Available via license: CC BY 4.0
Content may be subject to copyright.
A preview of the PDF is not available
Emerging Evidence for Cannabis' Role in Opioid Use Disorder
Abstract
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.
... Controlling severe, chronic pain with neuropathic and inflammatory components remains a modern therapeutic challenge [14]. Despite the crucial role of opioids in pain management, their prolonged use can result in severe adverse effects, physical dependence, tolerance development and the risk of overdose [15][16][17][18][19]. Moreover, the United States faces a major crisis due to excessive opioid use and overdose deaths [19,20] as patients with cancer pain alone receive enormous quantities of prescribed opioids each year [21]. ...
... Despite the crucial role of opioids in pain management, their prolonged use can result in severe adverse effects, physical dependence, tolerance development and the risk of overdose [15][16][17][18][19]. Moreover, the United States faces a major crisis due to excessive opioid use and overdose deaths [19,20] as patients with cancer pain alone receive enormous quantities of prescribed opioids each year [21]. It is worth mentioning that around half of palliative care patients feel anxious and uncer- Figure 1. ...
... Cannabinoids can modulate pain in a multifaceted manner, through many signalling pathways, including the endocannabinoid system [4,30]. Combining opioids and cannabinoids leads to a cumulative analgesic effect in patients with chronic pain, inhibits the development of tolerance, as well as enables patients to reduce doses of administered opioids to amounts previously ineffective [14,15,19,[29][30][31][32][33][34] -even by 40-60% [19]. Interestingly, patients not only report fewer side effects compared to using opioids but also express their preference for cannabinoids [19]. ...
... Throughout the world health care providers play a crucial role in facilitating patients to access medical cannabis.[10][11][12] Some of the previously reported literature suggested that only a minor population of health care providers believed that medicinal cannabis confers benefits to patients.13,14 In present study, we assessed knowledge, awareness and perception about indications, contraindications and hazards of prescribing medicinal cannabis among health care providers. ...
Background: Since the medicinal use of cannabis is well-known, there was a need to assess the knowledge, beliefs and experience regarding indications, safety and side effects of prescribing medicinal cannabis among Pakistani health workers. Material and methods: A cross-sectional survey was conducted among medical and dental students and practitioners selected from different campuses of the two public sector medical universities of Karachi. A self-reported questionnaire was used to record knowledge, beliefs and experience regarding indications, safety and side effects of prescribing medicinal cannabis on a 5-point Likert scale. Data & analyzed was described using IBM SPSS Statistics for Windows, v. 24.0. Results: A total number of 126 health professionals participated in this study with mean age 24.3 ± 2.5 years and more female (n=90) than males (n=36). The overall distribution of knowledge scores was obtained for 'neutral opinion'. Majority believed that medicinal cannabis can be used for treatment of dementia, chronic non-cancer pain, epilepsy and has anti-tumor effects. Conclusion: It can be concluded that medicinal cannabis knowledge is limited among health care professionals. Measures must be taken to eliminate the knowledge gap of the health care providers about effectiveness and qualifying conditions of these products.
... 2,3 There are currently limited treatment options available for opioid withdrawal and cannabidiol (CBD) has been identified as a potential novel therapeutic. 4 Current FDA-approved treatments for opioid use disorder include opioid maintenance therapies such as methadone and buprenorphine. Although these therapies are associated with a significant reduction in all-cause mortality, 5,6 they suffer from high rates of discontinuation, relapse, and overdose, 7,8 as well as restricted accessibility. ...
