Bone Nutrients:



Medicine often points the finger to high sodium levels as being contributory to heart disease when in fact the culprit may be low calcium, potassium or magnesium levels. These nutrients work as a team to conduct nerve impulses contract muscles. Bone nutrients must be present concurrently and in adequate amounts to form new bone tissue. 

Potassium, magnesium and calcium levels can be measured in blood serum. However, the calcium blood measurement is not so useful, because when blood calcium is low, the body takes calcium out of bone to raise the blood calcium levels. When bone tissue is broken down in this manner, both calcium and phosphate are released from the bone into the blood stream, thus elevating blood serum levels. This regulation process is important to keep nerves conducting and muscles contracting. However, the reabsorption process weakens bones because it removes calcium, phosphate, minerals plus collagen nutrients. If calcium, phosphate, minerals and collagen nutrients are never replaced in balanced amounts, bone tissue breakdown and eventually osteoporosis results.  Bone pain may result when nutrient levels are low due to damaged bone tissue effectively “stealing” nutrients from neighboring healthy bone tissue.  That neighborly reabsorption could be painful.  Supplying bone tissue with adequate nutrients eliminates the need for healing bone tissue to reabsorb healthy neighboring bone tissue. 

Since blood calcium measurements do not give us an accurate indication of whether calcium levels are being maintained, medicine measures bone calcium levels through density scanning techniques such as DEXA scan. DEXA scan measurements that are between +1 and -1 are considered normal. Measurements between -1 and -2.5 are considered osteopenic (reduced bone mass) and measurements less than -2.5 are considered osteoporosis. More information can be found on http://

Noticeable physical indications of low blood calcium levels include muscle cramps, restless legs and broken bones. Muscles need adequate calcium, sodium, and potassium to contract and relax. Calcium supplements help relax a muscle cramp. This is due to lactic acid build up during exercise. Calcium may bind lactic acid, relaxing the muscle and releasing the cramp. Sparkling water and club soda, given their alkali nature, also help to neutralize the lactic acid relieving a muscle cramp. While massaging and stretching a tight muscle feels good, this may damage the fibers. Muscle relaxation and contraction is best restored when adequate minerals are provided. While a calcium supplement and alkali water, club soda, or sparkling water may be a temporary remedy to relieve muscle cramps or restless legs, a long term dietary and supplement plan will be important to maintain muscle, bone, and nerve health.

Calcium Sources

Because calcium is critical to humans, the bones have been cleverly designed to be the body’s mini storage units for calcium. We maintain these bone storage units and blood calcium levels through food intake and supplementation. Some of the best calcium foods according to WebMD are “cheese, yogurt, milk, sardines, dark leafy greens (spinach, kale, turnips, and collard greens) and orange juice”. You can find specific food calcium and nutrient information on Some of the best calcium supplements contain calcium citrate, calcium phosphate, and magnesium. Many supplements contain calcium carbonate which is lime. Current calcium recommendations range from 1000mg – 1500mg/day. Vitamin D also has an important role in transporting calcium into bone, as does Vitamin K2 and Magnesium.  Be sure to have all of these nutrients in adequate amounts through either dietary or supplemental sources for strong bone formation.  Additionally, the thyroid regulates calcium absorption/replenishment in bones.  Make sure your thyroid is functioning properly.  The adrenals and and hormone levels should be appropriate such that your body system is in homeostasis.  A naturopath might be helpful to assess your body system.


Calcium supplementation is frequently recommended since calcium is the most abundant mineral.  Calcium citrate and phosphate are important supplements, given that they constitute a larger percentage of bone. The remaining portion of bone is composed of collagen. The collagen component of bone is rarely mentioned, yet collagen comprises anywhere from 10-30% of bone. Collagen is a flexible tissue found in young bone, tendons and ligaments. It forms the scaffolding for bone mineral deposition.  Collagen is found throughout the body in tissues, organs, joints, gums and teeth. In addition to calcium citrate and phosphate to make the calcium salts in bone, we need the nutrients to maintain the bone collagen network.  The collagen network is formed by vitamin C and the amino acids lysine, proline and glycine. Collagen fibers can be damaged by injury, repetitive use, stretches or strains when muscles are weak. Collagen can additionally be damaged by our immune system. This is due to the attachment of wheat gluten to collagen fibers throughout the body. Our immune system sees wheat gluten and wheat defense proteins as foreign invaders. This causes the secretion of immune system chemicals at the sight of wheat gluten attachment to collagen (lungs/joints/organs) contributing to asthma, arthritis, and many organ diseases. (More information can be found on (Teeth may be a lysine storage site, and adequate lysine and vitamin C levels may contribute to teeth and gum health.)

