Article

Cannabidiol Attenuates the Appetitive Effects of Δ9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis

Abstract and Figures

Worldwide cannabis dependence is increasing, as is the concentration of Delta(9)-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.
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Cannabidiol Attenuates the Appetitive Effects of
D
9
-Tetrahydrocannabinol in Humans Smoking Their
Chosen Cannabis
Celia JA Morgan*
,1
, Tom P Freeman
1
, Gra
´inne L Schafer
1
and H Valerie Curran
1
1
Clinical Psychopharmacology Unit, Research Department of Clinical, Health and Educational Psychology, University College London, London, UK
Worldwide cannabis dependence is increasing, as is the concentration of D
9
-tetrahydrocannabinol (THC) in street cannabis. At the
same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two
cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet
examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis
users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked
cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected
from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and
bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug
stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with
smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test
days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive
salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.
Neuropsychopharmacology (2010) 35, 1879–1885; doi:10.1038/npp.2010.58; published online 28 April 2010
Keywords: cannabis; THC; cannabidiol; attention bias; addiction; dependence
INTRODUCTION
Cannabis is the world’s most popular illicit substance.
Although cannabis dependence was a rare phenomenon
even a decade ago, data from the European Monitoring
Centre for Drugs and Drug Abuse (EMCDDA, 2006) show
that the numbers of people seeking treatment for
dependence have increased markedly since 1999. Over a
similar time period, there also seems to have been a marked
change in the constituents of the cannabis available on the
street.
Cannabis contains around 70 different chemicals, which
are unique to the plant and called cannabinoids. The main
psychoactive ingredient is D
9
-tetrahydrocannabinol (THC)
and this is thought to produce the effects that users seek
(Curran et al, 2002). When given intravenously to healthy
humans, THC produces psychotic-like and anxiogenic
effects (D’Souza et al, 2004, 2008). In contrast, cannabidiol
(CBD), another major constituent of most strains of
cannabis, seems to have anti-psychotic properties (Zuardi
et al, 2006), and is anxiolytic (Guimares et al, 1990) and
may be neuroprotective in humans (Hermann et al, 2007).
THC and CBD have been found to have opposing
neuropharmacological actionsFthe former is an partial
agonist, whereas the latter is an antagonist at CB1 and CB2
receptors (Pertwee, 2008). CBD has also been suggested to
inhibit the reuptake of the endogenous cannabinoid,
anandamide (Bitencourt et al, 2008). The relative THC/
CBD ratio of cannabis varies greatly. Levels of CBD can
range from virtually none to up to 40% (Hardwick and
King, 2008). Higher levels of THC are found in hydro-
ponically grown varieties such as ‘skunk’ and in cross-bred
strains, which are increasingly dominating the illicit drug
market.
In addition to effects on psychotic symptoms and anxiety,
THC and CBD may have opposing effects in the processes
involved in addiction. The reinforcing effects of THC have
been repeatedly shown. Synthetic THC produces condi-
tioned place preference in rats and decreases the threshold
for intercranial self-stimulation in animal studies (see
Cooper and Haney, 2009 for a review). CBD is not acutely
reinforcing in rats (Vann et al, 2008). However, CBD has
been shown to reverse the conditioned place preference
effect induced by THC in CBD : THC ratios of 1 : 1 and 1 : 10
(Vann et al, 2008), suggesting that it may modulate the
Received 13 January 2010; revised 18 March 2010; accepted 22 March
2010
*Correspondence: Dr CJA Morgan, Clinical Psychopharmacology Unit,
Research Department of Clinical, Health and Educational Psychology,
University College London, Gower Street, London WC1E 6BT, UK,
Tel: + 44 207 679 1932, Fax: + 44 207 916 1989,
E-mail: c.morgan@ucl.ac.uk
Neuropsychopharmacology (2010) 35, 1879 1885
&
2010 Nature Publishing Group All rights reserved 0893-133X/10
$
32.00
www.neuropsychopharmacology.org
reinforcing effects of THC. CBD has also been suggested to
have a function in the modulation of addictive behavior.
Preclinical studies have shown that acute administration of
CBD can enhance extinction of both cocaine and amphe-
tamine conditioned place preference (Parker et al, 2004).
CBD has also been found to attenuate the reinstatement of
opioid seeking in rats (Ren et al, 2009).
Given the opposing neuropharmacological actions of
THC and CBD, and the capacity of CBD to modulate the
acute reinforcing effects of THC in rats, we hypothesized
that CBD may also counteract some of the reinforcing
effects of THC in humans. This study set out to test these
hypotheses by using a novel methodology, which enabled
analysis of cannabinoids in the cannabis actually smoked by
each individual user.
