[Music] hello and welcome to this presentation entitled medical marijuana real medication or just Recreation some of you may be joining the program today because this is a question that you yourself have wondered about or perhaps you've been asked by patients who are considering marijuana as an alternative or complement for any given disease or treatment that they're currently using living in Colorado this is a question that has been asked for several years as many of you may know my personal primary areas of expertise have been in women's health and patient safety and I never really thought initially that marijuana would be a patient safety issue as we're thinking about it now but for many reasons it has become that way and my journey into learning about metao marijuana started I distinctly remember a day when I was in my family medicine clinic about 5 years ago when a medical resident had a patient that was breastfeeding and also smoking marijuana the resident had told the patient that it was totally fine and to smoke marijuana because it was quote safe although at that time I did not know the data around marijuana and breastfeeding I was pretty sure it wasn't totally fine or for that matter completely safe so began my journey into marijuana learning about how it works in the body and its potential benefits and risks since then I've been able to do local state and National presentations as well as publish a little bit about medical marijuana I hope that you'll find this program to be educational and interesting I know it certainly has been an interesting Journey for me I think it's important to let you know that I do not have any relevant Financial relationships and I actually do not have a strong position for or against the use of marijuana it may go without saying but I will be discussing unapproved drugs and unapproved uses for drugs as marijuana is not approved for anything and in fact remains illegal in our country due to my growing expertise in this area I have served as a member of the Colorado Department of Public Health and environment amendment 64 task force working group and this working group um working under this amendment of for marijuana legalization focused on consumer safety and social issues my primary concerns are really impatient safety and education so that people choosing to use marijuana are really well informed about what they consuming so my goal is really to help people make decisions knowing the potential benefits and risks of marijuana just as they should really know the potential benefits and risk of any drug that they decide to consume there are four major objectives that I'd like to make sure we get through in this presentation first is I want to be able to review with you the various dosage formulations of medical marijuana available to patients and as you'll soon learn it's not just typic Bally the marijuana that you often think of in terms of the' 60s and 70s when a lot of people were smoking joints there's a lot of different dosages and dosage forms available we're going to describe the clinical pharmacology of Botanical medical marijuana and its Active Components we're going to look at clinical studies that have been performed in patients with various conditions to determine the effectiveness of Botanical medical marijuana and lastly we're going to identify adverse effects psychiatric implications and potential drug interactions that can occur with the use of Botanical medical marijuana these are not poll questions but I'm just simply trying to get you to establish a baseline in terms of where you're at about thinking in regards to marijuana first of all I'd like you to think about whether or not you live in a state where medical marijuana laws are enacted and maybe how you feel about that how about whether or not you know people including patients that use medical marijuana or maybe even use marijuana recreationally and then lastly are you participating in this webinar to learn If there really is such a thing as medical use for marijuana now I'm asking you to think about these things really to encourage you to put you into an open mindset and put aside any perceptions that you might have about marijuana at this time what I'd like to know now is just initially start with a patient case of someone that we typically see here in Colorado this is a 47-year-old man coming to the pharmacy for refills of his pain medications and he's got a significant history with hypertension diabetes pral neuropathy and chronic pain for this pain he takes oxycotton twice daily and Oxycodone as needed and his medications haven't changed since 2010 and you notice that he hasn't been to the pharmacy for 2 months today he admits that he's been smoking marijuana twice daily for the past 2 years which has helped his pain and he's actually gone from an eight out of 10 to a 4 out of 10 on the Pain Scale however he's been afraid to tell the healthcare team about it Because he believes they will not quote approve of this treatment and he states that he saw a physician that was different from his PCP to get his marijuana card and prescription for medical marijuana now after hearing that patient case there might be a few questions that you are thinking in your own mind for example is it legal for this patient to use medical marijuana are there other ways for him to consume it maybe to avoid the risks of smoking how about is this actually effective for the treatment of pain and his pain in particular what adverse effects might this patient experience with chronic use of inhaled medical marijuana are there any drug interactions how might it impact his opioid use and how can I myself as a healthc care provider create an environment where patients feel safe to talk with me about any and all treatments they use even if and when they are considered to be illicit substances I'd like to begin this conversation really with a basic understanding of the different ways that marijuana is available first of all we have single molecule Pharmaceuticals and two are currently available in the United States dronabinol is a schedule 3 medication it is a synthetic Delta 9 Tetra hydroc canabidol or THC navalon is a