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).
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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