Medical Cannabis … Clinical and Legal Considerations Christine Roussel, PharmD, BCOP Director of Pharmacy, Doylestown Hospital Disclosures • No financial Disclosures Relevant to the Cannabis Industry • Program Director, Medical Cannabis Education Course, Philadelphia College of Pharmacy, University of the Sciences Outline • Endocannabinoid System • Cannabis Pharmacology and Formulations • Clinical Considerations and Adverse Effects • Legal Considerations Photo by C.Roussel Pharmacist Objectives 1. Describe key features of the endocannabinoid system, pharmacology, and non-cannabinoid components of cannabis. 2. Outline dosage forms, pharmacokinetics, potential adverse effects and adverse effects including use disorder. 3. Discuss medical cannabis risk versus benefits and patient counseling opportunities. 4. Review federal cannabis law and possible conflicts between state and federal law. Pharmacy Technician Objectives 1. Describe main components of cannabis and their pharmacology. 2. List dosage forms available and how they work differently. 3. Describe adverse effects associated with medical cannabis and identify resources for more information. 4. Review federal regulations and their conflict with state medical and recreational marijuana laws. Disclaimer • Cannabis is currently not FDA approved for any condition. • Cannabis is currently DEA Schedule 1 (Federal) under the Controlled Substance Act of 1970. • No currently acceptable medical use • High Potential for abuse • Investigational use only – IND applications must receive triple agency approvals: National Institute of Drug Abuse (NIDA) / DEA / FDA – Product for Federal Research is Sole Source through NIDA (Unless Import permission is granted) Cannabinoids as antioxidants and neuroprotectants US Government Owns Patent “Cannabinoids are found to have particular application as neuroprotectants, for eXample limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson’s disease and HIV dimension” https://patents.google.com/patent/US6630507B1/en - Worth Reading!!!! 7 U.S. Government Grows Cannabis and Supplies it to Patients 1977 – 1993 Federal Compassionate IND (n=13) Grown by University of Mississippi & NIDA Pictures by Irvin Rosenfield, author My Medicine. Used with Permission. 8 Nerve Communication https://www.shmoop.com/animal-systems/nervous-system.html Presynaptic 1. Neurotransmitters Neuro Signal Neuron Synthesized and Transmission stored in vesicles Across the until ready to release Synaptic Cleft 2. Neurotransmitter Binding to • Glutamate Corresponding • GABA Receptor • Acetylcholine • Norepinephrine • Dopamine 3. Initiates • 5-HT3 Postsynaptic Downstream • Cholecystokinin Neuron Effects Image by C. Roussel Presynaptic 3. Binding at the CB1 Neurotransmitter Neuron Receptor stabilizes Signaling vesicles to decrease neurotransmitter release Endocannabinoid Signaling is Retrograde Inhibition 2. Endocannabinoids (Anandamide, 2-AG) Synthesized on 1. Too demand for much Postsynaptic immediate release activity Neuron Image by C. Roussel CB1 Receptors CB1 – Primarily in Brain • NOT significant in brainstem (RR,HR) Other Locations • Adipocytes • Endocrine and Exocrine Glands • Liver • Heart, Vascular Smooth Muscle Cells Cannabinoid Pharmacology in CNS ● Parasympathetic ● Anti-Nociceptive Human brain after injection of radio tracer ● Neuroprotection to show the regional distribution of CB1R ● Neuroplasticity Originally publication: Burns, et al. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. PNAS June 5, 2007 vol. 104 no. 23. Pg. 9800–9805 © [2007] All rights reserved. Reprinted with permission." Shohami E and Horowitz M (ed). Cannabinoids in Health and Disease. Themed special issue, Journal of Basic and Clinical Physiology and Pharmacology 2016; 27(3). 12 CB2 Receptors • Signally ↓ release of activators and sensitizers Immunomodulation: • Monocytes and Macrophages • B-cells and T-cells Liver, Spleen, Tonsils Central & Enteric Nervous System Endocrine and Exocrine Glands "Originally publication: Ahmad R,, et al. 2016 Whole-body bio-distribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects. Mol Imaging Biol. 2013 Aug;15(4):384-90© [2013]All rights reserved. Reprinted with permission." 