Cannabis: Rocky Mountain Highlights for Health Care Providers

Cannabis: Rocky Mountain Highlights for Health Care Providers HASHing It Out: Overview of Medical Uses for Marijuana Skaggs School of Pharmacy Webinar Series Laura Borgelt, PharmD, FCCP, BCPS Associate Dean and Professor Departments of Clinical Pharmacy and Family Medicine June 2016 3 Disclosures Dr. Borgelt has no relevant financial disclosures. Dr. Borgelt will be discussing unapproved drugs and uses. Dr. Borgelt has served as a member of six working groups: Colorado Department of Public Health and Environment (CDPHE): Amendment 64 (Marijuana Legalization) Task Force Working Group: Consumer Safety and Social Issues State Licensing Authority Labeling, Packaging, Product Safety and Marketing State Licensing Authority Medical and Retail Marijuana Mandatory Testing and Random Sampling State Licensing Authority Serving Size and Product Potency CDPHE Retail Marijuana Public Health Advisory Committee CDPHE Pregnancy and Breastfeeding Guidelines Committee 4 Objectives Evaluate and discuss clinical studies using medical marijuana that have been performed in patients with neuropathic pain. Compare and contrast clinical studies that have evaluated medical marijuana use in patients with pediatric epilepsy and other neurologic disorders. Review clinical studies that have evaluated medical marijuana use in patients with gastrointestinal disorders. Discuss clinical studies that have evaluated medical marijuana use in patients with other medical conditions for which there may be benefit. 5 Patient Perspective 47 yo male with PMH of hypertension, diabetes, peripheral neuropathy, and chronic pain Pain Treatment Regimen» Oxycontin 30mg po BID and oxycodone 5 mg po prn» His pain medications have not changed in over one year» Today, he admits that he has also been smoking medical marijuana twice daily for the past two years to help his pain (decreased from 8/10 to 4/10)» He has been afraid to tell the healthcare team about this because he believes they will not approve of this treatment. He states he saw a different physician to get his card and recommendation for MMJ CANNABIS WEBINAR SERIES A Few Questions to Consider How did he gain access to marijuana? Are there other ways for him to consume MMJ to avoid the risks of smoking? Is MMJ effective for the treatment of pain? What adverse effects might this patient experience with chronic use of inhaled MMJ? Are there any drug interactions with MMJ? How might MMJ impact his opioid use? What other issues might this patient need to consider? How can I create an environment where patients feel safe to talk with me about any/all treatments they use? JUNE 2016 6 1

7 8 A Few Questions to Consider How did he gain access to marijuana? Are there other ways for him to consume MMJ to avoid the risks of smoking? Is MMJ effective for the treatment of pain? What adverse effects might this patient experience with chronic use of inhaled MMJ? Are there any drug interactions with MMJ? How might MMJ impact his opioid use? What other issues might this patient need to consider? How can I create an environment where patients feel safe to talk with me about any/all treatments they use? Cannabis Plant-derived cannabinoids 9 -tetrahydrocannabinol - THC 8 -tetrahydrocannabinol - THC Cannabidiol CBD Cannabinol - CBN Cannabigerol - CBG Cannabichromene - CBC Cannabicyclol - CBL Cannabielsoin - CBE Cannbitriol - CBT Miscellaneous Cannabinodiol (air-oxidation) Br J Pharmacology 2006;147:S163-71. Br J Pharmacology 2011;163:1344-64. Headache 2015;55:885-916. doi: 10.1111/head.12570 POLL QUESTION Which of the following receptors is a key target for THC? 1. Cannabinoid-1 receptor (CB1) 2. Cannabinoid-7 receptor (CB7) 3. Peroxisome Proliferator-Activated Receptors (PPAR) 4. G-protein receptor 55 (GPR55) Endogenous Cannabinoid System Endocannabinoids and their receptors found throughout body: brain, organs, connective tissues, glands, and immune cells. In each tissue, the cannabinoid system performs different tasks; goal is always homeostasis Endocannabinoids are substances our bodies make naturally to stimulate CB1 and CB2 Anandamide 2-arachidonoylglycerol (2-AG) When cannabinoid receptors are stimulated, a variety of physiologic processes occur CB1 receptors: nervous system, connective tissues, gonads, glands, organs CB2 receptors: immune system and associated structures http://norml.org/library/item/introduction-to-the-endocannabinoid-system Accessed June 9, 2015 Neuro Endocrinol Lett. 2008 Apr;29(2):192-200. Endocannabinoid System 12 Endocannabinoid System What happens when there is potential endocannabinoid deficiency, dysregulation, destabilization, or decreased binding? Reprinted with permission. Nat Rev Gastroenterol Hepatol. 