Tryptophan depletion methods are used to evaluate the role of serotonin in the central nervous system (for a review, see, e. g., J. G. Reilly et al., J. Psychopharmacol.

(1997) 11: 381-392). Brain serotonin has been implicated in many aspects of behavior including affect, cognition, sleep, circadian rhythms (S. L. Brown and H. M. van Praag, The role of serotonin in psychiatric disorders. New York: Brunner/Mazel Publ. 1991; H. Y. Meltzer and M. T. Lowy, The serotonin hypothesis of depression. In : H. Y. Meltzer ed. Psycho- pharmacology : the third generation of progress. New York: Raven Press, 1987: 513-526).

Therefore, altering the blood tryptophan levels using modified enteral nutrition is a method to study and treat diseases related to disturbed serotonin neurotransmission.

In a different study, G. Sarwar and H. G. Botting, J. Nutr. (1999) 129: 1692-1697, report the influence of tryptophan supplementation of human infant formulas, to more closely simulate tryptophan composition of human milk, on rat growth responses. In addition, non-hydrolyzed gelatin-based diets were found to reduce the brain tryptophan and serotonin concentration, underscoring the effect of gelatin-based diets on brain serotonin metabolism.

At present, the common method to induce an acute reduction of the blood tryptophan level is the intake of a liquid drink with certain specific compositions of amino acids but lacking the amino acid tryptophan. See, for example, T. Klassen et al., Biol Psychiatry (1999) 46: 489-497, F. A. Moreno et al., Biol Psychiatry (1999) 46: 498-505, and references cited therein. The oral intake of these amino acid mixtures leads to a relative decrease in the blood tryptophan concentration. In addition, since the transport of tryptophan to the brain is a competitive process between five different amino acids and tryptophan, there will be a reduced transport of tryptophan to the brain after intake of a large amount of these other amino acids.

However, the tryptophan depletion methods that have been described so far using oral liquid drinks containing free amino acids have a great disadvantage in that these drinks are badly tolerated by healthy and sick humans. The most frequently reported side effect of the drink is extensive nausea. Nausea is the main reason why a certain number of subjects did not and will not complete such studies. In addition, the side effects will interfere with the behavior that is assessed, which may lead to non-reliable test results. The negative side effects, therefore, limit the use of these methods to acute tryptophan depletion. Also, the liquid free amino acid drink that is presently known prohibits the use for long-term studies with reduced blood tryptophan concentrations.

Similar methods in which amino acid drinks have been administered to subjects have shown to be quite ineffective in animals, when given on a kg body weight basis. Thus, it has been observed that only a decrease of 40% in tryptophan levels can be achieved in animals. This moderate decrease prevents the use of this method in animals, because of the impossibility to enhance the quantity of amino acids in the amino acid drink. For various scientific questions, however, the use of animal studies may be crucial. The observed modest lowering in animals is probably related to the higher protein requirements in animals, which underscores the need for dense amino acid products.

Therefore, there is still a need for compositions lacking tryptophan which can be administered to mammals, both humans and animals, and which are well-tolerated without the side-effects mentioned above, so that they will be useful, for example, in a tryptophan depletion method for the study and treatment of the effects of serotonin metabolism.

In accordance with the present invention an edible well-tolerated composition is provided containing substantially no tryptophan and which is substantially odorless and/or tasteless, characterised in that said composition comprises a gelatin hydrolysate.

In another aspect of the invention said composition is preferably in the form of an enteral protein-based meal. The composition may further comprise one or more other ingredients, preferably carbohydrates and/or fats to compose a daily life type of enteral nutrition. These ingredients and their amounts are not critical for the inventive compositions and can be easily selected by a person skilled in the art.

In a further aspect of the present invention the use of a composition as defined above is provided for the manufacture of a food ingredient or food additive for affecting, upon consumption of said food ingredient or food additive, the serotonin metabolism in mammals, in particular humans, through the food.

In a still further aspect of the present invention the use of a composition as defined above is provided, for the manufacture of a preparation for the treatment and/or prophylaxis and/or study of certain mental disorders, such as aggression, depression, sexual disorders, to affect exercise capacity, or the like.

In a further aspect of the invention a method is provided for affecting the serotonin metabolism in mammals, in particular humans, by administering to said mammal an effective amount of a composition comprising a gelatin hydrolysate.

