## Abstract

Tryptophan is the precursor for several neurotransmitters and metabolic regulators, which, although quantitatively of little importance in determining the dietary requirement, have major importance for interpreting symptoms of dietary tryptophan deficiency and excess. The quantitative dietary tryptophan requirement appears to vary widely across species, so intakes relative to requirements are more appropriate expressions for comparison of adverse effects across species than daily intake or diet concentration. Symptoms of tryptophan deficiency may occur at intakes as little as 25% below the requirement. Symptoms include reduced feed intake and reduced growth rate but also impaired skeletal development and aberrant behavior. Older animals appear less susceptible than younger animals to tryptophan deficiency and females less than males. Symptoms of excess tryptophan intake include reduced food intake and growth rate. In growing animals, it appears that tryptophan intakes of >10 times the requirement are necessary before there are detrimental effects on growth performance. At still greater intakes, fatty liver and fibrotic changes in muscles, lung, and pancreas and the serotonin syndrome may develop. In pigs, tryptophan intake of 60 times the daily requirement did not cause mortality. The maximal tryptophan oxidation rate, measured in vivo using 13C universally labeled tryptophan, may be a possible marker of the intake above which increasing intake increases the risk of adverse effects. The advantage of the oxidation technique is that it does not necessarily rely on but still allows the identification and measurement of amino acid metabolites and is therefore simpler and more universally applicable.

## Introduction

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## Dietary Requirements for Tryptophan

### Pigs

The largest quantity of data on tryptophan requirement is for pigs, due to the economic importance of this knowledge. The daily requirement for tryptophan increases with the body weight of growing pigs and their realized growth potential (1). However, the tryptophan concentration in ideal protein, a protein that supplies all indispensable amino acids at requirement without excesses or deficiencies, appears to remain fairly constant. Because lysine is usually the first-limiting amino acid for growing pigs, tryptophan requirements are typically reported as a ratio to lysine. Susenbeth (2) reviewed a large number of dose-response experiments in growing pigs to derive the optimum tryptophan:lysine ratio, which he determined to be 0.174:1. This ratio was not affected by response criteria, e.g., body weight, performance level, protein or lysine level, or genetics of the animals. The constancy of this ratio implies that requirements of tryptophan, relative to lysine, are similar for growing pigs and pigs at maintenance.

There are few reports on the tryptophan requirement of mature pigs. Meisinger and Speer (3) concluded that an intake of 1.44 g/d tryptophan was sufficient to support optimal reproductive performance in pregnant sows, which was similar to the 1.4 g/d tryptophan proposed by Easter and Baker (4) for pregnant sows. Both the NRC (1) and Fuller et al. (5) suggested that the ratio of tryptophan:lysine was greater for maintenance, at 0.26:1 and 0.31:1, respectively, than for growth. More recently, Moehn et al. (6) determined the tryptophan requirement in pregnant sows to be 1.7 g/d in early and 2.6 g/d in late gestation and concluded that the optimum tryptophan:lysine ratio was 0.15:1. This was in contrast to the NRC (1), which suggested optimal ratios of 0.19 to 0.20:1 during gestation. Libal et al. (7) concluded that a dietary concentration of 1.7 g/kg tryptophan improved lactating sow performance over a concentration of 1.2 g/kg. Paulicks et al. (8) and Pampuch et al. (9) determined the dietary tryptophan requirement of lactating sows as 2.6 g/kg diet based on a variety of growth performance and plasma measurements. The tryptophan:lysine ratios in these lactation studies were 0.23 to 0.25:1 compared with the NRC (1) suggestion of 0.18:1. Because of the limited number of experiments and the greater variability in the results for the tryptophan requirements of sows, it cannot be ascertained whether the tryptophan requirement of pregnant or lactating sows, relative to lysine, is different from that of growing pigs.

