Clinical Education Initiative MEDICAL MARIJUANA: EXPLORING NEW CLINICAL OPTIONS. Jessica Robinson-Papp, MD

Clinical Education Initiative Support@ceitraining.org MEDICAL MARIJUANA: EXPLORING NEW CLINICAL OPTIONS Jessica Robinson-Papp, MD 12/20/2017

Medical Marijuana: Exploring New Clinical Options [Video Transcript] 00:00:06 - [Jessica Steinke] I'd like to introduce our speaker, Dr. Jessica Robinson-Papp. Dr. Robinson-Papp's clinical and research interests include neuropathy and the neurologic complications of HIV/AIDS, including chronic pain. She is the recipient of grants from the NIH to study HIV associated neuropathy and is the medical director of the Manhattan HIV brain bank. In addition to her research, Dr. Robinson- Papp performs electromyography or EMG, autonomic testing, intraoperative neurologic monitoring, and evoked potentials to aid in the diagnosis of neurologic disorders. She is the attending neurologist for the Jack Martin Clinic where she provides neurologic care to people living with HIV/AIDS. Dr. Robinson-Papp is board certified in Neurology by the American Board of Psychiatry and Neurology, and EMG by the American Board of Electrodiagnostic Medicine. So Dr. Robinson-Papp, at this time I'm going to turn it over to you. 00:01:06 - [Dr. Robinson-Papp] Thank you so much Jessica. So today we're going to be talking about medical marijuana, particularly how we are able to prescribe it in New York State, and what its indications might be, focusing on our HIV positive community. 00:01:23 I have no relevant disclosures on this topic. 00:01:27 So here are the learning objectives for today. We're going to start by describing the current landscape of medical marijuana. We want to compare the available forms of medical marijuana in New York State and their indication, and discuss the use of medical marijuana for people living with HIV and AIDS. 00:01:45 And this is the outline for how we're going to accomplish these goals. First I'll talk about a brief introduction to the history of cannabis as medicine. And then talk, sort of right away, about the nuts and bolts of the New York State program; we'll get all the very practical information in there right away- how do you register; how do you prescribe; how does the whole thing work. Then we'll talk in more detail about the overview of the physiologic effects of cannabis generally and also about the evidence for its efficacy and risks. 00:02:17 So just by way of introduction a little bit about cannabis- cannabis is one of the oldest cultivated plants known to mankind. There are two varieties which have two generally different uses: hemp and marijuana. Hemp has a very low concentration of THC which is the psychoactive component of medical 1

marijuana and it serves a variety of industrial purposes. It's used to make rope, clothes, and more recently, even food items. You might see in a supermarket something called hemp milk or hemp seeds that are supposed to have certain nutritional properties. Because hemp has very little THC in it, it is not regulated as a controlled substance and can be used as an industrial product for these purposes. Marijuana on the other hand has use for recreational and then also medicinal purposes. 00:03:07 So medical marijuana has been around for a really long time and the medical properties of marijuana have been acknowledged by cultures dating back as far as 2350 BC. Probably the first reference to it was in ancient Egypt. And you can see here on the right side of the screen there are different characters that were used in different ancient languages to refer to the cannabis plant. Marijuana is fairly ubiquitousit's been present in multiple cultures and in multiple different historic eras as far back as 2350 B.C. and then in 1700 B.C. for example, there's a text that's also from Egypt which references medical marijuana as a treatment for the eyes. Mixed with celery and hemp it is ground and left in the dew overnight. Both eyes of the patient are to be washed with it early in the morning. Several hundreds or thousands of years later and in Europe, medical marijuana is recommended again in a text which says, "The same decoction of the roots eases the pains of the gout, the hard tumors, or knots of the joints, the pains and shrinking of the sinews, and other the like pains of the hips. It is good to be used for any place that has been burnt by fire. If the fresh juice be mixed with a little oil or butter." So lots of medicinal purposes out there in traditional medicine. 00:04:33 So what are the active ingredients of medical marijuana? This plant has been studied a fair amount and already there have been greater than 400 distinct chemical entities found in the medical marijuana or marijuana plants in general. And there are greater than 60 different cannabinoid compounds. There are four major cannabinoid compounds, and two which are the major parts of the medicinal formulations that we have available to us today. That's THC and CBD. THC is the component that has the major psychoactive effects. It causes people to be hypoactive, hypothermic. It can cause short term memory impairments. CBD on the other hand does not have psychoactive effects, although it's thought to potentiate the psychoactive effects of THC. There are also lots of other compounds contained within naturally occurring marijuana that are not cannabidiols. And these are referred to as entourage compounds and they're generally into different categories: the terpenes and the flavonoids. The terpenes in particular receive a lot of attention and are thought to have some properties in and of themselves, which I'll talk about in a little bit. 00:05:45 So what is the New York State medical marijuana program? Well medical marijuana was legalized in New York State in 2014 by the Compassionate Care Act and it stipulated certain conditions for which medical marijuana might be prescribed. However despite this action by New York State, medical marijuana is still defined as a Schedule 1 substance by the federal government. And the Schedule 1 substance is defined as a drug with no currently accepted medical use and a high potential for abuse. So there is a discordance between how states have considered marijuana and how the federal government 2

