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May 2013

L-tryptophan in neuropsychiatric disorders: a review.

Animal data indicate that serotonin (5-HT) is a major neurotransmitter involved in the control of numerous central nervous system functions including mood, aggression, pain, anxiety, sleep, memory, eating behavior, addictive behavior, temperature control, endocrine regulation, and motor behavior. Moreover, there is evidence that abnormalities of 5-HT functions are related to the pathophysiology of diverse neurological conditions including Parkinson’s disease, tardive dyskinesia, akathisia, dystonia, Huntington’s disease, familial tremor, restless legs syndrome, myoclonus, Gilles de la Tourette’s syndrome, multiple sclerosis, sleep disorders, and dementia. The psychiatric disorders of schizophrenia, mania, depression, aggressive and self-injurious behavior, obsessive compulsive disorder, seasonal affective disorder, substance abuse, hypersexuality, anxiety disorders, bulimia, childhood hyperactivity, and behavioral disorders in geriatric patients have been linked to impaired central 5-HT functions. Tryptophan, the natural amino acid precursor in 5-HT biosynthesis, increases 5-HT synthesis in the brain and, therefore, may stimulate 5-HT release and function. Since it is a natural constituent of the diet, tryptophan should have low toxicity and produce few side effects. Based on these advantages, dietary tryptophan supplementation has been used in the management of neuropsychiatric disorders with variable success. This review summarizes current clinical use of tryptophan supplementation in neuropsychiatric disorders.

Int J Neurosci. 1992 Nov-Dec;67(1-4):127-44

Effects and side effects associated with the non-nutritional use of tryptophan by humans.

The daily nutritional requirement for L-tryptophan (Trp) is modest (5 mg/kg). However, many adults choose to consume much more, up to 4-5 g/d (60-70 mg/kg), typically to improve mood or sleep. Ingesting L-Trp raises brain tryptophan levels and stimulates its conversion to serotonin in neurons, which is thought to mediate its actions. Are there side effects from Trp supplementation? Some consider drowsiness a side effect, but not those who use it to improve sleep. Though the literature is thin, occasional side effects, seen mainly at higher doses (70-200 mg/kg), include tremor, nausea, and dizziness, and may occur when Trp is taken alone or with a drug that enhances serotonin function (e.g., antidepressants). In rare cases, the “serotonin syndrome” occurs, the result of too much serotonin stimulation when Trp is combined with serotonin drugs. Symptoms include delirium, myoclonus, hyperthermia, and coma. In 1989 a new syndrome appeared, dubbed eosinophilia myalgia syndrome (EMS), and was quickly linked to supplemental Trp use. Key symptoms included debilitating myalgia (muscle pain) and a high peripheral eosinophil count. The cause was shown not to be Trp but a contaminant in certain production batches. This is not surprising, because side effects long associated with Trp use were not those associated with the EMS. Over 5 decades, Trp has been taken as a supplement and as an adjunct to medications with occasional modest, short-lived side effects. Still, the database is small and largely anecdotal. A thorough, dose-related assessment of side effects remains to be conducted.

J Nutr. 2012 Dec;142(12):2236S-2244S

Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signalling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan.

World J Biol Psychiatry. 2009;10(4):258-68

Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.

J Neurochem. 2012 Jun;121(6):974-84

Modulation of central serotonin affects emotional information processing in impulsive aggressive personality disorder.

