Good day. I'm Ethan Russo. It's my pleasure to start our session today with Cannabis Components, Synergy of the Entourage for Pain and Palliation. This is my email if you'd like to contact me later. We'll be going through very rapidly, but you will have a PDF of the slides to which to refer subsequently. These are my disclaimers. I have a number of financial relationships. There are potential conflicts, but I would urge you to just read the source material. None of the relationships have any obvious financial relationships to the contents of the presentation. We're going to be discussing products that are not necessarily FDA approved. If any of these materials are used, clinical results will vary. Our subject today is cannabis sativa and the endocannabinoid system. It all began with a plant, cultivated cannabis, that produces these glandular trichomes, which in turn produce tetrahydrocannabinol, THC, and the other cannabinoids. Interestingly, THC, like the endogenous cannabinoid anandamide, is a weak partial agonist at the CB1 receptor. We'll talk about this in more detail. 2-arachidonoglycerol is the other main endogenous cannabinoid and is a full agonist at that receptor. The endocannabinoid system is thought of as primarily affecting the brain, but it's involved in every physiological system. It is an internal homeostatic regulatory system in chordates of three components, the endocannabinoids themselves, the CB1, CB2, TRPV1 receptors, and possibly others, such as the serotonin 1A receptor, and then the regulatory enzymes. In the nervous system, the endocannabinoids are produced on demand in the postsynaptic neuron and travel in a retrograde fashion to lodge at CB1, so anandamide or THC actually produce inhibition of the release of neurotransmitters. If this is a stimulatory glutamate synapse, then this inhibition will produce a net inhibition. If, on the other hand, this were a GABA receptor, the inhibition of the inhibition produces a net stimulation. It is important to note that there are active and inactive components of the endocannabinoid system that work together in what's been called the entourage effect. CB1 is highly expressed in the brain, particularly in nociceptive areas affecting pain, but also in the cerebellum, the limbic system, governing emotion, basal ganglia, and reward pathways. More in the brainstem, although there is a lot of CB1 in the substantia nigra and periaqueductal gray, there are virtually none in the medullatory center-subserving respiratory drive, so there is no dose of a cannabinoid that will produce respiratory depression the way opioids do. Again, the endocannabinoid system is not limited to the brain. We also find it in the spinal cord, where it modulates wind-up, central sensitization, etc. In the enteric nervous system, where it regulates both propulsion and secretion, and out in the periphery, again involved in peripheral nervous system. Professor DiMarzo characterized the role of the ECS as relax, eat, sleep, forget, and protect, but it is not limited to that and affects every other system. The CB1 is the most abundant G-protein-coupled receptor in the brain, exceeding all of the neurotransmitters combined. The ECS modulates pain, memory, movement, emotion, appetite, emetic threshold, seizure threshold, GI function, etc. There is also CB2 receptors, which are immunomodulatory and anti-inflammatory and analgesic, without having any psychotropic component. This is mainly peripheral, but can be upregulated in the brain under injury. CB2 agonists hold promise in treatment of fibrotic conditions, especially the liver, and also in treatment of addictions. Cannabis sativa, again, the provider of food, fuel, fiber, and pharmacy, which comes primarily from the unfertilized female flowering tops. This is a dioecious plant, meaning it has sexes on separate plants, and it's a member of the Cannabasii family, along with hops and a few other members. The main psychoactive component of cannabis is THC, which was first isolated and identified in 1964. Again, a weak partial agonist at the CB1 receptor with analgesic, anti-itch effects, bronchodilatory. It's also a neuroprotective antioxidant, and that's the basis of a U.S. patent that the government holds, actually. Beyond its effect on cannabinoid receptors, THC also has 20 times the anti-inflammatory power of aspirin and twice that of hydrocortisone. It's well known as a muscle relaxant, which is the basis for its approval in treating spasticity and MS with nabixamols in 30 countries, not the U.S. It is an anti-emetic. That's an approved indication for synthetic THC since 1985. It does all these things without being a COX-1 or COX-2 inhibitor and, interestingly, can reduce beta-amyloid formation, which is part of the pathophysiology of Alzheimer's disease. CBD actually has a broader pharmacology. It was first isolated in 1940, but only positively identified in 1963. It has the effect to reduce some of the side effects of THC, and this works, among other things, through a negative allosteric modulation on the CB1 receptor, making THC binding a little more difficult. It is also a neuroprotective antioxidant and strongly inhibits glutamate excitotoxicity from brain insults and is stronger as an antioxidant than Tocopherol and Ascorbate. It additionally is a TRPV1 agonist, analogous in potency to capsaicin but without the caustic effect, and this could be useful in treating pain as well. Until about 20 years ago, it was unknown how cannabidiol worked as an anti-anxiety agent, but our team at the University of Montana was able to demonstrate agonistic activity of CBD at the serotonin 1A receptor, which is the basis for its anxiolytic effect, but also reducing damage from strokes. It's anti-nausea effects, etc. Cannabidiol in regular use may inhibit the uptake of anandamide and inhibit its hydrolysis, thus increasing endocannabinoid tone. There are a lot of misconceptions about cannabidiol. Although it's very versatile, it's not a potent molecule, and usually large amounts are necessary clinically if it's going to be used in isolation without other components. You will commonly hear that it's a sedative. It is not. On low and moderate amounts, it's actually stimulatory, but many, particularly of the early chemovirus of cannabis that had cannabidiol in them, were also rich in myrcine, producing confusion. Its legal status is really still up in the air. Technically, this could be legal under the Farm Act of 2018, but the FDA considers it a Schedule I drug, except in the context of Epidiolex, a purified cannabis extract, 97% pure CBD, which is an unscheduled approved drug by the FDA for treatment of Lennox-Gastaut syndrome, Gervais syndrome, and seizures associated with tuberous sclerosis. Another myth is that CBD turns into THC in the body. There was a recent study in Brazil where hundreds of patients were given hundreds of milligrams of pure CBD and no THC was produced. A very important up-and-comer is cannabigerol, which is a precursor and mother of the phytocannabinoids. It has GABA uptake inhibition effects greater than THC or CBD, which could help explain its benefit in treating spasticity as well as anxiety. It's shown antidepressant effects in animals. It lowers blood pressure and intraocular pressure. It reduces keratinocyte formation and psoriasis. Epidinoidol showed powerful antibiotic activity against gram-positive bacteria, particularly methicillin-resistant Staphylococcus aureus. It also is an alpha-2 adrenoreceptor agonist, which could help explain its benefit in pain. It stimulates several TRIP channels, especially TRIP-M8, making it a very good candidate in treatment of prostate cancer. Last year, our team studied the effects of CBG in 127 people using predominantly CBG preparations with marked reported benefit on sleep, pain, anxiety, and depression, among others. This statement was made in 1999 by Professors Mishulam and Ben-Shabbat. This type of synergism may play a role in the widely held but not experimentally based view that in some cases plants are better drugs than the natural products isolated from them. Well, that was 23 years ago, and we now have a lot of ammunition to support that the concept is true. This is particularly true in cannabis, where we have a combination of 150 different phytocannabinoids along with some 200-odd terpenoids, the aromatic components of cannabis, that are not unique to cannabis but found in all these other plants that you see here. So certain cannabis terpenoids are painkillers or anti-inflammatory. They enhance mood or modulate THC side effects, thus producing synergy or an entourage effect with the phytocannabinoids. Just to mention a few of these, alpha-pining is the most widespread terpene in nature. However, it's not commonly seen in commercial types of cannabis. It is quite bioavailable, particularly by inhalation. It's a wide spectrum antibiotic in its own right, but its most important attribute is as an acetylcholinesterase inhibitor. This boosts acetylcholine, the memory molecule in the brain, and then it can reduce or eliminate short-term memory impairment from THC. It also may prevent oxidative damage in the CNS. It's a modulator of THC overdosage, and it's well known in Japan that walking in the forest, what they call shinrin-yoku, or forest bathing, helps clear the head, and that's certainly true in the Pacific Northwest, where there's a lot of pinene in the atmosphere. Citrus scent comes from D-limonene. In humans, this has been shown to be a potent antidepressant and immune stimulator on ambient inhalation, lowering Hamilton depression scores by half and allowing discontinuation of conventional antidepressant medication. It also is an agonist at the A2A adenosine receptor, which could have a role in treating inflammation, and it's additionally been shown to turn white fat, the storage fat of obesity, into brown fat, metabolically energy-producing fat, so this could have a role in obesity treatment. Linolool is well known from lavender, its main source in nature, a very strong anti-anxiety agent, again shown in humans in the context of agitation and Alzheimer's disease. It also is a powerful local anesthetic and has anti-convulsant and anti-glutamatergic properties. Beta-caryophyllene is a very interesting one. This is a sesquiterpenoid with 15 carbons. So, it is a terpenoid, but also a cannabinoid, because this is a selective, full agonist at the CB2 receptor. It had previously been known that this is a powerful anti-inflammatory, one that's used as copaiba balsam by indigenous people in the Amazon. So, its anti-inflammatory effects are comparable in potency to phenylbutazone, which is used for horses, but not men. What it lacks is a relation to other non-steroidal anti-inflammatories in that it protects the stomach. It's a gastric cytoprotective, so will not produce ulcers. And it may have a role in decreasing cocaine administration, analogous to other CB2 agonists. Now, shifting gears, let's look at the slide related to nabixamols. A trait named Sativex, an oral mucosal spray containing roughly equal amounts of THC and CBD, along with trace cannabinoids and terpenoids. There are always concerns about intoxication with cannabis-based medicines. But in this study, looking at visual analog scales of intoxication, we see single digits as compared to placebo. Just for context, 20 is a threshold at which people will feel some intoxication. 80 is desirable for recreational users of cannabis. How about tolerance? With opioids, we expect increasing doses due to tolerance are necessary over time. With nabixamols, in fact, over the course of a year and a half, there was actually a net small decrease in the number of sprays per day that were utilized by patients. In 2017, the National Academies came out with this book-length report, The Health Effects of Cannabis. Among other things, they recognized the benefit of cannabis-based preparations in treating chronic pain in adults. The data cutoff was before the best information on cannabidiol and its benefits in epilepsy came out. The next year, with Caroline McCollum, we published our own rendition of where cannabis-based medicines would be useful. Again, adult chronic pain treatment, multiple sclerosis spasticity symptoms, of course, treating nausea and vomiting associated with chemotherapy, and then in the case of CBD, treatment of intractable seizures. And then there are various studies supporting benefit in sleep disturbance, and we see other conditions where there's been a little bit less evidence, but many of these, I believe, will bear out over time. The adverse events associated with cannabis are well known. Some of these, such as cough, phlegm, and bronchitis, are purely related to smoking and will not be seen at all with oral preparations. But the most common ones are related to fatigue, psychiatric issues, and things like dry mouth, other cognitive effects, particularly short-term memory impairment. Less common are things like orthostatic hypotension, which certainly is a risk with high doses of THC, particularly with vapes or concentrates. And also possible is toxic psychosis, which is a temporary condition related to THC overdosage. Side effects associated with cannabis-based medicines are easily avoidable, however, and that's well demonstrated in this slide. This word in blue were the early MS studies of nabixamols. Initially, very high doses were allowed with a very rapid titration. It was noted, however, that doses above 12 sprays a day, which would be 32.4 milligrams of THC and 30 milligrams of CBD, produced a lot of side effects but not a lot of incremental benefit on treating symptoms. So 12 sprays a day was put as the cap. When this was done with a slow titration, the amount of the common side effects, dizziness, fatigue, somnolence, etc., was markedly reduced, cut in half or better. So this suggests the advisability of a lower and slower dose titration regimen. Let's look at some special cases. Cancer. Cannabis-based medicines provide symptomatic treatment in nausea and vomiting, as we've heard. There also were two positive Phase II randomized controlled trials in opioid-resistant cancer pain. Unfortunately, the Phase III studies did not read out, mainly working in Americans, but not in the bigger group from Eastern Europe, where the patients were measurably sicker at onset in the study. And treatment of insomnia and cancer, of course. As a primary treatment, it's important to note the cannabinoids are cytotoxic for cancer cells and promote apoptosis but are protective for normal cells. CBD in particular will reduce angiogenesis from the tumors and metastasis. Usually, hundreds of milligrams of mixed cannabinoids are needed a day on a long-term basis in association with conventional treatment, but better results have been seen with glioblastoma multiforme with nabixamals. And that is seen in this study, which was not published until 2021, but the work was done several years before. This is a Phase II RCT in 21 patients with recurrent glioblastoma multiforme already on temozolomide plus nabixamals versus placebo. Again, cap was 12 sprays a day, 32.4 milligrams of THC and 30 of CBD. The patients treated with nabixamals had an 83% one-year survival compared to 53% controls and survival was greater than 550 days versus 369 in controls. And there were two withdrawals in each group due to adverse events. This needs to be repeated and expanded. Special case is pain. It should be noted that cannabis has poor efficacy in acute pain, so you don't use a cannabis-based medicine for toothache, except possibly in conjunction with opioids. In chronic pain, it has a wide spectrum of activity, whether that's somatic or neuropathic in origin. It works differently to opioids. It may show its best effects not directly on the pain, but on its affective component. In other words, people feel the pain, but their reaction to it is blunted, and people can find that they function better and have a better attitude. The best documentation is for Type II preparations like nabixamals with equal amounts of THC and CBD. This is a listing of some prior studies of nabixamals in various types of pain, whether neurogenic, central neuropathic pain, peripheral neuropathic pain, rheumatoid arthritis, and cancer pain. These earlier studies totaled some 6,000 patient years of exposure, whereas smoked cannabis randomized control trials until a few years ago had only three patient years behind them. One of the issues is, can cannabis be used in people who've had opioid use disorder or even cannabis use disorder? Cannabis is commonly used concomitantly with opioids, even in those who are medically dependent, but close follow-up is necessary. After an interval in which the patient improves, a dose-tapering schedule should be initiated, but often patients manage this on their own. The medical patient who seems to use too much cannabis or qualifies as he has cannabis use disorder due to the development of tolerance could undergo a resensitization regimen from Dr. Sulek. Basically, the patient is asked to stop all use for 48 hours and then resume at half the prior dose. What's found is that the analgesic benefit seems to be just as good after this at half the dose. Another special case is fibromyalgia. This condition has three FDA approved drugs, duloxetine, minelacopran and pregabalin, but in a very large survey of fibromyalgia patients, more than 1300, they found these drugs very ineffective. In comparison, we see that over 60% of patients using cannabis found it very effective and only 5% found that it was not a benefit. Quick slide on sleep, and this is from a much older study, but almost every study of cannabis for treating medical conditions shows improvements in sleep. And we see the comparisons to placebo in almost every instance there is benefit. The difference between cannabis-based medicines for sleep and others is this is not a hypnotic effect, but rather the benefits on sleep come from a reduction of symptoms that interfere with sleep, whether it be pain, restless legs, bladder symptoms, et cetera. And this is long-term data showing a durable response over time and again, without dose escalation. On spasticity and MS, this was the pivotal study by Novotna et al. And it was a randomized withdrawal design, meaning unbeknownst to them, all the patients at the beginning got nabixamals. After a month of treatment, only the responders were then randomized to continue the same dose of nabixamals as seen here, or to be randomized onto equal numbers of sprays of a placebo that was masked by taste. And we see a marked divergence in effect subsequently over the next few months, and this was highly statistically significant. Dosing summary, and Dr. Sulak will be giving you much more information on this. This is not a milligram per kilogram drug. The dosing and tolerance depend on prior experience with cannabinoids, if any, and underlying endocannabinoid tone, which is a hard thing to measure these days. Our best advice is start low and go slow. 2.5 milligrams of THC, or equivalent, is the threshold dose for most patients, whereas five milligrams is usually efficacious and tolerated. 