There are a number of situations when animals can experience anxiety. For example, dogs can develop phobias towards loud noises such as fireworks. Other examples of causes of canine anxiety include:
- Separation (Separation anxiety)
- Kennelling and extended owner absence
- Veterinary or Groomer visits
When pets are subject to anxiety and stressful situations, it can be distressing for both the owner and the pet. As such, a number of treatments for relief of anxiety and/or phobias have been developed, particularly for dogs and cats.
Development of Anxiety and Phobias
Anxiety is a natural, emotional response to a potentially harmful stimulus (also known as a stressor). Fear inducing stimuli initiate two pathways within the brain, these pathways (discovered by Joseph LeDoux) are sometimes referred to as the ‘High Road’ and the ‘Low Road’.
Both pathways originate in the thalamus following exposure to a stressor, from there, the signal splits to follow two separate paths simultaneously – one taking the ‘low road’, the other taking the ‘high road’. Following the initial stimulus, a signal is generated in the thalamus and propagated directly to the amygdala – the primary processing unit for dealing with memories of emotional reactions. This results in the production of an immediate reaction to the stressor. A human comparison would be ‘jumping’ in response to a loud noise.
A signal is also simultaneously propagated along the ‘High Road’. The signal again, travels from the thalamus to the amygdala; however, it travels via the sensory cortex and the hippocampus. The result of this is the ability to associate the stressor with previous learned experiences, thus a more rational response to the stressor is produced (Neilson JC, 2002).
For example, a typical dog owner may regularly receive visitors to their home. As the dog is learning to interact with these visitors, they may feel threatened by the presence of someone new and show anxiety in the form of vocalisation i.e. barking. Over time however, the dog may learn to associate that the visitor is not a threat from previous experience and memories. Such behaviour would result from information being relayed to the amygdala via the ‘High Road’.
Output from the amygdala controls musculoskeletal responses and also activates the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is involved in the neurobiology of mood disorders, such as anxiety. This is because it controls (in response to a stressor) the release of the major stress hormone – cortisol (Le Doux 2000).
The amygdala also regulates the release of adrenaline, which promotes the sympathetic nervous system and noradrenaline another stress related hormone. Both adrenaline and noradrenaline are neurotransmitters.
Because the amygdala is able to generate a response to stressors based on memories, previous experiences and learnt responses, it ensures that in the majority of cases, an appropriate response is generated. Dysfunctional responses make up the basis of phobia development.
Anxieties and Phobias
Anxiety is a feeling of fear and apprehension. In dogs (as well as other animals and humans) anxieties can develop in to phobias. A phobia causes abnormal amounts of fear and stress in response to certain stimuli which typically are of a low threat level. Repeated exposure to a stressor which initiates a phobic response will not reduce stress levels upon further exposure, it may even exacerbate the phobia.
Because phobic responses put a large amount of stress of the individual, it is beneficial to attempt to ‘cure’ them. This is often achieved by pharmacological and/or behavioural management.
Below are a number of often-observed phobias and anxieties specifically seen in dogs.
One of the most common phobias exhibited by dogs is a phobia of noise. Typically, loud noises, such as fireworks, thunder or gunshot, can cause a dog to become excessively anxious. This anxiety is often expressed by trembling or vocalisation.
Almost half of dogs show an atypical anxiety response to loud noises – especially to fireworks. This anxiety is also more prevalent in older dogs and it is unlikely that they will spontaneously recover from such a phobia over time.
Due to the nature of this phobia, the best treatment would be one which is able to act quickly i.e. able to alleviate acute anxiety.
By nature, dogs are social animals, this means many can become stressed or experience anxiety when they are left alone – for instance, when their owner leaves for work.
