Tryptophan’s Affect on Depression: A Review Article

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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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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.

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Neurotransmitter Pathways affecting Concussion, TBI, Stress, Depression, Tremor, Stroke, and Anxiety

securedownloadNeurotransmitter Brain Food:  Rebuilding  the Acetylcholine (Choline or Lecithin),  Serotonin (5-HTP or tryptophan)  and Dopamine (Tyrosine) Neurotransmitter Pathways.  

A Case Study Attacks  Stress, Anxiety, and Tremor with pathway amino acids, choline (lecithin) and co-factors.

A middle-aged female with a family history of anxiety and Parkinson’s Disease developed a tremor and mild pain in her left arm. She had a history of painful joint injuries and anxiety due to job-related stress. She obtained little exercise and used ibuprofen (Advil) therapy for the  joint pain. At work she occasionally painted the interior of homes, often inhaling the fumes.  She reported awakening in the morning with an upper body tremor and a cold left arm.  Her fists would be tightened and her hands tingly. During the day, her extra-ocular muscles were painful and she had difficulty focusing.  She experienced somewhat normal energy levels during the early part of each day and then fatigued.  Athletic stress, work place stress, intense mental concentration, painting, an emotional event, sugar or deep-fried food ingestion stimulated the tremor and reduced her energy levels.  At bedtime, upon turning off the lights, she experienced vertical gaze problems.

Her daily vitamins included vitamin B complex (100mg b.i.d. (twice daily)), vitamin C (500mg t.i.d. (three times daily)), amino acids (1500mg t.i.d), fish oil (1g), calcium citrate (600mg), calcium phosphate (600mg), iron (65mg), coenzyme Q10 (200mg), lysine (500mg), beta-carotene (10,000 IU), zinc (50mg), and a multi-vitamin.

She has a family member who has been on standard of care therapy for Parkinson’s Disease for the past 7 years but the disease has progressed. To alleviate her left arm tremor, she began ingesting choline and lecithin in increasing amounts, until the tremor subsided.  During the first weeks of therapy, she experienced a mild frontal lobe headache, more significant on the right side.  Stressful days would be followed by the upper body shiver and left arm tremor, the next morning upon awakening.  Sugar ingestion stimulated the tremor within an hour.  A stressful work situation stimulated the upper body tremor. She slept quite heavily during the first two months of choline and lecithin therapy.  Attempts to reduce the choline and lecithin dosages re-established the tremor.

During the third month of therapy, heavy stress continued  at work. She was anxious and had a negative outlook. To alleviate the sleepiness brought on by the choline/lecithin supplements, provide more energy,  and support the dopamine pathway, she began taking tyrosine.  To fortify the serotonin pathway and improve her mental outlook, she added 5-hydroxytryptophan (5-HTP).  There were positive results the first day.  With the tyrosine and 5-HTP, she was able to perform more of her normal daily activities. In time, with the combination of these supplements, the natural oils returned to her skin and menses became painless.  She continued to decrease stress levels and overwork.  She rested frequently.

The adrenal glands are responsible for producing many neurotransmitters.  They are small walnut shaped glands resting on top of the kidneys which produce cortisone and neurotransmitters in response to stress.  To help her adrenals, she began taking a bovine adrenal rebuilder, the amino acid methionine (controls the adrenals), minimal amounts of sugar, no high fructose corn syrup, no deep-fried foods nor alcohol.

At the beginning of the fourth month, she continued 95% tremor free.  Her left arm continued to experience mild pain depending upon sugar and choline/lecithin levels.  She experienced improvement in her daily energy level and her arm tremor and pain resolved almost completely.  The left arm would experience some irritability after stressful days or skipped choline/lecithin supplements.

At 4 ½ months post tremor initiation, the subject was pricked with a garden thorn.  It appeared that her blood had thinned. She had experienced no side effects of choline (nausea, vomiting, diarrhea, sweating, increased sweating, or salivation (Livestrong Website)) nor side effects of lecithin (rash, low blood pressure, diarrhea, vision problems, fainting or loss of appetite (Headquarters Website)). However, internet research showed that blood thinning may occur with choline/lecithin. She began using  ibuprofen and aspirin sparingly. She decreased her dosage of lecithin, however, the tremor returned.  She resumed the lecithin dosage and purchased a multi-vitamin containing vitamin K and increased green food consumption.  (Vitamin K which is found in greens is important in the blood clotting process).