To index relevant aspects of reinforcing effects, we aimed
to tap into not only the explicit ‘liking’ of a drug, but also
the implicit ‘wanting’ (Robinson and Berridge, 2008). One
way in which the latter has been assessed is by examining
attentional bias to drugs of abuse. It is well known that
with the progression from drug use to abuse and on
to dependence, a drug user’s attention becomes drawn to
drug-related stimuli more than earlier reinforcing ‘natural’
rewards (Robinson and Berridge, 2001) and this can be
investigated by using attentional bias tasks. Degree of
attentional bias predicts relapse in cigarette smokers
(Waters et al, 2003) and opiate-dependent individuals
(Marissen et al, 2006) and as such relates to level of
dependence. Attentional bias toward cannabis-related
stimuli has been earlier reported in cannabis users
(Field et al, 2006), but no study has investigated the
impact of smoking different strains of cannabis may have
on such processes. We, therefore, used a ‘dot-probe’
paradigm as an attentional bias task to assess implicit
wanting of both cannabis stimuli and food stimuli (as a
natural reinforcer influenced by cannabis), and ratings of
pleasantness to assess the explicit liking of the cannabis and
food stimuli.
MATERIALS AND METHODS
Design and Participants
A repeated measures design compared a sample of 94
cannabis users aged between 16 and 24 years on two test
occasions approximately 7 days apart. Inclusion criteria
required that participants had English as a native language,
were not dyslexic, had no history of psychotic illnesses, and
had normal or corrected-to-normal color vision. Partici-
pants were also excluded if they gave a positive saliva
sample (above cutoffs for cannabis use in the past 4–6 h) for
THC or CBD on the non-intoxicated day. The cannabis-
using group was required to use the drug at least once a
month for at least 1 year. They were recruited by word of
mouth and ‘snowball sampling’ (Solowij et al, 1992). Data
are first reported on the overall sample; to facilitate analysis
of the impact of THC and CBD, the sample was divided into
upper and lower tertiles (each n¼32) on the basis of
individual CBD : THC ratios in the cannabis actually
smoked.
All participants provided written, witnessed, informed
consent on both occasions. This study was approved by the
UCL Graduate School Ethics committee and its aims were
supported by the UK Home Office.
Procedure
All participants were tested on two separate occasions. One
testing session occurred when cannabis users were under
the influence of the drug (intoxicated day) and the other
when drug free (drug-free day) with session order being
counterbalanced. Participants were required to abstain from
recreational drugs and alcohol for 24 h before testing
commenced. A sample of the cannabis each participant
smoked was taken on the intoxicated day and analyzed for
levels of THC and CBD (Forensic Science Service, UK).
Saliva samples were also taken for analysis of cannabinoids,
a screening analysis was performed, and then confirmation
analysis by liquid chromatography mass spectrometry. A
urine sample was collected before cannabis use on the
intoxicated day for later analysis of THC metabolite in
urine. Instant urine tests were administered on the drug-
free day to confirm abstinence from other drugs (opiates,
cocaine, amphetamine, benzodiazepines, and other related
compounds; a positive result for THC occurs if a minimum
of 50 ng/ml of THC metabolite is present in the urine
sample; however, THC remains detectable in the body for
up to 4 weeks so 24-h abstinence of cannabis users was not
verifiable). On the intoxicated day, participants smoked the
cannabis at the site of testing in front of the experimenter,
which was usually at their own home. They were asked to
smoke an amount of cannabis that was typical for them to
become ‘stoned.’ The experimenter weighed this sample
before they made the ‘joint’ and then collected 0.3 g of the
same cannabis for analysis. The experimenter noted
whether the sample was ‘skunk,’ herbal cannabis, or resin.
Participants then completed the assessments described
below beginning 1–5 min after they had finished smoking.
For cognitive and dependence-related measures, the task
versions were balanced across the two testing days and
session order. Participants also completed the Severity of
Dependence Scale (Gossop et al, 1995), a brief 5-item
questionnaire regarding their drug use, the Wechsler Adult
Reading Test (WTAR; Wechsler, 2001) to estimate their
reading ability as an analog of premorbid IQ, and self-
reported their drug use in a drug history questionnaire. The
assessments reported here formed part of a wider test
battery on which data collection is still underway. After
testing, participants were fully debriefed and compensated
for their time.
Assessments
Dot-probe task. A computer-based dot-probe paradigm was
used to assess attentional bias to both drug- and food-
related stimuli. The 10 color photographs of cannabis-
related stimuli and 10 color photographs of food-related
stimuli were used, with each image simultaneously paired
with a neutral photograph matched as closely as possible for
visual composition and complexity (see Figure 1 for an
example). A total of 80 of the 160 total trials were
critical trials of which 40 featured cannabis-related and 40
food-related stimuli, each presented twice for 250 ms and
twice for 2000 ms. These two exposure times were used to
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CJA Morgan et al
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tap automatic (250 ms) and controlled (2000 ms) proces-
sing. The critical (food- or drug-related) images appeared
once on the left and once on the right at each time
interval. The side at which the probe appeared was
counterbalanced across all the trials. An asterisk was used
as the probe.
A total of 10 neutral practice trial pairs were used as
training, followed by two blocks of 80 experimental trials.
