Tryptophan
Tryptophan is an essential amino acid, which means that it must be obtained from the diet in adequate quantities to meet the body's needs. In the central nervous system, it is converted into 5-HTP (hydroxytryptamine), which is then converted to serotonin and melatonin. Serotonin modulates mood and sleep patterns. Tryptophan reduces anxiety and depression. Low blood levels of tryptophan have been reported in depressed patients, which were corrected with tryptophan supplementation. Tryptophan has also been found to be useful in treating attention Deficit Disorder and autism in children, menopausal depressive conditions, fibromyalgia symptoms, and symptoms of restless leg syndrome. Serum tryptophan levels also correlate well with the presence of malignancy and cancer anorexia. Tryptophan is necessary for the production of vitamin B-3 (niacin) [please refer to vitamin B-complex]. The best food sources of tryptophan are oats, bananas, dried dates, milk, yogurt, cottage cheese, chocolate, fish, turkey, sesame, chickpea, sunflower seeds and peanuts.
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The increase of plasma free tryptophan concentrations is a common feature of both human solid and hematologic malignancies and some experimental tumors. Increased plasma tryptophan facilitates transport into the brain……..hypothalamic serotonergic activity is in fact stimulated in the presence of anorexia of cancer. The modulation of brain tryptophan entry and brain serotonin synthesis might prove a safe and effective therapeutic approach to improve food intake in anorectic cancer patients.
o Cynober, LA. (2004). Metabolic and therapeutic aspects of amino acids in clinical nutrition. Boca Raton, Florida: CRC Press.
The essential amino acid tryptophan is a constituent of proteins and is also a substrate for two important biosynthetic pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides…….. Low serum/plasma tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated tryptophan conversion. Thus, in states of persistent immune activation, low tryptophan concentration may contribute to immunodeficiency. Decreased serum tryptophan can also effect serotonin biosynthesis and thus contribute to impaired quality of life and depressive mood. As such, monitoring tryptophan metabolism in chronic immunopathology provides a better understanding of the association between immune activation and IDO and its role in the development of immunodeficiency, anemia and mood disorders.
o Schröcksnadel, K, Wirleitner, B, Winkler, C, & Fuchs, D. (2006). Monitoring tryptophan metabolism in chronic immune activation. Clinica Chimica Acta, 364(1-2), 82-90.
A correlation between anorexia and brain levels of serotonin and tryptophan (TRP) has been reported in tumor-bearing animals. In the present investigation 45 patients with various types of cancer and 13 control subjects were studied. Prior to the study the patients had received no antineoplastic therapy and were unaware of the malignancy of their disease……….. These findings seem to confirm that free TRP may play an important role in human cancer anorexia.
o Rossi Fanelli, F et al. (1986). Plasma tryptophan and anorexia in human cancer. Eur J Cancer Clin Oncol, 22(1), 89-95.
Eighteen untreated cancer patients and ten sex- and age-matched healthy volunteers were studied. In all patients eating behavior was investigated by means of a specific questionnaire from which the presence of anorexia and anorexia-related symptoms was assessed. To investigate the role of tryptophan in cancer anorexia, fasting plasma and CSF levels of tryptophan and other neutral amino acids were assayed in patients and controls. Cancer patients showed abnormally high plasma free tryptophan levels. In case of patients with cancer anorexia a significant rise of the ratio in plasma between free and tryptophan/large neutral amino acids, competing with tryptophan for its brain entry, was observed. This increase was correlated to a consistent rise of CSF tryptophan levels suggesting a specific role of the serotoninergic system in the pathogenesis of cancer anorexia.
o Cangiano, C et al. (1990). Plasma and csf tryptophan in cancer anorexia. J Neural Transm Gen Sect, 81(3), 225-33.