10 milligrams at once is a strong effect, except those with tolerance, and maybe too much for some. I like to limit overall THC to 15 milligrams a day, exceptionally 30 milligrams after tolerance might be attained. The presence of CBD and certain terpenoids may extend the therapeutic index, meaning allowing higher doses of THC to be used with fewer benefits. We generally recommend that patients should titrate to symptom reduction rather than to the point of being high. The correct dose is the lowest that produces a therapeutic benefit without associated adverse events. Standards for cannabis recommendation. Under federal law, as ruled in the Ninth Circuit, doctors may freely discuss the pros and cons of cannabis treatment with patients and can document this discussion. There should be a regular doctor-patient relationship with a complete history and physical in relation and with plans for follow-up. Certainly, the physician may provide a letter or other documentation to test the recommendation for cannabis use for medical purposes. Couple of examples. This is a phytofax that presents the amount of cannabinoids and terpenoids, donut showing the most common ones in this particular chemo bar, what the smell and taste are according to patients and their subjective impressions, along with bars showing the amounts of the terpenoids. So this is a type two agent, meaning CBD and THC together, and it's pinene dominant, low amounts of mercine, mercine being sedating. Alpha-pinene, in contrast, is again, capable of reducing short-term memory impairment from THC. So for someone with chronic pain, you've got analgesic and anti-inflammatory benefits from CBD and THC, and you have alpha-pinene to reduce short-term memory impairment, allowing better focus and concentration. And this is a very terpene-rich example. Often we see 1% or so. This is 3.9% with half being pinene. Another example, this is a type three agent, meaning that CBD is predominant. And in this one, CBG is the next one. There's very little THC. This one's caryophylline dominant. So there would be good stimulation of the CB2 receptor because there's little THC. This should be a non-intoxicating chemo bar. And limonene can produce some mood elevation. So what we see here is patients report comfort on an agent like this could be good for pain, inflammation, treatment of addiction from the CBD and caryophylline content, and also treatment of anxiety and depression. And I'm going to close there, and I guess we'll turn it over to Dr. Sulek. Thank you for your attention. Okay, great. Well, thank you for that. And this will be a really nice continuation. My goal is to help the participants understand the similarities and differences when recommending cannabis to some of the other agents that you may be familiar with in treating pain. I'll just give a little background about myself. I'm in private practice. I've been doing this for about 13 years with my patients. My background is as a traditional osteopath and with a focus in integrative medicine. Cannabis kind of took over my career in 2009 in Maine. I didn't necessarily expect it to do so, but I was one of the only clinicians in my state that was willing to recommend cannabis to patients when our state cannabis program expanded significantly. So I learned a lot from my patients. Thankfully, I had mentors like Dr. Russo that had been doing this for a long time and were able to confirm some of my early observations, which were quite distinct from what I had been exposed to in my training in terms of safety and efficacy, and also just the way in which people use this medicine. So let's jump in to cannabis dosing to maximize benefits and minimize adverse effects. And there's a little bit about me. I also have a book, Handbook of Cannabis for Clinicians, that makes it pretty straightforward for working with your patients. Quick financial conflict of interest disclosure. I am a equity owner and employee of a company called Healer, which provides free patient education, paid training for the industry. We also have hemp and cannabis products, formerly a paid scientific advisor for a cannabis research company, and then the author of the book that I mentioned. So in the next 20 minutes or so, 25 minutes, we'll cover a number of topics. Again, my goal is to help you be familiar with cannabis so that you can take this approach and work with your patients. So we'll look at the wide safe and effective dosing range, the non-linear dose response relationships, the therapeutic window of THC, using THC dominant versus mixed THC CBD dominant formulations, cover some practical dosing tips for people, patients that are naive to cannabis, talk about how to avoid impairment, and then some of the benefits of the psychoactive effects, and then a bit about delivery methods and dose layering. So let's just jump in. What are the goals of treatment? I think as pain management specialists, probably, oops, sorry about that. You probably understand this more than most that it's not a reduction in the visual analog scale that we're striving for necessarily, but it's improved function and improved quality of life. And during my interviews, I really like to elicit from the patients, what are these individually defined goals that are just congruent with their highest values in life? I think if we can keep a reminder of those and work towards those, it keeps both us and the patients on the right track. Another goal can be to reduce symptoms. I think that that's less important, to improve the safety and tolerability of other treatments. This is something we do. A lot of people are very frequently coming to me, striving to reduce or discontinue opioids, benzodiazepines, antidepressants, neuroleptics, you name it, and a substitution for more dangerous treatment. So to begin with, in cannabinoid medicine, we tend to treat the patient and not the diagnosis. What do I mean by this? Somebody might come in with a failed back surgery syndrome and chronic pain, and somebody else might come in with a similar condition and their two treatments, their two cannabis regimens might be completely different. Then I might see someone with that back syndrome and also PTSD or Crohn's disease. And these two very different diagnoses might have a very similar cannabis regimen. So it's really not about the diagnosis, it's about looking at the individual and finding the way to weave cannabis into their treatment plan that's the most supportive to them. And often we start with the barriers to healing. Like if somebody is not getting restorative sleep, that's a high impact area of their life to target, because of course everything's going to heal better once they're able to sleep. Same thing with having capacity for activity, social and spiritual connection and so forth. Now, how is cannabis different from a lot of the agents we were trained to use? First of all, this is a multi-compound, multi-target medicine. So much of our training focused on single molecule medications with single mechanism of action or single targets in the body. This is much different from that. Anytime we're using cannabis, there's dozens or even hundreds of therapeutically active compounds and most of them are targeting multiple proteins by your receptors, enzymes and so forth in the body. So it's a very complex picture. And I think our kind of tendency to want to reduce what we're doing in medicine to a kind of like a distinct like cause and effect. Oh, if I do this, this is what I can expect in the patient most of the time. With cannabis, it's quite different. And I think it requires zooming out and taking more of a complexity theory or systems biology approach, which I'll show you a symbol of on the following slide. Also we're interfacing with the endocannabinoid system, which is a homeostatic regulatory system that modulates all the other systems in the body. So it's really impossible to treat someone with cannabis without treating them holistically. That we are going to be impacting every system in their body when we treat with cannabis. And so this has nothing to do with cannabis. This is one compound that's well-known curcumin and a visualization of the network of interactions with this one compound curcumin with all of the different targets that may be involved in the pathophysiology of Alzheimer's disease. And you can see this gets really complex. Well, imagine cannabis has compounds that are equally as pleiotrophic as curcumin, but it has a lot of them in there. And these are very complex interactions. So we have to kind of become more comfortable with ambiguity not knowing everything that's going on, but working with our patients and following up with them to understand what kind of effects these treatments are having on them. Now, how do we talk about cannabis dosing? Can be harder and easier. And I suspect that some of the attendees are from different jurisdictions where there might be different levels of availability of standardized products in the marketplace, or maybe they're still illegal and people are just doing homemade products. When we're talking about cannabis inhalation, whether it's from a pipe or a vaporizer or something like that, we can't really accurately discuss how many say milligrams of active compounds they might be getting in a single session or a single dose. What I tend to ask is how many inhalations are you taking? How frequently? And then we can look at a trend, say over the course of a week, how much flour are you smoking or vaporizing throughout the course of the week? You know, an eighth of an ounce might be a low amount. Two ounces would be a very high amount. We can also ask qualities about the flour. High grade would be like a 20 to 25% THC per weight. Some people are smoking backyard herb that might be five to 10% THC by weight, and that can make a big difference. What we have here, two kind of artisanally made products. This would be like an infused oil or a tincture. This is something that often goes by a few different names, Rick Simpson oil, because of the Canadian activists that kind of popularized it, or a full extract cannabis oil, FICO, or just a couple of the names. This is an extremely concentrated product. Patients are often told to take a half rice grain or a rice grain size of it. It could be, you know, 50 to 90% THC by weight. It is, in my experience, one of the most common reasons that people have an overdose of THC and a very unpleasant experience with it. So we have to be really careful with things like that. But in a more regulated market, what we're striving for is an accurate way to communicate dosing. In other words, the number of milligrams of the active components that somebody might be taking, especially by mouth and the frequency. Those active components that we talk about are usually CBD and THC. And then there's other compounds that I think are worth discussing. A lot more attention recently, both in my practice and in this field, has been looking at the THCA and CBDA. These are acidic precursors. They're acidic because of this carboxylic acid group. In some circles, thought to be inactive precursors. Now we know that they're very active, even though they're non-psychoactive, and certainly worth discussing in terms of the amounts that people are taking. Now, looking at my practice, the oral dosing range that I've seen effective in my patients is extraordinarily broad. Now, this definitely includes some outliers, but if we were to dose cannabis by body weight, we might see it effective at doses as low as 0.01 milligrams per kilogram per day, and as high as 50 milligrams per kilogram per day. I don't think that we see this with just about any other medication we might use for our patients, especially not medications that could be used for pain. So someone my size might do well with as little as one milligram of cannabinoids per day, or do well with as high as three and a half thousand. And I've seen people on these surprisingly high doses, including a large portion of them, THC, literally thousands of milligrams of THC per day with no psychoactive side effects, no side effects at all. In fact, some people on those very high doses would come in and say, I feel 10 years younger. This is incredible. But again, these are outliers. Most patients do well in the range of 10 to 60 milligrams per day. This is where probably 75% of the patients will end up in this range. Now, even though 50 milligrams per kilogram per day seems very high, it's still well below the toxic threshold. Researchers have tried killing primates with THC. It's very hard to do. 9,000 milligrams per kilogram, single doses, and 250 milligrams per kilogram for 28 days. The monkeys still survived. Now, within this very wide, safe and effective dosing range, there are these nonlinear dose response effects, which means typically as somebody starts increasing their dose of cannabis, THC in particular, but this does apply to the other cannabinoids, as I'll show you in a subsequent slide. The therapeutic effects will get stronger and stronger up to a certain point. And then beyond that dose, as somebody continues to titrate upwards, they can lose efficacy of the therapeutic effects. And that's due to tolerance building. It's thought to be due to down-regulation and internalization of the CB1 receptor. What I've seen and what some of the data that Ethan presented previously is that when people find their optimal dose, they are able to remain at this dose for months, years, or even decades without loss of efficacy. And actually what tends to happen is a slow trend of this optimal dose decreasing over time. And perhaps that's because the internal environment and homeostatic function is improving and people are healing over time. Now, here's an example from a rat study looking at this nonlinear dose response effect, measuring the activity, the amount that the rodents are running around. And you can see the baseline activity here in zero, and then a variety of different dosages of THC administered from very low in rodents, 0.2 milligrams per kilogram of THC, all the way up to five. And what you can see is that at the lower doses of THC, activity levels decreased. As the THC was titrated, activity levels increased above their baseline. So this is one phase of the dose response effect. And then above this two milligrams per kilogram, as the dose was titrated up, the activity level decreased again, although not statistically significant. So what do we take from this? First of all, this is not only a biphasic dose response effect, there's actually bidirectionals, which means we can get the effect, the opposite effect, basically. One dose will decrease their motor activity. Another dose of the same compound will increase the motor activity. If this trend was analogous to spasticity, or pain, or anxiety, and something that we wanted to reduce, you might realize that, wow, a low dose could reduce that. Also a high dose could reduce that, but at the low dose, we're gonna get an even better response with less side effects. What do we mean by side effects? Well, in this chart, I think what's analogous to side effects would be here, catalepsy, which is remaining still in an unusual position. So the point is that there's a lot of inter-individual variability. There are some surprising dose response effects as the dose is titrated. And a lot of people wouldn't think that reducing the dose is going to create a stronger therapeutic effect. That's just counterintuitive, but that is often the case. Now, there's also something very interesting happening at the ultra low dose range of THC, which has been demonstrated in these three studies in mice. And I've also seen surprises there in my practice. Like I mentioned, somebody taking one milligram of THC per day can do really well with that. So 0.002 milligrams per kilogram of body weight is an extraordinarily low dose of THC for mice. Yet that dose has been shown in three different studies to produce long lasting activation of protective signaling molecules in the brain to reduce the damage and preserve cardiac function when administered two hours before an MI and to reduce the injury caused by hepatic ischemia and reperfusion, single dose of this tiny amount of THC. So I like to keep that in mind that little doses of THC might be doing a lot more than we expect them to. Now, here's a study for, this was looking at the addition of nabixamols, which Dr. Russo was discussing, for patients with cancer that were already treated with opioids and had poorly controlled pain. And this study used three different dosing quantities. One group, well, four, one group received placebo, one group received four sprays per day, which is about 20 milligrams total of THC and CBD, and then a higher, kind of a medium dose at 52 and a highest at around 80 milligrams total. And you can see the reduction in pain from baseline was strongest in the low dose group. So sometimes less is more. This trend also exists for CBD, although the biphasic effect tends to be at higher doses, which most people don't experience when they're buying CBD over the counter because it would get expensive. But this is one example, this is a model of anxiety, a public speaking test that compared three different doses of CBD, 100, 300, and 900 milligrams with placebo and also with clonazepam. And you can see that the 300 milligram dose of CBD performed much better than 100 or 900, which basically did nothing. 300 of CBD was actually superior to clonazepam in this test. So again, this can be very counterintuitive, but more is not always stronger when it comes to cannabis. Now talked briefly about the bidirectional effects, the same medicine can cause the opposite response in different individuals. You know, give the same dose of the same medicine to one person, they may become less anxious, give it to another person, they may become more anxious. Some people that might wake them up, some people that might make them feel sedated, some people might stimulate their appetite, same dose to someone else might suppress their appetite. And then we also have these opposite responses in the same individual. And the biggest reason for that would be different doses. If you look at the effects of a THC overdose, these are the symptoms that are typically ameliorated by an appropriate dose of THC. So a THC overdose, first of all, it's miserable, it's not dangerous per se, there's no brain damage or organ damage or anything like that. People think they're dying, but they're not, because they're typically experiencing increased anxiety, increased pain, nausea, vomiting, diarrhea, there can be twitches and muscle spasms, disorientation. Again, many of the effects, many of the symptoms that THC would help with in an appropriate dose. Also the external environment, the setting can precipitate these bi-directional effects, or if somebody's using cannabis in their home in a relaxed setting, they might feel more relaxed versus using it in a stressful setting like an oral surgeon's office that might make them more anxious. Let's talk a little bit about THC and how it affects people, especially people that are new to THC. Cannabis naive patients tend to have more frequent adverse effects, and regular users tend to have less of what would be considered the adverse effects, the psychotomimetic, perceptual altering, amnestic, and endocrine effects. And what's been proposed is that THC can widen its own therapeutic window, in part due to heterogeneous tolerance building to the various effects. It seems like the therapeutic effects of THC are more resistant to building tolerance than the side effects, and this probably has to do with different levels of sensitivity and rates of tolerance building in various regions of the brain. And so the kind of antinosusceptive and analgesic areas where the cannabinoids are working in the brain and spinal cord are more resistant to the development of tolerance than, say, the motor areas. So in the first week of someone using cannabis, they might feel kind of clumsy or dizzy. That goes away, but the benefits remain. This is important to remember. Dr. Russo did allude to this in some of the Sativex data, or Nabixymol's data that he presented, but I think that when we're working with people that are new to cannabis, keeping this in mind can be very useful. Now, I want to talk a little bit about the combination of THC with CBD, which is another strategy to widen the therapeutic window of THC. I think that CBD is a great therapeutic, lots of applications. As you heard from Dr. Russo's talk, probably one of the most relevant ways of using CBD, or the most important in my practice, is using it as an adjunct to THC. Here you can see, based on studies with dronabinol and synthetic THC, threshold for toxic psychosis could occur around 17, 18 milligrams. Give a single dose of 18 milligrams of THC to someone that has not built any tolerance or someone that's cannabis naive, and they could have a very bad temporary experience with that. It resolves on its own, but it's very unpleasant. Compare that to giving someone this combination of THC and CBD, and they might be able to tolerate almost 50 milligrams of THC before experiencing that same adverse effect. It's not just the most severe adverse effects that CBD can mitigate, it can help overall. Now, if we're comparing, especially in the treatment of pain, using THC-dominant versus mixed versus CBD-dominant preparations, one thing to remember is that a patient is going to need a higher number of total milligrams if they're including CBD in the treatment, or if they're leaning very heavily on CBD. This can make the treatment much more expensive for patients. Something to keep in mind, the cost-effectiveness. If we're working with people that have limited resources and need to make the most of the money that they have to spend on this over-the-counter treatment, we don't want to lean too far into the CBD-dominant realm. We would want to emphasize the THC. As Dr. Russo mentioned, CBD is an alerting compound. The confusion about higher doses of it acting as a sedative have more to do with some of these other compounds that are coming along with the CBD, like the sedating terpenes. Giving someone a CBD-dominant kind of artisanal preparation, hemp-based preparation, a lot of people can feel five milligrams. They might say a little more alert, a little less anxious. That's kind of the threshold where adults start to notice something. Many people won't notice something until they get into the kind of 10 or 15 milligram range. And some conditions, as you saw earlier, respond to hundreds of milligrams per dose. Very well tolerated. CBD is incredibly forgiving. Now, a lot of people are wondering, are these over-the-counter CBD preparations enough? What did I do? I think my camera just vanished. I was just plugging in my computer. Something happened. Let me get out of the screen for a second. And sorry about this technical difficulty. I am unable to start video. Let's see. Okay, great. I think we're back. Somebody, please tell me if you're unable to see my slides, but I'm going to continue. So are CBD-dominant preparations enough? There's a lot of them over-the-counter. First of all, a lot of them are mislabeled. They don't have in the bottle what it says on the label. But if you do get a good CBD product, is that enough to say treat moderate to severe chronic pain? Initially, I would have said no, because the results with THC-dominant or mixed THC, CBD, cannabis is just, they're so remarkable in the clinic. And with CBD, it can be a little less impressive. But now we have more and more data suggesting that in some cases, these preparations are enough. Here's one example of unpublished data. It's been presented at several conferences, though. This was a custom-made CBD formula given 10 milligrams three times a day to adults with anxiety who reported an 80% reduction in anxiety after four weeks, significant improvements in depression and mood and many cognitive domains. Those benefits were maintained at six months with improvements in sleep and quality of life measures and zero adverse effects. This is a very low dose of CBD. I hope that data like this is surprising to some people that it can be just that effective. Here's another study, three weeks. Both of these are open-label studies. This was in 31 subjects with diabetic peripheral neuropathy given 20 milligrams of CBD three times daily for three weeks. No adverse effects. All subjects experienced a significant reduction in pain. A third of them responded immediately. This might have been the placebo response, hard to say. Two thirds noticed a significant improvement after about a week. All 23 subjects that were taking other pain medications requested to reduce it or stop their prescription but were advised not to do so for the purpose of the study. Here's what looked like. This is their overall score before and after those three weeks. You can see no real difference in those that