Pets, Fear and Fireworks: The Fallout and Terrible Consequences of Fear and Anxiety for Our Pets. Part 4, Using Alternative, Non-Prescription Therapies

In Part 3 of this article, I presented an evidence-based summary of how and why psychoactive prescription medicines can – and in some dogs – should be used to manage fear and anxiety around fireworks. I described fear as an experience generated in the brain, so any effective therapy, regardless of what it is and how it is delivered, MUST ultimately interact with specific receptors in the brain that modulate the fear circuits in some way.

In this fourth and final part of this series on fear and fireworks in pets, I take a broad look at products that are marketed as ‘alternative remedies’, or ‘therapies’ for managing fear in pets.

IMPORTANT INFORMATION, PLEASE READ FIRST

This information is important and relevant for 2 audiences –

Dog Owners: those who want to know more about how alternative remedies might help with a behaviour problem in their own dog.
Canine Professionals: those working with other people’s dogs as trainers, behaviourists etc. and who want to know more about using alternative remedies for behaviour problems in their client’s dogs.

PLEASE SEE BOX 1 AT THE END OF THIS ARTICLE FOR THE INFORMATION YOU MUST BE AWARE OF

NOTE FOR CAT OWNERS

Although the information provided in this article is for dog owners, it is also relevant for cat owners. Additional information for cat owners can also be found at the following ICC resources –

Nutraceuticals

The term ‘nutraceutical’ is an ambiguous and poorly defined one used to describe a number of products including variously refined dietary supplements, plant extracts and phytonutrients, vitamins, minerals, whole-foods etc. A number of nutraceuticals are claimed to have anxiolytic properties.

Alpha-casozepine

One compound that has raised particular interest over the last few years is the peptide compound FOUND IN abundance in cow’s milk, alpha-casozepine. Alpha-casozepine also works through the GABA receptor, like the benzodiazepine drugs, and there is some research that shows the compound to be effective in some dogs with anxiety disorders. (Beata et al., 2007; Palestrini et al., 2010). Neither of these studies make a claim that the compound is effective for dogs with fears of fireworks, however. Alpha-casozepine is available in tablet form and also as part of specially formulated complete diets.

L-theanine

Another compound that has anxiolytic properties through the GABA receptor is the amino acid L-theanine, found in green tea. Trials investigating the use of L-theanine to reduce the fearful behavioural response of dogs towards unfamiliar humans have shown promising results (Araujo et al., 2010). However, there are lots and lots of dogs that are cautious around unfamiliar people. As we discussed in Part 1 of this series, fear is a graded response that is proportional the level of perceived threat. So, while compounds like L-theanine may help support nervous dogs, this does not mean that it will also be effective for dogs terrified of fireworks.

Inositol

Inositol is yet another intriguing compound that, in nature, is a constituent of cell membranes and is important for the regulation of cellular activity. Inositol does not have any anxiolytic or antidepressant properties of its own. Rather, it is an important compound for facilitating the activity of other neurotransmitters including serotonin. Inositol is synthesised as needed in the body, but it can also be supplemented through the diet. Studies in humans have shown that such supplementation is effective as an aid to helping treating depression in some cases (Levine et al., 1995; Levine, 1997). A proprietary version of inositol is available as a supplement for dogs, but there are no published scientific studies on its use or effectiveness.

L-tryptophan

L-tryptophan is an amino acid that has gained a great deal popularity in human health as some kind of ‘wonder supplement’ over the last couple of decades. L-tryptophan is one of the essential amino acids in mammals that are normally only available in proteins consumed in the diet. L-tryptophan is unusual because it is only available in some protein sources, for example animal muscle meat, and even then in relatively tiny amounts compared to the other amino acids. Once assimilated, the vast majority of L-tryptophan in the diet is used to build essential proteins used all over the body. A tiny amount is also used to synthesise the neurotransmitter, serotonin. Most of this serotonin is utilised in metabolic processes in the body’s organs such as the stomach and intestines.

In addition, a tiny amount of L-tryptophan enters the brain where it is also converted into serotonin. This brain serotonin is an important neurotransmitter for many normal bodily processes such as sleep regulation, body temperature regulation, appetite, the stress response, mood state and aggression. Over the last 50 years, serotonin has been a suspect neurotransmitter in many human psychiatric disorders such as panic, anxiety, depression, obsessive-compulsive disorder, attention deficit hyperactivity disorder, autism, schizophrenia and eating disorders. Specifically, much research has focused on the hope of finding a clear correlation between ‘low levels’ of brain serotonin and the symptoms of these patients.

One of the most promising findings in this area of research comes from many studies of dietary L-tryptophan depletion in humans and animal models, which rapidly leads to extremely low levels of brain serotonin. This can be achieved quickly and easily by simply feeding the test subjects L-tryptophan-free diets.

Alongside these L-tryptophan depletion studies, but separate to them, the cornerstone of the development of antidepressant drugs for humans over the last 50 years has been in synthesising drug molecules that raise the levels of available serotonin in the brain. Antidepressant drugs and the theory of depression is discussed in Part 2 and Part 3 of this article.

