Therapeutic Potential of Opioid/Cannabinoid Combinations in Humans: Review of the Evidence

Abstract

The endogenous opioid and cannabinoid receptor systems are widely distributed and co-localized throughout central and peripheral nervous system regions. A large body of preclinical evidence suggests that there are functional interactions between these two systems that may be leveraged to address various health conditions. Numerous animal studies have shown that cannabinoid agonists (e.g., delta-9-tetrahydrocannabinol [Δ⁹-THC]) enhance the analgesic effects of μ-opioid analgesics as evidenced by decreasing the opioid dose required for analgesia (i.e., opioid sparing) and extending the duration of the opioid analgesia. In contrast, controlled human laboratory studies and clinical trials have not demonstrated robust analgesic or opioid-sparing effects from opioid-cannabinoid combinations. Meta-analyses of the literature (clinical trials, controlled laboratory studies; some non-controlled studies/case reports) have examined the effects of cannabis/cannabinoids for pain relief in those taking a wide variety of analgesics, including prescription opioid medications. These data do not strongly support the use of cannabinoids for chronic pain nor do prospective studies demonstrate significant cannabinoid-mediated opioid-sparing effects. Preclinical studies have also suggested a role for cannabinoids for the treatment of opioid withdrawal. Controlled laboratory and clinical studies suggest that there may be a modest signal for Δ⁹-THC to suppress some opioid signs and symptoms but they are not completely ameliorated and there may also be concerns around safety of Δ⁹-THC administration in a state of heightened autonomic arousal as occurs with opioid withdrawal. Despite anecdotal and correlational reports suggesting a benefit of cannabis on reducing opioid overdose, there is no strong data supporting this contention and emerging reports have conflicting results. In summary, there is a groundswell of public advocacy supporting the use of cannabis and cannabinoids to replace opioid analgesics or to reduce opioid use; however, the extant controlled clinical data do not support the role of cannabinoids for opioid replacement or opioid-sparing effects when treating opioid use disorder or chronic pain.

Introduction

Psychoactive constituents naturally derived from plants have been used by humans for millennia to treat various ailments and produce altered states of consciousness. Opiate alkaloids (e.g., morphine) derived from the poppy plant were recognized for their potent analgesic activities and, along with subsequently developed semi-synthetic and synthetic opioids, are used worldwide. The cannabis sativa plant (i.e., cannabis, marijuana) produces altered perception largely though the activity of delta-9-tetrahydrocannabinol (Δ⁹-THC, one of its many chemical constituents) but also possesses therapeutic properties (e.g., antiemetic). Synthetic Δ⁹-THC has been marketed for therapeutic purposes as have other cannabinoid constituents. Both opioids and cannabis are available licitly in some settings and with specific restrictions, but both are extensively misused illicitly due to their mood-altering properties.

Importantly, there is substantial neurochemical and neuroanatomical overlap between the endogenous opioid and cannabinoid systems. Both cannabinoid (CB) receptors and μ-opioid receptors are G-protein-coupled receptors, which have downstream effects on adenylyl cyclase enzyme activity, Ca²⁺ channel activation and neurotransmitter release (Rios et al., 2006). They both have widespread and partially overlapping anatomical distributions in central and peripheral nervous system regions involved with analgesia (e.g. thalamus, spinal cord), drug reward and self-administration (e.g. nucleus accumbens), and opioid withdrawal (e.g. locus coeruleus; Pickel et al., 2004; Scavone et al., 2010; Welch, 2009). Neurochemical and behavioral preclinical studies reveal a significant degree of functional interaction between the opioid and cannabinoid receptor systems. Given the extensive overlap of the endogenous opioid and cannabinoid systems and their functional interactions, the potential therapeutic benefit of combining opioids and cannabinoids for treatment of various health conditions has been explored and reported in a growing body of literature (and large body of published anecdotal reports) (see Scavone et al., 2013; Nielsen et al., 2017).

The purpose of this paper is to review the currently available evidence from clinical studies that have examined opioid/cannabinoid interactions. This review will focus on clinical studies with appropriate experimental design and control conditions, when available, but will also describe studies with limited rigor. Moreover, as both opioids and cannabinoids are available in legal and illegal forms (depending on local laws and specific compound), given the focus here on controlled studies, we will largely describe studies of approved and marketed products rather than observational studies of illicit users. There are presently four cannabinoid products that are marketed in different countries around the world for clinical use for an array of indications. These are dronabinol (synthetic Δ⁹ -THC; Marinol®), nabilone (synthetic THC analogue; Cesamet®), nabiximols (Δ⁹-THC/cannabidiol mixture; 2.7/2.5 ratio, Sativex®) and cannabidiol (Epidiolex®). Cannabis (i.e., marijuana; contains multiple cannabinoids and varies significantly in strength) is legal in specified places. There are numerous marketed opioids that target opioid receptors with varying specificity for the receptor subtypes and are characterized as agonists, partial agonists and antagonists; study descriptions here will specify the compounds tested.