still considers marijuana. But within New York State medical marijuana is legal but only in its pharmaceutical form, not in the original plant form. So you'll see nothing green that is legal in terms of medical marijuana in New York State- these are all purified pharmaceutical forms of medical marijuana. And I'll talk about that in a little more detail a couple of slides from now. Not only has the government in New York State stipulated the form that allowed; they also stipulate the route of administration. So smoking is not a legal form of medical marijuana administration and- and recreational marijuana is still not legal in New York State. In order to prescribe medical marijuana to their patients, providers and this can be MDs, DOs, NPs, and physician assistants as well, with oversight. Must go through a specific training process and registration and the prescribing must occur as part of a normal clinical relationship. So this part of the law is meant to prevent doc-in-a-box type prescribing and it is meant to really prescribe that when a doctor is going to give or another provider is going to give medical marijuana, it really should be part of a normal patient-provider relationship; there should be regular follow up in place etc. 00:07:41 So these are the approved routes of administration for New York State. There are three different routes: vapor, sublingual tincture, and oral capsules. And they all have different benefits and different drawbacks. Starting at the top, the vapor is provided by most dispensaries in a special kind of capsule that goes into a special vaporization device. And so the patient can push the button. It vaporizes the medical marijuana solution and they can inhale it. The benefits to the vapor is that it's very quick and onset- it onsets in about 30 seconds to two minutes. So this is good for acute type symptoms for which acute relief is needed. Similarly though, it's a relatively short duration about one to two hours and it requires the special vaporization device which might be more expensive than some of the other routes of delivery. In between, we have the sublingual tinctures. So this is an oil-like substance that the patient is instructed to put under the tongue using an oral syringe. It has an onset which is a little bit longer- so it takes about two to 15 minutes to start working. But it last a little bit longer, too, about four to six hours. One of the drawbacks here is that patients have to be counseled not to swallow the liquid; it really needs to be maintained in the mouth. If they do swallow the liquid nothing bad happens. It's just at the onset of action is much slower more like the oral capsules. So they need to be aware of that. So they're not waiting for something to happen right away if they swallow it and then inadvertently take too much thinking that it's not having any effect. The oral capsules are much slower in onset- about one to two hours. And they're also longer in duration eight to 10 hours. The oral route also undergoes first pass hepatic metabolism, which is important if patient's taking other medications that might increase metabolism of the dose, or conversely if the patient is having liver abnormalities. 00:09:44 So New York State has also specified particular conditions and symptoms for which medical marijuana is indicated. And so you have to have both a severe debilitating condition and an associated condition or symptom. And here are the severe debilitating conditions listed here. You'll notice that many of these are neurologic conditions plus pain conditions and cancer. So there's chronic pain, neuropathy, cancer, spinal cord injury with spasticity, inflammatory bowel disease, multiple sclerosis, epilepsy Parkinson's disease, HIV, ALS, and Huntington's disease. So in addition to one of those diagnoses, you have to be 3

experiencing one of the following symptoms: severe or chronic pain, persistent or severe muscle spasms, severe nausea, cachexia or wasting, or seizures. And so you can pick any combination of these two conditions and symptoms. In the case of pain, you could conceivably pick chronic pain and chronic pain that can be both a condition and a symptom. Here are just some examples of combinations that might make sense, like HIV cachexia, neuropathy with chronic pain, or chronic pain with muscle spasms. Since I'm a neurologist working in an HIV clinic, most of my patients have a neurologic diagnosis in addition to their HIV so very often it's chronic pain or neuropathy, in which case I'll usually list something like neuropathy and chronic pain, saving the HIV diagnosis for if I absolutely need to write it just so I can maximize the patient's privacy. 00:11:25 So as a provider how do we become registered to prescribe medical marijuana? It's actually a pretty easy and straightforward process. You have to go through an educational course, of both of the courses are available online. There are two that have been approved by New York State. One is called The Answer Page, one is called the Medical Cannabis Institute. They both cost a little over two hundred dollars, and to provide continuing education credit. They are very straightforward to go through and actually pretty informative and interesting and you learn about the fair bit about medical marijuana by taking these courses. It's easy to register- all of this information is also online on the New York State Health Commerce System website. Many of you may be familiar with this website- it's the same one that we use to check I-STOP so if you prescribe controlled substances of any kind and you go on to check your patients record on I-STOP this is the same website that we use for that. Physician assistants of note who want to prescribe medical marijuana have to have the supervision of a physician who is also registered with the program. So both the PA and the doc would have to register. 00:12:38 So once you're registered then what you'll see on your screen in the in the system is an icon here, which I've circled in red, which is called MMDMS- it's the medical marijuana system there. And if you click on that icon then you'll come to this second page here, which I have outlined in it in black. And you'll have three choices, which is "View my patients," "View my certifications," or "Certify a new patient." And this is where we go to certify patients. So if you have a patient in your office and they're interested in medical marijuana, you would put all their information into here in order to sign them up. And then ask for some very simple information: basic demographics, the patient's contact information; the diagnoses that we have just gone over. And then it asks you to choose the medical marijuana product that you want to prescribe for your patients. I think once you get the hang of it, all this information can really be put in in about five minutes. It's pretty quick and straightforward. 00:13:34 So how do we go about selecting a product? So I spoke already about the different formulations that were available- the vapor versus the sublingual versus the capsule. Well the other choice that we can make is whether we want to prescribe a high THC formulation, a high CBD formulation, or a balanced formulation at a 1 to 1 ratio. I'm going to talk a little more about that in the subsequent slide- how you would pick one versus the other. And I'll also tell you later on in the talk all the different evidence 4