were or were not taking other pain medications. You can see also the maximum pain level decreased significantly over those three weeks as well. There were marked improvements in anxiety before and after and also improvements in sleep. Again, this is 20 milligrams of a CBD dominant hemp-based formula taken three times daily for three weeks. I think that's pretty impressive. One question, is it the CBD that's doing that? We would assume so because it's a CBD dominant preparation but I'll point out that in these hemp formulas that are 0.3 percent THC by weight or less, there is still a little bit of THC. A 20 milligram dose of CBD may have included a half a milligram of THC which sounds very low but could be significant. I just want to point out this study from Brazil with 17 women with fibromyalgia and they were given a THC-rich cannabis oil over the course of eight weeks. This was a placebo-controlled study. The initial dose was one drop of the oil which was 1.2 milligrams of THC and after eight weeks the average dose was 3.6 drops which was 4.4 milligrams of THC. That's the average. Some people were using less, some more but divided TID. We're talking just a little over one, one and a half milligrams of THC. Sounds like a very low dose. Look at these results. Total fibromyalgia score in the cannabis group went from 75 down to 30 compared to almost no change in the placebo group. So my point in showing this data, it's a small study but it is placebo-controlled. My point in showing it is that a very small amount of THC, certainly below the threshold of psychoactive effects as Dr. Russo mentioned, can be effective not just for pain but for a lot of other areas of life including anxiety and sleep and so forth. Now we've been focusing on just a few of the compounds and I want to remind you what Dr. Russo was talking about. There are many other cannabinoids besides THC and CBD and many other classes of compound in this plant that's just an incredible factory of therapeutic compounds. So here's where the rubber meets the road really quickly. This is a picture of my grandma at her 91st or 92nd birthday I believe. She died just a year or two after that. She's pictured with my dad here. She had fibromyalgia, arthritis, depression, trouble with sleeping. She was on corticosteroids and many other drugs for a long time. When she was about 82 we introduced a cannabis tincture. She had kind of a bias against the drug so we never told her what it was. She was living in a state where it was illegal. A family member grew it and made it for her. We didn't have any testing. We didn't know how potent it was. We tried to use the same recipe to get consistency from batch to batch. To her it was the herbal pain formula. We followed this regimen. You know what I'm showing here. We started subtherapeutic. We titrated it up until she could feel it just a little bit. Then we paused and then we increased the dose again after that. I think listening to my earlier slides you might begin to realize why did we pause. It has to do with allowing that therapeutic window of THC to widen. We're not titrating rapidly to achieve maximal effects. We're really going slow. The story with her is that she got off of most of her other drugs. She started sleeping. She became warm and affectionate. She started joking around. For me it was incredible because I was able to have a relationship with my grandmother who was pretty miserable for most of my earlier life. It is very clear that during her 80s and early 90s her quality of life was much better than it was during her 70s. It's just a profound effect on her life. What are some of the dosing tips here? Most people are going to be starting with oral dosing literally one to two milligrams of total cannabinoids up to three times daily. Some people will do fine but twice daily. If it's more of an episodic or breakthrough symptoms that we're trying to address with inhaled cannabis again it's one to two inhalations of cannabis vapor up to three times daily is usually a good starting place. If you don't know where to start with THC and CBD you can pick one-to-one like nabixamols that's broadly effective and well tolerated. Very important for patients to track and document their responses like it is for other treatments for pain. The first therapeutic goal is if they're not sleeping we want to get them sleeping. I wanted to show Dr. Russo mentioned kind of the nabixamols titration and the side effect profile. I just wanted to show what that is because it makes a lot of sense. So you can see here on day one no sprays in the morning, one spray in the evening. On day two again one just one spray in the evening. On day three we go up to two sprays. On day four stay at two sprays and then it's not until day five that one spray in the morning is introduced and they remain at two sprays in the evening and so forth. So again this is to allow patients to build some tolerance to the adverse effects of cannabis over the first four days before they start dosing it during the day maintaining this higher dose at night. I think that makes a lot of sense and as you can see there were much fewer adverse effects in the GW studies that use nabixamols that kind of switched over to this alternative titration schedule. Previously in the blue bars you can see much higher rates of adverse effects from a more aggressive titration regimen. A lot of people are going to say okay fine I'll use cannabis but I don't want to get high at all. You know how can we do this? First of all that can be done with THC dominant cannabis. You can do it with dronabinol just synthetic THC. I really want to emphasize that if you take this start low and go slow approach and allow THC's therapeutic window to widen there is a therapeutic window there. People can receive the analgesic effects at doses lower than will cause any side effects including the psychoactive side effects. But if you have the luxury of using a combination of THC and CBD leaning a little more into the CBD can decrease the likelihood of psychoactivity. The acidic cannabinoids that I mentioned earlier they are non-psychoactive. They are anti-inflammatory maybe a little slower to start working but very good for treating pain. And then topical cannabinoids can work really well for localized pain. Now just before I finish I want to point out the psychoactive effects although most people are wishing to avoid them these can actually be in my opinion perhaps the most therapeutic aspect of this plant especially for people with chronic pain. And I don't want to just kind of gloss over that and go along with people's notion that is usually fear-based. You know a lot of people think cannabis is going to create some kind of a hallucination or it's going to be like a psychedelic drug. Often when I'm seeing patients I say fine we don't have to have any psychoactive effects. They follow up maybe at their three or six month visit. I say okay now that that dose of THC that you've been taking before bed that's been helping you sleep so much why don't you try taking that a few hours earlier like around supper time. And you know just once or twice a week and let me know how those evenings go. And they come back and they say that's it you know that felt like a glass or two of wine but way more enjoyable. And they love it. It's well here are some of the benefits you know you look at the clinical trials of medical cannabis and euphoria is almost always listed as an adverse effect. Look up euphoria in the dictionary and it means feeling good despite having an illness. This is something that we want for our patients and they don't want to be in the state all day every day and they don't have to be. But to experience this from time to time can be so useful to have this especially this intensification of the natural reward from ordinary experiences really useful. People come back to me and say that you know cannabis helped them become more aware of themselves feel connected to something greater than themselves to see their problems from a different perspective or to have more acceptance over their condition. You know feel like their pain becomes more of a teacher and less of a tormentor and this increased flexibility and capacity to change. What's so beautiful about this though is that people will experience this during the psychoactive effects of cannabis. Those effects wear off but these lessons these new perspectives that they've gained persist beyond the effects of the drug. The last thing I want to talk about are delivery methods. This was a survey of 1300 people that were using cannabis to treat pain and I just want to point out that 93% of them were using two or more routes of delivery. 72% were using three or more. So what is this about? You know I think all of you are used to the idea of you know using long-acting opioids to treat baseline pain and then using short-acting to treat breakthrough pain and maybe there is localized pain and we're using like a diclofenac gel. Maybe there's muscle spasms and we're using you know muscle relaxants, sleep problems and there's a sleeping aid or an antidepressant that has sleep qualities. All of these things can be achieved with the same medicine cannabis but it usually looks like different products and different routes of delivery. So oral for baseline treatment, inhaled for breakthrough symptoms, inhaled can also be better than oral for spasticity, a more sedating formula for sleep and so forth. So I think this is the rule not the exception. Most people who do really well using cannabis to treat pain are using multiple products and multiple routes of administration and that is all I have. Thank you very much for your time. I know we ran a little bit over. Thank you Dustin. I apologize my audio was off that I didn't get to introduce you but I did also want to mention about your Handbook of Cannabis for Clinicians Principles and Practice. I think it's probably the closest thing we have to a medical textbook for physicians on the applications and understanding of of medical cannabis and I definitely recommend to our viewers to check it out and I also wanted to comment on your co-founding of thehealer.com which is really a remarkable medical cannabis educational resource. Thank you Mitch. All right do we have some questions? I hope they're coming in. We have at least one question for for both Ethan and Dustin. With COVID we're seeing a lot of long-term COVID patients and I was curious if you could each comment on where you see the role of medical cannabis for some of these patients who are coming in with a constellation of long-term complaints. Well I'm going to kick to Dustin since he's really the one in the trenches. I mean I hear that anecdotally that some people gain benefit particularly with long COVID and cannabis-based treatments but we don't have any randomized control trials from which to draw. Dustin what's your experience been? Sure well I actually want to start with acute COVID because I think there's been a really strong signal there that people using cannabis and many different kind of use patterns have found remarkable results with their symptoms and perhaps the course you know shortening the course but I've had a number of patients tell me that during the acute phase of COVID they use cannabis and they think they're all better and then the cannabis wears off and their symptoms start to come back but it can be extraordinarily effective for treating the headache, the body aches, the respiratory symptoms and so forth. I have been seeing more and more patients with the post-COVID syndrome which to me looks a lot like many other conditions that I treat especially here in Maine. We see a lot of tick-borne disease, we see mycotoxin illness, mast cell activation syndrome, you know these are these kind of chronic inflammatory dysregulations, multi-systemic involvement and I won't say that cannabis is a miracle cure for it. I haven't seen it to be that. I think we need to get people sleeping, we need to help their anxiety, get their autonomics back into balance. These are things that cannabis can be used to do but I haven't been overly impressed like give somebody cannabis and see their syndrome resolve. It hasn't been like that. What's your feeling Dustin on in terms of smoking or vaporization especially now in COVID where people are coming in with bronchial issues? Do you have them exclusively avoid smoking or do you still have patients who you will allow them to smoke since for many patients that's been the route that they're most used to? Yeah, so in general the inhaled cannabis can be very effective. You know sometimes the smoke itself is irritating and so if somebody's already having respiratory symptoms I typically encourage them to use an herbal vaporizer which for the attendees that aren't aware of this so this would be a device that's kind of like a convection oven. It'll heat up the herb to a temperature where all the medicine evaporates, but the plant matter itself doesn't combust. So you're basically inhaling a warm mist of evaporated cannabis oil. And that's gonna be the most gentle on the respiratory track. And yes, people will have improvements like rapid, two to five minutes later, improvements in their coughing, their wheezing, and their other respiratory symptoms. And this has also been suggested in animal studies of models of acute respiratory distress syndrome, which seem to respond well to the cannabinoids. But I also have my patients who just love smoking cannabis and they've only smoked cannabis and they're not interested in some of my other recommendations and they also tell me that smoking cannabis helps them when they have a cold or a flu or bronchitis or even COVID. Right, I found the same issue. I try to convert patients to using a vaporizer for the flower. And as many of my patients have pointed out, when they're buying a flower, as opposed to the oils, it's less expensive for them, at least in the state of Connecticut. So it goes a little bit, as you say, it goes a long way. I'm curious about being able to find specific, whether it's a strain or as we're talking about cultivars, as Dr. Russo said, to be able to control many of the constituents within cannabis, because you really have to look very carefully at whatever the producers are putting out in the state for medical cannabis. What is their CBD? What is their THC ratios? Do they list how much CBG, what the terpenes are? I mean, I've gotten pretty good at looking at it and talking to some of the people in the dispensary, but we can't control for that as much. And if there are certain formulations that both you and Dr. Russo feel, well, this formulation would be better for this clinical indication. How do we go about trying to control for that, working with the dispensary? Because the growers are only gonna produce what they're gonna produce. So I'm just wondering, how do you handle that? That's a huge problem, especially because of the continued prohibition of cannabis. We also have quality control issues. Are the labs accurate? Labeling, manufacturers are only gonna do what's required. Certainly Dustin has produced many good formulations. Credo Science, we have the Daygold preparations. But I think that this problem is only gonna be solved with better quality control that hopefully will be driven by the industry, plus having more liberalized laws that allow this kind of commerce and interstate commerce. And I'll just make a comment on that also. We had a cannabis analytic lab in my office for about four years. I know the problems with the analytic testing. Machines go down, what's coming from the third party. And now as Healer, a company that's producing products, we're often using two or three different independent third party labs because the results are all over the place. So it's really hard to trust these analyses of the products themselves. And it's also hard to predict. Even if the product is labeled accurately and you look at the label and it looks like, oh, this is a terpene profile that's gonna make this a really sedating, great kind of a nighttime formula. And then people take it and they say like, that thing kept me wired all night. There's just a lot of unknowns. We're just looking at the tip of the iceberg in these very complex products. So I would say, maybe 10 to 20% is based on what we think we know about its composition. And the other 80 to 90%, what I think speaks the loudest is the cash register. What are people with chronic pain purchasing and coming back to purchase again and again, or what are people with PTSD or anxiety purchasing? And so I think what's really valuable is having that line of communication between the clinician and whoever's running the dispensary and understanding what they're selling, what people are liking. Right, well, we're fortunate in Connecticut because we have a pharmaceutical model where all of the four producers are treated like pharmaceutical companies. So there's a very high level of transparency and testing, third-party testing. But as far as the dispensaries, they're only gonna get what the producers are making. And we haven't gone to full recreational dispensary use as they have in Massachusetts and other states. But it's a commentary that I have continually with the producers and the dispensary owners to try to figure out the best recommendations for my patients. But yeah, I think that if you wanna comment, but I think that's really an important role for all of us who involved as physicians, as a mediator between say the primary care doctors and the dispensary owners to be able to educate them as much as we can and as much control as we have. Yeah, I agree. Sure. Are there any other questions? I'm looking for the... In terms of CBD, you get a lot of patients, I know I do, who come into my office and ask me about full spectrum CBD products. And I know Ethan, you've spoken about this because you've mentioned that obviously, there's only one FDA approved CBD product out there on the market to treat childhood seizures. But how do we educate those patients who are coming in? I know I have my own impressions, but I'm curious what you guys, how do you advise patients about these products? I often say you want organic, you want full spectrum and so forth, you want a certificate of analysis. And so forth, you want a certificate of analysis, you want all of that. But are there any other guidelines that you have? Well, you've nailed it, but just to add to that experimentation, and I'm sure it's the same in PMR as it was in practice in neurology. There are a lot of first things you try that don't work and the motivated patient is gonna keep coming back and you've got to come up with something that's better or more effective. And that's often necessary. I think I've recently heard something to the effect of, it takes people six to nine months to find their preferred preparation. And I think it's easier if they see some incremental benefit, but not quite ideal. If people are willing to mix and match, they often can find what works best for them. Yeah, I often tell patients the CBD, you get a bed, bath and beyond is not gonna take care of your pain. But I've tried to vet certain companies and make sure that they have certificate of analysis, that they are full spectrum and so forth and look at some of those things. But yeah, the average consumer is really at a loss, I think. Sure, and then I'll just comment, typically the term full spectrum is used probably inappropriately to describe a CBD product that contains at least some THC in it. I think broad spectrum is like no THC, but some other components. You know, really full spectrum is taking the flower and putting it in your mouth and eating it. Any extraction and formulation process is going to lose some of the components, even though some producers are striving to keep as many of these therapeutic compounds in the final product as possible. One thing that we found is that the presence of CBDA, that precursor of CBD makes these products seem a lot stronger. People need less of them and they get better results. CBDA is up to 10 times more orally bioavailable and based on animal studies, ranges from like 10 to 50,000 times more potent, depending on what the target and the therapeutic model. And so, yeah, our company Healer has been selling CBDA and CBD products. And like over the last few months, the CBDA sales have exceeded CBD. Most people that were CBD users that are trying CBDA are switching over because they're using lower doses and getting better results. Right, and I see that there's even some of these hemp-based products that are CBD. They're coming in flower forms, not just tinctures. And there are patients who are using these through vaporizing or smoking. Can you comment on any of those products? Yeah, I've seen the smoked CBD dominant flower as an excellent substitute for tobacco. And I've had several patients that have used it as part of a cessation strategy. Very interesting. Okay, well, thank you guys so much for such a wonderful presentation. We are going to take a five to 10 minute break and we're gonna move on with our next clinical application starting with an introduction to Dr. Ari Greis. So thank you again, both of you. Happy Father's Day to you for your time this Saturday morning. Cheers. Thank you so much. See you soon. Okay, we are back. What a great hour we've had. Now we're on to the second hour. Hope everybody got something to drink and come on back this morning. Our second part is on clinical applications. And our first speaker is one of our own, Dr. Ari Greis is a board certified physiatrist who has fellowship trained in sports and spine rehabilitation and specializes in the non-operative treatment of spinal and musculoskeletal disorders. Dr. Greis is a clinical assistant professor of rehabilitation medicine at Thomas Jefferson University. I recently learned that Ari is also providing pain management services for the Philadelphia Eagles NFL team. He is the director of the medical cannabis department at Rothman Orthopedic Institute in Pennsylvania and was