Emerging Evidence for Cannabis’ Role in Opioid Use Disorder
1 Department of Psychology, University of Missouri–St. Louis, St. Louis, Missouri.
2 Department of Anesthesiology, Pain Center, Washington University School of Medicine, St. Louis, Missouri.
Adrianne R. Wilson-Poe
2 Department of Anesthesiology, Pain Center, Washington University School of Medicine, St. Louis, Missouri.
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.
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 coadministration 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, 488H 30 ) and KOR antagonism (naloxone 31,32 ) 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
The primary use for both prescription opioids and cannabis is for analgesia. Currently, up to 90% of patients in state-level medical cannabis registries list chronic pain as their qualifying condition for the medical program. 36 In an exhaustive review, the National Academies of Science and Medicine recently confirmed the efficacy of cannabis for chronic pain in adults. 36 Interestingly, when given access to cannabis, individuals currently using opioids for chronic pain decrease their use of opioids by 40–60% and report that they prefer cannabis to opioids. 37–42 Patients in these studies reported fewer side effects with cannabis than with their opioid medications (including a paradoxical improvement in cognitive function) and a better quality of life with cannabis use, compared to opioids. Despite the vast array of cannabis products and administration routes used by patients in states with medical cannabis laws, cannabis has been consistently shown to reduce the opioid dose needed to achieve desirable pain relief. 41,43
One of the mechanisms that may explain the opioid sparing effects of cannabis is its ability to produce synergistic analgesia. 44–46 In humans, subanalgesic doses of THC and morphine are equally unsuccessful at reducing the sensory or affective components of pain; however, when the same doses of THC and morphine are coadministered, they produce a significant reduction in the affective component of pain. 47 These synergistic effects are also observed when patients using opioids for pain vaporize whole-plant cannabis, as opposed to experimentally administered isolated THC. 48 Adjunct whole plant cannabis has no effect on the pharmacokinetics of opioids, which further supports a synergistic mechanism behind the opioid sparing and enhanced analgesia produced by cannabis. 48 Furthermore, in pre-clinical models, coadministration of opioids and cannabinoids attenuates the development of opioid tolerance. 49,50
Combined, these clinical and pre-clinical data suggest that analgesic synergy produced by coadministered cannabis and opioids could be harnessed to achieve clinically relevant pain relief at doses that would normally be subanalgesic. This strategy could have significant impacts on the opioid epidemic, given that it could entirely prevent two of the hallmarks of opioid misuse: dose escalation and physical dependence.
Because patients report substituting cannabis for several types of pharmaceutical drugs, including opioids, benzodiazepines, and antidepressants, 51 analgesic synergy may not entirely explain the opioid-sparing effects of cannabis in pain patients. Economic and lifestyle considerations may also play a pivotal role in opioid sparing and substitution. Patients report that their reasons for substituting cannabis for other medications include less severe side effects, less withdrawal potential, ease of access, and better symptom management for their conditions. 52
Although there is insufficient clinical literature to support the use of cannabis as a treatment for acute pain, there is a long-standing body of pre-clinical evidence that demonstrates the antinociceptive effects of cannabinoids in pain-free, drug-naive animals. 17,49,53–57 The mechanisms of cannabinoid antinociception are remarkably similar to those of opioid analgesics. Both the CB1 and MOR are G-protein coupled receptors, and agonist-initiated disinhibition of GABA release in the descending pain pathway is just one example of overlapping antinociceptive mechanisms between these drugs. 17,23,58–62 Evidence supporting the role of cannabis in acute, nonsevere pain management could lead to a substantial reduction in opioid prescription rates, thereby eliminating patient exposure to the risks of opioid dose escalation and physical dependence. This critical gap in the clinical literature and potential clinical impacts of this therapy warrants further exploration of the efficacy of cannabis for acute pain relief.
