nutrients

Review
The Effects of Magnesium Supplementation on
Subjective Anxiety and Stress—A Systematic Review
Neil Bernard Boyle *, Clare Lawton and Louise Dye
School of Psychology, University of Leeds, Leeds LS2 9JT, UK; [email protected] (C.L.);
[email protected] (L.D.)
* Correspondence: [email protected]; Tel.: +44-113-343-1403

Received: 31 January 2017; Accepted: 17 April 2017; Published: 26 April 2017

Abstract: Background: Anxiety related conditions are the most common affective disorders present
in the general population with a lifetime prevalence of over 15%. Magnesium (Mg) status is
associated with subjective anxiety, leading to the proposition that Mg supplementation may attenuate
anxiety symptoms. This systematic review examines the available evidence for the efficacy of
Mg supplementation in the alleviation of subjective measures of anxiety and stress. Methods:
A systematic search of interventions with Mg alone or in combination (up to 5 additional ingredients)
was performed in May 2016. Ovid Medline, PsychInfo, Embase, CINAHL and Cochrane databases
were searched using equivalent search terms. A grey literature review of relevant sources was also
undertaken. Results: 18 studies were included in the review. All reviewed studies recruited samples
based upon an existing vulnerability to anxiety: mildly anxious, premenstrual syndrome (PMS),
postpartum status, and hypertension. Four/eight studies in anxious samples, four/seven studies
in PMS samples, and one/two studies in hypertensive samples reported positive effects of Mg on
subjective anxiety outcomes. Mg had no effect on postpartum anxiety. No study administered a
validated measure of subjective stress as an outcome. Conclusions: Existing evidence is suggestive of
a beneficial effect of Mg on subjective anxiety in anxiety vulnerable samples. However, the quality
of the existing evidence is poor. Well-designed randomised controlled trials are required to further
confirm the efficacy of Mg supplementation.

Keywords: magnesium; anxiety; stress; intervention

1. Introduction
Magnesium (Mg) is an essential mineral utilized in the human body, as a cofactor, by in excess
of 300 biochemical reactions required to maintain homeostasis [1]. The biological functions of Mg
are broad and varied, and include the production of nucleic acids, involvement in all adenosine
triphosphate (ATP) fueled reactions, and modulation of any activity mediated by intracellular calcium
concentration fluxes (e.g., insulin release, muscle contraction [2]).
Dietary intake of Mg has been shown to be insufficient in Western populations [3–5]. Sixty-eight
percent of Americans [3] and 72% of middle aged French adults [6] have been shown to consume less
than the recommended levels of dietary Mg. This inadequate intake is linked with an array of poor
health outcomes including hypertension [7], cardiovascular disease [8], and type II diabetes [9].
Depletion and supplementation studies in animals and humans suggest that Mg may play an
important part in the etiology of affective mood disorders. A relationship between Mg and affective
depressive states has been established (for reviews see [10,11]). Magnesium plays a key role in
the activity of psychoneuroendocrine systems and biological and transduction pathways associated
with the pathophysiology of depression. For example, all elements of the limbic–hypothalamus–
pituitary–adrenocortical axis are sensitive to the action of Mg [12]. Magnesium has also been

Nutrients 2017, 9, 429; doi:10.3390/nu9050429 www.mdpi.com/journal/nutrients

Nutrients 2017, 9, 429 2 of 22

demonstrated to suppress hippocampal kindling [13,14], attenuate the release of, and affect adrenocortical
sensitivity to, adrenocorticotrophic hormone (ACTH) [15,16], and may influence the access of
corticosteroids to the brain at the level of the blood brain barrier via its action on p-glycoprotein [17–19].
Experimentally induced hypomagnesemia results in depression like behavior in rodents [20–23]
which is effectively treated by administration of antidepressants [21,23]. An impoverished Mg diet is
associated with depression in humans [24]. Low serum and cerebrospinal fluid Mg levels have also
been associated with depressive symptomology [25] and suicidality [26]. However, further evidence
of a relationship between raised Mg levels and depressive states [27–29] suggests the relationship
between Mg levels and depression is yet to be fully elucidated.
Further support for a relationship between Mg and affective states comes from evidence of
the efficacy of Mg supplementation in the treatment of depression. Magnesium intake reduces
depression-related behaviour in mice [30] and is effective as an adjunctive treatment for depression
in rodent models [31,32]. In humans, 12 weeks intake of 450 mg of elemental Mg has been shown
to be as effective in reducing depression symptoms as a tricyclic antidepressant (Imipramine 50 mg)
in depressed hypomagnesic elderly patients with type II diabetes [33]. Further evidence from
case studies suggests Mg is an effective adjunctive therapy for treating major depression [34,35].
However, the efficacy of Mg in the treatment of depression symptomology has not been consistently
reported [36]. Mood stabilizing effects of Mg supplementation have also been reported in additional
clinical samples, including the improvement of clinical signs of mania [37], rapid cycling bipolar
disorder [38], and alleviation of affective symptoms associated with chronic fatigue syndrome [39].
Depression is often comorbid with anxiety [40]. Anxiety related conditions are the most common
affective disorders present in the general population with a lifetime prevalence of over 15% [41].
The anxiolytic potential of Mg has been demonstrated in rodent models. Naturally and experimentally
induced hypomagnesemia elevates anxiety states in mouse models [12,21,42,43]. Blood plasma
and brain Mg levels are also significantly correlated with anxiety-related behavioral responses in
rodents [44]. Supplementing Mg levels in mice has been demonstrated to reduce the expression of
anxiety-related behavior [30,45].
A relationship between Mg status and anxiety is evident in humans. Test anxiety, related to
exposure to stressful exam conditions, increases urinary Mg excretion, resulting in a partial reduction
of Mg levels [46]. Further, dietary levels of Mg intake have been modestly inversely associated with
subjective anxiety in a large community-based adult sample [24]. Magnesium also modulates activity
of the hypothalamic pituitary adrenal axis (HPAA) which is a central substrate of the stress response
system. Activation of the HPAA instigates adaptive autonomic, neuroendocrine, and behavioral
responses to cope with the demands of the stressor; including increasing anxiety. Exposure to stress
moderates serum (noise stress; [47]) and intracellular (exam stress; [48]) Mg levels. Magnesium
supplementation has also been shown to attenuate the activity of the HPAA, including a reduction
in central (ACTH; [15]) and peripheral (cortisol; [49]) endocrine responses of this system. Therefore,
Mg may further influence anxiety states via the moderation of the stress response.
A number of potential mechanistic pathways have been described which may account for the
relationship between Mg and anxiety. Glutamate is the primary excitatory neurotransmitter in the
mammalian brain. Glutamate acts on Ca2+ channel coupled N-methyl-D-aspartate (NMDA) ionotropic
receptors which have been implicated in anxiety and panic disorders [50]. Magnesium reduces
neuronal hyperexcitability by inhibiting NMDA receptor activity [51]. Magnesium is also essential for
the activity of mGluRs—G-protein coupled receptors that are widely expressed in the brain [52,53].
The mGluRs receptors play a key modulatory role in glutamatergic activity, secretion and presynaptic
release of glutamate, activity of the GABA (γ-aminobutyric acid)ergic system, and regulation of
the neuroendocrine system. The action of glutamate on mGluRs receptors has been implicated in
responses to fear, anxiety and panic [53]. Magnesium may additionally modulate anxiety via increasing
GABAergic availability by decreasing presynaptic glutamate release [54]. GABA is a primary inhibitory
transmitters in the CNS that counterbalances the excitatory action of glutamate. An imbalance between
Nutrients 2017, 9, 429 3 of 22

GABA and glutamate is associated with neuronal hyperexcitability characteristic of pathological

anxiogenesis [55].
Evidence of the association between Mg and anxiety has increased interest in the potential efficacy
of Mg intake to attenuate anxiety symptoms. Prevalent pharmaceutical anxiolytic treatments for clinical
anxiety (e.g., benzodiazepines) are often characterized by multiple negative side-effects for many
patients. Therefore, the identification of new efficacious treatments to alleviate symptoms of anxiety
has great utility. This systematic review summarises the current available evidence for the efficacy of
Mg supplementation in the alleviation of subjective measures of anxiety. Considering the conceptual
and psychoneuroendocrine overlap between anxiety and stress, the review will also examine evidence
for potential effects of Mg intake on parameters of subjective stress. A previous systematic review of
the effects of nutritional and herbal supplements on anxiety and anxiety-related disorders summarised
the findings of three Mg intervention studies [56]. However, this review summarised the literature
prior to 2010 and, since searches were limited to only two databases, likely failed to identify all
relevant publications. Therefore, this is the first systematic review of the relationship between Mg
supplementation and subjective anxiety and stress.