senior fellow in the Institute of Emerging Health Professions at the Lambert Center for the Study of Medicinal Cannabis and Hemp. His main interest is in the treatment of chronic pain with cannabis as an alternative to opioids. Dr. Greis will be discussing recommending medical cannabis for orthopedic pain. Ari, it's all yours. Thank you so much for having me today. It's been really an honor to speak after Dr. Sulak and Dr. Russo. It's also been validating to hear their experience as I've made similar observations in my practice. I've been using medical cannabis to treat chronic orthopedic pain since legalization in the state of Pennsylvania back in 2018. And in our practice at Rothman Orthopedics, where we really do embrace innovation and best practices, I was given permission to start a cannabis program. I was sort of the guinea pig of the group. And after four years of recommending cannabis and collecting outcome measures on all of our patients for a variety of pain conditions, we are about to expand the program to 10 other physiatrists in our practice. And we hope to continue our research efforts on this topic. So thanks for including me. I have one disclosure. I'm doing some medical monitoring for a Canadian cannabis company, Canopy Growth, just approving patients for inclusion into their studies and being available if there are any adverse effects. So today I'd like to talk about appropriate candidates for medical cannabis treatment in orthopedic practice to help you guys understand the chemical constituents of cannabis, how to properly educate patients and inform them how to make wise decisions when they shop at dispensaries across the country. And also to determine the best practices for providing medical cannabis product recommendations, because it's an overwhelming process. As many of you know, physicians aren't prescribing cannabis. So patients have to decide for themselves what to purchase in dispensaries, and it can be an overwhelming process. So the more we're involved, I think the better the outcomes are. We all know that chronic pain is a humongous problem and that the population is aging. This is a big concern. We know that about 20% of the country suffers from chronic pain. It's over 50 million people. There are about 3 million new cases a year. And the cost to this country is over 600 billion a year. Globally, we have one and a half billion people living with chronic pain. And we know that these numbers are just gonna go up because as the population ages and patients over the age of 65 are expected to double in the next 40 years in this country, there are just gonna be more and more people to treat who are suffering with chronic degenerative orthopedic conditions. And we know very well that safety is a concern when you're treating any chronic medical condition. So the long-term use of cannabinoids needs to be explored further. So in the first section of my talk, I'd like to discuss the current state of the opioid crisis in the United States and also the state of medical cannabis. The opioid crisis is something that's affected all of us. I think we all know someone personally who suffered from an opioid use disorder. And many of us know people who have had an accidental overdose and died. And we know today that these numbers are only getting worse. This is data from a few years ago. It's over 130 people a day are dying from an accidental opioid overdose. And we also know that Americans as a country consume more opioids than any other country in the world by far. And we also know that the longer you use an opioid, the more likely you are to develop some physical dependence. And that really is the primary issue with opioids that after being on an opioid regularly for a week or so, physical dependence can occur. And withdrawal symptoms from opioids are obviously very strong and can cause a lot of anxiety and feelings of very severe flu-like symptoms. And the only way to manage some of these symptoms for most patients is to take another opioid pain medication and to feel sort of normal again. And so we are doing a better job in orthopedics explaining to patients that the lower the dosage, the shorter amount of time that they're using an opioid, the least chance of them developing dependency because the longer you're on these pills, the harder they are to stop. And we have seen three different waves of the opioid epidemic in this country. The first one beginning from prescription opioids, largely from pain doctors. And then there was a real rise in available and cheaper black tar heroin, which led to further overdoses and death. And in this third wave, we see synthetic opioids really dominating the market, largely coming from fentanyl-laced products that are produced in laboratories outside of the United States. And this problem is only getting worse. We know that largely due to COVID, the opioid death rates have gone up. In 2019, about 50,000 people in this country died from an opioid-related death. And the numbers spiked in 2020 to 68,000. So as much as we're aware of the problem, more needs to be done to address it. Medical cannabis, on the other hand, is becoming more widely accepted across the country. And surveys have shown that over 90% of the population in some surveys feel that cannabis should be legal as a medicine. Each year, more and more states pass legislation to legalize medicinal and recreational cannabis use. In the coming year, we expect North Carolina and Kansas to potentially pass legislation. And currently there are 37 states plus the District of Columbia that have legalized medical cannabis. That means that 74% of this country has access to medical cannabis. And whether or not clinicians embrace this or not, we know that our patients are more and more using cannabis. From a medical standpoint, it's estimated that 3.6 million Americans are using medical cannabis with a legal cannabis card approved by a physician, and that many more of our patients have access to recreational use products. We did a study at Rothman Orthopedics surveying over 2,500 orthopedic patients about their attitudes towards medical cannabis. And we found that one in 10 patients were already using medical cannabis for a condition. And of the people that were not using cannabis, 81% considered using cannabis for a chronic pain orthopedic condition. Most of them were aware of the legality of medical cannabis in their state, and most believe that medical cannabis should be legal throughout the United States. When we looked closer at barriers to accessing medical cannabis, we found that cost was the number one barrier to using medical cannabis as it's not covered by medical insurance. And that 71% of patients felt that they either couldn't afford it or it was just too expensive to take on. But three quarters of our patients agreed that cannabis was safe for most common orthopedic conditions. And 77% felt that it was safer than opioids for chronic pain. There was a discrepancy in age where younger patients under the age of 50 noted social stigma as a barrier. Many people felt that employment drug testing was also a barrier to accessing cannabis after cost. And older patients over 50 were less likely to feel that cannabis was safe to treat orthopedic conditions or that it was safer than opioids. But to conclude from our study, we found that our findings were in line with the nationwide trends that there's an increasing acceptance of using cannabis to treat orthopedic pain. And that the main barriers were again, cost, social stigma, and also employment related drug testing as a barrier to accessing this medicine. There are a number of repercussions of federal prohibition on cannabis, starting with preventing access to patients who might benefit from it. And again, our study did show that because cannabis is not available as a covered medical expense, many people who might benefit from cannabis simply can't access it. I also think this is a part of the sad story on cannabis prohibition, where we all know that lower socioeconomic status has led to mass incarceration of largely brown and black people in this country who currently might live in a state where cannabis is legal. And those are the same people that can't access cannabis as a medicine whereas people with the means and the money to afford cannabis certifications in the products at dispensaries do have access and have not been affected by prohibition in the same way. Cannabis is also very difficult to study because it is a Schedule I drug as per the Controlled Substance Act of 1970. Putting cannabis in a Schedule I category basically means that it has no medical use and has a high chance of harming the human body or potential for abuse. And because of the recognition of cannabis as a Schedule I drug, you need a special DEA license to study cannabis, you need funding for these studies, and it is a huge barrier to research, which is why a lot of the research that we're doing at Roth Northopedics is really prospective and observational. Because of the Controlled Substance Act, you also cannot prescribe medications in the Schedule I category. And so the whole point of this act is to give physicians control over substances that might have a therapeutic effect, but also come with some risks. And we acknowledge that opioids can treat acute pain but have risks of misuse and abuse, and therefore physicians are given the power to control how many pills patients get, at what dosages and for how long. But with medical cannabis, when we provide access at the state level, we have no control over what our patients are purchasing at dispensaries. They can purchase the most potent products and as much as their state will allow. There's also variation among state medical cannabis programs. And in medicine, you would like to think that how we treat chronic pain in Pennsylvania is similar to how we treat chronic pain in Texas. But again, patient access to these products is gonna vary as are the medical conditions that are approved in each state. There's huge missed tax revenue from cannabis sales. We know that this industry is also growing year by year. Current estimates are that the industry is bringing in about $20 billion annually for medical and recreational sales. And there are large employment and travel issues that our patients face because of federal prohibition. You're not able to cross state lines with medical cannabis, so you can have legal cannabis in the state of Pennsylvania, but not cross into any other states with your medicine. I've literally had a number of patients who I've weaned off of opioids in favor of cannabis to treat their chronic pain. And when they leave the state, they'll call me and ask for a one-week supply of an oxycodone or hydrocodone so they can manage their pain while they're out of town. So I'm going to move on to part two. We'll talk a little bit about what cannabis is and how we recommend it. Some of this will be review from the first talks in this program. So as we've already discussed, cannabis sativa is a flowering plant that contains over 100 different chemicals called cannabinoids. THC and CBD are the most prevalent. We find CBD more prevalent in hemp, which by definition has less than 0.3% THC. There are also minor cannabinoids that work together with THC and CBD to produce an entourage effect. And like Dr. Russo has mentioned, there are hundreds of terpenoids or terpenes, which are aromatic compounds that are also found in these plants that have potential physiological effects on the human body. And if you look closer at these flowers, it does look like hemp does not have as many of the chemicals as the traditional cannabis plant that is sold in dispensaries, which has more chemical makeup in it. So cannabis is essentially a constellation of compounds with different therapeutic actions, many of which are relevant to chronic pain patients, particularly in orthopedics, as they can have not only anti-spasmodic and anti-inflammatory effects, but provide analgesia and also have psychoactive effects, which Dr. Sulek has mentioned can help patients distract themselves from pain when they need a break. Unfortunately, a lot of the basic science is not being taught in our medical schools, and which is, I think, another reason why many clinicians have been hesitant to recommend cannabis to their patients. However, when you look at the endocannabinoid system compared to the opioid receptor system, you see many similarities. And although we are taught about the opioid receptors and some of the endogenous peptides that exist in our body, as of the early 1990s, we have been aware of two CB1 and CB2 cannabinoid receptors, which are very prevalent throughout the body, and two endogenous peptides that attach to these receptors in both our central nervous system and out in the periphery. And when we look at the known physiological functions of the endocannabinoid system, many of them are relevant to pain patients, again, providing analgesia and modulating stress. Stress in our bodies, obviously, can increase levels of pain and limit function as well. So, in this country, medical cannabis dispensaries are where our patients are obtaining their products. In Pennsylvania, part of our legislation allows the eight major medical institutions to partner with a cannabis company and to obtain what's known as a super license, which allows these cannabis companies and medical institutions to grow, process, and sell medical cannabis products in up to six different dispensaries across the state. Thomas Jefferson has partnered with this company, Ethos, and again, I find it ironic that we are participating in this program, selling cannabis products, and when I lecture to the medical students at Thomas Jefferson University, they are learning nothing about the endocannabinoid system to date. So, what's available in these dispensaries? A variety of different routes of delivery exist, including inhalation via vaporization or smoking. In Pennsylvania, you're not allowed to smoke, however, we do sell dried leaf or flower products. There are a number of oral routes of delivery, again, in my state. Edibles with sugar in them, such as baked goods, chocolates, and mints are not available, but we do have capsules, sublingual tinctures, and topical cannabinoids that are available. And in order to ease people into the use of cannabis, particularly ones who have not had experience using cannabis in the past, many times we augment the dosage of THC or the ratio of THC to CBD. And so, you can look at products that have low amounts of THC and equal or more amounts of CBD with the goal of minimizing intoxication, as discussed previously. So, in my experience recommending medical cannabis since the beginning of 2018, I've certified over 1,500 patients. Most of my patients are elderly with chronic degenerative pain conditions, including arthritis of the spine, peripheral joints, fibromyalgia, and neuropathies. Many of my patients are cannabis naive. Many are seeking to wean off of opioids or are afraid to use them again. And some of my patients use recreational cannabis, but note some of the medicinal effects with regards to sleep and treating anxiety or pain. What I have experienced, sorry, most notably is that anecdotally patients report decreased pain and improved sleep. There are very few side effects with low dose THC when combined with CBD, but the preferred route of delivery and dosage can vary amongst patients. And largely this is due to prior exposure to cannabinoids intolerance. However, I've had some naive elderly patients who required higher dosages to feel an effect and tolerated it well. So, in Pennsylvania and similar to many other states, patients have to first register with their health department. They have to be certified by an approved physician. In some states, there's no required training. In Pennsylvania, you're required as a clinician to complete a four-hour CME course on medical cannabis. Once certified, and the certification process is just confirming that a patient has one of the state's qualifying medical conditions. In Pennsylvania, there are 23. Patients then obtain a medical cannabis identification card, and then you have to shop at an approved dispensary within their state. And then we always recommend a follow-up with their physician. So, what I do during my medical cannabis visit is I have patients fill out an informed consent about the potential risks of cannabis. I have patients fill out outcome measures that are specific to their pain complaint, whether it's for low back pain, neck pain, knee pain, or hip pain. I do an online certification on the health department website. I discuss the active ingredients, the different delivery methods, which includes some of the pharmacokinetics because some of our products, such as vaporized products, are going to act on the body and produce an effect within minutes, whereas orally ingested products might take a half an hour to two hours before patients feel the effects. We discuss how to minimize toxication, and what I'll do is I'll pull up a local dispensary menu close to where a patient might shop, and I'll literally pick out some products that I think are medically appropriate for them to start off with and make product recommendations. Again, these are not prescriptions, but I am recommending products that I think will be least intoxicating. The dosing guidelines that I've learned to use just through personal experience have largely focused on using oral routes of delivery and topical cannabinoids, which seem to be the most tolerated. I find that sublingual tinctures are the easiest to help patients titrate, using, again, low dosages of a combination of THC and CBD, largely starting less than five milligrams of THC unless a patient has had prior experience with higher dosages or smoking. I have patients titrate up on their dose by one or two milligrams of THC every few days, and for some of my patients, they will use that tincture experiment to find the dose that works best for them, and if possible, finding an oral capsule or pill in a dose that comes in that range. Oftentimes, the pills are only in 5, 10, 25 milligram increments, and so if a patient needs something in between, like 7 or 13 milligrams, the tinctures are a little bit easier to work with. I have patients consider using higher dosages of CBD from hemp-derived products. As Dr. Sulak mentioned, these products are not cheap, and the more CBD that's present in a product, the more expensive they are. Sometimes hemp products are a little bit cheaper and can be obtained outside of the dispensary. I largely encourage the use of broad or full-spectrum products for longer duration of effect. The capsules can be used. I do consider vaporization as needed for breakthrough pain, and sometimes it is the preferred route of delivery. Some of my patients who like to use capsules but find they take two hours to kick in will maybe take one or two inhalations from a vaporization oil while they're waiting for that capsule to kick in. In my experience, I have found topical THC to be much more effective than I was expecting. Again, there's not much data on this, but anecdotally, topical CBD does not seem to be as effective for treating joint pain and inflammation as topical THC, and then once people are comfortable using THC, I have them increase their dose at night or as needed for higher levels of pain, but overall, the goal is to minimize intoxication and to figure out how frequently patients need to use this. In some of our studies, two to three times a day was adequate for most of our patients. To wrap things up, part three, I'll talk about medical cannabis research on chronic pain and provide some clinical case presentations from my practice. So, Dr. Russo had talked about the National Academy of Science review of all cannabis literature that found that chronic pain in adults was one of the conditions that had substantial evidence that it was effective, and one of the larger studies that they looked at was this one from JAMA in 2015, which is a systematic review and meta-analysis, and they looked at 28 randomized control trials in patients with chronic pain, over 2,000 participants, and of the plant-derived cannabinoid studies, there were 22, and 13 of them used nabixamols, which is, again, an oral mucosal spray with a one-to-one ratio of about two and a half milligrams of THC and CBD, and this is similar to some of the products that are available in dispensaries across the country, and was notable at improving pain by at least 30% compared to placebo. So, this study concluded that there was at least moderate quality evidence that cannabinoids can help treat chronic pain. What we did in our practice was we looked at patients that were using medical cannabis to treat chronic low back pain, and then we looked at patients in that subset that were using opioids, and the purpose of this study was to determine whether or not having access to medical cannabis reduced opioid prescriptions for patients with chronic musculoskeletal non-cancer back pain, and our secondary outcome measures sought to determine if pain and daily function improved. The hypothesis was that medical cannabis certification for chronic back pain would improve or decrease the opioid prescriptions filled and increase quality of life measures, and the way we did this was we looked at BAS scores and the Oswestry Disability Index at zero, three, six, and nine months after medical cannabis certification, and when we identified out of the 477 patients, we found a little over 200 of them were using controlled substances by looking at the Pennsylvania Drug Monitoring Program, which essentially is an objective measure of the number of prescriptions and pills filled at pharmacies. We excluded people that had spine surgery within the last six months or who did not have a spinal diagnosis, and we found 186 patients remaining, and we did a data analysis and looked at changes in their daily morphine milligram equivalents over the six months prior to and after cannabis certification, as well as looked at