An update on medical Use of Cannabis with new study Results

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1 Disclosures An update on medical Use of Cannabis with new study Results Jacquelyn Bainbridge, PharmD, FCCP, MSCS Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences & Department of Neurology Anschutz Medical Campus Oct. 5, 2018 Bend St. Charles Grand Rounds Dr. Bainbridge has two research grants funded by CDPHE Dr. Bainbridge is involved in one research grant funded by GW Pharmaceuticals/ Greenwich Pharmaceuticals Dr. Bainbridge is involved in one research grant funded by Corbus Pharmaceuticals Learning Objectives Review the pharmacology of cannabis (drug-drug interactions) Identify the disease states which may be treated with cannabis Review current medical literature and studies on the medicinal efficacy of cannabis Describe communication strategies for prospective patients considering or using cannabis treatment Discuss a case study and patient experience with diagnosis, treatment and management Identify the main constituents of cannabis and review the endocannabinoid system AZmarijuana.com

2 Cannabis Contains over 400 compounds Over 100 cannabinoids have been isolated Terpenes are variable, contribute to aroma (limonene, pinene) and serve as a precursor to cannabinoids Cannabinoids & terpenes are found in flowering tops > buds > top leaves > lower leaves > stems stalks Indica and sativa have been cross-bred so no generalizable characteristics Delta- 9 -tetrahydrocannabinol (THC) Major component of cannabis that causes the "high Mechanism of action: Partial CB1 agonist Beneficial effects Helpful in preventing nausea and vomiting due to cancer chemotherapy Appetite promoter Some medical conditions Adverse effects Short Term: Memory loss, loss of time, impaired coordination Altered thinking, panic, delusions & hallucinations, paranoia and psychosis Long term: Addiction (9% overall), altered brain development *, diminished life satisfaction and achievement *, cognitive impairment (lower IQ) *, symptoms of chronic bronchitis, increased risk of chronic psychosis disorders, and poor educational outcome. N Engl J Med 2014; 370: *Effect is strongly associated with initial marijuana use early in adolescence Borgelt LM, Franson KL, Nussbaum AM, Wang GS. Pharmacotherapy Cannabidiol (CBD) Major nonpsychotropic component of cannabis (no high) Precise mechanism of action unknown may be an antagonist Beneficial effects No significant neurologic effects No effects on vital signs or mood Enhance the activity of the endogenous cannabinoid (anandamide) Adverse effects Somnolence, decreased appetite, diarrhea, fatigue, and convulsion May increase risk of infection Industrialized Hemp Colorado Constitution defines Industrialized Hemp as a plant of the genus cannabis and any part of the plant, whether growing or not, containing a delta 9 tetrahydrocannabinol (THC) concentration of no more than 0.3 % on a dry weight basis. Cannabidiol (CBD) Registered industrial hemp farmer with the Colorado Department of Agriculture Marijuana is grown inside with regulated light, temperature, humidity, CO2 and O2 levels to maximized the THC concentration Hemp is grown outdoors to maximize size and yield, less attention is paid to individual plants Sievers is studying medicinal uses for hemp (Denver Post 7/26/18) Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The Pharmacologic and Clinical Effects of Medical Cannabis. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2013;33(2): , Epilepsia June ; 55(6): doi: /epi.12631, and Lancet Neurol Mar;15(3): doi: /S (15) Epub 2015 Dec 24.

3 Other Common Cannabinoids Anandamide, 2-AG Naturally-occurring endocannabinoids Dronabinol, nabilone THC molecule, Pharma products Epidiolex CBD extract, Pharma product Sativex THC & CBD extract, Pharma product Rimonabant CB1 receptor inverse agonist, Pharma product HU-210 Spice, synthetic street cannabinoid Most interact with the endocannabinoid system via G-protein-coupled receptors in the body, but not CBD Endogenous Cannabinoid System There are already different types of cannabinoids in our body that stimulate CB1 and CB2 receptor function Located in different parts of the body (i.e. brain, organs, connective tissue, glands, and immune cells) Each tissue has different tasks within the system to maintain homeostasis (balance) Examples of effects: Increased appetite Decreased nausea and vomiting Borgelt LM, Franson KL, Nussbaum AM, Wang GS. Pharmacotherapy to the endocannabinoid system Accessed 3/2/15 Frontiers in Pharmacology 2014;5:Article 37 Regulatory Effect of Cannabinoids at the CB1 Receptor 1. Inhibition of adenylyl cyclase activity 2. Alter second messenger systems so CA++ influx is inhibited Neuromodulation by anandamide is particularly relevant to modulation of GLU (shown), Ach, GABA, DA, NE Pertwee RG. Br J Pharmacology Functional effects of anandamide at CB1 receptors in the CNS Structure Anandamide Regulates Resultant effect Basal ganglia Modulate DA & GABA, motor activity Slowed reaction time Hypothalamus Appetite (2-AG) Stimulate DA & inhibit NE Appetite Inhibition of prolactin, enhances ACTH Amygdala Emotions, fear, anxiety Anxiety stimulation, reduction, & sedation Nucleus accumbens Motivation (2-AG) Engages reward pathway Hippocampus Inhibit release Ach, short term memory Inhibit release GLU, long term memory Impaired short term (working) memory Impaired long term memory consolidation Cerebellum Inhibit GLU, motor coordination Impaired coordination, balance Brain stem Modulates info transfer between brain & spinal cord Anti-nausea effects Hippocampus, TL, forebrain Inhibit GLU & neuronal excitability Increased seizure threshold

