{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T08:29:22Z","timestamp":1770884962802,"version":"3.50.1"},"reference-count":101,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,16]],"date-time":"2022-10-16T00:00:00Z","timestamp":1665878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Background: Down syndrome (DS) is the commonest of the congenital genetic defects whose incidence has been rising in recent years for unknown reasons. This study aims to assess the impact of substance and cannabinoid use on the DS Rate (DSR) and assess their possible causal involvement. Methods: An observational population-based epidemiological study 1986\u20132016 was performed utilizing geotemporospatial and causal inferential analysis. Participants included all patients diagnosed with DS and reported to state based registries with data obtained from National Birth Defects Prevention Network of Centers for Disease Control. Drug exposure data was from the National Survey of Drug Use and Health (NSDUH) a nationally representative sample interviewing 67,000 participants annually. Drug exposures assessed were: cigarette consumption, alcohol abuse, analgesic\/opioid abuse, cocaine use and last month cannabis use. Covariates included ethnicity and median household income from US Census Bureau; maternal age of childbearing from CDC births registries; and cannabinoid concentrations from Drug Enforcement Agency. Results: NSDUH reports 74.1% response rate. Other data was population-wide. DSR was noted to rise over time and with cannabis use and cannabis-use quintile. In the optimal geospatial model lagged to four years terms including \u03949-tetrahydrocannabinol and cannabigerol were significant (from \u03b2-est. = 4189.96 (95%C.I. 1924.74, 6455.17), p = 2.9 \u00d7 10\u22124). Ethnicity, income, and maternal age covariates were not significant. DSR in states where cannabis was not illegal was higher than elsewhere (\u03b2-est. = 2.160 (1.5, 2.82), R.R. = 1.81 (1.51, 2.16), p = 4.7 \u00d7 10\u221210). In inverse probability-weighted mixed models terms including cannabinoids were significant (from \u03b2-estimate = 18.82 (16.82, 20.82), p &lt; 0.0001). 62 E-value estimates ranged to infinity with median values of 303.98 (IQR 2.50, 2.75 \u00d7 107) and 95% lower bounds ranged to 1.1 \u00d7 1071 with median values of 10.92 (IQR 1.82, 7990). Conclusions. Data show that the association between DSR and substance- and cannabinoid- exposure is robust to multivariable geotemporospatial adjustment, implicate particularly cannabigerol and \u03949-tetrahydrocannabinol, and fulfil quantitative epidemiological criteria for causality. Nevertheless, detailed experimental studies would be required to formally demonstrate causality. Cannabis legalization was associated with elevated DSR\u2019s at both bivariate and multivariable analysis. Findings are consistent with those from Hawaii, Colorado, Canada, Australia and Europe and concordant with several cellular mechanisms. Given that the cannabis industry is presently in a rapid growth-commercialization phase the present findings linking cannabis use with megabase scale genotoxicity suggest unrecognized DS risk factors, are of public health importance and suggest that re-focussing the cannabis debate on multigenerational health concerns is prudent.<\/jats:p>","DOI":"10.3390\/ijerph192013340","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T00:04:55Z","timestamp":1665965095000},"page":"13340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Socioeconomic, Ethnocultural, Substance- and Cannabinoid-Related Epidemiology of Down Syndrome USA 1986\u20132016: Combined Geotemporospatial and Causal Inference Investigation"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3256-720X","authenticated-orcid":false,"given":"Albert","family":"Reece","sequence":"first","affiliation":[{"name":"Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia"},{"name":"School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Hulse","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia"},{"name":"School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.yapd.2012.04.006","article-title":"Medical update for children with Down syndrome for the pediatrician and family practitioner","volume":"59","author":"Hickey","year":"2012","journal-title":"Adv. Pediatr."