Cannabis Dampens the Effects of Music in Brain Regions Sensitive to Reward and Emotion

Abstract

Background:
Despite the current shift towards permissive cannabis policies, few studies have investigated the pleasurable effects users seek. Here we investigate the effects of cannabis on listening to music - a rewarding activity that frequently occurs in the context of recreational cannabis use. We additionally tested how these effects are influenced by cannabidiol (CBD), which may offset cannabis-related harms.

Methods:
Across three sessions, sixteen cannabis users inhaled cannabis with CBD, cannabis without CBD, and placebo. We compared their response to music relative to control excerpts of scrambled sound during functional Magnetic Resonance Imaging (fMRI) within regions identified in a meta-analysis of music-evoked reward and emotion. All results were False Discovery Rate corrected (p<0.05).

Results:
Compared to placebo, cannabis without CBD dampened response to music in bilateral auditory cortex (right: p=0.005, left: p=0.008), right hippocampus/parahippocampal gyrus (p=0.025), right amygdala (p=0.025) and right ventral striatum (p=0.033). Across all sessions, the effects of music in this ventral striatal region correlated with pleasure ratings (p=0.002) and increased functional connectivity with auditory cortex (right: p=0.000, left: p=0.000), supporting its involvement in music reward. Functional connectivity between right ventral striatum and auditory cortex was increased by CBD (right: p=0.003, left: p=0.030), and cannabis with CBD did not differ from placebo on any fMRI measures. Both types of cannabis increased ratings of wanting to listen to music (p<0.002) and enhanced sound perception (p<0.001).

Conclusions:
Cannabis dampens the effects of music in brain regions sensitive to reward and emotion. These effects were offset by a key cannabis constituent, cannabidol.

Full text

Received: May 4, 2017; Revised: August 16, 2017; Accepted: August 30, 2017
© The Author 2017. Published by Oxford University Press on behalf of CINP.
International Journal of Neuropsychopharmacology (2017) 00(00): 1–12
doi:10.1093/ijnp/pyx082
Advance Access Publication: September 2, 2017
Regular Research Article
1
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.
org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is
properly cited.
  
Cannabis Dampens the Effects of Music in Brain
Regions Sensitive to Reward and Emotion
Tom P.Freeman, Rebecca A.Pope, Matthew B.Wall, James A.Bisby,
MaartjeLuijten, ChandniHindocha, ClaireMokrysz, WillLawn, AbigailMoss,
Michael A.P.Bloomeld, Celia J.A.Morgan, David J.Nutt, H. ValerieCurran
Clinical Psychopharmacology Unit, University College London, United Kingdom (Dr Freeman, Dr Pope,
Dr Wall, Ms Hindocha, Dr Mokrysz, Dr Lawn, Ms Moss, Prof Morgan, and Prof Curran); National Addiction
Centre, King’s College London, United Kingdom (Dr Freeman); Imanova Centre for Imaging Sciences, Imperial
College London, Hammersmith Hospital, London, United Kingdom (Dr Wall); Neuropsychopharmacology
Unit, Division of Brain Sciences, Imperial College London, London, United Kingdom (Dr Wall and Prof Nutt);
Institute of Cognitive Neuroscience, University College London, United Kingdom (Dr Bisby); Behavioural
Science Institute, Radboud University, Nijmegen, The Netherlands (Dr Luijten); Psychiatric Imaging Group,
Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom (Dr
Bloomeld); Division of Psychiatry, University College London, United Kingdom (Dr Bloomeld); Department of
Psychology, University of Exeter, United Kingdom (Prof Morgan).
Correspondence: Tom Freeman, PhD, National Addiction Centre, King’s College London, UK (tom.freeman@kcl.ac.uk).
Abstract
Background: Despite the current shift towards permissive cannabis policies, few studies have investigated the pleasurable
effects users seek. Here, we investigate the effects of cannabis on listening to music, a rewarding activity that frequently
occurs in the context of recreational cannabis use. We additionally tested how these effects are inuenced by cannabidiol,
which may offset cannabis-related harms.
Methods: Across 3 sessions, 16 cannabis users inhaled cannabis with cannabidiol, cannabis without cannabidiol, and placebo.
We compared their response to music relative to control excerpts of scrambled sound during functional Magnetic Resonance
Imaging within regions identied in a meta-analysis of music-evoked reward and emotion. All results were False Discovery
Rate corrected (P < .05).
Results: Compared with placebo, cannabis without cannabidiol dampened response to music in bilateral auditory cortex
(right: P = .005, left: P = .008), right hippocampus/parahippocampal gyrus (P = .025), right amygdala (P = .025), and right ventral
striatum (P = .033). Across all sessions, the effects of music in this ventral striatal region correlated with pleasure ratings
(P = .002) and increased functional connectivity with auditory cortex (right: P < .001, left: P < .001), supporting its involvement
in music reward. Functional connectivity between right ventral striatum and auditory cortex was increased by cannabidiol
(right: P = .003, left: P = .030), and cannabis with cannabidiol did not differ from placebo on any functional Magnetic Resonance
Imaging measures. Both types of cannabis increased ratings of wanting to listen to music (P < .002) and enhanced sound
perception (P < .001).
Conclusions: Cannabis dampens the effects of music in brain regions sensitive to reward and emotion. These effects were
offset by a key cannabis constituent, cannabidol.
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2 | International Journal of Neuropsychopharmacology, 2017
Keywords: cannabis, music, reward, pleasure, emotion
Introduction
The main psychoactive constituent of cannabis, THC (delta-
9-tetrahydrocannabinol), produces subjective effects such as
feeling “stoned” and can impair memory and elicit transient
psychotic-like symptoms (Curran etal., 2016). Certain types of
cannabis also contain cannabidiol (CBD), which can have oppo-
site effects of THC on a range of functional neuroimaging tasks
(Bhattacharyya etal., 2010; Batalla et al., 2014). Moreover, CBD
has been found to offset harmful effects of THC (e.g., memory
impairment and psychotic-like symptoms) without inuencing
subjective intoxication (Curran etal., 2016; Englund etal., 2017).
Cannabis containing high THC and little if any CBD is becoming
increasingly prevalent (Hardwick and King 2008; ElSohly et al.,
2016) and has been linked to greater mental health and addic-
tion problems compared with less potent varieties of cannabis
(Di Forti etal., 2015; Freeman and Winstock 2015).
