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eural Basis of �-9-Tetrahydrocannabinol andannabidiol: Effects During Response Inhibition

tefan J. Borgwardt, Paul Allen, Sagnik Bhattacharyya, Paolo Fusar-Poli, Jose A. Crippa, Marc L. Seal,alter Fraccaro, Zerrin Atakan, Rocio Martin-Santos, Colin O’Carroll, Katya Rubia, and Philip K. McGuire

ackground: This study examined the effect of �-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on brain activation during a motornhibition task.

ethods: Functional magnetic resonance imaging and behavioural measures were recorded while 15 healthy volunteers performed ao/No-Go task following administration of either THC or CBD or placebo in a double-blind, pseudo-randomized, placebo-controlled

epeated measures within-subject design.

esults: Relative to placebo, THC attenuated activation in the right inferior frontal and the anterior cingulate gyrus. In contrast, CBDeactivated the left temporal cortex and insula. These effects were not related to changes in anxiety, intoxication, sedation, and psychoticymptoms.

onclusions: These data suggest that THC attenuates the engagement of brain regions that mediate response inhibition. CBD modulated

unction in regions not usually implicated in response inhibition.

ey Words: CBD, THC, fMRI, hippocampus, inferior frontal gyrus,esponse inhibition

annabis is the world’s most widely used illicit drug with5%–15% of young people in developed countries beingregular users (1). Behavioral studies indicate that both

cute (2) and chronic (3,4) exposure to cannabis is associatedith impairments in a range of cognitive processes, including the

ontrol of motor function (5) and response inhibition (6). Theseffects may underlie the adverse influence of regular cannabis usen driving safety and the operation of industrial machinery (7,8), asell as the disinhibited behavior that can follow acute intoxication

9,10). Cannabis use can also lead to acute psychotic symptoms andnxiety, but the extent to which its symptomatic effects are relatedo impaired response inhibition is unknown. At the molecular level,he central effects of �-9-tetrahydrocannabinol (THC) are mediatedy cannabinoid 1 (CB1) receptors that inhibit presynaptic neuro-ransmitter release (11). These CB1 receptors have a high density inhe anterior cingulate, prefrontal, and medial temporal cortex (12),reas that appear to be critical to inhibitory processes (13). How-ver, depending on the brain area and whether the local CB1eceptors are located on neurons that release gamma-aminobutyriccid (GABA) or glutamate, THC could have either inhibitory orxcitatory effects (14).

Functional neuroimaging provides a means to examine howannabis acts on the brain to affect response inhibition. Neuro-maging studies that have compared chronic cannabis users with

rom the Section of Neuroimaging (SJB, PA, SB, PF-P, VF, ZA, RM-S, CO, PKM)and Department of Child Psychiatry (KR), Institute of Psychiatry, King’sCollege London, United Kingdom; Departamento de Neuropsiquiatria ePsicologia Médica (JAC), Faculdade de Medicina de Ribeirão Preto, Uni-versidade de São Paulo, Brazil; Melbourne Neuropsychiatry Centre(MLS), The University of Melbourne, National Neuroscience Facility, Car-lton, Australia; and Psychiatric Outpatient Department (SJB), UniversityHospital Basel, Basel, Switzerland.

ddress reprint requests to Stefan J. Borgwardt, M.D., Section of Neuroim-aging, King’s College London Institute of Psychiatry, PO67 De CrespignyPark London SE5 8AF, United Kingdom; E-mail: s.borgwardt@iop.kcl.ac.uk.

eceived February 21, 2008; revised April 25, 2008; accepted May 20, 2008.

