Protein, aromatic amino acids (L-tryptophan, phenylalanine/tyrosine) and mood : "...dietary protein could influence the brain availability of their amino acid precursors. The synthesis of serotonin (5-HT) in brain neurons could, for instance, vary with the supply of its precursor, tryptophan. This is an indispensable amino acid provided from dietary protein, and the increase of tryptophan availability could lead to a greater 5-HT concentration in rat brain. Because of this relationship, brain 5-HT could be sensitive to the presence of specific proteins in a meal and because brain 5-HT has a key role in the regulation of stress, mood, and feeding behavior, protein ingestion could affect these processes. The rates of dopamine synthesis and its release are also directly modified by the brain concentrations of its amino acid precursors, tyrosine and phenylalanine" [1] Chronic ingestion of diets differing in protein source elicits marked differences in the brain tryptophan concentrations and serotonin synthesis [2] and tryptophan concentrations and serotonin synthesis in brain neurons are remarkably sensitive to which protein is present in a meal [3]. Whey protein has been proposed as a potential functional nutritional food supplement that prevents the progression of neurodegenerative disorders [4] and and useful for metabolic disorders [5,6] A hydrolyzed protein source may be more adequate to increase brain tryptophan and 5-HT function compared with intact alpha-lactalbumin protein or pure tryptophan [7]. While there have been "no significant changes in clinical outcomes" in some neurodegenerative disorders like Parkinson's in human studies, it improves some biomarkers [8] Whey consists of a heterogeneous group of proteins, including beta-lactoglobulin (35%), alpha-lactalbumin (12%), proteose peptone (12%), immunoglobulins (8%), and bovine serum albumin (5%) Due to greater solubility, more rapid digestion, and resultant higher plasma concentrations of amino acids, whey appears to be a favourable protein to provide nutritional and 1 functional benefits. alpha-lactalbumin: - Lactalbumin increased plasma tryptophan (3-fold) and the tryptophan ratio (50%) [9] - may enhance sustained alertness early in the morning after an overnight sleep, most likely because of improved sleep [10]. - Dietary protein rich in alpha-lactalbumin improves cognitive performance in stress- vulnerable subjects via increased brain tryptophan and serotonin activities. - Supplements of lactalbumin may be useful for nutrition research in relation to age- or disease-related memory decline [11] L-tryptophan "Trp influences behaviour along the agonistic–affiliative axis, it regulates the tone of interactions along the axis that runs from agreeable to quarrelsome to overt aggression. Serotonergic signalling impacts the two-way interaction between: mood and social behaviour, mood and cognition, social behaviour and cognition and increases prosocial behaviours" Tryptophan in studies: ⦁ promotes prosocial behaviour, including charitable giving. ⦁ promotes interpersonal trust. ⦁ causes greater sharing and helpfulness, greater perspective taking and emotion recognition. ⦁ improves control over antisocial behaviour - It allows regulation of aggression and positive social interactions, as well as emotional processing Note: A diet high in Trp, but with a large amount of LNAAs (leucine, isoleucine, tyrosine, phenylalanine, and valine), will not result in higher brain Trp levels, and may even decrease Trp uptake into the brain. An intervention rich in Trp relative to other LNAAs (including is needed in order to boost uptake of Trp, and consequently serotonin production, in the brain. It may be more difficult for the prefrontal cortex to control negative emotional responses that are generated within the amygdala under low serotonin, meaning Trp may help [12] Low tryptophan levels may significantly affect the mood and may contribute to anti-social, aggressive and impulsive behaviours [13] Tryptophan metabolism is disturbed in abstinence Studies have found disturbances of tryptophan metabolism and their association 2 with depression in heavy drinkers. Particularly, a