OBJECTIVES

1. Pennsylvania Act 16 and Medical MarijuanaKent E. Vrana, Ph.D.Elliot S. Vesell Professor and ChairDepartment of PharmacologyPenn State College of Medicinekvrana@psu.edu10th October 2018PA Activity Professional Association (PAPA) Conference(University Park, PA)

2. Describe PA Act 16 and the proposed medical marijuana program Compare and contrast the medical marijuana programs in PA and the rest of the nation Explore barriers to, and potential concerns for, medical marijuana research Detail recent progress and changes OBJECTIVES

3. ca 2900 BC – Chinese Emperor Fu Hsi: “Ma [cannabis] is a popular medicine with both yin and yang.” 1500 BC – Written reference to cannabis in Chinese pharmacopeia 1621 – English mental health book (depression) 1745-1824 – Washington/Jefferson cultivated hemp 1850 – Officially in the US Pharmacopeia Neuralgia - Tetanus Alcoholism - Dysentery Convulsive disorders - Insanity Historical Perspective - I www.medicalmarijuana.procon.org

4. 1906 – US Food and Drugs Act 1911-1927 – States begin prohibiting use of marijuana 1930s – “Reefer Madness” and Marijuana Tax Act (1937) although it was universally illegal at this point 1942 – Removed from the US Pharmacopeia 1964 – THC characterized 1968 – University of Mississippi designated as source 1970 – Controlled Substances Act declares “Marijuana is a drug with no accepted medical use” [Jeff Sessions] 1990 – Cannabinoid receptors discovered Historical Perspective - II www.medicalmarijuana.procon.org

5. Legalize everything – including recreational marijuana (e.g., Washington, Colorado) Legalize medical “pot” Legalize medical extracts Pennsylvania Act 16 (April 17, 2016) No legalization, but no prosecution of non-psychoactive molecules (e.g., CBD) What are the Options www.medicalmarijuana.procon.org

6. Medical Marijuana Act - Enactment • Act of April 17, 2016, P.L. 84, No. 16 (“Act 16”) • Establishing a medical marijuana program; providing for patient and caregiver certification and for medical marijuana organization registration; imposing duties on the Department of Health;

7. Medical Marijuana Act - Enactment • Act of April 17, 2016, P.L. 84, No. 16 (“Act 16”) • Establishing a medical marijuana program; providing for patient and caregiver certification and for medical marijuana organization registration; imposing duties on the Department of Health; Blah; Blah; Blah

9. Section 102 – The general assembly finds and declares as follows: 1) Scientific evidence suggests that medical marijuana is one potential therapy that may mitigate suffering in some patients and also enhance the quality of life. 2) Carefully regulating the program which allows access to medical marijuana will enhance patient safety . . . 3) It is the intent of the General Assembly to: i) Provide a program of access to medical marijuana. . ii) Provide a safe and effective method of delivery of medical marijuana to patients. iii) Promote high quality research . . . Pennsylvania Act 16 – Medical Marijuana Act

10. Act 16 – Approved Indications • Neuropathies • Huntington’s disease • Crohn’s disease • Post-traumatic stress disorder • Intractable seizures • Glaucoma • Sickle cell anemia • Intractable pain • Autism • Cancer • HIV/AIDS • Amyotrophic lateral sclerosis (ALS) • Parkinson’s disease • Multiple sclerosis • Spinal cord injury (with spasticity) • Epilepsy • Inflammatory bowel disease

11. Act 16 – Approved Indications • Neuropathies • Huntington’s disease • Crohn’s disease • Post-traumatic stress disorder • Intractable seizures • Glaucoma • Sickle cell anemia • Intractable pain • Autism • Cancer • HIV/AIDS • Amyotrophic lateral sclerosis (ALS) • Parkinson’s disease • Multiple sclerosis • Spinal cord injury (with spasticity) • Epilepsy • Inflammatory bowel disease May 15th, 2018 – added Opioid Addiction; Spasticity; Neurodegeneration; and Terminal Illness

12. Medical Marijuana Act – Act 16 • How are Act 16 and PA different from the majority of the US? • Licensing • Grower/Processors (12) • Dispensaries (27) • Clinical Registrant (grower/processor AND dispensary) (8) (each with 6 dispensaries) • Academic Clinical Research Center (8)

13. Medical Marijuana Act – Act 16; Chapter 20 • Clinical Registrants must partner with a single Academic Clinical Research Center • An accredited medical school in PA PSU COM University of Pennsylvania Pittsburgh Temple Drexel GCSOM Jefferson LECOM PCOM

14. Medical Marijuana Act – Act 16; Chapter 20 • Clinical Registrants must partner with a single Academic Clinical Research Center • An accredited medical school in PA PSU COM University of Pennsylvania Pittsburgh Temple Drexel GCSOM Jefferson LECOM PCOM As of May 15th, 2018