### Humans

The WHO (10) substantially revised the recommended daily intakes for protein and amino acids over earlier recommendations. This was necessitated by the emergence of improved methodologies for determination of amino acid requirements and a vastly expanded body of research. The tryptophan requirement for adult males was first determined by Rose et al. (11), who suggested the requirement to be 250 mg/d of tryptophan, based on N-balance studies. This value represented the greatest individual requirement; nevertheless, Rose et al. (11) cautioned that some individuals may require even greater amounts. Young et al. (12) found the tryptophan requirement of young adult men to be 2–3 mg/(kg·d), depending on the response criterion. Lazaris-Brunner et al. (13) determined the mean tryptophan requirement of adult, nonpregnant women to be 4.0 mg/kg body weight, using the indicator amino acid oxidation technique, with a safe intake of 5.0 mg/kg body weight. Consequently, the recommended daily intake of tryptophan was suggested as 4 mg/kg body weight for adult humans (10). In children, the recommended daily intake (10) decreases from 8.5 mg/kg body weight for infants 6 mo old to 6 mg/kg body weight for adolescents 18 y old, with the majority of change occurring in the first 10 y of life. Therefore, adult humans at maintenance appear to require a tryptophan:lysine ratio of 0.13:1, which is similar to the ratio suggested by WHO (10) for 6-mo-old infants. However, for children and adolescents between 3 and 18 y old, the WHO (10) suggested a tryptophan:lysine ratio of 0.18:0.20, which is similar to the optimum ratio (0.17:1) for growing pigs suggested by Susenbeth (2).

### Other monogastric animals

The NRC (14) recommended 0.5 g/kg diet of tryptophan for maintenance in rats and 2.0 g/kg diet of tryptophan for growth and reproduction. The recommended dietary lysine concentrations were 1.1 g/kg diet and 9.2 g/kg for maintenance and growth, respectively, giving tryptophan:lysine ratios of 0.45:1 for maintenance and 0.217:1 for growth and reproduction.

Baker and Czarnecki-Maulden (15) compared the tryptophan requirement, relative to lysine, for cats and dogs to those of pigs. The ideal ratio of tryptophan:lysine was 0.19 for cats and 0.22 for dogs. These are slightly greater than that suggested for pigs at 0.18, but the differences are probably within the margin of error in these experiments due to the relatively small numbers of animals.

### Summary

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### Tryptophan deficiency and excess

#### Behavior.

The effects of tryptophan on behavior are thought to be mediated by serotonin, which is involved in the regulation of feeding behavior, sleep-wake cycle, and sexual behavior (16). Serotonin concentrations are dependent on the ratio of plasma tryptophan:large neutral amino acids (17) that can be manipulated by offering carbohydrate or protein meals (18) or by the acute tryptophan depletion or loading techniques (19). Tryptophan depletion and loading typically elicit acute, transient responses in plasma tryptophan and brain serotonin (19).

Acute tryptophan depletion is associated with increased pain sensitivity, acoustic startle, motor activity, and aggression in humans (20). Tryptophan deficiency increases anxiety and irritability in humans and may modulate aggressiveness and the response to stress in animals (21). Opposed to these findings, based on acute depletion techniques, chronic, moderate tryptophan deficiency showed little effect on behavior of weaned pigs (22). Carruba et al. (23) found that tryptophan deficiency caused increased male-to-male mounting behavior that was not observed in rats given adequate tryptophan. Conversely, Benedetti and Moja (24) found no impact of tryptophan deficiency on the sexual behavior in female rats.

A moderate increase in dietary tryptophan to 1.5 times the requirement reduced aggressive behavior in pigs (25). Adeola and Ball (26) concluded that supplementing diets with 5 g/kg of tryptophan, ∼2 times the requirement, attenuated the pigs' response to stress. Li et al. (27) tested dietary tryptophan concentrations of 1, 2, and 4 times the requirement in growing pigs and reported that tryptophan supplementation increased the time spent laying down and reduced the time spent fighting among unfamiliar pigs. Conversely, Li et al. (28) found that increasing dietary tryptophan to 2.3 times the requirement did not effectively control aggression or the response to stress in sows. These differences in response may be caused by either a greater tolerance to excess tryptophan by adult compared with growing pigs or may be a reflection of the uncertainty of tryptophan requirement in sows. Poletto et al. (29) found increased lying down and reduced aggressive behavior in growing pigs fed tryptophan at 3 times the requirement for 1 wk. Koopmans et al. (3032) conducted a series of experiments in which the dietary tryptophan concentration was increased from 2.0 to 7.0 g/kg diet or to ∼3.5 times the tryptophan requirement. At the greater tryptophan level, Koopmans et al. (30) reported reduced baseline stress hormone levels and more rapid recovery in pigs without alterations in behavior pattern and also reported reduced activity of piglets (31). Koopmans et al. (32) found that increasing dietary tryptophan reduced fasting plasma cortisol and noradrenalin and urinary excretion of adrenalin and noradrenalin in growing pigs. In this study, they found reduced insulin sensitivity without affecting N excretion, indicating that lower basal levels of stress hormones were associated with insulin resistance (32). In none of the studies cited above were depressions in feed intake or performance reported. Therefore, tryptophan intake in the range of 2–4 times the requirement, although it does not result in detrimental effects on the performance of growing animals, appears to modify behavior.

