Cannabis and psychosis: what causes what?

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by  Castle, David J

Published:11January2013
©2013Facultyof1000Ltd
Cannabis and psychosis: what causes what?
David J Castle
Address:ChairofPsychiatry,StVincent’sHospitalandTheUniversityofMelbourne,POBox2900FitzroyVictoria3065,Australia
Email:[email protected]
F1000MedicineReports2013,5:1(doi:10.3410/M5-1)
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Abstract
Converging lines of evidence suggest that cannabinoids can produce a full range of transient
schizophrenia-like positive, negative and cognitive symptoms. Cannabinoids also produce some
psychophysiologicaldeficitsalsoknowntobepresentinschizophrenia.Itisalsoclearthat,inindividuals
withanestablishedpsychoticdisorder,cannabinoidscanexacerbatesymptoms,triggerrelapse,andhave
negative consequences on the course of the illness. Increasing evidence suggests that early and heavy
cannabis exposure may increasethe risk of developing apsychotic disorder such as schizophrenia.
Therelationshipbetweencannabisexposureandschizophreniafulfillssome,butnotall,oftheusual
criteria for causality. However, most people who use cannabis do not develop schizophrenia, and
many people diagnosed with schizophrenia have never used cannabis. Therefore, it is likely that
cannabisexposureisa“componentcause”thatinteractswithotherfactorsto“cause”schizophrenia
orotherpsychoticdisorders,butisneithernecessarynorsufficienttodosoalone.Furtherworkis
necessarytoidentifythefactorsthatunderlieindividualvulnerabilitytocannabinoid-relatedpsychosis
and to elucidate the biological mechanisms underlying this risk.
Introduction ThereislittledoubtthatingestionoftheplantCannabis
The term psychosis is often used rather broadly to sativa can cause positive psychotic-like symptoms.
encompass a group of symptoms, none of which is An early study by Ames [2] using the plant product
specifictoanydisorderassuch,andwhichcanmanifest showed a fairly uniform response in human volunteers,
in anyone given certain stimuli, such as exposure to with features including depersonalisation/derealisation,
dopaminergic agonists. Schizophrenia is a psychiatric aprolongedsenseofthepassageoftime,transientpara-
disorder characterised by psychotic symptoms: pragma- noid ideation and hallucinations. Of course, Cannabis
tically,albeitover-simplistically,thesesymptomscanbe sativa has multiple chemical constituents, but delta-9-
divided into “positive” (delusions and hallucinations) tetrahydrocannabinol (THC) confers the psychotomi-
and “negative” (apathetic withdrawal, reduced range of metic properties, acting via cannabinoid CB1 receptors,
emotions, diminished thought content – i.e. having a which are ubiquitously distributed in the brain [3].
paucity of thoughts, demonstrated by lack of sponta- Intriguingly, another constituent of the plant, cannabi-
neous speech and tendency to short unembellished diolseemstohaveantipsychoticeffects[4].Isbeletal.[5]
conversation). It is the latter that is arguably the core of usedsyntheticTHCandfoundadose-responserelation-
the schizophrenia syndrome, with positive symptoms shipwithpsychoticsymptomsinmostsubjects,although
being what may be considered “secondary”. Cognitive somehadanidiosyncraticallyprofoundresponsetoeven
deficitsarealsoconsideredpartofthecoresyndromeand, amodestdose.Moremodernstudiesusingmoresophisti-
alongwithnegativesymptoms,drivemostofthedisability cated techniques support these conclusions [6], whilst
associatedwiththecondition[1]. elegant work from Huestis et al. [7] has shown that the
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psychotomimetic effects of THC are mediated by the hadalifetimerateofcannabisexposureof97%,andlast-
cannabinoid CB1 receptor and that antagonism of the year rates of 49% [17]. This begs the question as to why
receptorblockstheseeffects. people with schizophrenia should use an agent that
worsens their illness course and makes their positive
Cannabis susceptibility to psychosis symptomsworse.Onewayoflookingatthisistoconsider
These findings suggest that some individuals are simply thatpeoplewithschizophreniahaveanexcessofnegative
more prone to the psychotomimetic properties of emotions and that these symptoms drive cannabis use in
cannabis. Verdoux and colleagues [8] confirmed this in much the same way as those that drive its use in people
a non-clinical sample, with the individuals’ degree of without schizophrenia [18]. So, the self-medication
“psychosis proneness” correlating with intensity of hypothesismaybetrue,butself-medicationisfornegative
psychosis-like symptoms upon exposure to cannabis in ratherthanpositivesymptoms[19].Thisconclusionis,in
a daily-life situation. Extrapolating from this, it would part at least, supported by a study of 42 patients with
seem obvious that people with schizophrenia are very psychosis and 38 controls, using experience sampling
“psychosis prone” and they would be expected to methodology: both groups experienced increases in
manifest positive symptoms of psychosis (delusions, positiveemotionsonexposuretocannabisand,inpatients,
hallucinations) at even low doses, similar to someone therewasalsoareductioninnegativeemotions[20].