High free tryptophan (F-TRP) plasma levels are found in cancer patients (CP). F-TRP plasma concentrations are affected by the levels of its carrier, albumin (ALB), and free fatty acids (FFA) competing with TRP for ALB binding sites. The lack of correlation between F-TRP, ALB and FFA in CP suggests a tumor-dependent effect on the rise in F-TRP. To verify this hypothesis, F-TRP, ALB and FFA levels were assayed in 12 lung and 16 breast CP susceptible to radical surgery, before and 15 days after surgical removal of the tumor. F-TRP levels significantly decreased after tumor ablation. Since no correlation was found between F-TRP, ALB and FFA variations, it is conceivable that the tumor itself may be responsible for the high F-TRP levels in CP.
o Cascino, A et al. (1991). Increased plasma free tryptophan levels in human cancer: a tumor related effect? Anticancer Res, 11(3), 1313-6.
Tumor growth is associated with a number of metabolic abnormalities. Glucose metabolism is deranged as frequently revealed by an impaired oral glucose tolerance test. Lipoprotein lipase activity is depressed, resulting in hypertrigliceridemia after an exogenous lipid load. Also protein metabolism is deranged in cancer patients, as revealed by changes of plasma amino acid profile. Our previous studies on plasma amino acids have shown that increased plasma free tryptophan levels are a frequent finding in cancer patients. To sustain a possible role for free tryptophan as a marker of neoplastic disease, we measured its plasma concentrations in 241 patients with cancer. Plasma free tryptophan concentrations were found to be significantly elevated with respect to healthy controls in patients with breast, lung, colon, stomach, and cancer from various origin. The sensitivity of this marker in predicting the presence of the tumor was highest for stomach and lung cancer patients. High plasma free tryptophan concentrations seem to be directly related to the presence of the tumor, since in breast cancer patients they returned to within normal range after eradicative surgery.
o Laviano, A, Cascino, A, Muscaritoli, M, Fanfarillo, F, & Rossi Fanelli , F. (2003). Tumor-induced changes in host metabolism: a possible role for free tryptophan as a marker of neoplastic disease. Adv Exp Med Biol, 527, 363-6.
Tumor cells constitutively express indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan and lowers tryptophan concentration in the local microenvironment. Such altered microenvironment protects tumor cells from rejection by the immune system, as T lymphocytes are exquisitely sensitive to tryptophan shortage. This may explain the low clinical efficacy of cancer immunotherapy based on vaccination. Preclinical studies indicate that this immune resistance mechanism can be blocked by systemic delivery of a pharmacological IDO inhibitor, 1-methyl-l-tryptophan. These results suggest the clinical efficacy of cancer immunotherapy can be boosted by combined treatment of cancer patients with an IDO inhibitor.
o Van den Eynde, BJ et al. (2007). Tumoral immune resistance based on tryptophan degradation by indoleamine 2,3-dioxygenase. International Congress Series, 1304, 274-7.
METHODS: A double-blind placebo-controlled cross-over study in which plasma tryptophan was manipulated by administration of a tryptophan-deficient amino acid mixture. In the placebo condition, all subjects received a nutritionally balanced amino acid mixture that contained tryptophan. To further standardize baseline amino acids, each subject was provided with a low-protein diet the day before amino acid challenges. Subjects were euthymic, healthy men aged 18 to 30 years with either a multigenerational family history of affective illness or no family history of psychiatric illness in the present or in the two previous generations. Each subject was screened with a structured clinical interview to rule out a personal history of psychiatric illness………….. CONCLUSIONS: Our data support the hypothesis that subjects with no prior depressive episodes but with a multigenerational family history of major affective disorder show a greater reduction in mood after tryptophan depletion. They are also consistent with theories that implicate deficient serotonergic function as one possible etiological factor in major depressive disorders.
o Benkelfat, C, Ellenbogen, MA, Dean, P, Palmour, RM & Young, SN (1994). Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. Arch Gen Psychiatry. 51(9), 687-97.