Prolonged and repeated separation anxiety can be caused by a number of factors including:
- A lack of prior habituation to an owner’s absence
- A change in the owner’s routine, resulting in different periods of absence
- Reinforcement of anxiety behaviour by giving lavish affection prior to departure and upon return
There are a number of tell-tale signs which show whether a dog is suffering from separation anxiety, these include:
- Causing damage and destruction to their environment (i.e. household furnishings) in your absence
- Become vocal before and shortly after you leave
- Soiling the household areas
- Causing self trauma such as ‘lick granulomas’ – inflammation due to excessive licking of an area
These actions can again be distressing for both the dog and the owner.
Situational phobias can arise for a number of reasons from varying environments and stimuli. Typically, such phobias develop due to a previous negative association with stimuli. They can also arise when a dog is exposed to a new situation or for seemingly no reason at all.
The clinical signs of a dog suffering from a situational phobia are the same, no matter what the trigger stimulus is. These signs can include any of the following; vocalisation, trembling, urination/defecation, attempted escape, reluctance to leave the owner’s side or in rare cases, aggression.
Some common examples of situational phobias include:
Travelling – Some dogs are quite happy to travel in a vehicle, some even enjoy it! However, there are a proportion of dogs that will experience varying levels of distress and anxiety from travelling.
Anxious dogs will be vocal and may be reluctant to remain still. They may also defecate or urinate whilst travelling and/or vomit.
It is possible that a vomiting dog is suffering from motion sickness and not anxiety; however, it is common for these conditions to co-exist. In fact, they often exacerbate one another. In such cases, the dog should initially be treated for anxiety and if the problem persists an anti-emetic such as CERENIA® should also be given.
Kennelling – Leaving a dog in kennels whilst away can be traumatic for a number of reasons. The dog is being introduced to a new, possibly hectic environment where contact with other dogs will be increased.
Daily routine will also be likely to alter; these factors combined with an absence of the owner can be distressing for the dog. Treating the dog pre-emptively for anxiety would obviously be beneficial.
Visits to a Groomer/Veterinarian – Dogs (and other animals) can quickly associate a visit to a vet (and in some cases, a Groomer) with a negative experience. As such, it is quite possible for phobias to develop. The associated clinical signs of anxiety will also develop, including aggression, vocalisation, defecation and urination.
Dogs are particularly prone to the development of aggression when visiting a vet or groomer due to the close contact nature of the respective professions with the animal. When aggression is shown, this can result in injuries towards the vet/groomer, the owner and even the dog itself.
Managing Anxiety and Phobias
A wide variety of treatments is currently used to control and limit anxiety and the development/progression of phobias. Such techniques include; training and behavioural programmes, the use of pheromones, dietary management, pharmaceutical use and nutraceutical use.
Training and Behavioural Programmes
A large proportion of anxiety disorders and phobias can be prevented by implementing correct training during the ’socialisation period’ of a puppy. The socialisation period, is the short length of time at the beginning of a puppy’s life when they are particularly receptive to stimuli, there are many thoughts on the actual length of this period but it generally agreed that it does not exceed the first 16 weeks. Correct introduction and exposure to stimuli and stressors during this period can help prevent the development of anxiety disorders or phobias during later life (Shepherd K, 2002). Of course, this isn’t always possible, for example, following the adoption of a previously ill-treated adult dog.
Reducing anxiety in older dogs through behavioural programmes is possible though. One technique is to follow a desensitisation programme. The best example of using a desensitisation programme to reduce anxiety is the use of recorded audio to treat noise phobias.
This type of programme would involve playing previously recorded audio of a known stressor (such as fireworks) repeatedly, building the volume slowly over time to enable the dog to become habituated to the sound. Desensitisation programmes are just used for dealing with noise phobias, the principle behind them can be applied to a number of situations to deal with anxiety and phobias. Another example of use would be using a desensitisation programme for the treatment of separation anxiety. This would involve mimicking signals typically associated with separation, such as picking up keys or putting on a coat. Over time, you would build this process up, possibly leaving the house for a couple of minutes then returning. If successful, this would eventually reduce the clinical signs of anxiety as the dog learns that separation need not be associated with a negative experience.