At five months post tremor her left arm was the same temperature as her right arm upon awakening. The fists and tingling findings were infrequent. The left arm continued to have some irritability after stressful events.  Exposure to paint fumes initiated the tremor. Relief from tremors, extraocular fatigue, body twitches, and spontaneous crying was found with additional choline and lecithin. She experienced some daily facial flushing and left sided chest pain/pressure with exercise.  Knowing methionine is stored in the heart, she reduced her daily methionine intake.

More research as to the benefits of choline, lecithin, methionine, and tyrosine to improve neurological health may be beneficial.  Urine amino acid testing is available and would be important to utilize more frequently to determine amino acid levels pre and post amino acid or pharmaceutical therapy.  Better availability of a urine amino acid neurotransmitter test that specifically provides tyrosine, tryptophan, choline and co-factor levels vital to support the three important neurotransmitter pathways would be beneficial.  We expect that Wellness 2020 will bring these advancements.  For a complete discussion of Wellness 2020 see the home page of http://www.wheatfreediseasefree.com.

Neurotransmitter  Discussion:

Nerves are key to communication within the body. They tell a muscle to move or an organ to function. It takes two nerves, one from brain cortex to the spinal cord and a second from the spinal cord to the foot, to make the foot move.  Nerves communicate through chemicals similar to a car battery.  The nerve running from the brain to the spinal cord will pass a chemical called a neurotransmitter to the nerve running between the spinal cord and the foot to stimulate the receiving neuron. Neurotransmitters travel from the sending neuron to the receiving neuron through a gap (cleft) and they are frequently recycled back into the sending neuron to use again.  The adrenal glands play a key role in producing neurotransmitters from amino acids and dietary protein.

Electricity traveling through a battery or a house is either turned on or off, making man’s design of current either excitatory or off.   The Creator’s design is a bit more elaborate in that it involves both excitatory and inhibitory transmissions.  Epinephrine, acetylcholine, and glutamate are mainly excitatory neurotransmitters while dopamine, norepinepinephrine, and GABA (gaba-amino-buteric-acid) are inhibitory.

On the Concussion Brain Food post at http://www.wheatfreediseasefree.com we discussed the importance of Omega-3 fatty acids (cell membrane formation), B-complex (nerve formation), and Amino Acids (protein/neurotransmitter formation) for healthy brain and nerve tissue.  This Neurotransmitter paper examines the three main neurotransmitter production pathways: ACETYLCHOLINE, DOPAMINE, and SEROTONIN and the amino acids and vitamins required to keep these cells healthy and alive.

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THREE NEUROTRANSMITTER PATHWAYS:

I.  Production of  ACETYLCHOLINE:

                  Phosphatidylcholine (Lecithin)   —->  Glycerophosphatidylcholine   —> Choline   

                    Then,  Choline  +   Acetyl  Coenzyme A  —->   ACETYLCHOLINE

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Acetylcholine functions as both an inhibitory and excitatory neurotransmitter controlling many of the body’s nerves including excitatory skeletal muscle contraction and inhibitory actions on the heart and brain.  The body can convert phosphatidycholine (lecithin) to glycerophosphatidylcholine and then to choline.  The body makes the acetylcholine neurotransmitter by adding acetyl coenzyme A to choline.  Choline is used for cell communication and used to produce phosphatidylcholine and sphingomyelin which make cell membrane (Linus Pauling Institute). Choline contributes to the production of the myelin coating around nerves (Oshida K et al., 2003) and it supports the folate pathway to produce DNA (Institute of Food, Medicine, and Nutrition Board, 1998). The three neurotransmitter pathways described in this paper appear to depend upon each other’s viability.  Acetylcholine, for example, has an important role in activating the Dopamine Pathway.  Normal levels of the dopamine pathway neurotransmitters may not be produced without sufficient levels of acetylcholine to act as a stimulus (Patrick RL et al.,1971).  Low choline and dopamine levels have been implicated in Parkinson’s Disease (Zurchovsky L, 2012).