Current Opioid Use Disorder Therapies and Their Shortcomings
The most prominent and pervasive problem in opioid use disorder (OUD) treatment is the prevention of drug relapse, which is extremely common during acute withdrawal (detoxification), as well as during protracted recovery after physical withdrawal symptoms have subsided. 63–66 Abstinence-based protocols are particularly ineffective, as 85% of individuals relapse within 12 months of the initiation of treatment. 65 In-patient residential treatment facilities do not appear to improve abstinence-based therapy, as relapse rates in this paradigm are as high as 80%, when measured 2 years after treatment initiation. 67 Compared to abstinence, opioid replacement and medication-assisted therapies, which began in the 1960s, are more efficacious for relapse prevention; however, there are currently only four FDA-approved medications for the treatment of OUD. 68–71 Off-label prescription medications such as benzodiazepines and antiemetics are also common, but these therapies are largely directed at symptom management during acute detoxification rather than relapse prevention. 72 In this review, we focus on the most widely used OUD therapies, their shortcomings, and the bottlenecks to accessing them. 11
Methadone, a full MOR agonist, was approved by the FDA in 1974 to aid in opioid cessation. 9,73 Individuals enrolled in consistent dose methadone maintenance programs are more likely to stop using nonprescribed opioids than individuals not enrolled in the maintenance program. 74 Although methadone has an encouraging safety profile, 75 it carries some risk for misuse and mortality when the dose exceeds the patient’s level of tolerance. 76,77 Withdrawal symptoms from methadone mimic those of other opioids when stopped abruptly or tapered too quickly, and these symptoms last up to 3 weeks longer than withdrawal from other opioids. 9,78,79 There are only 1590 methadone distributers in the United States, which are highly regulated clinics that are concentrated in urban areas, creating geographical disparities in OUD treatment. 10,11,79 In addition to geographical barriers, these clinics frequently have stringent and stigmatizing compliance requirements, such as daily visits and frequent urine screenings for illicit drugs. 11,80 Although these barriers to treatment could potentially be addressed through concerted efforts to expand access, 40% of patients still relapse within 1 year of initiating methadone therapy. 67
Buprenorphine (Subutex) is a partial MOR agonist and KOR antagonist that can reduce withdrawal symptoms, cravings, and additional opioid use. 76,81,82 The inclusion of naloxone in some buprenorphine formulations (Suboxone, Zubsolv) is intended to reduce misuse by precipitating withdrawal when it is used intravenously, 82,83 and despite the presence of naloxone, there is still some risk for misuse and overdose. 77,83,84 The inclusion of naloxone can also induce withdrawal when administered too soon after the most recent dose of other opioids. 63,67,85
Unlike methadone, Suboxone offers a primary care approach to medication-assisted therapy, as it can be dispensed by a pharmacy rather than a specialized clinic. 86,87 However, only 3% of physicians possess the additional Drug Enforcement Agency credentials required to prescribe buprenorphine, 76,88 and there are strict limits on the number of patients they are permitted to serve. 89 Buprenorphine-licensed physicians also tend to be concentrated in larger cities, leaving 46.8% of counties in the United States, especially rural areas and the Midwest, with a shortage in convenient access to these treatment options. 88,90,91 While long-term treatment retention with buprenorphine or Suboxone is not as well characterized as methadone, a Swedish study has shown retention rates of up to 75% following a year of buprenorphine/Suboxone treatment. 92 However, a 24-week clinical trial in the United States reveals that buprenorphine retention is only 46%. 93
Evidence suggests that the most effective tool for relapse prevention is medication-assisted pharmacotherapy, combined with social support. 76,78,94,95 Because of the overwhelming evidence that supports this concurrent treatment model, there is little rationale to deviate from this approach. However, expanded access to these therapies is highly warranted, as are novel and alternative therapies which improve efficacy, diminish geographical disparities, and eliminate the need for specialty physicians. 96
Cannabis During Acute Opioid Withdrawal
The first barrier to overcoming OUD is getting patients through the acute withdrawal period, or detoxification. Although pharmacotherapies such as methadone and buprenorphine are largely successful and widely utilized for this purpose, there are shortcomings to this approach, which are highlighted above. 9,76,78,80,82,83,87,89–91,97 In May of 2018, the FDA approved the use of lofexidine, an alpha-2 adrenergic receptor agonist for acute (14 day) opioid withdrawal. Lofexidine provides substantially more symptom relief than placebo; however, the comparative efficacy of lofexidine in combination with long-acting opioid agonists or opioid antagonists is still being characterized. 71,98–100