006-3223/08/$34.00oi:10.1016/j.biopsych.2008.05.011

control subjects have demonstrated altered resting activity inprefrontal and cerebellar regions (15,16) and differential activa-tion in the prefrontal and cingulate cortex during the StroopColor-Word Task, a test of interference inhibition (17). However,comparisons of chronic cannabis users and healthy controlsubjects are potentially confounded by demographic, psychiat-ric, and cognitive differences between these groups. Moreover,because cannabis comprises several psychoactive ingredients, itis unclear which of its constituents are responsible for thefindings. Its main psychoactive constituents are THC and canna-bidiol (CBD) (11). Whereas THC impairs performance on motorand response inhibition tasks (6,13) and induces acute psychoticsymptoms (18), CBD does not impair motor or cognitive perfor-mance (19–21) and has anxiolytic effects (22,23). Acute admin-istration of THC in chronic cannabis users has been associatedwith increased resting metabolism in the cerebellar, frontal, andtemporal cortices (24), as well as with increases in global activity(25). The only previous neuroimaging study of CBD found thatadministration of CBD was associated with increased resting bloodflow in the left parahippocampal cortex and decreased blood flowin the posterior cingulate cortex (26).

Response inhibition normally involves a network of brainregions including the inferior, dorsolateral, and medial frontalcortex, the anterior cingulate gyrus (ACG), the cerebellum andbasal ganglia (27–40). The Go/No-Go task is a classical responseinhibition paradigm that requires participants either to execute orinhibit a motor response. Performance of the task is associatedwith engagement of the inferior, medial, and dorsolateral pre-frontal and inferior parietal cortices as well as ACG (30,41,42). Arecent meta-analysis of 18 studies highlighted the involvement ofa right prefrontal region comprising the posterior part of theinferior frontal gyrus (IFG) and the adjacent part of the middlefrontal gyrus (MFG) in the inhibitory process during the Go/No-Go tasks (43). The ACG is also commonly activated duringGo/No-Go tasks but has been attributed a more generic role ofselective, executive attention, and performance monitoring (44),which is consistent with the finding of its activation in particularduring failed inhibition trials (38,39).

The aim of this study was to examine the effects of THC and

CBD on brain activation during response inhibition. We used

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unctional magnetic resonance imaging (fMRI) to study healthyolunteers while they performed a Go/No-Go task followingdministration of either THC or CBD or placebo in a double-lind, pseudo-randomized, placebo-controlled design. To mini-ize the potentially confounding effects of chronic use of

annabis and other illicit drugs, inclusion was restricted toeople who had used cannabis less than 15 times in their

ifetime. Our main hypothesis was that THC would modulate thengagement of prefrontal brain regions that are normally criticalor response inhibition. Because there is no evidence that CBDnfluences response inhibition, we predicted that these effectsould be specific to THC.

ethods and Materials

esignA double-blind, placebo-controlled, pseudo-randomized, within-

ubject study was conducted over three sessions (placebo,HC, CBD). Each participant was scanned three times with a-month interval between scans. The order of drug administra-ion across sessions was pseudo-randomized across subjects,uch that equal numbers followed each drug sequence.

articipantsFifteen healthy Caucasian right-handed men, aged 20 to 42

ears (average 26.7 years, SD 5.7) completed the study by takingart in all three imaging sessions. The total number of years ofducation was 16.5 (SD 3.9), the mean IQ (National Adulteading Test [NART]) (45) was 98.67 (SD 7.0). All participantsere native English speakers and had used cannabis 15 or fewer

imes in their lifetimes, with no cannabis use in the past month.istory of cannabis and other illicit substance use were assessedith the Structured Clinical Interview (SCID) and the Addictioneverity Index (46). Participants were told to abstain from illicitrug use for the duration of the study and from alcohol andaffeine intake for 24 and 12 hours, respectively, before eachtudy day. Two hours before each session, subjects had a lighttandardized breakfast. At the start of each study day, a urineample was collected for screening for amphetamines, benzodi-zepines, cocaine, methamphetamine, opiates, and THC usingmmunometric assay kits. None of the participants tested positiven any of the sessions. Participants were carefully screened usingsemistructured clinical interview to exclude psychiatric or

hysical illness or a family history of psychiatric illness. Volun-eers who had ever used any other illicit psychotropic drug, whoonsumed more than 21 units of alcohol per week, or who hadny psychiatric, neurologic, or severe medical illness historyere also excluded. The local ethical committee approved the

tudy, and all participants gave their informed consent after thetudy procedure had been explained to them in detail.