Choline is an essential nutrient and it is water soluble, therefore must be replenished daily in the diet.  Choline is found in foods such as eggs, fish, liver, milk, wheat germ, and quinoa and is available as a supplement as choline or lecithin.  Since choline plus acetyl coenzyme A make acetylcholine, sufficient quantities of both must be present. Adequate intake levels of choline for healthy individuals are 425-550mg/day (Linus Pauling Institute).

Low choline levels have been found to correlate with anxiety, intelligence and worry (Coplan JD et al., 2012).  Liver and muscle damage (Sha W et al., 2010) athlerosclerosis, neurological disorders (Ziesel SH, et al., 2009),  infertility (Johnson AR et al., 2012),  and growth impairment (De Simone R et al, 1993) are promoted with deficiencies. Those who do not eat enough whole eggs may be at risk (Hasler CM et al., 2000).  Choline is in high demand during pregnancy and helps to prevent neural tube defects (Pitkin RM, 2007).

Choline, B9 (folate), B12 (pyridoxal phosphate), and methionine have key roles in the methyl donor system and cancer protection (Kadaveru K, 2012). Diets rich in choline may lower the risk for breast cancer (Xu X et al., 2009), promote REM sleep (Kushikata F, 2006), and memory (Zhang W et al., 2012). Choline has been used as a treatment for Alzheimer’s disease (Zhang W, 2012), and stroke (Gutierrez-Fernandez et al., 2012).  Choline is being studied to help treat traumatic brain injury. Choline or lecithin can be useful in treating neurological disorders characterized by inadequate release of acetylcholine such as Tardive Dyskinesia (described as involuntary, repetitive facial or limb movements,  Growdon JH,1978). A single meal containing lecithin increases concentrations of choline and acetylcholine in rat adrenals and brain tissue (Hirsch MJ, 1978)  Perinatalcholine is neuroprotective for seizures, depression, and the effects of alcohol (Glenn MJ et al., 2012). Ninety percent of humans in a research study conducted had choline below adequate levels (Zeisel, 2009).

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II.  Production of  SEROTONIN:

                                  Tryptophan hydroxylase                                                Dopa Decarboxylase           

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

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

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.(Enzymes and cofactors required to produce 5-HTP and 5-HT from the Understand and Cure Website.)

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Tryptophan, an essential amino acid for humans, makes serotonin.  It must be included in the diet, humans are unable to produce it. Tryptophan is found in eggs, spirulina, fish, poultry, nuts, seeds, organic soybeans, milk, and cheese.

To convert tryptophan into 5-HTP and produce serotonin (5-HT, 5-hydroxytryptamine) an enzyme called tryptophan hydroxylase(TPH) is required with the cofactors vitamin B3 (niacin), B6 (pyridoxal-5-phosphate), B9 (folate), vitamin C (ascorbic acid), magnesium, iron, and calcium.  High  fructose corn syrup may decrease absorption of trytophan from the gut (Ledochowski M, et al., 2001) thereby reducing the quantity of TPH enzyme and serotonin produced.  The Parkinson’s medication carbidopa-levadopa (Drugs.Com Website) is known to interfere with tryptophan, thus TPH and serotonin production.

Ninety percent of serotonin is stored in the chromaffin cells of the intestines (Donnerer J, et al., 2006) where it regulates digestion and maintains stomach function. Additionally, the remainder of serotonin is found in platelets and the central nervous system where serotonin is produced in the raphe nuclei and pineal gland of the brain (Neurophysiology Website).  Nerve axons from the raphe nuclei cover the entire length of the brainstem and extend to all parts of the brain including the cerebellum and spinal cord where serotonin influences memory, learning, behavior, mood (well-being, happiness), appetite, sleep and regulates insulin (Young SN, 2007).

When a sending neuron releases serotonin to stimulate a receiving neuron, the neurotransmitter travels out the sending neuron, across a gap or cleft to receptors on the receiving neuron.  By design the neurotransmitter is quickly reabsorbed back into the sending neuron and recycled.  A drug that modifies this normal physiology by keeping serotonin in this gap between the neurons longer is called a serotonin re-uptake inhibitor (SSRI). The result of a SSRI is to create the physiological impression that more serotonin is present thus continuing the stimulation of the receiving neuron. Many antidepressants, anti-anxiety drugs and post-traumatic stress drugs function in this manner.  These drugs do not produce more serotonin to resolve a deficiency, but create the illusion that more is present.