Introduction: Opioid withdrawal is a powerful driver of drug-seeking behavior as relief from this aversive state through drug-taking is a strong negative reinforcer. There are currently limited treatment options available for opioid withdrawal and cannabidiol (CBD) has been identified as a potential novel therapeutic. This study explored the efficacy and dose dependency of CBD for reducing the severity of naloxone-precipitated and spontaneous oxycodone withdrawal (PW and SW, respectively) in male and female mice. Methods: Mice were administered saline or escalating doses of oxycodone, whereby 9, 17.8, 23.7, and 33 mg/kg oxycodone IP was administered twice daily on days 1-2, 3-4, 5-6, and 7-8, respectively. On the 9th day, a single 33 mg/kg dose of oxycodone (or saline) was administered. To precipitate withdrawal, on day 9, mice in the withdrawal conditions were administered an IP injection of 10 mg/kg naloxone 2 h after the final oxycodone injection and immediately before withdrawal testing. To elicit SW, a separate group of mice underwent withdrawal testing 24 h after their final oxycodone injection. Mice were treated with an IP injection of 0, 10, 30 or 100 mg/kg of CBD 60 min before testing. Withdrawal symptoms examined included gastrointestinal symptoms (fecal boli, diarrhea, and body weight loss), somatic symptoms (paw tremors), and negative affect (jumping). Results: A robust PW syndrome was observed in both male and female mice, whereas only male mice displayed an SW syndrome. CBD dose dependently reduced gastrointestinal symptoms during both PW and SW in male mice and during PW in female mice. CBD had no effect on PW- or SW-induced jumping in male mice. However, in female mice, the PW-induced increase in jumps was less pronounced in CBD-treated mice. The highest dose of CBD inhibited paw tremors during PW, but not SW, in male mice. Neither PW- nor SW-induced paw tremors were observed in female mice. Conclusions: The magnitude of effects on the gastrointestinal symptoms, their consistency across PW and SW, and both sexes, alongside the availability of CBD for clinical use, suggest further exploration of the potential for CBD to treat these symptoms could be justified.
... Our previous studies have also demonstrated that persistent pain promotes increased opioid self-administration in male rats [72]. Because cannabinoids could be used as an adjunct treatment to reduce opioid abuse liability [73], it was critical for us to evaluate the ability of WPE to reduce opioid self-administration behavior in the context of chronic neuropathic pain. ...
Chronic pain patients report analgesic effects when using cannabidiol (CBD), a phytocannabinoid found in whole-plant cannabis extract (WPE). Several studies suggest that cannabis-derived products may serve as an analgesic adjunct or alternative to opioids, and importantly, CBD may also attenuate the abuse potential of opioids. Vaping is a popular route of administration among people who use cannabis, however both the therapeutic and hazardous effects of vaping are poorly characterized. Despite the fact that chronic pain is more prevalent in women, the ability of inhaled high-CBD WPE to relieve pain and reduce opioid reward has not been studied in females. Here, we present a comprehensive analysis of high-CBD WPE vapor inhalation in female rats. We found that WPE was modestly efficacious in reversing neuropathy-induced cold allodynia in rats with spared nerve injury (SNI). Chronic exposure to WPE did not affect lung cytoarchitecture or estrous cycle, and it did not induce cognitive impairment, social withdrawal or anxiolytic effects. WPE inhalation prevented morphine-induced conditioned place preference and reinstatement. Similarly, WPE exposure reduced fentanyl self-administration in rats with and without neuropathic pain. We also found that WPE vapor lacks of reinforcing effects compared to the standard excipient used in most vapor administration research. Combined, these results suggest that although high-CBD vapor has modest analgesic effects, it has a robust safety profile, no abuse potential, and it significantly reduces opioid reward in females. Clinical studies examining high-CBD WPE as an adjunct treatment during opioid use disorder are highly warranted.
When experiencing mental health challenges, we all deserve treatments that actually work. Whether you are a healthcare consumer, student, or mental health professional, this book will help you recognize implausible, ineffective, and even harmful therapy practices while also considering recent controversies. Research-supported interventions are identified in this book and expanded upon in a companion volume. Chapters cover every major mental disorder and are written by experts in their respective fields. Pseudoscience in Therapy is of interest to students taking courses in psychotherapy, counseling, clinical psychology, and behavior therapy, as well as practitioners looking for a guide to proven therapeutic techniques.
