Welcome. My name is Dr. Mitchell Prywis, and I'm Session Director for this on-demand presentation related to medical cannabis. I'm delighted that you've decided to join us. Whether you are new to the use of cannabis as medicine or an experienced medical cannabis practitioner, you will find this presentation both valuable and informative. This marks my fifth consecutive year as our Session Director, together with my colleagues, Dr. Greg Carter and Dr. Stu Glassman, producing concise and informative information relating to the practice, science, research, and medical, legal, and regulatory aspects of this remarkable complex plant. We always look forward to your feedback and comments, and we encourage you to submit questions for our live Q&A, scheduled for the Friday morning of the annual Assembly meeting on November 12th. During this 60-minute session, we have three speakers. Dr. Glassman will update us on the medical, legal, and regulatory issues as more states begin to adopt medical cannabis use. I will share my experience as a private practitioner in Connecticut and Medical Marijuana Advisory Board member in our state, registering chronic pain patients for our medical marijuana program. But first, it is my honor and privilege to introduce and welcome our guest speaker, Dr. Ethan Russo. For those of you who are unfamiliar with Dr. Russo, he is one of the world's leading researchers on medical cannabis and one of the most knowledgeable physicians regarding cannabis therapeutics. He's a board-certified neurologist and author editor of seven books. He's published more than 50 peer-reviewed articles. He's the founder and CEO of Credo Science and was senior advisor to GW Pharmaceuticals for the clinical trials that brought to market the cannabis pharmaceutical Sativex for the treatment of spasticity in MS patients and Epidiolex, a CBD pharmaceutical for childhood seizure disorders. Dr. Russo will be discussing cannabis components and the synergy of its entourage effect in addressing pain and paleation. Dr. Russo? Thank you, Dr. Pryor. I'm going to share my screen. So I'm Ethan Russo. This is my email. If people would like to contact me afterwards, I'm going to be speaking very fast because we have a lot to cover, but you will have these presentations available for further study. This is my disclosure. I'm not going to go into it in detail, but you can study this later if you wish. But managing potential bias, none of what I'm discussing has any financial relationship to the content of this presentation. I will be talking about a lot of things that are not FDA approved, however. Our subject today is cannabis sativa, cultivated cannabis and its relation to the endocannabinoid system. It all began with a plant called cannabis, which makes these glandular trichomes, which produce the cannabinoids, specifically THC and others. But through study of cannabis, it was discovered that we have an endocannabinoid system with innate receptors and endogenous cannabinoids or endocannabinoids, anandamide and 2-arachidonal glycerol. THC binds to the CB1 receptor that also binds to these endogenous cannabinoids. The endocannabinoids are produced on demand in postsynaptic neurons and act in a retrograde fashion on CB1, where in the brain their main activity is to suppress release of various neurotransmitters. So if this is a glutamatergic neuron, and since glutamate is stimulatory, there will be a net inhibitory response. If on the other hand, this were a GABA neuron, inhibiting the inhibitory response is actually going to produce a stimulation. The endocannabinoid system is formed of three components. The endocannabinoids themselves, anandamide and 2-arachidonal glycerol. The cannabinoid receptors, CB1, CB2 and the TRPV1 receptors among others. Also the regulatory enzymes. Active and inactive components of the endocannabinoid system work together in what's called an entourage effect. CB1 is actually expressed in many areas of the brain, particularly nociceptive areas, the cerebellum, the limbic system, base of ganglion, reward pathways. Although it's prominent in the substantia nigra and the periaqueductal gray matter, there are very few cannabinoid receptors in the medullary areas that subserve cardiorespiratory functions, so there is no possibility of cannabinoids producing apnea or respiratory arrest. CB1 is actually the most common G-protein coupled receptor in the brain and its density exceeds that for all of the neurotransmitters combined. The endocannabinoid system is not confined to the brain, but it's also in the peripheral nervous system, the gut and every other area. The role of the endocannabinoid system has been nicely summarized by Professor DiMarzo as relax, eat, sleep, forget and protect. But we could have 30 other descriptors and it would not cover all the things that it does. The endocannabinoid system modulates pain, memory, movement, emotion, appetite, whether someone will vomit or not, seizure threshold, GI motility and secretion, etc., etc. There is also CB2 receptors, which are mainly active in the periphery and are immune modulators, but they have an important role in pain, inflammation and physiological defense without being psychoactive. So CB2 agonists hold promise in treating fibrotic conditions and many other conditions. Once again, this is cannabis sativa. Generally, it's the unfertilized female flowers that are of interest medically, but this plant provides food from the seed, fuel from the seed oil, fiber from the stalks and pharmacy, of course, primarily from the unfertilized female flowering tops. Cannabis is a dioecious annual plant assigned to the Cannabaceae family along with hops. The best known cannabinoid is delta-9-tetrahydrocannabinol, which was identified in 1964. It is a weak partial agonist at the CB1 and CB2 receptors in accordance with anandamide, the endogenous cannabinoid. It is an analgesic and antipyretic agent, also bronchodilatory. On the 19th century, there were cannabis cigarettes for asthma, believe it or not. This is a neuroprotective antioxidant. There's actually a U.S. patent on this Schedule 1 drug in that regard. THC is 20 times the anti-inflammatory power of aspirin and twice that of hydrocortisone, and this is independent of the CB1 receptor. It is a muscle relaxant. Sativex for spasticity and multiple sclerosis is approved in 30 countries. Also well known as an antiemetic, especially in chemotherapy associated with cancer treatment. It's a primary psychoactive component, but it's not a COX-1 or COX-2 inhibitor, so it does not