Another type of behavioural programme is ‘counter conditioning’; this is similar to classical conditioning (i.e. the process used to teach a dog tricks such as ‘sit’ or ‘stay’), but it attempts to replace the association of a stimulus with a negative experience, with a new, positive experience.
Extending the typical example of Pavlov’s dog allows for a simple explanation of counter conditioning. Imagine we make a dog learn to associate the ringing of a bell with a negative experience, such as a light electric shock (classic conditioning). Now, if we instead started giving food to the dog following the ringing of the bell, the dog would eventually learn to associate the bell with a new, positive experience. This is counter conditioning.
When care and time is invested in to training or behavioural programmes such as desensitisation or counter conditioning, they have been shown to decrease the fear response exhibited following exposure to a stressor, however each dog is different and will respond to the courses in their own time. This means the length of time to overcome anxiety by these means is often undeterminable.
Pheromones are volatile hormones, secreted outside of the body by a number of species. Pheromones initiate specific social responses in other individuals of the same species, the number of responses which can be initiated vary widely.
A pheromone of particular interest in dogs, for the treatment of anxieties, is a synthetically manufactured ‘appeasing pheromone’ known as Dog Appeasing Pheromone or DAP. DAP is a naturally occurring pheromone which was initially extracted from lactating bitches. DAP has been shown to support both puppies and adult dogs during stressful situations.
For therapeutic use in dogs, DAP is made airborne. This is achieved by using short range plug-in diffusers, sprays or heat activated collars. Once airborne, DAP reaches the vomeronasal organ of the dog which is located in close proximity to the oral cavity and the nasal passage. The role of the vomeronasal is to respond to chemical messengers i.e. pheromones and initiate the appropriate response. Each pheromone produces a single, specific response and can only achieve this response in conspecifics. DAP invokes a calm and reassured mood.
Due to the nature of how DAP works, the collars, diffusers and sprays must be sent up in advance of an expected stressful event (such as introduction in to a new home). CEVA, the animal health company behind DAP, market the product as Adaptil. They recommend attaching DAP-infused collars 24 hours before contact with an expected stressor (for example, a car journey). Also, because the collars are activated by heat, they must be attached with a tight fit which may prove uncomfortable for the dog. It is recommended, again by CEVA, that plug-in diffusers are installed around 2 weeks before exposure to the expected stimulus. Although it is claimed the diffuser is fully functional after 24 hours, they suggest waiting up to month before evaluating the diffuser’s effectiveness. DAP in spray form is faster acting, but has only a short, local area of effect.
Because of these limitations, pheromones, such as DAP, are not recommended for use in acute situations. The sole use of pheromones is not recommended for severe phobias, severe cases should incorporate pheromone use with other anxiolytics.
The use of pheromones is not without its doubts. Their efficacy has long been questioned, both in humans and animals. CEVA suggests that the efficacy of the Dog Appeasing Pheromone has been proven by a number of studies however, the Journal of American Veterinary Medical Association have published systematic reviews of pheromone associated clinical trials. In these reviews they suggest that the majority of the clinical trials provide insufficient evidence.
A more traditional method of reducing anxiety is by carefully controlling the diet, prior to an expected stressful event. By closely following the below feeding regime, it is possible to elevate levels of serotonin (of which low levels predispose individuals to mood and impulse control disorders).
Start by feeding the dog a large, protein rich meal, supplemented with 1mg of vitamin B6 per 1kg of body weight. Vitamin B6 plays an important role in the synthesis of serotonin and the metabolism of tryptophan to serotonin.
After 2-3 hours, the dog should be fed a small, carbohydrate meal – only 2g per 1kg of body weight, this has been shown to stimulate the production of insulin.
Insulin release induces uptake of large branched chain amino acids (excluding tryptophan) in to the muscles. Typically there is competition between tryptophan and other branched chain amino acids (BCAAs) for access to transporters at the blood-brain barrier and as such, there is also competition for uptake in to the brain tissue.
