European Neuropsychopharmacology (2020) 33, 1–35

www.elsevier.com/locate/euroneuro

REVIEW

The blind men and the elephant:

Systematic review of systematic reviews of cannabis use related health harms

a , b ,1 ,∗ a , b ,1 c E. Campeny , H. López-Pelayo , D. Nutt , a , b a ,b a , b d C. Blithikioti , C. Oliveras , L. Nuño , R. Maldonado , e f g h G. Florez , F. Arias , S. Fernández-Artamendi , J.R. Villalbí , a , b i , j k , l ,m ,n ,o , p J. Sellarès , M. Ballbè , J. Rehm , a , b ,2 a , b , 2 M.M. Balcells-Olivero , A. Gual

a Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain b Grup Recerca Addiccions Clinic (GRAC-GRE) Psychiatry Department, Neurosciences Institute, Hospital Clínic, Universitat de Barcelona, Spain c Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK d Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain e Hospital Universitario de Ourense, Ourense, Spain f Hospital Doce de Octubre, Madrid, Spain g Universidad Loyola Andalucía, Sevilla, Spain h Public Health Agency of Barcelona, Barcelona, Spain i Catalan Institute of Oncology, Barcelona, Spain j Institut d’Investigació Biomèdica de Bellvitge, Barcelona, Spain k Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, (CAMH), Canada l Campbell Family Mental Health Research Institute, CAMH, Canada m Addiction Policy, Dalla Lana School of Public Health, University of Toronto (UofT), Canada n Department of Psychiatry, Faculty of Medicine, UofT, Canada o Epidemiological Research Unit, Klinische Psychologie & Psychotherapie, Technische Universität Dresden, Dresden, Germany p Department of International Health Projects, Institute for Leadership and Health Management, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Received 24 April 2019; accepted 17 February 2020

∗ Corresponding author at: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Grup de Recerca Addiccions Clínic (GRAC- GRE), Psychiatry Department, Hospital Clínic, C/ Mallorca 183, 08036 Barcelona, Spain. E-mail address: [email protected] (E. Campeny). 1These authors share first co-authorship. 2These authors share senior co-authorship. https://doi.org/10.1016/j.euroneuro.2020.02.003 0924-977X/ © 2020 Elsevier B.V. and ECNP. All rights reserved. 2 E. Campeny, H. López-Pelayo and D. Nutt et al.

KEYWORDS Abstract Cannabis; Cannabis is the third most used psychoactive substance worldwide. The legal status of cannabis Harms; is changing in many Western countries, while we have very limited knowledge of the public Risks; health impact of cannabis-related harms. There is a need for a summary of the evidence of Mental health; harms and risks attributed to cannabis use, in order to inform the definition of cannabis risky Organic; use. We have conducted a systematic review of systematic reviews, aiming to define cannabis- injury related harms. We included systematic reviews published until July 2018 from six different databases and following the PRISMA guidelines. To assess study quality we applied the AMSTAR 2 tool. A total of 44 systematic reviews, including 1,053 different studies, were eligible for inclusion. Harm was categorized in three dimensions: mental health, somatic harm and physi- cal injury (including mortality). Evidence shows a clear association between cannabis use and psychosis, affective disorders, anxiety, sleep disorders, cognitive failures, respiratory adverse events, cancer, cardiovascular outcomes, and gastrointestinal disorders. Moreover, cannabis use is a risk factor for motor vehicle collision, suicidal behavior and partner and child violence. Cannabis use is a risk factor for several medical conditions and negative social consequences. There is still little data on the dose-dependency of these effects; evidence that is essential in order to define, from a public health perspective, what can be considered risky use of cannabis. This definition should be based on quantitative and qualitative criteria that informs and permits the evaluation of current approaches to a regulated cannabis market. © 2020 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction the harms associated to cannabis use is scarce and often inconclusive, not discriminating for instance between dif- Cannabis is the third most prevalent psychoactive sub- ferent types of marijuana (mixed delta-9THC/cannabidiol, stance worldwide, only after alcohol and tobacco. The mixtures from “skunk”). Narrative and systematic reviews annual global estimated prevalence of cannabis use, during have been conducted on several dimensions of cannabis the last 12 months, is about 3.9%, meaning that a total of related harm ( Hall, 2015 ; “WHO | Cannabis,” 2010). More approximately 192 million people aged between 15 and 64 specifically, the American Academies of Science report years have used cannabis in 2016 ( United Nations Office on summarizes the evidence regarding multiple health effects Drugs and Crime, 2018 ). of cannabis and cannabinoid use ( National Academies of Cannabis legislative frameworks are evolving worldwide. Sciences, Engineering, 2017 ). Nevertheless, a global view As of November 2017, medical use, and consequently, from a public health perspective is still lacking ( Fischer production and sale of cannabis is allowed in Australia, et al/, n.d.). Canada, Chile, Colombia, Germany, Israel, Jamaica, The Hence, the aim of this work is to systematically review Netherlands, Peru, and in 29 US states ( Abuhasira et al, all systematic reviews on cannabis related harms, as a 2018 ). The recreational use of cannabis has been approved first step in the assessment of global risks associated to in eight states of the USA, plus the District of Columbia, cannabis use, which in the end should inform the definition Uruguay and Canada, which means that new frameworks of cannabis risky use. for controlling the production, distribution and sale of cannabis have been put in place ( Government of Canada, 2018 ). In countries like Spain, Belgium and The Nether- 2. Experimental procedures lands, cannabis has an ambiguous legal situation and laws concerning production, distribution and sale are not settled This systematic review was based on the Preferred Reporting Items yet ( United Nations Office on Drugs and Crime, 2018 ). for Systematic Reviews and Meta-Analyses (PRISMA) guidelines These legal changes reflect in part a social perception ( Liberati et al., 2009 ). This protocol provides a checklist for report- of decreased risks associated to cannabis ( United Nations ing systematic reviews ( Table 1 ). The study protocol was registered Office of Drugs and Crime, 2017 ). In Western countries, and with PROSPERO (registration number: CRD42018089130). regardless of its legal situation, risk perception of cannabis use is closer to that of alcohol and tobacco than to illicit drugs such as cocaine or heroin. This could contribute to 2.1. Search strategy higher cannabis use prevalence ( Parker and Anthony, 2018 ) An electronic search was made in Science Direct (1823 –July and in fact, the prevalence of cannabis use in these coun- 2018), Medline (1950 –July 2018), EBM Reviews-Cochrane Database tries is much closer to alcohol and tobacco than to illegal of Systematic Reviews (2005 –July 2018), EBM Reviews –ACP drugs (United Nations Office on Drugs and Crime, 2018). Journal Club (1991 – July 2018), and EBM Reviews-Cochrane Central Such high prevalence and low social risk perception point Register of Controlled Trials (1991 –July 2018). The search was to the need to develop secondary prevention strategies split into six core concepts, for an explanatory purpose: a) social: aiming at the early identification of risky cannabis users social, economy, absenteeism, learning; b) organic: disease, ( Casajuana et al., 2016 ). However, an appropriate identifi- disturbances, “organic pathology”; c) mental health: “psychiatric cation of ‘risky use’ is still needed, since the literature on disorder”, “mental health”; d) injury: injury, violence, traffic; Cannabis use related harms 3