Serotonin (5-HT) has been implicated in the pathophysiology of depressive syndromes and in the mechanism of antidepressant drug action. Rapid dietary depletion of tryptophan (TRP) provides a paradigm for studying the role of 5-HT in depressed patients. Drug-free depressed patients do not show mood changes during TRP depletion but about one third have a clinically apparent, transient improvement in mood on return to normal TRP intake. Depressed patients in clinical remission after 6 to 8 weeks of antidepressant therapy experience a transient depressive relapse during acute TRP depletion.
o Miller, HL, Delgado, PL, Salomon, RM, Licinio, J, Barr, LC & Charney, DS (1992). Acute tryptophan depletion: a method of studying antidepressant action. J Clin Psychiatry. 53 (Suppl), 28-35.
Normal male human subjects ingested amino acid mixtures which were tryptophan-free, balanced or contained excess tryptophan. The tryptophan-free mixture causes a marked depletion of plasma tryptophan by 5 h. At this time the subjects in the tryptophan-free group had significantly elevated scores on the depression scale of the Multiple Affect Adjective Checklist. The tryptophan-free group also performed worse than the other two groups in a proofreading task carried out while listening to a tape with themes of hopelessness and helplessness (dysphoric distractor). Cognitive theories of depression predict greater distractability of depressed individuals by dysphoric themes. Thus, both measures indicate a rapid mood lowering effect of tryptophan depletion in normal males. This effect is probably mediated by a lowering of brain 5-hydroxytryptamine. Although the mood-lowering effect was not as great as that seen in depressed patients, our results suggest that low brain 5HT might be one factor precipitating depression in some patients.
o Young, SN, Smith, SE, Pihl, RO & Ervin, FR (1985). Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology (Berl). 87(2), 173-7.
In separate experiments we investigated the duration of the effects of acute tryptophan depletion (ATD) on mood and cognition. The results showed that ATD's effects consist of lowering of mood only in subjects with a family history of unipolar depression. A specific impairment of memory consolidation was seen in all subjects. In subjects without any vulnerability for mood disorders, performance on so-called 'frontal tasks,' measuring higher attentional functions tended to improve after ATD. The effects of ATD on mood and cognition were manifest as long as biochemical indices of low tryptophan remained low. In conclusion, ATD is a model for impairment of memory, next to being a model of mood disorders in vulnerable subjects. Moreover, ATD could be used as a challenge to demonstrate individual vulnerability of the serotonergic system.
o Riedel, WJ, Klaassen, T & Schmitt, JA (2002). Tryptophan, mood, and cognitive function. Brain Behav Immun. 16(5):581-9.
The present study evaluated whether the administration of cereals enriched with nutrients that are facilitators of sleep could help improve the sleep of infants who had sleep disorders at night time. Thirty infants aged 8-16 months with sleep disorders involving at least three nocturnal waking episodes took part in the study. They were given a night-time 'sleep facilitating cereal' product containing 225 mg tryptophan, 5.3 mg adenosine-5'-P, and 6.3 mg uridine-5'-P per 100 g of product. These cereals were given in a double-blind procedure lasting 5 weeks, with ingestion of the cereal between 18:00 and 06:00…………..The infants receiving the enriched cereal during the time of darkness showed improvements in their sleep parameters, regardless of whether the milk they took at night was standard or enriched with tryptophan, adenosine-5'-P, and uridine-5'-P. In summary, the administration of enriched cereals led to an improvement in sleep, regardless of the type of infant milk used. These results support the concept of chrononutrition since they confirm that the sleep/wake rhythm can be influenced by diet.
o Cubero, J, Chanclón, B, Sánchez, S, Rivero, M, Rodríguez, AB &, Barriga, C (2009). Improving the quality of infant sleep through the inclusion at supper of cereals enriched with tryptophan, adenosine-5'-phosphate, and uridine-5'-phosphate. Nutr Neurosci. 12(6), 272-80.
