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



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.
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
, A. S
, P. G
Faculty of Medicine, Masaryk University, Brno, Czech Republic
Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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
AEA = anandamide (N-arachidonoylethanolamine, CB
1, 2
receptor agonist), 2-AG = 2-arachidonoylglycerol
receptor agonist), 2-AGE = 2-arachidonyl glyceryl ether (noladin ether, CB
receptor agonist), AM 251=
N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (synthetic
receptor antagonist/inverse agonist), CB
= cannabinoid receptor type 1, CB
= cannabinoid receptor type 2,
CP-55,940 = (–)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (mixed
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
receptor agonist),
IgE= immunoglobulin E, MGL = monoacylglycerol lipase, NADA = N-arachidonoyl dopamine (CB
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
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).
Review Article Veterinarni Medicina, 61, 2016 (3): 111–122
doi: 10.17221/8762-VETMED
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
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-
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
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
and CB
), 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
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.
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
Veterinarni Medicina, 61, 2016 (3): 111–122 Review Article
doi: 10.17221/8762-VETMED
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
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
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
and CB
. Both these subtypes belong to
the large family of receptors that are coupled to G
proteins (Svizenska et al. 2008). Cannabinoid CB
receptors are among the most plentiful and widely
distributed receptors coupled to G proteins in the
brain (Grotenhermen 2006). The CB
receptor was
cloned in 1990 (Matsuda et al. 1990) and CB
1993 (Munro et al. 1993). CB
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
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
receptors and not of CB
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
and CB
(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
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).
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
receptors (Contassot
et al. 2004; Grotenhermen and Muller-Vahl 2012).
This complexity of interactions explains both the
Review Article Veterinarni Medicina, 61, 2016 (3): 111–122
doi: 10.17221/8762-VETMED
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%
Veterinarni Medicina, 61, 2016 (3): 111–122 Review Article
doi: 10.17221/8762-VETMED
Table 1. Examples of cannabinoid use in rodent models
Slavic et al. (2013) – blockade of CB
receptor with rimonabant (CB
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-
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
Grimaldi et al. (2006) – metabolically stable anandamide analogue, 2-methyl-2V-F-anandamide
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
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
receptor agonist) elicited anti-inflammatory and
peripheral analgesic activity
Xiong et al. (2012) – administration of cannabidiol (indirect antagonist of CB
and CB
receptor agonists)
significantly suppressed chronic inflammatory and neuropathic pain in rodents
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
receptor antagonist/
inverse agonist) and AM 251 (CB
receptor antagonist/inverse agonist) reverted these protective effects
Darmani et al. (2001a) – THC and CP-55,940 (synthetic agonist at CB
and CB
receptors) prevented
emesis produced by SR 141716A (CB
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
and CB
receptor agonists) reduced
lithium-induced vomiting in the house musk shrew (Suncus murinus)
El-Remessy et al. (2006) – cannabidiol (indirect antagonist of CB
and CB
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
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
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)
Review Article Veterinarni Medicina, 61, 2016 (3): 111–122
doi: 10.17221/8762-VETMED
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
and CB
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
Veterinarni Medicina, 61, 2016 (3): 111–122 Review Article
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
... Cannabis sativa L. is an ancient plant well known for pharmacological and psychotropic properties. It is rich in phytocannabinoids, a class of terpenophenolic compounds, including the delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (Landa et al., 2016). THC is more related to the psychotropic effects of the plant, while CBD is more related to the therapeutic effects (Greb and Puschner, 2018). ...
... Cannabis is used in the treatment of several illnesses and conditions in people, such as pain relief, epilepsy, nausea and vomiting, anorexia, anxiety, among others (Pratt et al., 2019). However, its use is illegal in some countries due to psychoactive effects and addictive potential (Landa et al., 2016). At the same time, in other countries, the use of cannabis-based products is already legal (Hall et al., 2019). ...
