Research Article Mismatch Negativity and P50 Sensory Gating in Abstinent Former Cannabis Users

12 Pages·2016·1.56 MB·English

Hindawi Publishing Corporation
Neural Plasticity
Volume 2016, Article ID 6526437, 11 pages
http://dx.doi.org/10.1155/2016/6526437
Research Article
Mismatch Negativity and P50 Sensory Gating in Abstinent
Former Cannabis Users
SamanthaJ.Broyd,1,2Lisa-marieGreenwood,1,2HendrikaH.vanHell,1,2
RodneyJ.Croft,1,2,3HannahCoyle,1BenLee-Bates,1JuanitaTodd,4,5StuartJ.Johnstone,1
PatriciaT.Michie,4,5andNadiaSolowij1,2,5
1SchoolofPsychology,UniversityofWollongong,Wollongong,NSW2522,Australia
2IllawarraHealthandMedicalResearchInstitute,UniversityofWollongong,Wollongong,NSW2522,Australia
3CentreforHealthInitiatives,UniversityofWollongong,Wollongong,NSW2522,Australia
4SchoolofPsychologyandPriorityResearchCentreforTranslationalNeuroscienceandMentalHealth,UniversityofNewcastle,
Newcastle,NSW2308,Australia
5SchizophreniaResearchInstitute,Sydney,NSW2021,Australia
CorrespondenceshouldbeaddressedtoNadiaSolowij;[email protected]
Received30September2015;Accepted20January2016
AcademicEditor:ChristianCasanova
Copyright©2016SamanthaJ.Broydetal. This is an open access article distributed under the Creative Commons Attribution
License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly
cited.
Prolongedheavyexposuretocannabisisassociatedwithimpairedcognitionandbrainfunctionalandstructuralalterations.We
recentlyreportedattenuatedmismatchnegativity(MMN)andalteredP50sensorygatinginchroniccannabisusers.Thisstudy
investigatedtheextentofbrainfunctionalrecovery(indexedbyMMNandP50)inchronicusersaftercessationofuse.Eighteen
ex-users(median13.5yearspriorregularuse;median3.5yearsabstinence)and18nonuserscompleted(1)amultifeatureoddball
taskwithduration,frequency,andintensitydeviantsand(2)aP50paired-clickparadigm.TrendlevelsmallerdurationMMN
amplitude and larger P50 ratios (indicative of poorer sensory gating) were observed in ex-users compared to controls. Poorer
P50gatingcorrelatedwithpriordurationofcannabisuse.DurationofabstinencewaspositivelycorrelatedwithdurationMMN
amplitude,evenaftercontrollingforageanddurationofcannabisuse.ImpairedsensorygatingandattenuatedMMNamplitude
tendedtopersistinex-usersafterprolongedcessationofuse,suggestingalackoffullrecovery.Anassociationwithprolonged
durationofpriorcannabisusemayindicatepersistentcannabis-relatedalterationstoP50sensorygating.Greaterreductionsin
MMNamplitudewithincreasingabstinence(positivecorrelation)mayberelatedtoeitherself-medicationoranacceleratedaging
process.
1.Introduction alterations to the regulatory role that the endocannabinoid
systemplaysinsynapticplasticity[7–10].Thelatteristhought
Regular and prolonged cannabis use is associated with a to occur, at least in part, via downregulation of N-methyl-
range of adverse psychological outcomes, including psy- D-aspartate (NMDA) receptor activity [7–9, 11]. Evidence
chosis [1–4]. The primary constituent of cannabis, Δ9- isalsoemergingforanalogousalterationsincannabisusers
tetrahydrocannabinol (THC), is a partial agonist at central and patients with schizophrenia, including cognition, brain
cannabinoidreceptor(CB1R)siteswhicharedenselylocated function, and structure, and there is increasing support
throughoutthebrainbutespeciallywithinregionscriticalto for an association between cannabis and schizophrenia in
attention,learning,andmemory,suchasthehippocampus, vulnerable individuals [12–14]. In light of this evidence,
amygdala, and prefrontal cortex [5]. It is these cognitive research has turned to examining common neurobiological
functions in particular that are impaired in cannabis users andneuropsychologicalmarkersofdysfunction(forareview,
(for a review, see [6]), arguably due to cannabis-related see[6]).
2 NeuralPlasticity
Twosuchcandidatemarkersarethemismatchnegativity determine the degree to which recovery may occur as a
(MMN) and the P50, event-related potential (ERP) brain functionofpriorcannabisexposureandlengthofabstinence.
markers of early sensory memory and of sensory gating, Theaimofthecurrentcross-sectionalstudy,inwhichwe
respectively. MMN issensitiveto NMDAreceptorfunction recruited former cannabis users with a range of abstinence
(for a review, see [15, 16]) and elicited by irregular acoustic andpriorhistoryofuse,wastoinvestigate(1)whetherMMN
deviations (“deviants”) in a predictable pattern of auditory amplitude and P50 sensory gating improve as a function
stimuli(calledstandards[17,18])reflectingevaluationofnew of increasing periods of abstinence following cessation of
auditorysensoryinputagainstcurrentmodelsoftheacoustic use and (2) the extent to which recovery may depend on
environment [18]. Robust reductions in MMN have been the degree of prior cannabis use. Consistent with previous
notedinpatientswithschizophrenia[19,20]andlessconsis- work, we predicted that ex-users would exhibit attenuated
tently in their first degree relatives [21–23]. Cannabis users frequencyanddurationMMN(impairedsensoryprocessing)
also show reduced MMN, with the strongest evidence for and larger P50 ratios and smaller P50 difference scores
alterations to frequency deviants [24–26], but three studies (poorer sensory gating) compared to nonuser controls and
have also reported group differences for duration deviants thatimprovementinbrainfunctionwouldbepositivelycor-
[24, 27, 28]. We recently reported significantly smaller relatedwithdurationofabstinenceandnegativelycorrelated
frequency MMN in both long-term and short-term users withdurationofpriorcannabisuse.
comparedtocontrols,whereasdurationMMNwasreduced
only in long-term users, and duration MMN amplitude 2.MaterialsandMethods
reductionwasassociatedwiththedurationofregularand,in
particular,dailycannabisuse[24].Consistentwithmounting 2.1. Participants. Twenty abstinent former cannabis users
evidence of an association between cannabis use and risk and 42 healthy nonuser controls took part in the current
for psychosis, reductions in duration and frequency MMN study.Ex-cannabisuserswererequiredtohaveusedcannabis
were associated with a retrospective measure of psychotic- regularly (≥3 times/week) for at least two years prior to
likesymptomsduringintoxication[24]. quitting and to have abstained for at least one month; two
P50sensorygatingisalsoimpairedinbothpatientswith wereexcludedforrecentotherdruguseleavingasampleof
schizophrenia [29, 30] and chronic cannabis users [31–34]. 18 ex-users. Nonuser control participants were required to
Sensory gating refers to the brain’s ability to regulate its have<20lifetimeoccasionsofcannabisuseandnoneinthe
response to incoming stimuli [35] or to “gate out” irrele- previous 12 months. Recruitment and exclusion criteria are
vantinformationfromfurtherprocessing[36–38].(Sensory describedinSupplement1inSupplementaryMaterialavail-
gating-“out”maybecontrastedwiththebrain’sabilityto“gate able online at http://dx.doi.org/10.1155/2016/6526437. Con-
in”novelornewinformation,ofwhichtheMMNisamarker trols were recruited as part of a larger study (see [24, 31]).