4 Functional effects of anandamide at CB1 & CB2 receptors Structure Anandamide regulates Resultant effect Spinal cord Inhibit GLU & info transfer between body & brain Decreased pain sensitivity Parasympathetic Inhibit Ach release, HR regulation, urination regulation HR stimulation, sometimes inhibits urination system Sympathetic system Inhibit NE release, HR regulation, blood vessel constriction Delayed reduction in HR and blood pressure Neuronal cells Inhibition GLU-induced excitotoxicity Neuroprotective effect to prevent cell injury Adipose tissue Stimulates lipogenesis Increased adiposity, insulin resistance Reproductive tissue Reduces testosterone, luteinizing hormone Reduced fertility, altered menstrual cycle Skin Reduces histamine Anti-pruritic effect General Role in relaxing, eating, sleeping, forgetting protecting Provide relief from stress, reduction of injury General Inhibits immune B lymphocytes, natural killer cells Anti-inflammatory activity Cannabis Activity At CB1 Receptors Structure THC effect CBD effect Neocortex Altered thinking, judgement Delayed onset time to intoxication with THC Basal ganglia Slowed reaction time Reduced psychomotor abnormalities from THC Hypothalamus appetite 1992 No to little effect on appetite Amygdala Panic, paranoia Decrease THC induced anxiety Nucleus accumbens Euphoria Attenuated THC induced euphoria Hippocampus Impaired memory Attenuated THC induced memory effects Cerebellum Impaired coordination Reduced coordination abnormalities from THC Brain stem Anti-nausea effects 1985 Hippocampus, forebrain Anti-epileptic effects? Anti-epileptic effects for certain populations Spinal cord Altered pain sensitivity TRPV reduction in pain 1996 Dose-response effects of CBD not established low dose < 300 mg inconsistent effects typical response can be seen at 600mg Study 1: GWPCARE4 Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomized, double-blind, placebo-controlled phase 3 trial Randomized, placebo-controlled trial. N = 171 Add-on to an anticonvulsant regimen for drop seizures in LGS refractory patients Patients age 2-55 years old What s Refactory? > 2 AED meds and > 2 drop seizures per week Doses: 20 mg/kg of cannabidiol or placebo (in addition to current therapy) Primary outcome: reduction in drop seizures. Secondary outcome: adverse events Followed for 14 weeks.

5 GWPCARE4 Results and Outcomes GWPCARE4 Take-home points Primary: drop seizure frequency percentage Treatment group: 43.9% (IQR to -1.9) Control group: 21.8% (IQR to 1.7) Secondary: adverse events Common (>10%): vomiting, diarrhea, decreased appetite, pyrexia, and somnolence. Serious: increased ALT, AST, and y-glutamyltransferase Cannabidiol 20 mg/kg was an effective treatment for reducing seizure rate in non-elderly LGS patients. Number needed to treat: 5 patients Generally well tolerated Effect of Cannabinidiol on Drop Seizures in the Lennox- Gastaut Syndrome Very similar to GWPCARE4 in structure: Multicenter, placebo-controlled trial 14 week treatment period 2-55 year old patients Primary outcome: percentage reduction in seizure rate from baseline. Secondary outcome: side effects Same exclusion criteria. Key differences: Patients with 2 or more drop seizures a week during a 4 week baseline period. 3 groups: 20 mg/kg, 10 mg/kg, or matching placebo in two divided doses N= 225

