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Magnesium For Depression: An Underexplored Treatment

Magnesium is regarded as an essential mineral for humans and functions as a cofactor in upwards of 300 biochemical processes throughout the body.  For example, magnesium is implicated in: ATP production, blood pressure regulation, bone development, glucose modulation, heart rhythm normalization, muscle and nerve function, plus protein synthesis.  Knowing that magnesium is essential for optimal biological function, professionals strongly emphasize meeting the recommended daily allowance (RDA) via dietary intake and/or supplementation.

The recommended daily allowance (RDA) of magnesium for adult men and women is 400-420 mg/day and 310-360 mg/day, respectively.  Reports published by the USDA suggest that over 57% of the U.S. population fails to meet the RDA for magnesium.  Based on this information, we can surmise that many individuals end up with a magnesium deficiency, whereby they become increasingly prone to serious medical conditions such as:  anxiety disorders, diabetes, cardiovascular disease, hypertension, muscle spasms, neurodegeneration, osteoporosis, and/or migraines. (Read: “Magnesium for Migraines“).

Preliminary evidence suggests that administration of supplemental magnesium is an effective treatment for major depression in a subset of persons.  Since an underlying magnesium deficiency can cause depression, and depression can exacerbate a magnesium deficiency, reversing the deficiency via supplementation might reduce the severity of one’s depression.  Moreover, it is possible that ingesting supratherapeutic doses of magnesium treats depression by altering CNS activity – regardless of whether the person was deficient prior to treatment.

How Magnesium Treats Depression (Mechanisms of Action)

There are numerous potential mechanisms by which magnesium may attenuate depression.  Perhaps the most obvious means by which magnesium supplementation treats depression is via reversing deleterious neurological changes implicated in magnesium deficiency.  Assuming someone is deficient in magnesium, he/she may exhibit: autonomic nervous system (ANS) imbalances, connectivity alterations within the brain, hormone irregularities, HPA axis dysregulation, inflammation, neuronal damage, neurotransmitter abnormalities, and/or impaired plasticity.  Administration of bioavailable magnesium should reverse unfavorable neurological changes associated with a deficiency, ultimately leading to mood improvement.

NMDA-receptor channel modulation: The antidepressant effects associated with magnesium are likely mediated in part through its modulation of activity at NMDA receptor channels.  NMDA receptors within the brain typically express one GluN1 splice variant, one or more GluN2 subunits, or GluN3 subunits.  The GluN2 subunits are stimulated by agonists such as glutamate in the extracellular space, whereas GluN1 subunits modulate the function of ion channels through binding co-agonists glycine or d-serine.

  • Neuroprotective effect: Magnesium prevents frequent opening of NMDA receptor channels which is protective against neuronal damage. It may also help neurons recover from preexisting damage and/or prevent neuronal death.
  • Nitric oxide downregulation: A downstream effect of NMDA receptor channel opening is increased production of nitric oxide. Magnesium administration should reduce excessive NMDA receptor channel opening to limit downstream nitric oxide generation.  With continued magnesium supplementation, nitric oxide levels may decrease, whereby mood improves directly from the nitric oxide reduction.  (High nitric oxide is sometimes implicated in certain neurobiological signatures of depression).
  • Synaptic normalization: Magnesium buffers against overstimulation of NMDA receptors from calcium ions and glutamate to reverse downstream synaptic dysfunction within the hippocampus. It also may augment formation of new synapses and/or strengthen favorable synaptic connections.

When glutamate and a co-agonist bind, NMDA receptor ion channels open.  Individuals with major depression are theorized to exhibit an overall bias towards NMDA receptor channels opening and/or hyperstimulation of NMDA receptors.  Over an extended duration, frequent opening of NMDA receptor channels is theorized to damage neurons, and as a result of the cumulative damage, individuals experience depression and/or symptoms that reflect a neuropsychiatric disorder.

In addition to the infliction of neuronal damage, frequent NMDA receptor channel opening can induce synaptic dysfunction (within the hippocampus) and increase nitric oxide production (altering blood flow and monoamine levels), each of which could cause and/or exacerbate depressive symptoms.  Studies of individuals with depression have revealed abnormalities in NMDA receptor activation such as hyperstimulation of NMDA receptor sites within certain regions of the brain.  There are numerous potential reasons as to why NMDA receptor channels may be prone to opening and/or excessive stimulation, including:  low magnesium ion concentrations, excessive glutamatergic transmission, high levels of calcium ions, and/or other ion imbalances.

Although NMDA receptors may exhibit abnormal activation in models of depression, mounting evidence suggests that NMDA receptor antagonists (e.g. ketamine) can effectively counteract some abnormalities via receptor blockade.  In preliminary studies, the blockade of NMDA receptors has been shown to rapidly alleviate severe depression.  While it is apparent that magnesium isn’t the same as ketamine, magnesium is understood to produce a voltage-dependent open channel block at membrane potentials to prevent excessive opening of NMDA receptor channels.

In fact, Murck (2013) reports that there’s considerable overlap in the mechanism of action associated with ketamine and that of high-dose magnesium in animal models whereby each modulate the NMDA complex to strengthen synapses and enhance slow-wave sleep (SWS).  When concentrations of magnesium ions are low, calcium and sodium ions uninhibitedly enter postsynaptic neurons, after which potassium exits.  Theoretically, ongoing administration of a magnesium supplement capable of penetrating the blood brain barrier (e.g. magnesium-l-threonate) might reduce excessive NMDA receptor channel opening by inhibiting calcium and sodium ions.

Support for the idea that magnesium interacts with NMDA receptors can be derived from research by Clerc, Young, Bordt, et al. (2013).  They discovered that administration of magnesium sulfate appears to act upon the NMDA receptor to inhibit glutamate-induced excitotoxicity, preserve ATP, and maintain normative mitochondrial respiration – each of which could improve a depressed mood.  A study by Poleszak, Wlaź, Wróbel, et al. (2008) documents that magnesium exerts an effect upon NMDA/glutamate pathways in mice to facilitate an anxiolytic effect, as measured by improvements on an elevated plus maze.

Prior research by Poleszak, Wlaź, Kedzierska, et al. (2007) supports the idea that magnesium antagonizes NMDA receptors to facilitate an antidepressant effect in mice.  Administration of magnesium appears to significantly reduce immobility times on a forced swim test (FST), suggesting lower depression.  That said, administration of N-methyl-d-aspartic acid (NMDA) offset the immobility reduction of magnesium on the forced swim test, suggesting that magnesium’s therapeutic antidepressant action is likely mediated through NMDA receptor/glutamate modulation.

Ongoing inhibition of NMDA receptor stimulation with magnesium supplementation may eventually reverse neuronal damage, normalize downstream synaptic function, plus downregulate nitric oxide levels to facilitate an antidepressant effect.  A report by Deutschenbaur, Beck, and Kiyhankhadiv (2016) lists magnesium as a potentially useful compound for the treatment of depression through its action within the NMDA system.  Though further research is necessary to confirm this suspected mechanism of antidepressant action in humans, preliminary data suggest that magnesium (especially high-doses) can alleviate depressive symptoms through modulation of NMDA receptors.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25747801
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HPA axis modulation: Many studies support the idea that HPA (hypothalamic-pituitary-adrenal) axis is overactive among persons with depression.  An overactive HPA axis is generally indicative of chronic anxiety and/or elevated stress hormones, each of which can contribute to depressed mood.  A review of evidence by Varghese and Brown (2001) discovered that HPA axis activation is common among depressed patients, a finding which is well-substantiated in scientific literature.

Upon considering the facts that: some depressed persons exhibit HPA axis overactivity AND magnesium attenuates HPA axis overactivity, it’s logical to surmise that magnesium supplementation may treat depression (in a subset of persons) through its effect upon the HPA axis.  Studies in numerous strains of mice report that magnesium (Mg2+) deficiencies increase transcription of prepro-CRH (preprocorticotropin releasing hormone) within the PVN, as well as plasma ACTH levels, both of which suggest that the HPA axis has become overactive.  Administration of magnesium (Mg2+) to correct the magnesium deficiency reduces HPA axis activity, and predictably, decreases levels of prepro-CRH and ACTH.

Studies in humans suggest that pharmaceutical antidepressants facilitate therapeutic benefit, at least in part, through attenuation of HPA axis overactivity.  In other words, ongoing administration of antidepressants mitigates depressive and anxious symptoms, and this symptomatic mitigation is correlated with an observable normalization of HPA axis activity.  Though not every person with depression will derive noticeable therapeutic benefit from magnesium-induced attenuation of HPA axis activation, some individuals might.

The degree of benefit derived from this mechanism of action may be contingent upon the degree to which HPA axis is implicated in the pathogenesis of a person’s depression.  If HPA axis overactivity is a chief facilitator of depression, it is reasonable to suspect that magnesium supplementation could act as a highly efficacious antidepressant.  On the other hand, if HPA axis activation is just one modest component of a person’s depression, the subjective benefit of magnesium supplementation may be less pronounced.

That said, it is important to avoid assuming that magnesium exerts a profound effect upon the HPA axis of depressed humans.  While we know that magnesium can stabilize the HPA axis in animal models, we cannot automatically assume that it exerts the same effect OR an effect of equal magnitude in humans.  Nonetheless, those who derive antidepressant benefit from magnesium should at least consider HPA axis modulation as a possible mode of action.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15014598
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Serotonergic modulation: Another mechanism by which magnesium might generate an antidepressant effect is through modulation of serotonin.  It is known that turnover rates and concentrations of serotonin within various regions of the brain can influence mood.  While not everyone with depression exhibits low serotonin signaling, it is widely accepted that increasing serotonin signaling with SSRI/SNRI antidepressants is an effective modality for improving mood (even if serotonergic abnormalities were not the chief underlying cause of depression).

Most evidence suggests that serotonergic deficits increase susceptibility to major depression.  Interestingly, there appears to be a close relationship between concentrations of magnesium and serotonergic activity.  For example, an analysis by Amyard, Leyris, Monier, et al. (1995) discovered that 5-HIAA (serotonin metabolite) concentrations within the brain were directly linked to magnesium levels in mice; the greater the magnesium levels, the higher the serotonin metabolites.

Another study conducted by Ruljancic, Mihanovic, Cepelak, et al. (2013) discovered that platelet serotonin and magnesium concentrations were lower among persons with depression and/or suicidality compared to healthy non-depressed volunteers.  It was concluded that magnesium status may directly influence serotonin levels, which as we know, influence mood.  Poleszak (2007) suggests that supplemental magnesium acts directly upon the serotonin system to improve mood.

His study showed that standalone magnesium (30 mg/kg) administration lead to significant performance improvements of mice on a forced swim test, indicative of an antidepressant effect.  In the same study, co-administration of magnesium plus citalopram OR tianeptine (each of which upregulate serotonin) strengthened antidepressant responses, signifying a synergistic serotonergic effect.  The strengthening of antidepressant response did not occur when magnesium was co-administered with reboxetine (a non-serotonergic medication).

What’s more, the antidepressant effect of magnesium was attenuated via pre-treatment with a serotonin synthesis inhibitor (p-chlorophenylalanine).  All observations considered, Poleszak had reason to believe that magnesium induces an antidepressant effect via the serotonin system.  Additional research by Cardoso, Lobato, and Binfaré (2009) showed that magnesium’s antidepressant effect in a forced swim test paradigm was mitigated upon pretreatment with serotonin receptor antagonists such as:  NAN-190 (5-HT1A antagonist), WAY-100635 (5-HT2A antagonist), ritanserin (5-HT2A / 5-HT2C antagonist), or ketanserin (5-HT2A antagonist) – implying that its action is serotonergic.

A study by Aloyo, Salt, Hoffman, and Harvey (1998) discovered that magnesium inhibits binding of drugs upon 5-HT2A receptors in rabbits.  Given that Guiard and Di Giovanni (2015) highlight a role of 5-HT2A receptor signaling dysfunction in depression, and the possibility that magnesium modulates 5-HT2A receptor activity, it’s reasonable to believe that this may promote an antidepressant effect for a subset of persons.  Moreover, it has been reported by Devinney and Wang (2008) that magnesium enhances function of 5-HT1A receptors, predominant targets of certain pharmaceutical antidepressants.

Other researchers such as Mauskop and Altura (1998) document that magnesium concentrations have an effect upon serotonin receptors, making it useful as a migraine prophylactic.  Magnesium clearly affects various facets of the serotonin system, some of which may include: serotonin synthesis, regional turnover, and 5-HT receptor activation.  Given the abundance of research highlighting serotonergic action of magnesium, it’s not farfetched to hypothesize that its antidepressant efficacy is mediated (at least in part) through serotonergic modulation.

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Synaptic density increase: Some research has discovered lower synaptic density among persons with depression in the prefrontal cortex.  The prefrontal cortex is a region associated with executive functions such as problem solving, organization of thoughts, planning, and emotional control.  The discovery of reduced synaptic density in the prefrontal cortex among individuals with depression has lead some to theorize that synaptogenesis (sprouting of new synapses) in this region may serve as a novel antidepressant intervention.

Consequently, researcher Guosong Liu and his team reported that increasing extracellular magnesium levels within the brain promotes synaptogenesis and bolsters synaptic plasticity.  The enhancement of synaptogenesis and synaptic plasticity from magnesium administration is mediated through NMDA receptors and associated with reduced calcium ion influx.  Ultimately, basal calcium ion levels decrease and NR2B-containing NMDA receptors are subject to upregulation, thereby increasing synaptic density.

Further research by Liu and colleagues suggests that administration of magnesium-l-threonate effectively increases NMDA receptor signaling and synaptic plasticity in the prefrontal cortex plus hippocampus of rat brains, leading to cognitive enhancement.  A study by Liu, Weinger, Lu, et al. (2015) tested MMF-01 (magnesium-l-threonate) in humans, finding that MMF-01 significantly improved cognitive function in older adults with impaired cognition, possibly through enhancement of synaptic density.  Although researchers knew that intraneuronal magnesium correlates with synaptic density, they had no way of measuring intraneuronal magnesium nor synaptic density in their participants.

Nonetheless, they discovered that degree of cognitive improvement in older adults with cognitive impairment significantly correlated with intracellular magnesium within red blood cells as measured by an RBC test.  What’s more, these correlations were only significant in persons taking magnesium-l-threonate, but not in controls – suggesting that the magnesium-l-threonate has an effect on synapses (in the prefrontal and hippocampal areas of the brain similar to rats).  Though additional research is necessary to confirm the effect of magnesium supplementation on synaptic density among individuals with major depression, there’s reason to believe that this is an important antidepressant mechanism.  That said, since not all types of magnesium effectively cross the blood brain barrier (BBB), this effect may only occur following administration of specific magnesium formats (e.g. magnesium-l-threonate).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26519439

Hormonal modulation: In some cases, depression is caused primarily by hormonal imbalances such as hypothyroidism, low testosterone, and/or high concentrations of stress hormones (e.g. cortisol).  When a person is severely deficient in magnesium, the neuroendocrine system becomes dysfunctional and hormone levels appear irregular.  Even if you’re experiencing hormonal abnormalities that aren’t associated with a magnesium deficiency, there’s reason to believe that magnesium administration may elicit an antidepressant effect through hormonal modulation.

