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C BY-NC-ND) (CC 4.0 NoDerivatives License distributed under is article access open This interest.y of conflict paper.y no the C.S.D. declare revised paper; authors per- critically the The S.C.G. wrote C.S.D. and K.H. and C.S.D. and and C.L.S. C.L.S. review; data; legal research; analyzed provided designed S.C.G. and K.H. C.L.S. and research; formed S.C.G., C.L.S., contributions: Author owo orsodnemyb drse.Eal [email protected] Email: addressed. be may correspondence whom To h ieto fteascainbtenmdclcannabis medical between association the of direction The d etrfrInvto oIpeetto,Vtrn far elhCare Health Affairs Veterans Implementation, to Innovation for Center b h ewr o ulcHat a,Crbr,N 27516; NC Carrboro, Law, Health Public for Network The a,d . y raieCmosAttribution-NonCommercial- Commons Creative www.pnas.org/lookup/suppl/doi:10. NSLts Articles Latest PNAS | f3 of 1

MEDICAL SCIENCES SOCIAL SCIENCES BRIEF REPORT Table 1. Age-adjusted opioid overdose death rate per 100,000 population Independent variables Bachhuber et al. (1999–2010) Replication (1999–2010) Extension (1999–2017) Expanded model (1999–2017)

Medical cannabis law −24.8 (−37.5 to −9.5) −21.1 (−35.7, −3.0) 22.7 (2.0, 47.6) N/A Prescription drug monitoring program 3.7 (−12.7 to 23.3) −2.8 (−16.7, 13.3) −2.7 (−15.9, 12.5) −4.0 (−17.1, 11.1) Law requiring or allowing pharmacists to request patient identification 5.0 (−10.4 to 23.1) 2.8 (−12.6, 20.9) 11.8 (−7.7, 35.5) 8.8 (−10.2, 31.9) Increased state oversight of pain management clinics −7.6 (−19.1 to 5.6) −6.9 (−18.4, 6.2) 9.0 (−15.6, 40.8) 13.7 (−11.2, 45.5) Annual state unemployment rate 4.4 (−0.3 to 9.3) 4.4 (−0.3, 9.3) 1.4 (−2.7, 5.5) 0.7 (−3.1, 4.6) Types of cannabis laws Recreational and medical cannabis law N/A N/A N/A −14.7 (−43.6, 29.0) Medical cannabis only N/A N/A N/A 28.2 (1.2, 62.4) Low-THC–only medical cannabis law N/A N/A N/A −7.1 (−29.1, 21.7)

All models also included year and state fixed effects. N/A denotes not applicable because variable was not included in model.

association was negative as reported in Bachhuber et al. (1). Sub- the individual level and (ii) the relationship is causal. The first sequently, the association became statistically indistinguishable conclusion is frequently incorrect across many research fields from zero before turning positive in 2017. owing to the ecological fallacy (9). Ecological correlations can- In the expanded model with indicators for different types of not establish individual-level relationships and indeed may run cannabis laws, having a comprehensive medical cannabis law in the directly opposite direction (e.g., higher rates of smoking was associated with a 28.2%, 95% CI (1.2, 62.4) higher opi- in French regions with lower rates of esophageal cancer should oid overdose mortality, while estimates for other laws were not be interpreted as evidence of a protective effect of smok- nonsignificant. The association between having a recreational ing) (10). In this case, compelling evidence exists that violates cannabis law and opioid overdose mortality was −14.7%, 95% the first assumption: A study of a nationally representative sam- CI (−43.6, 29.0). Having a low-THC-only medical cannabis law ple of individuals shows that use of medical cannabis is positively was associated with −7.1%, 95% CI (−29.1, 21.7) lower opioid correlated both with use and misuse of prescription pain relievers overdose mortality. For both of these laws, the wide CIs include (11). This positive correlation does not at all prove that medical strong positive, strong negative, and null associations, indicating cannabis causes individuals to use opioids because correlation of compatibility with a large range of true associations. nonexperimentally gathered data does not establish causation, a general principle that all parties to the current debate should Discussion bear in mind. We replicated Bachhuber et al.’s (1) finding of a negative asso- When multiple studies using similar methods generate a par- ciation between medical marijuana and opioid overdose deaths ticular result, and for the first time one of those studies fails to from 1999 to 2010. However, the association did not hold when replicate with more extensive data, there are multiple ways to more extensive data through 2017 were analyzed. Had the anal- explain the discrepancy. It could be that by bad luck the only ysis’ endpoint been between 2008 and 2012, the results would one of those studies whose initial findings would not stand up have been comparable to those obtained by Bachhuber et al. (1). to reanalysis with more recent data happened to be the one However, the association became equivocal in 2013; by 2017 it had reversed such that a study conducted in that year might lead some to conclude that medical cannabis laws were compounding opioid overdose mortality. 60 The mechanism theorized to describe a causal relationship 50