Prescribed cannabinoids are legal in the UK and are increasingly being used for a variety of conditions, with one of the most frequent conditions being chronic pain. Within this cohort, there is developing evidence that cannabis-based medicinal products are associated with opioid and other medication sparing. However, at present, the National Institute for Health and Care Excellence (NICE) does not recommend the prescription of cannabis-based medicinal products to treat chronic pain due to the lack of randomised controlled trial evidence for this condition. Here we present a case study of a 61-year-old woman with idiopathic small fibre neuropathy, who was prescribed the gabapentinoid pregabalin, in combination at different times with various other agents including amitriptyline, duloxetine, lamotrigine, meloxicam and topical capsaicin, over a 17-year period for the associated neuropathic pain. Although her pain was relatively well controlled, the patient reported hearing loss, sleepiness, tinnitus, confusion and worsening anxiety possibly as a result of prolonged pregabalin use. Efforts were made to reduce the pregabalin dose but any attempts to reduce below a total daily dose of 350 mg resulted in unacceptable pain for the patient. In 2021, the patient was enrolled in Project Twenty21, the UK's first medical cannabis registry, and prescribed full plant extract delta-9-tetrahydrocannabinol 10 mg: cannabidiol 15 mg/mL of oil, prescribed at a dose range of 0.1–0.5 mL twice daily. As a result, the patient managed to reduce her pregabalin down to 37.5 mg total daily dose. The patient now feels she has ‘been given a second chance at life’ and her husband describes her as ‘a new woman’. This patient feels that she is in a position to finally stop treatment with pregabalin, as a result of medical cannabis controlling her pain. Highlighting the potential benefits of cannabis-based medicinal products to treat chronic pain, our case study indicates the value of including real-world evidence when assessing the benefits and safety of cannabis-based medicinal products.
Introduction:
There is limited data on the awareness and use of synthetic cannabinoids (SCs) in high-risk population in Serbia, despite SCs becoming more and more common at illicit drug market.
Aim:
This pilot study aimed to examine the awareness and prevalence of use of SCs in patients with an opioid-use disorder and to identify patient characteristics and other factors associated with SCs use.
Patients and methods:
This cross-sectional study was conducted at the Clinic for Psychiatry, Clinical Center Vojvodina, Serbia, the largest tertiary health care institution in this region of the country. All patients hospitalized due to the treatment of opioid dependence during November and December 2017 were included (response rate 100%), and filled-out an anonymous questionnaire specifically developed for the purpose of this study. Differences between patients reporting SCs use and those who did not were compared using chi-square test with values of p < 0.05 were considered significant.
Results:
Out of 64 patients (median age 36.37 years), one third (32.81%) reported using SCs. Socio-demographic characteristics of the subjects were not associated with SCs use. There were differences in the most common sources of information reported between the SCs users and non-users. Majority of SCs users (76.0%) were informed about SCs through friends, compared with just 26.0% of non-users (<0.001). Nearly all study participants (93.8%) were daily tobacco users. The share of respondents reporting alcohol and marihuana use was significantly higher among the SCs users (52.0% vs. 20.9%, p = 0.011 and 15.6% vs. 12.5%, p = 0.015), respectively. Higher share of SCs users used multiple psychoactive substances (38.1% vs. 16.3%), and this difference was statistically significant (p = 0.047). The most commonly reported adverse effect of SCs among users included dry mouth (81.0%), trouble thinking clearly (52.4%) and panic attacks (52.4%).
Conclusion:
Understanding the awareness and use of SCs among high-risk drug users, as well as associated factors can help improve substance-use disorder treatment in our setting. Educational activities targeting public are urgently needed to raise awareness on SCs, considering that social contacts are the main sources of information on SC for this vulnerable population. Users of SCs have also reported using other psychoactive substances more often, and this calls for a holistic approach addressing multiple factors to improve substance-use treatment in our setting.
Introduction:
There is considerable interest in utilizing cannabis-based products as adjuvants to opioid agonist therapies as phytocannabinoids like Δ9-tetrahydrocannabinol (THC) or synthetic cannabinoid receptor agonists appear to enhance the pain-relieving effects of opioids without enhancing problematic effects of opioids. Cannabis is a pharmacologically complex plant with hundreds of compounds, some of which may have interactive effects. Therefore, studying compounds like THC in isolation does not accurately reflect the clinical use of cannabis.
Methods:
This study examined the effects of THC and cannabidiol (CBD), the two most prominent compounds in cannabis, on the reinforcing effects of fentanyl in rhesus monkeys in a food versus drug choice procedure. Responding on one lever was reinforced by delivery of a sucrose pellet, and responding on another lever was reinforced by delivery of an i.v. infusion of fentanyl. In each monkey, the largest dose of fentanyl that produced less than 20 % drug choice and the smallest dose of fentanyl that produced more than 80% drug choice was determined. Effects of pretreatment with THC and CBD, alone and in mixtures, were then examined.
