No one ever told me that grief felt so like fear.

–C.S. Lewis

roper nutrition is essential for far more than just building a better body or preventing the degenerative diseases of aging. Numerous studies have found that nutrition can also have a significant impact on our mood and social behavior – both in our formative childhood years and into adulthood.

Unique research has recently shown, for example, that malnutrition in early childhood is associated with reduced IQ and with various behavioral problems including aggression, hyperactivity, and delinquency:

Study Link – Malnutrition at Age 3 Years and Externalizing Behavior Problems at Ages 8, 11, and 17 Years.

Quote from the above study:

…[T]he relationship between malnutrition and externalizing behavior was not found to be an artifact of psychosocial adversity but was instead mediated by cognitive ability, indicating that malnutrition predisposes children to a lower IQ, which in turn predisposes them to externalizing behavior problems.

Other studies have found that the use of simple vitamin and mineral supplements by adult prison inmates significantly reduced the incidence of violence and antisocial behavior in the prison population:

Study Link – Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners.

Quote from the above study:

Antisocial behaviour in prisons, including violence, are reduced by vitamins, minerals and essential fatty acids with similar implications for those eating poor diets in the community.

But despite many such studies, the role of nutrition is usually given little more than a passing mention in relation to mood and behavioral disorders. Often, if the conditions are addressed at all, pharmaceutical interventions comprise the sole form of treatment.

Of course, pharmaceuticals can often combat mood disorders like depression and anxiety with a reasonable degree of safety, but antidepressants and anti–anxiety medications are also often associated with unforeseen and sometimes even life–threatening side effects. Though researchers and pharmacologists are quick to offer educated guesses as to how these drugs are affecting brain chemistry, in truth, many of the biological effects of these drugs remain a mystery to medical science. In many instances, nutrients alone may not be able to fully rectify mood or behavioral disorders, but some evidence suggests that select nutrients may be able to improve the effectiveness of drug and other therapies for disorders such as depression and anxiety. Ultimately, understanding the biology involved in these disorders may allow for safer, more holistic, and more effective treatments – i.e., treatments which are certain to include adequate nutritional support.

Neurons, Mood and the Brain

In the most basic sense, who we are – how we act, think, feel, move, and remember – is manifest biologically by the activity of our nervous system. The same basic principle holds true throughout the animal kingdom, and the relative intricacy of nervous systems in different animals helps to explain the varied physiological, mental, and emotional capacities of different species. The complexity of an animal’s nervous system depends upon the structure and organization of its constituent neurons – cells known for their unique means of transmitting electrical and chemical signals. Nervous systems of simple organisms, like worms or insects, allow these creatures to respond to chemical or tactile stimuli in their environment by means of mere neurological reflexes, whereas the nervous systems of higher organisms are progressively more complex and compartmentalized, ultimately culminating in full–fledged brains capable of information processing, emotion, thought, and memory.

By some estimates, the human brain consists of 100 billion neurons, containing 100 trillion synapses – gap–like locations where chemical transmissions occur. But although the human brain represents a remarkably complex network of neurons, and an astronomical ability for information processing via chemical transmission, our brain uses many of the exact same chemical messengers as its’ lowly evolutionary predecessors. The relatively–simplistic neuronal network of the flatworm, for example, operates on many of the same substances as the highly–exalted human brain.

This fact allows scientists to study neuronal transmission in simple organisms, and to extrapolate their findings to more complex neuronal systems like those found in humans. It also underscores how some of the most basic elements necessary for all life on earth – amino acids, minerals, and vitamins – can have profound effects on the human nervous system – including our capacity for thought, our mood, and our emotions.

Glutamate And The NMDA Receptor

One of the most fundamental forms of nervous transmission across species is triggered by the amino acid, glutamate – the most prevalent neurotransmitter in the human brain and nervous system. Glutamate is often said to be “excitatory” as, by and large, the amino acid triggers brain– and nervous system–stimulating activity. Glutamate acts upon three separate types of chemical receptors (fittingly called glutamate receptors), of which the NMDA (N–Methly D–Aspartate) receptor is the most common, and most extensively studied.

