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Saturday, March 24 - Cannabis: Weeding Out the Myths

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Cannabis: Weeding Out the Myths
0006-0000-18-003-L01-P | .1 CEUs |
Kari L. Franson, PharmD, PhD, BCPP

Published in: Health & Medicine
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Saturday, March 24 - Cannabis: Weeding Out the Myths

  1. 1. Cannabis Kari L. Franson, PharmD, PhD, BCPP Associate Dean and Associate Professor Department of Clinical Pharmacy University of Colorado Skaggs School of Pharmacy & Pharmaceutical Sciences I have nothing to disclose and no conflicts of interest or funding sources I will be discussing unapproved drugs and unapproved uses for drugs
  2. 2. Objectives At the completion of this activity, the participant will be able to: • Analyze the common conditions for which cannabis is used and the current supporting evidence (if any) • Describe the acute effects and long-term risk of cannabis, and its effect on the reward pathway of the brain. • Discuss cannabis dosing options and interpret possible drug interactions
  3. 3. •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 •indica and sativa have been cross-bred so no generalizable characteristics Borgelt LM, Franson KL, Nussbaum AM, Wang GS. Pharmacotherapy. 2013 A patient asks “So what is cannabis and what makes it such a wonder drug?”
  4. 4. Cannabis contains many different cannabinoids • ∆9 -tetrahydrocannabinol – THC; most psychoactive & has most medical claims • Cannabidiol – CBD; reduce THC effects & most medical ‘promise’ • Cannabichromene – CBC; anti-inflammatory, anti-bacterial/fungal • Cannabigerol – CBG; decrease GI inflammation • Tetrahydrocannabivarin – THCV; hypophagia possible diabetes treatment • Tetrahydrocannabinolic acid – THC-A; THC precursor, anti- spasmodic • Cannabinol – CBN; THC metabolite & less psychoactive Pertwee RG. Br J Pharmacology. 2006 Pertwee RG. Br J Pharmacology. 2008
  5. 5. Regulatory effect of endo- cannabinoids (anandamide and 2-AG) at the CB1 receptor Pertwee RG. Br J Pharmacology. 2008 1. Inhibition of adenylyl cyclase activity 2. Alter second messenger systems such that CA++ influx is inhibited Neuromodulation by anandamide particularly relevant to modulation of GLU (shown), Ach, GABA, DA, NE A patient asks “How is it possible that cannabis works on so many diseases?”
  6. 6. Structure Endocannabinoids Regulate 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 http://headsup.scholastic.com/students/endocannabinoid Endocannabinoids work at CB1 receptors all over the CNS
  7. 7. Structure Endocannabinoids regulate Resultant effect Spinal cord Inhibit GLU & info transfer between body & brain Decreased pain sensitivity Parasympathetic system Inhibit Ach release, HR regulation, urination regulation HR stimulation, sometimes inhibits urination Sympathetic system Inhibit NE release, HR regulation, blood vessel constriction Delayed reduction in HR and blood pressure 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 http://headsup.scholastic.com/students/more-facts-about-how-drug-abuse-puts- your-whole-body-at-risk And endocannabinoids work at CB1 & CB2 receptors all over the body
  8. 8. 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 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 Spinal cord Altered pain sensitivity TRPV reduction in pain Cannabis activity at CB1 receptors - possible entourage effect? A patient asks “How does cannabis work for my pain?” Teaching tool
  9. 9. A patient asks “If it is such a wonder drug, why isn’t big pharma involved?” • Dronabinol, nabilone (THC molecule Pharma products) • Epidiolex® (CBD extract Pharma product under development) • Sativex® (THC & CBD extract Pharma product only in Canada & Europe) • Rimonabant (CB1 receptor inverse agonist Pharma product pulled from market) • Most interact with the endocannabinoid system via G-protein- coupled receptors in the body, but not CBD Borgelt LM, Franson KL, Nussbaum AM, Wang GS. Pharmacotherapy. 2013
  10. 10. Number of states with various approved medical conditions Wong FH, Borgelt LA, Franson KL. Int Med Rev 2018 Alzheimer’s disease (11) Epilepsy/seizures (29) Nausea (21) ALS (18) Glaucoma (27) Pain (25) Arthritis (3) HIV/AIDS (28) Parkinson’s disease (10) Cachexia (24) Migraine (1) Peripheral neuropathy (5) Cancer (28) Multiple sclerosis (15) PTSD (24) Crohn’s disease (19) Muscle spasticity (22) Tourette’s syndrome (4) A provider asks “What can you tell me about the diseases that medical marijuana has been approved for?”
