WO2005049012A2

WO2005049012A2 - Tryptophan for use in promoting and maintaining abstinence

Info

Publication number: WO2005049012A2
Application number: PCT/GB2004/004787
Authority: WO
Inventors: Adrian Bonner; Colin Robert Martin; Andrew Lynch; Catherine Deering
Original assignee: Shs International Ltd
Priority date: 2003-11-13
Filing date: 2004-11-15
Publication date: 2005-06-02
Also published as: WO2005049012A3; GB0326477D0

Abstract

Tryptophan is disclosed as the active agent for a medicament for the promotion and/or maintenance of abstinence from an addictive substance, or addictive substances. The additive substance may be alcohol. The supplemental tryptophan changes the profile of kynurenines to a more neuroprotective balance. The treatment results in improvement in cognitive and other neural functions and aids the process of withdrawal and easies the remission phase after withdrawal is complete.

Description

Medicaments for use in promoting and maintaining abstinence.

The present invention relates to medicaments for use in promoting and/or maintaining abstinence from an addictive substance, or addictive substances, and/or from a reward-mediated behaviour, or reward-mediated behaviours. More particularly, although not exclusively, the invention relates to medicaments for promoting/and or maintaining abstinence from alcohol.

Dependence on addictive substances and reward-mediated behaviours (including eating disorders such as bulimia nervosa) are increasingly prevalent, and represent a source of increasing pressure on the health care system in most western countries.

Addiction to alcohol is among the most prevalent of such addictions. The diagnoses of "alcoholism" or "alcoholic psychosis" in the UK have assumed near epidemic proportions during recent years, increasing from 512 cases in 1952 to 25,903 cases in 1996. Alcohol-related deaths registered by hospitals increased from 3,000 in 1986 to 5,000 in 1997, although the total number of deaths associated with alcohol misuse is closer to 33,000 a year. Apart from the huge degree of human suffering which underlies these statistics, the economic impact includes an estimated cost of £200 million pounds to the National Health Service, in addition to £2.8 billion lost to industry due to sickness absence, unemployment and premature deaths. Additional costs accrue from alcohol-related road accidents (£189 million) and criminal activity (£68 million). The hidden costs of Britain's alcohol problem are expressed as violence, risky sexual behaviour and teenage pregnancy, in the family and in other parts of "included" and "excluded" society.

Although alcohol craving, dependency and withdrawal have a highly complex basis there are some common factors which appear to play a significant part in determining an individual's vulnerability. These include the socio-cultural environment, diet and individual metabolic profiles. The extensive literature on the metabolic vulnerability to and pathophysiological consequences of alcohol abuse points toward the central importance of the reward systems of the brain in initiating alcohol-seeking behaviour, craving and withdrawal. In particular, the dopaminergic mesolimbic system is regarded as the main functional system in the brain. The dopamine circuits have been investigated and a number of candidate genes, such as D4, have been associated with Novelty Seeking, a specific behaviour frequently observed in individuals who are most likely to abuse and become dependent on alcohol.

Such dopamine circuits are modulated by serotonergic neuronal inputs, and serotonin has also been implicated in alcoholism. It has therefore been postulated that serotonergic interventions may be of use in treatment of alcoholism. Recent results have been disappointing, however. For example, use of SSRIs, drugs that increase levels of serotonin in synapses, has generally been found to be ineffective in preventing relapse in recovering alcoholics. Thus it has been disclosed by Kranzler et al (Alcohol Clin Exp Res. 1996 Dec; 20 (9): 1534-41) that Fluoxetine treatment seems to reduce the beneficial effect of cognitive-behavioural therapy in Type B alcoholics. Also, craving, a significant factor determining relapse, is reduced by depletion of tryptophan (a fuller description of tryptophan is given below), an intervention which reduces serotonergic function in the brain. Thus, for example, Satel et al (Am J Psychiatry 1995 May; 152(5): 778-83) disclose that depletion of tryptophan reduced craving for cocaine.

Serotonergic treatments alone therefore seem to be ineffective in alcoholism, and cannot reduce craving in substance-dependent patients. However, serotonin has many potential mechanisms of action, and may be useful in modulating addictive behaviours through mechanisms other than craving.