In humans, tryptophan has been studied to treat depressive disorders. Doses of 3–8 g/d tryptophan alone showed mixed results with regards to effectiveness in treating clinical depressive disorders (19). However, when combined with monoamineoxidase inhibitors, doses of 6–18 g/d tryptophan showed positive effects in depression treatment (19). A dose of 3 g/d tryptophan is ∼12 times the requirement of an adult human. Therefore, it appears that tryptophan doses of at least 10 times the daily requirement are necessary to elicit pharmacological responses.

### Animal performance

Beeson et al. (33) described that lack of tryptophan decreased feed efficiency and feed intake and caused weight loss in weanling pigs. Henry et al. (34) observed reductions of feed intake in growing pigs when tryptophan was reduced by only 25% from 1.6 to 1.2 g/kg. The onset of feed intake reduction and its magnitude were dependent on the dietary protein concentration, with pigs being less sensitive to tryptophan deficiency at a low dietary protein concentration (35). Henry (36) showed that reduction of dietary tryptophan from 0.13 to 0.10% reduced feed intake, growth performance, and tissue gain in finishing pigs offered feed at 125 g/kg0.75 body weight. The negative effects were less pronounced in older pigs and castrated males compared with females (36). Henry et al. (34) replicated these results and found that additional protein depressed serotonin production more in tryptophan-deficient than tryptophan-adequate diets. Henry et al. (34) concluded that the effects of tryptophan on feed intake were mediated by serotonin. Ettle and Roth (37) found that tryptophan deficiency in pigs reduced growth performance and that pigs were able to detect tryptophan deficiency-induced metabolic changes, as indicated by an aversion against consuming the tryptophan-deficient diet. The competition for transport between tryptophan and large neutral amino acids (21) limits the transport of tryptophan across the blood-brain barrier more at greater protein intakes and thus may attenuate serotonin synthesis.

Lewis et al. (38) fed weaned piglets diets containing up to 3.6 g/kg tryptophan, approximately twice the requirement, at different lysine levels and observed no adverse effects on growth performance. In pregnant sows, a nonsignificant (P = 0.12) increase in indicator amino acid oxidation was observed (R.O. Ball, unpublished results) when the tryptophan intake approached twice the requirement. Edmonds and Baker (39) tested tryptophan additions of 5, 10, 20, and 40 g/kg diet to a 20% crude protein, corn-soybean meal diet formulated to meet all requirements. The weaned piglets reduced feed intake and growth rate only at the highest level of tryptophan supplementation. In a dose-response study with force-fed growing pigs, Chung et al. (40) observed an increasing incidence of diarrhea when tryptophan intake was increased up to 5.71 g/kg body weight. Therefore, it appears that detrimental effects on pig performance, similar to pharmacological effects in humans, do not manifest themselves at tryptophan intakes of less than ∼10 times the requirement.

Gross et al. (41) fed rats diets containing 20% casein with 10, 20, or 50 g/kg added tryptophan. The rats given the highest tryptophan level had reduced weight gain, but no mortalities were observed over a 12-wk period at any tryptophan level. Muramatsu et al. (42) observed a drastic reduction of growth rate when rats were fed a 6% casein diet supplemented with 50 g/kg tryptophan, but a 25% casein diet supplemented with 50 g/kg diet tryptophan did not result in any growth depression over a 3-wk period in the rats (43). This indicates that in rats, similar to pigs, adverse effects of excess tryptophan are unlikely to appear at intakes of <10 times the requirement. Additionally, it appears that increased dietary intake of large neutral amino acid can attenuate the detrimental effects of excess tryptophan in growing animals.

#### Pathological changes.

Tryptophan deficiency can cause pathological changes in animals. Sidransky (44) compiled results that described the development of cataracts and corneal vascularization, anemia and reduced plasma protein concentration, fatty liver, and pancreas atrophy in animals exposed to tryptophan deficiency. These changes may be related to the effect of tryptophan on protein synthesis. Omstedt et al. (45) and Naito and Kandatsu (46) showed decreased muscle protein synthesis but increased liver protein synthesis when rats were fed a tryptophan-deficient diet. Lenis et al. (47) reported impaired leg development in growing pigs when feeding tryptophan-deficient diets. Because deficiencies of other amino acids may elicit similar symptoms, except perhaps for cataract formation, Sidransky (44) suggested that tryptophan deficiency resembled protein deficiency.

