Marijuana: Is It Medicine Yet?

1. Marijuana: Is It Medicine Yet? CANNABIDIOL: The New Kid on the Block Donald I. Abrams, MD Chief, Hematology-Oncology Zuckerberg Francisco General Hospital Professor of Clinical Medicine, UCSF

2. Sanjay Gupta, MD Introduces Cannabidiol to the World on CNN

5. Cannabis as Medicine • Contains over 400 chemical compounds • Highest concentration of bioactive compounds in resin exuded from flowers of female plants • Main psychoactive component believed to be delta-9-THC • At least 100 other cannabinoids identified in combusted products • delta-8-THC similar in potency but only in small concentration

6. Non-THC Components of Cannabis • 9-tetrahydrocannabinol (THC) is the primary active ingredient of cannabis • Secondary compounds may enhance the beneficial effects of THC • Other cannabinoid and non-cannabinoid compounds may reduce THC-induced anxiety, cholinergic effects and immunosuppression • Terpenoids and flavonoids may increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens and provide anti-inflammatory activity

7. Non-THC Cannabinoids • Cannabidiol CBD • Cannabinol CBN • Cannabichromene CBC • Cannabigerol CBG • Delta-8-THC 8-THC • Tetrahydrocannabivirin THCV

8. Cannabinoid Receptors • CB1 and CB2 receptors identified • Receptors encoded by separate genes on separate chromosomes; share 48% amino acid identity • G-protein coupled receptors that inhibit adenylyl cyclase on activation • Decreases cyclic AMP and protein kinase A activity • Inhibition of Ca++ influx through various Ca++ channels • Stimulation of inwardly rectifying K+ channels and mitogen-activated protein kinase cascades

9. CB1 Receptor Activation • Overall effect is suppression of neurotransmitter release at both excitatory and inhibitory synapses • Inhibition occurs through a retrograde signaling mecahnism • ECs are synthesized and released from post-synaptic neurons • Diffuse backward across the synaptic cleft and bind to CB1 receptors on the pre-synaptic terminals

10. 5 4 4 5 6 6 3 3 Pre-synaptic terminal 2 2 1 1 MAGL STOP STOP + - Neurotransmitter vesicles K+ Ca2+ THC Dronabinol Nabilone THC Dronabinol Nabilone AA ETA Ca2+ K+ CB1 receptor CB1 receptor 2-AG 2-AG 2-AG AEA AEA Post-synaptic terminal PLD DAGL Neurotransmitter receptor NAPE Neurotransmitter receptor DAG FAAH AA Glycerol Health Canada 2016

11. Suppression of Neurotransmitter Release HEALTH CANADA

12. THC and CBD Features Compared Friedman and Devinsky, NEJM 2015

13. What About Cannabidiol (CBD)? • Modulates the pharmacokinetics of THC • Very low affinity for CB1 and CB2 receptors • Slight affinity for CB receptors as an antagonist • May modulate downstream signal transduction • Potent cytochrome P450 3A11 inhibitor thus blocking formation of 11-OH metabolite • Pre-administration of CBD may potentiate THC effects (PK mechanism) • Simultaneous co-administration may result in attenuation of some THC effects (PD mechanism)

14. CBD ALONE DOES NOT COMPLEX WITH THE RECEPTORS How CAN it work???

15. Deutsch, SUNY @ Stony Brook

16. CBD Effects • Beneficial effects of the non-psychotropic cannabinoid is derived from in vitro and animal studies • Few, if any, clinical studies of these substances exist • In vitro and animal studies do suggest many potential therapeutic applications

17. CBD Effects • Anti-inflammatory • Analgesic • Anti-nausea • Anti-emetic • Anti-psychotic • Anti-ischemic • Anxiolytic • Anti-epileptiform

18. Seizures (Surveys and Case Studies) • Cannabis preparations are commonly used and recommended for seizure disorders. • A survey of parents belonging to a Facebook group that focused on the use of cannabidiol-enriched cannabis for seizures in children with early-onset, severe forms of epilepsy found that 16/19 parent respondents reported reduced seizure frequency in their children during treatment with cannabidiol-enriched cannabis. • Two reported complete seizure freedom, and eight reported > 80% reduction in seizure frequency. (Porter and Jacobson 2013) • A case report of a child with Dravet syndrome found that a high concentration CBD:THC strain of cannabis, now known as Charlotte's Web, reduced seizure frequency from nearly 50 seizures per day to 2-3 nocturnal convulsions per month. • This effect has persisted for almost 2 years, and Charlotte was weaned off of other antiepileptic drugs.(Maa and Figi 2014)

19. Seizures (RCTs) There have been four small trials of CBD for seizures.

20. Seizures • Larger studies of CBD for seizures are needed. • Although robust evidence for the effectiveness of CBD for seizures is lacking, controlled clinical trials are ongoing. • For example, Epidiolex, a liquid form of CBD made by GW Pharmaceuticals, is being tested in a clinical trial that plans to enroll 150 pediatric patients age 1-18 with Dravet syndrome and other intractable epilepsies. Cannabis can be considered for intractable seizures not controlled with medications, or when patients are unable to tolerate seizure medications.