US-A-4 761 429 discloses the use of enkephalinase and endorphinase inhibitors (e.g. phenylalanine) as anti-craving agents, e.g. to reduce alcohol craving. In the Examples of the US patent, such agents are used in combination with substances that provide enhanced anti-craving for alcohol via direct or indirect interaction with the endorphinergic system and/or opioid receptor functions. The particular substances used are lithium carbonate, L-glutamine, L-tryptophan, ascorbic acid, niacinamide, Naltrexone and D-Leucine. The substances are disclosed as being less efficatious enkephalinase or endorphinase inhibitors in reducing craving but are synergistic when used in combination with such inhibitors (e.g. phenylalanine). Tryptophan is the natural amino acid precursor of serotonin (5-hydroxytrvptamine, 5- HT). 5-HT is a major neurotransmitter involved in the control of numerous central nervous system activities. It has a wide-ranging modulatory function in the brain, generally comprising control of motomeuron excitability, control of sensory transmission, and autonomic and endocrine functions. Serotonergic function has also been specifically linked with alcohol dependency, sleep, wakefulness and mood.

Tryptophan is an essential amino acid in humans and is derived from dietary protein. Its plasma level is determined by a panoply of factors consequent to dietary intake, such as how much is metabolised on first-pass through the liver, how much carbohydrate was consumed and its overall glycaemic index, the individual's lean body mass and his/her insulin sensitivity. Tryptophan is taken up into neurons by facilitated diffusion, converted by tryptophan hydroxylase to 5-hydroxytryptophan and then decarboxylated by a non-specific amino acid decarboxylase to 5- hydroxytrypamine (5-HT), a series of metabolic steps known as the indole pathway. An alternative pathway for tryptophan metabolism is the kynurenine pathway in the liver, which converts tryptophan to nicotinic acid through a series of steps initially catalyzed by tryptophan pyrollase. Under normal circumstances, high levels of tryptophan in the plasma induce increased liver pyrrolase activity. Figure 1 summarises the two pathways for metabolism of tryptophan.

The availability of tryptophan in the brain for the production of 5-HT is dependent on a range of factors, the most widely studied and important of which is the transport of plasma tryptophan across the blood brain barrier (BBB) by the L-transport system. The flux of tryptophan across the BBB is determined by competition with other large neutral amino acids LNAAs) including phenylalanine, tyrosine, valine, isoleucine, leucine, methionine and histidine, with the ratio of tryptophan to the sum of these LNAAs providing an index of tryptophan availability to the brain and thus the potential for 5-HT synthesis.

Tryptophan metabolism is implicated in the predisposition to becoming alcohol- dependent. Additionally, alcohol has a major effect on tryptophan metabolism via its perturbation of enzymes involved in the conversion of tryptophan into kynurenine- related metabolites; chronic ethanol intake inhibits tryptophan pyroUase activity, effectively increasing central 5-HT, the result of which is an increase in drinking and alcohol preference (Ho, 1974; Coscina, 1972). Studies in alcohol-dependent subjects appear to show that withdrawal from alcohol increases flux through the kynurenine pathway due to a removal of ethanol-dependent tryptophan pyroUase suppression, thus decreasing the availability of tryptophan to the brain for 5-HT synthesis (for example, see Badawy et al, Biochem. J. (1980) 192, 449-455). Mann et al. (Alcohol & Alcoholism (1999) Vol. 34, No. 4, 567-574) report that repeated withdrawal from alcohol has a detrimental effect on cognitive ability due to the repeated production of kynurenine metabolites during withdrawal.

The neuroactivity of the various kynurenine metabolites has been reviewed (Moroni 1999 Eur J Pharmacol 375:87-100) and some of these compounds have been suggested to have potent neurotoxic qualities (Harris et al, Br. J. Pharmacol. (1998) 124, 391-399). Indeed, kynurenines have been suggested to be linked to seizures. Disregulated kynurenine metabolism has a neuropathological effect on brain function via the relative influence of quinolinate (neurotoxic) and kynurenate (neuroprotective) on NMDA glutamate receptors in hippocampal neurones, which are believed to be central to memory function and learning via Long Term Potentiation. Quinolinate is known to have agonistic properties at the NMDA receptors, which can result in excitotoxic neuronal cell death; this is in contrast to the action of kynurenate which, via its antagonistic properties at NMDA receptors, provides protection from excitotoxic damage (Stone and Perkins, 1981, Freese et al, 199). It is also known that 3-hydroxykynurenine can induce neuronal apoptosis and necrosis (Eastman and Guilarte, 1989), whilst quinolinate has been shown to alter the functioning of brain proteins important for memory. Recent evidence suggests that kynurenine pathway metabolites rather than 5-HT levels per se may control some psychopathologies previously attributed to 5-HT.