Despite the changes currently occurring in cannabis legisla-
tion worldwide, including legalization of use for medicine and
pleasure (Room 2014), few studies have attempted to document
the effects that recreational users seek (Curran etal., 2016). The
limited evidence of positive effects tends to have arisen inciden-
tally in studies investigating cannabis-related harms. For exam-
ple, THC has been reported to increase phonological uency
(Curran etal., 2002), a measure of divergent thinking, especially
among people with low trait creativity (Schafer etal., 2012).
Cannabis has a strong historical link to music and is associated
with several distinct styles, including jazz, reggae, and rock (Booth
2004). Cannabis is reported to enhance appreciation of music (Tart
1970; Green etal., 2003), and its use is consistently high among
people who attend music festivals and nightclubs (Lim etal., 2008;
Van Havere etal., 2011; Palamar etal., 2015). This association may
be partly attributable to shared effects on reward circuitry between
drug and nondrug rewards (Berridge and Kringelbach 2015). Music
recruits key regions in the reward network, including ventral stria-
tum, mediodorsal thalamus, anterior insula, orbitofrontal cortex,
amygdala, and hippocampus (Koelsch 2014).
Many of these reward-related brain regions are character-
ized by a high density of Cannabinoid Type-1 Receptors (CB1Rs)
(Curran etal., 2016). THC is a partial agonist of CB1Rs and may
inuence response to music by interfering with endogenous
CB1R ligands such as anandamide (Thieme etal., 2014), which
plays a causal role in consummatory response to reward (Mahler
et al., 2007). Ahuman neuroimaging study found that THC (a
partial CB1R agonist) dampened the effects of monetary reward
feedback across a widespread network, including temporal and
orbitofrontal cortices, while leaving reward anticipation intact
(van Hell et al., 2012). By contrast, 7-day administration of a
CB1R antagonist was found to diminish response to food reward
in ventral striatum and orbitofrontal cortex (Horder etal., 2010).
Additionally, THC causes modest, regionally selective
increased dopamine release in limbic striatum (Bossong et al.,
2015). Such effects might enhance the rewarding experience
of music, which can also elicit dopamine release in ventral
striatum (Salimpoor et al., 2011) as well as enhancing activa-
tion and connectivity between mesolimbic brain regions (Blood
and Zatorre 2001; Menon and Levitin 2005; Koelsch et al., 2006;
Salimpoor et al., 2011; Trost et al., 2012). Functional connectivity
between ventral striatum and auditory cortex during listening
also predicts the rewarding experience of music (Salimpoor et
al., 2013; Zatorre and Salimpoor 2013; Martínez-Molina et al.,
2016).
Here, we conducted the rst controlled experimental study on
the interactive effects of cannabis and music. Based on previous
ndings that cannabis and music activate and increase connec-
tivity between common regions in the reward network, whereas
a CB1R antagonist dampened neural response to reward (Horder
et al., 2010), and observational data linking cannabis use and
music, we hypothesized that cannabis would increase haemo-
dynamic response to music in brain regions sensitive to reward
and emotion (Koelsch 2014) as well as subjective ratings (want-
ing to listen to music, pleasure of listening). Given that CBD and
THC can have opposing neural effects (Bhattacharyya et al.,
2010; Batalla etal., 2014) and CBD can attenuate THC harms
(Curran etal., 2016; Englund etal., 2017), we predicted that these
effects would be partially offset by CBD.
Methods
Design and Participants
A randomized, double-blind, crossover design compared can-
nabis with CBD (Cann+CBD), cannabis without CBD (Cann-CBD)
and matched placebo in 16 cannabis users. Experimental ses-
sions were separated by at least 1 week (>3 times the elimina-
tion half-life of THC) to minimize carryover effects (D’Souza
etal., 2004; Hindocha etal., 2015). In addition to the music task
described here, participants completed additional assessments
that are reported elsewhere (Lawn etal., 2016). Inclusion criteria
were uency in English, right-handedness, age between 18 and
70years, and self-reported current cannabis use (≥4 times in the
last year, ≤3 times/wk, ability to smoke a whole joint to oneself).
We did not collect data on participants’ typical method of admin-
istering cannabis. However, previous data from the UK suggest
that the majority (~76%) of cannabis users typically smoke can-
nabis together with tobacco in joints, and only a small minority
(~4%) use a vaporizer as their most common route (Hindocha
etal., 2016). Exclusion criteria were self-reported frequent and/
Signicance Statement
Here, we report that cannabis administration decreased response to music in several brain regions linked to reward and
emotion. These included right ventral striatum, which showed increased functional connectivity with auditory cortex
and correlated with pleasure ratings during musical listening, consistent with its critical role in reward processing.
These effects were offset when cannabis contained cannabidiol, a key cannabinoid that has been found to reduce some
harmful effects of cannabis.
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Freeman et al. | 3
or severe adverse reactions to cannabis, current use of illicit
drugs other than cannabis more than twice per month, cur-
rent alcohol use >4d/wk, signicant physical health problems,
color blindness, current treatment for a psychiatric disorder,
current/history of psychosis, and current/history of psychosis
in an immediate family member. This study was approved by
the UCL ethics committee, and all participants provided written
informed consent.
Procedure
Following telephone screening, eligible participants completed
a baseline session consisting of task training (outside of the MRI
scanner), video training for drug administration, drug history
(Freeman etal., 2012), and problematic cannabis use on Severity
of Dependence Scale (Gossop etal., 1995). The Beck Depression
Inventory-II (Beck et al., 1996) and Temporal Experiences of
Pleasure (Gard etal., 2006) were also administered. Each experi-
mental session began with a urinary drug screen to verify recent
use reported by Timeline Follow-back (Sobell and Sobell 1992).
Next, 11-point (0–10) Numerical Rating Scales were adminis-
tered ~0 minutes before drug inhalation (Pre-Drug), ~5 minutes
after rst drug administration (Post-Drug), and ~90 minutes
after rst drug administration (Post-Scan). The Numerical
Rating Scales “Want to Listen to Music” and “Enhanced Sound
Perception” were administered at all 3 of these time points; “Feel
Drug Effect,” “Like Drug Effect,” and “Want More Drug” were
administered only after drug administration (Post-Drug and
Post-Scan). Heart rate and systolic and diastolic blood pressure
were also recorded at the same 3 time points (Pre-Drug, Post-
Drug, Post-Scan).