behind using one formulation versus the other. But New York State has also given us a very easy option which is a relatively new one; it came out, I think, about a month or so ago, where we can simply say per pharmacist consultation. So if you don't want to make a decision, then you can just say per pharmacist consultation for both the THC/CBD ratio and the administration method. And then when the patient goes to the dispensary, he or she will have the opportunity to speak with the pharmacist who will go through all the different choices with them and will be able to inform them simultaneously of the prices and- and practical things of that nature. 00:14:48 So if you do want to make the decision yourself, then how do you choose THC versus CBD? Well in general, there are three formulations that are available at Columbia Care, which is the largest dispensary here in Manhattan. There's the 20 to 1 THC, the 20 the- 1 to 20 where the CBD is higher, and then the equal one. And there's a lot of lore surrounding what THC is good for and what CBD is good for. Some of it is scientifically based and some of it less so. What I think is clear is that the THC is the psychoactive component. And so if somebody has, for example, is experiencing a lot of pain at night and is having trouble sleeping because of the pain, then you might use the THC sedating effect for that. On the contrary if the patient is having a lot of symptoms during the day and has an active job where they need to focus and really wants to avoid any kind of sedating or psychoactive effects then the CBD dominant form might be the way to go there. We do think of the THC form as being better as a muscle relaxant and as an antiemetic they're both probably helpful- THC and CBD. And THC is probably better for appetite stimulation and for improving slowed GI motility. In pain in general THC may be better than CBD. That is at least the lore. There's not a lot of evidence for that, although there are some evidence to suggest that CBD might be particularly good also in neuropathic pain. We do know that CBD has anticonvulsive properties and also can be an anxiolytic medication, whereas THC can in fact exacerbate anxiety. So all of these things might be important to consider when you're deciding what to prescribe to your patient or you can allow the pharmacist the liberty to discuss this with the patient. It should also be noted that we can recommend which formulation we would like our patient to have but ultimately our choice is not binding and the patient and the pharmacist in consultation with one another do have the freedom to choose a different formulation than what you recommend. So that is something to bear in mind. 00:17:03 So after you have registered your patient in the online system, the system will instruct you to print out this paper document which you will sign and give to the patient, and the paper document will have some detailed instructions there about how the patient can log into a patient facing online system and register for medical marijuana. After they do that they will receive a card in the mail which shows that they are registered. This usually takes about 10 days. Of note to tell your patients on the website from their side, it will say that there is a fifty dollar fee. However the fifty dollar fee is currently being waived. I don't know for how long but they have not been charging that fifty dollar fee. So the Box still says you'll have to pay 50 dollars but it lets you go past it without actually paying it. I have had some of my lower education patients have difficulty with the website. It's not a difficult website, I think. I did go through it myself with one of my patients recently. But it's also not the most intuitive. So if there- if you're working 5