},{"key":"ref_2","unstructured":"(2022, August 02). Birth Defects: Facts about Down Syndrome, Available online: https:\/\/www.cdc.gov\/ncbddd\/birthdefects\/downsyndrome.html."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ccell.2019.07.004","article-title":"Mechanisms of Leukemia Evolution: Lessons from a Congenital Syndrome","volume":"36","author":"Birger","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ccell.2019.06.007","article-title":"Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome","volume":"36","author":"Labuhn","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_5","unstructured":"McCantz-Katz, E. (2018). Annual Report Snippets, NSDUH, SAMHSA, USA DHHS\u2014Selected Streamlined Trends, Substance Abuse and Mental Health Services Administration US Department of Health and Human Services, SAMHSA, DHHS."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1080\/15287390600748799","article-title":"Risk of selected birth defects with prenatal illicit drug use, Hawaii, 1986\u20132002","volume":"70","author":"Forrester","year":"2007","journal-title":"J. Toxicol. Environ. Health"},{"key":"ref_7","unstructured":"Public Health Agency of Canada, Health Canada (2013). A Perinatal Health Surveillance Report, Public Health Agency of Canada."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e195","DOI":"10.1097\/ADM.0000000000000638","article-title":"Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis","volume":"14","author":"Reece","year":"2020","journal-title":"J. Addict. Med."},{"key":"ref_9","unstructured":"(2020, January 11). National Cannabis Survey, Second Quarter. Available online: https:\/\/www.facebook.com\/StatisticsCanada\/posts\/1636405843137586:0."},{"key":"ref_10","unstructured":"Canada, S. (2019). Third Quarter National Cannabis Survey, Canada, Statistics Canada."},{"key":"ref_11","unstructured":"(2018). Birth Defect Data-Colorado Register of Congenital Surveillance Network, Department of Public Health and the Environment. [1st ed.]. Available online: http:\/\/www.chd.dphe.state.co.us\/cohid\/."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1177\/0009922819861281","article-title":"Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends","volume":"58","author":"Reece","year":"2019","journal-title":"Clin. Pediatr."},{"key":"ref_13","first-page":"1","article-title":"Queensland Mothers and Babies 2014 and 2015","volume":"1","author":"Health","year":"2018","journal-title":"Brisbane: Queensland Health"},{"key":"ref_14","first-page":"1","article-title":"Cannabinoid- and Substance- Relationships of European Congenital Anomaly Patterns: A Space-Time Panel Regression and Causal Inferential Study","volume":"8","author":"Reece","year":"2022","journal-title":"Environ. Epigenetics"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). Cannabis- and Substance- Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph191811208"},{"key":"ref_16","unstructured":"Colorado Department of Public Health and Environment (2020). THC Concentration in Colorado Marijuana, Colorado Department of Public Health and Environment."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13892","DOI":"10.1038\/s41598-021-93411-5","article-title":"Epidemiological Overview of Multidimensional Chromosomal and Genome Toxicity of Cannabis Exposure in Congenital Anomalies and Cancer Development","volume":"11","author":"Reece","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_18","unstructured":"Preedy, V., Patel, V., and London, U.K. (2022). Cannabis, Cannabinoids and Endocannabinoids, Elsevier. in press."},{"key":"ref_19","first-page":"1","article-title":"European Epidemiological Patterns of Cannabis- and Substance- Related Congenital Cardiovascular Anomalies: Geospatiotemporal and Causal Inferential Study","volume":"8","author":"Reece","year":"2022","journal-title":"Environ. Epigenetics"},{"key":"ref_20","first-page":"37","article-title":"Cannabis in Pregnancy\u2014Rejoinder, Exposition and Cautionary Tales","volume":"9","author":"Reece","year":"2020","journal-title":"Psychiatr. Times"},{"key":"ref_21","unstructured":"NBDPN (2018). National Birth Defects Prevention Network, National Birth Defects Prevention Network."},{"key":"ref_22","unstructured":"Substance Abuse and Mental Health Services Administration (2020, January 11). National Survey of Drug Use and Health, Available online: https:\/\/www.samhsa.gov\/data\/all-reports."