[36,37].)P50sensorygatingisimpairedinregularcannabis Whilst ex-users completed all experimental paradigms, not
userscomparedtobothnonusercontrols[31–34]andpatients allcontrolscompletedbothMMNandP50paradigms.There-
withschizophreniawithandwithoutcomorbidcannabisuse fore,twooverlappingsubsamples(𝑛 = 18each)ofthemost
[33]. Longer duration of use [33] and greater quantity of appropriately age-matched controls were blindly selected
monthlyuse[32]wereassociatedwithmorepronouncedP50 for MMN and P50 analyses, respectively, from the nonuser
gatingimpairments. sample reported in Greenwood et al. [24] (12 participants
Theexistenceofbrainalterationsincannabisusersleads wereincludedinbothcontrolgroups).Allparticipantswere
totheimportantquestionofwhethertheseareamenableto reimbursed AUD$50 for their participation. The study was
recovery following cessation of cannabis use. Persistent IQ approved by the University of Wollongong and Illawarra
declinehasbeenreportedinadultcannabisuserswhostarted ShoalhavenLocalHealthDistrictHealthandMedicalHuman
using cannabis during adolescence and who had recently ResearchEthicsCommittee.
abstainedorsignificantlyreducedcannabisuseforatleastone
year[39].Resultsfrommoresensitiveneuroimagingstudies 2.2. Demographic and Substance Use Variables. Participants
of users with at least 25 days abstinence indicate persistent underwent a comprehensive structured interview to assess
alterationstobrainfunction[40–46].Wepreviouslyreported demographic information, detailed history of current and
impairedERPmeasuresofselectiveattentioninformerusers previoussubstanceuse,andpsychiatrichistoryandex-users
withamean2-yearabstinencethatwereassociatedwithdura- providedaurinesampletoverifyrecentabstinence.Partic-
tionofprioruse[47].Pertinenttothecurrentstudy,Rentzsch ipantswereexcluded iftheyreportedapersonalorfamilial
etal.[33]identifiedpersistentdeficitsinP50sensorygating (first degree relative) history of any psychotic disorder.
in cannabis users who had been abstinent for at least 28 Participantsreported(i)thelasttimetheyusedanycannabis
daysandinasubsequentstudy[25]persistentreductionsin andhowmuch;(ii)theirpreviouspatternsofregularuse(i.e.,
frequencyMMNamplitudeinformeruserswithamean19- theirusualpatternofuse,periodswhentheyusedcannabis
monthabstinence.Neitherstudyinvestigatedtheassociation moreorlessfrequently,andperiodsofabstinence);and(iii)
between duration of abstinence or prior cannabis use and when they stopped using cannabis regularly. This informed
recoveryofbrainfunction.Therefore,althoughthesefindings twokeyvariablestodefinethedurationofabstinence:(i)time
suggestpersistentcannabis-relatedalterationstoMMNand sincelastuse,definedinyearssincelastuseofanycannabis
P50 sensory gating following cessation of cannabis use, and(ii)timesincelastregularuseofcannabis(>once/month
further research is required to replicate these findings and forany6-monthperiod).
NeuralPlasticity 3
The vocabulary and matrices subscales of the Wechsler Table1:Cannabisusemeasuresincludingabstinence,retrospective
Abbreviated Scale of Intelligence (WASI [49]) were used to measuresofdependenceandpsychologicalsymptomsduringintox-
estimatefullscaleIQ.TheReyAuditoryVerbalLearningTest ication,andwithdrawalsymptoms.
(RAVLT)wasalsoadministeredandparticipantscompleted
Ex-cannabisusers
the Community Assessment of Psychic Experiences (CAPE
Priorcannabisuse
[50])andSchizotypalPersonalityQuestionnaire(SPQ[51])to
assesspsychotic-likesymptoms,theBeckDepressionInven- Frequency(days/month) 30[15.0–30.0]
a
tory (BDI [52]), State Trait Anxiety Inventory (STAI [53]), Quantity(cones /month) 517.5[52.5–3150.0]
Edinburgh Handedness Inventory [54], and the Alcohol Ageofonset(years) 17[12.0–20.5]
UseDisordersIdentificationTest(AUDIT[55]).Ex-cannabis Durationofregularuse(years) 13.5[4.3–30.3]
users also completed the Marijuana Withdrawal Checklist Durationofdailyuse(months) 155.3[0.0–363.7]
(MWC [56]), Severity of Dependence Scale (SDS [57]), Timesincelastsmoked(years) 1.5[0.1–16.0]
and Cannabis Experiences Questionnaire (CEQ, [58]) to
Abstinencesinceregularuse(years) 3.5[0.1–16.0]
measuresymptomsofwithdrawalandretrospectiveseverity b
SDS 8.50[1.0–13.0]
ofdependenceandsymptomsexperiencedwhilstintoxicated. c
CEQ
Euphoria 40[32.0–52.0]
2.3.ExperimentalParadigms. ThepassivemultifeatureMMN
Paranoia 48[28.0–87.0]
paradigmandrecordingconditions,withduration(100ms),
frequency (1200Hz), and intensity (90dB; standards 50ms, Aftereffects 27[15.0–51.0]
1000Hz, 80dB) deviants, are described in Greenwood et Amotivation 18.5[10.0–31.0]
al. [24] and further in Supplement 1. For the MMN task Psychotic 8[4.0–20.0]
participants were instructed to ignore the tones and focus MWCd 10.5[0.0–37.0]
their attention on a silent film. The attended P50 paired-
Notes.Dataarereportedasmedian[range].
clickparadigm(inwhichparticipantswereaskedtosilently aConesusedinwaterpipe:3conesareequivalenttoonestandardsizedjoint
counttheclickpairsandrespondtoevery25thclickpairvia [48].
b
button press) and recording condition (ISI 9 seconds) were SeverityofDependenceScores(SDS)(retrospective)
c
CannabisExperiencesQuestionnaire(CEQ)(retrospective)
identicaltotheparadigmdescribedinBroydetal.[31]andin d
MarijuanaWithdrawalChecklist(MWC)(retrospective).
Supplement1.Participantswereseatedinacomfortablechair
approximately80cmawayfromamonitorinadimlylitroom.
