Presentation Outline. Learning Objectives 10/5/2016. Medical Marijuana in the Pharmacology of Cannabinoids. 1) Pharmacology of the cannabinoids

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1 Medical Marijuana in the Pharmacology of Cannabinoids Jane Ishmael, Ph.D. Associate Professor of Pharmacology Department of Pharmaceutical Sciences College of Pharmacy, Oregon State University Presentation Outline 1) Pharmacology of the cannabinoids 2) Recent trends in marijuana exposure 3) Approved uses, and rationale for the use, of medical marijuana 4) Potential for drug-induced short and long term adverse events Learning Objectives 1) Identify the mechanism by which major cannabinoids act in the central nervous system 2) Identify medical conditions for which medicinal marijuana is approved in Oregon 3) Describe prominent toxicities associated with marijuana exposure 1

2 The Oregon Medical Marijuana Act December 1998 Oregon voters approved Ballot Measure 67 Allowed medical use of marijuana in Oregonand established a state-controlled permit system -OMMP Protects medical marijuana users from prosecution states + Washington D.C. January 2014the Oregon State Legislature approved the establishment of Medical Marijuana Dispensaries (426 registered with the Oregon Health Authority) July 2015 recreational marijuana became legal for personal use (to be regulated by OLCC) October 2015 earlysales of recreational marijuana allowed at medical dispensaries October 2016 recreational marijuana stores open Cannabis sativa, American Medicinal Plants, 1887 Charles F. Millspaugh, National Library of Medicine 2

3 Along history of medicinal use in the U.S Listed in U.S. Dispensatory (American cannabis) Tincture of Cannabis was made my many companies e.g. Parke-Davis, Eli Lilly, Bristol- Meyers Squibb, Merck For: Insomnia Headaches Sexual dysfunction Eating disorders 1933 National Museum of American History 1941 Removed from American Pharmacopoeia Other Medicinal Plants, texts from Nicotiana Tabacum Vitus vinifera Papaver somniferum National Library of Medicine Erythroxylon coca National Library of Medicine Cocaine was the first natural product local anesthetic Circa (non-alcoholic beverage) 3

4 What is Medical Marijuana? A general term Cannabinoids are found: (1) Endogenously endocannabinoid system (2) Plant natural products numerous phytochemicals in the Cannabis plant including Δ9-THC and cannabidiol (3)Synthetic forms pharmaceutical grade Δ9-THC and a close isomer Plant-derived Cannabinoids compounds Cannabinoids 1930s Cannabinol(CBN) and Cannabidiol(CBD) isolated 1942 Δ 9 -tetrahydrocannabinol (THC)isolated 1964 (±)-Δ 9 THC and then (±)-CBD synthesized 1970 Marijuana listed as a Schedule Isubstance (negatively impacting research) 1990 CB 1 cannabinoidreceptor cloned 1993 CB 2 cannabinoid receptor cloned Cannabinoids are secondary metabolites to help the plant adapt to it s environment Reviewed by Andre et al. Frontiers in Plant Science, Feb

5 How do people use marijuana? Smoke (hand-rolled joints; pipes; water pipes) Vaporize(inhaled vapor) Ingest ( edibles ; teas ) Topically (oils; creams) Dried: flowers leaves stems seeds Hashish/hash traditionally made from trichosomes/ resin glands Δ 9 -tetrahydrocannabinol (THC) is the main psychoactive substance in Cannabis sativa Sativa Cannabis indicaplant is particularly high in THC now many hybrid strains Indica THC bindsto both Cannabinoid Receptors(CB 1 and CB 2) with good affinity (Ki =5-80 nm) CB 1 and CB 2 are located in the plasma membrane Image: JP Trostle 5

6 Low High Imaging agents developed by the National Institute of Mental Health CB 1 is considered a very abundant receptor target in the brain Neurons are specialized cells information travels in one direction nerves talk to other nerves at synapses Endogenous Cannabinoids are Neuromodulators CB 1 receptors are primarily located on presynaptic neurons to inhibit neurotransmitter release CB 2 receptors are primarily located on immune cells, periphery and on microglia Endogenous agonists for these receptors are lipid mediators - the endocannabinoids (isolated ) 6

7 Endogenous agonists are arachadonic acid derivatives e.g. Anandamide(AEA), N-acylethanolamine(NAE) 2-arachidonoylglycerol (2-AG) Bioactive lipids synthesized from membrane precursors Production is activitydependent Terminated by hydrolysis (Enzymes are potentially future drug targets) The acute action of Δ 9 -THC is to cause PRESYNAPTIC INHIBITION Synaptic Neuromodulation 7

8 Profiling marijuana (what dose?) Most dispensaries sell multiple strains of medical marijuana Quality control is based on analytical testing of plant material to yield a cannabinoid potency profile % weight cannabinoids/total plant weight Examples: % THC-total -Δ 9 -THC, Δ 8 -THC, CBN < 9% = LOW THC and >> 14% = HIGH THC % CBD-total Cannabidiol < 1% = LOW CBD and > 4% = HIGH CBD Dose for edibles is listed in mg (e.g. 5mg THC = 1 serving) development of single molecule oral drugs Two have been approved by the U.S. Food and Drug Administration (FDA) via the normal process: Dronabinol(Marinol ) 1992 Δ 9 -THC For severe nausea& loss of appetite resulting in weight loss (schedule III) Nabilone(Cesamet ) 1985 Synthetic analogue For severe nausea (schedule II) Adjunct for neuropathic pain Life of an U.S. FDA approved medicine Phase IV Post market surveillance Cannabis plant contain 100s of chemical compounds 8