2. Materials and Methods

2.1. Selection of Studies

The research synthesis was limited to intervention studies in human adult samples (≥18 years old.)
that administered a Mg dose in isolation or combined with a maximum of 5 additional ingredients,
and reported an outcome measure of subjective anxiety or stress. This included any general subjective
measure that included subscales related to stress and anxiety symptomology. Intervention studies
examining acute and chronic effects of Mg manipulations were included. Studies examining the effects
of Mg depletion (in the absence of an intervention) or increased consumption of diets associated
with high Mg content were excluded. Studies reporting effects in individuals with significant health
conditions (e.g., cancer, chronic fatigue syndrome) and developmental disorders (e.g., autism) were
excluded. Samples recruited on the basis of mild to moderate subjective anxiety, hypertension, or
subjective symptoms associated with premenstrual syndrome (PMS), were retained. The efficacy of Mg
intake has been examined as a novel and adjunct treatment approach for depression. This literature
has been adequately summarised in a number of previous systematic reviews (e.g., [10,11]). Therefore,
studies reporting the effects of Mg intake in depressed samples are not reviewed here. Publications
were required to be in the English, French or German languages to permit review by authors. Studies
failing to report sufficient detail to permit accurate characterisation of the methodological approach
were also not included in the review. Minimum reporting requirements were sample size and
composition, Mg dose and intervention length, and clearly defined outcome measures of subjective
anxiety or stress.

2.2. Literature Search

To identify relevant studies, computerised database searches were conducted in May 2016
on OVID MEDLINE (inclusive of records 1946–2016 and non-indexed citations, 2016), PsycINFO
(inclusive of records 1806–2016), EMBASE (inclusive of records 1806–2016, CINAHL (inclusive of
records 1960–May 2016), and the databases comprised under EBM REVIEWS (inclusive of records
1991–2016). The following search terms were used: ‘Magnesium$’; OR ‘Epsom’; OR ‘Mg citrate’;
OR ‘Mg oxide’; OR ‘Mg sulphate’; OR ‘Mg lysinate’; OR ‘Mg glycinate’; OR ‘Mg bicarbonate’; OR
‘Mg carbonate’; OR ‘Mg chloride’; OR ‘Mg hydroxide’; ‘Mg phosphate’; OR ‘Mg ascorbate’; OR ‘Mg
aspartate’; OR ‘Mg fumarate’; OR ‘Mg gluconate’; OR ‘Mg glutamate’; OR ‘Mg lactate’; OR ‘Mg
malate’; OR ‘Mg pidolate’; OR ‘Mg orotate’; OR ‘Mg taurate’ AND ‘Stress$’; OR ‘Strain’; OR ‘Tension’;
OR ‘Cortisol’; OR ‘Anxi$’; OR ‘Worry’; OR ‘Mood’. For searches of OVID MEDLINE, PSYCH INFO,
EMBASE the search field (tw—text word) was applied to all search terms. The search field (tx—full
Nutrients 2017, 9, 429 4 of 22

Nutrients 2017, 9, 429 4 of 22

text) was applied for searches of CINAHL and EBM REVIEWS. The additional filter ‘Human’ was
added to database
The all searches where supported.
searches returned atThe reference
total of 6573 lists of existing
articles. reviews
Publication andwere
titles identified articles
reviewed to
were
removehand searched
patently to supplement
irrelevant the electronic
and duplicate papers,searches.
leaving a total of 2094 articles selected for abstract
TheThe
review. database searches
full text returned
versions at total of
of 48 articles 6573retrieved
were articles. and
Publication
examinedtitles
forwere reviewed
eligibility. to remove
A further 34
patently irrelevant and duplicate papers, leaving a total of 2094 articles selected
articles were excluded (reasons for exclusion are shown in Figure 1) leaving 14 studies that met for abstract review.
the
The fullcriteria.
review text versions of 48 articles were retrieved and examined for eligibility. A further 34 articles were
excluded (reasons for exclusion are shown in Figure 1) leaving 14 studies that met the review criteria.

Figure 1.
Figure Electronic database
1. Electronic database study
study selection
selection summary.
summary.

A grey
greyliterature
literaturesearch
searchwaswas
alsoalso undertaken
undertaken (September,
(September 2016) 2016) usingliterature
using grey grey literature search
search engines,
engines,
a google ascholar
googlesearch,
scholarandsearch, and targeted
targeted websites websites
using theusing searchthe search
terms terms ‘magnesium’
‘magnesium’ AND
AND ‘anxiety’
‘anxiety’
OR ‘stress’.ORA‘stress’.
full listAoffull list of employed
employed grey resources
grey literature literature is resources
shown inisAppendix
shown in A. Appendix
A request A.for
A
request for unpublished data was also published in Magnesium Research
unpublished data was also published in Magnesium Research [57] and circulated on Researchgate.net. [57] and circulated on
Researchgate.net.
A A total ofwere
total of 10,395 citations 10395 citations
screened forwere screened
relevance. A for relevance.
summary A summary
of the of thesearch
grey literature grey
literature
is shown search
in Figureis shown
2. Theinsearch
Figurereturned
2. The search returned
4 relevant 4 relevant
studies whichstudies
were which
included werein included in
the review.
the 4review.
All studiesAllwere4 studies were unpublished
unpublished in full form atinthe
fulltime
form of at
thethe time of
search. Onethestudy
search. One in
is cited study is cited
a European
in
Fooda European Food Safety
Safety Authority (EFSA)Authority (EFSA)
scientific opinionscientific
claim on opinion claim on Mg supplementation
Mg supplementation [58]. Three internal[58].
Three
studiesinternal
conducted studies conducted
by Sanofi by Sanofi
S.A were S.A were
included in theincluded
review. Ainconference
the review.abstract
A conference abstract of
of the Rouillon et
the Rouillon
al. study wasetpublished
al. study inwas published
1995 [59]. Two in studies
1995 [59].
by Two studies
Caillard by Caillard
[60,61] have not[60,61] have not been
been published. Full
published.
data from theseFull data from
studies these
were studies were
provided provided
by Sanofi, by Sanofi,
France. A shortFrance.
summary A short summary
of these of these
data has been
data has been
published published
previously previously [62].
[62].
Nutrients 2017, 9, 429 5 of 22
Nutrients 2017, 9, 429 5 of 22

Figure 2.
Figure Greyliterature
2. Grey literature search
search study
study selection
selection summary.
summary.