Drug Administration
Cannabis was obtained from Bedrocan, The Netherlands and
used within 6 months of purchase. It was stored on site in
foil-sealed pouches at -20ºC and then at ambient temperature
prior to drug administration. Each dose was vaporized using a
Volcano Medic Vaporizer (Storz and Bickel) at 210ºC in 2 sequen-
tially administered balloons to minimize residual cannabinoids
(Lawn etal., 2016). Participants inhaled at their own pace (each
inhalation held for 8 seconds, enforced by the experimenter
using a stopwatch) until the balloon was empty, which lasted ~5
minutes for both balloons. All participants complied with this
administration protocol. Bedrobinol (12% THC, <1% CBD), Bediol
(6% THC, 7.5% CBD), and placebo cannabis were used to load
doses of 8mg THC + 10mg CBD (Cann+CBD), 8mg THC (Cann-
CBD), and placebo (Lawn etal., 2016). Placebo cannabis had a
comparable terpene prole to the 2 active forms of cannabis,
ensuring it was matched for smell. The same physical quantity
of cannabis/placebo (133.4mg) was administered across each
of the 3 sessions. This dose of THC has produced effects on
brain and behavior in studies with similar vaporizer protocols
(Bossong etal., 2009; Hindocha etal., 2015; Mokrysz etal., 2016)
and is roughly equivalent to one-quarter of a standard UK joint
(Freeman etal., 2014).
Music Task (Menon and Levitin 2005)
Six 21-second excerpts of standard instrumental classical
music were taken from compact disc recordings, adapted from
a previous study (Menon and Levitin 2005). Six scrambled ver-
sions were created by randomly drawing 250- to 350-millisec-
ond variable-sized sections from each piece and concatenating
them with a 30-millisecond linear cross-fade between excerpts
(Menon and Levitin 2005). Scrambled excerpts retain the same
distribution of pitch and loudness and the same spectral infor-
mation as normal music. However, they lack temporal structure
and are rated as less pleasurable than normal excerpts (Menon
and Levitin 2005).
To deliver clear audio during scanning, clips were adapted
to improve volume constancy during sections of low volume.
Output volume was adapted for each participant in the scanner
before the task commenced. Normal/scrambled excerpts were
delivered using PsychoPy (Version 1.79.01) through MR compat-
ible sensimetric earphones (http://www.sens.com/products/
model-s14/) in a standard blocked fMRI design. The 12 normal/
scrambled excerpts were presented in a pseudo-randomized
order across the 3 test sessions. Each 21-second excerpt was fol-
lowed by a 1-second interstimulus interval. Next, participants
rated the pleasantness of each excerpt using a 2-nger response
pad beneath their right hand (xed time of 8 seconds). The
numerical rating scale was anchored from 0 (not at all pleasant)
to 10 (very pleasant). This was followed by 12 seconds of pas-
sive xation (rest). The total task time was 8 minutes 24 seconds,
plus a 5-second end-buffer period.
fMRI Data Acquisition
Imaging data were collected using a Siemens TIM Avanto 1.5T
scanner, using a 32-channel receive-only head coil, at the
Birkbeck-UCL Centre for Neuroimaging, London. An automated
shim procedure was applied to minimize possible magnetic eld
homogeneities. Functional imaging used a multiband (accelera-
tion factor = 4) gradient-echo T2*-weighted echo-planar imag-
ing (EPI) sequence with 40 slices per volume (TR = 1000 ms;
TE = 55ms; in-plane matrix = 64 x 64; 3mm isotropic voxels; ip
angle = 75°; bandwidth = 1474 Hz/pixel; 509 volumes). The rst 8
scans were treated as “dummy” scans and discarded to avoid
T1-equilibrium effects. All scanning parameters were selected
to optimize the quality of the BOLD signal while maintaining
a sufcient number of slices to acquire whole-brain data. To
co-register the fMRI data into standard space, we also acquired
a MPRAGE structural sequence (TR = 2730 ms; TE = 3.57 ms;
matrix = 176 x 256 x 256; 1-mm isotropic voxels; ip angle = 7°;
bandwidth = 190 Hz/pixel; parallel imaging acceleration fac-
tor = 2), and a B0 eld map image (64 axial slices; TR = 1170 ms;
TE1 = 10.0 ms; TE2 = 14.76 ms; in-plane matrix = 64 x 64; 3 x 3 x
2mm voxels; ip angle = 90°; bandwidth = 260 Hz/pixel) to enable
distortion correction of the functional data.
fMRI Data Analysis
Preprocessing and data analysis were performed using
Statistical Parametric Mapping (SPM8; http://www.l.ion.ucl.
ac.uk/spm/software/spm8/). Standard preprocessing procedures
consisted of bias correction of EPI images to control for within-
volume signal intensity differences, realignment/unwarping
to correct for interscan movements, correction for differences
in slice acquisition timing, and normalization of the images to
an EPI template specic to our sequence and scanner that was
aligned to the T1 MNI template. Finally, the normalized func-
tional images were spatially smoothed with an isotropic 8-mm
FWHM Gaussian kernel.
At the rst level, the normal and scrambled epochs were
each modelled as a 21-second boxcar convolved with the canon-
ical hemodynamic response function combined with time and
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4 | International Journal of Neuropsychopharmacology, 2017
dispersion derivatives to create the contrast music>scrambled,
as previously used with this task (Menon and Levitin 2005).
The interstimulus interval, rating, and passive xation (rest)
were also modelled. Each subject’s movement parameters were
included as confounds. Low-frequency noise was removed with
a high-pass lter (cut-off frequency 1/128 Hz). Parameter esti-
mates pertaining to the height of the hemodynamic response
function for each regressor of interest were then calculated for
eachvoxel.
At the second level, the contrast music>scrambled was
entered into a within-subject ANOVA model with a single fac-
tor of drug (Cann+CBD, Cann-CBD, placebo). Within this ANOVA
model, we used t contrasts to investigate music>scrambled and
the reverse contrast (scrambled>music) across all scans. Drug
effects on music>scrambled were conducted using t contrasts
within this ANOVA model. To aid interpretation of signi-
cant drug effects (which could reect changes in response to
music, scrambled, or both), separate parameter estimates were
extracted from these coordinates for the contrasts music>rest
and scrambled>rest using the MarsBaR region of interest tool-
box; these were analyzed using repeated-measures ANOVA
inSPSS.