There is also nascent evidence that suggests that cannabis may be an efficacious tool during the acute opioid withdrawal period. Numerous pre-clinical studies have shown that cannabis and cannabinoids decrease opioid withdrawal symptoms. 6,33,34,97,101–103 Although this evidence supports the use of cannabinoids as a possible treatment in OUD treatment, 28 conflicting evidence demonstrates that CB1 agonism increases the rewarding properties of opioids 22,102 and may actually increase the severity of opioid withdrawal symptoms. 18,104 These conflicting data highlight the need for a mechanistic characterization of CB1 agonism as a therapeutic target for opioid withdrawal, a need that is further substantiated by the pharmacology of CB1 antagonism. For instance, some studies show that acute administration of SR-141716A, a CB1 antagonist, can reduce opioid withdrawal; however, this effect is profoundly affected by the experimental conditions. 22,105 Because this effect can be recapitulated in CB1 KO mice, CB1 antagonism only partially mediates these effects. 102 To complicate the story further, the administration of cannabidiol (CBD), a very promiscuous phytocannabinoid with at least a dozen mechanisms of action, also alleviates naloxone-precipitated withdrawal in morphine tolerant rats. 106–112
Although the mechanisms by which cannabinoids alleviate opioid withdrawal are complex and unclear, some reports suggest that cannabis may alleviate opioid withdrawal in humans. 18,113 For instance, patients engaging in medication-assisted detoxification from opioids reported using cannabis when opioid maintenance doses were not high enough to prevent withdrawal and cravings. 114 However, some individuals reported that cannabis was often ineffective and sometimes worsened overall severity of the withdrawal symptoms. Because the phytochemical makeup and cannabinoid content of cannabis have a significant effect on subjective human experiences, 115 it is plausible that these variable experiences are the result of variable phytochemistry in cannabis products that are self-selected by study participants. Unfortunately, blinded, placebo-controlled clinical trials evaluating the efficacy of cannabis, either alone or as an adjunct therapy for acute opioid withdrawal, are lacking. This is not entirely surprising, given cannabis’ status as a Schedule I substance in the United States, which precludes federal funding to investigate cannabis as a medication-assisted therapy.
Unlike whole-plant cannabis, dronabinol, an FDA-approved analog of THC, has been evaluated for opioid withdrawal relief in a placebo-controlled study in patients receiving the opioid antagonist naltrexone. Low-dose adjunct dronabinol improved the tolerability of symptoms such as insomnia, reduced appetite, and reduced energy levels during opioid detoxification, whereas adverse events such as tachycardia were reported at higher dronabinol doses. 113,116,117 In many studies, cannabinoids were safe and tolerable when coadministered with an opioid or opioid replacement medication. 47,113,118–120 However, the comparative efficacy of dronabinol or other cannabinoids versus traditional replacement therapies such as methadone or buprenorphine remains to be elucidated. Given the efficacy and tolerability of Sativex (a whole-plant cannabis derivative) for pain and spasticity, investigation of adjunct Sativex for opioid withdrawal is warranted. 121–123
Like opioids, chronic cannabis exposure induces the development of tolerance, physical dependence, and withdrawal symptoms during abstinence. Patients commonly report that cannabis withdrawal symptoms, most commonly anger, aggression, irritability, anxiety, decreased appetite, weight loss, restlessness, and sleeping difficulties, 124–129 are similar to those produced by nicotine withdrawal. 129 Comparatively, the magnitude and severity of cannabis withdrawal are significantly and substantially more benign than opioid withdrawal. 20,126 In addition, and unlike opioids, cannabinoid withdrawal and subsequent relapse are nonlethal after periods of abstinence. The reduced intensity of cannabinoid withdrawal symptoms compared to opioids could at least partially be explained by the prolonged period of metabolization of cannabinoids in the body, 102 contributing to the mounting support for cannabis as a harm-reduction tool to combat OUD.
Cannabis as a Harm Reduction Tool in OUD
Pre-clinical evidence suggests that the CB1 receptor plays a critical role in opioid reward. Cannabinoid antagonism reduces the rewarding properties of opioids and prevents reinstatement of drug seeking. 105,130,131 However, these effects were not reproducible in human clinical trials. 132–134 Unlike CB1 antagonism, CB1 agonism may play a role in OUD treatment. Several studies have shown that adjunct cannabis decreases opioid consumption or prevents opioid dose escalation. 37–42,121,135 Although these findings are promising, several other studies have shown that cannabis use either has no impact on opioid consumption or may increase nonmedical opioid use. 136–138
The mechanisms underlying cannabis alteration of opioid consumption are yet to be determined; however, there is significant pre-clinical evidence which suggests that CBD, one of the most prevalent cannabinoid molecules in cannabis, plays a critical role. CBD does not have reinforcing effects in rodents, which supports its low potential for misuse. 16,139 CBD has been shown to reduce the rewarding aspects of multiple drugs of abuse, such as cocaine, amphetamine, 16 and nicotine. 140 Administration of CBD also attenuates morphine CPP and cue-induced reinstatement of heroin self-administration in rats, without creating any aversive or rewarding effects on its own. 106,141–143
These findings provide promising rationale for the use of CBD in opioid relapse prevention in humans. In fact, pilot clinical studies have shown that in individuals recently abstinent from heroin, CBD reduces heroin craving. 142 This effect occurs as soon as 1 h after administration and lasts for up to 7 days. Adjunct CBD appears to be safe and tolerable, as 400 and 800 mg oral CBD administration does not intensify the effects of intravenous fentanyl or create any adverse effects. 118 Because CBD is neither intoxicating nor rewarding and has an extremely large therapeutic window and impressive safety profile, the use of CBD to inhibit opioid craving has great therapeutic potential.
