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A cannabigerol-rich Cannabis sativa extract, devoid of
Δ
9
-tetrahydrocannabinol, elicits hyperphagia in rats
Daniel I. Brierley
a,b
, James Samuels
a
, Marnie Duncan
c
,
Benjamin J. Whalley
b
and Claire M. Williams
a
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
9
-tetrahydrocannabinol, on feeding
behaviour. Following a 2 h prefeed satiation procedure, 16
male Lister-hooded rats were administered CBG-BDS (at
30–240 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
9
-
tetrahydrocannabinol in the extract. Behavioural
Pharmacology 00:000–000 Copyright © 2017 Wolters Kluwer
Health, Inc. All rights reserved.
Behavioural Pharmacology 2017, 00:000–000
Keywords: appetite, cannabigerol, cannabis, feeding, hyperphagia,
phytocannabinoid, rat
a
School of Psychology and Clinical Language Sciences,
b
School of Chemistry,
Food and Nutritional Sciences, and Pharmacy, University of Reading, Reading and
c
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
E-mail: claire.williams@reading.ac.uk
Received 17 October 2016 Accepted as revised 26 December 2016
Introduction
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
Δ
9
-tetrahydrocannabinol (Δ
9
-THC), we have previously
shown that C. sativa extracts containing little or no Δ
9
-
THC still stimulate appetite in rats (Farrimond et al.,
2011), and that purified pCBs other than Δ
9
-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
(120–240 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
9
-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
Copyright r2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
identical prefeed paradigm and dose range as that in our
study of purified CBG.
Methods
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].
Procedure
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.
Drugs
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
9
-THC. CBG-BDS or
sesame seed oil vehicle was orally administered to 16
male Lister-hooded rats (Harlan, UK; 200–225 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.
*P<0.05.
**P<0.01.
†
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 Friedman’s analysis of variance
and Wilcoxon’s signed rank comparisons. Results were
considered significant if Pvalues were less than 0.05.
Results
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
24
=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;
F
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
(F
4, 60
=0.88, NS) over the 2-h test (Table 2).
Discussion
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 Friedman’s 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.
Conclusion
Here we report for the first time that a CBG-rich BDS,
devoid of Δ
9
-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,
cannabigerol.
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.
Acknowledgements
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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