BACKGROUND: The mechanistic model whereby serotonin affects impulsive aggression is not completely understood. The purpose of this study was to test the hypothesis that depletion of serotonin reserves by tryptophan depletion affects emotional information processing in susceptible individuals. METHODS: The effect of tryptophan (vs placebo) depletion on processing of Ekman emotional faces was compared in impulsive aggressive personality disordered, male and female adults with normal controls. All subjects were free of psychotropic medications, medically healthy, nondepressed, and substance free. Additionally, subjective mood state and vital signs were monitored. RESULTS: For emotion recognition, a significant interaction of Aggression × Drug × Sex (F(1, 31) = 7.687, P = 0.009) was found, with male normal controls but not impulsive aggressive males showing increased recognition of fear. For intensity ratings of emotional faces, a significant interaction was discovered of Drug × Group × Sex (F(1, 31) = 5.924, P = 0.021), with follow-up tests revealing that males with intermittent explosive disorder tended to increase intensity ratings of angry faces after tryptophan depletion. Additionally, tryptophan depletion was associated with increased heart rate in all subjects, and increased intensity of the subjective emotional state of “anger” in impulsive aggressive subjects. CONCLUSIONS: Individuals with clinically relevant levels of impulsive aggression may be susceptible to effects of serotonergic depletion on emotional information processing, showing a tendency to exaggerate their impression of the intensity of angry expressions and to report an angry mood state after tryptophan depletion. This may reflect heightened sensitivity to the effects of serotonergic dysregulation, and suggests that what underlies impulsive aggression is either supersensitivity to serotonergic disturbances or susceptibility to fluctuations in central serotonergic availability.

J Clin Psychopharmacol.2012 Jun; 32(3):329-35

The effects of acute tryptophan depletion on reactive aggression in adults with attention-deficit/hyperactivity disorder (ADHD) and healthy controls.

BACKGROUND: The neurotransmitter serotonin (5-HT) has been linked to the underlying neurobiology of aggressive behavior, particularly with evidence from studies in animals and humans. However, the underlying neurobiology of aggression remains unclear in the context of attention-deficit/hyperactivity disorder (ADHD), a disorder known to be associated with aggression and impulsivity. We investigated the effects of acute tryptophan depletion (ATD), and the resulting diminished central nervous serotonergic neurotransmission, on reactive aggression in healthy controls and adults with ADHD. METHODOLOGY/PRINCIPAL FINDINGS:  Twenty male patients with ADHD and twenty healthy male controls were subjected to ATD with an amino acid (AA) beverage that lacked tryptophan (TRP, the physiological precursor of 5-HT) and a TRP-balanced AA beverage (BAL) in a double-blind, within-subject crossover-study over two study days. We assessed reactive aggression 3.25 hours after ATD/BAL intake using a point-subtraction aggression game (PSAG) in which participants played for points against a fictitious opponent. Point subtraction was taken as a measure for reactive aggression. Lowered rates of reactive aggression were found in the ADHD group under ATD after low provocation (LP), with controls showing the opposite effect. In patients with ADHD, trait-impulsivity was negatively correlated with the ATD effect on reactive aggression after LP. Statistical power was limited due to large standard deviations observed in the data on point subtraction, which may limit the use of this particular paradigm in adults with ADHD. CONCLUSIONS/SIGNIFICANCE:  Together with previous findings, the data provide preliminary evidence of an inverse association between trait-impulsivity and the ATD effect on reactive aggression after LP (as assessed by the PSAG) in patients with ADHD and that this relationship can be found in both adolescents and adults. Because of limited statistical power larger sample sizes are needed to find main effects of ATD/BAL administration on reactive aggression in adults with ADHD.

PLoS One.2012;7(3):e32023

Simultaneous determination of tyrosine, tryptophan and 5-hydroxytryptamine in serum of MDD patients by high performance liquid chromatography with fluorescence detection.

