CANNABIDIOL (CBD) THE BE ALL END ALL?

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1 CANNABIDIOL (CBD) THE BE ALL END ALL? John Schaeffer, DO PMG neurology specialists Clinical associate professor Department of neurology University of Washington school of medicine

2 CANNABIS BRIEF HISTORY Indiginous to Central and South Asia Used for millenia to produce hemp for rope, clothing and paper Used since about 2700 BCE, originally in China, for a large variety of conditions, including: - gout - rheumatism - gastrointestinal disorders - absent-mindedness - epilepsy - fever

3 CANNABIS BRIEF HISTORY Two major neuroactive components 1. Delta-9 Tetrahydro-cannabinol (THC) a. Psychoactive, produces the high b. Binds to CB1 and CB2 receptors 2. Cannabidiol (CBD) a. Non psychoactive (does not produce a high) b. May attenuate psychoactive effects of THC c. Binds weakly to CB1 receptors d. Does not bind to CB2 receptors e. Multiple other possible mechanisms

4 CANNABIS BRIEF HISTORY Species 1. Sativa a. High THC:CBD ratio b. Stimulating 2. Indica a. Lower THC:CBD b. Sedating

5 ENDOCANNABINOID SYSTEM CB1 receptors 1. Largely located in brain (high) 2. Cloned in Cause neuronal inhibition by decreasing neurotransmitter release CB2 receptors 1. Largely in immune and hematopoietic systems 2. Cloned 1993 Endocannabinoids (anandamide) 1. Partial agonist at CB1 and CB2 receptors 2. Can diminish psychoactive effects of THC 3. TRPV1 agonist

9 CBD MECHANISMS Inhibits orphan G-protein-coupled receptor (GPR55) 1. Decreases pre-synaptic calcium influx 2. Decreases excitatory neurotransmitter release Enhances alpha-1 and alpha-3 glycine receptors 1. Opens chloride channels 2. Inhibitory Enhances 5HT1a receptor activity

10 Vanilloid receptors CBD MECHANISMS 1. Large family of receptors that mostly mediate nociception for a variety of stimuli 2. CBD mostly active at: a. Inhibits Melastatin type 8 channel (TRPM8) - cold nociception b. Enhances transient receptor potential (TRP) ankyrin type 1 (TRPA1) - cold nociception c. Enhances TRP vanilloid type 1 (TRPV1) - heat nociception (capsaicin example) - can also mediate vasodilatation, bronchoconstriction - may inhibit tumor cell growth and apoptosis

11 CBD MECHANISMS Inhibits equilibrium nucleoside transporter (ENT) 1. Transports nucleosides across cell membrane 2. Poorly understood Activates nuclear peroxisome proliferator receptor gamma 1. Regulates gene expression (up or down) 2. Can have effects on nociception, immune system, metabolic functions, neoplasia, GI system, CV system Inhibits degradation of anandamide

13 CBD CLINICAL EFFECTS LIKELY EFFECTIVE EPILEPSY Epidiolex (cannabidiol) 1. FDA approved for Dravet and Lennox-Gastaut syndromes a. Dravet - 1:15,700 children - Seizures begin first year of life; frequent and long myoclonic, hemiclonic, GTC - Generally poor response to first line anticonvulsants - Most common cause is a sodium channel mutation (SCN1A) - Total seizure frequency decreased by 39% vs 13% for placebo

14 CBD CLINICAL EFFECTS LIKELY EFFECTIVE EPILEPSY Epidiolex (cannabidiol) 1. FDA approved for Dravet and Lennox-Gastaut syndromes b. Lennox-Gastaut /100,000 - Begins age 3-5 with multiple generalized seizure types; tonic, atonic, atypical absence - often poor response to first line anticonvulsants - numerous causes but all produce widespread CNS damage/dysfunction - Total seizure frequency decreased by 36-41% vs 14-18% for placebo 2. Efficacy signal in small numbers of other types of refractory seizure disorders Possible mechanisms include ENT, GPR55, TRPV1, Glycine receptors, 5HT1a

15 DS Clinical Trial Results

16 LGS Clinical Trial Results

17 LGS Clinical Trial Results

19 CBD CLINICAL EFFECTS INSUFFICIENT RELIABLE EVIDENCE TO RATE CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS Dystonia mg daily for 6 weeks produced 20-50% improvement in dystonia from Meige syndrome, L-Dopa, and primary dystonia 2. No controlled studies 3. Unclear mechanisms Parkinson disease 1. Flexible dose of at least 150 mg daily for 4 weeks improved psychosis 2. No controls 3. May worsen bradykinesia and tremor 4. Mechanisms unclear

20 CBD CLINICAL EFFECTS INSUFFICIENT RELIABLE EVIDENCE TO RATE CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS Huntington Disease - 10 mg/kg/day did not improve chorea or other symptoms compared to placebo Multiple Sclerosis mg/day might improve self reported pain and muscle spasm severity 2. No improvement in muscle spasm frequency, fatigue, bladder control, mobility, QoL 3. No improvement in Ashworth scale 4. Some in vivo and in vitro work suggests CBD modulates immune system function but no clinical effect seen in MS to date

21 CBD CLINICAL EFFECTS INSUFFICIENT RELIABLE EVIDENCE TO RATE CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS Schizophrenia 1. One positive study at 400 mg QID for 4 weeks 2. Other studies negative but different doses and duration 3. Mechanisms: Anandamide, TPRV1, 5HT1a Addictive Behaviors - May decrease cue-induced drug seeking behavior Anxiety/Social Phobia 1. Negative at 300 mg/day 2. At mg/day anxiety improved vs placebo 3. Imaging showed decreased activity in left temporal lobe and amygdala 4. Mechanisms: 5HT1a, TPRV1 (vanilloid) channels

