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The Roles and Risks of Cannabinoid Pharmacology

– Welcome, everyone, to Wednesday Nite @ the Lab. I’m Tom Zinnen, I work here at the UW-Madison Biotechnology Center. I also work for the Division of Extension and Wisconsin 4-H, and on behalf of those folks and our other co-organizers, PBS Wisconsin, the Wisconsin Alumni Association, and the UW-Madison Science Alliance, thanks again for coming to Wednesday Nite @ the Lab. We do this every Wednesday night, 50 times a year. Tonight, it’s my pleasure to introduce to you Natalie Schmitz of the School of Pharmacy. She was born in Prior Lake, Minnesota, and she went to high school at Holy Angels Academy in Richfield, Minnesota. And then she did not get a bachelor’s degree, ’cause she went through one of those six-year programs. So she has a master’s degree in public administration and a Doctor of Pharmacy from Drake University in Des Moines, Iowa. Then she went to the University of Minnesota in the Twin Cities to get her PhD in experimental and clinical pharmacology. And then in November of last year, she came here to UW-Madison.

Tonight she’s gonna be talking to us about something that has really changed a lot in the last year or two or three, and that’s the whole range of cannabinoid issues. The title of her talk is “Deep Into the Weeds: “Cannabinoid Pharmacology, Therapeutics, and Risks. ” Please join me in welcoming Natalie Schmitz to Wednesday Nite @ the Lab. [audience applauding]

– Thank you for the introduction. And just to give you guys a little bit more context of how I got started in this cannabinoid, cannabis space. So my PhD work was on the development of a drug for spasticity, and a year into my PhD work, medical cannabis became legal in Minnesota, and you needed to be a pharmacist to dispense medical cannabis. One of the qualifying conditions for medical cannabis in Minnesota, spasticity. So I thought, well, this would be a really cool way to get to know my spasticity population more clinically instead of just in a research setting, and gain a little bit of extra money on the side, ’cause let me tell you, PhD stipends are not cushy. [audience chuckling] So on the weekends I was a medical cannabis pharmacist, and it started just to supplement my PhD program, but it really grew into a passion of mine, because there’s so much more research that needs to be done on these therapies. So now that I’ve got my foundational knowledge from both my PharmD and PhD, and I have this clinical knowledge of cannabis therapies, I’m looking to unify those here at the University of Wisconsin to research both the safety and efficacy of these different compounds.

So I have no conflicts of interest, but to kind of go over what we’ll talk about today, we’ll go over the endocannabinoid system, different cannabinoid compounds, we’ll review the history and legal status of these different cannabinoids, the potential therapeutic applications, different risks, whether those be adverse effects or drug interactions, the impact of different routes of administration and formulations, as well as what the future may look like, what therapeutic challenges there are, and what research we’re doing here at UW. So to make sure we’re kind of all on the same page here, because the terminology that you both see in the media and that I’ll use throughout this presentation can be kind of confusing. So first, cannabis. Cannabis is the plant family and includes many different species, and we’ll break down some of these different varieties later on, but hemp is one of these varieties. And the hemp plant, traditionally used for making ropes, textiles, or other fibrous materials, has less than 0. 3% THC by a recent bill in 2018. Marijuana is another variety of the cannabis plant. Cannabinoids can be defined in many different ways. One of the ways is botanical definitions, so what compounds are present in the plant. Another way would be a chemical definition.

So, of these compounds, what are similar on their chemical makeup? And then the third way would be pharmacologic definitions. What compounds are interacting at the receptors that are in our endocannabinoid system within the animal body? So for today’s purposes, we will be using the definition that cannabinoids are chemical compounds that are found in the cannabis plant. And then there’s over 120 now different cannabinoids that are found in the cannabis plant. The two that we’ll be reviewing the most today and that have the most evidence behind them and potentially therapeutic potential are cannabidiol, or CBD, and delta-9-tetrahydrocannabinol, which is THC. And then there’s a number of different products. An isolate product is a pure cannabinoid, so that means it’s only CBD or only THC. A full spectrum product includes all of the different things of this plant. So the full range of cannabinoids, all of the terpenes which give a product its aroma, and all of the flavonoids which give a product its flavor. A broad-spectrum product would be nearly the full range of cannabinoids, terpenes, and flavonoids with the THC extracted from it. So now that we have kind of the terminology under our belt, let’s go over the endocannabinoid system and cannabinoids.