Levels of absolute brain serotonin can also be raised without the use of drugs. There are 2 methods of doing this and both include changes in the diet –

METHOD 1: Simply add extra L-tryptophan to the diet. This is the simplest and most direct way, and also the most ‘natural’ way because L-tryptophan is a dietary amino acid. L-tryptophan is a large molecule and it does not pass easily from the blood stream into the brain because the brain is partially isolated from the body’s circulation by a filtration system, the blood-brain-barrier (BBB). Furthermore, there is a bottleneck across the BBB – like a restriction in traffic across a narrow bridge on a busy road. This means that, inevitably, greater numbers of other large amino acid molecules such as tyrosine, travelling around in the blood alongside L-tryptophan, get across into the brain because there are more of them. By adding extra L-tryptophan to the diet its chances of getting into the brain are increased. Once in the brain, L-tryptophan needs to be converted into 5-hydroxytryptophan (5-HTP), which is an intermediary metabolite along the way to serotonin synthesis.
METHOD 2: Simply add 5-HTP to the diet. This is the fastest way to directly increase serotonin levels in the brain because 5-HTP is a small molecule and does not have the restrictions of its parent amino acid, L-tryptophan, crossing over from the blood stream into the brain. Furthermore, once 5-HTP is in the brain, it is instantaneously converted into serotonin. For this reason, some texts consider that 5-HTP is serotonin. This is not correct. 5-HTP needs to be converted into 5-hydroxytryptamine (5-HT), and the abbreviated name for this molecule is serotonin. In principle, it would seem that adding 5-HTP to the diet would be the preferred method for increasing brain serotonin. In practice, however this is not the case because it is dangerous. The limited passage of L-tryptophan into the brain (METHOD 1) is really important because it prevents the run-away synthesis of 5-HTP and then serotonin. Too high levels of brain serotonin can cause serotonin syndrome which throws important physiologically vital processes out of balance, such as body temperature regulation. The consequences of this can be fatal. A good example of serotonin syndrome is too often reported in the media. Coma and death of party-goers induced by the recreational use of the drug ecstasy (3,4-methylene-dioxy-methamphetamine MDMA) can cause the rapid accumulation of serotonin in the brain. In combination with dehydration, this is what precipitates an emergency out of a drug that is perceived as relatively safe and harmless. 5-HTP does not occur naturally in foodstuffs, so this is not a ‘natural’ method of increasing serotonin in the brain. It works more like a drug in fact, yet is still freely available in health food stores in some countries.

From these findings, one could reasonably expect that many of the psychiatric disorders listed above could be helped, or even cured, by simply increasing the levels of L-tryptophan in the diet. After all, the direct correlation between the dietary levels of L-tryptophan and its synthesis in the brain into serotonin has been confirmed in hundreds of studies.

Unfortunately, as it is so often the case with psychiatric disorders, it turns out to be considerably more complicated than that. Dietary L-tryptophan depletion DOES NOT cause any of the significant symptoms of the psychiatric disorders listed above. Neither does increasing the availability of L-tryptophan in the brain help with any of these disorders in real patients. The hundreds of studies carried out in animal models and in humans have yielded inconsistent and inconclusive results, except for one finding.

This finding is that lower levels of the amino acid L-tryptophan in the blood stream (not in the brain) is a reasonably consistent finding in human patients with severe types of depression.

So, the truth is this.

Despite all the hype about L-tryptophan and serotonin written on human health and welbeing websites, all we really know is that serotonin is important. However, we don’t know why, nor do we know how it affects emotional states and mood states.

All we can say with any degree of certainty is this.

The amino acid L-tryptophan is essential for the synthesis of serotonin. Given its relatively low levels in protein foodstuffs in general, a quality, well-balanced diet is absolutely essential. This may be more important for animals suffering from a stress-related disorder, but this is a guess, we don’t know for sure. However, any diet containing some extra, added L-tryptophan may help and, to our knowledge, will do no harm.

Given everything we have said above, it is hardly surprising that L-tryptophan, serotonin and the link to stress and anxiety has also gained prominence in the management of stress-related behaviours in cats and dogs.

This has led to the development of a number of commercial diets and supplements, along with all sorts of claims about what these products can do for your anxious pets. For some of these products, the manufacturers have supported their claims with the results from studies. For example, a study on one commercial diet for cats containing both alpha-casozepine and L-tryptophan reported that the diet reduced fear of unfamiliar locations, but did not make any difference to fear of the presence of an unfamiliar person (Landsberg et al., 2017). However, some manufacturers produce no reasonable data at all on the effects of their products, other than anecdotal reports from users of their products.

While anecdotes are better than no information at all, they are no substitute for well-designed and conducted clinical trials such as the Landsberg et al. study in cats.

Herbal remedies

There are a number of naturally occurring anxiolytic compounds available advertised as ‘safe alternatives’ to prescription pharmaceuticals, for example the herbs Valeriana officinalis, Magnolia officinalis, Passiflora incarnata, Piper Methysticum and Phellodendron amurense (for full discussions on possible therapeutic applications and adverse side effects see DePorter et al., 2012; Ernst, 2007; Hart, 2005; Lakhan et al., 2010; Tessier et al., 2003) The active anxiolytic compounds in these plants work, like the synthetic benzodiazepines discussed in Part 3, through the GABA receptor. Either alone or as proprietary combinations, they can help in reducing anxiety in some dogs and facilitating a desensitisation/counter-conditioning programme put in place by a good behaviourist.

In nature, there is a survival advantage in reducing anxiety, and this would suggest that there is an adaptive advantage in the development of the GABA receptor and its affinity to these naturally occurring anxiolytic compounds in plants.

These natural plant compounds do not, however have the additional amnesic properties of their synthetic benzodiazepine counterparts mediated through the NMDA receptor as discussed in Part 3.

For a wild animal like a gazelle in its natural environment, there are no evolutionary advantages in NOT remembering potentially dangerous events. If a young gazelle had a lucky escape from a crocodile while drinking at a waterhole, the animal needs to remember to be more cautious around waterholes in the future. It is the fear that the animal experienced during the attack that seals the memory forever deep inside its limbic system – ‘waterholes are dangerous places, approach with caution and be alert at all times’.