have that adverse event profile. It also reduces beta-amyloid formation and may be an intervention in treatment of Alzheimer's disease in the future. Cannabidiol has gained a lot more interest in the last 10 or 12 years. It was actually isolated in 1940, but positively identified in 1963. It actually doesn't work directly on the cannabinoid receptors, but is a negative allosteric modulator on the CB1 receptor and reduces THC-associated side effects. Again, a neuroprotective antioxidant, actually stronger than ascorbate or tocopherol in this regard. It's also a TRPV1 agonist with binding that's comparable capsaicin, so this may be another mechanism of action for its analgesic effects. Many of its effects, however, are modulated through the serotonin 1A receptor, including its anxiolytic effect, its ability to reduce damage from strokes, and its anti-nausea effect. It also inhibits the uptake of anandamide and inhibits its hydrolysis, thereby increasing what's called endocannabinoid tone. There are a lot of misconceptions about cannabidiol. Although a very versatile molecule, it's not very potent, so if there's one milligram or five milligrams in a preparation, it's not likely to do a great deal on its own. You also will hear that it's sedative, but this is generally not true except at extreme doses. In lower doses, it's actually a stimulating effect. Its legal status is hazy. It is legal under the hemp bill or the Agricultural Act of 2018, although if you ask FDA and DEA, it's still recognized as a Schedule I drug. Another falsehood is that it turns to THC in the body. There was a recent study out of Brazil giving hundreds of milligrams of pure CBD to many patients with no production of THC. An upper encumber is this agent, cannabidiol. This is the precursor to the other cannabinoids, but normally the plant doesn't stop there and is a high throughput to the others. But this is a very interesting molecule, which now is coming to the fore as selective breeding has made it more available. It is a GABA uptake inhibitor. This could account for its anti-anxiety effects and muscle relaxant effects. It's shown antidepressant effects in animals. It has a mild effect to lower blood pressure and interocular pressure. It decreases keratinocyte formation in psoriasis. And it's a powerful antibiotic against gram positives, including methicillin-resistant staph aureus. It also is a potent alpha-2 adrenoreceptor agonist, which could account for its analgesic effects as well. It also stimulates several TRIP channels, especially TRIP-M8, making it of interest in treatment of prostate cancer. Recently, our group completed a survey of human use of CBG-predominant material with many interesting findings. I've introduced the entourage effect with respect to endocannabinoids, but in 1999, Professor Misholm and Ben Shabbat said, 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. So that was considered theory in 1999, but in the intervening 22 years, we have a lot of evidence of the truth of this pronouncement. Very important in cannabis preparations are terpenoids, the aromatic molecules that accompany the cannabinoids. And we see here some of the common ones found in cannabis, which are common to other plants. So many of these are analgesic and anti-inflammatory in their own right. They enhance mood and may modulate the psychoactivity of THC in synergy with the phytocannabinoids. A few of these of interest, alpha-pinene is the most common terpenoid in nature, but unfortunately isn't found too much in modern chemical varieties or chemoviruses of cannabis. It is a powerful anti-inflammatory in its own right. It is a wide spectrum antibiotic, but its greatest role in cannabis preparations would be as an acetylcholinesterase inhibitor. So this is capable of reducing or eliminating the short-term memory impairment engendered by THC. It also may have antioxidant effects in the brain, seemingly as a modulator of THC overdosage, and is well known in Japan, Shinrin-yuku, or forest bathing, as a clearing of the head that one gets in nature, particularly in a coniferous forest. Another agent that we'd like to see more of in cannabis is limonene. This is a potent antidepressant and immune stimulator, and that's been demonstrated in humans. A study in Japan where Hamilton anxiety and depression scores were cut in half, allowing discontinuation of antidepressant medication in many of these hospitalized depressed patients. It also has activity at adenosine receptors that could synergize with that activity from THC and CBD. It may increase mitochondrial biogenesis, allowing the transformation of storage fat, white fat, into brown fat, which is metabolically active and could make this an interesting agent for weight loss. Linolool is common to lavender, well known as an anti-anxiety agent without being overtly sedating. It also has prominent local anesthetic activity and is an anticonvulsant and anti-glutamatergic agent in its own right. Beta-caryophyllene has been well known for centuries among indigenous people in South America as an anti-inflammatory. In the lab, this is proven comparable in potency to phenylbutazone via activity on prostaglandin E1. But unlike non-steroidal anti-inflammatories, this is actually a gastric cytoprotective, so will not produce ulcers. This is a selective CB2 full agonist, so without being intoxicating, can exert anti-inflammatory and analgesic effects in its own right. Other CB2 agonists have been shown to have a role in treatment of addiction, so this makes it a very interesting agent. Now, shifting gears, this is material from the Sativex program, so this is extracts of a high THC plant and high CBD plant with other components. People are often concerned about development of tolerance to analgesic agents as occurs with opioids, but if we look at long-term use of nabixamol, Sativex, over a year and a half, there was not an increase in dose, the number of sprays per day, actually a small decrease. Also of concern in medical use of cannabis are intoxication, and in this instance we see that there's no significant difference in intoxication with nabixamols as compared to placebo. This is a visual analog scale of intoxication, 20 would be you feel something, 80 would be desirable as a high from cannabis, but we're mainly in the low single digits here. In 2017, the National Academies released this, which was a snapshot of what they felt the situation was with clinical use of cannabis. So they recognized benefit in chronic pain in adults, among other things, but the cutoff was