The use of cannabinoids in animals and therapeutic implications for veterinary medicine: A review

Abstract

Cannabinoids/medical marijuana and their possible therapeutic use have received increased attention in human medicine during the last years. This increased attention is also an issue for veterinarians because particularly companion animal owners now show an increased interest in the use of these compounds in veterinary medicine. This review sets out to comprehensively summarise well known facts concerning properties of cannabinoids, their mechanisms of action, role of cannabinoid receptors and their classification. It outlines the main pharmacological effects of cannabinoids in laboratory rodents and it also discusses examples of possible beneficial use in other animal species (ferrets, cats, dogs, monkeys) that have been reported in the scientific literature. Finally, the article deals with the prospective use of cannabinoids in veterinary medicine. We have not intended to review the topic of cannabinoids in an exhaustive manner; rather, our aim was to provide both the scientific community and clinical veterinarians with a brief, concise and understandable overview of the use of cannabinoids in veterinary medicine.

Full text

111
Veterinarni Medicina, 61, 2016 (3): 111–122 Review Article
doi: 10.17221/8762-VETMED
e use of cannabinoids in animals and therapeutic
implications for veterinary medicine: a review
L. L
1
, A. S
2
, P. G
3
1
Faculty of Medicine, Masaryk University, Brno, Czech Republic
2
Central European Institute of Technology, Masaryk University, Brno, Czech Republic
3
Veterinary Hospital and Ambulance AA Vet, Prague, Czech Republic
ABSTRACT: Cannabinoids/medical marijuana and their possible therapeutic use have received increased atten-
tion in human medicine during the last years. This increased attention is also an issue for veterinarians because
particularly companion animal owners now show an increased interest in the use of these compounds in veteri-
nary medicine. This review sets out to comprehensively summarise well known facts concerning properties of
cannabinoids, their mechanisms of action, role of cannabinoid receptors and their classification. It outlines the
main pharmacological effects of cannabinoids in laboratory rodents and it also discusses examples of possible
beneficial use in other animal species (ferrets, cats, dogs, monkeys) that have been reported in the scientific lit-
erature. Finally, the article deals with the prospective use of cannabinoids in veterinary medicine. We have not
intended to review the topic of cannabinoids in an exhaustive manner; rather, our aim was to provide both the
scientific community and clinical veterinarians with a brief, concise and understandable overview of the use of
cannabinoids in veterinary medicine.
Keywords: cannabinoids; medical marijuana; laboratory animals; companion animals; veterinary medicine
Abbreviations
AEA = anandamide (N-arachidonoylethanolamine, CB
1, 2
receptor agonist), 2-AG = 2-arachidonoylglycerol
(CB
1
receptor agonist), 2-AGE = 2-arachidonyl glyceryl ether (noladin ether, CB
1
receptor agonist), AM 251=
N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (synthetic
CB
1
receptor antagonist/inverse agonist), CB
1
= cannabinoid receptor type 1, CB
2
= cannabinoid receptor type 2,
CP-55,940 = (–)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (mixed
CB
1, 2
receptor agonist), FAAH = fatty acid amide hydrolase, GABA = gamma-amino butyric acid, GPR18 =
G-protein coupled receptor 18, GPR55 = G protein-coupled receptor 55, GPR119 = G protein-coupled receptor
119, HU-210 = (6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]
pyran-9-methanol (synthetic mixed CB
1, 2
receptor agonist), HU-308 = [(1R,2R,5R)-2-[2,6-dimethoxy-4-(2-meth-
yloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl] methanol (highly selective CB
2
receptor agonist),
IgE= immunoglobulin E, MGL = monoacylglycerol lipase, NADA = N-arachidonoyl dopamine (CB
1
receptor
agonist), PEA = palmitoylethanolamide, SR144528 = N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1]heptan2-yl]-5-(4-
chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrazole-3-carboxamide (CB
2
receptor antagonist/inverse
agonist), THC = delta-9-tetrahydrocannabinol (mixed CB
1, 2
receptor agonist), TRPV1 = transient receptor potential
cation channel subfamily V member 1, WIN 55,212-2 = (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)
pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (synthetic CB
1, 2
receptor agonist)
is work was supported by the project CEITEC – Central European Institute of Technology. from European
Regional Development Fund (Grant No. CZ.1.05/1.1.00/02.0068).