Adjunct cannabis use alongside current treatment strategies could help to improve the number of individuals engaging in OUD treatment, as well as increase treatment retention rates. Both dronabinol and intermittent whole-plant cannabis appear to increase the length of time patients remain in treatment for OUD. 6,113 However, chronic cannabis consumption during naltrexone treatment was ineffective at improving treatment retention, highlighting the need for further research into the dose and frequency of cannabis use in OUD treatment retention and relapse prevention. 144 Although the ubiquitous and ever-growing regulated cannabis markets across North America could potentially address the aforementioned shortcomings in OUD treatment accessibility and retention, there are currently very few addiction and recovery centers that have embraced concurrent social support and cannabis-assisted OUD treatment. 51 This is unsurprising given the lack of empirical evidence to support this approach, and the lack of federal research funding that would support this work.
In addition to the clinical and experimental observations outlined above, epidemiological investigations in U.S. states with legal cannabis have provided insight into the promising role for cannabis in the opioid crisis. The implementation of both medical and adult-use cannabis laws appears to have a significant impact on opioid consumption and overdose. These states experience a 23% reduction in nonfatal opioid overdoses, as measured at hospital emergency departments. 145 By analyzing death certificates, Bachhuber et al. found a 24% reduction in the annual rate of fatal opioid overdoses in the first year following medical cannabis legalization, 146 an effect that gets larger the longer a state has had legal cannabis (33% in California, which has had medical use since 1996 and the lowest rate of opioid overdose fatalities in the country). 146,147 This finding was also seen in data from the FARS, which demonstrates a similar drop in mortalities of opioid positive automobile accidents in states with implemented cannabis legalization for individuals aged 21–40. 148 The mechanisms underlying cannabis’ ability to reduce opioid hospitalization and mortality are unclear; however, analysis of the Medicare Part D prescription drug program has unveiled the possibility that cannabis may be serving as an analgesic alternative to opioids for individuals living in these states. 149 The number of filled POAs is substantially lower in states with the most liberal cannabis laws, where there are 3.742 million fewer daily doses than in states with the most prohibitive laws. 150
These epidemiological impacts are not exclusive to opioid prescriptions, hospitalizations, and mortality; the U.S. economy could also benefit from expanded cannabis legalization. Opioids cost patients and insurance companies upwards of 2.6 billion dollars in healthcare costs annually. 151 While cannabis is still federally illegal, and in most cases dispensary purchases are not eligible to be covered under any healthcare insurance plan, states with legalized cannabis have seen significant decreases in Medicare Part D prescription drug spending, including, but not limited to, prescription opioids. 149,152–155 Reductions in spending from Medicare Part D were over $165 million dollars. 149 If cannabis were removed from Schedule I of the Controlled Substance Act and more patients had access to cannabis, savings from pharmaceutical costs incurred by the Medicare Part D prescription plan are projected to continue to climb. 149
Shortcomings of Cannabis in Medication-Assisted Therapy
Although the literature thoroughly supports the safety and tolerability of cannabis, 38,118,142,156 there is conflicting evidence for its efficacy as a treatment for opioid misuse. Throughout the history of methadone administration, patients have reported that cannabis provides relief from opioid withdrawal symptoms, as well as breakthrough pain and anxiety. 119 However, other evidence demonstrates that cannabis does not relieve withdrawal symptoms for individuals undergoing methadone tapering, and some participants even reported increased severity of their withdrawal symptoms. 104 All the participants in the latter study procured their own cannabis and reported smoking as the route of administration. Because the dose of cannabinoids and phytochemical makeup of whole-plant cannabis have significant impacts on physiological responses (such as tachycardia) and subjective experiences (such as anxiety), additional research is needed to characterize maximally efficacious treatment protocols. 116,157 When used to treat opioid withdrawal symptoms, undesirable side effects also occur in a dose-dependent manner for the FDA-approved cannabinoid dronabinol. 113 The homogenous and consistent formulation of this pharmaceutical combined with the logistical ease of prescribing the drug may make it more feasible than whole-plant cannabis for clinical trials on cannabinoid alleviation of opioid withdrawal symptoms and relapse prevention.