The NMDA receptor acts as a sort of gatekeeper of the neuron. In previous newsletters in this series, we saw how calcium influx into cells has a stimulating effect, and how magnesium is needed to prevent the excessive cellular influx of calcium which is an underlying facet of aging and disease. In neurons, this biology holds true, and magnesium is the primary element present within the calcium channel of the NMDA receptor. When sufficient glutamate is present, magnesium is dislodged from the NMDA receptor, allowing the neuron to “fire” as calcium enters. Sufficient magnesium, therefore, is needed to prevent the excessive calcium–mediated stimulation of neurons.

When all is functioning properly in the human brain, glutamate–induced NMDA activation (and the subsequent calcium influx into the neuron) is involved in establishing what’s known as synaptic plasticity – the ability of neurons to alter and strengthen their transmission once stimulated. Synaptic plasticity is thought to be the biological underpinning of the brain’s ability to reorganize neural pathways in response to new or repeated experiences. In simpler terms, we can think of synaptic plasticity as the biological basis for learning and memory. From our earliest childhood perceptions of the world around us, to the massive amount of information we process and retain during our school years, to the motor proficiency we gain by continually practicing a musical instrument, NMDA stimulation via glutamate plays a major role in building the neural pathways that translate our life experiences into the very fabric of our being.

But chronic over–stimulation of NMDA receptors is now also known to be a characteristic phenomenon of many seemingly disparate disorders. Alzheimer’s disease, chronic fatigue, chronic pain, obsessive–compulsive disorder, post–traumatic stress disorder, insomnia, addiction, and even obesity are united by the common biological thread of excessive NMDA stimulation via glutamate.

From a neurobiological standpoint, NMDA stimulation and synaptic plasticity is now thought to also play a role in the development of depression– and anxiety–related disorders. This fact has led some researchers to actually characterize these disorders as aberrant types of learning – a vantage point which has led to new avenues for treatment, as well as new perspectives on currently popular medications such as antidepressants.

Are Antidepressants NMDA Antagonists?

Despite the simplistic biochemical explanations proffered in drug advertising, medical science has yet to elucidate exactly how antidepressant drugs exert their effects. In fact, many incongruities exist between the “official” explanation for how these drugs work and actual research findings (and empirical observation). For example, if these drugs act as we are told in television commercials – by altering the brain–level of chemicals such as serotonin and norepinephrine – then the efficacy of these drugs would be nearly immediate. In actual practice, however, most of the current crop of “reuptake–inhibitor” antidepressants begin to exert their effects more slowly – over the span of several weeks or so.

This is one reason why many researchers believe that antidepressants function, not by increasing the brain’s circulating levels of serotonin or norepinephrine, but by possibly causing a reduction in the number of cellular receptors for these chemicals. Many (but not all) antidepressants have been found to reduce the number of beta–adrenergic receptors (i.e., receptors for norepinephrine – the “brain’s adrenaline.”) and also to reduce the number of serotonin receptors on certain structures of the brain. In this respect, these antidepressants work by actually reducing the effects of these chemicals, not increasing them as is the standard pharmaceutical–industry party line:

Article Link – Drugs: Guide and caveats to explanatory and descriptive approaches—I. A critical evaluation of the current status of antidepressant drugs.

Quote from the above study:

Major changes in monoamine function after repeated treatment with antidepressants include: a decrease in number of beta–adrenergic receptors, increased sensitivity of alpha 1– adrenoreceptors, down–regulation of serotonin 2 receptors, increased sensitivity to behavioural and electrophysiological effects of serotonin agonists, subsensitivity of presynaptic dopamine receptors and enhanced dopamine function.

But despite some enticing clues such as these, researchers seeking a common biological thread to unite the effects of numerous antidepressants have historically come up empty. Many drugs with clear anti–depressant activity have been found to exhibit decidedly different biological effects with regard to numerous brain chemicals and their receptors.