Table 1 PRISMA 2009 checklist. Section/topic # Checklist item Reported on page # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; 2 data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 3 Objectives 4 Provide an explicit statement of questions being addressed with reference to 3 participants, interventions, comparisons, outcomes, and study design (PICOS). METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web 4 address), and, if available, provide registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report 4 characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, 4 contact with study authors to identify additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any 4 limits used, such that it could be repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in 4 systematic review, and, if applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, 4-5 independently, in duplicate) and any processes for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding 4 sources) and any assumptions and simplifications made. Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including - studies specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). - Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, - including measures of consistency (e.g., I 2 ) for each meta-analysis. Risk of bias across 15 Specify any assessment of risk of bias that may affect the cumulative evidence - studies (e.g., publication bias, selective reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, - meta-regression), if done, indicating which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the 5-11 review, with reasons for exclusions at each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., 5-11 study size, PICOS, follow-up period) and provide the citations. Risk of bias within 19 Present data on risk of bias of each study and, if available, any outcome level - studies assessment (see item 12). Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) - studies simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and - measures of consistency. ( continued on next page ) 4 E. Campeny, H. López-Pelayo and D. Nutt et al.

Table 1 ( continued ) Section/topic # Checklist item Reported on page # Risk of bias across 22 Present results of any assessment of risk of bias across studies (see Item 15). - studies Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup - analyses, meta-regression [see Item 16]). DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main 12-15 outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at 14 review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, 15 and implications for future research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., 16 supply of data); role of funders for the systematic review. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta- Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097.

e) mortality: mortality, hospitalization, morbidity; f) somatic: 3. Results chronic, pathology ∗, “health impact ∗”, infect ∗, cancer, circulat ∗, ∗ ∗ ∗ ∗ ∗ respirat , pulm , gastro , bronch , pregnan , prenatal, HIV, skin. We found 6,725 unique entries of systematic reviews and A combination of the following key words was used with every core meta-analyses. Finally, 44 publications were included concept: cannabis, marihuana, delta 9-tetrahydrocannabinol, risk, ( Fig. 1 ). The results of the quality assessment indicated an harm, consequences, “systematic review” and meta-analysis.

A secondary search was performed, by reviewing reference lists AMSTAR 2 average of 60.1% affirmative punctuation. in order to find additional relevant studies. The six dimensions previously included for the search strategy resulted in three domains: 1) mental health ( Table 2 ); 2) somatic ( Table 3 ); 3) injury and mortality

2.2. Selection criteria (Table 4). Main results are synthesized in Table 5.

Full systematic reviews and meta-analyses of studies examining harms, risks and consequences of cannabis use up to July 2018, 3.1. Mental health harms were eligible for inclusion. Exclusion criteria were: Animal stud- ies, laboratory and neuroimaging studies, synthetic cannabinoid Nineteen systematic reviews were included, with an av- studies, studies based on proving the beneficial effects of cannabi- erage quality of 65.1% (AMSTAR 2). Reviews included the noids, studies based on proving the efficacy of treatments and following outcomes: psychosis, affective disorders, anxiety interventions, studies based on proving the efficacy of cannabis disorders, pathological gambling, personality disorders and use identification. No languages restrictions were applied. cannabis dependence.

