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
AIMS To summarize and evaluate our knowledge of the relationship between heavy cannabis use , Cannabis Use Disorder ( CUD ) , and the brain .
Associations Between Marijuana Use and Cardiovascular Risk Factors and Outcomes
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
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
AIMS To summarize and evaluate our knowledge of the relationship between heavy cannabis use , Cannabis Use Disorder ( CUD ) , and the brain .