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1. Introduction
Cannabinoids have been used in traditional
medicine for thousands of years. There are re-
ports going back to ancient China (Unschuld 1986;
Zuardi 2006), medieval Persia (Gorji and Ghadiri
2002) or in Europe to the 19
th
century (following
the Napoleonic invasion of Egypt) (Kalant 2001).
It is important to emphasise that the use of can-
nabinoids in ancient or medieval cultures was not
only because of the psychoactive effects of these
substances; treatment was largely aimed at vari-
ous somatic disorders including headache, fever,
bacterial infections, diarrhoea, rheumatic pain
or malaria (Kalant et al. 2001; Gorji and Ghadiri
2002; Zuardi 2006). Despite this fact, the use of
cannabinoids is still illegal in many countries due to
their psychoactive effects and addictive potential.
Attempts by pharmaceutical companies in the sixth
decade of the twentieth century to produce can-
nabinoids with pharmacological effects and with-
out psychotropic activity were not successful (Fisar
2009; Pertwee 2009), although cannabinoids with
very weak or no psychotropic activity are known
(e.g. cannabidiol, cannabigerol, cannabichromene)
(Izzo et al. 2009; Hayakawa et al. 2010).
Although cannabinoids have been attracting at-
tention for many years, the last four decades have
brought completely new and scientifically well-
founded insights into their therapeutic potential.
Since 1975 more than 100 controlled clinical tri-
als with cannabinoids (or whole-plant prepara-
tions) for several indications have been carried
out and the results of these studies have led to the
approval of cannabis-based medicine in various
countries (Grotenhermen and Muller-Vahl 2012).
Consequently, there is increasing interest, particu-
larly in companion animal owners, regarding the
possible use of cannabinoids in veterinary medi-
cine.
In order to cover this broad theme in a concise
manner the text will first be focused on the classifi-
cation of cannabinoids and cannabinoid receptors.
Attention will then be turned to the therapeutic
potential of cannabinoids with regard to veterinary
medicine.
2. The endocannabinoid system
andclassification of cannabinoids
The endocannabinoid system consists of sev-
eral subtypes of cannabinoid receptors (the best
characterised are subtypes CB
1
and CB
2
), endo-
cannabinoids (endogenous substances that bind
to the receptors) and enzymes involved in endo-
cannabinoid biosynthesis through phospholipases
or degradation: post-synaptically by FAAH (fatty
acid amide hydrolase) and pre-synaptically by MGL
(monoacylglycerol lipase) (Pertwee 2005; Muccioli
2010; Battista et al. 2012). This system represents
a ubiquitous lipid signalling system (that appeared
early in evolution), which plays important regula-
tory roles throughout the body in all vertebrates
(De Fonseca et al. 2005). Below, we will focus on
the cannabinoid receptors and their ligands (can-
nabinoids) because of their principal therapeutic
significance.
Cannabinoids are chemical substances which act
primarily on specific cannabinoid receptors and are
basically divided into three groups; beside endoge-
nous cannabinoids (endocannabinoids) also herbal
cannabinoids (phytocannabinoids) and synthetic
cannabinoids have been described (Fisar 2009).
Endocannabinoids are endogenously formed
from membrane phospholipids in response to in-
creases in intracellular calcium; they are immedi-
ately released and act as ligands of cannabinoid
receptors (Miller and Devi 2011). The first endog-
enous ligand, -arachidonoylethanolamine, was
identified in 1992 from porcine brain (Devane et
al. 1992). It was named anandamide (AEA) based
on the Sanskrit word ‘ananda’ which means ‘inter-
nal bliss’. Other endogenous cannabinoids include
2-arachidonoylglycerol (2-AG), 2-arachidonyl
glyceryl ether (2-AGE, noladin ether) (Hanus et al.