in a clinic that has, you know, nursing support or social work support and you have sort of lower education and/or lower technology literate population or an older population that might be something to consider. You can register your patients for up to one year at which point the registration expires and you have to renew it. And so for about 35,000 or greater than 35,000 patients have registered for medical marijuana in New York State. And as I've alluded to earlier, since this is part of a regular doctorpatient relationship, you should schedule regular follow-up with your patient as part of regular care to see if- to check on the effects of the cannabis that you have prescribed. 00:18:50 So once the patient gets their card, they can go to the dispensary. The dispensaries in general will not even let people in really unless they have the card so they can't really go in advance of being registered. The product as I've mentioned before in New York State is a pharmaceutical grade medical marijuana. So what that means is that the dispensaries are growing the medical marijuana themselves, converting it into the pharmaceutical product, whether it's the capsules or the vapor or the oil, and then also dispensing it. When the patient goes into the dispensary they usually have the opportunity to speak with the pharmacist to assess in decision-making. There are currently a number of different dispensaries operational in New York State. The two that are available in Manhattan are Columbia Care and Etain. Columbia Care is the larger of the two, and these are the other ones that are available throughout New York State: MedMen, PharmaCann, and Vireo Health. And I've noted the two that are available in the outer boroughs of New York City: PharmaCann and Vireo Health. Pricing for medical marijuana is not set by the state and then- and so therefore can vary by the dispensary. From the Vireo website, which is the only one that says anything about their pricing, they say the majority of our patients leave the dispensary on their first visit spending approximately 80 to 100 dollars, although some individual products may range up to 350 dollars. The price depends a lot on- it depends on how much the patient wants to take. So for example, if the patient is only going to use it, say, you know, as needed, maybe once or twice a week then they don't need so many doses and the price will be lower. If they're intending upon using it three times a day standing, then that's going to be a lot more doses and it will be more expensive. And it is currently not covered by any kind of insurance so these are all out-of-pocket medical expenses which have been limiting certainly for some of my patients. 00:20:50 So I'm going to switch gears now and talk more about the effects of cannabinoids on the body. The cannabinoid receptor system is an endogenous system. It was- the study of it really began in the late 1980s and early 1990s and two different receptors for cannabinoids have been identified- the receptor number one and receptor number two. The cannabinoid receptor number one is extensively expressed in the central nervous system, particularly various parts of the brain, including the substantia nigra, basal ganglia, limbic system, hippocampus, and cerebellum. This accounts for THC's effects on cognition, memory, motor movements, and pain. The number two receptor is not so much in the central nervous system, although a little bit, and also a little bit of the peripheral nervous system. But it has more systemic effects, such as immune cells, the spleen, and the gastrointestinal system. 6

00:21:54 Sorry I was just having some trouble advancing my slides but it seems back. So endocannabinoids are the chemicals that are the natural ligands of these cannabinoid receptors, so the things our bodies produce naturally. And there are two endogenous ligands- two main ones. There are and there are a number of other ones: AEA and 2-AG. And this system- the full effects of the endocannabinoid system are not yet fully understood. It's thought to be highly, highly pleiotropic, meaning that it has a lot of different roles, and that in general plays a pro-homeostatic role that is to balance different kinds of signaling systems. And as such it's found to be altered in a great variety of diseases particularly neurologic disease, which makes sense if you think about the fact that the cannabinoid receptor number 1 is very prominent within the brain. It also has multiple regulatory roles outside of the brain, including vascular, metabolic, immune, and reproductive systems. 00:23:01 So phytocannabinoids refers to the cannabinoids that are present in plants. And I alluded to some of this a little earlier, the varying effects of THC and CBD. THC works primarily on the number one receptor, CBD- more on the number two receptor. And there are an abundance of different effects that have been attributed to THC and CBD which are listed here in this table. This is from a comprehensive review article that was published by Atakan and colleagues in 2012. That's a nice review. Some of the things that I'll point out here that I did not mentioned before are the cardiovascular effects. So CBD tends to have a more calming effect on the cardiovascular system so it can cause bradycardia and hypotension, whereas THC is the opposite and can tend to cause tachycardia and hypertension. 00:23:54 What about the entourage effect. So I mentioned earlier that in addition to the cannabinoids there are a lot of other compounds that are present in the natural marijuana product. And the presence of all of these other compounds is one of the main arguments that proponents of natural marijuana products make about why their products are superior. And this is referred to as the entourage effect, that the other compounds are important and affect the way CBD and THC actually have their effects on the body. This has wide lay popularity and certainly within the medical marijuana industry, it's a very popular notion. But there is not a lot of scientific evidence to support it, yet. There isn't specific scientific evidence against it either. It's just not particularly known. And the two main categories of entourage compounds are terpenes and flavonoids. 00:24:50 So terpenes are aromatic compounds that are produced by lots of different kinds of plant species. And in general they protect the plant from predation and are used to attract pollinators. By way of reference, what you see as sold as essential oils that are derived from plants are typically terpenes. And there are eight different general classes of terpenes. They are reported to alter the effect of THC. This is not so important in the medical marijuana product that is available in New York State, since all these things are standardized and not something that we can manipulate in the products that were available- that are available for our patients. But in states where the actual marijuana plant is legal this is a large part of the marketing that goes on for medical marijuana. What kind of terpenes are in individual strains. And so 7

