By Alison Smith Ph.D.
A 2013 Global Burden of Disease study (Mathers et al., 2001) found mental disorders to be among the primary causes of disability worldwide.
According to Baxter et al. (2012), 7.3% of the total global population, that is every one in 14, suffers from an anxiety disorder.
In the 2012 Canadian Community Health Survey, Statistics Canada reports 2.4 million Canadians suffer from generalized anxiety disorder alone, with females (3.2%) affected more than males (2.0%) (Pearson et al., 2013).
However, only 37% of Canadians with an anxiety disorder actually seek treatment (Roberge et al., 2011), pointing to the need to educate Canadians about effective strategies to treat anxiety and how to access them.
Defining Anxiety and Panic Attacks
Anxiety disorders are those that feature panic and anxiety.
Panic is a fear response to imminent danger or a perceived threat, while anxiety is the anticipation of future danger (American Psychiatric Association, 2013). Panic and fear are associated with sympathetic nervous system arousal, the fight-or-flight response, thoughts of imminent threat, and escape behaviours.
Anxiety, on the other hand, is associated more with hyper vigilance, muscle tension, and the preparation to flee the scene because of perceived dangers (American Psychiatric Association, 2013).
Anxiety disorders include: generalized anxiety disorder, panic disorder, agoraphobia, social anxiety disorder, and phobias (Canadian Mental Health Association, 2013), and treatments include pharmacotherapy and cognitive therapy; nonetheless, natural treatments like magnesium are shown to have anxiolytic effects.
How Magnesium Mediates Anxiety
Magnesium is the second most abundant cation, intracellularly, and the fourth
most abundant cation in the whole body (Swaminathan, 2003). It acts as a cofactor in over 300 enzymatic reactions, including the maintenance of healthy brain function and mood (Wester, 1987; Sartori et al., 2012).
Studies show magnesium plays a role in keeping anxiety at bay through its modulation of neuronal receptors, neurotransmitters, and hormonal activity within anxiety-related brain regions, in addition to influencing the activity of the hypothalamic-pituitary adrenal (HPA) axis: the main stress response system (Sartori et al., 2012). Brain areas associated with anxiety include: the amygdala,
the hippocampus, and the ventromedial prefrontal cortex (Abumaria et al., 2011).
The neurophysiological etiology of anxiety is highly complex and not entirely
understood; however, rodent experiments have provided some useful details about the role magnesium plays in the pathophysiology of anxiety.
For example, under normal, healthy circumstances, N-Methyl-D-Aspartate (NMDA) receptors in brain regions associated with anxiety are typically inhibited by the presence of magnesium in the extracellular fluids. It’s as if magnesium is standing at a gate guarding against NMDA receptor stimulation (Lezhitsa et al., 2011).
NMDA receptors are stimulated by the excitatory neurotransmitter, glutamate,
which is the main neurotransmitter responsible for healthy and unhealthy nervous system function (Newcomer et al., 2000).
An adequate concentration of magnesium in the extracellular fluids is crucial to keep NMDA receptor activation stable. Excessive NMDA receptor activation by glutamate, causes hyperstimulation, excitotoxicity, and neuronal cell death, leading to cognitive and mood disorders like anxiety (Newcomer et al., 2000).
Magnesium deficiency resulting in hyperexcitability of NMDA receptors has been linked as one of the physiological origins of anxiety disorders (LeDoux, 2007; Grober et al., 2015; Poleszak et al., 2004).
As magnesium inhibits NMDA receptor activation, it also simultaneously
promotes gamma-aminobutyric acidA (GABAA) receptor function (Poleszak, 2008).
GABAA receptors are stimulated by GABA, an inhibitory neurotransmitter that promotes calm and relaxation. Once GABAA receptors are stimulated, chloride (an inhibitory anion) surges into the neuron thus causing hyperpolarization: a state that helps to prevent neuronal activation (Kandel et al., 2000).
In 2008, Poleszak demonstrated that magnesium provides anxiolytic effects not only through NMDA receptor inhibition (Poleszak et al., 2004), but through the potentiation of GABAA receptors as well. Magnesium helps to bind GABA to the GABAA receptor thus helping to prevent excessive neuronal stimulation that can result in anxiety (Moykkynen et al., 2001).
In addition to receptor stimulation, magnesium also modulates hormonal activity
associated with stress and anxiety.
Intense stress and anxiety can trigger the fight-or flight response: a state associated with hypothalamic-pituitary adrenal (HPA) axis activation and the secretion of stress-related hormones (Smith & Vale, 2006).