Contents
1. Introduction
2. The endocannabinoid system and classifica-
tion of cannabinoids
3. The use of cannabinoids in animals
4. Prospective veterinary use of cannabinoids
5. Conclusions
6. References

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2001), O-arachidonoylethanolamine (virhodamine)
(Porter et al. 2002) and N-arachidonoyldopamine
(NADA) (Bisogno et al. 2000; Gaffuri et al. 2012;
Mechoulam et al. 2014). Within the nervous system
endocannabinoids are released from post-synaptic
neurons (retrograde neurotransmission) and they
bind to presynaptic CB
1
receptors (see below)
which results particularly in inhibition of GABA
or glutamate release (Heifets and Castillo 2009). In
neuron-astrocyte signalling cannabinoids released
from post-synaptic neurons stimulate astrocytic
CB
1
receptors, thereby triggering glutamatergic
gliotransmission (Castillo et al. 2012).
Phytocannabinoids are chemicals produced es-
pecially by female plants of Cannabis sativa and
are present in the resin of the herb. It has been
found that these plants contain over 100 phyto-
cannabinoids (Hill et al. 2012). The most studied
cannabinoids from Cannabis sativa include e.g.
delta-9-tetrahydrocannabinol (THC), cannabidiol,
tetrahydrocannabivarin, tetrahydrocannabiorcol,
cannabichromene and cannabigerol (Maione et al.
2013). THC was first isolated in 1964 (Gaoni and
Mechoulam 1964) and the majority of the herbal
cannabinoids soon after.
Synthetic cannabinoids are manufactured com-
pounds which bind to cannabinoid receptors (with
either agonistic or antagonistic activity) and many
of them were originally synthesised for research
purposes in University scientific departments or
pharmaceutical companies. The most frequently
reported series are represented by JWH (John W.
Huffman, Clemson University), CP (Pfizer), HU
(Hebrew University), AM (Alexandros Makriyannis,
Northeastern University), WIN (Sterling Winthrop)
and RCS (Research Chemical Supply) (Presley et al.
2013). Both phytocannabinoids and synthetic can-
nabinoids mimic the effects of endocannabinoids
(Grotenhermen 2006).
Two cannabinoid receptors were initially recog-
nised, CB
1
and CB
2
. Both these subtypes belong to
the large family of receptors that are coupled to G
proteins (Svizenska et al. 2008). Cannabinoid CB
1
receptors are among the most plentiful and widely
distributed receptors coupled to G proteins in the
brain (Grotenhermen 2006). The CB
1
receptor was
cloned in 1990 (Matsuda et al. 1990) and CB
2
in
1993 (Munro et al. 1993). CB
1
receptors are present
primarily in the central nervous system in regions
of the brain that are responsible for pain modula-
tion (certain parts of the spinal cord, periaqueduct-
al grey), movement (basal ganglia, cerebellum) or
memory processing (hippocampus, cerebral cortex)
(Grotenhermen 2006).To a lesser extent, they can
also be found in some peripheral tissues such as
pituitary gland, immune cells, reproductive tissues,
gastrointestinal tissues, sympathetic ganglia, heart,
lung, urinary bladder and adrenal gland (Pertwee
1997).
CB
2
receptors are particularly expressed in the
periphery, in the highest density on immune cells,
especially B-cells and natural killer cells (Pertwee
1997) and also in tonsils or spleen (Galiegue et al.
1995); nevertheless, their presence has also been
described in the CNS (Van Sickle et al. 2005). The
frequently discussed psychotropic effects of can-
nabinoids are mediated only by the activation of CB
1
receptors and not of CB
2
receptors (Grotenhermen
and Muller-Vahl 2012).