The endocannabinoid system has evolved over 600 million years, and these receptors are present in every vertebrate that’s been investigated to date except invertebrates, and you can see that in this diagram here. This system is a balancing system, or kind of a homeostatic regulator. So it’s sending out neurotransmitters or messages to all different parts of your body to make sure everything’s working smoothly and confirm if anything needs to be rebalanced. When it finds something, a problem, it regulates it by sending out more neurotransmitters or instructions to help these receptors adjust the way you feel or think. This system is unique in that it has a negative feedback loop, or it communicates backwards. So this cell-to-cell communication inhibits immune response, inflammation, it relaxes muscles, lowers blood pressure, and normalizes overly-stimulated nerves. It’s basically one of our natural checks and balances to make sure there’s not too much happening before accepting more stimulation. There’s a number of different receptors in this system. The two that are most well-defined are CB1 and CB2. CB1 receptors are primarily located in the CNS, so the brain and the nervous system, but they’re also in the uterus, the testes, the gut, and adipose tissue.

So these areas are, the CB1 receptors are primarily found in areas that regulate appetite, memory, fear, and motor responses, and that’s seen with the blue dots. In contrast, CB2 receptors are mostly found in the peripheral organs and the immune system, and that is seen in the pink dots. There are other receptors that are being characterized, one of them is GPR55, and that is found to be expressed throughout the body as well. So much more still needs to be learned, but the two that are most well-defined again are the CB1 and CB2. We also have cannabinoids naturally native in our bodies, and those are the endocannabinoids. The endocannabinoids that are interacting naturally are created right at the site of action when we need them, they’re broken down when we don’t need them. So these signals are gonna be really quick and localized, and the two endocannabinoids that are most characterized are anandamide, or AEA, and 2-arachidonoylglycerol, 2-AG. Then there’s another bucket of cannabinoids, or exogenous cannabinoids, cannabinoids that we would ingest. And then it can be further broken down into phytocannabinoids, cannabinoids that are found in the plant, and synthetic cannabinoids made in a lab. So like I said, there’s over 120 different cannabinoids.

Many of these are thought to have therapeutic potential. Again, THC and CBD have the most research behind them at this point, and there are some approved formulations. So Epidiolex is a formulation of CBD that was approved for two rare seizure disorders, and that’s a plant-derived form of CBD. And Sativex is not approved in the U. S. , but it’s approved in 15 other countries, and that’s a combination of THC and CBD, and that’s also plant-derived. And then there are synthetic cannabinoids. Two forms of synthetic THC that are approved by the FDA are dronabinol and nabilone, and there’s also illegal recreational form, so that would be K2 and Spice. When these are ingested, they’re widely distributed throughout the body, and then they’re broken down by the liver. So the effect of these cannabinoids are gonna be longer, more sustained, and have a more global effect, so you may have some unwanted side effects from these sort of compounds.

Cannabis has a really rich history, and the policy today is of much debate. So let’s go through first the history. Cannabis sativa is one of the world’s oldest cultivated plants. In fact, in 1500 B. C. is when there’s the earliest written description of cannabis, and that’s in the Chinese Pharmacopoeia. There’s also evidence that it was used for medical healing in Egypt, India, Middle East, and Greece. And then, in 1611, the Jamestown settlers brought the hemp plant to the U. S. In 1612 to 1762, there’s a number of different medical books that suggest cannabis for healing of many different ailments: gout, knots in joints or arthritis, depression, just to name a few.

And then, in 1840, William O’Shaughnessy is an Irish physician who’s working in Calcutta, and he was one of the first to bring cannabis to Western medicine for the treatment of typhus and other convulsive diseases. By 1851, we have the marijuana listed in the U. S. Pharmacopeia for a number of different conditions. Neuralgia, cholera, rabies, leprosy, gout, convulsive disorders, tonsillitis, insanity, the list goes on. [audience chuckling] But then, things kind of start to turn in 1911. So Massachusetts was the first to outlaw cannabis. In 1930, the Federal Bureau of Narcotics was established. Reefer Madness is a movie that perpetuated the stigma, negative stigma of cannabis. The Marijuana Tax Act effectively made possession of cannabis and transfer illegal throughout the U. S. The Controlled Substance Act scheduled cannabis to a Class I classification, which indicates a high potential for abuse and no accepted medical use. Some other drugs that are in this classification are heroin, LSD, and peyote. There’s a number of different attempts to reschedule cannabis, but none of them have been successful. And then in 1996, we kind of start to see the change that we’re experiencing today when California legalized cannabis for medical purposes. So where are we at now? Cannabis is still a C-I; it’s still that same classification indicating high potential for abuse and no medical use. However, Epidiolex, the FDA-approved version of CBD, was scheduled as a C-V, which is the lowest regulated scheduled controlled medication. In 2018, the Farm Bill rescheduled hemp so that 0. 3% or less THC-containing plant and CBD made from hemp, so that’s no longer scheduled and that’s legal. And then, each state regulates cannabis products differently, whether it be recreational, medicinal, or CBD-only programs.

