Abstract: Background: Whilst many studies have linked increased drug and cannabis exposure to adverse mental health (MH) outcomes their effects on whole populations and geotemporospatial relationships are not well understood. Methods: Ecological cohort study of National Survey of Drug Use and Health (NSDUH) geographically-linked substate-shapefiles 2010–2012 and 2014–2016 supplemented by five-year US American Community Survey. Drugs: cigarettes, alcohol abuse, last-month cannabis use and last-year cocaine use. MH: any mental illness, major depressive illness, serious mental illness and suicidal thinking. Data analysis: two-stage, geotemporospatial, robust generalized linear regression and causal inference methods in R. Results: 410,138 NSDUH respondents. Average response rate 76.7%. When drug and sociodemographic variables were combined in geospatial models significant terms including tobacco, alcohol, cannabis exposure and various ethnicities remained in final models for all four major mental health outcomes. Interactive terms including cannabis were related to any mental illness (β-estimate = 1.97 (95%C.I. 1.56–2.37), P < 2.2 × 10− 16), major depressive episode (β-estimate = 2.03 (1.54–2.52), P = 3.6 × 10− 16), serious mental illness (SMI, β-estimate = 2.04 (1.48–2.60), P = 1.0 × 10− 12), suicidal ideation (β-estimate = 1.99 (1.52–2.47), P < 2.2 × 10− 16) and in each case cannabis alone was significantly associated (from β-estimate = − 3.43 (− 4.46 − −2.42), P = 3.4 × 10− 11) with adverse MH outcomes on complex interactive regression surfaces. Geospatial modelling showed a monotonic upward trajectory of SMI which doubled (3.62 to 7.06%) as cannabis use increased. Extrapolated to whole populations cannabis decriminalization (4.26%, (4.18, 4.34%)), Prevalence Ratio (PR) = 1.035(1.034–1.036), attributable fraction in the exposed (AFE) = 3.28%(3.18–3.37%), P < 10− 300) and legalization (4.75% (4.65, 4.84%), PR = 1.155 (1.153–1.158), AFE = 12.91% (12.72–13.10%), P < 10− 300) were associated with increased SMI vs. illegal status (4.26, (4.18–4.33%)). Conclusions: Data show all four indices of mental ill-health track cannabis exposure across space and time and are robust to multivariable adjustment for ethnicity, socioeconomics and other drug use. MH deteriorated with cannabis legalization. Cannabis use-MH data are consistent with causal relationships in the forward direction and include dose-response and temporal-sequential relationships. Together with similar international reports and numerous mechanistic studies preventative action to reduce cannabis use is indicated.