Endocannabinoids have also been shown to act on
TRPV1 receptors (transient receptor potential cat-
ion channels subfamily Vmember 1, also known as
the “capsaicin receptor” and “vanilloid receptor”1)
(Ross 2003). The existence of other G-protein can-
nabinoid receptors has also been suggested. These
proposed receptors (also called putative or non-
classical cannabinoid receptors) include GPR18,
GPR55 and GPR119 that have structural similarity
to CB
1
and CB
2
(Alexander et al. 2013; Zubrzycki
et al. 2014).
3. The use of cannabinoids in animals
It has been shown that the mechanism of action
of cannabinoids is very complex. The activation of
cannabinoid CB
1
receptors results in retrograde
inhibition of the neuronal release of acetylcholine,
dopamine, GABA, histamine, serotonin, glutamate,
cholecystokinin, D-aspartate, glycine and no-
radrenaline (Grotenhermen and Muller-Vahl 2012).
CB
2
receptors localised mainly in cells associated
with the immune system are involved in the control
of inflammatory processes. Their activation results
in, among other effects, inhibition of pro-inflam-
matory cytokine production and increased release
of anti-inflammatory cytokines (Zubrzycki et al.
2014). In addition, some cannabinoids were shown
to act not only at cannabinoid receptors but also at
vanilloid or serotonin 5-HT
3
receptors (Contassot
et al. 2004; Grotenhermen and Muller-Vahl 2012).
This complexity of interactions explains both the

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large number of physiological effects of cannabinoids
and the pharmacological influences of cannabinoid
preparations (Grotenhermen and Muller-Vahl 2012).
ere are a huge number of reports on the possible
beneficial effects of cannabinoids in human medi-
cine. eir therapeutic potential has been demon-
strated in the treatment of many disorders including
pain, inflammation, cancer, asthma, glaucoma, spinal
cord injury, epilepsy, hypertension, myocardial in-
farction, arrhythmia, rheumatoid arthritis, diabetes,
multiple sclerosis, Parkinson’s disease, Alzheimer’s
disease, depression or feeding-related disorders,
and many others (e.g. Porcella et al. 2001; Robson
2001; Rog et al. 2005; Blake et al. 2006; Pacher et al.
2006; Russo 2008; Scheen and Paquot 2009; Karst
et al. 2010; Lynch and Campbell 2011; Caffarel et al.
2012; Grotenhermen and Muller-Vahl 2012; Hill et
al. 2012; Maione et al. 2013; Lynch et al. 2014; Serpell
et al. 2014; Lynch and Ware 2015).
Information concerning the effects of cannabi-
noid on animals can be found on the experimen-
tal level and were obtained during the pre-clinical
testing of individual substances in mice, rats and
guinea pigs (i.e. laboratory rodents). Beneficial ef-
fects of cannabinoids in these animals have been
reported e.g. for disorders of the cardiovascular
system, cancer treatment, pain treatment, disorders
of the respiratory system or metabolic disorders,
and suggest the usefulness of further research in
this direction. Examples are summarised in Table 1.
For many further examples see the following re-
views: Croxford (2003), Guzman (2003), Croxford
and Yamamura (2005), Mendizabal and Adler-
Graschinsky (2007), Sarfaraz et al. (2008), Nagarkatti
et al. (2009), Steffens and Pacher (2012), Velasco et
al. (2012), Han et al. (2013), Massi (2013), Stanley
et al. (2013), Kucerova et al. (2014), Pertwee (2014),
Kluger et al. (2015).
Compared to reports from laboratory rodents,
there are a much smaller number of published pa-
pers dealing with pre-clinical testing of cannabinoids
in other species (rabbits, ferrets, cats, dogs), and an
even smaller number of reliable sources are available
to date concerning the clinical use of cannabinoids
in veterinary medicine for both companion and large
animals. Indeed, the majority of articles concerns ac-
tually marijuana poisoning and its treatment rather
than therapeutic applications (Girling and Fraser
2011; Meola et al. 2012; Fitzgerald et al. 2013).