rocedureBefore each scanning session, participants were given a

apsule of 10 mg THC, 600 mg CBD, or a placebo (flour). Theseoses of THC and CBD were selected on the basis of previousesearch (47–50) to produce an effect on regional brain functionithout provoking severe toxic, psychiatric, or physical symp-

oms, which might confound interpretation of the fMRI data andake it difficult for participants to tolerate the procedure.The capsules were identical in appearance and taste, and

either the participants nor experimenters were aware of whichrug was being administered. An intravenous line was inserted inhe nondominant arm of each participant at the start of the testing

ession to monitor drug whole blood levels. All participants were

physically examined before testing, and their heart rate andblood pressure were monitored at regular intervals (5 min/1hour) throughout each session. Of the 18 subjects initiallyincluded in the study, 3 reported frank psychotic symptomsfollowing THC administration and could not tolerate the subse-quent scanning procedure. Scanning was discontinued in thesethree subjects, and they were withdrawn from the study, leavinga final sample of 15 subjects who completed all parts of thestudy. Only the data from these 15 subjects were analyzed.

Symptom Ratings, Physiological and Biochemical VariablesSubjects were asked to provide comprehensive ratings of their

subjective experiences at baseline, immediately before scanning(1 hour), immediately after scanning (2 hours), and 1 hourpostscanning (3 hours) using the Visual Analogue Mood Scale(VAMS), the Spielberger State Trait Anxiety Inventory (STAI), anda visual analogue intoxication scale (AIS). The presence ofpsychotic phenomena and symptoms was assessed using thePositive and Negative Symptoms Scale (PANSS) at the same timepoints. Systolic blood pressure, diastolic blood pressure, heartrate, and blood levels of THC and CBD were obtained immedi-ately before and at 1, 2, and 3 hours after drug administration.Concentrations THC and CBD were measured by immunoassay.Positives were confirmed by gas chromatography–mass spec-trometry.

Functional MRI Activation Paradigm: Go/No-Go TaskA rapid, mixed trial, event-related fMRI design was used with

jittered interstimulus intervals (ISI) incorporating random eventpresentation to optimize statistical efficiency (51). The task is awell-validated paradigm requiring either the execution or theinhibition of a motor response depending on the visual presen-tation of stimuli (30,52). The basic Go task is a choice reactiontime paradigm: arrows pointing to either the left or right ap-peared on the screen for 500 msec with a mean ISI of 1800 msec(range � 1600–2000 msec). On Go trials, subjects were in-structed to press a left or the right response button according tothe direction of the arrow. Infrequently (on 11% of the trials),arrows pointing upward appeared. On these No-Go trials, par-ticipants were required to inhibit their motor response (and notpress any buttons). On another 11% of the trials, arrows pointingleft or right at a 23° angle were presented. Subjects were told torespond to these the same as for a Go prompt (even though theypointed obliquely). These “Oddball” stimuli were used to controlfor novelty effects associated with the low frequency and differ-ent orientation of the No-Go relative to the Go trials. In total,there were 24 No-Go stimuli, 164 Go stimuli and 24 Oddballtrials, and the task duration was 6 min and 14 sec. Throughoutimage acquisition, the accuracy and speed of the subjects’ buttonpress responses were recorded. Subjects practiced the entire task

Table 1. Mean Reaction Times and Error Rates by Drug Condition forGo/No-Go Task

Placebo THC CBD p

Reaction Time to GoSignals (msec) 463.5 (82.2) 441.7 (46.6) 448.8 (76.0) .37

Probability of Inhibition (%) 95.3 (7.9) 93.6 (8.5) 96.4 (6.3) .49Omissions to All Go Trials 1.1 (2.2) 1.2 (1.1) .8 (1.6) .77Left/Right Errors to All Go

Trials (%) .8 (1.0) 1.8 (1.9) 1.1 (1.0) .05

CBD, cannabidiol; THC, �-9-tetrahydrocannabinol.