9 Steady Increase in Potency start low go slow! NEJM 370: Trends: Out-of-State visitors to the ED Recent data from Colorado (NEJM 374;8 p 797 Feb. 2016) Visits related to Cannabis Use Residency determined by zip code ED visits from residents plateaued Steep increase in out-of-state residents Marijuana tourism highlights need for point-of-sale education for visitors Trends in marijuana use Increased exposure of children (especially edibles) Increased self-report and use in adults (now legal) Why do people seek medical attention after use: 1) Exacerbates an underlying condition (e.g. anxiety) 2) Those directly affected by marijuana use (e.g. motor vehicle collision) 3) Intoxication/over use (e.g. unpleasant experience, anxiety and fear of response) 9

10 Separating Recreational and Medicinal Use of Marijuana (1) Different primary motivation/goal Symptom relief versus pleasure (2) Preferred route of administration may / may not differ Smoking rapid and predictable bioavailability (allows self titration) Vapor release of cannabinoids without smoke combustion products Oral poorer bioavailability edibles have a longer activation time Recreational Use (1) Psychoactive substance (Δ 9 -THC plus the combination of other natural products in the plant) (2) Plant cannabinoids modulate neurotransmission within the reward center of the brain CNS effects: feelings of well being, euphoria, reduced anxiety, relaxation, altered perception, time distortion, enhanced pleasure from "normal" experiences (e.g. eating, sex) The Nucleus Accumbensis considered the reward center of the brain Dopaminergic neurons Cell Bodies in VTA projecting to the nucleus accumbens Neuronal circuitry that is used for natural rewards such as: Food, Social interaction, Sex Chemicals with abuse liability target this pathway provoke a strong desire to take the substance Explains: Risk of Cannabis Use Disorder Interest in marijuana as a modulator of this pathway in reward and addiction 10

11 Definitions (Oregon Medical Marijuana Act) Debilitating medical condition Degenerative/pervasive neurological conditions Cachexia Cancer Glaucoma HIV+/AIDS Nausea PTSD Severe Pain Seizures(including but not limited to epilepsy) Persistent muscle spasms(including but not limited to those caused by Multiple Sclerosis) OMMP Statistics (July 2016) 66,880 patients(can have more than 1 qualifying condition) 29,833 caregivers &1,692 physicians with OMMP patients Degenerative/pervasive neurological conditions 414 Cachexia 1,013 Cancer 4,263 Glaucoma 985 HIV+/AIDS 649 Nausea 8,998 PTSD 5,151 Severe Pain 60,324 Seizures 1,785 Persistent muscle spasms 19,498 Medicinal use of marijuana - pain Management of chronic pain, neuropathic pain, cancer pain & muscle spasms Good evidence that synthetic and endogenous cannabinoids are analgesic Activation of cannabinoid receptors induces analgesia in many animal models Cannabinoid receptors are located in the brain, spinal cord and periphery(cb 1 -and CB 2 -mediated responses) 11

12 Pain Signals Acute Pain normal in response to: trauma, surgery, burns, cuts, dental work (should go away after healing 6 months) Chronic Pain - persists after injury has healed, pain signals stay active causing physical and emotional effects Examples: neuropathic pain, arthritis pain, back pain, cancer pain, some headaches, phantom pain Crosstalk between two endogenous systems to modulate pain Endogenous opioid peptides (enkephalins, endorphins, dynorphins) Opioid (mu, kappa, delta) Receptors Endogenous cannabinoids (lipid modulators) CB 1 and CB 2 Cannabinoid Receptors Endogenous cannabinoids modulate pain perception under physiological conditions Efficacy of THC:CBD Approved in Canada, Australia, UK, Spain + others Persistent muscle pain of Multiple Sclerosis Manufactured in a standard way to control THC and CBD content (1:1 ratio) If approved -expense may not prove to be costeffective relative to medical marijuana Potential for potentiation of analgesic effects allowing a reduction in the dose of opioids Sativex is currently in several active phase III clinical trials in the US for cancer pain FDA fast track persistent pain in advanced cancer uncontrolled pain/unmet need 12

13 Nabiximols(Sativex ; GW Pharmaceuticals) A standardized pharmaceutical product THC:CBD - containing herbal extract of marijuana Non-opioid analgesic Endocannabinoid system modulator "Tinctures of cannabis" Medicinal use of marijuana - appetite Cachexia 1,013 Cancer 4,263 HIV+/AIDS 649 Nausea 8,998 Use of marijuana use to stimulate appetite, improve quality of life for anorexia/wasting syndromes Controlled studies are limited Knowledge of cannabinoid biology (pharmacology and genetic studies in CB 1 -deficient mice) support a role for the endocannabinoid system in the regulation of eating CB 1 -deficient mice revealed the importance of the receptor in regulation of eating and fat deposition Strong evidence that the endocannabinoid system is implicated in the control of: food intake regulation of bodyweight metabolic regulation 13