The situation for dogs is quite different.

Most pet dogs are necessarily confined within the boundaries of their human families properties. However, from the dog’s perspective during firework seasons, they are essentially held in captivity and repeatedly subjected to loud bangs over months or even years. The dog’s hard-wired, default fear response is escape and avoidance, but this avenue is not available to him. This is definitely not natural. For these dogs, NOT remembering how frightened they felt night after night is a distinct advantage.

This needs to be taken into consideration when counselling owners on the best therapeutic options available for the welfare and rehabilitation of their dogs. Specifically, would the dog benefit now from not remembering unavoidable fearful events?

A combination of the herbs Magnolia officinalis, Phellodendron amurense were tested in a group of dogs in ‘a thunderstorm situation’ and showed that this combination was effective in managing ‘fear-related inactivity’ (DePorter et al., 2012). However, recordings of thunderstorms were used, which is rather different from a real storm where there is also lightening, a drop in air pressure and other atmospheric changes that are likely to reinforce a dog’s fear. Fireworks are similarly multi-dimensional stimuli. Also, what was being measured in this study was a reduction in the dogs’ activity levels when they heard the recording. These dogs were alerted and worried, but they were not terrified.

Pheromones

Pheromones are naturally occurring chemicals present in released from the body of an animal into the surrounding environment. If another animal, generally of the same species, then comes into contact with the pheromone it can lead to changes in the physiology, the emotional state and therefore the behaviour of that animal. Pheromones are therefore another channel of communication between animals, generally in relation to sexual status and other social states. The term ‘pheromone’ is derived from the Greek words pherein (to transfer) and horman (to excite). An animal detects a pheromone signal through the vomeronasal organ (Jacobson’s organ), which is an additional specialised ‘extra-scent’ organ found in reptiles, amphibians and most mammals including cats and dogs, but not humans.

How pheromones actually work is not entirely clear and there have been few studies at a neurophysiological level. Brain scans have shown that different types of pheromone activate different areas of the brain associated with the particular communicative signal of that pheromone. Pheromones are quite different from prescription pharmaceuticals, herbal medicines, nutraceuticals, or any of the substances discussed in these articles, all of which work by modulating specific neurotransmitter systems. By contrast, pheromones are not committed to any particular neurotransmitter system, rather they act as additional communicative signals that either support or do not support the other intrinsic or extrinsic/environmental signals the animal is receiving at that time (Mills et al., 2013).

Take, for example, a dog that becomes anxious as evening approaches during the firework season. The owner purchases a plug-in diffuser and, after a few weeks use, proclaims that ‘it has not had any effect on her dog’. The reason for this apparent failure could be that all the auditory, visual, olfactory and other environmental signals that predict fireworks, and were therefore making the dog anxious in the first place (diminished light, drawn curtains, owner closing doors and preparing dinner etc.), are still present.

There is therefore a conflict between these ‘unsafe’ signals and the ‘safe’ signal conveyed by the pheromone. The information conveyed by a pheromone to an animal is not unconditional. That is, it is processed at a higher cognitive level and works by helping the animal make a decision about the safety, or otherwise, of his situation.

What does this actually mean?

Where an owner takes steps to mitigate the effects of negative environmental signals as part of a cat’s or dog’s behaviour modification program, the addition of pheromone can make a positive difference in the pet’s overall welfare and in the recovery process.

Pheromones vs. aromatherapy

It should also be noted here that aromatherapy, which is usually based on plant-derived essential oils, is not the same thing as pheromonatherapy. Pheromones are natural bodily secretions that are detected by the vomeronasal organ, while essential oils are not secretions produced within the body, and they are detected through an animal’s olfactory system. In other words, essential oils have a scent whist pheromones do not (any scent added to a pheromone product by the manufacturer is not an active ingredient).

For more information about using pheromones in dogs see Denenberg et al. 2008; DePorter et al., 2011; Gandia et al., 2006; Gaultier et al., 2003; Gaultier et al., 2008; Gaultier et al., 2009; Graham et al., 2007; Kim et al., 2010; Mills et al., 2006; Taylor et al., 2007.

For more information about using pheromones in dogs see Frank et al., 1999; Hunthausen, 2000; Mills and Mills, 2001; Mills et al., 2011; Ogata and Takeuchi; 2001; Pageat and Gaultier, 2003; Griffith et al., 2000.

Physical contact therapies

Swaddling, the once popular practice of wrapping new-born babies tightly in a blanket to simulate the comforting effects of being in the womb, is back in the news because of a link with developmental hip dysplasia in children.

The application of Deep Touch Pressure in the form of wraps, acupressure, T-Touch etc. has been shown to be effective for reducing some forms of anxiety in humans (Grandin, 1992) and this is the idea behind the development of tightly fitting elasticated Velcro proprietary vests – some even with anti-static linings – for dogs. For example, the Anxiety Wrap and Thundershirt.

The various manufacturers’ websites make lots of claims about their respective vests, but there are also some recent, independent studies (Cottam and Dodman, 2009; Cottam et al., 2013) that report a reduction of anxiety scores in dogs during thunderstorms. It should be noted that the addition of an antistatic lining by some of the manufacturers to the vests did not make any difference.

Another study compared the effects on stress-related behaviours in dogs of a properly worn tight vest, an improperly worn loose vest and no vest at all (King et al., 2014). The 12 stress-related behaviours measured were pacing, panting, yawning, tongue-flicking, drooling, elimination, barking, stress whining, howling, licking, door orientation, and calmness. The study found that the properly worn pressure vest reduced 2 of these 12 behaviours – tongue-flicking and yawning. The researchers concluded that “More research should be conducted with the ThunderShirt™ on behavioural outcomes. The ThunderShirt™ can be used with behaviour modification programming and medication as an adjunct treatment option to assist dogs diagnosed with anxiety disorder to reduce heart rate.”.