},{"key":"ref_23","unstructured":"Wonder, C.D.C. (2020, January 11). Natality Information, Live Births, Available online: https:\/\/wonder.cdc.gov\/natality.html."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.biopsych.2016.01.004","article-title":"Changes in Cannabis Potency Over the Last 2 Decades (1995\u20132014): Analysis of Current Data in the United States","volume":"79","author":"ElSohly","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1520\/JFS14636J","article-title":"Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from 1980\u20131997","volume":"45","author":"ElSohly","year":"2000","journal-title":"J. Forensic Sci."},{"key":"ref_26","unstructured":"Women and Newborn Health Service, and Department of Health, Government of Western Australia (2015). Western Australian Register of Developmental Anomalies 1980\u20132014, Western Australia Health."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1002\/bdra.20323","article-title":"National rates of birth defects among hospitalized newborns","volume":"76","author":"Bird","year":"2006","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1002\/pd.2910","article-title":"Prenatal diagnosis of Down syndrome: A systematic review of termination rates (1995\u20132011)","volume":"32","author":"Natoli","year":"2012","journal-title":"Prenat. Diagn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1002\/(SICI)1097-0223(199909)19:9<808::AID-PD637>3.0.CO;2-B","article-title":"Termination rates after prenatal diagnosis of Down syndrome, spina bifida, anencephaly, and Turner and Klinefelter syndromes: A systematic literature review. European Concerted Action: DADA (Decision-making After the Diagnosis of a fetal Abnormality)","volume":"19","author":"Mansfield","year":"1999","journal-title":"Prenat. Diagn."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the Tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"439","DOI":"10.32614\/RJ-2018-009","article-title":"Simple Features for R: Standardized Support for Spatial Vector Data","volume":"10","author":"Pebesma","year":"2018","journal-title":"R J."},{"key":"ref_32","unstructured":"Geofacet (2020, January 11). \u2018ggplot2\u2019 Faceting Utilities for Geographical Data. Available online: https:\/\/CRAN.R-project.org\/package=geofacet."},{"key":"ref_33","unstructured":"Corrgram (2020, January 11). Plot a Correlogram. Available online: https:\/\/CRAN.R-project.org\/package=corrgram."},{"key":"ref_34","unstructured":"Wright, K. (2013). Package \u2018Corrgram\u2019, CRAN."},{"key":"ref_35","unstructured":"(2020, January 11). Package \u2018plm\u2019. Available online: https:\/\/cran.r-project.org\/web\/packages\/plm\/plm.pdf."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lumley, T. (2010). Complex Surveys: A Guide to Analysis Using R, Wiley.","DOI":"10.1002\/9780470580066"},{"key":"ref_37","unstructured":"Bivand, R., Anselin, L., Berke, O., Bernat, A., Carvalho, M., Chun, Y., Dormann, C., Dray, S., Halbersma, R., and Lewis-Koh, N. (2007). The Spdep Package, CRAN."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.csda.2013.07.024","article-title":"Maximum likelihood estimation of spatially and serially correlated panels with random effects","volume":"71","author":"Millo","year":"2014","journal-title":"Comput. Stat. Data Anal."},{"key":"ref_39","first-page":"1","article-title":"Splm: Spatial Panel Data Models in R","volume":"47","author":"Millo","year":"2012","journal-title":"J. Stastistical Softw."},{"key":"ref_40","unstructured":"(2020, January 11). Broom. Convert Statistical Objects into Tidy Tibbles. Available online: https:\/\/CRAN.R-project.org\/package=broom."},{"key":"ref_41","unstructured":"(2020, January 11). Broom.mixed. Tidying Methods for Mixed Models. Available online: http:\/\/github.com\/bbolker\/broom.mixed."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jeconom.2006.09.004","article-title":"Panel Data Models with Spatially Correlated Error Components","volume":"140","author":"Kapoor","year":"2007","journal-title":"J. Econom."},{"key":"ref_43","unstructured":"Millo, G., and Piras, G. (2018). Package \u2018splm\u2019, CRAN (Central R-Archive Network). Available online: https:\/\/cran.r-project.org\/web\/packages\/splm\/splm.pdf."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Croissant, Y., and Millo, G. (2019). Panel Data Econometrics with R, Wiley and Sons.","DOI":"10.1002\/9781119504641"},{"key":"ref_45","first-page":"1","article-title":"Ipw: An R Package for Inverse Probabilty Weighting","volume":"43","author":"Geskus","year":"2011","journal-title":"J. Stat. Softw."