Here we have a map of the U. S. and the policies by state. So right now, the dark green states have recreational and medicinal programs, the true green are states that have medicinal programs, and those with the star in it indicate mandated pharmacist involvement in these medicinal programs. There’s seven different states that mandate that. The yellow states include CBD-only or low THC programs, and then the gray states have no policy surrounding this. What does the FDA have to say about all of this? So the FDA recognizes that there’s a significant public interest, but there’s still many unanswered questions on the safety and efficacy, and even quality of these products. The agency did hold a public hearing in the spring of 2019, and they’re currently collecting data through a public docket to answer some of these questions. However, CBD is still illegal to market as a food or a dietary supplement, and they’ve sent out many warning letters to different companies because they’re concerned that they’re providing misleading, unproven, or false claims surrounding CBD products that could lead consumers to put off getting an important medical diagnosis or treatment by self-medicating. And then, some of these products are also of unknown quality.

So in 2017, there was a paper showing that approximately 2/3 of products, CBD products online, were inaccurate in what they claim. So that’s another important thing for maintaining quality of products and knowing what you’re getting. So now that we know what the endocannabinoid system is, and cannabinoids, and have a little bit of the history and policy, let’s go through what’s in the plant, and these different, more specific cannabinoids. So there’s 120 different cannabinoids in the plant, and these are classified into 11 different types. This makes up approximately 24% of the total natural products in the plant. And then there’s also these terpenoids, and these terpenoids are thought to also have therapeutic potential. Just to pull out a couple of ’em, myrcene is one of the most common, abundant terpenes in cannabis. It’s also found in mango, thyme, and lemongrass. It’s thought to potentially have antiseptic and ant-inflammatory properties. Linalool is found in lavender.

I’m sure some people may infuse it for anti-anxiety or antidepressant effects, and then another one is humulene that’s really common in cannabis, and that’s thought to have antibacterial effects. Walking through some of the anatomy of the plant, we have the stem, the leaves, nodes, and then this is an unfertilized flower. On the unfertilized flower is this translucent crystal resin that coats the cannabis bud, and that’s referred to as the trichomes. These trichomes are rich in cannabinoids and are the primary location for those terpenoids. Looking at these different parts of the plant, they all have different concentrations of cannabinoids and terpenoids. So breaking down the cannabis plant, the stem and the roots and the leaves, the unfertilized flower, seeds, and seed sprouts have almost negligible cannabinoid amounts, but the unfertilized flower and the terpenoids are where the primary content of cannabinoids are. So if you’re buying hemp oil, you’re not gonna have any cannabinoids in that product. Breaking down the botany of the cannabis plant, there’s a lot of confusion on what’s hemp, what’s cannabis, what’s marijuana? So cannabis is a broad term that includes hemp, cannabis, and marijuana. They’re all the same plant species. And then, when we look at these different varieties, Cannabis sativa, indica, and ruderalis, traditionally, sativa’s thought to have high THC content, indica’s thought to have a mix of THC and CBD, and ruderalis is thought to be a high-CBD plant.

However, these concepts are oversimplistic and often inaccurate. There are tons of different things that can impact cannabinoid content, such as growing conditions, geographic location, plant processing, plant variety, and species combination. In fact, over the decades, we’ve seen an increase in THC content in the plant. And then these different domestic plants have undergone years of breeding and interbreeding, so traditionally these different varieties, Haze, G-13, White Widow were thought to be high THC content, and then Cannatonic, AC/DC were thought to be CBD dominant. But because these have been so crossbred and bleeding of the strains, these names are essentially meaningless. And then many of these are not being properly stabilized, so there’s gonna be differences between each lot or each batch. So what’s most important for these products is to get the chemical profile, so know exactly how much and what cannabinoids are in each product or plant. Now pulling out those two cannabinoids, THC and CBD, and going through their effects and how they work. THC works by binding directly to those CB1 and CB2 receptors and kind of mimicking our endocannabinoids. There is that stigma of the psychotropic effects of THC, and that’s a cause of the CB1 stimulation.