Psychophysiological interaction (PPI) analysis was per-
formed to assess task-related functional connectivity (O’Reilly
etal., 2012) using seed regions identied by drug effects. We
extracted the representative time-course from voxels in the
seed region (6-mm radius sphere) using the rst eigenvari-
ate calculated from singular value composition. This time
course (physiological) was entered into a General Linear Model
together with the contrast music>scrambled (psychological)
and their interaction (PPI). Motion parameters were included in
rst-level models as nuisance regressors. The PPI regressor was
analyzed using a within-subject ANOVA. We used t contrasts
to investigate PPI effects across all scans and to compare drug
effects.
A False Discovery Rate correction (P < .05) was applied to all
fMRI analyses. Regions of interest were dened from a previ-
ous meta-analysis of music-evoked reward and emotion (see
Figure1 and supplementary Table1 in Koelsch 2014) using the
MarsBaR toolbox. Firstly, each of the structures identied in the
meta-analysis was converted into a single sphere. Coordinates
were converted to MNI using the Yale BioImage Suite (Lacadie
etal., 2008). Sphere radius was estimated from the cluster size
reported in the meta-analysis. Where clusters contained mul-
tiple structures, size was determined using the cluster mean.
Subthreshold clusters were assigned a default size of 200mm3.
Each of these spheres was combined into a single mask that
was applied to second-level analysis. This mask (41 240mm3)
included bilateral hippocampal formation, bilateral amygdala,
bilateral auditory cortex, right ventral striatum, left caudate
nucleus, presupplementary motor area, frontomedian cortex,
rostral cingulate zone, pre-genual and middle cingulate cortex,
medial and laterial orbitofrontal cortex, right anterior insula,
mediodorsal thalamus, and superior parietal lobule.
Behavioral Data Analysis
SPSS version 21 was used to analyze all behavioral data and
parameter estimates extracted posthoc using MarsBaR. Outliers
(>3 times IQR) were winsorized within each session and time
point. Histograms were used to investigate normality, and
square root or log transformations were applied where appro-
priate. Trait measures (BDI, Temporal Experiences of Pleasure,
SDS, and drug history) were missing for one participant. Missing
data from experimental sessions (0.69% of Numerical Rating
Scale data, 0.69% of cardiovascular data) were imputed with the
mean for that session and time point to retain each participant
in the repeated-measures analysis. Repeated-measures ANOVA
models were used for all data collected on the 3 experimental
sessions, including within-subject factors of drug (Cann+CBD,
Cann-CBD, placebo) and time (Pre-Drug, Post-Drug, Post-Scan)
or (Post-Drug, Post-Scan) and additional factors where appro-
priate. Posthoc pairwise tests were Bonferroni-corrected locally
within each ANOVA model. Additional repeated-measures
ANOVA models were used to aid interpretation of interactions
where appropriate. The Greenhouse-Geisser correction was
applied where assumptions of sphericity were violated, with
degrees of freedom rounded to the nearest integer. To reduce
type Iand type II error rates, correlations with fMRI data were
collapsed across each of the sessions using mixed effects mod-
els, with a Bonferroni-adjusted α threshold. These accounted for
xed effects of drug and session order, with a random intercept
of participant and maximum likelihood estimation. Equivalent
mixed effects models were used to assess possible confound-
ing by cardiovascular measures, cannabis use, and session order.
Results
Participants
Seventeen participants completed the study. One participant
was excluded due to excessive head movement on one session
(exceeding thresholds for both translation [>6mm] and rotation
[>6º]) and was replaced, leaving a nal sample of 16. Demographic
and drug use data are shown in Table 1. The following num-
ber of participants completed each treatment order: Placebo,
Cann+CBD, Cann-CBD: n = 3; Placebo, Cann-CBD, Cann+CBD:
n = 2; Cann+CBD, Placebo, Cann-CBD: n = 3; Cann+CBD, Cann-
CBD, Placebo: n = 3; Cann-CBD, Placebo, Cann+CBD: n = 2; Cann-
CBD, Cann+CBD, Placebo: n = 3.
Behavioral Results
Subjective Effects
Subjective effects are shown in Figure2 . A main effect of drug
(F1,22 = 107.659, P < .001, ηp
2 = 0.878) emerged for Feel Drug Effect,
reecting increased scores following Cann+CBD (P < .001) and
Cann-CBD (P < .001) compared with placebo, but no differences
between Cann+CBD and Cann-CBD (P = 1.000). There was also
a main effect of time, indicating that scores decreased from
Post-Drug to Post-Scan (F1,15 = 19.057, P < .001, ηp
2 = 0.560), but
there was no evidence for an interaction between drug and
time (F2, 30 = 0.796, P = .461, ηp
2 = 0.050). Like Drug Effect showed
a similar prole of results. There was a main effect of drug
(F2,30 = 44.371, P < .001, ηp
2 = 0.747), reecting increased scores fol-
lowing Cann+CBD (P < .001) and Cann-CBD (P < .001) compared
with placebo but no difference between Cann + CBD and Cann-
CBD (P = 1.000). There was also a main effect of time, indicating
that scores decreased from Post-Drug to Post-Scan (F1,15 = 19.454,
P < .001, ηp
2 = 0.565). Again, there was no evidence for an inter-
action between drug and time (F2,30 = 0.589, P = .561, ηp
2 = 0.038).
For Want More Drug, there was no evidence for any effects or
interactions: drug by time (F2,30 = 2.462, P = .102, ηp
2 = 0.141), drug
(F2,30 = 1.329, P = .280, ηp
2 = 0.081), or Time (F1,15 = 0.388, P = .543,
ηp
2 = 0.025).
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Freeman et al. | 5
Cardiovascular Effects
Cardiovascular effects are shown in Figure 2. For heart rate
(BPM), a drug by time interaction emerged (F2,28 = 18.243, P < .001,
ηp
2 = 0.549) as well as main effects of both drug (F2,30 = 13.999,
P < .001, ηp
2 = 0.483) and time (F2,30 = 45.977, P < .001, ηp
2 = 0.754).
Heart rate increased from Pre-Drug to Post-Drug following
Cann+CBD (P < .001) and Cann-CBD (P < .001) but not placebo
(P = .456). It then decreased from Post-Drug to Post-Scan for
both Cann+CBD (P < .001) and Cann-CBD (P < .001) but did not
change on placebo (P = 1.000). When comparing the 2 types of
cannabis alone, there were no differences between the effects of
Cann+CBD and Cann-CBD on heart rate across the 3 time points
(drug by time interaction: F2,30 = 0.123, P = .885, ηp
2 = 0.008; main
effect of drug: F1,15 = 0.090, P = .768, ηp
2 = 0.006, main effect of time:
F2,30 = 87.391, P < .001, ηp
2 = 0.854). For systolic blood pressure, a
main effect of drug was found (F2,30 = 6.297, P = .005, ηp
2 = 0.296).