  11. 11. I believe that patients gain the most benefit using medical cannabis for: A. Nausea and vomiting control B. Appetite stimulation C. Pain control D. Seizure control E. Feeling of euphoria Tell me what you think
  12. 12. National Academies: Health Effects of Cannabis •Conclusive or substantial evidence that cannabis or cannabinoids are effective: • as anti-emetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids) • for treatment of chronic pain in adults (cannabis) • for improving patient-reported multiple sclerosis (MS) spasticity symptoms, but limited evidence for clinician- measured spasticity (oral cannabinoids) National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
  13. 13. National Academies: Health Effects of Cannabis •Moderate evidence that cannabinoids, primarily nabiximols, are effective: • to improve short-term sleep outcomes in patients with sleep disturbance associated with obstructive sleep apnea, fibromyalgia, chronic pain, and MS. National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
  14. 14. National Academies: Health Effects of Cannabis •Limited evidence that cannabis or oral cannabinoids are effective for: • increasing appetite and decreasing weight loss associated with HIV/AIDS (cannabis and oral cannabinoids) • improving symptoms of Tourette syndrome (THC capsules) • improving anxiety symptoms in individuals with social anxiety (cannabidiol) • improving symptoms of post-traumatic stress disorder (nabilone) • better outcomes (i.e., mortality, disability) after a traumatic brain injury or intracranial hemorrhage – statistical association National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
  15. 15. National Academies: Health Effects of Cannabis •Limited evidence that cannabis or oral cannabinoids are ineffective for: • improving symptoms of dementia (cannabinoids) • improving intraocular pressure associated with glaucoma (cannabinoids) • reducing depressive symptoms in individuals with chronic pain or MS (nabiximols, dronabinol, and nabilone) National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
  16. 16. National Academies: Health Effects of Cannabis •No or insufficient evidence to support or refute that cannabinoids are effective for: • cancer-associated anorexia cachexia syndrome and anorexia nervosa • cancers, including glioma • irritable bowel syndrome • epilepsy • spasticity in patients with paralysis due to spinal cord injury • chorea and certain neuropsychiatric symptoms associated with Huntington’s disease • symptoms associated with amyotrophic lateral sclerosis (ALS) • Parkinson’s disease or levodopa-induced dyskinesia • dystonia • treatment for mental health outcomes in individuals with schizophrenia or schizophreniform psychosis • achieving abstinence in the use of addictive substances National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
  17. 17. Chemotherapy induced nausea and vomiting •Small studies compared THC (dronabinol, nabilone) to dopamine antagonists • Dronabinol showed anti-emetic efficacy over neuroleptics (but high risk of bias) NNT = 3.4 • Depression (13%), hallucinations (6%), paranoid delusions (5%), occurred, but patients preferred cannabis over control (RR 0.33; 95% CI 0.24-0.44) • Smoking relief 70-100% vs. capsule relief 76-88% • The standard of care for prevention of CINV for highly and moderately emetogenic chemotherapy is: 5-HT3 receptor antagonist, dexamethasone, aprepitant/fosaprepitant Tramer MR, Carroll D, Campbell FA, et. al. BMJ 2001; Musty RE, Rossi R J Cannabis Ther 2001; Todaro B. J Natl Compr Canc Netw. 2012 Machado Rocha FC, Stefano SC, De Cassia Haiek R, et. al. Eur J Cancer Care 2008
  18. 18. Chronic (neuropathic and cancer) pain •Review of trials with >30% reduction in pain • 2 cancer pain trials • 6 neuropathic pain trials •Concluded moderate quality of evidence to support the use of cannabis for chronic pain Whiting PF, Wolff RF, Deshpande S, et al. JAMA 2015 Grant I. Report to the State of California 2010 Common analgesics for neuropathic pain *to achieve 30% reduction in pain