synthetic cannabinoid with a chemical structure similar to THC and it is a schedule 2 medication now there is also a liquid extract called nmoles or sax which is available and approved in eight different countries those countries include the UK Spain Germany Denmark the Czech Republic Sweden New Zealand and Canada currently in the US they are going through phase three trials to evaluate nmoles now the last one that we're primarily discussing in this particular context is the phyto canabo dense Botanicals or Cannabis sativa which is a medicinal plant and currently that is a schedule one so again I just want to emphasize that for the most part in this presentation when I'm referring to marijuana I'm really talking about the plantbased marijuana and when discussing the marijuana plant I'm really referring to the dried flowers leaves stems and seeds of that plant we use different parts of the plant and different products that we have available but I'm really in essence talking about the medicinal plant and not the other forms of marijuana that are currently available in our country and actually across the world I think it's important to provide some background about the regulation around marijuana and in fact it was considered illegal drug and in the United States pharmacopia prior to 1937 at that time it underwent Federal prohibition and it was prohibited by federal laws through the control sub Substances Act of 1970 and has been since 1937 now medical marijuana came to the four in 1996 and what this allowed was legal access under a physician supervision for marijuana and this has passed now in 18 states and the District of Colombia and what most of these laws say is that marijuana can be possessed or grown for use uh personally or by their primary or grown by their Primary Care Providers the amount of possession or amount of plants that can be grown can vary by state and then lastly most recently we've had legalization come to the four in two states Colorado and Washington since November of 2012 and this essentially eliminates the prohibition for possessing small amounts of marijuana but requires legislator now to regulate recreational use and in these states it's both uh in both States it's for patients 21 years of age and older although many practitioners professionally participate in State medical cannabis programs and maintain DEA registrations in good standing it must be noted that cannabis and many natural cannabinoids continue to be listed in the federal schedule one classification and just as as a reminder schedule one substances are those that have the following findings uh the drug has a high potential for abuse the drug has no currently accepted medical use in treatment in the United States and there is a lack of accepted safety for use of the drug under medical supervision so for all practical and actual purposes marijuana is an illegal substance still today in the United States under federal law now some states have opted to allow medical use and I've got those states listed here um where the use is decriminalized when used under a physician's supervision now what decriminalization does is that it removes the state level Crim criminal penalties for the private possession and responsible use of marijuana by adults including cultivation for personal use in terms of growing plants and Casual nonprofit transfers of small amounts um as I've already pointed out earlier Colorado and Washington now have laws that legalize the use of marijuana for recreational purposes as well now the focus of this presentation is on medical marijuana and I'm willing to speak to any of the legal ization issues at in the uh Q&A portion of the presentation if you'd like to know more about what's happening in Colorado in terms of legalization but again for purposes of this program I'll be focusing on medical use of marijuana let's start with some of the basics around the plant cannabis or marijuana marijuana contains over a 100 compounds called canabo and this list here is just a few of the known canabo probably the one that you are most familiar with is THC THC is the main component responsible for marijuana's mind altering effects and it's particularly the Delta 9 THC that we're talking about with that it's been shown to have actions for analgesia muscle relaxation enhanced well-being and effects with nausea and vomiting among many other conditions now the other prevalent uh compound is codol or CBD and uh this compound is the most prevalent compound found in hemp or the fiber plant although it's of course also found and used U medically and in fact it has had um some effects on pain inflamm nausea and again other conditions so again this whole list um is contained and many more in this uh plant medicine and really to better understand how the plant cannabis can exert it effects we really need to understand the cannabinoids that our body naturally provides in our system and so now I'm going to go back to our own endoc canabo system now before we can really get a good understanding of how the phyto canabo work we need to look at the endogenous cannaboid system and this is the can cannabinoids that our own body makes and these endocannabinoids and The receptors are found throughout the entire body as I've listed here in the brain organs connective tissues glands and immune cells and in each of these tissues the cannabinoid system is really performing different tasks all with the primary goal to maintain homeostasis now keep in mind that homeostasis is the maintenance of that stable internal environment despite fluctuations in the external environment so that when canono receptors are stimulated a variety of physiologic processes will occur to provide an appropriate homeostatic response now we predominantly have found two cannabinoid receptors the CB1 receptors are mostly present we think anyway in the nervous system connective tissues gonads glands and organs the CB2 receptors are predominantly found in the immune system and its Associated structures and may play a large part in anti-inflammatory and analgesic actions now many tissues contain both CB1 and CB2 receptors that are each linked to a different action researchers