13 Medical Cannabis vs Marijuana Cannabis sativa • Plant reliably grown and handled • Good Manufacturing Practices • Assayed, Labeled and Dated for cannabinoids and terpene content • Proven absence of typical contaminants: • Mold / Yeast • Pesticides • Heavy Metals Pictures from www.Steephill.com/science. All rights reserved. Reproduced with permission • Residual Solvents 14 Same Plant – With Different Cannabis Sativa Chemovars Hemp – Fiber Type Drug Type (aka Cannabis , Tall, thick stalk Marijuana ) THC + Terpenes Fiber Oil Food / Feed Cannabinoids Industrial Hemp: stalk and seeds are used for Cannabis / Marijuana: medicinal / teXtiles, paper, food, detergents, building recreational use of cannabinoids materials (eXcludes flower) THC content – 5 – 15+% THC Content < 0.3 – 1.5% DEA Controlled Substance Not Scheduled Seed to Sale Tracking Pictures by C. Roussel 16 CO2 Extraction Pictures by C. Roussel “Genetic tools weed out misconceptions of strain reliability in Cannabis sativa” No consistent genetic differentiation between the widely held perceptions of Sativa and Indica Cannabis types. Instances were found where samples within strains are not genetically similar. Schwabe A and McGlaughlin M. Genetic tools weed out misconceptions of strain reliability in 1 Cannabis sativa: Implications for a budding industry. bioRxiv preprint first posted online May. 28, 2018. NOT PEER REVIEWED 18 Cannabis: Entourage Effect THC CBD tetrahydro- cannabidiol Limonene Pinene cannabinol THC-A + CBC Myrcene Linalool THCV Tetrahydro- Tetrahydro- cannabinolic Cannabi- cannabivarin acid chromene Linalool Cannabinoids ß-Caryo- CBN Flavonoids phyllene CBG Lipids cannabigerol Cannabinol Terpenes Sterols 19 CB1 Endocannabinoids (Anandamide, 2-AG) Image by C. Roussel TETRAHYDROCANNABINOL (THC) • Partial Agonist of CB1 and CB2 • Euphoria • Analgesia (primary Pain relief molecule) • Muscle RelaXant • AnXiolytic (low dose) -> AnXiogenic (higher doses) Image by C. Roussel TETRAHYDROCANNABINOL (THC) ADVERSE EFFECTS Dizziness, Weakness Increase risk of falls Psychoactivity vs PsychotoXicity Tachycardia • Impaired cognition Vasodilation, Hypotension • Difficulty concentrating Addiction (1 in 10 chronic • Memory Impairment recreational users) Hypothermia Caution in patients with unstable mental health conditions (especially bipolar disorder and schizophrenia). Image by C. Roussel Cannabidiol (CBD) • Enhances natural endocannabinoid activity • inhibits anandamide hydrolysis • Agonist at 5-HT (anti-nausea) and TRPV1 (Pain relief) • Potent Immune Modulator = Strong Anti-Inflammatory Activity • Anti-seizure Negative Allosteric Modification • Neuroprotective • Decrease negative effects of THC (anXiety, memory impairment, psychoactivity) Image by C. Roussel Cannabidiol (CBD) ADVERSE EFFECTS Diarrhea Headache Suppress Appetite Stimulating (trouble sleeping) …. …..Somnolence Drug Interactions World Health Organization: Cannabidiol Critical Review TERPENES MYRCENE LINALOOL ß CARYOPHYLLENE PINENE Analgesic Sedative Select CB2 Agonist Anti-Inflammatory Anti-Inflammatory via AnXiolytic Analgesic Bronchodilator PGE-2 Analgesic Gastric Protective Acetylcholinesterase Anti-Convulsant Modulate GABA Anti-Inflammatory via Inhibitor (Aids memory) and Glutamate Skeletal Muscle RelaXant PGE-1 Russo, E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid 25 entourage effects. Br.J.Pharmacol. 163: 1344-1364. THC Inhalation Bioavailability is Variable due to smoking dynamics (10 – 60%) • Depth of inhalation • Duration of Breath Holding • Temp of Vaporizer Good For Titration and break through because of rapid effects Typical Onset 0 – 10 min Import to Teach: Duration 2- 4 hours • Patient Proper Technique • To wait 5 -10 minutes between inhalations during titration Huestis M. Human Cannabinoid Pharmacokinetics. Chem Biodivers. 2007 August ; 4(8): 1770–1804. MacCullum C and Russo E. Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine. 49 (2018) 12-19. Cannabis (THC) Oral Administration • Onset 30 – 120 min • ↑ Inter/Intra Patient Variable Absorption • Absorption ↑ w/ high fat meal • Duration 4 – 8 hours • *Up to 24 hours dose dependent • Lower Peak [THC] • ↑ [11-HydroXy-THC] – Longer T1/2 – More potent analgesic activity After Administration of 2.5 mg – More lipophilic Dronabinol Huestis M. Human Cannabinoid Pharmacokinetics. Chem Biodivers. 2007 August ; 4(8): 1770–1804. MacCullum C and Russo E. Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine. 49 (2018) 12-19. Oral Mucosal Products Bypasses Liver Metabolism Onset 15 – 60 mins Inhalation • higher doses that eXceed therapeutic threshold in most patients • poor ability to dose • delivers smaller doses • able to measure dose Don’t confuse Recreational and Medical. MacCullum C and Russo E. Practical considerations in medical cannabis More Appropriate for Medicinal Use administration and dosing. European Journal of Internal Medicine. 49 (2018) 12-19. Dustin Sulak, Heaer.com CBD Routes of Administration Oral CBD • bioavailability