Should the body be deficient or low on serotonin, only ingesting the proper foods or supplementing the diet with tryptophan or 5-HTP provides more serotonin to the brain and intestines. Studies have shown that a change in only 10% of the number of serotonin transporters will affect anxiety levels (Lesch KP, et al., 1996).  Research shows that supplementing tryptophan or 5-HTP (available at nutritional stores) helps to maintain serotonin levels and aids with depression and anxiety (Murphy SE, et al., 2006).  Providing adequate nutrients is important to maintaining healthy cells and production pathways.

 

III. Production of DOPAMINE, NOREPINEPHRINE, and EPINEPHRINE:

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                                          *Vitamin B9             Vitamin B9, iron               Vitamin B3 & B6, zinc                     

                     Phenylalanine  ——>  Tyrosine   —————->   DOPA     ——————>   DOPAMINE 

                                   

                                          Vitamin C                                            S-Adenylmethionine (SAMe)
                     Dopamine  ————>   NOREPINEPHRINE ——————->  EPINEPHRINE

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(*  Required reaction cofactors are listed above the arrows in italics.)

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This is a complicated pathway in that if  sufficient amounts of the amino acid phenylalanine or tyrosine, vitamin B9 (folate), iron, vitamins B3 (niacin) + B6 (pyridoxal phosphate), zinc, vitamin C (ascorbic acid), and methionine (used to produce SAMe) are all present, then the three catecholamine neurotransmitters in this pathway (dopamine, norepinephrine and epinephrine (adrenaline)) are produced to keep the pathway cells strong.  If production falls and pathway cells die off (apoptosis) Parkinson’s Disease or Altzheimer’s may develop.

Phenylalanine is found in fish, beef, chicken, milk, cheese, eggs, and nuts (www.livestrong.com/article/317897-list-of-foods-that-contain-phenylalanine/).

Tyrosine is found in beef, pork, turkey, duck, fish, egg whites, cheese, milk, and soy milk (www.livestrong.com/article/81485-foods-Ityrosine/).

Methionine is essential amino acid required in the diet.  It is found in popcorn, grass fed meat, brown rice, organic oranges, and yogurt.  SAMe (s-adenylsylmethionine) is made from methionine.  It’s production is influenced by the neurotransmitter acetylcholine produced in the Acetylcholine Pathway described above.  Methionine is also found in wheat and can be a deficiency in a wheat free diet. Methionine controls the adrenal glands which are the first responders under stress conditions.  Stress may deplete methionine stores. Methionine chelates metals and neutralizes harmful chemicals.  Painters and those exposed to chemicals may require additional methionine to neutralize these chemicals. Methionine is critical for donating a methyl group (-CH3) to norepinephrine to produce epinephrine in the Dopamine Pathway giving the body energy.  Adrenals that are subjected to low levels of methionine may be a contributing factor to Adrenal Insufficiency, Tremor, and Parkinson’s Disease.

Vitamin B3, Vitamin B6, Vitamin B9.  B-complex vitamins are water soluble and must be ingested daily.

Foods highest in Vitamin B3 (niacin) can be found at http://www.healthaliciousness.com/articles/foods-high-in-niacin-vitamin-B3.php.

Foods highest in Vitamin B6 (pyridoxal phosphate) can be found at http://www.healthaliciousness.com/articles/foods-high-in-vitamin-B6.php.

Foods highest in Vitamin B9 (folate) are found at

http://www.healthaliciousness.com/articles/foods-high-in-folate-vitamin-B9.php.

Vitamin C  is water soluble and must be ingested daily.  Vitamin C food sources are listed at http://www.healthaliciousness.com/articles/vitamin-C.php.  Vitamin C is the major vitamin keeping the adrenal organs healthy.

Zinc is an important mineral.  There is an informative web site listing zinc foods at http://www.healthaliciousness.com/articles/zinc.php.

Iron food sources are listed at  http://www.healthaliciousness.com/articles/food-sources-of-iron.php.

Dopamine is quickly degraded and excreted in the urine.  While there is some re-uptake, dopamine must be continually replenished.  Dopamine is produced in the adrenals, gastrointestinal tract, neurons, and brain generating either excitatory or inhibitory nerve impulses. It has important roles in reward and punishment brain activity, increased heart rate and blood pressure, sleep, mood, attention, working memory, learning, problem-solving, social behavior, cognition, voluntary movement, pain, and motivation.