In explaining how their products work, the manufacturers seem to refer back to the ideas around swaddling babies and the use of pressure devices to calm autistic children (Grandin, 1992).

We also checked out the T-Touch website (T-Touch, 2013) and they say very little about any kind of mode of action, other than it ‘works at the cellular level’ and that it was inspired by a ‘trust in divine guidance’ by its founder. These explanations are unhelpful because ALL biological processes work at a cellular level. The body’s cells contain all the DNA, enzymes and energy sources in the cell’s mitochondria. Where else could T-Touch work? And the term ‘divine guidance’ is beyond definition and quantification in science.

However, if we ignore the official explanations of how T-Touch might work and look elsewhere for some clarity, there have been some good studies on the effects of physical touch in dogs such as grooming.

For example, one study of kennelled dogs showed a significant reduction in heart rate irrespective of the area of the body being groomed, especially in Greyhounds (McGreevy et al., 2012).

Another study investigated the effect of three minutes of petting dogs by humans where the before– and after– levels of various hormones in the blood were measured along with heart rate (Handlin et al., 2011). The ‘feel-good’ hormones, oxytocin, prolactin and the endorphins, associated with positive emotional states, fell and continued to fall for 60 minutes in both the dogs and the humans. At the same time, the stress hormone, cortisol and heart rate fell. This is an interesting study because it adds further support to earlier studies on the positive effects of tickling to conditioned fear in rats, where the tickled rats showed a significant and sustained reduction in stress hormone levels compared to their non-tickled counterparts. Further neurophysiological studies have identified specific ‘systems’ in the brain responsible for social bonding and play in mammals (Panksepp, 1998).

The ‘social bonding system’ is driven by the ‘feel-good’ hormones oxytocin and prolactin, while the social play is driven by the endorphins. Social bonding obviously involves a great deal of physical contact, but actually so does play – just watch a couple of dogs playing together.

Given the information presented above, and setting aside the claimed intervention of the divine in T-Touch, it is likely that pressure vests, T-Touch etc. have their anti-anxiety effects through activation of one or even both of these systems.

Homeopathy and the placebo effect

There is absolutely no evidence that homeopathy is an effective treatment modality and it has no legitimate place in veterinary medicine (Cracknell and Mills, 2008, 2011; Overall and Dunham, 2009). For more information about the placebo effect, please see our blog HERE

For pets that are fearful, the recommendation and encouragement of homeopathic remedies to owners as alternative treatments in place of compounds that show clear evidence of effectiveness cannot be justified on the grounds of seriously detrimental consequences for the welfare of the animal.

Conclusions

The list of adjunctive treatment modalities discussed in this article is not exhaustive.

The remedies we have covered here are those where there is at least some objective data available to back up the claims made by manufacturers or therapists.

Finally, the one thing we can be certain of and that has been repeated several times throughout this series of articles, is this.

Fear is an experience generated in the brain so any effective therapy, regardless of what it is and how it is delivered, MUST ultimately interact with specific receptors that modulate the brain’s fear circuits in some way.

Chronic anxiety, like unresolved physical pain, is an extremely unpleasant emotional state that blights the lives of far too many cats and dogs (Conzemius and Evans, 2012; Malek et al., 2012). As their guardians and spokes-people it is up to us, the owners, and those of us working with pets professionally, to speak out for these pets and do what we can to make their lives better.

Sometimes this will require additional therapies along with a behavioural modification program, and having a fundamental knowledge of what is available and how it works can only be helpful.

It must be remembered that prescription medications can only be prescribed by veterinarians, and in any event pet owners should always be encouraged to seek advice from their vet.

Drugs, prescription or otherwise, including herbal remedies etc., do have side effects and the vet is in the best position to give advice in this regard, especially if the dog is already on medication for a medical condition.

That said, it is really important that a dog owner does not fall into the trap of denying a dog medication for a chronic anxiety disorder on the grounds that the side effects might be harmful (this is happening already with pain killers incidentally leaving dogs to suffer unnecessarily, see Conzemius and Evans, 2012; Malek et al., 2012).

The fact of the matter is that all of the prescription drugs and most of the other medications mentioned in this article have a good safety record and are well tolerated by pets if used correctly.

BOX 1: IMPORTANT INFORMATION, PLEASE READ FIRST

This information is important and relevant for 2 audiences –

Dog Owners: those who want to know more about how alternative remedies might help with a behaviour problem in their own dog.
Canine Professionals: those working with other people’s dogs as trainers, behaviourists etc. and who want to know more about using alternative remedies for behaviour problems in their client’s dogs.

The term ‘alternative remedy’ is used here to identify a range of substances including herbal medicines, nutritional supplements, pheromones, physical therapies and homeopathy.

Unlike the prescription medicines discussed in Part 3 of this series, of articles, these products are not tightly regulated. What this means for consumers of these products is that, where a list of ingredients is declared on the label, it may not reflect what is actually in the container and how much of each constituent is actually biologically available.

HERBAL REMEDIES

The manufacture and marketing of herbal products is an exception here as there is a licensing process in place for those manufacturers wanting to produce high-quality herbal products in terms of levels of active ingredients. The Traditional Herbal Registrations (THRs) system is a quality trade mark that manufacturers can use on their product labels to reassure users of the quality of their products.

