Magnesium Research 2008; 21 (2): 97-100 SHORT REPORT

Interactions between magnesium

and psychotropic drugs
Mihai Nechifor
Department of Pharmacology, University of Medicine and Pharmacy “Gr. T. Popa”, Iasi,
Romania
Correspondence: M. Nechifor, Department of Pharmacology, University of Medicine and Pharmacy “Gr. T. Popa”,
16, University Street, Iasi, Romania
<mnechif@yahoo.com>
Copyright © 2017 John Libbey Eurotext. Téléchargé par un utilisateur anonyme le 28/07/2017.

Abstract. Psychotropic drugs (antidepressants, antimanic drugs, antipsychotics,

analgesic opioids, and others) are among the most frequently used medicines.
Between these drugs and magnesium there are pharmacokinetic and pharmacody-
namic interactions. Erythrocyte magnesium is decreased in patients with severe
major depression (MD) vs normal subjects (44 ± 2.7 mg/L in MD group vs 59.1 ± 3.2
mg/L in control group, p < 0.01). Therapy with sertraline, 150 mg/day p.o. -21 days or
with amitryptiline 3 x 25 mg/day p.o. 28 days increases significantly erythrocyte
concentration of magnesium (56.9 ± 5.22 mg/L after sertraline vs 44 ± 2.7 mg/L
before sertraline, p < 0.01). In patients with acute paranoid schizophrenia, erythro-
cyte magnesium concentration is decreased vs healthy subjects. Haloperidol,
8 mg/day, p.o. for 21 days or risperidone, 6 mg/day p.o. for 21 days have increased
significantly erythrocyte magnesium concentration (46.21 ± 3.1 mg/L before halope-
ridol and 54.6 ± 2.7 mg/L after haloperidol, p < 0.05). Antimanic drugs (mood stabili-
zers) as carbamazepine, 600 mg/day, p.o.,4 weeks and sodium valproate, 900 mg/day
p.o., 4 weeks, increased significantly magnesium in patients with bipolar disorder
type I. Increased magnesium status positively correlated with enhancement of the
clinical state. The existent data sustain the idea that an increase of erythrocyte
magnesium is involved in the mechanism of action of some psychotropic drugs.
Magnesium supply decreased the intensity of morphine-induced physical drug
dependence. In heroin addicts, the plasma magnesium concentration is decreased.
Key words: psychotropic drugs, magnesium, major depression, bipolar disorder,
carbamazepine, sertraline, amitriptyline

Psychotropic drugs represent some of the most
important and frequently used drug categories.
There are several psychotropic groups such as: anxi-
olitics, antidepressives, antipsychotics, hypomania-
cals, etc.
Magnesium has complex actions at the central ner-
vous system (CNS) level. Both pharmacodynamic
and pharmacokinetic interactions have been noticed
doi: 10.1684/mrh.2008.0131
both directions. Data available about all these inter-
actions are, on the other hand, non-concordant.
Our research was aimed to determine variations in
magnesium and other bivalent cations in patients
with major depression and the effects of some anti-
depressives on serum and tissue magnesium levels.
Research was performed on a 76 adult patients of
both sexes (primarily women). Pregnant women,

between plasma/tissue magnesium concentration
and psychotropic drug actions. Interactions are in
Presented at the European Meeting on Magnesium, EuroMag,
Paris, May 15-17, 2008.
alcoholics, patients with kidney or liver failure or
those receiving medical drugs containing cations or
diuretics were not included in the study. Depression
severity was determined using the Hamilton rating
scale of depression. Only patients with medium or
severe major depression (MD) were included in the
study (Hamilton score 17 or over). Determinations of