before most of the information on the benefits of anticonvulsant effects of cannabidiol in epilepsy were reported. Subsequently, my colleague Caroline McCollum and I released this article to address some gaps that had appeared from the prior data. We looked at evidence of benefit in these various areas, showing conclusive or substantial evidence for adult chronic pain treatment, MS, spasticity symptoms, treatment of nausea and vomiting associated with chemotherapy, but also treatment of intractable seizures and Dravet and Lennox-Gastaut syndrome. And then, as you see, there are many other areas where cannabis has been used with lesser degrees of evidence, and this is worth studying at your leisure. The adverse events associated with cannabis are well known, and mainly are in the psychiatric realm. So most common are things like drowsiness, fatigue, dizziness, dry mouth, with smoking, cough, phlegm, and bronchitis, development of anxiety, et cetera. Other effects can include euphoria, production of headache, et cetera. The more serious things are pretty rare, particularly in medical usage of cannabis, such as orthostatic hypotension, toxic psychosis, et cetera. But these things certainly can occur, and I would add cannabinoid hyperemesis syndrome to this. A safety profile is really related to dosing, and this is well illustrated by this from nabixamols, again, not approved in the USA, but in 30 countries. What we see here in the blue are previous studies in multiple sclerosis, where very fast titration and high doses were allowed. In a subsequent trial that you see here in red, a slower titration with a maximum of 12 sprays a day, which would be 32.4 milligrams of THC and 30 milligrams of CBD were allowed, and you see that associated side effects were cut by half or more, particularly dizziness, fatigue, somnolence, et cetera. Let's look at some special cases. With respect to cancer, certainly cannabis has been used for symptomatic treatment of nausea and vomiting with chemotherapy and radiation. There were two positive phase II randomized controlled trials in opioid-resistant pain. Unfortunately, the phase III's didn't read out, mainly because the Eastern European patients were much sicker than the American patients that responded. Also treating insomnia quite nicely. In terms of primary treatment, cannabinoids are generally cytotoxic for cancer, promoting apoptosis, but protective for normal cells. CBD in particular reduces angiogenesis from tumors and the ability to metastasize. Generally, high doses are required to do these, but there have been better results at lower doses in treatment of glioblastoma multiforme with nubixamols. That study was finally reported some years later, earlier this year. So this is a phase II study of 21 patients with recurrent glioblastoma multiforme on high-dose temozolomide plus nubixamols. They were limited to 12 sprays a day. That should be 32.4 milligrams of THC and 30 milligrams of CBD, but there was an increase in one-year survival, 83% versus 53% in controls. Another special case is pain. We know that cannabis has poor efficacy for acute pain, except perhaps in conjunction with opioids, but it has a wide spectrum of activity in chronic pain, whether somatic or neuropathic. It really is not like opioids in reducing the pain directly, but its greatest effects are on the affective component of pain. Patients will report that they still feel the pain, but they don't feel as badly about it. The best documentation is for type 2 preparations, meaning those with both THC and CBD available. This is an older slide, but it's looking at randomized controlled trials of nabixamals in pain. All but one showed benefit, and actually there's been a great deal more experience, at least in RCTs, in using this agent as compared to smoked cannabis or vaporized cannabis, where there have been very few total patient years in actual RCTs. One question that comes up is whether cannabis can be used in someone who's had prior problems with cannabis or as an opioid use disorder. Cannabis clearly can be used concomitantly with opioids, even in those who have medical dependency, but they need close follow-up. After an interval in which there's benefit in pain, dose reduction or tapering schedule from the opioids could be initiated, but many patients actually do this on their own. My colleague, Dustin Sulak, has a resensitization procedure when people are seemingly taking doses of cannabinoids that are too high, having them stop for 48 hours and resuming at the prior dose, half the prior dose, I should say, and with equivalent control of pain. One demonstration of this is the use of cannabis and fibromyalgia. This is a survey done of some 1,300-plus fibromyalgia patients by the National Pain Report. What's interesting here is we see very poor efficacy for the three FDA-approved drugs, duloxetine, milnasaprin, and pregabalin, according to patient response. You'll see that most felt that they didn't help at all. As compared to cannabis, where 62% felt that it was very effective and only five felt that it didn't help at all. So this is clearly a difference. Effects on sleep. This is, again, an older study, but looking at the early nabixomal studies, and it's been the case with almost any study that's looked at cannabis-based preparations in the context of treating a disorder that has associated sleep disturbance that there's been improvement. But cannabis isn't primarily a hypnotic. Rather, it is a symptom reducer that allows more restful sleep. This is just, again, looking at the same issue, most patients reporting good responses. This was a pivotal trial of nabixomals in treating MS-associated spasticity using a randomized withdrawal design. Initially, all the patients got nabixomals, and only the responders after a month were then randomized to continue the same number of sprays of nabixomal a day or the same number of sprays of placebo. There you saw marked divergence with statistically significant differences. This is what led to the approval of nabixomals. Dosing summary for cannabis. What a patient needs isn't based on mass. It may depend on whether they've had prior experience with cannabis and any tolerance. Also, something we can't easily measure, their underlying endocannabinoid tone. Our best advice is always start low and go slow. 2.5 mg of THC is a threshold dose for most patients. 