title: Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study Cannabis use disorders in schizophrenia: Effects on cognition and symptoms Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. An Experimental Study of Catechol-O-Methyltransferase Val158Met Moderation of Δ-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition Cannabis use and transition to psychosis in people at ultra-high risk. The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Cannabis use and risk of schizophrenia: a Mendelian randomization study Epidemiological analysis of alcohol and drug use as risk factors for psychotic experiences. What causes psychosis? An umbrella review of risk and protective factors. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability Age‐varying effects of cannabis use frequency and disorder on symptoms of psychosis, depression and anxiety in adolescents and adults
abstract: Background Observational associations between cannabis and schizophrenia are well documented , but ascertaining causation is more challenging . We used Mendelian r and omization ( MR ) , utilizing publicly available data as a method for ascertaining causation from observational data . Method We performed bi-directional two- sample MR using summary -level genome-wide data from the International Cannabis Consortium ( ICC ) and the Psychiatric Genomics Consortium ( PGC2 ) . Single nucleotide polymorphisms ( SNPs ) associated with cannabis initiation ( p < 10−5 ) and schizophrenia ( p < 5 × 10−8 ) were combined using an inverse-variance-weighted fixed-effects approach . We also used height and education genome-wide association study data  , representing negative and positive control analyses . Results There was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [ odds ratio ( OR ) 1.04 per doubling odds of cannabis initiation , 95 % confidence interval ( CI ) 1.01–1.07 , p = 0.019 ] . There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation ( OR 1.10 per doubling of the odds of schizophrenia , 95 % CI 1.05–1.14 , p = 2.64 × 10−5 ) . Findings were as predicted for the negative control ( height : OR 1.00 , 95 % CI 0.99–1.01 , p = 0.90 ) but weaker than predicted for the positive control ( years in education : OR 0.99 , 95 % CI 0.97–1.00 , p = 0.066 ) analyses . Conclusions Our results provide some that cannabis initiation increases the risk of schizophrenia , although the size of the causal estimate is small . We find stronger evidence that schizophrenia risk predicts cannabis initiation , possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation OBJECTIVE Despite the controversy surrounding the possible causal link between cannabis use and the onset of schizophrenia ( SZ ) , data seeking to eluci date the effect of cannabis use disorders ( CUDs ) on the clinical presentation of SZ have produced mixed results . Although several studies have suggested that CUD in patients with SZ may be associated with variation in cognitive function , clinical presentation and course of illness , the effects have been inconsistent . METHODS We retrospectively ascertained a large cohort ( N=455 ) of SZ patients with either no history of a CUD ( CUD- ; N=280 ) or a history of CUD ( CUD+ ; N=175 ) . The groups were initially compared on key demographic variables including sex , race , age , age at onset of SZ , parental socioeconomic status , premorbid IQ , education level and global assessment of functioning . Covarying for any observed differences in demographic variables , we then compared groups on lifetime measures of psychotic symptoms as well as a brief battery of neurocognitive tests . RESULTS Compared to the CUD- group the CUD+ group demonstrated significantly better performance on measures of processing speed ( Trail Making Tests A and B ) , verbal fluency ( animal naming ) and verbal learning and memory ( California Verbal Learning Test ) . Moreover , the CUD+ group had better GAF scores than the CUD group . CONCLUSIONS Collectively , these findings suggest that SZ patients with comorbid CUD may represent a higher functioning subgroup of SZ . Future prospect i ve studies are needed to eluci date the nature of this relationship Cannabidiol is a component of marijuana that does not activate cannabinoid receptors , but moderately inhibits the degradation of the endocannabinoid an and amide . We previously reported that an elevation of an and amide levels in cerebrospinal fluid inversely correlated to psychotic symptoms . Furthermore , enhanced an and amide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition . In our translational approach , we performed a double-blind , r and omized clinical trial of cannabidiol vs amisulpride , a potent antipsychotic , in acute schizophrenia to evaluate the clinical relevance of our initial findings . Either treatment was safe and led to significant clinical improvement , but cannabidiol