Okay, good evening, everybody. Welcome to today's AOAAM webinar, Exploring the Interface of Cannabis, Cannabinoids, and Opioid Use Disorder by Dr. João de Aquino. My name is Julie Kmic and I'm your moderator for this session. This is the fourth of our spring webinar series on hot topics in the treatment of OUD and stimulant use disorders. I'd like to introduce our speaker. Dr. de Aquino is an Assistant Professor of Psychiatry at the Yale University School of Medicine and Assistant Chief of Inpatient Psychiatry at the Clinical Neuroscience Research Unit. In addition to treating persons with substance use disorders and co-occurring medical and psychiatric disorders, he combines behavioral pharmacology, computerized psychophysical techniques, and clinical trial methods to develop novel therapeutics for pain and addiction. So thank you so much for being with us today, Dr. Aquino, and I'm gonna turn it over to you. Thank you for the introduction, Dr. Kmic. I'm gonna share my screen so we can start. Are you seeing the slides? Yes. Okay. Thank you again for the introduction. Thank you for the invitation. It's a pleasure to be with you today. I'm looking forward to sharing insights and engaging in a dialogue about a topic that's highly relevant for the opioid crisis. I'd like to thank the Substance Abuse and Mental Health Services Administration for their support. The ORN webinar has been partially funded by SAMHSA, and the opinions expressed in the conference materials represent my views, and these are not necessarily aligned with the official stance of the Department of Health and Human Services. Also, the mention of any trade names, commercial practices, organizations is not an endorsement by the U.S. government. Here are my disclosures. I have received funding from NIDA and a couple of private foundations. Those are all administered by Yale University. I've also partnered with pharmaceutical companies in the form of consultancy or clinical trials, the latter involving only the provision of study medication. Our goals for today are to better understand the fundamental aspects of cannabinoid pharmacology, such as differences between cannabis-derived products, as well as regulatory issues potentially affecting opioid use disorder treatment. We'll explore the available evidence on potential pain-relieving opioid withdrawal suppressing and opioid-sparing effects of cannabis and its constituent cannabinoids. And finally, we'll discuss how to approach patients with opioid use disorder who use cannabis or cannabinoids and how to identify problematic patterns of use. On the left, you see the cover of Time magazine, and it asked, is America going to pot? That was in 2002. And around two decades later, we can confidently answer that question. This all happened while we are in the grip of the opioid crisis. Between 2016 and 2021, there was a staggering 275% surge in drug overdose deaths. And while fentanyl, a potent synthetic opioid well-known to this audience, has emerged as a primary driver of mortality, we cannot overlook the role of inadequately treated chronic pain in this crisis. In our lab, we have studied cannabinoids as a potential non-opioid analgesic solution for this population, while also looking at their adverse effects. And this decision stems from compelling preclinical data, and the need to rigorously address clinical questions regarding their analgesic efficacy during these rapidly changing attitude changes and legislative landscape changes in the United States. Pain is the most common indication for medicinal use of cannabis and its constituent cannabinoids at the state level. Moreover, a growing number of states has added alternative to opioids and opioid treatable conditions to the list of qualifying criteria. In some states, these have been interpreted as OUD itself. And the reason why I say cannabis and its constituent cannabinoids, by the way, is that there is a high degree of heterogeneity in cannabis-derived products. On the left here, you have herbal cannabis, usually the dried flower. You have cannabis concentrates, including wax or oils, and edible gummy bears, which contain various concentrations of different cannabinoids. The most commonly known ones are THC and CBD, but you also have minor cannabinoids such as tetrahydrocannabivari, or THCV, or cannabinol, or CBN, and cannabigerols, or CBG. It's a long list of 140 different cannabinoids in the plant. And on the right, you have FDA-approved products, including synthetic formulations of oral THC. These include dronabinol and labilone, which are approved to treat HIV-induced anorexia and chemotherapy-induced nausea. You have cannabidiol, which is FDA-approved to treat rare forms of childhood epilepsy. And in Canada and Europe, you have oral materials or formulations of THC and CBD, which are approved to treat multiple sclerosis-related spasticity. When people get a medical cannabis card, or in states where non-medical use is legal, like Connecticut, where I am right now, you go to the dispensary and you get any available product. So these unregulated products are not prescribed like FDA-approved medications are. Rather, often the person making recommendations is the butt tender. Like a bartender, a butt tender is someone who serves customers within a licensed establishment, but they're not healthcare professionals. Before we explore the potential of cannabinoids to ease pain in people with opioid use disorder, I'd like to first address the foundational question, which is, are they effective in opioid use disorder to begin with? There is considerable overlap between the cannabinoid and opioid receptor systems with colocalization of cannabinoid and opioid receptors in the periphery, in the spinal cord, in supraspinal areas. There's also lots of evidence of crosstalk between these two systems. With cannabinoids, for example, increasing opioid precursor genes and cannabinoid antagonists like rimonaban, reversing morphine-induced analgesia, for example. As of the latest review, we've identified roughly 50 randomized placebo-controlled clinical trials examining the pain-relieving properties of cannabis and its constituent cannabinoids. And these studies include a wide range of pain disorders, primarily neuropathic pain, seeing conditions such as HIV polyneuropathy, as well as pain associated with multiple sclerosis and cancer. And it's important to know that each one of these patient groups typically has a high rate of opioid use. In meta-analyses, there has been moderate quality evidence suggesting cannabinoids are beneficial for managing certain pain conditions. However, this conclusion comes with some important caveats. Many of the studies were short-term using low-potency cannabis or THC, and often relying on responder analysis