Behavioral effects of dietary neurotransmitter precursors: Basic and clinical aspects

Neuroscience and Biobehaviorai Reviews, Vol. 20, No. 2, pp. 313-323.1996

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Behavioral Effects of Dietary Neurotransmitter Precursors: Basic and Clinical Aspects SIMON N. YOUNG Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec, Canada H3A IA1 YOUNG, S.N. Behavioural effects of dietary neurotransmitter precursors: Basic and clinical aspects. NEUROSCI BIOBEHAV REV 2@(2)31.3-323,19%.-The levels and possibly function of several neurotransmitters can be influenced by the supply of their dietary precursors. The neurotransmitters include serotonin, dopamine, noradrenaline, histamine, acetylcholine and glyciue, which are formed from tryptophan, tyrosine, histidine, choline and threonine. Tryptophan has been tested more than the other precursors in clinical trials and is currently available in some countries for the treatment of depression. Other uses for tryptophan and the therapeutic potential of other neurotransmitter precursors have not been tested adequately. IGiven the relative lack of toxicity of dietary components, further clinical trials with neurotransmitter precursors should be carried out. Copyright Q 1996 Elsevier Science Ltd. Tryptophan Serobonin Tyrosine Phenylalanine Catecholamines Acetylcholine Antidepressant Aggression Analgesia Stress

INTRODUCTION

Threonine

Glycine

Choline

Lecithin

However, for a limited number of neurotransmitters, dietary precursor levels can in some circumstances influence the rate of synthesis and function of the product neurotransmitters. Relevant compounds are the biogenic amines (serotonin, dopamine, noradrenaline and histamine) which are formed from the aromatic amino acids tryptophan, phenylalanine, tyrosine and histidine, and also acetylcholine which is formed from the dietary constituent choline. Glycine may also be influenced in some circumstances by the availability of threonine. Factors within the brain also control the synthesis and function of these neurotransmitters and indeed are probably more important than precursor effects. However, precursor effects are large enough to influence mood and behavior in some circumstances, and administration of purified dietary components is a simple and convenient way of altering neurotransmitter metabolism for experimental or therapeutic purposes in humans. The purpose of this paper is to review the data concerning the clinical use of dietary neurotransmitter precursors. Because an understanding of the biochemistry and physiology of the systems involved is important in interpreting the clinical data, this is reviewed briefly for each compound before discussing the clinical results. Final sections deal with the toxicity and possible side-effects of neurotransmitter precursors as

THIRTY-FIVE YEARS ago, Lauer et al. (75) published the results of a study in which L-tryptophan was given to seven schizophrenic patients who were also receiving the monoamine oxidase inhibitor iproniazid. They found that “the patients exhibited an increase in energy level and motor activity and improvement in the ability to accept interpersonal relationships, and displayed more affect.” The rationale they gave for the treatment was that “if the degradation of serotonin could be impeded by a monoamine oxidase inhibitor, and its synthesis simultaneously accelerated by giving .the precursor from which it is formed (tryptophan) effects might be obtained which were more pronouncedl.” At that time it was generally considered that the brain was metabolically isolated from the rest of the body by the blood-brain barrier. However, the success of the strategy employed by Lauer et al. led to the realization that the brain might be influenced by the availability of dietary neurotransmitter precursors. Subsequently, it was shown that tryptophan administration did in fact increase the synthesis of its product neurotransmitter 5-hydroxytryptamine (5HT, serotonin) in the brain in both rats (62) and humans (36). The synthesis of most neurotransmitters and putative neurotransmitters is controlled only within the brain. 313

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well as debating the possibility that diet-induced changes in brain precursor levels may have functional significance. TRYI’TOPHAN

Biochemical

and Physiological Aspects

Tryptophan hydroxylase, the rate-limiting enzyme on the pathway from tryptophan to serotonin, is normally about half-saturated with tryptophan. This means that administration of tryptophan can increase the rate of serotonin synthesis two-fold, but no more. This seems to be true in both rats (2540) and humans (142). The extent to which increases in brain serotonin levels will lead to increased serotonin release from neurons is debatable. Animals studies show that acute administration of tryptophan can decrease the firing rate of serotonin neurons (124). This might tend to diminish any augmentation of serotonin release due to increased levels. As serotonin, like any neurotransmitter, must be released from serotonin neurons and act on receptors on postsynaptic neurons before it can have functional significance, it is release of the neurotransmitter rather than its level in brain that is relevant to the clinical use of tryptophan. Direct experimental evidence on this point has been obtained recently using in vivo dialysis in rodent brain. The results suggest that tryptophan administration can augment serotonin release acutely under some circumstances (24,106,109, 133). Tryptophan has been given clinically in disorders where a low level of serotonin has been suggested to be of etiological significance. The lack of a therapeutic effect in any condition does not necessarily imply that serotonin is not involved in the etiopathology. It may be that in that particular circumstances tryptophan administration increases serotonin synthesis but fails to potentiate serotonin release appreciably. Animal studies indicate that the rate of firing of serotonin neurons can be influenced by the level of behavioral arousal (125). This had led to the hypothesis that tryptophan may be more likely to exert an effect in subjects at a high level of arousal (140). The available clinical data, discussed below, may point slightly in this direction, but more evidence is required before this hypothesis can be tested adequately. However, factors such as differences in the level of arousal of patients in different studies may help to explain the apparent discrepancies in results from the many studies on the clinical use of tryptophan. Different studies reach very different conclusions, especially concerning the antidepressant action of tryptophan. Thus, it may be misleading to ask whether tryptophan is, for example, an antidepressant. A more relevant question may be under what particular circumstances can tryptophan exhibit an antidepressant action? The Effect of Tryptophan on Sleep and Arousal

More than 40 studies on the action of tryptophan on sleep have been published and several reviews are

available on this topic (3157,140). The consensus seems to be that tryptophan can reduce the time taken to fall asleep in subjects with mild insomnia, but it is not an effective hypnotic in subjects with severe insomnia. Doses down to 1 g are effective and doses of 5 g or below decrease sleep latency by one-half without producing any alteration in sleep stages (56). The maximum effect on sleepiness is seen at 45 min after ,administration (58). Thus, 1 g taken 45 min before bedtime should be an effective treatment for mild insomnia. The hypnotic effect of tryptophan may be mediated by an increase in melatonin, which also has a mild hypnotic effect (53). Tryptophan as an Antidepressant

At least 30 studies have followed up on the original observation of Lauer et al. (75) that tryptophan can elevate mood, and several detailed reviews are available on this topic (5,44,127,140). Some of the earlier studies looked at the ability of tryptophan to potentiate the action of monoamine oxidase inhibitors in depressed patients (3,33,47,101). In these double-blind studies, tryptophan potentiated both the therapeutic effect and the side-effects of monoamine oxidase inhibitors. This drug combination may be useful in treatment-resistant patients, but not in other circumstances. Tryptophan has not been shown to potentiate the action of tricyclic antidepressants (141). Studies on the action of tryptophan when it is given without other antidepressant treatments have given variable results. Promising results have been obtained in open studies and in comparisons with tricyclic antidepressants. However, in the open studies, some or all of the improvement with tryptophan may have been due to a placebo effect. In studies comparing tryptophan with a standard antidepressant treatment, the number of patients per group was, in most studies, smaller than the number which would normally be necessary to show a significant difference between a standard antidepressant such as imipramine and placebo. Thus, the fact that most of these studies found no difference between a standard treatment and tryptophan does not necessarily mean that tryptophan was better than placebo. Most of the studies comparing tryptophan with placebo have been carried out on severely depressed inpatients and indicated that tryptophan has little or no therapeutic effect. However, the largest and longest study comparing tryptophan with placebo was carried out on mildly or moderately depressed outpatients. In this situation tryptophan was significantly better than placebo (122). Overall, these results suggest that tryptophan is an effective antidepressant in mildly or moderately depressed patients, but is not as effective as standard antidepressant treatments in severe depression. This is similar to the conclusion that tryptophan is an effective hypnotic in mild insomnia, but not in severe insomnia. Single double-blind studies showed that tryptophan was better than placebo in seasonal affective disorder (SAD) (89) but not in maternity blues (55).

