Introduction
Magnesium is the second most abundant intracellular cation after potassium [1, 2]. It plays an essential physiological role in the body as an enzymatic cofactor in over 600 biochemical reactions [1]. The physiological impact of stress on intracellular and extracellular magnesium concentrations has been well described [3, 4]. Hormones released during stress, including catecholamines and corticosteroids, have been shown to enhance a shift of magnesium from the intracellular to the extracellular space, leading to increased urinary excretion of magnesium and subsequent decrease in serum magnesium concentrations [3, 5]. In turn, low serum magnesium concentrations increase the release of stress-associated hormones including catecholamines, adrenocorticotrophic hormone and cortisol in response to stress, and affect their access to the brain, creating a vicious circle of reduced resistance to stress and further magnesium depletion [4, 6].
The relationship between serum magnesium concentration and stress has been evidenced in a clinical trial that reported an association between low serum magnesium concentrations and greater perceived stress in otherwise healthy women [7]. Other studies have documented a positive effect of magnesium supplementation on symptoms and biomarkers of stress. In a double-blind, randomized trial of 46 healthy adults aged 60-75 years, magnesium supplementation (magnesium 500 mg per day administered as magnesium oxide tablets for 8 weeks) improved subjective measures of insomnia, which is recognized as a symptom of stress [8, 9]. Magnesium supplementation over a period of one month (magnesium 500 mg per day in a magnesium oxide tablet) has also been shown to significantly decrease basal serum cortisol concentrations, a biomarker of stress, in students [10].
High-dose (100-300 mg daily) pyridoxine (vitamin B6) has also been proposed as an anti-stress therapy; vitamin B6 exerts modulatory effects on neurotransmitters that affect depression and anxiety, and may reduce blood pressure and act peripherally to reduce the physiological impact of corticosteroid release [11]. In rodent studies, high-dose vitamin B6 was able to correct low serum and tissue magnesium concentrations induced by dietary magnesium depletion and prevent stress-induced gastric ulcers [12-14]. One proposed mechanism is that vitamin B6 facilitates cellular uptake of magnesium, which both limits excretion and increases its effectiveness (since the mineral is primarily an intracellular cation) [15, 16]. In light of the direct roles of magnesium and vitamin B6 in the modulation of stress and associated pathways, as well as their complementary effects, examination of the efficacy of magnesium and concomitant vitamin B6 supplementation in individuals with low concentrations of magnesium is warranted. However, as recently reviewed, no randomized clinical trial to date has investigated the efficacy of magnesium plus vitamin B6 supplementation on stress in such a population using a validated measure of perceived stress as an outcome [17].
A combination of magnesium lactate dehydrate and pyridoxine hydrochloride in a 10:1 ratio (magnesium lactate dehydrate 300 mg/pyridoxine hydrochloride 30 mg) is available as an over-the-counter supplement (e.g. Magne B6), and is indicated for the prevention and treatment of magnesium deficiency and associated symptoms (including fatigue, mild anxiety, and nervousness) (Magne B6 SmPC) [18]. This specific combination of magnesium and vitamin B6 in a 10:1 ratio has been shown to provide faster relief of magnesium-deficiency symptoms than magnesium alone in magnesium-deficient animals [12]. The objective of the current trial was to compare this magnesium-vitamin B6 combination versus magnesium alone in stressed healthy adults with suboptimal serum magnesium concentrations using the stress subscale of the validated Depression Anxiety Stress Scales (DASS-42) self-assessment tool [19].