3.1.1. Psychosis (number of systematic reviews and 2.3. Data extraction and quality assessments meta-analyses: 10)

EC and HL-P searched the articles and independently screened Multiple studies have revealed a clear relationship between titles and abstracts of retrieved studies for eligibility. Both review- cannabis consumption and psychotic symptoms. The risk ers met afterward to discuss inclusion/exclusion of the articles; for developing schizophrenia (OR 3.9 CI95% 2.84–5.34) any disagreement was discussed together with two senior re- and other psychotic disorders (OR 5.07 CI95% 3.62–7.09) is searchers (MB and AG). From the selected systematic reviews and higher among heavy cannabis users, compared to non-users meta-analysis the following information was extracted: authors, ( Marconi et al., 2016a ). Psychotic symptoms are attributed year of publication, aims, number of papers, number of subjects to cannabis use in different forms: using cannabis at least included, type of studies, age range, gender, pattern of cannabis five times per month (OR 2.2 CI95% 1.5–3.3), up to fifty times use, outcomes and limitations. per month (OR 3.1 CI95% 1.7–5.5), using cannabis before 15 To assess study quality, two researchers applied the AMSTAR 2 years old (OR = 4.5, CI 95% 1.1–18.2), and heavy cannabis tool “assessment of multiple systematic reviews”, for randomized and non-randomized systematic reviews of healthcare interven- use (OR 3.59 CI95% 2.42–5.32) (Le Bec et al., 2009; Marconi tions ( Shea et al., 2017 ). In case of doubts or discrepancy in any et al., 2016a ). The risk of psychotic disorders is increased by item, an agreement between both researchers was achieved. gene-environment interaction (e.g. with variants of COMT All reported results are statistically significant unless otherwise 158Val and DRD2 rs1076560 T) ( Misiak et al., 2017 ). Evi- specified. dence is still unclear concerning lifetime cannabis use (vs. Cannabis use related harms 5

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Fig. 1 PRISMA 2009 flow diagram. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). P referred R eporting I tems for S ystematic Reviews and M eta- A nalyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi: 10.1371/journal. pmed1000097 . no use) and incidence of psychosis: OR 1.41 CI95% 1.20–2.84 is associated with an increased risk of relapse or rehospi- ( Moore et al., 2007 ), OR 1.14 CI95% 0.86–1.52 ( Kraan et al., talization and lower treatment adherence; although the 2016 ). The association between cannabis use and transi- authors did not provide specific measures of this association tioning to a first episode of psychosis is well documented. ( Zammit et al., 2008 ). Cannabis use has an impact on incidence (OR1.77 CI95% Only one review did not find an association between 1.20–2.61) and prevalence (OR2.51 CI95% 1.84–3.43) of psy- cannabis use and psychosis. This could be due to that nearly chotic experiences ( Linscott and van Os, 2013 ). Moreover, all the reviewed studies had a cross-sectional design and age at onset of psychosis is 2.7 years earlier for cannabis the few longitudinal studies included had limited sample users (95% CI, −0.526 to −0.301) ( Large et al., 2011 ). sizes ( Large et al., 2014 ). Evidence supports that cannabis use worsens psychosis prognosis. Smoking cannabis is related with fewer total 3.1.2. Affective disorders (number of systematic neurological soft signs, defined as minor neurological ab- reviews and meta-analyses: 4) normalities in sensory and motor performance (OR 0.46 Several studies have suggested that cannabis consump- CI95% 0.07–0.98) ( Ruiz-Veguilla et al., 2012 ). Moreover, not tion may represent a risk factor for depression (OR 1.17 using cannabis is considered a protective factor on positive CI95% 1.05–1.30) ( Lev-Ran et al., 2014 ), mainly after (OR 0.42 CI95% 0.34–0.51) and negative symptoms (OR long-term and heavy consumption (at least one joint per 0.18 CI95% 0.15–0.21) and disorganization (OR 0.33 CI95% week or DSM-IV Cannabis Use Disorder) (OR 1.49 CI95% 0.27–0.40) ( Szoke et al., 2014 ). In addition, cannabis use 1.15–1.94) ( Moore et al., 2007 ) (OR 1.62 CI95% 1.21–2.16) Cannabis use related harms 21

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events events Area Traffic Traffic Violence

continued

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and

4 R.

of al. al.