Therapeutic Potential for Opioid and Cannabis/Cannabinoid Combinations in Pain Management

Opioids are generally recognized to be efficacious for acute pain; despite their efficacy, there are important public health harms associated with widespread use of opioids (e.g., sedation/impairment, misuse and dependence, unintentional poisoning, non-fatal or fatal overdose). There is a great need to develop opioid alternatives (Califf et al., 2016; Dowell & Haegerich, 2016) and find medications that boost the analgesic effects of opioids without increasing the opioid dose (known as opioid sparing), both of which are initiatives proposed by several agencies across the world (European Monitoring Centre for Drugs and Drug Addiction, 2019; U.S. Food and Drug Administration, 2018; World Health Organization, 1986). There is significant scientific interest, coupled with a changing legal landscape and strong current of public advocacy in several countries, to determine if medical cannabis and pharmaceutical cannabinoids can function as opioid substitutes or as opioid-sparing agents. The controlled data that speaks to these issues, particularly as it relates to clinical pain management, is summarized herein.

Dozens of studies conducted in rodents and monkeys have demonstrated that cannabinoid agonist pretreatment, often with doses that are otherwise inactive alone, produce clear, greater-than-additive, often synergistic interactions with opioid agonists, increasing opioid analgesic potency in the range of 0.5 – 25 fold (e.g., Cichewicz, 2004; Cichewicz et al., 1999; Cichewicz & McCarthy, 2003; Maguire et al., 2013; Welch, 2009; Welch & Eads, 1999). For example, in a comprehensive drug-drug interaction study in mice, pretreatment with an inactive, placebo-like dose (when given alone) of the CB₁/CB₂ partial agonist, Δ⁹ THC (20 mg/kg, p.o.), increased the analgesic potency of a wide range of doses of several μ-opioid drugs (e.g., hydromorphone, codeine) on the tail flick assay of nociception (Cichewicz et al., 1999). Compared to placebo pre-treatment, THC administration produced a 2.2 to 25.8-fold increase in analgesic potency of nine distinct μ-opioid agonists, decreasing the opioid dose necessary for analgesia (ED₅₀) between 55–98%. In a similar study, monkeys were administered a non-analgesic dose of THC (1.0 mg/kg, s.c.) prior to opioid agonist injection (e.g., fentanyl, morphine); THC produced a 0.55 to 20.6-fold leftward shift in the μ-opioid dose response curves, decreasing the opioid ED₅₀ by 69–94% (Maguire et al., 2013). One study also reported that cannabidiol (CBD) increases morphine analgesia on a thermal tail flick model in mice (Rodriguez-Munoz et al., 2018). Interestingly, the synergistic effects of opioid/cannabinoid combinations appear to be rather selective for nociception in animals, as other direct effects of cannabinoids (hypothermia, catalepsy, hypoactivity) and opioids (respiratory depression) are not potentiated by their co-administration (Welch, 2009). Taken together, data from these preclinical studies are rather consistent and suggest a favorable therapeutic profile of opioid/cannabinoid combinations. However, as detailed below, these findings have not been readily translated to the human laboratory and clinic.

Human Laboratory Studies

Although the animal data are quite compelling, it remains unclear if opioid/cannabinoid combinations are beneficial for analgesia in humans. There have been few rigorous studies that have examined 1) the analgesic effects of cannabinoid agonists alone for acute or chronic pain, or 2) cannabinoid agonist interactions with opioids on pain outcomes in humans. Placebo-controlled randomized laboratory studies have reported on the analgesic effects of cannabis/cannabinoid agonists alone on experimental pain tests (i.e., without concomitant opioid administration). Some of these have reported no cannabinoid agonist-induced analgesia with acute heat (Babalonis et al., 2019; Naef et al., 2003; Redmond et al., 2008), cold pressor (Babalonis et al., 2019; Naef et al., 2003; Redmond et al., 2008), or pressure (Babalonis et al., 2019; Naef et al., 2003) assays (acute oral doses: 2.5, 5 mg dronabinol [Babalonis et al., 2019]; 0.5 mg, 1 mg nabilone [Naef et al., 2003]; 20 mg THC [Redmond et al., 2008]). One reported analgesia from radiant heat pain after smoked cannabis (3.55% THC) (Greenwald & Stitzer, 2000), and one reported a small reduction in heat hyperalgesia in women only after 1 mg nabilone administration (Redmond et al., 2008). In contrast to these findings, three studies have reported cannabinoid agonist-induced hyperalgesia (i.e., increased pain) with heat/capsaicin (8% THC smoked cannabis [Wallace et al., 2007]) and electrical stimulation assays (15 mg oral dronabinol [Kraft et al., 2008], 12 mg smoked THC [Hill et al., 1974]; 20 mg oral THC [Walter et al., 2015]; see brief review by Walter et al., 2015).