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nce before scanning to ensure familiarity with task demand ando encourage optimal performance.

mage AcquisitionImages were acquired on a 1.5-Tesla Signa (General Electric,

ilwaukee, Wisconsin) system at the Maudsley Hospital, Lon-on. T2*-weighted images were acquired with a repetition timeTR) of 1.8 sec, echo time (TE) of 40 msec, flip angle 90° in 16xial planes (7 mm thick), parallel to the anterior commissure–osterior commissure line. To facilitate anatomic localization ofctivation, a high-resolution inversion recovery image data setas also acquired, with 3-mm contiguous slices and an in-plane

esolution of 3 mm (TR 16,000 msec, inversion time 180 msec, TE0 msec).

mage Processing and AnalysisData were analyzed using a nonparametric approach (XBAM

3.4; http://www.brainmap.co.uk). The data were first realigned53) and then smoothed using a Gaussian filter (full width at halfaximum 7.2 mm). Individual activation maps were createdsing two gamma variate functions to model the blood oxygenevel dependency (BOLD) response. The best fit between theeighted sum of these convolutions and the time series at eachoxel was computed using the constrained BOLD effect model54). Following a least squares fitting of this model, the sum ofquares ratio (SSQ) was estimated at each voxel, followed byermutation testing to determine significantly activated voxelspecific to each condition (55). The detection of activated voxelsas then extended from voxel to cluster level (53). The SSQ ratioaps for each individual were transformed into the standard

pace of Talairach (56) using a two-stage warping procedure57). Group activation maps were computed for each drug byetermining the median SSQ ratio at each voxel. Group differ-

nce maps were computed using BOLD effect maps rather than

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standardized measures such as SSQ ratio, F, or t because thesecontain explicit noise components (error SSQ or error variance),raising the possibility that group differences resulting from F,SSQ ratio, or t comparisons could reflect differences in noiserather then signal. These maps were compared using a nonpara-metric repeated-measures analysis of covariance (ANCOVA),

Figure 1. Time course of symptom scores. Shown aresymptom scores at baseline, immediately before scan-ning (1 hour), and immediately after scanning (2 hours)using the Visual Analogue Mood Scale (VAMS), the Spiel-berger State Trait Anxiety Inventory (STAI), a visual ana-logue intoxication scale (AIS), and the Positive and Nega-tive Symptoms Scale (PANSS). CBD, cannabidiol; THC, �-9-tetrahydrocannabinol.

Table 2. Regions Activated During No-Go Relative to Oddball TrialsFollowing Administration of Placebo, THC, and CBD

Cerebral Region Side

TalairachCoordinates

ClusterSizex y z

Placebo (p � .0025)Inferior Frontal Gyrus R 40 26 �7 34Medial Frontal Gyrus L �4 11 48 14Medial Frontal Gyrus R 11 7 53 6Anterior Insula R 29 19 9 6Anterior Cingulate Gyrus L �4 11 37 34

THC (p � .01)Fusiform/Parahippocampal Gyrus R 36 �48 �7 15Lingual Gyrus L �4 �70 �7 5Lingual Gyrus L 7 �70 �7 16Postcentral Gyrus R 43 �19 48 10

CBD (p � .0025)Middle Temporal Gyrus R 54 �7 �13 50Insula R 33 �22 15 37Superior Temporal Gyrus L �47 �15 �7 41Posterior Cingulate Gyrus R 14 �37 42 38

Shown are peak areas of activation in the x, y, and z coordinates inTalairach space. Coordinates refer to the stereotactic space as defined byatlas (56). All clusters are significant at a Type I error expectancy of less thanone false positive cluster per brain.

CBD, cannabidiol; THC, �-9-tetrahydrocannabinol.