For a manufacturer to call its herbal products ‘herbal medicines’, its claims must be supported by clinical trials data in the same way that is required for prescription medicines.

For more information about the legislation and licensing of herbal remedies, click HERE and HERE.

NUTRITIONAL SUPPLEMENTS

A nutritional supplement is defined by the government as ‘any food for the purpose of which is to supplement the normal diet and which is a concentrated source of a vitamin or mineral or other substance with a nutritional or physiological effect, alone or in combination and is sold in dose form’.

The legislation and licensing of nutritional supplements is very different to that of prescription medicines and herbal remedies because it is focused on food safety, not on therapeutic efficacy, side effects etc. The legislation for nutritional supplements is less rigorous, less demanding and less expensive than it is for prescription medicines and herbal remedies. Unfortunately, this leaves a loophole for manufacturers of nutritional supplements who want to make therapeutic claims for their products which could imply to users that they are equivalent to prescription medicines and herbal remedies.

For more information about the legislation and licensing of nutritional supplements, click HERE

BOTTOM LINE

The marketing of remedies, supplements etc. for pets is really a case of BUYER BEWARE.

The welfare of your dog or cat is, after all, your primary concern.

So we strongly recommend that, for all concerns about management of fears and anxieties in pets, you should consider the following –

For behavioural advice, consult a qualified behaviourist.
For advice about prescription medicines, consult a veterinarian.
For advice about herbal products and nutritional supplements, consult a veterinarian who is also qualified in herbal medicine.
For advice about other kinds of alternative therapies, for example acupuncture, consult a veterinarian who is also qualified in that particular therapy.

I cannot recommend the use of homeopathy, reiki, crystal healing, divine inspiration, or any other modality where, either the available evidence suggests the remedies do not work, or there is a paucity of any reliable evidence at all.

© copyright Robert Falconer-Taylor, 2017
This article is an original work and is subject to copyright. You may create a link to this article on another website or in a document back to this web page. You may not copy this article in whole or in part onto another web page or document without permission of the author. Email enquiries to robertft@emotions-r-us.com.

Images used in this article

Cow milking machine in action. By Copyright © 2004 David Monniaux (Own work) [CC BY-SA 2.0 fr (https://creativecommons.org/licenses/by-sa/2.0/fr/deed.en)], via Wikimedia Commons.
L-Tryptophan molecule. By Bin im Garten (Own work) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons.
Healing plants. By Julo (Der Neue Brockhaus (1937), vol. 1) [Public domain], via Wikimedia Commons.
Anxiety Vest fitted to a dog. By Anna Patfield Copyright © Anna Patfield, Pawsability, 2017.
Oxytocin molecule. By MindZiper (Own work) [CC0], via Wikimedia Commons.

References used in all 4 parts of this series of articles, and some additional resources that may be of interest

Adee Schoona, A., Berntsenb, T.G. (2011) Evaluating the effect of early neurological stimulation on the development and training of mine detection dogs. Journal of Veterinary Behavior: Clinical Applications and Research. Volume 6, Issue 2, Pages 150–157

Anand, A., Saraf, M.K., Prabhakar, S. (2007). Sustained inhibition of brotizolam induced anterograde amnesia by norharmane and retrograde amnesia by L-glutamic acid in mice. Behav Brain Res. 2007 Aug 22;182(1):12-20.

Anacker, C., Zunszain, P. A., Cattaneo, A., Carvalho, L. A., Garabedian, M. J., Thuret, S., Price, J., Pariante, C. M. (2011). Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011 Jul;16(7):738-50.

Araujo, J. A., de Rivera, C., Ethier, J. L., Landsberg, G. M., Denenberg, S., Arnold, S., Milgram, N. W. (2010) ANXITANE® tablets reduce fear of human beings in a laboratory model of anxiety-related behavior, J Vet Behav 5:268-275, 2010.

Battaglia, C.L. (2009) Periods of Early Development and the Effects of Stimulation and Social Experiences in the Canine. Journal of Veterinary Behavior: Clinical Applications and Research. Volume 4, Issue 5, Pages 203–210.

Beata, C., Beaumont-Graff, E., Diaz, C., Marion, M., Massal, N., Marlois, N., Muller, G., Lefranc, C. (2007) Effects of alpha-casozepine (Zylkene) versus selegiline hydrochloride (Selgian, Anipryl) on anxiety disorders in dogs. J Vet Behav 2:175-183, 2007.

Beracochea, D. (2006). Anterograde and Retrograde Effects of Benzodiazepines on Memory. TheScientificWorldJOURNAL (2006) 6, 1460–1465.

Blackwell, E.J., Bradshaw, J.W.S., Casey, R.A. (2013). Fear responses to noise in domestic dogs: Prevalence, risk factors and co-occurrence with other fear-related behaviour. Applied Animal Behaviour Science 145 (2013) 15– 25.

Braastad, B.O. (1998). Effects of prenatal stress on behaviour of offspring of laboratory and farmed mammals. Applied Animal Behaviour Science, Vol 61, Issue 2, 28 December 1998, Pages 159–180.

Brunton, P. J. and Russell, J. A. (2010), Prenatal Social Stress in the Rat Programmes Neuroendocrine and Behavioural Responses to Stress in the Adult Offspring: Sex-Specific Effects. Journal of Neuroendocrinology, 22: 258–271

BSAVA (2009) BSAVA Manual of Canine and Feline Behavioural Medicine, Chapter 13 Stress in Veterinary Behavioural Medicine. BSAVA Gloucester.

COAPE, Centre of Applied Pet Ethology Poland. (2013). Diploma in Companion Animal Training and Behaviour.