displayed a markedly superior side-effect profile . Moreover , cannabidiol treatment was accompanied by a significant increase in serum an and amide levels , which was significantly associated with clinical improvement . The results suggest that inhibition of an and amide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia OBJECTIVE Research in both animals and humans indicates that cannabidiol ( CBD ) has antipsychotic properties . The authors assessed the safety and effectiveness of CBD in patients with schizophrenia . METHOD In an exploratory double-blind parallel-group trial , patients with schizophrenia were r and omized in a 1:1 ratio to receive CBD ( 1000 mg/day ; N=43 ) or placebo ( N=45 ) alongside their existing antipsychotic medication . Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale ( PANSS ) , the Brief Assessment of Cognition in Schizophrenia ( BACS ) , the Global Assessment of Functioning scale ( GAF ) , and the improvement and severity scales of the Clinical Global Impressions Scale ( CGI-I and CGI-S ) . RESULTS After 6 weeks of treatment , compared with the placebo group , the CBD group had lower levels of positive psychotic symptoms ( PANSS : treatment difference=-1.4 , 95 % CI=-2.5 , -0.2 ) and were more likely to have been rated as improved ( CGI-I : treatment difference=-0.5 , 95 % CI=-0.8 , -0.1 ) and as not severely unwell ( CGI-S : treatment difference=-0.3 , 95 % CI=-0.5 , 0.0 ) by the treating clinician . Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance ( BACS : treatment difference=1.31 , 95 % CI=-0.10 , 2.72 ) and in overall functioning ( GAF : treatment difference=3.0 , 95 % CI=-0.4 , 6.4 ) . CBD was well tolerated , and rates of adverse events were similar between the CBD and placebo groups . CONCLUSIONS These findings suggest that CBD has beneficial effects  in patients with schizophrenia . As CBD 's effects do not appear to depend on dopamine receptor antagonism , this agent may represent a new class of treatment for the disorder Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase ( COMT Val158Met ) gene moderate the psychosis-inducing effect of cannabis . To replicate and extend this finding , a double-blind , placebo-controlled cross-over design was used in which patients with a psychotic disorder ( n=30 ) , relatives of patients with a psychotic disorder ( n=12 ) , and healthy controls ( n=32 ) were exposed to Δ-9-tetrahydrocannabinol ( Δ-9-THC , the principal component of cannabis ) or placebo , followed by cognitive assessment and assessment of current psychotic experiences . Previous expression of psychometric psychosis liability was also assessed . Models of current psychotic experiences and cognition were examined with multilevel r and om regression analyses to assess ( i ) main effects of genotype and condition , ( ii ) interactions between condition and genotype , and ( iii ) three-way interactions between condition , genotype , and psychometric psychosis liability . Carriers of the Val allele were most sensitive to Δ-9-THC-induced psychotic experiences , but this was conditional on prior evidence of psychometric psychosis liability . Δ-9-THC impacted negatively on cognitive measures . Carriers of the Val allele were also more sensitive to Δ-9-THC-induced memory and attention impairments compared to carriers of the Met allele . Experimental effects of Δ-9-THC on cognition and psychosis are moderated by COMT Val158Met genotype , but the effects may in part be conditional on the additional presence of pre-existing psychosis liability . The association between cannabis and psychosis may represent higher order gene – environment and gene – gene interactions BACKGROUND Cannabis use is associated with an increased risk of developing a psychotic disorder but the temporal relationship between cannabis use and onset of illness is unclear . The objective of this study was to assess prospect ively the influence of cannabis use on transition to psychosis in people at ultra-high risk ( UHR ) for the disorder . METHOD Lifetime and continued cannabis use was assessed in a consecutively ascertained sample of 182 people ( 104 male , 78 female ) at UHR for psychosis . Individuals were then followed clinical ly for 2 years to determine their clinical outcomes . RESULTS Lifetime cannabis use was reported by 134 individuals ( 73.6 % ) . However , most of these individuals had stopped using cannabis before clinical presentation ( n=98 , 73.1 % ) , usually because of adverse effects . Among lifetime users , frequent use , early-onset use and continued use after presentation were all associated with an increase in transition to psychosis . Transition to psychosis was highest among those who started using cannabis before the age of 15 years and went on to use frequently ( frequent early-onset use : 25 % ; infrequent or late-onset use : 5 % ; χ(2)1=10.971 , p=0.001 ) . However , within the whole sample , cannabis users were no more likely to develop psychosis than those who had never used cannabis ( cannabis use : 12.7 % ; no use : 18.8 % ; χ(2)1=1.061 , p=0.303 ) . CONCLUSIONS In people at UHR for psychosis , lifetime cannabis use was common but not related to outcome . Among cannabis users , frequent use , early-onset use and continued use after clinical presentation were associated with transition to psychosis Recent advances in the underst and ing of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis . In a 3-day , double-blind , r and omized , and counterbalanced study , the behavioral , cognitive , and endocrine effects of 0 , 2.5 , and 5 mg intravenous delta-9-tetrahydrocannabinol ( Δ-9-THC ) were characterized in 22 healthy individuals , who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder . Prospect i ve safety data at 1 , 3 , and 6 months post study was also collected . Δ-9-THC ( 1 ) produced schizophrenia-like positive and negative symptoms ; ( 2 ) altered perception ; ( 3 ) increased anxiety ; ( 4 ) produced euphoria ; ( 5 ) disrupted immediate and delayed word recall , sparing recognition recall ; ( 6 ) impaired performance on tests of distractibility , verbal fluency , and working memory ( 7 ) did not impair orientation ; ( 8) increased plasma cortisol . These data indicate that Δ-9-THC produces a broad range of transient symptoms , behaviors , and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses . These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders CONTEXT Cannabis sativa use can impair verbal learning , provoke acute psychosis , and increase the risk of schizophrenia . It is unclear where C. sativa acts in the human brain to modulate verbal learning and to induce psychotic symptoms . OBJECTIVES To investigate the effects of 2 main psychoactive constituents of C. sativa , Delta9-tetrahydrocannabinol ( Delta9-THC ) and cannabidiol , on regional brain function during verbal paired associate learning . DESIGN Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task . Each imaging session was preceded by the ingestion of Delta9-THC ( 10 mg ) , cannabidiol ( 600 mg ) , or placebo in a double-blind , r and omized , placebo-controlled , repeated- measures , within-subject design . SETTING University research center . PARTICIPANTS Fifteen healthy , native English-speaking , right-h and ed men of white race/ethnicity who had used C. sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime . MAIN OUTCOME MEASURES Regional brain activation ( blood oxygen level-dependent response ) , performance in a verbal learning task , and objective and subjective ratings of psychotic symptoms , anxiety , intoxication , and sedation . RESULTS Delta9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety , intoxication , and sedation , whereas no significant effect was noted on these parameters following administration of cannabidiol .  Performance in the verbal learning task was not significantly modulated by either drug . Administration of Delta9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident . Delta9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs , which was directly correlated with concurrently induced psychotic symptoms . In contrast , administration of cannabidiol had no such effect . CONCLUSION The modulation of mediotemporal and ventrostriatal function by Delta9-THC may underlie the effects of C. sativa on verbal learning and psychotic symptoms , respectively Cannabis use is observationally associated with an increased risk of schizophrenia  , but whether the relationship is causal is not known . Using a genetic approach , we took 10 independent genetic variants previously identified to associate with cannabis use in 32 330 individuals to determine the nature of the association between cannabis use and risk of schizophrenia . Genetic variants were employed as instruments to recapitulate a r and omized controlled trial involving two groups (  cannabis users vs nonusers ) to estimate the causal effect of cannabis use on risk of schizophrenia  in 34 241 cases and 45 604 controls from predominantly European descent . Genetically-derived estimates were compared with a meta- analysis of observational studies reporting ever use of cannabis and risk of schizophrenia or related disorders . Based on the genetic approach , use of cannabis was associated with increased risk of schizophrenia ( odds ratio ( OR ) of schizophrenia for users vs nonusers of cannabis : 1.37 ; 95 % confidence interval ( CI ) , 1.09–1.67 ; P-value=0.007 ) . The corresponding estimate from observational analysis was 1.43 ( 95 % CI , 1.19–1.67 ; P-value for heterogeneity = 0.76 ) . The genetic markers did not show evidence of pleiotropic effects and accounting for tobacco exposure did not alter the association ( OR of schizophrenia for users vs nonusers of cannabis , adjusted