their changes in pain and daily function, and if you look at column A, when you look at all comers, all dosages and morphine equivalents, there was a statistically significant reduction in opioid prescriptions filled in the six months after cannabis certification. Column B and C is just the difference between patients on low-dose opioids and higher-dose, which we determined to be 15 milligrams of morphine equivalents a day, and both groups showed statistically significant reductions in opioid prescriptions filled. However, the patients that were on lower dosages of opioids were more likely to discontinue opioids altogether, but when you look at all comers, 38 percent of our patients were able to completely stop using opioids after six months of having access to medical cannabis. It did not seem to matter which type of back pain patients had, whether it was radicular or more degenerative in nature or due to a spinal deformity like scoliosis. We also saw that within the first three months of a cannabis certification, there was a statistically significant improvement in BAS scores, back pain and leg pain intensity and frequency, and improvements in their disability index. We also found that patients that used multiple routes of delivery were more likely to completely stop using opioids after the six months, and that again is in line with some of Dr. Sulak's message that most of our cannabis patients are using some combination of tinctures and topicals and maybe vaporized products as well. So, we concluded that patients with chronic low back pain that had access to medical cannabis reduced their amount of opioid prescriptions, many of them were able to stop altogether, and that patients on lower dosages of opioids had a higher chance of stopping their opioid prescription. Pain and function also improved, and again, multiple routes of delivery may be more efficacious than a single route. So, to highlight this case, I had a real patient, a 65-year-old female with chronic neck and back pain. She had moderate multi-level cervical lumbar spondylosis and had failed conservative care, including physical therapy, a variety of pharmaceuticals, and injection therapy. Due to her lack of radicular symptoms and lack of severe stenosis on imaging, she was really deemed a non-surgical candidate, and for 10 years before coming to see me, she had been using 7.5 milligrams of hydrocodone four times a day. I certified her for access to medical cannabis. Her opioids really weren't working that great. She started using a very low dose of a sublingual tincture with 2.5 milligrams of THC and CBD. This was a tincture that had 5 milligrams per milliliter, and she started with a half of the dropper and worked her way up. She also started using topical THC lotion on her neck and back, and after a month or two, she started to titrate her dose up to 5 milligrams of THC and CBD. She started using vaporized cannabis oil at night just to help with sleep, and she started to reduce her opioid consumption. After six months, she had completely discontinued the hydrocodone that she had been taking for a decade prior. We did another study where we looked at the patients in our cannabis program that had degenerative joint disease in their hip, knee, and shoulder. Similarly, we looked at the Pennsylvania Drug Monitoring Program to assess whether or not there was a reduction in opioid prescriptions filled, and also looked at pain and daily function. Our numbers were not as large, but the process was similar. We looked at global mental and physical health as well as VAS at zero, three, and six months after cannabis certification. We threw out the spinal-related patients and people who've had surgery on their peripheral joint within six months, and we did an analysis looking at opioid consumption and changes in the pain scores. Of the 117 patients with osteoarthritis, 48 of them had been consuming opioids, eight had surgery and were removed from the pool. We were left with 40 patients. More of them had knee, then shoulder, then hip pain. We looked at their routes of administration. Again, tinctures and topicals seemed to predominate. We saw an improvement in opioid prescriptions filled post-medical cannabis certification, again, within three and then six months with improved baseline levels of pain and global mental and physical health. Again, we found that medical cannabis for osteoarthritic-related pain helped reduce the amount of opioid prescriptions filled six months after cannabis certification. Over a third of our patients no longer required opioids after using medical cannabis. Again, these patients also showed improved pain and quality of life measures. I had a patient who was 88 years old on supplemental oxygen for COPD with severe right hip osteoarthritis. He did not tolerate opioids due to a combination of dizziness and constipation. He could not take NSAIDs due to chronic kidney disease. He had an intra-articular corticosteroid injection that provided two weeks of relief. He was told that he was too sick and old to have his hip replaced. He was ambulating with a single-point cane, and he was using 1,000 milligrams of Tylenol three times a day with very minimal benefit. I certified him for access to medical cannabis. He started using sublingual tinctures and worked his way up to five milligrams of THC, tolerated it well. He switched over to a full-spectrum capsule twice a day. He added topical THC and CBD lotion to his hip as needed multiple times throughout the day. He ended up stopping acetaminophen and reported about a 50% improvement in his hip pain. He was relatively satisfied with the experience. What about intoxication? This has been talked about. You can overdose on cannabis. You can't die from it, but cannabis overdose is very uncomfortable. What I explain to people is consuming THC is very similar to consuming alcohol. The more you consume, the more intoxication and potential for impairment. But like Dr. Sulek had mentioned, one or two glasses of wine makes people sometimes feel happy, relaxed. I think that's a similar state to some of our cannabis patients are able to obtain, oftentimes with less side effects. Euphoria, happiness, relaxation, sedation, decreased anxiety. Again, I do agree that a big thing about cannabis in treating pain is how it affects our perspective on pain, what we see in our world, and what our attitudes are towards our pain and how we learn to live with it. Interestingly, when we looked at over 300 patients who were using medical cannabis, we found that a little over half of them denied any feeling of intoxication or being high. When you look at the patients who did not experience any intoxication in the lower right hand corner of the screen, you can see that 80% of them reported symptom relief. This was surprising to me, but again, I've seen it time and time again. Patients are using non-intoxicating dosages of cannabis, reporting symptom relief, and are overall happy with their medication as compared to others. When you look at the patients that did experience some intoxication, 59% of them felt that it didn't interfere with their daily activities, 26% actually enjoyed it, it made them feel better or happy, and a small percentage, 15%, did not like the effects of intoxication at all and discontinued their medicine. I had an 83-year-old male with a scooter, with a very severe chronic back situation, severe stenosis and lower extremity pain. He had a prior history of a decompression and fusion. He developed significant adjacent level stenosis. Again, he was told he was too old to have a revision surgery on his adjacent level. He had some epidural steroid injections that gave him about 50% improvement in pain for a week. His cardiologist did not recommend surgery, and he did not tolerate trials of gabapentin, pregabalin, and duloxetine. He came in with his wife. He had a scooter, a walker, and a cane attached to his scooter. And he came to me looking to try cannabis. He had read a little bit about it. He tried five milligrams of THC and CBD in a sublingual tincture. He did not find it helpful at all. He ended up getting recommended vaporized cannabis oil. He had a little disposable vape pen that he was using two to three times a day. He was using a full-spectrum product known as liquid live resin. His favorite strain was blueberry space cake, which I thought was rather funny. But he swore that this inhalation of this cannabis oil gave him energy. It kept him clear-headed, and it gave him pretty significant pain relief. And his wife attested that his mood was lifted when he used his medicine. He was using topical THC lotion as well. And again, very happy with this treatment decision. So in my experience, I feel that cannabis is better than opioids for chronic pain. There is some emerging evidence that cannabis can be used to treat acute pain. And we all know that opioids have their place in medicine with regards to treating fractures and when we wake up from anesthesia after surgery. But cannabis seems to be better tolerated with less side effects, less risk of dependence, very mild withdrawal symptoms. And again, there's no potential for overdose and death. So to wrap things up, we now know that cannabinoids work on receptors throughout our body and have a variety of therapeutic effects that can benefit pain patients. There's evidence that THC plus CBD in combination can improve chronic pain in adults. Cannabis seems to be safer and more effective than opioids for certain types of chronic orthopedic pain. And the big one for me is that when physicians are involved in the cannabis certification process, we can help patients reduce the incidence of intoxication and controlled substance use. These are some references. Thank you all for your attention. And I look forward to hearing our next speaker. Okay, thank you. Thank you for that Ari, that was great. We're running a little short on time. So I'm gonna go right into our next speaker, Dr. Mikhail Kogan, also known as Misha, is a leader in the newly established field of integrative geriatrics. He's chief editor of the first definitive textbook of the field entitled Integrative Geriatric Medicine, which is published by Oxford University Press as part of the Andrew Weil Integrative Medicine Library Series. He's one of the few people I know who is quadruple boarded in internal medicine, geriatrics, palliative medicine, and integrative medicine. He serves as the medical director of the GW Center for Integrative Medicine, associate professor of medicine in the Division of Geriatric and Palliative Care and associate director of Geriatrics Integrative Medicine Fellowship Programs. He's also the founder and executive director of AIM Health Institute, which is a 501C3 nonprofit organization in Washington, DC in the metropolitan area that provides integrative medicine services to low income and terminally ill patients, regardless of their ability to pay. He is a frequent speaker at international conferences on the topics of integrative medicine, geriatrics, healthy aging, as well as medical cannabis. While Dr. Kogan's main medical cannabis expertise is in treating older patients and palliating symptoms at the end of life, he also treats a wide range of internal medicine problems from chronic GI problems to cancers where use of medical cannabis can be beneficial. In October of last year, he, in collaboration with Dr. Joan Liebman-Smith and Penguin Random Publishing, published Medical Marijuana, an Evidence-Based Guide to the Health Benefits of Cannabis and CBD. Dr. Kogan will be discussing medical cannabis for older adults. Misha. Thanks, Mitch. But I wanna start with thanking you for not just inviting me and me being part of this esteemed group of speakers, but also timing this perfectly. So Ari, I don't know if you knew, but you guys operated on my dad four years ago and actually in that local office in Northeast Philly. That's where my parents live. My dad is now 85. He's one of the older running Philadelphia marathoners and he's been running it for about 27 years now. And right before the surgery, he took the first place at the age of 80. Well, there was only three of them, so he was first. So yeah, you guys put him together. I didn't know you guys were doing all this new work on cannabis. That's wonderful. And I did, this is back just before Pennsylvania approved cannabis. So we've treated him at home with some CBD and THC obtained by me, not through a very legal Pennsylvania route. And he did really well and he still runs not full marathon. He's now 85, but he still runs half a marathon and we will run again Philly race, although in the park rather, he's now afraid of COVID in a room. So thanks a lot for that. Great connectivity. I know, I was just like, we're walking back in some way. Yeah, and I also was listening to your talk and found it so inspirational because there's just not a lot of people I find in my area in orthopedics who are this knowledgeable and this supportive. So thank you so much. Okay, I'm gonna share my screen and see what happens here. So I started cannabis work in 2012, around the time DC has approved it. For me, it was really more, it's just kind of a natural flow into things because a lot of the patients started asking. Our clinic sees about between five to 6,000 patients a year. So it was pretty natural for us, for patients to start asking. And I kind of ended up saying, look, I got to learn this back then. There was not a whole lot of formal trainings like Dustin's formal training came somewhere around that time. So I had to learn a lot of things on the fly. And at this point we have about 15 faculty at university who are certifying patients. And we now have pretty much every division and every department having at least one provider interested in the topic and offering recommendations. And also in the same kind of a loop, I think the DC has moved to recreational, although the dispensation hasn't started. And all the areas around where I practice, DC and Maryland, they're all have a medical part. So a couple of disclosures, I do collect royalties from all those books listed. I also co-own and operate private practice where we use cannabis and as well as we have coaches, kind of coaches. And then I have multiple different consultant services. I'm not going to list them here, but I do collect no direct revenue from any of them, all the profit, all the income goes straight to the 501c3. So we're going to review some of the basic endocannabinoid system with aging. And then I'm going to talk about three targeted conditions. I'm going to kind of talk a little bit more about chronic pain, although I feel like I covered so much already, but I'm also going to talk about insomnia and some of the symptoms around the progressive Alzheimer's disease, what we often define as neuropsychiatric symptoms, which are often really difficult to treat. So cannabis is actually the fastest growing area in geriatrics in terms of the new areas of where the older adults obtaining treatment. So it's in percent wise, it may look pretty small, still at around 3%, but it's actually one of the fastest growing. And it seems like there was a belief about 10 years ago that the cannabis is going to cause potentially a lot of harm and side effects in older adults. And I've 10 years ago, or even five years ago, I would still get a lot of calls from experts, from specialists saying, what are you doing? You're putting my older adult on cannabis and is this safe? And now really more or less, I don't get those calls anymore, which is a good sign. So I think there's a more understanding of safety. So let's review a couple of basics of what actually happens with aging. I'm not going to cover what Ethan already covered. So it's a couple of critical things. So first of all, the tone that Ethan mentioned clearly decreasing with aging, it's corresponding with decrease in density of receptors. There's at least 50% drop by the age of 50, age of 65. And similarly, concentration of anandamide, which is one of the most prevalent endogenous cannabinoids is decreasing gradually with age. If you remove the CB1 receptor in mice, you develop a classic pathology of hypochemical volume loss, which is seen in Alzheimer's disease. It's interesting that it's a very tissue-specific aspect. And in my opinion, it's probably one of the most research-wise important things to pay attention in terms of the cannabinoids for Alzheimer's disease. And if you take the CB2 receptor, you basically end up with a osteoporosis-like picture. It appears that cannabinoids regulate autophagy, which is critical, kind of what often described as the endogenous cleaning process. We have to remove cells and the debris of cells that are no longer serving us. And if we fail to do so, we seemingly have an increase in organ dysfunction, and that strongly contributes to faster aging. And synaptic disruption is also one of the key theories of aging. I'm not going to go into details on that, but that's also a really critical aspect where exogenous and, of course, endogenous cannabinoids seemingly playing a critical role. Of course, inflammation is a big one. There's a whole term called inflamaging or aging related to the increase in inflammation. And again, cannabinoids definitely have a role there. And then if you inhibit degradation of amandamide, which actually is one of the ways in animal models to mimic treatment of Alzheimer's disease, you're basically decreasing loss of hypochemical volume. So there is a clear signals that the pathways can be modified. And then what do we know? A little bit of what we know about the aging of endocannabinoid system when you implement changes. There are seemingly, at least for now, clinically relevant shifts, although, of course, none of this has so far been tested in humans, and I hope it will be soon. So let's shift right away to clinical part. So this is similar to what Ari was talking about, taking in older adults and surveying them. So this is a bit older data now from Israel. Israel, of course, many of you may know, has approved cannabis long time ago for the medical cannabis for the entire country. Their product choices are very limited compared to what we have in US, but nonetheless, they have a history and they also have a capacity to do very large studies since the number of patients and the way we can reach them is larger and more standardized and also historically more stable. So this is the sizable cohort of nearly 3,000 patients, all of which were above 65. They were obtaining cannabis primarily for pain, as you can see, more than about two-thirds of them. And six months after treatment, nearly universally, so over 90% of respondents reported improvement, and improvement was on average eight points. So this is quite significant compared to a median of four with a, sorry, the reduction was from median of eight when they started to the four, so it's a 50% reduction. Now, this was not a control, so this is just an observational cohort. And so next we're gonna talk about side effects. So this is probably the largest cohort data we have to look into a total number of side effects we're observing in older adults. So they're very frequent. You're looking at about, on average, close to 10%, but look at the list. So none of them are quite severe. The delirium, which is what there's really fear of, is actually not truly happening. It's not been observed. You have some confusion and disorientation with higher doses in the morning or during the nighttime awakening, but it's really critical to notice that none of this leads to increase in falls, weight loss, or fractures. And more importantly, none of this leads to worsened sleep or worsened cognition. So this is some of the critical fears that in geriatric population we're always looking out for. And if I were to compare this to any other treatment modalities for pain that I can offer patients, especially for, as Ari discussed, the list of side effects and concerns is quite long. But also what's really interesting is that it similarly applies to benzodiazepines. We don't have a direct data yet on decrease in benzodiazepines, but we do have the Medicare data collected from Part D population, showing that in the states where you allow for cannabis lows to be implemented, if they have active dispenser, you have over three million fewer daily doses of opioids filled. And this is the data from 2014, 2015. There's a belief that this is actually right now even higher than that. And if you just do home cultivation, you have less, but it's still quite significant. So just pause for a second and think about the mass effect here. I mean, we're talking about millions of a daily taken decrease of opioids. And of course, it does translate to significant decrease in mortality. The previous data, this was published in 2018 in JAMA. A few years prior to that, we had a data coming from a Montefiore group showing that you have up to 30% decrease in opioid-related mortality in states that have implemented medical cannabis laws. So it's clearly working, otherwise we wouldn't be seeing this size of the signal. We are waiting for similar data to be analyzed for the benzodiazepines, and I expect even larger impact because what I see in clinical practice suggested that a lot more patients getting off of benzodiazepines for sleep especially, and so primarily not just benzodiazepines and the specific hypnotic agents for sleep. And that seems to be a much larger dose impact and just generally larger impact. So let's talk about three conditions, pain, insomnia, and agitation. So I'm gonna fly through pain a little faster since I already covered a lot of it, but I'll show you sort of how I see use of cannabis, and I'll show you some more complex cases that are more acute. So of course, in geriatrics, we generally prefer not to use medications if also positive possible, but there's a lot of restrictions. Seniors are often on budget limits. So integrative modalities that work reasonably well, such as acupuncture, massage, chiropractic, osteopathy, et cetera, are often simply not available. And even though acupuncture is covered by Medicare now, and most of the states have now set up the payment infrastructure, but just to give you a sense of reality here, Medicare pays up to $42 per acupuncture visit in contrast to the market rate in district right now, it's 120 to $150 per visit. And that's a top pay, their average is about $25. We don't have any acupuncturists in DC area that willing to take $25 for an hour with a patient. It seems a bit of underpayment. What's really critical is, again, Ari, I think mentioned that lower doses of medical cannabis, we're talking about sometimes even one to two to three milligrams can be quite effective. Specifically, I'm talking about THC equivalents here, and it makes it a lot cheaper than buying CBD either from dispensary or CBD containing products from hemp based producers. And also, it's not just the cost issue, you also get with the lower doses, a lot less side effects. And generally, when we're talking about the chronic pain, we are expecting most of our older adults being on a polypharmacy just for pain alone. I'm not even talking about the fact that 50% of 65 plus population as of now in the United States takes more than five medications, so that's an average. And in my practice, typically I see 10 to 20 medications on average with every single geriatric patient. Yes, our practice in university is skewed towards even older group of patients, somewhere around the age of 80 to 85. But nonetheless, that burden of total number of pills is ridiculous. And I think the goal is always to prescribe. Interestingly, to prescribe, you have to give patients something effective, right? So you can't just stop the medications that they're taking for pain and say, okay, well, now what? And that's when the cannabis comes in. So here's a case of peripheral neuropathy. This case has been presented, you can identify it and find it in different sources. So it's an older woman who was admitted to the hospital. She was first said that she will not survive this because of the severe delirium. She was intubated and there was an quote-unquote undiagnosed cause of delirium, no known etiology. So I had a wonderful geriatric fellow in service who within about four to five hours figured out that the patient had an increase of gabapentin dose a couple of days prior to admission. So this was a case of undiagnosed and missed gabapentin toxicity. 