using pain-intensive numeric rating scales. What that means is while patients reported reductions in pain intensity in these numeric rating scales, most studies did not consider pain-related functional improvement or quality of life. For example, in this early clinical trial, people with HIV associated polyneuropathy were given smoked cannabis with a concentration of roughly 4% by dry weight, administered three times daily over a five-day period. And the results were notable, with 52% of those receiving cannabis experiencing a pain reduction of over 30% in a numeric rating scale, compared to 24% in a placebo group. The placebo group is basically cannabis with a negligible amount of THC, but otherwise provides the same sensory sensation. To assess the pain-relieving efficacy of cannabis, we can turn to the number needed to treat, which tells us how many patients needed to be treated for one to benefit. In drawing from data in that study, we can compare cannabis to conventional pain medications. When we juxtapose cannabis with gabapentin, for example, we find that the NNT is in the same ballpark. However, clinical trials vary widely in their primary outcome measures. And because of this, directly comparing NNT figures is somewhat of an approximation. Still, this helps put in perspective the potential of cannabis-induced analgesia. But numerous confounding factors co-vary with pain in clinical populations, making the evaluation of analgesia in this context challenging. For example, for how long the person has coped with pain and disparities in pain treatment can influence pain responses. So in a meta-analysis of human lab studies enrolling healthy people and evoking pain artificially, experimentally, in the laboratory, the largest effect sizes in cannabinoid-induced analgesia is found in pain unpleasantness. There was also modest increases in pain threshold. One of the prevailing hypothesis is that although the analgesic effects of cannabinoids are likely complex, they might be primarily attributable to modulating affect-related pain processes, at least in healthy people. So to summarize, randomized controlled trials suggest that cannabinoids do have some analgesic benefit for some clinical populations. And these data are to some extent supported by human laboratory pain studies. But are they opioid-sparing, which is a different question that often gets conflated with the first question. There is in fact a compelling biological rationale for the assertion that cannabinoid agonists have the capacity to enhance the analgesic effects of opioids. And the opioid-sparing concept is grounded in meta-analysis of preclinical data, which suggests that co-administering THC, the primary analgesic and psychoactive component of cannabis with opioid agonists, such as morphine, can reduce the required dose of opioids by nearly tenfold to achieve comparable antinosusceptive or pain-relieving outcomes. And the reason why the therapeutic window might be widened is because the brainstem, you don't have a lot of cannabinoid perceptors in the brainstem. So unlike opioids, cannabinoid agonists do not induce respiratory depression. One example in the study is a study in which animals were first made opioid-dependent. They were trained to self-administer oxycodone. And then they had their oxycodone consumption attenuated by vaporized THC. And further, there was evidence of superior antinosusceptive effects following the THC-oxycodone combination compared to either drug alone. So there are promising animal study results, but this naturally leads us to the question of, do these findings hold true in humans? Until recently, most of what we had was observational evidence. There were several policy impact studies, survey studies, naturalistic research that was initially interpreted as suggestive of opioid sparing effects. And these studies, for example, reported lower rates of opioid overdose deaths in states that have medical cannabis laws in addition to decreased use of opioid analgesics at the state level. This is one example of Colorado where the legalization of recreational or non-medical cannabis was associated with what was seen as a reversal of the upward trend in opioid-related deaths in that state. And however, this is state-level data. State-level data rather than individual-level data. And there are several confounders here, including changes in opioid prescribing practices that occur around the same time, the expansion of treatments for opioid disorder, the expansion of prescription monitoring programs, the classical ecological fallacy. So while we must approach these findings with a degree of caution, they do add weight to the argument of conducting controlled human trials to address this question. And more recently, rigorous experimental studies started to emerge. Unlike the observational data, these studies were specifically designed to examine opioid sparing effects. And the primary outcome is analgesia as opposed to other outcomes that get conflated with it. This work, for example, was done by Kelly Dunn at Hopkins who showed that dronabinol at a low dose of 2.5 milligrams, dronabinol, again, it's a synthetic formulation of THC, had modest evidence of analgesic synergy with hydromorphone in healthy people. These were young people, an average age of about 30 years old without clinical pain. Although there was some increase in measures of abuse potential. And this study also administered higher doses of dronabinol at five and 10 milligrams, which did not provide synergistic analgesia. And previously, Zipa Cooper then at Columbia had shown that administering low potency cannabis of about 6% THC by weight combined with a sub-analgesic dose of oxycodone of 2.5 also provided synergistic analgesia. And the main outcome of the study was laboratory pain assessed with a cold pressure test, which is a widely used model of laboratory pain that's been found to have particular validity for the treatment of chronic pain. And it's how a lot of analgesics were developed. Gapotentinoids, SNRIs. And there was a roughly a 20% increase in pain threshold intolerance with the combination compared to the sub-analgesic doses of oxycodone alone. And the study noted comparable results in terms of abuse potential of the combination. Then in an extension of their earlier work, the group at Hopkins turned their attention to people with chronic pain. This is older sample of 61 years old on average. They had knee osteoarthritis and the majority of these patients were not receiving pain treatment at baseline. They exploited the interaction between dronabinol at a higher dose of 10 and the same dose of hydromorphone 4. And in this case, the combination showed minimal benefit over what was observed with the opioid alone. And this