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L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. In this review, after an look at the main natural sources of 5-HTP, the chemical analysis and synthesis, biosynthesis and microbial production of 5-HTP by molecular engineering will be described. The physiological effects of 5-HTP are discussed in both animal studies and human clinical trials. The physiological role of 5-HTP in the treatment of depression, anxiety, panic, sleep disorders, obesity, myoclonus and serotonin syndrome are also discussed. 5-HTP toxicity and the occurrence of toxic impurities present in tryptophan and 5-HTP preparations are also discussed.

Understanding of emotions and intentions are key processes in social cognition at which serotonin is an important neuromodulator. Its precursor is the essential amino acid tryptophan (TRP). Reduced TRP availability leads to weaker impulse control ability and higher aggression, while TRP supplementation promotes confidence. In a double-blind placebo-controlled fMRI study with 77 healthy adults, we investigated the influence of a 4 week TRP enriched diet and an acute 5-hydroxytryptophan (5-HTP) intake on two social-cognitive tasks, a moral evaluation and an emotion recognition task. With 5-HTP, immoral behavior without negative consequences was rated as more reprehensible. Additionally, during story reading, activation in insula and supramarginal gyrus was increased after TRP intake. No significant effects of TRP on emotion recognition were identified for the whole sample. Importantly, emotion recognition ability decreased with age which was for positive emotions compensated by TRP. Since the supramarginal gyrus is associated with empathy, pain and related information integration results could be interpreted as reflecting stricter evaluation of negative behavior due to better integration of information. Improved recognition of positive emotions with TRP in older participants supports the use of a TRP-rich diet to compensate for age related decline in social-cognitive processes.

Objectives: Concurrent with global aging epidemics, cognitive decline has become an increasing public health concern. Dietary supplementation may offer neuroprotective benefits, and 5-hydroxytryptophan (5-HTP) has gained interest due to its role in serotonin synthesis, thereby regulating cognitive function and mood. However, there is limited evidence on its effect on cognitive function, especially among older Asian adults. Therefore, the study aimed to investigate the effects of 5-HTP supplementation on cognitive function and mood in Singaporean older adults. Methods: This was a single-blinded, 12-week randomized controlled trial, and 30 participants (66 ± 3 years) were randomly assigned to consume 100 mg of 5-HTP daily or not consume it. Cognitive function and mood were assessed via the Montreal Cognitive Assessment (MoCA), Geriatric Anxiety Inventory (GAI), and Geriatric Depression Scale (GDS). Cognitive function-related blood biomarkers, including amyloid beta (Aβ)40, Aβ42, gamma-aminobutyric acid, and serotonin, were also determined. Results: A significant time effect was observed in the MoCA score, which was mainly explained by a significant increase in the 5-HTP group (week 0 vs. week 12: 26.6 ± 1.4 a.u. vs. 27.6 ± 1.4 a.u., p < 0.05). Moreover, the 5-HTP group showed a significant increase in serum serotonin levels. Additionally, the GDS score improved in the 5-HTP group (week 0 vs. week 8: 1.2 ± 1.7 a.u. vs. 0.7 ± 1.2 a.u., p < 0.05). However, no effects on GAI and other biomarkers were observed. Conclusions: 5-HTP supplementation can enhance cognitive performance and reduce symptoms of depression in Singaporean older adults, potentially through serotonergic modulation. However, given the relatively small sample size (n = 30) and short-term (12-week) intervention, these findings should be interpreted cautiously, and further long-term studies with a larger sample size are warranted to confirm these preliminary results.

