Getting Into the Weed: psychoactive roles they play Describe major - PDF document

4/13/2018 Objectives • Describe in simple terms the endocannabinoid system and which body systems are most affected by it • Differentiate the effects of THC and CBD and the physical and Getting Into the Weed: psychoactive roles they play • Describe major differences in effects between common dosage Potentials and Pitfalls Affecting forms of cannabis or cannabinoid medicines Medical Use • Describe common adverse effects and the populations at greatest risk for severe harm from cannabis use Cydney E. McQueen, PharmD • Use knowledge to aid in decision ‐ making and risk ‐ analysis when Clinical Associate Professor considering medical use recommendations for individuals or UMKC School of Pharmacy populations 2 Which is medicinal cannabis? The Definitions…. • Cannabinoids: a group of related chemicals from the Cannabis sativa Herbal/Botanical Medicine Drug plant that act on/with cannabinoid receptors • Complex, many “active” ingredients • Single “active” ingredient • Cannabimimetics: synthetic chemicals that mimic actions of cannabinoids (products can combine two or more drugs) • May have highly variable content of • Phytocannabinoids: chemicals from other plants that act on/with • Has generally consistent content of cannabinoid receptors ingredients in each batch ingredients in each batch • Endocannabinoids: chemicals made internally that act on/with • Used in raw plant form or extracts cannabinoid receptors in the body • Often available in a limited number • Often available in many dosage of dosage forms • Cannabinoid receptors: receptors that are effected by cannabinoids, forms endocannabinoids, or other chemicals • Dosage range generally defined • Dosage range may vary widely • Terpenes: chemicals in C. sativa that provide the characteristic odors and also have pharmacologic activity 3 5 1

4/13/2018 Think of cannabis as a chemical factory…. 6 7 Hashish: pressed kief Kief: resin separated from the rest of the buds 8 9 2

4/13/2018 Endocannabinoids • Multiple and more to discover! • anandamide (AEA) • 2 ‐ arachidonoylglycerol (2 ‐ AG) • palmitoylethanolamide (PEA) CC by upload.Wikimedia.org How can cannabis have medicinal use? • Signaling chemicals • Involved in many functions • Generally VERY short ‐ lived The endocannabinoid system • Act on more than just the CB 1 and CB 2 receptors = endocannabinoids + endocannabinoid receptors 10 11 CB 1 and CB 2 Receptors CB 1 CB 2 Immune system cells • Moderates movement of immune • cells and signaling Microglia • Possible role in neurodegenerative • disorders Adapted from: Franson, KL. What is Known About the Clinical 12 13 Pharmacology of Medical Cannabis? 5/2013. CC by aury_h 3

4/13/2018 Receptor Activity Neuronal and Cellular Signaling CC by Zou S, Kumar U. Intl J Mol Sci 2018;19(3):833 Nunn A, et al . Phil Trans R Soc B . 2012;367:3342 ‐ 3352. 14 15 Borgelt LM, et al. Pharmacotherapy . 2013;33(2):195 ‐ 209. Describe in simple terms the endocannabinoid system and Endocannabinoid which body systems are most affected by it System Involvement  Internal signaling/control/feedback system made up of endocannabinoids + cannabinoid and other receptors  Central and peripheral nervous system, the gut, and the immune system • Cardiovascular system 16 17 CC by Zou S, Kumar U. Intl J Mol Sci 2018;19(3):833 4

4/13/2018 Physiologic Effects Cannabinoids from C. sativa THC CBD • THC (tetrahydrocannabinol) • Psychoactive • Non ‐ psychoactive*; ameliorates some • THCV (tetrahydrocannabivarin) THC adverse/psychoactive effects • CB 1 R/CB 2 R partial agonist • CBD (cannabidiol) • Enhances or modulates activity of AEA • Inhibitor of 5 ‐ HT3 receptors and other cannabinoids for CB 1 R/CB 2 R • CBN (cannabinol – breakdown product) • Some activity on other receptors • Doesn’t directly bind CB 1 R/CB 2 R • CBC (cannabichromene) • Activities • Activities • Increased: vasodilation, somnolence, • CBG (cannabigerol) • Anticonvulsant, anxiolytic, antiemetic, analgesia, intraocular pressure neuroprotective, sleep ‐ promoting, • And on and on….. • Decreased: body temperature, anti ‐ inflammatory* cognition, memory, coordination, GI movement, inflammation 18 19 Terpene Components of Cannabis Entourage or Ensemble? • Limonene (anxiolytic, immunostimulant, antimicrobial, • Essential oil apoptosis of breast cancer cells) components •  ‐ pinene (acetylcholinesterase inhibitor, anti ‐ inflammatory, • In foods; GRAS bronchodilatory) status in US •  ‐ carophyllene (anti ‐ inflammatory, antimalarial, selective • Pharmacologic activity alone CB 2 agonist, gastric cytoprotective) • Synergistic with • Linalool (anti ‐ anxiety, local anesthetic, analgesic via various adenosine A 2A , anticonvulsant/anti ‐ glutamate) cannabinoids • Modulate •  ‐ myrcene (anti ‐ inflammatory via PGE ‐ 2, sedating, muscle receptor relaxant, hypnotic, blocks hepatic carcinogenesis by aflatoxin, activity analgesic antagonized by naloxone) 20 21 5