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ith a voxelwise threshold of p � .05 and the clusterwisehreshold set such that the total number of false-positive clusterser brain volume was � 1 per map, and quote the p value athich this occurred. The principal advantages of cluster-level

esting are that it confers greater sensitivity by incorporatingnformation from more than one voxel in the test statistic and alsoubstantially reduces the search volume or number of testsequired for a whole-brain analysis, thereby mitigating theultiple comparisons problem.We used nonparametric repeated-measures ANCOVA to iden-

ify brain regions that were activated by THC or CBD comparedith the placebo condition. For the event-related analysis, No-o, and Oddball trials were first contrasted against Go trial. Brainctivation during the successfully performed Oddball trials,hich controlled for novelty effects, was then subtracted fromrain activation during successful No-Go trials (No-Go–‘Odd-all’: the details of this analysis are described fully elsewhere30,52). This analysis was repeated for each drug treatment.SQ ratios for each subject were extracted from all clustersbtained from the repeated-measures ANCOVA brain activa-ion maps to assess the phase of these activations. To inves-igate the association between changes in brain activationrought about by administration of drugs during the task andubjective mental states (PANSS, STAI, AIS, VAMS) induced byhe drug, we used mean change (between baseline and 1 and

hours after administration of the drugs, the time when the

images were acquired) as covariates for the contrasts betweenTHC/CBD and placebo.

Behavioral and Symptom Rating AnalysesSPSS version 12.00 was used to analyze behavioral perfor-

mance and self-report questionnaire data. Measures of taskperformance, symptom ratings, physiologic data and drug levels,were analyzed using repeated-measures analyses of variance(ANOVAs) used to compare drug conditions. When significantdifferences were found, the Tukey Test for pairwise comparisonswas applied.

Results

Task PerformanceAll participants performed the task with a high degree of

accuracy. There were no significant differences for mean inhibi-tion errors or mean reaction times between placebo, THC, andCBD treatments (Table 1), although left/right errors were morecommon (p � .05) following both THC and CBD than placebo(Table 1).

Physiologic VariablesMean whole blood levels of THC at 1 and 2 hours after taking

the drug were 3.9 (SD 7.3) ng/mL and 5.1 (SD 5.6) ng/mL,

Figure 2. Areas activated during the Go/No-Go task ineach drug condition. (A) Under placebo conditions, acti-vation was evident in the right inferior frontal (Talairachcoordinates of peak focus x � 40 y � 26 z � –7) andinsular cortex (29 19 9), the medial frontal (11 7 53) andanterior cingulate cortex (�4 11 37 (p � .0025, � 1 false-positive cluster). (B) Following administration of �-9-tet-rahydrocannabinol (THC), activation was evident in theright parahippocampal gyrus (36 �48 �7) and the lingualgyrus (7 �70 �7) bilaterally (p � .01, � 1 false-positivecluster). (C) Following administration of cannabidiol(CBD), there was activation in the superior (47 �15 �7)and middle (54 �7 �13) temporal gyrus and the insula(33 �22 15) bilaterally, and in the right posterior cingulategyrus (14 –37 42) (p � .0025, � 1 false-positive cluster).The left side of the brain is shown on the left side of theimages.

respectively. Mean whole blood level of CBD at the same time

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oints were 4.7 (SD 7.0) and 17.0 (SD 29.0) ng/mL, respectively.hole blood THC level peaked after 2 hours and remained

levated beyond the duration of the study. There was noignificant drug effect on blood pressure; however, we diddentify a (nonsignificant) trend for an increase in heart rate withHC � 1.93 (SD 5.74) and � 8.79 (SD 16.31) at 1 and 2 hoursfter baseline.

ymptom ScoresNo significant differences were observed between the drug

onditions at baseline for any symptom variables. A repeated-easures ANOVA revealed an interaction between time and drug

or all of these symptom variables (Supplement 1). Post hoc testsevealed significant increases in ratings over time for mental andhysical sedation (VAMS, p �.01), intoxication (AIS, p � .01),nxiety (STAI, p � .01), and positive psychotic symptomsPANSS, p � .01) for THC versus placebo (Figure 1). There wereo significant changes in the corresponding ratings for the CBDondition. However, there was a trend for less anxiety followingBD relative to placebo (p � .06). To eliminate order effects,ymptom scores (STAI, AIS, VAMS, PANSS) were compared as aunction of session order irrespective of drug condition. Aepeated-measures ANOVA revealed that there were no signifi-ant effects of order for any of the symptom variables (F � 1.1,� .59).