Despite the promising results of reducing or maintaining a consistent opioid dose, it is plausible that the substitution of one rewarding substance (opioids) for another (THC) could be problematic, leading to cannabis use disorder (CUD). In 2016, ∼1.4–2.9% of adults over the age of 18 in the United States met criteria for CUD. 79 With revisions to the criteria of substance use disorders in 2013, ∼19% of individuals who use cannabis throughout their lifetime would eventually meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for CUD. 153 The interpersonal or employment hardships experienced by these individuals that resulted in the meeting of DSM criteria may have simply been due to the legality of cannabis use; that is, a false CUD diagnosis is less likely to occur in the postprohibition era, when patients are no longer breaking the law.
Risks of CUD seem to be correlated with higher THC concentrations, 153 which is a valid concern in legal markets where average THC potency is upward of 20%. 158 Recreational users of cannabis have historically consumed cultivars higher in THC and lower in CBD, due to the desired intoxicating effects of THC. 38 Medical users, however, have turned to cultivars higher in CBD and lower in THC in an attempt to optimize the medicinal benefits of cannabis. 38,153 Although misuse potential is a valid concern, it is notable that the misuse liability of cannabis is very low. 159 One possible approach to alleviate the concern of misuse is the concurrent administration of opioid antagonists. This approach seems to reduce the rewarding properties, but not the hyperphagia or withdrawal-relieving properties of THC. 160–164 These data suggest that combined cannabis and opioid-antagonist therapy could be an effective tool against OUD, while also minimizing the risk for CUD. Because cannabis does not carry the risk of fatal overdose, the use of cannabis as a harm-reduction treatment in the opioid epidemic warrants further investigation.
Summary and Future Directions
The opioid overdose epidemic is arguably the worst public health crisis in U.S. history. At the time of this publication, more people are dying than at the peak of the AIDS epidemic, and for the first time, drug overdoses outnumber automobile and handgun deaths. 165 A continental crisis of this magnitude warrants the immediate implementation of novel strategies that prevent opioid misuse, overdose, and death.
Growing pre-clinical and clinical evidence appears to support the use of cannabis for these purposes. The evidence summarized in this article demonstrates the potential cannabis has to ease opioid withdrawal symptoms, reduce opioid consumption, ameliorate opioid cravings, prevent opioid relapse, improve OUD treatment retention, and reduce overdose deaths. Cannabis’ greatest potential to positively impact the opioid epidemic may be due to its promising role as a first line analgesic in lieu of or in addition to opioids. The comparative efficacy of cannabis alone or in conjunction with current medication-assisted OUD therapies is not well characterized. However, no other intervention, policy, pharmacotherapy, or treatment paradigm has been as impactful as cannabis legislation has been on the rates of opioid consumption, overdose, and death.
Many of the barriers that prevent people from accessing traditional OUD treatment do not apply to cannabis therapy, and access to cannabis medicine is rapidly growing as more U.S. states roll back prohibition. However, a major barrier in universal patient access and improvement in the opioid epidemic is cannabis’ status as a Schedule I controlled substance. 166
Undoubtedly, more high-quality clinical evidence is needed to further support the use of cannabis to combat OUD; however, federal grant funding that would support these types of clinical trials is currently outside the scope of interest of the National Institutes of Health (because of Schedule I, cannabis is federally considered to have no medical benefit). Patients, healthcare providers, and regulating bodies would all greatly benefit from additional evidence that fills in massive gaps in the knowledge base about the utility of cannabis for OUD treatment: dosing, cannabinoid content and ratios, bioavailability, contraindications, misuse liability, route of administration, and many other questions remain. Even the clinical work that has been conducted thus far may have little validity in the modern landscape of legalized cannabis; all federally-funded cannabis research in the United States is conducted using a single source of cannabis (NIDA drug supply), which is notoriously low in potency and quality, and does not resemble the staggering phytochemical variability in whole-plant cannabis products in regulated state markets. 36 These barriers to research funding and access to “real world” cannabis for clinical research directly contribute to our inability to address the opioid epidemic with what appears to be a safe and efficacious tool.