Dopamine deficiency causes decline in memory, attention, problem-solving  and sociability.  Insufficient dopamine biosynthesis in the dopaminergic neurons can cause Parkinson’s Disease (Grace AA, 1984).  Stress increases the depletion of dopamine stores (Furuyashiki T, 2012).  Dopamine plays a role in pain processing (Viisanen H, et al., 2012 ),

Norepinephrine (noradrenaline) can be produced from tyrosine or phenylalanine in the presence of vitamin B9 (folate), iron, vitamin B3 (thiamine), vitamin B6 (pyridoxal phosphate), and zinc.  Norepinephrine is a neurotransmitter produced in the adrenal glands which helps control the body’s sympathetic system.  This system is responsible for the “fight or flight response” to danger (Guyton A, 2006). Norepinephrine is a stress hormone (Tanaka M, et al., 2000).  Its release increases heart rate, releases glucose from tissue, increases blood flow to skeletal muscle and brain oxygen levels.

Norepinephrine is important to prevent fainting (syncope) by preventing a drop in heart rate to maintain blood pressure.  Neurons project throughout the brain and spinal cord.

Norepinephrine has a role in behavior, motivation, attention, focus, decision making, learning,  motor output, response to performance error, negative feedback, monetary loss, cost benefit evaluation, task difficulty and the decision making process (Devauges V, et al., 1990) (Lutzenberger, W, et al., 1987) (Usher M, et al., 1999) (Eisenberger M, et al., 2003)(Falkenstein M, et al., 1991)(Genring WJ, et al., 1993) (Neurophysiologica 35), (Nieuwenhuis, S, et al., 2003). It has different actions upon different cell types.  Low levels of this neurotransmitter have a role in depression along with serotonin.

Norepinephrine is reabsorbed and degraded within seconds.  It works as an anti-inflammatory agent in brain tissue, suppressing cytokines.  In Alzheimer’s Disease the norepinephrine  producing cells may be affected (Szot P, et al., 2012).

Epinephrine (adrenaline) is an important component of the sympathetic fight or flight system.  Production of epinephrine occurs in the adrenals from phenylalanine and tyrosine.  It acts on most all body tissues.  Epinephrine increases blood glucose and fatty acid levels which provide energy for cells (Sabyasachi S, 2007).  Plasma levels of epinephrine may increase 10-fold during exercise and perhaps by 50-fold during stress requiring an ample supply of tyrosine (Raymondos, K, 2008) (Baselt, 2000).  Epinephrine is released during times of “physical threat, excitement, noise, bright lights, and high temperatures” (Nelson L, 2004). Stress causes the sympathetic nervous system to stimulate adrenocorticotrophic hormone (ACTH) which stimulates epinephrine release (by activating tyrosine hydroxylase and dopamine-B-hydroxylase).  It also stimulates cortisone production by the adrenals.

One study found that catecholamines (neurotransmitters derived from tyrosine in the dopamine pathway) in rat adrenals took  …FOUR  DAYS … yes,  FOUR  DAYS … to recover their original levels after being chemically depleted, and the regeneration of these neurotransmitters required acetylcholine (Patrick RL, et al., 1970).  A human taking a heavy examination may require several days to restore normal neurotransmitter levels, yet universities schedule mid-term and final exams on consequentive days allowing no time for neurotransmitter restoration.  When human adrenals are stressed they may take a significant amount of time and resources to regenerate neurotransmitters and cortisol. 

Tyrosine, vitamin B-complex, vitamin C, zinc, iron, and methionine or SAMe can be purchased at a health food store to supplement the diet and maintain a healthy dopamine pathway.