The human laboratory studies examining analgesic interactions of cannabinoid and opioid agonists have also reported mixed results. Four human studies have been conducted using experimental pain models enrolling healthy participants without recent histories of acute or chronic pain conditions (Babalonis et al., 2019; Cooper et al., 2018; Naef et al., 2003; Roberts et al., 2006). One study examined the effects of morphine (30 mg, p.o.), dronabinol (20 mg, p.o.) and their combination on pain threshold and tolerance on heat, cold, pressure and electrical stimulation assays. Dronabinol alone did not decrease pain and induced hyperalgesia on several outcomes, morphine alone produced mild analgesic effects; however, there were no interactions suggesting that dronabinol potentiated morphine analgesia (Naef et al., 2003). A similar study administered dronabinol (5 mg, p.o.), morphine (0.02 mg/kg, i.v.) and their combination to healthy participants and assessed subjective pain response from a thermal pain assay. There was one modest decrease in ratings of “bad” pain effects after the active dose combination (relative to either drug alone), but no other indications of analgesic interactions. A study by our research group tested a dose range of dronabinol (2.5, 5 mg, p.o.) and oxycodone (5, 10 mg, p.o.) alone and in combination on several experimental pain and subjective outcomes. The results indicated that oxycodone produced analgesia (e.g., pressure algometer); but dronabinol alone and dronabinol in combination with oxycodone did not produce analgesia. Importantly, dronabinol increased the abuse-related subjective ratings of oxycodone on several outcomes including ratings of global drug effect, high and drug liking (Babalonis et al., 2019). Lastly, an experimental pain study enrolling heavy cannabis smokers administered oxycodone (2.5, 5 mg, p.o.) alone and in combination with smoked cannabis (5.6% THC) and measured cold pressor response. The combination of 2.5 mg oxycodone and active cannabis increased cold pressor threshold and tolerance outcomes (i.e., increased analgesic effect) relative to either drug alone; however, this dose combination also increased the abuse liability of oxycodone (i.e., increases in ratings of drug liking, wanting to take the drug again; Cooper et al., 2018).

One additional clinical laboratory study was conducted in pain patients (various types of pain conditions, no experimental pain outcomes included) to assess if 5 days of smoked cannabis (up to 0.9 g of 3.6% THC cannabis, up to 3 times per day, as tolerated) altered self-reported pain scores or changed the pharmacokinetic profile of patient’s ongoing opioid analgesic regimens (morphine, oxycodone); however, a placebo control was not included for either outcome. The authors reported that cannabis decreased pain ratings by 10.7 units (baseline=39.6; after 4 days of cannabis = 29.1) and did not alter the pharmacokinetic profile of the patients’ opioid medications; however, cannabis increased subjective ratings of high. For example, in patients taking oxycodone, baseline ratings of high were 23.73 (±29.35 SD) and increased to 72.73 (± 23.22) with cannabis; a similar pattern was observed in those taking morphine (baseline = 13.6 [±24.57]; cannabis treatment = 54.7 [± 30.76]) (Abrams et al., 2011).

In summary, cannabinoid agonists alone (cannabis, THC, dronabinol, nabilone) have not consistently functioned as analgesics under experimental pain conditions. Cannabinoid/opioid combinations have also provided mixed results on experimental pain outcomes: 1) dronabinol did not augment opioid analgesia in studies enrolling healthy participants without pain conditions or drug use disorders (Babalonis et al., 2019; Roberts et al., 2006; Naef et al., 2003); and 2) cannabis-enhancement of opioid analgesia has been detected in two studies enrolling individuals with chronic pain/chronic opioid use (Abrams et al., 2011) and chronic cannabis use (Cooper et al., 2018). Importantly, in the studies that have examined subjective drug ratings, all have detected enhanced abuse potential when cannabinoid/opioid combinations were administered (Babalonis et al., 2019; Cooper et al., 2018; Abrams et al., 2011).

Overall, it is not clear why the preclinical results do not translate to the human laboratory studies, even when similar pain assays were implemented; however, there are noted limitations with animal pain models and analgesic drug development (e.g., differences in behavioral, pain and drug use histories in animal vs. human subjects, as well as species-specific physiological differences) that may decrease applicability to the human condition (see review by Burma et al., 2017).

