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A cannabigerol-rich Cannabis sativa extract, devoid of
-tetrahydrocannabinol, elicits hyperphagia in rats
Daniel I. Brierley
, James Samuels
, Marnie Duncan
Benjamin J. Whalley
and Claire M. Williams
Nonpsychoactive phytocannabinoids (pCBs) from Cannabis
sativa may represent novel therapeutic options for cachexia
because of their pleiotropic pharmacological activities,
including appetite stimulation. We have recently shown that
purified cannabigerol (CBG) is a novel appetite stimulant in
rats. As standardized extracts from Cannabis chemotypes
dominant in one pCB [botanical drug substances (BDSs)]
often show greater efficacy and/or potency than purified
pCBs, we investigated the effects of a CBG-rich BDS, devoid
of psychoactive Δ
-tetrahydrocannabinol, on feeding
behaviour. Following a 2 h prefeed satiation procedure, 16
male Lister-hooded rats were administered CBG-BDS (at
30240 mg/kg) or vehicle. Food intake, meal pattern
microstructure and locomotor activity were recorded over 2 h.
The total food intake was increased by 120 and 240 mg/kg
CBG-BDS (1.53 and 1.36 g, respectively, vs. 0.56 g in vehicle-
treated animals). Latency to feeding onset was dose
dependently decreased at all doses, and 120 and 240 mg/kg
doses increased both the number of meals consumed and
the cumulative size of the first two meals. No significant effect
was observed on ambulatory activity or rearing behaviour.
CBG-BDS is a novel appetite stimulant, which may have
greater potency than purified CBG, despite the absence of Δ
tetrahydrocannabinol in the extract. Behavioural
Pharmacology 00:000000 Copyright © 2017 Wolters Kluwer
Health, Inc. All rights reserved.
Behavioural Pharmacology 2017, 00:000000
Keywords: appetite, cannabigerol, cannabis, feeding, hyperphagia,
phytocannabinoid, rat
School of Psychology and Clinical Language Sciences,
School of Chemistry,
Food and Nutritional Sciences, and Pharmacy, University of Reading, Reading and
GW Research Ltd, Cambridge, UK
Correspondence to Claire M. Williams, PhD, School of Psychology and Clinical
Language Sciences, University of Reading, Harry Pitt Building, Early Gate,
Reading RG6 7BE, UK
Received 17 October 2016 Accepted as revised 26 December 2016
There is an urgent unmet clinical need for well-tolerated
pharmacotherapeutics for cancer-induced and chemotherapy-
induced cachexia. Phytocannabinoids (pCBs) from Cannabis
sativa may represent viable candidates for this indication
because of their pleiotropic pharmacological activities,
including modulation of feeding behaviour, metabolic home-
ostasis and inflammation (Brodie et al., 2015).
Although the appetite-stimulating properties of C. sativa
have historically been attributed to the psychoactive pCB
-tetrahydrocannabinol (Δ
-THC), we have previously
shown that C. sativa extracts containing little or no Δ
THC still stimulate appetite in rats (Farrimond et al.,
2011), and that purified pCBs other than Δ
-THC can
modulate feeding behaviours (Farrimond et al., 2012).
Recent studies have investigated isolated non-
psychoactive pCBs (with known anti-inflammatory and/
or anti-tumour activities) for their ability to stimulate
feeding, and thus their potential as novel cachexia
treatments. One such pCB is cannabigerol (CBG), which
attenuates inflammatory bowel disease and colon carci-
nogenesis in vivo (Borrelli et al., 2013, 2014) and has
in-vitro affinities for molecular targets involved in feeding
and metabolic regulation (Cascio et al., 2010; De
Petrocellis et al., 2011). Using a well-established prefeed
satiation paradigm, we have recently shown that purified
CBG stimulates multiple components of feeding beha-
viour, without detrimental motoric side-effects (Brierley
et al., 2016a). These previous data (reproduced here in
Table 1 for reference) showed that purified CBG
(120240 mg/kg) increased the total food intake over a
2-h test. CBG-induced hyperphagia was predominantly
due to increased appetitive behaviours, evidenced by
increased frequency of feeding, rather than effects on
meal sizes or durations.