All stimuli were presented binaurally using headphones
atapproximately6joints/dayonamedianof30days/month
(SennheiserHD215).MeasurementdetailsofMMNandP50
(see Table1). They had not used cannabis regularly for a
aredescribedinSupplement1andGreenwoodetal.[24]and
median of 3.5 years and had been totally abstinent (since
Broydetal.[31]respectively.
last occasion of any use) for a median of 1.5 years (range
of6weeksto16yearsforbothmeasuresofabstinence).No
2.4.StatisticalAnalysis. Toinvestigatepotentialgroupdiffer-
participants had used any substance other than alcohol or
encesondemographicfactors(age,gender,andIQ),psycho-
tobaccoregularly(definedasmorethanonce/monthfora6-
logicalsymptoms,verballearning,andalcoholandtobacco
monthperiod)inthepast5years.
use, independent sample 𝑡-tests or Mann-Whitney 𝑈 tests
(for data not normally distributed) were employed. Group
3.2. Group Comparisons on Demographic and Clinical Vari-
comparisons of MMN peak amplitude were performed
ables. No differences between ex-users and controls were
usingrepeatedmeasuresAnalysisofVariance(rmANOVA)
identified for age, gender, handedness, verbal learning (i.e.,
including a within-subject variable, condition (3: duration,
RAVLTperformance),orsymptommeasures(Table2)other
frequency,andintensitydeviant),andbetween-subjectfactor,
thantheSPQscoresreportedbelow.
group(2:controlandex-user).P50ratioanddifferencescores
werecomparedbetweengroupsusingMann-Whitney𝑈tests MMN Group Comparisons. Ex-users had fewer years of
as the data were not normally distributed. Correlational education (𝑍 = −3.64, 𝑝 < .001), tended to have lower
analysis investigated associations between MMN and P50 IQ (𝑍 = −1.80, 𝑝 = .073), consumed a greater quantity of
measures,cannabismeasures(durationofabstinenceandof alcohol (𝑍 = −2.08, 𝑝 = .04) with a trend toward greater
prioruse),andrelevantdemographic,clinical,andcognitive frequency(𝑍=−1.71,𝑝=.09),andsmokedmorecigarettes
measures in the ex-user sample. As prior research suggests thancontrols(𝑍 = −3.00,𝑝 = .003).Ex-usershadelevated
thatfrequencyanddurationMMNarereducedincannabis SPQsocialanxiety(𝑍 = −2.03,𝑝 = .04)andatrendtoward
users in particular [24], correlations between MMN and elevated SPQ total (𝑍 = −1.74, 𝑝 = .08) scores. None
cannabis use history including duration of abstinence were of these variables were correlated with MMN amplitude in
restrictedtothesedeviantconditions. any deviant condition and therefore none were included as
covariatesinanyfurtheranalyses(seeSupplement1).
3.Results
P50 Group Comparisons. Ex-users tended to have lower IQ
3.1. Cannabis Use History and Abstinence. Ex-users had scores(𝑍=−1.87,𝑝=.064)andhadfeweryearsofeducation
previouslyusedcannabisregularlyforamedianof13.5years (𝑍 = −3.92, 𝑝 < .001) than controls. They smoked more
4 NeuralPlasticity
Table2:Demographic,cognitive,andpsychologicalsymptommeasuresinex-cannabisusersandhealthynonusercontrolsforMMNand
P50analyses.
Ex-cannabisusers MMNcontrols P50controls
(𝑛=18) (𝑛=18) (𝑛=18)
Age(years) 39.1[20.8–56.0] 40.4[21.0–52.6] 31.2[20.1–52.6]
Gender(male/female) 10M/8F 10M/8F 9M/9F
Handedness Allright-handed Twoleft-handed Allright-handed
∗∗ ∗∗
Education(years) 12.0[10.0–16.0] 14.3[11.5–20.0] 14.5[11.5–20.0]
/ /
IQ 105.0[89.0–126.0] 115.5[89.0–133.0] 115.0[89.0–133.0]
RAVLTtrialsItoV 54.00[34.0–68.0] 54.5[29.0–69.0] 56.50[29.0–70.0]
RAVLTtrialVI 11.5[5.0–15.0] 12.0[4.0–15.0] 12.0[4.0–15.0]
RAVLTtrialVII 11.5[0.0–15.0] 11.0[3.0–15.0] 11.0[3.0–15.0]
a /
Alcoholfrequency 3.5[0.0–30.0] 1.0[0.0–12.0] 1.4[0.0–12.0]
b ∗
Alcoholquantity 16.8[0.0–180.0] 5.1[0.0–28.0] 6.3[0.0–70.0]
∗ ∗
Cigarettes(perday) 3.8[0.0–35.0] 0.0[0.0–12.0] 0.0[0.0–11.0]
Psychologicalsymptoms
K10 15.0[12.0–31.0] 14.0[10.0–19.0] 14.0[10.0–22.0]
BDI 6.5[0.0–18.0] 3.0[0.0–19.0] 3.0[0.0–19.0]
STAI-I 31.0[20.0–67.0] 32.0[20.0–45.0] 27.5[20.0–45.0]
STAI-II 39.0[21.0–62.0] 36.0[22.0–50.0] 32.5[20.0–45.0]
CAPE
Frequencytotal 58.0[46.0–76.0] 60.0[46.0–89.0] 59.0[47.0–89.0]
Distresstotal 20.0[4.0–51.0] 25.5[6.0–95.0] 22.0[5.0–50.0]
Negativefrequency 21.5[16.0–35.0] 21.5[12.0–31.0] 21.0[15.0–31.0]
Negativedistress 11.0[2.0–30.0] 10.5[2.0–41.0] 9.0[2.0–22.0]
Positivefrequency 23.5[20.0–31.0] 25.0[21.0–44.0] 26.0[20.0–44.0]
Positivedistress 5.5[0.0–20.0] 6.0[1.0–29.0] 6.0[0.0–18.0]
Depressivefrequency 12.5[9.0–16.0] 13.0[9.0–21.0] 12.0[9.0–21.0]
Depressivedistress 6.0[2.0–15.0] 8.0[2.0–25.0] 7.0[1.0–21.0]
SPQ
/ /
Total 18.0[9.0–32.0] 14.0[5.0–32.0] 12.0[2.0–39.0]
Ideasofreference 1.0[0.0–6.0] 1.0[0.0–4.0] 1.0[0.0–5.0]
∗ ∗
Socialanxiety 3.0[0.0–15.0] 2.0[0.0–6.0] 1.0[0.0–6.0]
Oddbeliefs 1.0[0.0–5.0] 0.0[0.0–5.0] 0.0[0.0–7.0]
Unusualperceptual 1.0[0.0–3.0] 1.0[0.0–2.0] 1.0[0.0–4.0]
Oddbehaviour 2.0[0.0–5.0] 0.0[0.0–6.0] 0.0[0.0–6.0]
Closefriends 2.0[0.0–8.0] 1.0[0.0–3.0] 1.0[0.0–4.0]
Oddspeech 4.0[0.0–7.0] 4.0[1.0–8.0] 3.0[0.0–8.0]
Constrictedaffect 1.0[0.0–5.0] 1.0[0.0–2.0] 1.0[0.0–4.0]
Suspiciousness 1.0[0.0–5.0] 1.0[0.0–3.0] 1.0[0.0–3.0]
Notes.Comparisonsbetweenex-cannabisusersandrespectivenonusercontrolsforeachparadigm(MMNorP50);/𝑝 < .10,∗𝑝 < .05,∗∗𝑝 < .001.Data
reportedasmedian[range].
a
Alcoholfrequencymeasuredasnumberofdayspermonthalcoholwasconsumed.
b
Alcoholquantitymeasuredasnumberofstandarddrinksconsumedpermonth.
