Neha Bhardwaj BS, PharmD
Philadelphia College of Osteopathic Medicine
SUMMARY POINTS
Medical marijuana is an effective form of pain management with considerably less potential for dependence and harm than prescription opioids.
Recent studies have examined the correlation between medical marijuana law implementation and presence of medical dispensaries and their associated potential reduction of opioid mortality/decreased opioid consumption.
Research on the effect of medical marijuana laws tends to have a lot of heterogeneity; more longitudinal analyses are necessary to fully comprehend its impact independent of other harm reduction strategies.
There are many barriers to usage of medical marijuana including physician and patient attitudes, a wide variety of dosage formulations, varying clinical efficacy, and racial/socioeconomic disparities in access to medical marijuana.
ANALYSIS
Background
Medical marijuana has become a topic of interest for healthcare providers across many disciplines, but it has gained traction particularly within the fields of pain management & addiction medicine. The rise of fatal opioid-related overdoses & resulting drive in harm reduction efforts have shed new light on alternatives for drug-based pain management solutions such as medical cannabis. Due to its classification as a Schedule I substance under the Controlled Substances Act, research can often be limited or costly and labs may be subject to monitoring and visitation from the DEA (1). Within the United States, 38 states allow the use of cannabis for medical purposes as of 2023, with specific legalization and decriminalization laws varying by state (2). Two important compounds in medical cannabis are the primary psychoactive compound called delta-9-tetrahydrocannabinol (d-9-THC), as well as cannabidiol, which is not psychoactive but has a variety of therapeutic effects that can contribute to treatment of symptoms of epilepsy, anxiety, and inflammation (3). These compounds are called phytocannabinoids, which are plant-based compounds that can act on the endogenous endocannabinoid system (ECS). The ECS contains CB1 & CB2 receptors, which are G-protein coupled receptors. The CB1 receptors are primarily located in the central nervous system in large quantities, while CB2 receptors are expressed in immune cells and the gastrointestinal system (3). CB1Rs influence the release of excitatory and inhibitory neurotransmitters such as dopamine, GABA, and glutamate, which contribute to their widespread effect on memory, pain, and movement (4). The body produces two endogenous cannabinoid neurotransmitters called 2-arachidonoylglycerol & anandamide, which are agonists of CB1 and CB2 receptors (3,4).
Image 1. The distribution of CB1 & CB2 receptors in the body and the binding sites of THC (a phytocannabinoid) and endogenous cannabinoids (2-AG and AEA). See Link: from Breijyeh, Z.; Jubeh, B.; Bufo, S.A.; Karaman, R.; Scrano, L. Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses. Toxins 2021, 13, 117.
The FDA has currently approved two forms of THC-based drug therapy (dronabinol & nabilone) for nausea treatment in chemotherapy patients, as well as appetite stimulation for cachexic patients experiencing AIDS (5). Medical marijuana, specifically inhaled cannabis, has been touted as an adjunctive or even a substitute for opioid use in pain management (6). There are many reasons to use medical marijuana as an alternative to opioids, and many cite the high addiction & overdose potential of opioids, as well as adverse effects of chronic opioid use such as respiratory depression, constipation, hyperalgesia, sedation, and miosis (7). Medical marijuana & its derivatives have been shown to reduce chronic & inflammatory pain symptoms, leading to their spotlight on the stage of alternative pain management strategies (6). Marijuana & opioids share potential for dependence, and marijuana can cause adverse psychomotor and cognitive effects such as anxiety, paranoia, and psychotic episodes. There have been no overdose deaths reported solely from marijuana use, making it a useful adjunctive agent (7).
Analysis
Medical marijuana legalization and decriminalization may contribute to decreased use of prescription opioids. One such study of 2011-2016 Medicaid prescription data allowed researchers to examine the state-level opioid prescribing rate for pain management. The study indicated that the implementation of medical marijuana laws decreased the rate of opioid prescribing among Schedule II, III, and V opioids covered by Medicaid (8). A further longitudinal analysis of Medicare Part D prescriptions demonstrated that in states with medical cannabis laws, there were statistically significant reductions in opioid prescribing (9). In examining specific medical cannabis laws, states with legal medical dispensaries demonstrated a significant decrease in the use of opioids, as evidenced by reduced daily doses of controlled substances (hydrocodone, morphine, etc) (9). Such studies provide some evidence that increasing access to medical marijuana may have a significant impact on opioid prescription rates & daily opioid use.