The present invention thus provides a composition comprising an edible well- tolerated hydrolyse gelatin preferably in the form of an enteral protein-based meal which is substantially free of tryptophan wherein the protein is substantially without smell and/or odor. Gelatin is the purified protein derived from the selective hydrolysis of collagen, which is devoid of tryptophan. Collagen is the principal organic component of the bones and skins of mammals. It will be understood that gelatin as such is not a suitable ingredient for the composition according to the invention, since it is too bulky to be consumed in large amounts. We have now found that gelatin in hydrolyse form is very suitable indeed for the purpose of the present invention in its various aspects, as defined above. Gelatin can be hydrolyse in various ways, for example chemically and enzymatically, and these methods are known to a person skilled in the art. A suitable and preferred method to prepare a suitable gelatin hydrolysate for the composition of the present invention is to hydrolyse gelatin enzymatically, for example with trypsin. A suitable and preferred gelatin hydrolysate for the composition of the present invention is the commercially available product Solugel@, manufactured by the firm Tessenderlo (http://www. tessenderlo. com).

The new compositions are administered orally to mammals, especially humans, in a variety of forms, such as, for example, in food or drinks. Suitable amounts of the compositions for administration depend on usual factors, such as the body weight of the subject to which the composition is administered and the result to be achieved. The composition of a treatment that leads to considerable tryptophan depletion is suitably in the range of 100 g gelatin and 50 gr maltodextrose, and more preferably 150 g gelatin and 75 g maltodextrose, leading to a decrease of more than 60% and usually of 80-90% of normal tryptophan plasma concentrations. These levels are reached 2-4 hours after the intake of the composition, depending on factors mentioned above such as the way of administration, the concentration of the protein (s), the weight of the consumer, or the like. Since the composition is substantially odorless and tasteless, the side effects mentioned above or similar adverse effects are minimized. The compositions have the further advantage that they do not cause side-effects like nausea, and therefore they will not interfere with the psychological test performance.

A further advantage of the compositions of the present invention is that they can be administered over longer periods, providing a tool for evaluating long-term changes in tryptophan levels. Also, in contrast to the previously used compositions, the new compositions allow the use in animals, for example rats, in which the tryptophan concentrations after acute administration are maximally lowered by 40% using the amino acid mixture. Using the composition described here, a decrease of about 80% can be achieved in rats (see example). Finally, the new composition also allows setting the level of tryptophan depletion by adding free tryptophan to the compositions.

It is noted that gelatin hydrolysates are known as ingredients in dietary food products, as described, for example, in GB 2019409A and US 4,495,206. However, such products usually include in addition essential amino acids, such as tryptophan, and other additives. ES 20293557 discloses a process for obtaining a highly concentrated solution of hydrolysed gelatin which is free from disagreeable odour or taste by the production of fine bubbling within the starting solution. The product obtained is said to be useful for the preparation of liquid phramaceutical preparations for the prevention and treatment of arthrosis, and to strengthen nails and hair.

Figure 1 shows the tryptophan/large neutral amino acids (Tryp/LNAA) ratio of rats treated with the new composition.

Figure 2 shows the Tryp/LNAA ratio in six humans administered with the new composition.

The following non-limiting example illustrates the invention.

Example 1 Five month old male Wistar rats were treated either with saline, or with a mixture of Solugel (1 g/ml) and maltodextrose (0.625 g/ml) with (tryp+, 0.28% of total protein) or without tryptophan (tryp-), respectively (n=8 per group). A suitable and preferred gelatin protein for the composition of the present invention is the commercially available product Solugel, manufactured by the firm Tessenderlo (http://www. tessenderlo. com).

They received an injection (5 ml per os) with the respective mixture at time points 0 h and 1.5 h. Blood samples were taken after 0,2, and 4 h.

Tryptophan levels were determined by HPLC using the method described by H. van Eijk, Analytical aspects to the study of amino acid metabolism, Thesis (1999), Maastricht University, The Netherlands). Briefly, plasma was deproteinised by the addition of 5-sulfosalicylic acid (6mg/100u1 plasma) and protein was spun down. Aliquots of the plasma supernatants were automatically reacted with o-phthaldialdehyde (OPA) [at room temperature] and separated through reversed phase high performance liquid chromato- graphy. OPA-amino acid derivatives were quantified using fluorescence detection.

The results are shown in Figure 1. It was found that the tryptophan level in the blood was reduced by 80% four hours after treatment with the solugel/maltodextrose mixture. The addition of an equivalent percentage of tryptophan completely reversed this effect.

Example 2 Six healthy volunteers participated in this experiment. They were given the same Solugel (E) mixture. They were given a total of 100 g in 100 ml milliQ of the mixture together with 50 g carbo-hydrate (Glucodry 200) in 80 ml milliQ. In addition, 0.57 g KCI and 13.9 g CaCI 2 Hydrat-kristal were added to the solution. Blood was collected before consuming the mixture and 1,2, and 3 h after intake. Tryptophan levels were determined as mentioned above. The results are shown in Figure 2. It can be seen that the TRP level was decreased by 65% 3 h after the intake.