Although testing the purified forms of pCBs is the
rational first step in determining their pharmacological
activities, in-vitro and in-vivo studies have shown that
their botanical drug substance (BDS) form may have
greater efficacy and/or potency (De Petrocellis et al.,
2011; Hill et al., 2013). Such BDSs (standardized extracts
from chemotypes in which a particular pCB is dominant
(De Meijer and Hammond, 2005)) may exert differential
effects to purified pCBs because of polypharmacology
with the other low-abundance pCBs and/or terpenoids
present, or by altered pharmacokinetics (Wagner and
Ulrich-Merzenich, 2009). The present study was thus
carried out to investigate the effects of a CBG-rich BDS
(devoid of Δ
-THC) on feeding behaviours using an
Research report 1
0955-8810 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FBP.0000000000000285
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identical prefeed paradigm and dose range as that in our
study of purified CBG.
The effects of CBG-BDS on feeding behaviour were
investigated using our prefeed satiation paradigm as fully
detailed in previous reports (Brierley et al., 2016a, 2016b).
All experiments were conducted in accordance with UK
Home Office regulations [Animals (Scientific Procedures)
Act 1986].
At the dark photoperiod onset, animals began a 2-h pre-
feed procedure, during which they had access to highly
palatable wet-mash feed. Animals were habituated to this
procedure until stable prefeed consumption levels were
observed over 4 consecutive habituation days, deter-
mined by a nonsignificant effect of day (F
3, 63
=0.56, NS).
On test days, animals completed the prefeed procedure
and were immediately administered CBG-BDS or vehicle
and returned to home cages for 1-h drug assimilation,
during which food was unavailable. They were then
placed into custom-designed feeder cages (270 ×405 mm)
for the 2-h test, during which food consumption and
locomotor activity were automatically recorded. Food
intake monitors (TSE Systems, Bad Homburg, Germany)
provided data on the time, duration and size of each
feeding bout, which were combined into meals, defined
as bouts consuming at least 0.5 g and separated by at least
900 s. Two levels of infrared activity monitors (Ugo
Basile, Varese, Italy) were arrayed alongside the feeder
cages, such that ambulatory locomotor activity was
quantified by horizontal beam breaks in a plane 20 mm
above the cage base and rearing behaviour by vertical
breaks in a plane 120 mm high.
CBG-BDS was supplied by GW Research (Salisbury,
UK), containing 72.2% w/w CBG, trace additional pCBs
(CBGV: 0.4%; CBGA: 0.3%; CBC: 0.7%) and a non-pCB
fraction including terpenoids and residual plant matter.
Notably, this BDS contained no Δ
sesame seed oil vehicle was orally administered to 16
male Lister-hooded rats (Harlan, UK; 200225 g on
delivery) using a within-subjects design. Animals thus
received doses of 0, 30, 60, 120 and 240 mg/kg (absolute
mass of CBG-BDS) according to a pseudorandom,
counterbalanced Latin square protocol, with at least 48 h
washout period.
Data analysis
Data were analysed to provide measures of appetitive
and consummatory behaviours using the parameters of