In summary, all of the nutrients: calcium citrate, phosphate, magnesium, vitamin D, vitamin C, vitamin K2, lysine, proline and glycine must be present concurrently to build flexible collagen and healthy bone tissue. They can be found in a variety of foods and these supplements are available at nutrition stores.

We discussed calcium’s importance to muscle and nerves, and the body’s brilliant regulation mechanism for calcium such that when blood calcium levels are low, the body removes calcium from bone to maintain the blood calcium levels. As we mentioned, this regulation mechanism is great for maintaining nerve and muscle function, but whether bone strength and density is maintained is not as apparent. A good visual analogy of building strong, nutrient rich bone might be a Corvette production line. All of the parts to build the Corvette must be supplied to build the car. If one part is missing, the technicians and robots build what looks like a car and feels like a car, but may not function like a car. One small part may make a huge difference in that new Corvette. Bones and collagen work the same way. They are composed of many “parts” (calcium citrate, phosphate, magnesium, vitamin D, vitamin K, vitamin C, lysine, glycine, and proline). All nutrients must be supplied in adequate amounts for your body to build elegant bone, tendon and ligaments.

If bone construction parts are missing, the body may build structures that look and feel like bone, tendon and ligaments, but they may not function that way. Bones may break easily and muscles may cramp easily. Restless legs may result. Tendons may tear. Adequate, viable parts produce beautiful, 0 to 60mph in 4 seconds, Corvettes.  Akin to adequate nutrients producing healthy, functional bones, tendons and ligaments.

Why is Calcium Removed from Bone ??

As we discussed, our bodies remove calcium from bone tissue to maintain critical muscle and nerve function. This eloquent measure is designed to maintain our most abundant blood calcium mineral level.  Alas, in osteoporosis, this calcium removal measure is being forced to work overtime. There is a second important reason calcium may be lost from bone. Many of our foods are acidic. The blood is carefully regulated to be around pH of 7.4, this is critical for chemical pathways. Acidic foods would drive the blood pH below 7.4.  Recycled bone calcium contains bicarbonate which acts as a pH buffer in the blood to balance these acidic foods, maintaining the pH. Alkali water, club soda, and sparkling water all bind acid to help maintain this normal blood pH. This process might be somewhat like bath water. If the bath water is too hot, cold water can be mixed with hot water to neutralize it’s effect. Finally, calcium can be removed from bone and excreted when the adrenals are fatigued. Both mental and physical stress, can fatigue the adrenals. Our high consumption of glyphosate laden, modified grains such as wheat gluten fatigues our adrenals. Due to the stress on the adrenal neurotransmitter production system, calcium leaves the body.  This adrenal stress is particularly noticeable during the puberty years when the child’s body needs extra bone nutrients plus extra protein for physical growth and to mentally handle school stress.

Calcium Buildup in Tissues Other than Bone

Often, calcium builds up in tissues other than bone. Calcium buildup is found in breast tissue, kidney stones, gallstones, cysts and many other tissues, where it doesn’t belong. Why? What should we do? Interestingly, calcium buildup in the wrong tissues appears to occur when individuals have insufficient dietary/supplemental calcium intake. Researchers have found that increasing dietary calcium and supplements decreases calcium buildup in the wrong tissues and builds up calcium in the right places such as in bone tissue (Gul and Monga, 2014).

Your curious mind may ask, why is calcium showing up in the wrong tissues when dietary/ supplemental calcium levels are low? We would like to propose a theory to answer this question. We know that when blood calcium levels are low, recycled calcium (and phosphate) being released from bone to raise blood calcium levels. It is likely that the recycled bone calcium is structurally different from the calcium we eat in food and/or supplement, and possibly the recycled calcium from bone cannot be redeposited into bone tissue once blood levels normalize. Perhaps, the body can’t easily excrete excess recycled bone calcium, thus it builds up in tissues where it doesn’t belong. Certainly, releasing calcium from bone, to maintain blood calcium levels, was meant to be a temporary measure, not a long term process.