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Tryptophan as an Antimanic Agent There are several reasons to test tryptophan as an antimanic agent. In experimental animals serotonin attenuates responses to a number of stimuli, while enhanced responsiveness to stimuli is a characteristic of manic patients. The results described in the section above on the effect of tryptophan on sleep and arousal indicate that tryptophan can have a mild sedative action, while low serotonin has been suggested as one factor involved in the etiology of mania (103). Small studies support the idea that tryptophan may be useful in acute mania. In one study tryptophan was slightly superior to a moderate dose of chlorpromazine (103) while in the other two tryptophan was better than placebo in some patients (29,%). One study found that tryptophan was no better than placebo, but this result might have been expe,cted as there were only five patients in each group (28). The preliminary indications that tryptophan may have a therapeutic effect in acute mania are worth Dollowing up in a large placebocontrolled trial. The Use of Tryptophan in Pathological Aggression A wealth of animal d:ata suggests that serotonin has an inhibitory effect on aggression, and the clinical data suggest that low brain serotonin is associated both with aggression directed towards others and the selfdirected aggression of suicide (2,82). Two studies have applied this information by testing the use of tryptophan in pathological agg,ression. In a preliminary study, the action of tryptophan or placebo was tested on 12 male aggressive schizophrenics at a hospital for mentally ill offenders. Tryptophan, relative to placebo, caused a significant reduction in incidents on the ward (93). In the other study, tryptophan did not decrease aggression but, relative to placebo, decreased the dose of neuroleptic needed to control aggressive patients (130). Further work is needed on the effect of tryptophan in pathological aggression. Also, given the relative safety of pure tryptophan, the effect of tryptophan on suicidal ideation or suicide should be studied. Tryptophan and Food Intake Animal studies suggest that serotonin is involved in the control of food intake, with high levels of serotonin either decreasing total calorie intake or selectively decreasing selection of carbohydrate relative to protein (15). The effect of tryptophan on food intake has been studied experimentally both in normal subjects and in patients. In a study on normal subjects, tryptophan in doses from 1 to 3 g, or placebo, was given 45 min before subjects were allowed to select from a buffet lunch. Whereas 1 g had no effect, both 2 g and 3 g reduced total calorie intake significantly (64). In a comparison of the effects of tryptophan (0.5 g) or placebo on various measures in a questionnaire, tryptophan had no effect on normal subjects’ rating of their hunger or carbohydrate/protein preference, even though they found tryptophan more sedating (78). Only one study found an effect of tryptophan on macronutrient selec-

tion in humans (63). Tryptophan at a dose of 1 g or placebo was given with a high protein or a high carbohydrate meal. Food intake was measured at a freeselection test meal 3 h later. Tryptophan did not influence total food intake. However, it caused a significant decrease in carbohydrate selection, but only when it was given with the high protein meal. In a study on bulimic patients and controls, the acute effects of tryptophan and the serotonin agonist mchlorophenylpiperazine (m-CPP) were tested against placebo (21). Three and a half hours after the treatments the subjects were allowed to eat from a standardized test meal. m-CPP, but not tryptophan, significantly decreased meal size in both the normal subjects and the bulimics. Tryptophan, given for several weeks, has been tested against placebo in two clinical studies to see whether it would decrease total calorie or carbohydrate intake of obese and/or carbohydrate-craving subjects (118,137). In neither of these studies was there any effect on the weight or food selection of the patients. In a single study, a mixture of rn-phenylalanine, L-glutamine and L-tryptophan, pyridoxal phosphate helped weight loss in carbohydrate-craving subjects (14). However, the open design and the mixture of compounds given make the results of this study difficult to interpret. Tryptophan and Pain Serotonin plays a role in inhibiting an animal’s response to diverse stimuli, among them pain (59,76). In humans, tryptophan has been tested both experimentally and clinically as an analgesic. In an experimental study, Seltzer et al. (108) gave tryptophan or placebo to 30 normal subjects and looked at the response to electrical stimulation of dental pulp. The threshold for perception of pain was not altered by tryptophan, but pain tolerance was significantly increased. Acute tryptophan also reduced pain sensitivity to a thermal stimulus in healthy men (81). However, 14 days of tryptophan treatment failed to alter radiant pain thresholds in groups of 20 female student volunteers (91). Several studies have investigated the efficacy of tryptophan in clinical pain. King (71) reported that tryptophan relieved the pain of patients in whom chronic pain had recurred after successful treatment by rhizotomy or cordotomy. While this study was uncontrolled, patients continued the treatment for periods up to 13 months, and patients with long-standing pain tend to withdraw from treatment if it is ineffective. In a controlled trial, Seltzer et al. (107) found tryptophan to decrease clinical pain in patients with chronic maxillofacial pain. Tryptophan has also been reported to reduce pain 24 h after endodontic surgery (110). While some of the clinical studies with tryptophan have revealed therapeutic effects, others have not. In patients with disk disease, no effect of tryptophan was found (117). Tryptophan was also ineffective when given at bedtime in patients with the fibrositis syndrome (92). In a recent study, tryptophan given preoperatively and postoperatively did not affect pain development or analgesic consumption after third

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molar surgery (38). Finally, in two studies on pain after abdominal surgery, intravenous tryptophan infusions failed to decrease pain or morphine requirements (27,42). The situation in which tryptophan has shown a therapeutic effect most frequently is chronic pain associated with deafferentation or neural damage. TYROSINE

Biochemical

and Physiological Aspects

Tyrosine is the precursor of the catecholamines, dopamine and noradrenaline. Under normal conditions in rat brain, tyrosine hydroxylase, the rate-limiting enzyme on the pathway from tyrosine to the catecholamines, is about 75% saturated with tyrosine (25). Thus, there is less scope for increasing catecholamine synthesis with precursor loading than for serotonin. Under normal circumstances tyrosine loading has little or no effect on catecholamine synthesis. However, if the firing rate of catecholaminergic neurons is increased, for example, by various types of drug treatment, then tyrosine can increase the synthesis of both dopamine and noradrenaline (90). This may be true in humans also. If the nigrostriatal dopamine pathway of a rat is partially lesioned, the remaining neurons fire at a faster rate. In patients with Parkinson’s disease who have degeneration of the nigrostriatal pathway, tyrosine increased accumulation of the dopamine metabolite homovanillic acid in the cerebrospinal fluid, indicating that it increased dopamine synthesis (51). In serotonin neurons, precursor loading usually increases serotonin synthesis, but may only sometimes increase serotonin release. In catecholaminergic neurons, precursor loading may only sometimes increase catecholamine synthesis. However, animal studies using dialysis indicate that precursor loading can, in some circumstances, increase brain extracellular catecholamine levels (126,133,136). The situation with respect to the clinical use of tyrosine is similar to that concerning tryptophan. Tyrosine loading will not necessarily affect all neuropsychology related to low catecholamine levels. Possible Clinical Uses of Tyrosine

Because of the theories suggesting that low catecholamine levels may be involved in the etiology of depression, the effect of tyrosine on mood has been studied. In normal subjects tyrosine did not influence mood (78,81), and in a clinical study tyrosine was no better than placebo in the treatment of depression (45). However, in case studies tyrosine was effective in alleviating depression (48), and in 10 depressed patients in a placebo-controlled study, tyrosine potentiated the antidepressant action of the serotonin precursor 5-hydroxytryptophan (128). Tyrosine was also found to be effective in the treatment of a particular class of depressed patients described by the authors as dopamine-dependent depression on the basis of polygraphic sleep recordings (94). These

preliminary results are interesting and suggest that further studies should be carried out. Catecholamines are involved in the control of blood pressure. Tyrosine can raise blood pressure in hypotensive animals and lower it in hypertensive animals (3290). The former effect has been attributed to an acceleration of catecholamine synthesis in sympathoadrenal cells and the latter to potentiation of CNS noradrenergic function. However, in humans tyrosine supplements failed to affect mild essential hypertension (113). In rats, acute stress increases brain noradrenaline turnover and decreases noradrenaline levels (19,80). This results in various behavioral deficits. Tyrosine supplementation in stressed rats reverses the decline in brain noradrenaline, overcomes motor deficits that occur after the stress, and can even increase survival in rats stressed by sepsis and acute hemorrhagic shock (19,80,112). In four studies of humans in stressful situations, tyrosine demonstrated some ability to overcome the effects of the stress. In male military personnel, a single dose of tyrosine significantly decreased symptoms, adverse moods and performance deficits after a 4.5-h exposure to cold and hypoxia (7) or after a sustained military operation (100). It also reversed cold-induced memory deficits (111) and improved performance on cognitive tasks in subjects exposed to a stressor consisting of a 90 dB noise (35). Finally, in a placebo-controlled study on narcoleptic patients, tyrosine produced significant improvement on scales for tiredness, drowsiness and alertness. However, this mild stimulant action was not considered clinically significant for the treatment of narcolepsy (39). L-PHENYLALANINE

