title: Cannabis cue-induced brain activation correlates with drug craving in limbic and visual salience regions: Preliminary results Verbal learning and memory in adolescent cannabis users, alcohol users and non-users Developmental sensitivity to cannabis use patterns and risk for major depressive disorder in mid-life: findings from 40 years of follow-up. Persistent cannabis users show neuropsychological decline from childhood to midlife Cannabidiol Attenuates the Appetitive Effects of Δ9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis Subjective Cannabis Effects as Part of a Developing Disorder in Adolescents and Emerging Adults A multi-site proof-of-concept investigation of computerized approach-avoidance training in adolescent cannabis users. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. What predicts incident use of cannabis and progression to abuse and dependence? A 4-year prospective examination of risk factors in a community sample of adolescents and young adults. Psychomotor Function in Chronic Daily Cannabis Smokers during Sustained Abstinence The association between cannabis use and mood disorders: A longitudinal study. The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis High-Potency Marijuana Impairs Executive Function and Inhibitory Motor Control Balanced placebo design with marijuana: Pharmacological and expectancy effects on impulsivity and risk taking Associations Between Marijuana Use and Cardiovascular Risk Factors and Outcomes Predicting the transition from frequent cannabis use to cannabis dependence: a three-year prospective study. A study investigating the acute dose— response effects of 13 mg and 17 mg Δ 9- tetrahydrocannabinol on cognitive—motor skills, subjective and autonomic measures in regular users of marijuana Psychobiological responses to unpleasant emotions in cannabis users The Cannabis Use Problems Identification Test (CUPIT): development, reliability, concurrent and predictive validity among adolescents and adults. Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction Acute effects of smoked marijuana on decision making, as assessed by a modified gambling task, in experienced marijuana users Inhibitory control contributes to "motor"--but not "cognitive"--impulsivity. CANDIS treatment program for cannabis use disorders: findings from a randomized multi-site translational trial. Cognitive impairment, retention and abstinence among cocaine abusers in cognitive-behavioral treatment. Cognitive and Mental Health Predictors of Withdrawal Severity During an Active Attempt to Cut Down Cannabis Use Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial. Working Memory Training for Adolescents With Cannabis Use Disorders: A Randomized Controlled Trial How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review Cue-induced striatal activity in frequent cannabis users independently predicts cannabis problem severity three years later
abstract: Craving is a major motivator underlying drug use and relapse but the neural correlates of cannabis craving are not well understood . This study sought to determine whether visual cannabis cues increase cannabis craving and whether cue-induced craving is associated with regional brain activation in cannabis-dependent individuals . Cannabis craving was assessed in 16 cannabis-dependent adult volunteers while they viewed cannabis cues during a functional MRI ( fMRI ) scan . The Marijuana Craving Question naire was administered immediately before and after each of three cannabis cue-exposure fMRI runs . FMRI blood-oxygenation-level-dependent ( BOLD ) signal intensity was determined in regions activated by cannabis cues to examine the relationship of regional brain activation to cannabis craving . Craving scores increased significantly following exposure to visual cannabis cues . Visual cues activated multiple brain regions , including inferior orbital frontal cortex , posterior cingulate gyrus , parahippocampal gyrus , hippocampus , amygdala , superior temporal pole , and occipital cortex . Craving scores at baseline and at the end of all three runs were significantly correlated with brain activation during the first fMRI run only , in the limbic system ( including amygdala and hippocampus ) and paralimbic system ( superior temporal pole ) , and visual regions ( occipital cortex ) . Cannabis cues increased craving in cannabis-dependent individuals and this increase was associated with activation in the limbic , paralimbic , and visual systems during the first fMRI run , but not subsequent fMRI runs . These results suggest that these regions may mediate visually cued aspects of drug craving . This study provides preliminary evidence for the neural basis of cue-induced cannabis craving and suggests possible neural targets for interventions targeted at treating cannabis dependence Rationale Long-term heavy cannabis use can result in memory impairment .  Adolescent users may be especially vulnerable to the adverse neurocognitive effects of cannabis . Objectives and methods In a cross-sectional and prospect i ve neuropsychological study of 181 adolescents aged 16–20 ( mean 18.3 years ) , we compared performance indices from one of the most widely used measures of learning and memory — the Rey Auditory Verbal Learning Test — between cannabis users ( n = 52 ; mean 2.4 years of use , 14 days/month , median abstinence 20.3 h ) , alcohol users ( n = 67 ) and non-user controls ( n = 62 ) matched for age , education and premorbid intellectual ability ( assessed prospect ively ) , and alcohol consumption for cannabis and alcohol users . Results Cannabis users performed significantly worse than alcohol users and non-users on all performance indices . They recalled significantly fewer words overall ( p < 0.001 ) , demonstrating impaired learning ( p < 0.001 ) , retention ( p < 0.001 ) and retrieval ( p < 0.05 ) ( Cohen ’s d 0.43–0.84 ) . The degree of impairment was associated with the duration , quantity , frequency and age of onset of cannabis use , but was unrelated to alcohol exposure or other drug use . No gender effects were detected and the findings remained after controlling for premorbid intellectual ability . An earlier age of onset of regular cannabis use was associated with worse memory performance after controlling for extent of exposure to cannabis . Conclusions Despite relatively brief exposure , adolescent cannabis users relative to their age-matched counterparts demonstrated similar memory deficits to those reported in adult long-term heavy users . The results indicate that cannabis adversely affects the developing brain and reinforce concerns regarding the impact of early exposure BACKGROUND Evidence regarding the association between cannabis use and depression  remain conflicting , especially as studies have not typically adopted a longitudinal design with a follow-up period that was long enough to adequately cover the risk period for onset of depression . METHOD Males from the Cambridge Study in Delinquent Development ( CSDD ) ( N = 285 ) were assessed seven times from age 8 to 48 years to prospect ively investigate the association between  cannabis use and risk of  major depressive disorder ( MDD ) .  