(2013) et (2018) et (2017) year publication Table Authors Elvik, Hostiuc, Choenni, Cannabis use related harms 23

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et et (2017) year publication Table Authors Li, Coentre, Cannabis use related harms 25

Table 5 Main results. Main affectations of cannabis use Mental health Psychosis (incidence, early onset, larger effects) Affective disorders (development of depression, suicidal ideation, development of bipolar disorder) Anxiety (development of anxiety symptoms and higher anxiety outcomes) Organic/somatic Respiratory (pneumothorax, emphysema, chronic obstructive pulmonary disease) Cancer (lung cancer and testicular germ cell tumor) Cardiovascular (tachycardia, hypertension) Sport (lower work-load and strength) Gastrointestinal (vomiting and diarrhea) Nervous system (dizziness, exacerbation of multiple scleroses, non-restful sleep) Cognitive (memory, psychomotor function, executive function, deleterious effect, sustained attention and educational attainment) Injury Suicidal behavior (ideation and attempt) Violence (intimate partner violence and child maltreatment) Motor vehicle collision

( Lev-Ran et al., 2014 ). One study found that cannabis use 3.1.6. Cannabis dependence (number of systematic in any form is associated with higher levels of depression reviews: 2) (correlation coefficient r 0.118 CI95% 0.068–0.168) ( Cairns Daily and weekly cannabis use, early onset of use (11- et al., 2014 ) and that co-occurring cannabis and tobacco 15 years) and positive psychotropic effects of cannabis use in adolescence is associated with increased depressive are predictive factors of cannabis dependence, although symptoms in adulthood and decreased life satisfaction, the authors did not provide specific measures of associ- but the authors did not provide specific measures of the ation ( Schlossarek et al., 2016 ). Moreover, adolescence association ( Peters et al., 2012 ). co-occurring cannabis and tobacco use are associated Any use of cannabis has been associated with bipolar dis- with cannabis abuse or dependence at age 24 (OR 27; order (OR 4.98 CI95% 1.80–13.81) ( Marangoni et al., 2016 ). CI not specified), and nicotine dependence between 23 One study found that frequent cannabis use increases the and 27 years old (OR 1.89; CI not specified). In addition, risk of bipolar disorders: 1-4 times of cannabis use per week co-occurring cannabis and tobacco users are more likely to (OR 8.93 CI95% 2.77–28.82). Another study found that daily report cannabis withdrawal syndrome symptoms, includ- use increases the risk for bipolar disorder (OR 2.47 CI95% ing depressed mood, headaches, sweating/heart-racing, 1.03–5.92) ( Marangoni et al., 2016 ). Moreover, one study nausea and yawning; the authors however did not provide found that cannabis abuse and dependence are risk factors specific measures of the association ( Peters et al., 2012 ). for the development of bipolar disorder (OR 2.12 CI95% Co-occurring cannabis and tobacco users presented a 1.10–4.08) ( Marangoni et al., 2016 ). lower mean of continuous cannabis abstinence during treatment compared to current dependent cannabis users 3.1.3. Anxiety disorders (number of systematic who never smoked cigarettes (2.8 weeks of abstinence vs. reviews: 3) 3.7 weeks) or were ex-cigarette smokers (2.8 weeks of Evidence supports that cannabis use is linked with the de- abstinence vs. 5.6 weeks) ( Peters et al., 2012 ). velopment of anxiety symptoms in general population (OR 1.15 CI95% 1.03–1.29) ( Tw o m e y, 2017 ), and also when there is co-occurrence of cannabis and tobacco use; although the 3.2. Organic/somatic risks authors did not provide specific measures of the association ( Peters et al., 2012 ). Moreover, cannabis use is a risk factor Seventeen systematic reviews were included, with a Qual- for anxiety disorders (OR 2.90 CI95% 1.11–7.57) ( Moore ity average (AMSTAR 2) of 56.5% affirmative punctuation. et al., 2007 ). Reviews included the following outcomes: respiratory ef- fects, cancer, gastrointestinal alterations, cardiovascular 3.1.4. Pathological gambling (number of systematic impairment, nervous system disorders, cognitive impair- reviews: 1) ment, sleep disturbances, motor coordination and postnatal The relationship between cannabis use and problem gam- consequences. bling remains still unclear. However, evidence supports that cannabis use is one of the multiple risk factors related with 3.2.1. Respiratory effects (number of systematic problem gambling ( Dowling et al., 2017 ). reviews and meta-analyses: 3) There is evidence of a respiratory harm attributable to mar- 3.1.5. Personality disorders (number of systematic ihuana smoking. There is an increased risk of lung cancer reviews: 1) ranging between 8% and 410% due to the use of inhalational The association of cannabis use and personality disorders marihuana (after adjusting for confounding factors); being has been scarcely studied and up to date results are such ample range a result of the heterogeneity of samples inconclusive ( Bouso et al., 2018 ). and study designs. Besides, inhalational marihuana has an 26 E. Campeny, H. López-Pelayo and D. Nutt et al. impact on the development of spontaneous pneumothorax, 3.2.6. Cognitive impairment (number of systematic bullous emphysema, bronchodilatation and chronic obstruc- reviews and meta-analyses: 6) tive pulmonary disease. Moreover, a variety of symptoms are There is enough evidence to endorse the claim of a negative associated to current marijuana smoking including wheez- impact of cannabis use on cognition, even after the person ing (OR 2.01 CI95% 1.50–2.70), shortness of breath, cough is no longer acutely intoxicated (“stoned”) by cannabis (OR 1.73 CI95% 1.21–2.47), phlegm production and chronic use. Memory is the most consistently impaired cognitive sputum production (OR 1.53 CI95% 1.08–2.18) ( Ghasemiesfe domain ( g = -0.761 CI95% −1.30 to −0.22) ( Bogaty et al., et al., 2018 ; Martinasek et al., 2016 ). Moderate to heavy 2018 ). Moreover, cannabis use leads to cognitive adverse marijuana smoking is associated with cough (OR 4.37 CI95% effects on multiple aspects of cognition. Cannabis use has 1.71–11.19), sputum production (OR 3.40 CI95% 1.99–5.79), detrimental effects on everyday cognition and reduces edu- wheezing (OR 2.83 CI95% 1.89–4.23) and dyspnea (OR 1.56 cational attainment (OR 5.6 95%CI 2.0–1.5) ( Macleod et al., CI95% 1.33–1.83) ( Ghasemiesfe et al., 2018 ). 2004 ), leading to memory and learning deficits ( r = 0.229, Only one review did not find any adverse effect on lung 95%CI 0.130–0.323) ( Bogaty et al., 2018 ; Broyd et al., function due to inhalational cannabis use ( Nugent et al., 2016 ; Carrigan and Barkus, 2016 ; Ganzer et al., 2016 ). 2017 ). Chronic cannabis use alters psychomotor ( r = 0.478, 95%CI 0.394–0.555), executive functions ( Broyd et al., 2016 ), attention and concentration ( r = 0.273, 95%CI 0.109–0.423) 3.2.2. Cancer (number of systematic reviews and ( Ganzer et al., 2016 ). Adolescent co-occurring cannabis and meta-analyses: 2) tobacco use is associated with fewer years of education, Evidence supports that cannabis use has an impact on tes- although the authors did not provide specific measures of ticular germ cell tumor (TGCT) development. Cannabis use the association ( Peters et al., 2012 ). up to 10 years (OR 1.50 CI95% 1.08–2.09), as well as using Evidence supports that an older age of users is predic- it weekly or more often (OR 1.92 CI95% 1.35–2.72), has an tive of worse performance in processing speed, sustained impact on TGCT development. More specifically, current attention and verbal memory ( Bogaty et al., 2018 ). cannabis use, defined as using at least on a weekly basis, is a risk factor for non-seminoma development (OR 2.09 CI95% 1.29–3.37) (OR 2.59 CI95% 1.60–4.19) ( Gurney et al., 2015 ). 3.2.7. Maternal-fetal health (number of systematic At the present time, there is no evidence of a rela- reviews and meta-analyses: 2) tionship between cannabis use and head and neck cancer Cognitive functioning and behavioral disturbances are the development (OR 1.021 CI 95% 0.912–1.14; p = 0.718) ( de most significant outcomes of impairment due to maternal Carvalho et al., 2015 ). marijuana use, although the authors did not provide specific measures of the association ( Irner, 2012 ). The other systematic review is inconclusive regarding the 3.2.3. Cardiovascular (number of systematic reviews impact of maternal cannabis use on offspring behavior (OR and meta-analyses: 2) 1.29 CI95% 0.93–1.81; I2 = 0) ( Ruisch et al., 2018 ). It is claimed that cannabis use increases the risk for car- diovascular diseases, particularly ischemic strokes (OR 2.68 CI95% 1.03–6.99), hemorrhagic strokes (OR 1.18 CI95% 1.12– 1.24), ischemic heart disease (OR 4.8 CI95% 2.9–9.5) and 3.3. Injury risks and social consequences thromboangiitis obliterans (TAO) (OR 3.5 CI95% 1.08–5.08) ( Jouanjus et al., 2017 ). Ten systematic reviews were eligible for the injury di- Marihuana precipitates angina at a lower work-load and mension and had a quality average of 52.4% affirmative probably reduces subject’s strength. Also aerobic exer- punctuation. Reviews included the following outcomes: cise causes small rises in THC concentrations ( < 1 ng/mL) impact on suicidal behavior and mortality, intimate partner ( Kennedy, 2017 ). violence, child maltreatment, motor vehicle collision.