Additional research examined patients actively receiving medical cannabis & the resulting changes in their opioid prescriptions via their opioid dosage’s associated morphine milligram equivalent (MMEs) changes. One cohort study of New York State Prescription Monitoring Program data assessed differences in medical cannabis duration among patients already receiving long-term chronic pain opioid therapy with varying baselines of opioid dosages. There was a significant decrease in patients’ mean daily MME when receiving longer durations of medical cannabis treatment (10). The study also demonstrated that MME reductions were found to be greater in those patients with higher initial opioid prescriptions compared to the reductions in patients with lower starting doses of opioids (10). Another single-center, retrospective, cohort study measured daily MMEs and diazepam equivalents at baseline, three, and six months. There was a statistically significant decrease in median MME measured from baseline to three months as well as from baseline to six months (11). This study was unique in its exploration of benzodiazepine equivalents, which can further increase the risk of opioid overdose. The seemingly positive impact of medical cannabis on MME reduction in the above studies provides an incentive for further research on the use of medical cannabis to reduce prescription opioid dosages via examination of changes in MME, however more specificity in the dosage of THC & significantly larger sample sizes are needed.
While the above studies on medical marijuana laws and medical cannabis implementation show promising results, there is conflicting evidence on the scope of the benefit of medical marijuana. A 2019 review conducted by Chihuri, et al. on state marijuana laws and opioid overdose mortality examined 16 studies relating to the impact of cannabis laws on opioid overdose mortality, prescriptions, and hospitalizations within the United States. In a sample of four studies on medical marijuana law implementation and impacts on opioid mortality rate, only one study found a statistically significant decrease in mortality, while two other studies found a reduction in mortality that were not statistically significant (12). In contrast, one study that was cited found a paradoxical increase in mortality that was statistically significant. The review also examined seven studies on the association between MMEs and rates of opioid prescriptions, in which four studies reported a statistically significant decrease in dispensing of opioids, while two other studies provided evidence for a decrease in prescription opioid dispensing that were not significant (12). There was insufficient evidence that legalization of medical marijuana was associated with reduced mortality, however a modest reduction in opioid dispensing was found to be associated with medical cannabis implementation (12). Furthermore, a 2020 systematic review examined nine studies examining the association between medical marijuana use and associated opioid dosages. The study found several statistically significant reductions in opioid dosage with the substitution and/or concurrent use of medical cannabis. Additionally reductions in emergency department visits and hospitalization due to chronic pain were noted in the US & Canada (13).
Discussion
While the evidence presented in these studies gives us much to consider about medical marijuana implementation for reduction of opioid use, it is important to take note of several potential study limitations. One such factor is the risk of confounding factors. For example, the presence of harm reduction strategies such as naloxone distribution, which could mask or inflate the true impact of medical cannabis on opioid overdose mortality rates and opioid dosage reductions. Additionally, it would be an incorrect assumption to believe that all patients living in states with legal medical cannabis are willing and able to pursue treatment. Patients who are already on a stable opioid dose may be unwilling to change their therapy or to consider alternative pain management.
From a therapeutic standpoint, there may be multiple barriers to achievement of therapeutic success with medical cannabis. The many formulations and variety in dosing (e.g., pills, edibles, vaporizers, oils) require more research to determine optimal THC doses and to determine which dosage form is the most effective for patients with chronic pain (14). From a socieconomic standpoint, there are broad differences in physician & patient attitudes towards marijuana, stigma, and racial or ethnic disparities in receiving medical marijuana. Patients with opioid use disorder were often excluded from studies, which restricts current knowledge on the impact of medical cannabis for a high-risk population. These factors may all contribute to inadequate pain management or decreased efficacy in combating the opioid epidemic through alternative pain management strategies. Due to the heterogeneity of results from multiple studies and systematic reviews, it is crucial that more studies are conducted utilizing longitudinal Prescription Drug Monitoring Program data, which include diverse populations and make considerations for varying efficacies of different formulations of marijuana.
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