Evidence table for systematic reviews

Transcription

1 Evidence table for systematic reviews Topic: Cannabis and Cognition Reviewer: CMF, MS Abbreviations: : reduced; : increased; : not altered; abstin: abstinence; adol: adolescent; CB: cannabis; CI: confidence interval; CSF: cerebrospinal fluid; ctl: control; GM: grey matter; HCp: hippocampus; n.r. not reported; OR: odd s ratio; p: value of significance; PFC: prefrontal cortex; r: correlation coefficient / effect size; SR systematic review; WM: white matter; y: years Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Batalla et al. SR 2013 Impact of chronic CBuse on brain structure and functioning in adulthood + adolescence EMBASE, Medline, Pubmed, LILACS All languages (until 08/2012) Yielded 142 papers > 43 studies included (14 structural, 29 functional imaging) > cross-sectional case control studies > study quality not accessed Chronic CBusers (several times/week, min. 2 y), naïve/healthy ctl. (< 15x CB/ lifetime) 563 adult CB users; 136 adol. CBusers Adult: 77% male (433) adol: 74% male (101) Adult: mean age Adol: mean age > Structural changes in CBusers: 4/11 studies no differences, global brain volume not altered, higher CSF; 3/7 studies reduced bilateral HCp volume (most consistent finding), volumetric changes in amygdala, cerebellum, frontal cortex, white matter (+integrity), correlation: HCp volume + CBexposure (3)/ CBdependence (1)/ severe psychotic symptoms (1) > resting state in CBusers: 4/8nstudies no difference, activity global(1), pfc (3), cerebellum (1), altered in striatum; 20% CB1receptor density in cortex/ limbic regions (neg. correlated with duration of CBuse) reversible after 1 month of abstinence > attention: 2/3 studies performance, 1/3 ; altered activation of pfc, parietal cortex, functional connectivity frontal cortex regions and occipitoparietal cortex after heavy+longterm CBuse > memory: 2/3 studies performance, 1/3 ; activity pfc (2), HCp (1); activity cerebellum, parietal cortex > inhibition/ impulsivity: 3/3 studies performance; activity anterior cingulated cortex Spanish grants (Plan Nacional sobre Drogas, DIUE of Generalitat de Catalunya, INCT-TM Brazil), Cinician Scientist award NIHR (UK), CNPq productiviy award (Brazil) >methodological differences between studies complicate interpretation and generalization of results > sociodemographic characteristics differ between studies (age of onset, gender bias, lifetime use, abstinence..) > THC content in cannabis complicates comparability of actual and older studies > modest sample size of some studies > pre-existing morphological or functional alterations cannot be ruled out > confounding + interaction effect of nicotine, alcohol or other drugs Methodological rating SIGN 4 High quality ++ 1

2 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] (acc) (3) + further distributed activity changes > decision making: 3/6 studies performance, 3/6 ; altered activity in reward-related structures (pfc, acc, striatum), single alterations could be correlated to extent of CBuse > motor performance: 1 study; speed+efficiency especially in CBusers; altered activity pattern > affective processing: 1 study; altered activity in acc and amygdala, alterations could be correlated to extent of CBuse > adolescence > structural changes in CBusers (3).: gender differences: vermis, pfc, amygdala; pfc, vermis, correlation: pfc + executive function > CBusers at risk > memory: 4/4 studies performance, activation in multiple regions might indicate higher neurocognitive effort for CBusers. > inhibition: 1 study, performance, activation in multiple regions Broyd et al Alteration of taskbased cognitive measures by acute, chronic and abstinent CB use; in adult and adolescent users; association to CB use metrics SR Pubmed + Scopus ( /20015) Yielded > 3220 papers > 105 included studies; memory: acute (33), chronic (44), abstin. (20) attention: acute (17), chronic (21), abstin. (10) psychomotor: acute (18), chronic (10), abstin. (6) executive function: acute (26), chronic (39), abstin. (14) decision making: acute (7), chronic (17), abstin. (3) > mostly cross-sectional case control studies, 2 longitudinal twin studies > study quality not accessed Naïve, occasional, chronic and abstinent Cbusers; adult and adolescent ( 18 years) users Total: 3437 controls, 4815 CBusers Predominan tly males in ca. 75% studies Mean age: y; 3 studies with older subjects y > memory: most consistently affected cognitive domain by CB; especially verbal learning/ memory impaired by acute and chronic CB exposure (also in occasional CBusers, adol. and young adults); performance associated to CBuse, age of onset; inconsistent findings for recovery after abstinence; working memory: inconsistent impairment by acute THC (18), impairment in chronic adolescent and young adult CBusers (4), recent or heavy users (1) but not older CBusers (1); impairments mostly resolve with longer abstinence (5) > attention: acute CB worsens focused, devided + sustained Australian Research Council Future Fellowship Grant, National Health and Medical Research Council Project Grant, Senior Research Fellowship Grant > complexity of data, heterogeneity of test paradigms > extent of CB exposure differs widely in samples > potential sex differences insufficiently addressed (75% studies male bias, 12% studies sex differences tested) > acute CB studies: different routes of administration, direct comparison of CBusers and controls often missing (4/38) >confounding effects of premorbid functionality/iq and > effect of CBtolerance in regular/heavy users unclear > duration of acute CBrelated cognitive impairment not investigated > progress of restoration of brain function and structure from current use/ cessation/ prolonged abstinence (prospective Methodological rating SIGN 4 High quality ++ 2