3.2.4. Gastrointestinal (number of systematic reviews 3.3.1. Suicidal behavior (number of systematic reviews and meta-analyses: 1) and meta-analyses: 3) Intensive vomiting and persistent diarrhea are the most Cannabis use has an impact on suicidal behavior. Suicidal prevalent side effects associated to medical use of cannabis ideation and suicide attempts are linked to cannabis use (OR ( Wang et al., 2008 ). 1.43 CI95% 1.13–1.83) (OR 2.23 CI95% 1.24–4.00). Moreover, depressive symptoms and cannabis use are predominant risk factors for suicide commitment ( Coentre et al., 2017 ). In 3.2.5. Nervous system (number of systematic reviews addition, heavy cannabis use is associated with higher risk and meta-analyses: 2) of suicide ideation (OR 2.53 CI95% 1.00–6.39) and attempt Dizziness (15.5%) and relapse of multiple scleroses (12.8%) (OR 3.20 CI95% 1.72–5.94) ( Borges et al., 2016 ). Suicidal in patients with this disorder are the most common side ef- ideation is also linked to frequent use (OR = 4.55, 95% CI fects reported in medical cannabis use ( Wang et al., 2008 ). 1.37–15.11) ( Moore et al., 2007 ). Recreational use of cannabis accounts for non-restful Association of cannabis use and other forms of mortal- sleep, and may particularly interrupt slow wave sleep ity has been scarcely studied and up to date results are ( Gates et al., 2014 ). inconclusive ( Calabria et al., 2010 ). Cannabis use related harms 27