for ever vs never smoker : 1.41 ; 95 % CI , 1.09–1.83 ) . This adds to the substantial evidence base that has previously identified cannabis use to associate with increased risk of schizophrenia , by suggesting that the relationship is causal . Such robust evidence may inform public health messages about cannabis use , especially regarding its potential mental health consequences Clinical and laboratory studies link alcohol and other drug use to the occurrence of psychotic experiences , but epidemiologic evidence has been lacking . In this study , the quantitative relationships between alcohol or other drug use and psychotic experiences were examined by analysis of prospect i ve data from 4994 adult household residents sample d in a multisite survey of mental disorders in the population , the NIMH Epidemiologic Catchment Area Program . After control for sociodemographic factors and preexisting psychiatric conditions , the risk for onset of self-reported delusions or hallucinations was observed to be greater for daily users of marijuana or cocaine and for users of anxiolytics or sympathomimetics compared with nonusers . After control for daily cocaine use and alcohol disorder , the risk of onset of psychotic experiences for daily users of marijuana was double that for nonusers .  Alcohol disorder in men  was associated with eightfold risk and in women with threefold risk . Baseline depressive episodes , manic episodes , agoraphobia , and obsessive-compulsive disorder also were associated with increased risk of onset of psychotic experiences Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested . This umbrella review aim ed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases . The Web of Knowledge data base was search ed to identify systematic review s and meta-analyses of observational studies which examined associations between socio-demographic , parental , perinatal , later factors or antecedents and psychotic disorders , and which included a comparison group of healthy controls , published from 1965 to January 31 , 2017 . The literature search and data extraction followed PRISMA and MOOSE guidelines . The association between each factor and ICD or DSM diagnoses of non-organic psychotic disorders was grade d into convincing , highly suggestive , suggestive , weak , or non-significant according to a st and ardized classification based on : number of psychotic cases , r and om-effects p value , largest study 95 % confidence interval , heterogeneity between studies , 95 % prediction interval , small study effect , and excess significance bias . In order to assess evidence for temporality of association , we also conducted sensitivity analyses restricted to data from prospect i ve studies . Fifty-five meta-analyses or systematic review s were included in the umbrella review , corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders . Only the ultra-high-risk state for psychosis ( odds ratio , OR=9.32 , 95 % CI : 4.91 - 17.72 ) and Black-Caribbean ethnicity in Engl and ( OR=4.87 , 95 % CI : 3.96 - 6.00 ) showed convincing evidence of association . Six factors were highly suggestive ( ethnic minority in low  ethnic density area , second generation  immigrants , trait anhedonia , premorbid IQ , minor physical anomalies , and olfactory identification ability ) , and nine were suggestive ( urbanicity , ethnic minority in high ethnic density area , first generation immigrants , North-African immigrants in Europe , winter/spring season of birth in Northern hemisphere , childhood social withdrawal , childhood trauma , Toxoplasma gondii IgG , and non-right h and edness ) . When only prospect i ve studies were considered , the evidence was convincing for ultra-high-risk state and suggestive for urbanicity only . In summary , this umbrella review found several factors to be associated with  psychotic disorders  with different levels of evidence . These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis Papers pp 1195 , 1199 The strongest evidence that cannabis use may be a risk factor for later psychosis  comes from a Swedish cohort study which found that heavy cannabis use at age 18 increased the risk of later schizophrenia sixfold . 