This reected increased blood pressure for both Cann+CBD
(P = .030) and Cann-CBD (P = .006), compared with placebo, but
no differences between Cann+CBD and Cann-CBD (P = 1.000).
There was no evidence for an interaction between drug and
Figure1. Subjective effects. Both types of cannabis increased ratings for (A) Feel Drug Effect and (B) Like Drug Effect but did not inuence (C) Want More Drug.
Cann + CBD, cannabis with cannabidiol (CBD); Cann-CBD, cannabis without CBD. ***P < .001.
Figure2. Cardiovascular effects. Both types of cannabis increased (A) heart rate and (B) systolic blood pressure. (C) Diastolic blood pressure increased from Pre- to Post-
Drug following cannabis without cannabidiol (CBD), but not following cannabis with CBD; Cann + CBD, cannabis with CBD; Cann-CBD, cannabis without CBD; *P < .05,
***P < .001; †Difference between cannabis types.
Figure3. Subjective music ratings. (A) Both types of cannabis increased ratings of Want to Listen to Music. (B) Both types of cannabis increased scores for Enhanced
Sound Perception and this increase was greater for cannabis with cannabidiol (CBD). (C) Neither type of cannabis inuenced the pleasure of listening to music or
scrambled sound clips. Cann + CBD, cannabis with CBD; Cann-CBD, cannabis without CBD. ***P < .001; †Difference between cannabis types.
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6 | International Journal of Neuropsychopharmacology, 2017
time (F4,60 = 0.953, P = .440, ηp
2 = 0.060) or a main effect of time
(F2,30 = 2.641, P = .088, ηp
2 = 0.150). For diastolic blood pressure,
an interaction between drug and time was found (F4,60 = 3.217,
P = .019, ηp
2 = 0.177) and a main effect of time (F2,30 = 7.702, P = .002,
ηp
2 = 0.339) but not drug (F2,30 = 2.975, P = .066, ηp
2 = 0.165). Diastolic
blood pressure increased from Pre-Drug to Post-Drug for Cann-
CBD (P < .001) but not Cann+CBD (P = .233) or placebo (P = 1.000).
It then increased from Post-Drug to Post-Scan following placebo
(P = .030) but not Cann-CBD (P = 1.000) or Cann+CBD (P = 1.000).
Subjective Music Ratings
Subjective music ratings are shown in Figure 3. For Want to
Listen to Music, we found a drug by time interaction (F4,60 = 5.256,
P = .001, ηp
2 = 0.259) and main effects of drug (F2,30 = 5.664, P = .008,
ηp
2 = 0.274) and time (F1,22 = 6.300, P = .012, ηp
2 = 0.296). Scores
increased from Pre-Drug to Post-Drug following Cann+CBD
(P < .001) and Cann-CBD (P = .002) but not placebo (P = 1.000).
Scores then decreased from Post-Drug to Post-Scan on Cann+CBD
(P = .028), but these tests did not reach signicance for Cann-
CBD (P = .553) or placebo (P = .199). However, analysis of all three
drug conditions suggested that the decrease in Want to Listen
to Music from Post-Drug to Post-Scan was equivalent across
the 3 sessions (drug by time interaction: F1,21 = 1.130, P = .321,
ηp
2 = 0.070; main effect of drug: F2,30 = 9.158, P = .001, ηp
2 = 0.379,
main effect of time: F1,15 = 7.164, P = .017, ηp
2 = 0.323). Moreover,
when comparing the 2 types of cannabis alone, there were no
differences between the effects of Cann+CBD and Cann-CBD on
Want to Listen to Music across the 3 time points (drug by time
interaction: F2,30 = 0.804, P = .457, ηp
2 = 0.051; main effect of drug:
F1,15 = 3.590, P = .078, ηp
2 = 0.193, main effect of time: F2,30 = 8.251,
P = .001, ηp
2 = 0.355).
For Enhanced Sound Perception, Pre-Drug scores were
removed from analysis due to oor effects on each session. Mean
(SD) values were 0.25 (0.45) on placebo, 0.00 (0.00) on Cann+CBD,
and 0.00 (0.00) on Cann-CBD. Analysis of variance was there-
fore restricted to 2 time points (Post-Drug, Post-Scan). Amain
effect of drug (F2,30
= 44.810, P < .001, ηp
2
= 0.749) reected increased
scores from placebo following Cann+CBD (P < .001) and Cann-
CBD (P < .001) and higher scores following Cann+CBD compared
with Cann-CBD (P = .015). There was no evidence for an interac-
tion between drug and time (F2,30
= 2.056, P = .146, ηp
2
= 0.121) or a
main effect of time (F1,15
= 1.248, P = .281, ηp
2
= 0.077). Finally, we
analyzed trial-by-trial pleasure ratings, recorded immediately
after listening to classical music and scrambled sound excerpts
during MRI scanning. There was a main effect of excerpt
(F1,15
= 133.860, P < .001, ηp
2
= 0.899), indicating that music was rated
as more pleasant than scrambled sound. However, there was no
evidence for a main effect of drug (F2,30
= 1.205, P = .314, ηp
2
= 0.074)
or a drug by excerpt interaction (F2,30
= 1.221, P = .309, ηp
2
= 0.075).
Next, we calculated a pleasure rating score (music>scrambled)
equivalent to our fMRI contrast of interest to provide compa-
rable metrics for brain and behavior. Mean (SD) pleasure rating
scores were 5.16 (2.27) for Cann+CBD, 4.78 (2.03) for Cann-CBD,
and 5.53 (1.99) for placebo. Analysis of these scores provided no
evidence for an effect of drug (F2,30
= 1.221, P = .309, ηp
2
= 0.075).
fMRI Results
Main Effect ofTask
All fMRI analyses were conducted among regions of inter-
est selected from a meta-analysis of previous studies (Koelsch
2014). Across all sessions, listening to music elicited activation
in bilateral amygdala, bilateral striatum, left hippocampus, and
left cingulate gyrus (see Table2). For completion, we also exam-
ined the reverse contrast (scrambled>music), which revealed
activation in bilateral auditory cortex (see Table2).