The clinical usefulness of tryptophan, particularly for the treatment of depression (van Praag 1981) and premenstrual syndrome and adjunctive use with antidepressants in the treatment of psychiatric disorders, has received recent attention (Eriksson and Walinder, 1998). Depression and anxiety states have long been recognised as co- morbid and presenting features of alcohol dependency (Allan, 1995; Brown et al, 1995).

According to a first aspect of the present invention there is provided the use of tryptophan for the production of a medicament for the promotion and/or maintenance of abstinence from an addictive substance, or addictive substances.

Thus the method according to the first aspect of the invention provides the manufacture of a medicament that may be used to promote and/or maintain abstinence from one or more addictive substance. The addictive substance may be alcohol.

The invention has been based on our surprising finding that tryptophan may be administered to alcohol-dependent individuals to help manage their withdrawal from alcohol. Tryptophan-containing medicaments may also be administered to individuals who have successfully withdrawn from alcohol, in order to maintain their abstinence. It will be appreciated that the continued use of medicaments of the invention thus provides a means by which alcohol-dependent subjects may first be withdrawn from alcohol, and then maintained in a state of abstinence.

As set out above, serotonergic modulation is an integral aspect of the functioning of all "novelty seeking" dopamine circuits in the brain involved in addiction and in reward-mediated behaviour. The present invention is thus applicable to the management of addiction to many addictive substances (through promotion and/or maintenance of withdrawal from such substances). The invention is applicable to management of addiction to drugs of abuse such as stimulants (e.g., cocaine, amphetamines), hallucinogens (e.g., LSD, mescalin, psilocybin, ecstasy), opiates (e.g., morphine, heroin), sedative-hypnotics (e.g., benzodiazepines, barbiturates), marijuana and nicotine. The invention is further applicable to the management of other reward- mediated conditions not involving substance abuse, such as bulimia nervosa, binge eating, other eating disorders, gambling. Thus, according to a second aspect of the invention there is provided the use of tryptophan for the production of a medicament for the production and/or maintenance of abstinence from a reward-mediated behaviour, or reward-mediated behaviours.

Thus the method according to the second aspect of the invention is suitable for the production and/or maintenance of abstinence from one or more reward-mediated behaviour. In the case of multiple reward-mediated behaviours these may be manifested concurrently or consecutively.

Tryptophan supplementation in alcohol-dependent subjects might be predicted to be inappropriate due to such subjects' abnormal tryptophan metabolism (vide supra) and consequent high levels of potentially neurotoxic kynurenine metabolites. High levels of plasma tryptophan, such as may be achieved by dietary supplementation, are known to upregulate liver tryptophan pyroUase (vide supra) and might therefore be expected to produce even higher kynurenine metabolite levels in this patient group.

Thus, in contrast to the teaching of the prior art suggesting that dietary supplementation with tryptophan would be likely to cause deleterious side-effects in alcohol-dependent subjects, the inventors have surprisingly found that a robust nutritional approach to increasing such patients' plasma tryptophan/LNAA ratio stimulates significant affective responses. The inventors performed a study (detailed in Example 1) to characterise the effects of additional tryptophan supplementation on the plasma levels of tryptophan and its metabolites in alcohol-dependent subjects. Their findings were that total kynurenine metabolite levels were not increased, and that the tryptophan/kynurenines ratio in fact increased after supplementation. Such results were highly unexpected and suggested the unpredicted possibility that dietary tryptophan supplementation may be useful in this patient group.

Further studies (described more fully in Example 2) to characterise the metabolic response to supplemented tryptophan revealed that whilst total kynurenine metabolite levels were unchanged, the profile of kynurenines changed to a more neuroprotective balance. Together, these highly surprising observations indicate that tryptophan supplementation in alcohol dependent patients may both enable enhancement of central serotonergic function and reduce the neurotoxic character of peripheral tryptophan metabolism, resulting in improvement in cognitive and other neural functions and therefore aiding the process of withdrawal and easing the remission phase after withdrawal is complete.