2014;11(3):142-3 Pertwee RG. Br J Pharmacology 2008;153:199-215. Smith SC. Neuro Endocrinol Lett. 2014;35(3):198-201. 2

Another Kid on the Block Cannabidiol (CBD) Little binding affinity to CB1/CB2 Suppresses enzyme fatty acid amide hydroxylase ( FAAH ) enzyme that breaks down anandamide Opposes THC at CB1 receptor Stimulates release of 2-AG TRPV-1 receptor agonist 5-HT1A receptor activation GPR55 antagonist Epilepsia 2014;55(6):791 802. http://www.projectcbd.org/news/how-cbd-works/ Accessed 06/13/16 Potential Physiologic Responses to Cannabis Improves sleep Anti-seizure effects and neuroprotection Reduces anxiety and psychotic symptoms/ptsd Prevents nausea and stimulates appetite Reduces intraocular pressure Bronchodilator Relaxes muscles and reduces muscle spasms Therapeutic Effectiveness of MMJ Relieves pain (especially neuropathic) Anti-inflammatory Anti-proliferative Anti-viral With potential adverse effects. Minnesota Medicine 2014:4:18-27. http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq. Accessed 6/13/16 How Should MMJ Be Studied? HIGHEST level of evidence A. Blog B. Case control study C. Case report D. Case series E. Cohort study F. Meta-analysis G. My opinion H. Randomized controlled trial I. Review article LOWEST level of evidence Objectives Evaluate and discuss clinical studies using medical marijuana that have been performed in patients with neuropathic pain. Compare and contrast clinical studies that have evaluated medical marijuana use in patients with pediatric epilepsy and other neurologic disorders. Review clinical studies that have evaluated medical marijuana use in patients with gastrointestinal disorders. Discuss clinical studies that have evaluated medical marijuana use in patients with other medical conditions for which there may be benefit. 18 3

20 Inhaled Cannabis for Neuropathic Pain: Meta-Analysis of Individual Data Synthesizes the individual participants' original data obtained from the studies' principal investigators Five randomized controlled trials evaluating inhaled cannabis Compared proportion of patients experiencing >30% clinical improvement in chronic neuropathic pain assessed with a continuous patient-reported instrument (e.g., visual analog scale) at baseline and after inhaled cannabis RESULTS 178 patients with 405 observed responses Estimated OR (CRI) for >30% in pain score: 3.22 (1.59-7.24) Number needed to treat (CRI): 5.55 (3.35-13.7) Note: gabapentin NNT 5.9 (4.6-8.3) for diabetic neuropathy J Pain 2015;16:1221-32. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007938. J Pain. 2015 Dec;16(12):1221-32. doi: 10.1016/j.jpain.2015.07.009. Epub 2015 Sep 9.. 21 Adverse Effects Serious Adverse Effects (SAEs)» Placebo: 1 (psychosis)» Cannabis: 2 (hypertension, increased pain) Mild adverse effects» Anxiety, disorientation, difficulty concentrating, headache, dry eyes, burning sensation, dizziness, and numbness» Psychoactive effects (such as feeling high ) were statistically significantly associated with treatment allocation in 2 studies and increased in frequency with increasing dose 22 Limitations and Conclusions Ineffective participant blinding Placebo effects likely Different causes of neuropathy Small number of studies and participants Difficult to estimate bioavailable cannabis Short-term data only (up to two weeks) Inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated. J Pain. 2015 Dec;16(12):1221-32. doi: 10.1016/j.jpain.2015.07.009. Epub 2015 Sep 9.. J Pain. 2015 Dec;16(12):1221-32. doi: 10.1016/j.jpain.2015.07.009. Epub 2015 Sep 9.. 