Magnesium suppresses the release of stress hormones like adrenocorticotropin hormone (ACTH) from the pituitary gland and the secretion of cortisol and epinephrine from the adrenal glands — the two main hormones responsible for the physiological cascade of the fight-or-flight response (Sartori et al., 2012).
Essentially, when it comes the stress response, magnesium acts like a warmly welcomed chill-pill.
The Cortical Landscape of Anxiety
Brain regions most associated with the state of anxiety include: the amygdala, the
hippocampus, and the ventromedial prefrontal cortex (VMPFC).
Magnesium plays an important role in the function and modulation of each region.
The amygdala is an almond-shaped structure located near the centre of the brain, within the medial temporal lobe. There are two amygdalas: one located in each hemisphere. Each amygdala is made up of separate subregions known as nuclei that connect to distinct cortical and subcortical circuitry (LeDoux, 2007; Pittman & Karle, 2015).
The amygdala is most associated with the emotional state of fear. In fact,
increased activation within the amygdala generates fear responses to non-threatening stimuli (Guyer et al., 2008).
During fear conditioning when repeated events trigger a learned fear response, neuronal plasticity occurs within the lateral amygdala thus forming fearful memories (LeDoux, 2007). Plasticity is the neuronal process that underlies learning. It involves rewiring of neuronal connections and synaptic activity to form new functional memories (Kandel et al., 2000).
From a basic neurophysiological standpoint, magnesium plays a critical role in
plasticity and the learning of new fearful memories within the amygdala (LeDoux, 2007).
When a person experiences something that their conscious or subconscious deems as dangerous, this triggers the release of the neurotransmitter glutamate within the lateral amygdala, which then stimulates NMDA receptors, thus exciting neuronal cells through a process called depolarization.
Typically, magnesium within the extracellular fluids blocks glutamate and NMDA receptor activation; however, the added shock of the perceived danger causes the magnesium to displace from its blocking position, thus allowing NMDA receptor excitation. If this excitation happens repeatedly, over and over again,
plasticity in the lateral amygdala occurs and a new fearful memory is learned (LeDoux, 2007). In essence, the amygdala houses the circuits for learned fear responses and drives the behavioural reactions to that fear (Abumaria et al., 2011).
Developing fearful memories and their related safety behaviours is crucial for
survival. As humans we need to recognize dangers and react to them — an ability that is definitely an evolutionary advantage (Abumaria et al., 2011). Our cavemen ancestors needed to recognize and escape from predatory animals and to spot poisonous plants.
Without the amygdala and the ability to form fearful, yet informative, memories and reactions, survival would only become precarious. If you remove the amygdala, the fear response disappears along with thoughts of self-protection (LeDoux, 2007).
However, experiencing excessive fear associated with objects or situations that are not innately dangerous can develop into a chronic anxiety disorder that can be resistant or remitting to pharmacological treatment or cognitive therapy (Abumaria et al., 2011).
The hippocampus is a part of the hippocampal formation located within the
medial temporal lobe in the same vicinity as the amygdala. And, just like the amygdala, there are two hippocampal formations within each hemisphere (Andersen, 2011).
Among its many functions, the hippocampus helps us to form fearful memories within the amygdala by providing spatial and temporal information about the stimulus that is deemed dangerous.
The hippocampus also plays a supportive role in the process of learning new, healthy memories that inhibit the fearful memories stored in the lateral amygdala — this process is known as extinction.
In terms of extinction, the amygdala generates and houses fearful memories, while the hippocampus and VMPFC form new memories that govern the expression of the fear response associated with the fearful memories (Abumaria et al., 2011).
Slutsky et al. (2010) reported that increasing magnesium concentration within the brain by administering magnesium L-threonate (MgT) to rodents enhanced learning-related plasticity within the hippocampus.
Since the hippocampus plays a role in the extinction of fearful memories, supplementing with magnesium might be a useful strategy to aid extinction, enhance memory, and prevent age-related cognitive and memory decline (Slutsky et al., 2010).
The Prefrontal Cortex
The prefrontal cortex (PFC), unlike the amygdala and hippocampus, is located
within the anterior portion of bilateral frontal lobes on the surface of the brain. It governs highly complex goal-directed behaviours, frequently classified as ‘executive functions’ (Funahashi & Andreau, 2013). The VMPFC has direct connections with the amygdala, and dysfunction within this connection can cause an anxiety disorder (Guyer et al., 2008).