As was already mentioned, lack of magnesium contributes to HPA (hypothalamic pituitary adrenal) axis dysregulation, whereby stress hormones such as CRH, ACTH, and cortisol increase.  This finding likely ties into the fact that magnesium concentrations throughout the body are typically inversely correlated with concentrations of norepinephrine (a stimulatory hormone and neurotransmitter released in times of stress).  Supplementation with magnesium appears to stabilize the HPA axis, thereby decreasing release of the aforestated stress hormones (CRH, ACTH, cortisol, norepinephrine, etc.).

For example, a study by Golf, Happel, Graef, and Seim (1984) discovered that magnesium supplementation significantly reduced aldosterone and cortisol secretion during exercise, as well as post-exercise cortisol levels.  It is also known that magnesium levels can affect parathyroid function, which in turn can affect mood, possibly contributing to depression if parathyroid concentrations are abnormally high or low.  Vetter and Lohse (2002) note that serum parathyroid and magnesium levels are dependent upon each other in a complex relationship, meaning that if magnesium intakes are poor, parathyroid problems may ensue.

Another important hormone that appears affected by magnesium is testosterone.  Maggio, De Vita, Lauretani, et al. (2014) report that magnesium appears to exert an effect on production or secretion of testosterone in men such that sufficient magnesium ensures normative testosterone levels.  A study by Cinar, Polat, Baltaci, and Mogulkoc (2011) tested the effect of magnesium supplementation on free and total plasma testosterone levels in sportsmen practicing tae kwon do over a 4-week duration.

Participants in the study were divided into 3 groups including: Group 1 (sedentary persons receiving 10 mg/kg/day magnesium), Group 2 (tae kwon do athletes receiving 10 mg/kg/day magnesium), and Group 3 (tae kwon do athletes receiving no magnesium).  Results indicated that magnesium supplementation increased free and total testosterone in both sedentary persons and athletes compared to the control group.  This provides reasonable evidence to support the idea that magnesium may normalize testosterone levels among individuals with suboptimal concentrations.

As is documented in the literature, abnormally low testosterone can cause and/or contribute to onset of an atypical depression.  Keep in mind that the effects of magnesium on hormone concentrations may not be limited to the aforestated stress hormones, parathyroid hormone, and/or testosterone.  That said, there’s clearly reason to believe that magnesium might promote mood improvements among persons with depression by modulating and/or correcting suboptimal hormones.

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Other mechanisms by which Magnesium may treat depression…

While the action of magnesium upon NMDA-coupled calcium channels, the HPA axis, and serotonergic transmission are hypothesized as the chief mechanisms by which magnesium alleviates depression, numerous other actions may be implicated in the antidepressant effect of magnesium.  Examples of antidepressant mechanisms possibly elicited by magnesium include: upregulation of BNDF, reduction of neuroinflammation, modulation of neurotransmitter systems (dopamine, GABA, norepinephrine), and decreasing oxidative stress.  Understand that the degree to which each of these mechanisms might contribute to the overall antidepressant effect of magnesium in humans remains unknown.

ANS regulation: Individuals with depression sometimes exhibit irregular ANS (autonomic nervous system) function.  Research by Hu, Lamers, de Geus, and Pennix (2016) discovered that persons with depression exhibit a combination of ANS hyporeactivity and hyperreactivity when exposed to various stressors, whereas non-depressed exhibit normative ANS function.  Although ANS dysfunction may not be the root cause of a person’s depression, correcting imbalances between sympathetic and parasympathetic branches might improve mood.

There’s reason to believe that magnesium supplementation may directly influence ANS activity, which in turn may uplift mood.  A study by Murasato, Harada, Ikeda, et al. (1999) indicated that the average blood pressure and catecholamine secretions were higher among rats with magnesium deficits than those with healthy magnesium levels.  An analysis revealed that magnesium deficits lead to sympathetic excitation, ultimately disrupting a healthy balance between sympathetic and parasympathetic branches of the ANS.

Shimosawa, Takano, Ando, and Fujita (2004) documented that magnesium inhibits norepinephrine secretion by blocking N-type calcium channels at sympathetic nerve endings, after which sympathetic tone decreases, and predictably, blood pressure drops.  Other studies have shown that magnesium supplementation decreases concentrations of stress hormones such as CRH, ACTH, and cortisol – partially through modulation of the HPA axis within the brain.  A decrease of stress hormones within the CNS should reduce the sympathetic “freeze-fight-flight” response in the peripheral.

Though a reduction in sympathetic tone may be an indirect effect from HPA axis modulation, it might also be a direct effect of increasing peripheral intracellular magnesium stores.  Martynov and Akatova (2011) note that magnesium-orotate significantly reduces sympathetic tone among patients with mitral valve prolapse, and that the sympathetic tone reductions are accompanied by improvement in quality of life.  In short, it is possible that magnesium-induced downregulation of sympathetic tone yields an antidepressant effect in some people.

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BDNF increase: Many experts believe that deficits in BDNF (Brain-Derived Neurotrophic Factor) concentrations within specific regions of the brain can: increase susceptibility to depression, directly cause depression, and/or exacerbate preexisting depressive symptoms.  Though BDNF abnormalities cannot be confirmed as a root cause of depression, it is understood that antidepressant medications and recovery from depression are each associated with elevations in hippocampal BDNF (compared to depressed states).  For this reason, it has been theorized that increasing hippocampal BDNF can directly attenuate depression.

Castrén and Rantamäki (2010) mention that expression of BDNF and its corresponding receptor TrkB are associated with neurogenesis, synaptic density, and neuroplasticity.  Individuals with depression often exhibit neurodegeneration, neuronal damage, synaptic dysfunction, and decreased plasticity – many of which may be related to BDNF irregularities.  Increasing BDNF has been suggested to reverse depression through: generation of new brain cells, synaptic strengthening, and remodeling of dysfunctional brain networks via plasticity.

Some evidence suggests that magnesium may interact with the BDNF pathway to improve mood.  Pochwat, Sowa-Kucma, Kotarska, et al. (2015) administered magnesium intraperitoneally once-daily at 3 doses (10, 15, or 20 mg/kg) to rats for 14 days and tested concentrations of BDNF in the prefrontal cortex and hippocampus.  Post-treatment analyses revealed significant increases in BDNF concentrations within both the prefrontal and hippocampal regions – the ideal areas for increases in BDNF expression.

Other work by Bachnas, Mose, Effendi, and Andonotopo (2014) reports that magnesium sulfate application increased cord blood BDNF levels among premature infants.  Abumaria, Yin, Zhang, et al. (2011) discovered that magnesium-l-threonate administration upregulates BDNF expression in the brains of rats, plus increases synaptic plasticity, learning, and memory.  Based on these findings, we might presume that antidepressant activity of magnesium is mediated (at least partly) through BDNF.

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Dopaminergic modulation: There’s mounting evidence to suggest that dopaminergic dysfunction is implicated in many neurobiological signatures of depression.  For this reason, many individuals report deriving significant antidepressant benefit after administration of dopamine reuptake inhibitors, dopamine releasers, and/or agents that increase dopamine throughout the brain.  Since data indicate that magnesium modulates dopaminergic processes, it’s possible that its modulation contributes to an antidepressant effect.

Initial data to support the idea that magnesium influences dopamine comes from a study by Izenwasser, Garcia-Valdez, and Kantak (1986).  The group of researchers theorized that magnesium affects aggression in mice through modulation of dopamine, norepinephrine, and serotonin.  They concluded that magnesium likely serves as a necessary cofactor in dopamine synthesis and activity.

Earlier research by Watanabe, George, and Seeman (1985) suggests that magnesium ions regulate dopaminergic activity through D2 dopamine receptor sites in the anterior pituitary region.  A study by Mizoguchi, Yokoo, Yoshida, et al. (1994) documented that magnesium inhibits amantadine-related increases in extracellular dopamine, suggestive of an ability to modulate dopamine.  Amyard, Leyris, Monier, et al. (1995) report that in mice with low blood magnesium levels, DOPAC (dopamine metabolite) concentrations within the brain appear to be reduced.

According to Okada, Mizuno, Okuyama, and Kaneko (1996), magnesium ions synergistically enhance the inhibitory effect of adenosine upon dopamine release in the striatum of rats.  Work by Okada and Kaneko (1998) reports that magnesium ion levels can affect concentrations of extracellular monoamines (including dopamine) generated by substances agonizing or antagonizing adenosine receptors.  Though the extent to which magnesium affects dopamine within the human brain isn’t known, it likely modulates some dopaminergic processes, each of which may contribute to an antidepressant effect.

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GABA modulation: Another mode of action by which magnesium might alleviate depression is through modulating the neurotransmission of GABA (Gamma-Amino-Butyric-Acid).  GABA is an inhibitory neurotransmitter within the brain, often associated with relaxation and decreased arousal.  Many anxiolytic medications such as the benzodiazepine classes function by allosterically modulating activation of GABAA receptors to deliver a sedative hypnotic effect, whereby stressors become more manageable.

Research by Möhler (2012) suggests that GABAergic abnormalities are often observed among persons with depression.  Particularly, individuals with major depression may exhibit deficits in GABAergic transmission, possibly as a result of excessive glutamate (an excitatory neurotransmitter).  Novel medications that act upon Alpha-2 and Alpha-3 GABAA receptors, and in some cases GABAB receptors, appear effective as antidepressants in preclinical trials.

A study by Möykkynen, Uusi-Oukari, and Heikkilä (2001) discovered that magnesium (Mg2+) modulates the effect of GABA upon GABAA receptors.  Another study by Poleszak (2008) discovered that magnesium interacts with BZD (benzodiazepine) or GABAA receptor sites in mice to facilitate anxiolytic effects.  Although the extent to which magnesium affects GABAergic transmission in humans remains unclear, some modulation is likely to occur.  Any modulation of the GABA system by magnesium may prove useful in facilitating an antidepressant response.

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Inflammation reduction: Many experts have acknowledged that depression may be directly caused by chronic inflammation.  Even if inflammation isn’t a direct cause of everyone’s depression, being depressed can lead to increased generation of proinflammatory cytokines.  For this reason, most persons with depression exhibit some inflammation which may perpetuate the existence and/or exacerbate the severity of depressive symptoms.

Berk, Williams, Jacka, et al. (2013) document that depression is associated with low-grade inflammatory responses, activation of cell-mediated immunity, and heightened activation of an anti-inflammatory reflex system.  Zunszain, Hepgul, and Pariante (2013) note that inflammation in depression may occur due to altered peripheral immune activity.  Impairments in cellular immunity can upregulate proinflammatory cytokine concentrations, which in turn modulate neurotransmitter levels in the brain and the entire neuroendocrine system.

Not only is systemic inflammation linked to depression, but it is also associated with suboptimal magnesium intake.  Research by Song, Li, van Dam, et al. (2007) discovered that magnesium intake was inversely associated with concentrations of several inflammatory markers including: CRP, E-selectin, and sICAM-1.  Work by Rayssiguier and Mazur (2005) revealed that magnesium modulates cellular events associated with inflammation.

Deficient magnesium intake leads to activation of macrophages which release inflammatory cytokines, but if extracellular magnesium concentrations are increased, inflammatory cytokine levels decrease.  Chandrasekaran, Weir, Alfraji, et al. (2014) theorize that magnesium ions interact with inflammatory mediators.  In vitro administration of magnesium ions leads to decreased expression of TNF-alpha and NFkB, each of which might cause neuroinflammation with corresponding depression.  In the event that magnesium supplementation significantly reduces systemic inflammation, this may be another mechanism by which it improves mood.

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Mitochondrial modulation:  Though not every person with major depression will exhibit mitochondrial abnormalities, evidence suggests that mitochondrial dysfunction may be a direct or contributing cause of depressive symptoms for others.  A report by Tobe (2013) suggests that mitochondrial dysfunction can disrupt normal brain function may lead to mood disorders such as major depression.  In his review, Tobe discovered that humans and animal models with depression often exhibited mitochondrial dysfunction in specific brain regions.

Bansal and Kuhad (2016) mention that mitochondria influence ATP production, intracellular Ca2+ signaling, reactive oxygen species (ROS) production, plus influence neurotransmission and plasticity.  For this reason, Bansal and Kuhad theorize that reversing mitochondrial dysfunction may prove useful for attenuating symptoms of depression in a subset of persons.  Normalizing mitochondrial function, especially in particular areas of the brain has potential to promote synaptic plasticity, neurogenesis, and should upregulate ATP levels.

Researchers Clerc, Young, Bordt, et al. (2013) note that excessive glutamate stimulation of NMDA receptors can decrease concentrations of neuronal ATP.  Nicholls (2004) highlights a relationship between mitochondrial dysfunction and glutamate excitotoxicity in neuronal cultures, it’s possible that the drop in ATP from unregulated glutamatergic transmission stems from downstream effects upon mitochondria.  More evidence linking magnesium to mitochondrial function comes from a study by Jia, Mou, Ma, et al. (2016).

The aforestated researchers discovered that magnesium exerts an effect upon mitochondria whereby mitochondrial membrane potential increases to promote neural stem cell proliferation within the hippocampus.  Additionally, it is known that magnesium is necessary for action of ATP synthase (an enzyme that manufactures ATP) within mitochondria, as well as for protecting mitochondria by antagonizing NMDA receptors.  Based on the evidence, it’s possible that supplementation with magnesium (assuming it crosses the blood-brain-barrier) may reverse mitochondrial dysfunction to enhance mood.

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Norepinephrine reduction: There’s some reasonable evidence to suggest that magnesium reduces norepinephrine concentrations, perhaps a significant mechanism by which it improves mood in a subset of depressed patients.  Although many individuals with depression are suspected to exhibit low norepinephrine signaling, whereby medications that enhance noradrenergic tone (e.g. SNRIs, NRIs, NDRIs, etc.) improve mood, other individuals will experience a worsening of depression from the enhanced norepinephrine signaling.  This is because certain neurobiological signatures of depression involve elevations in norepinephrine rather than deficits.

Evidence to support the idea that high norepinephrine could cause depression comes from research by Otte, Neylan, and Pipkin (2005) showing that severity of depressive symptoms can correlate directly with norepinephrine excretion.  Specifically, their research showed that individuals with depression exhibited the highest excretions of norepinephrine, whereas excretion of dopamine, epinephrine, and serotonin failed to differ between depressed and non-depressed persons.  Although this study involved patients with comorbid heart abnormalities, one might theorize that their particular neurobiological signature of depression involves heightened norepinephrine – rather than abnormalities throughout other neurotransmitter systems.

Goekoop, de Winter, and Wolterbeek (2012) discovered elevated plasma norepinephrine concentrations among persons with psychotic depression.  Given the fact that plasma norepinephrine is highly correlated with central noradrenergic activity, most would theorize that psychotic depression is associated with heightened norepinephrine levels within the brain.  Furthermore, the elevated central norepinephrine may be a principal cause of this depressive subtype.

