If I were an equine wish-granting genie working for all the top training barns, veterinary clinics, and farriers, I am guessing that the #1 wish would be for an easy-to-administer, palatable, non-testable supplement that makes horses have less stress, be calm and focused. With the discovery of alpha-casozepine, a naturally-occurring milk peptide and the active ingredient in the product Zylkene, this wish may well be within reach.

There are good reasons for trying to reduce equine stress levels. Stressed horses are a danger to themselves and to the people working around them. They are at increased risk of developing gastric ulcers. Stressed breeding stock may experience fertility and breeding performance issues. Stressed rehabbing horses are less likely to have a successful rehabilitation. It can ultimately cost them their lives if horses are euthanized because of stress-related behavioural problems.

Since it is unlikely that we will be sending our show horses to live on the range any time soon, trainers have often looked for pharmaceutical alternatives to help manage sport horses’ anxiety. Psychoptropic medications such as tranquilizers, anti-depressants, anxiolytics, and even anti-psychotic medications have all been used with varying success.

Anxiolytic benzodiazepines (i.e. anti-anxiety drugs such as Ativan) were the first generation of tranquilizers with anxiety-reducing effects. However, these drugs are also known for the adverse effects of disinhibition of aggression (particularly in stallions), and memory impairment across species. These side-effects are likely the key reason why this class of calmative agents has not had widespread use with horses (MacDonnell, 2013, 2014). The common practice of administering tranquilizers to horses before riding is not only of dubious safety for horse and rider, as the horse’s coordination is impaired, it actually does little to advance training, as the horse’s cognitive, and particularly memory, functions are also compromised.

How Does Zylkene Work?

Many of us may have coddled a mug of warm milk to deal with a sleepless night, and apparently the purported tranquilizing properties of cows’ milk have some credible scientific backing. Alpha-S1 casein is one of the major proteins in cows’ milk, and many of the peptides that make up this protein have biological effects on opioid systems (i.e. the ones that make us feel good). One of these peptides, alpha-casozepine, is thought to be the ingredient in mother’s milk that is responsible for the calming effect that newborns experience when nursing.

At the physiological level, alpha-casozepine is similar in structure and effect to anxiolytic benzodiazepines (such as Ativan). Both are believed to work through the GABA neurotransmitter system, widely known for its inhibitory effects on anxiety and stress-related disorders. Alpha-casozepine appears to be as effective as traditional benzodiazepines, but carries none of the accompanying side-effects typical of these drugs –such as increased aggression, drug tolerance (needing increasing amounts of the drug to derive the same benefit), and compromised cognitive function (MacDonnell, 2013 & 2014).

Results are consistent across multiple species. Studies with rats, cats, and dogs all demonstrated that, compared to control groups, alpha-casozepine-treated subjects show fewer sleep disturbances, reduced anxiety in meeting new people and exploring new environments, decreases in physiological markers of stress, and longer-term retention of learned behaviour (Messaoudi et al., 2009, Beata et al., 2007; Katoa, 2012). In human studies, alpha-casozepine has been shown to effectively suppress stress responses, blunt cortisol elevation, and eliminate stress-related symptoms, resulting in improved sleep and greater cognitive function in waking hours (Messaoudi, 2005).

Dr. Sue McDonnell at the University of Pennsylvania’s New Bolton Centre looked at the impact of Zylkene on ponies transitioning from semi-feral conditions to a managed environment. Over two weeks, ponies were exposed to trailer loading, grooming, clipping, washing, routine veterinary procedures, stabling, isolation, and so on. Across all situations, the Zylkene-treated ponies demonstrated consistently more compliant behaviour and more efficient learning than controls. In a follow-up study in 2014, MacDonnell looked at Zylkene’s impact on horses with established aversions to routine health care procedures and found similar anxiety-reducing effects for Zylkene-treated horses. Although the impact was not as pronounced as with her pony study, McDonnell notes that it is likely more difficult to rehabilitate established aversions, rather than training naïve ponies who have only good associations with human handlers.

Relationship to Learning

Since Zylkene is not a sedative and memory is not compromised, horses are able to learn on it in a way that they do not manage with traditional benzodiazepines or sedatives. Claude Beata, a veterinarian and researcher from the CETACE institute in Toulan, France, has been at the forefront of Zylkene research with both dogs and cats with anxiety-related behavioural issues (Beata et al., 2007). He notes that anxiety leads to a loss of adaptability and that the use of biologic compounds such as alpha-casozepine may be the most effective way of reducing that anxiety while also increasing the plasticity of the brain to learn new responses. He stresses the importance of using these agents in conjunction with behaviour modification training.