Clinical Trials in Chronic Pain Patients

Several high quality meta-analyses and systematic reviews have been conducted to determine the effects of cannabinoid agonists (e.g., nabiximols, cannabis, dronabinol, nabilone) on pain relief, including neuropathic pain (Mucke et al., 2018), chronic non-cancer pain (Stockings et al., 2018), and chronic pain of all types (Hauser et al., 2018; Martin-Sanchez et al., 2009; National Academies of Sciences, 2017; Whiting et al., 2015). However, these reviews do not detail the effects of cannabis or cannabinoid agonists in the context of opioid treatment; even though a subset of patients in each review are taking opioid analgesics for pain management, the data reported are collapsed across all analgesic treatments (e.g., opioid analgesics, NSAIDs). Overall, the conclusions drawn from these reviews is mixed, with some reports indicating quite strong support for the use of cannabinoid agonists for the treatment for pain, while others suggest limited efficacy. For example, the National Academies of Sciences, Engineering and Medicine report (2017) on cannabis and cannabinoids compiled results from systematic reviews and individual studies and concluded that there is substantial evidence that cannabis is an effective treatment for adults with chronic pain of various types. However, a recent review presents somewhat disparate findings. Stockings et al. (2018) conducted the most in-depth systematic review to date (47 randomized controlled trials, 57 observational studies) to determine the effects of cannabis and cannabinoid agonists for the treatment of chronic non-cancer pain. Amongst the controlled trials, there was a modest, yet significant effect of cannabinoid treatment for pain – the proportion of patients achieving a 30% reduction in pain was 29% in those treated with cannabinoids and 26% of those receiving placebo, suggesting only a 3% difference between the groups. Cannabinoids also reduced pain intensity relative to placebo; however, again, the magnitude of this reduction was estimated to be the equivalent to 3 mm decrease on a 100 mm visual analog scale of pain intensity ratings. Further, the rates of adverse events were 81% in the cannabinoid-treated groups in contrast to 66% in those receiving placebo. Overall, the authors conclude that there is limited evidence that cannabinoids are highly effective for the treatment of chronic non-cancer pain (Stockings et al., 2018).

One exemplar study is described here, as it utilized an interesting study design (e.g., a placebo-controlled study followed by an open-label follow on) and yielded results that are similar to those that are generally found in studies administering cannabinoid agonists to pain patients on top of their ongoing opioid analgesic regimens. In this study by Narang and colleagues (2008), the first phase was a within-subject design and administered acute, randomized doses of dronabinol (10, 20 mg, p.o.) and placebo to pain patients and measured their pain ratings prior to and for 8 hr post-dronabinol dose. The second phase was an open-label extension of the first phase and did not include a placebo control; participants were provided a prescription for dronabinol for 4 weeks, during which they were permitted to take between 5 – 60 mg dronabinol per day. Pain outcomes were measured by participant’s diary entries in which they recorded their pain intensity and pain relief from dronabinol. The results from the first (acute dosing) phase indicated that both 10 and 20 mg of dronabinol decreased pain scores relative to placebo, with relatively small magnitude effects on both standard pain scales (approximately 1.5 mean unit decrease [no statistical error term reported] on a scale ranging from 0–10) and total pain relief scores (placebo = 31.1; 10 mg dronabinol = 39.7; 20 mg dronabinol = 41.7 [error terms not reported]). In the second phase, similarly modest decreases in mean pain intensity ratings were reported across the four-week period, relative to baseline, with approximately 1.7 mean unit change in pain intensity (on a scale of 0–10) (Narang et al., 2008). Across studies, the findings do not suggest that cannabinoids are highly effective analgesics for pain conditions, including chronic pain and neuropathic pain.

Human Studies and Clinical Trials Examining Opioid Sparing Effects

At least four placebo-controlled studies have been conducted to determine if administration of cannabinoid agonists can produce opioid sparing effects and allow for a decrease in opioid doses while maintaining analgesia. One study enrolled patients undergoing a surgical procedure who were randomized to receive nabilone (0.5, 1 mg, p.o.) or placebo 1 hr prior to anesthesia and every 8 hr through 24 hr post-surgery along with allowed post-surgical opioid treatment. There were no significant differences in post-surgical morphine doses administered (via PCA pump) across the groups, indicating that nabilone was not opioid sparing. In addition, patients receiving nabilone (2 mg) exhibited greater post-surgical pain (instead of less) on both outcomes measured – pain at rest and pain during movement – relative to those who received placebo (Beaulieu, 2006). A similar study administered placebo or 5 mg dronabinol (total of 40 mg across 8 doses) prior to and through two days after surgery. All patients were given access to post-surgical PCA pumps administering the opioid agonist piritramide. The authors reported no significant differences in opioid doses between the two groups: placebo group median dose = 74 mg (interquartile range = 44–90 mg); dronabinol group median dose = 54 mg (interquartile range = 46–88 mg) (Seeling et al., 2006).