3 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] attention, often dose dependently; potential tolerance effect (less impairment) in daily users; impaired attention in chronic adol. and adult CBusers; deficits but also unaffected attention reported after CBabstinence; earlier age of onset correlated to poorer performance (2); attentional bias for CBrelated stimuli enhanced in chronic CBusers (7), not studied for abstinence psychomotor function: impaired after acute, chronic and abstinence ( 1y) from CB ; acute CB effects in occasional and heavy users (18); mixed findings in chronic CBusers (4, 2, 1 ); sign. Impairment after 25-35d abstinence (4), trend for lower performance after 1y abstinence (1) > executive function: subdomains differentially affected by acute/ chronic CB, sparse data on recovery after abstinence; (=planning, reasoning, interference control, problem solving); for acute CB 6 /3 across occational, moderate and heavy users; for chronic CB 11 /8, tendency for impairment in older samples/ after brain maturation; after CB abstinence: 3 (young samples) 2 (35-51y) abstin. period: 1+12 months; (inhibition) consistently reduced after acute CB in occasional and heavy CBusers, mixed findings for chronic CB; (verbal fluency) no acute CB impairment (3), mixed findings for chronic and abstin. CBusers: in older users performance more related to CBexposure, in adol. Users performance more related to intellect and study paradigm > decision making/reward-related behavior: risky decision making+ reward sensitivity inconsistently increased after acute CB, unclear effects for chronic CB and tobacco/alcohol/drug use often not assessed, accounted, and controlled which specificity of CBrelated effects studies needed) Methodological rating SIGN 3

4 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] abstinence ( decision making, risk taking and reported) > sex differences seldom studied, very few differences; acute CB stronger impairment in psychomotor function and working memory in (2/3); chronic CB: subtle (5/12) or no gender differences in cognitive impairment, in performance stronger related to CBexposure Ganzer et al Lasting CBeffects on neurocognitive, functional and structural changes after >14 days of CB abstinence Magnitude of effect size of changes Is early onset of CBuse enhancing these effects? SR/MA EMBASE, Ovid MEDLINER, PsycInfo, PSYNDEXplu s, manual search ( ) Yielded 1038 papers > 38 studies included; 31 neurocognitive/ behavioral studies, 27 imaging studies (17 functional, 10 structural) > cross-sectional case control studies > evidence rating (SIGN) for studies MA: Effect size: unweight correlation r on Fisher z- transformed values (study parameters were transformed in correlation r; multiple effects/study > mean r, no effect/study r=.00) Heterogeneity: Q statistic/ I² neurocognitive studies: N= 1428 imaging studies N=732 Not mentioned Not mentione d > Neurocognitive behavior globally impaired after >14d CBabstinence in chronic CBusers r(mean)=.305 (medium, sign. Effect) > attention: 5/10 studies impaired attention in CBusers, medium effect r=.273; 4/5 studies with early onset find impairments > executive function: 10/16 impaired function in CBusers, medium effect r=.294, mixed findings for inhibition, impulsivity, decision making but trend for impairment; 4/7 studies with early onset find impairments > motor function: 4/5 impaired function in CBusers, medium-high effect r=.478, unclear whether speed or accuracy is impaired; 1 study with early onset users n.s. > learning & memory: 7/16 impaired in CBusers, medium effect r=.229, especially disturbances in encoding, storage and retrieval; 7/12 studies with early onset find impairments > Visual-spatial: 2/4 studies alterations in CBusers (both directions); 3/3 studies with early onset find inconsistent results > functional imaging: 16/17 studies alterations in chronic CBusers, medium-high effect: r=.479, clear evidence for different activation pattern; 10/16 studies with early onset find alterations > structural: 9/10 studies changes in chronic CBusers, small effect r=.287, alterations in cortical regions, OFC, HCp and WMvolume (larger); 6/6 studies No funding >potential publication bias (17/38 studies published from the same group) > acknowledged > heterogenous CBuse history of samples >heterogeneous criteria definitions complicate study comparisons > association of functional/stru ctural changes with neurocognitive performance Methodological rating SIGN 4 High quality ++ 4