  19. 19. Multiple sclerosis-associated spasticity •American Academy of Neurology (AAN) evidence-based guideline recommendations •Oral cannabis extract, synthetic THC, Sativex® •Several double-blinded RCTs > 1,000 patients • Subjectively improved spasticity and pain • Sativex also helped with urinary frequency • Objective measures not significant •Smoked cannabis • Data inadequate to determine safety/efficacy Yadav V, Bever C, Bowen J, Bowling A, et. Al. Neurology 2014
  20. 20. Cachexia and appetite stimulation •8 controlled studies in AIDS- or cancer-related cachexia • 3 studies of smoked marijuana (up to 67 patients) • Others used dronabinol • Non-statistically significant weight gain, increase appetite, and improve functional status • Megestrol 750 mg weight gain > dronabinol 5 mg • Combo did not lead to additional weight gain • Cancer patient results were less consistent Abramovici H. Health Canada 2013 Timpone JG, Wright DJ, Li N, et. al. AIDS Res Hum Retro 1997
  21. 21. Seizures •Uncontrolled case series in intractable childhood- onset epilepsy • CBD : THC ratio 20 : 1 • Median monthly seizure frequency • Baseline 30.0 (interquartile range [IQR] 11.0–96.0) • After 12 week treatment 15.8 (IQR 5.6–57.6) • Some weaned patient from another AED after starting CBD •Adults case reports and patient surveys Seizure exacerbation with discontinuation German study no effect Friedman D, Devinsky D, NEJM 2015 Gloss D, Vickery B. Cochrane Database Syst rev 2014
  22. 22. Glaucoma •Systemic administration of cannabis ↓ IOP by 30% •Pilot study of 6 patients ↓ IOP for 2 hours •Uncontrolled study 9 patients with open-angle glaucoma THC qid ↓ IOP •Patients appeared to develop tolerance, and all discontinued the study Flach AJ. Trans-American Ophthalmological Society 202
  23. 23. How would you respond to a 60 yo patient who asks you to help them use cannabis for cancer pain? Tell me what you think
  24. 24. NIDA (http://drugabuse.gov/sciencefair/) The patient asks “Are you worried I am going to get addicted?”
  25. 25. Lifetime dependency risk with use 32% Hall and Degenhardt. Lancet. 2009 Strahny A. CBHSQ Report. 2013 23% 17% 15% 9% % 0 25 50 75 100 MJ addiction risk in teens
  26. 26. Brain development in adolescence Limbic region • Immediate rewards • Impulsive behavior Cortex • Long term gain • Thoughtful behavior http://erichengelhardt.net/neuro-facts.html accessed 5/28/2013 A mother asks “Is cannabis going to fry my son’s brain?”
  27. 27. Meier MH, et al. Proc Natl Acad Sci. 2012 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 100.64  Used, never regularly 101.24  Used regularly 90.77  Impairment of learning, memory, and executive functions Effect on neuropsychological functioning
  28. 28. Chronic cognitive effects of cannabis (A) Relation between amount of marijuana smoked2 and Repetition of Numbers Task, number correct for the high Shipley IQ group (squares) and the low Shipley IQ group (circles). (B) Relation between amount of marijuana smoked2 and performance on the Stroop task for the high Shipley IQ group (squares) and the low Shipley IQ group (circles) Bolla KI, et al. Neurology, 2002
  29. 29. Pierre JM. Current Psychiatry. 2011 Multiple studies have demonstrated an increased risk of psychosis in THC users • 3 meta-analyses have shown an odds ratio of 1.4 to 2.9 • Risk with cannabis use is up to 3 fold higher compared to those who did not use cannabis • After control for a variety of confounding factors including other drug use and socioeconomic variables Cannabis and psychosis
  30. 30. Potential AEs from chronic cannabis use Respiratory  Increased sputum production, wheezing, bronchitis  Potential increase in chronic bronchitis, emphysema, and airway inflammation Gastrointestinal  Cannabinoid hyperemesis syndrome Genitourinary  Increased risk of failing a drug test Reproductive  Menstrual cycle disruption  Decreased sperm count  Impotence and decreased libido  May decrease lactation Hematology/ Oncology  Potential increased risk of nasopharyngeal carcinoma  Potential for increased risk of lung cancer, however, data is inconclusive.  Many products may contain other carcinogens. Cannabis smoke contains known carcinogens. Metabolic/Endocrine  Potential to increase insulin resistance in adipose tissue 30 A patient asks “Are there other effects of cannabis besides in the brain?”