3.3.2. Violence (number of systematic reviews and has the lowest quality average (52.4%), and scores range meta-analyses: 3) from 12.5% to 78.1%, with higher quality scores found in There is evidence of a relationship between cannabis use studies linking cannabis use to traffic accidents and social and violence. Cannabis use is reported to be associated sequelae ( Table 4 ). These results compel us to interpret the with intimate partner violence and child maltreatment following conclusions with caution. perpetration, but effect sizes are not provided ( Choenni Moreover, causal inference is difficult to demonstrate et al., 2017 ). Moreover, there is a relationship (small, in observational studies of environmental risk factors positive and statistically significant) between cannabis ( Rothman and Greenland, 2005 ; Vandenbroucke et al., use and being a victim of homicide as 6% of them tested 2016 ). Despite this, we have screened for those systematic positive on marihuana use (CI95% 2–17%) ( Kuhns et al., reviews with at least a 70% AMSTAR quality and we have 2009 ). In addition, co-occurring cannabis and tobacco users searched for Mendelian Randomization studies (MR). In case have more legal problems and are more likely to have been there weren’t, the Bradford Hill criterions for causality drunk in the previous 30 days, although these results did not were applied ( Bradford et al., 1965 ). MR uses genetic differ from tobacco users. Authors did not provide specific variants to determine whether an observational association measures of association ( Peters et al., 2012 ). between a risk factor and an outcome is consistent with a causal effect. Remarkably, these studies are of great impor- 3.3.3. Motor vehicle collision (number of systematic tance given their high level of evidence. In line with this, reviews and meta-analyses: 5) MR showed a strong impact of cannabis use on psychotic Evidence clearly supports an association between cannabis disorders ( Gage et al., 2017 ; Vaucher et al., 2018 ), and a use and risk of collision (OR 1.92 CI95% 1.35–2.73). Being causal relationship between cannabis use and alcohol use considered responsible of the collision (OR 1.65 CI95% and tobacco smoking ( Verweij et al., 2018 ). 1.11–2.46; p = 0.07), non-fatal collisions (OR 1.74 CI95% According to the Bradford Hill criterions, 11 associated 0.88–3.46; p = 0.11), becoming involved in an accident (OR outcomes (anxiety, depression, cognition, TGCT, respiratory 2.66 CI95% 2.07–3.41) and increased crash risk (OR 1.92 outcomes, non-serious adverse events, lung cancer, motor CI95% 1.35–2.73) are attributable to cannabis use ( Asbridge vehicle collision, suicidal ideation, educational attainment et al., 2012 ; Elvik, 2013 ; Li et al., 2012 ). Fatal collisions are and other drugs use) were found (strength), and had at also associated to cannabis use (OR 2.10 CI95% 1.31–3.36) least one longitudinal study that found association (tempo- (OR 1.56 CI95% 1.16–2.09) ( Elvik, 2013 ; Hostiuc et al., rality). Then, six of the previous eleven outcomes (motor 2018 ). Moreover, heavy cannabis use ( > 50 times by age 18 vehicle collisions, suicidal ideation, anxiety, depression, years, or > 10 joints per week) has also an impact on fatal educational attainment and respiratory outcomes) had two motor vehicle accidents ( Calabria et al., 2010 ). or more prospective studies that support association to cannabis use (consistency). Regarding these last six final outcomes, we can affirm 4. Discussion that there is a causal relationship, since the following Bradford Hill criteria were met: dose-response, plausibility, This systematic review aimed to identify the impact of coherence and experiment ( Table 6 ). Cannabis use effects cannabis use on different health outcomes in order to were comparable with those of tobacco (combustion) and generate a global picture of cannabis-related harms. We alcohol (cognitive impairment). The criteria of specificity identified 44 systematic reviews, which included 1,053 may be hard to reach in this field since cannabis use is articles covering a broad spectrum of negative health often mixed with tobacco, alcohol and other psychoactive outcomes directly linked to cannabis use. However, some substances. Focusing on the mental health domain, we difficulties arise when pulling together the results. have found a causal association for psychosis, anxiety and Frequency and more particularly quantity of cannabis depression. In line with these outcomes, several studies used are usually vaguely defined. More specifically, there have reaffirmed that adolescent cannabis use has a strong is no consensus on the definition of heavy use and in some impact on psychosis and incidence of schizophrenia ( Di Forti cases this variable is not even defined or specified ( Borges et al., 2019 ; Hall and Degenhardt, 2009 ; Hjorthoj et al., et al., 2016 ; Ghasemiesfe et al., 2018 ; Marconi et al., 2018 ; Shahzade et al., 2018 ; Volkow et al., 2016 ). Recent 2016b ; Peters et al., 2012 ). The revised evidence does studies reported that higher levels of cannabis use increase not discriminate either between the different types of the risk for developing major depression and bipolar disor- marijuana (mixed delta-9THC/cannabidiol, mixtures from der, as well as for maintaining high levels of anxiety over “skunk”). Patterns of use are not clearly described, and time (Jacqueline Duperrouzel et al., 2018 ; Rasic et al., tobacco and alcohol are often confounding factors difficult 2013 ). to isolate. Moreover, the quality of most of the systematic We have found a causal association for lower educational reviews is between low and moderate according to AMSTAR attainment and respiratory outcomes. Additional evidence 2 (60.1% affirmative punctuation). Moreover, according to supports these outcomes, showing that regular cannabis AMSTAR 2, the quality of the reviews varies quite dramat- smokers are more prone to report chronic bronchitis and in- ically within the 3 studied domains. Mental health reviews creased respiratory infections ( Hall and Degenhardt, 2009 ; have the highest quality average (65.1%) and scores range Shahzade et al., 2018 ). More recent studies report a sig- between 37.5% and 87.5% ( Table 2 ); reviews included in nificant association between marijuana use and respiratory the organic domain have a quality average of 56.5% and diseases, lung cancer and chronic obstructive pulmonary scores range between 81.3% in the case of gastrointestinal disease ( Berthiller et al., 2008 ; José Miguel Chatkin et al., disorders and 25% for respiratory problems ( Table 3 ). Injury 2017 ). Additionally, reviewed evidence shows that chronic 28 E. Campeny, H. López-Pelayo and D. Nutt et al.