Preferably the use according to the invention may be for formulating a medicament such that it provides between lg and 7g of tryptophan daily to a patient receiving the medicament, equivalent to 14-100mg/kg body weight per day. More preferably the use is for formulating a medicament such that it provides 3 to 5g of tryptophan per day to a patient, equivalent to 40 - 70mg/kg bodyweight.

Tryptophan for use in accordance with the invention may be in the form of the free amino acid, or a salt thereof. It will be appreciated that use of either free tryptophan or tryptophan salts allows preparation of a protein-free medicament which avoids provision of other LNAAs hi the medicament, and thereby increases the ratio of tryptophan : LNAAs available for uptake at the blood brain barrier.

The tryptophan (or salt thereof) may be the sole amino acid present in the medicament.

Alternatively a medicament, according to the first or second aspects of the invention, maybe one in which some or all of the tryptophan content is provided in the form of a high tryptophan-containing protein, rather than free tryptophan. A high tryptophan- containing protein may contain at least 5% tryptophan by weight, for example 5-10% tryptophan by weight, e.g. about 7%.

The medicament is effective without the need to incorporate an enkephalinase or endo hinase inhibitor, e.g. phenylalanine. Thus preferred medicaments in accordance with the invention are free of phenylalanine (or other endorphinase or enkephalinase inhibitor) and comprise free tryptophan (or a salt thereof), most preferably as the sole amino acid in the formulation. The use according to the invention may preferably be for formulating a medicament in which the tryptophan is provided in combination with a carbohydrate. Provision of tryptophan in combination with carbohydrate confers an advantage in that the carbohydrate will induce an insulin surge which will promote uptake of LNAA by the ^■ muscles for incorporation into muscle protein. As tryptophan is contained in human proteins at relatively low frequency compared to the other LNAAs this response will aid the elevation of the tryptophan/LNAA ratio and hence transport of tryptophan into the brain.

Advantageously the use according to the first or second aspects of the invention is to provide a medicament comprising up to 60% carbohydrate by weight.

The carbohydrate source may be a single sugar or a combination of sugars or maltodextrin. Preferably the carbohydrate source provides 30 - 80% of the energy provided by the medicament, more preferably 60% of the energy.

The carbohydrate source is preferentially combined with a fat source, which is required for the formulation of a palatable product with good mouth-feel and taste. Palatability may also be enhanced by the use of artificial sweetening agents and flavourings. Palatability may be further enhanced by the use of various processing aids, including emulsifiers. Artificial sweeteners are also contemplated.

According to a preferred embodiment the use may be for the production of a medicament which further comprises vitamins.

Preferred vitamins which may be included in a medicament include vitamin A, vitamin D, vitamin E, vitamin C, vitamin K, thiamin, riboflavin, niacin, vitamin B₆, folic acid, vitamin B_12ιbiotin, pantothenic acid, choline and inositol.

Preferably, the vitamins if present are provided at about the following amount per day for an adult (within +/- 30% of the value stated):

vitamin A 350.5μg or 1165.5 IU vitamin D 7.5μg or 300 IU vitamin E 15 mg or 22.4 IU vitamin C 80.4 mg vitamin K 35 μg thiamin l mg riboflavin 1.3 mg niacin 6.9 mg vitamin B₆ 0.7 - 2 mg folic acid 200 μg vitamin B₁₂ 1.5 μg biotin 50 μg pantothenic acid 5 mg choline 175 mg inositol 22.5 mg

According to a preferred embodiment the use may be for the production of a medicament which further comprises minerals.

Preferred minerals which may be included in a medicament include sodium, potassium, chloride, calcium, phosphorus and magnesium.

Preferably, the minerals, if present are provided at about the following concentration per lOOg of medicament (within +/- 20% of the value stated):

Sodium 240 mg

Potassium 500 mg

Chloride 490 mg

Calcium 400 mg

Phosphorus 400 mg

Magnesium 190 mg According to a preferred embodiment the use may be for the production of a medicament which further comprises trace elements.

Preferred trace elements which may include iron, copper, zinc, manganese, iodine, molybdenum, selenium and chromium.