between medical cannabis laws and opioid overdose mortality 40 rests on several premises: (i) Cannabis is more available in states 30 with medical cannabis laws; (ii) people in these states substitute cannabis for opioids, whether for pain management, intoxica- 20 tion, or both; and (iii) this substitution occurs on a large enough 10 scale to impact the population-level overdose mortality esti- 0 mates. Under this model, states with highly restrictive medical -10

cannabis laws limited to low-THC products would be expected to -20 have a weaker association than states with comprehensive med- -30

ical cannabis, while states with recreational cannabis would be Point Estimate and 95% Confidence Interval expected to have a stronger association. Our results do not sup- -40 port this, as after adjusting for more and less restrictive types of -50 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 cannabis law (recreational and medical or low-THC only), states Study Endpoint with comprehensive medical cannabis laws still had a positive association with opioid overdose mortality. Fig. 1. Changes in point estimate and 95% CI of association between The Bachhuber et al. (1) study is one of several that find medical cannabis law and age-adjusted opioid overdose death rate by the the rate of cannabis access and some index of opioid-related last year included in the analysis since 1999. Fixed (year and state) and harm are negatively correlated in the aggregate (1, 5–7). Pol- time-varying effects (prescription drug monitoring program, state unem- icy that expands access to cannabis based on these findings ployment, pain management clinic oversight laws, and prescription drug assumes that (i) the same negative relationship is present at identification laws) were also adjusted for.

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T. 12. 1 .L aui .Hmhes eia aiun sr r oelkl oueprescription use to likely more are users marijuana Medical Humphreys, K. Caputi, L. T. 11. 0 .W iny .Hmhes .R ilhn .H ars h elhcr rcs per- process care health Why Harris, H. A. Kivlahan, R. D. Humphreys, K. Finney, W. J. 10. osntncsaiyrpeetteofiilveso h I rteauthors’ the or NIH and the authors of the views of official responsibility the employers. the represent necessarily solely not Career is does content Stan- Senior at The Professorship a University. Memorial Tsai Ting ford by Wu the Esther Administration, the supported and and Health Institute, Veterans DA035165 was Neurosciences the T32 from K.H. Award Award Scientist Institute. Health Research Neurosciences of Tsai Institutes National Wu the of Abuse ACKNOWLEDGMENTS. in available (iii are and (ii Data content, law, low-THC. 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Wilson, N. Mbabazi, K. Seth, P. Scholl, L. 8. ult naaye foii euain h aeo rsrpindu monitor- drug Research, prescription Economic of of Bureau case (National 2018). 24947 The MA, Paper Cambridge, regulation: Working opioid NBER programs, of ing analyses in quality Recommendations and Evidence of State Research Current for The Cannabinoids: and Cannabis check. reality a pass don’t marijuana medical about rg eial n nonmedically. and medically drugs (2011). omnemaue a aedfeetrltosist ucmsfrptet and patients for outcomes fallacy. to ecological relationships the different Understanding hospitals: have can measures formance (1950). 351–357 15, 2013-2017. States, (2018). United deaths, dose TeNtoa cdme rs,Wsigo,D,2017). DC, Washington, Press, Academies National (The ...wsspotdb ainlIsiueo Drug on Institute National by supported was C.L.S. .Adc.Med. Addict. J. ob otl ekyRep. Weekly Mortal. Morb. aae S1. Dataset m .Pbi Health Public J. 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