Among individuals exhibiting depression from abnormally high norepinephrine, one of the most effective treatments may be magnesium.  Studies show that magnesium levels throughout the body are inversely correlated with norepinephrine.  A study by Amyard, Leyris, Monier, et al. (1995) assessed catecholamine levels within the brain of 3 types of mice based on genetically-mediated magnesium levels, discovering that magnesium levels were inversely correlated with norepinephrine.

Specifically, “low magnesium” mice exhibited the highest quantities of norepinephrine within the brain, signifying a higher reactivity or sensitivity to stress.  Conversely, the mice with high magnesium and outbred Swiss mice exhibited lower levels of norepinephrine within the brain.  Ohtsuka, Oyake, and Seo (2002) discovered that administration of magnesium sulfate infusions to humans attenuates release of norepinephrine in a handgrip test.

Shimosawa, Takano, Ando, and Fujita (2004) document that magnesium inhibits N-type calcium channels at sympathetic nerve endings to reduce norepinephrine secretion in the peripheral.  Reductions in concentrations of peripheral norepinephrine could play an indirect role in the treatment of depression and/or certain symptoms, especially agitation and/or anxiety.  Assuming magnesium supplements cross the blood-brain-barrier (BBB), it’s reasonable to theorize that norepinephrine concentrations decrease within the brain, yielding a pronounced antidepressant effect among those with depression caused by high central norepinephrine.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16263855
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23983957
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7545412
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Neuroregeneration: Anyone that’s incurred brain damage from a traumatic brain injury (TBI) is at increased risk for developing neuropsychiatric disorders such as depression and/or anxiety.  In the book “Traumatic Brain Injury and Depression,” Guillamondegui, Montgomery, Phibbs, et al. (2011) report that depression is extremely common after a traumatic brain injury regardless of its form or severity.  Data indicate that approximately 30% of persons who experience a TBI will develop depression.

There are numerous reasons as to why someone may end up depressed following a traumatic brain injury including: brain damage, connectivity alterations, blood flow abnormalities, brain wave irregularities, and more.  Preliminary evidence indicates that magnesium administration following a TBI may limit glutamatergic neurotoxicity and/or additional damage, plus may facilitate restoration of damaged areas.  Assuming magnesium exerts a neuroregenerative and/or protectant effect following TBI in humans, it may prove effective as a treatment for TBI-induced depression.

After a traumatic brain injury, decreased magnesium levels allow influx of calcium ions and glutamate to postsynaptic neurons which can contribute to neurodegeneration and neuronal death.  Administration of supplemental magnesium might treat TBI-related depression if delivered within a specific post-TBI timeframe and/or at an optimal dose.  That said, more research is necessary to evaluate whether magnesium is useful in the prevention or management of post-TBI depression.

A study by Fromm, Heath, Vink, and Nimmo (2004) discovered that magnesium levels plummet after a traumatic brain injury, leading to neuronal death and neural dysregulation.  They report that 6-77% of the population experiencing a TBI ends up with neuropsychiatric symptoms such as depression and anxiety.  Although damage occurs after a traumatic brain injury, the researchers note that administration of magnesium sulfate appears protective against TBI-related depression and anxiety in animal models.

Li, Bai, Li, et al. (2015) conducted a systematic review and reported the efficacy of magnesium sulfate as an intervention for acute TBI in humans.  They discovered that scores on the Glasgow Outcome Scale and Glascow Coma Scale were superior among persons receiving magnesium than control groups.  Significant improvements in outcomes among TBI patients receiving magnesium suggests should be considered as potentially protective against depression; the better a person’s ability to function after injury, the less likely they’re going to feel depressed.

  • Source: http://www.ncbi.nlm.nih.gov/books/NBK62061/
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15466958
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25723660

Nitric oxide reduction: There’s evidence that nitric oxide abnormalities occur in a subset of persons with depression.  It is understood that excessive stimulation of NMDA receptors from glutamate and/or calcium ions leads to a downstream generation of nitric oxide, as can release of proinflammatory cytokines.  Nitric oxide is implicated in blood flow and can influence the production of monoamines (dopamine, norepinephrine, and serotonin) throughout the brain.

In addition to increasing blood flow in certain areas of the brain plus modulating monoamines, elevated levels of nitric oxide within specific regions of the brain may directly cause depression.  For this reason, it’s possible that magnesium may alleviate depressive symptoms in some individuals by decreasing nitric oxide levels and/or production.  Findings by Rock, Astier, Lab, et al. (1995) suggest that magnesium deficiencies lead to significant increases in nitric oxide within rats, supporting the idea that magnesium regulates nitric oxide.

Howard, Alexander, and Taylor (1995) document that increasing intracellular magnesium decreases nitric oxide concentrations.  Though the effect of magnesium upon central nitric oxide levels in humans isn’t well-researched, it’s possible that magnesium might decrease nitric oxide generation, likely mediated through its NMDA receptor antagonism.  It’s plausible that decreases in nitric oxide stemming from magnesium supplementation could reduce depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8845288
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7573390

Oxidative stress reduction:  Correlations between oxidative stress and depression have lead some to suspect that oxidative stress may play a causal role in depressive symptoms and/or exacerbation of depression.  A systematic review and meta-analysis by Black, Bot, Scheffer, et al. (2015) reported that markers of oxidative stress such as 8-OHdG and F2-isoprostanes appear significantly elevated among persons with major depression.  Based on this finding, as well as evidence suggesting that many antidepressants reduce oxidative stress, it is hypothesized that reducing oxidative stress may improve mood – especially among those with high concentrations of oxidative biomarkers.

Administration of magnesium supplements might attenuate oxidative stress, whereby the attenuation leads to partial (or perhaps significant) mood improvement.  Morais, Severo, and Santos (2016) report that magnesium deficiency leads to increased oxidative stress in obese individuals.  Keenoy, Moorkens, Vertommen, et al. (2000) discovered a relationship between magnesium stores within the body and oxidative stress.

The researchers mentioned that magnesium supplementation reduces markers of oxidative stress and bolsters the effect of other antioxidants.  Most would acknowledge that magnesium acts as an antioxidant, increases total antioxidant capacity, and can counteract the effects of oxidative stress.  It’s possible that ongoing magnesium supplementation could the reduce oxidative stress implicated in depression to improve one’s mood.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25462890
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/27444303
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/10872900

Sleep enhancement:  Researchers understand that there’s a bidirectional relationship between sleep and depression such that, modifying sleep quality can affect mood AND altering mood can affect sleep quality.  Though not everyone with depression exhibits sleep abnormalities, and certainly not all cases of depression are caused by poor sleep, enhancing sleep quality often provides some therapeutic antidepressant benefit.  It appears as though magnesium supplementation may enhance sleep quality, possibly contributing to mood improvements – especially among those with depression caused primarily by poor sleep.

Depoortere, Françon, and Llopis (1993) suggest that magnesium deficits significantly alter sleep quality and time in rats.  Lack of magnesium in rats is associated with increased wakefulness at the expense of slow wave sleep.  When magnesium intake remains deficient for an extended duration, neuronal excitability increases (possibly due to excessive NMDA receptor stimulation) and rats are only capable of getting light sleep.  (Interestingly, the NMDA antagonist ketamine appears to increase slow-wave sleep activity, leading to theories that this may be a mechanism of its antidepressant activity).

Increasing magnesium intake via food and water leads to restoration of sleep abnormalities in the rats.  Takase, Akima, Satomura, et al. (2004) report that sleep deprivation significantly decreases intracellular magnesium levels and heart-rate variability (HRV), and leads to increased norepinephrine (which is sometimes high among persons with depression).  A study by Nielsen, Johnson, and Zeng (2010) documents that magnesium significantly reduces inflammatory stress among adults with poor quality sleep, which was theorized to improve their sleep quality.

Evidence supporting the idea that magnesium supplementation improves sleep quality comes from a trial by Abbasi, Kimiagar, Sadeghniiat, et al. (2012).  This double-blind, placebo-controlled, randomized trial reported that magnesium supplementation improved insomnia, sleep efficiency, sleep time, sleep onset latency, early morning awakenings – plus biomarker levels such as serum renin, melatonin, and cortisol – in elderly persons with insomnia.  Knowing that magnesium can reduce severity of sleep disorders and enhance sleep quality, it’s possible that the sleep improvements contribute to the reversal of depression in some individuals.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8232845
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15754837
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21199787
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23853635

Understand that some of the mechanisms by which magnesium might improve mood may be interrelated.  As an example, magnesium’s antagonism upon NMDA receptors is associated with downstream reductions in nitric oxide, increased synaptic density, mitochondrial regulation, decreased inflammation, and lower oxidative stress.  Even though all these mechanisms improve mood, they each stem from the effect of magnesium upon NMDA/glutamate pathways.

That said, some mechanisms of magnesium’s antidepressant action may be unrelated, yet facilitate complementary benefit.  For example, magnesium may accumulate in peripheral cells to prevent secretion of norepinephrine in the peripheral nervous system (which may reduce restlessness and improve mood).  At the same time, magnesium may cross the blood brain barrier to modulate neurotransmission of serotonin – which also enhances mood.

It is reasonable to consider that magnesium may be effective in treating different types of depression through individually-relevant mechanisms of action.  For example, someone with depression caused by HPA axis dysregulation may benefit most from the attenuation of HPA axis activation by magnesium.  On the other hand, someone with depression cause primarily by excessive glutamatergic transmission or synaptic loss in the prefrontal cortex may benefit more from the NMDA antagonism of magnesium.

Another possibility is that someone’s depression may have been caused directly by an underlying magnesium deficit (centrally and/or peripherally).  Any deficit could’ve lead to a host of unfavorable biological adaptations such as inflammation, oxidative stress, glutamate-induced excitotoxicity, etc.  Though it may take some time to correct the magnesium deficiency, eventually the accumulation of magnesium stores should counteract the unfavorable biological adaptations to improve mood.

Benefits of Magnesium for Depression (Possibilities)

Included below is a list of potential benefits to be derived from administration of magnesium for depression.  Some of the most prominent benefits associated with magnesium supplementation as an antidepressant intervention include: limited side effects, few interactions, and zero withdrawal symptoms.  Other advantages associated with using magnesium to manage mood could include: adjunct efficacy, treatment of medical comorbidities, and/or its low cost.

Adjunct intervention: Magnesium may be a useful adjunct intervention for the treatment of depression.  In a subset of individuals, magnesium provides mood enhancement when administered as a standalone agent, plus appears to facilitate synergistic antidepressant effects when co-administered with SSRIs, NMDA antagonists, and caffeine.  Murch (2013) noted that administration of magnesium acts synergistically with conventional antidepressants in animal models and reduces likelihood of refractory depression.

A study by Poleszak (2007) discovered that magnesium (10 mg/kg) administered with serotonergic antidepressants (citalopram or tianeptine) to rats – generated a more noticeable antidepressant effect on the forced swim test (FST) compared to each as a standalone.  Vujovic, Vuckovic, Srebro, et al. (2015) reported a synergistic antinociceptive effect was derived from co-administration of magnesium and ketamine.  Considering the neurobiology of pain perception and mood overlap, we could speculate that inhibition of nociception could enhance mood, at least in a subset of persons.

Other preliminary research suggests that upregulation of intraneuronal magnesium may augment the antidepressant effectiveness of ketamine, such that the administration of magnesium prior to ketamine may yield superior long-term antidepressant effects than standalone ketamine.  What’s more, Serefko, Szopa, Wlaź, et al. (2016) documented synergistic antidepressant-like effects from administration of caffeine plus magnesium (and other NMDA antagonists).  Overall, it appears as though bioavailable magnesium supplementation works in synergy with many antidepressants, including SSRIs.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23541145
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17447000
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26214789
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26510772

Anecdotal efficacy: Anecdotal accounts circulating throughout the internet, as well as select medical databases suggest that magnesium supplementation is sometimes effective for the treatment of depression.  In fact, some individuals have mentioned magnesium supplementation as being a complete “cure” for their chronic, unremitting depression.  Although we must consider that individuals reporting significant antidepressant benefit from magnesium might have exhibited an underlying magnesium deficiency that caused their depression, we must also be open to the idea that increasing intraneuronal magnesium is a valid antidepressant intervention – even among those without deficiencies.

Some anecdotal reports discuss taking magnesium without knowing that it can improve mood.  Individuals may supplement with magnesium due to suspicion of a deficiency and/or after hearing that it may reduce symptoms of another health condition.  After supplementing with magnesium for several weeks or months, the person may notice that their depressive symptoms significantly decreased.  Though anecdotes are certainly not legitimate scientific data, the fact that anecdotes exist supports the idea that magnesium may treat depression – at least in some persons.

Cognitive enhancement: Many persons with depression experience severe cognitive dysfunction, ultimately impairing their academic and/or work performance.  The impairment may become so debilitating, that the person underperforms and gets fired from his/her job.  Another possibility is that individuals become so frustrated with their inability to think clearly, that they simply quit working – they feel disabled by their illness.

The cognitive dysfunction implicated in depression has many causes, some of which are likely individualized.  Nonetheless, it appears as though certain types of magnesium may facilitate cognitive enhancement.  In fact, magnesium preparations (e.g. L-threonate) may be among the most underrated cognitive enhancers and/or cognitive preservers on the market.

Magnesium ameliorates cognitive deficits primarily through action upon the NMDA receptors.  Research in animal models shows that magnesium-l-threonate increases synaptic density in the prefrontal cortex, promotes hippocampal neurogenesis, and bolsters neuroplasticity – all of which are associated with enhanced cognition.  Reversal of cognitive decline and/or improved cognitive abilities among depressed persons may contribute to the overall antidepressant effect.  When a person is able to think clearly, he/she is less likely to feel depressed.

Comorbid medical conditions: Magnesium is utilized as a supplement for the management of numerous medical conditions.  If you suffer from depression plus a neuropsychiatric comorbidity or medical condition, it’s possible that magnesium supplementation may help treat both conditions.  For example, many individuals with depression also deal with: anxiety, migraines, and insomnia – each of which are understood to benefit from magnesium administration.

Additionally, even unrelated or general health conditions may respond to magnesium supplementation.  Magnesium has “A”-level evidence to support its usage for the treatment of eclampsia, preeclampsia, rapid atrial fibrillation, and torsade de pointes, plus has “B”-level evidence backing its usage for the treatment of asthma, constipation, dyspepsia, and migraine.  Moreover, since many medical conditions are caused by magnesium deficiencies, increasing magnesium intake via supplementation may be an effective way to preserve long-term health – while simultaneously attenuating depression.

Depressive subtypes: Most researchers understand that there are many different neurobiological signatures implicated in major depression.  Two persons with major depression may exhibit radically different underlying neurobiological signatures, such that, one may have impaired activity in the prefrontal cortex from a brain injury and the other may carry a genetic polymorphism that alters serotonin concentrations in areas of the brain to provoke depressive symptoms.  It is thought that certain subtypes of major depression may respond especially well to ongoing magnesium supplementation.

The most likely subtype to respond is a person with depression caused by an underlying magnesium deficiency.  In terms of neurobiology, magnesium influences NMDA receptors, serotonin activity, norepinephrine, hormone production, autonomic nervous system activation, and more.  Anyone with depression caused by irregularities within the neurobiological systems that magnesium supplementation targets may experience profound symptomatic improvement.  Individuals with “anxious-depression” and “agitated-depression” are just a couple depressive subtypes that may benefit (at least slightly) from magnesium.