Because tryptophan is a precursor of serotonin, the lack of competition between tryptophan and other BCAAs increases the levels of serotonin in the brain, provided there are fewer BCAAs at the transporter.
The problem with dietary management to control anxiety, is that it requires adhering to the above, strict regime. Also, for this regime to work optimally, the dog would be required to have high, initial levels of tryptophan which is dependent on the quality of the protein meal. A tryptophan containing supplement would be more ideal. One other factor to consider is that controlling the diet would not be suitable for acute situations as preparation is required at least 2 hours in advance.
The neurobiology of anxiety involves a number of neurotransmitters; primarily serotonin, dopamine, GABA and noradrenaline. To medicate for anxiety, any dysfunction or imbalances in these neurotransmitters must be addressed.
When exposed to a stressor, the activity of the involved neurotransmitter pathway is altered. The activity of the serotonergic and GABAnergic pathways are decreased whilst the activity of noradrenaline pathways are increased.
GABA is a major inhibitory neurotransmitter, with around 50% of inhibitory synapses being GABA mediated; these inhibitory synapses are prevalent at all levels of the CNS. In response to a stressor, the overall activity of GABA is decreased which results in a decrease in brain inhibition and thus reduces the likelihood of the brain achieving a calm state.
Treating anxiety and phobias with pharmaceuticals can be achieved with a variety of drugs, each with different pharmacodynamics.
Anxiolytic and Amnesic Drugs
Anxiolytics such as benzodiazepines are used to provide short term relief from anxiety. Benzodiazepines such as diazepam provide short term CNS sedation. For treatment of serve anxiety and phobias, long term use of benzodiazepines may be prescribed by a veterinarian; however, this can lead to dependence and the development of withdrawal symptoms likened to Lyrica withdrawal symptoms in the past.
A popular benzodiazepine used in the treatment of canine anxiety is alprazolam (Xanax). Alprazolam is an anxiolytic which yields short term CNS sedation as well as anterograde amnesic effects. Anterograde amnesia is also known as short term memory loss i.e. an inability to recall the recent past. The benefit of being able to induce anterograde amnesia alongside general anxiolytic effects is that you are able to administer the drug either before or after a stressful event (You can click here for a full briefing of these drugs and their effects/side-effects). The anterograde effect of drugs such as alprazolam make it difficult for the dog recall the event, reducing anxiety and helping to prevent the development of phobias.
Alprazolam and similar drugs cause anxiolysis by acting as an agonist of the GABA receptor i.e. the drug mimics the structure of the GABA neurotransmitter and binds with efficacy to increase the action of inhibitory synapses. The short term memory loss induced by amnesic drugs is due to antagonism of NDMA receptors i.e. the drug binds without efficacy but with great affinity, essentially blocking the receptor.
Adverse effects of amnesic and anxiolytic drugs include; ataxia, paradoxical hyperexcitability, and disinhibition. Disinhibition is of concern as it increases the likelihood of aggression.
Sedative drugs such as acepromazine (ACP) cause sedation, but do not produce any anxiolytic effects. This means that a dog treated with a sedative drug would be immobilised and appear calm, yet in reality they are still aware of their environment and current situation. As such they can still form emotional responses to a stressor.
Because of the nature of such drugs, the intensity of the emotional impact from a stressor may actually increase, as the dog is aware of the situation but unable to react in a manner to reduce its anxiety. This will negatively impact on any previous existing anxieties or phobias, possibly undoing previous corrective action and creating negative associations for future interactions with the stimulus.
The reliability of sedative drugs when administered orally is unreliable and, as such, high doses of the drug may be required. Using high doses however, can cause systemic effects such as hypervolemia (increased blood-fluid volume), hyperexcitability and extrapyrimidal side effects such as akinesia (an inability to move) or akathisia (an inability to remain still).
Because of all the associated problems with sedative drug use, they are no longer recommended for use in treatment of phobias or anxiety (Neilson JC, 2002; Casey R, 2002).