BACKGROUND: Tyrosine (Tyr), Tryptophan (Trp) and 5-hydroxytryptamine (5-HT) are important amino acids in vivo and have been hypothesized to be involved in many mental disorders. We developed a rapid and sensitive HPLC method for simultaneous measurement of serum Tyr, Trp and 5-HT and explored the clinical

significances of Tyr, Trp and 5-HT and the 5-HT/Trp ratio for patients with major depressive disorder (MDD) disease. METHODS: Serum samples were deproteinized by 5% perchloric acid and separated on an Atlantis C18 column (4.6 × 150 mm, 5 µm) with the mobile phase consisting of 0.1 mol/l KH(2)PO(4) and methanol (85:15, V/V).The eluates were monitored by the fluorescence detection with programmed wavelength. RESULTS: Analysis was achieved in <12.0 min. The limits of quantification were 0.014, 0.005, and 0.024 µmol/l for Tyr, Trp and 5-HT, respectively. Reproducibility and recovery were satisfactory. Tyr, Trp and 5-HT and the 5-HT/Trp ratio were significantly decreased in patients with MDD. CONCLUSIONS: In diseases, like MDD, Tyr, Trp and 5-HT play an important role. This method can potentially be applied as prognostic or diagnostic tool or even to follow the evolution of the illness or of the treatment.

Clin Chim Acta. 2012 Jun 14;413(11-12):973-7

Tryptophan depletion and emotional processing in healthy volunteers at high risk for depression.

BACKGROUND: Studies in depressed patients have demonstrated the presence of emotional bias toward negative stimuli, as well as dysregulated brain serotonin function. The present study compared the effects of acute tryptophan depletion (ATD) on both an emotional processing and a planning task in never-depressed healthy volunteers at high and low familial risk for depression. METHODS: Young adults with no personal psychiatric history were stratified into two groups based on family history (n = 25). Participants were enrolled in a randomized, double-blind, placebo-controlled crossover ATD study and completed the affective go/no-go and Tower of London tasks once during each condition. RESULTS: There was a significant treatment by valence by group interaction on the affective go/no-go, driven primarily by a greater frequency of inappropriate responses to sad than to happy distracters in the high-risk group during ATD. No group differences were observed on the Tower of London. CONCLUSIONS: Asymptomatic individuals at high familial risk for depression showed abnormalities in emotional processing while undergoing experimentally induced tryptophan depletion. These findings support emotional processing disturbances as potential trait-level abnormalities associated with the risk of mood disorder.

Biol Psychiatry.2011 Apr 15;69(8):804-7

Acute tryptophan depletion increases translational indices of anxiety but not fear: serotonergic modulation of the bed nucleus of the stria terminalis?

Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders.

Neuropsychopharmacology. 2012 Jul;37(8):1963-71

The consumption of a Jerte Valley cherry product in humans enhances mood, and increases 5-hydroxyindoleacetic acid but reduces cortisol levels in urine.

PURPOSE: Jerte Valley cherries contain high levels of tryptophan, serotonin, and melatonin. These molecules have been shown to be involved in mood regulation. It has been suggested that a complex inter-relationship between brain serotonin, circulating levels of cortisol (the major stress hormone), and the hypothalamus-pituitary-adrenal axis exists in the regulation of stress responses, where cortisol and serotonin act as markers of mood disturbances. Moreover there is growing evidence that altered HPA activity is associated with various age-related pathologies. The present study evaluated the effect of the ingestion of a Jerte Valley cherry-based product, compared to a placebo product, on urine cortisol and 5-hydroxyindoleacetic acid (5-HIAA) levels, and on mood in young, middle-aged, and elderly participants.  METHODS: Cortisol and 5-HIAA acid levels were measured by commercial enzyme-linked immunosorbent assay kits. The mood state profile was analysed using a visual analogue scale and the state-trait anxiety inventory. RESULTS: Our findings showed that the ingestion of the Jerte Valley cherry product decreased urinary cortisol and increased urinary 5-HIAA levels in all the experimental groups. Moreover, the cherry product was able to lessen anxiety status in the middle-aged and elderly participants, and enhanced subjective mood parameters, particularly family relationships in young participants, and frame of mind and fitness in both middle-aged and elderly subjects. CONCLUSIONS: The consumption of the Jerte Valley cherry product may protect against stress and act as a mood enhancer by increasing serotonin availability to the organism, particularly with advancing age.

Exp Gerontol. 2012 Aug;47(8):573-80