There was a short break between blocks. Each trial began
with a central fixation cross shown for 1000 ms, after which
a pair of matched images would appear, one on each side of
the fixation cross, for either the long (2000 ms) or short
(250 ms) duration. Both images then disappeared revealing
the probe behind one of the two images. Participants were
required to respond to the probe as quickly as possible
by pressing a button corresponding to the relevant side of
the screen. Attentional bias was calculated as the difference
in reaction time between when the probe replaced the
neutral compared with the incentive (drug/food) stimulus
[RtneutralFRTincentive], such that a greater difference
indicated greater bias toward that stimulus.
Picture-rating task. After the dot-probe task, participants
completed a picture-rating task as a measure of explicit
liking for drug and food stimuli. They rated each picture
earlier used in the dot-probe task on a 7-point scale, ranging
from 3 (very unpleasant) to + 3 (very pleasant).
Marijuana craving questionnaire (Heishman et al, 2009).
A short 12-item questionnaire was given to assess current
craving for cannabis.
Visual analog scale. A 100 mm visual analog scale (VAS)
anchoring from ‘not at all stoned,’ to ‘extremely stoned’ was
administered.
Statistical Analysis
Data are first reported on the overall sample. Owing to trace
levels of CBD in the majority of the participants, therefore,
we subdivided the groups on the basis of CBD41% and
then excluded the middle third to compare equal group
sizes who differed in their CBD content. Using the
CBD : THC ratio groups, dependence-related data were
subjected to a 2 2 repeated measures ANOVA with ratio
(high CBD : THC; low CBD : THC) as the between subjects
factor and day (intoxicated, drug free) as the within subjects
factor. Post hoc comparisons were Bonferroni corrected
one-way ANOVAs to explore interactions, or Bonferroni
comparisons to explore main effects.
RESULTS
Demographics and Drug Use Data
Whole sample. Over the whole sample, the mean age of
participants was 21.3±1.42 years, there were 72 males and
22 females, and participants had spent a mean of
14.67±2.11 years in education with a mean WTAR score
of 42.86±6.52. Cannabis was used as a mean of 13.9±11.53
days per month.
Sub-group analyses. High CBD : THC ratio vs low
CBD : THC ratio groups. There were no differences in
demographic variables between these two cannabis smoking
groups (Table 1). There were also no differences in self-
reported use of cannabis or clinician rated dependence on
the SDS. However, for drug use variables, individuals from
the high CBD : THC ratio group drank alcohol more
frequently than the low CBD : THC group [F(1,57) ¼4.32,
p¼0.042]. There were no significant group differences for
when alcohol was last used before the non-intoxicated day.
Figure 1 An example of a cannabis/neutral and a food/neutral-matched pair of images.
CBD reduces the rewarding effects of THC
CJA Morgan et al
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Neuropsychopharmacology
There was significantly greater THC content [U¼286.0,
p¼0.002] and lower CBD content [U¼76.0, po0.001] in
the low CBD : THC ratio group.
Salivary levels on the intoxicated day showed only a trend
for a group difference in CBD [U¼248.5, p¼0.099], but no
differences in salivary levels of THC.
No significant difference was found between the two
groups of urinary levels of THC acid from the samples taken
on the intoxicated day. From the instant drug test results on
the non-intoxicated, day, w
2
analysis found no significant
group differences in positive results for THC metabolite.
The w
2
analysis also found a significant difference in the
type of cannabis smoked between the groups [w
2
(4) ¼43.79,
po0.001] reflecting that all the low CBD : THC ratio group
had smoked ‘skunk’ varieties (see Table 2).
Dependence-related measures. Dot-probe task Reaction
times o100 ms or 41000 ms were excluded from the
analysis in line with earlier dot-probe studies (Duka and
Townshend, 2004) and this excluded two participants, one
from each CBD : THC ratio group. A 2 222 repeated
measures ANOVA with the additional within subjects
factors of stimulus type (food, drug) and picture duration
(short, long) found a significant day CBD : THC ra-
tio duration interaction [F(1,57) ¼6.31, p¼0.015] and a
trend for a day type interaction [F(1,57) ¼3.31, p¼
0.073]. Post-hoc exploration of the three-way interaction
showed that the significant day ratio group interaction
was attributable to greater bias to both types of stimuli
in the low CBD : THC ratio group at the short picture
presentation interval on the intoxicated day [F(1,57) ¼5.63,
p¼0.021], but no difference on the non-intoxicated day
(see Figure 2a).
Picture-rating task.A223 repeated measures
ANOVA of ratings of pleasantness of the pictures presented
in the dot-probe task, with the additional factor of stimulus
type (food, drug, neutral) yielded a significant CBD : THC
ratio stimulus type interaction [F(2,118) ¼4.29, p¼
0.016], as well as main effects of stimulus type[F(2,118) ¼
46.52, po0.001] and CBD : THC ratio [F(1,59) ¼7.61,
p¼0.008], but not day. Exploration of the interaction,
depicted in Figure 2b, shows significantly lower ratings of
pleasantness for drug stimuli in the high CBD : THC ratio
group [F(1,59) ¼12.44, p¼0.001], a trend for lower ratings
of pleasantness for food stimuli in the high CBD : THC ratio
group [F(1,59) ¼2.81, p¼0.099], but no group differences
in ratings of neutral stimuli.