However, recent research on NMDA–receptor activation in depression (as well as numerous other mood and behavioral disorders) may offer clues to a unifying theory. Researchers have offered intriguing evidence that the common biological activity of antidepressant therapies may involve their effect on glutamate signaling and, in particular, glutamate signaling at the NMDA receptor. Drugs (and nutrients) which prevent NMDA receptors from being stimulated (i.e., NMDA antagonists) have often been found to exert anti–depressant effects:

Study Link – Functional antagonists at the NMDA receptor complex exhibit antidepressant actions.

Quote from the above study:

These findings indicate that the NMDA receptor complex may be involved in the behavioral deficits induced by inescapable stress, and that substances capable of reducing neurotransmission at the NMDA receptor complex may represent a new class of antidepressants. Based on these findings, the hypothesis that pathways subserved by the NMDA subtype of glutamate receptors are involved in the pathophysiology of affective disorders may have heuristic value.

Study Link – Adaptation of N–methyl–D–aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression.

Quote from the above study:

NMDA antagonists mimic the effects of clinically effective antidepressants in both preclinical tests predictive of antidepressant action and procedures designed to model aspects of depressive symptomatology...Based on the consistency of these effects across antidepressant treatments, we propose that adaptive changes in NMDA receptors may be the final common pathway for antidepressant action.

It has been found that NMDA antagonists cause a down–regulation of beta–adrenoceptors in certain areas of the brain in much the same way anti–depressants often do:

These findings led to experiments demonstrating that chronic administration of NMDA antagonists to rodents results in a downregulation of cortical beta–adrenoceptors, a phenomenon also observed following chronic treatment with many antidepressants.

Anti–depressant therapies have been shown to alter NMDA receptors, and the previously–mentioned delayed onset of anti–depressant action may be explained by the fact that this alteration occurs with chronic, but not acute, dosing:

Chronic (14 days) but not acute (1 day) administration of seventeen different antidepressants to mice produced adaptive changes in radioligand binding to NMDA receptors.

As further evidence of a role of a glutamate–NMDA association in depression, NMDA receptors in the frontal cortex of suicide victims have been found to be more–readily stimulated than those of control subjects:

Study Link – Alterations in the N–methyl–D –aspartate (NMDA) receptor complex in the frontal cortex of suicide victims.

Quote from the above study:

These data represent the first demonstration supporting the hypothesis that glutamatergic dysfunction is involved in psychopathology underlying suicide and, potentially in human major depression.

Interestingly, we find that it’s not just drugs which prevent excessive NMDA stimulation – nutrients such as magnesium and zinc do as well. As we’ve seen in previous newsletters in this series, the vast majority of modern diets are seriously lacking in magnesium. For this reason, it’s safe to say that any holistic attempt at addressing mood and/or neurological disorders must include sufficient magnesium and its accessory nutrients.

Study Link – Antidepressant activity of zinc and magnesium in view of the current hypotheses of antidepressant action.

Study Link – Rise in zinc affinity for the NMDA receptor evoked by chronic imipramine is species–specific.

Quote from the above study:

Zinc and magnesium are potent inhibitors of the NMDA receptor complex. Previous reports demonstrated that both zinc and magnesium, like other NMDA receptor antagonists, exhibit antidepressant–like effects in rodent screening tests.

Recent research has found that the anti–depressant action of magnesium is likely to be due to the mineral’s ability to reduce the over–stimulation of NMDA receptors. In the following study, low doses of NMDA antagonists and magnesium – doses of each which would have been ineffective when used alone – imparted a synergistic antidepressive effect when combined:

Study Link – NMDA/glutamate mechanism of antidepressant–like action of magnesium in forced swim test in mice.