finding suggests that the efficacy of these combinations of opioids and cannabinoids may vary based on the type of pain and the clinical demographic characteristics of the patient population. This likely higher dose of dronabinol used in the study also raises questions about the optimal dosing strategies for balancing analgesic synergy and adverse effects. So addressing the question of whether cannabinoids have opioid sparing effects, preclinical data suggests that they do, but human studies show mixed results. Additionally, there's evidence that combining cannabinoids with opioids could raise the potential for non-medical use. And importantly, these data do not include people with opioid use disorder who, as we discussed, have an extremely high tolerance to opioids. So in this case, what do we know about cannabinoids effects in person with opioid use disorder? OUD is characterized by relapsing remitting cycles of intoxication, withdrawal, and anticipation of opioid use. While the experience of pain is made worse by opioid withdrawal, it can pervade all phases of the cycle. Notably, each one of these phases has a host of different processes that are related to the pain experience, and that can be influenced by non-opioid analgesics, such as cannabinoids. As you will see in the following slides, however, most studies do not assess pain in people with opioid use disorder, which is why we have conducted studies to address this gap. We recently published a systematic review, and to my surprise, it received a lot of attention because it was a negative paper. And so briefly, we sought to quantify the impact of cannabis use on the risk of returning to use opioids non-medically among people receiving medications for opioid use disorder using a meta-analytical approach. And all the eligible studies were longitudinal, and they assessed the association between cannabis use and non-medical opioid use among people receiving propranorphine, methadone, or extended release intramuscular naltrexone. There were 10 studies that were included in the final meta-analysis. There were over 8,000 participants, and the average follow-up was of around nine months. Around 70% of people were receiving methadone, 20% propranorphine, and about 3% naltrexone. And if you look at the diamond here, the forest blot, you see that the pool loss ratio doesn't indicate that cannabis use significantly influences non-medical opioid use. So what this means is essentially these findings neither confirm concern about cannabis increasing non-medical opioid use through opioid treatment, nor do they endorse the efficacy, in this case of cannabis, in decreasing non-medical opioid use when it's used in conjunction with medications for OUD in a naturalistic context. And in contrast with these data, there are many opioid treatment programs in the United States that still have a blanket requirement of abstinence from cannabis to provide medications for OUD. And what we need really is an individualized approach for cannabis use during OUD treatment. The other observational studies in OUD have focused on whether cannabinoids impact treatment retention as opposed to pain. And as you can see in this table, the jury is still out as well, with studies suggesting cannabinoids associated with increased attrition, other studies suggesting increased retention or no change. Surprisingly, however, as I said, there are opioid treatment programs that do discontinue medications for OUD if there's laboratory evidence of cannabinoid exposure, which is at odds with the evidence base. The focus of most experimental studies has been on the potential of cannabinoids to suppress opioid withdrawal rather than their effects on pain. And we also systematically review this body of literature for further insights. In these studies, dronabinol, again, a synthetic formulation of TTC, was found to modestly alleviate opioid withdrawal. However, no pain outcomes were reported. And similarly, while another study conducted at Mount Sinai by Esmengherd showed that oral cannabidiol relieved cue-induced opioid craving, which is the type of craving provoked by visual opioid cues in recently abstinent people with OUD, no pain outcomes were reported. So to summarize, to date, studies have predominantly focused on retention rates, non-medical opioid use, suppression of opioid withdrawal, and the reduction of craving. However, the direct impact of cannabinoids or pain within this population has not been investigated. And this gap in knowledge is significant because pain can be a central element in the cycle of opioid addiction and often is a hindrance to recovery. So to address this gap, we have recently completed a human lab study examining acute dose-dependent effects of oral THC among patients receiving methadone treatment for opioid use disorder. And the study was designed to examine the acute effects of THC on pain, abuse potential, and cognitive performance measures. At the methodological level, we sought to integrate the study of outcomes that are crucial for both the treatment of pain and addiction. We opted for oral THC over smoked cannabis due to what is known about its analgesic effects in pharmacokinetics. Healthy human lab studies show equivalent analgesia, if you compare smoked cannabis and oral THC in laboratory pain measures. A second oral THC leads to a lower, more delayed THC plasma levels, allowing the study of potential pain relief over an extended period. And third, oral THC has a lower risk of non-medical use, which is exemplified by dronabinols moving to a less restricted scheduling category. There used to be schedule two, and it's now schedule three. The study is available in Addiction Biology. And this was a randomized placebo-controlled human lab study. It had a crossover design, so each participant received all dosing conditions and was their own control. All participants had opioid use disorder treated with methadone. They did not meet criteria for non-tobacco substance use disorders over the 12 months preceding study entry. Across three sessions, single doses of 10 milligrams of THC, 20 milligrams of THC or placebo were administered at trough methadone level. A washout period of three days separated each session to limit carryover effects. The primary outcomes were pain-related with the cold presser test, followed by self-reported measures of pain intensity and quality. And we also measured whether THC would have abuse potential or affect cognitive performance. We enrolled a total of 25 participants with an inclusion of approximately 25% female participants. Participants were required to test negative for cannabinoids before the first session. Moreover, those who had cannabis use disorder were excluded. The average methadone dose was quite high, with 