9/13/2017. Marijuana and the Brain Matthew Wong, MD Assistant Professor, Department of Neurology, Epilepsy Section. Disclosures.

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1 Marijuana and the Brain Matthew Wong, MD Assistant Professor, Department of Neurology, Epilepsy Section Disclosures Site principal investigator of studies of cannabidiol(epidiolex) in the treatment of severe pediatric and adult epilepsies. These studies are funded by GW Pharmaceuticals Charlotte Figi CNN.com 1

Dravet Syndrome Charlotte s Web Cannabis The genus of

and indica species Historically used for its fiber(hemp)

However can also be used for its psychoactive properties.

2 Dravet Syndrome Charlotte s Web Cannabis The genus of flowering plants that is mainly comprised of the sativa and indica species Historically used for its fiber(hemp) to make rope, clothing, and paper. However can also be used for its psychoactive properties. In this context, known as marijuana. Different parts of the plant have different properties. 2

Cannabis Cannabis as Medicine: History First definite documentation of

2500 BC Used in medieval times by Islamic physicians to treat nausea

medicine for many symptoms and diseases before it came under greater

3 Cannabis Cannabis as Medicine: History First definite documentation of Cannabis sativa uses for medicinal purposes comes from China circa 2500 BC Used in medieval times by Islamic physicians to treat nausea and vomiting, epilepsy, pain and fever Was used widely by Western medicine for many symptoms and diseases before it came under greater control in the 1930s. Cannabis for Epilepsy Gowers, 1881 Reynolds JR, Lancet,

Norman Rockwell Cannabis: From Medicine to Drug of Abuse Due to association with drug

chemical industry who had recently discovered nylon.

of cannabis Despite protests by the medical community removed from the United States

4 Norman Rockwell Cannabis: From Medicine to Drug of Abuse Due to association with drug abuse by minority and low income communities came under federal control Driven by the chemical industry who had recently discovered nylon. Marihuana Tax Act of 1937 imposed heavy tax on anyone using or associated with the use of cannabis Despite protests by the medical community removed from the United States Pharmacopoeia and National Formulary in 1941 In epilepsy, it was largely supplanted by the phenobarbital(1912), phenytoin(1938). 4

Cannabis: Return as a Medicine Drug of the 1960s, 1970s counter-culture Landmark case, Randall vs. U.S., 1976 won the right to use marijuana for the treatment of glaucoma.

5 Cannabis: Return as a Medicine Drug of the 1960s, 1970s counter-culture Landmark case, Randall vs. U.S., 1976 won the right to use marijuana for the treatment of glaucoma. Resulted in the compassionate investigational new drug program where the federal government provided marijuana for medicinal purposes for 31 patients, 4 still alive. California Prop 215, legalized marijuana for medicinal use in 1996 Medical Marijuana Laws by State Different standards for: Supply, distribution Formulations Lab testing Eligible Caregivers Pricing Conditions 5

6 Cannabinoids There are over 100 compounds known as cannabinoids in cannabis sativa, present in varying ratio depending on the strain. The two main neuroactive compounds are 9 tetrahydrocannabinol(thc) and cannabidiol. Other compounds of interest include cannabidivarin(cbdv) andtetrahydrocannabinolic acid(thca) Cannabinoid Pharmacology CBD was isolated in the 1940s and its structure was elucidated in 1963 by Raphael Mechoulam 9 - THC was isolated and characterized in 1964 It wasn t until the 1980s when two receptors for 9 - THC were identified, CB1 and CB2, both G- protein coupled receptors Shortly after anandamide and 2- arachidonoylglycerol, two endogenous ligands to CB1 and CB2 were found OH cannabidiol OH 6

Endocannabinoid System CB1 expressed primarily in the brain on

There is significant expression in the hippocampus and amygdala The

post-synaptic in response to membrane depolarization.

presynaptic neuron to inhibit release of the neurotransmitter.

Action Does not bind to CB1R or CB2R Multiple potential sites of

7 Endocannabinoid System CB1 expressed primarily in the brain on presynaptic neurons. There is significant expression in the hippocampus and amygdala The endogenous cannabinoids anandamide and 2-AG are synthesized by the post-synaptic in response to membrane depolarization. These endogenous cannabinoids then bind to the CB1 receptor on the presynaptic neuron to inhibit release of the neurotransmitter. Neurobiology: Cannabinoids act backwards MacDonald J. Christie and Christopher W. Vaughan Nature 410, (29 March 2001) Cannabidiol: Mechanism of Action Does not bind to CB1R or CB2R Multiple potential sites of action Agonist at 5-HT receptors, TRP channels and glycine receptors Antagonist at T-type voltage gated calcium channels and GPR55 Inhibits VDAC1 Medical Marijuana: Artisanal Formulations and Delivery Mechanisms 7

$trans-isomer of THC, complete agonist of CB1 Approved for refractory$ nausea and vomiting in cancer and loss of appetite and cachexia in HIV

vomiting associated with cancer chemotherapy.