the limonene terpenes for example are purported to create a more cerebral and euphoric effect of THC, while the myrcene terpenes are supposed to create a more physical and mellow, sleepy kind of feeling from the THC. Again, not particularly supported by science but certainly has a lot of lay appeal. 00:26:15 So there are also pharmaceutical cannabinoids that are available that are synthetic and not derived from the plant itself. Probably the one that providers are most familiar with is Dronabinol, or Marinol. This is synthetic THC. It's FDA approved. It comes in capsules and it is indicated as an antiemetic and an appetite stimulus. Nabilone is another one, which is referred to as Cesamat. This is a synthetic compound that is closely related to THC although it's not THC exactly. This is also FDA approved and available in capsule form and indicated as an antiemetic. The other major product that is out there are nabiximols, or Sativex is the commercial name for that. However this is not available in the US. This is a plant-derived extract of THC and CBD in a 1 to 1 ratio. It's approved in Canada and also multiple European countries as a buccal spray. And in the countries where it is approved, it is indicated as a nonopioid analgesic and a muscle relaxant, particularly for spasticity or neuropathic pain associated with multiple sclerosis and cancer pain. I do bring up Sativex here, even though we can't get it in the US because out of all of these products it's probably the one that's most similar to the compounds that we do have available here in New York, being plant-derived and then being available in this 1 to 1 THC/CBD ratio. 00:27:53 So as I go into the next section, the research that has been done on cannabinoids for various medical conditions, I want to just start by pointing out some of the barriers that there- there have been two effective cannabinoid research in the US. So I mentioned earlier that cannabis is a Schedule 1 controlled substance on a federal level. And that means that research using cannabinoids is very tightly regulated by the government. Currently, all cannabis that is used in research in the United States has to come from the government- from the National Institute of Drug Abuse (NIDA), which contracts with one universitythe University of Mississippi to grow this marijuana supply. This is a very restrictive process so there is sort of one- one place that you can go to get this medical marijuana and you have to do your research with that- with that particular product, unless you're doing research on an FDA approved product, like Miranol. In August of 2016, in recognition of this constructiveness, the DEA announced a new program to try to allow other manufacturers, such as the dispensaries like Columbia Care to register their products for research production. But although many of these dispensaries- the dispensary companies have registered with the DEA and applied, as of the time that I was doing the research for this presentation, so within the last month or so none of them had actually yet been approved or denied. So it was unclear exactly what was happening with this process and whether it will move forward. And so what this means is that although we as providers can prescribe these medical marijuana products to our patients we are not allowed by law to do research on their efficacy, which I think is a very strange position for us as doctors to be in. 8

00:29:59 So what kind of research do we have on the efficacy for cannabinoids in general, understanding that the specific products that we have here in New York State cannot be researched. And so do not have any direct research supporting or refuting their usefulness. Well, there is commercially- there's research available on the commercially available products: Dronabinol, nabilone, and then outside the U.S. the nabiximols. The cannabis itself, which is the NIDA product of the researches done in the US And there is, using these various formulations, a substantial body of research in neurologic disorders, cancer, chronic pain, and also a fair amount of research in HIV. Because of all these regulatory issues and the fact that that marijuana is a Schedule 1 substance, most studies using the smoked marijuana form that comes from NIDA, like studies actually using the leaf, have to be very short term. So you can't just design a study where you give out medical marijuana cigarettes to your participants and tell them to go home and take them over a certain amount of time. Most studies have been done in a very controlled hospital-based setting where the patient has to come in and smoke the marijuana and be observed while this is going on. And so understandably this is quite expensive to do this research and so longer term research is really not practical. There has been longer term research, particularly using the nabiximols product outside the US where this product is legal, and there's pretty good data that has efficacy, at least in pain. 00:31:35 So there is enough data out there that the National Academies of Sciences, Engineering and Medicine. In 2017 put out this monograph summarizing the known literature about the health effects of cannabis and cannabinoids, and has a lot of information- it's very helpful; it's very long. And what they really come to the conclusion is summarized in this box, which says that in adults with chemotherapy induced nausea and vomiting, oral cannabinoids are effective antiemetics. So this box just contains all the things for which there is very strong and convincing data. In adults with chronic pain patients who were treated with cannabis or cannabinoids are more likely to experience a significant reduction in pain symptoms. In adults with multiple sclerosis related spasticity, short term use of oral cannabinoids improves patient report spasticity symptoms, and for all the conditions the effect size of this cannabinoid treatment is relatively modest. And for- for conditions other than those listed above, there is inadequate information to assess their effects. 00:32:44 There was also a slightly older summary done by the Cochrane Library that looked specifically about medical marijuana for patients living with HIV for any kind of indication, including any morbidity and mortality. And this was a systematic review which found 8 randomized controlled studies. Four had a parallel group design; two had within-subject randomization; and two did a crossover design. I'm going to go through some of these studies specifically since we are focused on the care of HIV-infected patients. But on the whole some of the outcomes were that there was difficulty with blinding, not too surprising since cannabis has psychoactive effects. The patients were typically aware of what treatment arm they were assigned to, even though they had placebo controls. The outcome measures were variable in the studies. Some of the studies looked at changes in weight, body fat, appetite, nausea, and 9

