Associations between cannabis use, tobacco use and co-use with brain volume: a systematic review and meta-analysis

Background and Aims Cannabis is the most widely used illicit drug worldwide and is often co-used with tobacco, the leading cause of preventable death. Although cannabis and tobacco have distinct neurobiological actions, their associations with brain volumes are unclear. We aimed to systematically review brain volumes associated with cannabis use, tobacco use, and their co-use. Design Systematic review and meta-analysis (CRD42022356982). Setting SCOPUS, PubMed and PsycINFO were searched up to 5 September 2024 Participants Searches yielded 103 studies: 57 investigated cannabis use, 45 investigated tobacco use, and one investigated tobacco and cannabis co-use. Measurements We extracted adjusted and unadjusted estimates. Random effects meta-analyses were stratified by exposure and study design across 33 brain regions. Risk of bias was assessed using a modified version of the Newcastle-Ottawa scale. Findings Meta-analysis of adjusted estimates from cross-sectional studies indicated smaller amygdala volumes (k = 17, g = 0.13, 95%CI [0.03, 0.23]) in people who use cannabis compared to controls. Relative to controls, people who smoked tobacco had smaller volumes in the amygdala (k = 5, g = 0.17, 95%CI [0.04, 0.31]), insula (k = 5, g = 0.17, 95%CI [0.06, 0.27]), pallidum (k = 5, g = 0.17, 95%CI [0.13, 0.21]) and total grey matter volume (TGMV) (k = 7, g = 0.17, 95%CI [0.04, 0.30]). Longitudinal studies indicated a larger decrease in TGMV in people who smoke tobacco (k = 5, g = 0.05, 95%CI [0.01, 0.10]) relative to controls.

There was evidence that cannabis use was associated with smaller volume in the amygdala. Tobacco use was associated with smaller amygdala, insula, pallidum and total grey matter volume. Competing Interest Statement Gemma Taylor previously received funding from Pfizer, who manufacture smoking cessation products, for research unrelated to this study. Gemma Taylor previously worked at a health economics consultancy providing statistical and research support for pharmaceutical companies for medicines unrelated to this manuscript. There are no other conflicts of interest to declare. Funding Statement Katherine Sawyer, Constantinos Constantinides and Sorcha Hamilton are supported by grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. Tom P Freeman is funded by a UKRI Future Leaders Fellowship (MR/Y017560/1). Esther Walton is funded by UK Research and Innovation (UKRI) under the UK governments Horizon Europe / ERC Frontier Research Guarantee (BrainHealth, grant number EP/Y015037/1) and Wellcome (315898/Z/24/Z). Jorien Treur is supported by a European Research Council (ERC) Starting grant (UNRAVEL-CAUSALITY, grant number 101076686). Valentina Lorenzetti was supported by an AI and Val Rosenstrauss Senior Research Fellowship (2022-2026), by a National Health and Medical Research (NHMRC) Investigator Grant (2023-2027 ID:2016833), and by an Australian Catholic University competitive scheme. Anna Blackwell and Shadi Daryan are funded by a Cancer Research UK grant (PPRCPJT\100023). Chloe Burke was funded by a PhD studentship awarded by the Society for the Study of Addiction (SSA). Sarah Dance is funded by a University of Bath PhD studentship. Tom Jenkins receives PhD studentship funding from Mental Health Research UK and the Schizophrenia Research Fund. Gemma Taylor reports funding from a Cancer Research UK Population Researcher Postdoctoral Fellowship award (C56067/A21330), and project grant (PPRCPJT/100023). Funding sources were not involved in the study design, collection, analysis and interpretation of data, writing of the report and decision to submit the article for publication. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Conflicts of interest: Gemma Taylor previously received funding from Pfizer, who manufacture smoking cessation products, for research unrelated to this study. Gemma Taylor previously worked at a health economics consultancy providing statistical and research support for pharmaceutical companies for medicines unrelated to this manuscript. There are no other conflicts of interest to declare. Funding: Katherine Sawyer, Constantinos Constantinides and Sorcha Hamilton are supported by grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. Tom P Freeman is funded by a UKRI Future Leaders Fellowship (MR/Y017560/1). Esther Walton is funded by UK Research and Innovation (UKRI) under the UK government’s Horizon Europe / ERC Frontier Research Guarantee (BrainHealth, grant number EP/Y015037/1) and Wellcome (315898/Z/24/Z). Jorien Treur is supported by a European Research Council (ERC) Starting grant (UNRAVEL-CAUSALITY, grant number 101076686). Valentina Lorenzetti was supported by an AI and Val Rosenstrauss Senior Research Fellowship (2022–2026), by a National Health and Medical Research (NHMRC) Investigator Grant (2023-2027 ID:2016833), and by an Australian Catholic University competitive scheme. Anna Blackwell and Shadi Daryan are funded by a Cancer Research UK grant (PPRCPJT\100023). Chloe Burke was funded by a PhD studentship awarded by the Society for the Study of Addiction (SSA). Sarah Dance is funded by a University of Bath PhD studentship. Tom A Jenkins receives PhD studentship funding from Mental Health Research UK and the Schizophrenia Research Fund. Gemma Taylor reports funding from a Cancer Research UK Population Researcher Postdoctoral Fellowship award (C56067/A21330), and project grant (PPRCPJT/100023). Funding sources were not involved in the study design, collection, analysis and interpretation of data, writing of the report and decision to submit the article for publication. Data Availability All data produced in the present study are available upon reasonable request to the authors