Cannabis is used in the treatment of several human conditions; however, its use is still less explored in veterinary medicine. This systematic review aims to summarize the evidence of efficacy and safety of the use of cannabis for the treatment of animal disease. A literature search was performed for studies published until 16 March 2021 in five databases. Randomized clinical trials (RCTs) that reported the efficacy or safety of cannabis in the treatment of animal disease were included. The RoB 2 Tool was used to assess the risk of bias. A total of 2427 records were identified, of which six studies fully met the eligibility criteria. RCTs were conducted in dogs with osteoarthritis (n = 4), with epilepsy (n = 1), and with behavioral disorders (n = 1). All studies used cannabidiol (CBD) oil in monotherapy or in combination with other drugs. Studies used CBD at 2 or 2.5 mg kg −1 twice daily (n = 4), orally (n = 5), during 4 or 6 weeks (n = 3), and compared CBD with placebo (n = 5). CBD significantly reduced pain and increased activity in dogs with osteoarthritis (n = 3). Moreover, CBD significantly reduced the frequency of seizures in dogs with epilepsy (n = 1) and the aggressive behavior of dogs (n = 1). Although promising results were identified, studies were heterogeneous and presented risks of bias that required caution in the interpretation of findings. Therefore, there was some evidence to support the use of CBD in dogs with osteo-arthritis to reduce pain and increased activity, but limited evidence against epilepsy and behavioral problems. In addition, CBD was well tolerated with mild adverse effects. More RCTs with high quality of evidence are needed, including greater numbers of animal subjects, additional species, and clear readout measures to confirm these findings.
... Cannabidiol (CBD) is one of over 100 phytocannabinoids produced by glandular trichomes of Cannabis sativa (1)(2)(3). Cannabidiol has been proposed to induce a plethora of beneficial health effects, including anxiolytic, antipsychotic, antiinflammatory, analgesia, and immunomodulatory effects (4,5). The wide range of potential therapeutic effects are thought to be a result of multiple mechanisms of action on receptors known to be a part of the endocannabinoid system [ECS; (6,7)]. ...
... Cannabidiol is already being supplemented to dogs for its potential therapeutic applications including osteoarthritis, separation anxiety, noise phobias, and epilepsy (4,11). Several studies have evaluated its effectiveness in dogs with osteoarthritis (23,103,104) noise phobias (105), and epilepsy (106) with mixed results. ...
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Despite the increased interest and widespread use of cannabidiol (CBD) in humans and companion animals, much remains to be learned about its effects on health and physiology. Metabolomics is a useful tool to evaluate changes in the health status of animals and to analyze metabolic alterations caused by diet, disease, or other factors. Thus, the purpose of this investigation was to evaluate the impact of CBD supplementation on the canine plasma metabolome. Sixteen dogs (18.2 ± 3.4 kg BW) were utilized in a completely randomized design with treatments consisting of control and 4.5 mg CBD/kg BW/d. After 21 d of treatment, blood was collected ~2 h after treat consumption. Plasma collected from samples was analyzed using CIL/LC-MS-based untargeted metabolomics to analyze amine/phenol- and carbonyl-containing metabolites. Metabolites that differed — fold change (FC) ≥ 1.2 or ≤ 0.83 and false discovery ratio (FDR) ≤ 0.05 — between the two treatments were identified using a volcano plot. Biomarker analysis based on receiver operating characteristic (ROC) curves was performed to identify biomarker candidates (area under ROC ≥ 0.90) of the effects of CBD supplementation. Volcano plot analysis revealed that 32 amine/phenol-containing metabolites and five carbonyl-containing metabolites were differentially altered (FC ≥ 1.2 or ≤ 0.83, FDR ≤ 0.05) by CBD; these metabolites are involved in the metabolism of amino acids, glucose, vitamins, nucleotides, and hydroxycinnamic acid derivatives. Biomarker analysis identified 24 amine/phenol-containing metabolites and 1 carbonyl-containing metabolite as candidate biomarkers of the effects of CBD (area under ROC ≥ 0.90; P < 0.01). Results of this study indicate that 3 weeks of 4.5 mg CBD/kg BW/d supplementation altered the canine metabolome. Additional work is warranted to investigate the physiological relevance of these changes.
... Cannabinoids have gained attention in recent years for their potential efficacy as analgesics in patients with chronic pain. They have a complex mechanism of action, acting on peripheral, spinal and supra-spinal sites to exert antinociceptive and antihyperalgesic effects (Richardson 2000, Landa et al. 2016. ...