Serotonin [5‐hydroxytryptamine (5‐HT)] modulates ovarian function. The precursor of 5‐HT, 5‐hydroxytryptophan (5‐HTP), has been used to treat depression. However, the effects of 5‐HTP on ovarian and reproductive physiology remain unknown. In this research, we analysed the impact of 5‐HTP on the monoaminergic system and its interactions with the reproductive axis and ovarian estradiol secretion when administered by distinct routes. Female rats 30 days of age were injected with 5‐HTP i.p. (100 mg/kg), into the ovarian bursa (1.5 µg/40 µL) or into the median raphe nucleus (20 µg/2.5 µL) and were killed 60 or 120 min after injection. As controls, we used rats of the same age injected with vehicle (0.9% NaCl). Monoamine, gonadotrophin and steroid ovarian hormone concentrations were measured. The injection of 5‐HTP either i.p. or directly into the ovarian bursa increased the concentrations of 5‐HT and the metabolite 5‐hydroxyindole‐3‐acetic acid in the ovary. For both routes of administration, the serum concentration of estradiol increased. After i.p. injection of 5‐HTP, the concentrations of luteinizing hormone were decreased and follicle‐stimulating hormone increased after 120 min. Micro‐injection of 5‐HTP into the median raphe nucleus increased the concentrations of 5‐HT in the anterior hypothalamus and dopamine in the medial hypothalamus after 120 min. Our results suggest that the administration of 5‐HTP either i.p. or directly into the ovarian bursa enhances ovarian estradiol secretion. What is the central question of this study? Does the route of administration of 5‐hydroxytryptophan affect the synthesis of steroid sex hormones in prepubertal female rats? What is the main finding and its importance? The injection of 5‐hydroxytryptophan either i.p. or directly into the ovarian bursa in prepubertal female rats stimulated the serotoninergic system of the reproductive axis. In turn, this increased the secretion of estradiol, a gonadal hormone that regulates sexual maturation and several physiological processes in females.

5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR’s pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.

Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF)). Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF. Improved staging is desirable, as is the elimination of the need for lumbar puncture. Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages. Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations. Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity. Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan) showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples. Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5-hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of \"sleeping sickness\". Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity) and stage of disease (92% sensitivity and 81% specificity). A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages) versus control.

Psychiatric disorders, particularly depression and anxiety, are often associated with impaired serotonergic function. However, serotonergic interventions yield inconsistent effects on behavioral impairments. To better understand serotonin’s role in these pathologies, we investigated the role of serotonin in a behavior frequently impaired in depression and anxiety, attention. In this study, we used a quantitative, repeated, within-subject, design to test how L-5-hydroxytryptophan (5-HTP), the immediate serotonin precursor, modulates central serotoninergic function and attention in macaques. We observed that intramuscular 5-HTP administration increased cisternal cerebrospinal fluid (CSF) 5-HTP and serotonin. In addition, individuals’ baseline looking duration, during saline sessions, predicted the direction and magnitude in which 5-HTP modulated attention. We found that 5-HTP decreased looking duration in animals with high baseline attention, but increased looking duration in low baseline attention animals. Furthermore, individual differences in 5-HTP’s effects were also reflected in how engaged individuals were in the task and how they allocated attention to salient facial features—the eyes and mouth—of stimulus animals. However, 5-HTP constricted pupil size in all animals, suggesting that the bi-directional effects of 5-HTP cannot be explained by serotonin-mediated changes in autonomic arousal. Critically, high and low baseline attention animals exhibited different baseline CSF concentrations of 5-HTP and serotonin, an index of extracellular functionally active serotonin. Thus, our results suggest that baseline central serotonergic functioning may underlie and predict variation in serotonin’s effects on cognitive operation. Our findings may help inform serotonin’s role in psychopathology and help clinicians predict how serotonergic interventions will influence pathologies.