However, the CB1 stimulation also has therapeutic effects, such as anti-inflammation, potentially neuroprotection, so protecting our neurons, antinausea, pain relief from different forms of pain, neuropathic pain, chronic pain, cancer pain. And then, when THC is ingested, an active metabolite forms, and this active metabolite is thought to be four times more psychoactive than the parent compound of THC. So there may be different experiences in that psychoactivity based on the route of administration. So when people are using either CBD or THC for therapeutic purposes, it’s really an individualized approach, and often either self-tapered or increased under medical supervision. And the rule of thumb is, start low, go slow. So start with small doses and increase incrementally slowly over time, because with both THC and CBD, there’s biphasic effects. So at low doses it may have one effect, and then at high doses it’s gonna have the completely opposite effect. So for low doses for THC, there’d be mild euphoria, relaxation, potentially increased sociability, decreased anxiety, but at high doses you may experience a dysphoria, increased paranoia or anxiety, sensory distortions, maybe time distortions, or hallucinations. And this dosing outline is compiled from recreational experience and medicinal experience in the U. S. and Canada, and the low doses, 1 to 2. 5 milligrams, people can expect mild symptom relief and is best for first-time users. The next step of dose would be 2. 5 to 15, so it’d be stronger symptom relief, but it’s likely that patients would experience that high effect, impaired coordination and perception, so this may be most applicable to those with chronic illnesses.

Higher doses, you’re gonna increase euphoria and that impaired coordination, and start getting into that unwanted side effect. This would be most appropriate for those that are regular users, anyone that’s developed a tolerance, or maybe they have poor GI absorption due to a disease state or a surgery. And then those extremely high doses, 50 milligrams to 100 milligrams, can expect to have rapid heart rate, nausea, pain, impaired coordination, and this is for experienced or heavy users only, maybe patients that have severe, potentially terminal illnesses, and conditions that require high doses. Doses, anything exceeding 20 to 30 milligrams are thought to increase adverse events with little improvement and efficacy. Jumping over to CBD, CBD is thought to be an anxiolytic, antidepressant, and an analgesic, but it’s not known to have that same intoxicant or psychoactive effect, and this is because it isn’t binding in the same way as THC to that CB1 receptor particularly. It’s working by increasing your native cannabinoids in your body, binds to serotonin receptors, it stimulates GABA receptors, which are responsible for kind of calming down the nervous system.

It has more than 65 other cellular targets. Potential side effects with this, the most common ones would be diarrhea, dry mouth, low blood pressure, lightheadedness, and drowsiness. Some other side effects could be fatigue or changes in mood, particularly irritability or agitation with higher doses, and then some potential severe side effects would be liver injury. As far as dosing, chronic doses have been used, 30 milligrams for up to six months, and 1,200 to 1,500 milligrams have been taken for up to four weeks. And then that FDA-approved formulation of CBD, Epidiolex, is approved for 10 to 20 milligrams per kilogram per day. And that would be, for a 150-pound person, that would be equivalent to approximately 700 to 1,400 milligrams a day. So there’s a number of proposed pharmacologic effects of these cannabinoids, both THC and CBD, and these conditions that are listed are all conditions that are approved for medical cannabis use throughout the U. S. And we’re gonna pull out some of these different conditions and symptoms and talk about the evidence that’s behind these different indications. So first, for pain.

Pain is the most commonly cited use for medical cannabis, particularly THC, because the pain relief is thought to be mediated through that CB1 activation, and this is a separate mechanism from opioid analgesia. So it’s thought that potentially THC can augment the effects of pain medication, or that potentially cannabis could be used to replace conventional pain medication. And this has been shown by states that have approved medical cannabis, have shown a decrease in opioid prescribing and in opioid related deaths. Additionally, there’s some evidence that cancer patients who use cannabis needed fewer opioids if they were using cannabis. And then additionally, CBD could also have a role in opioid sparing. So in an animal model, CBD reduced drug-seeking behavior, so this may be a mechanism to help those that are using opioids avoid relapse by reducing some of the anxiety or cravings that could trigger a relapse. There’s a number of different reviews that have been pulled together to evaluate THC, specifically its effect on pain. One particular paper included 23 randomized controlled trials, and this looked at a number of different kinds of pain. Neuropathic pain primarily, but also included cancer pain, pain from multiple sclerosis, rheumatoid arthritis, musculoskeletal, and chemotherapy-induced pain. Most of the studies use plant-derived THC, but there were a couple of studies that used synthetic THC, and overall had a moderate increase, a decrease in pain.