decreased tryptophan ratio to other amino acids competing with tryptophan for brain entry has been studied - diminished supply of tryptophan would lead to serotonin deficiency and thus contribute to depression Experimental lowering of serotonin (5-HT) neurotransmission by acute tryptophan depletion (ATD) induces a transient depressed mood in 50–60% of patients treated with a selective serotonin reuptake inhibitor (SSRI) who are in remission from depression [14]. It has been claimed by some that simple dietary manipulation is not an effective method to increase brain Trp and 5-HT. Depressed individuals had significantly decreased ratios of plasma tryptophan to amino acids sharing with it the same transport carrier into the brain (tryptophan ratio). This ratio has been shown to predict the brain serotonin concentration. It is not presently known whether amino acid modifications disappear after a period of abstinence or persist [15]. Research has demonstrated a robust response to increasing plasma Trp/LNAA ratio, stimulating a significant affective response. Trp supplementation not only improved central serotonergic functioning but improved the profile of tryptophan metabolism [16]. The effect of a SSRI on extracellular 5-HT are dependent on the nutritional availability of Trp. Moreover, increased availability of TRP affects behaviour in a manner similar to SSRI administration. While caution is advised, it's being explored as an augmentation strategy "...nutritional factors play an important role in the biosynthesis of 5-HT. Increasing 5-HT levels by increasing the availability of TRP might augment the therapeutic efficacy of SSRIs, whereas malnutrition may render patients refractory to SSRI treatment.” Studies suggest long-term effects of dietary Trp on stress responsiveness Acute tryptophan depletion caused a significant decrease in perceived control and increase in interfering thoughts at the time of provocation in OCD. "Successful selective serotonin reuptake inhibitor treatment of obsessive-compulsive disorder may involve the ability of serotonin to switch habitual responding to goal-directed behaviour." and it has been proposed tryptophan or 5-HTP may augment the effectiveness of antidepressants. Trp supplementation seems to improve control over social behaviour in patients and individuals suffering from disorders or behaviours associated with dysfunctions in serotonergic functioning - in healthy humans supplementation seems to promote social behaviour [17]. In addiction: "Stress-related neuroendocrine adaptations in early abstinence are critical components of a concomitant brain-state shift from a hippocampal and PFC- mediated regulatory state to a more primitive and dysregulated amygdala 3 andinsula-mediated state underlying emotion dysregulation" Review: Effects of tryptophan loading on human cognition, mood, and sleep https://doi.org/10.1016/j.neubiorev.2009.08.005 L-tyrosine: ⦁ enhance cognitive performance (short-term stressful/cognitively demanding situations) [18] ⦁ may positively influence catecholamine-related psychological functioning [19] References: [1] https://doi.org/10.3945/an.112.002071 [2] https://www.ncbi.nlm.nih.gov/pubmed/23395255 [3] https://www.ncbi.nlm.nih.gov/pubmed/19454292 [4] https://www.ncbi.nlm.nih.gov/pubmed/29199432 [5] https://www.ncbi.nlm.nih.gov/pubmed/26516411 [6] https://www.ncbi.nlm.nih.gov/pubmed/25888881 [7] https://www.ncbi.nlm.nih.gov/pubmed/18648776 [8] https://www.ncbi.nlm.nih.gov/pubmed/27423583 [9] https://www.ncbi.nlm.nih.gov/pubmed/23395255 [10] https://www.ncbi.nlm.nih.gov/pubmed/15883425 [11] https://www.ncbi.nlm.nih.gov/pubmed/16174675 [12] https://www.cam.ac.uk/research/news/serotonin-levels-affect-the-brain%E2%80%99s- response-to-anger [13] https://www.salubrainous.com/tryptophan-for-alcoholism/ [14] https://grantome.com/grant/NIH/R01-AA006510-02 [15] https://patentimages.storage.googleapis.com/50/94/8b/2fef42545c61d4/WO2005049012A 2.pdf [16] https://www.sciencedirect.com/science/article/abs/pii/S0165032705000182 [17] https://doi.org/10.1016/j.neubiorev.2016.02.022 4 [18] https://doi.org/10.7205/milmed-d-14-00594 [19] https://doi.org/10.1016/j.pbb.2015.03.008 5