For aversion reconditioning, such as a fear of the farrier, Ela Misuno, the Technical Service Veterinarian representing Vetoquinol (which manufactures Zylkene), recommends beginning the product a few days prior to the farrier visit and systematically desensitizing the horse to the feared stimulus (handling the legs and feet initially without the farrier, and gradually increasing the length and intensity of having feet handled and eventually shod). Through the paired association of a previously stressful event with the anxiety-reducing properties of Zylkene, the horse comes to associate the farrier visit with feeling good, and will hopefully retain this association well after Zylkene has been terminated (in learning parlance, classical conditioning). As Misuno remarked in our interview, “On Zylkene, the world is just a bit more beautiful.”

Is it Legal?

Since Zylkene is a naturally-occurring peptide, it is difficult to recover in a drug test. At the time of this writing, Zylkene is not on the 2016 FEI’s banned substances list. However, any calming or performance-enhancing agent is not allowed, according to FEI regulations, placing Zylkene in a grey zone as a potential competition supplement.

Should it be Legal?

From a welfare standpoint, Zylkene seems to be a more humane way to help horses cope with the pressures, stressors, and challenges that they face on a daily basis. Certainly, it seems a kinder alternative to sedatives and benzodiazapines that compromise physiological and cognitive function. Some antipsychotic and antidepressant medications that are commonly used for human patients can be fatal for horses.

In an ideal world, it would be marvellous if we did not need any products to manage our horses’ anxiety – anxiety that is predominantly created by the extraordinary expectations we have of them in a world so foreign to the one for which they were evolutionarily designed. However, would it not be better for horses to take a supplement that seems to have no apparent downsides, rather than endure hours of lungeing, being kept awake, having food and even water withheld, or any of a myriad of psychological and physical tortures they endure in order to keep them calm and focused on their jobs?

I am currently using this product on a horse who has been given a 30-day stall-rest sentence. Although I do not know how he would have managed without it, his response to date seems rather miraculous, showing no evidence that his life as an athletic show horse with full-day turnout has been dramatically changed. There is no whinnying for his turn-out buddy, no stall-walking or wood-chewing, he is polite and easy to manage for hand-walking, and shows no indication of stress. The more I learn about this product – lowered anxiety, improved sleep, better focus, improved memory, increased cognitive function – I wonder who wouldn’t want that? I may just be tempted to dip into his stash!

Zylkene’s Upsides

• It is safe. Alpha-casozepine is a naturally-occurring dairy ingredient classified as a food rather than a drug, and has a GRAS (Generally Recognized As Safe) status by the FDA.

• It is easy to administer (added to feed) and palatable.

• Horses do not develop a tolerance over time.

• Non-addictive, so there are no withdrawal effects.

• May have residual positive benefit even after treatment is stopped.

• Unlike sedatives, horses are not compromised in their physiological function.

• Cognitive function is not compromised, so horses can learn.

• “Natural” compounds tend to be viewed more positively by owners.

Zylkene’s Downsides

• It’s expensive (approximately $110 for a 10-day supply).

• Manufacturer admits that not every horse will respond to Zylkene, although this may occur as a result of under-dosing.

• Research is still limited; there is much to learn about its long-term impact.


Below are a few of the literally hundreds of available calming agents, and the manufacturer’s claims about their effectiveness. Note that just because a product is “natural” does not necessarily mean it is legal. Equine Canada and FEI regulations prohibit the use of calming agents for competition, although there is not always a test to recover these agents. Check with your governing body for guidelines.

Calm and Cool

Produced by Riva’s Remedies, this product is purported to reduce anxiety, nervous muscle tension, and irritability.” It contains black cohosh, chamomile, lemon balm, and passion flower.

Calm and Collected

Hilton Herbs claims that this product is ideal for hot horses, containing a herbal blend of valerian, vervain, chamomile, hawthorn, marshmallow, and meadowsweet.


Produced by Omega-Alpha, “Chill” contains polygonum multiflori, albizia kalkora, zizyphus jujube, and biota orientalis, and is purported to reduce anxiety without impairment to cognitive or motor skills.

Divine Equine Pellets

This is an Oralx product with active ingredients L-tryptophan, valerian root, and other herbs “known to have a relaxing effect.” The manufacturers also carry Tryptoplex, which has similar calming properties, but minus the valerian root, which is a banned substance for some horse show associations.

Pureform CoolAsIce

This product uses botanical extracts (nutraceuticals) including tryptophan and valerian, to reduce anxiety for performance horses. Products are guaranteed to be 100% legal, yet valerian is a prohibited substance under many governing bodies including our own Equine Canada.


Foxden Equine claims that their product, which contains magnesium and chromium, supports proper nerve and muscle function, aids in weight loss, as well as having calming properties.