actually speculate there may be a third receptor or more waiting to be discovered now endoc canabo are substances our bodies make naturally to stimulate these receptors and the two most well understood of these molecules are anandamide and two aronal glycerol or 2 AG they are synthesized really on demand from the cell membrane arachidonic acid derivatives and they have a local effect in short halflife before being degraded by the enzymes um that are found there and essentially this endoc canabo system is a bridge between the body and mind and that's why when we stimulate it through phyto canabo we have many different effects that can occur in the mind in the body let's take a little bit closer look now at the brain's chemical anandamide compared to the drug chemical THC now actually the word anandamide comes from the word Ananda which is is the Sanskrit word for Bliss and is one of the chemicals activated when someone actually experiences a runner's high as you can see the natural bodies anandamide and the phyto canono THC may look very similar to a cannaboid receptor in fact both of these act as partial agonists on cd1 receptors as I mentioned earlier now the first what I'll call Bliss molecule THC was isolated in 1964 but it was only with the discovery of anandamide in 1992 did the significance of thc's Discovery really make sense when smoked or ingested THC and other cannabinoids in marijuana attached to the two receptors we talked about CB1 and CB2 like keys and a lock what I'm showing you here are the CB1 receptors these are most highly these are the most highly expressed you protein coupled receptors in the brain and are about 10 times more prevalent in the CNS compared to the MU opioid receptor which of course is a well studied receptor involved in pain now what you're seeing here is that the main chemical component of THC present in cannabis stimulates CB1 receptors which control body movement memory and vomiting and um this are just a few of the ways that it acts on CB1 and explains why marijuana use affects balance and coordination and maybe impairs short-term memory and learning and why it can be useful treatment in things like nausea pain and loss of appetite lastly I just want to point out that the cannabinoid receptors are located throughout the entire body and I've kind of alluded to that already therefore the impact that marijuana can have is extensive and hopefully by the end of this presentation you'll better understand the potential benefits as well as the risks of using such a substance in our body as it can have so many different effects here in the picture on the left I'm showing additional targets of cannabis in the adapost tissue where it actually typically resides as lipid soluble chemical um it also goes to the liver and the GI tract the picture on the right shows really the various therapeutic targets for which it has been treated or used for treatment we'll come back to these therapeutic issues in just a minute I'd like to just first start with some of the other information regarding the pharmacokinetic and pharmacodynamic effects that various formulations of marijuana can have as I mentioned earlier there are a lot of different marijuana formulations typically it is administered through three different rounds of administration in the lungs it can be either vaporized or smoked and the organic material of the plant is used some of you may or may not be familiar with cannabis vaporization this is essentially a technology for delivering inhaled THC and other cannaboids while reducing the toxic byproducts that can be caused by smoking and that is which is caused by combustion so in vaporization by heating the Cannabis to a temperature approximately between 180 and 200° C it's possible to vaporize the canabo that reside on the flowers and leaves while avoiding combustion which doesn't occur until about 230° and any of the other toxins that may come from smoke and so we have the ability to I guess more safely smoke the marijuana um rather than just you know good oldfashioned joints and cigarettes that are made from these materials now the other common way that marijuana is in adusted is through the gut and that is done orally um Edibles such as you know cookies brownies candies all kinds of things you've name it they've tried it and drinks primarily go through the gut um as a lipoic alcoholic super critical fluidic extract of plant material now what that means is essentially you're separating the components of the plant by using an extracting solvent and um usually that's done in a solid form but as mentioned here can also be done in a liquid form now tinctures are a little bit of a unique entity because they are actually Bucy absorbed or typically buy absorbed because it's a a concentrate of the Cannabis that's actually placed under the tongue rather than going through the gut lastly we have a topical application as well so there are lotions and creams available we don't have as much information on that particular application or administration of marijuana and we're not sure how much of the THC is actually absorbed in that process to a systemic level it may help um for skin conditions and things like that but systemically we don't have a lot of information about what happens with that now let me just walk you through a little bit of the phac kinetics with each of these particular ways of administration when we look at taking marijuana in through the lungs it appears very similar to an IV Bolis as you can see from the graph here we have passive diffusion into the a capillaries and the onset is very rapid within seconds to minutes and the maximal onset is about 30 minutes but can last as long as 2 to three hours and in fact often what we see is that Peak concentrations of the drug may occur um within that 30 minute to 2hour window but that the actual effects of the THC may not take place until a little but after that time frame now if it's smoked about 50% of the THC content is delivered through the smoke and some's lost to heat others lost from burning of the cigarette and so we kind of go through this process of losing the THC if and when it's smoked those the there is some