5 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] with early onset find alterations > global neurobiological alterations after >14d CBabstinence in chronic CBusers r(mean)=.446 (medium-high, sign. Effect) > early onset (<18y) CBusers less impaired in neurocognitive performance (compared to late onset users), but sign. more structural/ functional alterations > CBuse intensity might be stronger moderator of neurocognitive effects than age of onset > threshold for CB neurotoxic effects > duration and amount of CBexposure relevant > longitudinal study (Pardini) found no lasting cognitive impairments after prolonged abstinence in low-moderate CBusers > prospective longitudinal studies commonly observe cognitive and structural abnormalities after CBuse above/ beyond premorbid status Methodological rating SIGN James et al Effects of CB on brain structures and neuropsychometric functions during adolescence SR EMBASE, Medline, PubMed, PsycLIT, LILACS, book chapters all languages (until 12/2012) Yielded 141 studies > 24 included studies: in schizophrenia (2), structural MRI/ DTI (16), fmri (6) > cross-sectional case control studies > study quality not accessed 418 adol. CBusers, 475 adol. controls Mostly not reported, predominan tly M; 70-78% Mean age: y >normal developmental brain changes during adol.: GM region-specific, WM (steeper in males), sex-specific timing > no profound CBeffects on cognitive behavior and brain structure > OFC (12y) predicted initiation of CB (16y) (prospective study, 121 subjects) >cortical thickness in frontocortical regions, in temporal/ parietal/ paracentral regions in heavy CBusers (17.8y) > FA in rhcp in 11 CBusers (19.4y, 8d abstin) > HCp vol. (correlated with amount of CB used) + FA in fronto-temporal connections after >6 month abstin. from heavy CBuse > widespread FA also in frontal+ temporal connections (correlated with attention,working memory, speed) and FA in fronto-parietal connection none > limited research studies complicate general conclusions > heterogeneity of studies (CBuse history, abstinence period prior scanning, other drug use) > more potent CB (higher THC content) in last years complicates comparison of newer/older study results (commonly negative findings in older studies) >differing effects of cannabinoids (eg THC, cannabidiol) not tested in adolescence > need for powered longitudinal studies in adolescents for CBeffects on brain structure + function 4 High quality ++ 5

6 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] (correlated with verbal memory) in CB+Alc users > duration of abstin. matters: after 5d: resting state activity in frontal+temporal regions in CBusers, dissolved after 28d abstin. > cognitive effort but performance in inhibition task in CBusers; inhibition by dlpfc correlated with y of CBuse > Cerebellum: volume correlated with executive function; cerebellum volume (GM, WM) > gender differences: (2) pfc, amygdala volume; pfc, amygdala; correlation pfc with worse execut. functioning;, amygdala volume with internalizing symptoms (same lit. as in Batalla et al.) > cognitive performance: low cogn. demand, high cogn. demand in CBusers; recruitment of brain areas in CBusers correlated to better performance (compensation?); chronic CB related to less efficient general executive function/ attention; potential recovery with longer abstinence Martin-Santos et al Acute and chronic effects of CBuse on brain structure and functioning, focusing on cognitive changes SR EMBASE, Medline, Pubmed, PsycLIT, LILACS all languages (until 01/2009) Yielded 66 studies > 41 studies included; 8 structural, 33 functional > cross-sectional case control studies > study quality not accessed CBusers (n= 655), naïve (n= 402) Not mentioned Mean age: y > Definition CBuse: chronic (several times/week, > 2y), recreational (<4x/month), naïve (< 15x/ lifetime) > acute CB/ THC/ CBD: CB: global CBF and regional activity, CBF pos. corr. with plasma THC and signs of intoxication; THC: regional activity in ACC, insula, PFC, OFC, cerebellum, pos. corr. Of subjective intoxication with anterior/ posterior ratio of brain activation; CBD: temporal regions (amygdala, HCp), parahcp > different brain activation pattern of THC/ CBD > acute CB on cognition: attention: activation in frontal cortex, ACC, insula, cerebellum in regular and heavy CBusers psychomotor: activation in OFC, ACC, cerebellum, Psychiatric Research Grant (UK), Plan Nacional Sobre Drogas (Spain), CNPq Productivity Fellowship (Brazil) > resting state studies did not control spontaneous neural activity/ associated BOLD changes > functional studies focused on different brain functions; difficult comparability > few studies on each sub-domain of cognition Methodological rating SIGN 4 High quality ++ 6

7 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] activation in temporal/ occipital regions, dlpfc in recreational+ heavy CBusers; frontal effects stronger in recreational CBusers; impaired self-pacing after CB inhibition: activation in frontal cortex, ACC, activation in temporal region, HCp, posterior ACC in naïve controls emotional processing: activation in frontal/ parietal cortex in naïve, activation in amygdala in naive + recreational CBusers during watching angry/ fearful faces > Non-acute CB on cognition: (chronic CBuse) Structural: no volumetric differences (3/5), HCp volume (2/5) and amygdala (1/5); no structural changes in WM (2/3), WM diffusity in CC; likely after heavy/longterm CBuse Resting state: global CBF (2/7) after approx. 1 week abstinence (reversible after prolonged abstinence), altered PFC (1x, 2x ) and ACC activity(2x, 1x ) cognition: most consistently PFC activity (7/10), altered activity in several spread regions after 25h 25days abstinence; recruitment of focal, task-typical regions but activity in additional/ widespread regions indicate compensatory mechanisms/ higher cognitive effort; mixed behavioural findings Quickfall & Crockford, 2006 Structural and functional alterations due to CB and their correlation with neurobiologicql and neuropsychological findings SR Medline english (until 02/2005) Yielded 112 papers > 31 studies included; 10 structural, 21 functional (12 abstinence, 12 acute intox) > cross-sectional case control studies > study quality not accessed Chronic CBusers: n=638, ctl: 282 Not mentioned Not mentione d > no structural changes after chronic CBuse (only 3/10 studies methodologically rigorous; 2/3 no difference, 1/3 GM and WM volume in parahippocampus; 1/10 studies sign. Correlation age of onset and total brain volume [lack of ctl. group, pos. replications]) > global cortical activity: after acute CB/THC administration (7/7 studies), during abstinence (1x unchanged, 2x, 1x in male, early-onset CBusers) > frontal lobe activity: after acute CBexposure (5/5 studies) in Not mentioned > quantity of CBuse + duration of abstinence most critical moderators; not consistently reported > duration of abstinence ranged hours - years > heterogeneous study characteristics (definition of CBuse and dependence, CB exposure of controls, inclusion/ exclusion criteria, demographic features) lower generalization > increasing THCcontent in CB complicates > need for further studies with standardized diagnostic criteria, longer abstinence periods of CB, pairing of neurocognitive testing with functional imaging > persistent or transient CBeffects Methodological rating SIGN 4 Acceptable + 7