A combination of multiple analyses ( logistic regression , Cox regression , fixed-effects analysis ) was employed to explore the strength and direction of effect within different developmental stages . RESULTS Multiple regression analyses revealed that early-onset cannabis use ( before age 18 ) but not late-onset cannabis use ( after age 27 ) was associated with a higher risk and shorter time until a subsequent MDD diagnosis . This effect was present in high-frequency [ ( odds ratio ( OR ) 8.83 , 95 % confidence interval ( CI ) 1.29 - 70.79 ] ; [ hazard ratio ( HR ) 8.69 , 95 % CI 2.07 - 36.52 ) ] and low-frequency early-onset users ( OR 2.41 , 95 % CI 1.22 - 4.76 ; HR 2.09 , 95 % CI 1.16 - 3.74 ) . Effect of increased frequency of cannabis use on increased risk of subsequent MDD was observed only for use during adolescence ( age 14 - 18 ) but not at later life stages , while controlling for observed and non-unobserved time-invariant factors . Conversely , MDD in adulthood ( age 18 - 32 ) was linked to a reduction in subsequent cannabis use ( age 32 - 48 ) . CONCLUSIONS The present findings provide evidence implicating frequent cannabis use during adolescence as a risk factor for later life depression . Future studies should further examine causality of effects in larger sample Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health . Concomitantly , adolescents are initiating cannabis use at younger ages , and more adolescents are using cannabis on a daily basis . The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users . Participants were members of the Dunedin Study , a prospect i ve study of a birth cohort of 1,037 individuals followed from birth ( 1972/1973 ) to age 38 y.  Cannabis use was ascertained in interviews at ages 18 , 21 , 26 , 32 , and 38 y.  Neuropsychological testing  was conducted at age 13 y , before initiation of cannabis use , and again at age 38 y , after a pattern of persistent cannabis use had developed . Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning , even after controlling for years of education . Informants also reported noticing more cognitive problems for persistent cannabis users . Impairment was concentrated among adolescent-onset cannabis users , with more persistent use associated with greater decline . Further , cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users . Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents Worldwide cannabis dependence is increasing , as is the concentration of Δ9-tetrahydrocannabinol ( THC ) in street cannabis . At the same time , the concentration of the second most abundant cannabinoid in street cannabis ,  cannabidiol  ( CBD ) , is decreasing . These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory . No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans . A total of 94 cannabis users were tested 7 days apart , once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures . Using an unprecedented methodology , a sample of cannabis ( as well as saliva ) was collected from each user and analyzed for levels of cannabinoids . On the basis of CBD : THC ratios in the cannabis , individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs , explicit liking , and implicit attentional bias to drug stimuli . When intoxicated , smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC . Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days . Our findings suggest that CBD has potential as a treatment for cannabis dependence . The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders In light of exp and ing legalization of cannabis and swelling debate about the potential risks , particularly for younger users , underst and ing acute cannabis effects among adolescents and emerging adults is more important than ever . Contemporary models of addiction development identify subjective drug responses as central to the developmental unfolding of drug use disorders . Despite this , surprisingly little is known about cannabis ’s acute subjective effects in human youths . This research utilized ecological momentary assessment ( EMA ) in the natural environment to identify the typical situational context of cannabis use among 85 frequent cannabis users , ages 15–24 years ( M = 19.8 , SD = 2.0 ; 48.2 % female ) . Study aims were to ( a ) characterize momentary changes in several subjective states ( i.e. , stimulation , sedation , tension , craving , and high ) when not using , just before cannabis use , and after use , and ( b ) evaluate whether cannabis responses varied with cannabis use disorder ( CUD ) severity or across the transition from adolescence to emerging adulthood in a correlational manner . Use of cannabis produced measurable reductions in craving and tension , as well as increases in stimulation , sedation , and “ high . ” Participants with more CUD symptoms reported greater relief of craving and increased stimulatory response and high following use . In contrast , emerging adults reported diminished stimulatory response and high following use , relative to adolescents . Results highlight the utility of EMA for characterizing cannabis response as this behavior unfolds in daily life , during a key developmental timeframe in the pathogenesis of cannabis-use pathology BACKGROUND Few effective treatment options exist for cannabis-using youth . This pilot study aim ed to test Approach-Avoidance Training to reduce cannabis use with non-treatment-seeking adolescents . METHODS Eighty cannabis-using non-treatment-seeking adolescents ( average age 19 ) were recruited from San Diego , California and Charleston , South Carolina , and r and omized to complete either six sessions of Cannabis Approach-Avoidance Task Training ( CAAT-training ) design ed to reduce automatic approach biases for cannabis cues or CAAT-sham training . Change in two primary outcome variables was examined : 1 ) cannabis approach bias and 2 ) percent cannabis use days over study enrollment . Change in percent alcohol use days over study enrollment was explored as a secondary outcome . RESULTS A mixed models repeated measures analysis confirmed the group by time interaction effect for approach bias failed to reach statistical significance ( p = .06 ) . Significant group by time interaction effects ( ps < 0.05 ) predicted percent days of cannabis and alcohol use over study enrollment . Participants r and omized to the avoid cannabis condition ( CAAT-training ) reported 7 % fewer days of cannabis use compared to 0 % change for sham ; unexpectedly , those in the avoid cannabis condition reported 10 % percent more alcohol use days compared to 3 % more for sham . CONCLUSIONS Computerized cognitive bias modification paradigms may have utility in reducing  adolescent cannabis use . Future work should consider developing a paradigm that addresses both cannabis and alcohol , as well as alternative computerized approaches for coping with addictive behavior in conjunction with bias modification CONTEXT Cannabis use can both increase and reduce anxiety in humans . The neurophysiological substrates of these effects are unknown . OBJECTIVE To investigate the effects of 2 main psychoactive constituents of Cannabis sativa ( Delta9-tetrahydrocannabinol [ Delta9-THC ] and cannabidiol [ CBD ] ) on regional brain function during emotional processing . DESIGN Subjects were studied on 3 separate occasions using an event-related functional magnetic resonance imaging paradigm while viewing faces that implicitly elicited different levels of anxiety . Each scanning session was preceded by the ingestion of either 10 mg of Delta9-THC , 600 mg of CBD , or a placebo in a double-blind , r and omized , placebo-controlled design . PARTICIPANTS Fifteen healthy , English-native , right-h and ed men who had used cannabis 15 times or less in their life . MAIN OUTCOME MEASURES Regional brain activation ( blood oxygenation level-dependent response ) , electrodermal activity ( skin conductance response [ SCR ] ) , and objective and subjective ratings of anxiety . RESULTS Delta9-Tetrahydrocannabinol increased anxiety , as well as levels of intoxication , sedation , and psychotic symptoms , whereas there was a trend for a reduction in anxiety following administration of CBD . The number of SCR fluctuations during the processing of intensely fearful faces increased following administration of Delta9-THC but decreased following administration of CBD . Cannabidiol attenuated the blood oxygenation level-dependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing intensely fearful faces , and its suppression of the amygdalar and anterior cingulate responses was correlated with the concurrent reduction in SCR fluctuations . Delta9-Tetrahydrocannabinol mainly modulated activation in frontal and parietal areas . CONCLUSIONS Delta9-Tetrahydrocannabinol and CBD had clearly distinct effects on the neural , electrodermal , and symptomatic response to fearful faces . The effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety , whereas the anxiogenic effects of Delta9-THC may be related to effects in other brain regions OBJECTIVES To determine risk factors of incident onset of use , abuse and dependence of cannabis in a community sample of adolescents and young adults . METHODS Risk factors were examined in a prospect i ve longitudinal design across 4 years in a representative sample ( N = 2,446 ) aged 14 - 24 at the outset of the study ( EDSP ) . Patterns of DSM-IV defined cannabis use , abuse and dependence were assessed with the Composite International Diagnostic Interview ( M-CIDI ) . Potential risk factors were assessed at baseline . Incident cannabis use , abuse and dependence at second follow-up ( on average 42 months after baseline ) were the main outcome measures in this study . Associations were analyzed with logistic and negative binomial regressions . RESULTS Using 11 of a total of 56 variables examined , the predictive value of the final multiple logistic regression for incident cannabis use was moderately good ( area under the ROC curve = 0.78 ) . Cannabis use frequency was predicted in the final model by 18 variables , cannabis abuse by two variables in the younger sub sample and nine factors in the older group , and dependence by eight variables ( dependence : ROC curve area = 0.97 ) . Incident cannabis use was predicted mainly by availability of drugs , peers ' drug use , a more ' positive ' attitude towards future drug use , and regular previous use of licit drugs , while cannabis dependence was predicted primarily by parental death before age 15 , deprived socio-economic status , and baseline use of other illicit drugs . CONCLUSION Different factors predict the onset or severity of cannabis use and the progression to abuse and dependence . In addition to well-documented risk factors such as peer group pressure , drug availability , and low self-esteem , findings suggest that family history ( e.g. parental mental disorders , early parental death ) , and prior experiences with legal drugs play a significant role in the initiation of cannabis consumption and the transition to cannabis use disorders in adolescents and young adults . Findings suggest that early intervention and prevention might be improved by better targeted treatment Background The present study assessed psychomotor function in chronic , daily cannabis smokers during 3 weeks continuously monitored abstinence on a secure research unit . We hypothesized that psychomotor performance would improve during abstinence of chronic , daily cannabis smokers . Methodology /Principal Findings Performance on the critical tracking ( CTT ) and divided attention ( DAT ) tasks was assessed in 19 male chronic , daily cannabis smokers at baseline and after 8 , 14–16 and 21–23 days of continuously monitored abstinence . Psychomotor performance was compared to a control group of non-intoxicated occasional drug users . Critical frequency ( λc ) of the CTT and tracking error and control losses of the DAT were the primary outcome measures . Results showed that chronic cannabis smokers ’ performance on the CTT ( p<0.001 ) and the DAT ( p<0.001 ) was impaired during baseline relative to the comparison group . Psychomotor performance in the chronic cannabis smokers improved over 3 weeks of abstinence , but did not recover to equivalent control group performance . Conclusions / Significance Sustained cannabis abstinence moderately improved critical tracking and divided attention performance in chronic , daily cannabis smokers , but impairment was still observable compared to controls after 3 weeks of abstinence . Between group differences , however , need to be interpreted with caution as chronic smokers and controls were not matched for education , social economic status , life style and race BACKGROUND The association between cannabis use and mood disorders is well documented , yet evidence regarding causality is conflicting . This study explored the association between  cannabis use , major depressive disorder ( MDD ) and bipolar disorder ( BPD )  in a 3-year prospect i ve study . METHODS Data was drawn from waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions ( NESARC ) . MDD and BPD were controlled at baseline and defined as meeting full criteria in the 12 months prior to the follow-up . Initiation of cannabis use was defined as any cannabis used by former lifetime abstainers in the time period between baseline and follow-up . RESULTS Cannabis use was not significantly associated with increased incidence of MDD ( Adjusted Odds Ratio ( AOR ) for daily use=0.58(0.22 - 1.51 ) ) . Weekly to almost daily cannabis use was associated with increased incidence of BPD ( ( AOR for weekly to daily use=2.47(1.03 - 5.92 ) ) ; daily use was not ( AOR=0.52(0.17 - 1.55 ) ) . Baseline MDD was associated with initiation of cannabis use ( AOR=1.72(1.1 - 2.69 ) ) . A crude association between baseline BPD and incidence of cannabis use was not maintained in adjusted models ( AOR=0.61(0.36 - 1.04 ) ) . LIMITATIONS Lack of information regarding frequency of cannabis use at follow-up and limitations regarding generalization of the results . CONCLUSIONS Our findings do not support a longitudinal association between cannabis use and incidence of MDD . Results regarding the association between cannabis use and incidence of BPD are conflicting and require further investigation . Baseline MDD , but not BPD , may be associated with future initiation of cannabis use . This may have implication s for clinical , social and legislative aspects of cannabis use 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 Human performance studies have usually relied on low-potency marijuana ( 4 % THC ) for determining THC-induced impairment . The present study was design ed to assess the effects of high-potency marijuana ( 13 % THC ) on human performance . In all , 20 recreational users of marijuana participated in a double-blind ,  placebo  controlled , three way cross-over study . The treatments consisted of single doses of 0 , 250 , and 500 μg/kg THC .  