95 milligrams per day. Approximately 44% of the sample was receiving methadone doses lower than that, of around 63 milligrams per day, and the rest, 56%, was receiving doses higher than that, of around 120 milligrams a day. And I'd like to draw your attention to the substantial daily opioid dose of our participants. When converted to morphine milligram equivalents, MME, the average dose of methadone in the sample is around 13 times higher than what is typically considered high-dose opioid therapy. And this isn't a perfect conversion, once daily methadone dose to MME, but this still implies that our participant had a profound opioid analgesic tolerance, which is a critical factor when considering the impact of analgesic interventions. In assessing the impact of THC on pain via the cold presser test, we measured the pain threshold, which is the time until the participant first reports pain, and the pain tolerance, which is the time at which the participant removes their hand from the electronic cold water bath. On the left, we have pain threshold, on the right, pain tolerance. And while not statistically significant, there is a discernible trend with the 10 milligram THC condition, the lower dose. Participants had higher mean values for both pain threshold and tolerance. The green bar here, particularly noticeable at the 180 minute time point, which aligns with the expected peak effects of oral THC. And this observation is consistent with what is often referred to as biphasic effects of cannabinoid agonists, where lower doses may have a different, potentially more beneficial effect on pain perception than higher doses. Turning our attention to the results from the McGill Pain Questionnaire, which assesses intensity and quality of the pain experience, we find significant evidence of THC's analgesic effects. After participants completed the cold presser test, they were immediately assessed with the McGill Pain Questionnaire. And in these assessments, we observed that both doses of THC, 10 milligrams and 20 milligrams, showed significant separation from placebo in terms of total pain scores. And notably, the lower dose of 10 was associated with superior pain relief compared to the higher dose of 20, once again, aligning with the notion of biphasic effects. And further analysis revealed that the pain relieving effect mainly reduced the sensory aspect of pain. And effective pain was less affected, possibly related to the sensitivity of the measure for this construct, or to a salient effect of methadone, or unique characteristics of her sample, allowing a limited additional effect from THC. Using the Drug Effects Questionnaire, we analyzed participant responses across three key domains, stimulatory effects, pleasurable effects, and aversive effects, to quantify the subjective drug experience. And both doses of THC mildly increased the perception of stimulatory effects compared to placebo, with a clear dose-response relationship. However, the increase in stimulatory effects did not correspond to increases in pleasurable or aversive effects, which remained indistinguishable from placebo across the two doses. We also looked at opioid withdrawal symptoms, and there was a trend for milder withdrawal under the lower dose of 10 milligrams of THC. But since the study was done in the outpatient setting, the short time of observation may not have been enough to see full withdrawal symptoms. We used the Continuous Performance Test and the Hopkins Verbal Learning Test to evaluate the effects of THC on attention and verbal memory. At 10 milligrams of THC, the higher dose we noted mild cognitive impairments, but at 10, these effects were not evident, indicating a dose threshold for cognitive impairment. And our analysis did not show any interaction between THC and methadone for any of the outcomes. In summary, THC adrenalinol has demonstrated preliminary evidence of analgesic properties in methadone-treated patients with opioid use disorder, based on self-reported measures of pain. This is consistent with prior clinical trials in which participants had some level of physiological opioid dependence at baseline. While the potential for abuse is a concern, or non-medical use is a concern, particularly given our patient population, it is worth noting that the increases in abuse liability measures produced by active doses of THC measured approximately 18 millimeters in a 100 millimeter scale, suggesting limited abuse potential. If you look, for example, at studies administering opioids to the same population, you have an increase of 60% in this scale, compared to 18%. Possible explanations are the unique characteristics of the sample, which is very used to the effects of drugs that have a much higher abuse liability, like opioids, as well as possible cross-tolerance between opioids and cannabinoids for abuse potential-related outcomes. Further, THC's cognitive effects were dose-dependent, with only the higher dose consistently leading to cognitive impairments. And this reinforces the importance of dose consideration when weighting the benefits and risks of cannabinoid agonists in this context. And our analysis did not reveal any interaction between THC and methadone doses, indicating that the effects of THC on these specific outcomes were independent of the amount of methadone that participants were receiving. As we continue to explore the therapeutic potential of cannabinoids, we've started another randomized controlled clinical trial focusing on low doses of THC. This trial is currently examining effects of 2.5 to 5 milligrams of cannabinoid in people with opioid use disorder, who are receiving, there's two arms, one arm methadone, the other arm buprenorphine. And given the promising indications for both our work and previous research, that lower doses may be more effective and have fewer adverse effects. The study is designed to investigate whether these subtler doses can be an adjunctive strategy at critical time points during treatment. Currently, the data from the study is blinded, and the hope is that these lower doses could offer a viable adjunctive treatment. Expanding on our initial studies, we're now exploring how CBD or cannabidiol, the second most dependent cannabinoid in the plant, may simultaneously alleviate pain or reduce opioid craving in methadone-treated patients with opioid use disorder who also have co-occurring chronic pain. And we're using a comprehensive psychophysical battery, quantitative sensory testing that includes mechanical, pressure, and thermal tests to measure pain responses and comprehensively assess the somatosensory system. And currently, we're conducting a dose-finding study to identify an effective dose of CBD. The chosen dose will then be used in an upcoming treatment trial