MCQ (Table 3) There were no group differences in
craving as assessed by the Marijuana Craving Scale across
the 2 days.
VAS (Table 3) There were no group differences in
‘stoned’ ratings on either day and both groups had similarly
higher ratings on the intoxicated compared with the drug-
free day [F(1,59) ¼299.53, po0.001].
DISCUSSION
The main findings of this study were of reduced attentional
bias to drug and food stimuli in intoxicated individuals
smoking cannabis with a high CBD : THC ratio. We also
found evidence of an overall reduction in ratings of liking of
drug stimuli in high CBD : THC cannabis smokers.
Attentional Bias to Drug Stimuli
Attentional bias to drug stimuli in users when they were
drug free was observed in both CBD : THC groups at the
short, but not the long stimulus exposure interval. This
differentiation most likely reflects automatic processing at
the short interval and accords with ‘incentive sensitization’
processes described in Robinson and Berridge’s (1993,
2003) model of addiction, which is thought to be an
automatic process. The presence of an attentional bias at
this short time interval is consistent with some other studies
(eg Morgan et al, 2008). In drug users, incentive sensitiza-
tion is thought to accumulate over time, whereby drugs of
abuse come to grab attention or act as ‘motivational
magnets,’ eventually more so than natural reinforcers in
Table 1 Demographic and CBD and THC Data Across the Two
User Groups in the Sample
Low CBD : THC
ratio (N¼30),
mean (SD)
High CBD : THC
ratio (N¼31),
mean (SD)
Age 21.19±1.53 21.6±1.22
Number of years in education 14.55±1.85 15±1.78
Age at which cannabis first tried 15.34±2.36 14.77±1.98
How often cannabis is used (days
per month)
13.33±10.93 14.55±12.3
Time to smoke 1/8th ounce of
cannabis (days)
11.43±12.90 25.00±35.60
SDS total 3.06±2.7 2.8±2.28
Total WTAR score 42.78±4.99 44.17±6.53
Number of units used per session 10±4.6 8.44±4.43
How often is alcohol drunk (days
per month)
8.6±5.88 12.27±7.4*
Number of days since last alcohol
use
5.067±10.929 10.138±38.80
Salivary THC intoxicated (ng/ml) 21.20±42.7 15.97±28.81
Salivary CBD intoxicated (ng/ml) 0.14±0.51 2.48±7.17
CBD content (% of sample) 0.14±5.41 2.64±2.54*
THC content (% of sample) 11.92±5.41 7.74±4.20*
CBD : THC ratio (CBD/THC) 0.01±0.01 0.35±0.31*
Urinary THC acid : creatinine ratio 90.78±187.88 49.54±109.27
Abbreviations: SDS, severity of dependence scale; WTAR, Wechsler test of
adult reading. *po0.05.
Table 2 Types of Cannabis Collected, Number of Samples in
Each Group, and Corresponding Means (±SD) of CBD/THC
Ratios in Each Sample
Low CBD : THC
ratio
High CBD : THC
ratio
CBD/THC,
mean±SD
Skunk 32 6 0.02±0.02
Herbal 0 11 0.24±0.35
Resin 0 15 0.53±0.22
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the environment (Berridge et al, 2009). The present findings
are consistent with those of earlier studies showing that
cannabis, such as other recreational drugs, elicits atten-
tional bias in its users (Field et al, 2006).
When intoxicated with their own chosen cannabis, only
the low CBD : THC group showed an attentional bias to drug
stimuli. In contrast, the high CBD : THC group showed no
evidence of any bias. Thus, even when intoxicated, cannabis
stimuli grabbed the attention of the low CBD : THC
smokers. One might expect that having smoked cannabis,
both groups would reach a level of satiety and so attentional
bias would reduce as motivational state is thought to
modulate the magnitude of conditioned responses on this
task (Duka and Townshend, 2004). However, some research
suggests that endocannabinoids may modulate afferent
satiety signals (Rodriguez et al, 2001), related to cannabis’
capacity to stimulate appetite, which could explain this
finding in the low CBD : THC group.
Higher levels of CBD seemed to remove the attentional
bias to drug stimuli at the short picture presentation
interval. Owing to the short presentation time (250 ms), this
Figure 2 (a) Attentional bias to food and drug stimuli across day, CBD : THC ratio group, and picture presentation interval. (b) Pleasantness rating across
stimulus type and CBD : THC ratio group across both days.