vomiting. Others looked at pain or mood. And the overall conclusion was that the evidence for substantial effects on morbidity and mortality in HIV is limited. 00:33:55 So what are some of the specific cannabis HIV studies? So Abrams and colleagues in 2007 studied 50 HIV infected participants with painful neuropathy. They were randomized to smoke cannabis versus placebo cigarettes which they took three times a day for five days, again in a controlled hospital setting. They found that smoked cannabis reduced the average daily pains for by 34 percent, compared to placebo. And that greater than 30 percent reduction in pain, which is considered a clinically significant outcome was reported by 52 percent of the patients who were given the cannabis cigarette and by 24 percent of the patients in the placebo group. They found that the first cannabis cigarette reduced chronic pain by a median of 72 percent compared to 15 percent in the placebo. And there were no serious adverse events. Ellis and colleagues did a similar type study except this was a double-blind crossover study which means that all the 28 participants had a period in which they were getting the placebo and a period in which they were getting the active cannabis. There is a period in between where they wash out and then they cross over to the other side and they're randomized in terms of which treatment they get first. And this time they were smoking four times a day, for five days, and they had the same outcome of participants achieving at least a 30 percent reduction in pain. And they found that 46 of the cannabis smokers achieved this outcome versus 18 percent in placebo. 00:35:27 There have also been some studies looking specifically at Dronabinol, which is the synthetic pharmaceutical version of THC versus smoked marijuana for cachexia in HIV. And these were two very small studies, both performed by the same group. One found that both Dronabinol and marijuana groups had an increase in caloric intake. That was their primary outcome. And then one found that there was a significant increase in body weight in marijuana smokers, as compared to the Dronabinol group. So this in some cases might be a good thing in patients who have cachexia in HIV. It's also can be a downside. In my practice at least, obesity in my patients is an increasingly problematic issue. And so it's something to be aware of that this treatment with medical marijuana could exacerbate that. 00:36:22 Here's a slide that's adapted from a systematic review that was published in 2016, which just showed all the different studies for Dronabinol for cachexia in HIV, which for the most part were positive clinical trials, usually fairly small but I've just put this here for reference, so I'm showing that there is a fair amount of data at least for the synthetic form. 00:36:50 So those were all clinical trials looking at the effect of cannabis. Well, what about our patients who are using cannabis on their own. What do they say cannabis' effective for- effective for, why are they using it. So a study to answer this question was performed by Woolridge and colleagues in 2005 and they surveyed 523 people living with HIV who are attending a large clinic. And 27 percent of these patients overall reported using cannabis for treating their symptoms, and what they reported using cannabis for 10

were the following symptoms: appetite, pain, nausea, anxiety, muscle vs nerve pain, depression, and paresthesias. And 47 percent of these users did report that there was some deterioration in their memory function associated with their cannabis use. 00:37:43 And nabiximols as I alluded to earlier have been studied a fair amount for chronic pain, although these are not specifically HIV related studies, I'm including them here because pain is probably one of the most common things that I use medical marijuana for, at least in my HIV patients. And there're two studies here- Roq and colleagues in 2005, who treated 66 patients with central pain related to multiple sclerosis for five weeks. They found a reduction in the mean intensity of pain that was significant compared to placebo. So 3.4 points on a visual analog scale versus two points reduction. They also found that nabiximols were helpful for sleep. They were generally well tolerated, although more patients on the nabiximols than placebo reported side effects of dizziness, dry mouth, and somnolence. And they also had some cognitive side effects which are not too surprising. Nurmikko et al in 2007 also had a randomized placebo controlled double-blind trial, in which they treated 125 patients with neuropathic pain characterized by allodynia, allodynia being hypersensitivity to touch. And this was a five week long trial. They also had a significant outcome, although it's modest, they've reduced their pain intensity on the visual analog scale by 1.48 points versus point 0.52 points. And they also had a positive Patient Global Impression of Change. The Global Impression of Changes is an outcome that is often used in pain clinical trials. It's a very simple question, which just has the patient rate on a Likert scale, whether they think that their overall status is better or worse or somewhere in between, as compared to the beginning of the study. This study also had a 52-week open label extension arm, which found that pain relief and safety was maintained during this time period. 00:39:43 Two other studies that looked at nabiximol for chronic pain included a study by Portenoy in 2012. This was a little different; they were looking at opioid-treated cancer patients who were poorly controlled. This poorly controlled in terms of pain, this was a negative clinical trial. But did have some positive findings on the secondary outcomes. It may not be too surprising that this was negative since these were patients who were already taking opioids and were not having their pain well-controlled. So they were pretty treatment resistant patients. And then Serpell et al in 2014, again did neuropathic pain with allodynia, a fairly large sample and met their primary outcome of a 30 percent reduction in pain and improved sleep quality and Patient Global Impression of Change. 00:40:33 So those were a summary of the potential benefits of medical marijuana. Well, what about the risks. So a comprehensive assessment of the risks of medical marijuana or cannabis in general is also included in this monograph by NASEM. And they looked at health risks associated with cannabis in 10 different domains, including cancer, cardio-metabolic risk, respiratory disease, immune function, injury, death, pregnancy, or death- death due to injury specifically, pregnancy, and then psychosocial and mental issues, including risk for problematic use and the development of substance use and abuse disorders, 11

