Weeding out the Truth: Cannabinoids in the Treatment of Neurological Disorders Barbara S. Koppel, MD New York Medical College American College of Medical Toxicology March 18-19, 2016
Cannabis species (or subspecies) Wikipedia from Wikimedia and
Historical aspects (Hemp = 4000 BC, medicine=2000bc, India)
AEA also an endovanalloid at TRPV1 (with 5-20-fold lower affinity cf with CB1); also PPARy Key ECS Elements
--Dec. 31, 2008 2011 update: a PubMed search for scientific journal articles published in the last 20 years containing the word "cannabis" revealed 7,704 results. Add the word "cannabinoid," and the results increase to 15,899 articles. That's an average of more than two scientific publications per day over the last 20 years! (Source: Dustin Sulak, DO)
Why AAN got involved Patients were beginning to demand attention be paid, and science needed review before politics dictated actions Research was hampered by Schedule I classification, unchanged since 1970, but was going on outside US Charlotte, with a severe epileptic syndrome, sparked families to move to Co. Alternative MJ, such as Spice was causing severe neurologic symptoms
AAN Guideline Process Clinical Question Evidence Conclusions Recommendations Slide 8
Literature Search/Review Rigorous, Comprehensive, Transparent 1729 abstracts Inclusion criteria: - Human randomized, controlled trials (RCTs); cohort studies; case-control studies; and case series (N 10 or addressing efficacy of marijuana Exclusion criteria: - Case series with N < 10 - Review articles - Anonymous questionaires 63 full text,33 included Slide 9
FDA-Regulated Cannabinod-Based Medicines: Chemicals, Extracts, Botanicals Photo from pharmer.org Photo from epocrates.com Photo from nida.org Photo from Russo et al. 2002 Dronabinol (Marinol ) Nabilone (Cesamet ) Cannabis Sativa L. Extracts (Sativex ) Cannabis Sativa L. Cigarettes Photo from Russo et al. 2002 Photo from wikipedia.org 1985 1985 2006 Approximately 460 chemical constituents, >100 phytocannabinoids 1976
PK: Common Routes of Administration Lungs by inhalation of vaporized or smoked organic plant material Akin to IV bolus passive diffusion Rapid onset (secs to mins), maximal effect ~30mins, duration 2-3 hrs Gut by ingestion of lipophilic, alcoholic, or supercritical fluidic extracts More variable absorption time Onset 30mins-2hrs, more constant duration of action of 5-8hrs Skin by topical application of extracts
Oral Cannabis Extracts Cannabis extract (Cannador)THC 2.5 :CBD 1.25 mg Mean 0.146 mg/kg/d up to maximum of 1.25 mg/kg/d (Carroll 2004);mean 1.25 mg/kg/d up to maximum of 25 mg/d; Cannabis extract THC 2.5 mg:cbd 0.9 mg Mean 0.146 mg/kg/d up to maximum of 0.25 mg/kg/d (Vaney 2004) Cannabis extract 100 mg CBD 100 300 mg/d (Cunha 1980) Cannabis extract 100 mg CBD 10 mg/kg/d (Consroe 1991, Curtis 2009) Abbreviations: CBD = cannabidiol, a major less-psychoactive resin extract constituent of the plant Cannabis sativa L (marijuana); THC -9 tetrahydrocannibidiol Slide 12
Oromucosal spray administration Nabiximols (Sativex) Ratio of THC 2.7 mg:cbd 2.5 mg/spray Mean 7.19 mg/d (Kavia 2010) Maximum 65 mg/d (Collin 2010); 120 mg/d (Wade 2004) Slide 13
Oral formulations (approved for nausea and anorexia) Dronabinol (Marinol) 2.5 mg D9-THC Maximum of 10 mg/d (Svendsen 2004, Müller-Vahl 2003);maximum of 25 mg/d (Freeman 2006,Zajicek 2003) Nabilone (Cesamet) 100 mg CBD 100 mg (Curtis 2009); 0.03 mg/kg (Fox 2002) Slide 14
More oral formulations Oromucosal spray administration Nabiximols (Sativex) Ratio of D9-THC 2.7 mg:cbd 2.5 mg/spray Mean 7.19 mg/d (Kavia 2010) Dosage varied by study; maximum 65 mg/d (Collin 2010); maximum 120 mg/d (Wade 2004) Slide 15
Smoked (inhaled) marijuana Marijuana 4% THC 4 puffs (hits)/d (Corey-Bloom 2012); 3.5%THC (Abrams 2007);3.5% 7% (Wilsey 2008); 1% 8% THC (Ellis 2009); 0% 9.4%(Ware 2010) Only Corey-Bloom and Abrams were included in guideline Slide 16
Tobacco Vaporizer Slide 17
Proposed Real World Function of CBD Suppress fear and anxiety of unpleasant but necessary activity, so can continue longterm exercise because don t remember the pain and don t mind it Modulates pain systems, such as opiate and serotonin (headache), not directly analgesic Promote sleeping, eating, make food tasty even if not hungry