Coppinger, R., Coppinger, L. (2001) Dogs: A Startling New Understanding of Canine Origin, Behavior and Evolution. Scribner, New York.

Cottam, N., Dodman, N. H. (2009). Comparison of the effectiveness of a purported anti-static cape (the Storm Defender®) vs. a placebo cape in the treatment of canine thunderstorm phobia as assessed by owners’ reports. Applied Animal Behaviour Science, volume 119 issue 1 Pages 78-84.

Cottam, N., Dodman, N. H., Ha, J. C. (2013). The effectiveness of the Anxiety Wrap in the treatment of canine thunderstorm phobia: An open-label trial. J Vet Behav 8:154-161, 2013.

Conzemius, M. G., Evans, R. B. (2012). Caregiver placebo effect for dogs with lameness from osteoarthritis. J Am Vet Med Assoc. 2012 Nov 15;241(10):1314-9.

Cracknell NR, Mills DS. (2008) A double-blind placebo-controlled study into the efficacy of a homeopathic remedy for fear of firework noises in the dog (Canis familiaris). Vet J. 2008;177: 80– 88.

Cracknell, NR, Mills, DS. (2011) An evaluation of owner expectation on apparent treatment effect in a blinded comparison of 2 homeopathic remedies for firework noise sensitivity in dogs. J Vet Bheav: Clin Appl Res. 2011;6: 21– 30.

Curran, H. V., Bond, A., O’Sullivan, G., Bruce, M., Marks, I., Lelliot, P., Shine, P., Lader, M. (1994). Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder. Psychol Med. 1994 Nov;24(4):969-76.

DEFRA. 2013. Department for Environment, Food & Rural Affairs. https://www.gov.uk/guidance/animal-welfare-legislation-protecting-pets (accessed 9th October, 2017).

Denenberg, S., Landsberg, GM. 2008. Effects of dog appeasing pheromone (DAP) on anxiety and fear in puppies during training and on long-term socialisation. Journal of the American Veterinary Medical Association, 233, 1874-1882.

DePorter, TL., Landsberg GM., Beck, A. 2011. Efficacy evaluation of DAP diffuser versus placebo diffuser for guide dogs completing the final stage of training program leading to graduation as a working guide dog with a visually impaired person. Proceedings of the Companion Animal Behaviour Therapy Study Group, 2011 www.leaderdog.org (Michigan, USA).

DePorter, T. L., Landsberg, G. M., Araujo, J. A., Ethierd, J. L., Bledsoee, D. L. (2012) Harmonease chewable tablets reduces noise-induced fear and anxiety in a laboratory canine thunderstorm simulation: A blinded and placebo-controlled study. J Vet Behav 7:225-232, 2012.

Dogs Trust. (2012). SHOCKING SURVEY REVEALS EFFECT FIREWORKS SEASON HAS ON OUR FOUR LEGGED FRIENDS. www.dogstrust.org.uk/mediacentre/newsreleases/pr12fireworks.aspx (accessed 30 December, 2013).

Duffy, D.L., Serpell, J.A. (2009) Effects of early rearing environment on behavioral development of guide dogs. Journal of Veterinary Behavior: Clinical Applications and Research. Volume 4, Issue 6, Pages 240–241

Duman, R. (2004). Depression: A Case of Neuronal Life and Death? Biological Psychiatry 2004;56:140–145.;65(5):392-400.

Ernst, E. (2007). A re-evaluation of kava (Piper methysticum). Br J Clin Pharmacol. 2007 Oct;64(4):415-7. Epub 2007 Jun 6.

Frank D, Erb HN, Houpt KA. (1999) Urine spraying in cats: presence of concurrent disease and effects of pheromone treatment. Appl Anim Behav Sc. 1999;61: 263, 272.

Gandia Estellés, M., Mills, D. 2006. Signs of travel-related problems in dogs and their response to treatment with dog appeasing pheromone. Veterinary Record 159:143-148.

Gaultier, E., Pageat, P. 2003. Effects of a synthetic dog appeasing pheromone (DAP) on behaviour problems during transport. Proceedings of the 4th International Behaviour Meeting, Caloundra, Australia, 2003; 33-35.

Gaultier, E., Bonnafous, L., Vienet-Legue, D., Falewee, C., Bougrat, L., Lafont-Lecuelle, C., Pageat, P. 2008. Efficacy of dog appeasing pheromone (DAP) in reducing stress associated with social isolation in newly adopted puppies. Veterinary Record, 163, 73-80.

Gaultier, E., Bonnafous, L., Vienet-Legue, D., Falewee, C., Bougrat, L., Lafont, C., Pageat, P. 2009. Efficacy of dog appeasing pheromone (DAP) in reducing behaviours associated with fear of unfamiliar people and new surroundings in newly adopted puppies. Veterinary Record, 164, 708-714.

Gazzanoa, A. (2008) Effects of early gentling and early environment on emotional development of puppies, Applied Animal Behaviour Science, Vol 110, Issues 3–4, Pages 294–304

Goswami, S., Rodríguez-Sierra, O., Cascardi, M., Paré, D. (2013). Animal models of post-traumatic stress disorder: face validity. Front Neurosci. 2013 May 31;7:89.

Grandin, T. (1992). Calming effects of deep touch pressure in patients with autistic disorder, college students, and animals. J Child Adolesc Psychopharmacol. 1992 Spring;2(1):63-72.

Gregory, N. G. (2004). Physiology and Behaviour of Animal Suffering. UFAW Animal Welfare Series, Blackwell Publishing, Oxford.