both of cannabis and then other substances. They found, unfortunately that the data was limited in many of these areas, but they were able to make a couple of firm conclusions. 00:41:22 So these were the conditions for which they found a clear and well-supported association between cannabis use and the following adverse outcomes. Chronic cough and phlegm production; that one is fairly straightforward and seems to be particularly associated with cannabis smoking. I imagine this would not be the case with our products here in New York State, except possibly the vaporizer. Some of my patients have reported difficulty tolerating the vaporizer. Lower birth weight in pregnancy is a side effect and in general we consider prescription of cannabinoids to pregnant women to be contra indicated. There is impairment in cognitive function certainly with acute use of cannabis and it may persist in former users with cannabis. If cannabis use starts early such as in adolescence, it may be associated with a reduced future achievement. This is- this next one is an important one. There is a fairly strong association between cannabis and risk of schizophrenia and other psychoses. It's not clear that cannabis is causative. The link may be more correlatives than causative. But it is important; I typically consider schizophrenia or other psychotic disorders, for example like a mood disorder with psychotic symptoms to be a contraindication for cannabis prescription. Cannabis can also worsen preexisting bipolar symptoms with daily use, it can worsen or cause it or has been associated with the development of social anxiety disorders, increased risk of suicidal thoughts, and also risk of developing substance use disorders including alcohol, tobacco, and other illicit drugs. 00:43:14 They found fairly convincing evidence against an association between cannabis use and the development of depression, anxiety, and PTSD. And so this seems a little contra- counterintuitive compared to what was on the other slide. But I think, instead this is what this means is that a person who does not have depression, anxiety, or PTSD disorders is unlikely to go ahead and develop these disorders because of cannabis use, but that if a person is using cannabis use and has a history of any of these disorders that can be exacerbated by the cannabis use. Or if they had a risk factor for one of these disorders it may be unmasked by the cannabis use. Encouragingly, they also found decent evidence against an association between cannabis use in head and neck and lung cancers. So that's reassuring. 00:44:07 They also addressed the risk factors for developing problematic use of cannabis. And these were some of the risk factors. They're not absolute contraindications, but there are things to bear in mind. So people were more likely to develop a problematic cannabis use disorder if they were male, if they smoked cigarettes; the cigarette smoking is probably just indicative of a predisposition or a vulnerability to addiction, initiating use at an earlier, earlier age, heavier use, or a preexisting major depressive disorder. 00:44:43 So I had mentioned about psychosis and schizophrenia a few minutes ago and I think I'll just spend a moment here discussing this. There is an entity of cannabinoid induced psychosis that we should be 12

aware of. This table here is from that review article I mentioned earlier by Atakan and colleagues. And these are the risk factors for development of psychosis when cannabis is prescribed. So a predisposition to psychosis is a risk factor and that might be determined by a family history of psychotic illness or some prodromal type psychotic symptoms in the patients. Certainly there are psychosis susceptibility genes which we're not going to be testing clinically in our patients but it is a known risk factor for developing psychosis. And then a preexisting schizo-type of personality disorder may also be a risk factor. So it's something that I think is worth inquiring about, generally the psychiatric history, if you're considering prescribing medical marijuana to one of your patients. 00:45:50 So we've talked there quite extensively about the risks of medical marijuana and then some of its benefits. And then I just bring up this slide which is sort of an intriguing side benefit that medical marijuana might have. So I think some of the reason that there's been so much emphasis on medical marijuana is that many providers think of it as a way to spare the use of opioids for patients who have chronic pain syndromes, and indeed it is used that way by many providers. This was a paper that came out in JAMA Internal Medicine a couple of years back. It is an epidemiologic study which looked at states that had enact or legalized medical marijuana in some form and then compared that with their rate of overdose from opioid analgesics. And what they found was that when states legalized medical marijuana their- in general their opioid analgesic overdose mortality rate went down in the years after the implementation of these laws. And so you can see in the figure- marked figure two here, that the first year after the law implementation, the mortality rate went down on average by 20 percent and then stayed pretty steady in the first couple of years and then went down even more to about 30 percent less in years five and six. And so while this is not clear evidence of causality, it is intriguing that these two things tend to happen at the same time. 00:47:27 So we're drawing near to the end of the hour so I'll stop to summarize now and then we'll leave a little time for questions at the end. So in summary, we talked about how cannabis is one of the oldest cultivated plants which has been used as medicine by humans for millennia. Despite the significant regulatory barriers that are in place, there is significant research which demonstrates that cannabis is effective for chronic pain, anorexia, and as an antiemetic for spasticity in MS. There is also some limited data that cannabis can be helpful for other indications as well. And New York State has given us a list of the indications that it believes are have adequate evidence for us to prescribe for. Safety profile of medical marijuana is in general favorable. It's relatively contraindicated in patients with preexisting psychotic symptoms and probably should not be used in pregnant women either. The caveat to all of this is that the specific preparations that are available in New York State and other states that have legalized marijuana have not been subjected to research in and of themselves, because this is currently illegal. So we don't have research about our actual products, although our actual products are manufactured according to a very high pharmaceutical level standard. 13