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attain- ment vehicle crash ∗ ∗∗ Table Educational Motor CU Cannabis use related harms 31 heavy use may impact fluency abilities and acutely impair heart disease, which are the main causes of death ( West, attention, concentration, decision making, inhibition, im- 2017 ). pulsivity and working memory ( Crean et al., 2011 ), and This review has several limitations. Firstly, a system- similar results have been shown in daily chronic users (10 atic review of systematic reviews may not include all the years or more) ( Hall and Degenhardt, 2009 ). In line with relevant recent studies, and some breaking advances on this, young people who use cannabis are at increased risk cannabis-related harms might have been excluded. Nev- for poor school performance, reduced educational attain- ertheless, we can guarantee that the results gathered in ment and early school leaving and ( Danielsson et al., 2015 ; our study, and their discussion, are strongly supported by Hall, 2015 ; Boden et al., 2017 ; Tu et al., 2008 ). However, previous systematic reviews. Secondly, gender differences temporality was difficult to establish, since only one of the cannot be taken into account, since most studies do not included studies was longitudinal, and as a consequence provide results by gender. Further studies in the field should chronicity of alterations was not able to define. address this issue. Thirdly, dose and frequency are not pre- Referring to injury, we found a causal relationship be- cisely described in most of the reviewed literature, which tween cannabis use and both motor vehicle crashes and sui- limits the accurate interpretation of specific dose-effect cidal ideation. Recent studies confirm that cannabis use in- relationships. This highlights the pressing need to include creases the risk of suffering motor vehicle accidents ( Balzo data on quantity, frequency and patterns of use in future et al., 2018 ; Wettlaufer et al., 2017 ), but much of this data studies. Despite these limitations, our systematic review of has been criticized for systematic bias ( Rogeberg, 2019 ). systematic reviews provides a comprehensive overview of Moreover, our review found that cannabis use is associ- the multiple harms related to cannabis use that can pave ated with some other outcomes, even though causality was the way both for future research and policies. not well established. Recent studies support that cannabis In conclusion, cannabis use is associated to relevant use leads to cannabis withdrawal syndrome ( Budney et al., harms in the mental health domain (psychosis, bipolar dis- 2019 ; Livnea et al., 2019 ). Also, using cannabis immediately order, depression, anxiety and cannabis dependence), the prior to or while gambling was associated with greater organic domain (respiratory, cardiovascular, gastrointesti- gambling amounts, frequency, negative consequences and nal, nervous system, cognitive functions and some cancers) problem severity ( Cronce et al., 2017 ). In the organic and injuries (motor vehicle collisions, violence and suicidal domain, a recent study found that cannabis use during behavior). However, evidence of causality for many of these pregnancy was a risk factor leading to adverse outcomes in outcomes is missing. Therefore, the reviewed evidence the newborn ( Petrangelo et al., 2018 ). Another study found shows that cannabis use related harms are not limited to that depressive symptoms and shorter breastfeeding in the the more widely-studied psychosis or other mental health baby are linked to marijuana use ( Ko et al., 2018 ). In the issues, and that these effects compel us to considerate injury domain, one study showed a significant association cannabis use as a relevant public health problem. However, between marijuana use and psychological, physical and sex- there is still little data on the dose-dependency of these ual intimate partner violence perpetration ( Shorey et al., effects; evidence that is essential in order to define, from 2018 ). In the same line, a study reported that persistency of a public health perspective, what can be considered risky cannabis use is associated with an increased risk of subse- use of cannabis. This definition should be based on quanti- quent violence ( Dugré et al., 2017 ). Moreover, cannabis use tative and qualitative criteria that informs and permits the during adolescence increases levels of callous-unemotional evaluation of current approaches to a regulated cannabis traits, which in turn lead to problematic behaviors ( Hawes market. et al. , n.d.). The National Academies of Science (2017) reported ev- idence concerning to cannabis use related harm and, even though we found similar outcomes, our results partially Funding differ. In fact, our systematic review adds to the NAS report evidence for cardiovascular risk (ischemic strokes, hyper- This study is funded by the Spanish grant of Plan Nacional tension and TAO), cognitive attainment (fewer years of Sobre Drogas, Ministerio de Sanidad y Consumo (PNSD education, lower education attainment, concentration al- 132373 - 2017I053 - 603 ; Antoni Gual Solé). The conclusions teration and detrimental effects on everyday cognition), in- of the article are only the responsibility of the authors jury implications (violence perpetration, homicide victims, and do not necessarily represent the official views of crash responsibility and crash involvement) and prenatal ex- the institutions, who had no further role in study design, posure (cognitive dysfunction and behavioral disturbances) collection, analysis and interpretation of the data; in the ( National Academies of Sciences, Engineering, 2017 ). writing of the paper; or in the decision to submit the paper When comparing cannabis-related harms with those for publication. associated to alcohol use, evidence is stronger for the lat- H.L.-P. received funding from the S panish Ministry of est. Particularly, the following diseases are more intensely Economy and Competitiveness, Instituto de Salud Carlos related to alcohol rather than cannabis: unipolar depressive III through a ‘Rıo Hortega’ contract ( CM17/00123 , to Dr. disorders, ischemic heart disease, ischemic stroke, road López-Pelayo), FEDER. traffic accidents, self-inflicted injuries and violence ( Rehm This work is supported by the following institutions: et al., 2009 ). In the case of tobacco smoking related-harms, Institut d’Investigacions Biomèdiques August Pi i Sunyer evidence is more conclusive than that of cannabis use. (IDIBAPS), University of Barcelona, Hospital Clínic i Univer- Strong evidence supports that tobacco smoking causes lung sitari de Barcelona and CERCA Programme / Generalitat de cancer, chronic obstructive pulmonary disease and coronary Catalunya. 32 E. Campeny, H. López-Pelayo and D. Nutt et al.