In this paper, tryptophan, tyrosine and histidine refer exclusively to the natural L-isomers. However, both D and r_-phenylalanine have been investigated, and they will be discussed separately. L-Phenylalanine is the direct precursor of tyrosine and therefore is also a precursor of the catecholamines. Phenylalanine is converted to tyrosine in the liver, but this process can also occur in catecholamine neurons in the brain (139). One difference between phenylalanine and tyrosine is that phenylalanine can be decarboxylated to phenylethylamine. Phenylethylamine occurs in the brain in very small amounts and its role in brain function is uncertain. However, both in its structure, and in its behavioral effects when given to animals, it resembles amphetamine (139). It is not known whether phenylethylamine is produced in sufficient quantities to modify phenylalanine-mediated behavioral effects, but it is quite possible that the behavioral effects of tyrosine and phenylalanine might differ, even though they are both catecholamine precursors. L-Phenylalanine has been tested only as an antidepressant. In one study depressed patients were treated with a combination of the monoamine oxidase inhibitors deprenyl and phenylalanine. At least 80% of the 155 patients responded well (13). However, as the

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dose of phenylalanine used (250mg/day) was only about 10% of the normal daily dietary intake of phenylalanine, it is doubtful whether any of the therapeutic effect was due to phenylalanine. In a second open study, 31 of 40 depressed patients responded to doses of phenylalanine up to l4 g/day (104). However, before this result can be accepted, replication in a doubleblind placebo controlled trial will be necessary.

ble that the effect of phenylalanine was only a placebo effect. Placebo has a large effect in depressed patients and a large sample is necessary to show a significant difference between imipramine and placebo. However, the fact that only two of 11 patients responded to D-phenylalanine at a dose of 600 mg/day, even though eight of them subsequently responded to tricyclic antidepressants (&I), indicates that D-phenylalanine is not an effective antidepressant at these dosage levels.

Biochemical and Physiological Aspects

D-Phenylalanine in the Treatment of Pain

D-Phenylalanine does not occur naturally in any large amount in living organisms, and it is discussed here only because it has a close relationship to Lphenylalanine and may be converted to the L-isomer, and because phenylalanine is often given as the DL mixture. Nonetheless, D-phenylalanine is detectable in some foods, particularly those that are fermented (22). Metabolic studies of Dphenylalanine in humans show that after oral ingestion its level in the plasma rises more quickly than that of L-phenylalanine and falls more slowly. About one-third of a dose of D-phenylalanine is excreted in ,the urine (a negligible pathway for the L-isomer), while another third is converted to the L-isomer (79,123). Conversion probably occurs by oxidation of the D-amino acid to the ketoacid and subsequent reanimation of the ketoacid to L-phenylalanine (139). It has been claimed that D-phenylalanine is an efficient precursor of phenylethylamine in mouse brain (17). However, in this study the level of phenylethylamine in brain, which was measured by a gas-liquid chromatographic method, was considerably higher than that reported with a more specific mass spectrometric method (18). Thus, the substance of this report must remain in doubt. Another area of interest in relation to D-phenylalanine is its possible interaction with endogenous opiates. In vitro, D-phenylalanine can inhibit degradation of Met-enkephalin by carboxypeptidase A or which normally readily degrade aminopeptidase, enkephalin in vivo (37). Because of this, D-phenylalanine might be expected to potentiate the action of enkephalin.

Because of its action inhibiting the degradation of enkephalin, D-phenylalanine has been tested for its action on pain. In studies on rodents it has a definite analgesic effect at doses around 250 mg/kg (37). However, in primates no analgesic action could be seen even at a dose of 500 mg/kg, suggesting possible species differences (54). In human studies the doses given were very much smaller. An analgesic effect in a variety of different types of pain has been reported in open studies with doses up to 1 g/day (4,49,72). However, in a placebo-controlled cross-over study, D-phenylalanine (1 g/day) and placebo were each given to 30 subjects with chronic pain of varied etiology for 4 weeks of treatment. No therapeutic effect was seen (132). Obviously more weight should be given to the placebo-controlled study than to the open studies, and it remains for the proponents of Dphenylalanine to demonstrate its clinical efficacy as an analgesic, if it has, under any circumstances, analgesic properties.

D-Phenylalanine as an Antidepressant The antidepressant action of D-phenylalanine has been tested in three open studies and one controlled study. In an open study a good response was seen in 10 out of 11 depressed patients receiving 200 mg/day of D-phenylalanine (115). In a second open study 16 out of 20 patients receiving 200 mg/day of DL-phenylalanine responded well (11). As the dose of L-phenylalanine that these patients received was less than 5% of their daily dietary intake, the therapeutic effect, if any, must have been due to the D-isomer. In a doubleblind controlled study the same dose of DL-phenylalanine was found not to be significantly different from imipramine in its theralpeutic effect (10). However, the sample size was relatively small and it is quite possi-

D-Phenylalanine in the Treatment of Attention-Deficit Disorder Nineteen adults with attention-deficit disorder, residual type (adult hyperactivity), were given a 2-week double-blind cross-over trial of DL-phenylalanine (up to 1.2 g/day, which is equivalent to 600 mg D-phenylalanine/day) versus placebo (135). Phenylalanine caused significant improvement in the patients’ mood and mood lability and a strong trend towards significance on a measure of overall functioning. However, in an open trial at the end of the controlled trial all patients became tolerant to the therapeutic effect after 2-3 months. HISTIDINE Histamine metabolism can be altered more by changes in precursor availability than any other neurotransmitter (65,120). Histidine given to animals can have behavioral effects (66,102). However, it has not been tested in humans. Histaminergic neurons, like serotonergic neurons, project to all regions of the brain and can modulate a wide variety of brain functions. Histamine has been implicated in the control of arousal, brain energy metabolism, locomotor activity, release of hormones, feeding, drinking, sexual behavior and pain perception (99,131). Studies on the effects of histidine in humans would be of interest.

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Biochemical and Physiological Aspects Choline is the precursor of the neurotransmitter acetylcholine. Unlike tryptophan, tyrosine, phenylalanine and histidine, which are amino acids, choline is present in the diet in phosphatidylcholine, a constituent of fat. Phosphatidylcholine is also referred to in the scientific and medical communities as lecithin. However, it should be noted that to the food and chemical industries the word lecithin refers to a mixture of phosphatide compounds, only 15-20% of which may contain choline. In this article lecithin refers to phosphatidylcholme. Choline loading is capable of increasing brain acetylcholine synthesis (16,138) and, under some circumstances, acetylcholine release (6785). The effects of choline and lecithin are not necessarily mediated by changes in acetylcholine function, as choline is metabolized to a variety of other molecules that have imporsuch as sphingomyelin, platelettant functions, activating factor and plasmalogen. Lecithin catabolites may also modulate protein kinase C function (23). Both choline and lecithin have been used clinically. Lecithin is preferable for human use. Free choline, but not lecithin, can be acted on by bacteria in the intestine to form methylamine, which has, and gives to the patient, an unpleasant fishy odor. Choline and Tardive Dyskinesia Tardive dyskinesia is a neurological disorder characterized by uncontrollable movements of the lips, tongue, jaw, or more rarely the arms, legs and trunk. It is a side-effect of long-term neuroleptic use. Although the biochemical basis of tardive dyskinesia remains unclear, one theory suggests that it results from an imbalance between brain dopamine and acetylcholine (6). This has prompted trials of both tardive dyskinesia and lecithin in choline (8,20,34,43,50,68,119). Although the numbers of subjects in these trials were in general small, some of the trials were placebo controlled and all the studies gave positive results. Thus, present evidence indicates that choline or lecithin is useful in the treatment of tardive dyskinesia, but the magnitude of the effect is limited. Choline and Alzheimer’s Disease In Alzheimer’s disease there is degeneration of acetylcholine neurons in the brain, while animal experiments have shown that dietary choline supplementation can overcome some of the deficits that occur in rodents with aging (77). In addition, lecithin can in some circumstances increase memory in normal subjects (73). These results provide the rationale for testing acetyl choline precursors in Alxheimer’s disease. However, a review of 17 such studies indicates that results were almost invariably negative; when benefits were seen they were small (9). This may be due to the fact that choline has a limited action on

acetylcholine function and is failing to correct other neurotransmitter deficits. Alzheimer’s disease is not a simple acetylcholine deficiency disease, in the way that Parkinson’s disease is a disorder related to dopamine deficiency, and choline would not necessarily be expected to have a significant therapeutic effect on Alzheimer’s disease. Choline and Mania Pharmacological experiments indicate that potentiation of acetylcholine function causes a lowering of mood in humans (69). This has led to trials of cholinergic agonists in acute mania. Two small studies on the use of lecithin in acute mania (30,105) have produced encouraging results. This effect of lecithin should be tested in full-scale placebo-controlled trials. THREONINE