Modulating central serotonergic function by acute tryptophan depletion (ATD) has provided the fundamental insights into which cognitive functions are influenced by serotonin. It may be expected that serotonergic stimulation by tryptophan (Trp) loading could evoke beneficial behavioural changes that mirror those of ATD. The current review examines the evidence for such effects, notably those on cognition, mood and sleep. Reports vary considerably across different cognitive domains, study designs, and populations. It is hypothesised that the effects of Trp loading on performance may be dependent on the initial state of the serotonergic system of the subject. Memory improvements following Trp loading have generally been shown in clinical and sub-clinical populations where initial serotonergic disturbances are known. Similarly, Trp loading appears to be most effective for improving mood in vulnerable subjects, and improves sleep in adults with some sleep disturbances. Research has consistently shown Trp loading impairs psychomotor and reaction time performance, however, this is likely to be attributed to its mild sedative effects.
o Silber, BY & Schmitt, JA (2009, Aug 26). Effects of tryptophan loading on human cognition, mood, and sleep. Neurosci Biobehav Rev.
BACKGROUND: Over the past 10 years the technique of tryptophan depletion has been used increasingly as a tool for studying brain serotonergic systems. AIMS: To review the technique of tryptophan depletion and its current status as a tool for investigating psychiatric disorders. METHOD: Systematic review of preclinical and clinical studies. RESULTS: Tryptophan depletion produces a marked reduction in plasma tryptophan and consequently brain serotonin (5-HT) synthesis and release. In healthy volunteers the effects of tryptophan depletion are influenced by the characteristics of the subjects and include some mood lowering, some memory impairment and an increase in aggression. In patients with depression tryptophan depletion tends to result in no worsening of depression in untreated subjects but a relapse in those who have responded to antidepressants (particularly serotonergic agents). In panic disorder the results are similar. CONCLUSIONS: The findings that tryptophan depletion produces a relapse of symptoms in patients with depression and panic disorder who have responded to treatment with antidepressants suggests that enhanced 5-HT function is important in maintaining response in these conditions.
o Bell, C, Abrams, J & Nutt, D (2001). Tryptophan depletion and its implications for psychiatry. Br J Psychiatry, 178, 399-405.
Animal data indicate that serotonin (5-HT) is a major neurotransmitter involved in the control of numerous central nervous system functions including mood, aggression, pain, anxiety, sleep, memory, eating behavior, addictive behavior, temperature control, endocrine regulation, and motor behavior. Moreover, there is evidence that abnormalities of 5-HT functions are related to the pathophysiology of diverse neurological conditions including Parkinson's disease, tardive dyskinesia, akathisia, dystonia, Huntington's disease, familial tremor, restless legs syndrome, myoclonus, Gilles de la Tourette's syndrome, multiple sclerosis, sleep disorders, and dementia. The psychiatric disorders of schizophrenia, mania, depression, aggressive and self-injurious behavior, obsessive compulsive disorder, seasonal affective disorder, substance abuse, hypersexuality, anxiety disorders, bulimia, childhood hyperactivity, and behavioral disorders in geriatric patients have been linked to impaired central 5-HT functions. Tryptophan, the natural amino acid precursor in 5-HT biosynthesis, increases 5-HT synthesis in the brain and, therefore, may stimulate 5-HT release and function. Since it is a natural constituent of the diet, tryptophan should have low toxicity and produce few side effects. Based on these advantages, dietary tryptophan supplementation has been used in the management of neuropsychiatric disorders with variable success.
o Sandyk, R. (1992). L-tryptophan in neuropsychiatry disorders: a review. Int J Neuroscience, 67(1-4), 127-44.