5 mg is usually efficacious and tolerated by most, but 10 mg at once in the uninitiated is probably too much. We generally recommend that doses greater than 20 mg to 30 mg of THC a day be the limit. More than that risks psychoactive and other adverse events. The presence of CBD and other terpenoids may significantly increase the therapeutic index of THC. Patients should titrate to symptom control, whether it be spasticity, treatment of pain, etc., rather than trying to attain a psychoactive state. The correct dose is the lowest one that produces a therapeutic effect without associated psychoactive side effects. In terms of cannabis recommendations, doctors should and may freely discuss pros and cons of cannabis treatment with their patients. That's the law. The discussion should be documented. This should be in conjunction with the full history and physical. There must be appropriate plans for follow-up. The physician may provide a letter or other documentation to attest to a recommendation to use cannabis for medical purposes. A couple of examples. This is what's called a phytofax that reports the percentages of cannabinoids and terpenoids. Also the tastes and smells, what patients report. I especially like that there are these bars to show the entourage compounds, the terpenoids. This is what's called a type 2 preparation with both CBD and THC. It has high pinene. That will reduce short-term memory impairment from THC, allowing focus and concentration. Because this has both THC and CBD, this should be a good agent for treating pain, especially for those that need to be able to work or study during the day. This is a type 3 agent, CBD predominant. It's also predominant in caryophylline. Here you see the blue bar. It also has a lot of limonene. Patients report comfort. This agent could be good for pain, inflammation, or treatment for addiction from the CBD and caryophylline content. It also may have benefits on anxiety and depression. That's it for my section. Thank you for your attention. Okay. I have no disclosures or conflicts of interest relating to my presentation. This is my private practice in Danbury, Connecticut, where I treat the traditional panatoply of musculoskeletal and occasionally neuropathic pain conditions facing a PMNR physician. Over my three decades of practice, it has evolved into what I'd like to consider an integrative pain management model. We offer mostly non-pharmaceutical therapeutic approaches. I was fortunate early in my career to pursue training in osteopathic medicine, medical acupuncture, nutritional and botanical medicine, mind-body medicine, in addition to employing an extremely dedicated and talented physical therapist. Over the last six years, as you can see from this slide, we added medical cannabis registration for many chronic pain patients as our state adopted medical cannabis legislation. I'm in pain. Can you give me some medical marijuana? We're against it. It leads to unintended consequences. I'm prescribing OxyContin instead. OxyContin appeared in the South Florida Sun-Sentinel in 2014 in reaction to the Florida Medical Association's opposition to a medical marijuana amendment. It became approved only for compassionate use in 2015 and later for medical use in 2016 via a constitutional amendment. This slide illustrates how out of step most physicians are when it comes to medical cannabis. It also demonstrates the misinformation surrounding its safety profile compared with opiates. As Dr. Russo pointed out, because of its lack of effect on the medullary respiratory center, you can't overdose and die with cannabis as you might with opiates. The previous cartoon is also out of step with what's occurring across our nation as clearly two-thirds of the country has already adopted a form of medical cannabis legislation and nearly a third have moved towards recreational use. Your lab work came in and, well, there's no easy way to say this, you're just too healthy for medical marijuana. So who qualifies for medical use and how do you make that determination? Well, since marijuana is still a class one federally illegal substance, you first need to start with state legislation. In Connecticut in 2012, Public Act 1255 outlined three main tenets. It was designed to enable the palliative use of marijuana for seriously ill patients while preventing misuse or diversion. It held harmless all of those people involved, including patients, caregivers, physicians, and market participants. And number three, it created a framework for a medically focused program. This is a timeline in Connecticut beginning 2013, 2014, and again through 2014. It just demonstrates that it can take up to two years from the time the law is passed until it actually goes into practice providing the necessary infrastructure. This is the website for the Connecticut DCP, the Department of Consumer Protection, or as I like to refer to it, our DEA. This website provides information for the public and physicians regarding the qualifications, dispensary facilities, statistics, and et cetera. In a population of approximately 3.6 million, Connecticut has only 1,500 physicians registering patients and about less than 54,000 registered patients currently. This is a timeline for the state of Connecticut in 2013, 2014, and again through 2014. It was the DCP's intention to involve physicians on a medical advisory board from the program's inception. This eight-physician panel required at least one pediatrician. I am the only physiatrist. The other members include two anesthesiology pain management doctors, a surgeon, a radiation oncologist, and two Yale psychiatry researchers. This outlines the logistics and the mechanics for the Connecticut Medical Marijuana Program. Physicians do not prescribe marijuana in the same way as other prescriptions. We certify utilizing the department's form online. And so diagnosed with a disease that makes the patient eligible for the palliative use based on medically reasonable assessment of their history, their medical condition, and explaining the potential benefits from the palliative use that would outweigh the health risks. The assessment must be done in the course of a bona fide physician-patient relationship. In other words, you can't just phone it in. In addition, the physician must explain the potential risks and benefits of the palliative use to the patient or their legal guardian. There was one exception to the exam. Since COVID, telehealth services permitted the certification for a qualifying patient, and the DCP isn't allowing this until June 30th of 2023. Many of you may know that medical cannabis dispensaries were considered essential services during the COVID shutdown last year. So this is Connecticut's