RAVLT:ReyAuditoryVerbalLearningTest;K10:KesslerPsychologicalDistressScale;BDI:BeckDepressionInventory;STAI-I:StateAnxietyIndexStatescore;
STAI-II:StateAnxietyIndexTraitscore;CAPE:CommunityAssessmentofPsychicExperiences;SPQ:SchizotypalPersonalityQuestionnaire.
cigarettesperday(𝑍=−2.97,𝑝=.01)butdidnotdifferfrom 3.3.MismatchNegativityinEx-UsersandControls. Mismatch
controls in quantity or frequency of alcohol use (𝑝 > .10). negativity difference waveforms at Fz for duration and fre-
Ex-usersagainhadelevatedSPQsocialanxiety(𝑍 = −2.43, quencyconditionsareshowninFigure1(a)andgrandmean
𝑝=.015)andatrendtowardselevatedSPQtotal(𝑍=−1.76, ERP waveforms at Fz to the standard and deviant stimuli
𝑝=.079)scores.Noneofthesevariableswerecorrelatedwith are shown in Figure1(b). Despite visible group differences
P50metricsandthereforenonewereincludedascovariatesin in the standard ERP around N1 (explored in Supplement
anyfurtheranalyses(seeSupplement1). 1), there were no significant differences between ex-users
NeuralPlasticity 5
Duration Frequency
−6 −6
−4 −4
−2 −2
−100𝜇V) 0 100 200 300 400 −100𝜇V) 0 100 200 300 400
( 0 ( 0
2 2
4 4
Ex-user Ex-user
Control Control
(a)
−6 Duration −6 Frequency
−4 −4
−2 −2
−100𝜇V) 0 100 200 300 400 −100 0 100 200 300 400
( 0 0
2 2
4 4
Ex-user standard Control standard Ex-user standard Control standard
Ex-user deviant Control deviant Ex-user deviant Control deviant
(b)
Figure1:(a)Mismatchnegativity(MMN)waveformsatFzdisplayedforeachconditionforex-cannabisusers(greyline)andnonusercontrols
(blackline).(b)MastoidreferenceunsubtractedERPwaveformsatFztostandard(solidline)anddevianttones(dashedlines)forex-cannabis
users(greylines)andnonusercontrols(blacklines).Amplitudeisshownin𝜇Vonthe𝑦-axisandtimeinmillisecondsalongthe𝑥-axis.
andcontrolsinmeanamplitudeforstandardERPsoverthe thepatternofresultsnotappreciablyaffectedbycontrolling
latencywindowsusedforMMNpeakdetection. for either duration of use (partial 𝑟 = .72, 𝑝 = .001 and
Ex-users had visibly smaller MMN amplitudes than 𝑟 = .74, 𝑝 = .001, resp.) or age (partial 𝑟 = .63, 𝑝 = .007
controls, although this did not reach significance as a main and𝑟 = .65,𝑝 = .005,resp.)separatelyorcombined(partial
effectofgroup(𝐹(1,34)=1.02,𝑝=.32).However,therewas 𝑟 = .42, 𝑝 = .053 and 𝑟 = .47, 𝑝 = .032, resp.). However,
amaineffectofcondition(𝐹(2,68) = 38.63,𝑝 < .001)anda age and duration of use were not correlated with duration
significantconditionbygroupinteraction(𝐹(2,68) = 3.34, MMNaftercontrollingfortimesinceregularuse(age:partial
𝑝 = .042) (Table3(a)). Univariate ANOVAs were used to 𝑟 = −.10,𝑝 = .72;durationofregularuse:partial𝑟 = .05,
decomposethesignificantcondition×groupinteractionand 𝑝 = .85)ortimesincelastuse(age:partial𝑟 = .10,𝑝 = .69;
compared ex-users and controls in each deviant condition duration of regular use: partial 𝑟 = .13, 𝜌 = .61). These
separately.MMNineachdeviantconditionrevealednoeffect
resultsindicatesmallerdurationMMNwithlongerperiods
of group for frequency MMN (𝐹(1,34) = 1.99, 𝑝 = .17)
ofabstinence(Figure2).
or intensity MMN (𝐹 < 1.0), although groups differed at
trend level for duration MMN (𝐹(1,34) = 2.97, 𝑝 = .09;
𝑝 = .08 with age included as a covariate (see Supplement 3.4. P50 Sensory Gating in Ex-Users and Controls. Grand
1))withsmallerdurationMMNamplitudesinex-users.Age meanERPwaveformsatCztothefirst(S1)andsecond(S2)
of onset of regular use, duration of regular and daily use, clickarepresentedforex-usersandcontrolsinFigure3,and
and quantity and frequency of prior cannabis use were not P50amplitudestoS1andS2,P50ratio,anddifferencescores
significantly correlated with either frequency or duration inTable3(b).Ex-usersdidnotdifferfromcontrolsintermsof
MMNamplitude(all𝑝>.09).However,durationMMNwas P50differencescore(𝑍 = −1.23,𝑝 = .23).Therewasatrend
positivelycorrelatedwithabstinence(timesinceregularuse: toward larger P50 ratios in ex-users compared to controls
𝜌=.65,𝑝=.004;timesincelastuse:𝜌=.56,𝑝=.016),with (𝑍=−1.68,𝑝=.097).
6 NeuralPlasticity
−2.0 −2.0
V) −3.0 V) −3.0
𝜇 𝜇
N ( −4.0 N ( −4.0
M M
M M
n −5.0 n −5.0
o o
urati −6.0 urati −6.0
D D
−7.0 −7.0
0.0 5.0 10.0 15.0 20.0 0.0 5.0 10.0 15.0 20.0
Abstinence since regular use (years) Abstinence since last use (years)
(a) (b)
Figure2:ScatterplotsshowingassociationbetweendurationMMNamplitude(𝜇V)anddurationofabstinencesincelastregularcannabis
use(a)andabstinencesincethelastoccasionofuse(b).
Table3:(a)Mean(SD)MMNamplitude(𝜇V)andlatency(ms)at notcorrelatedwithP50metricsaftercontrollingforduration
Fzand(b)median[range]P50metrics(𝜇V)atCzforex-cannabis ofregularordailyuse(timesinceregularuse:all𝑝>.3;time
usersandhealthynonusercontrols. sincelastuse:all𝑝>.6).