14 Medicinal use of marijuana - glaucoma Goal is to reduce intraocular pressure (IOP) Marijuana does lower IOP in normal and glaucoma patients Problem is the short and transient duration of action (3-4 h) American Glaucoma Society does not recommend marijuana for treatment of glaucoma Medicinal use of marijuana reduces anxiety Agitation related to Alzheimer's disease Post Traumatic Stress Disorder Best explained as a result of the direct action of marijuana on the CNS: to produce feelings of well being, calming, relaxing, improved sleep Medicinal use of marijuana - seizures Changes in seizure threshold are most easily explained by the ability of marijuana to treat somepatients with epilepsy Human data is limited and the science to determine mechanism of action lags behind 14

15 CBD and Drug-resistant Epilepsy The story of Charlotte Figi(born 2006) Age 3 months: Diagnosed with Dravet syndrome or Severe Myoclonic Epilepsy of Infancy Age 5: Refractory to treatment-50 + generalized tonic-clonic(gtc) seizures per day Sublingual extract of a high cannabidiol(cbd) strain began as an adjunct therapy now down to 2-3 seizures per month Epilepsia(2014) 55: Charlottes Web Strain Developed and grown in Colorado Springs Considered a hemp product (0.3% Δ9-THC) Low in Δ9-THC / high in CBD (17 %) Cannabidiol(CBD) Does not bind CB 1 or CB 2 receptors Considered non-psychoactive Anti-epileptic mechanism and target unknown Controlled studies lacking > patients treated with reports of efficacy 2013 Orphan Drug Designation granted for a purified extract of (99% CBD (Epidiolex )) to treat children with two different intractable epilepsy syndromes (randomized trials) Preliminary report treatment of 137 children at 12 weeks median reduction in seizures was 54 % 15

16 Marijuana as medicine considerations (1) Psychoactive effects may not be tolerated especially in naïve users that have no prior experience (2) Risk of dependence Cannabis Use Disorder (3) Perceived safety in young individuals and potential role as a "gateway drug Developing brain is more vulnerable to extrinsic/environmental inputs than the mature brain (age 21) (4) Contraindicated in pregnancy and during lactation - like many other medicines Early onset side-effects (1) Increased heart rate (2) Vasodilation (3) Decreased heart rate and lower blood pressure (4) Red eyes (dilation of capillaries in the eyes); pupils may dilate, blurred vision Potential Adverse Effects of Short-Term Use (1) Impaired short-term memory may compromise ability to learn and retain information (2) Impaired motor co-ordination driving skills (3) Altered judgment and perceptions of safety (4) Some individuals experience paranoia, psychosis at high doses relatively rare These are all predicted by actions of marijuana as a neuromodulator of CNS signaling and largely considered reversible upon abstinence 16

17 *Cannabinoid Hyperemesis Syndrome Counterintuitive (first described in 2004) Associated with chronic, heavy use of cannabis (presumably recreational or medical) Recurrent episodes of severe nausea, retching and cyclical vomiting in the absence of other pathology Abdominal pain, temporary relief from hot showers/baths triggering compulsive showering! Symptoms stop after cannabinoid cessation but resume within weeks of resuming Recognized Adverse Effects of Long-Term Use (1) Risk of addiction and dependence (CNS) (2) Negative effect on pre-existing psychiatric illness risk worsening symptoms; medical marijuana is not advised in these patients (3) Symptoms of bronchitis in habitual smokers Cough, sputum production, wheezing Symptoms are similar to cigarette smokers and additive Central airway inflammation and pathological change Metabolism and Elimination (1) Substrate of Cytochrome P450 CYP3A4 and CYP2C9 (2) Cannabinoids are lipophilic relatively long elimination (3) Renal elimination (50 ng/ml cutoff urine test) THC is metabolized to a metabolite, 1-nor-9-carboxy- 9-tetrahydrocannnabinol (THCCOOH), conjugated with glucuronic acid and eliminated in urine Very long "detection times" in habitual users 27 days versus 3 days complicates interpretation of "new" versus "past" use in the workplace by immunoassay 17

18 Drug Drug interactions (1) CNS actions of marijuana: impaired cognitive function and motor function caution against combining medical marijuana with sedatives/hypnotics ( benzodiazepenes, medications for insomnia, barbiturates, anti-histamines)and other central acting medications including alcohol (2) Multiple anecdotal reports of interactions intensifies side effects or changes marijuana response/experience (3) We are in a phase of post-market evaluation so far relatively safe in monotherapy! Summary (1) There are large gaps in our knowledge of the endocannabinoidsystem research, safety and efficacy studies lag behind (2) Medical marijuana users have a significant burden of chronic disease and unmet need for alternatives (3) THC is the best studied natural cannabinoid but the mechanistic basis of medical marijuana (i.e. the mixture of compounds) is not understood Thank you for inviting me! 18