recentstructuralmagneticresonanceimaging(MRI)stud-ieshavealsoreportedcontradictoryfindings,rangingfromno global or regional changes in brain tissue volume orcomposition
or in focal regions, most notably in thehippocampal and parahippocampal areas.
However,thesepreviousstudiesusedimagingtechniqueswithrela-tivelycoarse spatial andanatomical resolution andtypi-callyfocusedonsampleswithmultiplesubstanceuseorcomorbidpsychiatricdisordersandononlymoderatelev-els of cannabis use (ie,
2 joints per day). Indeed, de-spite strong evidence of neurotoxicity in the animal lit-erature,
toourknowledge,noneuroimagingstudyhasexaminedtheneurobiologicsequelaeoflong-termheavycannabis use while controlling for the important con-founds of polydrug abuse and co-occurring psychiatricdisorders.Inthisstudy,weusedhigh-resolution3-TMRItoas-sess volumetric changes in 2 cannabinoid-rich regionsofthebrain(thehippocampusandtheamygdala)knowntobesusceptibletotheneurotoxiceffectsofcannabisex-posure in a sample of long-term heavy users carefullyscreened for polysubstance abuse and mental disorders.Giventhegrowingliteratureregardinganassociationbe-tween cannabis use and the development of psychosis
and cognitive impairment,
we also assessed for sub-threshold psychotic symptoms and verbal learning abil-ity in this otherwise psychologically healthy sample.
Male cannabis users with long histories of regular and heavycannabis use (n=15) and nonusing healthy male volunteers(n=16)matchedonage,estimatedpremorbidintelligence(Na-tional Adult Reading Test),
years of education, and state andtraitanxiety(SpielbergerState-TraitAnxietyInventory)
wererecruited from the general community via a variety of adver-tisements (
). Cannabis users had lower Global Assess-mentofFunctioningscalescoresandgreaterdepressivesymp-toms(asmeasuredusingtheHamiltonDepressionRatingScale)
than the comparison group; however, there were no currentorlifetimehistoriesofdiagnosablemedical,neurologic,orpsy-chiatricconditionsasassessedusingthe
Axis I Disorders, Patient Edition
Axis I Disorders, Non-Patient Edition
Subthresh-old psychotic symptoms were probed using the Scale for theAssessment of Positive Symptoms
and the Scale for the As-sessment of Negative Symptoms.
Regarding alcohol use, thegroups did not differ in levels of current consumption, life-time use, or history of abuse or dependence; and no partici-pant drank more than 24 standard alcoholic drinks per week.Significantly more cannabis users were also tobacco smokers(
.001)(Table).Forallusers,cannabiswasthepri-marydrugofabuse,withonlylimitedexperimentaluseofotherillicit drugs (generally
10 lifetime episodes).
Participantswereassessedon2occasions,usually1weekapart.In the first test session, participants completed demographic,clinical, and substance use history assessments. In the secondtestsession,theycompletedtheReyAuditoryVerbalLearningTest (RAVLT) and underwent structural MRI.Participantswereaskedtoabstainfromusingsubstancesforat least 12 hours before each test session, and cannabis usersreportedabstainingfromcannabisforameanof21.3hoursbe-forethefirsttestsession(median,14hours;range,10-72hours)and a mean of 19.8 hours before the second test session (me-dian, 17 hours; range, 12-48 hours). Urine samples were ob-tained from users on 4 occasions and from controls on 2 oc-casionstocorroborateself-reportedabstinence.Specifically,forcannabis users, samples were obtained on the evening beforeeachtestsessionandonthedayoftesting.Forcontrols,sampleswerecollectedonlyonthedayoftesting.Examinationofthesesamples demonstrated that all but 1 cannabis user had canna-binoid metabolites (11-nor-
9-tetrahydrocannabinol-9-carboxylicacidcreatininenormalized)detectedinurinesamplesfrom the first test session, and levels were generally high(evening: median, 467 ng/mg [range, 0-2320 ng/mg]; day of testing:median,447ng/mg[range,0-11293ng/mg]).Fromthesecond test session, 2 users returned a 0 reading; otherwise,cannabinoid metabolite levels were again high (evening: me-dian, 456 ng/mg [range, 0-3511 ng/mg]; day of testing: me-dian,389ng/mg[range,0-4470ng/mg]).Thelevelsofurinarycannabinoid metabolites generally corroborate the self-reported patterns of heavy cannabis use in the sample. All but2 control subjects returned a 0 reading for cannabinoid me-tabolites across both test sessions. The 2 controls with posi-tive urine samples reported only minimal and very occasionalexposure to cannabis. The median level of cannabinoid me-tabolitesincontrolsatthefirsttestsessionwas0ng/mg(range,0-184ng/mg)andatthesecondtestsessionwas0ng/mg(range,0-180 ng/mg).
The MRI data were obtained using a 3-T scanner (Intera; Phil-lips Medical Systems NA, Bothell, Washington) at the Sym-bionClinicalResearchImagingCentre,PrinceofWalesMedi-cal Research Institute, Sydney. A 3-dimensional volumetricspoiled gradient–recalled echo sequence generated 180 con-tiguous coronal slices. The imaging parameters were as fol-lows: echo time, 2.9 milliseconds; repetition time, 6.4 milli-seconds;flipangle,8°;matrixsize,256
voxels.Hippocampal, amygdala, whole brain, and intracranial vol-umes were measured using established reliable protocols
andweredelineatedbyatrainedrater(S.W.)maskedtogroupinformation.Specifically,thehippocampalboundarieswereasfollows:posterior,theslicewiththegreatestlengthofcontinu-ous fornix; medial, the open end of the hippocampal fissureposteriorly,theuncalfissureinthehippocampalbody,andthemedialaspectoftheambientgyrusanteriorly;lateral,thetem-poralhornofthelateralventricle;inferior,thewhitematterin-feriortothehippocampus;superior,thesuperiorborderofthehippocampus; and anterior, the alveus was used to differenti-atethehippocampalheadfromtheamygdala.Theanteriorbor-derwasthemostdifficulttoidentifyconsistentlyandwasaidedby moving between slices before and after the index slice. Theamygdala boundaries were as follows: posterior, the appear-ance of amygdala gray matter above the temporal horn; su-perolateral,thethinstripofwhitematterthatseparatestheamyg-dalafromtheclaustrumandthetailofthecaudate;medial,theangular bundle, which separates the amygdala from the ento-rhinal cortex; superomedial, the semilunar gyrus; inferior, thehippocampus;inferolateral,thetemporallobewhitematterandthe extension of the temporal horn; and anterior, the slice an-terior to the appearance of the optic chiasm. Whole brain vol-umeswereestimatedusingtheBrainExtractionToolmethod
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