Ex-cannabis
Controls
(𝑛u=ser1s8) (𝑛=18) 4.Discussion
(a)MMN GivenmountingevidenceofalteredMMNandP50sensory
DurationMMN gatinginchroniccannabisusers,thecurrentstudysetoutto
Amplitude(𝜇V) −4.60(1.26) −5.65(2.26) examine the degree to which impairments in early sensory
processingmightrecoverwithabstinencefromcannabis,as
Latency(ms) 183.9(20.6) 183.8(17.2)
afunctionofthedurationofabstinenceandhistoryofprior
FrequencyMMN
use.Wereporttrendstowardimpairedsensorygating(larger
Amplitude(𝜇V) −2.74(1.21) −3.34(1.35)
P50 ratios) and reduced duration MMN amplitude in ex-
Latency(ms) 167.6(22.2) 173.1(21.7) cannabis users compared to nonuser controls. An associa-
IntensityMMN tion between the duration of prior cannabis use and P50
Amplitude(𝜇V) −3.25(1.51) −2.92(1.87) metrics suggests that persistent impairments in P50 gating
may be related to prior exposure to cannabis. In contrast,
Latency(ms) 153.6(27.6) 142.4(25.9)
the association between MMN amplitude and duration of
(b)P50
abstinence was not in the expected direction, with smaller
P50S1amplitude 2.59[0.36–5.14] 2.80[0.39–9.52]
amplitudes associated with longer abstinence. The P50 data
P50S2amplitude 1.83[0.03–3.20] 1.27[0.0–3.62] extend the findings of Rentzsch et al. [33] who found that
P50ratio 0.53[0.01–4.19] 0.37[0.0–1.41] P50 sensory gating was reduced in former cannabis users
P50differencescore 1.66[−1.15–3.12] 1.83[−0.40–5.90] who were abstinent for at least 28 days: the ex-cannabis
users of the present study had been abstinent for a median
of 3.5 years (range of 6 weeks to 16 years). The observed
association between greater P50 impairment and duration
In ex-users, no correlation was observed between age ofpriorregularanddailycannabisuseinthisstudy,andin
of onset of regular cannabis use, quantity or frequency of Rentzsch et al. [33], and no association with the duration
priorcannabisusepermonth,timesincelastregularuseor ofabstinence,highlightsthepossibilitythatthesepersistent
time since last use, and either P50 ratio or difference score effectsmayresultfromprolongedexposuretocannabisand
(all 𝑝 > .10). However, duration of prior regular use and may not recover with abstinence. The findings concur also
durationofpriordailyusewerebothsignificantlycorrelated with previous research in current cannabis users (with 12–
with P50 ratio (regular use: 𝜌 = .61, 𝑝 = .007; daily use: 24hoursofabstinencetocontrolforacuteeffects[31,32,34,
𝜌 = .50, 𝑝 = .033, Figure4) and P50 difference score 59]), implicating an association between cannabis exposure
(regularuse: 𝜌 = −.60, 𝑝 = .008; daily use: 𝜌 = −.55, 𝑝 = andfunctioningofneuronalgeneratorsinvolvedinsensory
.019,Figure4).Thesecorrelationsremainedsignificantafter gating.UnlikeRentzschetal.[25],thecurrentstudydidnot
controllingforthedurationofabstinencesinceregularusein find frequency MMN amplitude to be reduced in ex-users
partialcorrelations(P50ratio,regularuse:𝑟 = .63,𝑝 = .006; relativetocontrols.
dailyuse:𝑟 = .57,𝑝 = .02;P50differencescore,regularuse: There is increasing evidence that regular exposure to
𝑟=−.64,𝑝=.006;dailyuse:𝑟=−.55,𝑝=.02).Further,time cannabisoveranextendedperiodoftimeisassociatedwith
sincelastregularuseortimesincelastoccasionofanyusewas reduced frequency MMN [24–26] and more recently, in
NeuralPlasticity 7
P50 to first click (S1) P50 to second click (S2)
−2 −2
−1 −1
−100 0 100 200 300 −100 0 100 200 300
0 0
V) 1 V) 1
𝜇 𝜇
( (
2 2
3 3
4 4
Controls Controls
Ex-users Ex-users
(a) (b)
Figure3:ERPwaveformstothefirst(S1;(a))andsecond(S2;(b))clickatCzforex-cannabisusers(grey)andnonusercontrols(black).
Amplitudeisshownin𝜇Vonthe𝑦-axisandtimeinmillisecondsalongthe𝑥-axis.
4.5 4.5 4.5
3.5 3.5 3.5
o 2.5 o 2.5 o 2.5
rati rati rati
50P 1.5 50P 1.5 50P 1.5
0.5 0.5 0.5
−0.5 −0.5 −0.5
0.0 10.0 20.0 30.0 0.0 100.0 200.0 300.0 400.0 0.0 5.0 10.0 15.0 20.0
Duration of regular cannabis use (years) Duration of daily cannabis use (months) Abstinence since regular use (years)
(a) P50ratio
4.0 4.0 4.0
3.0 3.0 3.0
ore ore ore
nce sc 21..00 nce sc 12..00 nce sc 21..00
differe 0.0 differe 0.0 differe 0.0
0 0 0
5 −1.0 5 −1.0 5 −1.0
P P P
−2.0 −2.0 −2.0
0.0 10.0 20.0 30.0 0.0 100.0 200.0 300.0 400.0 0.0 5.0 10.0 15.0 20.0
Duration of regular cannabis use (years) Duration of daily cannabis use (months) Abstinence since regular use (years)
(b) P50differencescore
Figure4:ScatterplotsshowingassociationbetweenP50metricsanddurationofregularcannabisuseinyears(left),durationofdailycannabis
useinmonths(middle),anddurationofabstinencesinceregularuse(right)forex-cannabisusers.P50ratioshownonthetoprow(a)and
P50differencescoreshownonthebottomrow(b).
long-termusers,attenuateddurationMMNaswell[24].We alterationstobrainfunctionassociatedwithsoundduration
havearguedthatreductionindurationMMNmaymanifest processing following more prolonged exposure to cannabis
onlyafterprotracted(andespeciallydaily)cannabisuse.We [24].Inthecurrentstudyofformerusers,wedidnotobserve
suggested that attenuated frequency MMN in short- and anassociationbetweendurationofregular(ordaily)cannabis
long-term users may be related to altered gyrification and useandattenuateddurationMMN,although,unexpectedly,
cortical thinning in temporal and frontal regions observed wefoundthatlongerdurationsofabstinence(bothsincelast
to be unrelated to the extent of exposure to cannabis in regularuseandsincethelastoccasionofuse)werecorrelated
users[60],whiledurationMMNmaybesensitivetobroader with greater reductions in duration MMN amplitude. This
8 NeuralPlasticity
relationship is difficult to interpret, as it is not possible use,andforthisreasonitwasnotpossibletosuperviseabsti-
in the current sample to definitively dissociate aging from nenceinawayconsistentwithprotocolsemployedinprior
length of abstinence (or duration of cannabis exposure). research examining short durations of abstinence (e.g., 28
Nevertheless,partialcorrelationscontrollingforageandfor days)[68].Assuch,thedurationofabstinenceinthissample
durationofpriorregularuserevealedthatageandduration wasbroadlydistributed,butmorethanhalfhadabstainedfor
of prior regular use did not account for this relationship. theperiodbetween6weeksand5years,whichshouldhave
Thisassociationspeakstothreepossiblehypotheses:first,that capturedanyevidenceforeitherabruptorgradualrecovery
theassociationbetweendurationMMNandabstinencemay duringtheearlyperiodfollowingcessationofuse,aswellas
reflectacceleratedaging,withpersistentandnonlineareffects enablingdetectionofevidenceforanygradualrecoverythat
beyondcessationofcannabisuseinformerusers.Second,itis mightrequireasignificantperiodofabstinence.Noevidence
possiblethatindividualswhohaveusedcannabisandsubse- for any such patterns was observed; however, this requires
quentlychosentoabstaindifferfundamentallyfromnonus- replication in a larger sample of ex-cannabis users. Second,
ing individuals on a third unmeasured variable for which despiteourobservationthatalteredP50metricsweresignif-
durationofabstinenceisactingasproxy.Neverthelessfurther icantlyassociatedwiththedurationofexposuretocannabis,
analysis (reported in Supplement 1) suggests that duration the extent to which these alterations to brain function are
of abstinence was not correlated with neuropsychological present prior to cannabis exposure remains unknown and
functioning,alcoholorcigaretteuse,psychosis-proneness,or maybeansweredbylongitudinalstudies.Third,weacknowl-
priorcannabisuse.Athirdhypothesismaythereforebethat edgeanargumentthatwhileeducationandIQdidnotcorre-
cannabis use may have “medicated” a preexisting deficit in latewithourERPmeasuresandwerethereforeinappropriate
formerusersandthatthisdeficitisprogressivelyunmasked ascovariatesinouranalyses,thegroupdifferencesonthese
with ongoing abstinence. That duration MMN, previously measuresmaypointtodifferencesincognitivefunctionthat
demonstrated by us to correlate with longer duration of couldaffectpotentialrecoveryorevenpredatecannabisuse.