Quote from the above study:

Magnesium–induced antidepressant–like activity was antagonized by N–methyl–d–aspartic acid (NMDA). Moreover, low, ineffective doses of NMDA antagonists (CGP 37849, L–701,324, d–cycloserine, and MK–801) administered together with low and ineffective doses of magnesium exhibit significant reduction of immobility time in FST. The active in FST doses of examined agents did not alter the locomotor activity (with an exception of increased activity induced by MK–801). The present study indicates the involvement of NMDA/glutamate pathway in the antidepressant–like activity of magnesium in mouse FST and further suggests antidepressant properties of magnesium.

Just as a lack of nutrients such as magnesium and zinc can lead to excessive NMDA stimulation, so too can the inclusion in the diet of certain foods and food additives. The flavor–enhancer, monosodium glutamate (MSG), is, logically, a source of glutamate, and has long been suspected of triggering various neurological side effects. The amino acid, aspartate is similar to glutamate in that both are able to stimulate the NMDA receptor (the receptor is, in fact, named due to its ability to be maximally stimulated by a particular variant of aspartate, N–Methyl–D–Aspartate).

The artificial sweetener, aspartame, contains aspartate, and studies have found that aspartame may significantly worsen depression. In the following study, for example, the depression–exacerbating effects of aspartame were so severe that the experiment was halted early for ethical reasons:

Study Link – Adverse reactions to aspartame: double–blind challenge in patients from a vulnerable population.

Quote from the above study:

Although the protocol required the recruitment of 40 patients with unipolar depression and a similar number of individuals without a psychiatric history, the project was halted by the Institutional Review Board after a total of 13 individuals had completed the study because of the severity of reactions within the group of patients with a history of depression.

Fear, Learning, And The Amygdala

Centuries ago, while delving deep within the temporal lobes of the human brain, anatomists first discovered two almond–shaped structures which, collectively, have come to be known as the amygdala. But while the presence of these brain structures has been known for centuries, only recently have advances in brain–mapping technology allowed researchers to gain an understanding of the amygdala’s actual function.

The amygdala is now known to be intimately involved in emotional responses and fear conditioning. In a general sense, fear conditioning converts neutral sensory stimuli into emotional stimuli. It’s because of fear conditioning, that a driver who has been in a car accident, for example, may feel his palms start to sweat and notice his heart beating faster while approaching the intersection where the accident previously occurred – even if there are currently no other cars in sight.

Mental phenomena such as this can occur because the amygdala receives only some of its chemical input and imprinting from the higher “rational” portion of the brain, the cerebral cortex (i.e., the part of the brain that “knows” that there’s no imminent danger). But, in what amounts to a biological basis for the dichotomy between reason and emotions, the additional neuronal input the amygdala receives comes directly from the “lower,” sensory, elements of the brain and nervous system. In other words, both “rational” and sensory inputs (sight, sounds, smell, etc.) are capable of imprinting the amygdala. The fact that NMDA receptors (and other glutamate receptors, called AMPA receptors) seem to dominate in the amygdala, helps to explain why the “learning” of fear can bypass and override all rational interpretation.

Study Link – Synaptic Plasticity in the Lateral Amygdala: A Cellular Hypothesis of Fear Conditioning.

A particularly compelling illustration of the fear–biology involved in anxiety disorders is that of posttraumatic stress disorder.

Glutamate, NMDA, and Posttraumatic Stress Disorder

Post–traumatic stress disorder (PTSD) is a type of pathological anxiety which typically develops after the exposure to severe emotional trauma. The disorder often affects combat veterans, or survivors of terrorist attacks, abuse, assault, or natural disasters.

Neurologists have known for some time that emotional inputs play important roles in learning and memory. In many instances, these emotional connections can be decidedly positive – leading to vivid recollections of “unforgettable” life events such as our first kiss, a romantic encounter, or the birth of our children. But emotional inputs which are decidedly traumatic can leave their mark on our brains as well. The “fight–or–flight” response, which is engaged by imminent danger (real or perceived), triggers massive glutamate signaling in the amygdala. Because the amygdala is able to receive signals, more or less, directly from sense organs (i.e., without being “filtered” by the cortex to discern whether or not these stimuli are actually dangerous), intense emotional experiences can “hardwire” the sensory input of traumatic experiences directly into our emotional brain.

