This meta-analysis found much support for the marijuana protection hypothesis [30–31] Consistent with previous systematic reviews, this meta-analytic review observed consistent inverse associations between cannabis legalization and opioid-related harms. Ten of the 11 primary studies analyzed, in fact 14 of 15 of their outcomes, supported the hypothesis. Such is based on the theory that with increased availability of legalized marijuana, and through formal and informal substitutions by physicians, patients, addicts and others, opioid related harms are reduced. The evidence in support of the marijuana protection hypothesis remains correlational, but we think that this study bolstered confidence in is causal interpretation in several ways. First, it systematically replicated the findings of two previous synthetic research groups. Second, ten primary research groups replicated significant cannabis use-opioid harm reduction correlations across diverse opioid-related outcomes: prescriptions, hospitalizations, motor vehicle crash fatalities and ultimately, overdose mortality. Third, the primary studies provided some measure control for potential time-dependent and numerous other confounds though their longitudinal designs and regressions. Fourth, it was systematically replicated by peer-reviewed published and unpublished or gray literature research so it probably cannot be explained by publication bias. Fifth and most importantly, this meta-analytic study was able to characterize the size of the observed cannabis-opioid harm reduction correlations. For example, it allowed for the central estimates that opioid prescription rates and overdose mortality rates decreased, respectively, by approximately 10% and 25% post-marijuana legalization. Given the commonness of opioid prescribing in North America as well as the horrible consequent loss of life due to opioid-related overdoses, such holds the promise of saving hundreds of thousands of lives over the next generation. At the population level, the cannabis-opioid correlations observed here and the preventive impacts that they represent may, we think, be deemed huge.
The marijuana protection hypothesis was not unequivocally supported, however. In fact, one study’s findings were distinctly counter-hypothetical. Having extended this field’s cohort to 2017, it observed a pattern of null findings, culminating in the estimation of an approximate 25% increase in opioid overdoses in 2017 . Certainly, such an outlier cannot merely be dismissed. It extended a previous study’s cohort by seven years , but did not otherwise “use the same methods” as claimed. Notably, the most recent, but counter-hypothetical study, attempted to control for more potential confounds than did the earlier study. One of these covariates was whether the states had legalized recreational marijuana (in assessing the impact of medical marijuana legalization). Given this study’s finding of the incremental harm-reducing impact of recreational marijuana, typically after medical marijuana legalization, we think that such an adjustment may have overcontrolled for the key predictor—increased cannabis use consequent to its greater availability. We also think that the single counter-hypothetical finding of increased overdose mortality in 2017 could be explained by the contemporaneous prevalent intrusion of illicitly manufactured fentanyl into communities across North America [54–57]. That substance may have been so unpredictable and dangerous as to overwhelm any cannabis-based protections among prescription opioid patients and or vulnerable people such as addicts aiming to curb their abuse of opioids other than fentanyl. For now, we think the preponderance of correlational evidence supports the marijuana protection hypothesis. Clearly, better controlled designs that ultimately randomize some aspect of cannabis availability and use will be needed to resolve the debate.
Potential Limitations and Future Research Needs
As this field’s primary studies measured their critical variables at the state-level (e.g., binary cannabis legalization and adjusted mortality rates) they are legitimately vulnerable to criticism related to the ecological fallacy. Admittedly, because their central unit of analysis was states they did not actually measure the specific behaviors of specific individuals. A now well-known epidemiologic principle contextualizes this criticism. “Perils are posed not only by the ecological fallacy, but also by the individualistic fallacy” . In other words, personal behaviors are probably critically important here, but so too are social forces like the marijuana policies studied so far. This field’s next generation seems to call logically for the multilevel study of personal behavior by social force interactions.
Relatedly, it has been noted that a number of interrelated policies have not been well accounted for yet among this field’s primary studies . They are other progressive or liberal policies that might also reduce opioid-related harms: methadone and buprenorphine made available to assist in the treatment of opioid dependence, more liberal treatment (other than imprisonment) of opioid users, and the ready community distribution of naloxone. These are policies that tend to be internally consistent and along with marijuana legalization generally fit a progressive political world view; views that are generally found in so-called blue, rather than red states. Because of their strong, perhaps nearly perfect intercorrelations, each of their specific independent effects may not be knowable. Still it would be very instructive to better understand the aggregate protective effects of such progressive policies. Future individual-state multilevel research might be even further advanced by incorporating the blue-red state dichotomy.
This meta-analytic study may have also been limited by its inability to specifically target vulnerable populations who may stand to benefit most from cannabis substitutions. For example, five of its primary studies sampled special populations such as Medicare or Medicaid enrollees or young people, but six of its primary studies were of the general population of adults. As one might expect the greatest cannabis-based reductions in opioid-related harms among such vulnerable populations as patients and or addicts seeking solutions, this study’s observed associations indicative of harm reductions among the general population may be underestimates of the truth among vulnerable populations . Alternatively, it stands to reason that cannabis is not only not a panacea for all medical ills, physical and mental, its more ready availability through legalization may increase harms among certain populations (e.g., young nonusers or addicts not seeking treatment). For example, one of the studies we previously cited as reporting the substitution of cannabis for their prescribed opioid medications (41%) also indicated that some of them used both, and nearly one of every ten such patients (8%) reported that they consequently increased their opioid usage.22 Future research ought to more specifically link patient, addict and general population characteristics to outcomes, to better understand who stands to benefit or to be harmed most by cannabis legalization.
Relatedly and finally, we do not think it premature to consider cannabis-based harm reduction clinical interventions. The population-based evidence seems suggestive enough to begin explorations and ultimately trials perhaps among the most vulnerable people for whom other extant treatments have not worked well: opioid addicts or chronic alcoholics who have experienced multiple treatment failures and or perhaps for whom traditional, abstinence-based treatments do not seem a good fit. We are unaware of a single systematic review of rigorously evaluated interventions, suggesting that little such clinical experimentation has yet been accomplished. We hope that the substantially loosened legal restrictions across Canada and parts of the USA will open the door to such a novel and potentially groundbreaking clinical research agenda.