Glycine is a non-essential amino acid that is also a neurotransmitter. In the central nervous system glycine can be synthesized from glucose as well as from serine and threonine. In the rat, administration of threonine increases central nervous system glycine levels (83), but in one study threonine did not increase brain or spinal cord extracellular glycine levels (26). In the spinal cord glycine is an inhibitory neurotransmitter and threonine has been used in the treatment of spastic@. In one open study (52) and one placebocontrolled study (60), threonine caused a modest decline in the clinical signs of spasticity. TOXICITY AND SIDE-EFFECl-S OF NEUROTRANSMKI’ER PRECURSORS

Probably the most common side-effect for all the precursors is nausea. However, side-effects in general are well tolerated by patients. Toxic effects have not in general been reported, but this may reflect in part the lack of enquiry into this area. The precursor most studied for adverse reactions is tryptophan. Reviews of this topic (114,140) point to the importance of maintaining adequate protein intake when taking any amino acid supplement, and also makes recommendations concerning possible clinical conditions which might make tryptophan supplements hazardous. In general, neurotransmitter precursors should only be given with caution and side-effects should be carefully monitored. This applies especially to D-phenylalanine, which is not normally ingested in appreciable amounts and which has not been studied for possible toxic effects. Recently, tryptophan has been associated with a the eosinophilia-myalgia serious adverse effect, syndrome (EMS) (12,97,129). EMS was not caused by tryptophan itself but by a contaminant in some batches of tryptophan from a single manufacturer. In Canada tryptophan is sold as a prescription drug for the treatment of depression. The tryptophan used in this preparation was not obtained from the manufacturer referred to above, and no cases of EMS were associated with its ingestion (134). Tryptophan has remained

319 on the market in Canada, and was recently reintroduced in Britain, where it is also available as an antidepressant (74). NEUROTRANSMITTER PRECURSORS AND DIET.ARY INTAKE

If dietary neurotransmitter precursor levels can influence brain function then it is pertinent to ask whether dietary intake can also influence brain function. Dietary intakle can influence brain levels of aromatic amino acids and their neurotransmitter products in rat brain, but the changes are not always what would be expected (138). This is because all large neutral amino acids compete for a transport system that carries them into the brain. After ingestion of protein, plasma levels of tryptophan rise. However, tryptophan is the least abundant amino acid in protein, and plasma levels of the other amino acids increase even more. Thus, competition for entry into the brain increases and the levels of tryptophan and serotonin in the brain actually decline. However, carbohydrate causes a decline in the plasma level of the branched chain amino acids, leucine, isoleucine and valine. Therefore, there is less competition for the transport system and brain trypl.ophan and serotonin increase. This explains why protein foods, which contain tryptophan, lower brain tryptophan and serotonin, while carbohydrate, which contains no tryptophan, raises them. In a balanced m,eal containing normal amounts of both carbohydrate and protein the neurochemical effect of the protein will predominate. While these effects have been well documented in rats it is tmcertain whether they occur to any extent in humans. The effects of carbohydrate and protein meals on human cerebrospinal fluid (CSF) levels of the amino acids tryptophan and tyrosine and the biogenic amine metabolite levels has been studied in patients, average age 71 years, who were suffering from normal pressure hydrocephalus (121). As part of testing to determine whether a ventricular shunt would be therapeutic, the patients had three lumbar punctures in the space of a week. For the research study they were asked to ingest either water, a carbohydrate breakfast (100 g carbohydrate), or a protein breakfast (45 g protein) 2.5 h before the lumbar puncture. Relative to the control water meal the carbolhydrate meal failed to have a significant effect on CSF levels of tryptophan or on the serotonin metabolite 5hydroxyindoleacetic acid (SHIAA) (a rough index of CNS serotonin turnover). The protein meal also did not affect CSF levels of tryptophan or SHIAA, but did cause a significant rise in CSF tyrosine, but not in CSF levels of the dopamine metabolite homovanihic acid or the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol. The increase in CSF tyrosine after a protein meal is consistent with animal data, as the increase in brain tyrosine when a rat ingests a protein meal is greater than any change in brain tryptophan after meals (46). Overall, the data suggest that protein and carbohydrate meals can affect brain serotonin in the rat. However, rats ingest a much higher percentage of their body weight in food every day than do humans. As a

result, changes in the human plasma tryptophan ratio are in general smaller in humans than in rats, and meals probably do not affect human brain serotonin under most circumstances. The study of the acute behavioral effects of food is still in its infancy and it is too early to attribute foodmediated alterations in behavior to specific neurotransmitter changes. However, there is one situation where an effect of food is consistent with the neurotransmitter changes known to occur in the rat. A carbohydrate meal at lunch-time causes drowsiness relative to a protein meal, especially in older people (116). Tryptophan is known to cause drowsiness (see section above on the effect of tryptophan on sleep and arousal), and therefore this effect has been attributed to an increase in brain tryptophan and serotonin. However, in a recent study the effect of a carbohydrate meal was compared with that of a balanced (proteincontaining) meal and ingestion of water alone in newborn infants (98). While both calorie-containing feedings increased sleep equally relative to the water control, sleep was increased more by the balanced meal than by the carbohydrate meal. Thus, while protein and carbohydrate meals can influence brain serotonin levels in the rat, and protein and carbohydrate meals definitely can influence CNS function in humans, there is no direct evidence that the behavioral effects of food in humans are mediated by altered brain tryptophan and serotonin levels. Evidence for dietary effects on tyrosine and the catecholamines is also lacking. Less is known about the dietary intake of choline than of amino acids. However, the decline in fat intake that has occurred in the North American population because of concern about cholesterol (41) has probably also decreased choline intake (23). This is because foods high in cholesterol, such as beef, liver and eggs, are also high in choline. The implications of lowered choline intake are not known. While lowered cholesterol levels may be related to increased impulsivity, as indicated by increased mortality from accidents and suicide (95) this relationship, if real, may be due to a direct effect of cholesterol on serotonin (70) rather than an indirect effect related to choline intake. The study of the acute effects of dietary intake on neurotransmitter metabolism and behavior in humans is in an early stage of development, but almost nothing is known about the implications of long-term differences in the dietary intakes of neurotransmitter precursors. Very few studies have attempted to tackle this problem. In one, the cross-national relationship between corn consumption and homicide rates was attributed to the low tryptophan content of corn, and thus low serotonin levels in the populations ingesting the corn (86). However, the proposed mechanism, while amusing, cannot be taken seriously given the multitude of possible confounding factors. Indeed, any attempts to relate human mood or behavior to chronic ingestion of specific dietary components will be difficult. Diet could influence brain function through a variety of mechanisms other than alterations in neurotransmitter precursor availability. For example, rats ingesting different fats (other than cholesterol) behave

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differently, possibly because of alterations in the lipid content of neuronal membranes (87,88). Indeed, rats ingesting different nutritionally adequate diets were found to differ in a number of measures related to brain biogenic amine metabolism (60) although the reason for this is not known. The study of how chronic intake of different diets, within the nutritionally adequate range, affects brain function in humans is likely to progress very slowly. The only satisfactory methodology would be to put different groups of subjects on diets differing in only one main component. It is doubtful whether compliance could be maintained in studies of this type if they looked at chronic dietary intake, and the monetary cost of such studies would be great. CONCLUSIONS