So there’s some evidence of its use for pain, and that’s supported by these well-controlled clinical trials. But still, a lot isn’t known about specifically what dose to use, what route of administration for each condition is most effective, and then this long-term safety for these products. Another condition that has a wealth of evidence behind it is seizures. So for animal models, both THC and CBD have been shown to prevent seizures, but the only FDA-approved formulation of– to prevent seizures is Epidiolex, and that’s approved for Lennox-Gastaut and Dravet, which are two severe childhood onset forms of epilepsy. The role of THC or CBD in anorexia and weight loss is important, because a lot of different conditions may have anorexia as a side effect, particularly cancer. CBD hasn’t been shown to have any appetite-inducing effects. Particularly, one study in rats actually showed a decrease in appetite after administration of CBD for 14 days, and then there’s some conflicting studies on how effective THC is for anorexia nervosa, or wasting syndrome. So in a study of using oral cannabis, they saw an increase in weight in HIV patients who had wasting syndrome and anorexia nervosa, but on the other hand, another study in patients with cancer showed no benefit from use of cannabis. And the differences in these studies may be due to that they’re small studies, they’re short in duration so we don’t know the long-term efficacy, or they’re not at the optimal dose. And there’s a lot of questions on how both THC and CBD affect sleep, and this varies by cannabinoid, as well as combining these different cannabinoids.

So THC is thought to decrease sleep latency or how long it takes you to fall asleep, but there’s conflicting studies on the quality of sleep that you have once you are asleep. The combination of THC and CBD is thought to increase wakefulness, and then CBD has that biphasic effect. So at low doses, it increases time of waking throughout the night, but at high doses, it increases sleep time and sedation. It’s also been shown in case studies to positively affect REM sleep behavior disorder, which causes patients to act out their dreams, whether that be talking, shouting, or complex movements. So it’s been shown to positively affect those patients. And this may depend on both the route of administration and the timing of administration. So this we’ll go through later, these different routes of administrations are gonna have different onsets of action and last for different amounts of time. Because there are so many different assessments used and the quality of these studies are so variable, there’s no definite conclusions that are available yet. Anxiety and depression, specifically for CBD, there’s some evidence that CBD improves anxiety symptoms, and this was assessed by a public speaking test. So they gave 600 milligrams to patients, and then they had them give a public talk.

Unfortunately, today is not part of that study. [audience laughing] But they measured their heart rate, their blood pressure, conductance on their skin, and were able to show that improved or decreased their anxiety. On the other hand, daily cannabis use, or THC, is associated with increased anxiety symptoms. And for depression, there haven’t been any clinical trials assessing the effects of these different cannabinoids on major depressive disorder. There’s some thought that different cannabinoids have antitumor effects, and the mechanism behind this is thought to be encouraging cell death and inhibiting new cell growth. The animal studies demonstrated a reduction in tumor volume, with lung cancer, breast cancer, and then virus-induced leukemia in mice. But most of the clinical studies are in brain tumors or gliomas, and the endocannabinoid system is thought to be upregulated in brain tumors, and these tumors have been shown to express the CB1 and the CB2 receptors. So there’s a phase two clinical trial of these glioblastoma patients, and they were treated with chemotherapy, and then one group was given a placebo in addition, and the other group was given cannabis in addition. The cannabis group has had an 83% survival rate, the placebo group had a 53% survival rate at one year. So that is moving forward into clinical trials.

And this is just kind of a summary of all of the different evidence that we’ve walked through, the different target symptoms and these two different cannabinoids. So for specifically for that THC, the most evidence for its use is neuropathic pain, nausea and vomiting, and spasticity. The most evidence behind use of cannabinoids is primarily inflammation and seizures at this point. But using these cannabinoids don’t come without a cost, so there’s different potential risks. Right now, it hasn’t been associated with lung cancer or head and neck cancer, but there is some evidence between an association with testicular cancer. Liver injury is included as a warning with Epidiolex. This in a clinical scenario can be monitored and managed with medical supervision; however, if patients are self-medicating, they may be unaware that they’re injuring their liver, particularly if they’re on other medications that impact the liver; this is really important. Different respiratory disease risks. So long-term cannabis smoking could cause more frequent bronchitis episodes and worsened respiratory symptoms, and this is shown to be worse with smoking than with vaporization, and this is kind of separate from the vape-induced injuries. But upon cessation of cannabis, the respiratory symptoms return to baseline.

