CBD Oils; • Discuss Updated Prescribing Models for Medical Cannabinoids in the US

7/16/19

To CBD or Not to CBD: That is the Question?

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Clinical Associate Professor University of Georgia College of Pharmacy [email protected]

Learning Objectives

Participants will: • Evaluate medical cannabinoid products and their beneficial potential; • Contrast the various legalization processes of medical cannabinoids in the US; • Formulate the profile of adverse drug effects of CBD oils; • Discuss updated prescribing models for medical cannabinoids in the US.

Oh Boy-Another Talk on Marijuana- Let’s Get Stoned!!!!! • What are the benefits of marijuana? • Is marijuana a medicine? • Does marijuana have beneficial components to treat incurable chronic diseases? • Should marijuana be legalized? If so, how should marijuana be regulated? • List 5 adverse drug effects of THC. • List 5 adverse drug effects of CBD. • Should marijuana be a RX or OTC? • At what age should some be allowed to purchase marijuana? • What penalties should be in place for illegal use of marijuana?

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What is the uproar over CBD oils about?

• With the legalization of cannabis products (THC and CBD) for medical and recreational purposes in many states and with a majority of US citizens advocating for the legal right to consume these products, the use of THC and CBD products will increase and may impact the human brain in many ways. The human brain can experience multiple complications with regular use of cannabis products and the long- term effects of these complications are unknown. Are CBD oils beneficial or do they cause long term dysfunctions of the central nervous system?

The Hysteria Over CBD Medical Claims Is Not New To Our Culture • DMSO • Herbal Compounds • Sugar Substitutes • Botox • Diet Plans-Grapefruit Diet-Ephedra • Anti-Aging preparations • Vitamin Supplements • Potency Products

Physician Prescribing Background • The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research • 440 pages | 6 x 9 | PAPERBACK • ISBN 978-0-309-45304-2 | DOI: 10.17226/24625 • Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda; Board on Population Health and Public Health Practice; Health and Medicine Division; National Academies of Sciences, Engineering, and Medicine

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Schedule 1-5 drugs

• Examples of substances listed in • Schedule 2: Vicodin, Cocaine, Schedule I:Marijuana (cannabis) Meth, OxyCodin, Adderall • Heroin • Schedule 3: Tylenol with • LSD Codeine, Steroids, Ketamine, • Peyote (mescaline) Testosterone • Methaqualone (Quaalude) • • 3,4-methylenedioxymeth Schedule 4: Xanax, Valium, amphetamine (“ecstasy”) Darvon, Ativan, Ambien, • “bath salts” Traumadol • Schedule 5: Robitussin AC, Lomotil, Motofin, Lyrica

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History of Medical Cannabis • >2000 years of therapeutic use • As late as 19th century, cannabis preparations widely prescribed by ‘Western’ doctors. • bronchitis, epilepsy, burns, hypnotic, analgesia, PMS • Prohibition since early 20th Century led to abandonment of cannabis as therapeutic agent • Interest rekindled since 1980’s • Consumer advocacy • Scientific developments

Varieties of Cannabinoids

Synthetic Endocannabinoids Phytocannabinoids cannabinoids

In your brain and body In plants From the lab

Anandamide, 2-AG, Noladin THC, CBD, CBG, CBDV, THCV, Nabilone, HU-210, AB-PINACA, ether CBC, CBN, THCVA JWH-018, etc. etc. etc

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Brain regions that express the CB1 cannabinoid receptor

Red = abundant CB1 receptor expression Black = moderately abundant CB1 receptor expression

Adapted from Joy JE et al, eds. Marijuana and Medicine. 1999.

CB2 Receptors: immune system modulators

• CB2 receptors found in spleen, tonsils, thymus gland, bones, skin • Localised in monocytes, macrophages, B-cells and T-cells • Limited CB2 in brain, except in inflammatory states (microglia) • Stimulation of CB2 can reduce inflammation and neuropathic pain

Varieties of Cannabinoids

Synthetic Endocannabinoids Phytocannabinoids cannabinoids

In your brain and body In plants From the lab

Anandamide, 2-AG, Noladin THC, CBD, CBG, CBDV, THCV, Nabilone, HU-210, AB-PINACA, ether CBC, CBN, THCVA JWH-018, etc. etc. etc

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>100 cannabinoids in the plant. Most are non-psychoactive.

Each has its own pharmacological actions and therapeutic potential.

“Entourage” effects

Hemp vs Marijuana

• Both are considered Cannabis sativa but there is a distinction between hemp and marijuana. • Marijuana contains significant amounts of the psychoactive phytocannabinoid known as THC. • Industrial Hemp is cultivated very differently and has very little if any THC after extraction. • Cannabidiol (CBD) - the non-psychoactive component of marijuana. • Hemp CBD products can technically come from either cannabis plant – it just really boils down to being below that magic number of 0.3% of THC in the product.