“Parkinson’s Disease is associated with the depletion of tyrosine hydroxylase, dopamine, serotonin, and norepinephrine” and “administration of L-dopa may deplete L-tyrosine, L-tryptophan and 5-hydroxytryptophan (5-HTP), serotonin and sulfur amino acids (cysteine, methionine)” (Hinz M, et al., 2011).  Researchers found that co-administration of L-dopa with 5-HTP, L-tyrosine, L-cysteine and cofactors enabled more effective treatment for Parkinson’s Disease by allowing optimal dosing of L-dopa for symptom relief without the barriers imposed by side effects and adverse reactions.  (Hinz M et al., 2011)

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THE  CRITICAL  ADRENALS:

We have discussed three important pathways for producing neurotransmitters. The organs most responsible for this job are the adrenals.  The adrenals are critical to brain health. They are small, walnut shaped glands positioned on top of the kidneys.  Back pain can be felt below the rib cage on either side when the adrenals are over-stressed.  These organs produce neurotransmitters, sex hormones, and cortisol.  Under athletic, academic, work-related, emotional, food-related, disease or inflammation-related stress conditions, the adrenals are the first to respond by producing high amounts of cortisol.  The body tends to prioritize, so high cortisol production may come at the cost of reduced sex hormone and  neurotransmitter production.  We may see this in the triathlete with sporadic menses or the businessperson or student with high anxiety levels. The adrenals are prioritizing cortisol production to cope with the acute or chronic stress over the production of sex hormones and neurotransmitters

Upon the realization that these tiny organs are responsible for handling these vital functions, keeping the adrenals healthy becomes of critical importance.  We have described the three neurotransmitter pathways to reinforce the importance of providing the proper amino acids and vitamins to the body to keep these pathways alive and well. Cells die off when adequate nutrients are not present.  Vitamin C  and the amino acid methionine are important for general adrenal function. Methionine is found in wheat, so wheat free diets may be deficient in methioinine.  Glandular adrenal rebuilders are available at health food stores.  Sugar, high fructose corn syrup, alcohol, and deep fried food consumption stress out the adrenals and make them work hard.   There is an excellent book written by Dr. James Wilson, entitled “Adrenal Fatigue – The 21st Century Stress Syndrome”, (Smart Publications, 2001).  A future http://www.wheatfreediseasefree.com post will discuss adrenal insufficiency, methionine and a wheat free diet.  Restoring adrenal health and providing sufficient neurotransmitter substrate may be critical to restoring neurotransmitter supplies and eliminating disease.  More research should be completed and better monitoring of neurotransmitter nutrient pathways through physician and home based testing would be helpful.

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Street Drugs, Nicotine, Caffeine, and Neurotransmitters:

The street drug cocaine is a triple re-uptake inhibitor in that it blocks the re-uptake of serotonin, dopamine and norepinephrine (Fattore L, et al., 2009 ).  Street drugs can increase dopamine levels 10 fold and temporarily cause psychosis (Williams).  Amphetamines are similar in structure to dopamine.   MDMA (ecstasy) releases serotonin, norepinephrine and dopamine and then inhibits their transport which increases concentrations within cell cytoplasm (Bogen IL, et al., 2003) (Fitzgerald JL, et al., 1990).

Amphetamines increase the concentrations of dopamine, serotonin and norepinephrine possibly by reversing the transport of dopamine and serotonin back into the gap or cleft between the neurons (Florin SM, 1994) (Jones S, et al., 1999). Dextromorphan, a cough suppressant, works as an SSRI (Schwartz AR, et al., 2008). LSD is a serotonin agonist in that it stimulates the serotonin receptor on the receiving neuron by mimicking serotonin (Titeler M, et al., 1988). Caffeine increases activity of serotonin, acetycholine, epinephrine, dopamine, and norepinephrine. Nicotine is thought to increase acetylcholine and dopamine levels.  Street drugs, caffeine, and nicotine force the body to release stores of neurotransmitters and then keep the neurotransmitter in circulation by inhibiting the reuptake.  Again, these drugs are not making more neurotransmitter but they are depleting current stores and tricking the body into thinking there is more chemical.  The only way to enable the body to produce more neurotransmitters is to provide the proper nutrients through diet or supplements.  

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Analysis Unique to the Wheat Free Diet:

Many individuals damage their adrenals through alcohol, sugar, high fructose corn syrup, deep fried foods, low vitamin C and low nutrient intake causing depression, fatigue and eventually tremor.  The case above is unique, because this patient eats a healthy diet with the exception of wheat which contains the amino acids methionine and lysine.  Thus, her diet may be deficient in methionine.  However, nutritiondata.com shows detailed analysis that if she consumes meat, ample methionine should be present. Unlike earlier times, most cattle and fish are no longer raised in the wild.  Do they still contain adequate amino acids?  If this subject typically eats meat, containing several grams of amino acids per day, why would 500mg – 1g of supplemental methionine improve her condition?