Preferably, the trace elements, if present are provided at about the following concentration per lOOg of medicament (within +/- 30% of the value stated):

Iron 2.4 mg

Copper 0.6 mg

Zinc 7.3 mg

Manganese 1.25 mg

Iodine 68.4 μg

Molybdenum 99.8 μg

Selenium 60.4 μg

Chromium 25.1 μg

Persons subject to abnormal tryptophan metabolism, for example those withdrawing from addictive substances (such as alcoholic dependent subjects) or those suffering from reward-mediated conditions, are usually found to be deficient in vitamins, minerals and trace elements. Further, certain vitamins, minerals and trace elements are implicated in neurotransmitter functionality. The addition of vitamins, minerals and trace elements to a medicament produced according to the first or second aspects of the invention may therefore provide a synergistic rather than additive effect in relation to the efficacy of the nutritional supplement.

A medicament produced according to the first or second aspects of the invention may further comprise a fat source. The fat source preferably provides between 10% and 35% of the energy provided by the medicament.

Preferably a medicament produced according to the first or second aspects of the invention is a powder which may be reconstituted. However it is also contemplated that the medicament may be provided as a biscuit or bar or breakfast cereal or ready- to-take liquid.

The use according to the first or second aspects of the invention produces a medicament that provides a tryptophan source which increases tryptophan availability in the brain to produce serotonin with a concomitant improvement in the neuroprotective balance of kynurenine metabolites produced by the liver. Thus a medicament produced according to the first or second aspects of the invention maybe used to treat diseases and disorders where either central serotonin deficiency or upregulation of peripheral tryptophan metabolism is involved, with inducing potential secondary neurotoxic side effects through increased kynurenine metabolism.

For example, withdrawal from alcohol is known to be associated with depression and impaired cognitive function due to a surge in neurotoxic kynurenine metabolites during the early stages of detoxification. By providing tryptophan in a medicament produced according to the invention the inventors propose that the positive effects of tryptophan in the brain are maintained, to enhance serotonin production and therefore improve mood, providing neuroprotection, whilst the negative effects of kynurenine metabolism of impairing cognitive function and inducing memory loss are reduced.

The use according to the first aspect of the invention produces a medicament that is particularly suitable for use in aiding withdrawal from addictions, such as alcoholism, and subsequently maintaining abstinence. Thus, preferably, a medicament produced according to the first aspect of the invention may be used to both promote and maintain abstinence from an addictive substance, or addictive substances. However, it will be appreciated that such a medicament may suitably be used either to promote abstinence alone, or solely to maintain abstinence.

According to a third aspect of the invention there is provided a method of promoting and or maintaining abstinence from an addictive substance, or addictive substances, the method comprising administering to a person in need of such promotion and/or maintenance a medicament comprising tryptophan. The method of the third aspect of the invention may be used solely to promote withdrawal from an addictive substance, or addictive substances, or may be used solely to maintain abstinence from an addictive substance, or addictive substances, or may preferably be used first to promote withdrawal, and then the use continued to maintain abstinence.

The method of the third aspect of the invention is preferably effected using a medicament produced according to the first aspect of the invention.

According to a fourth aspect of the invention there is provided a method of promoting and/or maintaining abstinence from a reward-mediated behaviour, or reward-mediated behaviours, the method comprising administering to a person in need of such promotion and/or maintenance a medicament comprising tryptophan.

The method of the fourth aspect of the invention may be used solely to promote withdrawal from a reward-mediated behaviour, or reward-mediated behaviours, or may be used solely to maintain abstinence from a reward-mediated behaviour, or reward-mediated behaviours, or may preferably be used first to promote withdrawal, and then the use continued to maintain abstinence.

The method of the fourth aspect of the invention is preferably effected using a medicament produced according to the second aspect of the invention.

The present invention will be described, by way of example only, with reference to the following drawings, in which:

Figure 1 shows the two pathways of tryptophan metabolism;

Figure 2 is a bar graph illustrating the effect of Trp/carbohydrate vs. carbohydrate alone on serum levels of LNAAs; Figure 3 illustrates the effect of Trp/carbohydrate vs. carbohydrate alone on serum tryptophan/LNAA ratio;

Figure 4 illustrates the effect of Trp/carbohydrate vs. carbohydrate alone on serum tryptophan total kynurenine ratio; and

Figure 5 illustrates the ratio of kynurenate to total kynurenines and the ratio of kynurenate to 3-hydroxykynurenine + 3-hydroxyanthranilate after a tryptophan/carbohydrate-supplemented breakfast.