6 Results Primary Outcome: 20 mg/kg: 41.9% 10 mg/kg: 37.2% Placebo: 17.2% Comparisons of Primary Outcome between groups: 20 mg/kg to placebo: 21.6 (95% CI, 6.7 to 34.8; p=.005) 10 mg/kg to placebo: 19.2 (95% CI, 7.7 to 31.2; p=.002) NNT: 4 Secondary Outcome: A lot of the same side effects seen with GWPCARE4. Big picture: 10 mg/kg had less side effects than 20 mg/kg Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome Cannabidiol in Dravet syndrome Double-blind, placebo-controlled trial of 120 patients. Patients 2-18 years old with refractory seizures. 2 arms: 20 mg/kg of cannabidiol (twice daily in equal doses) vs. placebo as an add-on to standard AED regimens. Patients inadequately controlled on >1 AED with >4 seizures during the baseline period. Results Treatment Group: (-38.9% IQR to -4.8) Placebo Group: (-13.3% IQR to 20.2) Other: Interactions with Valproate: increased AST and ALT, but no effect on serum levels

7 Dosing and administration consensus Starting dose is recommended at 2.5 mg/kg twice daily, with titration to 5 mg/kg twice daily as a maintenance dose after one week. Cannabidiol (Epidiolex ) First FDA approved cannabinoid prescription drug Treatment of Lennox-Gastaut syndrome and Dravet syndrome Oral solution 100 mg/ml Starting dosage 2.5 mg/kg twice daily; maximum 10 mg/kg twice daily Drug Interactions Use with strong CYP3A4 or CYP2C19 inducers may decrease cannabidiol plasma concentration Potential enzyme activity inhibition; reduce dose of substrates of UGT1A9 (Propofol, fenofibrate, diflunisal), UGT2B7 (Gemfibrozil, lamotrigine, morphine, lorazepam), CYP2C8 (Phenytoin), and CYP2C9 (Phenytoin) when used with Epidiolex Potential induction and inhibition of enzyme activity; adjust dosage of substrates CYP1A2 (theophylline, caffeine) and CYP2B6 (bupropion, efavirenz) when used with Epidiolex Cannabidiol (Epidiolex ) Cannabidiol (Epidiolex ) Drug Drug Interactions Effect of Epidiolex on the other drugs: UGT1A9 diflunisal, propofol, fenofibrate UGT2B7 gemfibrozil. Lamotrigine, morphine, lorazepam CYP1A2 theophylline, caffeine, clozapine CYP2B6 bupropion, efavirenz CYP2C8 phenytoin CYP2C9 Carvedilol, celecoxib, glipizide, ibuprofen, irbesartan, losartan CYP2C19 Omeprazole, phenobarbital, phenytoin, diazepam Increases plasma concentration of drug Drug Drug Interactions Effect of other drugs on Epidiolex: Metabolized by 3A4 and 2C19 so Coadministration with moderate to strong inhibitors will increase Epidiolex concentration 3A4 inhibitors diltiazem, verapamil, ketoconazole, itraconazole, erythromycin 2C19 Inhibitors Fluvoxamine, isoniazid (INH), ritonavir Coadministration with strong inducers will decrease Epidiolex concentration 3A4 inducers Carbamazepine, St. John's wort, phenobarbital, phenytoin, rifampin 2C19 inducers Carbamazepine, phenytoin, rifampin

8 Drug Interactions *Epidiolex + Clobazam Cannabidiol (Epidiolex ) Produces 3-fold increase in plasma concentrations of active metabolite of clobazam (substrate of CYP2C19) Epidiolex + Valproate Concomitant use increases the incidence of liver enzyme elevation * Epidiolex + Rufinamide or topiramate Increased serum concentration of rufinamide or topiramate *Gaston TE et al., Epilepsia 2017 Sept;58(9): Warnings Cannabidiol (Epidiolex ) Epidiolex causes dose-related elevations of ALT and AST In 2/3 cases, discontinuation or reduction of Epidiolex resolved transaminase elevations In 1/3 cases, elevations resolved without dose reduction of Epidiolex Dose adjustment recommended in patients with moderate (Child-Pugh B) or severe (Child- Pugh C) hepatic impairment. Slower dose titration may be necessary Increased the incidence of liver enzyme elevations with valproate administration Epidiolex meets highest standards for safety and quality, unlike other medical marijuana products Expected to be made available in specialty pharmacies in Fall 2018 DEA scheduled V THC Dosing Is Known; But Not Known For Other CBs Typical effective dosing of inhaled THC Low dose < 7 mg Medium dose = 7 18 mg High dose > 18 mg Known tolerance to THC down regulation of CB1 receptors, and G- protein activation High probability of tolerance with chronic use, and low with intermittent Chronic = daily for a week, intermittent = weekly Case Study 1 CB is a 10 year old male who has a diagnosis of Dravet Syndrome. CB is currently experiencing 4 seizures per day on average. CB has been on multiple anti-seizure medications including topiramate and phenytoin with no decrease in seizures. Currently he has been placed on clobazam and dose escalated to 20 mg orally twice daily. Two weeks ago his parents entered him into a clinical trial with Epidiolex. CB reports ataxia and sedation to the point of not being able to get out of bed. What is the source of his CNS toxicity? L Zuurman, et al. Br J Clinical Pharmacology. 2008