within a real-world opioid treatment setting. In an FDA-requested initial phase, we evaluated the safety of combining CBD with methadone, focusing on the risk of sedation. Participants took an average methadone dose of 90 milligrams per day, and they were given escalating doses of CBD up to 1,200 milligrams, which is close to the maximum FDA-approved dose of 20 milligrams per kilogram. And each dose was given three days apart. The results show that there was no increase in sedation, suggesting that at these relatively high CBD doses, they do not intensify methadone's depressant effects, which is crucial for safety. And these preliminary findings from the open-label phase are promising, but we wait for their data from the ongoing blind and placebo-controlled phase to investigate CBD's safety and efficacy in individuals with co-occurring OUD and chronic pain. And our strategy is to combine lab research with clinical trials, examining various facets of pain in a controlled setting and extending our observations to daily life. By tracking pain-related functioning outside the lab, we aim to comprehensively understand the treatment efficacy. Ultimately, we hope our lab findings translate into tangible benefits for managing pain and addiction in the real-world setting. We have been fortunate to receive an R01 grant by NIDA to focus on people with simultaneous diagnosis of opioid disorder and chronic pain, also who are receiving methadone therapy. And it's a hybrid design, combining elements of a parallel group and a crossover study. It's also a randomized placebo-controlled double-blind study. And the structure of the study is such that there's an initial randomization to three doses of THC, five, 10, and placebo. And then each subject undergoes a series of crossover doses of CBD. And the goal is to understand how different doses and ratios of these two cannabinoids affect people with co-occurring opioid disorder and chronic pain. Like any other substance, cannabinoids also have adverse effects. We spoke about some of them. And one way to quantify the risk of adverse effects is by looking at the number needed to harm, which estimates how many people need to be exposed to the intervention for one to develop a negative outcome. So unlike the number needed to treat, the ideal number needed to harm would be a high number. So here you can see rough estimates of the number needed to harm for perception, motor, and cognitive-related adverse events, which when considered in relation to the number needed to treat we spoke, we presented earlier for efficacy, suggests a relatively narrow therapeutic index for most cannabinoid agonists. So THC, cannabis, and analogous cannabinoid agonists. And it's important to understand that in addition to those dependent effects, cannabinoids agonists like THC have also time-dependent effects, meaning that the initial or acute effects may be different than sub-acute or chronic effects as tolerance develops. And once tolerance established, the individual may experience Cannabis Withdrawal Syndrome upon a dose reduction or cessation of use. And Cannabis Withdrawal Syndrome was recognized as its own entity for the first time in DSM-5. And it's characterized by irritability, anxiety, changes in mood, and sleep. One typical occurrence is that patients say they're having vivid dreams when they stop using cannabis. And that's likely because THC produces, like alcohol, a compression of REM sleep. So once people stop using, they experience a compensatory REM rebound. And this is important to note for patients with co-occurring PTSD who may experience a temporary suppression of nightmares and please also note that patients may not realize that they're experiencing Cannabis Withdrawal Syndrome and they may not seek assistance from a mental health professional. THC can also induce tachycardia and counteract the effects of some antihypertensives. Smoked cannabis or vaporized cannabinoids can exacerbate COPD. And there are known pregnancy-related complications. And finally, persons with a predisposition to psychotic disorders or those with already diagnosed psychotic disorders may have their symptoms exacerbated by cannabis or cannabinoid agonists. In the general population, about, if you look at NISARC data, for example, epidemiological data from longitudinal studies and large-scale studies, about one in three people who use cannabis regularly will develop a cannabis use disorder, which is a maladaptive pattern of use that leads to impairment or distress. And these are the 11 criteria. Three need to be met, at least to diagnose people with cannabis use disorder. And the criteria are the same criteria for other substance use disorders, such as using more than intended, wanting to quit but failing to quit, having a substantial amount of time investing, seeking cannabis, craving an intense urge or desire to use cannabis, a failure in fulfilling major obligations, social and interpersonal problems, abandoning activities, risky use, for example, operating machinery, continued use despite problems, and intolerance and withdrawal. Those are the 11 criteria. And my impression is this is an under-recognized problem. Especially after the attitudinal changes towards cannabinoids. There is a dearth of data on the clinical and demographic correlates of people who have both opioid use disorder and cannabis use disorder. So we used a nationwide VA data set, and we compared the social demographic and clinical characteristics of patients diagnosed with both opioid use disorder and cannabis use disorder to people who have only one of the two disorders, and people who have other substance use disorders. So compared to the opioid use disorder only group, people with co-occurring OUD and CUD, cannabis use disorder, had a lower number of non-MOUD opioid prescriptions, but a higher likelihood of inpatient psychiatric admissions, and they were also more likely to be homeless. So this analysis was done a while back, and these data highlighted the need to investigate whether these complex effects of cannabis use on patients with opioid use disorder were counterbalanced by potential benefits or reducing opioid prescribing. And they led to the experimental data that we discussed. In doing this research, we also realized that cannabinoids can have a specific risk-benefit ratio in people with opioid use disorder. In other words, it's hard to extrapolate data from healthy people, or people who have only chronic pain, to people with opioid use disorder who have this high level of opioid use neuroadaptations. They're taking extremely high doses of opioids. And drawing from preclinical research, we're also looking into potential moderating effects of childhood trauma, which is quite prevalent in our population. And