Results:
THC, CBD, and THC:CBD mixtures did not reliably enhance or diminish choice for fentanyl up to doses that suppressed responding in most monkeys, though some individual differences were observed, with THC and THC:CBD mixtures decreasing choice for large doses of fentanyl in one monkey and increasing choice for small doses of fentanyl in another.
Conclusions:
Phytocannabinoids like THC and CBD, administered alone or in mixtures, do not appear to reliably alter the reinforcing effects of opioids.
Background
The past two decades have seen an increase in cannabis use due to both regulatory changes and an interest in potential therapeutic effects of the substance, yet many aspects of the substance and their health implications remain controversial or unclear.
Methods
In November 2020, the American Society of Regional Anesthesia and Pain Medicine charged the Cannabis Working Group to develop guidelines for the perioperative use of cannabis. The Perioperative Use of Cannabis and Cannabinoids Guidelines Committee was charged with drafting responses to the nine key questions using a modified Delphi method with the overall goal of producing a document focused on the safe management of surgical patients using cannabinoids. A consensus recommendation required ≥75% agreement.
Results
Nine questions were selected, with 100% consensus achieved on third-round voting. Topics addressed included perioperative screening, postponement of elective surgery, concomitant use of opioid and cannabis perioperatively, implications for parturients, adjustment in anesthetic and analgesics intraoperatively, postoperative monitoring, cannabis use disorder, and postoperative concerns. Surgical patients using cannabinoids are at potential increased risk for negative perioperative outcomes.
Conclusions
Specific clinical recommendations for perioperative management of cannabis and cannabinoids were successfully created.
Background:
Neonatal opioid withdrawal syndrome (NOWS) is a growing public health problem associated with complex and prolonged medical care and a significant resource utilization burden. The objective of this study was to compare the cost of different convalescent care settings for infants with NOWS.
Methods:
Retrospective comparison study of infants with NOWS discharged directly from NICU, transferred to an acute care pediatric floor (PPCU) or rehabilitation hospital (PRH). Primary outcomes were length of stay (LOS) and cost of stay (COS).
Results:
Infants had 1.3 (95% CI: 1.1,1.6) times and 2.5 (95% CI: 2.1,3.1) times significantly longer mean LOS for PPCU and RH discharges compared to NICU discharges. NICU discharged infants had the lowest mean COS ($25,745.00) and PRH the highest ($60,528.00), despite PRH having a lower cost per day. PRH discharged infants had higher rates of methadone and benzodiazepine and less buprenorphine exposure than NICU/PPCU discharged. Infants born to mothers on marijuana and buprenorphine had a 28% lower mean COS compared to unexposed infants. Median treatment cumulative morphine doses were six-fold higher for PRH than NICU discharge.
Conclusions:
Infants transferred to convalescence care facilities had longer and more costly admissions and received more medication. However, there may be a role for earlier transfer of a subset of infants at-risk for longer LOS as those exposed to methadone and/or benzodiazepines. Further studies exploring differences in resource utilization, convalescent care delivery and cost expenditure are recommended.
Background:
Interest in the use of cannabis and cannabinoids to treat chronic non-cancer pain is increasing, because of their potential to reduce opioid dose requirements. We aimed to investigate cannabis use in people living with chronic non-cancer pain who had been prescribed opioids, including their reasons for use and perceived effectiveness of cannabis; associations between amount of cannabis use and pain, mental health, and opioid use; the effect of cannabis use on pain severity and interference over time; and potential opioid-sparing effects of cannabis.
Methods:
The Pain and Opioids IN Treatment study is a prospective, national, observational cohort of people with chronic non-cancer pain prescribed opioids. Participants were recruited through community pharmacies across Australia, completed baseline interviews, and were followed up with phone interviews or self-complete questionnaires yearly for 4 years. Recruitment took place from August 13, 2012, to April 8, 2014. Participants were asked about lifetime and past year chronic pain conditions, duration of chronic non-cancer pain, pain self-efficacy, whether pain was neuropathic, lifetime and past 12-month cannabis use, number of days cannabis was used in the past month, and current depression and generalised anxiety disorder. We also estimated daily oral morphine equivalent doses of opioids. We used logistic regression to investigate cross-sectional associations with frequency of cannabis use, and lagged mixed-effects models to examine temporal associations between cannabis use and outcomes.