What is the impact of having recycled calcium delivered to the wrong tissues? “Insufficient intake of dietary calcium (<600mg/day) can increase… the risk of stone formation“, (Gambara, 2016). Gambara confirms that “stone formation is frequently associated with other diseases of affluence such as hypertension, osteoporosis, cardiovascular disease, metabolic syndrome, and insulin resistance.” Research studies such as the 2012 NHANES find “a 70% increase from the 1994 NHANES” in urinary tract stone disease, (Gul and Monga, 2014). Thus, our calcium deficiencies are worsening. These researchers report that “newer research is finding that stones are associated with several serious morbidities”.

Researchers have found that calcium buildup in the form of hydroxyapatite in breast tissue contributes to breast cancer (Cooke, 2003). Let’s repeat this sentence. Calcium build up in breast tissue is involved with breast cancer. One in eight women will have breast cancer. Researchers also recognize that radiation can modify healthy cells and turn them into uncontrollable cancerous cells. Mammograms contain radiation and radiation damage is additive in the body. Researchers have found that citrate and phosphate may have a role in removing hydroxyapatite deposits in breast tissue.  In one research study, women taking phosphate bone density drugs had reduced incidence of breast cancer.

How to Deliver Calcium to Bone

Given this information, how shall we best increase calcium in our bones and decrease calcium tissue deposits and stones?

One common solution, is to take a calcium supplement such as calcium citrate and/or calcium phosphate. Bone is composed of calcium citrate, calcium phosphate, magnesium, vitamin D, vitamin K2, and collagen (vitamin C, lysine, proline, and glycine). It used to be that many calcium supplements were composed of calcium carbonate. Calcium carbonate is lime. Many supplements are now changing ingredients to calcium citrate or calcium phosphate. We need both.

Why calcium citrate? Citrate works in two ways. First, citrate is a buffer. Therefore, when the blood pH is low, citrate will buffer the pH and calcium will not be pulled from bone tissue to normalize pH. Alkali water, club soda or sparking water are alkali drinks that help to increase blood pH. Secondly, calcium citrate is found to combine well with phosphate and collagen components to make bone. Calcium citrate appears to be a key strength component in bone tissue. More information on citrate properties: 2011/06/110608153548.htm. Finally, citrate and phosphate help remove calcium buildup in the wrong tissues: %2C+citrate%2C+phosphate. Researchers found that citrus bioflavonoids and lemon peel inhibit stone formation: This is critical information to the long term prevention calcium build up in the wrong tissues and maybe critical to the long term prevention of breast cancer. Many calcium supplements are now calcium citrate.

Calcium phosphate is the other important component of bone. Calcium citrate and phosphate can be found in supplements. Researchers have found that citrate and phosphate may have a role in removing hydroxyapatite deposits in breast tissue. These deposits found on mammograms may contribute to the formation of breast cancer. In one research study, women taking phosphate bone density drugs had reduced incidence of breast cancer.

The Linus Pauling Institute has found that many other minerals and vitamins are found in bone such as magnesium, fluoride, sodium, vitamin A, D and K. More information can be found on: More individuals than recognized may be deficient in vitamin A, as seen in dry eyes and in vitamin K as seen in nose bleeds. (Caution: vitamin K, found in leafy green vegetables, allows the blood to clot when vessels are damaged. Blood thinners interfere with vitamin Ks ability to clot blood. Ingesting additional vitamin K interferes with blood thinner drugs)

Secondly, drink plenty of fluids to produce at least 2.5L of urine per day (Gul and Monga, 2014). Gul recommends avoiding the colas which are acidic, yet not being quite as concerned with the “citric acid containing sodas, which include most clear soft drinks.” As we learned above, citric acid found in lemons and limes can be beneficial to bone health.

Remember that if you are eating a lot of protein, taking amino acids for brain or sports health, or drinking wine your blood may be more acidic which will pull carbonate from your bones to buffer the pH of your blood. So you may want to increase your calcium citrate or alkali water, club soda, and/or sparkling water consumption to balance these actions.