metabolism in the lungs which occurs at about a 10 to 25% rate now vaporizing um provides a similar THC effect but has lower carbon monoxide levels and other combustion products such as poly aromatic hydrocarbons and things like that in general when people are um using marijuana this way they tend to self- titrate to obtain their desired level of THC and they can do this rather quickly because that onset is fairly quick again with that seconds to minutes they start feeling the effect and so that self-titration piece can be very um quick overall now when someone decides to use marijuana orally and it comes through the gut it's an entirely different story than when it's absorbed through the lungs there is highly variable absorption and bioavailability can range anywhere from 5 to 20% now the variable absorption is really dependent upon the gastric contents and the bioavailability is often lower and variable due to gastric degradation and an extensive first pass effect and we've even heard anecdotally that um people at dispensaries are recommending that people who use um the oral route that they take it with a full glass of milk on an empty stomach to maximize the absorption and the reason for that is because that milk is going to be very lipid soluble and it will enhance the absorption and effect of the drug now again another difference is that the onset is much longer and the duration is much longer so that onset is anywhere from 30 minutes to 2 hours with the duration last 5 to 8 hours now this becomes very difficult in terms of self-titration because you don't get that immediate effect you could eat a small portion of a brownie or cookie or a gummy and you may not feel what happens with that for a couple hours and so because of that um it becomes much more difficult to get an accurate dose at least when initially starting so even in going to dispensaries and talking to them about what do they recommend for for patients what they are saying is you know take a Saturday to determine what your proper dose is now I'm not saying that's right or wrong it's just that that's what they're kind of recommending so people can have the proper um dosing that they believe will give them the effect that they want now another complication is that there's High intrapatient variability so between patients it's also very difficult to determine or predict what a response will be and so overall we end up in a more difficult situation dealing with self-titration for appropriate dosing now the flip side of that is that patients often like the oral route because it doesn't have the risks that they perceive that smoking or vaporizing would have and it may also eliminate some of the social stigma involved with smoking or vaporizing dosing is extremely difficult because there are hundreds to thousands of cannabis plant strains available and every cannabis plant strain has a different amount of canabo and each canabo can be presentent at differing cont concentrations and these are just some of the variables as to how dosing could be affected uh potency may be affected by not only the concentration of the plant but also the storage conditions of the plant and we know that marijuana potency has significantly increased over the past four decades or so with about a 6 to sfold increase coming from less than 1% THC in the early 1970s to about 10 to 11% in the early 2000s so we looked at there was a review published of 165 studies which attempted to normalize the THC dosing and what they found was that a low dose THC could be defined at less than 7 Mig a medium dose would be 7 to 18 mg and a high dose would be greater than 18 Mig of THC however we know that based on use of marijuana either uh chronically or heavily that the dose that someone may quote need to get the desired effect could be much higher than even these high doses um and then lastly I just wanted to point out to you this dosing model which was presented through these rational guidelines for dosing in which they base the uh dosing of marijuana on THC content so you look at the percent of THC in the Cannabis and then you can correlate that to a daily dosage of 2.5 to 90 mg of THC based on the weight of the marijuana that may be that may be used now this particular group really focused on and advocated for self-tie trating so using um cannabis in in the smoked form anyway um in a self-titration model being that that would be acceptable and it is not unique to other drugs that we use such as gabip pettin for example um now the reason I wanted to present to you some of this dosing because it will vary so much from person to person is that it will give you some framework as we move to talk about studies and the doses that were used in those clinical trials now when we look at the pharmacodynamic effects I mentioned briefly this study or this uh publication of 165 studies that evaluated the effects of marijuana and they really looked to determine consistent pharmacodynamic effects with 2 to 10 milligrams of THC so again kind of towards that low to medium dose range and what they found consistently in that from a pharmacodynamic standpoint and terms of adverse effect was an elevation in heart rate an increase in a subjective feeling of high a decrease in alertness and a decrease in motor instability or body sway now this slide really depicts for you visually these particular pharmacokinetic and pharmacodynamics occurring with THC the subjects were given increasing doses at 2 46 8 mg via the vaporizer at 1 and 1 half hour intervals and what you see here in the graphs is a is an increase in in heart rate that steady increase in feeling high and again you're seeing this effect over uh 6 to8 hours and then a decrease in the alertness now all of these are probably typical side effects that you might expect to see from um acute intake of marijuana so so far we have covered the various formulations of marijuana as well as the pharmacology and pharmacodynamics of how marijuana may work in our bodies I'd like to transition now to looking at the therapeutic effectiveness of medical marijuana as I mentioned earlier the phyto canabo can Target a number of different areas in our body and that begs