unctional MRI: Task-Related Activation in the Presence ofach Drug

Placebo Condition. Following administration of placebo,o-Go relative to oddball trials were associated with activation in

he orbital part of the right inferior frontal gyrus and in thedjacent anterior insula, the ACG and the supplementary motorrea (Table 2, Figure 2A).

THC Condition. Following administration of THC, No-Goelative to Oddball trials were associated with activation in theight hippocampus, the right postcentral gyrus, and the lingualyrus bilaterally (Table 2, Figure 2B).

CBD Condition. Following administration of CBD, No-Goelative to Oddball trials were associated with activation in theuperior and middle temporal gyrus and the insula bilaterally,nd in the right posterior cingulate gyrus (Table 2, Figure 2C).

ffects of THC and CBD on ActivationTHC. Compared with placebo, THC reduced activation in

he right IFG and in the ACG and precuneus bilaterally (Table, Figure 3A). Conversely, THC was associated with morectivation than placebo in the right hippocampus/parahippocampalyrus, the right superior and transverse temporal gyri, the rightusiform gyrus, extending into the right caudate and thalamus, andn the left posterior cingulate and precuneus.

CBD. Relative to placebo, CBD deactivated the left insula andhe left superior and transverse temporal gyri (Table 3, FigureB). CBD was not associated with any significant increases inegional activation relative to placebo.

iscussion

In this study, we used fMRI to investigate how the two mainsychoactive ingredients of cannabis (THC and CBD) modulaterain function during response inhibition. We employed aouble-blind, placebo-controlled, repeated-measures within-ubject design, measuring the BOLD response while subjectserformed a Go/No-Go paradigm (52) following oral challenge

ith THC, CBD, or placebo. Consistent with our hypothesis, we

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found that THC attenuated activation in the right IFG and ACG.This effect was specific to THC; CBD was associated withdeactivation in the left lateral temporal cortex and insula.

Neural Effects of THC and CBDConsistent with data from previous studies (30,52,58), under

placebo conditions the Go/No-Go task activated a network ofbrain areas including the orbital part of the right IFG, the anteriorinsula and head of the claustrum, and the ACG and medial frontalcortex. Our prediction that THC but not CBD would modulateactivity in areas that mediate response inhibition was confirmed,with the effects of CBD evident in other regions, the left superiorand transverse temporal gyri and in the posterior part of the leftinsula. An effect of THC on the neural substrate of responseinhibition is consistent with the adverse effects of cannabis useon motor control (2), driving safety (7,8) and evidence that THCimpairs performance on tasks that engage response inhibition(6). The effect of THC on ACG is likely to reflect an effect onselective attention and performance monitoring rather thaninhibition per se, given the role of ACG in these former functions(39,44,58). These findings might explain the impaired perfor-mance of cannabis abusers on the Stroop Color-Word Task,given the critical role of the anterior cingulate cortex in this task(59). Although this was not predicted, THC also enhancedactivation in areas not implicated in response inhibition, such asthe right hippocampus, transverse temporal gyrus, and fusiformgyrus. However, in some areas, such as the right hippocampus,this partly reflected of the effect of THC on activation during theoddball condition.