Two randomized, placebo-controlled studies examined the effects of nabiximols (THC:CBD oromucosal spray) in the management of moderate-to-severe cancer-related pain (Johnson et al., 2010; Portenoy et al., 2012). Portenoy and colleagues (2012) randomized patients to 5 weeks of active drug or placebo across three regimens: low (1–4 sprays/day); medium (6–10 sprays/day) or high dose nabiximols (11–16 sprays/day). Each spray of nabiximols contained 2.7 mg THC and 2.5 mg CBD. The results indicated low- and medium-dose groups displayed a greater pain reduction than placebo groups; however, no there was no effect of nabiximols relative to placebo in the number of patients achieving a 30% reduction in pain from baseline. Nabiximols did not change regularly prescribed opioid dose or the number of opioid doses required for breakthrough pain. Johnson and colleagues (2010) enrolled patients with moderate-to-severe cancer pain (n=177) were randomized to receive nabiximols (2.7 mg THC, 2.5 mg CBD/spray), THC extract alone (2.7 mg THC/spray) or placebo for 2 weeks; patients were permitted to self-titrate the total number of sprays across the first week and were encouraged to maintain their optimal dose during the second week (mean number of sprays in Week 2: nabiximols = 8.75 [± 5.14]; THC = 8.34 [5.17]; placebo = 9.61 [4.67]). The results indicated that there were no changes amongst the groups in the opioid doses needed to control their pain. However, patients taking nabiximols had lower pain scores compared to placebo and more patients in this group achieved reduction in pain relief than THC alone or placebo groups. Thus, both studies indicated no differences amongst the cohorts in background opioid medication doses or the number of opioid doses required for breakthrough pain.

Lastly, one large-scale naturalistic study assessed pain and opioid sparing effects of medical cannabis. The POINT study conducted in Australia (Campbell et al., 2018) prospectively enrolled 1514 patients with chronic non-cancer pain who were prescribed opioids and collected data on the cohort annually for 4 years. The study examined pain, anxiety, depression and opioid use outcomes in those who elected to use cannabis for pain. The authors found that cannabis worsened patient outcomes – patients who were using cannabis had greater pain severity, greater pain interference in their daily activities, and greater anxiety scores than the patients who were not using cannabis. Cannabis did not reduce needed opioid doses, and it did not change the number of patients who were able to stop taking opioids (Campbell et al., 2018).

Thus, all prospective studies examining cannabinoid agonist pre-treatment on subsequent opioid dose requirements have demonstrated no opioid sparing effects. Nielsen and colleagues (2017) completed a meta-analysis of the opioid sparing effects of cannabinoids and arrived at the same conclusion - the authors indicated that there were no high-quality data available that indicated cannabinoid-mediated opioid sparing effects in humans. In some cases, the addition of cannabinoid agonists may serve as an effective add-on treatment to ongoing opioid analgesic therapy and help reduce pain in some patients; however, there is no signal that this improvement allows patients to reduce the dose (and thus the risks) associated with opioid analgesic treatment.

Role for Cannabinoids to Treat Opioid Use Disorder/Opioid Dependence

Preclinical studies have reported findings indicating significant and meaningful interactions between the cannabinoid and opioid systems related to reinforcing efficacy, development of tolerance and expression of physiological withdrawal. Activation of CB₁ and μ-opioid receptors both increase the release of dopamine in the nucleus accumbens, and systemic pretreatment with the opioid antagonist naloxone can block this release (Tanda et al., 1997). With regard to withdrawal, administration of Δ⁹-THC and other CB₁ agonists have been shown to decrease the development of opioid tolerance (e.g., Cichewicz & Welch, 2003; Fischer et al., 2010) and expression of opioid withdrawal signs in morphine-dependent rodents (e.g., Bhargava, 1976; Cichewicz & Welch, 2003; Hine et al., 1975; Lichtman et al., 2001). Conversely, administration of CB₁ antagonists (e.g., SR 141716A) can precipitate opioid withdrawal (Navarro et al., 1998). While these observed effects often appear bidirectional in nature, it seems neither practicable nor prudent to pursue opioids for the treatment of cannabis use disorders (as opioids have greater abuse potential and physiological dependence liability). However, the prospect of employing cannabinoids for the treatment of opioid use disorder (and other substance use disorders [George et al., 2010; Maldonado & Berrendero, 2010; Soyka et al., 2008 and see Sloan et al., 2017]) has been considered.

Dronabinol, a CB₁/CB₂ partial agonist, has been examined for its ability to suppress opioid withdrawal in two controlled clinical studies. In the first, adults with opioid dependence were enrolled in this randomized, double-blind, placebo-controlled study who were undergoing detoxification/opioid taper with the ultimate aim of transferring onto depot naltrexone for ongoing treatment (Bisaga et al., 2015). Participants received either oral dronabinol (n=40) or placebo (n=20) using a dose run-in (Days 2, 3 and 4 receiving 10, 20 and 30 mg/day, respectively) and then maintenance (30 mgs) for 5 weeks. The primary findings related to dronabinol treatment were that scores on a subject-rated opioid withdrawal scale (SOWS; Handelsman et al., 1987) were lower in the active treatment group compared to the placebo group on days 2 through 4 even in the presence of acute buprenorphine and non-opioid ancillary symptomatic treatments. However, there was no difference between the groups with respect to study retention or rates of successful induction onto naltrexone.