the question in terms of what should be studied what I have listed on the slide here are some of the condition and only some of the conditions that have been evaluated with marijuana in terms of addressing the issues so you can see that it includes an entire variety anywhere from things related to the central nervous system to the GI tract and even things like glaucoma uh cancer and things like that now this is not a poll question but I just want to kind of get you thinking about what you think is the most common reason that medical marijuana is used in the United States would you say that it's due to cancer or used for cancer glaucoma muscle spasms nausea or pain just take a second to think about how you would respond to that question now across the country the most common reason that medical marijuana is used is pain so hopefully that's maybe what you thought or at least considered in your response to the questions what I'm showing you on this slide are the data Registries from Colorado and Arizona and the reason that I have these particular States identified is because they are um two states that have fairly re rigid guidelines in terms of tracking who is getting medical marijuana cards and what are they using it for now the data that I'm showing here is current as of January 31st 2013 and you can see down the middle of the slide these are the different indications that Colorado has for medical marijuana and you can see that 94% of patients in Colorado are using it for pain uh another 16% for muscle spasms and then the rest of the patients really for a variety of conditions in Arizona in addition to the um things listed here they also have other indications including hepatitis C Crohn's disease sclerosis and Alzheimer's now 71% of the Arizona population is using marijuana for pain but I want to just point out that that 20% that's indicated there is really that stating that 20% of these patients have two or more conditions but the exact conditions that they had were not specified so again I'm just reiterating the point that the most common reason we see medical marijuana being used is for paint and because of that and because of such a large percentage of patients I'm really going to focus my therapeutic Effectiveness piece on medical marijuana for treating pain now if we know that medical marijuana is used mostly for pain I think the next logical question is well how should it be studied so we can get the best evidence to provide that so what I've done here on this slide is just get you thinking about the different ways that you can get information and evidence put together and I'd like you to just in your own mind maybe think about how you would rate the lowest level of evidence and where that what type of evidence that would be at the bottom of the pyramid with what would be your ideal or highest level of evidence and kind of putting that at the top of the pyramid now I'm guessing that many of you probably put the randomized control trial at the top of your evidence pyramid and I agree with that the issue that occurs with especially medical marijuana is that we have very small trials with small number of patients and a lot of that has to do with the fact that it is a schedule one substance so it's very difficult to study and so I'm going to ask you to consider and maybe entertain me in also acknowledging that metaanalyses in this particular situation may be even more appropriate to look at the effectiveness of medical marijuana and I'm going to be talking both about some meta analyses as well as randomized controlled trials but in this particular situation because of the low number of patients that are found in trials we're going to consider the metaanalysis to actually be the preferred level of evidence now this study was a systematic review of randomized trial and included 766 patients uh looking at the treatment of chronic non-cancer pain so the conditions really included things like neuropathic pain fibromyalgia rheumatoid arthritis and some mixed chronic pain now I'm drawing your attention specifically to those four trials that looked at smoke cannabis and all trials in this particular study found positive effect by improving neuropathic pain versus placebo with no serious adverse effects now overall these authors concluded that there was evidence that canabo are safe and modestly effective in neuropathic pain and there was also some preliminary evidence based on the other studies for efficacy in fibromyalgia and rheumatoid arthritis so again it's only four trials and I do just want to bring up the fact that there often is publication bias in that positive results tend to get published more than negative results so you have to keep all that in mind as you're evaluating the evidence here but again looking at the smoked cannabis trials in non-cancer pain we find that there was a significant positive effect let's now take a look at this systematic review and meta analysis this was looking specifically at cannabis treatment for chronic pain it was uh considering 8 double blind randomized control trials and they included a lot of different forms of cannabis so again kind of combining all that data together with things like uh dronabinol and na naalone now the efficacy outcome in this trial was intensity of Pain by visual analog scale and so they're actually looking at a scale typically from 0 to 10 to determine how intense the pain is zero being no pain at all 10 being the worst imaginable pain they could have ever had and the harms are the number of Adverse Events that occur Now They concluded moderate efficacy but that the risks may be greater than the benefit and let me show you why if we look at the change in the intensity of pain we can see that cannabis treatment did reduce the intensity of Pain by 0.6 on that scale now we typically think of a change of about3 being significant clinically So Not only was this statistically significant it also was clinically significant now the other side of that is that there were a lot of outcomes or adverse effects now none none of these were considered to be serious and by that probably means that nobody was um had a death or significant morbidity through