EXAMPLES:

The present investigators hypothesised that a robust nutritional approach to increasing the plasma tryptophan/LNAA ratio might stimulate more significant affective responses. With the abnormal tryptophan metabolism in this patient group in mind, we performed another study (Example 1) to characterise the effects of additional tryptophan supplementation on the plasma levels of tryptophan and its metabolites in alcohol-dependent subjects. The observations that total kynurenine metabolite levels were not increased and that the tryptophan/kynurenines ratio in fact increased after supplementation were highly unexpected and suggested the unpredicted possibility that tryptophan supplementation maybe useful in this patient group.

Further characterisation of the metabolic response to supplemented tryptophan (Example 2) revealed that whilst total kynurenine metabolite levels were unchanged, the profile of kynurenines changed to a more neuroprotective balance. Together, these highly surprising observations indicate that tryptophan supplementation in this patient group may both enable enhancement of central serotonergic function and reduce the neurotoxic character of peripheral tryptophan metabolism.

Example 1

Effect of Tryptophan supplementation on Total Kynurenine Metabolism

Twenty two subjects (mean age 45.56yr SD. 6.35) with DSM-IV criteria for alcohol dependency were used in a counterbalanced, randomised design. The subjects were given carbohydrate breakfast and carbohydrate breakfast enriched with a Trp Supplement on 3 separate days. Blood samples were taken before and 3 hours after breakfast and the procedures outlined in Martin & Bonner (2000) Alcohol & Alcoholism 35:49-51 were adopted.

Tryptophan Supplementation was provided by administering 6g of tryptophan powder in 200ml of orange juice, based on a body weight of 70kg (range 61 -89kg). To improve the palatability of the drink, the equivalent of 6g of sugar per 200ml orange juice was used.

The tryptophan supplementation caused a highly significant (p<0.001) increase in blood tryptophan levels (figure 2) and highly significant increase in the tryptophan/LNAA ratio (figure 3) compared to control. There was no significant impact on total kynurenine metabolism, but a highly significant elevation of the tryptophan/total kynurenines ratio (figure 4).

These results illustrated the unexpected idea that a dietary approach using tryptophan supplementation to manage tryptophan metabolism is safe in this patient group, in that no negative impact on total kynurenine metabolism was observed. The present investigators accordingly undertook another study to further characterise these intriguing findings by assaying more specifically the response of individual kynurenine metabolites to tryptophan supplementation.

Example 2

Effect of Tryptophan Supplementation on Specific Kynurenine Metabolites

9 subjects undergoing detoxification were supplemented with a low (50mg/kg) or high (lOOmg/kg) tryptophan dose in a nutritional formulation containing 65% carbohydrate and 30% fat. The procedure was repeated on each individual two days later with the alternative dose. Bloods were taken throughout each day of supplementation and assayed for LNAA and kynurenine pathway metabolite levels

Both the high and low doses resulted in significant raising of the tryptophan/LNAA ratio over several hours, extending and confirming the data collected in Example 1, and also confirmed that no increase in total kynurenine metabolite levels is stimulated. Kynurenine metabolite analysis further revealed a significant modulation of their profile, with a relative increase in the levels of the neuroprotective kynurenate compared to the neurotoxic 3-hydroxykynurenine and 3-hydroxykynurenine (Figure 5). These data collectively suggest the novel and unexpected scenario that tryptophan supplementation in this patient group may not only improve central serotonergic function, but may also improve the neuro-active character of peripheral tryptophan metabolism through the kynurenine pathway.

Example 3

A nutritional formulation which embodies the type of composition claimed.

Nutrition Information Per 1 OOg Powder

Ener y kJ 1790 kcal 421

Protein Equivalent g 5.1 Total Amino Acids g 5.25

Carbohydrate g 63

Fat g 16.5

% energy from carbohydrate 59% % energy from fat 35%

Amino Acid Profile Per 1 OOg Powder

L-Tryptophan g 5.25

Vitamins Per 1 OOg Powder

Vitamin A μg RE 615 IU 2048

Vitamin D μg 13.2 IU 528

Vitamin E mg α T.E. 26.3 IU 39.2 Vitamin C mg 141 Vitamin K μg 61.4 Thiamin mg 1.75 Riboflavin mg 2.3 Niacin mg 12.1 Niacin equivalent mg NE 99.6 Vitamin B₆ mg 1.2 Folic Acid μg 351 Vitamin B_J μg 2.6 Biotin μg 87.7

Pantothenic Acid mg 8.8 Choline mg 307 Inositol mg 39.5

Minerals Per 1 OOg Powder

Sodium mg All Potassium mg 880 Chloride mg 860 Calcium mg 702 Phosphorus mg 702 Magnesium mg 334

Trace Elements Per 1 OOg Powder

Iron mg A.l Copper mg 1.05 Zinc mg 12.8 Manganese mg 2.2 Iodine μg 120 Molybdenum μg 175

Selenium μg 106

Chromium μg 44

Claims

Claims:

1. The use of tryptophan for the production of a medicament for the promotion and/or maintenance of abstinence from an addictive substance, or addictive substances.