22 CBD CLINICAL EFFECTS INSUFFICIENT RELIABLE EVIDENCE TO RATE CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS Depression 1. Animal studies favorable 2. Mechanism: 5HT1a Bipolar Disorder mg/day for 25 days did not improve manic episodes 2. Case reports mostly

23 CBD CLINICAL EFFECTS INSUFFICIENT RELIABLE EVIDENCE TO RATE CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS Insomnia mg before bed improved sleep duration (but not 40 or 80 mg) compared to placebo 2. No effect on sleep onset latency 3. No morning hangover 4. Mechanism unclear

24 CBD CLINICAL EFFECTS INSUFFICIENT RELIABLE EVIDENCE TO RATE CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS Crohn s Disease - 10 mg SL BID for 8 weeks did not improve disease activity or CRP Type II Diabetes mg BID for 13 weeks did not improve lipid levels, glucose or inflammatory markers Graft vs Host Disease (GVHD) mg BID for 5-6 weeks delayed GVHD prior to day 100 but not at 12 months 2. Not clear if longer treatment duration would further delay GVHD

25 CBD CLINICAL EFFECTS INSUFFICIENT RELIABLE EVIDENCE TO RATE CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS Anti-Tumor Effects 1. No human studies 2. Cell culture studies show inhibition of malignant cell proliferation, inhibition of invasion and metastasis, and decreased tumor mass 3. Mechanisms unclear

26 CBD CLINICAL EFFECTS INSUFFICIENT RELIABLE EVIDENCE TO RATE CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS Pain 1. Recent review in PAIN (October 2018) a. Pooled 104 RCT and observational studies of cannabanoids in chronic noncancer pain b. 29.0% vs 25.9% (placebo) for 30% reduction in pain (p<0.05) - NNTB: 24 c. 18.2% vs 14.4% (placebo) for 50% reduction in pain (p>0.05) d. 18.9% vs 11.8% (placebo) for patient global impression of change (p<0.05) - NNTB: 38 e. 81.2% vs 66.2% (placebo) for all AE s - NNTH: 6 f. 15.8% vs 4.6% (placebo) for AE s leading to study withdrawal - NNTH: 40

30 CBD Pharmacokinetics 1. Bioavailability a. Oral: 13-19% b. Inhaled: 11-45% 2. Half-life hours 3. Excretion - in urine, either unchanged or as glucuronide metabolite or mostly in feces

31 CBD Formulations 1. Capsules 2. Sublingual spray 3. Oil based solution Dosing 1. Data best for Epidiolex (oil based solution) a. Usually 5-20 mg/kg/day for epilepsy b. Doses as high as 50 mg/kg/day have been used 2. BIG problems with other commercially available products

32 The Trouble with CBD Oil Epidiolex (cannabidiol) unlikely to be approved for off-label usage CBD content in over the counter CBD oil is unpredictable Possible THC contamination Other contamination- Fertilizer, pesticides ect.

33 Toxicology CBD 1. LD50 for IV is 212 mg/kg 2. LD50 for oral route not established but likely 20-50X that for IV Adverse Effects (appear dose related) 1. Dry mouth 2. Diarrhea 3. Vomiting 4. Decreased appetite 5. Weight loss 6. Somnolence 7. Fatigue 8. Elevated liver transaminases

34 CBD Drug Interactions 1. CYP2C19 Substrates a. Clobazam (ONFI) - major b. Topiramate major c. Interactions not significant for other anticonvulsants 2. Valproic Acid a. Elevated liver transaminases b. Thrombocytopenia

35 WHAT I LEARNED FROM THIS There is at least one clinical use for CBD epilepsy VERY messy overall (this also makes it fun) Strange situation a drug in use for millennia just now being examined with basic science and clinical studies - The political, social, and marketing campaigns only serve to worsen the confusion We need better dose-response data for the various illnesses being investigated We need formulations of CBD whose composition we can be confident about Make it Schedule II?

43 REFERENCES Nucleosides Nucleotides Nucleic Acids Jan 2; 36(1): J Med Chem Nov 23;59(22): Epub 2016 Aug 1. Neurology April 10, 2018; 90 (15 Supplement) Neurochem Res Aug;30(8): Neuropharmacology May 1;133: doi: /j.neuropharm Epub 2018 Feb 1. Epilepsia, 55(6): , 2014 Journal of Pharmacology and Experimental Therapeutics June 2008, 325 (3) Int. J. Mol. Sci. 2018, 19(11), 3320 Br J Pharmacol Jun; 173(12): Curr Neuropharmacol Jan; 4(1): Curr Med Chem. 2010; 17(14): Transl Psychiatry Mar; 2(3) National Academies of Sciences, Engineering, and Medicine The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. herbs-supplements/professional.aspx?productid=1439

Cannabinoids and Epilepsy. Michael Ciliberto, MD University of Iowa Stead Family Department of Pediatrics

Cannabinoids and Epilepsy. Michael Ciliberto, MD University of Iowa Stead Family Department of Pediatrics Cannabinoids and Epilepsy Michael Ciliberto, MD University of Iowa Stead Family Department of Pediatrics Cannabinoids Cannabinoids= terpenophenolic compounds (give a scent) >80 in Cannabis sativa Cannabidiol