The second study employed a different methodological approach and explored repeated controlled periods of observed opioid withdrawal rather than abrupt withdrawal and sustained observations. Individuals with diagnosed opioid use disorder/dependence who were not seeking treatment were enrolled in this inpatient, randomized, double-blind, placebo-controlled within-subject design (Lofwall et al., 2016). Participants were maintained on oxycodone (30 mg, p.o., QID) to stabilize their physical dependence. Under double-blind conditions, placebo was substituted for the oxycodone maintenance dose for three consecutive doses leading to the controlled emergence of spontaneous withdrawal. Dronabinol (10, 20, 30 and 40 mg, p.o [n=2]), oxycodone (30 & 60 mg, p.o) and placebo were each tested during one of 7 test sessions (in randomized order) for their ability to substitute for the maintenance dose and suppress opioid withdrawal signs and symptoms. Dronabinol significantly increased heart rate and, at the highest dose (40 mg), produced panic-like reactions; thus, dronabinol, which is known to produce tachycardia, significantly enhanced the already withdrawal-induced elevation of heart rate (Jicha et al., 2015). Lower doses of dronabinol (20 & 30 mg) produced significant but moderate decreases on subjective and observer-rated measures of opioid withdrawal, but this suppression was less than that produced by oxycodone. These findings indicated that, while dronabinol can suppress the expression of opioid withdrawal, it is only moderately effective and higher doses are associated with adverse effects.

Hurd and colleagues explored the potential efficacy of cannabidiol for reduction of opioid craving and anxiety during heroin abstinence using a double-blind, placebo-controlled randomized design (Hurd et al., 2019). The study population is described as individuals meeting criteria for heroin dependence (DSM-IV criteria), using heroin primarily by the intranasal route, and who had become recently abstinent (the majority abstinent for less than 30 days), although the method by which they achieved recent abstinence is not described. Individuals were assigned to one of three treatment groups (0, 400 and 800 mg, p.o. cannabidiol) and participated in four test sessions as outpatients. Presentation of heroin cues increased ratings of craving and anxiety compared to neutral cues as expected. Treatment with cannabidiol reduced ratings of craving and anxiety in response to heroin cues in comparison with placebo pretreatment in the laboratory, but there was no concurrent reduction of heroin craving scores for data collected at home and not in the test sessions.

In conclusion, there is some evidence that cannabinoids (e.g., dronabinol, CBD) may produce some modest and short-duration therapeutic effects in those with opioid use disorder; however, a great deal more research is needed before clear conclusions can be drawn on the use of cannabinoids for the management of opioid withdrawal/opioid use disorder.

Correlational and Non-Controlled Studies: Potential Involvement of Cannabinoids in Opioid Overdose?

A 2014 paper published in JAMA Internal Medicine (Bachhuber et al., 2014) received considerable attention from both the popular press and scientific and medical communities – it reported on the association between medical cannabis laws (MCLs; the specific criteria defining medical cannabis laws was not provided) and rates of opioid overdose mortality in the U.S. The authors examined the opioid-related death rates (confirmed by death certificate reports) in all 50 U.S. states for several years before and after MCLs were enacted in a time-series analysis (spanning 1999–2010, three states had pre-existing laws, ten states adopted laws). When an age-adjusted model was implemented, states with MCLs had higher rates of opioid overdose deaths compared to states with no MCLs. However, when the models were further adjusted to capture enacted laws (when citizens of the state actually had access to cannabis, rather than the year the law was passed), the opposite relationship emerged – MCLs decreased the rates of opioid overdose deaths by 24.8% annually (Bachhuber et al., 2014). Another large-scale study (Kim et al., 2016) assessed the effect of operational MCLs on the prevalence of opioid-positive drug screens in fatally injured drivers (i.e., sample of all-cause mortality decedents with known opioid toxicology results). Across the entire sample, there was no association between the number of opioid-positive decedents and the presence of MCLs, but, in a subset of drivers ages 21–40, MCLs were associated with a decreased number of opioid-positive decedents (Kim et al., 2016). Overall, the data from these studies only suggest a correlation between cannabis availability and opioid-related mortality rates and is subject to several confounds.

If it is cannabis use itself that provides a protective effect, there are no data to directly support this – there is no information regarding the rates of cannabis use (e.g., post-mortem THC-positive samples) in those who died vs. a comparator group across states. Importantly, there have been two recent analyses of opioid mortality data that suggest the opposite relationship – the presence of MMLs is associated with increased rates of opioid overdose deaths across the past several years (Bleyer & Barnes, 2018; Shover et al., 2019). However, Shover and colleagues suggest that any association that is detected between cannabis laws and opioid overdose may be spurious due to the relatively low rates of cannabis exposure in the general population, the use of large-scale aggregate data to discern this type of interaction and the numerous factors that influence opioid overdose rates.