23 Inhaled Cannabis: Painful Diabetic Neuropathy Randomized, double-blind, placebo controlled crossover study 16 patients Evaluated short-term efficacy and tolerability of inhaled (aerosolized) cannabis» Four single-dosing sessions separated by two weeks Placebo Low (1% THC) Medium (4% THC) High (7% THC) J Pain. 2015 Jul;16(7):616-27. doi: 10.1016/j.jpain.2015.03.008. Epub 2015 Apr 3. CANNABIS WEBINAR SERIES 24 SPOTANEOUS PAIN Average pain intensity score for placebo dose: 0.44 points higher than the pain score in the low dose (P =.031) 0.42 points higher as compared to the medium dose (P =.04) 1.2 points higher as compared to the high dose (P <.001). J Pain 2015; 16:616-27 4

25 26 Results, con t Results, con t Placebo Low Dose (1% THC) Medium Dose (4% THC) High Dose (7% THC) SPONTANEOUS PAIN % reduction in pain 52.8 (±40) 63.8 (±37) 64.8 (±36)* 69.6 (±32)** Pain reduction 30% 10 (62) 10 (67) 12 (80) 13 (81) EVOKED PAIN (FOAM BRUSH) % reduction in pain 60.0 (±39) 63.8 (±39) 66.7 (±36) 68.6 (±33) Pain reduction 30% 10 (62) 11 (73) 12 (80) 14 (88) EUPHORIA % (p-value)* SOMNOLENCE % (p-value)* *Compared to placebo Placebo Low Dose (1% THC) Medium Dose (4% THC) High Dose (7% THC) 56.2 66.7 (.43) 86.7 (.042) 100 (.002) 37.5 26.7 (.49) 60.0 (.12) 73.3 (.018) J Pain. 2015 Jul;16(7):616-27. doi: 10.1016/j.jpain.2015.03.008. Epub 2015 Apr 3. J Pain. 2015 Jul;16(7):616-27. doi: 10.1016/j.jpain.2015.03.008. Epub 2015 Apr 3. CANNABIS WEBINAR SERIES JUNE 2016 27 Limitations and Conclusions Ineffective participant blinding Placebo effects likely Small number of participants Difficult to estimate bioavailable cannabis Short-term data only This trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain J Pain. 2015 Jul;16(7):616-27. doi: 10.1016/j.jpain.2015.03.008. Epub 2015 Apr 3. Crossover Study: Low-dose Vaporized Cannabis Objective: evaluate analgesic efficacy in patients with neuropathic pain despite traditional treatments Visual analog scale (0-100) 39 patients with previous cannabis exposure» 28 male/11 female» Avg age 50 years Vaporized cannabis» Medium-dose (3.53%)» Low-dose (1.29%)» Placebo J Pain 2013;14:136-48 INHALED CANNABIS Number of 111 episodes 30% in VAS Placebo Low-dose Med-dose Statistical significance P vs Low: p=0.0069 P vs Med: p=0.0023 Low vs Med: p=0.7 NNT: Low 3.2 NNT: Med 2.9 Number [% (95%CI)} 10/38 [26% (15-42%)] 21/37 [57% (41-71%)] 22/36 [61% 45-75%)] Smoked Cannabis for Chronic Neuropathic Pain 21 adults post-traumatic or post-surgical neuropathic pain Cannabis 25 mg at 0%, 2.5%, 6%, and 9.4% THC smoked 3x/day Four 14-day periods in crossover trial Primary outcome: pain intensity (11-item scale) RESULTS Pain intensity 9.4%: score = 5.4 0%: score = 6.1 (p=0.023; difference 0.7, 95% CI 0.02-1.4) Sleep (more drowsiness, getting to sleep more easily, faster, and with less wakefulness) 9.4% vs 0%: p<0.05 Anxiety and depression improved (EQ5D) 9.4% vs 0%: p<0.05 Adverse events 248 mild; 6 moderate (fall, pain, numbness, drowsiness, pneumonia) MMJ in Painful HIV-Associated Sensory Neuropathy: Systematic Review and Meta-Analysis Objective: evaluate clinical effectiveness of various analgesics Total of 14 trials evaluated Smoked cannabis 1-8% and capsaicin 8% found to be effective SMOKED CANNABIS Number of episodes 122 30% improvement in VAS 31/61 50% improvement in VAS 15/61 RR (95% CI) 2.38 (1.38 to 4.10) NNT (95% CI) 3.38 (2.19 to 7.50) *NNT for capsaicin 8% = 6.46 (3.86-19.69) CMAJ 2010;182:E694-701. PLoS ONE [Electronic Resource]. 5(12):e14433, 2010 5

31 Cannabis: Treatment-Resistant Chronic Pain Prospective, open-label study to determine the long-term effect of cannabis on pain and functional outcomes Primary outcome» Change in pain symptom score on the S-TOPS (Treatment Outcomes in Pain Survey - Short Form) Secondary outcomes» Change in S-TOPS physical, social and emotional disability scales, pain severity and pain interference on brief pain inventory (BPI), sleep problems, and change in opioid consumption Six month follow-up in intent-to-treat population 32 Cannabis Dosing Protocol Initial recommended cannabis dose was 20 grams/month» Smoked cannabis (patients could either roll the cigarette themselves or obtain pre-filled1 gram cannabis cigarettes)» Same monthly amount dispensed in baked cookies» Same monthly amount dispensed as an olive oil extract (drops). Instructed to titrate cannabis dose» Start with one cigarette puff (or 1 drop of cannabis oil) a day» Increase by increments of 1 puff/drop per dose, to frequency of up to 3 times a day until satisfactory pain relief was achieved, or side effects appeared. Cannabis was to be consumed at the home address only. Instructed to refrain from driving for at least 6 hours after consuming cannabis or longer if they felt disoriented/drowsy. 