Spasticity, Central Pain, Bladder Problems, Tremor - Parkinson s

8 Pharmaceutical Formulations Current Indications Dronabinol (-) trans-isomer of THC, complete agonist of CB1 Approved for refractory nausea and vomiting in cancer and loss of appetite and cachexia in HIV disease Nabilone synthetic CB1 agonist Approved for nausea and vomiting associated with cancer chemotherapy. American Academy of Neurology Guidelines - Multiple Sclerosis: Spasticity, Central Pain, Bladder Problems, Tremor - Parkinson s Disease: Uncontrolled Movements - Huntington s Disease - Tourette Syndrome: Tics - Cervical Dystonia - Epilepsy AAN,

9 Multiple Sclerosis No evidence that it is disease modifying. Spasticity Studies have looked at both patient reported and objective measures Strong evidence that oral cannabis extract(oce) reduces subjective spasticity scores in MS THC and nabiximols probably effective at reducing patient reported scores, but again probably ineffective objectively. Insufficent evidence for smoked marijuana Multiple Sclerosis Central Pain OCE is effective for reduction of central pain THC or nabiximols are probably effective Smoked marijuana of uncertain efficacy Bladder Dysfunction Nabiximols is probably effective for reducing number of bladder voids, but of unknown efficacy for reducing all bladder symptoms THC and OCE are probably ineffective. Tremor: THC and OCE are probably ineffective, and nabiximols are possibly ineffective. Movement Disorders Huntington s Disease nabilone and CBD were tested. Both suggest lack of benefit, but both were underpowered. Parkinson s Disease Looked at on dyskinesias OCE probably ineffective Tourette Syndrome Trials are insufficient to support or refute efficacy for the use of THC. Cervical Dystonia dronabinol studied data insufficient to support or refute efficacy. 9

Epilepsy At the time(2014), AAN found that there

randomized controlled trials for the treatment of

10 Epilepsy At the time(2014), AAN found that there was no data to support or refute the efficacy of marijuana for epilepsy. Since that time there have been three completed randomized controlled trials for the treatment of severe pediatric and adult epilepsy(1 Dravet Syndrome, 2 Lennox Gastaut Syndrome). 10

received artisanal preparations of marijuana for their

improvement Families who moved to Colorado for CBD treatment

11 Colorado Experience Chapman et al. presented the results of 58 children and adolescents who received artisanal preparations of marijuana for their severe epilepsy 31% had a >50% reduction; 48% reported an improvement Families who moved to Colorado for CBD treatment were three times as likely to have a 50% reduction than families who were from CO(52% vs 17%) 11

, 2017) No published prospective studies of the anxiolytic effects of cannabis in smoked or vaporized

12 American Psychiatric Association Position Statement APA, 2013 Anxiety Ranks in the top 5 health conditions that individuals are treating with marijuana(turna et al., 2017) No published prospective studies of the anxiolytic effects of cannabis in smoked or vaporized forms. Purified THC has been show to both induce and decrease levels of anxiety in health adults, while CBD appears to have purely anxiolytic effects 12

13 Social Anxiety Disorder Double blind RCT, 24 SAD patients given single dose of 600mg of CBD before simulated public speaking tasks(bergamaschi et al. 2011) Had significant decreased in subjective anxiety(p=0.012) when compared with placebo group Double blind trial of 400mg of CBD in 10 men undergoing neuroimaging(crippa et al. 2011), found a significant difference during the scanning. Generalized Anxiety Disorder Single dose of nabilone or placebo given to 4 patients in both a phase 1(1-5mg), and phase 2(1-4mg). In phase I anti-anxiety effects were noted in 2 patients at doses of 1-2mg. No antianxiety effects were noted in phase II. (Glass, 1981) Depression Thought to induce a sense of euphoria, and cannabis use is common during depressive episodes(feingold et al, 2015) Knock out models of CB1 receptors results in depressive like symptoms(aso et al. 2011) In a double blind placebo-controlled trial, THC(0.3mg/kg bid)x 7 days failed to show significant euphoria or anti-depressant effect(kotin 1973) A second double blind study induced dysphoria(ablon 1974) Only case reports are available for plant based or synthetic cannabinoids. 13

14 Vandrey et al. tested 75 edible medical cannabis products purchased in California Of 75 products tested, 17% were accurately labeled, 23% were under-labeled and 60% were over-labeled for 9 - THC In addition, in 2015 the FDA tested 15 formulations fof CBD oil, 8 contained no CBD Possible Drug Interactions Pharmocokinetic or pharmodynamic interactions are not well understood; DDI studies are underway. CBD is an potent inhibitor of 2C19 and less so 3A4; Main psychiatric drugs that could be effected citalopram, escitalopram, imipramine, haloperidol, aripiprazole, lurasidone, benzos, some opiates Preliminary data suggests that CBD may contribute to hepatotoxicity in patient s who are taking valproic acid 14

Contamination: Fungus, Pesticides, Heavy Metals McPartland et al reviewed a number of studies and found marijuana to be contaminated by fungus and bacteria.

Cost Adverse Effects of Marijuana on the Brain Particular concern before the age of 21.

15 Contamination: Fungus, Pesticides, Heavy Metals McPartland et al reviewed a number of studies and found marijuana to be contaminated by fungus and bacteria. There is almost no scientific data on pesticide contamination or heavy metal contamination. Cost Adverse Effects of Marijuana on the Brain Particular concern before the age of 21. Persistent marijuana use may result in significant IQ drop from childhood to midlife(meier et al, 2012) May result in impaired memory(hanson et al. 2007) Concern that it may increase the risk of psychosis in those at risk (Andreasson et al. 1987, Arseneault et al, 2002). May decrease axonal fiber connectivity(zalesky et al. 2012) 15

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Research on Cannabis and PD: Is there any evidence?

Research on Cannabis and PD: Is there any evidence? Benzi M. Kluger, MD, MS Associate Professor of Neurology and Psychiatry Director Movement Disorders Center University of Colorado Denver DISCLOSURES