To fully understand whether cannabis could provide some pharmacological protection against opioid overdose, carefully controlled studies examining the pharmacological interactions of cannabinoid and opioid agents are needed. In addition to the experimental pain studies reviewed above, there are two non-controlled studies that provide some data on this interaction. One study examined the physiological effects of oxymorphone, a μ-opioid analgesic, in combination with THC in a sample of healthy participants (n=8, all male) (Johnstone et al., 1975). A fixed intravenous dose of oxymorphone (1.0 mg/70 kg) was administered and peak effects were allowed to emerge; this was followed by staggered, escalating doses of intravenous THC (cumulative doses of 27, 40, 60, 90 and 134 ug/kg). THC alone did not alter respiratory function; however, THC potentiated oxymorphone-induced respiratory depression. Specifically, lung volume function (V_E, liters/min, lower numbers indicate greater respiratory depression) was substantially different across treatment conditions: baseline V_E = 21–28; THC=25, oxymorphone=14, THC + oxymorphone=7, suggesting that THC may increase opioid-induced respiratory depression. Global sedation was also enhanced by THC, with three participants unable to stay awake/conscious after receiving the dose combination. This study had several design limitations, including no placebo control conditions - the authors used historical data from another study for THC alone (which precluded direct examination of the full time course of each drug alone). Nonetheless, it provides some indication that there may be physiological interactions that adversely impact safety and tolerability. A more recent study involved a retrospective chart review of 250 patients presenting for endoscopic surgery in Colorado (Twardowski et al., 2019). The authors randomly reviewed 250 patient charts to determine if surgery sedation requirements (i.e., dose of fentanyl, midazolam or propofol) differed between patients who self-reported daily or weekly use of cannabis (n=25) or no cannabis use (n=225). The authors indicated that patients who reported frequent cannabis use required more of each drug for sedation (which appears to be in contrast the oxymorphone/THC presented above). Specifically, the fentanyl dose requirement was 14% higher in the cannabis users in comparison to non-users (125.93 vs. 109.91 ug [no statistical error term reported]); however, this effect was not specific to opioids, as midazolam and propofol requirements were 20% and 220% greater in cannabis users than non-users. Inadequate experimental control and the sample size limit the conclusions that can be drawn, but it is possible that these data may reflect a general sedative-drug cross tolerance or a non-cannabis related difference between the two groups, rather than a specific drug-drug interaction.

Conclusions

Despite the functional overlap between the endogenous opioid and cannabinoid systems and a growing body of preclinical evidence suggesting therapeutic benefit of combining opioid and cannabinoid agonists on various outcomes, including pain and opioid withdrawal, the clinical data generally do not conform with the preclinical findings and are, at best, mixed. Despite the limited controlled evidence (and often negative findings) on the therapeutic co-use of opioid and cannabinoid agonists, there has been a strong public movement to advocate for replacing therapeutic opioid use with cannabinoid agonists (e.g., medical marijuana/cannabis, CBD). For example, several international jurisdictions are allowing or considering allowing physicians/providers to recommend medical cannabis products for those with opioid use disorder, despite no controlled evidence for its efficacy and the availability of several approved medications to treat the disorder with proven efficacy. Unfortunately, this is an area where public opinion and anecdote are driving new policy decisions rather than the scientific evidence. For example, while there are ample testimonials from the popular press and even published case reports suggesting that individuals with pain may benefit from cannabis use and may even experience individual reductions in their opioid use, the totality of the extant controlled and prospective clinical data do not support an analgesic opioid-sparing benefit of cannabis or cannabinoid agonists, and it has been challenging to demonstrate a direct analgesic effect of cannabinoid agonists alone in controlled studies. Similarly, while correlational reports describing decreased opioid overdose deaths in response to legalization of cannabis, those reports do not include individual-level data suggesting that those actually taking medical cannabis are the same patients decreasing or stopping opioid use. The failure to interpret the scientific evidence accurately easily leads to erroneous conclusions. The reality is that controlled clinical trials of cannabinoids and opioids have failed to produce evidence supportive of cannabinoid agonists as opioid sparing for chronic pain and yielded modest evidence for benefit in opioid withdrawal-but this was coupled with some potential risk. To date, there are no controlled data suggesting that cannabis provides some type of pharmacological protection against opioid overdose or misuse in those seeking to decrease their use and suggesting otherwise is not scientifically sound and potentially dangerous. It is possible that additional prospective, well controlled studies may yield new information to guide any potential use of cannabinoids for enhancing opioid analgesia or to treat other conditions. Unfortunately, at this time, it seems that anecdote, news reports and commercial interests are driving widespread changes in clinical practice and policy supplanting the place of strong scientific evidence.

TABLE 1.