Efficacy: Preclinical animal model research suggests that magnesium supplementation effectively treats depression.  In animal testing, administration of magnesium appears to reduce immobility times on the forced swim test (FST) equally as much as conventional antidepressants.  Although there is a paucity of research testing the antidepressant effects of magnesium in humans with depression, the available studies support the hypothesis that it is likely effective.

The first test of magnesium for the treatment of depression was by Weston in 1922.  He reported that injections of magnesium sulfate appeared useful in the management of depressive symptoms, especially among those with comorbid agitation.  Another study tested the effect of magnesium supplementation among elderly patients with diabetes, hypomagnesemia, and depression and discovered that supplementation lead to significant mood improvements.

While the evidence supporting the usefulness of magnesium as an antidepressant may not be strong, it’s necessary to highlight the fact that there’s no evidence indicating that it may be ineffective for the treatment of depression.  Zero of the available studies have concluded that magnesium is useless, ineffective, and/or harmful for the treatment of depression.

Few interactions: Although magnesium can interact with other substances (pharmaceutical drugs and medications), the number of substances with which it interacts is limited.  Those taking magnesium for the treatment of depression will be most concerned with whether magnesium could interact with another neuropsychiatric medication.  Anytime you introduce a new supplement to your regimen, including magnesium, it is important to confirm safety and efficacy with your doctor.

That said, it appears as though magnesium is unlikely to provoke interaction effects when co-administered with most neuropsychiatric medications.  Preliminary research in animal models suggests that co-administration of magnesium plus conventional serotonergic antidepressants caused zero overt interaction effects.  The lack of interaction effects might make magnesium a favorable option over other adjunctive interventions.

Inexpensive: Many magnesium supplements are extremely inexpensive.  If magnesium supplementation improves your mood, it may turn out to be significantly cheaper than new antidepressants and visits to a doctor or psychiatrist.  A problem for many individuals seeking mental health treatment is often that certain medications are unaffordable – even with health insurance and/or coupons.

For example, a 30-day supply of the relatively new SNRI “Pristiq” (Desvenlafaxine) costs around $300 or around $10 per day of treatment.  If you end up paying out of pocket, a 1-year supply of Pristiq will be around $3,650.  Comparatively, even the most expensive form of magnesium (e.g. magnesium-l-threonate) is approximately 1/10th the cost of Pristiq at around $1 per day of treatment, making it significantly less expensive.

Limited side effects: Assuming you aren’t taking substances that interact with magnesium and/or you don’t have a health condition in which magnesium supplementation is contraindicated, you probably won’t experience many side effects.  Many people taking magnesium supplements don’t notice any side effects.  Others may report mild drowsiness and/or relaxation if they take a large amount.

Still, even at fairly high doses, the side effects of magnesium are generally manageable.  Common side effects associated with magnesium supplementation include diarrhea, nausea, and upset stomach.  Moreover, the side effect profile of magnesium is likely preferable over that associated with conventional antidepressants (e.g. cognitive deficits, weight gain, sexual dysfunction).

Non-pharmaceutical: Many individuals refuse to use prescription antidepressants because they’ve either tested them with limited symptomatic improvement and/or they fear them.  Some won’t take prescriptions because they believe big pharmaceutical companies are conspiring to induce dependence among users.  Regardless of a person’s reason for avoiding pharmaceutical antidepressant interventions, untreated depression will remain a serious problem.

It is reasonable to believe that some individuals who refuse prescription drugs might be willing to test non-pharmaceutical alternatives such as magnesium to treat their depression.  The non-pharmaceutical status of magnesium may be viewed as favorable in that a person can purchase it legally online and/or at a health store.  Additionally, doctor visits, corresponding payments, and waiting in line at pharmacies (for prescriptions) won’t be necessary among those treating depression with magnesium.

Safety: There are no reports of severe adverse events occurring as a result of administering magnesium supplements for the treatment of depression.  Researchers believe that, even if an adverse reaction were to occur, it could easily be counteracted with supplemental calcium.  Among persons who administer normative doses of magnesium and confirm with a professional that magnesium is safe to take in accordance with their current medication regimen and/or medical conditions – there shouldn’t be significant safety concerns, even over a long-term.  In fact, some would argue that it may be safer to supplement with magnesium than endure a long-term, unmanaged magnesium deficit.

Sleep enhancement: A complaint among many individuals with depression is poor sleep.  Depression can interfere with the transition from wakefulness to sleep, alter the duration of REM sleep, and may prevent slow wave sleep in a subset of persons.  Additionally, those with depression exhibit extremes in terms of sleep length such as under 7 hours/night or in excess of 10 hours/night.  Magnesium supplementation is known to expedite the transition from wakefulness to sleep and can alleviate insomnia.  Moreover, research in rodents suggests that magnesium supplements can improve sleep architecture.

Zero withdrawal symptoms: In the event that you take magnesium and discontinue supplementation abruptly (e.g. cold turkey), you probably won’t notice any withdrawal symptoms.  You might subjectively notice a gradual change in your functioning if you consume zero dietary magnesium after discontinuation, but this is likely be due to depletion of magnesium stores from lack of intake – not a withdrawal effect.  The fact that there’s no withdrawal after magnesium supplementation is favorable when compared to conventional antidepressants.

For the sake of comparison, ceasing usage of pharmaceutical antidepressant treatments commonly leads to debilitating withdrawal symptoms – many of which persist for months after your final dose.  Even if the pharmaceutical didn’t effectively improve your mood, it will have altered the connectivity and neurotransmission within your brain significantly.  When you stop taking the pharmaceutical antidepressant, your brain will take awhile to reconfigure itself, and for this reason, withdrawal symptoms are endured.  Magnesium is an element that your brain is naturally adapted to utilize, an SSRI is not – hence withdrawals from one and not the other.

Drawbacks of Magnesium for Depression (Possibilities)

It is important to be critical of the idea that magnesium supplementation is a utopian intervention for depression.  There are many drawbacks associated with using magnesium for depression, including potential contraindications, interactions, and the total cost of supplementation.  Perhaps the most logical reason to avoid magnesium supplementation is that numerous interventions (pharmaceutical and non-pharmaceutical) have more evidence supporting their efficacy.  Moreover, researchers still aren’t sure what dosage or format of magnesium may be most effective for the treatment of depressive symptoms.

Contraindications: There are certain individuals for whom magnesium supplementation is contraindicated.  For these individuals, supplementing with magnesium, especially in particular formats, might be harmful.  Some sources suggest that magnesium should be avoided or used with caution among persons with: auto-immune diseases, certain gastrointestinal disorders, diabetes, a history of hypotension (magnesium lowers blood pressure), intestinal blockage, kidney dysfunction (may exacerbate the dysfunction).  While some of these contraindications are likely questionable, it is important to realize that even dietary supplements might be harmful for a subset of the population.

Cost: Some might consider supplementing with magnesium to be expensive, especially if magnesium-l-threonate turns out to be the most effective formulation for altering brain function.  Research in animal models supports the idea that magnesium-l-threonate crosses the blood-brain-barrier more efficiently than other preparations.  Assuming you need to take magnesium-l-threonate for the management of your depression, it may cost around $1 per day.  If you supplement daily for an entire year, that’s $365 worth of magnesium.  Some suppliers may manufacture this supplement for a lower cost (e.g. $0.66 per day), however, certain individuals may claim that even this is unaffordable.  By comparison, generic antidepressant medications typically cost less than half of magnesium-l-threonate for a 30-day supply.

Exacerbation of symptoms: Though preliminary evidence suggests that magnesium supplementation is likely to facilitate an antidepressant effect, it is possible that certain magnesium formats and/or dosages may exacerbate depressive symptoms.  Any worsening of depressive symptoms might further impair one’s ability to cope with major depression and/or may induce suicidal ideation.  Despite the fact that symptomatic exacerbation hasn’t been reported in the literature, anecdotes have documented unwanted mood swings and severe neuropsychiatric symptoms shortly after initiation of magnesium supplementation.  Although worsening of depression may be nothing more than a transient adaptation response to magnesium that subsides after several days or weeks, it is important to acknowledge that certain magnesium supplements may be of detriment to the mental health of select individuals.

Ineffective: Magnesium appears useful as an antidepressant among animal models of depression.  Administration of magnesium reduces immobility times on the forced swim test as well as FDA-approved antidepressant drugs.  That said, just because magnesium works well in rats and mice with depression does not mean that these benefits will be attained in humans.  Many substances appear to alleviate depressive behaviors in animals, yet when tested in humans with depression, they fail miserably as antidepressants.

As of current, there are only a couple studies that have sought to test the antidepressant potential of supplemental magnesium in humans.  Although both of these studies documented mood enhancement, one involved a population with hypomagnesemia – a condition characterized by low serum magnesium that can directly cause depression.  In the hypomagnesemia study, it would be expected that magnesium supplements improve hypomagnesemia, and consequently, mood.

The other study was published in 1922 and was uncontrolled, non-randomized, and non-blinded – meaning that a placebo effect may have occurred.  Furthermore, even if magnesium is effective for a subset of persons with major depression, not everyone will derive significant benefit.  It is likely that magnesium supplementation (in proper dose and format) will improve symptoms among those with specific depressive subtypes (e.g. depression caused by excessive glutamate or ionic stimulation of NMDA receptors).

Interactions: There are some substances that could interact with magnesium supplements, especially if administered at the exact same time.  For this reason, if you’re on another pharmaceutical drug or supplement stack, you may be unable to take magnesium due to a possible adverse reaction.  Research suggests that magnesium supplements may cause interaction effects when administered with: antihypertensive and blood pressure medications (e.g. calcium channel blockers), diabetic medications (blood glucose regulators), diuretics, hormone replacement therapy drugs, etc.

What’s more, magnesium supplements can interfere with absorption of antibiotics (e.g. quinolones, tetracycline, etc.), osteoporosis medications, and certain psychiatric drugs (e.g. gabapentin, pregabalin, etc.).  Usually interference of absorption isn’t a big deal and can be avoided by separating administration times of each respective substance.  That said, interaction effects of certain magnesium supplements administered with another substance could lead to a medical crisis in select persons.

Magnesium specifics (unknown): Another likely drawback associated with using magnesium as a treatment for depression is that not all formats and dosages may work equally well.  Upon hearing that magnesium effectively treats depression, someone may purchase a bulk supply of magnesium oxide pills only to derive zero benefit.  Since magnesium oxide isn’t very bioavailable and is extremely unlikely to cross the blood brain barrier, chances are that it won’t be useful as an antidepressant.

On the other hand, forms of magnesium such as: citrate, glycinate, and/or l-threonate might prove effective for managing depression by crossing the blood-brain-barrier (BBB).  That said, no definitive protocols have been established for using magnesium as an antidepressant.  Until rigorous clinical testing is conducted, it’s impossible to know if any format reaches the brain in sufficient quantity to alleviate depressive symptoms.

Side effects: Despite the fact that unwanted side effects seldom occur from magnesium supplementation, it’s possible that a small percentage of individuals may report that side effects of magnesium supplements are difficult to tolerate.  Examples of side effects that could occur from magnesium supplements include: diarrhea, gastrointestinal issues, nausea, stomach aches, and vomiting.  In the event that you experience diarrhea each time you take magnesium, you’ll probably discontinue even if it was helping your depression.  Ongoing unwanted side effects, even if they only occur in select persons, should be listed as a rare potential drawback of magnesium supplementation.

Superior options: Most people with depression want and/or need relief from their depressive symptoms as soon as possible.  Untreated depression can affect all facets of life including: relationships, occupational status, and physical health.  If depression isn’t treated in a timely manner, an individual may experience thoughts of helplessness and/or hopelessness, followed by suicidal ideation – and possibly, suicide.

Unfortunately, magnesium supplements haven’t been rigorously tested in controlled trials among humans with major depression.  This means that anyone taking magnesium in hopes of treating depression won’t have any idea as to whether it’s even likely to work.  For this reason, for the quickest possible relief from depressive symptoms, it makes sense to choose an intervention that has a track-record of efficacy and safety.  Many pharmaceutical drugs (SSRIs, SNRIs, TCAs, MAOIs) and even some dietary supplements (e.g. St. John’s wort) should be considered superior interventions [to magnesium] for the treatment of depression.

Unknown long-term efficacy: Even if it turns out that magnesium supplementation induces a significant antidepressant response over a short-term, it’s unknown as to whether the therapeutic response would persist for a longer duration.  Many substances effectively attenuate depressive symptoms when administered for a brief duration, yet when continued for an extended term, the therapeutic effect of the substances dwindle, and the depression returns.  Unfortunately, at this time, no research has evaluated outcomes among humans with major depression receiving magnesium supplements for a long-term.

In fact, there isn’t even research testing the long-term effect of magnesium supplementation in animal models.  Preliminary data indicate that magnesium supplementation appears useful as a mood enhancer over a period of several weeks, but it is unclear as to whether the antidepressant effect is continually reaped indefinitely.  Some might speculate that the reported mood boosting effect derived from magnesium may be nothing more than a transient adaptation-type effect that inevitably ceases.

Magnesium for Depression (Review of Research)

Included below are summaries of studies that have sought to either: elucidate the relationship between magnesium intake and depression and/or test the therapeutic potential of magnesium supplementation for the treatment of depression.  Understand that many of the studies were conducted using animal models (rats and mice), meaning the results cannot be automatically generalized to humans.  Nonetheless, most data are consistent in the finding that low dietary magnesium intake is strongly correlated with depression.  Moreover, in both humans and animal models, administration of magnesium supplements effectively attenuates depression resulting from an underlying magnesium deficiency.  Further research is warranted to determine if supratherapeutic magnesium supplementation may treat depression among those without measurable deficiencies.

2015: Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behavior.

Researchers Winther, Jørgensen, Elfving, et al. (2015) note the fact that gut microbiota can influence rodent behavior, and might also affect human behavior, through the gut-brain-axis (GBA).  In their article, it was noted that composition of gut microbiota is influenced principally via dietary intake.  For this reason, researchers hypothesized that modification of essential nutrient intake may deleteriously affect the gut microbiome and induce unfavorable behavioral changes.

Given that previous research suggested magnesium deficiencies provoke anxiety and depression in rodents, researchers sought to investigate whether restricting dietary magnesium would alter gut microbiota composition, as well as behavior.  A study was organized in which mice (C57BL/6) were assigned to receive a standard diet (including magnesium) OR a magnesium-deficient diet – for a duration of 6 weeks.  After the 6-week duration, researchers compared each group of mice on: the forced swim test (FST) to measure depressive behavior, a glucose tolerance test (GTT) to gauge metabolism, neuroinflammation assays, and gut microbiota tests to determine differences in gut bacteria.

Results indicated that mice receiving magnesium-deficient diets exhibited significantly greater immobility on the FST, indicative of depression.  Although no changes were apparent between the two groups of mice on glucose tolerance tests, gut microbiota tests revealed significant changes in microbial composition among the magnesium-deficient mice compared to those eating standard diets (with magnesium).  Furthermore, the greater the degree to which gut microbiota was altered by the magnesium deficiency, the more pronounced the depressive behavior.

