Appendix C - Therapeutic Mechanisms of Supplemental Free-Form Amino Acids

Possible Therapeutic Mechanisms of Supplemental Free-Form Amino Acids

  • Affect drug distribution and binding
  • Facilitate neurotransmitter synthesis and function in the brain
  • Replete conditionally essential amino acids depleted in stress conditions
  • Facilitate repair of cellular infrastructure

Affect drug distribution and binding

Intake of amino acids leads to increased serum amino acids and proteins, which in turn lead to increased drug binding and reduced pharmacological effects.

In the bloodstream, drugs are transported partly in solution as free (unbound) drug and partly as drug reversibly bound to blood components, including albumin, other serum proteins, free amino acids, and blood cells. Only unbound drug, which is available for passive diffusion to extravascular tissue, is thought to be responsible for drug concentration at the active site and, therefore, for the pharmacological effects. Dietary protein (including Hardy Nutritionals™ Balanced Free Form Amino Acids) stimulates albumin production and increases free amino acids in the serum, both of which interact with drugs in solution, increasing the bound drug fraction.
Beers MH, Editor. Merck manual of diagnosis and therapy. 17th Ed. Whitehouse Station N.J. 1999. 2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Accessed 05 October 2017.

Supporting Evidence
“The protein component of the meal was sufficient to stimulate albumin synthesis in both the elderly (147 +/- 14 mg . kg body wt(-1) . d(-1)) and the young.”

“Elderly subjects have lower rates of albumin synthesis than do young subjects during fasting, but they stimulate albumin synthesis proportionately in response to the oral ingestion of protein. The intakes of additional fat and carbohydrate do not stimulate albumin synthesis further.”

Caso G, Feiner J, Mileva I, Bryan LJ, Kelly P, Autio K, Gelato MC, McNurlan MA. Response of albumin synthesis to oral nutrients in young and elderly subjects. Am J Clin Nutr. 2007 Feb;85(2):446-51.

“Recent research documents that albumin synthesis rate is influenced comparably in younger and older adults by dietary protein ingestion and changes in dietary protein quantity. This emphasizes the importance for all adults to consume an adequate amount of dietary protein.”

Thalacker-Mercer AE, Campbell WW. Dietary protein intake affects albumin fractional synthesis rate in younger and older adults equally. Nutr Rev. 2008 Feb;66(2):91-5.

“When solutions of the amino acids are mixed with solutions of the drugs, characteristic changes in electronic spectra are observed … suggesting that intermolecular complexes are formed.”

Samarskii V.A. Donor-acceptor interactions of pilocarpine and atropine with amino acids. Pharm Chem J. 1996 Feb; 30(2):72-73.

Facilitate neurotransmitter (NT) synthesis and function in the brain

Intake of amino acids leads to increased neurotransmitter synthesis, neurotransmitter activity, or signal sensitization.



 Amino Acid Precursor/Modulator

 Serotonin, melatonin


 Dopamine, Norepinephrine, Epinephrine (catecholamines)

 L-Tyrosine, L-Phenylalanine



 Unaltered AAs which act as neurotransmitters

 L-Glutamate, L-Aspartate, L-Cysteine, L-Homocysteine, Glycine, Taurine, L-Arginine


 L-Glutamate, L-Glutamine





 NMDA Receptor Agonists

 L-Serine, Glycine, L-Glutamate, L-Aspartate, L-Arginine

 Phenethylamine, N-methylphenethylamine


 Tyramine, Octopamine, Synephrine

 L-Tyrosine, L-Phenylalanine

 Tryptamine, N-methyltryptamine


Meyers S. Use of neurotransmitter precursors for treatment of depression. Altern Med Rev. 2000 Feb;5(1):64-71.

Supporting Evidence

“Aromatic amino acids in the brain function as precursors for the monoamine neurotransmitters serotonin (substrate tryptophan) and the catecholamines [dopamine, norepinephrine, epinephrine; substrate tyrosine (Tyr)]. Unlike almost all other neurotransmitter biosynthetic pathways, the rates of synthesis of serotonin and catecholamines in the brain are sensitive to local substrate concentrations, particularly in the ranges normally found in vivo. As a consequence, physiologic factors that influence brain pools of these amino acids, notably diet, influence their rates of conversion to neurotransmitter products, with functional consequences.”

Fernstrom JD, Fernstrom MH. Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. J Nutr. 2007 Jun;137(6 Suppl 1):1539S-1547S; discussion 1548S.

Fernstrom JD. Effects on the diet on brain neurotransmitters. Metabolism. 1977 Feb;26(2):207-23.