Table 3. Activations in Placebo versus THC and Placebo versus CBDContrast in the Go/No-Go Task (for No-Go Relative to Oddball)

Cerebral Region Side

Talairach CoordinatesCluster

Sizex y z

Placebo � THC (p � .0025)Inferior Frontal Gyrus R 43 26 �7 21Precuneus L �18 �70 26 14Anterior Cingulate

GyrusR 7 1 37 20

Precuneus R 7 �60 48 15THC � Placebo (p � .025)

Hippocampus R 29 �37 4 84Transverse Temporal

GyrusR 26 �30 15 9

Parahippocampal Gyrus R 29 �44 7 7Caudate R 22 �30 20 7Precuneus L �14 �52 31 6Fusiform Gyrus R 25 �41 �18 6Posterior Cingulate

GyrusL �14 �52 26 25

Placebo � CBD (p � .01)Posterior Insula L �40 �19 �7 45Superior Temporal

GyrusL �43 �22 �2 11

Transverse TemporalGyrus

L �36 �33 9 4

CBD � Placebo (p � .01)Null

Shown are peak areas of activation in the x, y, and z coordinates inTalairach space. Coordinates refer to the stereotactic space as defined in theatlas (56). All clusters are significant at a Type I error expectancy of less thanone false-positive cluster per brain.

CBD, cannabidiol; THC, �-9-tetrahydrocannabinol.

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ffects of THC and CBD on Performancen the Go/No-Go Task

Neither THC nor CBD had a significant effect on task perfor-ance, save for an effect on the frequency of left/right errors. Arevious study (6) investigated the acute effects of THC on fourehavioral measures of impulsivity (including a Go/No-Go task)n recreational marijuana users. THC impaired performance on atop task but did not have a significant effect on Go/No-Goerformance, suggesting that THC may increase certain forms of

mpulsive behavior more than others. A recently published fMRItudy of a Go/No-Go task in long-term cannabis users reportedhat they showed differences in prefrontal, insular, and parietalctivation relative to control subjects, but there were differencesn task performance (60).

Significant effects on activation but not task performance is aommon finding in neuroimaging studies involving pharmaco-ogic challenges (61,62), including studies involving the Go/o-Go task (52). Although the statistical power of fMRI data haseen shown to be relatively robust with small subjects numbers72), this is not the case for neuropsychologic data. Functionaleuroimaging techniques detect changes at the physiologic levelnd are more sensitive than behavioral measures (63), and thistudy was powered to detect drug effects on activation ratherhan on task performance. The effect of both THC and CBD oneft/right errors was unexpected. However, this may reflect anffect on selective attention, which is known to be impaired inannabis users (64).

Because there were no significant effects on task perfor-ance, the BOLD changes we observed after administration ofHC and CBD are unlikely to be secondary to an effect of

ehaviors. Wilkinson and Halligan (63) suggested that the de-

mand for behavioral corroboration in functional imaging exper-iments should only be tempered when we know about whichparts of cognitive processes produce behavioral responses, andwhich parts produce the neural activations. In this case, thisneuroimaging study was designed to measure the effects of THCon brain function as opposed to task performance. The changesin the BOLD signal are also unlikely to reflect the effect ofincreased symptoms (anxiety, intoxication, sedation, psychoticsymptoms) because all our imaging results remained significantafter covarying for these changes.

Differential Effects of THC and CBDThe differential effects of THC and CBD on activation were

expected on the basis of previous evidence of differences in theirbehavioral effects and pharmacologic profile. Thus whereas THCcan induce psychotic symptoms and anxiety (5,65–67), CBD hasanxiolytic effects (22,23). The effects of THC are mediatedthrough CB1 receptors (68,69), whereas CBD does not bind tothese receptors, and its mechanism of action at the molecularlevel is unclear (70,71). The effects of THC and CBD on brainactivation in humans have not been directly compared before.Neuroimaging studies that have involved THC in long-term usershave reported effects on frontal activation, either at rest or duringperformance of cognitive tasks (73). The only previous neuro-imaging study of CBD found that it altered resting activity in thecingulate and medial temporal cortex (26).