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Canine osteoarthritis is a significant cause of pain in many dogs and can therefore compromise animal welfare. As the understanding of the biology and pain mechanisms underpinning osteoarthritis grows, so do the number of treatments available to manage it. Over the last decade, there have been a number of advances in the pharmaceutical treatment options available for dogs with osteoarthritis, as well as an increasing number of clinical trials investigating the efficacy of pre‐existing treatments. This review aims to examine the current evidence behind pharmaceutical treatment options for canine osteoarthritis, including non‐steroidal anti‐inflammatory drugs, piprants, monoclonal antibodies, adjunctive analgesics, structure modifying osteoarthritis drugs and regenerative therapies.
... Gamble et al. showed increased comfort and activity in dogs diagnosed with osteoarthritis after treatment with CBD (1). From the limited studies completed, CBD seems to be therapeutic without significant adverse effects (1,(3)(4)(5)(6). ...
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Cannabidiol (CBD), the non-psychotropic component of cannabis, has drawn increased interest amongst some medical professionals for its potential therapeutic effects. Human and canine work has been done to describe CBD where it is already widely used, however, little is known about the effects of CBD in livestock species. The purpose of this descriptive study was to determine the pharmacokinetics (PK) of CBD in calves after a single oral exposure to CBD oil. Seven male Holstein calves received a single oral dose of 25 mg/mL CBD oil to achieve 5 mg/kg dose of CBD. Blood samples were collected for 48 (h) after dosing. The CBD geometric mean maximum concentration of 0.05 ug/mL was reached 7.5 h after administration. The geometric mean half-life was 23.02 h. Cannabidiol administered orally to cattle is slowly absorbed and has an extended elimination half-life compared to other species.
... In the early 20th century, however, due to attitude change, cannabis was first classified as a restricted drug and eventually became prohibited as an illegal drug in North America (Carter, 2020). Although cannabis is recently legalized in Canada in 2018 and eleven states of the USA as well as the District of Columbia over the years (Carter, 2020), the use of cannabinoids remains illicit in many countries due to their psychoactive effects and addictive potential (Landa et al., 2016). As a result, the medicinal properties of cannabis remain underexplored. ...
Recent advances in cannabidiol (CBD) use in canines and felines for anxiety management, pain management, and anti-inflammatory effects were reviewed using a literature search conducted with the following keywords: CBD, anxiety, inflammation, pain, dogs, cats, and companion animals. For decades, research on CBD has been hindered due to the status of cannabis (C. sativa L.) as an illicit drug. Limited safety data show that CBD is well-tolerated in dogs, with insufficient information on the safety profile of CBD in cats. Upon oral supplementation of CBD, elevation in liver enzymes was observed for both dogs and cats, and pharmacokinetics of CBD are different in the two species. There is a significant gap in the literature on the therapeutic use of CBD in cats, with no feline data on anxiety, pain, and inflammation management. There is evidence that chronic osteoarthritic pain in dogs can be reduced by supplementation with CBD. Furthermore, experiments are required to better understand whether CBD has an influence on noise-induced fear and anxiolytic response. Preliminary evidence exists to support the analgesic properties of CBD in treating chronic canine osteoarthritis; however, there are inter- and intra-species differences in pharmacokinetics, tolerance, dosage, and safety of CBD. Therefore, to validate the anxiety management, pain management, and anti-inflammatory efficacy of CBD, it is essential to conduct systematic, randomized, and controlled trials. Further, the safety and efficacious dose of CBD in companion animals warrants investigation.
The use of cannabis-based products for therapeutic purposes is a reality in the field of animal health. However, although cannabis is considered safe when appropriately used by human patients, cannabis-based products can pose a risk to companion animals such as dogs, depending on their composition or route of administration. Thus, this article discusses aspects of the safety and efficacy of different cannabis-based products in dogs' treatment through an integrative review. The review was systematically performed in Medline (via Pubmed®) and Latin American and Caribbean Health Sciences Literature (LILACS) databases, with period restriction (between 1990 and 2021). The qualified articles (n=19), which met the previously established inclusion criteria, were critically evaluated. Based on the literature review, it is possible to infer safety in the administration of cannabis-based products for the treatment of dogs, especially products rich in cannabidiol (CBD), free or with low concentrations of tetrahydrocannabinol, under the conditions evaluated. In addition, CBD products potentially promote improved quality of life and reduce pain perception in animals affected by canine osteoarthritis. Finally, owing to the lack of large-scale and robust clinical research studies, the performance of clinical trials, considering the individual characteristics of each cannabis-based product (composition, concentration, nature of adjuvants, dosage form, route of administration), is strongly encouraged.