Performance tests were conducted at regular intervals between 15 min and 6 h postsmoking and included measures of motor control ( Critical tracking task ) , executive function ( Tower of London ) motor impulsivity ( Stop signal task ) , and risk taking ( Iowa gambling task ) . THC significantly impaired performance in the Critical tracking task and decreased the number of correct decisions in the Tower of London task . In addition , THC significantly increased stop reaction time and the proportions of commission and omission errors in the Stop signal task . THC-induced impairments lasted up to 6 h postsmoking as indicated by the absence of a THC × Time after smoking interaction . Effect sizes for performance impairments produced by THC 250 μg/kg were relatively low but generally increased by a factor of two in case of THC 500 μg/kg . These data suggest that high potency marijuana consistently impairs executive function and motor control . Use of higher doses of THC in controlled studies may offer a reliable indication of THC induced impairment as compared to lower doses of THC that have traditionally been used in performance studies Rationale Marijuana is believed to increase impulsivity and risk taking , but the processes whereby it affects such behaviors are not understood . Indeed , either the pharmacologic effect of delta-9-tetrahydrocannabinol ( THC ) or the expectancy of receiving it may lead to deficits in cognitive processing and increases in risk taking . Objectives and methods We examined the relative effects of expecting to receive active marijuana and the pharmacological drug effects using a balanced placebo design . Young adult regular marijuana users ( N = 136 ) were r and omly assigned into one of four groups in a two × two instructional set ( Told THC vs. Told no THC ) by drug administration ( smoked marijuana with 2.8 % THC vs. placebo ) design . Dependent measures included subjective intoxication , behavioral impulsivity , and decision-making related to risky behaviors . Results Active THC , regardless of expectancy , impaired inhibition on the Stop Signal and Stroop Color-Word tasks . Expectancy of having smoked THC , regardless of active drug , decreased impulsive decision-making on a delay discounting task among participants reporting no deception and increased perception of sexual risk among women , consistent with a compensatory effect . Expectancy of smoking THC in combination with active THC  increased negative perceptions from risky alcohol use . Active drug and expectancy independently increased subjective intoxication . Conclusions Results highlight the importance of marijuana expectancy effects as users believing they are smoking marijuana may compensate for expected intoxication effects when engaged in deliberate decision-making by making less impulsive and risky decisions . Effects of marijuana on impulsive disinhibition , by contrast , reflect direct pharmacologic effects for which participants did not compensate As more states legalize the sale and consumption of marijuana , the number of Americans using it continues to rise ( 1 , 2 ) . This increase in the use of marijuana highlights the need for a better underst and ing of its risks and benefits . One area of importance is its effect on cardiovascular disease , the number one cause of morbidity and mortality worldwide ( 3 ) . Marijuana may affect cardiovascular health in several ways . Like other psychoactive drugs , it may have hemodynamic effects that can precipitate events ( 4 ) . The active ingredient in marijuana is 9-tetrahydrocannabinol ( THC ) ( 5 ) , which is responsible for the psychoactive effects of marijuana through its interaction with cannabinoid receptors . These receptors are ubiquitous in the brain and its vasculature and present throughout the body , including the myocardium , coronary endothelium , and smooth muscle cells ( 6 , 7 ) . In vitro and animal studies have reported that THC can modulate cannabinoid receptors on human cardiomyocytes and vascular smooth muscles , result ing in ischemia ( 7 , 8) . In vitro studies also have demonstrated that THC influences the regulation of glucose and lipid metabolism , suggesting a possible effect on vascular risk factors ( 9 , 10 ) . At the cellular level , THC may cause inflammatory cytokine release , alteration in lipid metabolism ( 11 , 12 ) , and reactive oxygen species formation ( 13 ) . These effects may potentiate the progression of vascular disease .  Marijuana smoking , the predominant method of use , causes a 5-fold increase in the blood carboxyhemoglobin level and a 3-fold increment in the quantity of tar inhaled compared with tobacco ( 14 ) . Studies on secondh and marijuana smoke have found endothelial dysfunction in rats after exposure ( 15 ) . Given the myriad ways in which marijuana might potentiate vascular disease , we conducted a systematic review to assess the effect of regular marijuana use on cardiovascular outcomes and their associated risk factors . Methods The protocol was registered at PROSPERO ( CRD42016051297 ) ( 16 ) at the start of our investigation . This review focuses on studies examining marijuana use and cardiovascular risk factors and outcomes ; our protocol also includes search es and a review of hemodynamic changes associated with marijuana use that are not reported here . Data Sources and Search es We search ed several online data bases ( PubMed , MEDLINE , EMBASE , PsycINFO , and the Cochrane Library ) for titles and abstract s between 1 January 1975 and 30 September 2017 . We chose a 1975 start date because that was the year the Alaska Supreme Court ruled that the Alaska constitution 's right to privacy protects an adult 's ability to use and possess a small amount of marijuana in the home for personal use ( 17 ) . We also conducted reference and author tracking to identify additional articles and search ed Clinical Trials.gov and the National Institutes of Health Research Portfolio ( NIH RePORTER ) for ongoing or completed studies not reported in the literature . For search terms and details , see Supplement 1 . Supplement . Supplementary Material Study Selection All titles and abstract s were independently screened by 2 review ers ( M.G. and D.R. ) . We included observational studies ( cohort , casecontrol , cross-sectional ) and interventional studies ( r and omized controlled trials , experimental studies ) that enrolled participants older than 12 years and were published in English . The exposure criterion was any form of marijuana ( plant or pharmaceutical ) . The main outcomes of interest were cardiovascular risk factors and outcomes . We excluded case reports , case series , review articles , editorials , and in vitro and animal studies . The same 2 investigators independently review ed the full texts of selected articles to identify those that met our inclusion criteria . Disagreements regarding inclusion were resolved by a third review er ( S.K. ) . Interrater reliability for the abstract selection process and the concurrent decision to include the article in the review was excellent ( Cohen , 0.87 ) . For the selection process , see Supplement 2 . Data Extraction and Quality Assessment For each included study , the review ers collected information on study design ( observational or experimental ) , the study population ( for example , healthy volunteers , regular users , or hospitalized patients ) , age distribution , cannabis make-up ( plant based or pharmaceutical ) , route of exposure ( smoking , vaporizing , eating , or injecting ) , exposure duration , and funding source . Four investigators ( D.R. , M.G. , S.K. , and D.K. ) independently rated study quality as low , moderate , or high risk of bias ( ROB ) . We assessed ROB for outcomes in trials with the Cochrane Risk of Bias Tool ( 18 ) , and for outcomes in observational studies with the Newcastle-Ottawa scale ( 19 ) . Disagreements were resolved by consensus . Risk-of-bias tools and scoring are available in Supplement 3 . Data Synthesis and Analysis We performed a qualitative assessment and synthesis of evidence . Because of the heterogeneity of outcomes and lack of reporting of effect sizes , we did not pool any data . Through group discussion , we grade d the overall strength of the evidence for each outcome as insufficient , low , moderate , or high on the basis of methods outlined by the Agency for Healthcare Research and Quality ( 20 ) . Role of the Funding Source The NIH had no role in the design , analysis , interpretation of data , preparation or approval of the manuscript , or decision to su bmi t the manuscript for publication . Results Literature Search Our search yielded 3006 abstract s , 1669 of which were selected for further evaluation . Among these , 140 were selected for full-text review . Another 7 articles were added via author and reference tracking . Of these 147 papers , 24 met our inclusion criteria ( Figure ) . Figure . Evidence search and selection . Study Characteristics The evidence included 9 prospect i ve cohort studies , 3 retrospective cohort studies , 2 casecontrol studies , 2 interventional studies ( 1 experimental study and 1 r and omized trial ) , 7 cross-sectional studies , and 1 case-crossover study . Thirteen studies assessed  cardiovascular risk factors  , and 11 examined  cardiovascular diseases .  