cannabis use (particularly daily use) [24], suggests that any This cannot be easily ruled out. Nevertheless, ex-cannabis
potentialpreexistingdeficitwasneverthelessexacerbatedby usersinthecurrentstudydidnotdifferfromnonusercontrols
long-term cannabis use, perhaps interacting with the aging in terms of verbal learning and memory performance, and
process.Currentlyspeculative,furtherresearchisrequiredto there were very few differences between groups in terms
(dis)confirmthesehypotheses. of psychological wellbeing, including psychosis-proneness.
Theprecisemechanismsbywhichprolongedexposureto Future research should examine the functional significance
cannabismightaltertheneuronalsubstrateswhichunderpin of these apparently persistent alterations in sensory gating
P50 indices of sensory gating remain unclear [61]. The inlong-termformercannabisusersandtheextenttowhich
generatorsoftheP50evokedpotentialhavebeenlocalisedto theymayimpactuponfunctioningindailylifeand/orpredate
Heschl’sgyrusintheprimaryauditorycortex[62–64].Less cannabis use affecting recovery of function. We acknowl-
clear are the neurobiological substrates involved in sensory edge that the sample size of the ex-user group was small.
gating[63].Currentlyitisthoughtthatinhibitoryinputsfrom Nevertheless, the sample represents a unique population of
theCA3regionwithinthehippocampus,whilstnotdirectly clean cannabis users (unconfounded by other drug use or
related to P50 generation [65], may act to suppress activity psychopathology) with long histories of prior cannabis use
in the primary auditory cortex linked with P50 generation and with prolonged abstinence, a sample that is difficult to
to the second click [63]. Potential generators in the frontal recruitandisrarelyreportedintheliterature.
lobe [63] and superior temporal gyrus [66] have also been
implicated, in addition to several neurotransmitter systems 5.Conclusions
includingdopaminergic,serotonergic,andglutamatergicsys-
tems[67].Apossibility,therefore,isthatTHCimpactsupon Insummary,thetrendlevelpatternofresultsofthecurrent
inhibitoryinputsfromthehippocampusviadenselylocated study suggests that cannabis-related alterations to MMN
CB1 receptors alter an individual’s sensory gating capacity. and P50 may not fully recover following cessation of long-
Furthermore,aswehavesuggestedpreviously[31],theremay termcannabisuse.Instead,thecurrentdatasuggestthat(i)
be a threshold of exposure associated with the duration of prolongedexposuretocannabisaltersP50sensorygatingand
regular or daily cannabis use over which impairments in thesealterationsmaypersistbeyondcessationofuseand(ii)
sensorygatingariseandthismayaffectthedegreetowhich MMN amplitude may reduce further with increasing absti-
these deficits persist after cessation of use and similarly the nence.Theresultsraisethepossibilityofpersistentalterations
degree to which they recover. Future research might take a totheregulatoryroleoftheendocannabinoidsystemonbrain
longitudinalapproachtofurtherexamineP50metricsbefore function,affectingthebrain’sabilitytoregulateitsresponse
andaftercessationofcannabisuse,toassesspotentialchanges toincomingstimuliortofilterirrelevantinformation.These
overtimewithinthesameindividuals. resultsrequirereplicationinfuturestudiesofbrainfunctional
There are a number of limitations in the current study plasticity-relatedrecoveryinabstinentcannabisusers.
which may be addressed by future work. First, as a cross-
sectionalandnaturalisticstudywereliedonparticipantself- ConflictofInterests
reportforthedurationofabstinenceandhistoryofcannabis
use.ThecurrentstudysetouttoexamineMMNandP50met- Allauthorsreportnobiomedicalfinancialinterestsorpoten-
ricsasafunctionofabroaddurationofabstinenceandprior tialconflictofinterests.
NeuralPlasticity 9
Acknowledgments [12] D.C.D’Souza,R.A.Sewell,andM.Ranganathan,“Cannabis
and psychosis/schizophrenia: human studies,” European
This study was funded by the National Health and Medical ArchivesofPsychiatryandClinicalNeuroscience,vol.259,no.7,
Research Council (Project Grant 1007593) and the Aus- pp.413–431,2009.
tralian Research Council (FT110100752). Preliminary data [13] C.Henquet,M.diForti,P.D.Morrison,R.Kuepper,andR.M.
and results from this study were presented at the following Murray, “Gene-environment interplay between cannabis and
conferences:2ndNationalCannabisConference,2012,Bris- psychosis,”SchizophreniaBulletin,vol.34,no.6,pp.1111–1121,
bane, Australia;BiologicalPsychiatry AustraliaConference, 2008.
2012, Melbourne, Australia; Australasian Psychophysiology [14] R. M. Murray, P. D. Morrison, C. Henquet, and M. D. Forti,
Society Conference, 2013, Wollongong, Australia; and they “Cannabis, the mind and society: the hash realities,” Nature
werepublishedinthefollowingabstract:Websteretal.[69]. ReviewsNeuroscience,vol.8,no.11,pp.885–895,2007.
[15] M. I. Garrido, J. M. Kilner, K. E. Stephan, and K. J. Friston,
“Themismatchnegativity:areviewofunderlyingmechanisms,”
References
ClinicalNeurophysiology,vol.120,no.3,pp.453–463,2009.
[1] L. Degenhardt and W. Hall, “Extent of illicit drug use and [16] J. Todd, L. Harms, P. T. Michie, and U. Schall, “Mismatch
dependence, and their contribution to the global burden of negativity:translatingthepotential,”FrontiersinPsychiatry,vol.
disease,”TheLancet,vol.379,no.9810,pp.55–70,2012. 4,article171,2013.
[2] C. Henquet, L. Krabbendam, J. Spauwen et al., “Prospective [17] R. Na¨a¨ta¨nen, “The mismatch negativity: a powerful tool for
cohortstudyofcannabisuse,predispositionforpsychosis,and cognitiveneuroscience,”EarandHearing,vol.16,no.1,pp.6–18,
psychoticsymptomsinyoungpeople,”BritishMedicalJournal, 1995.
vol.330,no.7481,pp.11–14,2005. [18] I. Winkler, “Interpreting the mismatch negativity,” Journal of
[3] R.Kuepper,J.vanOs,R.Lieb,H.-U.Wittchen,M.Ho¨fler,and Psychophysiology,vol.21,no.3-4,pp.147–163,2007.