While it would be difficult to study how chronic dietary intake influences behavior, the study of the behavioral effects of isolated neurotransmitter precursors is entirely practical and has been going on for 30 years now. The use of purified dietary components is pharmacological rather than nutritional, but dietary components have advantages over some compounds that are unambiguously drugs in that they can be relatively specific in their biochemical effects, and are usually relatively free of important toxic effects and side-effects. However, in spite of several decades of work, hard conclusions concerning the clinical indications for the precursors are sparse. This is mainly because of the paucity of large placebo-controlled studies. Nonetheless, interesting results have been obtained, some indications are well established, and valuable leads are available for further research. For tryptophan, further studies are needed to test whether it is therapeutically useful in mania and pathological aggression. In view of the indications that tryptophan can improve both depressed mood and aggression, and is also relatively non-toxic, an obvious, although difficult, study would be to look at the effect of tryptophan on suicidal ideation or acts. Studies on the effect of tryptophan in pain suggest that it is effective in chronic

pain associated with deafferentiation or neural damage. In rats tryptophan decreased autotomy induced by nerve lesions (l), suggesting that it might be effective in the treatment of phantom limb pain. As there is no accepted treatment for phantom limb pain, a study of the therapeutic effects of tryptophan in this condition would be worthwhile. Most of the studies of tyrosine as an agent counteracting the effects of stress have been sponsored by the military. It would be interesting to know whether tyrosine can counteract the cognitive or mood deficits that are associated with stresses that are less esoteric than hypoxia or cold stress. Phenylalanine is the precursor of tyrosine, and a comparison of the effects of phenylalanine and tyrosine on stress-related deficits, as far as effects and side-effects are concerned, would be an informative if somewhat mundane study. The suggestion that choline or lecithin may be useful in the treatment of mania needs following up given the lack of toxicity of lecithin, and the side-effects seen with lithium and neuroleptics, the main drugs used in the treatment of mania. While lecithin is unlikely to be useful by itself, it may be a worthwhile adjunct for the treatment of mania that will lower the requirement for more toxic drugs. The need for future research on the therapeutic effects of tryptophan, tyrosine and phenylalanine are clear. The possibilities concerning threonine and histidine are more open, because of the lack of clinical studies to date with these compounds. However, progress in research on the clinical effects of neurotransmitter precursors is likely to be slow. The therapeutic effect of neurotransmitter precursors is no longer a fashionable topic in academic settings, while the interest of drug companies in dietary components is usually limited by the lack of commercial possibilities. ACKNOWLEDGEMENT

Work in the author’s laboratory is supported Medical Research Council of Canada.

by the

REFERENCES 1. 2.

3. 4.

5. 6.

Abbott, F. V.; Young, S. N. The effect of tryptophan supplementation on autotomy induced by nerve lesions in rats. Pharmacol. Biochem. Behav. 40~301-304; 1991. .&.&erg, M.; Schalling, D.; Traskman-Ben&, L.; Wagner, A. P sychobiology of suicide, impulsivity, and related phenomena. In: Meltzer, H. Y., ed. Psychopharmacology: The third generation of progress. New York: Raven Press; 19m655-668. Ayuso Gutierrez, J. L.; Lopez&or Alino, J. J. Tryptophan and an MAO1 (nialamide) in the treatment of depression. Int. Pharmacopsychiitry 6:92-97,197l. Balagot, R. C.; Ehrenpreis, S.; Greenberg, J.; Hyodo, M. DPhenylalanine in human chronic pain. In: Ehrenpreis, S.; Sicuteri, F., eds. Degradation of endogenous opioids: Its relevance in human pathology and therapy. New York: Raven Press; 1983:207-215. Baldessarini, R. J. Treatment of depression by altering monoamine metabolism: precursors and metabolic inhibitors. Psychopharmacol. Bull. 20&!4-239; 1984. Baldessarhri, R. J.; Tarsy, D. Dopamine and the pathophysiology of dyskinesias induced by antipsychotic drugs. Annu. Rev. Neurosci. 323-41; 1980.

7.

8. 9. 10. 11. 12.

13.

Banderet, L. E.; Lieberman, H. R. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Brain Res. Bull. 22~759-762; 1989. Barbeau, A. Emerging treatments: replacements therapy with choline or lecithin in neurological d&eases Can. J. Neural. Sci. 5:157-16031978. Bartus, R. T.; Dean, R. L.; Beer, B.; Lippa, A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 217408-414; 1982. Beckmamt. H.; Athen, D.; Olteanu, M.; Zimmer, R. DLPhenylalanine versus imipramine: A double-blind controlled study. Arch. Psychiat. Nerve&r. 227~49-58; 1979. Beckmann, H.; Strauss, M. A.; Ludolph, E. Lx.-Pheny&nine in depressed patients: An open study. J. Neural Transm. 41:123-1x, 1977. Belongia, E. A.; Hedberg, C. W.; Gleich, G. J.; White, K. E.; Maveno. A. N.: Loetterinz. D. A.: Dunnette. S. L.: Pirie. P. L.: MacDonald, K: L.; &e.&oim. M. T. An investigation ‘of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N. Engl. J. Med. 323:357-365; 1990. Birkmayer, W.; Riederer, P.; Linauer, W.; Knoll, J. L-Deprenyl

DlETARY

14.

15. 16. 17.

18.

19.

20.

21.

22.

23. 24.

25.

26.

27.

28. 29.

30.

31.

32.

33.

34. 35.

36.

37.

NEUROTRANSMI’ITER

321

PREXXJRSORS

plus L-phenylalanine in the treatment of depression. J. Neural Transm. 5981-87; 1984. Bhun, K.; Trachtenberg, M. C.; Cook, D. W. Neuronutrient effects on weight loss in carbohydrate bingers: An open clinical trial. Curr. Ther. Res. 48:217-233; 1990. Blundell, J. E. Serotonin and appetite. Neuropharmacology 23:1537-1551; 1984. Blusxtajn, J. K.; Wurtman, R. J. Choline and cholinergic neurons. Science 221:61462Q 1983. Borison, R. L.; Maple, IP. J.; Havdala, H. S.; Diamond, B. I. Metabolism of an amino acid with antidepressant properties. Res. Commun. Chem. Pathol. Pharmacol. 21:363-366; 1987. Boulton, A. A. Trace amines in the central nervous system. In: Tipton, K. F., ed. International review of biochemistry: Physiological and pharmacological biochemistry. Baltimore: University Park Press; 1979:179-206. Brady, K.; Brown, J. W.; Thurmond, J. B. Behavioral and neurochemical effects of dietary tyrosine in young and aged mice following cold-swim stress. Pharmacol. B&hem. Behav. 12667-674; 1980. Branchey, M. H.; Branchey, L. B.; Bark, N. M.; Richardson, M. A. Lecithin in the treatment of tardive dyskinesia. Commun. Psychopharmacol. 3:303-307; 1979. Brewerton, T. D.; Murphy, D. L.; Jimerson, D. C. Testmeal responses following m-chlorophenylpiperaxine and L-tryptophan in bulimics and controls.:. Neuropsychopharmacology 11:63-71; 1994. Bruckner, H.; Hausch, M. Detection of free D-amino acids in food by chiral phase capillary gas chromatography. J. High Res. Chromatogr. 12:680-684:, 1989. Canty, D. J.; Zeisel, S. H. Lecithin and choline in human health and disease. Nutr. Rev. .52:327-339; 1994. Carboni, E.; Cadoni, C.; Tanda, G. L.; Di Chiara, G. Calclumtetrodotoxin-sensitive stimulation of cortical dependent, serotonin release after a tryptophan load. J. Neurochem. 53976-978; 1989. Carlsson, A.; Lindqvust, M. Dependence of 5HT and catecholamine synthesis on concentrations of precursor amino acids in rat brain. Naunyn Schmiedebergs Arch. Pharmacol. 303:157-164,1978. Castagne, V.; Finot, P. ,4.; Maire, J. C. Effects of diet-induced hvperthreoninemia. (II) Tissue and extracellular amino acid levels in the brain. Liie’Sci. 5441-48, 1993. Ceccherelli. F.: Diani. M. M.: Altafini. L.: Varotto. E.: Stefecius. A.; C&ale; R:; Costola, A.: Giron, ‘G.‘P. Postoperative pain treated by intravenous L-tryptophan: A double-blind study versus placebo in cholecystectomixed patients. Pain 47:163-172; 1991. Chambers, C. A.; Naylor, G. J. A controlled trial of L-tryptophan in mania. Br. J. Ps,ychiatry 132: 555-559; 1978. Chouinard, G.; Young, S. N.; Annable, L. A controlled clinical trial of L-tryptophan in acute mania. Biol. Psychiatry 20:546-557; 1984. Cohen, B. M.; Lipinski, J. F.; Altesman, R. I. Lecithin in the treatment of mama: double-blind, placebo-controlled trials. Am. J. Psychiatry 139:1162-1164,1982. Cole, J. 0.; Hartmann, E.; Brigham, P. L-Tryptophan: clinical studies. In: Cole, J. O., ed. Psychopharmacology update. Lexington, MA: Collamore Press; 1980:119-148. Conlay, L. A.; Maher, T. J.; Moses, P. L.; Wurtman, R. J. Tyrosine’s vasoactive effect in the dog shock model depends on the animal’s starting blood pressure. J. Neural Transm. 586974; 1983. Coppen, A.; Shaw, D. M.; Farrell, J. P. Potentiation of the antidepressive effect of a monoamine-oxidase inhibitor by tryptophan. Lancet iz79-81; 1963. Davis, K. L.; Berger, P. A.; Hohister, L. E. Choline for tardive dyskinesia. N. Engl. J. Med. 293:152; 1975. Deijen, J. B.; Orlebeke, J. F. Effect of tyrosine on cognitive function and blood oressure under stress. Brain Res. Bull. 33319-323; 1994. Eccleston. D.: Ashcroft. G. W.: Crawford. T. B. B.: Stanton. J. B.; Wood; D.: McTurk.’ P. H. Effect of tryptophan’administration on SHIAA in osrebrospinal fluid in man. J. Neurol. Neurosurg. Psychiatry 33:269-272; 1970. Ehrenpreis, S.; Balagot, R. C.; Greenberg, J.; Myles, S.; Ellyin, F. Analgesic and other pharmacological properties of D-pheny-