Mice consuming diets lacking magnesium exhibited substantial inflammation within the hippocampus as evidenced by heightened concentrations of interleukin-6.  Based on these results, researchers postulate that a magnesium-deficient diet alters gut bacteria composition and gut-brain-axis (GBA) activation to cause depressive behavior in animal models.  Despite this theory, it is necessary to realize that altered gut microbe composition and gut-brain-axis (GBA) activity are unlikely the sole mechanisms by which a magnesium deficiency induces depression.

A myriad of biological changes throughout the brain and body occur when magnesium levels are low, many of which could contribute to depressed mood.  Additionally, since this study was conducted in mice, we must consider that the findings may not generalize to humans.  Overall, this study supports the idea that magnesium deficiencies can induce depressive behavior in animal models, in part by altering microbial composition of the gut.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25690713

2015: Magnesium intake and depression in adults.

Tarleton and Littenberg (2015) discuss the fact that magnesium supplementation appears to alleviate depressive symptoms among many individuals diagnosed with major depressive disorder (MDD).  For this reason, researchers conducted a study analyzing the relationship between dietary magnesium intake and depression.  Researchers examined data compiled by the National Health and Nutrition Examination survey from 2007 to 2010, encompassing a total of 8,894 adults.

From the survey, adults with Patient Health Questionnaire (PHQ) scores greater than 5 were considered depressed, and adults consuming less than 184 mg/day were considered to have low magnesium intakes.  Even after ruling out potential confounds, there was a strong and statistically significant relationship between depression and low magnesium intake among the adults.  The relationship between depression and low magnesium intake was most pronounced in younger adults (under the age of 65).

Considering these findings, it is reasonable to hypothesize that adequate dietary magnesium intake may protect against onset of depression.  Of interest is the fact that, opposite to findings in younger adults, high magnesium intake was associated with increasing rates of depression in elderly persons (over 65 years of age).  That said, the correlation between high magnesium intake and depression in elderly patients is not as strong as the relationship between low magnesium intake and depression in younger adults.

Authors mention that randomized controlled trials (RCTs) are necessary to substantiate preliminary links between magnesium intake and depression.  These would likely involve assigning individuals at random to receive either magnesium supplements (to meet the RDA) OR a placebo (control) and documenting mood over an extended duration.  Although a strong correlation does not prove causation (even after ruling out confounds), it supports the hypothesis that low magnesium intake may cause and/or increase susceptibility to depression in humans.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25748766

2014: Essential elements in depression and anxiety. Part I.

Młyniec, Davies, de Agüero Sánchez, et al. (2014) discuss the fact that essential nutrients are important for maintaining healthy function of the human body.  In the event that a person exhibits an essential nutrient deficiency, he/she is at risk for developing serious health conditions, and in extreme cases, the deficiency could lead to premature death.  Authors also mention that suboptimal intake of essential nutrients can cause and/or exacerbate neuropsychiatric disorders such as anxiety and depression.

In animal models, any significant nutrient deficiency induces anxious and depressive behavior.  As expected, when dietary supplements are administered to animal models for the correction of a significant deficiency, the supplements significantly attenuate deficiency-related anxious and depressive behaviors.  What’s more, administration of dietary supplements appears to bolster the therapeutic efficacy of neuropsychiatric medications and often attenuates unwanted antidepressant side effects.

Common essential nutrients that are deficient among persons with major depression include:  zinc, lithium, iron, calcium, chromium – and magnesium.  From the perspective of researchers, the effectiveness of a specific essential nutrient for the treatment of depression is largely subject to individual variation based on depressive subtype (neurobiological “depressive” signature).  In other words, some persons with depression will exhibit dysfunctional neurotransmission and receptor activation, in such a way, that magnesium supplementation acts as a highly-effective intervention.

Another subset of individuals with depression may administer magnesium and find that it fails to improve mood.  That said, those who don’t benefit from magnesium supplementation may find that supplementation with another essential nutrient such as zinc lifts their mood quickly.  Realize that yet another subset of patients with major depression might benefit most from administering a unique blend of supplemental nutrients such as: iron, magnesium, and zinc – each in different quantities based on individual neurobiology.

Perhaps the most logical method for determining if you’d benefit from a nutritional supplement to alleviate depressive symptoms is through testing.  Subjecting yourself to the most accurate medical testing can determine if you’re deficient in any nutrients, and if so, which deficiencies can be reversed through supplementation.  Overall, this publication supports the idea that magnesium (and other elements) can attenuate symptoms of depression for certain individuals when administered at optimized dosages.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24948052

2014: New paradigms for treatment-resistant depression.

Zarate, Duman, Liu, et al. (2014) review the facts that depression is a serious neuropsychiatric condition affecting approximately 15% of the population and is associated with symptoms such as:  anhedonia, low mood, and loss of interest in daily activities.  Authors further note that depression, especially over a long-term, increases risk of cardiovascular events and suicide.  For the past half-century, depression has been treated with pharmacological interventions such as:  MAOIs, TCAs, SNRIs, and SSRIs – each of which modulate the neurotransmission of monoamines (serotonin, norepinephrine, and dopamine) to enhance mood.

Despite the fact that neuropsychiatric antidepressant medications are clinically effective, they are far from perfect.  Various limitations associated with antidepressant medications include: slow-onset of action (sometimes taking between 4 and 8 weeks to “kick in”), lack of efficacy (many patients don’t respond to treatment), worsening of depression and suicidality (in some patients), side effects (cognitive deficits, sexual dysfunction, weight gain), and the fact that they stop working after an extended term of administration (due to tolerance).  Due to the problems associated with currently-available antidepressants, researchers are creating new antidepressants.

Some of the newer antidepressants in the pipeline function as NMDA antagonists, whereby they bind to NMDA receptor sites and inhibit glutamatergic-induced activation.  Additional investigations have revealed substantial abnormalities in glutamatergic transmission among persons with major depressive disorder, making NMDA antagonists (e.g. intranasal ketamine) appealing as prospective treatments.  Although potent pharmaceuticals are being investigated to normalize glutamatergic signaling, most professionals haven’t considered the “bigger picture” importance of magnesium.

Zarate, Duman, Liu, et al. highlight the fact that magnesium homeostasis interacts with stress pathways, which in turn are linked with glutamatergic abnormalities implicated in depression.  In animal models, magnesium depletion leads to overactivity of NMDA receptors and corresponding depression plus anxiety symptoms, along with: elevated cortisol, sleep disturbances (reduced slow-wave sleep), and neuroinflammation.  For this reason, authors of this paper hypothesize that magnesium deficits can induce depression, and speculate that magnesium supplementation may augment preexisting antidepressant interventions.

Liu and his laboratory discovered that deliberately increasing extracellular magnesium concentrations promotes synaptogenesis and synaptic plasticity, each of which may prove useful in attenuating depression.  Specifically, when extracellular magnesium concentrations are increased, calcium influx via NMDA receptors is selectively reduced.  The downregulation in basal calcium upregulates NR2B subunits within NMDA receptors, yielding enhancement of synaptic plasticity.

Knowing that magnesium within the brain can enhance synaptic plasticity and protect against depression, Liu and his team sought to devise ways in which magnesium could be effectively shuttled across the blood-brain-barrier (BBB) for enhanced synaptic plasticity.  Most already-available magnesium supplements exhibited low bioavailability plus did not exert an effect upon brain function.  Liu and others eventually formulated a compound known as Magnesium-L-Threonate (Magtein™) which effectively increased brain-concentrations of magnesium in rodents.

Thereafter, researchers examined the effect of Magnesium-L-Threonate administration on the brain.  It was discovered that Magnesium-L-Threonate increased synaptic density and plasticity in the prefrontal cortex and hippocampus via enhancement of NMDA receptor signaling, each of which are associated with cognitive enhancement and emotional control, respectively.  Animal models of depression exhibit reduced immobility times on the forced-swim test (FST) when given Magnesium-L-Threonate, suggesting that it could treat certain types of depression.

What’s more, Magnesium-L-Threonate completely reverses escape deficits in a learned-helplessness paradigm plus decreases anxiety in several models including: elevated plus maze, novelty-suppressed feeding test, and open field tests.  The work by Liu substantiates the idea that supplementation with the right format of magnesium (Magnesium-L-Threonate) may prove useful for the treatment of major depression in humans, as well as comorbidities such as cognitive dysfunction and/or anxiety.  Additional research by Simone Sartori from the University of Innsbruck shows that central NMDA receptor activity is influenced by magnesium.

Unpublished data from Sartori shows that magnesium deficits in animal models leads to elevated body temperature, behavioral despair, and anhedonia – as evidenced by immobility times on forced-swim tests (FST) and tail-suspension tests (TST).  There’s also evidence that magnesium deficiencies can cause simultaneous onset of anxious plus depressive behavior in animal models.  Since over half of the U.S. population is deficient in magnesium, and rates of depression plus anxiety continue to increase, it’s reasonable to suspect that chronic ongoing magnesium deficits may be a primary cause – for a subset of persons.

By assessing protein expression in magnesium-deficient rodents, researchers discovered that magnesium deficiencies may lead to hyperactive NMDA receptor and nitric oxide (NO) signaling to cause depressive and anxious behaviors.  It also appears as though magnesium deficiencies increase secretion of stress hormones such as ACTH32 and aldosterone in mice, ultimately impairing mood control and immune function.  Authors suggest that rodents with magnesium deficiencies share many commonalities with depressed humans, including: NMDA receptor overactivation, stress pathway overactivation, monoaminergic imbalances, and anxious/depressed behavior.

Allegedly, magnesium-deficient rodents are among the most useful animal models for testing new antidepressants due to the fact that magnesium deficiency disrupts a host of neurobiological processes that cumulatively contribute to depressed mood.  Furthermore, when considering magnesium deficiencies substantially alter neurobiology to cause depression, we must consider that ramping up magnesium intake via diet and/or supplements (e.g. Magnesium-L-Threonate) could prove extremely effective as an antidepressant intervention.  Overall, this paper supports the idea that low magnesium (especially in the brain) can cause depression and that magnesium supplementation is likely useful as a standalone or adjunct antidepressant treatment.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23876043

2013: Magnesium and depression: a systematic review.

Derom, Sayón-Orea, Martínez-Ortega, and Martínez-González (2013) report that diagnoses of depression throughout the world appear to be increasing.  The team of researchers also mentioned that magnesium appears to act as a depression prophylactic and as an antidepressant by ameliorating already-occurring depressive symptoms.  What’s more, biological pathways influenced by magnesium and those implicated in the pathogenesis of major depressive disorders appear to overlap.

For this reason, researchers sought to conduct a systematic review to explore the relationship between magnesium intake and depression in humans.  To conduct the review, researchers collected data from 21 cross-sectional studies, 3 intervention trials, 1 prospective study, 1 case study, and 1 case series study – each of which met inclusion criteria.  Assessment of the data revealed that high dietary magnesium intake was strongly associated with less depression.

That said, there was no conclusive relationship between magnesium concentrations in blood or CSF (cerebrospinal fluid) and depression.  Despite the finding that high magnesium intake via diet is associated with lower depression, it is important to avoid automatically assuming that high magnesium intake is protective against depression.  It’s possible that some individuals developed depression with adequate magnesium intakes, and once their depression became severe, they had a difficult time adhering to a nutrient-dense diet, ultimately leading to low intakes and/or a deficiency.

Another possibility is that persons with low dietary magnesium intakes might be less likely to consume nutrient-dense foods, whereby they might end up with excessive levels of certain vitamins (e.g. from fortified, processed foods), insufficient amounts of other nutrients (e.g. magnesium), and excessive inflammation from omega-6 fatty acids – all of which might induce depressive symptoms.  Authors also propose that abnormalities in magnesium metabolism could increase susceptibility to magnesium deficiencies corresponding depression.  Though more research is necessary to evaluate whether lack of dietary magnesium can cause depression, this review supports the idea that it could.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23321048

2013: Magnesium in depression.

A report by Serefko, Szopa, Wlaź, et al. (2013) mentions that magnesium is among the most essential minerals within the human body.  According to researchers, magnesium intakes affect neurochemistry and neuronal membrane fluidity.  Individuals with magnesium deficiencies typically exhibit a myriad of neuropsychiatric symptoms, one of which is depression.

Despite the fact that plasma magnesium concentrations do not correlate with depression, preliminary evidence suggests that low levels of magnesium within the brain can lead to depression.  Authors of this report note that magnesium supplements are being used frequently by medical professionals as a standalone or adjunct treatment for migraine, alcoholism, asthma, heart disease, arrhythmias, and muscle tension.  What’s more, it appears as though various formats of magnesium might be effective for attenuating the symptomatic severity of depression.

At the time of this report, the mechanisms by which magnesium may facilitate an antidepressant effect aren’t understood.  It was suggested that magnesium likely modulates many neurobiological systems implicated in the pathogenesis of depression.  Nonetheless, reports of using magnesium for the management of depression date back nearly 100 years.

Among the first reports documenting the efficacy of magnesium was published in 1921, noting that hypodermic (i.e. subcutaneous) magnesium sulfate effectively treated persons exhibiting “agitated depression.”  Since then, many preclinical trials support the idea that magnesium supplementation is generally safe and helpful for reducing depression.  For this reason, researchers infer that magnesium supplementation should be perceived as a potentially useful pharmacological intervention for the management of depressive disorders.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23950577

2010: Magnesium for treatment-resistant depression: a review and hypothesis.

Eby and Eby (2010) document that 60% of individuals diagnosed with depression fail to derive therapeutic benefit from conventional antidepressants.  In their paper, Eby and Eby discuss the fact that magnesium might be an effective intervention for attenuating the severity of depressive symptoms among persons with treatment-resistant depression.  Over half of the population is deficient in magnesium, and as a result of the deficiency, NMDA-coupled calcium channels are more prone to opening.

Frequent opening of NMDA-coupled calcium channels is associated with neuronal injury and neural dysfunction, each of which could provoke onset of depression.  Furthermore, administration of oral magnesium supplements to animal models yields therapeutic mood enhancement on par with potent antidepressant medications.  Authors also document the fact that, among persons with treatment-resistant depression and/or suicidal ideation, concentrations of magnesium within cerebral spinal fluid (CSF) appear abnormally low.

Although low blood and cerebral spinal fluid (CSF) magnesium levels are not strongly correlated with depression, neuroimaging data (collected with phosphorous nuclear magnetic resonance spectroscopy) reveal deficits in magnesium throughout the brain among those with treatment-resistant depression.  Additionally, similar to other reports, authors reference a publication from 1921 in which magnesium sulfate was administered to 250 patients with “agitated depression,” whereby it successfully alleviated symptoms for 220 of the 250.  Despite preliminary research from the 1920s suggesting that magnesium may counteract depressed moods, few follow-up studies were conducted.

Nonetheless, a randomized controlled trial (RCT) from 2008 discovered that magnesium was equally as effective as imipramine (an FDA-approved tricyclic antidepressant) for the treatment of depression in diabetic patients.  In the aforestated trial, recipients of magnesium not only experienced significant reductions in depressive symptoms, but zero unwanted side effects occurred, making it a potentially favorable option to imipramine.  Other studies support the idea that intravenous and oral magnesium preparations can rapidly mitigate treatment-resistant depression without side effects.