It is therefore interesting that Mechoulam (2005)
reported the use of cannabinoid acids (which are
precursors of the neutral cannabinoids, such as
THC and cannabidiol) for veterinary purposes in
Czechoslovakia already in the 1950s because of
their antibiotic properties. The use of cannabinoids
as antibiotic drugs, however, was not further in-
vestigated, although it has been shown that can-
nabinoids exert antibacterial activity (Appendino
et al. 2008; Izzo et al. 2009).
The most frequently reported use of cannabi-
noids in companion animals (on a pre-clinical ba-
sis) is in association with the topical treatment of
glaucoma. Pate et al. (1998) administered AEA, its
R-alpha-isopropyl analogue, and the non-classical
cannabinoid CP-55,940 into the eyes of normoten-
sive rabbits. These substances were dissolved in
an aqueous 10–20% 2-hydroxypropyl-beta-cyclo-
dextrin solution (containing 3% polyvinyl alcohol).
The doses were 25.0 μg for CP-55,940 and 62.5 μg
for AEA and R-alpha-isopropyl anandamide. The
low solubility of the cannabinoids in water was
modified with cyclodextrins. It was shown that
CP-55,940 had considerable ocular hypotensive
effects, R-alpha-isopropyl anandamide exerted
these effects to a smaller extent and AEA caused
a typical bi-phasic initial hypertension and subse-
quent decrease in intraocular pressure (Pate et al.
1998). Song and Slowey (2000) administered the
substance WIN 55212-2 (CB
1, 2
receptor agonist)
topically into the eyes of healthy rabbits at doses
of 4, 20 and 100 μg. WIN 55212-2 at a dose of
100 mg significantly reduced intraocular pressure
at 1, 2, and 3 h after application. The effects of
the substance peaked between 1 and 2 h after ad-
ministration and intraocular pressure returned to
control levels at 4 h after application. The effects of
WIN 55212-2 on intraocular pressure were dose-
dependent. Twenty mg of the substance produced
a smaller effect than 100 mg and 4 mg of the drug
elicited non-significant lowering effects (Song and
Slowey 2000). Fischer et al. (2013) tested the effects
of topical administration of an ophthalmic solution
containing THC (2%) on aqueous humour flow rate
and intraocular pressure in 21 clinically normal
dogs. Topical administration of THC ophthalmic
solution led to a moderate reduction in mean in-
traocular pressure in these animals. Chien et al.
(2003) used cannabinoids in both normotensive
and glaucomatous monkeys (Macaca cynomolgus).
WIN 55212-2 (CB
1, 2
receptor agonist) dissolved in
45% 2-hydroxylpropyl-β-cyclodextrin was admin-
istered at concentrations of 0.07%, 0.2%, and 0.5%

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Table 1. Examples of cannabinoid use in rodent models
Cardiovascular
disorders
Slavic et al. (2013) – blockade of CB
1
receptor with rimonabant (CB
1
receptor antagonist/inverse
agonist) improved cardiac functions after myocardial infarction and reduced cardiac remodelling
Di Filippo et al. (2004) – administration of WIN 55,212-2 (synthetic CB
1, 2
receptor agonist) signifi-
cantly decreased the extent of infarct size in the area at risk in a model of mouse myocardial ischae-
mia/reperfusion
Batkai et al. (2004) – endocannabinoids tonically suppressed cardiac contractility in hypertension
in rats
Mukhopadhyay et al. (2007) – treatment with rimonabant significantly improved cardiac dysfunction
and protected against doxorubicin-induced cardiotoxicity in mice
Steffens et al. (2005) – oral administration of THC (CB
1, 2
receptor agonist) inhibited atherosclerosis
in mice
Cancer
Grimaldi et al. (2006) – metabolically stable anandamide analogue, 2-methyl-2V-F-anandamide
(CB
1
receptor agonist) significantly reduced the number and dimension of metastatic nodes in mice
Guzman (2003) – in vivo experiments revealed that cannabinoid treatment of mice slowed down the