2. The use according to claim 1, wherein the addictive substance is alcohol.

3. The use of tryptophan for the production of a medicament for the promotion and/or maintenance of abstinence from reward-mediated behaviour, or reward- mediated behaviours.

4. The use according to any preceding claim, for providing between lg and 7g of tryptophan daily to a patient receiving the medicament.

5. The use according to claim 4, for providing between 3g and 5g of tryptophan daily to a patient receiving the medicament.

6. The use according to any preceding claim, wherein the tryptophan is provided in the form of the free amino acid.

7. The use according to any one of claims 1 to 5, wherein the tryptophan is provided in the form of a salt thereof.

8. The use according to claim 6 or claim 7, wherein the medicament is substantially protein-free.

9. The use according to any one of claims 6 to 8 wherein the tryptophan is the sole amino acid in the medicament.

10. The use according to any of claims 1 to 5, wherein tryptophan is provided in a high tryptophan-containing protein.

11. The use according to any preceding claim wherein the medicament does not contain an enkephalinase or endorphinase inhibitor.

12. The use according to any one of claims 1 to 10 wherein the medicament does not contain phenylalanine.

13. The use according to any preceding claim, wherein the medicament further comprises a carbohydrate.

14. The use according to claim 13, wherein the medicament comprises up to 60% carbohydrate by weight.

15. The use according to claim 13 or claim 14, wherein the carbohydrate is a single sugar or a combination of sugars.

16. The use according to any of claims 13 to 15, wherein the carbohydrate comprises dextrose, sucrose, maltose, maltotriose or higher saccharides

17. The use according to any of claims 13 to 16, wherein the carbohydrate provides more than 50% of the energy of the medicament.

18. The use according to claim 17, wherein the carbohydrate provides between 65- 70% of the energy of the medicament.

19. The use according to claim 18, wherein the carbohydrate is provided at a concentration of 70g per 1 OOg of the medicament.

20. The use according to any preceding claim, wherein tryptophan provides 4-5% of the energy of the medicament.

21. The use according to any preceding claim, wherein tryptophan is provided at a concentration of 5 - 6g per lOOg of the medicament.

22. The use according to any preceding claim, wherein the medicament further comprises vitamins.

23. The use according to claim 22 in which the vitamins are selected from vitamin A, vitamin D, vitamin E, vitamin C, vitamin K, thiamin, riboflavin, niacin, vitamin B₆, folic acid, vitamin Bi₂,biotin, pantothenic acid, choline and inositol.

24. The use according to any preceding claim, wherein the medicament further comprises minerals.

25. The use according to claim 24, wherein the minerals are selected from sodium, potassium, chloride, calcium, phosphorus and magnesium.

26. The use according to any preceding claim, wherein the medicament further comprises trace elements.

27. The use according to claim 26, wherein the trace elements are selected from iron, copper, zinc, manganese, iodine, molybdenum, selenium and chromium.

28. The use according to any preceding claim, wherein the medicament further comprises a fat source.

29. The use according to claim 28, wherein the fat source provides between 10 and 35% of the energy of the medicament.

30. The use according to claim 29, wherein the fat source provides about 30% of the energy of the medicament.

31. The use according to any preceding claim, wherein the medicament is in the form of a powder.

32. The use according to any preceding claim, wherein the medicament is milk protein free, gluten free and lactose free.

33. A method of promoting and/or maintaining abstinence from an addictive substance, or addictive substances, the method comprising administering to a person in need of such promotion and/or maintenance a medicament comprising tryptophan.

34. A method according to claim 33, wherein the addictive substance is alcohol.

35. A method of promoting and/or maintaining abstinence from reward-mediated behaviour, or reward-mediated behaviours, the method comprising administering to a person in need of such promotion and/or maintenance a medicament comprising tryptophan.

36. A method according to any one of claims 31 to 33, the method comprising administering a medicament produced according to any of claims 1 to 30.