unique pharmaceutical framework. Physicians and APRNs who can also register patients play a prominent gatekeeper role for the program and also advise the department. Patients and caregivers must meet strict requirements and act responsibly. The producers are regulated like pharmaceutical manufacturers, meeting very strict guidelines. And dispensary facilities are regulated like pharmacies. In other words, every dispensary has at least one licensed pharmacist who has training in medical cannabis. The products are treated like other controlled substances. So in a sense, we have done what the federal government has yet refused to do to basically declassify cannabis as a class two, much like opiates. Research programs must be appropriately designed and administered. And the state has really encouraged research programs. I know there are a few ongoing programs now at Yale. So the registration process, a physician, APR, and must certify the patient has a debilitating medical condition is appropriate candidate for medical marijuana. There's an asterisk there because the state does not allow incarcerated individuals to be eligible for the program. I also might add that during my screening process, I also try to make sure that patients do not have current ongoing addictions for which they are not receiving treatment. There is a need for a caregiver, whether the patient has any cognitive or physical impairments, the caregivers will also be certified. In minor patients, that is patients under the age of 18, it has to be supported by two physicians, usually one of them being a pediatrician, the parent or legal guardian serves as the caretaker, and they have a limited group of debilitating conditions and they may not purchase smokable or inhalable or vaporized products. Now this looks like a very exhaustive list and it is of the adult conditions for which you can be approved in the state of Connecticut. We started out as you saw initially for most of the typical conditions of cancer and glaucoma and Crohn's disease and many pain conditions. Now it allowed patients to come before the state capitol in Hartford to petition if their condition was not on the list. But as time went on, gradually, we as a medical advisory group tried to make the job a little bit easier and we had a chronic pain of at least six months duration associated with a specific underlying chronic condition refractory to other treatment intervention effectively last year. And this mirrors what New York State has done. For minor patients under the age of 18, there is obviously a more limited list of conditions. Producers are limited and tightly regulated. There are only four licensed producers in the state, secure indoor facilities, they meet health, safety, security, and other requirements. They manufacture pharmaceutical-grade marijuana, FDA good manufacturing standards, homogenization of the product, and laboratory testing. This is a sample label of what would be on a typical medical marijuana prescription. You can see it has the producer's name, the packaging, the expiration date, it's microbiology testing for funguses, as well as for heavy metals and pesticides. We are also, I think, one of the few states that also tests for the terpenoids that was mentioned in Dr. Russo's talk. This is another label. Again, it has all the active ingredients, including the terpenes, the amount of THC and CBD, and also its acid form. These are some of the available products. Obviously, there's flour, vaporized cartridges, edibles, sublingual strips, concentrates, oils, as well as pills and sprays that are now available. So what's the difference between medical marijuana and something that someone might get on the street? Well, obviously, pharmaceutical-grade, as I mentioned, laboratory tested, labeled with active ingredients, unadulterated, a variety of dosage forms, tamper-resisted packaging, and nonrecreational naming protocol. So how does one go about dosing medical cannabis? Well, this is a dosing chart that I give every new patient who I register for the program. It can seem a little bit overwhelming to a patient when they start out because there are four producers. They all produce very similar products with different names. So I hand this dosing chart to them on the initial registration. They put in the product, the time, the route, the percentage of THC to CBD, the dose, the time of onset, uh, what kind of effects they experienced with it and any side effects. And then during our follow-up in three to six months, we review it. So in summary, the medical marijuana consultation, we perform a standard H&P just as you would with any new patient that you see in your office. You establish that doctor-patient relationship. You review all of the available medical and surgical records to make sure that they meet the criteria and eligibility for the state. We provide guidance. We inform all of the treating physicians. And here I think it's really important because prior to my registering patients, I noticed that some of my patients were being registered by other practitioners and I never received a carbon copy or an email or any consultation from these physicians. And I think it's very important that this is something that you include because sometimes patients are being followed by multiple physicians, whether they're psychiatrists, cardiologists, and you want to inform them and make sure that they're okay with their registration. And then, as I mentioned, we track their progress within a reasonable timeframe within three to six months. Now, Connecticut has now legalized marijuana for adult use. However, the dispensaries are not yet carrying products for adult use until sometime next year. So the question is why remain a medical marijuana program holder if you can get it as adult use? Well, the number one universal aspect is that medical marijuana purchases will remain untaxed. Adult use, if we look at other states like Massachusetts, the adult use can be taxed up to 20%. So from a purely financial perspective, most patients want to maintain their medical cannabis registration. In our state, the patients who have medical marijuana may not be subject to potency limits. Also, the law currently allows patients to grow their own plants. That's a new adoption. They're considering it also for adult use next year. I believe in Connecticut, you can have three adult plants and three immature plants. Medical marijuana patients will always receive priority. Dispensary facilities will soon be able to deliver to medical marijuana patients. I