Nutraceuticals in Behaviour

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Overview

A nutraceutical is defined as "a substance that is produced in purified or extracted form, administered orally to provide agents required for normal body structure and function with the intent of improving the health and well-being of animals" [1]. Nutraceuticals are not regulated in the same way as pharmaceuticals and do not have to undergo the same rigorous testing to be approved. Efficacy has not been properly evaluated for most nutraceuticals.

Alpha-Casozepine

Alpha-casozepine is a trypsin hydrolysate of bovine milk casein with anxiolytic and anti-epileptic effects in laboratory rodent models[2]. It has been shown to have potential anxiolytic effects in cats and dogs in two open label trials[3] [4]. However, only one of these studies included a control group, the inclusion criteria were very broad, the populations small and outcomes were measured using questionnaires that had not been validated or checked for test-retest reliability. More studies are required to confirm clinical efficacy.

L-Theanine

L-Theanine is an amino acid that is found almost exclusively in certain species of tea plant. It has been shown to have positive effects on activation and anxiety symptoms in human patients with schizophrenia[5], and beneficial effects on stress responses and the ability to concentrate during cognitive tasks[6].

L-Theanine has a range of effects, including binding to glutamate receptor subtypes (AMPA, kainate, and NMDA receptors) and blocking of the binding of L-glutamic acid to the glutamate receptors in cortical neurones[7].

In a small open label trial without a control group, l-theanine reduced a range of anxiety signs in cats with behavioural problems[8]. However, this study was not presented as a full article in a peer reviewed journal, and the lack of detail on the methodology or statistical significance of the findings makes the results impossible to interpret. In a study of the effects of l-theanine on fear of human beings in laboratory beagles, treated dogs showed greater human interaction and approach than the placebo control group[9]. Whether this could translate into a clinical effect in dogs with fear rested problems is not known.

Melatonin

Melatonin has been shown to impair the acquisition of fear, but not its expression in rats[10]. It has been used to treat seasonal affective disorder, and possibly other conditions such as bipolar disorder in which circadian disturbances are observed[11]. Melatonin may be used to correct sleep disturbance in people, such as multiple sclerosis patients[12], and may be involved in the phenomenon of worsening clinical signs in Alzheimer's patients in the late afternoon and evening (known as "sundowning")[13]. In one study, treatment with melatonin produced improvements in cognition and sleep quality of Alzheimer's patients[14]. This suggests a potential role in canine and feline cognitive dysfunction syndrome. There is a single report of the use of melatonin to treat fear of loud noises in a dog[15].

Tryptophan

L-Tryptophan is large neutral amino acid (LNAA) which acts as a precursor for serotonin. L-Tryptophan is actively transported across the blood brain barrier by the L1 carrier[16]. It is therefore in competition for this carrier with other LNAAs (such as leucine, valine, methionine, histidine, isoleucine, tyrosine, phenylalanine, and threonine) leading to theories that l-tryptophan supplementation might increase serotoinin availability and therefore alter mood and behaviour. However, l-tryptophan is converted to kynurenine by the enzyme indoleamine 2,3,-dioxygenase (IDO), which is activated by cortisol or pro-inflammatory cytokines[17]. Activation of IDO leads to depletion of l-tryptophan, and therefore of serotonin, which indicates a significant role in anxiety and depression[18] [19]. Through IDO there is therefore an interaction between stress hormones (e.g. cortisol), inflammation and serotonin production. Supplementation of l-tryptophan in stressed individuals may therefore be expected to have variable effects. Supplementation with 5-hydroxytrptophan, which is converted directly to serotonin and bypasses IDO, might be expected to circumvent this problem. However, despite a large number of trials, evidence of the clinical effect of l-tryptophan supplementation in humans is weak, with a Cochrane Report concluding that evidence for effect above placebo was positive but of insufficient quality to be conclusive both for l-tryptophan and 5-hydroxytryptophan [20].

Dysfunction of the serotonergic neurotransmitter system in dogs has been linked to a number of problems, including aggression[21]. However, evidence for the efficacy of l-tryptophan supplemented diets is as equivocal and unreliable as in humans.

In both dogs and cats fed a l-tryptophan supplement, lower levels of behaviours related to stress and fewer signs of anxiety were seen in one study, but this was not in a peer-reviewed journal[22]. In another study, an anxiolytic effect was found, but the diet contained alpha-casozepine as well as l-tryptophan, so any effect cannot be ascribed to amino acid acid supplementation alone[23]. A randomised double-blinded, placebo-controlled study showed no effect of an l-tryptophan enriched diet on behaviour or salivary cortisol in dogs, despite measurable increases in plasma levels of the amino acid[23][24].