Table 3 Means (±SD) on Self-Ratings of Marijuana Craving and
‘stoned’ of Each CBD : THC Group Across Test Days
Low CBD : THC ratio,
n¼30, mean±SD
High CBD : THC ratio,
n¼31, mean±SD
Intoxicated Drug free Intoxicated Drug free
MCQ 40.52±11.94 41±12.35 37.88±10.48 36.28±11.55
Ratings of
‘stoned’
6.63±2.0 1.34±1.41 6.45±1.94 1.33±1.06
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is very unlikely to be a conscious mechanism of attention
aversion. Instead, it may reflect automatic or non-conscious
processing, of which the individual is unaware. This is
commensurate with a lack of CBD : THC group differences
in explicit processing engaged both at the longer stimulus
exposure time in the attentional bias and in self-ratings of
craving and dependence on questionnaire measures. At
longer durations, drug users may use conscious attentional
aversion mechanisms, as drug stimuli may provoke
undesired craving. Greater automatic attentional bias to
drug-related stimuli has been shown to predict relapse in
cigarette smokers (Waters et al, 2003) and opiate users
(Marissen et al, 2006), respectively. Our present findings
may, therefore, also shed new light on the increasing
incidence of cannabis dependence, as the CBD content of
street cannabis has been declining over the past 20 years
(Hardwick and King, 2008). Recent research has also shown
training attentional bias away from alcohol stimuli to be
effective in reducing alcohol consumption, and this effect
was still evident at a 3-month follow-up (Fadardi and Cox,
2009), therefore, CBD might be a potentially beneficial
adjunct in this training.
THC and CBD Effects on Explicit Liking
Cannabis users in this study who smoked high CBD
cannabis rated their explicit liking for the drug stimuli as
less than the low CBD group. This subjective measure of
‘liking’ can be thought of as reflecting hedonic processes
involved in drug abuse. The endocannabinoid system is
known to be involved in mediating ‘liking’ reactions and
microinjection of anandamide into the nucleus accumbens
doubles the level of ‘liking’ of sucrose taste in rats (Mahler
et al, 2007). Given that the high CBD cannabis users are
smoking as much cannabis as the low CBD group, that they
explicitly ‘like’ the drug less may seem counterintuitive.
However, this may relate to the notion that it is implicit
drug ‘wanting’ and not explicit ‘liking’ that mediates drug
seeking behavior, which is particularly evident in drug
addicts who will continue wanting the drug, in the absence
of any explicit liking (Robinson and Berridge, 2003). When
drug free, there was no difference in implicit attentional
bias across the groups, which is tentative support for the
suggestion that it is this process and not explicit ‘liking’ that
mediates cannabis use.
Attentional Bias to Food Stimuli
We expected that acute cannabis would increase bias to
food stimuli, in line with the drug’s well-documented
abilities to promote eating (Chopra and Chopra, 1957). The
findings in the low CBD : THC group, at the short time
interval, were consistent with this. Earlier work has shown
that the appetite stimulating, or hyperphagic, actions of
THC are mediated predominantly by CB1 receptors (Chopra
and Chopra, 1957). Our findings are thus compatible with
suggestions based on animal research that CB1 agonists
increase the incentive value, or salience, of food (Kirkham,
2009). That higher CBD : THC ratios in the cannabis
markedly attenuated acute bias to food stimuli may be
explained by the antagonistic, or even inverse agonistic,
properties of CBD at the CB1 receptor (Pertwee, 2008).
Earlier research has shown that the CB1 antagonist,
rimonabant, reduces desire to eat in humans consistent
with its earlier use in the treatment of obesity (Christensen
et al, 2007). However, rimonabant was recently withdrawn
from clinical use because of reports of depression and
anxiety after treatment (Taylor, 2009). As CBD possesses a
different mechanism of CB1 antagonism to rimonobant, and
a much better side-effect profile, these preliminary findings
may suggest a clinical use for CBD in the treatment of
obesity. However, clearly to establish this, studies would
need to control for many factors not assessed here, such as
food satiety and body weight.
Limitations
This study was subject to some limitations. Estimates of
THC levels in urine at baseline were not taken on the
intoxicated test day and these may have varied between
subjects, which may possibly have influenced results on the
drug-free day. In addition we did not breathalyze subjects
on the testing days; however, none showed any visible signs
of acute alcohol intoxication, as rated by the experimenter.
There were no differences between the groups in levels of
salivary THC on the intoxicated day, which is interesting as
levels of THC in the cannabis were significantly lower in the
high CBD : THC group. However, salivary estimates of
metabolites of cannabis are not possible; therefore, it is
possible that salivary THC and CBD levels are as a result of
contamination of the oral cavity and may be inaccurate
measures of true cannabis consumption.
Conclusions
When people are given a choice between marijuana
cigarettes with different THC concentrations, those with
higher THC content are preferred over those containing
lower THC concentrations (Chait and Zacny, 1992; Kelly
et al, 1997). The constituents of street cannabis have
changed over the past decade or so with high THC, low CBD
strains such as skunk and sinsemilla now dominating the
market (Hardwick and King, 2008). This change was
thought to be in part to be driven by user preference for
lower CBD strains, because of CBD’s potential to modulate
the psychotomimetic effects of the drug and reduce the
‘stoned’ feeling (Zuardi et al., 2006). However, the findings
of this study suggest instead that one reason may be CBD’s
capacity to modulate both the ‘wanting’ and the ‘liking’ of
THC without affecting the ‘stoned’ feeling. Our findings
suggest that lower CBD in cannabis may result in greater
salience of drug cues when intoxicated, potentially invoking
more associative learning around drug cues in users of high
THC/low CBD cannabis, which could speculatively result in
a higher chance of later addiction. The research reported
here also contributes to the growing body which suggests a
range of potential therapeutic uses of CBD, including the
ability to acutely modulate the reinforcing properties of
drugs.