2.3. Data
2.3. Data Extraction
Extraction
The following
The following information
information was was extracted
extracted from from the
the reviewed
reviewed studies:
studies:
Study Design: the experimental designs
Study Design: the experimental designs employed in employed in each
each study
study were
were coded
coded as as randomised
randomised
controlled trial
controlled trial (RCT);
(RCT); parallel
parallel groups
groups (P);
(P); randomised
randomised crossover
crossover (R-Cross); and non-randomised
(R-Cross); and non-randomised
crossover (NR-Cross). Condition: all of the reviewed studies recruited
crossover (NR-Cross). Condition: all of the reviewed studies recruited samples based upon samples based upon aa specific
specific
inclusion criterion;
inclusion criterion;namely,
namely,mildmildtoto moderate
moderate subjective
subjective anxiety,
anxiety, premenstrual
premenstrual syndrome
syndrome (PMS),
(PMS), <48
<48 h postpartum, and mild hypertension. The specific inclusion criterion,
h postpartum, and mild hypertension. The specific inclusion criterion, and the measure/method and the measure/method
employed to
employed to identify
identify suitable
suitable samples,
samples, were
were extracted. Sample Characteristics:
extracted. Sample Characteristics: the the sample
sample size
size and
and
composition (male
composition (male(M),(M),female
female(F),(F),
mixedmixed(nM:nF)), and age
(nM:nF)), and(mean, SD andSD
age (mean, range
and reported
range if available).
reported if
Treatment: the form (when reported) and dose of Mg administered
available). Treatment: the form (when reported) and dose of Mg administered and additional and additional ingredients were
reported in were
ingredients milligrams
reported(mg). Control: the
in milligrams (mg).type of control,
Control: if employed,
the type of control,administered
if employed, (e.g., placebo,
administered
activeplacebo,
(e.g., Duration:
verum). active the length
verum). of time
Duration: thethelength
Mg intervention
of time thewas intervention Results:
Mgadministered. a summary
was administered.
of the analyses including means and SDs (if reported) of any significant findings.
Results: a summary of the analyses including means and SDs (if reported) of any significant findings. Effect Summary: the
reported
Effect effects of
Summary: theMg administration
reported effects ofwere summarised aswere
Mg administration positive effect (+),asno
summarised ×), negative
effect (effect
positive (+), no
effect ( − ), and (?) if there exists some doubt regards the reported outcome.
effect (×), negative effect (−), and (?) if there exists some doubt regards the reported outcome.
Nutrients 2017, 9, 429 6 of 22

3. Results and Discussion

From the 18 studies meeting the review inclusion criteria, ten recruited mixed sex samples.
Eight studies that examined the effects of Mg intake on PMS symptomology, and one study assessing
postpartum anxiety, recruited female samples. The Mg doses administered ranged from 46.4–600 mg.
Only one study adjusted a Mg dose relative to body weight (intravenous Mg sulphate infusion
0.1 mmol/kg; [63]) and one study considered potential dose response effects (administering 200,
350, and 500 mg doses; [64]). Magnesium lactate was the most commonly administered Mg form
(n = 5 studies) followed by Mg oxide (n = 4). Seven studies combined Mg with vitamin B6 and two
studies administered Mg with extract of Hawthorn.
All the reviewed studies recruited samples based upon specific anxiety ‘vulnerability’ criteria.
Eight studies recruited individuals reporting mild to moderate subjective anxiety; the majority of
which (6/8 studies) applied a score range of 10–30 on the Hamilton Anxiety Scale (HAM-A) [65] as
an eligibility criterion. Seven studies recruited women reporting mild to moderate PMS symptoms.
Eligibility was determined during menstrual cycle(s) prior to study entry using the Moos Menstrual
Distress Questionnaire [66], menstrual health questionnaires [67], or subjective report. One study
examined the effects of Mg intake on postpartum anxiety ratings [68]. Two studies recruited
participants with mild hypertension, defined as diastolic blood pressure (BP) 85–100 mmHg [69],
or diastolic and systolic BP > 90 mmHg and 140 mmHg respectively [70].
No study administered a validated measure of subjective stress as an outcome. A number of
general well-being measures were employed that included stress-related subscales (e.g., tension,
concerns about the future). However, these offer insufficient evidence to form any valid judgement
on the efficacy of Mg on subjective measures of stress. Validated measures of subjective anxiety
(e.g., HAM-A; Spielberger State Trait Anxiety Inventory (STAI) [71]), and menstrual symptom and
general well-being measures which included subscales specifically related to subjective anxiety
(e.g., Moos Menstrual Distress Questionnaire (MDQ) [66]) were employed. Evidence of the effect
of Mg intake on subjective anxiety outcomes is reviewed separately for each anxiety vulnerability
subgroup type.

3.1. Mild Anxiety

A summary of studies examining the effects of Mg intake in anxious samples is shown in Table 1.
Three of the eight studies which recruited samples based upon pre-existing levels of mild subjective
anxiety reported positive effects of Mg supplementation on anxiety outcomes. Two unpublished
RCTs compared six weeks administration of 192 mg Mg lactate + vitamin B6 (20 mg) vs. placebo.
A greater change from baseline reduction in the HAM-A ratings after 21 days of Mg + vitamin B6 intake
compared to the placebo was reported (p < 0.03; [60]). However, this superiority of Mg over placebo
was not maintained after 42 days. A RCT, identical in design and dose, in a larger sample focussed
on the somatic features of anxiety. This reported significantly lowered somatic anxiety symptoms
on the HAM-A scale after 21 (p < 0.004) and 42 (p < 0.02) days treatment with Mg + vitamin B6 vs.
placebo ([61]). Whilst both studies demonstrated a greater reduction in anxiety after Mg + vitamin B6
compared to placebo, a sizeable placebo effect was also evident.
Hanus et al. [72] reported positive effects of 12 weeks intake of 75 mg Mg combined with Hawthorn
(75 mg) and California poppy (20 mg) extracts vs. a placebo in individuals reporting mild anxiety or
symptoms of general anxiety disorder. Consistent positive effects on three anxiety outcome measures
were reported. A significant decrease from baseline in HAM-A total anxiety score was demonstrated
in both Mg and placebo conditions after 90 days intake. However, the effect was significantly greater
in the Mg treatment group (p = 0.005). A comparable pattern of effect was shown for HAM-A somatic
anxiety (p = 0.054). Both Mg treatment and placebo also demonstrated a significant reduction from
baseline after 90 days on a subjective anxiety visual analogue scale (VAS). The reduction was again
greater in the treatment group (p = 0.005). Finally, a physician global impression rating, a subjective
Nutrients 2017, 9, 429 7 of 22