Finally, stressing your adrenals, the little walnut shaped organs that sit on top of your kidneys, (the adrenals produce neurotransmitters) results in the loss of calcium. Minimizing both mental stress activities and physical stress, often caused by the consumption of manufactured wheat and sugar, will help the adrenals. High glucose (grains, sugars) levels result in high stone levels (Gul and Monga, 2014).

Best Wishes and Blessings Friends and Remember to Exercise!


Cooke MM1, McCarthy GM, Sallis JD, Morgan MP. Phosphocitrate inhibits calcium hydroxyapatite induced mitogenesis and upregulation of matrix metalloproteinase-1, interleukin-1beta and cyclooxygenase-2 mRNA in human breast cancer cell lines. Breast Cancer Res Treat. 2003 May;79(2):253-63.

Gambaro G1, Trinchieri A2., Recent advances in managing and understanding nephrolithiasis/ nephrocalcinosis. F1000Res. 2016 Apr 18;5. pii: F1000 Faculty Rev-695. doi: 10.12688/ f1000research.7126.1. eCollection 2016

Gul Z1, Monga M2., Medical and dietary therapy for kidney stone prevention.
Korean J Urol. 2014 Dec;55(12):775-9. doi: 10.4111/kju.2014.55.12.775. Epub 2014 Nov 28.

Additional Materials:

Citrate helps reduce stone formation:

Chronic alcohol use may weaken bones:

EGCG (epigallocatechin gallate) found in green tea shows promise inhibiting the formation of kidney stones in rats:

Mediterranean/fruit/vegetable diet may protect against stone formation:

Disclaimer: The ERB is a literature research team presenting the findings of other researchers. The ERB is not licensed medical nor dietary clinicians and will not give medical nor dietary advice. Any information presented on this website should not be substituted for the advice of a licensed physician or nutritionist. Users of this website accept the sole responsibility to conduct their own due diligence on topics presented and to consult licensed medical professionals to review their material. We make no warranties or representations on the information presented and should users utilize this research without consulting a professional, they assume all responsibility for their actions and the consequences.


Tryptophan’s Affect on Depression: A Review Article



The Amino Acid Tryptophan produces the Neurotransmitter Serotonin.  Does Supplementing Tryptophan produce additional Serotonin to Attenuate Depression and Mood Disorders?

Southern California stood on high alert as depressed weapons expert, Christopher Dorner, declared war on fellow police officers. For days, he traveled through populated cities ambushing law enforcement officers. When Dorner was finally located in the remote San Bernardino forest, gunfire erupted. One officer died at the scene and a second was gravely injured. Both officers were medivaced to our Emergency Department at Loma Linda University. Hundreds of other police officers held a vigil in the parking lot. The injured officer was rushed past me into surgery. He would not survive. The following day, Christopher Dorner, an honorably discharged Navy reservist and former Los Angeles Police officer, took his own life.

Depression, according to World Health Organization estimates, will be the second highest cause of death (Muszyndska, et al., 2015). The affect of depression in the U.S. alone cost $210 billion in 2010 (Reus et al, 2015). Society experiences the increasingly common display of these depressive disorders on nightly television in the form of violent outbreaks, suicides, and school shootings.

Thus far, the major treatment for depression has been anti-depressant drugs. Although, treatment resistance occurs in over 20% of cases (Reus et al, 2015) and 50% of the patients experiencing Major Depressive Disorder will have episodic recurrences and chronic disease (Reus et al, 2015). During the first month of anti-depressant therapy, there is often no improvement in the depressive condition. Suicidal tendencies and inflicting self harm are a major side effect (Reus et al, 2015). Anti-depressant drugs are often designed to recycle the neurotransmitter chemicals present in an individual (Reus et al, 2015), typically not providing additional nutrients to raise neurotransmitter levels and rebuild damaged pathways. As a result, individuals are likely to be dependent upon anti-depressant drugs for an extended period. Eventually, the drug may no longer work or the individual may become treatment resistant ( Reus et al, 2015).
II. Tryptophan, Serotonin and the Alteration of Human Mood

The eventual cure for treating depression and mood disorders may be to provide nutrient based therapies with the goal of rebuilding major components of the neurological pathway systems involved with depression. One neurological pathway critical to affecting mood disorders generates the neurotransmitter serotonin (Bravo et al, 2013). Rebuilding the serotonin pathway to improve depressive-like symptoms may involve supplying the brain with the amino acid precursor, tryptophan.
Tryptophan hydroxylase Dopa Decarboxylase