latency to first meal and meal number (appetitive) and
meal size and duration (consummatory). Ambulatory
activity and rearing were quantified using horizontal and
Table 1 Hourly food consumption and meal pattern analysis data
CBG-BDS (mg/kg, orally) Purified CBG (mg/kg, orally)
0 30 60 120 240 0 30 60 120 240
Hour 1 consumption (g) 0.21 ±0.18 0.29 ±0.20 0.52 ±0.26 0.70 ±0.27 0.57 ±0.22 0.47 ±0.22 0.40 ±0.25 0.55 ±0.25 1.06 ±0.30 0.89 ±0.25
Hour 2 consumption (g) 0.35 ±0.18 0.64 ±0.23 0.08 ±0.06 0.83 ±0.21 0.78 ±0.27 0.38 ±0.18 0.49 ±0.20 0.46 ±0.17 0.59 ±0.15 0.99 ±0.19**
Total consumption (g) 0.56 ±0.26 0.93 ±0.29 0.60 ±0.27 1.53 ±0.39* 1.36 ±0.39** 0.85 ±0.28 0.89 ±0.40 1.01 ±0.29 1.66 ±0.37* 1.89 ±0.38**
Latency to first meal (min) 108.9 ±7.4 95.1 ±9.0* 84.1 ±11.9* 71.1 ±12.7** 74.3±11.8* 83.3 ±12.5 93.7 ±11.0 78.9±11.2 59.1 ±12.0 54.3 ±13.2*
Latency to second meal (min) 112.9 ±5.1 107.7±7.3 105.6 ±8.2 95.6 ±9.4 95.8 ±8.7 105.3 ±8.7 108.2 ±6.8 106.4 ±5.4 95.7±8.3 92.1 ±8.5
Number of meals 0.50 ±0.22 0.69 ±0.24 0.63 ±0.20 1.13 ±0.24** 1.19 ±0.31** 0.63 ±0.20 0.75 ±0.32 1.00 ±0.26 1.44 ±0.33* 1.44 ±0.29**
Meal 1 size (g) 0.29 ±0.12 0.59 ±0.19 0.32 ±0.11 0.86 ±0.22 0.59 ±0.16 0.65 ±0.23 0.38 ±0.16 0.57 ±0.19 0.93 ±0.18 1.04 ±0.23
Meal 2 size (g) 0.19 ±0.13 0.26 ±0.14 0.29 ±0.17 0.59 ±0.21 0.57 ±0.21 0.20 ±0.11 0.30 ±0.15 0.22 ±0.09 0.57 ±0.23 0.64 ±0.18
Meal 1 + 2 size (g) 0.48 ±0.21 0.85 ±0.26 0.61 ±0.27 1.45 ±0.37* 1.16 ±0.32** 0.85 ±0.28 0.68 ±0.30 0.79 ±0.24 1.51 ±0.31 1.68 ±0.34*
Meal 1 duration (min) 0.9 ±0.5 2.8 ±0.9 1.4 ±0.7 4.7 ±1.7 3.9 ±1.6 5.9 ±2.7 1.1 ±0.7 3.1 ±1.2 4.0 ±1.1 5.9 ±1.9
Meal 2 duration (min) 0.8 ±0.7 0.9 ±0.7 1.1 ±0.6 3.0 ±1.6 2.0 ±0.9 0.3 ±0.2 0.8 ±0.5 0.5 ±0.3 2.4 ±1.5 2.9 ±1.1
Meal 1 + 2 duration (min) 1.7 ±0.9 3.6 ±1.1 2.5 ±1.2 7.7±2.9 5.9 ±2.0 6.2 ±2.7 1.9 ±1.1 3.6 ±1.3 6.4 ±1.8 8.7 ±2.3
All meals duration (min) 1.8 ±0.9 3.7 ±1.1 2.5 ±1.2 8.5 ±2.9 6.4 ±2.2 6.2 ±2.7 3.0 ±1.5 3.6 ±1.3 8.7 ±2.7 9.1 ±2.3
Data presented as group mean ±SEM, analysed by one-way repeated-measures ANOVA and planned comparisons of all dose groups versus vehicle.
All groups n=16.
ANOVA, analysis of variance; BDS, botanical drug substance; CBG, cannabigerol.
Data for purified CBG have been published previously (Brierley et al., 2016a) and are reproduced here for comparison with CB G-BDS.
2Behavioural Pharmacology 2017, Vol 00 No 00
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vertical infrared beam breaks. Data were analysed by
one-way repeated-measures analysis of variance, with
significant overall effects followed by planned compar-
isons of all dose groups versus vehicle. Nonparametric
data were analysed using Friedmans analysis of variance
and Wilcoxons signed rank comparisons. Results were
considered significant if Pvalues were less than 0.05.
Consistent with previously reported effects of purified
CBG, CBG-BDS significantly increased the total food
intake during the test (Fig. 1a; F
2.2, 33.2
=3.84, P<0.05).
The total intake was increased following the adminis-
tration of CBG-BDS at 120 mg/kg (F
1, 15
=8.23, P<0.05)
and 240 mg/kg (F
1, 15
=11.10, P<0.01), with animals
consuming 1.53 ±0.39 and 1.36 ±0.39 g, respectively,
compared with 0.56 ±0.26 g vehicle intakes.