C.Henquet,“Continuedcannabisuseandriskofincidenceand [19] R.Na¨a¨ta¨nenandS.Ka¨hko¨nen,“Centralauditorydysfunctionin
persistence of psychotic symptoms: 10 year follow-up cohort schizophreniaasrevealedbythemismatchnegativity(MMN)
study,”TheBritishMedicalJournal,vol.342,articled738,2011. and its magnetic equivalent MMNm: a review,” International
[4] S. Zammit, P. Allebeck, S. Andreasson, I. Lundberg, and JournalofNeuropsychopharmacology,vol.12,no.1,pp.125–135,
G. Lewis, “Self reported cannabis use as a risk factor for 2009.
schizophreniainSwedishconscriptsof1969:historicalcohort [20] D. Umbricht and S. Krljesb, “Mismatch negativity in schizo-
study,”BritishMedicalJournal,vol.325,no.7374,pp.1199–1201, phrenia:ameta-analysis,”SchizophreniaResearch,vol.76,no.
2002. 1,pp.1–23,2005.
[5] H. D. Burns, K. Van Laere, S. Sanabria-Boho´rquez et al., [21] F.Jessen,T.Fries,C.Kucharskietal.,“Amplitudereductionof
18
“[ F]MK-9470,apositronemissiontomography(PET)tracer themismatchnegativityinfirst-degreerelativesofpatientswith
for in vivo human PET brain imaging of the cannabinoid-1 schizophrenia,”NeuroscienceLetters,vol.309,no.3,pp.185–188,
receptor,”ProceedingsoftheNationalAcademyofSciencesofthe 2001.
UnitedStatesofAmerica,vol.104,no.23,pp.9800–9805,2007.
[22] P. T. Michie, H. Innes-Brown, J. Todd, and A. V. Jablensky,
[6] N.SolowijandP.T.Michie,“Cannabisandcognitivedysfunc- “Durationmismatchnegativityinbiologicalrelativesofpatients
tion:parallelswithendophenotypesofschizophrenia?”Journal withschizophreniaspectrumdisorders,”BiologicalPsychiatry,
ofPsychiatry&Neuroscience,vol.32,no.1,pp.30–52,2007. vol.52,no.7,pp.749–758,2002.
[7] R. E. Hampson, F. Miller, G. Palchik, and S. A. Deadwyler, [23] A. E. S¸evik, A. E. A. Yagcioglu, S. Yagcioglu, S. Karahan, N.
“Cannabinoid receptor activation modifies NMDA receptor Gu¨rses,andM.Yildiz,“Neuropsychologicalperformanceand
mediated release of intracellular calcium: implications for auditoryeventrelatedpotentialsinschizophreniapatientsand
endocannabinoid control of hippocampal neural plasticity,” theirsiblings:afamilystudy,”SchizophreniaResearch,vol.130,
Neuropharmacology,vol.60,no.6,pp.944–952,2011. no.1–3,pp.195–202,2011.
[8] B.D.HeifetsandP.E.Castillo,“Endocannabinoidsignalingand [24] L.-M.Greenwood,S.J.Broyd,R.Croftetal.,“Chroniceffects
long-termsynapticplasticity,”AnnualReviewofPhysiology,vol. ofcannabisuseontheauditorymismatchnegativity,”Biological
71,pp.283–306,2009. Psychiatry,vol.75,no.6,pp.449–458,2014.
[9] A. F. Hoffman, M. Oz, R. Yang, A. H. Lichtman, and C. R. [25] J. Rentzsch, E. Buntebart, A. Stadelmeier, J. Gallinat, and M.
Lupica,“OpposingactionsofchronicΔ9-tetrahydrocannabinol C. Jockers-Scheru¨bl, “Differential effects of chronic cannabis
andcannabinoidantagonistsonhippocampallong-termpoten- use on preattentional cognitive functioning in abstinent
tiation,”LearningandMemory,vol.14,no.1,pp.63–74,2007. schizophrenic patients and healthy subjects,” Schizophrenia
[10] E. Puighermanal, A. Busquets-Garcia, R. Maldonado, and A. Research,vol.130,no.1–3,pp.222–227,2011.
Ozaita,“Cellularandintracellularmechanismsinvolvedinthe [26] P. Roser, B. Della, C. Norra, I. Uhl, M. Bru¨ne, and G. Juckel,
cognitiveimpairmentofcannabinoids,”PhilosophicalTransac- “Auditory mismatch negativity deficits in long-term heavy
tionsoftheRoyalSocietyofLondonSeriesB,BiologicalSciences, cannabis users,” European Archives of Psychiatry and Clinical
vol.367,no.1607,pp.3254–3263,2012. Neuroscience,vol.260,no.6,pp.491–498,2010.
[11] N.Fan,H.Yang,J.Zhang,andC.Chen,“Reducedexpressionof [27] D. Impey, N. El-Marj, A. Parks, J. Choueiry, D. Fisher, and
glutamatereceptorsandphosphorylationofCREBarerespon- V. J. Knott, “Mismatch negativity in tobacco-na¨ıve cannabis
sible for in vivo Δ9-THC exposure-impaired hippocampal users and its alteration with acute nicotine administration,”
synapticplasticity,”JournalofNeurochemistry,vol.112,no.3,pp. Pharmacology Biochemistry and Behavior, vol. 136, pp. 73–81,
691–702,2010. 2015.
10 NeuralPlasticity
[28] N. Pesa, D. F. Hermens, R. A. Battisti, M. Kaur, I. B. Hickie, [44] D. A. Eldreth, J. A. Matochik, J. L. Cadet, and K. I. Bolla,
and N. Solowij, “Delayed preattentional functioning in early “Abnormalbrainactivityinprefrontalbrainregionsinabstinent
psychosispatientswithcannabisuse,”Psychopharmacology,vol. marijuanausers,”NeuroImage,vol.23,no.3,pp.914–920,2004.
222,no.3,pp.507–518,2012. [45] K.I.Bolla,K.Brown,D.Eldreth,K.Tate,andJ.L.Cadet,“Dose-
[29] E.Bramon,R.J.Croft,C.McDonaldetal.,“Mismatchnegativity relatedneurocognitiveeffectsofmarijuanause,”Neurology,vol.
inschizophrenia:afamilystudy,”SchizophreniaResearch,vol. 59,no.9,pp.1337–1343,2002.
67,no.1,pp.1–10,2004. [46] K.I.Bolla,D.A.Eldreth,J.A.Matochik,andJ.L.Cadet,“Neural
[30] O. M. de Wilde, L. J. Bour, P. M. Dingemans, J. H. T. substrates of faulty decision-making in abstinent marijuana
M. Koelman, and D. H. Linszen, “A meta-analysis of P50 users,”NeuroImage,vol.26,no.2,pp.480–492,2005.
studies in patients with schizophrenia and relatives: differ-
[47] N.Solowij,“Docognitiveimpairmentsrecoverfollowingcessa-
encesinmethodologybetweenresearchgroups,”Schizophrenia
tionofcannabisuse?”LifeSciences,vol.56,no.23-24,pp.2119–
Research,vol.97,no.1–3,pp.137–151,2007.
