Cannabis as a Gateway Drug for Opioid Use Disorder

Arthur Robin Williams

New York Psychoanalytic Society and Institute | Columbia University

For example, when naloxone and anandamide are co-administered (i.e. in the same NAc microinjections), endocannabinoid “liking” was muted in the presence of naloxone, hedonic response to cannabinoids may require concurrent endogenous opioid signaling on some level.33 Additionally, rodent investigations exploring the potential gateway effects of cannabis (studies examining adolescent rodent exposure to cannabinoid agonists or THC) provide evidence of enhanced opioid intake and adult sensitivity later in life to opioids.34 Hurd and colleagues developed an experimental rodent model that could mimic periodic adolescent use of cannabis use, finding that adult male rats with low to- moderate THC exposure during adolescence exhibited enhanced heroin self-administration.35 As the endocannabinoid system is dynamically altered during adolescence in brain areas central to reward, decision-making, and motivation (e.g. the limbic system VTA and striatum, mentioned earlier) suggests that cannabis use during these critical developmental phases may impact long-term potentiation in the mesocorticolimbic system (spanning the mesocortex in the frontal lobes and the limbic system), impacting later-life drug use and addiction proneness. In conclusion, Hurd writes that, “vulnerability involves a delicate balance between factors that promote and protect against disease, and adolescent cannabis use, an environmental factor, may tip this balance in teens with high-risk genotypes and behavioral traits.”37 In summary, several converging lines of inquiry have shown that adolescent and young adult (i.e. through age 24) brain development is key to executive functioning and behavioral control, that cannabis can change adolescent gene expression and alter these key periods of neurodevelopment, that genes can predict the priming impact of cannabis on opioids and that there is likely individual variation in the risk of cannabis use in adolescence having a deleterious effect on adolescent brain maturation and downstream vulnerability to opioid exposure and addiction. Olfson and colleagues found that among NESARC respondents in waves I and II (the same group of roughly 35,000 individuals were re-interviewed three years apart in 2001–2002 and 2004–2005) that cannabis users were less likely to decrease opioid use than non-users.42 In part due to these findings and other studies, Humphreys and Saitz recently cautioned in JAMA that, “aggregate population associations (eg, between medical cannabis and opioid overdose) may be opposite of those seen within individuals.43 In the only individual-level analysis, which included 57,146 people aged 12 and older, of a nationally representative sample, medical cannabis use was positively associated with greater use and misuse of prescription opioids.44 Their suggestion is that while states with medical cannabis programs may have been associated with slower increases in rates of opioid overdose following their implementation,45 that this may be an ecological fallacy unrelated to individuals’ experiences with cannabis and the progression of opioid use and OUD. In conclusion, for some at risk individuals, through a combination of genetic and environmental factors, it is highly likely that adolescent cannabis use can meaningfully increase risk of the initiation of opioid use and development of OUD. In summary, several converging lines of inquiry have shown that adolescent and young adult (i.e. through age 24) brain development is key to executive functioning and behavioral control, that cannabis can change adolescent gene expression and alter these key periods of neurodevelopment, that genes can predict the priming impact of cannabis on opioids and that there is likely individual variation in the risk of cannabis use in adolescence having a deleterious effect on adolescent brain maturation and downstream vulnerability to opioid exposure and addiction.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359408/