Drug Effects
Response to music>scrambled was greater on placebo com-
pared with Cann-CBD in bilateral auditory cortex, right hip-
pocampus/parahippocampal gyrus, right ventral striatum, and
right amygdala (see Table2 and Figure4). There was no evidence
for any differences when comparing Cann+CBD with placebo or
Cann+CBD with Cann-CBD.
To aid interpretation of these ndings (which may have been
driven by drug effects on music, scrambled sound, or both), we
extracted parameter estimates from each of the clusters iden-
tied in this drug effect (Table 2, bottom panel) for separate
contrasts of music>rest and scrambled>rest. ANOVA revealed
an interaction between drug (placebo, Cann-CBD) and contrast
(music>rest, scrambled>rest) (F1,15
= 37.851, P < .001, ηp
2
= 0.716).
This interaction indicated that relative to placebo, Cann-CBD
decreased parameter estimates for music>rest (P = .009, mean
difference -0.195, standard error 0.065). However, there was no
evidence for drug effects on scrambled>rest (P = .130, mean dif-
ference 0.103, standard error 0.064). There were no other ndings
involving drug (drug by contrast by region interaction: F4,60
= 0.687,
P = .604, ηp
2
= 0.044; drug by region interaction: F4,60
= 0.919, P = .459,
ηp
2
= 0.058; main effect of drug: F1,15
= 0.585, P = .456, ηp
2
= 0.038).
This suggests that Cann-CBD dampened response to music to a
similar extent across each of these regions (right auditory cor-
tex, left auditory cortex, right hippocampus/parahippocampal
gyrus, right ventral striatum, and right amygdala) while having
negligible effects on response to scrambled sound.
Brain-Behavior Correlations
Next, we sought to examine correlations between brain
(music>scrambled, extracted from the 5 clusters shown in
Table1. Demographic and Drug Use Data
Mean/
frequency SD
Age 26.25 7.35
Gender (male/female) 8/8 -
Days of cannabis use per month 8.06 5.48
Years of cannabis use 8.94 7.02
Days since last cannabis use 19.25 45.28
Days to smoke 3.5g cannabis 25.88 33.73
Severity of dependence scale (cannabis) 1.13 1.26
Alcohol use (yes/no) 16/0 -
Days of alcohol use per month 10.81 4.86
Number of UK alcohol units (8g) per
session
5.93 2.08
Current tobacco use (yes/no) 15/1 -
Days of tobacco use per month 11.30 10.27
Cigarettes per day 3.63 3.62
Current MDMA use <twice a month (yes/
no)
6/10 -
Current cocaine use <twice a month (yes/
no)
3/13 -
Current ketamine use <twice a month
(yes/no)
2/14 -
Beck Depression Inventory-II 3.38 3.12
Temporal experiences of pleasure
(anticipatory)
42.06 4.85
Temporal experiences of pleasure
(consummatory)
43.50 5.61
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Freeman et al. | 7
the bottom panel of Table 2) and behavior (pleasure ratings
for music>scrambled, Post-Drug Want to Listen to Music and
Enhanced Sound Perception). Data were combined across
all sessions to minimize type I and type II error using mixed
effects models, resulting in a total of 15 correlations. One cor-
relation reached statistical signicance. This showed a positive
Table 2. MNI Coordinates for the Contrasts Music>Scrambled (Main Effect of Task, Top Panel) and Scrambled>Music (Main Effect of Task, Middle
Panel) across All Sessions. The bottom panel shows brain regions in which participants’ response to music>scrambled was dampened follow-
ing cannabis without CBD compared with placebo; +: additional peak within cluster. All P values are thresholded at P < .05 (FDR-corrected for
multiple comparisons)
x y Z mm3
ZP
Main effect of task (music>scrambled)
L Caudate -12 6 6 540 4.45 .006
L Amygdala -15 -3 -15 486 4.32 .006
L Hippocampus -18 -12 -18 + 3.59 .027
R Caudate/thalamus 9 3 6 594 3.91 .014
R Pallidum 15 -3 -6 54 3.33 .031
L Cingulate gyrus -6 -15 42 27 3.16 .035
R Amygdala 18 -3 -18 54 2.99 .040
Main effect of task (scrambled>music)
R Planum temporale 60 -12 3 3834 6.61 <.001
R Planum temporale 54 -24 6 + 6.54 <.001
L Planum temporale -48 -33 9 2511 6.16 <.001
L Heschls gyrus -42 -24 3 + 5.26 <.001
Drug effect (placebo>cannabis without CBD)
R Superior temporal gyrus 51 -27 6 2484 4.51 .005
R Planum temporale 60 -12 3 + 3.55 .016
R Planum temporale/heschls gyrus 42 -18 0 + 3.15 .026
L Planum temporale -42 -33 9 972 4.04 .008
R Hippocampus/parahippocampal gyrus 33 -18 -24 81 3.23 .025
R Amygdala 27 3 -27 27 3.19 .025
R Ventral striatum 15 15 -12 54 2.90 .033
Figure4. Cannabis without cannabidiol (CBD) dampened brain response to music across several regions sensitive to music-evoked reward and emotion. (A) Bilateral
auditory cortex activation clusters visualized on the cortical surface of a standard template (MNI152). (B) Aventral view of the same template showing right-hemi-
sphere amygdala and hippocampal clusters. (C) Axial slice views of the same contrast showing amygdala, hippocampal, ventral striatal (top row), and auditory cortex
(bottom row) activation clusters. All activation maps thresholded at P < .05 (FDR corrected for multiple comparisons). A, anterior; L, left hemisphere; P, posterior; R, right
hemisphere.
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8 | International Journal of Neuropsychopharmacology, 2017
relationship between pleasure ratings and response to music
in right ventral striatum (F1,34
= 11.447, P = .002; Figure 5). The
same relationship was found using a Pearson correlation analy-
sis across all scans (r = 0.463, P = .001). This correlation did not
contain any outlying values (all data points were <3 times the
interquartile range). However, there was still evidence for a cor-
relation after excluding the 2 data points showing the highest
and lowest right ventral striatum response to music (mixed
effects model: F1,41
= 4.438, P = .041; Pearson correlation analysis
r = 0.318, P = .032).