},{"key":"ref_46","unstructured":"Pinheiro, J., Bates, D., DebRoy, S., Sarkar, D., and Team, R.C. (2020). Nlme: Linear and Nonlinear Mixed Effects Models, Comprehensive R Archive Network."},{"key":"ref_47","unstructured":"(2022, August 02). Package \u2018Evalue\u2019 Online Document. Available online: https:\/\/cran.r-project.org\/web\/packages\/EValue\/EValue.pdf."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/jci-2018-0007","article-title":"Technical Considerations in the Use of the E-Value","volume":"7","author":"VanderWeele","year":"2019","journal-title":"J. Causal Inference"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s12035-011-8202-4","article-title":"Genes and pathways co-associated with the exposure to multiple drugs of abuse, including alcohol, amphetamine\/methamphetamine, cocaine, marijuana, morphine, and\/or nicotine: A review of proteomics analyses","volume":"44","author":"Wang","year":"2011","journal-title":"Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.mrfmmm.2016.05.002","article-title":"Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity","volume":"789","author":"Reece","year":"2016","journal-title":"Mutat. Res.\/Fundam. Mol. Mech. Mutagen."},{"key":"ref_51","unstructured":"Nahas, G.G., Sutin, K.M., Harvey, D.J., and Agurell, S. (1999). Changes in human spermatozoa associated with high dose marihuana smoking, Humana Press."},{"key":"ref_52","first-page":"95","article-title":"Cytogenetic Studies of Cannabinoid Effects","volume":"Volume 1","author":"Braude","year":"1987","journal-title":"Genetic and Perinatal Effects of Abused Substances"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Nahas, G.G., Sutin, K.M., Harvey, D.J., Agurell, S., and Totowa, N.J. (1999). Marihuana and Medicine, Humana Press.","DOI":"10.1007\/978-1-59259-710-9"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3109\/10826089009067003","article-title":"Genetic effects of marijuana","volume":"25","author":"Zimmerman","year":"1990","journal-title":"Int. J. Addict."},{"key":"ref_55","first-page":"25","article-title":"Effects of cannabis and natural cannabinoids on chromosomes and ova","volume":"44","author":"Morishima","year":"1984","journal-title":"NIDA Res. Monogr."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00439-008-0603-8","article-title":"Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: A report from the Atlanta and National Down Syndrome Projects","volume":"125","author":"Allen","year":"2009","journal-title":"Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1002\/ajmg.a.32932","article-title":"Etiology of Down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations","volume":"149","author":"Ghosh","year":"2009","journal-title":"Am J Med. Genet A"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1089\/gtmb.2011.0066","article-title":"Down syndrome: Parental origin, recombination, and maternal age","volume":"16","author":"Vranekovic","year":"2012","journal-title":"Genet Test Mol Biomarkers"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1080\/15592294.2018.1554521","article-title":"Cannabinoid exposure and altered DNA methylation in rat and human sperm","volume":"13","author":"Murphy","year":"2018","journal-title":"Epigenetics"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1080\/15592294.2019.1656158","article-title":"Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm","volume":"15","author":"Schrott","year":"2019","journal-title":"Epigenetics"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Almouzni, G., Altucci, L., Amati, B., Ashley, N., Baulcombe, D., Beaujean, N., Bock, C., Bongcam-Rudloff, E., Bousquet, J., and Braun, S. (2014). Relationship between genome and epigenome--challenges and requirements for future research. BMC Genom., 15.","DOI":"10.1186\/1471-2164-15-487"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3389\/fcvm.2018.00089","article-title":"Integrating Genes Affecting Coronary Artery Disease in Functional Networks by Multi-OMICs Approach","volume":"5","author":"Vilne","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/eep\/dvab009","article-title":"Refraining from use diminishes cannabis-associated epigenetic changes in human