Tryptophan ————–> 5-Hydroxytryptophan ————> Serotonin
(5-HTP) (5-HT, 5 -Hydroxytryptamine)

Cofactors: Vitamin B3, B9, Iron and Calcium Zinc, Vitamin B6 and C, Magnesium

(Educational Research, 2012)
This pathway illustrates the chemicals involved with the production of the neurotransmitter serotonin from the amino acid tryptophan. Tryptophan is a protein that cannot be made by humans, and thus is essential in the diet (Yao et al., 2011; Sarris & Byrne 2011). This pathway shows how tryptophan in the presence of the enzyme tryptophan hydroxylase (TH) and cofactors, vitamin B3, B9, iron and calcium, produces 5-hydroxytryptophan (5-HTP) (ERB, 2012). 5-HTP is able to cross the blood brain barrier (Patrick &Ames, 2015) where it is absorbed by brain nuclei which convert 5-HTP to serotonin (HT-hydroxytryptamine) in the presence of the enzyme dopa decarboxylase, and cofactors: zinc, vitamin B6, vitamin C, and magnesium (ERB, 2012). Cognitive behavior, sleep and mood are regulated by the neurotransmitter serotonin in humans, and pathway disturbances have been shown to exhibit anxiety, depression and cognitive disorders in humans (Cubero et al.,2011; Mendelsohn et al., 2009; Markus et al.,2005).

The serotonin production pathway is enhanced with many tryptophan or serotonin containing natural products in diets around the world. The natural plants, herbs and fungi that enhance the serotonin system include: Chinese saffron, Siberian Ginseng, African Griffonia, St. John’s Wort grown in Europe-Asia- Africa, African Kanna, Kava Kava from the Western Pacific, and mushrooms (Muszynska et al., 2015). The United States was prevented from using tryptophan and 5-HTP supplements late in the 1990s when a Japanese company supplied a tainted batch of product. The tainted batch caused eosinophilia-myalgia syndrome (EMS) in 1500 individuals including some deaths (Hill, et al., 1993; Druker, 2001). As a result, the FDA kept supplemental tryptophan unavailable until 2005. The scientific experiments described below will explore the use of supplemental tryptophan for the relief of depression and mood disorders in humans.

Tryptophan’s Effect on Human Mood

In this first experimental study, Mohajeri’s team hypothesized that positive emotional stimuli could be enhanced and negative stimuli reduced through dietary tryptophan. The article is titled “Chronic treatment with a tryptophan-rich protein hydrolysate improves emotional processing, mental energy levels and reaction time in middle-aged women”. Fifty-nine healthy women, 45-65 years old were randomly selected (age stratified) to compare a tryptophan fortified drink with placebo (Mohajeri, et al., 2015). Subjects experiencing psychiatric, neurological gastrointestinal disorders, receiving pharmaceuticals, diabetic, or pregnant, were excluded.

Subjects were baseline tested with four personality questionnaires: Dutch Personality Inventory, Depression Anxiety and Stress Scale, Aggression Questionnaire, and Barratt Impulsiveness Scale (Mohajeri, et al, 2015). Sleep/mood diaries were kept by the women. A large battery of pre and post tests assessed mental and physical sensations. Each woman was given tryptophan rich drinks for 19 days (Mohajeri, et al., 2015).

The experimental findings were similar between the placebo and tryptophan fortified drink in neuroticism, anxiety, impulsivity, depression and aggression. Cognitive results evaluated with the Rotary Pursuit Task, Rapid Visual Information Processing Task, Verbal Recognition Memory Test, and Driver Hazard Perception Test were similar (Mohajeri, et al, 2015). Final treatment increased high energy ratings on the Mental and Physical Sensations Scale. The Affective Go/No-Go Task slowed the negative word response time of the tryptophan drink group. The Facial Emotional Expression Rating Task showed no treatment effect, however, the intensity of anger lessened and overall happiness/mood improved (Mohajeri, et al, 2015)

These findings further showed that in the Simple Reaction Time Task, shorter reaction times resulted with the tryptophan drink. The Match to Sample Visual Search Task demonstrated an overall faster reaction time for the tryptophan supplemented group in locating targets (Mohajeri, et al., 2015). Evening mood and quality of sleep was evaluated through the self reported diary, Leeds Sleep Evaluation Questionnaire, and Thayer’s energetic arousal. ANCOVA found sleep and evening moods improved with the tryptophan drink (Mohajeri, et al, 2015). Subjects awoke fewer times during the night and rated their happiness higher. Mohajeri’s experiment found that the effect of the protein drink reduced anger, increased happiness/mood, improved sleep habits, and resulted in shorter reaction times. These four criteria relate directly to the depression related criteria analyzed in NHANES, as well as relate to criteria analyzed in the Beck Depression Inventory and Hamilton Psychiatric Rating Scale (Su et al, 2008; Raimo et al, 2015).