a hospitalization but you can see that patients experienc four times the amount of euphoria about 2 and a half times the amount of dysphoria eight times the amount of blurred vision two times the amount of t uh t ttis three times the amount of disorientation and confusion and again this is all with the Cannabis therapy there's also significant increases and speech disorders a taxia numbness impaired memory and attention disturbances now none of these really are surprising because we know that cannabis can cause many of these adverse effects but you're really weighing the benefit of reducing the pain intensity by 6 with the potential for some of these adverse outcomes now another systematic review of meta analysis that was fairly recently performed was done in a group of patients with painful HIV Associated sensory neuropathy and the objective of this trial was to evaluate the clinical effectiveness of various analgesic analgesics and they included things like cannabis like I mentioned but they also included amitryptiline Gabapentin pregabalin lamotrin maxatin and uh caps now a total of 14 trials were evaluated but of all those treatments I just mentioned mentioned the ones that were found to be effective by a statistically significant degree was the smoked cannabis which ranged in potency from 1 to 8% and a high dose caps of 8% when we look at the results of this study we can see that the smoked cannabis was actually quite effective there were 122 episodes that were evaluated and we see that about half of the patients had a 30% or more Improvement in their visual analog scale and about a quarter of those patients had a 50% or more Improvement in their visual analog scale so a lot of these patients experiencing significant improvements so much so that they were about twice as likely to have reliefs compared to other therapies and the number needed to treat meaning the the number of people you would need to treat with smoked cannabis to get some benefit was anywhere between three and four patients now notably that number for caps 8% which is also found to be effective that number needed to treat was between six and seven patients so in this trial the smoked cannabis actually ended up being the most effective treatment for this group of patients so that is a recap of the meta analyses that we currently have available I want to just take you quickly now through a few controlled clinical studies that have been done and what I've done for you here is summarize uh based on um a kind of a compilation of Trials published through about 2011 the number of trials that have been published regarding chronic pain with the various cannabinoids so dronabinol the smoked cannabis and then oral or sublingual cannabis and I'm really just trying to highlight here for you that there really is not very many trials available for us to make uh significant associations or or recommendations now there was another trial very recently published that did a pub Med search kind of along similar similar lines and they found that 71% of uh randomized control trials evaluating various cannabinoid medicines did find demonstratable pain relieving effects 29% of those did not now you could again argue the publication bias you could also say well there essentially could be quite a bit of Effectiveness that we see with this type of medicine this is an example of one trial that was performed using smoked cannabis for chronic neuropathic pain and again a small trial with only 21 adults and the Cannabis was given at 25 mgram dosing so a higher dose at 0% 2.5% 6% and 99.4% and they were patients were instructed to smoke it three times per day and what they did was a crossover trial so in these 14-day periods there was uh 5 days of study drug given and then nine days of wash out and then they repeated that cycle four times the primary outcome for this trial was pain intensity again on that 11 item scale so if we take a look at the pain intensity changes we can see that there was a trend towards better pain relief in the 9.4% THC group with a difference of 7 that was statistically significant that P value being equal to 0.023 and so it was statistically significant and fairly similar pain reduction to what we saw in that previous trial now in terms of statistically significant results from the from other um outcomes secondary outcomes what they found was that sleep was actually easier and they had less wakefulness um in the 99.4% group anxiety and depression also seemed to improve and that was measured by an eq5d which is a validated questionnaire and then in terms of Adverse Events there were 248 mild events and six moderate events which I've listed there for you um and no serious events in this patient population in terms of adverse effects the last clinical trial I want to show you was 28 participants in a phase 2 single group double blind placeable controlled crossover trial of smoked cannabis for short-term treatment of neuropathic pain associated with HIV infection and how they did this particular trial was start with a wash out and then administered 5 days of cannabis or Placebo to the patients and again they started actually at a 4% THC concentration and had the person titrate up or down depending upon the effect that that they needed and then they went into a two we wash out period And Then followed that by five days of the other treatment that they did not receive the first time around and Then followed that by two weeks wash out and they did measurements um at each of these time points now the measurement that they primarily used what was called the descriptor differential scale and this is a ratio scale containing 24 words describing pain intensity and unpleasantness and these ratings are aggregated to provide a summary score on a 0 to 20 point scale and they use and the and the participants rate their pain magnitude relative to these descriptions they also did do a visual analog scale but the results that I'm showing you here came from the DDS and what you see here is that there was a median difference in the pain severity with a change of about 3.3 points on that 20 point scale this was statistically significant with a P value of 