know that they talked about doing this early on for patients who are in hospice care. And having experienced pharmacists and pharmacy technicians in our state available to answer questions and provide suggestion for healthcare goals is a big plus. We don't know what it will be like for the adult use end yet. Also, the monthly allotment is now above two and a half ounces. The DCP is evaluating what the appropriate amount would be for recreational use in light of the public health concerns and the need to ensure sufficient supply. Well, this is my final slide. I know it appears overwhelming for the average medical practitioner to navigate this cannabis maze of products in an ever-changing environment. However, with continued research by physicians like Dr. Russo and a greater understanding about the medical applications of cannabis and its relationship to the endocannabinoid system, it is incumbent on all of us as physiatrists to recognize that this plant has enormous potential in the treatment of chronic pain, spasticity, and the rehabilitation of our patient population. I now turn this over to Dr. Glassman. Dr. Glassman is in solo practice in Concord, New Hampshire, where he served on multiple therapeutic cannabis committees in New Hampshire. He is Assistant Clinical Professor in the Department of Community and Family Medicine at the Geisel School of Medicine at Dartmouth and Clinical Instructor in the Department of PM&R at Tufts University School of Medicine. He's no stranger to our academy, having taken on many leadership roles. He's one of the AAPM&R's National Delegates to the AMA and Vice Chair for its PM&R Section Council. He's also involved currently with the AMA's Cannabis Task Force. Dr. Glassman. Thank you for that wonderful presentation. I'm going to share my screen now. All right. And we will be talking about medical, legal, and regulatory issues. What do we tell our patients and our colleagues? Let me go to full screen here. All right, great. And I am the owner of Granite Physiatry in Concord, New Hampshire. I'm a Clinical Assistant Professor at the Geisel School of Medicine at Dartmouth and also Clinical Instructor at Tufts University School of Medicine. All right. So a couple of objectives. We're going to review the current state medical cannabis laws briefly. Dr. Pryoris will also cover that as well. We'll have a discussion about proposed federal legislation concerning medical cannabis. There are four major federal proposed laws in play at this point. We want to improve the attendee awareness of workplace issues concerning therapeutic cannabis and also enhance understanding about medical cannabis and veterans' health care regulations, as well as update some information about the American Medical Association Cannabis Task Force activities, which our academy is a member of. And I have no financial disclosures at this time. All right. So this is the infamous state medical cannabis map from the National Conference of State Legislatures. This has been evolving year by year. You've got states that have adult and medical regulation use, states with no medical regulated programs, states with a comprehensive medical cannabis program, states with a CBD low THC program, and some states with no public cannabis access. So there are currently 36 states and four territories. Think about those locations in the Caribbean or Pacific Ocean. We have areas for state medical use. We have 11 states that have a low THC, high CBD therapeutic use regulations. And for non-medical adult use, which you might call legalization, we have 18 states, four territories, and the District of Columbia. It's important to understand that the Biden administration at this point is still operating under the idea that the Department of Justice should have sort of a hands-off approach to state medical therapeutic cannabis programs. They're not enforcing regulations about that, even though marijuana is still federally Schedule I. And it's unclear exactly what will expand over time federally from the White House administration. All right. But in the meantime, there have been a number of congressional bills proposed, introduced over the last couple of years. The four main ones we'll be talking about is the Cannabis Administration and Opportunity Act, which was the draft of it was released in July of this year. H.R. 3727, the Medical Marijuana Research Act was introduced in July of 2019. The Common Sense Reform for Veterans, Small Businesses, and Medical Professionals Act had a draft legislation released in July of this year as well. And then H.R. 3617, the Marijuana Opportunity Reinvestment and Expungement Act, or the MORE Act, was reintroduced in May of this year by Jerry Nadler from New York, and it had originally been introduced in 2019. All right. So the Cannabis Administration and Opportunity Act, there was a lot of focus on this in the summertime in July. Senator Schumer, Wyden, and Booker presented it. It would remove marijuana from the Controlled Substance Act, which is important for federal regulation and employer issues. It would allow states to determine their own cannabis laws. It would direct that a new definition of cannabis be established within the Federal Food, Drug, and Cosmetic Act for regulation of cannabis in foods, dietary supplements, drugs, and cosmetics. The new definition would retain the existing exemptions for hemp from the 2018 bill. This act would also transfer primary regulatory responsibility over cannabis from the DEA to Alcohol and Tobacco Tax and Trade Bureaus, the Food and Drug Administration, and the Bureau of Alcohol, Tobacco, Firearms, and Explosives. So taking it away from an enforcement criminal entity to an entity within the government that really deals with taxation and revenue, thinking that over time it becomes legalized, that'll be the better place for it to be. It would also direct federal departments and agencies to study and report on several important areas for public health and safety. These departments would include the General Accountability Office, the Health and Human Services, NIH, and the Department of Transportation. The next federal legislation bill, H.R. 3727, the Medical Marijuana Research Act, was introduced a few years ago, July 2019, by Representative Rumenauer from Oregon. It would ensure a supply of marijuana for research purposes through the National Institute of Drug Abuse Drug Supply Program. As of right now, the main supply for research is out of the University of Mississippi. A couple of omnibus bills opened up other growing