Take the example of a war veteran whose brain has been altered in such a way by the sensory input of combat – the sights and sounds of gun and mortar fire are indelibly linked with the horrific sights of destruction and bloodshed. The emotional intensity of the experience overwhelms rational interpretation via cortical structures of the brain, and the mere sensory perception of stimuli, such as loud noises and flashes of light, leave their emotional mark on the amygdala.

Back home, thousands of miles and even decades removed from the heat of battle, the neural circuits in the soldier’s brain are still wired to respond with a hearty fight–or–flight reaction in response to similar sensory stimuli. A flash of lightning, a clap of thunder or even an exploding firecracker may be sufficient to trigger the exact same biological spiral of panic the gunfire elicited on the battlefield. The soldier feels particularly helpless, as he consciously knows that no imminent danger exists – yet the actions of his brain and body are completely beyond his conscious control.

But, while this model of PTSD offers an intriguing insight into the disorder, effective therapies remain elusive. Increasingly, however, researchers are finding that anti–glutamate / NMDA antagonist drugs may be uniquely effective. Preliminary studies have found the anti–glutamate drug, lamotrigine, for example, to be a promising candidate for the treatment of PTSD:

Study Link – A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder.

Quote from the above study:

Lamotrigine may be effective as a primary psychopharmacologic treatment in both combat and civilian PTSD and could also be considered as an adjunct to antidepressant therapy used in the treatment of PTSD.

Very few, if any, studies have directly examined the role of nutritional support in PTSD, but noting that magnesium is well–documented to reduce depression and anxiety after traumatic brain injury, some researchers have called for magnesium to be studied as a substance with possible therapeutic benefit in PTSD:

Study Link – Magnesium Attenuates Post–Traumatic Depression/Anxiety Following Diffuse Traumatic Brain Injury in Rats.

Quote from the above study:

Whether Mg may be of benefit in post–traumatic stress disorder (PTSD) has not been previously investigated and no published literature exists describing the free blood Mg status in patients with PTSD. It would therefore be of interest to examine whether altered Mg status exists in PTSD patients, and whether subsequent treatment with Mg would in fact provide any benefit in this condition.

Somewhat surprisingly, however, some animal studies have shown that magnesium–deficient diets actually inhibited fear conditioning in mice – it made the animals less apt to “learn” fear.

Study Link – Magnesium deficiency impairs fear conditioning in mice.

Quote from the above study:

Magnesium–deficient mice exhibited impairments in contextual and cued fear conditioning.

Of course, magnesium deficiency is decidedly harmful (e.g., the magnesium–deficient mice in the above study were more susceptible to seizures because of enhanced NMDA signaling in the absence of magnesium), but this study may be a clue that disorders of magnesium metabolism (and not simply a lack of magnesium) may need to be rectified in order to provide nutritional support in anxiety disorders.

As research into brain science advances, scientists are continuing to uncover the chemical basis of mood and emotional disorders. One could optimistically envision how this research may not only help to provide for more effective treatments, but also, how it may help to end the social stigma many of those with mental and behavioral disorders endure. While pharmacological treatments for depression and anxiety have allowed the chemical nature of some mood disorders to enter into the public consciousness, one of the saddest consequences of the scientific illiteracy of our culture is the tendency of the typical layperson, fully–ignorant of the biology involved, to, nevertheless, condemn the mentally–ill as merely lazy, weak–willed, or genetically–flawed. We still find these sorts of shortsighted social stigmas prevalent today, especially with regard to disorders such as addiction and obesity – conditions which, in actual fact, bear a direct relationship with all aspects of brain chemistry and nutrition so far discussed. In upcoming Integrated Supplements Newsletters, we’ll examine the biological and nutritional facets of these disorders which have been uncovered by recent advances in neurological research.

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