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.

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 [3,4,5]. 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 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 [17,18,19].

Experimentally induced hypomagnesemia results in depression like behavior in rodents [20,21,22,23] 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 [27,28,29] 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 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 text) was applied for searches of CINAHL and EBM REVIEWS. The additional filter ‘Human’ was added to all searches where supported. The reference lists of existing reviews and identified articles were hand searched to supplement the electronic searches.

The database searches returned at total of 6573 articles. Publication titles were reviewed to remove patently irrelevant and duplicate papers, leaving a total of 2094 articles selected for abstract review. The full 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.