8 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Schoeler et al Non-acute effects of CBuse on memory function in nonpsychotic (and psychotic) users > domain-specific memory effects of CB? > CBuse characteristics modulate memory effects of CB? MA guidelines (Higgins & Green, 2008; Beller et al. 2013) MEDLINE english language (until 06/2014) Yielded 1731 papers > 88 studies included > cross-sectional case control studies > study quality not accessed MA > effect size: Cohen s d or standardized mean difference >Random-effects model > heterogeneity test: Q statistic/ I² > sensitivity analysis in sub-samples applying the same test paradigm > meta-regression for duration, frequency, abstinence from CB, age of onset, cigarette and alcohol use, year of publication N= 7697 healthy subjects Not mentioned Not mentione d occasional + chronic CBusers, correlates with subjective intox., during abstinence (5x, 1x, 1x unchanged) under resting and cognitive testing conditions > temporal lobes activity: limited and conflicting results (5) > anterior cingulate activity: after acute CB/THC administration (4/4 studies), during abstinence (2/2) under cognitive testing > HCp activity: mixed results, unaltered or (2/12) after acute+high doses of THC in heavy CBusers, during CBabstinence impaired memory and taskrelated activation of HCp > cerebellum activity: after acute CB/THC administration (5/5 studies), during abstinence (2/2, earlier SPECT studies not sensitive for subcortical activity > no findings) > cannabis use associated with significantly (p0.05) impaired global (Cohen s d = 0.27) and prospective memory (d = 0.61), verbal immediate (d = 0.40) and delayed (d = 0.36) recall as well as visual recognition (d = 0.41) in healthy individuals > global memory effect survived correction for publication bias (d= 0.18, p< 0.001); significant heterogeneity between subdimensions of memory > sensitivity analysis: stronger effects for immediate recall and verbal learning (both d = 0.52) > CBusers display level of deression / functioning than naïve controls, correlated with global memory > moderators of memory: age (neg. corr.) CBabstinence (pos. corr.) CBuse intensity (neg. corr.) CBduration (trend, neg. corr.) Age of onset (no corr.) Alcohol/ nicotine (no corr.) Year of publication (sign. Effect on effect size; published <2000 small effect size (d= 0.12, sign.), NIHR Clinical Scientist Award, UK; UK Medical Research Council NIHR Mental Health Biomedical Research Centre at South London, Maudsley NHS Foundation Trust, King s College London comparability of old + new studies > withdrawl symptoms + residual effects may affect outcomes in abstinence measurements (hoursdays) > old studies ( ) > very low quality criteria for study inclusion > no causality for CBeffects > heterogeneous cognitive paradigms for same memory dimension > different assessments for functioning, depression and IQ limits generalizability > CBuse criteria very heterogeneous, assessment by self-rating less reliable > potential interaction of different moderator variables on memory > generalization limited to Europe, North America and Australia > lack of longitudinal high-quality studies to assess effects of regular CBuse on memory Methodological rating SIGN 4 High quality ++ 8