Researchers Eby and Eby hypothesize that insufficient dietary magnesium may be the chief cause of treatment-resistant depression in a subset of patients.  Furthermore, due to the fact that many individuals with major depression consume processed foods (which lack magnesium, but also contain aspartate, calcium, and glutamate – each of which might exacerbate neurological dysfunction from insufficient magnesium), supplementation with magnesium may be extremely helpful.  This paper advises medical professionals to evaluate dietary magnesium intakes of patients with severe depression and administer supplements to those with inadequate intakes.

Though it wasn’t mentioned in this report, medical professionals should be cognizant of the fact that a serum magnesium test is relatively useless for ruling out a magnesium deficiency.  As of current, the most accurate means by which magnesium levels can be tested is through an EXA test, which involves scraping and analyzing buccal cells from the inner cheek.  Assuming intracellular magnesium concentrations are low, supplementation with a highly-bioavailable form of magnesium may prove most effective for attenuating depressive symptoms.

It’s also necessary to consider that not all magnesium formulations effectively cross the blood-brain-barrier (BBB).  Knowing that low brain magnesium may be implicated in depression, it may be best to recommend formulations such as Magnesium-L-Threonate which have proven effective in penetrating the blood-brain-barrier.  Moreover, based on the facts that: suboptimal magnesium intake leads to low serotonin; depression itself depletes magnesium; and antidepressants increase magnesium within the brain – it’s reasonable to speculate that magnesium supplementation is useful for all patients with depression, regardless of its severity.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19944540

2009: Magnesium in major depression.

A report by Nechifor (2009) mentions the fact that, although studies have investigated relationships between magnesium levels and/or intakes and the occurrence of major depressive disorder (MDD), the findings from these studies are mixed.  In other words, some evidence supports the idea that abnormally low magnesium concentrations and/or intakes might cause depression, whereas other data suggests that depression is likely to occur irrespective of magnesium levels.  Additionally, Nechifor discusses how first-line antidepressant medications affect magnesium concentrations during treatment.

Research by Nechifor and his team discovered that red blood cell (RBC) concentrations of magnesium were approximately ~44.39 mg/L among persons with major depression, compared to 59.1 mg/L in euthymic (non-depressed) controls.  Serum magnesium tests of individuals with severe depression (HAM-D scores over 23) recorded magnesium concentrations at 17.7 mg/L compared to 22.9 mg/L for non-depressed controls.  While there are differences in average magnesium concentrations between depressed and euthymic individuals, the differences weren’t as large as expected.

It is necessary to note that red blood cell and/or serum magnesium may not correlate as well with depressed mood as brain magnesium.  Perhaps it would’ve been more appropriate to investigate a relationship between levels of magnesium within the brain and mood.  Nonetheless, it appears as though individuals with depression are exhibit lower average magnesium concentrations in both red blood cell and serum assays compared to non-depressed individuals.

Ongoing treatment with antidepressants is also understood to modulate concentrations of magnesium within red blood cells.  Research suggests that administration of the tricyclic antidepressant amitriptyline (25 mg, t.i.d.) OR the SSRI sertraline (50 mg, t.i.d.) for a 4-week duration leads to a statistically significant increase in erythrocyte magnesium concentrations compared to pre-treatment.  It is also worth mentioning that both amitriptyline and sertraline administration for the 4-week duration significantly increased plasma levels of zinc compared to pre-treatment.

Based on these findings, Nechifor believes that increasing intracellular concentrations of magnesium might be an overlooked mechanism of antidepressant action.  Other work by Nechifor tested the effect of magnesium on the reward systems of lab rats, discovering that magnesium administration (MgCl2 0.2 mM/kg/day) increases time spent in a rewarding environment from ~290.6 seconds (pre-administration) to ~363.3 seconds (post-administration).  This suggests that magnesium moderately stimulates the reward system in rats, thereby attenuating anhedonia, a common symptom of severe depression.

When considering the findings presented in this paper such as: average magnesium levels are lower in persons with major depression than euthymic controls; antidepressants increase intracellular magnesium after 4 weeks; and magnesium ameliorates reward deficits in rats – it is reasonable to surmise that magnesium might be useful as a standalone or adjunct antidepressant.  Though magnesium is unlikely to alleviate depressive symptoms in every person with major depression, it may prove more efficacious than expected.  Overall, this report supports the theory that low magnesium levels may cause depression, and that increasing intracellular magnesium levels could treat depressive symptoms.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19780403

2009: Association between magnesium intake and depression and anxiety in community-dwelling adults: The Hordaland Health Study.

Jacka, Overland, Stewart, et al. (2009) highlight links between systemic inflammation, magnesium intake, and major depression.  There appears to be a strong relationship between systemic inflammation and depressive disorders, and there is preliminary data suggesting that insufficient magnesium intake may cause depression.  Knowing that adequate magnesium intake is protective against inflammation, it’s reasonable to hypothesize that magnesium may prevent and/or treat depression, in part, through counteracting inflammatory effects.

Nevertheless, researchers conducted a study specifically to investigate the relationship between magnesium intake and depression in community-dwelling men and women.  A total of 5,708 individuals between ages of 46-49 or 70-74 enrolled and participated in this study.  All participants were assessed for depression and anxiety with Hospital Anxiety and Depression Scale, and magnesium intake was estimated based on a food frequency questionnaire.

Results of the study revealed an inverse relationship between depression scores and magnesium intake.  What’s more, the inverse relationship between depression scores and magnesium intake remained statistically significant even after adjusting for confounds such as: age, blood pressure, body composition, and sex.  Although adjustments for socioeconomic status and lifestyle factors reduced the strength of the aforestated inverse relationship, it still remained statistically significant.

That said, since correlation does not equal causation, it is possible that depressed individuals (on average), consume fewer nutrient-dense foods than euthymic persons for a myriad of reasons including: lack of self-care, preference for convenient or processed foods, etc.  Considering the findings from this study, one might suspect that increasing magnesium levels (via diet and/or supplementation) among persons with both depression plus low magnesium intakes – might ameliorate depressive symptoms.  This research provides additional support for the idea that a magnesium deficiency might increase likelihood of depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19085527

2008: Depression-like and anxiety-related behaviour of rats fed with magnesium-deficient diet.

Spasov, Iezhitsa, Kharitonova, and Kravchenko (2008) examined the effect of magnesium-deficient diets on rats.  Specifically, researchers sought to determine how feeding rats a magnesium-deficient diet for a duration of 49 days would affect psychomotor activity and emotional status.  After the 49-day magnesium deficiency, researchers wanted to test whether administration of magnesium plus vitamin B6 would act as an antidepressant, anxiolytic, and/or reduce the time necessary to recover from a magnesium-deficient state.

For the study, 79 rats were fed a magnesium-deficient diet (less than 15 mg/kg) and given demineralized water for 7 weeks, leading to hypomagnesemia.  A total of 8 rats were used as the control group and fed a standard diet (containing magnesium) and typical water supply.  Assays conducted by researchers revealed depleted intracellular and plasma magnesium stores among the 79 rats fed the magnesium-deficient diet – compared to the 8 rats eating standard chow.

Additionally, the magnesium deficiency lead to depressive and anxious behaviors in the rats as evidenced by performance on an open field test, an elevated plus maze, and forced-swim test.  On the open field test, magnesium-deficient rats exhibited decreases in: number of crossed squares (locomotor activity), standing on hind paws (vertical activity), and visiting central squares – all of which suggest heightened anxiety.  In the elevated plus maze, the magnesium-deficient rats visited fewer open arms and residence time decreased compared to the control group, indicating anxiety.

Results from the forced swim test (FST) suggested that magnesium-deficient rats exhibited significantly greater immobility (70.2%) and swimming time (15%) than the non-deficient control group, each of which is suggestive of depression.  Clearly the magnesium deficiency significantly increased both anxiety plus depression in the rats.  After behavioral tests were conducted, all rats were assigned to receive 1 of 6 supplements: Mg-L-aspartate; Mg-L-aspartate plus pyridoxine; MgCl2 x 6H2O alone; MgCl2 x 6H2O plus pyridoxine; Mg lactate plus pyridoxine (Magne B6); or Mg sulfate (50 mg Mg and 5 mg vitamin B6 per kg).

Administration of magnesium salts (standalone or with vitamin B6) significantly increased intracellular and plasma magnesium concentrations.  Additionally, administration of Mg-L-aspartate and MgCl2 x 6H2O combinations reversed behavioral abnormalities observed in the magnesium-deficient rats.  It appears as though, in the event of a magnesium deficiency, supplementation with various magnesium preparations effectively upregulates biological magnesium stores, while simultaneously mitigates anxiogenic and depressive behaviors associated with the deficiency.

It is worth noting that most humans will not exhibit extreme deficiencies in serum magnesium concentrations (i.e. hypomagnesemia) on par with the rats in this study.  Still, many humans exhibit deficits in intracellular magnesium content, possibly leading to onset of anxious and/or depressive behaviors.  Although the results of this study cannot be generalized to humans, we can hypothesize that long-term magnesium deficiencies might alter human behavior similar to the rats.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18825946

2008: Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial.

Barragán-Rodríguez, Rodríguez-Morán, and Guerrero-Romero (2008) conducted a trial testing the safety and efficacy of oral magnesium chloride (MgCl2) supplementation for the treatment of both hypomagnesemia and depression.  All 23 participants in this study were elderly (over age 65) and diagnosed with depression, hypomagnesemia, and type-2 diabetes.  Exclusion criteria for the trial included any persons with: alcoholism, CNS degeneration, diarrhea, recent diabetes diagnoses, and renal dysfunction.

Users of antidepressants and diuretics were also excluded from participation, as were individuals who divorced or widowed within 6-months of the trial.  Researchers randomly assigned participants to receive either: 5% magnesium chloride solution (50 mL per day) OR imipramine (50 mg per day) for a duration of 12 weeks.  Magnesium status was monitored using serum magnesium tests and severity of depression was documented with Yasavage and Brink scores.

Prior to the trial, there were no differences among participants in terms of: age, duration of diabetes, serum magnesium levels, nor depression severity.  After 12 weeks, depression scores dropped from 17.9 (Group A) and 16.1 (Group B) on the Yasavage and Brink scale to 11.4 and 10.9, respectively.  Both MgCl2 and imipramine significantly improved moods of the participants, but neither intervention was superior to the other as an antidepressant.

As expected, serum magnesium levels were significantly greater among recipients of MgCl2 (50 mL per day of a 5% solution) compared to recipients of imipramine (50 mg per day).  It was concluded that MgCl2 is effective for the treatment of depression among elderly populations exhibiting hypomagnesemia, diabetes, and depression.  Knowing that hypomagnesemia can directly cause depression, the findings do not come as a surprise.

Perhaps surprising is the finding that imipramine (50 mg per day) alleviated depressive symptoms without correcting the underlying cause of depression (hypomagnesemia).  For this reason, one might suspect that a subset of individuals exhibiting depression as a result of low magnesium have pursued treatment with pharmaceutical antidepressants, whereby their mood improved, but their magnesium levels remained deficient.  In other words, for a subset of patients, antidepressants may mask the root cause of depression (by alleviating symptoms), possibly yielding deleterious long-term effects from an uncorrected nutrient deficiency.

Limitations associated with this study include: the sample size (just 23 participants) and the highly-specific demographic (elderly patients with depression, hypomagnesemia, and type-2 diabetes).  For this reason, it is impossible to know whether similar results would occur among younger adults without type-2 diabetes – solely with hypomagnesemia and depression.  It may have been useful to test different doses and/or formats of supplemental magnesium, and possibly assign a third group of patients to receive both magnesium plus imipramine.  That said, this study provides evidence suggesting that MgCl2 (50 mL per day of a 5% solution) can treat hypomagnesemia and comorbid depression among elderly patients with type-2 diabetes if administered for 12 weeks.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19271419

2006: Rapid recovery from major depression using magnesium treatment.

Eby and Eby (2006) report upon the usage of magnesium to treat major depression.  The report mentions the fact that that individuals diagnosed with major depression often feel hopeless, inadequate, pessimistic, and may exhibit anhedonia.  In severe cases, untreated depression can lead to cognitive decline, impaired social relationships, and suicide.

Although pharmaceutical antidepressants are helpful for many individuals with depressive disorders, they are far from utopian interventions.  Many antidepressant users report experiencing an array of unwanted side effects from their medications such as brain fog, emotional numbness, sexual dysfunction, and weight gain.  What’s more, some individuals will find conventional antidepressants to be downright ineffective.

In extreme cases, antidepressants may worsen the underlying depression and/or provoke suicidal thoughts.  Due to the imperfections associated with pharmaceutical antidepressants, researchers discuss magnesium as a potential alternative treatment for depression.  This report notes that magnesium deficiencies can provoke neuropsychiatric symptoms, including depression, and that many individuals throughout the United States are likely suffering from a magnesium deficiency.

One way in which a lack of magnesium may lead to depression is associated with unregulated flow of calcium ions through calcium channels, ultimately leading to increased generation of nitric oxide and neuronal damage.  It is the cumulative neuronal damage resulting from intraneuronal magnesium deficiencies that, over an extended timeframe, may manifest as depression.  Consuming sufficient magnesium to replenish intraneuronal magnesium concentrations should regulate calcium ion flow and corresponding nitric oxide to prevent additional damage.

Eby and Eby theorize several common causes of intraneuronal magnesium depletion, including:  upregulated stress hormones, excessive calcium intake, and/or inadequate consumption of magnesium.  They reference case studies in which individuals rapidly recover from major depression in less than 1 week from administering 125 mg to 300 mg magnesium (glycinate or taurinate) with each meal, plus at bedtime.  To put things in perspective, assuming 3 meals are consumed each day, this treatment protocol involves administering between 500 mg and 1200 mg magnesium per day.

Magnesium is often effective, at least partially, for the treatment of clinical depression and case studies suggest that it is often useful for the management of other neuropsychiatric conditions such as:  addiction, anxiety, headache, irritability, insomnia, and traumatic brain injury (TBI).  When a magnesium deficiency becomes severe and calcium intake and/or stress remains high, individuals may experience disconcerting symptoms such as: anxiety, cognitive decline, confusion, fatigue, hallucinations, hyperexcitability, irritability, and sleeplessness.  For this reason, authors recommend fortifying refined grains and drinking water with bioavailable magnesium.

They believe magnesium deficiencies are a chief cause of many depressive disorders and can compromise brain development.  Furthermore, researchers suggest that lacking dietary magnesium reduces IQ (intelligence quotient) of the general population.  While many may not agree with fortification of grains and drinking water with magnesium, most will acknowledge that lack of magnesium consumption is associated with potentially life-altering consequences, including onset of major depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16542786

2004: Magnesium attenuates post-traumatic depression/anxiety following diffuse traumatic brain injury in rats.