38.

39.

40.

41.

42.

43. 44.

45.

46.

47. 48. 49.

50.

51.

52.

53.

54.

55. 56. 57.

58. 59.

h&mine. In: Ehrenpreis, S.; Sicuteri, F., eds. Degradation of endogenous opioidsz Its relevance in human pathology and therapy. New York: Raven Press; 1983:171-187. Ekblom, A.; Hansson, P.; Thornsson, M. L-Tryptophan supplementation does not affect postoperative pain intensity or consumption of analgesics. Pain 44%~254; 1991. Elwes, R. D. C.; Chesterman, L. P.; Jenner, P.; Crewes, H.; Summers, B.; Binnie, C. D.; Parkes, J. D. Treatment of narcolepsy with L-tyrosine: Double-blind placebo-controlled trial. Lancet ii:1067-1069; 1989. Femstrom, J. D.; Wurtman, R. J. Brain serotonin content: Physiological dependence on plasma tryptophan levels. Science 173:149-152; 1971. Frank, J.; Winkleby, M. A.; Fortmann, S. P.; Rockhill, B.; Farquhar, J. W. Improved cholesterol-related knowledge and behavior and plasma cholesterol levels in adults during the 1980s. J. Am. Med. Assoc. 26815661572; 1992. Franklin, K. B. J.; Abbott, F. V.; English, M. J. M.; Jeans, M. E.; Tasker. R. A. R.: Youne. S. N. Trvotoohan-morohine interactions and postoperativg pain. Pd&col. Biochem. Behav. 35:157-163; 1990. Gelenberg, A. J.; Doller-Wojcik, J. C.; Growdon, J. H. Choline and lecithin in the treatment of tardive dyskinesia: preliminary results from a pilot study. Am. J. Psychiatry 136772-776; 1979. Gelenberg, A. J.; Gibson, C. J.; Wojcik, J. D. Neurotransmitter precursors for the treatment of depression. Psychopharmacol. Bull. 18:7-l& 1982. Gelenberg, A. J.; Wojcik, J. D.; Falk, W. E.; Baldessaxini, R. J.; Zeisel, S.-H.; Schoenfeld, D.; Mok, G. S. Tyrosine for depression: A double-blind studv., J. Affective Disord. 19:125-132: 1990. Glaeser, B. S.; Maher, T. J.; Wurtman, R. J. Changes in brain levels of acidic, basic, and neutral amino acids after consumption of single meals containing various proportions of proteins. J. Neurochem. 41:10161021; 1983. Glassman, A. H.; Platman, S. R. Potentiation of a monoamine oxidase inhibitor by tryptophan. J. Psychiat. Res. 7:83-88, 1969. Goldberg, I. K. r_-Tyrosine in depression. Lancet ii:364-365; 1980. Goodfraind, J. M.; Plaghki, L.; De Nayer, J. A comparative study on the effects of o-phenylalanine, lysoxyme and ximelidine in human lubosacral arachno-epiduritis, a chronic pain state. In: Bromm, B., ed. Pain measurement in man: Neurophysiological correlates of pain. New York Elsevier; 1984:501-511. Growdon, J. H.; Hirsch, M. J.; Wurtman, R. J.; Weiner, W. Oral choline administration to patients with tardive dyskinesia. N. Engl. J. Med. 2w524-527; 1977. Growdon, J. H.; Melamed, E.; Logue, M.; Hefti, F.; Wurtman, R. J. Effect of oral L-tyrosine administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson’s disease. Life Sci. 303827-832; 1982. Growdon, J. H.; Nader, T. M.; Schoenfeld, J.; Wurtman, R. J. LThreonine in the treatment of spasticity. Clin. Neuropharmacol. 14403412; 1991. Hajak, G.; Huether, G.; Blanke, J.; Blomer, M.; Freyer, C.; Poeggeler, B.; Reimer, A.; Rodenbeck, A.; Schulzvarszegi, M.; Ruther, E. The influence of intravenous r_.-tryptophan on plasma melatonin and sleep in men. Pharmacopsychiatry X17-20; 1991. Halpem, L. M.; Dong, W. K. D-Phenylalanine: A putative enkephalinase inhibitor studied in a primate acute pain model. Pain 24:223-220; 1986. Harris, B. Prospective trial of L-tryptophan in maternity blues. Br. J. Psychiatry 137:223-235. 1980. Hartmann, E.; Cravens, J.; List, S. Hypnotic effects of L-tryptophan. Arch. Gen. Psychiatry 31:394-397; 1974. Hartmann, E.; Greenwald, D. Tryptophan and human sleep: An analysis of 43 studies. In: Schlossberger, H. G.; Kochen, W.; Linxen, B.; Steinhart, H., eds. Progress in tryptophan and serotonin research. Berlin: Walter de Gruyter; 1984297-304. Hartmann, E.; Spinweber, C. L.; Ware, C. L-Tryptophan, Lleucine, and placebo: Effects on subjective alertness. Sleep Res. 5:57; 1976. Harvey, J. A.; Simansky, K. J. The role of serotonin in modulation of nociceptive reflexes. In: Gabay, S.; Issirorides, M. R.; Alivisatos, S. G. A., eds. Serotonin: Current aspects of neurochemistry and function, vol. 133, Advances in experimental medicine and biology. New York: Plenum Press; 1981:125-151.