Tricyclic Antidepressants (TCAs) & Selective Serotonin Re-uptake Inhibitors (SSRIs) – These two variants of antidepressants both work in a similar manner, the increase the amount of available serotonin in the synaptic cleft. This is achieved by blocking re-uptake of serotonin after its release; this makes stimulation of post synaptic responses possible which includes some secondary messenger systems.
Enhancing secondary messenger systems in this way is beneficial as the systems involved contribute towards cell memory which plays an important role during training programmes such as counter conditioning.
There are a number of side effects associated with these drugs including; unwanted sedation, constipation, diarrhoea, urinary retention, appetite changes, ataxia, cardiac arrhythmia and alterations in blood pressure.
The above-mentioned side effects are why acquiring the necessary skills from Tallahassee BLS CPR Class on how to combat a cardiac arrest and having the right counter medication is always necessary.
Monoamine Oxidase Inhibitors (MAOIs) – MAOIs, specifically monoamine oxidase B inhibitors, inhibit the MAO enzyme responsible for the breakdown of MAO neurotransmitters. Presently, few studies support the use of MAOIs for phobias; however there is one licensed veterinary preparation available for purchase (Selgian) which has been used to treat sound and noise related phobias.
CEVA, the producers of Selgian, state that it can take anywhere from 4 to 8 weeks before the clinical signs of anxiety associated with noise related phobias are reduced.
Also worth noting is that MAOIs are contraindicated with many other drugs, including TCAs and SSRIs and therefore they should not be administered together as drug-induced CNS toxicity can develop. Other side effects of MAOIs include; possible aggression, excess salivation, vomiting and serotonin sickness (caused by a large excess of serotonin).
Beta blockers, such as propranolol, are best used to treat cases of mild anxiety which is indicated by trembling, tachycardia (increased heart rate) and tachyponea (increased ventilation rate).Beta blockers are typically used pre-emptively to modulate the body’s response to neurochemical signals initiated by exposure to a stressor.
It is also possible to use beta blockers to amend the long-term potentiation of a phobic response, but this requires early action. Cases are typically not presented early enough to follow this course of action however.
The use of beta blockers with SSRIs and TCAs is considered safe.
Nutraceuticals are available for the treatment of a variety conditions and due to their natural sources, efficacy and lack of side effects they are widely praised. In terms of treating anxiety and phobias in dogs, there are currently two main products, these are Zylkéne and CALMEX®.
Zylkéne is a natural product derived from cow’s milk, it has been clinically proven to “help cats and dogs manage stress and facilitate adaption to change.”
The active ingredient of Zylkéne is alpha-casozepine, a decapeptide which is isolated from bovine tryptic-casein. It is worth noting that Zylkéne relies solely on this single active ingredient.
In clinical trials, Zylkéne has only been tested for its long term effects (tested over a period of 56 days). A reduction in anxiety related clinical signs following the use of Zylkéne were only observed after a couple of weeks. The use of casein tryptic hydrolysate i.e. Zylkéne has not been recommended as an alternative to benzodiazepine for acute treatment of anxiety (recommendation made by Jamie Rushton, a clinical Behaviourist and Veterinarian), despite often being referred to as ‘the natural benzodiazepine’.
The actual method in which Zylkéne is able to manage anxiety is currently unknown. It is believed it may be due to the affinity of alpha-casozepine for GABA receptors due to its structural similarities to the GABA neurotransmitter.
Another nutraceutical product is CALMEX®, a unique combination of two amino acids, a psychoactive plant extract and numerous B Vitamins. These ingredients produce a synergistic effect by modulating neurotransmitter production and multiple other pathways within the brain. The result is acute anxiolysis and mild sedation. CALMEX® can be used alone or in conjunction with behavioural programmes.
CALMEX® includes the essential amino acids L-theanine and L-tryptophan. L-theanine (found in green tea), is both fast acting and safe, with a GRAS approval by the FDA.