33 Results 176 patients included» 127 male, 79 female» Pain types: musculoskeletal (30%), peripheral neuropathic (24%), radicular low back (19%)» Dosage forms Cannabis cigarettes: 136 Cigarettes + drops: 8 Drops only: 17 Cookies: 9 Cookies + drops: 6» Mean (SD) monthly prescribed amount of cannabis at follow-up (in any route of administration) was 43.2 (17.9) grams 34 Results, con t Primary outcome» S-TOPS pain symptom score improved from 83.3 (95% CI 79.2-87.5) to 75.0 (95% CI 70.8-79.2), p<0.001» Overall, pain symptom score was improved in 65.9% of subjects, did not change from baseline in 8.0%, and deteriorated in 26.1% Secondary outcomes» S-TOPS family-social disability, role-emotional disability, satisfaction with outcomes, and sleep problem index all improved from baseline, P<0.001» Of 73 subjects on opioid therapy at baseline, 32 discontinued at follow-up Represents a 44% reduction from baseline (41 versus 73, P<0.001)» Median oral morphine equivalent dose decreased from 60 mg (95% CI 45.0-90.0) to 45 mg (95% CI 30.0-90.0), P=0.19 35 36 Results, con t Adverse Effects (AEs) 9 discontinued due to mild to moderate (AEs) Sedation, heaviness, nervousness, difficulty concentrating 2 discontinued due to serious side effects Elevated liver transminases, confusion state (elderly patient) Limitations and Conclusions Variability in active cannabinoid concentrations Lack of control group Lack of frequent periodic assessment of all AEs Association nor causality of cannabis and opioid use can be determined Cannabis treatment in a mixed group of patients with treatment-resistant chronic pain may result in improved pain, sleep, QoL outcomes, and reduced opioid use. 6

Treatment of Chronic Non-Cancer Pain: Systematic Review of Randomized Trials Cannabinoid Smoked cannabis (n=4) Oromucosal extracts (n=7) Nabilone (n=4) Dronabinol (n=2) THC-11-oic acid analogue - CT-3 or ajulemic acid (n=1) Overall result All trials found positive effect by improving neuropathic pain vs placebo with no serious adverse effects. 6/7 trials demonstrated positive analgesic effects for neuropathic pain, RA, mixed chronic pain. In one trial evaluating RA, significant decrease in disease activity (28 joint disease activity score). Three showed significant analgesic effect in spinal pain, fibromyalgia, and spasticity related pain vs placebo. One showed similar effect in neuropathic pain vs dihydrocodeine. Significant reduction in central pain (MS) vs placebo. Significantly greater analgesia vs placebo for mixed chronic pain on opioids. Ajulemic acid led to significant improvement in neuropathic pain intensity at 3 hours, but no difference at 8 hours compared with placebo. 38 Medical Cannabis and Opioid Use Br J Clin Pharmacol 2011;72(5):735-44 40 From: Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010 States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate (95% CI, 37.5% to 9.5%; P =.003) compared with states without medical cannabis laws. This association strengthened over time Year 1 ( 19.9%; 95% CI, 30.6% to -7.7%; P =.002) Year 2 ( 25.2%; 95% CI, 40.6% to 5.9%; P =.01) Year 3 ( 23.6%; 95% CI, 41.1% to 1.0%; P =.04) Year 4 ( 20.2%; 95% CI, 33.6% to 4.0%; P =.02) Year 5 ( 33.7%; 95% CI, 50.9% to -10.4%; P =.008) Year 6 ( 33.3%; 95% CI, 44.7% to -19.6%; P <.001) Mean Age-Adjusted Opioid Analgesic Overdose Death RateStates with medical cannabis laws compared with states without such laws in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668-1673. doi:10.1001/jamainternmed.2014.4005 Date of download: 6/14/2016 Copyright 2016 American Medical Association. All rights reserved. Medical Cannabis and Opioid Use 244 medical cannabis patients with chronic pain in Michigan Survey of 46 questions» Medical condition(s) for which cannabis was used» Method/frequency of cannabis use» Changes in noncannabis medication use» Changes in medication side effects» Quality of life changes since starting cannabis use» Demographic information» 2011 Fibromyalgia Survey Criteria (0-31 score) J Pain. 2016 Jun;17(6):739-44. doi: 10.1016/j.jpain.2016.03.002. Epub 2016 Mar 19. 