Tryptophan’s Effect on Human Mood and Sleep

This next experimental study is entitled “Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans” by R. Bravo and co-researchers. The hypothesis was whether sleep and depression/anxiety could be improved through a tryptophan rich cereal. This experiment is based upon the brain utilizing tryptophan to produce serotonin to regulate depression and anxiety (Cubero et al, 2011; Mendelsohn et al., 2009; Markus et al, 2005). Serotonin is then absorbed by the pineal gland to produce melatonin which is able to regulate sleep cycles and circadium rhythms (Bubenik & Konturek, 2011). Circadium rhythm disorders have been found to be related to depression and anxiety (Most et. al, 2010), and tryptophan supplementation has been found to increase circulating levels of both serotonin and melatonin (Aparicio et al, 2007)(Paredes et al., 2007)(Sanchez et. al., 2008a,b).

This tryptophan cereal experiment was performed with 35 caucasian volunteers (ages 55-75). These were healthy volunteers who experienced difficulty sleeping. They were not alcohol, drug users or smokers (Bravo et al., 2015). Individuals slept in their own homes and were asked to eat cereal for breakfast and dinner. During the first week of the experiment, Blevit Plus 8 control cereals containing (75mg tryptophan in 100g cereal) were eaten (Bravo et al, 2015). The second week, the Blevit Plus 8 experimental cereal (200mg tryptophan in 100g cereal) was eaten. The third week subjects returned to their normal diets (Bravo et al, 2015).

To analyze results, Sleep Analysis 5v.5.48 software and wrist actimetry were utilized to measure numerous sleep variables including actual sleep time, sleep efficiency, and number of awakenings (Bravo et al, 2015). Pre-test/post-test urinalysis through DRG kits were performed to measure 6-sulfatoxymelatonin (aMT6s) and 5-hydroxyindoleacetic acid (5-HIAA) which are melatonin and serotonin metabolites, respectively. The Cayman kit measured total antioxidant capacity of the urine to quantify the anti-oxidant activity of tryptophan (Bravo et al, 2015). Baseline Beck Depression Inventory and State-Trai Anxiety Inventory (STAI) tests were completed to evaluate pre-test/post-test depression and anxiety levels.

Bravo and colleagues found that when comparing sleep results during the tryptophan cereal treatment week with the control and normal diet weeks that sleep habits improved during the treatment week. Increased urine serotonin and melatonin metabolite findings following the high tryptophan cereal diet were statistically significant, as was urine anti-oxidant levels (Bravo et al, 2015). Trait anxiety did not differ from controls, however state anxiety reduced slightly. The Beck’s Depression Test results decreased, demonstrating fewer depression-like symptoms following the tryptophan cereal treatment diet (Bravo et al, 2015). Bravo and colleagues found that mood was positively correlated with the tryptophan diet.

III. A Systems Approach to Rebuilding the Serotonin Pathway

The experimental studies discussed in the last section found that supplementary tryptophan improved mood/depression-like disorders. The review studies discussed below reach beyond evaluating tryptophan as a single nutrient. These researchers have reviewed the mechanisms of the serotonin production pathway system and have considered the roles of additional nutrients that regulate and affect serotonin production. The first review paper evaluates the impact of omega-3 fatty acids which build brain tissue and suppresses inflammation. Additionally, this paper analyzes vitamin D’s role in regulation of the tryptophan hydroxylase enzyme which converts tryptophan to serotonin. The second review paper evaluates the biomarkers of gastrointestinal disease, including inflammation, as related to the biomarkers of depression.