Contributions Broyd, S.J., van Hell, H.H., Beale, C., Yücel, M., Solowij, N., 2016. Acute and chronic effects of cannabinoids on human cognition—

MB, AG and HL-P designed the study. EC, HL-P, MB and a systematic review. Biol. Psychiatry 79 (7), 557–567. https:// doi.org/10.1016/j.biopsych.2015.12.002 . AG wrote the first draft of the manuscript. All the other Budney, A.J. , Sofis, M.J. , Borodovsky, J.T. , 2019. An Update on authors reviewed and approved the final paper. Cannabis Use Disorder with Comment on the Impact of Policy Related to Therapeutic and Recreational Cannabis Use, 269, pp. 73–86 .

Conflict of interest Cairns, K.E., Yap, M.B.H., Pilkington, P. D . , Jorm, A.F., 2014. Risk and protective factors for depression that adolescents can mod- ify: a systematic review and meta-analysis of longitudinal stud-

H.L.-P.: has received travel grants from the laboratories ies. J. Affect. Disord. 169, 61–75. https://doi.org/10.1016/j. honoraria and travel grants from Janssen and Lundbeck, jad.2014.08.006 . none of these COI are related to the current research. The CALABRIA, B., DEGENHARDT, L., HALL, W., LYNSKE Y, M., 2010. Does other authors declare that they have no known conflicts of cannabis use increase the risk of death? Systematic review of interest. epidemiological evidence on adverse effects of cannabis use. Drug Alcohol Rev. 29 (3), 318–330. https://doi.org/10.1111/j. 1465-3362.2009.00149.x . Carrigan, N., Barkus, E., 2016. A systematic review of the relation- Acknowledgements ship between psychological disorders or substance use and self- reported cognitive failures. Cogn. Neuropsychiatry 21 (6), 539– CERCA Programme / Generalitat de Catalunya. 564. https://doi.org/10.1080/13546805.2016.1250620 . Institut d’Investigacions Biomèdiques August Pi i Sunyer Casajuana, C., López-Pelayo, H., Balcells, M.M., Miquel, L., (IDIBAPS), University of Barcelona, Hospital Clínic i Univer- Colom, J., Gual, A., 2016. Definitions of risky and sitari de Barcelona. problematic cannabis use: a systematic review. Subst. Use Misuse 51 (13), 1760–1770. https://doi.org/10.1080/10826084. Plan Nacional Sobre Drogas, Ministerio de Sanidad y Con- 2016.1197266 . sumo. Choenni, V. , Hammink, A., van de Mheen, D., 2017. Association be-

Ministry of Economy and Competitiveness, Instituto de tween substance use and the perpetration of family violence in Salud Carlos III through a ‘Rıo Hortega’ industrialized countries. Trauma, Violence Abuse 18 (1), 37–50. Janssen and Lundbeck. https://doi.org/10.1177/1524838015589253 . Coentre, R., Talina, M.C., Góis, C., Figueira, M.L., 2017. Depressive

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