it affects brain development, it affects stress responses, and it may thereby affect the effectiveness and the risk of cannabinoids in this population. And by understanding these factors, our goal is to create safer, more personalized treatment approaches. This was a post-hoc analysis of the human lab study that we've just discussed, and in this post-hoc analysis, we evaluated how childhood trauma affects the subjective experience of THC. And our specific objective here was to analyze the interaction between THC and childhood trauma on the severity of THC's aversive effects. At a certain dose, THC becomes aversive to most people. So our results, which are shown in this graph, indicated that people with low childhood trauma reported, as expected, higher aversive effects at high THC doses. In contrast, people with high levels of childhood trauma found that the high dose of THC was actually less aversive compared to placebo. So these findings suggest that childhood trauma may modify the subjective effects of THC, and it's crucial to consider childhood trauma when treating and researching patients with opioid use disorder. So these insights are important to understand THC's risks and benefits in subgroups of people with opioid use disorder. We're approaching the end of the talk, and I'll be open for questions, but I'd like to leave you with a couple of suggestions on how to approach patients with opioid use disorder who use cannabis and cannabinoids. First, it's important to weigh the risks against benefits. The therapeutic goals, potential relief of symptoms, and improvement in quality of life must be balanced with the risk of adverse effects and the possibility of developing cannabis use disorder. Comprehensive assessment is key. Patients often present with complex medical histories, including psychiatric conditions and other substance use disorders. Each one of these factors can influence the effects of cannabinoids. It must be taken into account. Understanding the patient's pattern of cannabis use with some granularity is crucial. We need to evaluate the method of consumption, dose. This is hard to estimate those. There are studies, for example, that show that what's in the label of the product purchased at a dispensary might not be reflective in the actual product if you send it for an independent analysis. And that's something that I believe needs to be communicated to patients. Also assessing, sometimes people know the THC content of the product that they're getting, but also assessing frequent abuse, the source of cannabis, whether it's edibles, oils, herbal extracts, route of administration, changes, defects, as we discussed. And this helps us identify whether is there a need for an intervention. And identifying and addressing problematic use is essential. The focus should be in harm reduction strategies. This includes mitigating withdrawal symptoms, avoiding escalation to higher doses or more potent forms of cannabinoid products, which may increase the risk of adverse outcomes. And in cases where patients show signs of cannabis use disorder, or there are psychiatric disorders that are exacerbated by chronic high-dose cannabinoid use, consider referral to an addiction specialist. And collaboration with specialized care can ensure that patients receive the appropriate treatment, which is often behavioral for cannabis use disorder. We don't have FDA approved medications for this condition. To conclude, there is an urgent need for comprehensive research on how cannabis and cannabinoids affect people with Alzheimer's disorder. The current understanding is quite limited given the dearth of experimental studies in this population and the changing landscape and legalization of use. It's vital that we bridge this knowledge gap. For clinical studies are a goldmine of data and can shape our approach to human trials. They allow us to anticipate how individuals may respond to treatments, both positively and negatively, and tailor our clinical research, including randomized clinical trials. It's crucial to measure both the potential benefits of cannabis and cannabinoids. At the same time, we must remain vigilant about possible adverse effects. So this requires an advanced approach that combines methodologies from various research fields, including pain and addiction. In control, lab studies provide us with a direct line to understand the neurobiological and behavioral impacts of cannabis and cannabinoids. And these insights can be instrumental in developing more effective large-scale clinical trials. By linking lab findings with clinical applications, we can enhance patient outcomes in a real-world setting. I'd like to extend my gratitude to all our patients and participants whose contributions and experiences have been indispensable to this research and all the members of our pain and addiction interaction neuroscience lab. Special thanks to Dr. Kimmick and the ORN for this invitation and to multiple institutions that provided the essential conditions for this work. Thank you for listening. I'd be happy to answer any questions. Okay, thank you so much. That was very comprehensive, very interesting information that you provided. We do have time for questions. So if you have a question for the doctor, please enter it into the Q&A box and I'll get to those. I did have one question just to start off since we don't have any questions yet. When you were looking over that study with the aversive effects from THC and childhood trauma, what do you think, did you ask anything about desired effects or pleasurable effects and what, or is that to be further studied? So just make sure, do you mean the ratio between pleasurable and aversive effects? No, I mean like if somebody had a history of a lot of trauma or high childhood trauma and then would they find more pleasurable effects at the 20 or at the 10, what are your thoughts on that if you haven't studied it or if you have studied it? Thank you, yeah, that's a great question. In these analyses, we looked at pleasurable. So these are just for context. The drug effects questionnaire has around 14, some were up to 16 items and they're grouped into these three subscales, pleasurable, aversive, and stimulatory effects. So we looked at all three subscales and in these analyses, there was a moderating effect of childhood trauma on the aversive effects but not pleasurable or stimulatory effects. There is, however, some literature suggesting that childhood trauma may also influence pleasurable effects of drugs with addictive potential which is believed to be part of the reason why people with childhood trauma may be more prone to developing substance use disorders. And there's plenty of data, for example, for opioids. If you give people morphine in a laboratory