24 hours after admission, the patient still had a very elevated level of gabapentin. And so she was quickly tapered off and actually not just survived but returned completely to her baseline. And patient is still seeing me almost a decade later in the clinic. So she has been discharged, but the question is now what do you do here? Patient is back in pain, obviously you don't want to give her gabapentin or she will not accept it even if you try. So, you know, the typical regimen in my practice would be something like this where there would be a couple of evidence-based supplements, weekly acupuncture if they can afford it or have insurance to cover it. And then starting with a low dose, one-to-one FECO, full extra cannabis oil, sublingual usually that's also where I start and titrate it up slowly. And so this is kind of a standard geriatric mantra by the way, which is start low, go slow with every drug. It applies even more so for cannabis I feel like. And I tend to like using variety of acidic forms and a very highly mixed products. DC has been at this for quite some time. So they have good choices of products, not just a flower, but also a lot of sublingual products, topical and oral. I do like to use suppositories a lot, especially in population that is cognitively unaware. So advanced Alzheimer's patients or patients who are near end of life, suppositories seem to treat well a pain that's in the pelvis or lower back pain. It doesn't really cause a lot of toxicity per se, even at the doses of 50 milligrams of THC, we don't really see a lot of alteration, although sometimes it can happen. The only problem with suppositories is their ridiculous cost. So I have a protocol which teaches patients how to make it at home. And usually you would need to have a pretty willing family member to do it, one of the kids, because the process is pretty involved. So I wanna say a word about CBD. I find it highly important in older adults. Basically I use it instead of NSAIDs and I use it very aggressively. Usually start with just five to 10 milligrams twice a day and then rapidly go up. I do see a lot of pretty severe inflammatory conditions like rheumatoid arthritis respond very well, even have cases of people not needing any rheumatologic medications to disease modifying modifications at all. So it's definitely out there. I don't think there's a lot of data. We definitely need a data on dosing and also on how to combine the CBD with other products, with other cannabinoids. It seems to be, since it's much more bioavailable, you don't really have to apply it sublingually. Patients can swallow it, which makes it a bit more palatable for many patients. So let's move to insomnia, a very common condition. Problem with insomnia, not that itself, it's directly causing necessarily a whole lot of issues. Although if somebody is really poorly sleeping, they can get up in the middle of the night and miss the step and fall, that's a problem. But it's linked to a lot of other problems and it is linked to increase in overall mortality. There's a very, very big need for better treatment of chronic insomnia and not just for older adults, for all of the adults. And the standard treatments, which are non-pharmacologic considered to be CBT, really it's just simply not available. There are not enough CBT trained specialists who specialize in insomnia. And we've done a number of trials that are practiced in the university to compare CBT-I to mind-body groups, which we've been doing for more than 10 years. And this seems to work, but again, this is often not available. It's not often covered by insurances. It's a complex process. You have to really have patients be willing to participate in the group and come to classes every week. And it's really not appropriate for some patients also. Somebody with cognitive impairment won't be able to engage in this. So what do we do? Well, I mean, we typically put older adults on hypnotic agents, drugs like Ambien. And unfortunately, those all increase mortality. They're all on Beers List criteria. Beers List is a list of geriatric no-nos, which is very long and actually has most of the common drugs that we use every day. Even NSAIDs are in that. Some of them are in the Beers List criteria and all of the opioids are too. So here's a case of the patient who was basically walked into office with suitcases of different records from most esteemed institutions, including Mayo Clinic, and none of the institutions have been able to help his sleep. He's been poorly sleeping for decades, and just with a touch of THC and with a slow titration, he's gotten a whole lot better. He has tried other cannabinoids before, edibles and smoking, and found them too intoxicating, so he wasn't doing it when he came in, but we taught him how to do it slowly and strategically. And so he did really well. By the way, on admission to the clinic, this is the list of his medication, high-dose trazodone, Seroquel, and lithium. And so he'd gotten up to about six milligrams, and now he's still, I think, on about eight milligrams of THC equivalent at bedtime, and he still sleeps completely normal seven to eight hours a night, and now it's been about six years that he's been doing this quite successfully with just managing his bipolar disease with low-dose quetiapine and lithium. So let's switch to the Alzheimer's, which is the last topic. So unfortunately, these neuropsychiatric symptoms of Alzheimer's are nearly a hallmark. Pretty much 100% of patients will get them. As Ethan mentioned, in 2017, a report by National Academies of Sciences, the report basically said there's no conclusive data that cannabis is effective for neuropsychiatric symptoms of Alzheimer's, but since we've had more data come out, that's strongly suggestive that actually it is effective. It is on the list of approved use in Canada, and it's seemingly a tool that is rapidly increasing in utilization because of the upcoming data that we have. The big concern with management of neuropsychiatric symptoms is that there is really no good approach. So the non-pharmacological treatments such as pet therapy, music, melatonin, and others are almost always just partially effective. They're never fully effective. They're also not easy to implement in a structured setting. Pet therapy often is not possible to do in a nursing home for infectious disease reasons. So often, it all falls down to the use of antipsychotics. Seroquel mentioned in the case before is a very common medication in cases like this. Unfortunately, they're all not just in the Beardsley's criteria, but they regressively monitored, and so if a patient is in an institutional setting like a nursing home, the office of Medicare and Medicaid monitors all of the nursing homes to make sure that the use is minimized. Unfortunately, of course, everybody knows that that's still the primary source of treatments for this condition. So the theory behind using cannabinoids here is quite clear. Again, clinical trials in terms of randomizations are lacking. We basically have just more total data showing that in non-controlled format, it seems to work. But fatty acid aminohydrolase, which goes…increases associated with cannabis withdrawal-like effects, so agitation and insomnia, so you're basically increasing degradation, and so if you somehow substitute for that, you potentially have a clear theoretical base on how to use it. This is the data seen in what happens with patients with Alzheimer's. You can see that both inflammatory markers like COX-2 go up, and also if age goes up with age. And so, by the way, the COX-2 increase has been targeted, so there's some of these molecules have already been targeted by medications, but we also should be thinking, well, is it possible that molecules like CBDA, for example, which is the COX-2 suppressor, can in the long run be something that can be used not just for symptom management, like in this case, but also for just the pathology of Alzheimer's itself. So this is a case of a patient of mine. It's actually a mother of one of our practitioners who was in a group home at age of 93, and she was in her last years, and she started to have this really severe nighttime agitation. They were threatening to discharge her because she was interfering with the sleep of other residents in there. So this was the protocol, so this patient, by the way, will not be able to comply with inhaled route or sublingual route. She's not really following directions very well at this point, but she still eats pretty reasonably well, so we gave her some yogurt popsicles that some made at home with CBD, and also we obtained the one-to-one THC-CBD product and then mixed it into the brownie, and so this was her nighttime brownie, which luckily for us, after we've had this prolonged conversation with the group home director, that they agreed to do this, and this is, by the way, was in Virginia and even before the Virginia legalized it. So, you know, with a careful negotiation, you can make this happen, although of course there's a very significant institutional challenges. This was a small group home. I think that's why we were successful, but if you're looking at the larger facility, their overarching structure may simply completely prohibit anything like this, and even in the states that have approved cannabis, some nursing homes will not allow because they're obtaining funding from, or their Medicare funding comes from the Medicaid, comes from the government, and so they're viewing this topic as something they shouldn't get involved with, although American Medical Directors Association, so it's a nursing home director association, put a very strong statement maybe four or five years ago stating that, yes, the nursing homes in the states where cannabis is legalized should offer it. So think of when you're using it for the symptoms. Think of mixing CBD and THC different times. Always think of edibles because patients probably will not be able to comply well with keeping things sublingual, and of course inhaled route usually is completely prohibited for any institutional settings, and then you have to make it tasty, so they need to like to take whatever the food that carries the molecules. So some of the takeaways for today for what I just mentioned. So we have tools to avoid over-medication of our older adults. Cannabis fits very, very well there, and with the standard geriatric mantra, one part of that mantra is deliver where it needs to go, so topical or rectal, for example, when it's more appropriate. So with that, if you're interested, there's a longer version of this talk for a full hour on the CannabisClinicians.org, and hand it back to Mitch. Stuart, I apologize for jumping over the top of you there. You're having some AV issues. I'll do a self-introduction. My name is Mike Salino. I am chair of physical medicine and rehabilitation at Cooper University Healthcare in Camden, New Jersey and South Jersey. As well as a professional colleague with Dr. Grace at Sidney Kimmel of the Jefferson Medical College, and my topic for the next little bit, joining this very terrific group of speakers, is to discuss medical legal concerns regarding medical cannabis use. So these are my disclosures. My other area of interest is neuromodulation, and many of these disclosures are relative to that the only relevant disclosure is I am a certifying physician for medical marijuana in both Pennsylvania and New Jersey. Objectives for the next little bit is to discuss the medical legal environment surrounding a medical cannabis practice, as well as to review policy creation and development if you're interested in adding medical cannabis into your practice. First, as a disclaimer, I am not an attorney, and nothing that I say over the next couple of minutes should be construed as legal advice. Everything that I'm going to present is gathered from reputable sources, and I would put that as a caveat out there that there are a lot of unreputable sources out there, as well as my experience in setting up medical cannabis policies at a number of different institutions. So as Dr. Grace mentioned, the Controlled Substance Act of 1970 put medical marijuana in Schedule I, which means that it was classified as having no safe medical use or providing a tremendous degree of harm, and as recognized by a number of speakers now, there is no physician or no typical physician in the United States who can prescribe, to the definition of prescription, medical marijuana. We are used to prescribing therapies and medications all the time, in which the specificity of the prescription allows for content, amount, dosing, et cetera. That is not the case in medical marijuana, as we'll see as we go through. And again, this overlaps a little bit with Dr. Grace's comments. Medical marijuana is becoming increasingly common in the United States. 55 million Americans currently report marijuana use. 78 million Americans, or almost a quarter of Americans, reported using marijuana at least once. And the most recent compilation of registrants in the United States is about three and a half million, or 1% of the population now has a, or at least at one point has obtained a medical marijuana card. From a little bit of historical perspective, and this will become important as we move along, the first state who approved medical marijuana was California. Now, over 25 years ago, it has the most experience. The most recent passage was Mississippi and Alabama in 2022. As Dr. Grace mentioned, both North Carolina and Kansas are expected to join the majority of states in this undertaking. Right now, 39 states and four of the five US territories have legalized at least some form of medical marijuana, although some do limit the THC content. This does not include states that have legalized CBB-only products, so I excluded that from the analysis. As Dr. Grace mentioned, this is the current medical marijuana map. The green represents states that have only medical marijuana laws on the books right now. The orange are those who have both recreational and medical, and the light gray are those states that have none. I think in the effort of keeping everyone informed, there was a proposal that was put forth to reschedule marijuana to level three. This was initially proposed in 2019 by Representative Gregory Stube, a California, I'm sorry, a Florida Republican. If a bill doesn't have any movement at the end of the congressional term, it quote, dies. Representative Stube reintroduced this last year. It was assigned to two House committees, both Commerce and Judiciary. Why that's important is the more committees that an individual bill is assigned to, the more regulatory hurdles that have to occur and decreases the likelihood of passage. These two House committees then moved on to two subcommittees, one Health and the other Crime, Terrorism, Homeland Security. Since the reinitiation of 2019, there have been no hearings, discussions, or recommendations by these subcommittees and no votes undertaken by any of the committees, the House as a whole, or the Senate as a whole. I am not a political scientist and would never put myself out to be, but in looking at various political science websites that actually look at and try to predict passage of individual bills, either House or Senate, they put the passage likelihood of this act at about 4%. I think for the immediate future, it would suspect that marijuana will stay as a schedule one drug. As you might have imagined from our previous speakers, there are a number of layers of administration that overlap medical cannabis use. As mentioned, it is illegal and under federal law. Thus, entities that receive federal funding can be very wary of any interface with medical marijuana. Financial institutions might be concerned over seizure of assets. Early on, you could not finance any kind of medical marijuana business or proposition with a U.S. financial institution. Folks went offshore for loans, etc. Healthcare institutions, I'm sorry for that typo, can be concerned about Medicare funding. Potentially, this could be a reason to remove Medicare funding because you are violating federal law. Also noted, there is no federal trademark protection for any marijuana product. Dr. Grace's patient who uses Blueberry Space Cake in Pennsylvania, if they move to Florida and go to a dispensary in Florida and ask for Blueberry Space Cake, it could be an entirely different product. You can have some state trademark registration protection, but it is not enforceable at a federal level. The aggressiveness of prosecution is very much dependent on who the current Attorney General or President is. I'll demonstrate that over the next few slides. James Cole, who was the Attorney General under President Obama, issued a memorandum. This was a pretty historic moment and began an exponential increase in medical marijuana applications in a number of states. Cole advised the Justice Department not to enforce federal marijuana prohibition as long as a group was operating lawfully within a U.S. state or territory, basically saying that as long as a particular entity was operating lawfully within a state, the federal government would not expend resources towards any kind of prosecution. The Cole memorandum was rescinded by Jeff Sessions, who was Attorney General under President Trump. His direct quote is, we will enforce the law as written. However, Attorney General Sessions stopped short of explicitly directing prosecution. He was silent on that issue. He did not direct the Justice Department to specifically go after any particular entity or state. This leads to the current Attorney General Merrick Garland, who had this statement actually yesterday. That's about as current as you can get, which basically says that as long as, similar to the Cole memorandum, as long as an individual, an entity is operating lawfully within a state or territory, they would not use prosecutorial resources to go after that entity because their concerns were more with more violent crimes and other crimes that issue society in general and in gender communities. It actually promised further clarification and direction to the Justice Department this week. You could see that literally who the Attorney General is, and even more indirectly, who the President is, does have an influence on federal approaches towards medical cannabis use. Again, as mentioned, it was Prop 215 in 1996 that really opened the door for compassionate use. There's been a slow but consistent progress over the last two and a half decades, as shown by that map. Adult recreational use is also increasing across the states, but lags medical use by about a decade. You can see this if you put a timeline of states with medical versus recreational. You can see there's usually about a decade lag. Some states have integrated their recreational and medical use. Others have it as separate pathways. Others have it as an integrated pathway. Again, you'll hear this. If there was one take-home message from my talk, it's please stay informed as to what your state is doing because literally, it can change almost on a daily basis and often somewhat subtly without folks even knowing it. At the state level, there are really four layers of administration. Those entities that actually produce the product commercially, growers, cultivators, or processors, sometimes that is integrated as one group, sometimes there are individual groups, dispensaries, which are the entities that are allowed to dispense marijuana products, us, the providers, and then finally, the patients. I'll go through each one of these layers in some detail. First, the grower, cultivator, processors, because it is illegal