Section A Mental illness 1 Close parallels between cannabis use and deteriorating US Mental Health at four levels supports and extends the epidemiological salience of demonstrated causal mental health relationships: A geospatiotemporal study Introduction Methods - Analysis plan - Statistical considerations - Data availability - Assessing causality Results - National level - Regional level - State level - Substate level - Considerations of causality - Koch''s postulates - Hills'' causal algorithm - Brain disease pathways and mechanisms - Cannabis and mass violence Brain - Endocannabinoid system in the brain - Dopamine - Other - Mitochondriology - Immunome - Genomic studies - Cannabinoid-opioid interactions Conclusion Section B Autistic spectrum disorder 2 Linked rise of cannabis use and autism incidence demonstrated by close three-level geospatiotemporal relationships, USA, 1990-2011 Introduction Methodological comment - Assessing causality - Data availability Results - National level data - Regional level - State level data - Impact of cannabis legal status on autism rates - Causal inference Discussion - Mechanistic considerations - European neuroteratology studies - Morphogen gradients guide brain development - Retinoic acid - Slit-Robo - Neurexin-neuroligin - DSCAM and DLGAP2 - Oligodendrocytes and myelination - Genomic studies - Epigenomic studies - Pediatric poisonings Conclusion General questions Case studies - Case 1 - Case 2 - Case 3 Section C Congenital anomalies 3 Geospatiotemporal and causal inferential analysis of United States congenital anomalies as a function of multiple cannabinoidand substance-exposures: Phenocopying thalidomide and hundred megabase-scale genotoxicity Executive summary - Introduction - Methods - Ethics - Results - Cannabis-related defects - Upper quintile threshold discontinuity Conclusion Cannabis-related congenital anomalies - Cannabis-related anomalies by geotemporospatial criteria, N=38 - Cannabis-related anomalies by prevalence ratio criteria, N=44 - Cannabis-related anomalies by prevalence ratio criteria, N=42 Introduction - Methodology - Data sources - Cannabis consumption quintiles - Data analysis - Statistics - Broom-Purrr multimodel assessments - Matrix multiplication - Geospatial modeling - Two phases of data analysis - Spatial error structures - Spatial model specification - Corrections for multiple testing - Assessing causality - Data availability - Ethics Results - Section one: Drug use by ethnicity and age - Section two: Drugs and congenital anomalies overview - Section three: Chromosomal defects - Section four: Gastroschisis and body wall - Section five: Atrial septal defect (secundum type) - Section six: Cardiovascular defects of interest - Section seven: Hawaiian--American review Discussion - General considerations - Bivariate analysis Summary observations - Data summary - Forest plot - Canada - Australia - Mechanistic summary - Multivariable analysis - Multivariable causal analysis - Multivariable causal analysis - Effect of cannabis legalization - Considerations of causality - Geotemporal trimodality - Causality and the hill criteria - Causal inference - Causal assignment - Commonality Pathways and mechanisms - Genotoxic mechanisms - Morphogen gradients control body formation and patterning - Cannabinoid modulation of other morphogenetic pathways Specific organ systems - Heart - Respiratory defects - Face - Gastrointestinal tract - Urinary tract - Body wall anomalies - Limbs - Chromosomal defects Interactions of other major morphogen systems with cannabinoids - Cannabinoid teratology - Chromosomal mechanics and dynamics - Sperm and cannabinoids - Oocytes and cannabinoids - Embryonic development Conclusion - Directions for future research Congenital anomalies general questions and case studies - General questions - Case studies -- Case 1: Jodie -- Case 2: Jennifer Section D Cancer and Heritable Cancer 4 Geospatiotemporal and causal inferential epidemiological survey and exploration of cannabinoidand substance-related carcinogenesis in the United States from 2003 to 2017 (Online chapter) Section E Epigenetics and aging 5 Multivalent cannabinoid epigenotoxicities and multigenerational aging Introduction Definitions Epigenetic layers Hallmarks of aging Methodology - Data - Computations - Ethical permission Results and discussion - Historical studies - Mitochondrial inhibition - Important earlier epigenomic studies - Longitudinal human sperm study - Detailed analysis of longitudinal sperm study results - Perturbation of fundamental epigenomic machinery - Stem cell genes - Age-related immunometabolic genes - Chromosomes, centrosomes, and kinetochores - DNA repair - Epigenomics Epigenomics of cannabinoid teratology - Brain - Cannabinoid neurotoxicity - Cannabinoid epigenomic neurotoxicity - Summary of cannabinoid neurotoxicity - Cardiovascular system - Other organs and systems - Chromosomal anomalies - Uronephrology - Body wall - Teratological summary Epigenomics of cannabinoid-related cancers Epigenomics of aging - Overview of conceptual aging paradigm - Aging is driven by a loss of epigenetic information - Epigenomics - Overall pattern of cannabis toxicity - Hallmarks of cannabinoid accelerated aging Epigenomic--genomic overlap in aging syndromes - Heterochronic parabiosis - Haemopoietic stem cells - Heterochronic CSF circulation - Movement in fibroblasts - Ovarian aging - Mouse aging Epigenomics and pathobiology of aging - Inflammation and stem cells - Cardiovascular disease - Hematopoietic stem cells - Skeletal muscle - Summary genomic-epigenomic tables - Summary of cannabinoid aging acceleration Overall summary of multivalent cannabinoid epigenotoxicities Case studies--Epigenetics and aging - Leonard - Case description - Case questions - Q multiple choice 6 Conclusion.