Opioid/cannabinoid studies in humans examining outcomes related to abuse potential and opioid withdrawal

Abuse Potential Outcomes
	Study sample and brief method synopsis	Cannabinoid: doses, route	Opioid: doses, route	Study details	Summary of outcomes
Babalonis, Lofwall, Sloan, Nuzzo, Fanucchi & Walsh (2019)	Healthy participants (n=10) Acute administration of dronabinol and oxycodone	Dronabinol: 0, 2.5, 5 mg, oral	Oxycodone: 0, 5, 10 mg, oral	Placebo-controlled Randomized Double-dummy Double-blind Within-subject Outpatient	↑ Dronabinol increased the abuse potential of oxycodone across several outcomes (e.g., drug effect, like drug effects; feeling high), relative to placebo and/or oxycodone alone ↑ Dronabinol also increased oxycodone ratings of bad drug effects (5 mg dronabinol + 5 oxycodone; 2.5 mg dronabinol + 10 mg oxycodone)
Cooper, Bedi, Ramesh, Balter, Comer & Haney (2018)	Frequent cannabis users (n=18) Acute administration of cannabis and oxycodone	Cannabis: 0.0%, 5.6% THC, smoked (approx. 30 mg THC/dose available)	Oxycodone: 0, 2.5, 5 mg, oral	Placebo-controlled Randomized Double-dummy Double-blind Within-subject Outpatient	↑ Increase in abuse potential of 2.5 mg oxycodone + active cannabis, relative to cannabis alone (ex: increases in ratings of good drug effect, drug liking, take again) ↑ Increase in abuse potential of 5 mg oxycodone + cannabis, relative to placebo (ex: ratings of good drug effect, take again) → No statistically significant change in cannabis self-administration as a function of oxycodone pre-treatment
Abrams, Couey, Shade, Kelly & Benowitz (2010)	Pain patients maintained on short-acting oral opioid analgesics (n=21) Patients maintained on opioid analgesics were administered vaporized cannabis 1–3 times per day for 8 days	Cannabis: 3.56% THC, vaporized (approx. 32 mg THC/dose available) Participants were asked to inhale as much of the available dose as possible	Patients taking their ongoing oral opioid analgesic regimens (morphine, oxycodone)	No placebo control(s) Between-group Inpatient	↑ Increase in ratings of feeling high when receiving the drug combination (however, no placebo control for the opioid or cannabinoid drug administration)
Opioid Withdrawal Outcomes
Lofwall, Babalonis, Nuzzo, Elayi & Walsh (2016)	Opioid-dependent participants (n=12)	Dronabinol: 10, 20, 30 mg, oral	Oxycodone (daily maintenance): 30 mg four times per day, oral Oxycodone dose omission for 21 hrs prior to sessions (to produce opioid withdrawal) Oxycodone probe doses: 30, 60 mg	Placebo-controlled Randomized Double-dummy Double-blind Within-subject Inpatient	↓ Opioid withdrawal was modestly suppressed by dronabinol (20, 30 mg) → Lower doses of dronabinol (5, 10 mg) were placebo-like on opioid withdrawal outcomes ↑ Dronabinol also produced tachycardia, anxiety particularly at higher doses
Bisaga, Sullivan, Glass, Mishlen, Pavlicova, Haney, Raby, Levin, Carpenter, Mariani & Nunes (2015)	Opioid-dependent participants (n=60) Participants undergoing inpatient detoxification and naltrexone induction Randomized into two groups (placebo and dronabinol)	Dronabinol group (n=40): 30 mg/day, oralPlacebo group (n=20): blinded matched placebo, oral Participants received blinded dronabinol/placebo on an inpatient basis for 8 days; outpatient basis for 8 weeks	No opioid agonist administration; oral naltrexone was administered to all participants on study days 5–7; two total injections of extended release naltrexone (day 4 inpatient; week 4 outpatient)	Randomized Placebo-controlled Between-group Inpatient for 8 days Outpatient for 8 weeks	↓ Opioid withdrawal was somewhat suppressed in the dronabinol group (as measured by SOWS scores) during days 2–4 of opioid detoxification (prior to naltrexone administration). → No effect of dronabinol on opioid withdrawal once naltrexone was initiated → No difference in rates of retention ↑ When examined as a co-variate, cannabis use during the outpatient phase increased treatment retention across treatment groups
Cue-Induced Responses in Opioid Abstinent Individuals
Hurd, Spriggs, Alishayev, Winkel, Gurgov, Kudrich, Oprescu & Salsitz (2019)	Abstinent heroin users randomized into 3 groups: placebo (n=15) 400 mg CBD (n=14) 800 mg of CBD (n=13) Participants (n=42 completers) were: 1) opioid abstinent for less than 30 days up to 3 months, 2) not exhibiting opioid withdrawal, 3) not taking medication for opioid use disorder	Cannabidiol: 0, 400, 800 mg, oral	No opioid doses administered	Placebo-controlled Randomized Double-blind Between-group Outpatient	→ CBD did not alter heroin craving (Heroin Craving Questionnaire) ↓ CBD (400, 800 mg) decreased cue-induced craving relative to placebo during the first session; no significant drug effects occurred in subsequent sessions ↓ CBD (400, 800) decreased anxiety ratings during some of the sessions → CBD did not alter negative affect scores (PANAS)