Anxitane (l-theanine) for Anxiety in Dogs

Introduction
I was recently asked to look into the evidence concerning a potential therapy for anxiety in dogs, a supplement called Anxitane. It is always challenging to evaluate the effects of any therapy for anxiety in any species. Anxiety is a subjective and highly variable state, and how it is triggered, experienced, and manifested is unpredictable. An objective, consistent measure of anxiety is very difficult to find.

In humans, a researcher can ask people to report their level of anxiety, but this can be problematic since many factors besides the treatment being studied can affect the feeling and how the patients report it. In dogs, of course we cannot directly ask them to report their level of anxiety. We can try to correlate specific behaviors or physiological measurements with what we believe to be anxiety or anxiety-inducing experiences, but there is still a great deal of subjectivity and uncertainty to this. And, as is the case for pain and other subjective outcomes, there are many factors besides the treatment being studied which can influence how humans evaluate the effect on the dogs being studied, the so-called caregiver placebo effect.

Nevertheless, it dogs do appear to suffer from states that seem equivalent in many ways to what humans would label anxiety, and since their brains are similar in many important ways to ours, it is reasonable to expect their internal states and the external factors that can affect them will be similar in some ways. So treatments for anxiety in dogs are appropriate to study even if we cannot perfectly delineate the problem we are treating or the outcomes we seek to measure.

What Is It?
Anxitane is a product containing an amino acid, L-theanine, derived from green tea. Amino acids of various kinds have important effects as neurotransmitters in the brain, are supplements with amino acids in them may have important effects of brain chemistry and hence emotional states. L-theanine is structurally very similar to the amino acid neurotransmitter glutamate, and may exert effects in the brain by stimulating glutamate receptors.

Does It Work?
There have been some studies suggesting l-theanine may reduce anxiety in humans. However, the consensus appears to be that there is not yet sufficient evidence to show this amino acid has a meaningful or consistent effect on anxiety in people. A recent systematic review concluded that there were effects seen in some studies but not in others, and no general recommendation could be made based on the existing evidence:

For state anxiety ratings (STAI-S), meta-analysis on the effects of 200 mg of L-theanine at 40–50 minutes post dose did not reveal any significant effects on anxiety.

[Other study] findings provide preliminary evidence to suggest that L-theanine may ameliorate the effects of acute stress, yet may not noticeably reduce baseline levels of anxiety. However, it is important to note that this sample included a certain proportion of high anxiety-prone individuals. While it would not be expected that these participants would respond differentially to placebo and L-theanine, conclusions derived from such a sample should be viewed with caution.

Similarly, the WebMD review of the evidence states that, “Preliminary evidence suggests that taking theanine might make unstressed people feel more tranquil. But theanine doesn’t seem to have this effect on people who are anxious to start with.”

There have been two published studies in dogs evaluating l-theanine for anxiety. The first was a preliminary study in 12 dogs with noise phobia.

V. Bertesell¹; M. Michelazzi. Use of L-theanine tablets (Anxitane) and behaviour modification for treatment of phobias in dog: A preliminary study. J Vet Behav. May-June 2007;2(3):101.

The results were not evaluated statistically, because there were too few subjects, and the report does not report if subjects were randomly assigned to groups, if investigators evaluating the response were blinded, or other important indicators of risk of bias and error. The authors indicate there was some apparent effect, but it isn’t clear if it was a true effect or clinically significant:

This is a preliminary study and the number of the subjects is too small to have significant results…Comparison of groups A [Anxitane and behavioral therapy] and B[behavioral therapy alone] showed an improvement in the phobic behavioral manifestations with respect to the dogs’ responses and severity.

The second study compared treatment with Anxitane and a placebo in two groups of 5 laboratory beagles judged subjectively to be afraid of humans.

Joseph A. Araujo; Christina de Rivera; Jennifer L. Ethier; Gary M. Landsberg; Sagi Denenberg; Stephanie Arnold; Norton W. Milgram. ANXITANE® tablets reduce fear of human beings in a laboratory model of anxiety-related behavior. J Vet Behav. September 2010;5(5):268-275.

Dogs were randomly assigned to the two groups, tested before administration of the treatment, and retested after 8 weeks of treatment. The testing consisted of putting the dogs in a field, with and without a human who did not intentionally interact with them, and then measuring the dogs’ behaviors and the extent to which they approached the person when there was a human in the field. The study also evaluated overall level of activity, using activity monitors attached to the dogs, and monitored for any apparent adverse effects.

At baseline, the only difference was that the dogs in the treatment group were more active overall than the dogs in the placebo group. After the 8-week treatment period, there were no differences between the groups in the amount of change in activity level or on the dogs’ behaviors alone in the field. The dogs in the treatment group spent more time near the human and interacted with the human more than the dogs in the placebo group. No obvious adverse effects were seen.

There are a number of limitations to this study. The most obvious are the small number of dogs (5 in each group), and the artificial nature of the study population and the tests. Whether or not this result is applicable to pet dogs with anxiety disorders in the real world is an open question. There were also some other methodological concerns. There were statistically significant differences in three of four measures compared, however the p-value for one of these was barely significant (P=0.0472), and it is not clear if any correction was made for multiple comparisons. And the measures of time spent near the human and interaction with the human actually decreased for both groups after treatment on three out of four measures. It is puzzling why a decrease in fear of humans would lead to less interaction with the human compared to baseline. Finally, it is worth noting that the study was funded by the manufacturer of Anxitane.

Is It Safe?
There is very little evidence concerning the effects of l-theanine in general, however there is no obvious indication of risks in the studies that have been conducted. As an amino acid, the substance is likely to be safe at doses similar to what would be consumed in food, though there could potentially be side effects at much higher doses.

Bottom Line
The theoretical reasoning behind the potential value of l-theanine for treatment of anxiety in dogs is plausible, which means it could work. The research in humans shows some weak evidence for a possible benefit, but the evidence is not sufficient to allow firm conclusions. Likewise, the research evidence in dogs is limited and weak, and it is not possible to say with any confidence whether or not l-theanine has a meaningful benefit for dogs with anxiety. It could work, but at this point we don’t know if it actually does.

Since the product is likely safe, there is little risk in trying it in dogs with anxiety. However, without stronger evidence for a benefit, it should not be viewed as a substitute for therapies with better evidence of efficacy.

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