L-theanine is able to cross the blood brain barrier within 30 minutes of ingestion (Bryan J, 2008); upon crossing the blood brain barrier L-theanine almost instantly begins inducing the production of alpha waves by the brain. Alpha waves are associated with the relaxed state of mind.
Other functions of L-theanine include:
- Increasing GABA neurotransmitter production, the main neurotransmitter associated with inhibition and a relaxed state
- Decreasing noradrenaline production, an excitatory neurotransmitter which is normally present in elevated levels during periods of anxiety
- Increasing the concentration of serotonin in the stratum, hippocampus, and hypothalamus. Serotonin is proven to alleviate anxiety
Clinical trials have shown that L-theanine is effective in reducing fearful behaviour and its use for treating anxiety related behaviour is supported (Araujo et al, 2010). It has been shown to have a regulatory role within the CNS which can modulate and tone down CNS response.
L-tryptophan is a precursor of serotonin, an important hormone and neurotransmitter involved in regulating mood, behaviour and cognition. L-tryptophan has also been shown to decrease aggression in dogs (De Napoli et al, 2000), as well as decrease stereotypies and stress responses (Pereira et al, 2010).
Because L-tryptophan, like L-theanine, is an essential amino acid, dietary depletion results in reduced plasma concentration. This consequently leads to a reduction in the synthesis and release of serotonin in the brain (Bell C et al, 2001).
CALMEX® also includes a psychoactive plant extract, Piper methysticum, which, when taken orally, has been used for thousands of years for the treatment of anxiety, stress and insomnia. P.methysticum, or Kava as it is commonly known, can also be applied topically to produce analgesic and wound healing effects.
The clinical effects produced by P. methysticum are similar to benzodiazepines. It has anxiolytic, sedative and anticonvulsant properties and is also used as a muscle relaxant (Jussofie at al. 1994).
In terms of safety P. methysticum has been clinically proven to be both a safe and effective treatment for anxiety, with strong evidence to support its anxiolytic effects (Sarris, 2011; Lakhan S.E., 2010).
The anxiolytic effects of P. methysticum are achieved by:
- Modulation of GABA activity by altering the lipid membrane structure – interfering with voltage-gated ion channels (Sarris, 2011)
- Producing reversible MAO-B inhibition and is increasing dopamine levels in the brain
- Inhibiting dopamine and noradrenaline re-uptake
The sale of P. methysticum for oral use in humans was prohibited in the UK in 2003 based on theories that there may be an associated risk between hepatotoxicity and Piper methysticum.
Some experts, however, argue that causality between the adverse effect and use of P. methysticum has not been established with sufficient certainty. In several cases, liver damage could have been due to other drugs or alcohol taken concomitantly. In other instances, excessive and prolonged doses of P. methysticum had been used (Ernst E, 2007).
In terms of veterinary use, P. methysticum has been listed on the European Feed Additive list since 2005 and remains on the list to date after being reviewed again in 2010.
A number of B vitamins responsible for essential maintenance of the nervous system are included within CALMEX®. These include vitamins; B1, B3, B6, B8 and B12.
It has been proven that these vitamins support the availability and production of key neurotransmitters such as; serotonin, noradrenaline, GABA and dopamine (Combs GF, 2008). Vitamin B6 is also important in the synthesis of coenzyme pyridoxal phosphate which is essential in metabolism of serotonin.
Synergistic Properties of CALMEX®
CALMEX® ingredients utilise multiple pathways of the brain involved with mood regulation to achieve a synergistic result. Only pure, natural ethically sourced products are used which have been proven to be effective. The synergistic action of these ingredients produces anxiolysis and mild sedation making CALMEX® a perfect choice for dealing with anxiety and phobias.
Because the active ingredients of CALMEX® work rapidly, it can be used for acute situations without requiring prior preparation, perfect for unexpected situations.