under federal law, all medical cannabis products must be grown and processed in the state in which it's going to be administered. This sometimes leads to shortages, especially when a state opens up a new indication such as adult recreational use. The cannabis plants itself work in hot, humid conditions. Those of us who practice in areas that are not hot or not humid, that often means that dedicated greenhouses must be utilized for growing and production. Additionally, product cannot be shipped across state lines, even between two states that have very similar cannabis regulations. A much, much smaller minority of states do allow for personal production. Again, as mentioned, even under personal production, hot and humid conditions are necessary. Most states for commercial products have some degree of regulatory standards, although it was mentioned earlier in others' talks, the process for regulating and knowing content of THC and CBD in individual products has been called into question in many, many circumstances. The batch-to-batch consistency has also been called into question. Contamination has actually been reported both by personal and commercial growers, and this includes things that antimicrobials, funguses have been reported to make it into commercial products that even have survived inhalation use. There is also concern about teratogenic compounds entering into the supply chain as well as other issues. Tinctures and topicals are the most arduous to produce, so going from the plant and the dry products to actually create them into a tincture product or topical products are the most difficult to produce by the growers and processors, and that's what increases the costs. Some jurisdictions actually limit the THC content that can be produced in the various products tinctures or topicals are inhaled. Each state has the ability to set their own regulations. As mentioned, some states allow for trademark registrations of the marijuana products, which might provide some protection from local competitors but would not provide protection across state lines. Moving on to dispensaries. Dispensaries are locations that are allowed to dispense marijuana products. Just as a side note, for those of you who may not have these in your area, these are aesthetically pleasing places. It's not like going up some dark back alley that seems unsavory in any way. Most of my medical marijuana patients describe it like going into a spa. To add an even another layer of regulations, even though a medical marijuana may be allowable at a state level, individual local jurisdictions can restrict dispensaries in their jurisdiction, the not in my backyard effect. This is very prevalent in New Jersey that towns, townships, and local municipalities have actually restricted marijuana dispensaries in their locality. As mentioned, some dispensaries are medical only, some are recreational, some are combined. In New Jersey, one of the states that I'm licensed to practice, right now only medical dispensaries exist, even though recreational use is allowed. If you are certified as a recreational user, you have to go to the medical dispensary. Where this comes into play is by regulation, most of those states that have combined medical and recreational use, the medical patients have priority. In fact, some products might be restricted from recreational use and only allowed by medical use. Even if you reside in a recreational state, there is significant benefit in your patient obtaining the medical qualification for use. Usually, in the vast majority of states, only a cardholder or a designated caregiver is actually allowed to enter the site. There is usually a significant security presence at these dispensaries. You cannot even get in the door unless you are a caregiver or cardholder. Most states require that they have a pharmacist on site to answer questions that a patient cardholder might have about marijuana products. Having said that, many states have no standards, and at best, you could say the standards are variable for pharmacist expertise. Literally, someone who graduated from a pharmacy school yesterday could be hired by a dispensary to give out advice. Usually, dispensaries are not allowed to advertise products and costs external. What do I mean by that? Meaning that they can't put a billboard up or a sign on the front of their building advertising what products they have or cost for those individual products. Many dispensaries are allowed to distribute product lists and costs associated to individuals who have visited the dispensary through, say, an internal mailer or an internal list server on their internal website, but not on an external website. The status of discounts is also variable across states. In Pennsylvania, as well as in New Jersey, there's two states that I'm certified in, dispensaries are allowed to provide discounts for, say, disabled individuals, veterans, etc. They could even be a frequent flyer discount in certain situations. Moving on to us providers, states regulate who can certify patients. Physicians licensed in that state are almost universally accepted. Physicians not licensed in that state are typically excluded from certifying patients, although some states are allowing physicians licensed in neighboring states to become certifying providers, but that's the exception rather than the rule. Some states restrict providers to only the conditions that the physician already treats. This is good for us as physiatrists because pain, spasticity, movement disorders, neurologic conditions, orthopedic conditions are very common in our practice, and those are some of the most common qualifying conditions. But for example, some states might restrict us from not certifying an individual with, say, glaucoma or Crohn's disease, etc. The certifying and maintenance standards are quite variable, as mentioned by Dr. Grice in Pennsylvania. You do need to do a CME course with one of the accrediting bodies, medical colleges in Pennsylvania. The maintenance certification is relatively minimal. Other states, you just need to show some educational understanding of medical cannabis products. In some states, some other professionals might also be considered certifying providers, such as chiropractors, podiatrists, psychologists, advanced practice providers. Again, the qualifying standards are up to each state. Very important, if you're thinking in setting up a medical cannabis practice, definitely look at your state's website to see if advertising is allowed. In Pennsylvania, individual practitioners cannot directly advertise that they are a medical cannabis certifying physician. In fact, the State Board of Medicine has issued some citations to providers that they have advertised this service. What is interesting is third parties are allowed to advertise. For example, if you go on a place like marijuanadoctors.com and you search for Dr. Grice or myself, you'll probably find this. But Dr. Grice or myself cannot directly advertise that we provide this service in Pennsylvania. Some states require providers to do a concomitant PDMP check along with certification. You have to make sure that you are registered with your state's PDMP website and that you are qualified to prescribe controlled substances in your state so that you can access this database. Some states require a pre-existing doctor-patient relationship. Some states specifically define what that is. For example, in New Jersey for new patients, you have to have four visits before you can certify a patient for medical cannabis. Sometimes it's not very specific whether it is with that doctor as an individual or that doctor's group. But again, it's important to read the state's websites very clearly. Prior to COVID, almost always a live appointment was needed. Obviously, we all recognize that during COVID, telemedicine became a quite ubiquitous situation. Some states have returned to the requirement to live appointments. Others have allowed telemedicine to continue. Some locations will allow providers to restrict quantity and allow providers the number of patients that they are allowed to certify. For example, in New Jersey, the maximum quantity that I can certify a patient for is three ounces. For those of you who have been on this course for the last two hours or so, recognizing that that doesn't make a whole lot of sense. Two ounces of one product or three ounces of one product would certainly not equal three ounces of another product. Certainly, it's appropriate to check with your malpractice provider. In the number of times that I've queried the malpractice providers in the institution that I've worked with, it should not change your malpractice coverage because you're actually not prescribing it. But in my most recent malpractice questionnaire by our providers, interestingly, they did have a check-off box and say, do you provide for medical cannabis certification or not? I'm not exactly sure what the purpose of that is, but it's certainly appropriate to at least check with your malpractice provider. Most physician providers are specifically prohibited from having a direct financial interest in any production or dispensary entity within their individual states. Obviously, you could do things like this with more global education or out of the country, but not directly involved in your state's production or dispense of product. On the patient side, patients register directly usually through the state website with very exacting name requirements. Don't use your nickname. If there's a junior on your driver's license, that has to be included. You also need to demonstrate active state residency in many situations, such as a utility or tax bill within the last year. Caregivers similarly need to register with the state website. Oftentimes, the background check is deeper than for patients itself. Sometimes caregivers need to actually be fingerprinted in order to receive a caregiver card. In non-recreational states that only allow for medical, again, only patients and caregivers can enter the dispensaries. Patients also need to tell their physicians, even those physicians outside of their certifying physician, that they're on medical marijuana due to concerns of interactions with other medicines. Certainly, I would put a big proviso out there to my colleagues. If you're going to certify an individual who is on Warfarin for anticoagulation purposes, make sure that the person prescribing the Warfarin knows about it, because there has definitely been drug-drug interactions seen with Warfarin with some very untold results. As mentioned previously and also earlier in this talk, because it's federally illegal, the costs associated with medical marijuana procurement by patients is not covered by any commercial or governmental insurance. That includes registration with the state, cost of product certification with providers, recertification, etc. Be very, very cautious with workman's compensation patients. Some workman's compensation patients are a bit liberal, others are very restrictive. Oftentimes, patients on workman's compensation are asked to have independent medical examinations by other providers, and we'll drug test those individuals, and that can, again, result in unsavory results. Some health savings accounts are allowing use, and I think this is going to increase a little bit. After all, it is your own money that you're putting in the health savings account. Again, because of the concerns of seizure of assets by financial institutions, early on, this was almost exclusively a cash-only proposition. Increasingly, dispensaries and providers are allowing for other forms of payments such as credit cards. I almost always advise patients or family members to seek a qualifying condition who would treat their condition regardless. I think it's mentioned by my colleagues that medical cannabis should be a component of the treatment plan, not the totality of it. Because it's not prescribed, we have no way of advising patients on how to use this unless they keep a journal of their use and the effects of their use, both positive and negatives. I would also stress that to patients and to us as providers, that if a patient is seeking, it does have a cannabis adverse effect, that they can seek emergency care without fear of retribution or activity by law enforcement. I had one individual who I'm treating with medical cannabis who certainly has some cardiac risk factors, obesity, and hypertension. Specifically, who got a claustrophobic effect from a particular medical cannabis product and began to develop some chest pain. She was reluctant to go to an emergency department because of concerns over law enforcement. That is not the case. You are actually covered and are relieved from prosecution with medical cannabis use. Certainly don't have patients discontinue other medications unless directed by a physician. Important for patients to recognize that there is no ADA school or workplace protection for medical marijuana use in general. Some states are moving towards specific prohibition of testing for marijuana during pre-employment physicals. At last note, there were 11 states that had some discriminatory language on this, including Nevada and New York are probably the two biggest ones, that you cannot test for marijuana during a pre-employment physical. You cannot test for it routinely, randomly, unless you're in a certain profession like law enforcement or school bus driver, etc. As mentioned, be very wary of interstate travel. Because even though one state might have very similar regulations, patients will be legal in one state and one state only. Gun ownership is a very hot topic for a number of reasons, but medical cannabis and gun ownership has a particularly interesting interaction. When you purchase a handgun at a store, not at a gun show, you have to fill out a federal form. One of the questions on that federal form is, have you ever committed a federal crime? Well, technically, utilizing cannabis is a federal crime. If you check yes, you have committed a federal crime, you might be restricted from your gun ownership. If you say no, you've now lied on a federal form, which is also a federal offense. I certainly ask patients now about gun ownership, if they're interested in medical cannabis, and at least make them aware of this particular concerns. Sports leagues, especially the professional and collegiate ranks, often have specific prohibition on use, even if it is legal in a particular state or locality that the league occurs in. Leagues can often supersede the workplace protection because the collective bargaining agreements are a part of that. Hopefully, that will begin to soften as time passes. Recognize that certain special licenses, such as commercial driver's license in aircraft, air pilots, helicopter pilots, have the potential for random drug testing. I always ask patients interested in medical cannabis, do you hold a CDL? Do you have a pilot's license? Talk about that with them. I will say that there's at least a handful of patients that have been interested in medical cannabis who also can commonly hold a CDL and don't want to risk that, because of that restriction. A little bit about drug testing as it interfaces with the medical legal world. The vast majority of urine drug tests look for THC, although some are now testing for CBD also. Some places or some testing sites will actually look at THCV. The reason for that is conceivably someone on an FDA-approved product like Sessoment or Dronabinol will have THC in it, but will not have THCV, which would at least suggest recreational, but the potential for recreational use. Important to recognize what you're actually testing. The typical cutoff is 50 nanograms for ML. A very common question that patients will ask, if I have to undergo urine drug testing, how long do I need to be off marijuana for before I would test positive? Because marijuana products are so lipophilic, they can hide in fat stores and for chronic users can last for an awful long time. Typically, a single exposure can be positive for up to three days, a moderate four days, heavy use positive up to 10 days, and chronic heavy use up to 30 days. Passive exposure usually results in less than 10 nanograms for ML, and is not a valid explanation for a positive drug test. Patients can say, I was at a party and someone was smoking and I didn't use it, but it just got in my system through secondary means that should not result in a positive urine test. Blood and plasma levels. Smoking leads to a pretty quick increase in plasma levels within minutes, and usually drops to less than five nanograms per ML within three hours. Oral preps have a lower peak, but a longer duration. Washington State has a very strict blood THC level being defined as driving under the impairment. That's five nanograms per ML and potentially begins to flirt with the possibility of being positive under passive exposure. The majority of other states define driving under the influence based on behavior, meaning that if you are driving erratically under any condition and THC is found in your system, then you're driving under the influence. I would recommend folks read an article that was published last year in Lancet, that did a pretty good analysis of driving performance under laboratory conditions with THC. For the most part, most experienced drivers will return to baseline levels of driving performance about four hours after a single marijuana administration. That's a pretty safe number that you could work with patients on in terms of driving. Salivary analysis is becoming increasing popular, especially for point-of-care testing. It's a pretty good approximation to plasma levels, except if done right after an oral or buccal administration, they are relatively inexpensive. It should definitely be followed up with quantitative testing if positive, and that usually takes about 24-48 hours. There have been some issues with false positives reported. The industry is working to refine that process. Breath analysis is not commercially available yet, but definitely on the horizon. My colleagues at the Cooper Center for Integration is actually working on breath test technology that seems to have good sensitivity, specificity, and reliability. It will be somewhat interesting, and the next level of analysis for us will be to look to see the relationship to levels on breath analysis to impairment as well as timing. Hair analysis, relatively rare, but can detect exposure up to 90 days of exposure, and certainly can happen after passive exposure. This happens most commonly in the legal world for cases involving probation, child custody, adoption, and domestic violence. There have been some court cases where children were subjective to hair analysis and came up positive, and that resulted in some difficulties in that child custody case being concerned that was the child actually exposed to marijuana over the last 90 days. There are some federal employees who must submit to hair sampling at the time of initial employment. Again, things to counsel your patients on as you're going through this. Quickly following up about setting up a medical marijuana practice, it certainly takes a village. Do not try to do this in isolation all by yourself. There are lots of touch points. Consult your legal counsel, consult with human resources, consult with your palliative care physicians, your pain management groups, etc. Make sure that there are no contraindications to existing policies or other departments. The last thing you want to do is get a call from your human resources department saying that the practice that you set up is in direct contradiction to something that they already have on the books. As mentioned, the inpatient settings are the most problematic. Some inpatient facilities absolutely prohibit marijuana use. Other places will allow patients to utilize their cannabis products, but will not allow staff to help administer or will not store the product while the patient is an inpatient. Family members are required to bring the product in, the patient can utilize it, and then have to leave with the caregiver or family member. There is no fee schedule for anything that we talked about over the last couple of minutes. You can charge whatever you want. You could not charge at all. You can give it away for free if you would like. My colleague, Dr. Glassman, will pick up the issues about diversity and equity in just a moment, but that is certainly something to consider while you're creating your fee schedule. Revise your policy often. You'll never know when exceptions to your rules might come up. Absolutely check the state website regularly. I would recommend at least on a monthly basis and maybe even more frequently to make sure that changes haven't popped up that are in contradiction to your existing policy that you might need to revise, and absolutely stay informed. I will humbly state that this part of my medical practice is the thing that I need to take the most time in making sure that I am up-to-date and informed. Products like the Academy is putting on here today is certainly very appropriate. Again, I want to thank my colleagues for the opportunity to present here. I think in the interest of time, we're not going to take any questions. I will move it on to my colleague, Dr. Glassman. Thank you so much, Dr. Salino. Can you hear me? Yes, we can. Excellent. Great lecture. Appreciate you covering those areas. Now I'm going to share my screen. For anyone that has questions, you can always put them in the chat box for Dr. Salino or the others. Let me get on here. All right, can you see the slides now? All right, great. So I'm Dr. Stuart Glassman. I am the president and owner of Granite Physiatry in Concord, New Hampshire. I'm a clinical assistant professor with the Geisel School of Medicine at Dartmouth, clinical instructor at Tufts University School of Medicine, but I'm also the deputy chief of physical medicine and rehabilitation at the Veterans Administration, Greater Los Angeles Healthcare System. And I'm also one of your two AMA