setting and if you ask their experience with childhood trauma, there is high quality experimental data showing that those who have a history of childhood trauma may find morphine more pleasurable than those without a history of childhood trauma. But in our analysis with THC in this population, we did not find that. We only found an association between aversive effects of THC and childhood trauma. Okay, thank you. Let's see here. So, oh, go ahead. Sorry, and I think just one additional comment. The risk of developing a substance use disorder, one way to think about it is there's a trade-off between pleasurable and stimulatory effects and aversive effects. For example, if someone has a hangover, if they drink, even though they may experience pleasurable effects from alcohol, that may deter them from. So, it is important to look at both, but in this analysis, we only found the association between childhood trauma and aversive effects, but you're right that both are important. Okay, thank you. So, we have some questions. The strength of THC is significantly higher now. Where did you get your oral THC? The question was the concentration of THC is higher now? Yeah, and so where did you get the THC from your study? I think- Yeah, good question. So, just to follow up on the initial comment, if you look at data from the 90s, the concentration of THC in herbal cannabis and the dried flower, which is the most commonly consumed product was around 4% by weight, 4 to 7%. If you look at data from the last 10 years or so, it's from 12 to 17%. So, it's true that people want harder, better, faster, stronger, and these are market forces and the THC concentration in cannabis has gone up over time. However, the product that we administered is synthetic dronabinol, which is an FDA approved medication. So, it's THC only, it's not cannabis, and it's 100% THC basically. It's made in a lab, it's not plant derived. And we chose to do that because of the experience with dronabinol in prior studies and the fact that it has a very low abuse potential precisely because it's very slowly delivered to the brain. Like when people smoke cannabis, your lungs are the size of two tennis courts. So, you have a very rapid absorption of THC that's quickly delivered to the brain. With dronabinol, it goes first past metabolism. You have a slope, increasing plasma levels. So, we wanted to study the pain experience over several hours while mitigating the risk for non-medical use. That's why we chose dronabinol. So, it is, just to clarify, it is THC, just THC, and it's an FDA approved medication that's commercially available. Thank you. Regarding the stimulatory effects, can you explain more in what you were looking at? Like what were some of the questions that patients were asked or study participants were asked? Sure, so the questions are, I feel the drug strength, let me, there, I can tell you the exact, just a minute, I have it here. So, stimulatory effects are the average of feel stimulated, feel the drug strength, and feel high. Those are the three items in the stimulatory. Pleasurable, or just to contrast with pleasurable, these are like the drug effect, feel good, and want more of the drug. And the grouping of these subcategories, the FDA often uses the subjective responses as a way to quantify or estimate the likelihood that a substance has addictive potential. So, these are subjective scales. The gold standard is self-administration, but subjective measures are used by the FDA to try to estimate how likely is this medication should be used in a way different than it was prescribed. Okay, got a couple of questions. Are there any studies using buprenorphine instead of methadone, looking at cannabinoids or cannabis? There are a couple of studies, registering clinical trials. So, there are some pilot studies that were published with cannabidiol. So, a very low number of participants looking at primarily cue-induced craving or attentional bias, essentially looking at the reaction time to opioid-related cues, visual cues, in relation to neutral cues, but not with THC, to my knowledge. And that's why we're conducting studies to close that gap. So, we're doing that study, getting very low doses of dronabinol to two arms, one buprenorphine and one methadone. And it might be different, right? Because methadone and buprenorphine, they are different from a pharmacodynamic level, a pharmacokinetic level. Buprenorphine has a longer half-life. So, even the question of whether they have different effects on the pain experience, it's very complicated. We don't know which one, but these patients are demographically matched and one arm has methadone, the other arm's getting buprenorphine. So, hopefully we'll have data to address that question of whether the acute effects of THC differ as a function of what medication people are getting at baseline. We don't have that yet. Okay, we have another question. And this one is, can you say more about cannabinoid antagonist effect on the opioid receptor and clinical implications this might have? Sure, great question. So, probably what they're referring to is, when I mentioned the preclinical data, there's a medication called Rivonabat, which was actually banned. People may have heard about it. It was approved in Europe to treat obesity. So, it's an appetite suppressant. And I said it was a cannabinoid one receptor antagonist, it was actually an inverse agonist. So, it binds to the cannabinoid receptor one and it has the opposite action of an agonist. It's kind of like flamazenil for benzos. When someone has a benzo overdose, you get the flamazenil or naloxone. And if you give, if you treat animals with morphine, the prototypical mu opioid receptor agonist, and you give them this medication Rivonabat, you can block the antinosusceptive effects of morphine, which again suggests that there's crosstalk at the functional level between the opioid system and the cannabinoid system. I'm not aware of studies that gave Rivonabat to people getting opioid therapy. Because Rivonabat was banned, the reason why it was banned is it led to suicidal thinking. So, it's no longer available. Just to be clear, if you give THC to people who are getting opioid therapy, it's not like the THC will counteract the effects of the opioids, is that there's cross tolerance. And one example of that is, if you give 20 milligrams of THC to someone who's opioid naive, most people will find that aversive. They will have tachycardia, they may have some anxiogenic effects. When we gave 20 milligrams of methadone to THC, to people getting methadone, this high dose opioid therapy, they might have some aversive effects, but the magnitude of these aversive effects is very different than someone who's opioid naive, which I believe is, aligns