Five healthy volunteers given L-tryptophan for ten consecutive nights had an increase in non-rapid-eye-movement sleep (non-R.E.M.) and delta wave sleep while they manifested a decrease in R.E.M. sleep. Seven patients with insomnia receiving L-tryptophan for either 5 or 10 consecutive nights had increases in total sleep and non-R.E.M. sleep when compared with placebo control periods. Since reducing brain serotonin by synthesis inhibition reduces R.E.M. sleep and increasing brain serotonin by 5-hydroxytryptophan administration increases R.E.M. sleep, it seems likely that L-tryptophan produces its sleep effects through a non-serotonin mechanism. Further evidence for this hypothesis derives from the finding that L-tryptophan produced significant increases in non-R.E.M. and decreases in R.E.M. sleep when given in the presence of p-chlorophenylalanine, a drug which blocks the metabolism of tryptophan to serotonin.
o Wyatt, RJ et al. (1970). Effects of l-tryptophan (a natural sedative) on human sleep. The Lancet, 296(7678), 842-6.
Background: It is now well established that major depression is accompanied by an immune-inflammatory system response and that indicators of the latter are inversely correlated with lower availability of plasma tryptophan in depression. Inflammation and infection can alter sleep architecture, whereas sleep disturbances can impair immune functions………… Conclusions: The results suggest that (i) there is an activation of the immune-inflammatory response system in primary sleep disorders and depression; and (ii) the decreased availability of plasma tryptophan may be related to the inflammatory system response.
o Song, C et al. (1998). The Inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression . Journal of Affective Disorders, 49(3), 211-9.
The tryptophan depletion test is a research strategy to investigate the functional consequences of decreasing the brain serotonin metabolism. Because serotonin is involved in sleep regulation and the regulation of affective states, we studied the acute polysomnographic effects of tryptophan depletion and expected to induce similar changes of sleep EEG as observed in depressed patients…………. After tryptophan depletion but not placebo, significant effects on sleep EEG were observed in terms of decreased non-rapid eye movement (non-REM) stage 2, increase of wake %, and of rapid eye movement (REM) density compared with baseline. REM latency was not altered, however the first and second REM period interval were significantly shorter after tryptophan depletion. This study underlines the impact of the serotonergic system on sleep maintenance and on REM sleep.
o Volderholzer, U et al. (1998). Impact of experimentally induced serotonin deficiency by tryptophan depletion on sleep eeg in healthy subjects. Neuropsychopharmacology, 18(2), 112-24.
Attention Deficit Disorder and Autism:
In order to examine the serotonin metabolism in children with attention deficit disorder (ADD), plasma tryptophan, which is the precursor of serotonin, was measured in 10 children with ADD and 12 normal children. The mean plasma total tryptophan level in the children with ADD was not significantly different from that of the normal children. The mean plasma free tryptophan level in the children with ADD was significantly higher than that in the normal children. There tended to be a positive correlation between the plasma free tryptophan level and the Werry-Weiss-Peters Activity Scale in children with ADD. In other words, the more severe the hyperactivity of ADD, the higher the plasma free tryptophan level. The mean ratio of plasma free to total tryptophan levels in the children with ADD was significantly higher than that in the normal children, which means that the children with ADD showed a high amount of free tryptophan in the total tryptophan level. These results suggest that there might be some disturbance in the tryptophan-serotonin metabolism in the brain of a child with ADD.
o Hoshino, Y, Ohno, Y, Yamamoto, T, Kaneko, M, & Kumashiro, H. (1985). Plasma free tryptophan concentration in children with attention deficit disorder. Folia Psychiatr Neurol Jpn, 39(4), 531-5.
The plasma free and total tryptophan (TRP) and blood serotonin levels in autistic children were examined simultaneously in order to establish a relationship between these parameters and the pathophysiology of infantile autism. The subjects were 37 autistic children, 28 normal adults and 12 normal children……….. The mean plasma free TRP level in autistic children was significantly higher than those in normal children and adults. A significant positive correlation was found between the plasma free TRP level and CPRS-1 or WWPAS score in autistic children. Moreover, there tended to be a negative correlation between the plasma free TRP level and DQ. These findings suggest the presence of some defect in the metabolic system for TRP-serotonin in the brain of autistic children.
o Hoshino, Y, Yamamoto, T, Kaneko, M, & Kumashiro, H. (1986). Plasma free tryptophan concentration in autistic children. Brain Dev, 8(4), 424-7.