322 60. Hauser, S. L.; Doolittle, T. H.; Lopez-Bresnahan, M.; Shahani, B.: Schoenfeld. D.: Shih. V. E.: Growdon. J. H.: Lehrich. J. R. An antispastichy effect of thrednine in multiple sclerosis.‘Arch. Neural. 49923-926; 1992. 61. Heroux, 0.; Roberge, A. G. Different influences of two types of diets commonly used for rats on a series of parameters related to the metabolism of central serotonin and noradrenahne. Can. J. Physiol. Pharmacol. 59108-112; 1980. 62. Hess, S. M.; Doepfner, W. Behavioral effects and brain amine content in rats. Arch. Int. Pharmacodyn. Ther. 13489-99; 1961. 63. Hill, A. J.; Blundeil, J. E. Role of amino acids in appetite control in man. In: Huether, G., ed. Amino acid availability and brain function in health and disease: NATO AS1 Series H, CelI biology, vol. 20. Berlin Springer; 1988:239-248. 64. Hrboticky, N.; Leiter, L. A.; Anderson, G. H. Effects of Ltryptophan on short term food intake in lean men. Nutr. Res. 5:595-607; 1985. 65. Imura, K.; Kamata, S.; Hata, A.; Okada, A.; Watanabe, T.; Wada, H. Effects of dietary histidine and methionine loading in rats with a portacaval shunt. Pharmacol. B&hem. Behav. 241323-1328; 1986. 66. Itoh, Y.; Oishi, R.; Nishibori, M.; Saeki, K.; Furuno, K.; Fukuda, T.; Araki, Y. Lack of evidence for the involvement of catecholaminergic mechanisms in the behavioral anti-methamphetamine effect of L-histidine in the mouse. Pharmacol. Biochem. Behav. 24571-574; 1986. 67. Jackson, D. A.; Kischka, U.; Wurtman, R. J. Choline enhances scopolamine-induced acetylcholine release in dorsal hippocampus of conscious, freely-moving rats. Life Sci. 5645-49; 1994. 68. Jackson, I. V.; Nutah, E. A.; Ibe., I. 0.; Perez-Cruet, J. Treatment of tardive dyskinesia with lecithin. Am. J. Psychiatry 136:14581460; 1979. 69. Janowsky, D. S.; Risch, S. C. Cholinometic and antichohnergic drugs used to investigate an acetylchohne hypothesis of affective disorders and stress. Drug Devel. Res. 4125-142; 1984. 70. Kaplan, J. R.; Shively, C. A.; Fontenot, M. B.; Morgan, T. M.; Howell, S. M.; Manuck, S. B.; Muldoon, M. F.; Mann, J. J. Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys. Psychosom. Med. 563479-484; 1994. 71. King, R. B. Pain and tryptophan. J. Neurosurg. 53:652; 1980. 72. Kitade, T.; Minamikawa, M.; Nawata, T.; Shinohara, S.; Hyodo, M.; Hosoya, E. An experimental study on the enhancing effects of phenylalanine on acupuncture analgesia. Am. J. CIin. Med. 9:243-248,1981. 73. Ladd, S. L.; Sommer, S. A.; Laberge, S.; Toscano, W. Effect of phosphatidylcholine on explicit memory. Clin. Neuropharmacol. 16540-549; 1993. L-tryptophan. Hum. M. The return of 74. Lader, Psychopharmacology 9:365-366,1994. 75. Lauer, J. W.; Inskip, W. M.; Bemsohn, J.; Zeher, E. A. Observations on schizophrenic patients after iproniazid and trvotoohan. A. M. A. Arch. Neurol. Psvchiatr. 80:122-130: 1958. 76. LeIBah, D. Serotonin and pain. In: Osborne, N. N.; Ham&, M., eds. Neuronal serotonin. New York: Wiley; 1988:171-229. 77. Leathwood, P. D. Neurotransmitter precursors: From animal experiments to human applications. Nutr. Rev. 44:193-204, 1986. 78. Leathwood, P. D.; Pollet, P. Diet-induced mood changes in normal populations. J. Psychiat. Res. 17:147-154; 1983. 79. Lehmann, W. D.; Theobald, N.; Fischer, R.; Heinrich, H. C. Stereospecificity of phenylakmine plasma kinetics and hydroxylation in man following oral application of a stable isotope-labelled pseudo-racemic mixture of L- and o-phenvlala_ nine.-Chn. Chim: Acta 128181-198; 1983. 80. Lehnert. H.: Reinstein. D. K.: Strowbridee. B. W.: Wmtman. R. J. Neurdchemical and ‘behavioral conseq&rces of acute m&ntrollable stress: Effects of dietary tyrosine. Brain Res. 303:215-223; 1984. 81. Lieberman, H. R.; Corkin, S.; Spring, B. J.; Growdon, J. H.; Wurtman, R. J. Mood, performance, and pain sensitivity: Changes induced by food constituents. J. Psychiat. Res. 17135-145; 1983. 82. Innoila, M.; Virkkunen, M. Biologic correlates of suicidal risk and aggressive behavioral traits. J. Clin. Psychopharmacol. 12:s19-!320; 1992. 83. Maher, T. J.; Wurtman, R. J. L-Threonine administration

YOUNG

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97. 98.

99.

100.

101. 102. 103. 104.

105. 106.

increases glycine concentrations in the rat central nervous system. Life Sci. 261283-1286, 1980. Mann, J. J.; Peselow, E. D.; Snyderman, S.; Gershon, S. DPhenylalanine in endogenous depression. Am. J. Psychiatry 137:1611-1612; 1980. Marsha& D. L.; Wurtman, R. J. Effect of choline on basal and stimulated acetylchohne release. An in vivo microdialysis study using a low neostigmine concentration. Brain Res. 629269-274; 1993. Mawson, A. R.; Jacobs, K. W. Corn consumption, tryptophan, and cross-national homicide rates. J. Orthomolec. Psychiatry 7~227-230; 1978. McGee, C. D.; Greenwood, C. E. Effects of dietary fatty acid composition on macronutrient selection and synaptosomal fatty acid composition in rats. J. Nutr. 1191561-1568, 1989. McGee, C. D.; Greenwood, C. E.; Cinader, B. Dietary fat composition and age affect synaptosomal and retinal phospholipid fatty acid composition in C57BU6 mice. Lipids 29605-619; 1994. McGrath, R. E.; Buckwald, B.; Resnick, E. V. The effect of Ltryptophan on seasonal affective disorder. J. Chn. Psychiatry 51:162-163; 1990. Milner, J. D.; Wurtman, R. J. Catecholamine synthesis: physiological coupling to precursor supply. Biochem. Pharmawl. 35:875881; 1986. Mitchell, M. J.; Daines, G. E.; Thomas, B. Effect of L-tryptophan and phenylalanine on burning pain threshold. Physical Ther. 67:20>205; 1987. Moldofsky, H.; Lue, F. A. The relationship of alpha and delta EEG frequencies to pain and mood in ‘fibrositis’ patients treated with chlorpromazine and L-tryptophan. EEG Clin. Neurophysiol. 50:71-80; 1980. Morand, C.; Young, S. N.; Ervin, F. R. Chnical response of aggressive schizophrenics to oral tryptophan. Biol. Psychiatry 18575-578: 1983. Mouret, 5.1 Lemoine, P.; Minuit, M. P.; Robehn, N. La Ltyrosine guerit, immediatement et a Ion terme, les depressions dopamino-dependantes (DDD). B tude chnique et polygraphique. C. R. Acad. Sci. 306:93-98; 1988. Muldoon, M. F.; Manuck, S. B.; Mathews, K. M. Lowering cholesterol concentration and mortality: A quantitative review of primary prevention trials. Br. Med. J. 3013309-314; 1990. Murphy, D. L.; Baker, M.; Goodwin, F. K.; Miller, H.; Kotin, J.; Bunney, W. E. L-Tryptophan in affective disorders: Indoleamine changes and differential clinical effects. Psychopharmawlogia 34:11-20; 1974. Nightingale, S. L. Update on EMS and L-tryptophan. J. Am. Med. Assoc. 268:1828; 1992. Oberlander, T. F.; Barr, R. G.; Young, S. N.; Brian, J. A. Shortterm effects of feed composition on sleeping and crying in newborns. Pediatrics 90:733-740,1992. Onodera, K.; Yamatodani, A.; Watanabe, T.; Wada, H. Neuropharmacology of the histaminergic system of the brain and its relationship with behavioral disorders. Prog. Neurobiol. 42685-702; 1994. Owasoyo, J. 0.; Neri, D. F.; Lamberth, J. G. Tyrosine and its potential use as a countermeasure to performance decrement in military sustained operations. Aviat. Space. Environ. Med. 63:364-369; 1992. Pare, C. M. B. Potentiation of monoamine-oxidase inhibitors by tryptophan. Lancet ii:527-528; 1963. Pile, A.; Rogoz, Z.; Skuza, G. Hi&dine-induced bizarre behavior in rats: The possible involvement of central chohnergic system. Neuropharmawlogy 21:781-785; 1982. Prange, A. J.; Wilson, I. C.; Lynn, C. W. L-Tryptophan in mania: Contribution to a permissive hypothesis of affective disorders. Arch. Gen. Psychiatry 3a56-62; 1974. Sabelh, H. C.; Fawcett, J.; Gusovsky, F.; Javaid, J. I.; Wynn, P.; Edwards, J.; Jeffries, H.; Kravitz, H. Clinical studies on the phenylethylamine hypothesis of affective disorder: Urine and blood phenylacetic acid and phenyIaIanine dietary supplements. J. Chn. Psychiatry 4766-70; 1986. Schreier, H. A. Mania responsive to lecithin in a 13-year-old girl. Am. J. Psychiatry 139:108-110; 1982. Schwartz, D. H.; Hemandez, L.; Hoebel, B. G. Tryptophan increases extracellular serotonin in the lateral hypothalamus of food-deprived rats. Brain Res. BuII. 25803-807; 1990.