Fromm, Heath, Vink, and Nimmo (2004) conducted a study assessing the effect of magnesium administration on the emergence of depression and anxiety following a traumatic brain injury (TBI) in rats.  It is known that following a traumatic brain injury, many brain cells die and cognitive function is often compromised.  According to researchers, administration of magnesium following a traumatic brain injury ameliorates cognitive and motor deficits, however, its effect on treating TBI-related depression and anxiety isn’t well-researched.

Given statistics estimating that up to 77% of individuals suffer from depression and/or anxiety following a traumatic brain injury, it’s practical to test whether magnesium supplementation could attenuate these symptoms.  For this reason, researchers induced a diffuse (widespread) TBI in 32 anesthetized adult rats using a 2 m impact-acceleration model of injury.  Approximately 30 minutes post-TBI, half of the rats received intravenous injections of MgSO(4) 250 micromol/kg, whereas the other rats received nothing to serve as controls.

Prior to the deliberately-induced diffuse TBI, all rats underwent an open-field, spontaneous activity test to gauge depression and anxiety.  This test involves placing rats on a 1-meter square box with 100 squares marked on the base.  Recorded pre-TBI data indicated that, on average, rats entered 201 squares over a 5-minute duration, suggestive of the fact that the rats were neither anxious nor depressed.

Post-TBI, rats were subjected to the same open-field, spontaneous activity testing.  Results indicated that, at 1-week post-TBI, the control group (untreated) entered an average of 62 squares on the test, whereas the rats given intravenous MgSO(4) entered an average of 144 squares.  Researchers approximated that 61% of the untreated rats experienced depression and/or anxiety, whereas just 30% of those given MgSO(4) were depressed and/or anxious.  The differences between the rats given MgSO(4) and the control group remained statistically significant throughout 6 weeks post-TBI.

It was concluded that administration of magnesium after a traumatic brain injury functions as a neuroprotective agent.  Not only does it improve cognitive and motor faculties, but it alleviates depression and anxiety in animal models.  Knowing that a subset of humans will experience onset of depression and anxiety following traumatic brain injury, it is reasonable to theorize, based on the outcome of this study, that timely administration of magnesium might reverse and/or attenuate TBI-related depressive and anxious symptoms.

That said, since this study was conducted in animal models with diffuse TBI, it is difficult to know whether the antidepressant and anxiolytic effects derived from magnesium supplementation are similar for humans with diffuse TBI – or other forms of brain injury.  Furthermore, due to the fact that cognitive function is intricately linked with mood, one might suspect that cognitive recovery from post-TBI magnesium administration leads to a reduction in depression and/or anxiety.  While more research is necessary to determine the usefulness of magnesium for the management of TBI-related depression and/or anxiety, this study suggests that it is likely effective.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15466958

2004: Magnesium-deficient diet alters depression- and anxiety-related behavior in mice–influence of desipramine and Hypericum perforatum extract.

Singewald, Sinner, Hetzenauer, Sartori, and Murck (2004) highlight the fact that there is no conclusive data linking low magnesium intake to mood disorders.  Although some studies suggest that inadequate magnesium intake increases risk of depression, results from other studies report zero increased risk.  Due to the inconsistent data, researchers sought to determine whether magnesium depletion in animal models would increase the occurrence of depressive and/or anxious behaviors.

This study involved dividing mice into 2 groups and assigning them to receive either: magnesium-deficient diets (10% of the recommended daily allowance) OR standard diets.  After several weeks, researchers exposed mice to a forced-swim test, light/dark test, and open-field test.  Results suggested that the mice consuming a magnesium-deficient diet exhibited significant increases in immobility times on the forced-swim test, indicative of depressive behavior.

What’s more, the mice consuming the magnesium-deficient diets exhibited anxious behavior in the light/dark test and open field test compared to the mice eating standard chow.  Clearly, the suboptimal intake of magnesium in the animal models lead to depressive and anxious behaviors.  Based on this finding, it is reasonable to hypothesize that restricting humans to 10% of the RDA magnesium for several weeks might prompt the onset of depression and/or anxiety.

After the initial finding that magnesium-restricted diets induced depressive and anxious behavior in mice, researchers aimed to determine whether antidepressants could reverse these behaviors.  The magnesium-deficient mice received either desipramine (30 mg/kg/day) or Hypericum extract LI160 (380 mg/kg/day) for a set duration and were reevaluated on the forced-swim test, light/dark test, and open-field test.  Results suggested that both the desipramine and Hypericum extract LI160 effectively prevented depressive behavior on the forced swim test, plus Hypericum extract LI160 reversed displays of anxious behavior on the open field test and light/dark test.

The finding that antidepressant medications/supplements reverse magnesium deficiency-related depression and anxiety may have significant implications.  Perhaps the most profound implication is that some individuals with an underlying magnesium deficiency may experience depression or anxiety from the deficiency, ultimately seeking antidepressant treatment.  The antidepressant medication may prove effective in managing symptoms, however, the underlying cause (low magnesium) will remain unaddressed.

Although this study was conducted in mice and not humans, based on the findings, it is reasonable to recommend that everyone diagnosed with depression (regardless of whether treated with an antidepressant) undergo testing of magnesium levels.  If magnesium levels are low, perhaps certain antidepressant users can supplement with magnesium to mitigate depressive or anxious symptoms – rather than take a pharmaceutical-grade medication.  In summary, magnesium depletion induces noticeable depression and anxiety, to such an extent, that researchers propose magnesium-depleted animal models to test the efficacy of new antidepressants.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15567428

2004: A use of Magne-B6 in the treatment of anxiety-depressive states in patients with epilepsy.

Kalinin, Zheleznova, Rogacheva, et al. (2004) evaluated the therapeutic potential of Magne-B6 (combination of magnesium and vitamin B6) among 25 patients with various types of epilepsy.  All patients were reported to have comorbid symptoms of depression, anxiety, and in some cases, signs of psychosis.  For a duration of 28 days, the 25 patients received Magne-B6 in conjunction with conventional anticonvulsant treatment.

To measure the effectiveness of Magne-B6, researchers conducted pre-trial evaluations using self-rating scales such as:  the Zung anxiety and depression scale, SCL-90, and Clinical Global Impression (CGI) scale.  After the trial, researchers concluded that Magne-B6 favorably improved psychological states of patients with epilepsy, substantially attenuating symptoms of depression.  Statistically significant therapeutic mood improvements were observed approximately 2 weeks after initiation of treatment and retained throughout the remainder of the 4-week trial.

Researchers reported that Magne-B6 was most useful among epileptic patients with asthenia (weakness and/or fatigue) and depression.  Additionally, Magne-B6 didn’t cause any unwanted side effects, suggesting that it’s well-tolerated.  Overall, it appears as though Mangne-B6 might be useful as an anticonvulsant adjunct among patients with epilepsy for the management of depressive symptoms.

That said, there are some serious limitations associated with this trial.  The most substantial limitation is that the study was not randomized nor controlled.  Lack of randomization and controlling means that the therapeutic effects credited to Magne-B6 may have been nothing more than a placebo effect or fully explained by the anticonvulsant medication (many anticonvulsants can help regulate mood).

Additionally, even if we were to assume that the magnesium and B6 combination (Magne-B6) facilitated an antidepressant effect in patients with epilepsy, it’s difficult to know if the bulk of the mood enhancing effect was derived entirely from one constituent of Magne-B6.  For example, the magnesium constituent may have been therapeutic but the vitamin B6 may have been nothing more than filler; or vice-versa.  Perhaps each ingredient in Magne-B6 is useful, however, no trial has compared the effects of vitamin B6, magnesium, and Magne-B6 as anticonvulsant adjuncts.

It’s possible that standalone magnesium or standalone vitamin B6 would’ve worked just as well as Magne-B6 (assuming it elicited a therapeutic effect).  Moreover, just because Magne-B6 might reduce depression among patients with epilepsy does not mean that it’ll yield similar antidepressant effects among individuals with unipolar major depressive disorder (MDD).  Though this trial provides proof of safety and the concept that magnesium (as part of a proprietary blend) could mitigate depressive symptoms as an adjunct, further quality research is necessary to verify speculative benefit.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15554143

1991: Red blood cell magnesium and chronic fatigue syndrome.

Cox, Campbell, and Dowson (1991) theorized that individuals diagnosed with chronic fatigue syndrome (CFS) may exhibit deficient magnesium concentrations within red blood cells.  Furthermore, they speculated that if a deficiency in red blood cell magnesium was found, the administration of supplemental magnesium might improve wellbeing.  For this reason, researchers decided to compare the red blood cell (RBC) concentrations of magnesium in 20 patients with chronic fatigue syndrome to 20 healthy controls – matched for age, sex, and socioeconomic status to avoid confounds.

Red blood cell testing revealed that persons with chronic fatigue syndrome exhibited significant reductions in red blood cell magnesium than the healthy controls.  Thereafter, researchers organized a randomized, double-blinded, placebo-controlled trial that involved 32 patients with chronic fatigue syndrome.  Patients were divided into 2 groups and assigned to receive either: magnesium sulfate every week for 6 weeks (15 patients) OR a placebo control (17 patients).

Results indicated that recipients of magnesium exhibited significant changes on the Nottingham health profile, reporting: emotional improvement, increased energy, and reduced pain.  A total of 12 of 15 magnesium recipients claimed to have derived benefit from its administration, whereas just 3 of 17 control recipients claimed to have derived benefit from the placebo.  Additionally, red blood cell concentrations of magnesium normalized among all patients receiving magnesium sulfate, but failed to normalize in the placebo group.

Given the fact that depression and chronic fatigue syndrome are comorbid conditions and overlap in terms of symptomatic presentation, it’s reasonable to assume that magnesium functioned as an antidepressant among recipients.  Those who received magnesium reported improved emotional control, an energy boost, and less pain – all of which signify an antidepressant effect.  At the very least, this study highlights the importance of screening patients with neuropsychiatric conditions via red blood cells for a magnesium deficiency, and if a deficiency is present, treating it.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/1672392

1990: A pilot study of magnesium aspartate hydrochloride (Magnesiocard) as a mood stabilizer for rapid cycling bipolar affective disorder patients.

Chouinard, Beauclair, Geiser, and Etienne (1990) recruited 9 patients with rapid-cycling bipolar disorder for an open label trial testing the therapeutic potential of magnesium.  All patients were assigned to receive a magnesium aspartate hydrochloride preparation referred to as “Magnesiocard.”  The Magnesiocard was administered at a dose of 40 mEq/day for a total duration of 32 weeks.

Results of the study indicated that Magnesiocard treatment attenuated bipolar symptoms as effectively as lithium (a first-line agent) in half of the patients.  That said, since this was an open-label study (uncontrolled, non-randomized, non-blinded), researchers note that results should be cautiously interpreted.  Clearly, randomized controlled trials are needed to confirm the speculation that magnesium preparations could stabilize mood.

Nonetheless, this study provides preliminary data supporting the idea that magnesium preparations are useful in the management of bipolar depression (and mania).  Also, given the comparisons of magnesium to lithium, it’s reasonable to speculate that it may prove useful as an antidepressant augmentation strategy among those with refractory or difficult-to-treat depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2309035

1989: Depression and magnesium deficiency.

Rasmussen, Mortensen, and Jensen (1989) were among the first to report upon the occurrence of psychiatric symptoms resulting from an underlying magnesium deficiency.  In their report, researchers mention vague, unspecific symptoms ranging from apathy to psychosis among persons with magnesium deficits.  Unfortunately, what often happens is that symptoms resulting from magnesium deficiencies are mistakenly attributed to a specific medical condition.

What’s more, any suspected medical conditions resulting form magnesium deficiencies may end up getting treated, however, the underlying cause (deficient magnesium) remains.  To further complicate things, symptoms of magnesium deficiencies are often subject to variation based on: the individual, significance of the deficiency, as well as the duration over which a person has been deficient.  For this reason, researchers recommend that all persons exhibiting symptoms reflective of a magnesium deficiency receive serum magnesium testing.

Additionally, researchers suggest that medical professionals screen any patients “at-risk” for magnesium deficits such as from:  alcoholism, diuretic usage, GI disorders, malnutrition, etc.  Serum magnesium is useful for the diagnosis of hypomagnesemia, which can cause depression.  That said, since serum magnesium only accounts for 1% of magnesium within the body, it is advisable for professionals to administer more precise tests such as the EXA or RBC to measure intracellular magnesium concentrations throughout most of the body.

It was noted that hypomagnesemia can be treated with oral or intravenous magnesium, whereby any hypomagnesemia-related symptoms such as depression should subside.  Furthermore, it is important to realize that chronically low intracellular magnesium stores may necessitate daily magnesium supplementation over an extended duration to normalize levels.  Overall, this report supports the idea that any form of magnesium deficiency may yield depressive symptoms, as well as that treating the deficiency should attenuate those symptoms.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2722406

1922: Magnesium as a Sedative.

In the early 1920s, Paul G. Weston was first to formally report upon the therapeutic potential of magnesium for the management of neuropsychiatric disorders.  At the time, Weston administered magnesium sulfate (MgSO4) to 50 patients in disturbed mental states, some of whom were characterized as exhibiting “agitated depression.”  Specifically, all 50 patients received 1 to 2 c.c. injections of a sterile, 25-50% magnesium sulfate solution.

Patients responded to the intravenously administered magnesium sulfate in a predictable manner in that the magnesium induced sedation.  Most patients became drowsy and drifted off to sleep for a duration of 4 to 6 hours after their magnesium injections.  Weston reported that magnesium appeared to be a useful “chemical restraint” due to the fact that it calmed patients without adverse reactions or unwanted side effects.

Furthermore, it was reported that, should an adverse reaction occur from high-dose magnesium injections, the reaction could be offset via intravenous injections of calcium chloride.  (The calcium chloride counteracts the effect of supraphysiological magnesium doses).  Although Weston didn’t conduct a follow-up randomized controlled trial (RCT) to confirm his observation that magnesium delivers a therapeutic sedative effect to persons with neuropsychiatric disorders (including depression), later research would substantiate his findings.

  • Source: http://ajp.psychiatryonline.org/doi/abs/10.1176/ajp.78.4.637

Limitations associated with the Research of Magnesium for Depression

There are numerous limitations associated with the research of magnesium for depression.  The most significant limitation is the lack of studies testing the effect of magnesium supplementation in humans with major depressive disorders.  Furthermore, even though a couple trials have sought to evaluate the antidepressant effect of magnesium in humans with depression, the corresponding evidence is considered weak due to poor study designs.  Other limitations include inconsistencies with magnesium dosing and/or formats, plus extremely short-term trial durations.