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Untargeted metabolomics has been increasingly used to evaluate metabolic alterations caused by diet, disease, or other factors in animals. The purpose of this exploratory study was to evaluate the impact of Cannabidiol (CBD) supplementation on the canine carboxyl and hydroxyl submetabolomes. Sixteen dogs (18.2 ± 3.4 kg BW) were utilized in a completely randomized design with treatments consisting of control and 4 mg CBD/kg BW/d. After 21 d of treatment, blood was collected approximately 2 h after morning treat consumption. Plasma collected from samples was analyzed using CIL/LC-MS-based untargeted metabolomics to analyze carboxyl- and hydroxyl-containing metabolites. Metabolites that differed (fold change (FC) ≥ 1.2 or ≤ 0.83 and FDR ≤ 0.05) between the two treatments were identified using a volcano plot. Biomarker analysis based on Receiver Operating Characteristic (ROC) curves was performed to identify biomarker candidates (area under ROC ≥ 0.90) of the effects of CBD supplementation. Volcano plot analysis revealed that 42 carboxyl-containing metabolites and 32 hydroxyl-containing metabolites were differentially altered (FC ≥ 1.2 or ≤ 0.83, FDR ≤ 0.05) by CBD; these metabolites were involved in the metabolism of lipids, amino acids, carbohydrates, and more. Biomarker analysis identified 23 carboxyl-containing metabolites and 15 hydroxyl-containing metabolites as candidate biomarkers of the effects of CBD (area under ROC ≥ 0.90; P<0.01). Results of this study indicate that 4 mg CBD/kg BW/d supplemented for 3-weeks altered the canine carboxyl and hydroxyl submetabolomes and may indicate potential mechanisms by which CBD exerts some of its effects. Future work is warranted to investigate these potential mechanisms.
Cannabidiol (CBD) has gained widespread popularity as a treatment for osteoarthritis (OA) in pets; however, there is minimal scientific evidence regarding safe and effective dosing. This study determined plasma and tissue pharmacokinetics after oral CBD oil suspension administration in Hartley guinea pigs (Cavia porcellus), which spontaneously develop OA at 3 months of age. Ten, 5-month-old, male guinea pigs were randomly assigned to receive 25 (n = 5) or 50 mg/kg (n = 5) CBD oil once orally. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h timepoints. Open-field enclosure monitoring revealed no adverse effects. After euthanasia, stifle cartilage and infrapatellar fat pads were collected to quantitate CBD. CBD concentrations were determined using a validated liquid chromatography-mass spectrometry method, and pharmacokinetic parameters were calculated using noncompartmental analysis. The area under the plasma concentration-versus-time curve was 379.5 and 873.7 h*ng/mL, maximum plasma concentration was 42 and 96.8 ng/mL, time to maximum plasma concentration was 1.6 and 4.8 h, and terminal phase half-life was 8.1 and 10.8 h for the 25 and 50 mg/kg doses, respectively. CBD was detected in joint tissues of all animals. Further studies, including work in female guinea pigs, are needed to determine the efficacy of CBD for OA.
Medical use of Cannabis (or hemp) began thousands of years ago. In the 20th century, mechanisms of action were demonstrated with the discovery of its active substances, the phytocannabinoids, and its pharmacological targets, the endocannabinoid system. This system is composed of receptors, endogenous substances, and enzymes, and it participates in the modulation of physiological mechanisms in several species, including dogs. Studies indicate that changes in this system may contribute to the genesis of some diseases. Therefore, the use of substances that act on its components may help in the treatment of these diseases. The main phytocannabinoids described are Δ9−tetrahydrocannabinol (THC) and cannabidiol (CBD). In humans, the benefits of using CBD in several diseases have been demonstrated. The popularization of this type of treatment has also reached veterinary medicine, which on one hand was related to an increase in adverse event records, but on the other also allowed reports of anecdotal evidences of its effectiveness and safety in animals. Clinical studies published so far indicate that the use of CBD in dogs can be safe at given doses and can contribute to osteoarthritis and idiopathic epilepsy treatments. Clinical and pre-clinical studies and case reports were reviewed in this report to identify the main characteristics of hemp-based therapies in dogs, including its pharmacokinetics, pharmacodynamics, safety, and efficacy in the treatment of diseases.
