MARIJUANA AS MEDICINE: CURRENT UNDERSTANDING AND TRENDS Penelope P. Ziegler, M.D. Medical Director Professionals Resource Network (PRN)

Primary Psychoactive Ingredient- Tetrahydrocannabinol

THC Mimics Neurotransmitter Anandamide in the Brain’s Endocannabinoid System

Cannabis Is a Plant 484 known biological compounds Flowers, seeds, leaves and stems are consumed Smoking Vaporization Concentrated oils Infused “teas” Edibles, plant usually cooked into foods At least 84 brain-active cannabinoids THC Cannabidiol (CBD) Cannabinol (CBN) Many others with unclear or unknown effects

Marijuana Has Been Used As Medicine Throughout History Ancient History Used in Chinese medicine dating back 10,000 years; still a basic herbal in Traditional Chinese Medicine Ancient Egypt- hemorrhoids and other inflammatory conditions India- used for insomnia, pain, digestive problems Ancient Greece- extensive veterinary uses, also in humans (nosebleeds, tapeworms, etc.) Middle East- used as antiemetic, diuretic, antiepileptic, anti-inflammatory Western Medicine Europe- used for muscle spasms, stomach cramps America- widespread use in “patent medicines” Modern times- Advocates Support Use for Many Conditions Insomnia Pain Nausea and vomiting Decreased appetite with weight loss Muscle spasms Epilepsy Glaucoma

What Is the Evidence for Cannabis as a Medication? Nausea and vomiting in cancer chemotherapy (CINV) 2010 Cochran review- “probably effective” in children but with high incidence of side effects; inadequate evidence for effectiveness in adults European meta-analysis of synthetic cannabinoids showed superior anti- emetic effects but higher side effects Additional concern- cannabis induced hyperemesis Glaucoma- probably not effective in reasonable doses Wasting syndrome in AIDS- inadequate evidence, studies flawed Muscle spasms, spasticity- variable results with MS, small studies Insomnia- small study showed improvement in sleep patterns in fibromyalgia patients Pain- reviews show some benefits but studies are hard to compare

Recent Review of Medical Marijuana in Neurological Disorders Koppel BS, Brust JCM, Fife T et al Neurology. 82: Spasticity Oral cannabis extract (OCE) effective, nabiximols and THC probably effective for reducing patient-centered measures OCE and THC possibly effective for both patient-centered and objective measures at 1 year Central pain, painful spasms OCE effective THC and nabiximols probably effective Urinary dysfunction Nabiximols probably effective for reducing voids/day THC and OCE probably ineffective for reducing all bladder complaints Tremor THC and OCE probably ineffective Nabiximols possibly ineffective Other conditions Unknown efficacy in Huntington’s disease, Tourette syndrome, cervical dystonia, epilepsy Probably ineffective in Parkinson disease High incidence of serious adverse reactions (almost 1%) and side effects

What Are Risks, Adverse Effects Side effects Addiction Impaired motor skills Cognitive impairment Motivational impairment Risks associated with method of consumption Special risks for adolescents Impact on brain development Psychotic syndromes Cyclic vomiting syndrome

FDA- Approved Cannabinoids Are Already Available in U.S. Dronabinol (Marinol®)- Schedule III, approved for CINV, wasting syndrome in AIDS Nabilone (Cesamet®)- Schedule II, approved for CINV Nabiximols (Sativex®)- oral mucosal spray, not approved in U.S., used in Canada and Europe. Currently in Phase III trials in US for MS, cancer pain, CINV

What Is “Charlotte’s Web” “Charlotte’s Web” or “Realm Oil” is extracted from a strain of marijuana bred by crossing Cannabis sativa (marijuana) and Cannabis indica (hemp) that has low levels of THC and high levels of CBD (cannabidiol) Developed by the Stanley brothers, major marijuana growers in Colorado Named after Charlotte Figi, a seven year old diagnosed with Dravet Syndrome or SMEI, who had intractable seizures until tried on Realm Oil This strain of cannabis is not associated with a “high” because of its low THC level and, if imported, would be classified as hemp. Originally called “Hippie’s Disappointment” The Stanleys plan to move their Realm Oil operations to Uruguay and import the oil to the U.S. as hemp oil Hemp oil is legal in all 50 states but most lacks the high levels of CBD

Recent References Degenhardt L, Lintzeris N, Campbell G, et al. Experience of adjunctive cannabis use for chronic non-cancer pain: Findings from the Pain and Opioids IN Treatment (POINT) study. Drug Alcohol Depend. 2015;147: Koppel BS, Brust JC, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology Neurology. 2014;82: Kahan M, Srivastava A, Spithoff S, Bromley L. Prescribing smoked cannabis for chronic noncancer pain: Preliminary recommendations. Can Fam Physician. 2014;60: Borgelt LM1, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy. 2013;33: Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and smoked marijuana in daily marijuana smokers. Neuropsychopharmacology : Bostwick M. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. February (2): Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: A systematic review and meta-analysis. JAMA (24):