9 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] >2000 moderate effect size (d= 0.31, sign.) Methodological rating SIGN Schreiner & Dunn MA for short and lasting (>25days) residual effects of CB on cognitive performance MA PsycInfo, PsycARTICLE S, Pubmed, Medline (from /12) Yielded 800 papers > 33 studies included for MA1 (abstinence < 25d); 13 studies for MA2 (abstinence > 25d) > cross-sectional case control studies, 1 longitudinal twin study > study quality not accessed MA > Hedge s g for effect size > outcomes: global neuocognitive performance, 8 subcategories of cognition (applying guidelines for categorizing outcomes by Grant et al. > heterogeneity: Q statistic/ I² > random-effect model > publication bias controlled with fail-safe procedure > meta-regression for moderator variables MA1: N= 1010 CBusers, 839 controls MA2: N= 388 CBusers, 387 controls Not mentioned Adult and adolescen t samples, age range 17-47y > 2 types of residual effects: active THC metabolites that affect brain, effects persisting after wash-out of THC and its active metabolites > cognitive performance measures: global, abstraction/executive, attention, forgetting/retrieval, learning, motor, perceptual-motor, simple reaction time, verbal/language > residual effects (< 25days CBabstinence): global cognitive performance slightly but significantly lower in CBusers (Hedge s g:= -0.29); significant heterogeneity of effect sizes between single studies (except executive, motor, perceptualmotor) and cognitive subdomains; perceptual-motor, simple reaction time, 6/8 sub-domains sign., fail-safe N for global effect: 256 > lasting effects (> 25days CBabstinence): global cognitive performance not significantly impaired in CBusers (Hedge s g ), all sub-domains n.s., heterogeneity n.s. > neither age nor duration of CBuse sign. moderated short/ lasting residual effects > persistent cogn. effects after acute CBintoxication, but not anymore after 1 month abstinence > replication of earlier MA results of cognitive performance and no moderating effect of CBuse duration > 2 longitudinal studies found cognitive performance in current, but not abstinent (< 3 month) CBusers, twin study found cognitive performance in abstinent (> 1y) and CBnaive twins > CBwithdrawl symptoms peak after 2-6days of cessation & last 4-14 days; timepoints of measurement commonly 4h 10days abstinence; withdrawl as confounder (just in 4/33 studies accounted) > no lasting CBeffects might be limited by: small sample size (13 studies), large variation of age, frequency and duration of CBuse, 6/13 studies with adolescent samples exclusively, 5/13 studies did not report for CBduration > frequency/amount of CBuse not assessable > unclear whether effect sizes reflect residual CBeffects, CBwithdrawl effects or both (assessment necessary) > moderating effect of frequency/ amount of CBuse > premorbid cognitive performance level (longitudinal studies necessary) > more studies on long-term abstinence > monitored abstinence with drug testing would be more reliable than just selfreproted abstinence 4 High quality ++ 9

10 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence Methodological rating SIGN [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Solowij & Battisti, SR Web of N= 797 CBuser, Not reported 4 Acceptable Science N= 618 controls, Wrege et al Long-term effects of CB on memory; extent of memory dysfunction in chronic CBusers in untoxicated state and association with specific CBuse parameters Effects of CB on impulsive behaviour and functional/ structural brain correlates SR (01/ /2007) Yielded 250 papers Pubmed English, German or Spanish > 24 studies included; 5 working memory, 12 memory, 7 CB and codrug studies; > mostly cross-sectional case control studies, 1 longitudinal twin study > study quality not accessed > 13 studies included; 3 acute effects, 11 nonacute effects (6 functional, 5 structural) > cross-sectional case > acute CBeffects: N= 36 (CBusers)/ 15 (naïve) Predominan tly males; proportion not reported Not mentioned Mean age y Not mentione d > working memory: 5 studies, 2/5 performance in moderate and heavy long-term CBusers in simple task, 3/5 spatial working memory / recognition in adult heavy-longterm and adolescent CBusers; in adolescence CBuse inversely correlated with performance (even after 10 month abstinence)) > verbal memory: most consistently affected cognitive function after acute/ chronic CB, long-term heavy CBuse learning, immediate/ delayed recall, recognition [inconsistently], deficits related to CBuse frequency, duration and lifetime exposure, more persistent effects in CBusers with early age of onset, lower IQ and higher CBuse intensity > adolescent CBusers more vulnerable for impaired learning, memory, attention, executive function after longer abstinence (23d +) > persistency of deficits: inconsistent, lack of data, selective impairment in delayed recall and general IQ after 20y CBabstinence (non-regular use) > prenatal CBexposure: inconsistent slight impairment in memory (at ages 4-22y), processing speed, altered neural activity (mainly PFC) > similar impairments after acute and chronic CBuse > memory deficits with CBuse + task complexity > latency + processing speed indicate neural inefficiency > widespread neural activation but focal activation in taskrelevant brain regions > stronger impairments in adol. and older CBusers > U-shaped relation? > acute CB/THC: 1/3 motor control accuracy (more virtual wall hits) and accelerated selfpaced behaviour (1/3) in CBusers; ACC+ frontal lobe activity (2/3) > multiple measures of CBuse between studies + inconsistent documentation > highly variable abstinence periods (3h 20y) > Bias of stronger CB effects on impulsive behaviour in mere behavioural studies compared to > long-term studies for shorter and longer-lasting effects after CBabstinence > persistency of structural alterations after prolonged CBabstinence 4 High quality ++ 10