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This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing canna- binoids in pain treatment. Tetrahydrocannabinol (THC, Marinol ® ) and nabilone (Cesamet ® ) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC (partial CB 1 receptor agonist ) and can- nabidiol (CBD, a non-euphoriant, anti-infl ammatory analgesic with CB 1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numer- ous randomized clinical trials have demonstrated safety and effi cacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profi les. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
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Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB(1) cannabinoid receptor (K(i) = 21.2 +/- 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB(2) receptor (K(i) > 3 microM).
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Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.
T cells are sensitive to modulation by cannabinoids as evidenced by their ability to inhibit expression of cytokines, including interleukin (1L)-2 and IL-4. Because T cells play a key role in the pathophysiology of allergic asthma by expressing T helper cell (Th)2 cytokines, the objective of the present studies was to examine the effect of cannabinoids on immunologic and pathologic features associated with the allergic airway response induced by ovalbumin (Ova). A/J mice were systemically sensitized with Ova and subsequently challenged with aerosolized Ova. The steady-state mRNA expression of IL-2 and Th2 cytokines (IL-4, IL-5, and IL-13) was markedly increased in the lungs of Ova-sensitized mice 24 h after a single Ova challenge. Concordantly, the level of total and Ova-specific serum immunoglobulin (1g)E and intraepithelial mucosubstances in the axial intrapulmonary airway of Ova-sensitized mice was robustly elevated 96 h after the second Ova challenge. Cannabinol (CBN) or Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 50 mg/kg, ip), administered daily for 3 consecutive days before sensitization and then before challenge, significantly attenuated the elevation of IL-2, IL-4, IL-5, and IL-13 steady-state mRNA expression elicited by Ova challenge in the lungs. In addition, the elevation of serum IgE and the mucus overproduction induced by Ova challenge was also markedly attenuated by CBN or Delta(9)-THC administration in Ova-sensitized mice. These results suggest that plant-derived immunomodulatory cannabinoids exhibit potential therapeutic utility in the treatment of allergic airway disease by inhibiting the expression of critical T cell cytokines and the associated inflammatory response.
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
The psychostimulant methamphetamine (Met), similarly to other drugs of abuse, is known to produce an increased behavioural response after its repeated application (behavioural sensitisation). It has also been described that an increased response to a drug may be elicited by previous repeated administration of another drug (cross-sensitisation). We have previously shown that the CB1, CB2 and TRPV (vanilloid) cannabinoid receptor agonist methanandamide, cross-sensitised to Met stimulatory effects in mice. The present study was focused on ability of the more selective and potent CB1 receptor activator arachidonylcyclopropylamide (ACPA) to elicit cross-sensitisation to the stimulatory effects of Met on mouse locomotor behaviour in the Open field test. Male mice were randomly divided into three groups and on seven occasions (from the 7th to 13th day of the experiment) were administered drugs as follows:(a) n1: vehicle at the dose of 10 ml/kg/day; (b) n2: Met at the dose of 2.5 mg/kg/day; (c) n3: ACPA at the dose of 1.0 mg/kg/day. Locomotor behaviour in the Open field test was measured (a) after administration of vehicle on the 1st experimental day, (b) after the 1st dose of drugs given on the 7th day, and (c) on the 14th day after the "challenge doses" administered in the following manner: n1: saline at a dose of 10 ml/kg, n2,3: Met at a dose of 2.5 mg/kg. The observed behavioural changes consisted in: (a) gradual development of habituation to the open field conditions in three consecutive tests; (b) development of behavioural sensitisation to the stimulatory effects of Met after repeated treatment; (c) insignificant effect of repeated pre-treatment with ACPA on the stimulatory effects of Met challenge dose. The results of our study give rise to the question which of the cannabinoid receptor mechanisms might be most responsible for the neuroplastic changes inducing sensitisation to the stimulatory effects of Met.