Griffith CA, Steigerwald ES, Buffington CA. (2000) Effects of a synthetic facial pheromone on behaviour of cats. J AM Vet Med Assoc 2000; 15:1154-1156

Handlin, L., Hydbring-Sandberg, E., Nilsson, A., Ejdebäck, M., Jansson, A., Uvnäs-Moberg, K. (2011). Short-term interaction between dogs and their owners – effects on oxytocin, cortisol, insulin and heart rate – an exploratory study. Anthrozoos 24, 301–316.

Hajszan, T., Dow, A., Warner-Schmidt, J. L., Szigeti-Buck, K., Sallam, N. L., Parducz, A., Leranth, C., Duman, R. S. (2009). Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry. 2009 Mar 1

Hart, B. L. (2005). The evolution of herbal medicine: behavioural perspectives. Anim. Behav. 70, 973–989.

Haussmann, M. F., Longenecker, A. S., Marchetto, N. M., Juliano ,S. A., Bowden, R. M. (2012). Embryonic exposure to corticosterone modifies the juvenile stress response, oxidative stress, and telomere length. Proc Biol Sci. 2012 Apr 7;279(1732):1447-56.

Hunthausen W. (2000) Evaluating a feline facial pheromone analogue to control urine spraying. Vet Med. 2000;95: 151â€“ 156.

Jia, N., Yang, K., Sun, Q., Cai, Q., Li, H., Cheng, D., Fan, X. and Zhu, Z. (2010), Prenatal stress causes dendritic atrophy of pyramidal neurons in hippocampal CA3 region by glutamate in offspring rats. Devel Neurobio, 70: 114–125.

Kapoor, A., Dunn, E., Kostaki, A., Andrews, M. H., and Matthews, S. G. (2006) Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol 572.1 pp 31–44 31

Kapoor, A. and Matthews, S. G. (2011), Testosterone is involved in mediating the effects of prenatal stress in male guinea pig offspring. The Journal of Physiology, 589: 755–766.

Kato, M., Miyaji, K., Ohtani, N., Ohta, M. (2012). Effects of prescription diet on dealing with stressful situations and performance of anxiety-related behaviors in privately owned anxious dogs. J Vet Behav 7:21-26, 2012.

Kilac, C., Curran, H. V., Noshirvani, H., Marks, I. M., Basoglu, M. (1999). Long-term effects of alprazolam on memory: a 3·5 year follow-up of agoraphobia/panic patients. Psychological Medicine, Vol 29 Is 01, 1999, pp 225-231.

Kim YM, Lee JK, Abd el-aty AM, Hwang SH, Lee JH, Lee SM. 2010. Efficacy of dog-appeasing pheromone (DAP) for ameliorating separation-related behavioral signs in hospitalized dogs. Can Vet J. April; 51(4): 380–384.

King, C., Buffington, L., Smith, T.J. and Grandin, T., 2014. The effect of a pressure wrap (ThunderShirt®) on heart rate and behavior in canines diagnosed with anxiety disorder. Journal of Veterinary Behavior: Clinical Applications and Research, 9(5), pp.215-221.

Korpivaara, M., Laapas, K., Huhtinen, M., Schöning, B. and Overall, K., 2017. Dexmedetomidine oromucosal gel for noise-associated acute anxiety and fear in dogs—a randomised, double-blind, placebo-controlled clinical study. Veterinary Record, pp.vetrec-2016.

Lakhan, S. E., Vieira, K.F. (2010). Nutritional and herbal supplements for anxiety and anxiety-related disorders: systematic review. Nutr J. 2010 Oct 7;9:42.

Landsberg, G., Milgram, B., Mougeot, I., Kelly, S. and de Rivera, C., 2017. Therapeutic effects of an alpha-casozepine and L-tryptophan supplemented diet on fear and anxiety in the cat. Journal of feline medicine and surgery, p.1098612X16669399.

LeDoux, J. E. (1996). The emotional brain. New York: Simon & Schuster.

Leroy, H., Depiereux, E., Giffroy, J. M., Diederich, C. (2009) Effect of prenatal environment on learning abilities in puppies and in adult dogs Journal of Veterinary Behavior: Clinical Applications and Research, Vol 4, Issue 6, Page 253

Levine, J., Barak, Y,. Gonzalves, M., Szor, H., Elizur, A., Kofman, O., Belmaker, R. H. (1995). Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry. 1995 May;152(5):792-4.

Levine, J. (1997). Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol. 1997 May;7(2):147-55.

Lord K A (2012). Comparison of the Sensory Development of Wolves (Canis lupus lupus) and Dogs (Canis lupus familiaris). Ethology 118, 1–11

Maccari S, Darnaudery M, Morley-Fletcher S, Zuena AR, Cinque C, Van Reeth O. (2003) Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neuroscience and Biobehavioral Reviews 27 119–127

Malek, S., Sample, S. J., Schwartz, Z., Nemke, B., Jacobson, P. B., Cozzi, E. M., Schaefer, S. L., Bleedorn, J. A., Holzman, G., Muir, P. (2012). Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis. BMC Vet Res 2012, 8:185

Marneros, A. (2007). Mood disorders: epidemiology and natural history. Psychiatry , Psychiatry 8(2):52-55, 2007.

Martínez-Téllez, R. I., Hernández-Torres, E., Gamboa, C. and Flores, G. (2009), Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring. Synapse, 63: 794–804.

McGreevy, P. D., Righetti, J., Thomson, P. C. (2012), The reinforcing value of physical contact and the effect on canine heart rate of grooming in different anatomical areas. Anthrozoos, Volume 18, Number 3, August 2012, pp. 236-244.

McManus, F. V. (2007). Assessment of anxiety. Psychiatry , Psychiatry 3(4):16-21.