Multitude of CBDs/Therapeutic Uses Adapted from Izzo et al, Trends Pharmacol. Sci. 2009 Our results follow
Findings from our review Spasticity Central pain Tics Dopa-induced Dyskinesias Bladder overactivity Huntington Chorea
Dopa-induced Dyskinesias in PD and Dystonia Moderate evidence THC is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson disease (1 Class I study). Insufficient evidence For patients with cervical dystonia, data are insufficient to support or refute the efficacy of dronabinol (1 Class III study). Slide 21
Why cannabis in pain Endocannabinoids contribute to homeostasis (stimulate appetite, emotions and learning, pain perception) No direct action at opiate receptors but indirectly allow painful activities to be forgotten or ignored
ECB Receptor Sites: PAG, Thalamus, Medulla, DRG, Amygdala, Cortex
Pain responds to cannabis Pain is very difficult to study, requires individual pt rating rather than unbiased observer, so not included in original guideline. Smoked form works best (many self reports, surveys of testimonials)
Bayesian analysis of 77 pain studies 30% clinical improvement in chronic neuropathic pain assessed with a continuous patient reported instrument, NNT inhaled cannabis results in short term NNT of 5.6, 1 of 6 respond,128 pts Andreae MH J Pain 201516:1221-32
Neuropathy HIV pain relieved by smoked MJ 50 pts 3.5%THC sig (>30%) pain reduction Abrams D2007 Neurology 68:515-517 28 pts, 1-8%THC significant pain relief Ellis RJ Neuropsychoppharmacology 2009 34:672-680 Nabilone for general neuropathy Frank 2008 Nabiximols for brachial plexus avulsion Berman 2004
Headache ECB modulate pain signaling in DRG and nausea in area postrema, inhibit blood vessel dilation, improve serotonin relase (like triptans) ECB deficiency noted in migraineurs and others with chronic pain condition, dec cluster also Baron EP 2015 Headache 55:885-916 Dec migraines from 10 to 4/month with inhaled or edible medical marijuana Rhyne DN Pharmacotherapy 2016 epub1002
Why cannabis in movement disorders CB1 receptors in GABAergic neurons of caudate, striatum, presynaptic terminals in the globus pallidus, substantia nigra and in glutamatergic projections to and from cortex and subthalamic nucleus. Endocannabinoids also indirectly influence dopaminergic pathways, suppressing movement Koppel Neurotherapeutics 2015:12:788-792
Predicting response to cannabis in movement disorders is difficult Receptors increase with PD, and ECB antagonist may help hypokinesis, while ECB agonists help excess movements (HD, Tourettes, tics) but degeneration may change # of receptors. Indirect effects common as ECB influence other transmitters
PARKINSON DISEASE Cannabis extract Cannador Not stated Dopa-induced Dyskinesias/ Dystonia Tremordystonia Dopa-induced dyskinesias Δ 9 -THC 2.5-25mg +CBD 100-600mg/d 0.03mg/kg/d 0.03mg/kg/d 75mg/d (Carroll 2004; I) Consroe1986 (Fox 2002) Sieradzan 2001 (Chagas 2014) Rimonabant (CBD antagonist) Inhaled botanical marijuana SR141716 Dopa-induced dyskinesias - Parkinson tremor and dyskinesias experimental (Mesnage 2004) 0.5gm/cig 1 cig 2.9%THC Survey of unsupervised smoked MJ Lotan 2014 (Frankel 1990) Venderova 2004 Finseth 2015 Nabilone Cesamet Levodopainduced Dyskinesias - 0.03 mg/kg 0.03 mg/kg (Fox 2002) Sieradzan 2001
Tourette Syndrome Botanical smoked MJ 0.5-2 cig/dy 1 cone /night Sandyk 1988 Hemming 1993 Survey (Selfprescribed) Müller-Vahl 1998 THC capsule Tics, vocalizations 2.5 mg Δ 9 -THC Max 10mg/d Müller-Vahl 2002;Class II, Muller-Vahl 2003;Class III
Dystonia Dronabinol Marinol Cervical Dystonia Dystonia+ Tics in MultipleSclerosis 7.5mg bid 2.5mgbid (Zadikoff 2011) Deutsch 2008 CBD or cannabis extract None Primary Dystonias 10 mg/kg/d up to 75mg/dy 100 mg CBD Consroe 1986 (Chagas 2014) Curtis 2009 Inhaled botanical MJ Spasms Hemidystonia Not stated 1MJ Cigarette/dy Marsden 1981, Chatterjee 2002 (In Wilson Disease) 3-4g/dy Uribe 2004
Epilepsy Insufficient evidence For patients with epilepsy, data are insufficient to support or refute the efficacy of cannabinoids in reducing seizure frequency (2 Class IV studies, no Class I III studies).