ACKNOWLEDGEMENTS
This work was supported by a grant to HVC and CJAM
from the Medical Research Council (UK). We thank the
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Home Office and the Forensic Science Service for their
support of the study. We also thank all the participants who
donated their time and cannabis.
DISCLOSURE
The authors declare no conflict of interest.
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CBD reduces the rewarding effects of THC
CJA Morgan et al
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Neuropsychopharmacology
... It should be noted that the majority of papers were based on the adult demographic, with the exception of the first two references, which were based on adolescent and prenatal age groups, respectively. [193] Mice Acute Male 10 mg/kg Intraperitoneally ↓ food intake [194] Note: CBD = Cannabidiol, ↑ = Observed increase, ↓ = Observed decrease, ↔ = No observed change. ...
... Within the few studies that observed the direct effects of CBD on body weight and food intake, a great bulk of them observed a hypophagic effect along with a decrease in body weight among adults (Table 4). For instance, within a study measuring the appetitive effects that CBD had on THC-induced human subjects, it was found that CBD attenuated the hyperphagic response demonstrated by THC administration [193]. Similar results were observed within male Wistar rats, as CBD administration at 20 mg/kg attenuated the response of the CB1R agonist WIN55,212-22, which increased the overall food intake of the rats [188]. ...
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The Cannabis sativa plant has historically been used for both recreational and medical purposes. With the recent surge in recreational use of cannabis among adolescents and adults in particular, there is an increased obligation to determine the short- and long-term effects that consuming this plant may have on several aspects of the human psyche and body. The goal of this article was to examine the negative effects of obesity, and how the use of Δ9-tetrahydrocannibinol (THC) or cannabidiol (CBD) can impact rates of this global pandemic at different timepoints of life. Conflicting studies have been reported between adult and adolescents, as there are reports of THC use leading to increased weight due to elevated appetite and consumption of food, while others observed a decrease in overall body weight due to the regulation of omega-6/omega-3 endocannabinoid precursors and a decrease in energy expenditure. Studies supported a positive correlation between prenatal cannabis use and obesity rates in the children as they matured. The data did not indicate a direct connection between prenatal THC levels in cannabis and obesity rates, but that this development may occur due to prenatal THC consumption leading to low birthweight, and subsequent obesity. Due to the fact that there are not many studies that directly measured the effects that prenatal THC administration has on obesity risks within offspring, this could potentially be a topic of interest to investigate closer in the future.
... 17,18 In both animal and human models of addiction, CBD has been shown to reduce attentional bias to drug-related cues, cue-induced craving, and cueinduced drug reinstatement. [19][20][21] This has led to studies evaluating the possible therapeutic applications of CBD for OUD. In prior studies of individuals with OUD, CBD reduced cue-induced craving for opioids for up to a week after administering CBD 400 or 800 mg for 3 days. ...
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... Accordingly, future studies of cannabinoid treatment for sleep disorders should consider using a more balanced CBD to THC ratio. Indeed, recreational cannabis strains that contain high THC and low CBD concentrations were associated with serious adverse events when used during youth, including decreased motivation [63][64][65], addiction [66], mild cognitive decline [64,[67][68][69], and schizophrenia [64,[70][71][72]. However, all of these risks are higher in cannabis strains with a high ratio of THC to CBD [73], than in the more balanced strains. ...
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... Currently, there are no FDA-approved treatments for cannabis use disorders, however, research to find one is actively being done [265]. A plethora of drugs such as rimonabant [266][267][268], N-acetyl cysteine [269], Gabapentin [270,271], Cannabidiol [272][273][274][275], Dronabinol [23,[276][277][278][279][280][281], Naltrexone [158,282], Zolpidem (for the treatment of sleep disturbance associated with cannabis withdrawal) [276] are currently under investigation as a potential treatment for cannabis use disorder. Despite all these drugs are currently in preclinical and clinical phases, a few SR preparations have been reported that are discussed below. ...
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Substance use disorders (SUDs) are a leading cause of death and other ill health effects in the United States and other countries in the world. Several approaches ranging from detoxification, behavioral therapy, and the use of antagonists or drugs with counter effects are currently being applied for its management. Amongst these, drug therapy is the mainstay for some drug abuse incidence, as is in place specifically for opioid abuse or alcohol dependence. The severity of the havocs observed with the SUDs has triggered constant interest in the discovery and development of novel medications as well as suitable or most appropriate methods for the delivery of these agents. The chronic need of such drugs in users warrants the need for their prolonged or sustained systemic availability. Further, the need to improve patient tolerance to medication, limit invasive drug use and overall treatment outcome are pertinent considerations for embracing sustained release designs for medications used in managing SUDs. This review aims to provide an overview on up-to-date advances made with regards to sustained delivery systems for the drugs for treatment of different types of SUDs such as opioid, alcohol, tobacco, cocaine, and cannabis use disorder. The clinical relevance, promises and the limitations of deployed sustained release approaches along with future opportunities are discussed.