9 Case Study 1 Follow Up Epidiolex + Clobazam Produces 3-fold increase in plasma concentrations of active metabolite of clobazam (substrate of CYP2C19) The dose of clobazam should be decreased by 50 percent and re-evaluated Without knowing his previous regimen if he presented with LFTs that are elevated 6 times the ULN. Which antiseizure drug would you suspect to be the most likely to cause this in combination with Epidiolex? MEDICAL USES OF CANNABIS Evidence from the National Academies: Health Effects of Cannabis A provider asks We never learned about cannabis in medical school, what can you tell me about the diseases that medical marijuana has been approved for? Number of States with Various Approved Medical Conditions States cannabis legal status Medical: 29 states & D.C. Recreational: AK, CA, CO, D.C., MA, ME, NV, OR, WA Alzheimer s disease (7) Epilepsy/seizures (24) Nausea (19) ALS (9) Glaucoma (21) Pain (20) Arthritis (3) Hepatitis C (10) Parkinson s disease (5) Cachexia (21) HIV/AIDS (24) PTSD (6) Cancer (25) Multiple sclerosis (21) *decriminalization laws Crohn s/gi disorders (16) Muscle spasticity (22) By Lokal_Profil, CC BY-SA 2.5,

10 Approved medical conditions Approved medical conditions National Academies of Sciences, Engineering, and Medicine The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press doi: /24625 National Academies of Sciences, Engineering, and Medicine The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: / Approved Medical Conditions Current legislation is misleading Cannabis may alleviate symptoms but not actually treat the disease MS, cancer, HIV/AIDS, hepatitis C, Crohn s and Alzheimer s disease Do our patients/consumers know the difference? RISKS ASSOCIATED WITH CANNABIS

11 Lifetime Addiction Risk with Use Brain Development in Adolescence % MJ addiction risk in teens Limbic region Immediate rewards Impulsive behavior Cortex Long term gain Thoughtful behavior accessed 5/28/2013 Hall and Degenhardt. Lancet Strahny A. CBHSQ Report ) The Reward Pathway Study comparing the acute effects of inhaled cannabis in male adolescents (n = 20; years old) and adults (n = 20; years old). Participants completed two test sessions that lasted for 80 minutes each and was separated by at least 7 days. NIDA ( Inhaled medicinal grade Bedrobinol (THC 12.0%) or placebo (THC <0.3%) via a volcanic medic vaporizer. Weight based dosing; 0.89 mg/kg -1 of cannabis ~8.0 mg of THC for an person weighing 75 kg Translational psychiatry (2016) 6, e961;doi: /tp ; published online 29 November 2016

12 Acute Effects Adolescents Felt less stoned Dry mouth No difference in alertness or anxiety Fewer psychotomimetic symptoms Impaired response inhibition Lacked satiety and wanted more cannabis Translational psychiatry (2016) 6, e961;doi: /tp ; published online 29 November 2016 Adults More anxious Increased dry mouth Less alert Greater cognitive impairment Longer response times Spatial working memory tasks Showed satiety and did not want more cannabis No difference in verbal IQ, Beck anxiety and depression inventory, short version of impulsive behavior scale (SUPPS-P), Schizotypal personality questionnaire and both had increased heart rate A prospective longitudinal study investigating the correlation between persistent cannabis use over 20 years in a birth cohort of 1,037 individuals. Also observed the effect of cannabis cessation and the restoration of neurophyschological function for adolescents who were former persistent cannabis users. Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proceedings of the National Academy of Sciences. 2012;109(40). doi: /pnas Effect on Neuropsychological Functioning Persistent cannabis users show neuropsychological decline from childhood to midlife Prospective study of 1,037 individuals followed from birth (1972/1973) to 38 years of age Within-person IQs : Never used Used, never regularly Used regularly Impairment of learning, memory, and executive functions Older Adult Data Data suggest that substance abuse in the elderly is rising Multiple reasons that it is initiated later in life including coping with loss Brain It continues to change even in elderly years There is scant data on how drugs of abuse, including marijuana, interact with these continuing brain changes From Emergency Department (ED) mentions of illicit drug use have risen among patients 55+ Marijuana; 300 to 1700 respectively ( ) Meier MH, et al. Proc Natl Acad Sci Dowling GJ, Weiss SRB, Condon TP. Drugs of Abuse and the Aging Brain. Neuropsychopharmacology. 2007;33(2):