Tryptophan, Vitamin D, and Murine Omega-3 Fatty Acids

In this review article written by Dr. Rhonda Patrick and Dr. Bruce Ames of the Nutrition and Metabolism Research Center in Oakland, California entitled “Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior” a physiological systems approach is applied. The authors discuss how serotonin pathway regulation and receptor access play important roles in pathway function. They write that when the serotonin pathway and the influential mechanisms are not working properly, a plethora of psychiatric disorders may arise including depression (Patrick & Ames, 2015) and social disturbances (Way et al, 2007; Varnas et al, 2004; Sanfey et al, 2007). Additionally, serotonin transporter polymorphisms have been identified which increase the risk of these psychiatric disorders in genetically predisposed individuals (Blair et al, 1995; Greenberg et al, 2000; Retz et al, 2004, Nielsen et al, 1994; Lesch et al, 1996). These researchers evaluate the mechanisms of vitamin D, eicosapentanoic acid (EPA), and docosahexanoic acid (DHA) in serotonin production.

Vitamin D regulates the conversion of tryptophan into serotonin by binding vitamin D response elements (VDRE) and transcriptionally acting upon the enzyme trytophan hydroxylase 1(TH1) (Patrick & Ames, 2015). TH1 is the enzyme responsible for converting tryptophan into serotonin in brain tissue (Patrick & Ames, 2015). Vitamin D has been found to be deficient in up to 70% of adults (Ginde, et al, 2009; Bailey et al, 2012; Mansbach et al, 2009). Deleterious cognitive effects of a vitamin D deficiency have been found in mice with genetic polymorphisms in their TPH genes (Zhang et al, 2004; Groves et al, 2013). These authors support vitamin D supplementation to help reduce psychiatric disease (Patrick & Ames, 2015).

EPA has a role in both the regulation of serotonin secretion and the suppression of inflammation (Gunther et al, 2010; Schlicker et al, 1987; Portanova et al, 1996). EPA inhibits generation of prostaglandins which decrease the release of serotonin and promote inflammation. EPA resolves depression caused by inflammatory cytokines (Su et al, 2014). In patients with gene polymorphisms the inflammatory process is pronounced (Su et al, 2010). While no mechanism has been found to explain how inflammation causes depression, it is known that serotonin is not released when inflammation is present. Stress and inflammatory cytokines are found to convert tryptophan into kynurenine instead of serotonin (Kiank et al, 2010) leading to increased anxiety (Patrick & Ames, 2015). EPA assists serotonin in performing its role to enhance positive social behavior and regulate mood (Patrick & Ames, 2015). In the average adult, dietary surveys show that a deficiency of EPA exists (U.S. Department of Agriculture, 2014).

DHA is important in the construction of the serotonin receptor (Patrick & Ames, 2015). The long chained, double bonded, DHA builds a fluid neuronal membrane allowing for proper positioning of the serotonin and dopamine receptors (Heron et al, 1980; Paila et al, 2010; Heinrichs et al, 2010). The serotonin receptors depend upon this accessibility given that receptor chains pass through the cell membrane seven times (Wassal et al, 2009; Escriba et al, 2007). Neuronal transmission of serotonin has found to decrease when omega-3 fatty acids are low (Chalon et al, 2006; de laPresa Owens & Innis, 1999). When additional omega-3 fatty acids are provided to humans, an increase of the serotonin metabolite 5-Hydroxyindoacetic acid (HIAA) has been found in the urine (Hibbeln et al, 1998). These authors recommend 1 gram per day of DHA and 2 grams of more of EPA (Patrick & Ames, 2015).

Patrick and Ames also highlighted the effectiveness of giving patients tryptophan or 5-HTP supplements to stimulate positive behaviors (Hudson et al, 2007; Young et al, 2007; aan het Rot et al, 2006). They stress the importance of exercise which causes branched chained amino acids (BCAA) to be utilized by muscle tissue, thereby increasing the tryptophan to BCAA ratio. Elevating this ratio increases tryptophan transport across the blood-brain barrier. Vitamin B6 and iron are important cofactors in serotonin production (Patrick & Ames 2015). In conclusion, these authors promote additional studies on the efficacy of utilizing tryptophan/5-HTP, murine omega-3 fatty acids (EPA and DHA), vitamin D, exercise, vitamin B6 and iron to restore normal cognitive function and acceptable social behavior in humans (Patrick & Ames, 2015). They see applications of this simple therapy in our prison system, where rehabilitation of individuals who impulsively display violent behavior could be most beneficial to society.