2126,1995.
[31] S. J. Broyd, L.-M. Greenwood, R. J. Croft et al., “Chronic
[48] L. Sobell and M. Sobell, Timeline Followback User’s Guide: A
effectsofcannabisonsensorygating,”InternationalJournalof
CalendarMethodforAssessingAlcoholandDrugUse,Addiction
Psychophysiology,vol.89,no.3,pp.381–389,2013.
ResearchFoundation,Toronto,Canada,1996.
[32] C.R.Edwards,P.D.Skosnik,A.B.Steinmetz,B.F.O’Donnell,
[49] D.Wechsler,WechslerAbbreviatedScaleofIntelligence(Wasi),
and W. P. Hetrick, “Sensory gating impairments in heavy
HarcourtAssessement,SanAntonio,Tex,USA,1999.
cannabisusersareassociatedwithalteredneuraloscillations,”
[50] N.C.Stefanis,M.Hanssen,N.K.Smirnisetal.,“Evidencethat
BehavioralNeuroscience,vol.123,no.4,pp.894–904,2009.
threedimensionsofpsychosishaveadistributioninthegeneral
[33] J. Rentzsch, A. Penzhorn, K. Kernbichler et al., “Differen-
population,”PsychologicalMedicine,vol.32,no.2,pp.347–358,
tial impact of heavy cannabis use on sensory gating in
2002.
schizophrenicpatientsandotherwisehealthycontrols,”Experi-
[51] A.Raine,“TheSPQ:ascalefortheassessmentofschizotypal
mentalNeurology,vol.205,no.1,pp.241–249,2007.
personality based on DSM-III-R criteria,” Schizophrenia Bul-
[34] G.PatrickandF.A.Struve,“ReductionofauditoryP50gating
letin,vol.17,no.4,pp.555–564,1991.
responseinmarihuanausers:furthersupportingdata,”Clinical
[52] A.T.Beck,C.H.Ward,M.Mendelson,J.Mock,andJ.Erbaugh,
EEG(Electroencephalography),vol.31,no.2,pp.88–93,2000.
“An inventory for measuring depression,” Archives of General
[35] D. L. Braff and M. A. Geyer, “Sensorimotor gating and
Psychiatry,vol.4,pp.561–571,1961.
schizophrenia.Humanandanimalmodelstudies,”Archivesof
GeneralPsychiatry,vol.47,no.2,pp.181–188,1990. [53] C.D.Spielberger,R.L.Gorsuch,R.Lushene,P.R.Vagg,and
G. A. Jacobs, Manual for the State-Trait Anxiety Inventory,
[36] N. N. Boutros and A. Belger, “Midlatency evoked potentials
ConsultingPsychologistsPress,PaloAlto,Calif,USA,1983.
attenuationandaugmentationreflectdifferentaspectsofsen-
sory gating,” Biological Psychiatry, vol. 45, no. 7, pp. 917–922, [54] R.C.Oldfield,“Theassessmentandanalysisofhandedness:the
1999. Edinburghinventory,”Neuropsychologia,vol.9,no.1,pp.97–113,
1971.
[37] K.Gjini,C.Arfken,andN.N.Boutros,“Relationshipsbetween
sensory ‘gating out’ and sensory ‘gating in’ of auditory [55] J.B.Saunders,O.G.Aasland,T.F.Babor,J.R.DelaFuente,
evokedpotentialsinschizophrenia:apilotstudy,”Schizophrenia and M. Grant, “Development of the alcohol use disorders
Research,vol.121,no.1–3,pp.139–145,2010. identification test (AUDIT): WHO collaborative project on
earlydetectionofpersonswithharmfulalcoholconsumption
[38] L.Hu,N.N.Boutros,andB.H.Jansen,“Sensorygating-outand
II,”Addiction,vol.88,no.6,pp.791–804,1993.
gating-in in normal and schizophrenic participants,” Clinical
EEGandNeuroscience,vol.43,no.1,pp.23–31,2012. [56] A. J. Budney, J. R. Hughes, B. A. Moore, and R. Vandrey,
“Reviewofthevalidityandsignificanceofcannabiswithdrawal
[39] M. H. Meier, A. Caspi, A. Ambler et al., “Persistent cannabis
syndrome,”AmericanJournalofPsychiatry,vol.161,no.11,pp.
users show neuropsychological decline from childhood to
1967–1977,2004.
midlife,”ProceedingsoftheNationalAcademyofSciencesofthe
UnitedStatesofAmerica,vol.109,no.40,pp.E2657–E2664,2012. [57] M. Gossop, J. Marsden, and D. Stewart, “Dual dependence:
assessmentofdependenceuponalcoholandillicitdrugs,and
[40] S. F. Tapert, A. D. Schweinsburg, S. P. A. Drummond et
therelationshipofalcoholdependenceamongdrugmisusers
al., “Functional MRI of inhibitory processing in abstinent
topatternsofdrinking,illicitdruguseandhealthproblems,”
adolescentmarijuanausers,”Psychopharmacology,vol.194,no.
Addiction,vol.97,no.2,pp.169–178,2002.
2,pp.173–183,2007.
[58] E.J.Barkus,J.Stirling,R.S.Hopkins,andS.Lewis,“Cannabis-
[41] J. T. Sneider, H. G. Pope Jr., M. M. Silveri, N. S. Simpson, S.
induced psychosis-like experiences are associated with high
A.Gruber,andD.A.Yurgelun-Todd,“Differencesinregional
schizotypy,”Psychopathology,vol.39,no.4,pp.175–178,2006.
bloodvolumeduringa28-dayperiodofabstinenceinchronic
cannabis smokers,” European Neuropsychopharmacology, vol. [59] G.PatrickandF.Struve,“ReducedP50sensorygatinginheavy
18,no.8,pp.612–619,2008. marihuanausers,”InternationalJournalofPsychophysiology,vol.
[42] S. S. Pillay, J. Rogowska, G. Kanayama et al., “Cannabis and 45,pp.33–34,2002.
motorfunction:fMRIchangesfollowing28daysofdiscontin- [60] I.Mata,R.Perez-Iglesias,R.Roiz-Santian˜ezetal.,“Gyrification
uation,”ExperimentalandClinicalPsychopharmacology,vol.16, brain abnormalities associated with adolescence and early-
no.1,pp.22–32,2008. adulthoodcannabisuse,”BrainResearch,vol.1317,pp.297–304,
[43] L.Chang,R.Yakupov,C.Cloak,andT.Ernst,“Marijuanause 2010.
isassociatedwithareorganizedvisual-attentionnetworkand [61] D.W.N.Dissanayake,R.Mason,andC.A.Marsden,“Sensory
cerebellarhypoactivation,”Brain,vol.129,no.5,pp.1096–1112, gating,cannabinoidsandschizophrenia,”Neuropharmacology,
2006. vol.67,pp.66–77,2013.