Findings:
1514 participants completed the baseline interview and were included in the study from Aug 20, 2012, to April 14, 2014. Cannabis use was common, and by 4-year follow-up, 295 (24%) participants had used cannabis for pain. Interest in using cannabis for pain increased from 364 (33%) participants (at baseline) to 723 (60%) participants (at 4 years). At 4-year follow-up, compared with people with no cannabis use, we found that participants who used cannabis had a greater pain severity score (risk ratio 1·14, 95% CI 1·01-1·29, for less frequent cannabis use; and 1·17, 1·03-1·32, for daily or near-daily cannabis use), greater pain interference score (1·21, 1·09-1·35; and 1·14, 1·03-1·26), lower pain self-efficacy scores (0·97, 0·96-1·00; and 0·98, 0·96-1·00), and greater generalised anxiety disorder severity scores (1·07, 1·03-1·12; and 1·10, 1·06-1·15). We found no evidence of a temporal relationship between cannabis use and pain severity or pain interference, and no evidence that cannabis use reduced prescribed opioid use or increased rates of opioid discontinuation.
Interpretation:
Cannabis use was common in people with chronic non-cancer pain who had been prescribed opioids, but we found no evidence that cannabis use improved patient outcomes. People who used cannabis had greater pain and lower self-efficacy in managing pain, and there was no evidence that cannabis use reduced pain severity or interference or exerted an opioid-sparing effect. As cannabis use for medicinal purposes increases globally, it is important that large well designed clinical trials, which include people with complex comorbidities, are conducted to determine the efficacy of cannabis for chronic non-cancer pain.
Funding:
National Health and Medical Research Council and the Australian Government.
This report summarizes the epidemiology of overdose deaths from 2015–2016, highlighting the key findings of this health crisis.
Introduction:
Medical cannabis (MC) is commonly claimed to be an effective treatment for chronic or refractory pain. With interest in MC in the United States growing, as evidenced by the 29 states and 3 US districts that now have public MC programs, the need for clinical evidence supporting this claim has never been greater.
Methods:
This was a retrospective, mirror-image study that investigated MC's effectiveness in patients suffering from chronic pain associated with qualifying conditions for MC in New York State. The primary outcome was to compare European Quality of Life 5 Dimension Questionnaire (EQ-5D) and Pain Quality Assessment Scale (PQAS) scores at baseline and 3 months post-therapy. The secondary outcomes included comparisons of monthly analgesic prescription costs and opioid consumption pre- and post-therapy. Tolerability was assessed by side effect incidence.
Results:
This investigation included 29 subjects. Quality of life and pain improved, measured by change in EQ-5D (Pre 36 - Post 64, P < .0001) and change in PQAS paroxysmal (Pre 6.76 - Post 2.04, P < .0001), surface (Pre 4.20 - Post 1.30, P < .0001), deep (Pre 5.87 - Post 2.03, P < .0001), unpleasant (Pre "miserable" - Post "annoying", P < .0001). Adverse effects were reported in 10% of subjects.
Discussion:
After 3 months treatment, MC improved quality of life, reduced pain and opioid use, and lead to cost savings. Large randomized clinical trials are warranted to further evaluate the role of MC in the treatment of chronic pain.
Background:
Cannabis is commonly used to alleviate symptoms of negative affect. However, a paucity of research has examined the acute effects of cannabis on negative affect in everyday life. The current study provides a naturalistic account of perceived changes in symptoms of depression, anxiety, and stress as a function of dose and concentration of Δ9tetrahydrocannabinol (THC) and cannabidiol (CBD).
Method:
Data from the app StrainprintTM (which provides medical cannabis users a means of tracking changes in symptoms as a function of different doses and chemotypes of cannabis) were analyzed using multilevel modeling. In total, 11,953 tracked sessions were analyzed (3,151 for depression, 5,085 for anxiety, and 3,717 for stress).