In contrast, a commonly cited cross-sectional study, the NHANES study, didn’t show any adverse effects of lung function with marijuana use. There is some thought that acutely, on short circumstances, use of cannabis improves airway dynamics. In Minnesota, now one of the qualifying conditions is sleep apnea, but with chronic use that has not been shown. And then, cannabis has not been associated with COPD. Different cardiometabolic risk. Some case reports have associated cannabis use with acute coronary syndrome, arrhythmias, sudden cardiac death, cardiomyopathy, stroke, and diabetes. And there’s again this biphasic effect. So acutely, this can raise the heart rate, but when patients use it for a long period of time, they may develop bradycardia. And then there’s also changes in blood pressure. With very high doses, it can cause orthostatic hypotension, but when used acutely, it can increase the blood pressure.

It also increases risks for users for angina or angina. How does this impact mental health? So specifically, with heavy use in early life is associated with an increased risk of developing psychotic disorders. There’s thought that early use in life may alter brain development, and that would cause some of these psychiatric disorders. But it’s kind of a chicken or the egg scenario. Is it that cannabis use alters brain development and causes these psychiatric disorders, or is it that those that are predisposed to these psychiatric disorders are more likely to seek out these, cannabis? And at this point, it’s not known. It could also be a timing thing. So when adolescents are more likely to seek out cannabis is also around the time that some of these psychiatric illnesses, particularly schizophrenia, manifest. But there is some evidence with these individuals that have schizophrenia or with a history of cannabis use to link to better performance on learning memory and tasks. And specifically, there was a study of one single dose of CBD, 600 milligrams, was given to patients with recent onset schizophrenia. This was found to normalize the regions of the brain that become dysfunctional during a schizophrenic episode.

So although there may be some association with the development of schizophrenia, it may also be an important therapy for those with psychiatric disorders. However, one psychiatric disorder that has been shown to increase the symptoms for is bipolar disorder, and it has not been shown to increase the likelihood of developing depression, anxiety, or PTSD. So looking at some different drug safety components, people that should definitely not use cannabis, and this is primarily for THC products, those that have unstable psychiatric condition, any severe or unstable cardiopulmonary disease, those that are pregnant or breastfeeding, or have a history of substance abuse should not use cannabis. And then, those that should use caution include any severe cardiovascular, immunologic, liver, or kidney disease, history of arrhythmias, there’s a personal history of psychiatric disorder or a familial history of schizophrenia, pediatric or elderly patients, those with taking drugs that may interact, and those that have experienced hyperemesis syndrome. Hyperemesis syndrome is typically in those that have used frequently for a long period of time at a high dose, and one of the hallmark symptoms is taking scalding hot showers, and that’s the only thing that will relieve the vomiting. A lot of times, these patients are hospitalized because they need IV fluids to rehydrate. Cannabis use disorder can also develop. So only about 10% of those that use cannabis are regular users, and a third of those may have cannabis use disorder. And this is characterized by neglecting their personal roles, and that can cause social problems, if they’re putting themselves or others at hazard to use, if they develop withdrawal when trying to stop, or they have repeated attempts to quit, any physical or psychological dependence on the cannabis, or they’re giving up activities to use cannabis. Any patients that are exhibiting cannabis use disorder and have in the past should not use again.

And I mentioned those that are on drugs that may interact with cannabis, and these are just some of the drugs that have been studied, but there’s many others that have potential interactions. So specifically with these five different groups, warfarins, THC and CBD have been shown to increase the blood levels of warfarin, which increases INR and increasing bleeding risk. Alcohol increases THC levels and also has additive CNS depressant effects. Theophylline, a drug used to treat asthma and other lung problems like emphysema or chronic bronchitis, so cannabis decreases the theophylline levels and potentially decreasing its efficacy. CBD increases the active metabolite of clobazam, a anti-seizure medication, so it could increase the adverse effects from that drug. And then any CNS depression, whether that be alcohol, barbiturates, benzodiazepines, it’s gonna have additive CNS depressant effects with cannabis. So now, looking at how different formulations of these different cannabinoids would differ. So there’s a number of different formulations and routes of administration. Inhalation formulations may include vaporizers, or joints, or smoking. Oral products could be edibles, oral solutions, capsules, sublingual, maybe an orally disintegrating tablet, a tincture, a lozenge, and then there’s topical products as well.