In light of the evidence presented in this article, and despite a lack of FDA approval, some U.S. states and private treatment centers have already begun to include cannabis as a part of OUD treatment protocols. The state of New Jersey recently added OUD to their list of qualifying conditions for participation in the state’s medical cannabis program. 167,168 Some private treatment centers are also citing the benefits of harm reduction, which greatly outweigh the risks of cannabis use during the first 28 days of recovery, a critical time period for patient survival. 76
Many clinicians remain skeptical of cannabis as a viable treatment option, either due to the stigma surrounding cannabis use or the belief that there is not enough clinical evidence for them to feel confident providing patients with cannabis recommendations. 169 This is unsurprising, given that 85% of recent medical school graduates still receive no education whatsoever about cannabis throughout their training, residencies, or fellowships. 170 As the evidence in this field accumulates, it will be critically important to widen opportunities for clinicians to participate in Continuing Medical Education programs, which include the harm reduction and medical benefits that cannabis could provide. Evidence-based opioid prescription and cannabis recommendation practices are a critical component of continuing education, so that clinicians can continue to uphold their Hippocratic oaths to “do no harm.”
Pa. patients swear by cannabis as a tool to fight opioid addiction. The research still isn’t there.
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BERNVILLE — The back pain started when Luke Shultz was a teenager, and it got worse. When he was in his late 30s, he said, it led him to leave his job as a park ranger with the U.S. Army Corps of Engineers. Around the same time, since it hurt too much to sit for very long, he stopped driving. The family set up a cot in the back of a minivan so he could lie down while someone else drove.
“That really makes it tough,” said Shultz, now 59 years old. “You’re stuck at home and you can’t even go to the grocery store.”
Over the years, the Berks County resident tried different treatments: back braces, surgery, physical therapy, and prescribed opioids and other medication. Eventually, he turned to cannabis and became an advocate for its benefits.
In 2018, as a member of Pennsylvania’s newly formed Medical Marijuana Advisory Board, he helped push the state Department of Health to expand the list of serious medical conditions that makes someone eligible for cannabis to include opioid use disorder.
He and some other members of the panel saw the expansion as one more way for Pennsylvania — which has one of the highest drug overdose death rates in the country — to respond to the opioid epidemic.
“Cannabis can offer pain relief and has been reported by patients to ease the symptoms and process of opioid withdrawal,” the advisory board said in an April 2018 report. “It has been used by patients as an ‘exit drug’ to get off of heroin and other opiates.”
State officials accepted the recommendation, and at the time, Gov. Tom Wolf’s administration said Pennsylvania was the first state to take such action.
More than three years later, Pennsylvania remains an outlier in its approach. The Department of Health allows doctors to approve cannabis as a supplement to conventional opioid use disorder therapies, such as buprenorphine and methadone, which are approved by the federal government and studies have found to be highly effective.
But there’s a potentially riskier scenario: Physicians can also approve cannabis if those conventional therapies are “contraindicated,” a medical term generally meaning they could be risky, or “ineffective.” Treating patients that way raises concerns even among some medical professionals who see cannabis as relatively safe.
How many of the state’s roughly 550,000 registered cannabis patients use marijuana for opioid use disorder is not publicly known. The Pennsylvania Department of Health would not provide that information to Spotlight PA, despite the state previously making similar statistics public in early 2020.
In a presentation made at a Medical Marijuana Advisory Board meeting, one of the slides said 3% of patients listed opioid use disorder as their primary medical condition, making it the sixth most popular choice.
One of the main reasons the state’s former health secretary, Dr. Rachel Levine, approved opioid use disorder as a qualifying condition was so eight medical schools could study cannabis’ impact on it. The program, which the department said is the first of its kind, is supposed to fill critical information gaps.
But that kind of rigorous research can often stretch for many years, and the state’s research program hit some early challenges, including a lawsuit filed by a group of medical marijuana companies. The department denied Spotlight PA’s public records request seeking information on ongoing studies, and none of the eight medical schools provided findings related to opioid use disorder from their research programs.
The policy has met fierce resistance from some medical groups, who warn that the state’s endorsement of cannabis could lead patients to pass over proven medications.
The American Society of Addiction Medicine tells health care professionals not to recommend cannabis for the treatment of opioid use disorder and urges those professionals to use “great caution” when recommending it for any reason to someone who has a substance use disorder.
In a 2019 petition urging the state to reverse its decision, the Pennsylvania Psychiatric Society’s then-president, Dr. M. Ahmad Hameed, wrote that patients should “not be given sham treatments or those which might worsen their addiction.” Group leaders echoed those concerns again in April 2021, writing that the state already has “many effective treatments which may be ignored based on the commonwealth’s endorsement of a regimen unsupported by science.”
Gov. Tom Wolf’s administration has stood by its decision to add opioid use disorder to the list of qualifying conditions.
“Every individual is different and should work with their doctor to create and implement a treatment plan that meets their needs,” health department spokesperson Maggi Barton said in an email.
