Emerging Evidence for Cannabis’ Role in Opioid Use Disorder, Beth Wiese and Adrianne R. Wilson-Poe, 2018

Emerging Evidence for Cannabis’ Role in Opioid Use Disorder

Beth Wiese and Adrianne R. Wilson-Poe

Cannabis and Cannabinoid Research, 2018, Volume 3.1,179-189.

Doi : 10.1089/can.2018.0022



Introduction : The opioid epidemic has become an immense problem in North America, and despite decades of research on the most effective means to treat opioid use disorder (OUD), overdose deaths are at an all-time high, and relapse remains pervasive.

Discussion : Although there are a number of FDA-approved opioid replacement therapies and maintenance medications to help ease the severity of opioid withdrawal symptoms and aid in relapse prevention, these medications are not risk free nor are they successful for all patients. Furthermore, there are legal and logistical bottlenecks to obtaining traditional opioid replacement therapies such as methadone or buprenorphine, and the demand for these services far outweighs the supply and access. To fill the gap between efficacious OUD treatments and the widespread prevalence of misuse, relapse, and overdose, the development of novel, alternative, or adjunct OUD treatment therapies is highly warranted. In this article, we review emerging evidence that suggests that cannabis may play a role in ameliorating the impact of OUD. Herein, we highlight knowledge gaps and discuss cannabis’ potential to prevent opioid misuse (as an analgesic alternative), alleviate opioid withdrawal symptoms, and decrease the likelihood of relapse.

Conclusion : The compelling nature of these data and the relative safety profile of cannabis warrant further exploration of cannabis as an adjunct or alternative treatment for OUD.

Keywords : cannabis; opioid addiction; opioid treatment; relapse prevention



The opioid epidemic has become an increasingly pressing problem with an estimated 26–36 million people abusing opioids around the world.1 At the time of this publication, the Centers for Disease Control reports that 115 people die every day of an opioid related cause in the United States, and more than 33,000 people lost their lives to an accidental opioid overdose in the United States in 2015 alone.1–4 The United States consumes 80% of the world’s supply of prescription opioid analgesics (POAs), and opioid prescriptions have climbed by 300% since 1991.5 The rise in opioid prescriptions
has also widened the demographic of individuals dying from opioid overdose; historically, overdose
was most prevalent in urban, minority adolescent males; however, today these lethal effects are similar
across race, gender, socioeconomic status, and geography. 7–11 The spike in prescriptions has also directly contributed to an increase in the number of first-time consumers of illicit opioids (heroin, which is commonly laced with fentanyl or its analogs), which has continued to climb since the mid 1990’s.6 Patients who become physically dependent upon POAs frequently switch to illicit opioids because POAs are more costly and/or difficult to obtain.3,8,12,13 However, ease of access is a dangerous tradeoff for the lethal risk that is associated with synthetic opioids. Fentanyl, for instance, is 100 times more potent than morphine, which partially explains why there was a 250% increase in synthetic opioid mortality between 2012 and 2015.14,15

This unprecedented public health crisis warrants the investigation of novel sustainable interventions which would directly address the current opioid misuse crisis, complement current treatment strategies, and prevent future misuse through alternative first line analgesics.

Mechanistic Interactions between Cannabis and Opioids

The endocannabinoid and opioidergic systems are known to interact in many different ways, from the distribution of their receptors to cross-sensitization of their behavioral pharmacology. Cannabinoid-1 (CB1) receptors and mu opioid receptors (MORs) are distributed in many of the same areas in the brain, including but not limited to the periaqueductal gray,16,17 locus coeruleus, 18,19 ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex (PFC),20 central amygdala (CeA), bed nucleus of stria terminalis (BNST),21 caudate putamen (CP), substantia nigra, dorsal hippocampus, raphe nuclei, and medial basal hypothalamus.22 The extent of this overlapping expression and frequent colocalization
of the CB1 and MOR provide clear morphological underpinnings for interactions between the opioid and
cannabinoid systems in reward and withdrawal.19,23

There is a bidirectional relationship between MORs and CB1 receptors in the rewarding properties of drugs of misuse.20,24–28 That is, modulation of the CB1 receptor has profound effects on the rewarding properties of opioids, and vice versa. For example, MOR and CB1 receptors are reciprocally involved in the development of drug-induced conditioned place preference (CPP). Coadministration of a cannabinoid antagonist and morphine attenuates the development of morphine CPP,26 and co-administration of an opioid antagonist blocks tetrahydrocannabinol (THC)-induced CPP.25 Interestingly, microinjections of CB1 agonists into the medial PFC creates an aversion to doses of morphine that are normally rewarding (CPP), while CB1 antagonism in this brain region creates a rewarding effect of subthreshold morphine doses.24 In addition, administration of cannabinoids to MOR knockout (KO) mice produces a weaker CPP compared to wild-type animals, 22 reviewed in Wills and Parker.27 This mutual involvement in reward is at least partially mediated by presynaptic cannabinoid and opioid disinhibition of dopamine neurons in the VTA, a well-characterized mechanism in the rewarding properties of drugs of misuse.20 Although these mechanisms have not been well studied in humans, one study has found CB1 upregulation in the reward pathway of individuals who use opioids, which supports a role for the endocannabinoid system in the development of opioid misuse.29

There is abundant support for the role of CB1 receptors in the rewarding effects of opioids and the amelioration of tolerance. However, the effects of endogenous and exogenous cannabinoids in opioid withdrawal are somewhat paradoxical: endogenous cannabinoids seem to have no role in somatic withdrawal,27,30–32 yet exogenous CB1 agonists readily alleviate somatic symptoms such as escape jumps, diarrhea, weight loss, and paw tremors.28,33,34 Endogenous cannabinoid tone within the amygdala is also involved in the affective component of opioid withdrawal, as blockade of CB1 receptors in the CeA or BNST ameliorates opioid withdrawal.21 The kappa opioid receptor (KOR) system may also play a role in cannabis’ impact on the affective opioid withdrawal, given its pivotal contributions to dysphoria and negative effect.35 However, both KOR agonism (with U50, 488H30) and KOR antagonism (naloxone31,32) have both been shown to attenuate conditioned place aversion in CB1 KO mice.30 These contradicting data highlight the need for additional mechanistic insights into the involvement of the CB1 receptor in opioid reward and withdrawal.

Cannabis as a First Line Analgesic