15. Medical Marijuana:The Pharmacology of Medicinal Cannabinoids

16. Medicinal Cannabinoids:Endocannabinoids

17. Medicinal Cannabinoids:Medical Marijuana

18. Cannabinoid Receptors • Four types of cannabinoid receptors (CB1, CB2, GPR-55 (CB3?), and TRPV1 (capsaicin receptor) • 7TM-GPCRs (CB1/2, GPR-55) and cation channel (TRPV1) • CB1 is in brain and periphery and most abundant GPCR – responsible for psychoactive effects • CB2 in periphery promising target for therapeutics

22. Medicinal Cannabinoids:Medical Marijuana • THC is a partial agonist • CBD is controversial (weak antagonist, inverse agonist at CBs, but weak agonist at TRPV1), but clearly not psychoactive

23. Marinol (dronabinol) Appetite stimulant (HIV/AIDS; cancer chemotherapy) Syndros (liquid dronabinol) Cesamet (nabilone) Structure similar to Δ9-THC Antiemetic (treat nausea and vomiting) Sativex (equal parts Δ9-THC and CBD [plus other cannabinoids]) Treating spasticity in MS; approved in 16 countries outside US) Acomplia (rimonabant) Potent CB1 inverse agonist/antagonist (weak at CB2) Appetite suppressant in Europe (withdrawn in 2009) Legal Cannabinoid Drugs

25. 17th April 2016 Pennsylvania Act 16

26. Section 303 – Medical marijuana may only be dispensed in the following forms: Pill Oil Topical forms Form for vaporization Tincture Liquid Medical marijuana may notbe dispensed to a patient in dry leaf or plant form. May not grow or prepare in edible form (flexibility at home) Legal Cannabinoid Delivery

27. Section 303 – Medical marijuana may only be dispensed in the following forms: Pill Oil Topical forms Form for vaporization Tincture Liquid Medical marijuana may notbe dispensed to a patient in dry leaf or plant form. Not anymore (as of April 16th, 2018) May not grow or prepare in edible form (flexibility at home) Legal Cannabinoid Delivery

28. Supercritical CO2 Extraction • Medicinal cannabinoids are very hydrophobic (lipophilic) compounds • Carbon dioxide usually behaves as a gas in air at standard temperature and pressure or as a solid called dry ice when frozen. If the temperature and pressure are both increased at or above the critical point for carbon dioxide it can adopt properties midway between a gas and a liquid. It behaves as a supercritical fluid above its critical temperature (87.98 °F) and critical pressure (72.9 atm), expanding to fill its container like a gas, but with a density like that of a liquid.

29. Columbia Care, PA Medicinal Cannabinoids:Medical Marijuana

30. Dosages • Sativex (~2.5 mg THC and CBD) • Dronabinol (2.5, 5.0, 10 mg THC) • Typical dosages of medical marijuana in PA will be 10 mg of THC • Diversion is a minor concern: • Low dose (esp. compared to marijuana cigarette) • Expensive • Centralized state-wide tracking

31. Permits Certification (Card) Recommendation

32. Cerberus – The Three-Headed Hound of Hades • Grower/Processors (must be grown in PA) • Dispensaries • Vertically-integrated Clinical Registrants (CR) in partnership with an Academic Clinical Research Center (ACRC; e.g., Penn State College of Medicine)

33. Grower/Processors 6-12-2017 – State awarded 12 G/P licenses The G/P officially have 6 months to become operational Dispensaries 6-29-2017 – State awarded 27 licenses for dispensaries Clinical Registrants In progress – Preliminary regulations released Current Status

34. Academic Clinical Research Centers (ACRCs) 5-15-2018 – State approved eight ACRCs (including Penn State College of Medicine) New laws signed June 22nd (to clarify language and to address a lawsuit filed by existing G/P and dispensaries). New ACRC applications being filed. Dispensaries Progress has been slow and spotty (G/Ps) 4-16-2018 – Dr. Rachel Levine approved sale of dry leaf material for vaporization Clinical Registrants Are now preparing applications (partners have been generally been identified) Current Status

35. PSU ACRC – PAOfW CR Partnership

37. Clinical Registrants and Academic Clinical Research Centers • May 22nd, 2018 – Commonwealth Court of Pennsylvania issued a temporary injunction preventing DOH from permitting Clinical Registrants. This was issued to “prevent immediate and irreparable harm” to existing G/Ps and dispensaries. • June 22nd, a new bill was signed into law that addressed the concerns of the injunctions. New applications became available on September 6th, and PSU will reapply to be an ACRC. • Mandates a Research Advisory Committee (RAC) from the medical center to advise the vertically integrated CR on clinical research and to provide support to the ACRC to conduct research.

38. Potential CR/ACRC Research Initiatives • Clinical Trials • Outcomes-Based Research • Preclinical Research • Analytical/Medicinal Chemistry • Barriers • Schedule I drug (federal) • Vaporization/Smokable

39. Questions?