Functional Connectivity
Previous research has shown that the rewarding experience of
music is predicted by increased functional connectivity between
right ventral striatum and auditory cortex (Salimpoor etal., 2013;
Zatorre and Salimpoor 2013; Martínez-Molina etal., 2016). To test
this, we conducted PPI analyses. These analyses were conducted
posthoc, informed by our ndings that Cann-CBD blunted partic-
ipants’ response to music in right ventral striatum and auditory
cortex. Within-subjects ANOVA revealed that across all sessions,
the right ventral striatum region (15, 15, -12) identied in our
analysis showed a robust increase in functional connectivity with
bilateral auditory cortex (and to a lesser extent, right caudate)
during music relative to scrambled sound (Table3). For comple-
tion, we conducted the reverse contrast. However, we found no
evidence for any regions showing reduced connectivity with this
region during music relative scrambled sound. Next, we exam-
ined drug effects using t contrasts. Compared with Cann-CBD,
greater functional connectivity occurred on Cann+CBD between
right ventral striatum and bilateral auditory cortex (Table 3;
Figure6). We also conducted a PPI analysis using an auditory cor-
tex seed (right superior temporal gyrus 51, -27, 6). However, this
PPI analysis did not identify any regions that showed increases
in functional connectivity with the seed region.
Possible Confounding
Cardiovascular Drug Effects
We conducted correlations between all Post-Drug cardiovascu-
lar measures (heart rate, systolic and diastolic blood pressure)
and the 9 clusters showing evidence of drug effects (see Tables
2 and 3) across all sessions (total 27 correlations). We found no
evidence for any association between cardiovascular and fMRI
data (all P > .05).
CannabisUse
We also explored correlations between levels of cannabis of use
and our main ndings. These were conducted between (1) years
of cannabis use, (2) days of cannabis use per month and the 9
clusters showing evidence of drug effects (Tables 2 and 3), Want
to Listen to Music (Post-Drug), Enhanced Sound Perception (Post-
Drug), and pleasure rating scores. Of the 24 correlations, we found
Table 3. Functional Connectivity Analysis. MNI coordinates showing increased functional connectivity with right ventral striatum for
music>scrambled across all sessions (main effect, top panel). Functional connectivity between right ventral striatum and auditory cortex
increased on cannabis with CBD compared with cannabis without CBD (drug effect, bottom panel); +Additional peak within cluster. All P values
are thresholded at P < .05 (False Discovery Rate-corrected for multiple comparisons)
X y z mm3ZP
Main effect
R Planum temporale 60 -12 6 5319 6.43 <.001
R Heschls gyrus/planum polare 48 -12 0 + 6.42 <.001
R Planum temporale 48 -27 9 + 6.26 <.001
L Heschls gyrus -42 -24 12 3429 6.31 <.001
L Planum temporale -42 -30 6 + 6.27 <.001
L Planum temporale -33 -33 15 + 5.48 <.001
R Caudate 9 15 9 54 2.42 .037
Drug effect (cannabis with CBD>cannabis without CBD)
R Heschls gyrus 42 -18 9 1620 4.63 .003
L Hippocampus -30 -18 -21 81 3.64 .009
L Heschls gyrus -36 -27 9 54 3.08 .030
L Heschls gyrus -45 -24 15 27 3.05 .031
Figure 5. Correlation between brain and behavior. (A) Axial slice of right ventral striatal region of interest, identied from voxelwise analysis. (B) Sagittal slice of the
same region. (C) Across all scans, activation in right ventral striatum for the contrast music>scrambled correlated positively with pleasure ratings.
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Freeman et al. | 9
no evidence for any associations (all P > .05) apart from a trend
negative correlation between years of cannabis use and functional
connectivity between right ventral striatum and left hippocampus
(F1,48 = 4.984, P = .030). However, this did not reach signicance at a
Bonferroni-corrected threshold (α = 0.0021). Moreover, the effect of
drug remained signicant in this model (F1,48 = 7.455, P = .002).
Order Effects
Because the same music and scrambled sound excerpts were
presented across each of the 3 sessions, we investigated pos-
sible order effects. For all fMRI results showing drug effects, the
effect of drug remained signicant, and there was no evidence
for an effect of session order (all P > .05). There was no evidence
for effects of drug or session order for pleasure rating scores
(all P > .05). Analysis of Want to Listen to Music (Post-Drug) and
Enhanced Sound Perception (Post-Drug) scores showed effects
of drug (both P < .001) but not session (both P > .05).
Discussion
To our knowledge, this is the rst controlled experiment inves-
tigating the interactive effects of cannabis and music. Cannabis
dampened response to music in several regions implicated in
music-evoked reward and emotion (Koelsch 2014): bilateral audi-
tory cortex, right amygdala, right hippocampus/parahippocam-
pal gyrus, and right ventral striatum. Across all scans we found
a positive correlation between response to music in this ventral
striatal region and the pleasure of listening to the same sound
clips, consistent with several studies implicating the ventral stri-
atum in musical pleasure (Blood and Zatorre 2001; Koelsch et al.,
2006; Salimpoor et al., 2011; Trost et al., 2012). The same ventral
striatal region showed increased task-related functional connec-
tivity with bilateral auditory cortex, an effect that has previously
been shown to predict musical reward value (Salimpoor et al.,
2013; Zatorre and Salimpoor 2013; Martínez-Molina et al., 2016).
These ndings were contrary to our prediction that cannabis
would increase the rewarding effects of music, which can acti-
vate and increase connectivity within mesolimbic brain regions
(Blood and Zatorre 2001; Menon and Levitin 2005; Koelsch et al.,
2006; Salimpoor et al., 2011; Trost et al., 2012) and, in common
with THC, may increase striatal dopamine release (Salimpoor et
al., 2011; Bossong et al., 2015). Moreover, observational data sug-
gests that cannabis is frequently used in the context of music
and may enhance its effects (Tart 1970; Green et al., 2003; Lim et
al., 2008; Van Havere et al., 2011; Palamar et al., 2015).
One possible explanation for our ndings is that THC inter-
fered with the endocannabinoid system, which plays a critical
role in reward processing (Parsons and Hurd 2015). For example,
acute THC may deplete the CB1R ligand anandamide (Thieme
etal., 2014), which increases consummatory response to reward
in the nucleus accumbens shell (Mahler etal., 2007). Disruption
of the endocannabinoid system could explain why neural
response to reward was previously dampened by 7-day admin-
istration of a CB1R antagonist (Horder etal., 2010) as well as a
single dose of the partial CB1R agonist THC (van Hell etal., 2012).