sperm","volume":"7","author":"Schrott","year":"2021","journal-title":"Environ. Epigenetics"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s40360-020-00450-1","article-title":"Broad Spectrum epidemiological contribution of cannabis and other substances to the teratological profile of northern New South Wales: Geospatial and causal inference analysis","volume":"21","author":"Reece","year":"2020","journal-title":"BMC Pharmacol. Toxicol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis. Mendeley Data.","DOI":"10.3390\/ijerph192416721"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. (2022). Cannabis, Cannabidiol, Cannabinoids and Multigenerational Policy. Engineering, in press.","DOI":"10.1016\/j.eng.2022.07.012"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Reece, A.S., and Hulse, G.K. Extending the \u201cParacentral Dogma\u201d of biology with the metabolome: Implications for understanding genomic-glycomic-metabolic-epigenomic synchronization. Engineering, 2022. in press.","DOI":"10.1016\/j.eng.2022.07.011"},{"key":"ref_68","unstructured":"Causal Inference in Statistics (2020, January 11). A Gentle Introduction. Available online: http:\/\/bayes.cs.ucla.edu\/jsm-august2016-bw.pdf."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"268","DOI":"10.7326\/M16-2607","article-title":"Sensitivity Analysis in Observational Research: Introducing the E-Value","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_70","unstructured":"Pearl, J., and Mackenzie, D. (2018). The Book of Why. The New Science of Cause and Effect, Basic Books."},{"key":"ref_71","first-page":"295","article-title":"The Environment and Disease: Association or Causation?","volume":"58","author":"Hill","year":"1965","journal-title":"Proc. R Soc. Med."},{"key":"ref_72","first-page":"431","article-title":"Prenatal Exposure to Cannabis and Fetal Development","volume":"1","author":"Nahas","year":"1999","journal-title":"Marijuana in Medicine"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/0091-3057(91)90372-9","article-title":"Influence of marihuana on cellular structures and biochemical activities","volume":"40","author":"Tahir","year":"1991","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s00204-018-2322-9","article-title":"Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells","volume":"93","author":"Russo","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"(1976). McClean DK, Zimmerman AM: Action of delta 9-tetrahydrocannabinol on cell division and macromolecular synthesis in division-synchronized protozoa. Pharmacology, 14, 307\u2013321.","DOI":"10.1159\/000136610"},{"key":"ref_76","first-page":"461","article-title":"The Effects of Maternal Marijuana Use During Pregnancy on Fetal Growth","volume":"Volume 1","author":"Nahas","year":"1999","journal-title":"Marijuana in Medicine"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1139\/o92-162","article-title":"Cytoskeletal organization following cannabinoid treatment in undifferentiated and differentiated PC12 cells","volume":"70","author":"Tahir","year":"1992","journal-title":"Biochem. Cell Biol."},{"key":"ref_78","first-page":"71","article-title":"Action of delta 9-tetrahydrocannabinol on the pool of acid soluble nucleotides","volume":"40","author":"Thomas","year":"1984","journal-title":"Cytobios"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1159\/000137442","article-title":"Influence of cannabinoids on somatic cells in vivo","volume":"21","author":"Zimmerman","year":"1980","journal-title":"Pharmacology"},{"key":"ref_80","first-page":"469","article-title":"The effect of a crude marihuana extract on embryonic and foetal development of the rabbit","volume":"22\u201323","author":"Cozens","year":"1978","journal-title":"Adv. Biosci."},{"key":"ref_81","first-page":"359","article-title":"Effects of Marijuana Inhalation on Spermatogenesis of the Rat","volume":"Volume 1","author":"Nahas","year":"1999","journal-title":"Marijuana in Medicine"},{"key":"ref_82","first-page":"371","article-title":"Hypoploid metaphases in cultured lymphocytes of marihuana smokers","volume":"22\u201323","author":"Morishima","year":"1978","journal-title":"Adv. Biosci."},{"key":"ref_83","first-page":"1748","article-title":"Effects of cannabinoids on macromolecular synthesis and replication of cultured lymphocytes","volume":"36","author":"Nahas","year":"1977","journal-title":"Fed. Proc."