Results:
Medical cannabis users perceived a 50% reduction in depression and a 58% reduction in anxiety and stress following cannabis use. Two puffs were sufficient to reduce ratings of depression and anxiety, while 10+ puffs produced the greatest perceived reductions in stress. High CBD (>9.5%)/low THC (<5.5%) cannabis was associated with the largest changes in depression ratings, while high CBD (>11%)/high THC (>26.5%) cannabis produced the largest perceived changes in stress. No changes in the perceived efficacy of cannabis were detected across time. However, baseline symptoms of depression (but not anxiety or stress) appeared to be exacerbated across time/tracked sessions.
Limitations:
The primary limitations are the self-selected nature of the sample and the inability to control for expectancy effects.
Conclusions:
Cannabis reduces perceived symptoms of negative affect in the short-term, but continued use may exacerbate baseline symptoms of depression over time.
Background and Aims
While the US has been experiencing an opioid epidemic, 29 states and Washington DC have legalized cannabis for medical use. This study examined whether statewide medical cannabis legalization was associated with reduction in opioids received by Medicaid enrollees.
Design
Secondary data analysis of state‐level opioid prescription records from 1993‐2014 Medicaid State Drug Utilization Data. Linear time‐series regressions assessed the associations between medical cannabis legalization and opioid prescriptions, controlling for state‐level time‐varying policy covariates (such as prescription drug monitoring programs) and socioeconomic covariates (such as income).
Setting
United States.
Participants
Drug prescription records for patients enrolled in fee‐for‐service Medicaid programs that primarily provide healthcare coverage to low income and disabled people.
Measurements
The primary outcomes were population‐adjusted number, dosage, and Medicaid spending on opioid prescriptions. Outcomes for Schedule II opioids (e.g., Hydrocodone, Oxycodone) and Schedule III opioids (e.g., Codeine) were analyzed separately. The primary policy variable of interest was the implementation of statewide medical cannabis legalization.
Findings
For Schedule III opioid prescriptions, medical cannabis legalization was associated with a 29.6% (p=0.03) reduction in number of prescriptions, 29.9% (p=0.02) reduction in dosage, and 28.8% (p=0.04) reduction in related Medicaid spending. No evidence was found to support the associations between medical cannabis legalization and Schedule II opioid prescriptions. Permitting medical cannabis dispensaries was not associated with Schedule II or Schedule III opioid prescriptions after controlling for medical cannabis legalization. It was estimated that, if all the states had legalized medical cannabis by 2014, Medicaid annual spending on opioid prescriptions would be reduced by 17.8 million dollars.
Conclusion
Statewide medical cannabis legalization appears to have been associated with reductions in both prescriptions and dosages of Schedule III (but not Schedule II) opioids received by Medicaid enrollees in the US.
Background and purpose:
We sought to understand why (-)-cannabidiol (CBD) and (-)-cannabidiol-dimethylheptyl (CBD-DMH) exhibit distinct pharmacology, despite near identical structures.
Experimental approach:
HEK293A cells expressing either human type 1 cannabinoid receptor (CB1R) or type 2 cannabinoid receptor (CB2R) were treated with CBD or CBD-DMH with or without the CB1R and CB2R agonist CP55,940, the CB1R allosteric modulator Org27569 or the CB2R inverse agonist SR144528. Ligand binding, cAMP levels, and βarrestin1 recruitment were measured. CBD and CBD-DMH binding was simulated with models of human CB1R or CB2R, based on the recently published crystal structures of agonist-bound (5XRA) or antagonist-bound (5TGZ) human CB1R.
Key results:
At CB1R, CBD was a negative allosteric modulator (NAM) and CBD-DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist-bound model of CB1R (5TGZ), but shared a binding site with CP55,940 in the agonist-bound model of CB1R (5XRA). The binding site for CBD-DMH in the CB1R models overlapped with CP55,940 and Org27569. At CB2R, CBD was a partial agonist, and CBD-DMH was a positive allosteric modulator of cAMP modulation, but a NAM of βarrestin1 recruitment. CBD, CP55,940, and SR144528 shared a binding site in the CB2R models that was separate from CBD-DMH.