4/13/2018 Differentiate effects of THC and CBD and their physical and psychoactive roles THC CBD THC+CBD Terpenes “high” or “intoxication”  Anticonvulsant activity   Pain relief     Differences in Dosage Forms Decreased intraocular   ?  pressure    Antiemetic activity Anxiolytic    Cardiovascular effects (hypotension, tachycardia)  ?  Sedation/somnolence  22 23 Inhalation ‐ Classic …not classy Boiling Points Cannabinoid °F Terpenoids • Fastest absorption CBC and THCV 428 • Fastest onset of action 388 Linalool CBN 365 • Exposes lungs to CBD 356 combustion products 350 Limolene • Risk of second ‐ hand 330 Myrcene exposure to others  ‐ pinene 329 THC 315  ‐ pinene 313  ‐ carophyllene 246 24 25 CBG (melting) 125 6

4/13/2018 Inhalation Oral… The Volcano – used in many of the Israeli medical studies CC NAFMO Disposable Medicinal versus Primarily Recreational CBD vape pen 26 27 …and Oral Sublingual/Buccal • For cannabis ‐ naïve patients • less stigma • Recreational and medicinal products • more like “medicine” • Slower absorption • Mucosal absorption – • More intra ‐ patient directly into bloodstream, variability in absorption avoids first pass effect of and bioavailability liver metabolism • Products are often a mix of mucosal and oral absorption 28 29 7

4/13/2018 Describe major differences in effects between common dosage Topical Homemade forms of cannabis or cannabinoid medicines Inhalation Fastest onset of action – within When fast symptom relief is important, such as minutes for pain Avoid first pass effect entirely Oral Slow onset of action – 1 ‐ 2 hours For chronic symptoms Longer duration of action Bioavailability affected by first pass metabolism More patient ‐ to ‐ patient variability Commercially available Sublingual/buccal Faster absorption and onset than For chronic symptoms oral, but slower than inhalation Some avoidance of first pass effect Topical For local action; some systemic When pain is localized and/or occasional and absorption, but is much slower need to avoid systemic side effects 30 31 Adverse Effects – Short ‐ Term • Many fairly well ‐ known, primarily associated with THC component • Variable severity, generally dose ‐ related • Red eyes Adverse Effects and Risks of •  hunger • Dry mouth Cannabis Use • Sedation, somnolence •  heart rate, hypotension/postural hypotension • Coughing, wheezing , increased mucus, dysphagia (smoked) • Mood changes,  /  anxiety, temporary paranoia/psychosis •  /impaired reaction time, lack of coordination • Impaired cognition, altered time perception, memory loss 33 34 8

4/13/2018 Adverse Effects – Long ‐ Term Adverse Effects – Long ‐ Term • Not as well ‐ understood, may or may not be primarily associated with • Allergies and skin reactions THC component • Information primarily based on recreational users vs medicinal users • Psychological and physical dependence leading to addiction  • Cannabis/cannabinoid hyperemesis syndrome cannabis use disorder (CUD) • Severe cyclic vomiting • Addiction potential compared to other substances of abuse • New data ‐ CBD may ease physical withdrawal symptoms • Worsening psych disorders, lethargy/apathy, depression/anxiety • Lung cancer (smoked) ? • Impaired cognition, memory loss • Basic science – both help and harm in cancer studies are documented • Decreased GI motility • Thyroid and breast cancer more problematic •  immune response,  sperm production ? 35 36 Adverse Effects ‐ Populations • Pregnancy • maternal use before and during  increased risk of acute nonlymphoblastic leukemia (ANLL) • lower birthweight ? • ??? Adverse Drug Interactions • Adolescent use The great unknown…. • more likely to develop CUD • changes in brain development  decreased IQ ? • earlier onset/increased schizophrenia ? 37 38 9