41 42 4 OUTCOME OF INTEREST PATIENT RESPONSES (n=244) Mean (SD) Fibromyalgia score (0-31) 9.23 (5.52) Opioid use change 63% (46%) Degree to which side effects of medication affect daily 6.44 (2.91) function (before using medical cannabis); scale from 1 to 10 Degree to which side effects of medication affect daily 2.77 (2.35) function (after using medical cannabis); scale from 1 to 10 Number of medication classes used (before cannabis use) 2.35 (1.43) Number of medication classes used (after cannabis use) 1.82 (.94) Quality of life change 45% (28%) Summary Cannabis may have a role in chronic pain, especially neuropathic pain when patients have failed other treatments. Mortality from and use of opioids appears to decrease with cannabis use. Adverse effects do occur so benefits and risks should be weighed for individual patients while considering patient safety and public health concerns. J Pain. 2016 Jun;17(6):739-44. doi: 10.1016/j.jpain.2016.03.002. Epub 2016 Mar 19. 7

43 Objectives Evaluate and discuss clinical studies using medical marijuana that have been performed in patients with neuropathic pain. Compare and contrast clinical studies that have evaluated medical marijuana use in patients with pediatric epilepsy and other neurologic disorders. Review clinical studies that have evaluated medical marijuana use in patients with gastrointestinal disorders. Discuss clinical studies that have evaluated medical marijuana use in patients with other medical conditions for which there may be benefit. Pediatric Epilepsy: AES Annual Meeting 2015 261 children (average age 11 years) Severe epilepsy not responding to other treatments Epidiolex given in increasing doses with other AEDs (avg=3) After 3 months of treatment» 45% lower frequency of seizures» 47% experienced 50% reduction in seizures» 9% seizure-free» Dravet syndrome patients: 62% reduction in seizures, 13% seizure free» Lennox-Gastaut patients: 71% reduction in atonic seizures Adverse effects (>10%)» Sleepiness, diarrhea, fatigue (4% discontinued treatment) Serious adverse effects: 5% treatment-related» Altered liver enzymes, status epileptus, diarrhea and others Lack of efficacy caused 12% withdrawal http://www.medicalnewstoday.com/articles/303725.php Accessed 6/13/16 45 46 Pediatric Epilepsy: Israeli Experience Retrospective review of 74 patients (1-18 years) with intractable epilepsy using CBD-enriched medical cannabis Resistant to >7 antiepileptic drugs Treated with CBD-enriched product for at least 3 months» CBD:THC 20:1 Results (n=74 patients) 70 60 60 50 40 30 24 Seizure Reduction with Cannabis Use» CBD dose ranged from 1-20 mg/kg/day Seizure frequency assessed by parental report 20 10 0 14 8 10 4 4 5 1 1 <10 mg/kg/d >10 mg/kg/d 3 14 0% reduction <25% reduction 25-50% reduction 50-75% reduction >75% reduction Total Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6. Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6. 47 Adverse Effects Reported in 34/74 patients» Seizure aggravation: 13 (18%)» Somnolence/fatigue: 16 (22%)» Gastrointestinal problems and irritability: 5 (7%) Note: side effects led to withdrawal in 5 patients 48 Limitations and Conclusions Lack of a control group No consistent rate of dosage elevation Reliance upon parental report on seizure frequency Short duration of the study Lack of long-term outcome No EEG results and no measurement of other drug levels Results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6. Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6. 8