Replete conditionally essential AAs depleted in stress conditions


Intake of amino acids decreases the likelihood of chronic or situational deficiency.


By definition, the demand for essential and conditionally essential nutrients must be met through oral ingestion, as the body is either incapable of endogenous production or situationally incapable of adequate endogenous production.

Essential Amino Acids: Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine

Conditionally Essential Amino Acids: Glutamine, Arginine

Supporting Evidence

“Glutamine and arginine are conditionally essential amino acids because depletion occurs in stressed conditions.”

Moïse C, Pierre D. Combined infusion of glutamine and arginine: does it make sense? Curr Opin Clin Nutr Metab Care. 2009 Nov 9.

“amino acids, … are able to modulate inflammation and the associated oxidative stress, and maintain or improve immune function”

Xu J, Yunshi Z, Li R. Immunonutrition in surgical patients. Curr Drug Targets. 2009 Aug;10(8):771-7.

Fernstrom JD, Faller DV, Shabshelowitz H. Acute reduction of brain serotonin and 5-HIAA following food consumption: correlation with the ratio of serum tryptophan to the sum of competing amino acids. J Neural Transm. 1975;36(2):113-21.

“Under conditions of extreme physical exertion, trauma and severe infections, the rate of utilization of glutamine is more than its rate of synthesis, resulting in a significant decline in plasma glutamine concentration.”

Rao R., Chaudhry K. (2015) Glutamine Protects GI Epithelial Tight Junctions. In: Rajendram R., Preedy V., Patel V. (eds) Glutamine in Clinical Nutrition. Nutrition and Health. Humana Press, New York, NY.

Facilitate repair of cellular infrastructure


Intake of amino acids leads to the repair and building of tissue.


Multiple mood disorders are characterized by significant physical loss of neural tissue. Rebuilding lost nervous tissue mass and repairing damaged neurons increases energy & protein demands similarly to the healing of any other wound. Supplementing amino acids has been shown to accelerate tissue healing.

Supporting Evidence

“The undernourished category of malnutrition leads to loss of body cell mass, which, together with inflammation diminish host response and quality of life”

Soeters PB, Schols AM. Advances in understanding and assessing malnutrition. Curr Opin Clin Nutr Metab Care. 2009 Sep;12(5):487-94.

"Consistent neuroimaging abnormalities include the presence of ventricular enlargement and white matter abnormalities in patients with BD."

Langan C, McDonald C. Neurobiological trait abnormalities in bipolar disorder. Mol Psychiatry. 2009 Sep;14(9):833-46.

"Multiple deficits, including cell atrophy and loss, have been observed in limbic and cortical brain regions of patients with mood disorders."

Tanis KQ, Duman RS. Intracellular signaling pathways pave roads to recovery for mood disorders. Ann Med. 2007;39(7):531-44.

"Nonetheless, there is enough evidence to suggest that white-matter abnormalities are reported with a greater frequency in BPD patients than in patients with UPD or schizophrenia."

Osuji IJ, Cullum CM. Cognition in bipolar disorder. Psychiatr Clin North Am. 2005 Jun;28(2):427-41.

"…mood disorders are characterized by marked reductions in glial cell number and density in addition to subtle alterations in the density and size of cortical neurons in frontolimbic brain regions … that suggest cell atrophy, cell loss, or impairments in neuroplasticity and cellular resilience may underlie the neurobiology of major depressive disorder and bipolar manic-depressive disorder."

Rajkowska G. Cell pathology in mood disorders. Semin Clin Neuropsychiatry. 2002 Oct;7(4):281-92.

"Nutrition profoundly influences the process of wound healing. Nutritional depletion exerts an inhibitory effect, and nutritional supplementation with such positive effectors as arginine can stimulate wound healing."

Williams JZ, Barbul A. Nutrition and wound healing. Surg Clin North Am. 2003 Jun;83(3):571-96.

"The use of glutamine and arginine supplements enhances wound healing and should be increased. Nutritional care is cost-effective."

Wallace E. Feeding the wound: nutrition and wound care. Br J Nurs. 1994 Jul 14-27;3(13):662-7.

“Arginine … is involved with protein synthesis … with cell signaling through the production of nitric oxide and cell proliferation through its metabolism to ornithine and the other polyamines. Because of these multiple functions, arginine is an essential substrate for wound healing processes. The requirement for this amino acid in tissue repair is highlighted.”

Witte MB, Barbul A. Arginine physiology and its implication for wound healing. Wound Repair Regen. 2003 Nov-Dec;11(6):419-23.