areas, but this would really allow for better access to marijuana for research. It would also direct the Food and Drug Administration to issue guidelines on the production of marijuana. The third bill we'll talk about is H.R. 3105, a Common Sense Cannabis Reform for Veterans, Small Businesses, and Medical Professionals Act. Again, draft legislation released in July by Representative Joyce, who's a Republican from Ohio. It would de-schedule marijuana from the Controlled Substance Act, similar to the bill from Schumer and Booker. It would create explicit safe harbors so that licensed cannabis businesses can bank with financial institutions. As of right now, because of prostate business regulations, a lot of cannabis industries, dispensaries, really can't do banking across state lines because marijuana is federally legal. This would help to create a safe harbor to eliminate that restriction. It would also allow military veterans to access state legal marijuana programs. We'll talk about the veterans issue in more detail in a little bit, but because marijuana is still federally legal, veterans have limited access to, no access to the VA health system. Lastly, H.R. 3617, the Marijuana Opportunity Reinvestment and Expungement Act, or the MORE Act, was initially introduced in 2019 and reintroduced in May of this year by Representative Nadler of New York. It would remove marijuana or cannabis from the list of federally controlled substances. It would authorize the provision of resources funded by a federal tax on marijuana sales to address the need for communities that have been seriously impacted by the war on drugs. This is the language from the bill, not mine specifically, including increasing the participation of communities of color in the virgin cannabis market. And lastly, would provide for the expungement of federal marijuana convictions and arrests. There's been a lot of focus on this aspect of criminal expungement of records and really changing the viewpoint of what cannabis or marijuana is going forward. All right. Now we're going to shift to the issue of workplace issues in therapy and cannabis, because understand that, you know, many patients who are certified through medical marijuana programs in their state might actually be working as well. Some states over the last couple of years have put in regulations and laws that prohibit pre-employment screening for marijuana, especially in some states where marijuana has been legalized or has non-medical use. However, this prohibition does not affect positions within the federal government or Department of Transportation positions, such as truck drivers, because they are still under federal oversight. And again, cannabis is legal federally. Some examples in Maine and Massachusetts, employers can drug test for specific causes or randomly in certain industries. Employers in Maine have to receive approval from the state before enacting a workplace drug testing program. And in California and Nevada, workplace drug testing is mostly restricted to employers that work in the public safety or related public sector jobs. So a lot more acceptance of marijuana for citizens. And as far as overlapping with the workplace, trying to have less restrictive regulations. In Washington state, employers are required to notify applicants beforehand, and can only test applicants who have already received a conditional offer of employment. There are 18 states, as mentioned previously, that have legalized marijuana, which may affect drug screen evaluations and interpretations for non-federal testing by employee medical review officers. I am a certified medical review officer, and I do regular reviewing of pre-employment, random post-injury testing, and marijuana comes up every week on it. Many states now have laws that prohibit employers from discriminating against medical marijuana patients using marijuana off-duty, but they don't have to accommodate for on-duty use or allowing employees to work under the influence. It's important to understand that the Americans with Disabilities Act does not have any input or oversight for medical marijuana use, so it's not covered under the federal ADA. So what about actual testing for marijuana use? What's the actual sort of process for it? And this is pulling off of my medical review officer experience since 2006. Typically, it's a five-panel test, which looks at THC, opiates, which include codeine, morphine, and heroin, PCP, cocaine, and amphetamines. A 10-panel test for workplace testing includes THC, PCP, amphetamines, opiates, cocaine, as well as benzodiazepines, barbiturates, methadone, propoxypene, and methylcholine. The initial screening for THC testing for a positive value is 50 nanograms per ml, but the confirmatory positive test is 15 nanograms. Now, that may seem counterintuitive. How could the initial screening be higher than the confirmatory in this process? Well, it turns out that the initial screening for THC looks at all the cannabinoids that are available in the urine sample, and there's more than one. There's hundreds of cannabinoids that you can test for in the screening. But the positive testing looks at delta-9 THC. So a way to think about this is if you need 50 cents to buy something in the store, but of that 50 cents, you have to have three nickels. That's how you think about it. If you had two nickels, a quarter, and a dime, and five pennies, you would not be positive. But if you had a quarter, a dime, and three nickels, you would be positive. So that's the way to think about it, is that the screening looks at all the THC components that are available in the urine, but a positive test is only the one specific delta-9 THC, and that value can be lower than overall screening. You can have a positive urine test up to 30 days after use. So it's important to realize that for your patients. And if you certify a patient for therapeutic cannabis, make sure you discuss with them, are they working? Are they going for a job? They may test positive. They may not get offered an employment position because of that. All right. So as an example, just recently I had a 24-year-old male who had a pre-employment testing, which was for a non-DOT employee in New Hampshire. This was last month. His marijuana metabolites in his urine was 614 nanograms per mL. So remember the cutoff is 15 nanograms, because the final metabolite value is the delta-9 THC. Okay. So this cutoff value was about 41 times the cutoff. I spoke with him when the 24-hour results were available. And he told me he was certified in Massachusetts