Systematic Review: Efficacy and Safety of Medical Marijuana in Selected Neurologic Disorders Report of the Guideline Development Subcommittee of the American Academy of Neurology In Patients with Multiple Sclerosis Condition Effective Possibly effective Spasticity OCE Nabiximols, THC Central pain or OCE Nabiximols, THC painful spasms Urinary Nabiximols dysfunction Tremor *OCE= oral cannabis extract Probably or possibly ineffective THC, OCE THC, OCE, nabiximols The risks and benefits of medical marijuana should be weighed carefully. Comparative effectiveness of medical marijuana vs other therapies is unknown for these indications. 50 Indications for Whole Plant Extracts Nabiximols (Sativex )» Spasticity (muscle stiffness/spasm) due to MS» Neuropathic pain in MS» Adjunctive analgesic treatment in patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain Cannabidiol (Epidiolex )» Pediatric epilepsy Lennox-Gastaut Syndrome Dravet Syndrome Neurology. 2014;82(17):1556-63 121 adults with primary diagnosis of migraine Cannabis treatment or prophylaxis recommended by provider Sept 2010-Jan 2014 with at least one follow-up Migraine Headache 12 10 8 6 4 2 0 10.4 4.6 Migraine headaches per month Baseline Follow-up p<0.001 Positive effects reported in 48 (39.7%) patients: prevention, frequency, abort HA Negative effects reported in 14 (11.6%) patients: somnolence, difficult control 52 Objectives Evaluate and discuss clinical studies using medical marijuana that have been performed in patients with neuropathic pain. Compare and contrast clinical studies that have evaluated medical marijuana use in patients with pediatric epilepsy and other neurologic disorders. Review clinical studies that have evaluated medical marijuana use in patients with gastrointestinal disorders. Discuss clinical studies that have evaluated medical marijuana use in patients with other medical conditions for which there may be benefit. Pharmacotherapy. 2016;36(5):505-10 53 Irritable Bowel Syndrome & Crohn s Disease 54 Symptom Improvement in IBD Patients 313 patients with irritable bowel disease surveyed at University of Calgary Comparison of patients that used cannabis and those that did not 17.6% of respondents used cannabis to relieve IBD symptoms Most chose inhalation route of administration (96.4%) Improved symptoms of IBD (next slide) Cannabis use >6 months at any time for IBD symptoms was a strong predictor of requiring surgery in patients with Crohn's disease (OR = 5.03, 95% CI = 1.45 17.46) 90 80 70 60 50 40 30 20 10 0 Symptom improvement (%) 83.9 76.8 48.2 28.6 Abdominal pain Abdominal cramping Joint pain Diarrhea Inflamm Bowel Dis. 2014 Mar;20(3):472-80. doi: 10.1097/01.MIB.0000440982.79036.d6. Inflamm Bowel Dis. 2014 Mar;20(3):472-80. doi: 10.1097/01.MIB.0000440982.79036.d6. 9

55 Other IBD Studies Prospective cohort survey study of 292 patients Among current and past users (51.3%), 16.4% of patients used marijuana for disease symptoms Majority felt marijuana was "very helpful" for relief of abdominal pain, nausea, and diarrhea Observational study of 30 patients with Crohn's disease (CD), Medical cannabis associated with improvement in disease activity Reduction in the use of other medications Placebo-controlled study in 21 chronic CD patients Decrease in CD activity index >100 in 10 of 11 subjects on cannabis compared to 4 of 10 on placebo Complete remission was achieved in 5 of 11 subjects on cannabis group and 1 of 10 on placebo Observational study (number of participants not provided) Low-dose cannabidiol did not have an effect on CD activity. Dig Dis. 2014;32(4):468-74. doi: 10.1159/000358155. Epub 2014 Jun 23. Inflamm Bowel Dis. 2013 Dec;19(13):2809-14. doi: 10.1097/01.MIB.0000435851.94391.37 56 Objectives Evaluate and discuss clinical studies using medical marijuana that have been performed in patients with neuropathic pain. Compare and contrast clinical studies that have evaluated medical marijuana use in patients with pediatric epilepsy and other neurologic disorders. Review clinical studies that have evaluated medical marijuana use in patients with gastrointestinal disorders. Discuss clinical studies that have evaluated medical marijuana use in patients with other medical conditions for which there may be benefit. Other Interesting Clinical Findings Pediatric treatment-resistant epilepsy: parental reports Epilepsy Behav 2015;47:138-41 Epilepsy Behav 2015;45:49-52 Epilepsy Behav 2013;29:574-7 PTSD: cannabis used more frequently for sleep and coping Drug and Alcohol Dependence 2014;136:162 5 J Psychoactive Drugs 2014;46:73-7 Alzheimer s Disease Clin Pharmacol Ther. 2015 Jun;97(6):597-606 J Neuroimmune Pharmacol. 