97
 M. NECHIFOR
plasmatic and erythrocyte magnesium and copper,
zinc, iron and manganese levels in plasma were per-
formed before starting antidepressive therapy and
after 28 days of treatment. Some of the patients
received sertraline (Zoloft®, Pfizer, 150 mg/day per
os at least for 28 days) while the other group received
amitriptiline 3 x 25 mg/day per os at least for 28 days.
Our data show that the erythrocyte magnesium
level was significantly decreased in the group with
MD (44 ± 2.7 mg/L in MD group vs 59.1 ± 3.2 mg/L in
control group, p < 0.01). In both sertraline and amit-
ryptiline groups, the erythrocyte magnesium level
increased (57.6 ± 4.5 mg/L in amytryptiline group
and 56.9 ± 5.22 mg/L in sertraline group, p < 0.01 vs
Copyright © 2017 John Libbey Eurotext. Téléchargé par un utilisateur anonyme le 28/07/2017.
before treatment) [1]. The magnesium plasma level
was significantly lower vs. controls only in the severe
MD group (Hamilton score > 23) (17.8 ± 2.2 mg/mL
vs 22.9 ± 1.9 mg/mL in healthy controls, p < 0.05) [1].
Meanwhile, the plasma copper concentration was
found to be significantly increased in MD patients
(0.86 ± 0.05 mg/L vs 0.63 ± 0.01 mg/L in control
group). The zinc plasma level was decreased in the
MD group [2, 3].
Also, we could establish a positive correlation
between an increase in the erythrocyte and plasma
magnesium concentrations and the patient’s clinical
state. No changes in serum calcium concentration
after sertraline or amytryptiline treatment could be
established [4]. Our research showed partially con-
cordant results with these of Schlegel-Zawadzka
et al. [5], who observed a significant increase in zinc
serum levels after amytriptiline therapy in an experi-
mental model of depression in rats. Also, our results
are concordant with Levine et al. [6], who reported a
significant increase in the Ca/Mg ratio in cerebrospi-
nal fluid (CSF) and in serum in patient with MD
before beginning any treatment.
Schizophrenia is considered the most severe psy-
chosis. Our data, referring to intra- and extra-cellular
magnesium concentrations in patients diagnosed
with schizophrenia, are relatively contradictory.
Some authors found increased levels of magnesium
in CSF and serum [7, 8]. We studied serum and eryth-
rocyte magnesium concentrations in a group of 56
adult patients (32 women and 24 men) with paranoid
schizophrenia (DSM IV) admitted with psychiatric
attacks to the clinical psychiatric hospital in Socola
Iaşi (Romania) and who received antipsychotic treat-
ment before hospitalisation. Patients with chronic
renal failure, cardiac failure, chronic ethanol intake,
malabsorption syndromes, and patients treated with
diuretics or magnesium containing drugs were not
included in the study. Plasma and erythrocyte magne-
sium concentrations were determined on admittance
98
and after 30 days of therapy. Patients received, in a
randomised manner, haloperidol 8 mg/day, for
21 days or risperidone (Rispolept®, Janssen Cilag),
6 mg/day for 21 days. Serum and erythrocyte magne-
sium levels were also determined in a group of
healthy people, with the same sex and age distribu-
tion pattern as the studied groups. Previous studies
showed no statistically significant differences
between serum magnesium levels in patients with
schizophrenia vs controls [9, 10]. On the other hand,
there is a significant decrease in magnesium ery-
throcyte levels (59.2 ± 4.1 mg/L in control vs
46.21 ± 3.1 mg/L in schizophrenic patients, p < 0.05).
After 3 weeks of antipsychotic treatment, in both
haloperidol and risperidone treated patients, the
magnesium erythrocyte concentrations expressed a
significant increase (up to 54.6 mg/L in haloperidol
treated patients and up to 52.8 mg/L in the risperidone
treated group, p < 0.05 vs before treatment levels).
Together with a significant increase in magnesium
erythrocyte levels, we also demonstrated a signifi-
cant decrease in serum copper levels in both risperi-
done and haloperidol treated groups (0.8 ± 0.15 mg/L
before treatment vs 0.62 ± 0.08 mg/L after risperi-
done treatment, p < 0.01) [9].
Bipolar disorder (BD) (also called maniac-
depressive psychosis) is included in the group of
affective psychosis. BD is a heterogeneous disease
with many clinical aspects. There is more than one
form of BD. Data existing about changes in plasmatic
and cellular levels of magnesium are contradictory. It
is possible that the heterogeneity of data about mag-
nesium in patients with BD results from studies on
different types of BD.
The number of drugs used in the therapy of this
disease has markedly increased from lithium salts to
new mood stabilizers (such as sodium valproate,
lamotrigine, carbamazepine, etc) [11]. There is a
competition between Li+ and Mg2+ for some intra-
neuronal binding sites [12]. Administration of lithium
salts increases intracellular concentration of magne-
sium. We searched for the influence of carbam-
azepine (600 mg/day per os for 4 weeks) and sodium
valproate (Orfiril®, Desitin Arzneimittel GmbH; 900
mg/day per os for 4 weeks) in patients with BD admit-
ted in an acute manic episode, without previous
therapy. Both carbamazepine and sodium valproate
in the above mentioned doses significantly increased
concentrations of intracellular magnesium after 4
weeks (initial Mg concentration 45.01 ± 1.87 mg/L vs
52 ± 0.9 mg/L after sodium valproate, p < 0.05) [13].
Total magnesium concentrations in erythrocytes in
BD patients during the acute episode were signifi-
cantly decreased vs control group (45.01 ± 1.87 mg/L