21. Cannabidiol in Epilepsy • Open label trial in 162 pts under 30 with severe, intractable seizures on stable Rx • Enrolled at 11 US centers 1/14-1/15 and followed for at least 12 weeks • CBD up-titrated to max of 25 mg/kg or 50 mg/kg daily • 79% with adverse events (somnolence, ↓ appetite) • Median monthly frequency of motor seizures reduced from 30.0 to 15.8. Median reduction 35.5% (IQR 0-64.7) • Devinsky, Lancet Neurol 2016 • But not randomized, blinded or placebo-controlled

22. Cannabidiol in Huntington’s Disease • Randomized double-blind placebo-controlled crossover trial in 15 patients with HD • CBD 10 mg/kg/day or placebo for 6 weeks • Examined effects on chorea severity, other symptoms, toxicity • No difference seen in symptoms or toxicity between CBD and placebo • Consroe, Pharmacol Biochem Behav, 1991

23. Cannabidiol in Parkinson’s Disease • Open label pilot of oral CBD in 6 pts with PD and psychosis • Psychosis improved as did overall PD symptoms • Zuardi, J Psychopharmacol 2009 • 3 arm RCT in 21 pts with PD (placebo, CBD 75 mg/day, CBD 300 mg/day) • No difference in motor and general symptom scores • CBD 300 mg group had improved QOL and well-being compared with placebo (p=0.05) • Chagas, J Psychopharmacol, 2014

24. Cannabidiol in Schizophrenia • Hypothesis that enhanced anandamide signaling with CBD will diminish psychotic symptoms • Phase II randomized double-blind controlled trial of CBD or amisulpride in 42 adult inpatients • Ramped up to 800 mg/day each drug for 28 days • Standardized scales to measure effects on psychoses and extrapyramidal side effects • Significant clinical improvement seen in both groups, NS • CBD associated with less extrapyramidal sx, wt gain and lower prolactin increase (marker of sexual dysfunction) • Leweke, Trans Psychiatry, 2012

25. Cannabidiol in Opioid Addiction • Double blind placebo-controlled study of CBD 400 or 800 mg/day in heroin users abstinent for 7 days • CBD reduced heroin-related cue-induced craving • CBD’s attenuation of craving lasted ~7d after last administration • CBD’s strongest effects were on the attenuation of anxiety induced by heroin cues • Hurd, Neurotherapeutics 2015

26. Cannabidiol and Cancer • Id helix-loop-helix proteins control processes related to tumor progression • CBD down-regulates Id-1 expression in aggressive human breast cancer cells in vitro McAllister et al, Breast CA 2011 • Addition of CBD to colorectal cancer cell lines led to reduced cell proliferation • In mice, treatment with CBD decreased azoxymethane induced aberrent crypt foci, polyps and tumor formation Aviello et al, J Molec Med 2012

27. CBD:THC Ratios • CBD-mediated attenuation of THC-induced effects observed when CBD:THC is > 8:1 • CBD-mediated potentiation of THC-induced effects seen when CBD:THC is ~2:1 • In rats and mice! • Zuardi 2012 • There is NO information in scientific or medical literature on the effects of varying CBD:THC ratios in the Rx of medical disorders

28. From Werner: Marijuana Gateway to Health, 2011

29. Cannabis in Sickle Cell Disease • Transgenic mice expressing human sickle hemoglobin (HbS) demonstrate increased hyperalgesia attenuated by morphine Kohli et al Blood 2010 • CP55940 is a CB1 and CB2 agonist that also markedly attenuates hyperalgesia at a dose of 0.3 mg/kg comparable to 20 mg/kg morphine • Retrospective survey of 86 SCD pts revealed 52% reported cannabis use decreases pain, anxiety and depression Howard et al Br J Haematology 2005 • NHLBI has funded human proof of principle trial with vaporized 4.7% THC/5.1% CBD

30. CBD Misconceptions • CBD is non-psychoactive and non-psychotropic • Benefits anxiety, schizophrenia, addiction and depression • Preferably should be termed “non-intoxicating” • Lacks reinforcement, craving and compulsive use lowering risk of abuse • Russo, Trends in Pharmacological Sciences, 2017

31. CBD Misconceptions • CBD is sedating • Low to moderate doses are distinctly alerting • CBD counteracts the sedative effects of THC • Studies of CBD 600 mg po show no evidence of sedation • CBD as Epidiolex in high doses to treat epilepsy is sedating b/o traces of THC and terpenoids • Russo, Trends in Pharmacological Sciences, 2017

32. CBD Misconceptions • CBD is legal in all 50 states • Although unscheduled in most nations, CBD is a Schedule I agent in USA • Despite this prohibition, domestic commerce in CBD is rampant • If Epidiolex is approved in a less restricted schedule, will not change CBD status • Russo, Trends in Pharmacological Sciences, 2017

34. Selected Cannabidiol Bibliography • Devinsky O, Marsh E, Friedman D et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol, 2016; 15: 270-278. • Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. NEJM, 2015; 373:1048-1058 • Hurd YL. Cannabidiol: Swinging the marijuana pendulum from “weed” to medication to treat the opioid epidemic. Trends in Neuroscience, 2017; in press • Leweke FM, Piomelli D, Pahlisch F et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry, 2012; 2:e94. • McAllister SD, Murase R, Christian RT et al. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat, 2011; 129:37-47. • Russo EB. Cannabidiol claims and misconceptions. Trends in Pharmacological Sciences, 2017; in press • Werner CA. Marijuana Gateway to Health: How Cannabis Protects Us from Cancer and Alzheimer’s Disease. Dachstar Press, 2011. • Yeshurun M, Shpilberg O, Herscovici C et al. Cannabidiol for the prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation: results of a phase II study. Biol Blood Marrow Transplant, 2015; 21:1770-1775.