Complicating the situation is the ongoing conflict between the state and federal governments. While Pennsylvania endorses cannabis for treating opioid use disorder, the federal government has discouraged it.
In at least one case, as Spotlight PA reported in June, failure by the state to clarify federal rules had serious consequences: A Bucks County man was wrongly denied addiction treatment funding because of his medical marijuana card and soon after died of an overdose.
In the absence of the kind of proof that exists for federally approved medications, there are patients who say their lives have been transformed by cannabis.
Several years ago, Luke Shultz set up a blacksmithing workshop in his backyard. He can spend a few hours doing the work despite his chronic pain. “It keeps me active. It keeps the blood flowing, gives me something to do,” he said. “It’s a great creative outlet.”
Shultz is now certified to use marijuana for both pain and opioid use disorder. He’s been able to drastically reduce the number of opioids he takes to about one Percocet tablet daily, he said. With the pain he has now, Shultz can drive about 20 minutes on a good day.
“I don’t have the science to back it up. I typically go by anecdotal evidence — myself included — that basically for real people it’s had real, positive effects,” Shultz said. “Hopefully, at some point, the science will show that.”
Chris Braddock, a 37-year-old house painter from Washington County, said he struggled with opioid addiction for several years, going through periods of using traditional treatment options. But he said he couldn’t break a cycle of relapsing until he received approval for cannabis almost three years ago.
“I see how it works on me and people I know. I mean, that’s all the scientific evidence I need,” Braddock said. “I’m content. I’m happy. My life is good.”
Dr. Peter Grinspoon — an instructor at Harvard Medical School and a board member of Doctors for Cannabis Regulation, a group that supports cannabis legalization for adults — said he’s heard a lot of anecdotal evidence like Braddock’s. But he said anecdotal evidence has its limits.
If a patient has a headache and wants to try marijuana, Grinspoon said, the worst-case scenario is the cannabis doesn’t work and their migraine sticks around.
“Then we try something else,” said Grinspoon, who has talked publicly about his own experience with opioid addiction and recovery.
But the risk of failure is higher when treating a potentially deadly condition. If a patient were to rely solely on cannabis to treat opioid use disorder, there’s a big fear: They could relapse, overdose on opioids, and die.
The research vacuum
Views on the benefits and potential risks of cannabis use vary among medical professionals. Grinspoon’s position is nuanced.
He believes the drug can have a significant, positive role in responding to the opioid crisis, as patients can use cannabis for chronic pain instead of opioids or to lower the doses of opioids they use. And he supports using cannabis in addition to other treatments, including for treating withdrawal symptoms.
But Grinspoon said he would not recommend patients use cannabis as their primary treatment for opioid use disorder. There’s research showing significantly lower overdose death rates for people who use buprenorphine and methadone, two approved medication-assisted treatments, compared to people who don’t.
“We just don’t have that data yet for cannabis,” Grinspoon said.
Shalawn James, a prominent mental health advocate, is one of the state’s advisory board members who supported adding opioid use disorder. James said a chronic illness led her son to use prescribed opioids, and she was alarmed to see his tolerance increase.
She saw the addition of opioid use disorder as a qualifying condition as one more way to give patients options.
Still, she said it wasn’t an easy vote.
“I think with all of the votes, we want to see the research,” James said, but “a lot of the research that could happen doesn’t happen because of the federal restraints.”
The U.S. Drug Enforcement Administration classifies cannabis as a Schedule I drug — a category that includes heroin, ecstasy, and LSD. The designation means the agency considers cannabis to have no currently accepted medical use and a high potential for abuse.
“It’s a catch-22,” said Shultz, the advisory board member from Berks County. “There’s not enough research to show the value of medical marijuana, but yet it’s almost impossible to do the research properly.”
He said the research he found primarily dealt with cannabis being used for pain control as a substitute for prescribed medicine, but he said the studies didn’t directly support using marijuana to suppress a person’s addiction to opioids. He advocated for the addition anyway.
The health secretary conducted her own review, and the department provided a list of studies and articles in response to Spotlight PA’s public records request for resources that informed the agency’s decision.
The department’s press office declined to say how the materials supported or informed the decision. Some of the articles directly acknowledged the complexity of the issue.
In a 2017 article, neuroscientist Yasmin Hurd wrote that one of the compounds of cannabis, THC, “is not a suitable treatment option, given that it can even enhance opioid reward self-administration and induce other psychopathologies,” but there was a strong scientific basis for considering another compound, CBD.
Since then, Hurd’s research has continued to find CBD has potential medical benefits but, she said in 2020, the only way to get definitive information on its full safety and efficacy is through large, clinical trials.