efficacy ratio rating of the benefit vs. risk of a treatment, was significantly higher for Mg treatment vs.
placebo (p = 0.0018).
Cazaubiel and Desor [58] reported a significant reduction in the anxiety subscale of the Hospital
Anxiety and Depression Scale (HADS; [73]) in a mildly anxious sample following 4 weeks intake of a
fermented milk drink combined with 48 mg Mg. However, this finding can be considered unreliable as
it reflects a post hoc analysis on restricted data (post hoc re-categorisation of ‘mild stress’) in a reduced
subsample (n = 15).
Three studies compared Mg + vitamin B6 with a pharmaceutical anxiolytic as a positive verum.
Two studies compared six weeks intake of 300 mg Mg lactate + vitamin B6 (20 mg) vs. 3 mg [74] or
2 mg [75] of Lorazepam vs. Lorazepam combined with 300 mg Mg + vitamin B6 . A reduction in
HAM-A rating was evident in all treatments but no significant differences between the conditions were
found. Similarly, despite a reduction in ratings in both conditions, Rouillon, Lejoyeux, & Martineau [59]
found no significant difference between 192 mg Mg lactate + vitamin B6 vs. 40 mg Buspirone on
HAM-A ratings after 6 weeks intake. An initial 7 day placebo washout period was employed prior
to full study participation in this study to remove participants that exhibited sizeable placebo effects
(≥50% improvement in total HAM-A score). Comparable efficacy with pharmaceutical anxiolytics
may be considered evidence to support the positive effect of Mg on subjective anxiety. However, the
lack of placebo control in these studies should be noted, particularly in the light of the significant
placebo response seen in the 3 studies in which a placebo was administered. Further, the addition of a
positive verum in studies that did administer a placebo control, which would have permitted both a
non-active, and a proven, active comparison, would have provided a more distinct measure of the
efficacy of Mg.
The final study reporting no effects of Mg compared pre-exam test anxiety in university students
after 5 days intake of 300 mg Mg citrate vs. placebo [76]. The authors categorised participants into four
anxiety groups based on subjective ratings prior to the intervention, ranging from normal to very high
subjective anxiety. No differences between anxiety ratings (STAI) on the eve of the exam were found
between conditions or as a function of anxiety group categorisation. This lack of effect may be due
to contextual differences in the form of anxiety examined. Whilst positive evidence of the anxiolytic
effects of Mg has been shown in chronically anxious samples (i.e., those demonstrating moderate
anxiety scores on the HAM-A), Gendle et al. [76] examined the effects of Mg on responses to an acute,
anxiety-provoking situation-specific context. Whilst the authors did take into account pre-existing
levels of anxiety in the sample, this was ascertained by the Westside Test Anxiety Scale [77] which is a
short measure specifically designed to assess exam-specific, not clinical, anxiety and was used as a
covariate in the analysis rather than to select an anxiety vulnerable sample. Therefore, both the context
and sample differ from the other studies reviewed which recruited chronically anxious individuals
using a clinical measure; the HAM-A.
Examining the efficacy of Mg to reduce subjective anxiety in anxious individuals is a valid
approach. The positive effects of nutritional interventions are often demonstrated in those with specific
pre-existing vulnerabilities (e.g., low socio-economic status [78]; low IQ [79]; high neuroticism [80]).
However, six out of eight studies examining the effects of Mg intake in anxious samples employed the
HAM-A both as an inclusion criterion and primary outcome variable. This practice has the effect of
constraining the variance of responses at inclusion, increasing the likelihood of regression to the mean
post-intervention [81] and may therefore mask some of the true effect if it exists in the population [82].
The employment of a measure to identify anxious samples that is distinct from the subjective anxiety
outcome measure is preferable.
Nutrients 2017, 9, 429 8 of 22

Table 1. Summary of studies reporting the effects of Mg on subjective anxiety/stress in mild to moderately anxious individuals.

Study Sample Outcome Effect

Author Condition Sex Age (year) Treatment (s) Control Duration Results
Design (N) Measure Summary
(i) Mg 300 mg as Lorazepam
Mild anxiety (Hamilton N = 81 Hamilton Reduced anxiety scores in all treatments.
lactate + vit B6 750 mg; 3 mg
Bourgeois et al. [74] RCT Anxiety Scale (n = 27 per 20M:61F 18–65 6 weeks Anxiety No significant differences x*
(ii) Lorazepam 3 mg; (positive
score 10–30) condition) Scale between treatments.
(iii) (i) + (ii) combined verum)
N = 133
(i) Mg 300 mg as Lorazepam
Mild anxiety (Hamilton (Treatments Hamilton Reduced anxiety scores in all treatments.
lactate + vit B6 750 mg; 2 mg
Scharbach [75] RCT Anxiety Scale (i) n = 44; 32M:109F 18–65 6 weeks Anxiety No significant differences x*
(ii) Lorazepam 2 mg; (positive
score 15–30) (ii) n = 46; Scale between treatments.
(iii) (i) + (ii) combined verum)
(ii) n = 43)
Significant change from baseline (Total
Mild anxiety/general
score) between groups at Day 21 (Mg +
anxiety disorder
Hamilton vit B6 : x = 12.1 (SD = 6.0); placebo: x =
(Hamilton Anxiety Scale x = 41 (SD Mg 192 mg as lactate +
Caillard [60] RCT N = 93 25M:68F Placebo 6 weeks Anxiety 15.5 (SD = 5.8)) vs. Day 0 (Mg + vit B6 : x +
score 15–30 & general = 12; 18–65) vit B6 20 mg
Scale = 21.0 (SD = 4.5); placebo: x = 22.6 (SD =
anxiety disorder (DSM
4.4); p < .03). No significant differences
III criteria))
between Day 0 & Day 42.
Mild anxiety/general
anxiety disorder N = 99 (Mg Buspirone Decrease in anxiety scores in both
x = 37.7 Hamilton
Hamilton Anxiety Scale n = 51; Mg 192 mg as lactate + 40 mg treatment groups across intake. No
Rouillon et al., [59] RCT 38M:61F (SD = 10.7; 6 weeks Anxiety x*
score 15–30 & general Buspirone vit B6 20 mg (positive significant difference between the
19–65) Scale
anxiety disorder (DSM n = 48) verum) efficacy of Mg + vit B6 & Buspirone.
III-R criteria))
Symptoms of functional
impairment associated Significantly lower somatic anxiety
Hamilton
with anxiety or a rating after treatment at Day 21 (x = 8.4
Anxiety
somatic disorder x = 37 Mg 192 mg as lactate + (SD = 3.8); p = 0.004) & Day 42 (x = 6.5
Caillard [61] RCT N = 103 26M:77F Placebo 6 weeks Scale +
(Hamilton Anxiety Scale (18–65) vit B6 20 mg (SD = 3.0); p = 0.02) vs. placebo (Day 21:
1 ; Raskin depression (somatic
x = 9.9 (SD = 2.9); Day 42: x = 7.8
score)
scale < 7; COVI anxiety (SD = 3.6)).
scale = 7)
Total anxiety score: Significant decrease
in both conditions. Effect larger in
treatment group. Mean change from
baseline between Day 0 & Day 90
Hamilton
significantly greater in treatment group
Anxiety
Mild anxiety/general (x = −10.6 (SD = 1.2)) vs. placebo
Placebo: x Scale
anxiety order (Hamilton N = 264 (x = −8.9 (SD = 1.2); p = 0.005). Somatic
= 44.5 Hawthorn extract 75 Self-reported
Anxiety Scale score (Treatment score change from baseline: Treatment
(18–82); mg, California poppy anxiety
Hanus et al. [72] RCT 16–28 & somatic score ≥ n = 130; 26M:213F Placebo 12 weeks (x = −6.5 (SD = 0.7)) Placebo (x = −5.7 +
Treatment: 20 mg + elemental Mg (100 mm
50% total score; & Placebo n = (SD = 0.7); p = 0.054). Self-rated anxiety
x = 44.8 75 mg (Sympathyl® ) VAS)
general anxiety 134) VAS: Mean change from baseline
(19–81) Physician
disorder) DSM-III-R)) between Day 0 & Day 90 significantly
global
greater in treatment group (x = −38.5) vs.
impression
placebo (x = −29.2; p = 0.005). Physician
global impression: benefit > risk rating
significantly greater in treatment (90%)
vs. placebo (80%; p = 0.0018).
Nutrients 2017, 9, 429 9 of 22

Table 1. Cont.