in BD group vs 59.15 ± 2 mg/L in control group,
p < 0.01) [14]. Increasing intracellular brain levels of
magnesium determines a decreasing glutamate-
induced activation of NMDA receptors and conse-
quently alleviates maniac psychomotor hyperactivity
(figure 1). Because psychotropic drugs with differ-
ent chemical structures and different mechanisms of
action increase magnesium concentrations in the
erythrocytes of BP patients, we consider this
increase an important element in mechanism of
action of mood stabilizers in BD.
There are interactions between magnesium and
opiate analgesics. We searched for the influence of
magnesium in morphine-induced experimental drug
Copyright © 2017 John Libbey Eurotext. Téléchargé par un utilisateur anonyme le 28/07/2017.
dependence in rat. We administrated morphine for
11 days in a group of rats in progressively increased
doses (5 mg/kg/day s.c. on the first day to
90 mg/kg/day s.c. on the eleven day). A second group
received morphine (as the first group) and magne-
sium acexamate (MgAcx) 0.5 mEq/kg i.p. daily, 1 h
before the morphine for 11 days. Withdrawal
syndromes were induced after the 11th day with
Lithium salts Carbamazepine
INCREASE+
+
Mg2+
Figure 1. Drugs - Mg2+ relations in psychoses (+ stimulating effect) (from [10]).
MAGNESIUM AND PSYCHOTROPIC DRUGS
naloxone (1 mg/kg i.p.) and symptoms were fol-
lowed. Our results [15] show a significant decrease in
the intensity of withdrawal syndromes (especially
grooming, locomotor activity, aggressive postures)
in the group that received magnesium during
morphine-induced dependence. We consider that
this indicates that magnesium decreased the inten-
sity of morphine-induced dependence. It is not a
direct action of magnesium during the withdrawal
syndrome, magnesium intake ceasing before the
naloxon administration. Our results correlate with
data showing that the plasmatic level of magnesium
is decreased in heroin addicted patients [16, 17]. We
consider that magnesium may modulate the intensity
of psychotropic drug -induced dependence.
We consider that magnesium-psychotropic drug
interactions play an important role in the pharmaco-
dynamic effects of this group of drugs, although the
proven number of psychotropic drugs that influence
plasmatic and intracellular magnesium level is rela-
tively limited. This effect might play a role in their
therapeutic effect.
Sodium
valproate
+
Partially block the
Ca2+ channel
coupled with
NMDA receptor
99
 M. NECHIFOR
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