growth of various tumour xenografts, including lung carcinomas, gliomas, thyroid epitheliomas, skin
carcinomas and lymphomas
Pain
Luongo et al. (2013) – chronic treatment with palmitoylethanolamide (endogenous cannabinoid-like com-
pound in the central nervous system) significantly reduced mechanical allodynia and thermal hyperalgesia
Pascual et al. (2005) – WIN 55,212-2 (synthetic CB
1, 2
receptor agonist) reduced neuropathic nocicep-
tion induced by paclitaxel in rats
Hanus et al. (1999) – HU-308 (highly selective CB
2
receptor agonist) elicited anti-inflammatory and
peripheral analgesic activity
Xiong et al. (2012) – administration of cannabidiol (indirect antagonist of CB
1
and CB
2
receptor agonists)
significantly suppressed chronic inflammatory and neuropathic pain in rodents
Asthma
Jan et al. (2003) – THC and cannabinol exhibited potential therapeutic utility in the treatment of allergic
airway disease by inhibiting the expression of critical T cell cytokines and the associated inflammatory
response in an animal model of mice sensitised with ovalbumin
Giannini et al. (2008) – CP-55,940 (CB
1, 2
receptor agonist) showed positive effects on antigen-induced
asthma-like reaction in sensitised guinea pigs and conversely, both SR144528 (CB
2
receptor antagonist/
inverse agonist) and AM 251 (CB
1
receptor antagonist/inverse agonist) reverted these protective effects
Vomiting
Darmani et al. (2001a) – THC and CP-55,940 (synthetic agonist at CB
1
and CB
2
receptors) prevented
emesis produced by SR 141716A (CB
1
receptor antagonist/inverse agonist) in in the least shrew
(Cryptotis parva)
Darmani (2001b) – THC reduced the percentage of animals vomiting and the frequency of vomits pro-
voked by cisplatin in the same animal species
Parker et al. (2004) – THC and cannabidiol (indirect antagonist of CB
1
and CB
2
receptor agonists) reduced
lithium-induced vomiting in the house musk shrew (Suncus murinus)
Diabetes
El-Remessy et al. (2006) – cannabidiol (indirect antagonist of CB
1
and CB
2
receptor agonists) reduced
neurotoxicity, inflammation, and blood-retinal barrier breakdown in streptozotocin-induced diabetic rats
Weiss et al. (2006) – cannabidiol significantly reduced the incidence of diabetes in young non-obese
diabetes-prone female mice
Weiss et al. (2008) – cannabidiol ameliorated the manifestations of diabetes in non-obese diabetes-prone
female which were either in a latent diabetes stage or with initial symptoms of the disease
Retinitis
pigmentosa
Lax et al. (2014) – HU-210 (CB
1, 2
receptor agonist) preserved cone and rod structure and function,
thus showing neuroprotective effects on retinal degeneration in a rat model for autosomal dominant
retinitis pigmentosa
Food intake,
body weight
Hildebrandt et al. (2003) – AM 251 (CB
1
receptor antagonist/inverse agonist) reduced inguinal subcutane-
ous, retroperitoneal and mesenteric adipose tissue mass in Western diet-induced obese mice. Anorectic
effects of AM 251 were also reported by e.g. Slais et al. (2003), Chambers et al. (2006) and Tallett et al. (2007)

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Five normal monkeys received 50 µl (2 × 25 µl) of
WIN 55212-2 to the right eye, and an equal volume
of the vehicle to the left eye. In glaucomatous mon-
keys, 50 µl of WIN 55212-2 was administered to the
glaucomatous eye only. Moreover, a multiple-dose
study was carried out in 8 monkeys with unilateral
glaucoma. WIN 55212-2 (0.5%) was administered
to the glaucomatous eye twice daily at 9:30 AM and
3:30 PM for five consecutive days. It was shown that
in the five normal monkeys unilateral application
of the substance significantly decreased intraocular
pressure for up to 4, 5, and 6 h following adminis-
tration of the 0.07%, 0.2%, and 0.5% concentrations,
respectively. The maximum changes in intraocular
pressure were found at 3 h after drug application.