11 Reference Research Parameters Population Outcomes Funding Additional comments Bibliographic reference Research question Theoretical approach Data collection Study type and quality Population and sample collection Gender Age Key themes Source of funding Limitations Evidence gap OCEBM level of evidence [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] language control studies > non-acute : N= > study quality not 157 (CBuseres)/ accessed 16 (naïve) ( /2012) Yielded 774 papers during no-go and pacing task (healthy+chronic CBusers); frontal (1/3), occipital lobe (1/3), cerebellar (1/3) activity in CBusers > non-acute CB/THC: inhibitory task performance, tendency towards faster reaction time, more risky decisions and pos. correlation of age of onset and inhibitor control (2/11) in CBusers; higher scores for selfrated impulsivity in CBusers; taskrelated activity middle cingulate gyrus (3) and unspecific/widespread regions(4), ACC (3) and lateral PFC (2) in CBusers; frontal activity correlated with earlier age of onset (1) and more heavy CB use (3); no structural differences (3/5) or FA in frontal lobe in heavy CBusers (1) or OFC volume in occasional CBusers (1); both reductions correlated with earlier age of onset; different metabolism and more WM diffusity (2/5) in heavy CBusers > threshold effect of CB > alterations preferably in heavy + regular users (with adolescent onset more structural changes) > THC and CBD contrary effects; THC impairs frontal brain areas assoc. with response inhibition > functional data indicate taskand region-specific activation in PFC, OFC and ACC (acute and nonacute) with diffuse, bilateral activation pattern > growing evidence for morphological changes in CB1Rrich brain regions (most consistently HCp, Cerebellum) and structural disintegration after prolonged CBexposure neuroimaging studies > different definition of CB exposure in studies limits comparability; only few studies provide absolute numbers (continuous variable) > different CBuser types > small sample sizes > lack of control for couse of substances > no longitudinal study to disentangle preceding impulsivity from CBrelated impairments on inhibitory control Methodological rating SIGN 11

12 Evidence table for cohort studies Topic: Cannabis + cognition, long-term effects on IQ Reviewer: CMF, MS Abbreviations: CB: cannabis; IQ: intelligence quotient; j/wk: joints per week; sign: significant; y: years Reference Study Characteristics Outcomes Funding Additional comments Bibliographic reference Study type number of patients (males) Patient characteristics Prognostic factors (age, gender, amount of drug exposure) Outcome measures Results Source of funding Additional comments [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] OCEBM level of evidence Length of followup Methodological rating SIGN Fried et al 2005 Jackson et al Prospective cohort study Longitudinal twin studies 113 (63) > Ottawa Prenatal Study (1978); no psychotropic medication, further drug use than alcohol/ nicotine > CBuse: current heavy ( 5 j/wk n=19), current moderate (< 5 j/wk n=19), former regular (< 2 j/last 2 month n=16), naïve (n=59) > more positive DSM IV criteria in CBusers (few) RFAB 789 (379), MTFS 1527 (748) > 2 different twin studies: RFAB (2001) from South California with diverse SES/ ethnicity and MTFS (1990/1996) from Minnesota with 93% caucasian > CBuse: naïve (314; 1455); CBuser (475; 822) with 49/37% > 30times CB and ca. 21% daily CBusers IQ at 9-12y (pre-cb) 8-9 y IQ at 17-21y (general IQ, processing speed, memory, vocabulary, attention, abstraction) > IQ at 9-10y (vocabulary, similarities, block design, reasoning from WASI; RFAB) or 11-12y (vocabulary, information, block design, picture arrangement from WISC-R; MTFS) > cumulative lifetime CBuse 6-10y IQ at 19-20y (WASI; RFAB) or 17-19y (WAIS-R; MTFS) > lower IQ and memory in current heavy CBusers, but not current moderate or former CBusers compared to naïve > after controlling for pre-cb performance: sign. lower IQ, immediate/delayed memory and processing speed in current heavy users > controlling for pre-cb performance changed relationship of CB effects on processing speed, vocabulary and category test > former CBusers not different from naïve controls, also former use intensity had no effect > transient CB deficits > visual processing speed most vulnerable cognitive domain to CBeffects > controlling for SES, age, sex, nicotin/ alcohol use (no influence on performance) and DSM IV scores > similar CBuser groups between both studies > sign. IQ decline in CBusers mean 4 (RFAB) or 3.4 points (MTFS) and sign. lower vocabulary scores; lower information score did not survive control for other substances > no effect of CBuse amount/ frequency, twin IQ, or dose-response effects > binge-alcohol drinking abolished CB-related deficits in vocabulary scores (MTFS) > deficits rather correlated to general drug exposure > low IQ may be risk factor for CBuse Not reported National Institute of Mental Health 2 Acceptable + 3 Acceptable +