Increased intake was predominantly driven by stimula-
tion of appetitive feeding, evidenced by the dose-
dependently decreased latency to feeding onset
(Figs. 1b and 2; χ
=10.42, P<0.05). All doses of CBG-
BDS significantly decreased this latency, with maximal
effects observed at 120 mg/kg (Z=2.81, P<0.01),
which advanced feeding onset by 40 min. The fre-
quency of feeding was also increased, as shown by a
significantly increased number of meals (Fig. 1c;
4, 60
=3.76, P<0.01). In contrast, although an increase
in the cumulative size of the first two meals was observed
(Table 1; F
2.1, 32.7
=3.35, P<0.05), the duration of meals,
another measure of consummatory behaviour, was not
significantly affected, including the cumulative duration
of the first two meals (F
1.8, 26.4
=2.58, NS) or of all meals
combined (F
1.9, 27.7
=3.10, NS). Corroborating the pre-
viously observed lack of detrimental motoric side-effects
of purified CBG, CBG-BDS had no effect on either
ambulatory activity (F
4, 60
=1.89, NS) or rearing
4, 60
=0.88, NS) over the 2-h test (Table 2).
CBG-BDS, at doses matched to our study of purified
CBG, had similar effects on feeding patterns, despite the
effective doses of CBG itself being 30% lower. Overall,
animals administered CBG-BDS began feeding sooner,
consumed more meals and consumed more within these
meals. However, subtle differences were evident, indi-
cating that although CBG-BDS has similar efficacy in this
paradigm, it has apparently greater potency than purified
CBG in stimulating feeding behaviours. The total intake
over the test duration was maximally increased by 1g
following doses of 120 mg/kg, a three-fold increase versus
vehicle. Purified CBG elicited a similar maximal increase
of 1 g; however, this only represented a two-fold
increase and was observed following the 240 mg/kg
dose. Appetitive feeding behaviour, measured by
decreased latency to feeding onset, was dose dependently
stimulated by all doses of CBG-BDS, with a maximal
reduction at 120 mg/kg of 40 min. In contrast, purified
CBG only significantly advanced feeding onset at 240 mg/
kg, by 30 min. Both the number of meals and the
Fig. 1
Total food intake (a) and meal pattern microstructure parameters of latency
to feeding onset (b) and number of meals consumed (c). Data presented as
group mean ±SEM, analysed by one-way repeated-measures ANOVA
(latency by Friedmans ANOVA) and planned comparisons of all dose
groups versus vehicle. *P<0.05, **P<0.01. ANOVA, analysis of variance;
BDS, botanical drug substance; CBG, cannabigerol.
CBG-rich extract elicits hyperphagia Brierley et al. 3
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cumulative size of the first two meals were approximately
doubled by both 120 and 240 mg/kg CBG-BDS, in this
case showing a consistent pattern of feeding stimulation
to purified CBG. It is thus apparent that CBG-BDS is
similarly efficaceous to purified CBG at stimulating
feeding behaviours, but as the maximal effects were
observed following doses of 120 mg/kg, it may be more
potent, and shows a ceiling effect not observed following
purified CBG.
Although determining the mechanism of action for this
hyperphagia was beyond the scope of these studies, we
have previously speculated on putative mechanisms on the
basis of the published in-vitro affinities and activities of
CBG (Brierley et al., 2016a). In light of the apparent greater
potency of CBG-BDS, such speculation can be extended
on the basis of the differential affinities and activities
reported in comparative in-vitro studies of the purified and
BDS forms (De Petrocellis et al., 2011). Although both have
little affinity or activity at cannabinoid 1 or 2 receptors, they
have similar efficacy as inhibitors of anandamide (AEA)
reuptake, and may thus elicit hyperphagia by upregulation
of orexigenic endocannabinoid tone. CBG-BDS has four-
fold greater potency as an inhibitor of monoacylglycerol
lipase (De Petrocellis et al., 2011), the hydrolytic enzyme
for 2-arachidonoylglycerol (2-AG). Given that 2-AG also
elicits hyperphagia (Kirkham et al., 2002), it is possible that
the increased potency of CBG-BDS is due to concurrent
elevation of 2-AG and AEA. The apparent ceiling effect of
CBG-BDS at 120 mg/kg, not observed for purified CBG,
also points to the potential involvment of another
mechanism, involving the endocannabinoid-degrading
enzyme N-acylethanolamine acid amide hydrolase.