In 37 autistic children and 67 normal control subjects, determinations of plasma free and total tryptophan and blood serotonin levels were made simultaneously in order to establish a relationship between these parameters and the clinical rating scales: Children's Psychiatric Rating Scale (CPRS-1), Werry-Weiss-Peters Activity Scale (WWPAS), and Developmental Quotient (DQ). The plasma free tryptophan level was significantly higher in autistic children than in normal control subjects. There tended to be a significant positive correlation between the plasma free tryptophan level and CPRS-1 or WWPAS score and a negative correlation between the plasma free tryptophan level and DQ. The blood serotonin level was significantly higher in autistic children than in normal control subjects…………. These results suggest that autistic children have some defect in tryptophan-serotonin metabolism in the brain, which is responsible for the clinical manifestations and behavioral abnormalities of infantile autism.
o Hishono, Y et al. (1984). Blood serotonin and free tryptophan concentration in autistic children. Neuropsychobiology, 11(1), 22-7.
The efficacy and tolerability of 5-hydroxy-L-tryptophan (5-HTP) were studied in an open 90-day study in 50 patients affected by primary fibromyalgia syndrome. When all the clinical variables studied throughout the trial (number of tender points, anxiety, pain intensity, quality of sleep, fatigue) were compared with baseline results, they all showed a significant improvement (P less than 0.001). The overall evaluation of the patient condition assessed by the patient and the investigator indicated a 'good' or 'fair' clinical improvement in nearly 50% of the patients during the treatment period. A total of 15 (30%) patients reported side-effects but only one patient was withdrawn from the treatment for this reason. No abnormality in the laboratory evaluation was observed. It is concluded that 5-HTP is effective in improving the symptoms of primary fibromyalgia syndrome and that it maintains its efficacy throughout the 90-day period of treatment.
o Puttini, PS, & Caruso, I. (1992). Primary fibromyalgia syndrome and 5-hydroxy-l-tryptophan: a 90-day open study. J Int Med Res, 20(2), 182-9.
Objective: Most patients with fibromyalgic syndrome (FMS) complain of sleep disturbances, fatigue, and pain. These symptoms might be a consequence of changed melatonin (MT) secretion, since MT is known to have sleep promoting properties. Moreover, serum concentrations of two MT precursors (tryptophan and serotonin) — affecting both sleep and pain perception — appear to be low in patients with FMS. Therefore, the objective of this investigation was to study whether serum MT (s-MT) level is also low in these patients……….Conclusion: Patients with fibromyalgic syndrome have a lower melatonin secretion during the hours of darkness than healthy subjects. This may contribute to impaired sleep at night, fatigue during the day, and changed pain perception.
o Wikner, J, Hirsch, U, Wetterberg, L, & Röjdmark, S. (2002). Fibromyalgia — a syndrome associated with decreased nocturnal melatonin secretion. Clinical Endocrinology, 49(2), 179-83.
BACKGROUND: Preclinical and clinical studies suggest that lowered brain serotonin neurotransmission may contribute to the pathophysiology of bulimia nervosa (BN). The aim of our study was to test this hypothesis by examining the psychological effects of a dietary-induced impairment in serotonin activity in subjects known to be at risk for manifestation of the clinical syndrome of BN………… CONCLUSIONS: Our results suggest that diminished serotonin activity may trigger some of the cognitive and mood disturbances associated with BN. Our findings support suggestions that chronic depletion of plasma tryptophan may be one of the mechanisms whereby persistent dieting can lead to the development of eating disorders in vulnerable individuals.
o Smith, KA, Fairburn, CG, & Cowen, PJ. (1999). Symptomatic relapse in bulimia nervosa following acute tryptophan depletion. Arch Gen Psychiatry, 56(2), 171-6.