Conclusion and implications:
The pharmacological activity of CBD and CBD-DMH in HEK293A cells and their modelled binding sites at CB1R and CB2R may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB1R and CB2R.
Importance
Overprescribing of opioids is considered a major driving force behind the opioid epidemic in the United States. Marijuana is one of the potential nonopioid alternatives that can relieve pain at a relatively lower risk of addiction and virtually no risk of overdose. Marijuana liberalization, including medical and adult-use marijuana laws, has made marijuana available to more Americans.
Objective
To examine the association of state implementation of medical and adult-use marijuana laws with opioid prescribing rates and spending among Medicaid enrollees.
Design, Setting, and Participants
This cross-sectional study used a quasi-experimental difference-in-differences design comparing opioid prescribing trends between states that started to implement medical and adult-use marijuana laws between 2011 and 2016 and the remaining states. This population-based study across the United States included all Medicaid fee-for-service and managed care enrollees, a high-risk population for chronic pain, opioid use disorder, and opioid overdose.
Exposures
State implementation of medical and adult-use marijuana laws from 2011 to 2016.
Main Outcomes and Measures
Opioid prescribing rate, measured as the number of opioid prescriptions covered by Medicaid on a quarterly, per-1000-Medicaid-enrollee basis.
Results
State implementation of medical marijuana laws was associated with a 5.88% lower rate of opioid prescribing (95% CI, −11.55% to approximately −0.21%). Moreover, the implementation of adult-use marijuana laws, which all occurred in states with existing medical marijuana laws, was associated with a 6.38% lower rate of opioid prescribing (95% CI, −12.20% to approximately −0.56%).
Conclusions and Relevance
The potential of marijuana liberalization to reduce the use and consequences of prescription opioids among Medicaid enrollees deserves consideration during the policy discussions about marijuana reform and the opioid epidemic.
Importance
Opioid-related mortality increased by 15.6% from 2014 to 2015 and increased almost 320% between 2000 and 2015. Recent research finds that the use of all pain medications (opioid and nonopioid collectively) decreases in Medicare Part D and Medicaid populations when states approve medical cannabis laws (MCLs). The association between MCLs and opioid prescriptions is not well understood.
Objective
To examine the association between prescribing patterns for opioids in Medicare Part D and the implementation of state MCLs.
Design, Setting, and Participants
Longitudinal analysis of the daily doses of opioids filled in Medicare Part D for all opioids as a group and for categories of opioids by state and state-level MCLs from 2010 through 2015. Separate models were estimated first for whether the state had implemented any MCL and second for whether a state had implemented either a dispensary-based or a home cultivation only–based MCL.
Main Outcomes and Measures
The primary outcome measure was the total number of daily opioid doses prescribed (in millions) in each US state for all opioids. The secondary analysis examined the association between MCLs separately by opioid class.
Results
From 2010 to 2015 there were 23.08 million daily doses of any opioid dispensed per year in the average state under Medicare Part D. Multiple regression analysis results found that patients filled fewer daily doses of any opioid in states with an MCL. The associations between MCLs and any opioid prescribing were statistically significant when we took the type of MCL into account: states with active dispensaries saw 3.742 million fewer daily doses filled (95% CI, −6.289 to −1.194); states with home cultivation only MCLs saw 1.792 million fewer filled daily doses (95% CI, −3.532 to −0.052). Results varied by type of opioid, with statistically significant estimated negative associations observed for hydrocodone and morphine. Hydrocodone use decreased by 2.320 million daily doses (or 17.4%) filled with dispensary-based MCLs (95% CI, −3.782 to −0.859; P = .002) and decreased by 1.256 million daily doses (or 9.4%) filled with home-cultivation–only-based MCLs (95% CI, −2.319 to −0.193; P = .02). Morphine use decreased by 0.361 million daily doses (or 20.7%) filled with dispensary-based MCLs (95% CI, −0.718 to −0.005; P = .047).
Conclusions and Relevance
Medical cannabis laws are associated with significant reductions in opioid prescribing in the Medicare Part D population. This finding was particularly strong in states that permit dispensaries, and for reductions in hydrocodone and morphine prescriptions.