Although neither forms of CBG have appreciable activity
as fatty acid amid hydrolase inhibitors, CBG-BDS alone is a
potent inhibitor of N-acylethanolamine acid amide hydro-
lase, which would result in a selective inhibition of pal-
mitoylethanolamine (PEA) hydrolysis over AEA. Given
that PEA attenuates hyperphagia (Mattace Raso et al.,
2014), it is plausible that at CBG-BDS doses more than
120 mg/kg, PEA is elevated to physiologically relevant
levels, attenuating CBG-induced hyperphagia mediated by
other mechanisms. Although neither the minor pCBs nor
terpenoids present in CBG-BDS have known appetite-
stimulating properties per se, they may improve the bioa-
vailability of CBG and hence contribute toward the
apparent greater potency of the BDS by pharmacokinetic
effects (Wagner and Ulrich-Merzenich, 2009). Indeed, a
recent study of the anticonvulsant effects of
cannabidivarin-BDS showed that a pCB-free BDS was
without intrinsic effect, but apparently slightly increased
the efficacy of the purified pCB, supporting such a phar-
macokinetic effect (Hill et al., 2013). Although no direct
pharmacokinetic comparison of purifed CBG and CBG-
BDS has been published to date, it should be noted that
purified forms of several major pCBs have shown differ-
ential brain concentrations dependent on the route of
admininistration, with CBG reaching higher concentrations
by the intraperitoneal route, in contrast to cannabidiol and
CBDV for which the oral route was more effective (Deiana
et al., 2012). Further studies investigating the effects of
intraperitoneal purified CBG and CBG-BDS on feeding
behaviours may thus be warranted to determine which
form, dose level and route of administration may have the
greatest translational potential for cachexia.
Here we report for the first time that a CBG-rich BDS,
devoid of Δ
-THC or other pCBs with known hyper-
phagic activity, stimulates appetite in presatiated rats.
Fig. 2
Graphical summary of group mean meal pattern microstructure
parameters for meals 1 and 2. Boxes are positioned along the x-axis
according to meal latencies, box widths are scaled to meal durations
and meal sizes are given above. Where individual animals did not
consume a second meal, minimum (size and duration) or maximum
(latency) values were imputed. Asterisks indicate significantly decreased
latencies compared with the vehicle, *P<0.05, **P<0.01. BDS,
botanical drug substance; CBG, cannabigerol.
Table 2 Hourly and total ambulatory and rearing activity in
feeder cages
CBG-BDS (mg/kg, orally)
0 30 60 120 240
Ambulatory activity (horizontal beam breaks)
Hour 1 1875 ±162 1784 ±112 2238 ±263 2229 ±183 2238 ±194
Hour 2 789 ±114 1033 ±101 1037±122 1127 ±134 973 ±153
Tot al 26 64 ±208 2816 ±167 3275 ±343 3355 ±275 3211 ±241
Rearing activity (vertical beam breaks)
Hour 1 279 ±43 279 ±37 3 36 ±51 304 ±46 285 ±42
Hour 2 89 ±24 113 ±2150±39 136 ±26 163 ±53
Total 368 ±57 3 92 ±50 486±76 441 ±66 448 ±73
Data presented as group mean ±SEM, analysed by one-way repeated-measures
ANOVA and planned comparisons of all dose groups versus vehicle.
All groups n=16.
ANOVA, analysis of variance; BDS, botanical drug substance; CBG,
4Behavioural Pharmacology 2017, Vol 00 No 00
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CBG-BDS appears to have similar efficacy but greater
potency than purified CBG, and warrants investigation as
a potential novel treatment for cachexia.
Conflicts of interest
This research was supported by grants to C.M.W. and
B.J.W. by GW Research and Otsuka Pharmaceuticals,
and in part by the University of Reading Research
Endowment Trust Fund to D.I.B., M.D. is an employee
of GW Research. The original study concept was dis-
cussed with the sponsor (GW Research), although all
subsequent study design, data collection, analysis and
interpretation were performed independently by the
authors. The report was approved by the sponsor com-
pany before submission and the authors retain full control
of all primary data.