Study Sample Outcome Effect

Author Condition Sex Age (year) Treatment (s) Control Duration Results
Design (N) Measure Summary
HADS
No significant difference between
Fermented cow’s milk Symptom
treatment & placebo on study outcome
N = 80 drink (100 mL) Checklist
Mild anxiety (Hospital measures. Post hoc analysis on restricted
(Treatment containing milk Cohen
Cazaubiel & Depression & Anxiety Not data (HADS anxiety subscale score 4–8,
RCT n = 40; 26M:54F protein hydrolysate Placebo 4 weeks Perceived +2
Desor [58] Scale (HADS) reported excluding scores ≥ 9) revealed
Placebo 222 mg + Mg 48 mg Stress Scale
score 4–12) significant decrease of 31% in treatment
n = 40) (Mg form unknown) + Vitaliano
group (n = 15) vs. placebo (n = 16) on the
blackberry puree Coping
anxiety sub-scale of the HADS (p < 0.05).
scale
Subjective anxiety
(Westside Test Anxiety Spielberger
x = 19.3 No significant difference between
Scale; normal anxiety; Mg 300 mg as Mg Placebo State-Trait
Gendle et al. [76] RCT N = 122 31M:91F (SD = 1.17; 5 days treatment and placebo on pre-exam x
elevated normal anxiety; citrate (gelatin) Anxiety
18–22) anxiety rating.
high anxiety; very Inventory
high anxiety)
1 Total Score > 20, with sum of 2 first items < 5 & score for item 6 (depressed mood) < 2; 2 Post hoc analyses; * No difference between treatments; Mg—Magnesium; mg—milligrams;

VAS—visual analogue scale; + positive treatment effect; x—no treatment effect; RCT—randomised controlled trial; Hospital Anxiety & Depression Scale—HADS; SD—standard deviation.
Nutrients 2017, 9, 429 10 of 22

Summary of Effects of Mg in Anxious Samples

Findings to date offer modest support that Mg intake confers benefits for individuals with
pre-existing mild to moderate levels of anxiety. Four out of eight studies reported positive effects of
Mg intake on anxiety outcomes. However, three studies are unpublished and one of these reports
unreliable post hoc analyses in a significantly reduced subsample. Those studies which reported
positive effects all administered Mg in combination with additional ingredients (e.g., vitamin B6 ,
extract of Hawthorn and California poppy). None of the studies examined the effects of the included
ingredients in isolation. Therefore, it is not possible to distinguish the relative contribution of each
ingredient or confirm whether the positive effects observed are additive or synergistic. Three studies
reported comparable efficacy between Mg and pharmaceutical anxiolytics. Whilst the strength of this
evidence is diminished by a lack of a placebo comparator, it is indicative of the potential positive
efficacy of Mg. Non-inferiority in treatment effect of Mg supplementation compared to a proven,
efficacious anxiolytic (e.g., Buspirone [83,84]) is suggestive of a promising role for Mg supplementation
in the alleviation of subjective anxiety symptomology; especially considering the negative side effects
associated with pharmaceutical anxiolytic intake and comparative safety of Mg supplementation.
Mg All of the studies which included a placebo demonstrated significant placebo effects. Whilst
positive effects of Mg were reported to be in excess of the effects of placebo, significant placebo effects
suggest that any intervention in anxiety vulnerable samples may result in an amelioration of subjective
anxiety complaints. The inclusion of an appropriate placebo to evaluate the effects of Mg interventions
is therefore critical.

3.2. Premenstrual Syndrome

A summary of studies examining the effects of Mg intake in samples reporting PMS symptoms is
shown in Table 2. Four of the seven studies recruiting samples based upon pre-existing PMS symptoms
reported positive effects of Mg supplementation on anxiety outcomes. However, this positive evidence
is undermined by a number of methodological limitations. De Souza et al. [67] administered 200 mg
Mg oxide alone and combined with vitamin B6 (50 mg) vs. vitamin B6 (50 mg) alone vs. a placebo for
five consecutive menstrual cycles in a crossover manner. A significant reduction of anxiety-related
premenstrual symptoms (nervous tension, mood swings, irritability, and anxiety) vs. baseline and
placebo was reported after 200 mg Mg oxide + vitamin B6 (p = 0.04). However, no overall treatment
effects were found; the effect reported is the result of a priori planned treatment contrasts.
Quaranta et al. [85] administered 250 mg Mg in a modified release capsule for three menstrual
cycles. Treatment significantly reduced total score on the Moos MDQ (including nervous tension
and anxiety subscales; p < 0.001), and on an anxiety subscale of a monthly PMS symptom diary
(p < 0.001). However, these effects were relative to screening visit and baseline scores respectively.
This study failed to administer any form of control or placebo. This is a methodological concern
given evidence of the significant placebo effects previously discussed and demonstrated in PMS [86].
Indeed, Fathizadeh et al. [87] reported that 250 mg Mg, alone and combined with vitamin B6 , and
a placebo, all resulted in a significant reduction in subjective PMS symptoms. Whilst the authors
report that 250 mg Mg + vitamin B6 resulted in the greatest symptom amelioration (p < 0.05), these
findings emphasise the robustness of the placebo effect in PMS samples and the need to evaluate
active treatments against placebo treatments. The authors also analysed the effects of treatments on
specific subjective PMS symptom subscales and reported a main effect of treatment on anxiety-related
symptomology. However, appropriate follow up tests were not performed to distinguish between the
treatment groups.
Nutrients 2017, 9, 429 11 of 22

Table 2. Summary of studies reporting the effects of Mg on subjective anxiety/stress in individuals reporting premenstrual syndrome symptoms.