13 Cannabis Drug Interactions Further Dosing Considerations THC substrate of CYP3A4 & 2C9 CBD substrate of CYP3A4 & 2C19 Possible drug interactions sedation, ataxia: CNS depressants, anticholinergics heart rate: sympathomimetics effects of: hexobarbital, hydrocortisone, clozapine, phenytoin, warfarin effects of: propofol, indinavir, theophylline Horn JR, Pharmacy Times 2014 Drug-Drug interactions CBD and AEDs Study looked at effect of CBD oil (Epidiolex) on serum concentrations of AEDs N = 81: 39 adults/42 pediatric patients; initiated at 5 mg/kg/day, titrated up to efficacy, max dose of 50 mg/kg/day Significant increase in serum levels of topiramate, rufinamide, desmethylclobazam (active metabolite of clobazam), in all patients. Drug-Drug interactions CBD and AEDs Decrease in levels of clobazam as CBD increased No significant interactions between CBD and levetiracetam, lacosamide, perampanel Clinical significance: patients on clobazam or valproate, with adjunctive CBD use, experienced increased sedation that required dose adjustments Significant increase in serum levels of zonisamide and eslicarbazepine, only in adults AES Abstract 2.208: Gaston T, Liu Y, Cutter G, et al. Drug interactions between pharmaceutical grade cannabidiol (CBD) oil and commonly used anti-epileptic drugs (AEDs). Szaflarski J, et al. How does cannabidiol interaction with antiepileptic drugs? Neurology Reviews. January AES Abstract 2.208: Gaston T, Liu Y, Cutter G, et al. Drug interactions between pharmaceutical grade cannabidiol (CBD) oil and commonly used anti-epileptic drugs (AEDs). Szaflarski J, et al. How does cannabidiol interaction with antiepileptic drugs? Neurology Reviews. January 2017.

14 Drug-Drug interactions - CBD and Clobazam (CLB) Study looked at CBD and clobazam use in 13 pediatric patients Initiated at 5mg/kg/day and titrated up to goal dose of 25mg/kg/day Measured serum concentrations of clobazam and desmethylclobazam at baseline, 4 weeks, and 8 weeks Mean increase in CLB levels: 60% Mean increase in nclb levels: 500% Nine subjects saw >50% decrease in seizure frequency Ten subjects saw increase in sedative side effects, which was alleviated with CLB dose reductions THC Drug-Drug Interactions THC is metabolized by CYP3A4 and 2C9 Valproate inhibition of CYP2C9 can potentiate psychotropic effects of THC through a decrease in THC plasma clearance In vitro evidence shows THC is an inhibitor of CYP2C9, 2C19, 3A4 and 1A2 Evidence that THC increases phenytoin concentrations through CYP2C9 inhibition Has potential drug drug interactions with CYP3A4 inhibitors and inducers Geffrey AL, Pollack S, Bruno P, Thiele E. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015; 56(8): Anderson, G.D. & Chan, LN. Clin Pharmacokinet (2016) 55: doi: /s Inhaled Cannabis vs. Edibles How is Cannabis Consumed?

