human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 ventrostri 
    Output:
    
agent
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 .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 ventrostri 
    Output:
    