00:48:54 The New York State product is a derivative of the cannabis plant. So it is a naturally derived substance that has gone through a pharmaceutical process. And so this makes it different than the synthetic products that are available like Miranol or Dronabinol. The plant derived products all have two main components, which is THC and CBD, and those are the components that you can adjust when you make your prescription asking for either high THC, high CBD, or a balanced approach. They also have these entourage compounds which come along for the ride, which may have active properties as well but are much- that are much less well studied than THC and CBD themselves. THC is the cannabinoid that has the main psychoactive effects and this is because of its diffuse actions at the CB1 receptor which has wide distribution throughout the brain and spinal cord. There is somewhat better evidence for THC on GI symptoms, although CBD also has antiemetic properties. THC is probably also better for pain, particularly severe pain, other than neuropathic pain which also responds well to CBD. And CBD can also be used as an anxiolytic and anticonvulsant. 00:50:13 Finally the process of becoming a registered provider and then the process of registering patients is fairly straightforward. Everything is internet based so you can do everything from your office. I don't think I mentioned also that the- the training programs- the 4 hour training programs- don't have to be done in one single four hour chunk. So it's something that you can start if you have a little bit of time and then come back to later on at your convenience. The whole process of prescribing is really even simpler now that we have this new option to allow the pharmacist to assist us with product selection so we can just select pharmacist consultation for both CBD/THC ratio and for the product that we would like- vaporizer oil or the pill. And finally prescribing should be done as part of a standard therapeutic relationship with regular follow up between patient and provider, similar to any other treatment that you would be providing to your patients. 00:51:16 So I'm going to stop there and just mention once again that this presentation is sponsored by the Clinical Education Initiative. This is the CEI hotline here, which is a toll free number that can be called for expert advice regarding a number of different conditions related to HIV, STDs, Hepatitis C or a pre- or postexposure prophylaxis. 00:51:40 And with that I will open it up to any questions. Thank you. 00:51:45 - [Jessica Steinke] Thank you so much Dr. Robinson-Papp. That was very interesting and very comprehensive. We do have some questions here so we can go ahead and present those. So one question we have is about the actual prescription. And so is the prescription written to include a quantity or a day's supply or is that something that's up to patient and pharmacist consultation. 14

00:52:06 - [Dr. Robinson-Papp] That's a great question. Usually we do write something like tid/prn so we'll write some kind of instruction. We do not write a dispense like you would for like 60 pills or something like that. And the main reason for that is because- I think because of cost. So, you know, when the patient goes they can decide how many or how much they want to buy of anything. However again, whatever you write on that prescription is nonbinding. So it's not like a regular prescription where if I write, you know, say Neurontin 300 milligrams tid for my patient number 90, that's what they get. This is really- it shouldn't even really be called a prescription. It's really more of a registration and a recommendation because the patient can ultimately get whatever they want. 00:52:51 - [Jessica Steinke] Great. Thank you. Another question. So we talked about physicians being able to do this and PAs doing it in consultation with physicians. Are nurse practitioners also able to do so, and if so do they also be the cooperating physician? 00:53:06 - [Dr. Robinson-Papp] Yeah. So the- I believe that a nurse practitioner does need a collaborating physician. The website specifically says that physician assistants need the collaborating physician to be registered as well, whereas it does not say that for nurse practitioners. I- I'm not I cannot be 100 percent sure that that's not an omission on the part of the state. But from what is printed on the website it appears that a nurse practitioner does not need to have the supervising provider be also registered. 00:53:37 - [Jessica Steinke] OK. Thank you. So I know you talked some about, you know, what might seem like contradictory information around anxiety. So one question we have is if medical marijuana has been approved for PTSD or anxiety generally and just, you know, so a little bit more information around that. 00:53:53 - [Dr. Robinson-Papp] Right. So there's good information. It has not been approved- so the simple answer is that that's not one of the indications that- that is listed. So PTSD and anxiety is not a qualifying condition in New York State. The THC component of medical marijuana can go both ways. So some people find THC calming and relaxing and some people find THC anxiety provoking. So it can be really either. CBD probably does have- there's decent data that it does have an anxiolytic effect. So if your patient- you can't recommend medical marijuana in New York State for anxiety. If you were recommending it for- or another indication and your patient also happened to have anxiety, you might want to be careful to just warn them about that. And I would probably recommend starting with a CBD dominant formulation. 00:54:49 - [Jessica Steinke] Great. Thank you. Another question here. So how does one decide what dose to initiate? And are doses titrated up based on patient responds, or is there a therapeutic dose or concentration to target. 15