15 Cannabis-Infused Creams, Lotions and Oils Transdermal Patches Lipophilic delivery vehicles plausible due to high lipophilicity of THC CB receptors innervate: Epidermal homeostasis Pain sensation Skin inflammation Development, maintenance, and function of hair follicles and sebaceous glands Patch or gel designed to be absorbed through skin to blood stream Reservoir & occlusion provides constant & complete dosing Increase bioavailability of cannabinoids by skipping first-pass metabolism MJ Caterina ACS Chem Neurosci 2014 Images from: Communication Strategies Facilitating Physician and Patient Communication about Cannabis Current problem: Inadequate information that is needed to help providers determine whether cannabis should be considered as a treatment option for their patients Cannabis stigma Solutions: increased awareness Conferences Clinical trials Primary Literature Presentations

16 Important Considerations- Provider Perspectives When did the patient start using cannabis? How is the patient using cannabis? (smoking, vaporizing, eating, oils, etc.) How often does the patient use cannabis? What medications and over the counter medications is the patient taking? Overall expectations- what benefit does the patient expect from the use of cannabis? Important Considerations- Patient Perspectives What studies have been done that use cannabis to alleviate symptoms associated with my patients condition? Are there any side effects or potential complications I should be aware of? Will cannabis have interactions with any of the medications I am currently taking? What are the different forms of cannabis available, and what healthcare costs can I expect? Willie Nelson Grows Cannabis Empire With New Line of CBD Oil Products Questions? Amie, Biggie, Gucci

17 Which AED has a major drug-drug interaction with CBD (Epidiolex)? Levetiracetam Lacosamide Clobazam Perampanel Which AED has a major drug-drug interaction with CBD (Epidiolex)? Levetiracetam Lacosamide Clobazam ANSWER Perampanel Which of the following is a condition that has evidence backing the use of cannabis for treatment? Irritable bowel syndrome Nausea and vomiting related to chemotherapy Achieving abstinence in the use of addictive substances Parkinson s or levodopa related muscle movements Which of the following is a condition that has evidence backing the use of cannabis for treatment? Irritable bowel syndrome Nausea and vomiting related to chemotherapy ANSWER Achieving abstinence in the use of addictive substances Parkinson s or levodopa related muscle movements

18 Which is false about the use of cannabis edible preparations? Edible cannabis has the fastest onset of action, taking 5-10 minutes The duration of effect is longer than smoking or vaporizing cannabis Edibles contain more 11-OH-THC, which is more potent than standard THC Production of edibles requires a lower temperature than vaporizing or smoking cannabis Which is false about the use of cannabis edible preparations? Edible cannabis has the fastest onset of action, taking 5-10 minutes ANSWER The duration of effect is longer than smoking or vaporizing cannabis Edibles contain more 11-OH-THC, which is more potent than standard THC Production of edibles requires a lower temperature than vaporizing or smoking cannabis What is the CBD:THC ratio or THC concentration used in the FDA-approved CBD preparation for Epidiolex? 30:1 15:1 10:1 Up to 1% THC Up to 0.15% THC This preparation does not contain THC What is the CBD:THC ratio or THC concentration used in the FDA-approved CBD preparation for Epidiolex? 30:1 15:1 10:1 Up to 1% THC Up to 0.15% THC ANSWER This preparation does not contain THC

19 According to the Colorado Constitution, what is the maximum THC concentration that is allowed in industrial hemp on a dry weight basis? 0.01% 10% 12% 0.3% 22% According to the Colorado Constitution, what is the maximum THC concentration that is allowed in industrial hemp on a dry weight basis? 0.01% 10% 12% 0.3% ANSWER 22% Current Clinical Trials at The University of Colorado Anschutz Medical Campus A study of tolerability and efficacy of cannabidiol on tremor In Parkinson s disease Efficacy and safety of cannabidiol as add on therapy in patients with tuberous sclerosis complex who experience inadequately controlled seizures CURRENT RESEARCH CDPHE and other funding A phase 3, double-blind, randomized, placebo-controlled multicenter study to evaluate safety, tolerability, pharmacokinetics, and efficacy of Lenabasum in systemic sclerosis

20 A Double-Blind, Placebo-Controlled Crossover Study Comparing the Analgesic Efficacy of Cannabis versus Oxycodone; Questions we are trying to answer Pain Control Is cannabis effective at relieving chronic spine pain? Does it increase the threshold for perceiving pain? How does it compare to an opioid (pain medicine) for pain? Study Design Subjects come in for 3 separate 4-hour study visits Vaporized Cannabis + Placebo pill Vaporized Placebo + Oxycodone pill Vaporized Placebo + Placebo pill Side Effects How do the side effects of cannabis compare to the side effects of the opioid (pain medicine)? Outcomes (What are we measuring) Pain control Patient reported pain Pain sensitivity with experimentally induced pain Side effects Mood changes (feeling high, confused, paranoid, etc...) Cognitive changes (memory, attention, concentration, etc...)