Study Treatment Effect

Author Condition Sample (N) Age (year) Control Duration Outcome Measure Results
Design (s) Summary
Moos Menstrual
Placebo: 2 months baseline + 4
Distress Questionnaire Mg significantly reduced negative affect
Premenstrual symptom x = 31.6 menstrual cycles.
Mg 360 mg (8 symptom categories: ratings in the placebo crossover group
complaints Moos (SD = 5.9; Treatment: Mg x 2 2
RCT Cross as Mg pain, inability to (x = 0.51 (SD = 0.45)) vs. placebo intake
Facchinetti et al. Menstrual Distress 24–39); cycles; placebo:
Placebo N = 28 pyrrolidone Placebo concentrate, autonomic (x = 0.76 (SD = 0.70); p < 0.05) & in the Mg +
[88] Questionnaire (2 Treatment: placebo x 2 cycles +
Cross carboxylic reactions, water treatment group after 2 (x = 0.44
consecutive cycles x = 32.4 Mg x 2 cycles (intake
acid retention, negative (SD = 0.47)) & 4 (x = 0.45 (SD = 0.46))
(DSM-IIIR criteria)) (SD = 6.2; during luteal
affect, arousal, cycles vs. baseline (p < 0.02).
24–39) phases only)
total score).
Premenstrual symptom 22 item ordinal daily
18–50
complaints Menstrual menstrual symptom
(71%–18–25; No significant effect of treatment on
Health Questionnaire Mg 200 mg Placebo 4 menstrual cycles (2 diary (6 symptom
Walker et al. [89] R-Cross N = 38 7.9%–26–34; anxiety related premenstrual syndrome x
(MHQ; retrospective as Mg oxide (cellulose) cycles per treatment) categories: anxiety;
13.2%–35–41; symptoms.
assessment of symptoms cravings; hydration,
7.9%–45–50)
during last cycle) depression, other, total)
No overall treatment effect. Predefined
(i) Mg
Premenstrual symptom 30 item ordinal daily factorial treatment contrasts of adjusted
200 mg; (ii)
complaints Menstrual menstrual symptom mean scores showed a significant effect of
vit B6 50 mg;
Health Questionnaire 5 consecutive diary (6 symptom Mg 200 mg + vit B6 50 mg (x = 16.3) for
De Souza et al. [67] R-Cross N = 44 x = 32 (iii) Mg Placebo +1
(MHQ; retrospective menstrual cycles categories: anxiety; reducing anxiety related premenstrual
200 mg + vit
assessment of previous cravings; hydration, symptoms vs. baseline (x = 29.3) &
B6 50 mg (as
month and baseline) depression, other, total) placebo (x = 19.8; p = 0.04) for one
Mg oxide)
menstrual cycle.
Premenstrual symptom (i) Mg 20 item ordinal daily Significant reduction in anxiety-related
complaints Menstrual 200 mg; (ii) menstrual symptom premenstrual symptoms after 2 months
Placebo
Health Questionnaire Mg 350 mg; 2 menstrual cycles per diary (6 symptom placebo (sorbitol) intake (x = 1.7 (SD = 2))
Walker et al. [64] R-Cross N = 85 x = 35 (sorbitol x
(MHQ; retrospective (iii) Mg condition categories: anxiety; vs. 200 mg (x = 3.6 (SD = 2)), 350 mg
1305 mg)
assessment of previous 500 mg (all cravings; hydration, (x = 2.8 (SD = 2)) & 500 mg (x = 3.2
month and baseline) as Mg oxide) depression, other, total) (SD = 2)) Mg treatments.
No significant mood changes in controls.
Control:
Premenstrual complaints Spielberger State-Trait Evidence of improved VAS mood ratings
x = 28.6 Mg sulphate
/ Premenstrual Dysphoric Anxiety Inventory in initial 6 PMDD women after Mg
N = 31 (SD = 6.4; intravenous
Disorder (PMDD) Daily Premenstrual Premenstrual Tension infusion resulted in post hoc initiated
P Post-hoc (PMDD n = 20–43); infusion
Khine et al. [63] premenstrual symptoms complaint-free 24 h post infusion Scale (Subjective & RCT-cross with remaining 10 PMDD x
R-Cross 17; Placebo n PMDD: 0.1mmol/kg
VAS (3 months) & controls Objective) 100 mm women receiving Mg & placebo infusion.
= 14) x = 37.4 body mass
retrospective DSM-IV premenstrual symptom Mg infusion subsequently demonstrated
(SD = 4.4; (4 h)
criteria for PMDD VAS to have no mood improvement effects
20–43)
above placebo.
Nutrients 2017, 9, 429 12 of 22

Table 2. Cont.

Study Treatment Effect

Author Condition Sample (N) Age (year) Control Duration Outcome Measure Results
Design (s) Summary
Moos Modified Menstrual Distress
Questionnaire: Total score: Significant
reduction after 3 months (x = 19.7
(SD = 7.6)) vs. screening visit (x = 30.5
Moos Modified
(SD = 4.5); p < 0.001). Monthly subjective
Premenstrual Distress
PMS symptom diary: Total score:
Premenstrual symptom Questionnaire
Significant reduction at month 1 (x = 23.3
complaints Moos x = 32.6 Mg 250 mg (including symptom
(SD = 10.6)), month 2 (x = 19.6 (SD = 7.8)),
Quaranta et al. [85] NR-Cross Modified Menstrual N = 38 (SD = 8.0; (Mg form None 3 menstrual cycles categories: nervous +
& month 3 (x = 17.9 (SD = 7.3)) with
Distress Questionnaire 18–45) unknown) tension, mood swings,
treatment vs. baseline months 1 (x = 31.8
(baseline score ≥ 25) irritability, anxiety).
(SD = 6.4)) & 2 (x = 31.3 (SD = 8.4);
Monthly subjective
p < 0.001). PMS anxiety subscale:
PMS symptom diary
Significant decrease in anxiety subscale
ratings at month 1 (x = 6.3), month 2
(x = 5.3), & month 3 (x = 5.0) with
treatment vs. baseline (x = 8.4; p < 0.001).
Significant reduction in total PMS
symptoms in all conditions. Mg + vit B6
Placebo:
N= 116 (i) Mg Daily menstrual resulted in greatest reduction (p < 0.05).
x = 28.03;
Premenstrual symptom (Treatments 250 mg; (ii) symptom diary (6 Significant main effect of treatments on
Treatment
Fathizadeh et al. complaints Daily (i) n = 38; (ii) Mg 250 mg + symptom categories: change from baseline anxiety ratings
RCT (i): x = 28.71; Placebo 2 months +?
[87] premenstrual symptoms n = 41; vit B6 40 mg anxiety, cravings, (Mg + vit B6 : x = −22.61 (SD= 20.36); Mg:
Treatment;
record (2 months) Placebo (Mg form hydration, depression, x = −12.14 (SD = 26.14); placebo: x = 0
(ii): x = 30.02
n = 37) unknown) somatic, total) (SD = 20.41); p < 0.001). However, no
(all 15–45)
between treatment planned contrasts or
post-hoc tests reported.
1Post hoc analyses; Mg—Magnesium; mg—milligrams; PMDD—Premenstrual Dysphoric Disorder; PMS—premenstrual syndrome; VAS—visual analogue scale; MHQ—Menstrual
Health Questionnaire; + positive treatment effect; x no treatment effect; ?—doubts about outcome; RCT—randomised controlled trial; P—parallel groups; R-Cross—randomised crossover;
NR-Cross—non-randomised crossover; B6 —vitamin B6 ; SD—standard deviation.
Nutrients 2017, 9, 429 13 of 22

The final study reporting positive effects of Mg administered 360 mg pyrrolidone carboxylic acid
Mg vs. placebo [88]. Magnesium intake significantly reduced subjective premenstrual negative affect
symptoms on the Moos MDQ, which includes the symptoms anxiety and tension [66]. This effect of
Mg was shown in a placebo/treatment crossover condition (2 months placebo intake vs. 2 months Mg
intake; p < 0.05), and after 2 and 4 months intake (vs. baseline) in a Mg treatment condition (p < 0.05).
Three studies reported no effects of Mg intake on anxiety-related PMS symptoms. Walker et al. [89]
found no effects of 2 months administration of 200 mg Mg oxide on PMS symptomology. A further
study by this group examined potential Mg dose-response effects by administering 200, 350, and 500 mg
Mg oxide in a placebo controlled crossover trial [64]. Placebo intake (1305 mg sorbitol) significantly
reduced subjective total and anxiety-related PMS symptoms after 2 months compared to all doses
of Mg (p < 0.001). The authors suggest the positive effects of sorbitol may be due to the raising of
depleted intracellular sorbitol concentrations caused by hypoglycaemia, which is a suggested—though
unconfirmed—symptom of PMS. Therefore, the effect of sorbitol may be specific to the PMS sample.
Indeed, the authors additionally demonstrated that sorbitol reduced urinary Mg excretion in PMS
(vs. baseline and Mg treatments), but not asymptomatic controls (vs. baseline and cellulose placebo).
The dose and duration of intake may also be relevant since effects were not evident after one month,
and the Mg treatments contained smaller doses of sorbitol (Mg 200 mg = 1050 mg; 350 mg = 830 mg;
500 mg = 717 mg sorbitol). It is not possible to discern the extent to which this finding is of relevance
to other PMS studies reporting placebo effects as the nature of the placebo has rarely been detailed.
Only Walker et al. [89] report the form of placebo administered (cellulose). Therefore, the potential
impact of placebo content on the effects observed in PMS symptom samples is not known.
In a methodologically flawed study, Khine et al. [63] initially adopted a parallel groups design
comparing women reporting PMS complaints or meeting the criteria for premenstrual dysphoric
disorder (PMDD) with non PMS controls. The authors administered 0.1 mmol/kg body mass of
Mg sulphate via intravenous infusion over four hours. The acute subjective effects of Mg infusion
were assessed 24 h later by the STAI, the Premenstrual Tension Scale [90] and a PMS symptom VAS.
The study design was altered mid-testing after improved VAS mood ratings were reported in the
PMS/PMDD participants only (n = 6). The Mg and a placebo infusion were subsequently administered
to 10 more PMS/PMDD women in a crossover manner. No significant differences between Mg
and placebo were demonstrated on any subjective outcomes in this subsequently combined sample.
Moreover, any outcomes are crucially compromised due to the decision to alter the study design based
upon emerging data.
The heterogeneity in the evidence for the efficacy of Mg in treatment of anxiety-related PMS
symptoms may be explained by the divergent methods employed to characterise PMS samples. For
example, four studies [64,67,85,89] employed retrospective assessment of PMS symptoms over the
previous month and/or at baseline. The reliance on retrospective diagnosis has been criticized [91]
since these often result in inflated estimates of symptom severity [92]. Only Facchinetti et al. [88] report
the assessment of daily PMS symptoms in the 2 months prior to study commencement to identify
eligibility (according to DSM-IIIR criteria). Khine et al. [63] and Fathizadeh et al. [87] also collected
daily symptom records in the months (3 and 2 months respectively) prior to study commencement.
However, not enough detail is reported to determine by which criteria participant eligibility was
ascertained. Therefore, it is not easy to assess the equivalency of PMS symptom severity across the
samples. This is problematic if, for example, the potential functional effects of Mg supplementation
operate as a function of PMS symptom severity (e.g., attenuating symptoms in mild or very severe
cases). A more consistent approach to assessing PMS symptomology prior to inclusion may reduce
some of the variability evident in the existing literature.