Activities of the endocannabinoid system are believed to be substantially involved in psychostimulant and opioid addiction. Nevertheless, interactions between cannabinoid and opioid systems are not yet fully understood. Thus, the aim of the present study was to investigate the interaction between morphine and the cannabinoid CB1 receptor agonist arachidonylcyclopropylamide (ACPA) in behavioural sensitisation. Sensitisation occurs after repeated exposure to drugs of abuse including morphine and cannabinomimetics and it has been suggested to mediate craving and relapses. Male mice were randomly allocated into three groups and were seven times (from the 7th to 13th day of the experiment) administered drugs as follows: (a) n1: vehicle at the dose of 10.0mg/kg/day; (b) n2: morphine at the dose of 10.0mg/kg/day; (c) n3: ACPA at the dose of 1.0mg/kg/day. Changes in locomotor behaviour were measured in the Open Field Test: (a) after administration of vehicle on the 1st experimental day, (b) after the 1st dose of drugs given on the 7th day, and (c) on the 14th day after "challenge doses" given in the following way: n1: saline at the dose of 10ml/kg, n2, 3: morphine at the dose of 10.0mg/kg. Registered behavioural changes unambiguously showed the development of behavioural sensitisation to the stimulatory effects of morphine on locomotion after its repeated administration (P < 0.05). However, surprisingly, taking into account reports on synergistic effects of opioids and cannabinoid receptor stimulation, a significant decrease (P < 0.05) in behavioural sensitisation to morphine occurred when the drug challenge dose was given following repeated pre-treatment with the CB1 receptor agonist ACPA, i.e. suppression of cross-sensitisation to morphine.
Synthetic cannabinoid analogs have gained a great deal of attention from the forensic community within the last four years. The compounds found to be of most interest to forensic practitioners include those of the following series: JWH, CP, HU, AM, WIN, RCS, and most recently, XLR and UR. Structurally the HU compounds are most similar in structure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. The novel compounds include cyclohexylphenols, naphthoylindoles, naphthylmethylindoles, naphthylmethylindenes, benzoylindoles, naphthoylpyrroles, phenylacetylindoles, adamantoylindoles, and tetramethylcyclopropylindoles. Many of these compounds are cannabinoid receptor agonists and were originally synthesized for medical research purposes but have recently been appropriated into the illicit drug market. Their psychoactive effects, mimicking those of marijuana, as well as their indeterminate legal status, have made them popular for recreational use. Solutions of the compounds dissolved in organic solvents are sprayed onto botanical material and sold as "herbal incense" products via the Internet, and in smoke shops, convenience stores, and gas stations around the world. Many of the products are labeled "Not for human consumption" in an attempt to circumvent legislation that bans the sale and manufacture of certain compounds and their analogs for human use. The compounds that were first detected following forensic analysis of botanical materials included JWH-018, JWH-073, and CP 47,497 (C7 and C8 homologs). However, in the four years since their appearance the number of compounds has grown, and additional diverse classes of compounds have been detected. Governments worldwide have taken action in an attempt to control those compounds that have become widespread in their regions. This article discusses the history of synthetic cannabinoids and how they have been detected in the illicit drug market. It also discusses the analytical methods and techniques used by forensic scientists to analyze botanical products obtained via the Internet or from law enforcement investigations and arrests. Copyright © 2013 Central Police University.
Persistent pain in neuropathic conditions is often quite refractory to conventional analgesic therapy, with most patients obtaining, at best, only partial relief of symptoms. The tendency still exists to treat these complex pains with one or a combination of two analgesics at the most. Given the complex nature of the underlying pathogenesis, this approach more often than not fails to produce a meaningful improvement. New targets are therefore badly needed. In this regard non-neuronal cells - glia and mast cells in particular - are emerging as new targets for the treatment of neuropathic pain. An extensive preclinical database exists showing that the naturally occurring fatty acid amide palmitoylethanolamide is endowed with anti-inflammatory activity, and clinical trials assessing the efficacy and safety of palmitoylethanolamide in neuropathic pain have been successful in generating proof-of-concept for treatment in man. Here I will review salient preclinical and clinical evidence supporting non-neuronal cells as viable targets in the treatment of neuropathic pain. This will be followed by a discussion of recent proof-of-concept clinical trials demonstrating the efficacy and safety of palmitoylethanolamide in the treatment of various neuropathic pain states.