... The increasing concentration of THC in modern cannabis (which also often has relatively low levels of CBD; Freeman and Lorenzetti, 2020;Niesink et al., 2015) is thought to be a major factor in the increase of cannabis related-health issues, in particular dependence (Freeman and Winstock, 2015). The finding here that CBD blocks the disruptive effect on limbic striatum connectivity is also consistent with previous behavioural work showing that CBD attenuates the appetitive and incentivesalience effects of THC and other drugs (Hindocha et al., 2018;Morgan et al., 2010). Taken together, these various findings suggest a possible physiological mechanism whereby THC promotes dopamine release in the ventral striatum (possibly via the increase in glutamate concentrations reported by Mason et al., 2019), making users who consume relatively pure-THC strains vulnerable to addiction. ...
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Background Cannabidiol (CBD) and Δ ⁹ -tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Aims To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). Method Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. Results Study 1 ( N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 ( N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. Outcomes THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.
... THC is the cannabinoid most closely associated with euphoria, dependence, and mental health side effects associated with cannabis consumption (10)(11)(12). CBD, which is another main cannabinoid in the Cannabis plant, did not have THC psychoactivity (10,13). CBD holds a complicated pharmacodynamic profile, as a whole, as we know to interact with an extensive type of molecular targets. ...
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As a strong and addictive psychostimulant, methamphetamine (METH) is often misused worldwide. Although relapse is the greatest challenge to the effective treatment of drug dependency, now, for METH addiction, there is not available accepted pharmacotherapy. To characterize a probable new target in this indication, a biological system comprised of endocannabinoids, known as the endocannabinoid system (ECS), has been advised. As a non-psychotomimetic Phytocannabinoid in Cannabis sativa, cannabidiol (CBD) has been used in preclinical and clinical studies for treating neuropsychiatric disorders. In this review article, we focus on the effects of CBD in the treatment of addiction in a preclinical investigation concerning the pharmaceutic effectiveness and the underlying mechanisms of action on drug abuse specially METH. Growing evidence shows that CBD is a potential therapeutic agent in reducing drug reward, as evaluated in conditioned place preference (CPP), brain-stimulation reward paradigms, and self- administration. Furthermore, CBD plays an effective role in decreasing relapse in animal research. Through multiple-mechanisms, there is a belief that CBD modulates brain dopamine responding to METH, resulting in a reduction of METH-seeking behaviors. As our studies indicate, CBD can decrease METH addiction-associated problems, for example, symptoms of withdrawal and craving. It is needed for conducting more preclinical investigations and upcoming clinical trials to entirely assess the CBD capability as interference for METH addiction.
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Introduction Cannabidiol (CBD) is a phytocannabinoid found in the Cannabis plant. CBD has received significant medical attention in relation to its anticonvulsant, anxiolytic, and antipsychotic characteristics. An increasing number of studies focusing on the anti-addictive properties of CBD have recently been published. In this systematic review, we aim to offer a comprehensive overview of animal and human studies regarding the impact of CBD on substance use disorders (SUDs). Methods A systematic search was performed on the PubMed database in February 2021. We included all articles assessing the effects of CBD on substance use disorders. Results The current systematic review suggests that CBD might offer promising therapeutic potential for the treatment of SUD, based on available animal and human studies. Animal studies showed a positive impact of CBD in the context of alcohol, opioids, and methamphetamine use (e.g., diminishing of drug-seeking behaviors). The results for cocaine use were mixed among reviewed studies, and CBD was not found to have an effect in animal studies on cannabis use, No animal study was identified that focused on the impact of CBD on nicotine use. Human studies showed a positive impact of CBD in the context of nicotine, cannabis, and opioid use (e.g., frequency and quantity of consumption). In contrast, CBD was not found to have an effect in human studies on cocaine or alcohol use. No human study was identified that investigated the impact of CBD on methamphetamine use. Conclusions CBD might offer promising therapeutic potential for the treatment of SUD, especially for nicotine, cannabis, and opioid use disorders, based on available human studies. The available research evidence is, however, sparse and more research on humans is needed.