Most studies ( n= 16 ; 66.7 % ) did not report the chemical constitution ( for example , THC vs. cannabidiol ) of the marijuana used in the study . Among articles that specified the form of marijuana used , the plant-based form was predominant ( n= 7 ) . Among those that specified the route of exposure , smoking was predominant ( n= 11 ) , followed by oral use ( n= 2 ) . Eleven papers did not report the specific route or form of marijuana administration ( such as edible or smoked ) . Tables 1 to 4 of Supplement 3 detail the quality assessment s for individual studies . Cardiovascular Risk Factors Metabolic Parameters : Lipid and Glucose Levels and Diabetes Eleven studies provided data on 1 or more metabolic parameter outcomes , including hyperglycemia , dyslipidemia , and diabetes ( Appendix Table 1 ) . Appendix Table 1 . Studies That Examined Exposure to MJ and CVD Five cross-sectional studies ( 3 low and 2 high ROB ) examined the association between marijuana use and hyperglycemia , dyslipidemia , metabolic syndrome , or diabetes ( 2125 ) . Marijuana use was measured by self-report in all studies . Four studies were based on 3 different waves of the NHANES ( National Health and Nutrition Examination Survey ; 1988 to 1994 , 2005 to 2010 , and 2005 to 2012 ) ( 2123 , 25 ) . Three of the 4 used multivariable analysis to examine the association between marijuana use and metabolic parameters after adjustment for baseline characteristics . All 3 studies reported that marijuana use had different favorable associations , including a lower prevalence of diabetes ( 22 ) , lower glucose levels ( 25 ) , or higher high-density lipoprotein cholesterol concentrations ( 21 , 22 , 25 ) . The fourth NHANES study ( 2005 to 2012 ) used both regression models and an instrumental variable analysis to examine associations ( 23 ) . Marijuana use was associated with a beneficial metabolic effect in the regression model evaluation ; no such effect was seen in the instrumental variable analysis . The final cross-sectional study was an exploratory analysis based on a small sample of 30 persons who were heavy marijuana users and 30 control participants matched for age , sex , ethnicity , and body mass index ( BMI ) ( 24 ) . The authors identified no differences between groups in glucose tolerance or fasting glucose , total cholesterol , or triglyceride levels . Three prospect i ve studies ( 1 low , 1 moderate , and 1 high ROB ) examined the association of marijuana use with risk factors ( 2628 ) . Two were based on the CARDIA ( Coronary Artery Risk Development in Young Adults ) cohort study , which examined the development and determinants of clinical and sub clinical cardiovascular disease and its risk factors ( 26 , 28 ) . The CARDIA study began in 1985 to 1986 with 5113 black and white men and women aged 18 to 30 years . It included comprehensive in-person baseline and outcome data ( sociodemographic characteristics ; fasting glucose levels ; BMI ; diet and physical activity ; and use of tobacco , alcohol , and other substances ) and several exposure assessment s during a long follow-up . Questions pertaining to marijuana use lacked detail on the form used , and exposure was quantified differently in each study . The low-ROB CARDIA-based study reported no associations between marijuana use and changes in glucose , high-density lipoprotein cholesterol , or triglyceride levels among heavy users ( > 1800 days of use ) compared with nonusers during 15 years of follow-up ( 26 ) . The moderate-ROB CARDIA-based study examined the association between marijuana use and diabetes and prediabetes ( 28 ) . Marijuana use was ascertained in year 7 of the prospect i ve cohort , and exposure was very limited : The highest category of use was a lifetime frequency of more than 100 times . Incidence of diabetes and prediabetes assessed at 4 subsequent follow-up examinations over 18 years was based on laboratory assessment ( oral glucose BACKGROUND Frequent cannabis users are at high risk of dependence , still most ( near ) daily users are not dependent . It is unknown why some frequent users develop dependence , whereas others do not . This study aims to identify predictors of first-incidence DSM-IV cannabis dependence in frequent cannabis users . METHODS A prospect i ve cohort of frequent cannabis users ( aged 18 - 30 , n=600 ) with baseline and two follow-up assessment s ( 18 and 36 months ) was used . Only participants without lifetime diagnosis of DSM-IV cannabis dependence at baseline ( n=269 ) were selected . Incidence of DSM-IV cannabis dependence was established using the Composite International Diagnostic Interview version 3.0 . Variables assessed as potential predictors of the development of cannabis dependence included sociodemographic factors , cannabis use variables ( e.g. , motives , consumption habits , cannabis exposure ) , vulnerability factors ( e.g. , childhood adversity , family history of mental disorders or substance use problems , personality , mental disorders ) , and stress factors ( e.g. , life events , social support ) . RESULTS Three-year cumulative incidence of cannabis dependence was 37.2 % ( 95 % CI=30.7 - 43.8 % ) . Independent predictors of the first incidence of cannabis dependence included : living alone , coping motives for cannabis use , number and type of recent negative life events ( major financial problems ) , and number and type of cannabis use disorder symptoms ( impaired control over use ) . Cannabis exposure variables and stable vulnerability factors did not independently predict first incidence of cannabis dependence . CONCLUSIONS In a high risk population of young adult frequent cannabis users , current problems are more important predictors of first incidence cannabis dependence than the level and type of cannabis exposure and stable vulnerability factors Heavy use of marijuana is cl aim ed to damage critical skills related to short-term memory , visual scanning and attention . Motor skills and driving safety may be compromised by the acute effects of marijuana . The aim of this study was to investigate the acute effects of 13 mg and 17 mg Δ 9-tetrahydrocannabinol ( THC ) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana . Fourteen regular users of marijuana were enrolled . Each subject was tested on two separate days . On each test day , subjects smoked two low-nicotine cigarettes , one with and the other without THC . Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day . The sequence of cigarette types was unknown to the subject . During smoking , heart rate and blood pressure were monitored , and the subjects performed a virtual reality maze task requiring attention and motor coordination , followed by 3 other cognitive tasks ( Wisconsin Card Sorting Test ( WCST ) , a “ gambling ” task and estimation of time and distance from an approaching car ) . After smoking a cigarette with 17 mg THC , regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC ; this effect was not seen in patients after they smoked cigarettes with 13 mg THC . Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC . Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC , but not with 13 m THC . Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction , drug “ effect ” and drug “ high ” . These findings imply that smoking of 17 mg THC results in impairment of cognitive — motor skills that could be important for coordinated movemen and driving , whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana Aim of this paper is to investigate the psychobiological reactions to experimentally induced negative emotional states in active marijuana-dependent smokers and whether changes in emotional reactivity were reversed by prolonged abstinence . Twenty-eight patients were r and omly included into group A ( fourteen active marijuana-dependent smokers ) or group B ( fourteen abstinent marijuana-dependent subjects ) .  Emotional response evaluation of group B subjects was assessed after 6 months of abstinence .  Fourteen healthy volunteers , matched for age and sex , were used as controls .  Psychometric and emotional response evaluations were performed by administering Symptoms Check List-90 and State-Trait Anxiety Inventory Y-1 ( STAI ) . Neutral and unpleasant set of pictures selected from the international affective picture system and the Self-Assesment Manikin procedure ( SAM ) have been used to determine ratings of pleasure and arousal . Before and after the experimental session , blood sample s were collected to determine ACTH and cortisol plasma levels . Active cannabis users displayed significantly higher levels of pleasantness SAM scores and lower levels of arousal SAM scores compared to abstinent cannabis users and controls in response to emotional task . In a close parallel with psychological data , hormonal findings indicate a persistent hyperactivity of hypothalamus – pituitary – adrenal ( HPA ) axis in cannabis users , particularly among active marijuana smokers , and an impaired hormonal reaction to negative emotions , in comparison with healthy subjects . The capacity of the HPA axis to respond to stressful stimuli/negative emotions seems to be only partially recovered after 6 months of abstinence . Ours findings , although obtained in a small number of subjects , suggest an association between active cannabis use , subjective reduced sensitivity to negative emotions and threat and HPA axis dysfunction AIMS To describe the empirical construction and initial validation of the Cannabis Use Problems Identification Test ( CUPIT ) , a brief self-report screening instrument for detection of currently and potentially problematic cannabis use . DESIGN In a three-phase prospect i ve design an item pool of c and i date questions was generated from a literature review and extensive expert consultation . The CUPIT internal structure , cross-sectional and longitudinal psychometric properties were then systematic ally tested among heterogeneous past-year users . PARTICIPANTS Volunteer participants were 212 high-risk adolescents ( n = 138 ) and adults ( n = 74 ) aged 13 - 61 years from multiple community setting s. MEASUREMENTS The comprehensive assessment battery included several established measures of cannabis-related pathology for CUPIT validation , with DSM-IV/ICD-10 diagnoses of cannabis use disorders as criterion st and ard . FINDINGS Sixteen items loading highly on two subscales derived from principal components analysis exhibited good to excellent test-retest ( 0.89 - 0.99 ) and internal consistency reliability ( 0.92 , 0.83 ) , and highly significant ability to discriminate diagnostic subgroups along the severity continuum ( non-problematic , risky , problematic use ) . Twelve months later , baseline CUPIT scores demonstrated highly significant longitudinal predictive utility for respondents ' follow-up diagnostic group membership . Receiver operating characteristic ( ROC ) analysis identified a  CUPIT score of 12 to be the optimal cut-point for maximizing sensitivity for both currently diagnosable cannabis use disorder and those at risk of meeting diagnostic criteria in the following 12 months . CONCLUSIONS The CUPIT is a brief cannabis screener that is reliable , valid and acceptable for use across diverse community setting s and consumers of all ages . The CUPIT has clear potential to assist with achievement of public health goals to reduce cannabis-related harms in the community BACKGROUND Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders . METHODS In a 3-day , double-blind , r and omized , placebo-controlled study , the behavioral , cognitive , motor , and endocrine effects of 0 mg , 2.5 mg , and 5 mg intravenous Delta-9-tetrahydrocannabinol ( Delta-9-THC ) were characterized in 13 stable , antipsychotic-treated schizophrenia patients . These data were compared with effects in healthy subjects reported elsewhere . RESULTS Delta-9-tetrahydrocannabinol transiently increased 1 ) learning and recall deficits ; 2 ) positive , negative , and general schizophrenia symptoms ; 3 ) perceptual alterations ; 4 ) akathisia , rigidity , and dyskinesia ; 5 ) deficits in vigilance ; and 6 ) plasma prolactin and cortisol .  Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects . There were no serious short- or long-term adverse events associated with study participation . CONCLUSIONS Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia . These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis . Furthermore , Delta-9-THC might differentially affect schizophrenia patients relative to control subjects . Finally , the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia The impact of regular marijuana use on executive cognitive abilities , including decision making , is not well understood . While cross-sectional studies have suggested that substance abusers exhibit impaired decision making , as assessed by the Iowa Gambling Task , the direct role of marijuana use in the Gambling Task performance of marijuana smokers has not been well defined . In this report , we present data on performance on a modified Gambling Task  in experienced marijuana users after they had smoked marijuana under controlled laboratory conditions . A total of 36 marijuana users , who reported smoking approximately 24 marijuana cigarettes per week , completed this 3-session outpatient study . During each session , these volunteers completed the Gambling Task once at baseline and 3 times after smoking a single marijuana cigarette ( 0.0 , 1.8 , or 3.9 % Δ9-THC ) . Marijuana cigarettes were administered in a double-blind fashion , and the sequence of Δ9-THC concentration was balanced across volunteers . Marijuana increased the time required to complete the task . However , advantageous card selection and money earned on the task were not disrupted by marijuana . These data are consistent with previous findings that indicated that speed of performance on tests of executive function , but not accuracy , is disrupted in experienced marijuana users during marijuana intoxication Literature on impulsivity regularly cl aims inhibitory control deficits underlie impulsive behavior . The current study investigated whether taxing inhibitory control will increase reflection ( decision making under conditions of uncertainty ) , temporal ( delay of gratification ) , and motor impulsivity ( behavioral disinhibition ) . Inhibitory control was challenged , via a r and om letter generation task presented during responding to three impulsivity measures : the Information Sampling Task ( IST ) , Single Key Impulsivity Paradigm , and the Stop Signal Task ( SST ) .  