  • Administration details: Magnesium can be administered numerous ways such as orally, intravenously, subcutaneously, transdermally, sublingually, etc. In the research, the most common modes of magnesium administration include intravenous and oral.  No studies have compared the effectiveness of intravenous and oral magnesium supplementation for the treatment of depression.  It’s possible that one mode of administration may be significantly more effective than another in terms of potency and/or onset of antidepressant effect.
  • Adjunct efficacy: In the animal model trials, it was reported that magnesium plus serotonergic antidepressants (e.g. SSRIs) facilitates a synergistic antidepressant effect greater than each as a monotherapeutic intervention.  Murch (2013) states that magnesium acts synergistically with conventional antidepressants and reduces likelihood of refractory depression.  Additionally, many studies have highlighted pharmacodynamic similarities between magnesium and lithium, a scientifically-substantiated antidepressant adjunct.  Despite evidence suggesting magnesium is likely to serve as an effective antidepressant adjunct, no researchers have evaluated its adjunctive efficacy in humans. (Source: http://www.ncbi.nlm.nih.gov/pubmed/23541145).
  • Depressive subtypes: Based on available data, we may infer that magnesium is more effective for certain depressive subtypes than others. Individuals with agitated, anxious, psychotic, and/or restless depression may benefit significantly from magnesium compared to others.  It appears as though magnesium reduces overactivity within the CNS, ultimately helping those with agitated-depression to calm down.  In terms of neurobiological markers, it seems as though magnesium may be most helpful for depressed individuals with: high norepinephrine, HPA axis dysregulation, upregulated stress hormones (ACTH, CRH, cortisol), and excess glutamatergic transmission.  Future studies may wish to recruit patients with some of the aforestated depressive subtypes that are most likely to derive benefit from magnesium.
  • Dosing protocols: Another limitation associated with research of magnesium for depression is inconsistent dosing protocols and/or recommendations. Researchers know the dose of magnesium that seems to improve depressive symptoms in animal models, but they haven’t confirmed an optimal dose for humans.  A study from 1922 documented the usefulness of 25-50% magnesium sulfate injected at a dose of 1 to 2 c.c. for the management of depression.  In patients with hypomagnesemia, it seems as though magnesium chloride solution administered at 50 mL per day leads to mood improvement.  Administration of 125 to 300 mg magnesium glycinate or taurinate with each meal, plus at bedtime was documented as an effective antidepressant in case studies.  That said, there are no clear-cut guidelines for dosing among those taking magnesium for depression.  The optimal magnesium dosage for depression is probably contingent upon pre-treatment magnesium status, and the format administered.
  • Lack of human trials: The lack of human trials evaluating the antidepressant efficacy of magnesium is somewhat disappointing, especially considering that preliminary evidence suggesting that magnesium injections could manage depressive symptoms has been around since 1922. Throughout the 1900s and 2000s, case studies suggest that magnesium can rapidly alleviate symptoms of depression.  Despite reason to believe that magnesium may function as an antidepressant, trials evaluating its efficacy among patients diagnosed with unipolar depression are nonexistent.
  • Magnesium format: It isn’t known as to whether one format of magnesium may be superior to that of another for the treatment of depression. For example, magnesium glycinate and magnesium citrate are significantly more bioavailable than magnesium oxide.  This means that your body is efficiently absorbing a greater percentage of your magnesium dose if you were to take glycinate compared to oxide.  When treating depression, the goal is likely to increase magnesium stores within the brain.  Though magnesium within the body is said to eventually reach the brain, the fastest antidepressant action may be derived from magnesium formats that are engineered to rapidly cross the blood-brain-barrier.  Since magnesium-l-threonate has been shown to cross the blood-brain-barrier more efficiently than all other magnesium formats, some theorize that this may be the most useful supplement for persons with depression.  That said, it’s possible that format of magnesium makes little difference when administered over an extended duration.  Additional research should attempt to determine whether formatting (along with dosing and mode of administration) matters for the treatment of depression.
  • Research incentive: There’s little incentive for researchers to allocate precious research dollars to test the efficacy of supplemental magnesium for the treatment of depression. While individuals with major depression may wish to know whether magnesium is legitimately effective as an antidepressant, researchers simply don’t have the money to test it.  Most research money is supplied by pharmaceutical companies, biotech companies, or someone who engineered a specific patented format of magnesium (e.g. magnesium-l-threonate).  One could argue that magnesium-l-threonate may be profitable for patent holders if found effective as an antidepressant, however, at this juncture, it makes more sense to test the magnesium-l-threonate format for the treatment of cognitive impairment.  Unless someone engineers and patents a magnesium preparation that is extremely efficient in crossing the blood-brain-barrier (e.g. substantially better than magnesium-l-threonate), there won’t be much incentive to investigate its mood enhancing abilities in a randomized controlled study.
  • Small-scale trials: Most studies evaluating the effect of magnesium supplementation among persons with depression are extremely small-scale. In the earliest study published in 1922, there were 50 participants, but not all the participants were diagnosed with depression.  Another study incorporated 23 participants, but only around half received magnesium, whereas the other half received a control.  In addition to the 2 aforestated small-scale trials, there are only case studies.  Larger numbers of participants are needed (in RCTs) to confirm that magnesium is actually effective for the management of depression.
  • Study designs: Many interventions initially appear to be effective for the treatment of depression in open-label and pilot studies, yet when tested in randomized controlled trials, the efficacy is lacking. A significant limitation associated with the research of magnesium for depression is poor quality study designs.  Only 1 study is randomized, controlled, and blinded – but involves testing magnesium in a very specific population: elderly patients with hypomagnesemia, diabetes, and depression.  For the most part, there’s no convincing data to suggest that magnesium supplementation alleviates depression in humans.  Conducting a randomized controlled trial with a large sample size should give us a better idea as to whether magnesium really attenuates symptoms of depression.

Verdict: Magnesium is likely helpful for a subset of patients with depression

Upon review of the research, there’s no strong evidence to suggest that magnesium is an effective intervention for the treatment of depression in humans.  Nonetheless, there is reason to believe that magnesium supplementation could enhance mood and/or improve overall health among a subset of patients with depression.  In animal models, we know that a magnesium-deficient diet (under 10% of the RDA) induces a combination of depressive and anxious behaviors.

Administration of magnesium to animals that are deficient in magnesium reverses depressive and anxious behaviors, as evidenced by behavioral changes on forced swim tests (FSTs) and elevated plus mazes (EPMs).  Additionally, administration of standalone magnesium to animal models of depression and anxiety yields therapeutic benefit.  Research suggests that magnesium reverses depressive symptoms in animal models as effectively as an SSRI (selective-serotonin reuptake inhibitor).

What’s more, co-administration of magnesium plus a serotonergic antidepressant medication appears to alleviate depressive symptoms to a greater extent than either as a standalone – suggestive of a synergistic effect.  Clearly, there’s strong evidence supporting the antidepressant efficacy of magnesium in animal models.  That said, we cannot extrapolate results from animal trials and conclude magnesium is effective in humans; many substances that work for mice/rats yield no therapeutic effect (or sometimes generate an unwanted effect) in people.

Nonetheless, it is known that over half of the United States population is deficient in magnesium.  Anyone with a magnesium deficiency, especially over an extended duration, is at risk for developing neuropsychiatric conditions such as major depression as a direct result of the deficiency.  In select cases, the underlying root cause of a person’s depression may be a nutrient deficiency such as magnesium, and upon correction of the deficiency, mood miraculously improves.

Even if a deficiency isn’t the root cause of a person’s depression, normalizing intracellular magnesium stores through supplementation could boost mood.  Intriguingly, it is known that, when an individual is treated with conventional antidepressants for 4 to 8 weeks, magnesium levels tend to increase.  Some have theorized that the increase in magnesium that occurs during antidepressant treatment may play an important role in mood enhancement.

Additionally, there’s some data indicating that magnesium supplementation, regardless of magnesium status, may effectively managed symptoms of depression.  Paul G. Weston was the first to report that high-dose magnesium injections elicited a sedative effect that was especially helpful for patients with agitated depression in that it acted as a “chemical restraint.”  In an open-label trial by Kalinin, Zheleznova, Rogacheva, et al. (2004), 25 patients with epilepsy and comorbid depressive symptoms were theorized to have derived an antidepressant effect from Magne-B6, a substance containing magnesium plus vitamin B6.

Eby and Eby (2006) document case reports of rapid recovery from depression within 1-week from daily, high-dose magnesium supplementation.  Lastly, Barragán-Rodríguez, Rodríguez-Morán, and Guerrero-Romero (2008) discovered that oral magnesium supplementation significantly reduced depressive symptoms among elderly patients diagnosed with depression, type 2 diabetes, and hypomagnesemia.  Though this should’ve been expected due to the fact that hypomagnesemia can cause depression, it underscores the antidepressant potential of magnesium, especially among persons with deficits.

Despite the quality of evidence from human trials being poor, zero trials have implied that magnesium may be an ineffective antidepressant intervention.  Knowing that magnesium is implicated in hundreds of neurobiological processes, it’s not a stretch to consider that supplementation, either to reverse a deficiency or maximize magnesium ions in the brain, might treat depression.  Understand that not all patients with major depression will respond to magnesium, but some probably will.

How much magnesium should you take for depression?

The dosage of magnesium used to treat depression should be tailored to the individual based on his/her medical history, medication/supplement regimen, and current magnesium levels.  For this reason, the first step anyone with depression should take prior to supplementing with magnesium is get their levels tested.  There are many ways in which magnesium levels can be tested, including: serum tests, red blood cell tests, and EXA tests – just to name a few.

The serum tests are great for diagnosing hypomagnesemia, which can cause depression, however, only 1% of magnesium throughout the body will be present in the serum.  For this reason, serum tests are usually the least accurate way to test for magnesium.  A red blood cell (RBC) test is far more accurate than a serum test and should give you a better idea regarding the degree to which you may be deficient in magnesium.

The EXA test is the most accurate way to test your magnesium levels and involves a scrape of buccal cells from within the cheek.  These cells then undergo Energy-dispersive X-ray Analysis (EXA) to determine whether you have a magnesium deficiency.  Your doctor should be able to help interpret the results from these tests and give you a recommendation regarding the type of magnesium you should supplement with, as well as the dosing – you should take the minimal effective dose to normalize magnesium stores.

Adverse reactions associated with taking too high of a magnesium dose can usually be offset with supplemental calcium.  If you don’t want to follow through with recommended magnesium testing and just want to know of dosing protocols that have helped people with depression, the literature yields a few results.  Prior to implementing any of these protocols, it is recommended to confirm safety and hypothesized efficacy with a licensed psychiatrist with a knowledge of magnesium supplements.

  • Rapid antidepressant protocol: The most logical protocol to test among persons with major depression who want to supplement with magnesium is the rapid antidepressant protocol. Though this protocol wasn’t evaluated in randomized controlled trials, exceptional results were documented in case reports.  Using this protocol, patients with severe depression exhibited symptomatic remission in less than 1-week.  This rapid antidepressant protocol involves administration of: 125 mg to 300 mg of magnesium glycinate OR magnesium taurinate with each meal, plus at bedtime.  This means that individuals are taking between 500 mg and 1200 mg magnesium per day (divided up into 4 doses).
  • Weston protocol: In the early 1920s, Weston tested injections of magnesium sulfate (MgSO4) in patients with agitated depression. He used a sterile, 25-50% magnesium sulfate solution and administered 1 to 2 c.c. injections which facilitated a therapeutic effect.  It seems as though this high-dose injectable dosing protocol may be most useful for attenuation of depression accompanied by agitated symptoms.  Keep in mind that this method was more of a restraint than an effective treatment, but may be worthwhile for its calming effect.

Realize that there are many types of magnesium that an individual can take.  Some may argue that magnesium-l-threonate (magnesium bound to threonic acid, an isomer of ascorbic acid) might prove most effective for the treatment of depression due to the fact that more magnesium may reach the brain with this preparation.  Animal studies suggest that magnesium-l-threonate is capable of getting significantly more magnesium to the central nervous system than other formats.

That said, some have questioned whether magnesium-l-threonate is really more effective than other magnesium formats in crossing the blood-brain-barrier (BBB) of humans.  Since human testing hasn’t confirmed animal model data suggesting a higher CNS bioavailability of magnesium-l-threonate, it’s reasonable to be skeptical of claims that it’s a better supplement for depression.  It may turn out that other preparations such as magnesium-glycinate, magnesium-citrate, et al. are transported just as efficiently to the CNS of humans.

Still, there don’t appear to be any safety concerns or drawbacks from magnesium-l-threonate other than its higher cost.  If people are able to take lower doses of magnesium-l-threonate and get a significantly greater amount of magnesium to their brain, it may be worth the cost.  At this point we don’t know whether the bioavailability % justifies the increased cost.

Therefore, it’s up to you and your psychiatrist to determine which type of magnesium you want to utilize for the management of depression.  Assuming you increase magnesium throughout the body with supplements, some will inevitably get shuttled to the CNS and reach your brain.  Some solid alternatives to magnesium-l-threonate include: glycinate, malate, citrate, taurate, sulfate, and ZMK.

Note: Forms of magnesium supplements to avoid for various reasons (side effects, poor bioavailability, etc.) include: aspartate, pidolate, hydroxide, oxide, and lactate.  It may also be equally as effective and more tolerable to consume magnesium via whole foods (e.g. leafy greens) instead of taking supplements.

Have you tested magnesium for depression?

If you’ve tested the efficacy of magnesium for the treatment of depression, share your experience in the comments section below.  On a scale of 1 to 10 (with “1” as least effective and “10” as highly-effective) what number would you rate the magnesium for the reduction of your depression?  To help others get a better understanding of your situation, provide some details associated with the magnesium you used such as: the brand, format (e.g. glycinate), daily dosage (e.g. 1000 mg), mode of administration (e.g. orally), and administration details (e.g. divided doses with each meal).

Assuming you derived therapeutic benefit from magnesium supplementation, how long after initiation of supplementation did it take for you to notice an antidepressant or mood stabilizing effect?  Document whether you were taking magnesium as a standalone agent or along with psychiatric medications and/or other supplements.  If you took magnesium with other substances, can you be sure that the mood enhancement (or perhaps lack of mood improvement) wasn’t attributable to the co-administered substances?

While taking magnesium for depression, did you notice any unwanted and/or adverse side effects?  For those that failed to reap therapeutic benefit from magnesium for the treatment of depression, what was the cumulative duration over which you supplemented?  Did you give it several weeks to take effect like you would a pharmaceutical antidepressant, or did you cease usage within a week or two?

In summary, magnesium is likely an underrated supplement for persons with depression.  Those supplementing with magnesium are unlikely to experience unwanted side effects and, as a whole, there is little downside to magnesium supplementation.  If you want to try magnesium as an intervention for your depression, work with a medical professional (preferably psychiatrist) to confirm safety.

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{ 4 comments… add one }
  • Steve June 12, 2017, 8:38 pm

    Wow, so glad I found this article. I’ve been using magnesium for years to treat anxiety, depression and body aches. I’ve just started experimenting with the threonate form and found it good for sleep. Conversely, I find the opposite effect with calcium, mainly in supplements but also when I overdo dairy.

  • Karen Joyce December 11, 2016, 1:23 pm

    A highly comprehensive evaluation and one that has led me to purchase a supply of magnesium-l-threonate today. After having no success with most anti-depressants on the market for over 10 years, including Lithium, I am willing to try anything, especially a more ‘natural’ approach. I will certainly comment on my progress in the hope that the information might be able to help others lead a normal life, instead of this hideous fragmentation of self and its associated effects on daily living.

    • Jigna March 7, 2017, 11:19 pm

      Have you had any success with magnesium?

  • H. Rae November 14, 2016, 6:45 pm

    Excellent, very thorough article!!! Much appreciated!

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