References

  1. ↑ Anonymous. Council defines "nutraceutical." Journal of the American Veterinary Medical Association 1996; 209:1986.
  2. ↑ Miclo, L., Perrin, E., Driou, A., Papadopoulos, V., Boujrad, N., Vanderesse, R., Boudier, J.F., Desor, D., Linden, G., Gaillard, J.L. (2001) Characterization of α-casozepine, a tryptic peptide from bovine αs1-casein with benzodiazepine-like activity. FASEB J.15(10):1780-2.
  3. ↑ Beata, C., Beaumont-Graff, E., Diaz, C., et al. Comparison of the effect of alpha-casozepine (Zylkene) versus selegiline hydrochloride on anxiety disorders in dogs. J Vet Behav 2007;2:175-83.
  4. ↑ Beata, C., Beaumont-Graff, E., Coll, V., et al. Effect of alpha-casozepine (Zylkene) on anxiety in cats. J Vet Behav 2007;2:40-6.
  5. ↑ Ritsner, M.S., Miodownik, C., Ratner, Y., Shleifer, T., Mar, M., Pintov, L., Lerner, V.M. (2011) L-Theanine Relieves Positive, Activation, and Anxiety Symptoms in Patients With Schizophrenia and Schizoaffective Disorder: An 8-Week, Randomized, Double-Blind, Placebo-Controlled, 2-Center Study. J Clin Psychiatry. 72(1).
  6. ↑ Kimura, K., Ozeki, M., June, L.R., Ohira, H. (2006) L-Theanine reduces psychological and physiological stress responses. Biological Psychology.
  7. ↑ Kakuda, T., Nozawa, A., Sugimoto, A., Nino, H., (2002). Inhibition by theanine of binding of [3H]AMPA, [3H]Kainate, and [3H]MDL 105,519 to glutamate receptors. Bioscience, Biotechnology, and Biochemistry 66, 2683– 2686.
  8. ↑ Dramard, V., Kern, L., Hofmans, J., et al. Clinical efficacy of l-theanine tablets to reduce anxiety-related emotional disorders in cats: a pilot open-label clinical trial. J Vet Behav 2007;5:85-6.
  9. ↑ Araujo, J.A., de Rivera, C., Ethier, J.L., et al. Anxitane tablets reduce fear of human beings in a laboratory model of anxiety-related behaviour. J Vet Behav 2010;5:268-75.
  10. ↑ Yang, Z., Li, C., Huang, F. (2013) Melatonin impaired acquisition but not expression of contextual fear in rats. Neurosci Lett. 27;552:10-4.
  11. ↑ Bhattacharjee, Y., (September 2007). "Psychiatric research. Is internal timing key to mental health?". Science 317 (5844): 1488–90.
  12. ↑ Adamczyk-Sowa, M., Pierzchala, K., Sowa, P., Mucha, S., Sadowska-Bartosz, I., Adamczyk, J., Hartel, M. (2014) Melatonin Acts as Antioxidant and Improves Sleep in MS Patients. Neurochem Res.
  13. ↑ Volicer, L., Harper, D.G., Manning, B.C., Goldstein, R., Satlin, A. (2001). "Sundowning and circadian rhythms in Alzheimer's disease". Am J Psychiatry 158 (5): 704–11.
  14. ↑ Wade, A.G., Farmer, M., Harari, G., Fund, N., Laudon, M., Nir, T., Frydman-Marom, A., Zisapel, N. (2014) Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer's disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 18;9:947-61.
  15. ↑ Aronson, L. Animal behaviour case of the month. A dog was evaluated because of extreme fear. J Am Vet Med Assoc 1999;215:22-4.
  16. ↑ Hawkins, R.A., O’Kane, R.L., Simpson, I.A., Vin ̃az, J.R. (2006) Structure of the Blood–Brain Barrier and Its Role in the Transport of Amino Acids. J. Nutr. 136: 218S–226S.
  17. ↑ Oxenkrug, G.F. (2010) Tryptophan–Kynurenine Metabolism as a Common Mediator of Genetic and Environmental Impacts in Major Depressive Disorder: The Serotonin Hypothesis Revisited 40 Years Later. Isr J Psychiatry Relat Sci. 47(1): 56–63.
  18. ↑ Wichers, M.C., Maes, M. (2004) The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Neurosci. 29(1):11-7.
  19. ↑ Elovainio, M., Hurme, M., Jokela, M., Pulkki-Råback, L., Kivimäki, M., Hintsanen, M., Hintsa, T., Lehtimäki, T., Viikari, J., Raitakari, O.T., Keltikangas-Järvinen, L. (2012) Indoleamine 2,3-dioxygenase activation and depressive symptoms: results from the Young Finns Study.Psychosom Med. 74(7):675-81.
  20. ↑ Shaw, K.A., Turner, J., Del Mar, C. (2008) Tryptophan and 5-Hydroxytryptophan for depressions.The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  21. ↑ Rosado, B., Garcia-Belenguer, S., Leon, M., et al. Blood concentrations of serotonin, cortisol, and dehydroepiandrosterone in aggressive dogs. Appl Anim Behav Sci 2010; 123:124-30
  22. ↑ Da Graca Pereira, G., Fragoso, S., L-tryptophan supplementation and its effect of multi-housed cats and working dogs. Proceedings of the 2010 European Veterinary Behaviour Meeting. Hamburg, 2010, 30-35
  23. ↑ 23.0 23.1 Kato, M., Miyaji, K., Ohtani, N., et al. (2012) Effects of prescription diet on dealing with stressful situations and performance of anxiety-related behaviours in privately owned anxious dogs. Journal of Veterinary Behavior: Clinical Applications and Research. 7(1). 21–26.
  24. ↑ Bosch, G., Beerda, B., Beynen, A.C., van der Borg, J.A.M., b, van der Poel, A.F.B., Hendriks, W.H., (2009) Dietary tryptophan supplementation in privately owned mildly anxious dogs. Applied Animal Behaviour Science. 121. 197–205
  • Crane, S.W., Griffin, R.W. and Messent, P.R., 2000. Introduction to commercial pet foods. In: M.S. Hand, C.D. Thatcher, R.L. Remillard and P. Roudebush (eds), Small Animal Clinical Nutrition, 4th edition (Mark Morris Institute, Topeka, Kansas, USA)

This article has been expert reviewed by Jon Bowen BVetMed DipAS(CABC) MRCVS.

Date reviewed: July 2, 2014


The creation of this content was made possible by Ceva Santé Animale as part of the feline behaviour project. Ceva logo.jpg


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