Tryptophan, Gastrointestinal Disease, and Inflammation

This second review article by Dr. Marta Martin-Subero and colleagues from Spain and Australia is entitled “Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways”. This article is most current in addressing the systemic effects of gut inflammation given the recent attention given to leaky gut syndrome. Much of leaky gut syndrome can be attributed to the high consumption of wheat germ agglutinun lectins and gluten proteins (Falth-Magnusson et al., 1995) in the diet. Martin-Subero and colleagues sought to connect the inflammatory pathologies of irritable bowel disease (IBD), ulcerative colitis (UC), and Crohn’s Disease (CD) and depression.

In comparing depression with IBD, both have alternating remissions and inflammatory episodes that appear to concurrently exist (Martin-Subero et al, 2015). Patients with IBD have a 2-3x greater likelihood of having depression (Martin-Subero et al, 2015). One case-controlled study of 12,500 individuals, found that depression and anxiety preceded a UC diagnosis (Kurina, MMS (15)). Chronically, a damaged leaky gut may deliver intestinal lipopolysaccharide from gut bacterial capsules and wheat lectins/gliadins into the blood serum resulting in a systemic inflammatory response (Falth-Magnusson et al., 1995). This inflammation may attenuate the release of serotonin promoting depression and psychosomatic disorders (Martin-Subero et al, 2015).

Researchers found that there are several pathways utilized by both IBD and depression. Initially, the levels of interleukins, tumor necrosis factor alpha, and interferon are increased in both conditions while levels of immune suppressive cytokines are decreased (Martin-Subero et al, 2015). Acute phase proteins and C-reactive protein are both increased in depression and IBD. Second, increased levels of protein, DNA, and lipid damage are seen, as well as decreased levels of some anti-oxidants. Oxidative and nitrosative stress plus reactive oxygen and nitrogen species are increased, (Martin-Subero et al, 2015) possibly due to mitochondrial dysfunction. Lower zinc levels are found in both conditions. Third, similar levels of serum antiphospholipid antibodies have been found in CD, UC, and depressed individuals. Autoimmune disorders are common with IL-6 and Th-17 levels increased (Martin-Subero et al, 2015).

In a fourth coordination of concurrent biomarkers in depression and gastrointestinal disease, both conditions activate indoleamine 2,3-dixoygenase (IDO) which converts tryptophan to kynurenine, transcending down the TRYCAT (tryptophan catabolism) pathway such that serotonin cannot be produced (Reus et al, 2015). Increased TRYCAT levels in conjunction with lower plasma tryptophan levels contribute to neurotoxic processes and depression-like symptoms (Martin-Subero et al, 2015; Maes et al, 2011). These results, including the presence of a leaky gut, cytokine elevations, TRYCAT induction and oxidative/nitrosative stress (Martin-Subero et al, 2015) in both conditions lead these researchers to propose an association between depression and IBD (Martin-Subero et al, 2015). To provide further evidence that some association exists, they note that TNF-alpha antagonist and anti-depressant drugs improve both IBD and depression( Banovic et al, 2009; Raison et al, 2013; Goodhand et al, 2012; Martin-Subero et al, 2015).

IV. Conclusion

As depression becomes the second highest cause of death, society will continue to suffer from the acts of the psychologically disturbed. The neurotransmitter serotonin has been found to improve mood and depressive disorders. Anti-depressant drugs costing millions of dollars have helped with short term treatment, but are not replacing the nutrient deficiencies in these affected individuals. An inexpensive and long term solution might be to utilize the basic biochemistry and physiological sciences taught in our medical professions to design therapies that provide adequate levels of all nutrients involved in neurotransmitter pathway systems. Fortifying food with tryptophan in conjunction with necessary cofactors produces serotonin and improves psycho-social behaviors. Fortifying individuals with vitamin D activates the conversion of tryptophan to serotonin. Fortifying individuals with the murine fish oils, EPA and DHA, decreases inflammation and improves the accessibility of serotonin binding receptors on neurons. Treating the complete serotonin pathway system may well provide an inexpensive, scientifically based, long-term solution. These treatments may benefit society through the attenuation of the potentially aggressive behaviors caused by depression and mood disorders.

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