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Background Anorexia (loss of appetite) is a prevalent and distressing symptom in people with cancer, with limited effective interventions. Medicinal cannabis has shown promise in improving appetite-related symptoms in people with cancer. Aim To assess the efficacy of medicinal cannabis for improving appetite-related symptoms in people with cancer, considering measures and outcomes, interventions and toxicity. Design Systematic review with narrative approach to synthesis and meta-analysis. Data sources Databases (MEDLINE, CINAHL, CENTRAL), websites and trials registries were searched from inception to February 2021. Included studies were randomised controlled trials (RCT) in English peer-reviewed journals comparing medicinal cannabis with placebo and/or another intervention. Study quality was assessed using the Cochrane risk of bias tool. Results Five studies were included that compared medicinal cannabis interventions (dronabinol, nabilone and cannabis extract) either with placebo ( n = 4) or megestrol acetate ( n = 1). Measures and trial endpoints varied, but efficacy was demonstrated in one trial only, in which dronabinol significantly improved chemosensory perception and other secondary outcomes (taste of food, premeal appetite, proportion of calories consumed as protein) compared with placebo. Cannabis interventions were generally well tolerated across studies, regardless of the product or dose, although the comprehensive measurement of toxicities was limited. Conclusion Evidence from RCTs that medicinal cannabis increases appetite in people with cancer is limited. Measures, outcomes and interventions were variable, and toxicities have not been comprehensively evaluated. Future research should carefully consider biological mechanisms to guide more nuanced selection of endpoints and interventions, including product, dose and administration.
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This paper presents a biopsychological theory of drug addiction, the 'Incentive-Sensitization Theory'. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether 'wanting' drugs (drug craving) is attributable to 'liking' drugs (to the subjective pleasurable effects of drugs)? The theory posits the following. (1) Addictive drugs share the ability to enhance mesotelencephalic dopamine neurotransmission. (2) One psychological function of this neural system is to attribute 'incentive salience' to the perception and mental representation of events associated with activation of the system. Incentive salience is a psychological process that transforms the perception of stimuli, imbuing them with salience, making them attractive, 'wanted', incentive stimuli. (3) In some individuals the repeated use of addictive drugs produces incremental neuroadaptations in this neural system, rendering it increasingly and perhaps permanently, hypersensitive ('sensitized') to drugs and drug-associated stimuli. The sensitization of dopamine systems is gated by associative learning, which causes excessive incentive salience to be attributed to the act of drug taking and to stimuli associated with drug taking. It is specifically the sensitization of incentive salience, therefore, that transforms ordinary 'wanting' into excessive drug craving. (4) It is further proposed that sensitization of the neural systems responsible for incentive salience ('for wanting') can occur independently of changes in neural systems that mediate the subjective pleasurable effects of drugs (drug 'liking') and of neural systems that mediate withdrawal. Thus, sensitization of incentive salience can produce addictive behavior (compulsive drug seeking and drug taking) even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family. We review evidence for this view of addiction and discuss its implications for understanding the psychology and neurobiology of addiction.
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The effects of Δ 9-tetrahydrocannabinol (THC) content on choice of marijuana, number of marijuana cigarettes smoked, and ratings of marijuana's effects were examined in 6 adult male marijuana smokers during a residential study consisting of four 3-day blocks of 2 sample days and 1 choice day. Days were divided into 6.5-hr work and social-access periods, beginning at 1000 and 1700. On sample days, marijuana cigarettes containing different THC concentrations (0.0% vs. 3.5% and 2.0% vs. 3.5% THC) were smoked at least once during each period. On choice days, independent choices between previously sampled marijuana cigarettes were made during each period. A maximum of 8 cigarettes could be smoked per day, and drug ratings were obtained after each period. Only choice behavior was sensitive to changes in THC content, whereas only the number of smoked marijuana cigarettes was related to context (i.e., work and social-access period).
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The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana were studied in two groups of regular marijuana users. One group (N=10) was tested with smoked marijuana and the other (N=11) with oral THC. Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions. Subjective effects and heart rate were measured before and after drug administration. Smoked active marijuana was chosen over placebo on both choice occasions by all subjects. Similarly, oral THC was chosen over placebo on both occasions by all but one subject. Both active drug treatments produced qualitatively and quantitatively similar subjective effects, and both significantly increased heart rate, although the time course of effects differed substantially between the two treatments. The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions. The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans.
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The effects of Δ–9-tetrahydrocannabinol (THC) content on choice of marijuana, number of marijuana cigarettes smoked, and ratings of marijuana's effects were examined in 6 adult male marijuana smokers during a residential study consisting of four 3-day blocks of 2 sample days and 1 choice day. Days were divided into 6.5-hr work and social-access periods, beginning at 1000 and 1700. On sample days, marijuana cigarettes containing different THC concentrations (0.0% vs. 3.5% and 2.0% vs. 3.5% THC) were smoked at least once during each period. On choice days, independent choices between previously sampled marijuana cigarettes were made during each period. A maximum of 8 cigarettes could be smoked per day, and drug ratings were obtained after each period. Only choice behavior was sensitive to changes in THC content, whereas only the number of smoked marijuana cigarettes was related to context (i.e., work and social-access period).
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This paper presents a biopsychological theory of drug addiction, the ‘Incentive-Sensitization Theory’. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether ‘wanting’ drugs (drug craving) is attributable to ‘liking’ drugs (to the subjective pleasurable effects of drugs)? The theory posits the following.