Interestingly, Sidransky (44) listed fatty liver as a pathological change following excess tryptophan intake, which was suggested to be related to increased fatty acid synthesis after tryptophan dosing rather than the impairment of lipoprotein release that occurs in tryptophan deficiency. Occasionally, fibrotic changes in lungs, muscle, and pancreas have been described, but it is open to debate whether tryptophan excess was the cause (44).

### Tryptophan toxicity

Gullini et al. (48) reported the LD50 value, the dose that is lethal for 50% of animals tested, for tryptophan in rats as 1.6 g/kg body weight when administered i.p. The LD50 after i.v. or i.p. administration of tryptophan in mice and rabbits was ∼2 g/kg body weight. Conversely, when administered orally, the LD50 in mice and rabbits was between 5 and 16 g/kg bodyweight. Oral doses of 5.71 g/kg body weight applied by stomach tubes, i.e., amore than 3 times the i.p. LD50 for rats and ∼60 times the requirement of pigs, caused no mortality in pigs of 50 kg body weight (40). Sidransky (44) concluded that tryptophan had generally low acute toxicity or could be considered as nontoxic. In their review, Benevenga and Steele (49) summarized these and other data and argued that the toxicity of tryptophan was low, because toxic effects were not observed until intake was >30 times the oral requirement. However, route of administration, dietary protein, and food intake appear to influence the manifestation of toxic symptoms.

Toxicity of tryptophan differs among species (44). These differences appear to be related to the presence or absence of the apoenzyme for tryptophan 2,3-dioxygenase or hormonal induction mechanism. Species that lack the apoenzyme or induction mechanism are more sensitive to the toxicity of tryptophan and are thus not suitable as models for studying human tryptophan metabolism (50). These species include cat, gerbil, hamster, guinea pig, sheep, and cow. Species that express the apoenzyme, pig, rat, human, and dog, are more tolerant to tryptophan excess. Therefore, rats, dogs, and pigs appear most suitable as models to study the detrimental effects of excess tryptophan intake in humans.

## Safe Intake of Tryptophan

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Noguchi et al. (51) suggested a metabolomic approach to identify the upper safe limit of amino acid intake, whereas Okuno et al. (52) suggested analysis of urinary excretion of tryptophan metabolites. A third possibility is to determine intake at which the maximum rate of amino acid oxidation occurs (53). At intakes below the maximum rate of oxidation, the risk is generally assumed to be low, whereas at intakes greater than the maximum rate of oxidation, the risk of adverse effects is predicted to increase. This approach has been successfully used to determine the upper safe intake of phenylalanine in piglets (54) and leucine in rats (55) and humans (56). These authors used the direct oxidation technique and found that leucine oxidation plateaued at ∼10 times the estimated average requirement. The direct oxidation technique is generally limited in its application to essential amino acids, where the carboxyl group is directly released into the bicarbonate pool and will therefore readily appear in breath (53). An option would be the use of universally labeled amino acids, which may be expected to be less sensitive than using 1-13C-labeled amino acids but would still allow the determination of the maximum rate of oxidation. In addition, the appearance of label in metabolites following administration of universally labeled tryptophan could be measured as indicators of potential for adverse effects. No reports were found in the literature on the upper limits of tryptophan oxidation. The advantage of the oxidation technique is that it does not necessarily rely on the identification and measurement of amino acid metabolites and is therefore simpler and more universally applicable. This last point is important, because it allows a direct comparison of safe levels of intakes using the same methodology, based upon maximum rate of oxidation, across all of the amino acids.

## Acknowledgments

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## Footnotes

1

Published in a supplement to The Journal of Nutrition. Presented at the 8th Workshop on the Assessment of Adequate and Safe Intake of Dietary Amino Acids, held in Washington, DC, November 10–11, 2011. The conference was sponsored by the International Life Sciences Institute Research Foundation. The Organizing Committee for the workshop included Sidney M. Morris Jr, Dennis M. Bier, Luc A. Cynober, Motoni Kadowaki, and Andrew G. Renwick. The views expressed in these papers are not necessarily those of the Supplement Coordinator or Guest Editors. The Supplement Coordinator for this supplement was D'Ann Finley, University California, Davis. Supplement Coordinator disclosures: D'Ann Finley received travel support and compensation from ICAAS for editorial services provided for this supplement publication. The supplement is the responsibility of the Guest Editor to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The Guest Editor for this supplement was Harry Dawson. Guest Editor disclosure: Harry Dawson had no conflicts to disclose. Publication costs for this supplement were defrayed in part by the payment of page charges. This publication must therefore be hereby marked “advertisement” in accordance with 18 USC section 1734 solely to indicate this fact. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the Publisher, Editor, or Editorial Board of The Journal of Nutrition.