0.016 and you can see there by the graph as well the significant difference in these um pain scores there were uh some adverse effects reported including concentration difficulties fatigue sleepiness sedation uh and increased duration of sleep which again are not surprising and somewhat expected they also did report some changes in heart rate in blood pressure initially but those resolve spontaneously and cause no symptoms so in terms of the efficacy side and in summarizing the clinical trials that we've looked at so far with pain I do think that canabo have a role for the treatment of refractory pain especially neuropathic pain which has been probably the most studied pain condition the appropriate and consistent dosing or concentrations of marijuana is extremely difficult for a lot of the reasons that we've already talked about and of course there are study limitations such as small sample size publication bias a short duration and very subjective outcomes um we really do need to do more research and it may have an unfavorable side effect profile and from here I kind of want to focus on maybe that aspect of using medical marijuana now I want to just remind you that there are adverse effects of medical marijuana that seem to be more immediate and those more immediate effects are increasing heart rate and increasing blood pressure and of course that over time could lead to an increased risk of heart attack in terms of smoking there are also risk with smoking which may lead to an increased risk of heart attack now vaporizing May mitigate that risk and again many people are preferring vaporizing over smoking in terms of a way to consume marijuana now when we look at the overall adverse effects of medical marijuana it's really important to consider studies that have included Botanicals many of the meta analyses or systematic reviews that have been published have looked at all formulations of marijuana and I really want to um really focus here on that initial systematic review that I covered with you looking at the 766 patients with chronic non non-cancer pain in this particular study no ad serious Adverse Events were reported and of the adverse effects that were reported they were considered to be well tolerated and either transient or mild to moderate now the most common effects that we that we heard in this patient group was sedation dizziness dry mouth nausea and disturbances in concentration again not surprising less commonly reported side effects included poor concentration taxia headache paranoid thinking agitation and things like that now interestingly I think it's just good to point out that the adverse effects did not lead to withdrawal from the study and that is really quite surprising especially compared with other pain studies like opioid studies where there's an abandonment or withdrawal rate of approximately 33% so I've pointed out some somewhat quote Common Sense type of adverse effects that can occur with marijuana but I think there are some more significant consequences when this drug is chosen the psychiatric implications can be quite significant there are two things I just kind of want to mention here there is such a thing as an acute cannabis psychosis where when very large doses of can cannabinoid Botanical are consed assumed typically through oral ingestion where there's a concentrated preparation we see a high level of agitation confusion and sedation and it puts them in kind of this psycho psychotic or psychosis type of state now this is generally self-limiting and will disappear after the drug has been metabolized or excreted and you can imagine that the reason we see this with oral ingestion is because people eat something they don't feel an effect and so they eat more and this continues to happen and as we talked about earlier that armet is so much slower and the full duration is so much longer that it can take a while for that drug to accumulate in the body and so when it does hit there's now a lot of THC in the body and they can get this acute cannabis psychosis the other thing I want to talk about is an acute schizophreniform reaction or essentially a schizophrenia like reaction and we have seen this very um more much more commonly in young adults under stress who have other vulnerabilities or predisposition positions to a schizophreniform illness now what we have also seen is that smoking or eating marijuana early and using it heavily may increase the risk of a psychotic disorder just developing such as schizophrenia and really my other piece of this is that in our younger population their brains are still developing they brains really don't mature until they're about 25 years old and so if there's a high-risk population in my mind it's really those people that are uh younger in their adolescence and still developing in their brains and so I'm recommending that we carefully monitor or preferably avoid marijuana in early teens or pre-teens especially if they have pre-existing symptoms of mental illness or patients who have significant family or personal histories of family illness as pharmacist I think it's really important for us to think about potential drug interactions for patients who are using marijuana now THC is metabolized to several Hydrox metabolites in the liver by the cytochrome p450 2c9 and the Sip 3a4 systems and so we really need need to be paying attention to drugs that may be metabolized through those Pathways and it may be more critical for oral Administration since there is going to be a significant first pass metabolism with oral products even more so than with um those that are ingested through the lung LS now I've highlighted for you here the various medications that we would really want to monitor for and through case reports the symptoms that have been seen so for example when marijuana has been used with tricyclics there has been teoc cardia and delirium reported with ssris Manic symptoms have been reported and then on the other side uh with CP 3a4 mediated metabolism there have been uh known proteas inhibitor drug interactions um where a redu of the medication a reduction in the concentration of medication occurs now we don't know for sure whether