Participants ( n = 33 ) were assigned to the inhibitory control challenging ( experimental ) condition , or to a control condition in which inhibitory control was not challenged . The SST was affected by the inhibitory control challenge : participants in the experimental condition displayed increased motor impulsivity , evidence d in longer stop signal reaction times ( SSRTs ) compared to the control group . The manipulation did not affect reflection- or temporal- impulsivity measures . These data support the suggestion that the mechanisms underlying the motor subtype of impulsivity are dissociable from the temporal and reflection subtypes , and that engagement of inhibitory control is not necessary to prevent impulsive decision making BACKGROUND In a recent paper , we reported the efficacy of a modular cognitive-behavioral intervention for treating adolescents and adults with cannabis use disorders ( CUD ) . In this study , we examine the outcome of this intervention after translating it into clinical practice . METHODS A multi-site , r and omized controlled trial of 279 treatment seekers with ICD-10 cannabis use disorders aged 16- 63 years was conducted in 11 outpatient addiction treatment centers in Germany . Patients were r and omly assigned to an Active Treatment ( AT , n=149 ) or Delayed Treatment Control ( DTC , n=130 ) . Treatment consisted of 10 sessions of fully manualized individual psychotherapy that combined Cognitive-Behavioral Therapy , Motivational EnhancementTherapy and problem-solving training . Assessment s were conducted at baseline , during each therapy session , at post-treatment and at three and six month follow-ups . RESULTS At post assessment 53.3 % of AT patients reported abstinence ( 46.3 % negative urine screenings ) compared to 22 % of DTC patients ( 17.7 % negative drug screenings ) ( p<0.001 , Intention-to-treat analysis ) . AT patients improved in the frequency of cannabis use , number of cannabis dependence criteria , severity of dependence , as well as number and severity of cannabis-related problems . Effect sizes were moderate to high . While abstinence rates in the AT group decreased over the 3-month ( negative urine screenings : 32.4 % ) and 6-month ( negative urine screenings : 35.7 % ) follow-up periods , the effects in secondary outcomes were maintained . CONCLUSIONS The intervention can successfully be translated to and applied in clinical practice . It has the potential to improve access to evidence -based care for chronic CUD patients Cognitive-behavioral therapy ( CBT ) depends on adequate cognitive functioning in patients , but prolonged cocaine use may impair cognitive functioning . Therefore , cognitive impairment may impede the ability of cocaine abusers to benefit from CBT . To begin to address this issue , we investigated the relationship between cognitive impairment and two treatment outcomes , therapy completion and abstention .  Eighteen carefully screened non-depressed cocaine-dependent patients in a psychopharmacological clinical trial were administered the MicroCog computerized battery to assess cognitive performance at treatment entry .  T-tests were used to compare cognitive functioning between completers ( patients remaining in treatment at least 12 weeks ) and dropouts . The results indicated that treatment completers had demonstrated significantly better cognitive performance at baseline than patients who dropped out of treatment . Cognitive domains that significantly distinguished between treatment completers and dropouts were attention , mental reasoning and spatial processing . This study provides preliminary evidence that cognitive impairments may decrease treatment retention and abstinence in CBT of cocaine dependence A milestone in cannabis research is the establishment of a clinical ly relevant cannabis withdrawal syndrome , yet little is known about the underlying mechanisms . We investigated the predictive role of mental health and cognitive factors in withdrawal severity during an active attempt to cut down , relative to uninterrupted cannabis use . Ninety heavy cannabis users were r and omly assigned to an experimental or control group . The experimental group was asked to cut down substance use for 1 week . Past week substance use , substance use-related problems , depressive symptoms , cravings , and cognitive control were assessed at baseline . Past week substance use and withdrawal severity were assessed at follow-up . The experimental group reduced their cannabis use more and experienced more withdrawal than the control group . Hierarchical regression analysis per predictor indicated that cannabis use-related problems , depressive symptoms , and cannabis craving , but not cognitive control , predicted stronger withdrawal . Craving uniquely predicted withdrawal in the experimental group . A combined hierarchical regression indicated that only depressive symptoms and cannabis use-related problems uniquely predicted withdrawal across groups . These results suggest that depressive symptoms and cannabis use-related problems are generally indicative of cannabis withdrawal severity , whereas craving specifically predicts cannabis withdrawal during an active attempt to cut-down cannabis use The main active ingredient in cannabis , delta-9-tetrahydrocannabinol ( THC ) , can acutely induce psychotic symptoms and impair episodic and working memory . Another major constituent , cannabidiol ( CBD ) , may attenuate these effects . This study aim ed to determine the effects of THC and CBD , both alone and in combination on psychotic symptoms and memory function . A r and omised , double-blind crossover design compared the effects of ( i ) placebo , ( ii ) THC 8 mg , ( iii ) CBD 16 mg and ( iv ) THC 8 mg + CBD 16 mg administered by inhalation through a vaporiser . Using an experimental medicine approach to predict treatment sensitivity , we selected 48 cannabis users from the community on the basis of ( 1 ) schizotypal personality question naire scores ( low , high ) and ( 2 ) frequency of cannabis use ( light , heavy ) . The Brief Psychiatric Rating Scale ( BPRS ) , Psychotomimetic States Inventory ( PSI ) , immediate and delayed prose recall ( episodic memory ) , 1- and 2-back ( working memory ) were assessed on each day . Results indicated that THC increased overall scores on the PSI , negative symptoms on BPRS , and robustly impaired episodic and working memory . Co-administration of CBD did not attenuate these effects . CBD alone reduced PSI scores in light users only . At a ratio of 2:1 , CBD does not attenuate the acute psychotic and memory impairing effects of vaporised THC . Frequent cannabis users may show a blunted anti- psychotic response to CBD , which is of concern due to the high rates of cannabis use disorders in patients with schizophrenia BACKGROUND Cannabis is one of the most widely used drugs worldwide . Cannabis use disorder is characterised by recurrent use of cannabis that causes significant clinical and functional impairment . There are no approved pharmacological treatments for cannabis use disorder . One approach is to potentiate endocannabinoid signalling by inhibiting fatty acid amide hydrolase ( FAAH ) , the enzyme that de grade s the endocannabinoid an and amide . We aim ed to test the efficacy and safety of the FAAH-inhibitor