History of use in epilepsy Epidemiology favored anticonvulsant effect Ng 1990 NEJM Series of 15 pts, worked in 7 of 8 Cunha 1980 Pharmacology Charlotte Figi, pt with Dravet, grew cannabis with more CBD, less THC in Colorado where it was legal Maa &Figi 2014 Epilepsia 55:783-6 Devinsky: Cannabinoids in the treatment of epilepsy NEJM 2015 373:1048-1058
Endocannabinoids and neuronal excitabilityy Defects in EDC system in patients with TLE, and seizures activate the system EDC anandamide levels lower in pts with seizures CBD binds to cation channels which dec release of glutamate, inhibit adenosine reuptake Mostly surveys and anecdones, need rct Etiolex = spray with CBD>THC being studied
Nejm table 1
Nausea/ Appetite CB 1 receptors in limbic system to affect reward aspects of eating CB1 in lateral hypothalamus affects hunger CB1 affects peripheral metabolism Olfactory frontal cortex ; chemosensory perception of food (eg chemo makes food taste bad, MJ can offset it) Brisbois et al Annals of Oncology 2011
Many Studies establish weight gain, number of eating times, calories consumed 469 Ca/wt loss pts. Dronabinol appetite 49% wt >10% Megesterol appetite 75% wt >10% Combination appetite 66% wt >10% (note additive effect) Jatoi J Clin Conc 2002
Other HIV studies 139 pts dronabinol caused stable weight, placebo lost wt. Beal et al 1995 J Pain Symp Mgt and 1997 same dronabinol no effect compared with megestrol Timpone et al 1997 AIDS Res Hum retrovir Also measure eating occasions, food intake, calorie consumption, self-reported appetite and nausea Abrams et al 2003 Ann Int Med Haney et al 2007 JAIDS Bedi et al 2010 Psychopharm Foltin 1988 Appetite Riggs 2012 Brain Res
Other conditions AD food refusal responded to THC in 15 subjects Volicer et al 1997 Int J Ger Psych Anorexia Treat Obesity with antagonists of CBD Rimonabant causes weight loss, dec waist circumference, triglycerides, inc HDL cholesterol, inc adiponectin levels and reduces taste for sweet foods (studied with chocolate) rather than all food
Adverse Effects No more than other meds used for pain or spasticity, eg somnolence, slowed cognition or motor performance, balance and coordination in studies (doses of THC varied especially between pills, sprays and smoked forms) Interaction or metabolism of other medications being used and underlying brain disease esp MS
Potential adverse effects Clinical Context In the reviewed studies, cannabinoids were generally well tolerated, although some SAEs were reported. Mild or moderate AEs were common (reported in approximately 50% 80% of study subjects) and appeared to be of similar prevalence in subjects receiving cannabinoids and in those receiving a placebo control intervention. Most studies of cannabis for efficacy were of short duration, ranging from 6 15 weeks. No evidence was available for evaluating the safety and efficacy of smoked cannabis, although results from a single Class III study e72 suggest that decline in cognitive performance may be an SAE. Slide 42
Specific findings of MJ problems Drop outs occurred in 6.9% of 619 treated and 2.2% of placebo Most common symptom: dizziness (up to 50%) Symptoms reported in at least 2 studies: nausea, fatigue, increased weakness, behavioral or mood changes, suicidal ideation, hallucinations, feelingsof intoxication (high). Notably absent: Psychosis, dysphoria, and anxiety One death possibly related to treatment (seizure followed by aspiration pneumonia). In a year-long study of 207 patients, 15% stopped CBD, 14% stopped THC and 10 % placebo Slide 43
Herbs: Cannabis, cont. Clinical Context, cont. Because cannabinoids have known psychoactive properties, their potential for psychopathological and neurocognitive AEs is a concern especially in a patient population that may be vulnerable due to underlying disorders such as MS. Clinicians should therefore counsel patients about the potential for psychopathologic/cognitive AEs as well as other AEs associated with cannabinoids. Sativex oromucosal cannabinoid spray is not US Food and Drug Administration (FDA) approved and is not available in the United States. In the United States, caution should be exercised with regard to the extrapolation of the results of trials of standardized OCEs (which are not commercially available) Slide 44 to other, nonstandardized and nonregulated, cannabis extracts (which may be commercially available in states with medical marijuana laws).
More unique problems MJ is added to other neurotoxic medications for pain and spasticity Patients with CNS disease may already be cognitively impaired MJ acts on hepatic enzymes to interfere with levels of other medications, especially pain meds Slide 45
Recreational Use different THC content has gone much higher than past, and hard to know. Edible products have delayed onset so can ingest too much while waiting to feel effect Synthetic marijuana extremely potent, floods many receptors, associated with stroke, seizures, aggressive psychosis, 4 deaths Schneir J Med Tox 2012 8:62-64 Zawiska JB I J Neuropsychopharm 2015 17:508-525 Castaneto 2015 Drug Alc Depend epub
Harlem Hospital experience In 4 months there were 9 patients with seizures (7, 4 with history of epilepsy but long seizure-free interval) psychosis (1) stroke (1) or encephalopathy due to K2
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