Hurd, director of the Addiction Institute of Mount Sinai in New York, told Spotlight PA there is not adequate data to support the position that cannabis is effective for treating opioid use disorder, even when used alongside other medications. She hopes researchers can find alternative medications to help with opioid use disorder, but she’s cautious.
“We all would love for this to be true, but that has not been proven,” Hurd said.
At Thomas Jefferson University in Philadelphia, Dr. Brooke Worster said researchers don’t know enough about cannabis to recommend it as a replacement for the conventional treatments that exist for substance use disorder. She’s leading efforts to learn more as part of Pennsylvania’s research program.
The university has nearly completed a study that followed about 215 Pennsylvanians over the course of a year, assessing the type of cannabis they were using and its impact on quality of life and various symptoms.
Her team is now recruiting people who use opioids for chronic pain or have opioid use disorder for another study. Researchers will collect daily data on people’s pain levels, cravings, cannabis use, and opioid use after being exposed to three different cannabis formulations.
Worster said she understands objections to placing opioid use disorder on the list of qualifying conditions in Pennsylvania, but many people with addiction were already using marijuana — regardless of whether policymakers acknowledged it.
Medical professionals can choose to study the good and the bad, “or we can continue not to — and sort of pretend it’s not happening or not acknowledge that it’s happening,” Worster said. “And then it’ll just keep happening. Right? Because cannabis isn’t going away.”
Luke Shultz’s chronic pain left him unable to drive, so his family set up a cot in the back of a minivan so he could lie down while someone else drove. He says cannabis has transformed his life: “I don’t have the science to back it up. I typically go by anecdotal evidence — myself included — that basically for real people it’s had real, positive effects.”
‘This has saved my life’
Since Pennsylvania added opioid use disorder to its list of qualifying conditions, officials in New York, New Jersey, and New Mexico have taken similar steps.
Some states, including Maryland, give health-care practitioners greater discretion to decide when cannabis is OK for patients, including for addiction treatment. Still, the Maryland Medical Cannabis Commission in 2019 warned against adding opioid use disorder to its list, saying that doing so without substantial clinical research “presents significant public health and safety concerns.”
In Pennsylvania, more than 1,300 physicians were authorized to certify patients for cannabis as of 2020, the Department of Health said in a report. Currently, a few dozen are described as addiction specialists in a public list maintained by the agency
Spotlight PA spoke to seven doctors, including four in Pennsylvania, who said they approve cannabis for patients with opioid addiction. Their experiences and views varied, but several emphasized that cannabis is just one part of someone’s treatment, along with counseling and social support programs.
Some made distinctions between treating opioid use disorder itself and treating related problems, like anxiety or insomnia. They acknowledged the limited research but argued for the importance of doctors using their own clinical judgment.
In Blair County, Dr. Lawrence Levinson runs a small clinic specializing in opioid use disorder. He treats patients with Suboxone — a combination of the opioid medication buprenorphine and overdose-reversing drug naloxone — and he also certifies people to use cannabis.
The vast majority of his patients became addicted to opioids because of underlying pain, Levinson said. He said he’s “extremely hesitant” to certify patients for cannabis who became addicted to opioids through recreational use.
Over the past few years, he’s come to see more benefits to cannabis. “I hear continuously, ‘This has saved my life,’” Levinson said.
Dr. James Latronica in Allegheny County, listed in the state’s medical marijuana directory as an addiction specialist, told Spotlight PA he would not recommend cannabis to treat opioid use disorder for any reason. He sees some potential benefits, but worries about the lack of control he would have over his patients’ marijuana use.
Patients, like 36-year-old Michael Silver from Chester County, are figuring out their own approaches. Silver said his opioid addiction started when he got his wisdom teeth removed as a teenager.
“That was the first time I had ever taken an opioid,” Silver said. “And I just immediately fell in love.”
Pain pills led to heroin and fentanyl. He overdosed in late 2017, was revived, and went to rehab. He was prescribed Suboxone, and it worked for a while. But he relapsed near the end of 2018 and went back to rehab in the spring of 2019.
Silver had trouble sleeping after leaving rehab and smoked cannabis for relief. When he went to a doctor for Vivitrol, another federally approved treatment option, the cannabis showed up during a drug test. Silver’s doctor told him if cannabis was helping, he could keep taking it.
Silver has been certified for cannabis for opioid use disorder since then. He uses it as needed —when he’s feeling anxious or having trouble sleeping — along with a monthly Vivitrol injection.
“For me,” he said, “the combination of the two has just been a godsend.”
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