PF-04457845 in reduction of cannabis withdrawal  and cannabis use in men who were daily cannabis users . METHODS We did a double-blind , placebo-controlled , parallel group phase 2a trial at one site in men aged 18 - 55 years with cannabis dependence according to DSM-IV criteria ( equivalent to cannabis use disorder in DSM-5 ) . After baseline assessment s , participants were r and omly assigned ( 2:1 ) to receive PF-04457845 ( 4 mg per day ) or placebo using a fixed block size of six participants , stratified by severity of cannabis use and desire to quit . Participants were admitted to hospital for 5 days ( maximum 8 days ) to achieve abstinence and precipitate cannabis withdrawal , after which they were discharged to continue the remaining 3 weeks of treatment as out patients . The primary endpoints were treatment-related differences in cannabis withdrawal symptoms during hospital admission , and week 4 ( end of treatment ) self-reported cannabis use and urine THC-COOH concentrations in the intention-to-treat population . The study is registered at Clinical Trials.gov , number NCT01618656 . FINDINGS Between Sept 12 , 2012 , and Jan 18 , 2016 , 46 men were r and omly assigned to PF-04457845 and 24 to placebo . Adherence to study medication was 88 % , as confirmed by video-calling and pill count , and corroborated by corresponding drug and an and amide concentrations in blood . Relative to placebo , treatment with PF-04457845 was associated with reduced symptoms of cannabis withdrawal ( first day of treatment mean symptom score 11·00 [ 95 % CI 7·78 - 15·57 ] vs 6·04 [ 4·43 - 8·24 ] ; difference 4·96 [ 0·71 - 9·21 ] ; padj=0·048 ; second day of treatment 11·74 [ 8·28 - 16·66 ] vs 6·02 [ 4·28 - 8·47 ] ; difference 5·73 [ 1·13 - 10·32 ] ; padj=0·035 ) and related mood symptoms during the inpatient phase . Additionally , treatment with PF-04457845 was associated with lower self-reported cannabis use at 4 weeks ( mean 1·27 joints per day [ 95 % CI 0·82 - 1·97 ] vs 0·40 [ 0·25 - 0·62 ] ; difference 0·88 [ 0·29 - 1·46 ] ; p=0·0003 ) and lower urinary THC-COOH concentrations ( mean 657·92 ng/mL [ 95 % CI 381·60 - 1134·30 ] vs 265·55 [ 175·60 - 401·57 ] ; difference 392·37 [ 17·55 - 767·18 ) ] ; p=0·009 ) . Eight ( 17 % ) patients in the PF-04457845 group and four ( 17 % ) in the placebo group discontinued during the treatment period . During the 4-week treatment phase , 20 ( 43 % ) of 46 participants in the PF-04457845 group and 11 ( 46 % ) of 24 participants in the placebo group had an adverse event . There were no serious adverse events . INTERPRETATION PF-04457845 , a novel FAAH inhibitor , reduced cannabis withdrawal symptoms and cannabis use in men , and might represent an effective and safe approach for the treatment of cannabis use disorder . FUNDING United States National Institute of Drug Abuse ( NIDA ) ABSTRACT Adolescent cannabis use is associated with working memory impairment . The present r and omized controlled trial assigned adolescents ages 14 to 21 enrolled in cannabis use treatment to receive either working memory training ( experimental group ) or a control training ( control group ) as an adjunctive treatment . Cognitive function , drug use , and other outcomes were assessed before and after training . We observed few differences in cognitive , functional , or self-reported drug use outcomes as a function of training group , although tetrahydrocannabinol ( THC ) urinalysis results favored the experimental group . These findings are similar to previous studies in substance users , which have shown limited transfer effects for working memory training We conducted a review of systematic review s ( SRs ) and r and omized-controlled trials ( RCTs ) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders . Five data bases were systematic ally search ed ( 2006—August 2018 ) ; 4 SRs ( of 11 RCTs ) and 14 RCTs ( 1629 participants ) were included . Diagnoses were : dementia , cannabis and opioid dependence , psychoses/schizophrenia , general social anxiety , posttraumatic stress disorder , anorexia nervosa , attention-deficit hyperactivity disorder , and Tourette`s disorder . Outcome variables were too heterogeneous to conduct a meta- analysis . A narrative synthesis method was applied . The study quality was assessed using the risk-of-bias tool and SIGN-checklists . THC- and CBD-based medicines , given as adjunct to pharmaco- and psychotherapy , were associated with improvements of several symptoms of mental disorders , but not with remission . Side effects occurred , but severe adverse effects were mentioned in single cases only . In order to provide reliable treatment recommendations , more and larger RCTs with follow-up assessment s , consistent outcome measures and active comparisons are needed Cannabis is the most frequently used illicit drug worldwide , but little is known about the mechanisms underlying continued cannabis use . Cue-reactivity ( the physical , psychological , behavioural and neural reaction to substance-related cues ) might be related to continued cannabis use . In this 3-year prospect i ve neuroimaging study we investigated whether cannabis cue-induced brain activity predicted continued cannabis use and associated problem severity 3 years later . In addition , baseline brain activations were compared between dependent and non-dependent cannabis users at follow-up . Analyses were focussed on brain areas known to be important in cannabis cue-reactivity : anterior cingulate cortex , orbitofrontal cortex , ventral tegmental area , amygdala and striatum . At baseline , 31 treatment-naive frequent cannabis users performed a  cue-reactivity functional magnetic resonance imaging task . Of these participants , 23 completed the 3-year follow-up . None of the cue-induced region of interest activations predicted the amount of cannabis use at follow-up . However , cue-induced activation in the left striatum ( putamen ) significantly and independently predicted problem severity at follow-up ( p < 0.001 ) as assessed with the Cannabis Use Disorder Identification Test . Also , clinical ly dependent cannabis users at follow-up showed higher baseline activation at trend level in the left striatum compared with non-dependent users . This indicates that neural cue-reactivity in the dorsal striatum is an independent predictor of cannabis use-related problems . Given the relatively small sample size , these results are preliminary and should be replicated in larger sample s of cannabis users
target: RESULTS Although causality is unclear , heavy and dependent cannabis use is consistently associated with a high prevalence of comorbid psychiatric disorders and learning and memory impairments that seem to recover after a period of abstinence .
  Evidence regarding other cognitive domains and neurological consequences including cerebrovascular events is limited and inconsistent .
  Abstinence after treatment is only achieved in a minority of cases ; treatment targeted at reduction in use appears have some success .
  Potential moderators of the impact of CUD on the brain include age of onset , heaviness of use , CUD severity , the ratio of ∆9-tetrahydrocannabinol to cannabidiol , and severity of comorbid disorders .
  Current evidence of long-term effects of daily cannabis use and cannabis use disorder on brain-related outcomes is suggestive rather than conclusive but use is associated with psychiatric morbidity and with cognitive impairments that recover after a period of abstinence
background: AIMS To summarize and evaluate our knowledge of the relationship between heavy cannabis use , Cannabis Use Disorder ( CUD ) , and the brain .