2015 Jun;10(2):268-80 Bladder Cancer Urology. 2015 Feb;85(2):388-92. Established the Medical Marijuana Research Grant Program per C.R.S. 25-1.5-106.5 in May 2014 Funds research regarding the efficacy of marijuana and its component parts as part of medical treatment and monitors the progress of the funded research studies Coordinates the Medical Marijuana Scientific Advisory Council Applicant Project title Primary investigator Edward J. Hoffenberg, Do Adolescents and Young Adults with Inflammatory Bowel Disease Anschutz Medical School of Medicine at the Anschutz Medical Benefit from Use of Marijuana?, Children s Hospital Colorado A Randomized, Double-blind, Placebo-controlled Crossover Study of Maureen A. Leehey, Department of Anschutz Medical Tolerability and Efficacy of Cannabidiol (CBD) on Tremor in Neurology, School of Parkinson's Disease Medicine at the Anschutz Medical University of Pennsylvania School of Medicine Anschutz Medical Denver Anschutz Medical Anschutz Medical Multidisciplinary Association for Psychedelic Studies Anschutz Medical Treating PTSD with Marijuana: Clinical and Functional Outcomes Cannabidiol (CBD) and Pediatric Epilepsy Medical Marijuana in the Pediatric Brain Tumor Population (palliative care) Use of Medicinal Cannabinoids as Adjunctive Treatment for Medically Refractory Epilepsy (pediatric epilepsy) Placebo-controlled, Triple-Blind, Randomized Crossover Pilot Study of the Safety and Efficacy of Four Potencies of Smoked Marijuana in 76 Veterans with Chronic, Treatment- Resistant Post Traumatic Stress Disorder (PTSD) A Double Blind, Placebo-Controlled Cross Study Comparing the Analgesic Efficacy of Cannabis versus Oxycodone Colorado Cannabis Cohort: Efficacy, Safety, and Usage Patterns of National Jewish Health Medical Marijuana for Sleep TOTAL Medical Marijuana Research Grant Recommendations https://www.colorado.gov/pacific/cdphe/medical-marijuana-research-grant-recommendations Marcel O. Bonn-Miller, Dept. of Psychiatry, University of Pennsylvania, and VA National Center for PTSD George Sam Wang, Department of Pediatrics, School of Medicine at the Anschutz Medical and Children s Hospital Colorado Nicholas Foreman, Dept. of Pediatrics, Pediatric Neuro-oncology, Children s Hospital Colorado Kelly Knupp, Dept. of Pediatrics, Children s Hospital Colorado and School of Medicine at the Anschutz Medical Marcel O. Bonn-Miller, University of Pennsylvania and VA National Center for PTSD Emily Lindley, Dept. of Orthopedics, University of Colorado School of Medicine at the Anschutz Medical Updated grant amount $1,191,329*** $1,028,981** $1,181,127*** $576,350*** $1,041,256*** $631,835** $2,156,000*** $743,122** Russell Bowler, National Jewish Health $450,000* $9,000,000 Future Research Improvements Report as much as possible about beneficial and harmful effects of cannabis in medical conditions Report as much as possible about strains of cannabis Concentration of cannabinoids in plant Concentration of cannabinoids in blood of participants Do not equate effects of cannabis in human samples with effects of synthetic THC and CBD Plant has complex set of interactions with cannabinoids and terpenes (among other components) Need to study strains used in real world Challenges can be overcome with high-quality clinical research by trained individuals British Journal of Pharmacology. 2011;163:1344 1364. J Clin Pharmacol 2015;55:839-41. 10

61 62 Conclusions Medical marijuana appears to be effective in neuropathic pain; reserved for patients that do not respond to or tolerate current prescription therapies Medical marijuana may have a role in pediatric epilepsy and other neurologic conditions; more data are needed Limited evidence for medical marijuana use in gastrointestinal disorders Hypotheses regarding medical marijuana use have been generated for other medical conditions; high quality research is needed QUESTIONS? Laura.Borgelt@ucdenver.edu 11