Summary of Effects of Mg in PMS Samples

The findings to date suggest a potential positive role for Mg supplementation on subjective
anxiety in women reporting PMS symptoms. Positive effects of Mg were reported both in isolation
Nutrients 2017, 9, 429 14 of 22

and when combined with vitamin B6 . Studies reporting positive effects of Mg combined with vitamin
B6 demonstrated effects superior to those of Mg administered alone. However, evidence of the effects
of Mg intake on subjective PMS related anxiety are undermined by a number of methodological issues.
A lack, or inappropriate application, of a placebo control, and design and analysis issues all contribute
to the ability to draw clear conclusions as regards this problem. Careful selection of an appropriate
placebo control for samples of this nature (sub-clinical complaints) is also highlighted by the apparent
specific functional effects of sorbitol on women with PMS. A more consistent approach to diagnosis
(preferably using DSM-IV criteria and characterising PMS samples is required to permit better
assessment of the equivalency of PMS symptom severity and response to treatment between studies.

3.3. Postpartum Anxiety

One study examined the capacity of Mg intake to ameliorate postpartum (≤48 h) anxiety in a
healthy sample (Table 3). No significant effects on subjective anxiety rating (STAI) in the eight weeks
following child birth were recorded following daily supplementation with 64.4 mg Mg (vs. placebo
and zinc; [68]).

Summary of Effects of Mg in Postpartum

There is currently no evidence to support the efficacy of Mg intake in the reduction of postpartum
subjective anxiety.

3.4. Mild Hypertension

A summary of studies examining the effects of Mg intake in mild hypertensive samples is
shown in Table 4. Both studies employed general subjective measures of quality of life (QoL) and
well-being which comprised subscales related to stress and anxiety. Therefore, the findings are
considered to contribute only modest evidence to support the examination of the efficacy of Mg intake
on anxiety/stress. Borrello et al. [70] administered 200 mg Mg oxide vs. placebo for 12 weeks in a
hypertensive sample. Magnesium intake resulted in significantly higher QoL ratings (inclusive of
scales measuring subjective emotional behaviour and concerns about the future) vs. placebo and
baseline at 12 weeks (p < 0.05). Conversely, Walker et al. [69] found no effects of 10 weeks intake
of 600 mg Mg chelate on a subjective well-being measure (comprising an anxiety subscale) when
administered in isolation or in combination with Hawthorn extract (500 mg).

Summary of Effects of Mg in Hypertensive Samples

Evidence of specific anxiety/stress reducing effects of Mg intake in hypertensive individuals is
weak due to the inconsistency of evidence and failure to employ specific subjective anxiety/stress
outcome measures. However, the capacity for Mg intake to affect subjective indices of mood (QoL)
suggests further examination of the efficacy of Mg in hypertensive samples is warranted. Evaluating
the efficacy of Mg on subjective anxiety in samples with clinical conditions is complicated by the
underlying clinical complaint. For example, an improvement in subjective anxiety may be as a
result of an improvement in the clinical symptomology rather than a direct effect of Mg on anxiety.
However, this is contradicted by the current available evidence as both studies in hypertensive samples
demonstrated Mg reduced blood pressure responses but did not affect subjective anxiety levels.
Nutrients 2017, 9, 429 15 of 22

Table 3. Summary of studies reporting the effects of Mg on subjective anxiety/stress in postpartum women.

Study Outcome Effect

Author Condition Sample (N) Sex Age (year) Treatment (s) Control Duration Results
Design Measure Summary
(i) Zinc sulphate No
Treatments: (i) x = 29.4 Placebo Spielberger
N = 95 (Treatments: 27 mg (11 mg significant
Postpartum (SD = 5.4); (ii) x = 26.4 (lactose, starch, State-Trait
Fard et al. [68] RCT (i) n = 31; (ii) n = 31; F elemental zinc); (ii) 8 weeks differences x
≤48 h (SD = 4.8); Placebo cellulose, Mg Anxiety
Placebo: n = 33; Mg sulphate 320 mg between
x = 27.6 (SD = 5.1) stearate) Inventory
(64.6 elemental Mg) treatments
Mg—Magnesium; mg—milligrams; + positive treatment effect; − negative treatment effect; x no treatment effect; RCT—randomised controlled trial.

Table 4. Summary of studies reporting the effects of Mg on subjective anxiety/stress in individuals with mild to moderate hypertension.

Study Sample Effect

Author Condition Sex Age (year) Treatment (s) Control Duration Outcome Measure Results
Design (N) Summary
Significantly higher
44 item Quality of
Mild total quality of life
N = 83 Life Likert
hypertension rating after 12 weeks
(Treatment questionnaire
(Diastolic Placebo: x = 49; treatment (x = 67.58
Borrello et al. [70] RCT n = 42; 30M:53F Mg oxide 200 mg Placebo 12 weeks (subscales: +
BP > 90 mmHg Treatment: x = 51 (SD = 5)) vs. baseline
Placebo emotional behaviour
or Systolic BP (x = 73.58 (SD = 6)) &
n = 41) & concerns about
> 140 mmHg) placebo (x = 73.23
the future)
(SD = 8); p < 0.05).
Placebo: x = 49; (i) Mg amino acid Subjective
Mild Treatment (i): chelate (600 mg well-being
N = 36 (9 No significant effects
hypertension x = 53.2; Treatment elemental Mg/day); Placebo questionnaire
Walker et al. [64] RCT per 18M:18F 10 weeks on subjective x
(Diastolic BP (ii): x = 53; (ii) Hawthorn extract (cellulose) (subscales: vitality,
condition) well-being.
85–100 mmHg) Treatment (iii): 500 mg; (iii) (i) + (ii) anxiety &
x = 48.8 combined depression)

Mg—Magnesium; mg—milligrams; + positive treatment effect; − negative treatment effect; x no treatment effect; RCT—randomised controlled trial.
Nutrients 2017, 9, 429 16 of 22

