recommended daily intake of 600 to
tensity of depression symptoms . Depressive
800 mg of magnesium, with the exception of ineffec-
states and paresthesia immediately resolved after in-
travenous administration of magnesium sulfate to 69-year-old woman with Gitelman’s syndrome . References: Magnesium preparations
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547 Review Œ Magnesium in depression.
Anna Serefko, Aleksandra Szopa, Piotr Wla�, Gabriel Nowak, Maria Radziwoñ-Zaleska, Micha³ Skalski, Ewa Poleszak
555 Review Œ Hippocampus, hippocampal sclerosis and epilepsy.
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566 Differential behavioral profile induced by the injection of dipotassium chlorazepate within brain areas that project to the nucleus accumbens septi.
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593 Repeated central administration of selegiline attenuated morphine physical dependence in rat.
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642 Melatonin-induced augmentation of collagen deposition in cultures of fibroblasts and myofibroblasts is blocked by luzindole Œ a melatonin membrane receptors inhibitor.
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666 Long-term inhibition of intestinal lipase by orlistat improves release of gut hormones increasing satiety in obese women.
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Il padre desidera che il ragazzo stia sempre Rifiuta momenti individuali durante le ore di Chiede e ottiene di inviare una consulente di sua fiducia a fare osservazione in classe• Quando L deve svolgere un qualsiasi tipo funzione di attirare l’attenzione e di • Se esibiti durante momenti di inattivitàovvero in momenti in cui l’insegnante non autostimolazione sensoriale e/o di atti
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