A phobia can quickly develop in dogs and there are many occasions where anxiety arises. These situations can be stressful for both the dog and owner. Dogs can be put under immense emotional stress which can affect their state of mind, just as it would with a human, which is why owners should seek advice or help if they notice the clinical signs of anxiety.
From the techniques and treatments listed earlier, you can see that each have their own pros and cons, those treatments again in summary:
- Training and behavioural programs – No use of products required however varied results and the programmes can last a long time which requires a lot of commitment from the owner
- Pheromones – Controversy still surrounds their actual efficacy, DAP does show some promise however its use requires prior preparation meaning it is not suitable for acute development of anxiety such as that experienced with sudden fireworks.
- Dietary Management – Not suitable for acute development of anxiety and the anxiolytic effects are limited. Much more beneficial to use a tryptophan supplement.
- Pharmaceuticals – Can have good anxiolytic effects (and in some cases amnesic). The optimal pharmaceutical for anxiety treatment would be benzodiazepines however; it can produce a number of side effects including paradoxical hyperactivity.
- Nutraceuticals – Natural ingredients and good efficacy.
Araujo et al. 2010. Anxitane tablets reduce fear of human beings in a model of anxiety-related behaviour. Journal of Veterinary Behavior 5, 268-275
Bell C, Abrams J, Nutt D, 2001. Tryptophan depletion and its implications for psychiatry. Br J Psyschiatry. 2001 May; 178:399- 405
Bryan J. 2008. Psychological effects of dietary components of tea: caffeine and L-theanine. Nutr Rev. 2008 Feb;66(2):82-90.
Casey R, 2002. BSAVA Manual of Canine and Feline Behavioural Medicine. Chpt 15. Edited by D. Horwitz, D. Mills and S. Heath
Combs, G.F. 2008. The Vitamins: Fundamental Aspects in Nutrition and Health. San Diego: Elsevier
De Napoli et al. 2000. Effect of dietary protein content and tryptophan supplementation on dominance aggression, territorial aggression, and hyperactivity in dogs. Journal of the American Veterinary Medical Association Vol. 217, No. 4, Pages 504-508
Ernst, E. 2007, “A re-evaluation of kava (Piper methysticum)”, British journal of clinical pharmacology, vol. 64, no. 4, pp. 415-417.
Lakhan SE, Vieira KF 2010. Nutritional and herbal supplements for anxiety and anxiety-related disorders: systematic review. Nutr J. 2010 Oct 7;9:42
Jussofie at al. 1994. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berl). 1994 Dec;116(4):469-74.
Le Doux 2000. Annual Review Neuroscience 23:155–184. Emotion Circuits in the Brain.
Le Doux et al 1988. The Journal of Neuroscience. 8(7): 2517- 2529; Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear
Neilson JC, 2002. BSAVA Manual of Canine and Feline Behavioural Medicine. Chpt 18. Edited by D. Horwitz, D. Mills and S. Heath
Pereira et al. 2010. Effect of dietary intake of L-Tryptophan supplementation on working dogs demonstrating stress related behaviours. BSAVA congress 2010 Scientific Proceedings.
Sarris 2011 Kava: a comprehensive review of efficacy, safety, and psychopharmacology. Australian and New Zealand Journal of Psychiatry 2011; 45:27–35
Schmidt, M., Nahrstedt, A. & Lüpke, N.P. 2002, “Piper methysticum (Kava) in der Diskussion: Betrachtungen zu Qualität, Wirksamkeit und Unbedenklichkeit***”, Wiener Medizinische Wochenschrift, vol. 152, no. 15-16, pp. 382-388.
Stevinson, C., Huntley, A. & Ernst, E. 2002, “A systematic review of the safety of kava extract in the treatment of anxiety”, Drug safety : an international journal of medical toxicology and drug experience, vol. 25, no. 4, pp. 251-261.
Young, S.N. & Leyton, M. 2002, “The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels”, Pharmacology, biochemistry, and behavior, vol. 71, no. 4, pp. 857