3.5. Moderating Variables

3.5.1. Dosage and Differential Bioavailability of Mg Forms

No clear dose effect of Mg emerges from the reviewed studies. Positive effects of Mg intake on
subjective anxiety outcomes are reported with both low (75 mg [72]) and higher (360 mg [88]) Mg doses.
One study that systematically examined the potential dosing effects of Mg (administering 200, 350,
and 500 mg) reported no effects of any dose [64]. Examination of the effect of Mg dose is further
complicated by a number of the studies reporting positive outcomes combining Mg with additional
ingredients (e.g., Hawthorn extract [72]). Therefore, it is difficult to assess if it is Mg administered at a
particular dose that is efficacious, or the additional ingredients acting in isolation or synergistically
with Mg.
An additional factor that needs to be acknowledged is the variable bioavailability of different
Mg forms. Magnesium chloride, sulphate, citrate, lactate, malate, glycinate and taurinate are highly
biologically available whilst Mg oxide appears to be significantly less bioavailable [93–95]. However,
there is no consistent moderating effect of Mg form on reported anxiety outcomes. Four studies
administered Mg oxide [64,67,70,89]. Two studies reported positive effects of Mg oxide intake, however,
positive effects were observed only when combined with vitamin B6 [67] and on a subjective general
well-being questionnaire including anxiety-related factors rather than specific measures of anxiety [70].
Two of five studies administering Mg lactate reported positive effects of this Mg form. One study
reported pyrrolidone carboxylic acid reduced subjective negative affect. Conversely, no effects of
citrate, sulphate (intravenous) or amino acid chelate Mg forms have been demonstrated. Therefore,
whilst the bioavailability of Mg forms should be considered when planning an intervention, the
current available evidence is not sufficient to determine the relative efficacy of specific Mg forms in the
attenuation of subjective anxiety outcomes.

3.5.2. Duration of Intake

The majority of the existing evidence of the positive effects is from studies administering Mg for
6–12 weeks. However, this is also true for studies reporting no effects of Mg. Hence, intervention
length may not be the principal moderating variable contributing to the heterogeneous effects. There
is a paucity of research assessing the acute effects of Mg intake in humans. Gendle et al. [76] reported
no effects after 5 days but the sample and anxiety context were markedly different to those sub-clinical
and chronically anxious samples recruited in studies reporting positive effects of Mg. Khine et al. [63]
reported no effect of an acute intravenous Mg dose but methodological flaws in this study undermine
interpretation of the findings.

3.5.3. Mg Status
The majority of studies summarised cite the observed relationship between Mg depletion and
affective states as a rationale to hypothesise a potential positive effect of Mg supplementation on
subjective anxiety. The exclusive selection of anxiety vulnerable samples (e.g., moderately anxious,
PMS symptomology) is based on an assumption that the positive effects of Mg supplementation are
more likely observed in those that are compromised or depleted in some way. However, none of
the reported studies specifically recruited samples depleted in Mg to assess the effect of Mg intake.
A number of studies measured urinary and/or serum Mg status at baseline and over the course/at
the completion of the study. These measures were recorded only to confirm the equivalence of
treatment groups at baseline and increased Mg bioavailability in Mg conditions or protocol compliance.
No attempt was made to incorporate basal Mg status in the statistical analyses of Mg outcomes.

4. Conclusions and Research Recommendations

In conclusion, there is suggestive but inconclusive evidence for a beneficial effect of Mg
supplementation in mild anxiety. Similarly the evidence from studies of women who complain
Nutrients 2017, 9, 429 17 of 22

of premenstrual symptoms also suggests that Mg could confer benefits. In both cases this is based on
a reasonable number of studies which have used appropriate measures of symptoms. However, the
weaknesses in the designs highlighted and the substantial placebo response noted in most studies
preclude strong recommendations for Mg as a treatment option at this stage. The evidence for Mg
in hypertension is based on only two studies, both of which do not measure specific symptoms but
generic quality of life indices which are unlikely to detect changes in underlying specific symptoms.
The quality of studies was generally poor. Studies that included a placebo condition often failed
to evaluate effects appropriately. Studies were marred by inappropriate selection of samples, failure
to confirm diagnosis, lack of placebo controls, and weak statistical analysis. It is clear therefore that
well-designed randomised controlled trials are required. Such trials should include careful screening
of samples and confirmation of the presence of anxiety at levels where a treatment effect would be
noticeable (e.g., mild, moderate) on measures with sufficient range. The specific examination of Mg
efficacy in individuals with lowered Mg resources is also recommended considering the evidence
of the relationship between the depleted state and affective pathologies. The inclusion of a placebo
control (with documented content) is crucial as is appropriate power to detect treatment effects and
an appropriate statistical analysis strategy, which includes consideration of baseline symptoms as a
covariate rather than relative to screening along with planned comparisons against the placebo
treatment. Longer term studies should also consider the inclusion of a placebo run-in, whilst
acknowledging that placebo response can be quite prolonged in studies of subjective symptoms
such as anxiety or PMS. The lack of significant differences between proven anxiolytic pharmaceuticals
and Mg intake in the alleviation of subjective stress ratings suggests study designs may also benefit
from the inclusion of a positive verum. This would permit a fair assessment of the efficacy of Mg.
The effects of Mg on clinical affective disorders and experimental studies of anxiety in animal
models provide a clear rationale to propose that Mg supplementation will have a beneficial effect
on mild/moderate anxiety. There is also sufficient potential mechanistic pathways via which Mg
could modulate affective states. It is the quality of the available evidence rather than the absence of a
potential mechanism which has hindered convincing demonstration of such effects.
The potential effect of Mg in attenuating psychological response to stress merits further
investigation since stress is a ubiquitous feature of modern lives. The modulation of the HPA axis
by Mg, which has been demonstrated to reduce central (ACTH; [15]) and peripheral (cortisol; [49])
endocrine responses, suggests that behavioural effects of stress exposure such as anxiety could be
attenuated by Mg supplementation.

Acknowledgments: The authors N.B. and C.L. received funding from Sanofi to conduct the initial systematic
publication database search of the effects of Mg on subjective stress and anxiety. Sanofi also provided access to
data from 3 unpublished Mg intervention studies.
Author Contributions: N.B. and C.L. conducted the systematic database and grey literature search. N.B., C.L.
and L.D. contributed equally to the writing of the review.
Conflicts of Interest: N.B. and C.L. declare no conflict of interest. L.D. is currently a member of the
Sanofi Consumer Healthcare Advisory Board. Sanofi had no role in the collection, review or interpretation
of data; in the writing of the manuscript, and in the decision to publish the review.

Appendix A
Grey Literature Search Resources
PsychExtra: www.apa.org/pubs/databases/psycextra/
Open Grey: www.opengrey.eu/
Google Scholar (first 1000 returns per search): https://scholar.google.co.uk/
TRIP database: https://www.tripdatabase.com/
Information for Practice: http://ifp.nyu.edu/
Grey Literature Report: http://www.greylit.org/
Latin American Open Archives Portal: http://lanic.utexas.edu/project/laoap/
Nutrients 2017, 9, 429 18 of 22

British Library EThOS eThesis online service: http://ethos.bl.uk/Home.do

National Institute for Health Research (INVOLVE): http://www.invo.org.uk/
The OAlster Database: www.oclc.org/oaister.en.html
Health Management Information Consortium: www.lshtm.ac.uk/library/resources/databases/
info_hmic.html
UK Department of Health: www.gov.uk/government/organisations/department-of-health
Centers for Disease Control and Prevention: www.cdc.gov
National Institute of Health: www.nih.gov
World Health Organization: www.who.int/en/
European Food Safety Authority: www.efsa.europa.eu

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