with diabetes eating sugar and becoming hyperglycae-
mic.Anassociationbetweencannabisconsumptionand Hence, the message must be that anyone highly prone
worse psychotic symptoms and an overall more severe to psychosis should avoid cannabis: the tough part is
illness course has been pretty consistently shown in the helping people with negative emotions to find alter-
schizophrenia literature, be it in chronic [9] or first- nativewaysofamelioratingthosesymptoms.Indeed,the
episode [10] patients (see review by Linszen et al. [11]); effectivemanagementofpeoplewithschizophreniaand
however, confounding and other methodological pro- cannabis use remains suboptimal and requires much
blems do bedevil this literature [12]. Also, a distinction more research [21,22].
needs to be drawn between acute effects (i.e. precipita-
tionofanacuteepisodeofillness)andlonger-term,more Can cannabis cause schizophrenia?
insidious detrimental effects: obviously the former are A rather more contentious issue is whether cannabis can
easier to demarcate in terms of temporal sequence of actually cause schizophrenia. This, of course, is very
cannabisexposureandsymptomexacerbation. difficult to determine definitively, and the best study
designisthelongitudinalcohort.Cohortstudieshavethe
Cannabis and negative symptoms great advantage of determining temporal sequence of
Anotherproblemisthattheliteraturehaslargelyfocussed putative cause and putative effect: any causal model of
on positive rather than negative or cognitive symptoms. cannabis forschizophreniawouldnecessarilyrequire the
Itisclearthatcannabisandrelatedcompoundscancause cannabisexposuretoantedatetheillness,assymptomsof
acute transient impairments in memory, attention, and the illness can drive cannabis consumption, as detailed
executive function [13]. But whether exposure to canna- above.A problem,though, even for the cohort design, is
binoids is associated with persistent cognitive deficits is that non-specific symptoms characterised by negative
notasclear,morecontroversialanddifficulttostudy[14]. emotions (see above) and sub-threshold positive symp-
In terms of negative-like symptoms, an “amotivational tomscanoccurintheprodromalphaseheraldingthefirst
syndrome”hasbeendescribedinchronic,heavycannabis definitive psychotic episode [23], and might lead to
users.Thesyndromeresemblesthenegativesymptomsof cannabisconsumption(discussedbyKuepperetal.[24]).
schizophrenia and is characterized by apathy, amotiva- But thisaside, a numberofcohortstudies fromdifferent
tion, social withdrawal, narrowing of interests, lethargy, parts of the world have converged in finding an associa-
impaired memory, impaired concentration, disturbed tion between cannabis consumption in youth and later
judgment,andimpairedoccupationalachievement.How- schizophrenia/schizophreniform disorder. The first of
ever,polydruguse,poverty,lowsocio-economicstatus,or these was a study of 50,087 Swedish conscripts [25],
pre-existingpsychiatricdisordersconfoundinterpretation whichshowedanadjustedhazardratioforschizophrenia
of these studies and other investigators have argued that of3.1(CI1.7,5.5),withadose-responserelationshipwith
thesyndromedoesnotexist[15]. increasingexposuretocannabis.TheDunedinbirthcohort
[26] is particularly instructive in that it assessed indivi-
What has been consistently found is that people with duals from a representative birth cohort at a number of
schizophrenia use more cannabis than the general timepointsandhadexcellentparticipantretention.Inthat
population. For example, in the recent Australian Study study,theriskofschizophreniformpsychosisatage26was
ofHighImpactPsychoses[16],peoplewithschizophrenia 10.3%inthose who had usedcannabis in theirteens, as
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opposed to 3% in the rest of the cohort (adjusted odds Disclosures
ratio 2.9 [CI 1.2, 7.0]). Relevant to the cause-effect issue The authordeclaresthat he has no disclosures.
discussedabove,itwasthoseindividualswho,atage11,
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