or not that is going to be clinically significant the ranges were anywhere from 14 to 19% reductions in those protas Inhibitors and so it may or may not be clinically significant and then also there's been interactions reported with selenop now Warren has also had some case reports where an increased INR has been reported with frequent marijuana use and then there can be of of course additive depressant effects when using marijuana with other CNS depressants so it's not necessarily a sip 2c9 or 3a4 interaction but there is an interaction where additive uh depressive effects can occur so things like barbituates alcohol benzo diazines antihistamines or narcotics would be examples of medications where we wouldn't want to use those with marijuana now one of the other issues that I think is important for pharmacists to recognize is how does mariju marijuana of such opioid use and what we see is that in a lot of studies when marijuana is used in conjunction with opioids as a complement to their therapy canabo can lead to Greater cumulative relief of pain and potentially reduce the amount of opiates that people use and we saw that happen in our patient case now the comparisons for analgesia um really again this is coming from older data here but they equated 10 Mig of THC to be a little bit less effective than 60 Mig of coding but 20 Mig of THC to be more effective than 120 Mig of Codine and what it may do is help prevent the development of tolerance to and withdrawal from opiates and maybe potentially rekindle any opiate analgesia if there's been uh some tolerance built after a prior dosage has become ineffective now there are some arguments out there that marijuana May potentially be less dangerous than opiates because they're has been and cannot be a direct death due to marijuana and that has to do with the way that it acts in the brain stem um now I'm not saying that it doesn't cause death because I think if people drive impaired there certainly could be indirect consequences to that but there have been no direct deaths reported due to marijuana use now let's go back to our patient in Colorado after considering all these issues this patient is walking into this dispensary in which you can see here uh the buds available on the left and the various edible products um on the right and I just want to show this to you because some of you may not live in states where dispensaries are available this is a very typical kind of presentation for dispensaries in terms of what's available a patient walks in right now with their medical card and they show them their card and then they go through the process of choosing and selecting the appropriate Mar marijuana product that they want to try now keep in mind when a patient goes into that dispensary what they are going to get is the natural THC uh typically THC Rich product now there are CBD Rich products as well but we're really talking about products that have been derived from the plant material that will either be inhaled ingested orally or applied topically um there are no official indications again that time frame for onset and duration can vary widely depending upon the dosage and and formulation that they choose I thought it would be a good idea to give you a closer look at some of the products that a patient may see in that dispensary so on the upper left here we've got the actual buds kind of in containers these would be the the buds that would be smoked or or vaporized typically hash is made from a concentrate um a concentrated form of the the oils of the U plant material Edibles of course also made in a concentrated form here we see a variety of uh cookies brownies um and really good-looking desserts but then again on the left I've listed for you the other types of products that are commonly chosen such as tinctures chews or uh gummies uh and as well as drinks such as sodas or teas and as I mentioned earlier topicals are also available so I think as we go back and look at our patient and what we need to consider we have to understand that there are many strains of mar available there are hundreds of strains each with different potencies and plant properties and addition to that dosing and response will vary greatly between individuals and absorption rates will vary depending upon the formulation and the administrative r that they choose there could be drug interactions that exist and the thing that I think is key is that the person at the dispensary is really the person helping that patient make their medical marijuana decisions and so there really may be no patient provider relationship ship at all outside of that dispensary provider and so in terms of a health care provider that may not be present outside of the fact that they went to go see somebody to get their card they're not the ones necessarily helping them choose a product that they're going to get and so I really think it's important for us to help create safe environments for patients to discuss all of their drug use including illicit substances and help them understand that there are benefits and risks choosing any drug including marijuana Iana let me go through now my final conclusions there are many types of medical marijuana available to patients most of which have not been well studied and I'm certainly hopeful that you can appreciate that now more than ever going through most of the trials that have been published and looking at pain THC is the best studied cannabinoid and is known to have psychoactive Effects by targeting specifically CB1 receptors in the brain and clinical studies indicate that medical marijuana because of these mechanisms and the other cannabinoids in the system may have a role in patients with pain especially those that are refractory to other treatments now the risk for potential Adverse Events may or may not outweigh the benefit of that treatment provided I think we as pharmacists need to be aware of potential drug interactions and the psychiatric implications and make sure we're informing patients of those potentials and really to continue and ask for the research that we need to really help determine the most appropriate uses and the doses of medical marijuana [Music]