Background Chronic kidney disease (CKD) in cats often remains stable over time, but some cats experience progressive kidney dysfunction without an identifiable cause. Objectives Identify differences in serum and urine compounds related to tryptophan metabolism and gut‐derived uremic toxins between cohorts with non‐progressive and rapidly progressive CKD. Animals Forty‐two client‐owned cats diagnosed with CKD were divided into a rapid progression group (n = 8) and a non‐progressive control group (n = 34). Methods Prospective cohort study with comparative analysis of predictors using targeted metabolomics. Rapid progression was defined as a 25% increase in serum creatinine concentration over 6 months. Results Serum metabolite ratios of the serotonin pathway showed promising potential for predicting rapid CKD progression in cats: L‐tryptophan/5‐hydroxytryptophan (area under curve [AUC]: 0.89; 95% CI: 0.78–1; p < 0.01; sensitivity: 85.7%; specificity: 78.8%) and serotonin/5‐hydroxyindole‐3‐acetic acid (AUC: 0.83; 95% CI: 0.64–1; p < 0.01; sensitivity: 87.5%; specificity: 76.5%). Cats with rapidly progressive CKD had significantly lower baseline urinary indoxyl‐sulfate (median [Interquartile range, IQR], 0.25 [0.07–0.46] vs. 0.53 [0.36–0.81]; p = 0.04) and p‐cresyl‐sulfate (median [IQR], 0.13 [0.01–0.79] vs. 0.83 [0.32–1.27]; p = 0.04). Logistic regression analysis identified an association between decreased urinary indoxyl‐sulfate (odds ratio [OR]: 0.03; 95% CI: 0–1; p = 0.04) and rapidly progressive CKD, following a similar pattern after correcting for serum creatinine concentration (p = 0.06). Conclusions Metabolites of the serotonin pathway: L‐tryptophan, 5‐hydroxytryptophan, and 5‐hydroxyindole‐3‐acetic acid may serve as potential candidates for further predictive validation in CKD progression in cats. Decreased uremic toxin excretion in rapidly progressive CKD may underlie disease progression.

Background 2′-Fucosyllactose (2′-FL) is one of the major oligosaccharides found in human breast milk, with several recognized beneficial effects on the host. Extensive research has indicated positive effects of 2′-FL on cognitive development in the brain, yet its molecular mechanisms have remained elusive. This study aimed to assess the impact of 2′-FL on the gut-brain axis microbiota and cognitive function in growing mice, along with its potential mechanisms of action. Results Following long-term supplementation for 4 weeks, 2′-FL was found to enhance cognitive memory function in growing mice (3 weeks old) as assessed through Y-maze, novel object recognition, and water maze tests. Analysis via 16S rRNA sequencing revealed significant alterations in gut microbiota diversity and composition induced by 2′-FL, notably increasing the relative abundance of Bacteroides and Lactobacillus genera. Additionally, 2′-FL significantly elevated levels of 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (5-HTP) in the hippocampal tissue. However, antibiotic intervention abolished the cognitive advantage conferred by 2′-FL, highlighting the critical role of gut microbiota in mediating its effects. Similarly, short-term supplementation with 2′-FL for 7 days indicated rapid changes in gut microbiota composition preceding cognitive improvements, further suggesting a potential causal relationship between gut microbiota characteristics and cognition. Further, in vitro experiments with mouse feces suggested that 2′-FL may influence tryptophan hydroxylase levels in the gut microbiota and inhibit the activity of 5-hydroxytryptophan decarboxylase, potentially leading to increased accumulation of 5-HTP. Additionally, 2′-FL may indirectly impact tryptophan hydroxylase levels in enterochromaffin cells by promoting short-chain fatty acid production, which could support 5-HTP synthesis. Elevated 5-HTP produced by the gut system enters the bloodstream, crosses the blood–brain barrier, and may potentially enhance brain 5-HT levels. Conclusion This study offers preliminary evidence that the cognitive-promoting effects of 2′-FL in mice may be closely associated with gut microbiota and 5-HT. The findings suggest that 2′-FL contribute to cognitive development in growing mice, potentially by modulating gut microbiota and enhancing 5-HT levels in the brain. --Bqwh4V_uMUFsc_Sq3c6B Video Abstract

Hinz M, Stein A, Uncini T. Neuropsychiatr Dis Treat.2012;8:323-328.The Editor-in-chief and Publisher of NeuropsychiatricDisease and Treatment wish to retract the publishedarticle.This review article cites several original research articlespublished by the authors, which have recently beenretracted. This article draws on the findings from thoseoriginal research articles to form central arguments anddiscussion, and as a result of the research articles' retraction,the argument presented in this article is no longervalid and the editor has determined it should be retracted.Our decision-making was informed by our policy on publishingethics and integrity and the COPE guidelines onretraction.The retracted article will remain online to maintain thescholarly record, but it will be digitally watermarked oneach page as \"Retracted\".This retraction relates to this paper