Additionally, methionine is responsible for chelating harmful chemicals such as those found in paint. She may require additional methionine to detoxify the fumes.   This subject is highly stressed which would cause the adrenals to produce more cortisone. Regulation of the adrenal-pituitary-hypophyseal axis  requires methionine.  Perhaps a combination of low dietary intake plus a high methionine requirement resulted in damaging her adrenals and a reduction of neurotransmitter production.

Case Study References:

Livestrong website:  http://www.livestrong.com/article/458050-choline-risks/

Headquarters Website:  http://www.nutritionalsupplementshq.com/soy-lecithin-side-effects/

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Acetylcholine References:

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Coplan JD, Hodulik S, Mathew SJ, Mao X, Hof PR, Gorman JM, Shungu DC. The Relationship between Intelligence and Anxiety: An Association with Subcortical White Matter Metabolism. Front Evol Neurosci. 2011;3:8. Epub 2012 Feb 1

De Simone R, Aloe L.  Influence of ethanol consumption on brain nerve growth factor and its target cells in developing and adult rodents. Source Istituto di Neurobiologia, Consiglio Nazionale delle Ricerche, Rome, Italy.  Ann Ist Super Sanita. 1993;29(1):179-83.

Glenn MJ, Adams RS, McClurg L. Source Department of Psychology, Colby College, 5550 Mayflower Hill Dr., Waterville, ME 04901, USA. Supplemental dietary choline during development exerts antidepressant-like effects in adult female rats. Brain Res. 2012 Mar 14;1443:52-63. Epub 2012 Jan 17.

Growdon JH, Gelenberg AJ, Doller J, Hirsch MJ, Wurtman RJ. Lecithin can suppress tardive dyskinesia. PMID: 642995 [PubMed – indexed for MEDLINE]. N Engl J Med. 1978 May 4;298(18):1029-30.

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.

Street Drugs, Nicotine, Caffeine, Alcohol and Neurotransmitters:

Bogen IL, Haug KH, Myhre O, Fonnum F (2003). “Short- and long-term effects of MDMA (“ecstasy”) on synaptosomal and vesicular uptake of neurotransmitters in vitro and ex vivo”. Neurochemistry International 43 (4–5): 393–400. doi:10.1016/S0197-0186(03)00027-5. PMID 12742084.

Fattore L, Piras G, Corda MG, Giorgi O (2009). “The Roman high- and low-avoidance rat lines differ in the acquisition, maintenance, extinction, and reinstatement of intravenous cocaine self-administration”. Neuropsychopharmacology 34 (5): 1091–101. doi:10.1038/npp.2008.43. PMID 18418365.

Fitzgerald JL, Reid JJ (1990). “Effects of methylenedioxymethamphetamine on the release of monoamines from rat brain slices”. European Journal of Pharmacology 191 (2): 217–20. doi:10.1016/0014-2999(90)94150-V. PMID 1982265.

Florin SM, Kuczenski R, Segal DS (August 1994). “Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment”. Brain Res. 654 (1): 53–62. doi:10.1016/0006-8993(94)91570-9. PMID 7982098.

Jones S, Kauer JA (November 1999). “Amphetamine depresses excitatory synaptic transmission via serotonin receptors in the ventral tegmental area”. J. Neurosci. 19 (22): 9780–7. PMID 10559387.

Schwartz AR, Pizon AF, Brooks DE (September 2008). “Dextromethorphan-induced serotonin syndrome”. Clinical Toxicology (Philadelphia, Pa.) 46 (8): 771–3. PMID 19238739.

Titeler M, Lyon RA, Glennon RA (1988). “Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens”. Psychopharmacology (Berl.) 94 (2): 213–6. PMID 3127847.

Williams:  http://www.williams.edu/imput/synapse/pages/IIIB5.htm

Copyright © 2012.  All rights reserved.

12-02-12

To request specific dosage data for this case study, please send an email to wheatfreediseasefree@gmail.com.

Photograph: Jordanelle Reservoir, Park City, Utah

A Special Thanks to Billie Jay Sahley PhD. and her books on amino acids including her book “The Anxiety Epidemic” for inspiring research with neurotransmitter pathways, substrates and cofactors.

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.