Direct Effects of THC and CBD on Blood FlowfMRI measures the BOLD response, which reflects the local

vascular response to neural activity rather than neural activity per

Figure 3. Effects of �-9-tetrahydrocannab-inol (THC) and cannabidiol (CBD) on activa-tion. (A) Administration of THC was associ-ated with reduced activation in the rightinferior frontal gyrus (Talairach coordi-nates of peak focus x � 43 y � 26 z � �7)and anterior cingulate cortex (7 15 37) (p �.025, � 1 false-positive cluster; blue/darkvoxels). Conversely, THC augmented acti-vation in the right hippocampus (29 �37 4)and parahippocampal gyrus (29 �44 7) (p� .025, � 1 false-positive cluster; red/bright voxels). Covarying for the positivepsychotic symptoms (Positive and Nega-tive Symptoms Scale [PANSS]), level of anx-iety (Spielberger State Trait Anxiety Inven-tory [STAI]), sedation (Visual AnalogueMood Scale [VAMS]), and intoxication (vi-sual analogue intoxication scale [AIS]) hadno effect on the effects of THC on activa-tion in any area. Examination of the SSQratios from the right IFG revealed that THCreduced activation in this region duringNo-Go trials but had little effect on activa-tion during Oddball trials. Conversely, inthe right hippocampus, THC increased ac-tivation during No-Go trials and reducedactivation during Oddball trials. (B) Pla-cebo � CBD (blue/dark voxels) in the lefttemporal cortex (�43 �22 �2) and insula(�40 �19 �7) (p � .01, � 1 false-positivecluster). Covarying for psychotic symp-toms (PANSS-P), sedation (VAMS), anxiety(STAI), and intoxication (AIS) had no effecton these effects. The left side of the brain isshown on the left side of the images.

se. This raises the possibility that the effects of THC and CBD we

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bserved were secondary to the modulation of cerebral bloodlow as opposed to neural activity. However, the analysis con-rolled for variation in global blood flow, and the effects of therugs were both region- and condition-specific. For example,dministration of THC was associated with an increased BOLDesponse in the hippocampus during the No-Go condition but aecreased hippocampal response during the Oddball condition:or this to have had a vascular basis, it would require that theame drug had opposite effects on blood flow to the same arean the same subjects, at different times within a brief period. Ithus seems unlikely that the modulation of activation we ob-erved with THC and CBD were a consequence of vascularffects. It is likely that the neural effects of THC seen in thesereas in our subjects were a result of THC induced inhibition ofABA release, which thereby reduced the amplitude of inhibi-

ory postsynaptic currents in pyramidal neurons (74,75).

imitationsAs in previous functional neuroimaging studies (72), our

roup sizes were modest because these pseudo-randomized,lacebo-controlled, repeated-measures, within-subject designtudies are logistically demanding. We therefore cannot excludehe possibility that we would have detected more extensiveffects of THC or CBD on activation, as well as at the behavioralevel had the sample size been larger. In addition, the version ofhe Go/No-Go task used in our study had a relatively long ISI1800 msec), which could have led to ceiling effects and contrib-ted to the lack of a drug effect on task performance.

A further caveat is that there is a difference between oralngestion of THC or CBD and smoking cannabis. Following oralngestion, the intoxication effect starts about an hour later andradually increases to a plateau, which lasts approximately 3 hours,hereas the effect following inhalation begins fairly immediatelynd reaches a peak within an hour and declines fairly rapidly (11).dditionally, these effects are dose dependent. Our aim was to usedose that would be associated with significant effects on neuro-

ognitive function while having as low a risk of severe adverseffects as possible. We therefore selected a 10-mg dose. A furtheronsideration was that the dose should approximately correspondo the THC content of a typical cannabis cigarette (“joint”), and thequivalent dose is around 10 mg (76).

This study was supported by grants from the Psychiatry Researchrust, United Kingdom. SB is supported by an MRC Clinicalesearch Training Fellowship. PFP is supported by the Guy’s & St.homas’ Charitable Foundation, New Services and Innovations inealth Care. All authors have agreed to the submission of this article

n this form, and we do not have any conflict interests that might benterpreted as influencing its content.

The authors reported no biomedical financial interests orotential conflicts of interest.

Supplementary material cited in this article is availablenline.

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