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Full-text available
Rationale Anticipatory nausea (AN) is a poorly controlled side effect experienced by chemotherapy patients. Currently, pharmacotherapy is restricted to benzodiazepine anxiolytics, which have limited efficacy, have significant sedative effects and induce dependency. The non-psychoactive phytocannabinoid, cannabidiolic acid (CBDA), has shown considerable efficacy in pre-clinical AN models, however determination of its neuromotor tolerability profile is crucial to justify clinical investigation. Provisional evidence for appetite-stimulating properties also requires detailed investigation. Objectives This study aims to assess the tolerability of CBDA in locomotor activity, motor coordination and muscular strength tests, and additionally for ability to modulate feeding behaviours. Methods Male Lister Hooded rats administered CBDA (0.05–5 mg/kg; p.o.) were assessed in habituated open field (for locomotor activity), static beam and grip strength tests. A further study investigated whether these CBDA doses modulated normal feeding behaviour. Finally, evidence of anxiolytic-like effects in the habituated open field prompted testing of 5 mg/kg CBDA for anxiolytic-like activity in unhabituated open field, light/dark box and novelty-suppressed feeding (NSF) tests. Results CBDA had no adverse effects upon performance in any neuromotor tolerability test, however anxiolytic-like behaviour was observed in the habituated open field. Normal feeding behaviours were unaffected by any dose. CBDA (5 mg/kg) abolished the increased feeding latency in the NSF test induced by the 5-HT1AR antagonist, WAY-100,635, indicative of anxiolytic-like effects, but had no effect on anxiety-like behaviour in the novel open field or light/dark box. Conclusions CBDA is very well tolerated and devoid of the sedative side effect profile of benzodiazepines, justifying its clinical investigation as a novel AN treatment.
Full-text available
Cannabigerol (CBG) is a safe non-psychotropic Cannabis-derived cannabinoid which interacts with specific targets involved in carcinogenesis. Specifically, CBG potently blocks transient receptor potential (TRP) M8 (TRPM8), activates TRPA1, TRPV1 and TRPV2 channels, blocks 5-HT1A receptors and inhibits the reuptake of endocannabinoids. Here, we investigated whether CBG protects against colon tumorigenesis. Cell growth was evaluated in colorectal cancer cells using the MTT and NR assays; apoptosis was examined by histology and by assessing caspase 3/7 activity; ROS production by a fluorescent probe; cannabinoid (CB) receptors, TRP and CHOP mRNA expression were quantified by RT-PCR; shRNA-vector silencing of TRPM8 was performed by electroporation. The in vivo antineoplastic effect of CBG was assessed using mouse models of colon cancer. Colorectal cancer cells expressed TRPM8, CB1, CB2, 5HT1A receptors, TRPA1, TRPV1 and TRPV2 mRNA. CBG promoted apoptosis, stimulated ROS production, up-regulated CHOP mRNA and reduced cell growth in colorectal cancer cells. CBG effect on cell growth was independent from TRPA1, TRPV1 and TRPV2 channels activation, was further increased by a CB2 receptor antagonist, and mimicked by other TRPM8 channel blockers but not by a 5-HT1Aantagonist. Furthermore, the effect of CBG on cell growth and on CHOP mRNA expression was reduced in TRPM8 silenced cells. In vivo, CBG inhibited the growth of xenograft tumors as well as chemically-induced colon carcinogenesis. CBG hampers colon cancer progression in vivo and selectively inhibits the growth of colorectal cancer cells, an effect shared by other TRPM8 antagonists. CBG should be considered translationally in colorectal cancer prevention and cure.
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Increased food consumption following ∆(9)-tetrahydrocannabinol-induced cannabinoid type 1 receptor agonism is well documented. However, possible non-∆(9)-tetrahydrocannabinol phytocannabinoid-induced feeding effects have yet to be fully investigated. Therefore, we have assessed the effects of the individual phytocannabinoids, cannabigerol, cannabidiol and cannabinol, upon feeding behaviors. Adult male rats were treated (p.o.) with cannabigerol, cannabidiol, cannabinol or cannabinol plus the CB(1)R antagonist, SR141716A. Prior to treatment, rats were satiated and food intake recorded following drug administration. Data were analyzed for hourly intake and meal microstructure. Cannabinol induced a CB(1)R-mediated increase in appetitive behaviors via significant reductions in the latency to feed and increases in consummatory behaviors via increases in meal 1 size and duration. Cannabinol also significantly increased the intake during hour 1 and total chow consumed during the test. Conversely, cannabidiol significantly reduced total chow consumption over the test period. Cannabigerol administration induced no changes to feeding behavior. This is the first time cannabinol has been shown to increase feeding. Therefore, cannabinol could, in the future, provide an alternative to the currently used and psychotropic ∆(9)-tetrahydrocannabinol-based medicines since cannabinol is currently considered to be non-psychotropic. Furthermore, cannabidiol reduced food intake in line with some existing reports, supporting the need for further mechanistic and behavioral work examining possible anti-obesity effects of cannabidiol.