In the eight glaucomatous monkeys the administra-
tion of WIN 55212-2 also resulted in a significant
decrease in intraocular pressure (Chien et al. 2003).
Other potential and promising indications for
cannabinoid use in veterinary medicine include in-
flammation and pain treatment as well as possible
applications in dermatology and oncology. With
respect to inflammation and pain, Re et al. (2007)
authored a review in which they focused on the role
of an endogenous fatty acid amide analogue of the
endocannabinoid AEA – termed palmitoylethan-
olamide (PEA) – in tissue protection. PEA does not
bind to CB
1
and CB
2
receptors but has affinity for
the cannabinoid-like G-coupled receptors GPR55
and GPR119. It acts as a modulator of glia and mast
cells (Keppel Hesselink 2012), and has been shown
to enhance AEA activity through a so-called “entou-
rage effect” (Mechoulam et al. 1998). Re et al. (2007)
concluded that the use of natural compounds such as
PEA influences endogenous protective mechanisms
and can represent an advantageous and beneficial
novel therapeutic approach in veterinary medicine.
Regarding dermatology, Scarampella et al. (2001)
administered the substance PLR 120 (an analogue
of PEA) to 15 cats with eosinophilic granulomas or
eosinophilic plaques. Clinical improvements of signs
and lesions were evident in 10 out of 15 cats, suggest-
ing that PLR-120 could be a useful drug for the treat-
ment of these disorders (Scarampella et al. 2001).
Similarly, Cerrato et al. (2010) isolated mast cells
from the skin biopsies of 18 dogs, incubated these
cells with IgE-rich serum and challenged them with
anti-canine IgE. Subsequently, histamine, prosta-
glandin D2 and tumour necrosis factor-alpha release
was measured in the presence and absence of in-
creasing concentrations of palmitoylethanolamide.
e authors found that histamine, prostaglandin D2
and tumour necrosis factor-alpha release induced by
canine anti-IgE were significantly inhibited in the
presence of PEA. us, it can be concluded that PEA
has therapeutic potential in the treatment of derma-
tological disorders involving mast cell hyperactivity
(Cerrato et al. 2010). Moreover, Cerrato et al. (2012)
evaluated the effects of PEA on the cutaneous aller-
gic inflammatory reaction induced by different im-
munological and non-immunological stimuli in six
spontaneously Ascaris-hypersensitive Beagle dogs.
ese dogs were challenged by intradermal injec-
tions of Ascaris suum extract, substance P and anti-
canine IgE, before and after PEA application (orally
at doses of 3, 10 and 30 mg/kg). e results have
shown that PEA was effective in reducing immediate
skin reaction in these dogs with skin allergy (Cerrato
et al. 2012). With respect to oncology, Figueiredo
et al. (2013) found that the synthetic cannabinoid
agonist WIN-55,212-2 was effective as a potential in-
hibitor of angiogenesis in a canine osteosarcoma cell
line. Although further in vivo research is certainly
required, the results thus far indicate that the use of
cannabinoid receptor agonists as potential adjuvants
to chemotherapeutics in the treatment of canine
cancers could be a promising therapeutic strategy.
Looney (2010) reported the use of cannabinoids for
palliative care in animals suffering from oncological
disease to stimulate eating habits. Finally, McCarthy
and Borison (1981) reported antiemetic activity of
nabilone (synthetic CB
1, 2
agonist) in cats after cis-
platin (anti-cancer drug) treatment and similarly Van
Sickle et al. (2003) reported that THC (0.05–1mg/kg
i.p.) reduced the emetic effects of cisplatin in ferrets.