  31. 31. How would you respond to the patient who says “no one has ever died from using cannabis”? Tell me what you think
  32. 32. Acute cardiovascular effects of THC Heart rate HRV • The variation in the time interval between heartbeats (RR-interval) • ↓ HRV is a predictor of mortality after MI L Zuurman, et al. Br J Clinical Pharmacology. 2008
  33. 33. Kaplan-Meier estimates of post-MI survival among 87 cannabis users and 174 propensity-matched nonusers. Frost L, et al. American Heart Journal. 2013 Cannabis use and long-term mortality among survivors of AMI
  34. 34. The most concerning cardiac effect of cannabis is: A. Increased blood pressure B. Decreased heart rate C. Increased automaticity D. Decreased heart rate variability Tell me what you recall
  35. 35. 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 There is a 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 L Zuurman, et al. Br J Clinical Pharmacology. 2008 A patient asks “I still want to try it…How much should I take?”
  36. 36. The safest and more effect manner to administer THC to treat pain is: A. Smoking a joint B. Eating a marijuana infused chocolate bar C. Vaporizing ground flower D. Dabbing a concentrate E. Applying a topical cream Tell me what you think
  37. 37. Smoking cannabis plant •Burns 500-2000°F, cannabis combusts at > 392°F •Benzo[a]pyrene is formed from partial combustion, binds to DNA guanine causes distortions and leads to mutations, causes drug interactions •Immediate effects, feedback possibly leads to moderation, less consumption •Less erratic absorption than FDA medications Image from: https://www.addict-help.com/cannabis/smoking-weed.asp A patient asks “There are so many ways to use cannabis. What are my options?”
  38. 38. Vaporizing cannabis plant or concentrate •Same immediate effects and benefits as smoking •Heats 285 - 392°F vaporizing CBs •Conductive vs. convective heating Images from: www.cannastick.com; https://spendabit.co/go?q=vape&offset=0 ; www.procon.org
  39. 39. Dabbing cannabis concentrates •CBs are extracted by solvents •Butane hash oil (BHO), dabs, earwax, butter or shatter •>90% of CBs •Superheat nail (with blow torch) and add dab •Users quickly develop tolerance Images from: https://www.zamnesia.nl/dabbing/2365-glazen-olie-bong-blaze-swirl.html
  40. 40. Edible baked goods, candies, tinctures •Edibles have CBs added, or are infused with CB butter, oil or alcohol •10mg serving size and 100mg max •Doesn’t release toxins •Discreetly consumed •Must exit dispensary in child resistant packaging •Now also prohibit edibles that resemble animals, people or fruit Images from: http://www.leafscience.com/2015/10/27/beginners-guide-marijuana-edibles/
  41. 41. Cannabis infused creams, lotions and oils • THC not charged, but lipophilic properties limit it getting to site of action • Most products claim no psychoactive effects, so THC not getting absorbed • Patch with occlusion and vehicle to enhance absorption Images from: http://dailyleafdeals.com/apothecanna-product-review ; http://www.americanpharmaceuticalreview.com/Featured- Articles/170872-Lipids-in-Transdermal-and-Topical-Drug-Delivery
  42. 42. PK profile of smoked THC • Smoking cannabis turns ~50% of the THC content into smoke • Up to 50% of inhaled smoke is exhaled again, and some undergoes localized metabolism in the lung • Bioavailability of a inhaled dose of THC is between 10-25% • Effects are perceptible within seconds and fully apparent in a few minutes • Effects last about 3 hours Strougo A, et al. J Psychopharmacology. 2008 A patient asks “How often should I take it?”
  43. 43. PK profile of oral THC • Onset of effect is delayed: 1-3 hours due to slow absorption from the gut • Bioavailability of THC after oral ingestion ranges from 5-20% in the controlled environment of clinical studies • Weight, metabolism, gender and eating habits play a role in absorption • Effects last about 6 – 12 hours Agurell S, Halldin M, Lindgren JE, et al. Pharmacological reviews. 1986
  44. 44. PK profile of oromucosal THC/CBD - Nabiximols • One study did not find difference between oral THC capsules and oromucosal spray PK • Peak concentration THC 1.5 hours • Peak concentration CBD 1.3 hours • 2-fold inter-patient variability in peak THC and CBD levels Karschner EL, Clin Chem 2011
  45. 45. 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
  46. 46. Review today’s session •Analyzed the common conditions for which cannabis is used and the current supporting evidence •Described the acute effects and long-term risks of cannabis, and its effect on the reward pathway of the brain. •Discussed cannabis dosing options and interpreted possible drug interactions

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