},{"key":"ref_84","first-page":"1259","article-title":"Drug-Induced (Thalidomide) Malformations","volume":"87","author":"Ing","year":"1962","journal-title":"Can. Med. Assoc. J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"754","DOI":"10.2174\/092986708783955473","article-title":"New tubulin polymerization inhibitor derived from thalidomide: Implications for anti-myeloma therapy","volume":"15","author":"Kizaki","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_86","first-page":"163","article-title":"Novel tubulin-polymerization inhibitor derived from thalidomide directly induces apoptosis in human multiple myeloma cells: Possible anti-myeloma mechanism of thalidomide","volume":"21","author":"Iguchi","year":"2008","journal-title":"Int. J. Mol. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/S0190-9622(96)90122-X","article-title":"Rediscovering thalidomide: A review of its mechanism of action, side effects, and potential uses","volume":"35","author":"Tseng","year":"1996","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"8573","DOI":"10.1073\/pnas.0901505106","article-title":"Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation","volume":"106","author":"Therapontos","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1002\/bies.200900103","article-title":"Thalidomide-induced limb defects: Resolving a 50-year-old puzzle","volume":"31","author":"Vargesson","year":"2009","journal-title":"Bioessays"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/bdrc.21096","article-title":"Thalidomide-induced teratogenesis: History and mechanisms","volume":"105","author":"Vargesson","year":"2015","journal-title":"Birth Defects Res. Part C: Embryo Today: Rev."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1038\/s41598-017-01641-3","article-title":"A HAND to TBX5 Explains the Link Between Thalidomide and Cardiac Diseases","volume":"7","author":"Khalil","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0140-6736(03)15279-8","article-title":"Health of thalidomide victims and their progeny","volume":"363","author":"McBride","year":"2004","journal-title":"Lancet"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1177\/2040620711413165","article-title":"The rise, fall and subsequent triumph of thalidomide: Lessons learned in drug development","volume":"2","author":"Rehman","year":"2011","journal-title":"Ther. Adv. Hematol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1016\/S0140-6736(04)16308-3","article-title":"Thalidomide","volume":"363","author":"Franks","year":"2004","journal-title":"Lancet"},{"key":"ref_95","first-page":"271","article-title":"Thalidomide and Congenital Abnormalities","volume":"7223","author":"Linz","year":"1962","journal-title":"Lancet"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1016\/j.biocel.2007.01.022","article-title":"The thalidomide saga","volume":"39","author":"Melchert","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1186\/s12889-020-09748-5","article-title":"Co-occurrence across time and space of drug- and cannabinoid- exposure and adverse mental health outcomes in the National Survey of Drug Use and Health: Combined geotemporospatial and causal inference analysis","volume":"20","author":"Reece","year":"2020","journal-title":"BMC Public Health"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1","DOI":"10.35248\/2572-0775.19.4.155","article-title":"Epidemiological Associations of Various Substances and Multiple Cannabinoids with Autism in USA","volume":"4","author":"Reece","year":"2019","journal-title":"Clin. Pediatr. Open Access"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1","DOI":"10.35248\/2572-0775.19.4.154","article-title":"Effect of Cannabis Legalization on US Autism Incidence and Medium Term Projections","volume":"4","author":"Reece","year":"2019","journal-title":"Clin. Pediatr. Open Access"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1001\/jamasurg.2018.4694","article-title":"Gastroschisis and Autism-Dual Canaries in the Californian Coalmine","volume":"154","author":"Reece","year":"2019","journal-title":"JAMA Surg."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"31","DOI":"10.15585\/mmwr.mm6802a2","article-title":"Gastroschisis Trends and Ecologic Link to Opioid Prescription Rates\u2014United States, 2006\u20132015","volume":"68","author":"Short","year":"2019","journal-title":"Morb. Mortal. Wkly. 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