4. Prospective veterinary use of cannabinoids
As can be seen from the above instances, can-
nabinoids have a myriad of pharmacological effects
and the beneficial impact of different cannabinoids
has been proven and documented many times in
various laboratory/companion animals. It has been
shown that the same cannabinoid drug can elicit
divergent responses in humans and animals. For ex-
ample, Jones (2002) reported increased heart rate
and slightly increased supine blood pressure after
THC administration in humans, whereas the car-
diovascular effects in animals were different, with
bradycardia and hypotension (Jones 2002). us,
a definite advantage of the use of cannabinoids in

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doi: 10.17221/8762-VETMED
animals is that the research and pre-clinical testing
was carried out on various animal species and these
categories can now represent target species in the
case of veterinary use. In other words, the risk of di-
vergent responses to the same drug, which has been
described for humans and animals, is much lower.
It should also be taken into account that the ma-
jority of cannabinoids possess psychotropic prop-
erties which may change the behaviour of animals
(e.g. locomotion) and that these substances have
addictive potential (Fattore et al. 2008; Landa et
al. 2014a; Landa et al. 2014b). On the other hand,
other drug classes with even stronger effects on
the CNS and addictive properties have been used
therapeutically in both humans and veterinary
medicine for centuries (e.g. opioids) because their
benefit outweighs the risks.
Cannabis-based medical products were intro-
duced to human medicine in the last years in
many countries (among others Austria, Canada,
Czech Republic, Finland, Germany, Israel, Italy).
Preparations approved for use in human medicine
include Cesamet, Dronabinol, Sativex, Bedrocan,
Bedrobinol, Bediol, Bedica or Bedrolite. For dogs
and cats, the veterinarian-recommended, ready-
made hemp based supplement Canna-Pet is pres-
ently available (containing non-psychoactive
cannabidiol). PEA can at present be used to restore
skin reactivity in animals in a veterinary medication
sold under the trade name Redonyl (LoVerme et al.
2005). It is therefore not surprising that owners of
animals are also exhibiting increasing interest in the
possible use of cannabinoids/medical marijuana in
veterinary medicine as can be seen by the number
of internet forums concerned with this issue (e.g.
dvm360 magazine, Cannabis Financial Network
or Medical Daily). In the Journal of the American
Veterinary Medical Association, Nolen (2013) re-
ported anecdotal evidence from pet owners de-
scribing beneficial effects of marijuana use in dogs,
cats and horses and, moreover, also the opinions of
professionals who believe in the potential useful-
ness of cannabis use in veterinary medicine. The re-
luctant attitude of veterinarians towards the use of
cannabinoids/medical marijuana in animals could
be associated with the risk that owners will make at-
tempts to treat their animals using cannabis-based
products, which can lead to intoxication. In the
article by Nolen (2013), Dr. Dawn Boothe (Clinical
Pharmacology Laboratory at Auburn University
College of Veterinary Medicine) concluded that
veterinarians should be part of the debate about
the use of cannabinoids/medical marijuana, e.g. by
means of a controlled clinical trial dealing with the
use of marijuana to treat cancer pain in animals.
5. Conclusions
The isolation of THC in 1964 represented a
breakthrough in research progress concerning can-
nabinoids. The discovery of the cannabinoid recep-
tors and their endogenous ligands, definition of the
endocannabinoid system and description of other
cannabinoid substances elicited increased interest
in this research and in the possible therapeutic po-
tential in animal models. The results from this basic
research finally led to the addition of cannabinoids/
medical marijuana to the spectrum of therapeutic
possibilities for various disorders in humans. The
therapeutic effects of cannabinoids/medical mari-
juana on companion animals are now the subject
of discussion in numerous internet forums and
such debate could result in attempts at treatment
using cannabinoids without the necessary safety
precautions. Thus, the prospective use of cannabi-
noids for veterinary purposes needs to be taken
seriously; this could decrease the risk of attempts
at unauthorised and non-professional treatment by
animal owners. Legislative regulations may differ
in various countries and the use of cannabinoids/
medical marijuana must be in accordance with the
respective rules.
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Received: 2015–11–13
Accepted after corrections: 2016–02–05
Corresponding Author:
Alexandra Sulcova, CEITEC Masaryk University, Kamenice 5/A19, 625 00 Brno, Czech Republic
E-mail: sulcova@med.muni.cz