delegates from the AAPMNR to the American Medical Association. All right. So, and I just want to shift some things around here. All right. So for our objectives, we're going to describe the equity concerns of patient populations who could benefit from medicinal cannabis use. We'll have review strategies to address potential barriers to medical cannabis use ownership of underserved populations and discuss unique issues in medicinal cannabis and medical cannabis access for veterans, one of the underserved populations. Nothing to disclose financially, but I do have to say the views and opinions presented during this presentation do not represent those of the Department of Veterans Affairs or the United States government. One of the greatest disclosures you can ever have in a presentation. All right. So we're going to start this off talking about Brittany Griner, which I think many of you probably heard about the last few months. She was the number one ranked high school female basketball player in the United States in 2009. She has been a three-time All-American at Baylor University. Associated Press Player of the Year, SB Female Athlete of the Year, Women's Final Four Collegiate Most Outstanding Player, two-time Olympic Gold Medalist. She plays with the Phoenix Mercury and WNBA. She has been a WNBA champion, seven-time All-Star. In February of this year, she flew from New York City to Russia to play in the Russian Premier League because it was the off season. When she landed in Moscow on February 17th, she was detained by Russian customs agents because of having vape cartridges containing hash oil, which is made up of a combination or solitary of CBD or THC. She's also African-American and lesbian. Under Russian law, smuggling hash oil, marijuana, CBD is a criminal offense for large-scale transportation of drugs punishable by 10 years in a Russian prison. She most recently, two days ago, had her detention since February, now extended to July 2nd. She hasn't had any phone calls with her United States advocates in four months, although she has met with the Russian legal team. And of course, one of the questions in the context of the war with Ukraine is, is she a political pawn? But we have to understand if there were any famous male basketball players, football players, Tom Brady, LeBron James, Steph Curry in a similar situation, would it have dragged out this long? Think about equity issues every time you hear Brittany Ryder's issue. All right. So patient equity concerns in medical cannabis. Are there equity disparities for patient access to medical cannabis? Are there concerns about limited minority ownership of medical cannabis dispensaries or growers? Is there any variability in therapeutic cannabis patient certification because of health inequities? So there's been some studies looking at this. October, 2021, the BMC Family Practice Journal looked at physician experiences, attitudes, and beliefs towards medical cannabis. It did a literature review, 21 articles in five countries. Those physicians who were experienced in certifying medical cannabis patients were more convinced of its benefits and less concerned about side effects than non-experienced physicians. That's why courses just like this are so important for helping to educate our clinicians. Most physicians actually have a lack of knowledge of beneficial effects, adverse effects, and how to advise patients, which may compromise barriers towards certification. Many of the physicians at the American Medical Association meetings that I go to often indicate if marijuana was legalized throughout the United States, they wouldn't have to be caught in the middle of certifying patients, which may be somewhat true, except for those between the ages of 18 and 21 who wouldn't qualify for legal access to marijuana because of their age gap. Even with dozens of states that have passed medical marijuana programs, are there ongoing barriers for equal patient access? So in 2017, a systemic review was done looking at structural barriers for access to medical marijuana in the United States. It was noted that medical marijuana use is more common among individuals who are employed, have health insurance, and earn high incomes. Again, we've heard from other speakers, insurance doesn't cover it, and getting access to even a dispensary may often be where you live. And if anything else, my time serving six years on the New Hampshire Therapy to Cannabis Advisory Board, and also on the Governor's Commission for Legalization of Marijuana, showed that the black market for marijuana is cheaper than buying it at a dispensary. Patients who actually go through the accepted process for medical marijuana access are paying more than if they went to do it outside of that system. Medical marijuana use is more prominent amongst white Americans, less likely among Latino, Asian, and foreign-born individuals. Marijuana possession remains a federal crime, and ethnic minorities continue to be charged significantly more frequently than white males for marijuana-related offenses. Over 26% of marijuana-related arrests are in the black and African-American population. What about the racial-ethnic differences in medical cannabis use? There was a study done in September, 2021, looking at 838,000 participants. Those 51.5% were female. Looking at recreational cannabis laws that were passed, and how marijuana use changed after that passage. Marijuana use increased in Hispanic and non-Hispanic white populations at age 21 and older, but there were no increases seen in the non-Hispanic black populations after the passage of recreational cannabis laws. Cannabis use disorder risk did increase in other populations after the passage of recreational cannabis laws. What about the availability of medical cannabis looking at racial, social, and geographic characteristics? This was a study done in New York State. It was published a few months ago by BMC Public Health. It looked at 2018 census data for New York State. They broke down New York State into 4,858 census tracts. Only 22% of those census tracts had certifying providers. And only 0.8% of those tracts had dispensaries. So you see that there really wasn't much access at all for dispensary throughout the entire state. Suburban areas had a 62% less chance of having one certifying provider. But here's where the figures get really interesting. For every 10% increase in the proportion of black residents, the census tract was 5% less likely to have at least one certifying provider. And conversely, for every 10% increase in the proportion of residents with a bachelor's degree or higher, the census tract was 30% more likely to have at least one certifying provider. So if you look deeply at the details and the information available, you see there is a definite difference in access to marijuana based upon socioeconomic issues and racial issues. So therefore, in New York State, medical cannabis services are least available in neighborhoods with black residents and most available in urban neighborhoods with highly educated residents. Obviously, the benefits of legal cannabis should be shared by communities disproportionately harmed by illegal cannabis. So again, much more to look at with this. So we've seen this map a few times already, but I want you to look at it in a different way. Don't look at where cannabis programs exist. I want you to look at it where they don't exist. That would be the gray areas and the light green areas because the light green areas are CBD or low THC programs. So not full access to THC. So we're talking about North Carolina, South Carolina, Georgia, Texas, Tennessee, Kentucky, Indiana, Wisconsin, Iowa, Wyoming, and then of course, Idaho, Nebraska, and Kansas. So again, access in certain states is limited and clearly since it's still federally illegal, the whole issue of the justice effects of cannabis use are very prominent in those states. So now shifting to the issue of the business of medical cannabis, one of the benefits of having obtained my MBA degree is looking at healthcare with a business perspective and a financial perspective at times. The cannabis industry in the United States is felt to have been about $24 billion last year alone, projected to be $70 billion worldwide in about six years. Looking at marijuana business ownership in the United States from five years ago, 81% of the ownership was white ownership, 5.7 was Hispanic, 4.3 black, 2.4 Asian, clearly discrepancy in the ownership of marijuana businesses and why is that? There are local government regulations. There may be lack of resources and lack of access to capital funding. There have been the establishment of medical cannabis social equity programs seen in multiple states. They provide favorable access for diverse community members to consider entering the cannabis industry. This is for the ownership and involvement of the industry, not for the patient access to cannabis itself. One example is Long Beach, California, the cannabis equity program requirements. So there are a few different requirements. You have to meet at least one of them. You have to have a family income that was 80% or less of Los Angeles, Long Beach or Glendale median income. You have to also satisfy one of these three criteria. You have to reside in Long Beach for at least three years or have been arrested or convicted for a crime related to the possession, sale or use of cannabis in Long Beach before marijuana was legalized in the state in 2016, or you are a Long Beach resident receiving unemployment benefits. So those are criteria looking at diversity and equity access or involvement from the business side of the cannabis industry. But since 2018 of 93 participants who went through the program, only one has received the cannabis business license. So while the program exists, has it led to more diversity and ownership? It does not look like it has helped at this point. What about other state cannabis equity programs? In Massachusetts, only 1.2% of cannabis businesses are owned by racial minorities despite social equity efforts. In Illinois, there were 89 dispensaries, none are minority owned. In Chicago, there are 16 dispensaries in the city, but there's only two located in black or brown communities. There is something called the Minority Cannabis Business Association that was established in 2015, which is a trade association representing minority and allied cannabis businesses, aspiring entrepreneurs and supporters who share a vision of equitable, just and reasonable cannabis industry. So again, trying to impact the diversity and ownership in the cannabis industry. What about women and minorities in the cannabis industry? Looking at data from 2021, women were only in executive leadership in the cannabis industry, 22% of the data compared to 30% for mainstream United States businesses. So less executive involvement. Minorities had similar involvement at the executive level to the national business landscape, 13%. Again, some of the limiting factors, access to capital for application, licensing fees and high startup rates. When you think about opening up a cannabis business, you have real estate costs, you have renovations to a building, you have utility issues, you have security innovation. It is not cheap and the access to capital is crucial. All right. So there's been some federal legislation looking at access from the business side for medical cannabis. This is HR 3617, which is the Marijuana Opportunity Reinvestment and Expungement Act or the MORE Act. It was introduced last year from Representative Nadler from New York. It would remove marijuana or cannabis from the federal controlled substance lists. It would authorize the provision of resources funded by a federal tax on marijuana sales to address the needs of the communities that have been seriously impacted by the war on drugs, including increasing the participation of communities of color in the burgeoning cannabis market, which we just reviewed, and would provide for the expungement of federal marijuana convictions and arrests. So again, a really important legislation to follow. All right. Now we're going to shift to underserved populations in medical cannabis and specifically military veterans. Again, I've been at the great Los Angeles VA health system since October of last year, and I've had a chance to sort of see what's going on with this population. So 65% of veterans suffer from chronic pain, and they are twice as likely to die from an accidental prescription opioid overdose as non-veterans. We've heard from Dr. Bryce and others, the issue of opioid concerns in patients with chronic pain. Medical cannabis may be a viable alternative to opioid use. It's also felt that upwards of 20% of the 2.7 million Iraq and Afghanistan veterans will experience post-traumatic stress disorder or depression. The United States Department of Veteran Affairs, being a federal agency, is required to follow all federal laws, including those regarding marijuana. As long as the FDA classifies marijuana as Schedule I, VA health care providers may not recommend it or assist veterans to obtain it that is directly from the VA handle. So if you don't know about the Veterans Health Administration, it's the largest health system in the United States. It employs more than 371,000 healthcare professionals. It staffs over almost 1,300 healthcare facilities, including 171 VA medical centers and over 1,100 outpatient centers. The Veterans Health Administration budget for this past year is $240 billion, which was in the President's budget passed by Congress. The budget projected for next year to start on October 1st is $300 billion for the VHA. That is a 20% increase in one year. So there is a large focus from the President and from Congress on veterans health care. It's been a focus no matter who has been in the White House for the last decade. It is the United States' largest provider of graduate medical education with 113,000 health professional trainees and 16,000 affiliated medical faculty. The VA treats over 9 million patients every year. They have patient advocates at every medical center. And they even have a VA hotline to the White House in case they're not happy with the care they're getting or have a crisis. And they can even write their congressman for complaints if they're dissatisfied. And the phone number is listed there as well, if any of you are veterans. So VA clinicians are not allowed to recommend medical marijuana to patients, but veterans would not be denied VA benefits if they are using marijuana through state-certified use. They are encouraged to discuss marijuana use with their VA providers, but VA clinicians cannot recommend medical marijuana at this time. VA health care providers can and should record marijuana use in their VA medical record in order to have the information available for treatment planning. It becomes part of their confidential medical record and is protected under patient privacy and confidentiality laws and regulations. However, VA clinicians cannot complete paperwork or forms required for veteran patients to participate in state-approved marijuana programs. They can't register them or certify them. And the VA will not pay for any medical marijuana prescriptions or certifications from any source. The VA pharmacies can't fill or dispense medical marijuana, but VA scientists can conduct research on marijuana benefits and risks if it's under regulatory approval. The use or possession of marijuana is prohibited at all VA medical centers, locations, and grounds. Realize that when you're on a VA facility, it is a federal property, and the federal law is enforced, not the laws of the state. You step across the sidewalk onto the other side of the street and you're in California, yes, it's legal. But if you step back on the VA property, it's illegal. And veterans who are VA employees are subject to drug testing under the terms of their employment. So there actually have been a couple of studies looking at cannabis use in veterans. There's been a study looking at the short-term impact of three smoke cannabis preparations versus placebo for PTSD symptoms in veterans. This came out in 2021. They looked at four different concentrations of a THC-CBD mixture, as well as placebo. Each participant did one combination for three weeks, had two weeks of a washout, and then did it again for another couple of weeks. This study really did not find any significant difference in the change of PTSD symptoms between certain concentrations and placebo at the end of stage one. So this study really didn't show there was any benefit for PTSD symptoms. There is currently a research study going on, which is the Cannabidiol and Prolonged Exposure Trial. It's through the VA and the University of California, San Diego. Recruitment started in 2018. It's supposed to complete in 2024. It's going to be a randomized controlled trial looking at the efficacy of CBD with prolonged exposure therapy for PTSD treatment. It'll be a sample of 136 military veterans with PTSD at the San Diego Medical Center. Prolonged exposure is a specific type of cognitive behavioral therapy that teaches individuals to gradually approach trauma-related memories, feelings, and situations. It'll be a 16-week trial, drug or placebo. The CBD amount will be 600 milligrams, and there'll be 12 sessions of prolonged exposure therapy, cognitive behavioral therapy. Again, no study results available yet. As far as the FDA medications, we've heard this before, which are approved. Epidiolex, the plant-based CBD extract used for severe epilepsy, Marinol, Syndros, or the Dronabinol synthetic THC, and Sesamato and Nabilone, also synthetic THC. All right. There are some veterans organizations trying to assist veterans in getting cannabis access. The Veterans Cannabis Project focuses on improving veterans' access to medicinal cannabis. The Disabled American Veterans is trying to help improve access to medical cannabis as an alternative to opioids for chronic pain, and the American Veterans Organization, or AMVETS, does support the use of medicinal cannabis by veterans. In March of this year, multiple veteran service organizations did meet with congressional members asking to increase and improve medical marijuana access through the VA. There has also been some federal legislation for medicinal cannabis use in veterans. The original VA Medicinal Cannabis Research Act came out in 2019, but then was reintroduced last year as HR 2916, introduced by Representative Correa from California, Democrat, and Representative Meijer from Michigan, Republican. It does direct the Veterans Affairs Department to perform clinical research on the safety and efficacy of medical cannabis in treating PTSD and chronic pain, looking at multiple strains of cannabis for that treatment. The VA does not support this specific bill. The companion Senate bill is Senate Bill 1467. It was introduced by Senator Tester of Montana, Democrat, and Senator Sullivan of Alaska, Republican. Again, the last Senate hearing was about a year ago for that. There's also the HR 3105 bill, Common Sense Cannabis Reform for Veterans, Small Businesses, and Medical Professionals Act. Again, descheduling marijuana from the Controlled Substance Act, creating safe harbors that licensed cannabis businesses can bank with financial institutions so that it's not all cash only, and then allowing military veterans to access state legal marijuana programs. If you think about it, and I'll go back quickly, think about how many patients the VA serves. If it ever became legalized, it would be not just thousands, but probably hundreds of thousands of patients who could actually access and be part of a study nationwide. Just quickly to finish up, the American Medical Association Cannabis Task Force, AMA, is made up of multiple organizations. This task force has about 25 different organizations, and the AAPMNR is one of those members of that task force. Dr. Camisha DeLisa from Virginia is a designated representative for the AAPMNR. I'm the alternate, as I'm an AMA delegate. The meeting of the task force was in July of last year. We helped educate issues on workforce concerns in cannabis, and there was a focus on highway safety and vehicle crash data. Most recently at the AMA's house delegates meeting that happened earlier this week, there were a number of resolutions passed looking at medical cannabis safety issues and marketing concerns. All right. To sum up, social equity issues exist for many medical cannabis patients. The ownership of medical cannabis businesses does show significant disparities, even with access programs in place in certain states. Veterans as an underserved population have basically limited access to cannabis really only through research. They really can't get it any other way. The importance of physicians outside the VA is crucial for veterans to certify for state programs. We are fortunate to be involved as the academy with the AMA Cannabis Task Force, and there has been congressional proposed legislation to try to improve medical cannabis equity and access. So hopefully you think about these issues and the 30,000 foot view of what's actually going on, both within the industry itself and for patient access, depending on where they live and their racial. So thank you. I will stop sharing. Okay. All right. So I know that we are certainly way past the three hours planned initially. I want to thank everyone for attending and staying this long. You can certainly put some questions into the chat as you have been. Please let other colleagues know about this program if they want to access it. And I want to make sure that if you get any surveys for evaluations, consider filling those out. And if you have any suggestions for further programs, education on this topic, either virtually or at the annual assembly going forward, please let us know. I'll turn it over to Brian for any last comments if you have that. And I want to thank everyone for being here and have a great rest of the weekend. Father's Day.

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