for the medical use of marijuana program through certification, that he got through an internet physician. So he didn't even see someone live. And he sent me a copy of his Cannabis Control Commission certification card from the state of Massachusetts, because I had to look at what could I actually obtain to verify what he said. He never sent me the actual documentation of his evaluation by an internet physician. So the MROs of which I am one, we are bound by the MRO manual 6th edition, which came out in June of this year. And they specifically have a section on medical cannabis. And what they said is that no federal or state law directs medical review officers to accept marijuana as an explanation. Ratification of marijuana as a medicine by voters or legislators does not make it a legitimate medication. As an MRO, the best practice is to stick to the science and standards of practice. So this is from the MRO 6th edition manual. And again, this is a case of someone applying for a job in New Hampshire who said he was certified in another state. My determination was that the drug testing was positive. I explained to the employee and the employer that even though he was certified, there's no state law in New Hampshire that requires that I accept any certification from another state to turn this positive testing to a negative. And the employee understood, the employer understood, and then the employer was going to follow up with the employee concerning what the next steps will be. So the role of the MRO was not to decide employer human resources law, but decide what is the medical explanation, what's positive and what's negative. All right, moving on to Veterans Healthcare and Medical Cannabis. Veterans Administration clinicians are not allowed to recommend medical marijuana to their patients because it's Schedule I and it's federally illegal. However, Veterans are not denied VA benefits because of marijuana use. Veterans are encouraged to discuss marijuana use with their VA providers, but the VA clinicians cannot recommend medical marijuana, but they will record marijuana use in the Veteran's VA medical record in order to have the information available for treatment plan. It becomes part of the confidential medical record for the Veteran and it's protected under patient privacy and confidentiality laws and regulations. VA clinicians may not complete paperwork or forms required for Veteran patients who participate in state-approved marijuana programs and the VA will not pay for medical marijuana prescriptions from any source. So Veterans are sort of operating in a different sort of federal universe than the state they live in as well. The VA pharmacies may not fill, and it's not really prescriptions for medical marijuana because it's a certification. They're not a dispensary, typically you have to go to a state dispensary to get that. VA scientists can conduct research on marijuana benefits and risks and potential for abuse under regulatory approval. The use or possession of marijuana is prohibited on all VA medical center grounds and locations. And when you're on a VA facility, federal law is in force, not the laws of that state. And Veterans who are VA employees are subject to drug testing under the terms of employment and there's a whole section of information that's available on the VA website. And lastly, the American Medical Association Cannabis Task Force update. The AAPMNR is a member of the American Medical Association Cannabis Task Force. The position representative for the Academy is Dr. Tanisha Delisa from Virginia. I've served as an alternate recently for that when Dr. Delisa was not available. The staff member is Reba Singh. The most recent meeting for the AMA Cannabis Task Force was in July of this year. Input that I helped bring to the task force dealt with the issue of workplace issues in cannabis, which I just covered earlier. And the task force does now want to add a whole new education focus and section on workplace issues in cannabis. So I feel pretty honored that my input was accepted by the task force, which was very helpful, as well as all the work Dr. Delisa has done. The meeting also reviewed highway safety and legal crash data, as well as state legalization of cannabis and education areas that the public and physicians will need, including health effects, impact on children's and adolescent health, pregnancy issues, mental health impact of cannabis for treatment, such as PTSD and anxiety and depression, as well as side effects of cannabis use, addiction risks, and public health effects. And the next meeting will be in the fall of this year. So to summarize and review, there's a lot of intersection between state and federal laws. It's a moving target, but it does seem that there is a lot of support for getting cannabis and marijuana to go from schedule one to schedule two. It's for no other reason than for research, but also for some other economic and for veterans health access. For the work safety issues, their employee versus employer concerns, especially in a COVID-19 workplace reality where many people are working from home. And what about the issue of unemployment versus unpaid jobs? A lot of employers that I've done MRO work for are faced with, if they test for marijuana and it's positive, that's someone that can't offer a job too many times. So often, they don't want to test for it, but they take the risk of what happens if a problem occurs under the influence down the road and never tested someone for it. Veterans access to marijuana and cannabis is an ongoing issue. You know, one of the federal proposed legislation laws is looking at that. And it brings to light the importance of physicians outside the VA who can certify for state programs. And then lastly, the valuable involvement of our academy and the Cannabis Task Force. So I'm glad to be part of that. Thank you very much. Please contact me for any questions and I will send it back to Dr. Pryor-West for some final thoughts. Thank you. Thank you, Dr. Glassman, for that update on the regulatory issues pertaining to medical cannabis and the medical legal aspects. I also want to thank Dr. Ethan Russo for that stirring discussion. I want to thank everybody at the academy who's put this together for us. And I just want to remind everybody to put out some questions for our Q&A, which will be on November 12th. Thank you again.

medical cannabis

on-demand presentation

endocannabinoid system

THC

CBD

therapeutic effects

entourage effect

federal legislation

workplace issues

research