13 Reference Study Characteristics Outcomes Funding Additional comments Bibliographic reference Study type number of patients (males) Patient characteristics Prognostic factors (age, gender, amount of drug exposure) Outcome measures Results Source of funding Additional comments [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] OCEBM level of evidence Length of followup Methodological rating SIGN Meier et al Mokrysz et al Prospective birth cohort study Prospective cohort study 1037 (539) 2235 (1041) > gender: 47-55% male CBusers > 60% (RFAB) vs. 36% (MTFS) previous CBuse > baseline IQ difference with lower information, block design and vocabulary scores in later CBusers (MTFS), no differences in RFAB > Dunedin study (1972/73); primarily Caucasian, representative SES > CBuse/ dependence: naïve (n=242), experienced/never dependend (n=479), 1 diagnosis (n=80), 2 diagnoses (n=35) 3+ diagnoses (n=38) > gender: experienced: 50/50%, 3+ diagnoses: 80% male > Avon Longitudinal Study (UK, ) > CBuse: naïve (n=1709), <5 (n=248), 5-19 (n=133), (n=71), 50 (n=74) > gender: equal distribution, 60% male in strongest CBuse-group IQ (mean from 7,9,11 and 13y) (pre-cb) CBuse intensity (dependence and regular use at 5 assessments [18, 21, 26, 32, 38y]) Functional problems in daily life IQ at 8y (WISC-III) Cumulative lifetime CBuse (times) 25y 7y Intra-individual comparison of IQ change from 13y to 38y (executive, memory, processing speed, reasoning, verbal comprehension) IQ at 15y (Reasoning from WASI) Educational attainment at 16y > more persistent IQ decline with more persistent CBdependence/ regular CBuse (mean 8 IQ points for most persistent CBusers) > global impairment across 5 cognitive domains, strongest impairments in executive function and processing speed > controlling for recent CBuse, tobacco, alcohol, hard drugs, schizophrenia, years of education did not affect sign. CBeffect > more attention/ memory problems in daily life with more persistent CB dependence > adolescence: CBdependence < 18y tended to become more persistent CBusers, persistent IQ decline also after cessation of CBuse ( 1y) in adol. onset users, but not adult-onset users > higher CBuse at 15y associated to earlier age of onset and earlier regular use > unadjusted analysis no IQ differences, after adjusting for pre-cb IQ sign. negative correlation of cumulative CBuse and IQ (2.9 points lower for 50-group) > higher cumulative CBuse sign. correlated with poorer educational performance at 16y (still after correcting for school performance 11y) > controlling for nicotine, alcohol, other drugs attenuated association of CB + IQ/school New Zealand Health Research Council, UK Medical Research Council, US National Institute of Aging, US National Institute of Mental Health, US National Institute of Drug Abuse, Jacobs Foundation UK Medical Research Council, Wellcome Trust, University of Bristol > modest CBuse not related to cognitive decline at 15y > nicotine important confounder 2 High quality ++ 2 Acceptable +

14 Reference Study Characteristics Outcomes Funding Additional comments Bibliographic reference Study type number of patients (males) Patient characteristics Prognostic factors (age, gender, amount of drug exposure) Outcome measures Results Source of funding Additional comments [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] perform., strongest effect for nicotine; small attenuating effects for maternal and early life behavior and mental health > unadjusted analysis: CBuse associated with maternal tobacco and CBuse, truancy from school, childhood hyperactivity/ conduct problems/ depressive symptoms, drug use > nicotine exposure solely associated with IQ decline at 15y of 6.2 points and poorer educational performance OCEBM level of evidence Length of followup Methodological rating SIGN

15 S I G N Methodology Checklist 1: Systematic Reviews and Metaanalyses SIGN gratefully acknowledges the permission received from the authors of the AMSTAR tool to base this checklist on their work: Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C,. et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007, 7:10 doi: / Available from [cited 10 Sep 2012] Study identification (Include author, title, year of publication, journal title, pages) Batalla et al Structural and functional imaging studies in chronic cannabis users: a systematic review of adolescent and adult findings. PLOSone Guideline topic: CB and cognition Key Question No: Before completing this checklist, consider: Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO reject. IF YES complete the checklist. Checklist completed by: CMF Section 1: Internal validity In a well conducted systematic review: 1.1 The research question is clearly defined and the inclusion/ exclusion criteria must be listed in the paper. Does this study do it? If no reject 1.2 A comprehensive literature search is carried out. 1.3 At least two people should have selected studies. 1.4 At least two people should have extracted data. 1.5 The status of publication was not used as an inclusion criterion. If no reject x 1.6 The excluded studies are listed. 1.7 The relevant characteristics of the included studies are provided.

16 1.8 The scientific quality of the included studies was assessed and reported. 1.9 Was the scientific quality of the included studies used appropriately? 1.10 Appropriate methods are used to combine the individual study findings The likelihood of publication bias was assessed appropriately. x x 1.12 Conflicts of interest are declared. SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 What is your overall assessment of the methodological quality of this review? High quality (++) x Acceptable (+) Low quality (-) Unacceptable reject Are the results of this study directly applicable to the patient group targeted by this guideline? 2.3 Notes:

17 S I G N Methodology Checklist 1: Systematic Reviews and Metaanalyses SIGN gratefully acknowledges the permission received from the authors of the AMSTAR tool to base this checklist on their work: Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C,. et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007, 7:10 doi: / Available from [cited 10 Sep 2012] Study identification (Include author, title, year of publication, journal title, pages) Broyd et al Acute and chronic effects of Cannabinoids on human cognition A systematic review. Biol Psychiatry Guideline topic: CB and cognition Key Question No: Before completing this checklist, consider: Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO reject. IF YES complete the checklist. Checklist completed by: CMF Section 1: Internal validity In a well conducted systematic review: 1.1 The research question is clearly defined and the inclusion/ exclusion criteria must be listed in the paper. Does this study do it? If no reject 1.2 A comprehensive literature search is carried out. 1.3 At least two people should have selected studies. 1.4 At least two people should have extracted data. 1.5 The status of publication was not used as an inclusion criterion. If no reject x 1.6 The excluded studies are listed. x 1.7 The relevant characteristics of the included studies are provided.