It should also be noted that our ndings of dampened response
to music occurred in the context of increased wanting to listen
to music. These ndings are broadly consistent with previous
ndings that THC may have dissociable effects on anticipatory
(“wanting”) and consummatory (“liking”) components of reward
(van Hell et al., 2012; Jansma et al., 2013), although our task
lacked a neural index of reward anticipation.
Cannabis with CBD did not differ from placebo on any fMRI
measures. Furthermore, it resulted in greater task-related func-
tional connectivity between ventral striatum and auditory
cortex compared with cannabis without CBD. These ndings
suggest that CBD was able to offset some effects of THC, consist-
ent with previous research (Curran etal., 2016; Englund et al.,
2017) and evidence that THC and CBD can have opposite neu-
ral effects (Bhattacharyya etal., 2010; Batalla etal., 2014). For
example, activation in right superior temporal gyrus (a region
identied in our study) during word listening relative to rest was
previously found to be decreased by THC but increased by CBD
(Winton-Brown etal., 2011). Moreover, CBD may increase con-
centrations of anandamide (Bisogno etal., 2001; Leweke etal.,
2012). We found some evidence that CBD interacted with THC
on additional measures. Taken together, CBD appeared to par-
tially offset some negative effects of THC (increase in diastolic
blood pressure, decreased response to music) while preserv-
ing or potentiating desirable ones (enhanced sound perception,
Figure 6. Functional connectivity analysis. (A) Seed region in right ventral striatum. (B) This seed region showed increased task-related functional connectivity with
bilateral auditory cortex following cannabis with cannabidiol (CBD) compared with cannabis without CBD (C). Axial slices depicting the same data in bilateral auditory
cortex and additional left hippocampal cluster. All activation maps visualized on MNI152 and thresholded at P < .05 (FDR corrected for multiple comparisons). L, left
hemisphere; R, right hemisphere.
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10 | International Journal of Neuropsychopharmacology, 2017
functional connectivity with ventral striatum during musical
listening).
In terms of clinical implications, the effects of acute can-
nabis administration here are similar to previous ndings in
people with depression, who also show a blunted response to
music in ventral striatum as well as medial orbitofrontal cortex
(Osuch etal., 2009). In this respect, acute cannabis administra-
tion may transiently mimic the diminished response to reward
characteristic of some mental health disorders. The impact of
chronic cannabis administration remains unclear. However, a
4-year prospective study found that increased cannabis use
was associated with subsequent reductions in ventral striatal
response to reward anticipation (Martz etal., 2016). It there-
fore is possible that effects of cannabis on reward processing
may contribute to an increased risk of developing depression
(Zhang etal., 2013; Lev-Ran etal., 2014) as well as other disor-
ders characterized by reward dysfunction such as addiction and
psychosis (Radua etal., 2015; Luijten etal., 2017). Moreover, our
ndings support the potential utility of CBD in reducing can-
nabis harms while maintaining the positive effects users seek
(Englund etal., 2017).
Strengths of this study include its controlled experimen-
tal design, comparison of cannabis with and without CBD (but
matched for THC), a music task previously validated using fMRI
(Menon and Levitin 2005), and regions of interest informed by
meta-analysis (Koelsch, 2014). Our sample size was equivalent
or larger than previous studies with comparable designs (van
Hell et al., 2012; Jansma et al., 2013) and neuroimaging music
studies of music (mean n = 14.5 across 22 studies (Koelsch
2014)). We used a xed set of classical music excerpts, com-
mensurate with previous use of this task (Menon and Levitin,
2005) and many other studies (Koelsch, 2014). Advantages of
this approach include the absence of lyrics (which would inu-
ence neural response due to speech) and ease of comparison
with existing data. Although participants rated classical sound
clips as highly pleasant (~7.5 of 10), results may have differed if
preferred music was preselected by participants (Osuch et al.,
2009). Drug order was not completely balanced in this study,
and the same sound clips were presented on each of the 3 ses-
sions. However, we found no evidence that session order inu-
enced our results. We screened for personal/family history of
psychosis and current treatment for a psychiatric disorder,
but not for lifetime history of other mental health problems.
Additionally, our sample were cannabis users, which may have
prolonged cannabinoid clearance between sessions. However,
we found minimal evidence for associations between cannabis
use and fMRI ndings, and their response to cannabinoids may
be more representative of typical use than healthy volunteers
who never use cannabis.
In conclusion, cannabis dampened the effects of music in
bilateral auditory cortex, right hippocampus/parahippocampal
gyrus, right amygdala, and right ventral striatum. During musi-
cal listening, this ventral striatal region correlated with pleas-
ure ratings and showed increased functional connectivity with
auditory cortex. By contrast, cannabis containing cannabidiol
did not inuence the effects of music in brain regions sensitive
to reward and emotion.
Funding
T.P.F.was funded by the UK Medical Research Council and a Senior
Academic Fellowship from the Society for the Study of Addiction.
This study was funded by Drug Science/Channel 4 television.
Acknowledgments
These data were presented in preliminary form at the CINP
World Congress in Seoul, South Korea, the BAP Summer Meeting
in Brighton, UK, and the ECNP Workshop for Junior Scientists
in Nice, France. We are grateful to Marty Sereno, Joseph Devlin,
and the Birkbeck-UCL Centre for Neuroimaging team for their
assistance.
Statement of Interest
H.V.C.is a member of UK MRC boards and Drug Science. D.J.N.is
an advisor to the British National Formulary, MRC, GMC,
Department of Health; President of European Brain Council; Past
President of British Neuroscience Association and European
College of Neuropsychopharmacology, Chair of Drug Science
(UK); Member of International Centre for Science in Drug Policy;
advisor to Swedish government on drug, alcohol, and tobacco
research; editor of the Journal of Psychopharmacology; mem-
ber of advisory boards of Lundbeck, MSD, Nalpharm, Orexigen,
Shire, MSD; has received speaking honoraria (in addition to
above) from BMS/Otsuka, GSK, Lilly, Janssen, Servier, AZ, and
Pzer; is a member of the Lundbeck International Neuroscience
Foundation; has received grants or clinical trial payments from
P1vital, MRC, NHS, Lundbeck, RB; has share options in P1vital;
has been an expert witness in a number of legal cases relat-
ing to psychotropic drugs; and has edited/written 27 books,
some purchased by pharma companies. C.J.A.M.has consulted
for Janssen and GlaxoSmithKline and received compensation.
M.B.W. is employed by Imanova Ltd., a private company that
performs contract research work for the pharmaceutical indus-
try. The other authors declare no potential conicts of interest.
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