1 2 This study could not establish whether adolescent cannabis use was a consequence of pre-existing psychotic symptoms rather than a cause . We present the first prospect i ve longitudinal study of adolescent cannabis use as a risk factor for  adult schizophreniform disorder  , taking into account childhood psychotic symptoms3 antedating cannabis use . View this table : Association between  cannabis use in adolescence and schizophrenia and depressive symptoms and disorders at age 26 ( n=759 ) , controlling for childhood psychotic symptoms and use of other drugs in adolescence The Dunedin multidisciplinary health and development study ( a study of a general population birth cohort of 1037 individuals born in Dunedin , New Zeal and , in 1972 - 3)4 has a 96 % follow up rate at age 26 . It obtained information on psychotic symptoms at age 11 and drug use at ages 15 and 18 from self reports and assessed Cannabis use is a heritable trait that has been associated with adverse mental health outcomes . In the largest genome-wide association study ( GWAS ) for lifetime cannabis use to date ( N = 184,765 ) , we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions . All measured genetic variants combined explained 11 % of the variance . Gene-based tests revealed 35 significant genes in 16 regions , and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers . The strongest finding across the different analyses was CADM2 , which has been associated with substance use and risk-taking . Significant genetic correlations were found with 14 of 25 tested substance use and mental health – related traits , including smoking , alcohol use , schizophrenia and risk-taking . Mendelian r and omization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use . Overall , our study provides new insights into the etiology of cannabis use and its relation with mental health . A GWAS of lifetime cannabis use reveals new risk loci , shows that cannabis use has genetic overlap with smoking and alcohol use , and indicates that the likelihood of initiating cannabis use is causally influenced by schizophrenia Abstract Aims We tested the age‐varying associations of  cannabis use ( CU ) frequency and disorder ( CUD ) with  psychotic , depressive and anxiety symptoms in adolescent and adult sample s. Moderating effects of early onset ( ≤ 15 years ) and sex were tested . Design Time‐varying effect models were used to assess the significance of concurrent associations between CU and CUD  and symptoms of psychosis , depression and anxiety at each age . Setting and Participants Adolescent data ( V‐HYS ; n = 662 ) were collected from a r and omly recruited sample of adolescents in Victoria , British Columbia , Canada during a 10‐year period ( 2003–13 ) . Adult cross‐sectional data ( NESARC‐III ; n = 36 309 ) were collected from a representative sample from the United States ( 2012–13 ) .  Measurements Mental health symptoms were assessed using self‐report measures of diagnostic symptoms . CU was based on frequency of past‐year use . Past‐year CUD was based on DSM‐5 criteria . Findings For youth in the V‐HYS , CU was associated with psychotic symptoms following age 22 [ b = 0.13 , 95 % confidence interval ( CI ) = 0.002 , 0.25 ] , with depressive symptoms from ages 16–19 and following age 25 ( b = 0.17 , 95 % CI = 0.003 , 0.34 ) , but not with anxiety symptoms . CUD was associated with psychotic symptoms following age 23 ( b = 0.51 , 95 % CI = 0.01 , 1.01 ) , depressive symptoms at ages 19–20 and following age 25 ( b = 0.71 , 95 % CI = 0.001 , 1.42 ) and anxiety symptoms ages 26–27 only . For adults in the NESARC‐III , CU was associated with mental health symptoms at most ages [ e.g. psychotic symptoms ; age 18 ( b = 0.22 , 95 % CI = 0.10 , 0.33 ) to age 65 ( b = 0.36 , 95 % CI = 0.16 , 0.56 ) ] . CUD was associated with all mental health symptoms across most ages [ e.g. depressive symptoms ; age 18 ( b = 0.96 , 95 % CI = 0.19 , 1.73 ) to age 61 ( b = 1.11 , 95 % CI = 0.01 , 2.21 ) ] . Interactions with sex show stronger associations for females than males in young adulthood [ e.g. V‐HYS  : CUD × sex interaction on psychotic symptoms significant after age 26 ( b = 1.12 , 95 % CI = 0.02 , 2.21 ) ] . Findings were not moderated by early‐onset CU . Conclusions Significant associations between cannabis use ( CU ) frequency and disorder ( CUD ) and psychotic and depressive symptoms in late adolescence and young adulthood extend across adulthood , and include anxiety
target: The results show that , in particular , frequent cannabis use , especially daily use , and the consumption of high-potency cannabis are associated with a higher risk of developing psychosis .
  Moreover , several genotypes moderate the impact of cannabis use on psychosis risk , particularly those involved in the dopamine function , such as AKT1 .
  Finally , cannabis use is associated with an earlier psychosis onset and increased risk of transition in individuals at a clinical high risk of psychosis .
  These findings indicate that changing cannabis use behavior could be a harm reduction strategy employed to lower the risk of developing psychosis .
background: Increasing evidence indicates a relationship between  cannabis use and psychosis risk .
  Specific factors , such as determinants of cannabis use or the genetic profile of cannabis users , appear to moderate this association .
  The present systematic review presents a detailed and up-to- date literature overview on factors that influence the relationship between cannabis use and psychosis risk .