with this notion of cross tolerance between cannabinoids and opioid agonists. Okay. Let's see here. We have some questions. I guess some people are thinking about using THC from either dispensary or off the street. How do you think your research translates to this, or can it translate? That's a, yeah, that's a great question. That's the holy grail of cannabinoid research. I would say, it is, unless people are getting an FDA approved product, if they're getting dronabinol or epidiolex, FDA approved formulation of CBD, it's hard to know exactly what. And it has become easier and cheaper to test. So I would say if patients are, have the means, it may be unfeasible logistically or financially, but that's the only way to know and what they're actually getting. How to generalize, I would say, people getting medications for opioid disorder, specifically methadone, what people, how people can apply this in the real world. I think we have reasons to believe that these people might be more tolerant to the effects of cannabis and cannabinoid agonists than people who are not getting opioids. However, they may still be susceptible to some of the pain relieving and adverse effects. And generally, if the goal is to relieve pain, or if the goal is to, you know, when I say the goal, I mean the goal identified by the patient is to reduce anxiety. The advice I would give to people is you might want to use lower doses. You might want to choose lower potency products because you wanna minimize the risk of tolerance, withdrawal and you wanna minimize the risk of adverse effects, cognitive impairment. So that, at this point, at the clinical level, that would be, and also if oral products have a lower abuse potential than smoked or vaporized products. I hope that more data will become available with different routes of administration and looking at other outcomes, not just pain, and that we'll be able to tailor our approach to specific populations, method of group and working. But at this point, those would be the main takeaways, lower dose, oral formulation to mitigate adverse effects. Let's see. Is there evidence that cannabis use in samples of patients and treatment for other substance use disorders influences the risk of return to substance use for these other substances, non-opioids? That's a great question. There are, I mean, there are observational. So one explanation is what we typically call polysubstance use, right? People who are using multiple, a lot of times people who are using cannabis are using other drugs. To address this question, I imagine we'd have to do something similar to what we've done with this meta-analysis where we specifically looked at opioid use status at baseline, and then over time as a function of cannabinoid use. I'm not aware of similar meta-analyses specifically focusing at other substance use disorders, for example, tobacco use disorder or cocaine use disorder. But I do believe that is an important question that needs to be addressed. Okay. And we have one minute, so one last question. Does the issue of cross tolerance have implications for how we assess cannabis potency used by patients on MOUD and how we respond? My experience in treatment environments was that patients with pain and or trauma were able to moderate their use, but not discontinue their use of cannabis. So the question is whether the... Implications for how we assess cannabis potency used by patients on MOUD and how we respond. Yeah. With that issue of cross tolerance. Right, yeah. So from the data that we have in this study, what we can say is that, again, the most commonly identified reasons for use are relief of pain or relief of anxiety or sleep induction. Pain and anxiety are very intertwined. And with these data, we can say that lower doses are more likely to have that effect. I think what happens with people with trauma is they might have that initial effect, but they develop tolerance, so they increase the dose. And as they increase the dose, they might be... And we also have data to suggest that they might have a blunted response to the adverse effects, which leads them to further escalate the dose. And eventually develop cannabis disorder or a maladaptive pattern of use that makes it harder to stop. Because once you stop, you have cannabis withdrawal syndrome, it's harder to sleep. So those are the types of discussions I think we can have with patient, with the limited data that we have available now. You might wanna use lower doses, you might wanna have intervals so you don't develop tolerance. There's data from studies done at Yale by Surya D'Souza and his group showing that once people stop using cannabis, their cannabinoid receptor availability in the brain can return to normal after around two weeks or so. So having these quote unquote holidays might be a way to avoid getting into withdrawal. But once people go to the dispensary, like I said, the person often giving recommendations might recommend a product that has a high potency. And I think as healthcare professionals, we can prepare people for those discussions and understand that nuance, understand this notion of biphasic effects. So if they're going to use, how can we mitigate the risk of developing this maladaptive pattern that may make it harder to stop down the road, especially if people have a blunted response to aversive effects like our patients often do. So with the limited high quality experimental data that we have, I do think that those data are enough to bring nuance to those discussions and guide these shared decisions with patients. And I think it's important to meet patients where they are instead of shunning the discussion about cannabis. I'd rather know what people are using, how they're using and give them advice based on the available evidence than have them not feel comfortable talking to us about their cannabis use. Exactly. Okay, well, it looks like it's six o'clock. I'd like to thank you very much for the opportunity to learn from you and your studies on cannabis and cannabinoids with opioid use disorder. And this is going to conclude today's webinar. Next week, we have Dr. Gail D'Onofrio speaking on the Emergency Department Treatment of Opioid Use Disorder. And that will be at five o'clock on Wednesday, May 1st. So if you'd like a copy of the slides, go onto our AOAM website where you registered, complete your evaluation of this webinar, and then you can go on that same site and get a PDF of the copy of the slides. So thank you so much again. And thanks everybody for attending. Thank you so much for the invitation. It's a pleasure. Bye-bye.

cannabis

cannabinoids

opioid use disorder

non-opioid analgesic

chronic pain

substance use disorders

THC

methadone treatment

cannabis use disorder

individual factors