323 107. Seltzer, S.; Dewart, D.; IPoUack,R. L.; Jackson, E. J. The effects of dietary tryptophan on chronic maxiiiofacial pain and experimental pain tolerance. J. Psychiat. Res. 17:181-185; 1983. 108. Seltzer, S.; Stoch, R.; Marcus, R.; Jackson, E. J. Alteration of human pain thresholds by nutritional manipulation and Ltryptophan supplementation. Pain 13:385-3X& 1982. 109. Sharp, T.; Bramweil, S. R.; Grahame-Smith, D. G. Effect of acute administration of L-tryptophan on the release of 5-I-H in rat hippocampus in relation to serotoninergic neuronai activity: an in-Give microdiaiysis study. Life Sci. 5:i215-1223; 1992. _ 110. Shneen. S. E.: Morse. I). R.: Furst. M. L. The effect of trvotoph& on postoperative tendodontic pain. Oral Surg. 58:446&~ 1984. 111. Shurtleff, D.; Thomas, .I. R.; S&rot, J.; Kowaiski, K.; Harford, R. Tyrosine reverses a cold-induced working memory deficit in humans. Pharmacol. B&hem. Behav. 47:935-941; 1994. 112. Simon, R.; Wetzel, W.; Winsey, K.; Levenson, S. M.; Demetriou, A. A. Supplemental dietary tyrosine in sepsis and acute hemorrhagic shock. Arch. Surg. 12278-81; 1987. 113. Sole, M. J.; Benedict, C. R.; Myers, M. G.; Leenen, F. H.; Anderson, G. H. Chronic dietary tyrosme supplements do not affect mild essential hypertension. Hypertension 7:593-596; 1985. 114. Sourkes, T. L. Toxicology of monoamine precursors. In: van Praag, H. M.; Mendlewicz, J., eds. Management of depressions with monoamine precursors, vol. 10. Advances in biological psychiatry. Basel: Karger; 1983:16&175. 115. Spatz, H.; Heller, B.; Nachon, M.; Fischer, E. Effects of Dphenylalanine on clinical picture and phenylethylaminuria in depression. Biol. Psychiatry 10235-239; 1975. 116. Spring, B. J.; Maller, 0.; Wurtman, J. J.; Digman, L.; Cozolino, L. Effects of protein and carbohydrate meals on mood and performance: interactions with sex and age. J. Psychiat. Res. 17:155-167; 1983. 117. Stembach, R. A.; Janowsky, D. S.; Huey, L. Y.; Segal, D. S. Effects of altering brain serotonin activity on human chronic nain. In: Bonica. J. J.: Albe-Fessard. D., eds. Advances in lain iesearch and therapy: New York: Raven Press; 1976:601-&X. 118. Strain, G. W.; Strain, J. J.; Zumoff, B. L-Tryptophan does not increase weight loss in carbohydrate-craving obese subjects. Int. J. Obes. 9375-380; 1985. 119. Tamminga, C. A.; Smith, R. C.; Ericksen, S. E .; Chang, S.; Davis, J. M. Cholinergic influences in tardive dyskinesia. Am. J. Psychiatry X&76%774; 1977. 120. Taylor, K. M.; Snyder, S. H. Dynamics of the regulation of histamine levels in mlouse brain. J. Neurochem. 19341-354; 1972. 121. Teff, K. L.; Young, S. N.; Marchand, L.; Botez, M. I. Acute effect of protein and carbohydrate breakfasts on human cerebrospinal fluid mouoamine precursor and metabolite levels. J. Neurochem. 52:235-241; 1989. 122. Thomson, J.; Rankin, H.; Ashcroft, G. W.; Yates, C. M.; McQueen, J. K.; Cummings, S. W. Tbe treatment of depression in general practice: A comparison of L-tryptophan, amitriptylie, and a combination of L-tryptophan and amitriptyhne with placebo. Psychol. Med. 12:741-751; 1982. 123. Tokuhisa, S.; Saisu, K.; Naruse, K.; Yoshikawa, H.; Baba, S. Studies on phenylalanine metabolism by tracer techniques. IV. Biotransformation of D- and L-phenylalanine in man. Chem. Pharm. Bull. 29514-51.8; 1981. 124. Trulson, M. E.; Jacobs, B. L. Dose-response relationship between systemically administered L-tryptophan or L-5-hydrox-

125.

126.

127. 128.

129.

130.

131.

132. 133.

134. 135.

136.

137.

138. 139.

140.

141.

142.

ytryptophan and raphe unit activity in the rat. Neuropharmacology 15:339-w, 1976. Trulson, M. E.; Jacobs, B. L. Raphe unit activity in freely moving cats: Correlation with level of behavioral arousal. Brain Res. 163:135-150; 1979. Tsukada, H.; Lmdner, K. J.; Hartvig, P.; Iangstrom, B. Effect of 6R-L-erythm5,6,7,&tetrahydrobiopterin on the extracellular levels of dopamine and serotonin in the rat striatum: A microdialysis study with tyrosine or tryptophan infusion. Brain Res. 635~59-67; 1994. van Praag, H. M. Management of depression with serotonin precursors. Biol. Psychiatry 16291-310; 1981. van Praag, H. M. Catecholamine precursor research in depression: The practical and scientific yield. In: Richardson, M. A., ed. Amino acids in psychiatric disease. Washington: American Psychiatric Press; 1990:77-97. Varga, J.; Uitto, J.; Jimenez, S. A. The cause and pathogenesis of the eosinophilia-myalgia syndrome. Ann. Intern. Med. 116:140-147; 1992. Volavka, J.; Crowner, M.; Brizer, D.; Co&t, A.; van Praag, H. M.; Suckow, R. F. Tryptophan treatment of aggressive psychiatric inpatients. Biol. Psychiatry 28728732; 1990. Wada, H.; Inagaki, N.; Yamatodani, A.; Watanabe, T. Is the histaminergic neuron system a regulatory center for wholebrain activity? Trends Neurosci 14415-418; 1991. Walsh, N. E.; Ramamurthy, S.; Schoenfeld, L.; Hoffman, J. Analgesic effectiveness of D-phenylaianine in chronic pain patients. Arch. Phys. Med. Rehabil. 67436439; 1986. Westerink, B. H. C.; De Vries, J. B. Effect of precursor loading on the synthesis rate and release of dopamine and serotonin in the striatum: A microdialysis study in conscious rats. J. Neurochem. 56:228-233; 1991. Wilkins, K. Eosinophilia-myalgia syndrome. Can. Med. Assoc. J. 142:1265-1266,199O. Wood, D. R.; Rein&err, F. W.; Wender, P. H. Treatment of attention deficit disorder with DL-phenylalanine. Psychiatry Res. 1621-26; 1985. Woods, S. K.; Meyer, J. S. Exogenous tyrosine potentiates the methylphenidate-induced increase in extracellular dopamine in the nucleus accumbens: A microdialysis study. Brain Res. 56097-105; 1991. Wurtman, J. J.; Wurtman, R. J.; Growdon, J. H.; Henry, P.; Lipscomb, A.; Zeisel, S. H. Carbohydrate craving in obese people: suppression by treatments affecting serotoninergic transmission. Int. J. Eating Disord. 1:2-15; 1981. Wurtman, R. J.; Hefti, F.; Melamed, E. Precursor control of neurotransmitter synthesis. Pharmacol. Rev. 32315-335; 1981. Young, S. N. The significance of tryptophan, phenylalanine, tyrosine, and their metabolites in the nervous system. In Lajtha, A., ed. Handbook of neurochemistry, vol. 3. New York: Plenum; 1983:559-581. Young, S. N. The clinical psychopharmacology of tryptophan. In: Wurtman, R. J.; Wurtman, J. J., eds. Nutrition and the brain, vol. 7, Food constituents affecting normal and abnormal behaviors. New York: Raven Press; 19ti49-88. Young, S. N. Use of amine precursors in combination with other antidepressant treatments: A review. J. Psychiatr. Neurosci. X1241-246,1991. Young, S. N.; Gauthier, S. Effect of tryptophan administration on tryptophan, 5-hydroxyindoleacetic acid, and indoleacetic acid in human lumbar and cistemal cerebrospinal fluid. J. Neurol. Neurosurg. Psychiatry 44:323-327; 1981.