Since the VMPFC, with the aid of the hippocampus, creates new learned
memories that can extinguish fearful memories housed within the amygdala, finding a way to stimulate learning-related plasticity within these regions would be an advantage and potentially helpful to those suffering from an anxiety disorder (Abumaria et al., 2011).
From a natural medicine perspective, preliminary research in the rodent model
shows administering oral magnesium supplementation, in the form of magnesium Lthreonate (MgT), can enhance the formation of extinction memories not only within the hippocampus (Slutsky et al., 2008), but the VMPFC as well (Abumaria et al., 2011; Fitzgerald et al., 2013).
Abumaria and colleagues (2011) demonstrated that administering
MgT improved working memory, learning ability, and short and long-term memory in the rodent model.
Is it then possible for MgT to enhance memory production and extinction in the VMPFC and hippocampus of humans to hasten anxiety disorder treatment and recovery? That is a question that still needs to be explored.
Anxiety and Magnesium Deficiency
Despite the critical role that minerals play in healthy brain function, most
Canadian diets are sorely deficient in essential minerals, thus predisposing a significant portion of the population to anxiety related disorders, not to mention other mental health issues (Health Canada, 2013).
According to Health Canada, 45% of Canadians fail to consume the minimum daily requirement of 250 mg of magnesium (Health Canada, 2013; Canadian Food Inspection Agency, 2016). That’s a shocking 10.4 million Canadians at risk of developing magnesium deficiency and subsequent anxiety disorders.
To make matters worse, Canadians who are chronically magnesium deficient
cannot simply add additional magnesium rich foods to their diet hoping to solve their hypomagnesemia. In the last 100 years, mineral concentration in agricultural soil has significantly decreased, making it difficult for people to consume adequate amounts of minerals like magnesium from harvested food (Marler & Wallin, 2006).
Therefore, in moderate to severe cases of magnesium deficiency, supplementation is the only course of treatment (Durlach et al., 1994).
Inadequate blood magnesium concentration triggers symptoms such as anxiety,
nervousness, agitation, low stress tolerance, weakness, and depression (Grober et al., 2015).
In rodent experiments, brain and blood plasma levels of magnesium are significantly correlated with anxiety behaviours (Laarakker et al., 2011), and magnesium supplementation has been shown to have anxiolytic and antidepressant effects by acting as an NMDA receptor antagonist, as long as magnesium blood serum concentration was raised by at least 58% (Poleszak et al., 2004).
Treating Anxiety with Magnesium
Taking all of the information discussed into consideration, it is scientifically
evident that magnesium supplementation has the potential to reduce anxiety by: (1) inhibiting NMDA receptor activation (Lezhitsa et al., 2011), (2) potentiating GABAA receptor activation (Moykkynen et al., 2001), (3) reducing the secretion of ACTH, cortisol, and epinephrine from the pituitary and adrenal glands respectively (Sartori et al., 2012), and (4) enhancing neuronal plasticity for new extinction memories within the hippocampus and VMPFC (Poleszak, 2004 & 2008).
To date, cognitive behavioural therapy is considered the most effective form of
treatment for anxiety disorders (Rector et al., 2016). Pharmacotherapy treatments for clinical anxiety (antidepressants, serotonin-specific reuptake inhibitors (SSRIs), and benzodiazepines) are available, but they can come with a host of negative side effects like decreased alertness, dependency, sexual dysfunction, and even suicidal thoughts (Lakhan & Vieira, 2010).
For some, pharmacotherapy simply is not an option: they would prefer a
more natural solution. Therefore, studying the efficacy of natural treatments like
magnesium has great clinical significance (Boyle et al., 2017).
Several human studies have investigated the effects of magnesium in combination with zinc, calcium, or plant extracts, demonstrating that combined therapy is effective to reduce anxiety (Carroll et al., 2000; De Souza et al., 2000; Hanus et al., 2004).
However, to get a real sense of the effectiveness of magnesium, it would be prudent for researchers to focus on the mono-mineral rather than in combination.
Experiments in the rodent population have shown significant anxiolytic effects
using the following magnesium derivations: mg-aspartate, mg-chloride, mg-L-threonate, mg-lactate, mg-oxide, or mg-pyroglutamate (Abumaria et al., 2011; Lezhitsa et al., 2011); however, there are no studies to date that have definitively determined which form of magnesium is the best to reduce anxiety.
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