Mills DS, Mills CB. (2001) Evaluation of a novel method for delivering a synthetic analogue of feline facial pheromone to control urine spraying by cats. Vet Record. 2001;149: 197, 199.

Mills, DS., Ramos, D., Gandia Estelles, M., Hargrave, C. 2006. A triple-blind placebo-controlled investigation into the assessment of the effect of dog appeasing pheromone (DAP) on anxiety related behaviour of problem dogs in the veterinary clinic. Applied Animal Behaviour Science, 98, 114-126.

Mills DS, Redgate SE, Landsberg GM. (2011) A meta-analysis of studies of treatments for feline urine spraying. PloS ONE. 2011;6: e18448.

Mills, D., Braem Dube, M., Zulch, H. 2013. Stress and Pheromonatherapy in Small Animal Clinical Behaviour. Wiley-Blackwell; 1 edition (7 Dec 2012).

Möhler, E., Parzer, P., Brunner, R., Wiebel, A., Resch, F. (2006). Emotional stress in pregnancy predicts human infant reactivity. Early Hum Dev. 2006 Nov;82(11):731-7. Epub 2006 May 6.

Mychasiuk, R., Gibb, R. and Kolb, B. (2012), Prenatal stress alters dendritic morphology and synaptic connectivity in the prefrontal cortex and hippocampus of developing offspring. Synapse, 66: 308–314

Ogata N, Takeuchi Y. (2001) Clinical trial of a feline pheromone analogue for feline urine marking. J Vet Med Sci. 2001;63: 157– 161.

Overall, KL, Dunham, AE. (2009) Homeopathy and the curse of the scientific method. The Veterinary Journal. 2009;180: 141– 148.

Pageat P, Gaultier E. (2003) Current research in canine and feline pheromones. Vet Clin North Am Small Animals. 2003;33: 187– 211.

Palestrini, C., Minero, M., Cannas, S., Berteselli, G., Scaglia, E., Barbieri, S., Cavallone, E., Puricelli, M., Servida, F., Dall’Ara, P. (2010). Efficacy of a diet containing caseinate hydrolysate on signs of stress in dogs. J Vet Behav 5:309-317.

Panksepp, J. (1998). Affective neuroscience. The foundations of human and animal emotions. New York: Oxford University Press.

Panksepp, J. (2005). Affective consciousness: Core emotional feelings in animals and humans. Consciousness and Cognition, 14, 30-80.

Peterson, C., Maier, S., and Seligman, M.E.P. (1993). Learned Helplessness: A Theory for the Age of Personal Control. New York: Oxford.

Phillips, C. (2002). Cattle Behaviour and Welfare. Blackwell Publishing, Oxford.

Rang, H. P., and Dale, M. M. (2012). Rang & Dale’s pharmacology, 7^th Ed. Edinburgh: Churchill Livingstone.

Rice, F., Jones, I. and Thapar, A. (2007), The impact of gestational stress and prenatal growth on emotional problems in offspring: a review. Acta Psychiatrica Scandinavica, 115: 171–183.

Scott, J.P., Fuller, J.L. (1965). Genetics and the social behavior of dogs Chicago: University of Chicago Press

Sheline, Y. I., Wang, P. W., Gado, M. H., Csernansky, J. G., Vannier, M. W., (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996 April 30; 93(9): 3908–3913.

Singh, N., Sharma, A., Singh, M. (1998). Possible mechanism of alprazolam-induced amnesia in mice. Pharmacology. 1998 Jan;56(1):46-50.

Tallman, J. F., Paul, S. M., Skolnick, P., Gallager, D. W. (1980). Receptors for the age of anxiety: pharmacology of the benzodiazepines. Science. 1980 Jan 18;207(4428):274-81.

Tan, K. R., Rudolph, U., Lüscher, C. (2011). Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011 Apr;34(4):188-97

Taylor, K., Mills DS. 2007. A placebo-controlled study to investigate the effect of dog appeasing pheromone (DAP) and other environmental and management factors on the reports of disturbance and house soiling during the night in recently adopted puppies (Canis familiaris). Applied Animal Behaviour Science, 105, 358-368.

Tessier, D. J., Bash, D. S. (2003) A surgeon’s guide to herbal supplements. J Surg Res. 2003 Sep;114(1):30-6.

T-Touch. (2013). What is TTouch? www.ttouch.com/whyTTouch.shtml. (accessed 1st October, 2017).

Vaidya, V. A., Duman, R. A. (2001). Depression – emerging insights from neurobiology. Br Med Bull (2001) 57 (1): 61-79.

Vallée M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S. (1997) Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J Neurosci. 1997 Apr 1;17(7):2626-36.

Volodina, M.A. (2012) Correction of Long-Lasting Negative Effects of Neonatal Isolation in White Rats Using Semax, Acta Naturae., 4(1): 86–92.

Wan M, Bolger N, & Champagne FA (2012). Human perception of fear in dogs varies according to experience with dogs. PLoS One. 7(12):e51775.

Weinstock, M. (2008). The long-term behavioural consequences of prenatal stress Neuroscience and Biobehavioral Reviews 32 (2008) 1073–1086

Welberg LA, Seckl JR. (2013) Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol. 2001 Feb;13(2):113-28.

Yang, J., Han, H., Cao, J., Li, L. and Xu, L. (2006), Prenatal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring. Hippocampus, 16: 431–436.

Yeh, C. M., Huang, C. C. and Hsu, K. S. (2012), Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro-brain-derived neurotrophic factor (BDNF) to mature BDNF. The Journal of Physiology, 590: 991–1010.