18 1.8 The scientific quality of the included studies was assessed and reported. 1.9 Was the scientific quality of the included studies used appropriately? 1.10 Appropriate methods are used to combine the individual study findings The likelihood of publication bias was assessed appropriately. x x 1.12 Conflicts of interest are declared. SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 What is your overall assessment of the methodological quality of this review? 2.2 Are the results of this study directly applicable to the patient group targeted by this guideline? 2.3 Notes: High quality (++) x Acceptable (+) Low quality (-) Unacceptable reject 0

19 S I G N Methodology Checklist 1: Systematic Reviews and Metaanalyses SIGN gratefully acknowledges the permission received from the authors of the AMSTAR tool to base this checklist on their work: Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C,. et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007, 7:10 doi: / Available from [cited 10 Sep 2012] Study identification (Include author, title, year of publication, journal title, pages) Ganzer et al Weighing the Evidence: A Systematic Review on Long-Term Neurocognitive Effects of Cannabis Use in Abstinent Adolescents and Adults. Neuropsychol Rev Guideline topic: CB and cognition Key Question No: Before completing this checklist, consider: Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO reject. IF YES complete the checklist. Checklist completed by: CMF Section 1: Internal validity In a well conducted systematic review: 1.1 The research question is clearly defined and the inclusion/ exclusion criteria must be listed in the paper. Does this study do it? If no reject 1.2 A comprehensive literature search is carried out. 1.3 At least two people should have selected studies. 1.4 At least two people should have extracted data. 1.5 The status of publication was not used as an inclusion criterion. If no reject 1.6 The excluded studies are listed. x 1.7 The relevant characteristics of the included studies are provided.

20 1.8 The scientific quality of the included studies was assessed and reported. 1.9 Was the scientific quality of the included studies used appropriately? 1.10 Appropriate methods are used to combine the individual study findings The likelihood of publication bias was assessed appropriately Conflicts of interest are declared. SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 What is your overall assessment of the methodological quality of this review? High quality (++) x Acceptable (+) Low quality (-) Unacceptable reject Are the results of this study directly applicable to the patient group targeted by this guideline? 2.3 Notes:

21 S I G N Methodology Checklist 1: Systematic Reviews and Metaanalyses SIGN gratefully acknowledges the permission received from the authors of the AMSTAR tool to base this checklist on their work: Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C,. et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007, 7:10 doi: / Available from [cited 10 Sep 2012] Study identification (Include author, title, year of publication, journal title, pages) James et al The brain effects of cannabis in healthy adolescents and in adolescents with schizophrenia: a systematic review. Psychiatry Res Neuroimaging Guideline topic: CB and cognition Key Question No: Before completing this checklist, consider: Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO reject. IF YES complete the checklist. Checklist completed by: CMF Section 1: Internal validity In a well conducted systematic review: 1.1 The research question is clearly defined and the inclusion/ exclusion criteria must be listed in the paper. Does this study do it? If no reject 1.2 A comprehensive literature search is carried out. 1.3 At least two people should have selected studies. 1.4 At least two people should have extracted data. 1.5 The status of publication was not used as an inclusion criterion. If no reject x 1.6 The excluded studies are listed. x 1.7 The relevant characteristics of the included studies are provided.

22 1.8 The scientific quality of the included studies was assessed and reported. 1.9 Was the scientific quality of the included studies used appropriately? 1.10 Appropriate methods are used to combine the individual study findings The likelihood of publication bias was assessed appropriately. x x 1.12 Conflicts of interest are declared. x SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 What is your overall assessment of the methodological quality of this review? High quality (++) x Acceptable (+) Low quality (-) Unacceptable reject Are the results of this study directly applicable to the patient group targeted by this guideline? 2.3 Notes:

23 S I G N Methodology Checklist 1: Systematic Reviews and Metaanalyses SIGN gratefully acknowledges the permission received from the authors of the AMSTAR tool to base this checklist on their work: Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C,. et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007, 7:10 doi: / Available from [cited 10 Sep 2012] Study identification (Include author, title, year of publication, journal title, pages) Martin-Santos et al Neuroimaging in cannabis use: a systematic review of the literature, Psychol Med Guideline topic: CB and cognition Key Question No: Before completing this checklist, consider: Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO reject. IF YES complete the checklist. Checklist completed by: CMF Section 1: Internal validity In a well conducted systematic review: 1.1 The research question is clearly defined and the inclusion/ exclusion criteria must be listed in the paper. Does this study do it? If no reject 1.2 A comprehensive literature search is carried out. 1.3 At least two people should have selected studies. 1.4 At least two people should have extracted data. 1.5 The status of publication was not used as an inclusion criterion. If no reject x 1.6 The excluded studies are listed. 1.7 The relevant characteristics of the included studies are provided.

24 1.8 The scientific quality of the included studies was assessed and reported. 1.9 Was the scientific quality of the included studies used appropriately? 1.10 Appropriate methods are used to combine the individual study findings The likelihood of publication bias was assessed appropriately. x x 1.12 Conflicts of interest are declared. SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 What is your overall assessment of the methodological quality of this review? 2.2 Are the results of this study directly applicable to the patient group targeted by this guideline? 2.3 Notes: High quality (++) x Acceptable (+) Low quality (-) Unacceptable reject 0