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Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG). We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice. All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile. These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.
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The herb Cannabis sativa (C. sativa) has been used in China and on the Indian subcontinent for thousands of years as a medicine. However, since it was brought to the UK and then the rest of the western world in the late 19th century, its use has been a source of controversy. Indeed, its psychotropic side effects are well reported but only relatively recently has scientific endeavour begun to find valuable uses for either the whole plant or its individual components. Here, we discuss evidence describing the endocannabinoid system, its endogenous and exogenous ligands and their varied effects on feeding cycles and meal patterns. Furthermore we also critically consider the mounting evidence which suggests non-Δ(9) tetrahydrocannabinol phytocannabinoids play a vital role in C. sativa-induced feeding pattern changes. Indeed, given the wide range of phytocannabinoids present in C. sativa and their equally wide range of intra-, inter- and extra-cellular mechanisms of action, we demonstrate that non-Δ(9) tetrahydrocannabinol phytocannabinoids retain an important and, as yet, untapped clinical potential.
It has been suggested a role of fatty acid ethanolamides in control of feeding behavior. Among these, palmitoylethanolamide (PEA) has not been directly implicated in appetite regulation and weight gain. The aim of this study was to investigate the effect of PEA on food intake and body weight and the interaction between PEA and hypothalamic leptin signaling in ovariectomized rats. Ovariectomy produced hyperphagia and increased weight gain, making it an useful model of mild obesity. Ovariectomized rats were treated with PEA (30 mg kg(-1) s.c.) for 5 weeks. Then, blood was collected and hypothalamus and adipose tissue were removed for histological, cellular and molecular measurements. We showed that PEA caused a reduction of food intake, body weight, and fat mass. The mechanisms underlying PEA effects involved an improvement in hypothalamic leptin signaling, through a raise in signal transducer and activator of transcription 3 phosphorylation. We also reported that PEA reduced AMP-activated protein kinase (AMPK)-α phosphorylation and modulated transcription of anorectic and orexigenic neuropeptides in the hypothalamus. Moreover, PEA increased AMPK-α phosphorylation and carnitine palmitoyltransferase 1 transcription in adipose tissue, suggesting an increase in ATP-producing catabolic pathway. PEA also polarized adipose tissue macrophages to M2 lean phenotype, associated to a reduction of inflammatory cytokines/adipokines. To demonstrate the direct effect of PEA on leptin sensitivity without interference of adiposity loss, we obtained consistent data in PEA-treated SHAM animals and in vitro in SH-SY5Y neuroblastoma cell line. Therefore, our data provide a rationale for the therapeutic use of PEA in obese postmenopausal woman.
Epilepsy is the most prevalent neurological disease and is characterised by recurrent seizures. Here we investigate: (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDS) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors. The anticonvulsant profiles of two CBDV BDSs (50-422 mg kg(-1) ) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip-strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays. CBDV BDSs exerted significant anticonvulsant effects in the PTZ (≥100 mg kg(-1) ) and audiogenic seizure models (≥87 mg kg(-1) ), and suppressed pilocarpine-induced convulsions (≥100 mg kg(-1) ). The isobolographic study revealed the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip-strength were found. The Δ(9) -THC and Δ(9) -THCV content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV. CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor, and were of comparable efficacy to purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for treatment of epilepsy.
This paper aims to clarify the genetic mechanism that is responsible for the accumulation of cannabigerol (CBG) in certain phenotypes of Cannabis sativa L. CBG is the direct precursor of the cannabinoids CBD, THC and CBC. Plants strongly predominant in CBG have been found in different fibre hemp accessions. Inbred offspring derived from one such individual were crossed with true breeding THC predominant- and CBD predominant plants, respectively. The segregations in the cross progenies indicate that CBG accumulation is due to the homozygous presence of a minimally functional allele, tentatively called B0, at the single locus B that normally controls the conversion of CBG into THC (allele BT) and/or CBD (allele BD). The fact that CBG accumulating plants have so far been found in European fibre hemp populations that are generally composed of BD/BD plants, and the observation that the here investigated B0 allele possesses a residual ability to convert small amounts of CBG into CBD, make it plausible that this B0 is a mutation of normally functional BD. Therefore, B0 is considered as a member of the BD allelic series encoding a CBD synthase isoform with greatly weakened substrate affinity and/or catalytic capacity.
Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.