So specifically for the inhalation route of administration, this is a really variable route of administration because of so many different inhalation techniques. Anywhere from 20 to 70% of the product will reach the lungs, and 30% of that will reach your bloodstream. But this is the shortest onset of action, making adjustments pretty simple. So it’s a simple and effective route of administration, but some of the disadvantages are it’s short-acting, so it’s not gonna act for as long as some of the other routes of administration, and it may contain irritants, and it may not be appropriate for people with certain disease states, whether that be emphysema or asthma. Oral administration, again, that may include oral solutions, capsules, edibles. This is gonna have a delayed onset of action, so usually roughly about two hours, but it’s gonna have a longer duration of action, so about eight hours. The absorption through the GI tract varies quite a bit, and it’s usually less than 15%, but it can be increased with a very fatty meal. And additionally, remember that THC is metabolized into the active metabolite, so this route of administration is more likely to have psychoactive effects. Sublingual route of administration, a spray, a tincture, lozenge or an orally disintegrating tablet. This’ll have mixed absorption, so some is gonna go through the mucosal membranes and the rest of it would be ingested through the gut.

So the onset of action is usually 15 to 30 minutes, with about four hours in duration. These next two routes of administration have the least amount of literature behind them. So for topical there are creams, ointments, transdermal patches, but the pharmacology is poorly understood, but we do know it is systemically absorbed. And then there are rectal formulations out there. This is shown to be stable and absorbable. The absorption is typically two times that of oral administration and has a fast onset of action, and it doesn’t result in that same active metabolite. Just a summary of all the different onsets of action and duration of action, the inhalation are gonna have the fastest onset of action but the shortest duration of action, the oral formulations have the longest onset of action and the longest duration of action, and then the sublingual or oral mucosal is somewhere in between those two. So kind of where do we go from here? What can you guys really take away from this? So if anyone is considering particularly a CBD product, there’s a number of things that you need to keep in mind. Cannabis is a phytoremediator, meaning it’s sucking up everything from the soil. There’s tons of cannabis plants planted around Chernobyl to try to purify the soil.

So keep that in mind, these plants are pulling up fungal and bacterial pathogens, pesticides, heavy metals, so it’s really important to know the quality of the plant. Additionally, we talked a little bit before about the labeling accuracy and how some of these products aren’t accurate, so with both of these it’s important to have third-party testing, a company that is not associated with the manufacturer, to evaluate each lot of the product to verify that there are none of these contaminants and that the amount of CBD is accurate to what they claim. And this is important to have separate for each lot, because there may be those batch-to-batch inconsistencies. So there could either be a label on the container, or they may have this information available on their website. So although research has been increasing over the last couple decades, particularly the amount of available reviews. Unfortunately, the amount of clinical trials aren’t increasing at the same rate. So we really need more research available before we can make any of these efficacy or safety claims. So some of the therapeutic challenges we have, patients have a risk for drug-drug interactions, and we may not even know all the potential drug-drug interactions. We haven’t defined the safety, especially in vulnerable populations, especially children or elderly. There’s limited funding for this research, and then there’s significant regulatory barriers with it being a Class I substance, which results in those limited randomized controlled trials, which are really our gold standard for evidence, and limited long-term safety.

There’s those standardization and quality control problems, as well as the long-term outcomes are unclear. So what we’re doing at the University of Wisconsin right now and in the future, one study that we’re doing right now is looking at the labeling accuracy of local CBD products. We’ll also be looking at those that take CBD chronically and if they’re testing positive on urine drug screens, looking at how much is absorbed in a topical formulation of CBD, and how efficacious that formulation of CBD is for patients with neuropathic pain, and then the impact of CBD on sleep in different patient populations, one being that REM sleep behavior disorder, one being restless leg syndrome, and another, patients with traumatic brain injury. So I included some additional references that could be important. This top reference is a summary, a very exhaustive summary of the different evidence and risks behind cannabinoid therapies. This is kind of a good, quick primer for medical cannabis use. This is one of the systematic reviews that I went over, specifically with pain, and this outlines different FDA regulations and cannabis policy as well. So at this point, I would like to open it up for questions, and appreciate your guys’ attention. [audience applauding]