The role of L-tryptophan/alpha-casozepine - Veterinary Practice
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The role of L-tryptophan/alpha-casozepine

Lee Danks in this last in a series of columns from Royal Canin looks at the role of L-tryptophan and alpha-casozepine in veterinary diets and whether they can have a positive impact on anxiety.

ONE starting point whenever dealing with an anxious pet is to remind ourselves (and the owner) that stress is a normal (and often understandable) reaction to an environment which is beyond the dog or cat’s control.

The long-term aim is firstly to appreciate normal animal behaviour, then relate this to the often complex milieu of how the pet’s experience and present circumstance have led to a chronic state of stress.

While stress can be protective in the short-term (think “fight or flight”), for extended periods the pet might be said to enter a state of negative apprehension.

We all appreciate that causes of stress and anxiety are complex. Altered living conditions (a new home, boarding kennels/cattery or a holiday), temporary environmental changes (unexpected noises such as reworks, storms, jarring music or even solitude) or changes in routine (timing of walks or meals) is just the start of a long list.

Particularly for cats, triggers might include the presence of other cats, territorial changes, con ned living conditions, veterinary treatment/hospitalisation or even owner stress.

This excessive chronic stress or “anxiogenic situation” leads first to the physiological changes we’re all familiar with (increased heart and respiratory rates, increased blood pressure, etc.) before more serious imbalances occur (shivering, alopecia, ptyalism, vomiting and diarrhoea, for example) and then chronic neuro-hormonal reactions lead to behavioural changes (such as vocalisation, altered sleeping and eating patterns or abnormal toileting habits).

While conventional treatments – such as behavioural therapy and medical agents like benzodiazepines and pheromones – can be beneficial in tackling these symptoms, nutritional solutions should also be considered. The right ingredients fed in the right manner can play a very valuable role in supporting a distressed animal.


One nutraceutical of great interest is alpha-casozepine, a milk-derived bioactive peptide. The first human studies on the anxiolytic effects of milk originated in the 1930s, based on the observation that “drinking milk at bedtime makes one sleep better”. The post-prandial calming properties of milk are well known in the infant and young animals (i.e. the sleeping phase after ingestion of maternal milk).

Remember, however, that the enzymatic digestive process changes in the growing animal. Trypsin is already active at the time of birth, while peptic activity only becomes effective when a puppy is 21 days old (Buddington, et al, 2003) for example.

We need to take this into account when considering using alpha-casozepine as a nutraceutical. Research relating to these bioactive peptides tells us that increased bioavailability can be achieved via tryptic hydrolysis. This means that the casozepine parent protein requires technological processing before it can be integrated into a diet, to become useful to the pet.

In humans, alpha-casozepine reduces the neuro-vegetative signs linked to stress and the intensity of extreme emotion; it also regulates sleep and reduces fear reactions (Kim, et al, 2006). In the cat, alpha-casozepine has been proven to improve reactions when interacting with strangers, signs linked to fear (including aggression), as well as organo-vegetative signs, often linked to anxiety.

The anxiolytic effects tend to be observed by cat owners from the eighth day of administration and in practical applications (such as moving house, the arrival of a new pet or the advent of show season) considerable safety of use is demonstrated, with no signs of side-effects (Beata et al, 2007).

Studies also show that the anxiolytic effect of alpha-casozepine is comparable to that of diazepam (Violle et al, 2006) but without the latter’s side-effects. The compound renders a benzodiazepine-like reaction, but as a nutraceutical there is no dependence, habituation or even rebound effect upon changes in intake.


Another nutrient of interest is the amino acid L-tryptophan, the metabolic precursor of the neurotransmitter serotonin. Early, largely anecdotal reports linking diet with behaviour focused on the influence of protein (and the misconception that it causes hyperactivity). Many studies have since shown that the proportional presence of L-tryptohan over other amino acid groups leads to an increased release of serotonin.

Tryptophan must pass from the bloodstream into the brain to be used as a precursor in the synthesis of serotonin. In order to traverse the blood-brain barrier, tryptophan competes with other amino acids for a carrier. Therefore, uptake depends on the relative presence of tyrosine, phenylalanine, valine, leucine and isoleucine.

By increasing the tryptophan:large neutral amino acid ratio, the availability of tryptophan increases, producing greater concentrations of serotonin. As we know, serotonin then plays an essential role in the regulation of mood, anxiety, appetite and sleep, thus L-tryptophan has the properties of a natural anti-depressant.

Studies show that dietary supplementation of tryptophan has promising effects on dog behaviour. DeNapoli (in 2000) reported behaviour-moderating effects (with improvements in anxiety-related signs) of a diet with an increased ratio of L-tryptophan/large neutral amino acids.

We all know that anxiety causes a pet, and often its owner, genuine discomfort. As our understanding of natural and pathological behaviour has evolved, so have our behavioural therapies.

Just the same as environmental modifications and neuro-active medications can provide solutions that improve the animal’s coping abilities and increase its resistance to stressful stimuli, so can what we put in our pets’ bowls. The door to new understandings in how best to feed in stressful situations is now, thankfully, very much open.

References and further reading

Buddington, R. K., Elnif J., Malo, Ch. and Donahoo, J. B. (2003) Activities of gastric, pancreatic and intestinal brush-border membrane enzymes during postnatal development of dogs. American Journal of Veterinary Research 64 (5): 627-634.

Kim, J. H. et al (2006) Efficacy of [alpha]s1-casein hydrolysate on stress-related symptoms in women. Eur J Clin Nutr 61 (4): 536-541.

Beata, C. et al (2007) Effect of alpha-casozepine (Zylkene) on anxiety in cats.

Violle, N. et al (2006) Ethological comparison of the effects of a bovine alpha s1-casein tryptic hydrolysate and diazepam on the behaviour of rats in two models of anxiety. Pharmacology, Biochemistry and Behavior 84 (3): 517-523.

DeNapoli, J. S. et al (2000) Effect of dietary protein content and tryptophan supplementation on dominance aggression, territorial aggression, and hyperactivity in dogs. JAVMA 217 (4): 504-508.

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