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Phytocannabinoids Marijuana vs Hemp • Tetrahydrocannabinol (THC) • Cannabidiol (CBD) • Psychoactive • Not Psychoactive • Has medicinal value • Has anxiety relieving properties • Antagonises effects of THC • Has medicinal value

www.DrJeffreyTucker.com

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Cannabidiol (CBD) modulates many of the effects of THC in cannabis

THC and CBD =

THC only =

Preclinical research identifies a range of possible therapeutic effects from phytocannabinoids

Cannabinoid( Intoxicates?( Possible(Medicinal(Application( THC( √! Nausea!and!Vomiting,!Muscular!Spasms,!PTSD,!Pain,!Cancer,!Inflammation,!! CBD( x! Epilepsy,!Psychosis,!Anxiety,!PTSD,!Addiction,!Dementia,!Cancer,!Insomnia! CBDA( x! Epilepsy,!Nausea!and!Vomiting,!Cancer! CBDV( x! Epilepsy! THCA( x! Nausea!and!Vomiting,!Epilepsy! THCV( x! Diabetes,!Obesity,!Pain,!Inflammation,!Epilepsy! THCVA( x! Under!investigation! CBG( x! Glaucoma,!Cancer,!Inflammation,!Anxiety,!Huntingdon’s!Disease! CBGA( x! Under!investigation! CBN( x! Anxiety,!Insomnia,!Epilepsy,!AntiHbacterial!effects! CBC( x! Pain,!Inflammation,!Cancer! !

AVERAGE THC CONCENTRATIONS IN CANNABIS SEIZED BY DEA 1980 TO 2014

14 12.3 11.84 12 THC 9.75 10 8.76 8.14 8

6.11

PERCENT 6 4.9 3.87 4 3.3 3.04 3.08 2.36 CBD 2 1.24 0.55 0.51 0.28 0.41 0.46 0.28 0.17 0.15 0 YEAR 80 83 86 89 92 95 98 2001 2004 2007 2010 2013 2014

18 ElSohly, et al. Biological Psychiatry 79:613 (2016) ElSohly, et al., Journ of Forensic Sci 45:24 (2000)

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http://patientsoutoftime.org/wp-content/uploads/2015/01/cannabis-states.png

Farming Act

• Hemp Farming Act of 2018 became law December 20, 2018 removing hemp (defined as cannabis with less than 0.3% THC) from Schedule I controlled substances and making it an ordinary agricultural commodity.

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Farm Bill passed but the FDA…

• Hemp (contains no more than .03% THC) has been removed from the Government’s Controlled Substance Acts. • However, the Food and Drug Administration (FDA) has not approved CBD’s use in food or beverages. • The FDA controls the regulation of Cannabidiol (CBD), NOT the Farm Bill.

www.DrJeffreyTucker.com

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Depending on where you live, you may be able to obtain a medical cannabis card for conditions like:

• Alzheimer's – interference with amyloid plaque formation • Glaucoma – lowers intraocular pressure • Multiple sclerosis – may relieve painful muscle contractions • Crohn's Disease/IBD - enhanced gut permeability • Adverse effects of chemo/Anorexia – appetite-stimulating effects • PTSD – improvement in symptoms, undergoing further research • Arthritis – e.g. RA & OA; pain reduction & improvement in mobility • Epilepsy – e.g. Darvet’s Syndrome • Chronic pain HelloMD with Brightfield Group. Usage study. 2017.

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CANNABINOIDS Endocannabinoid system (ECS) Phytocannabinoids (Flowers) Synthetic cannabinoids

ECS plays a critical role in most major functions of the body… inflammation motor control and coordination memory and learning anxiety and stress reward and addiction... and a lot more. Globally, the ECS is primarily involved in maintaining balance in the body (homeostasis). There are many conditions associated with reduced levels of endocannabinoids in the body…that’s why we take it from flowers!

www.DrJeffreyTucker.com

PubMed.gov

THC (Tetrahydrocannabinol) CBD (Cannabidiol) • Non-psychoactive • Psychoactive • Analgesic • Analgesic • Anti-inflammatory • Anti-inflammatory • Antioxidant • Antioxidant • Anti-emetic • Anti-emetic • Anxiolytic • Euphoric • Anti-psychotic • Anti-neoplastic • Anti-convulsant/spasmotic • Anti-epileptic • Anti-spasmodic • • Anti-tremor Immunomodulatory • Neuroprotective • Appetite Stimulant • Decrease THC psychoactivity

www.DrJeffreyTucker.com

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Terms - Hemp

• CBD - is from flower only. • Hemp oil - a carrier oil made from seed and/or stalk. • Full spectrum – is from the whole (full) plant. • Isolate – extracts are rendered down to a single molecule – CBD using a variety of post processing steps.

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Labeling

• Hemp extract is code word for CBD (ex. 28 mg per 1 ml serving) • Hemp seed is made from the seed and virtually no CBD; they contain omega 3 & 6 • Hemp oil is a carrier or base that they are using - does not have CBD • Hemp stalk is a source of many beneficial phytocannabinoids • Phytocannabinoid may contain some CBD • CBDA – cannabinoid; you won’t know how much is CBD unless you test it.

www.DrJeffreyTucker.com

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Labels

• Hemp oil • Isolates • “whole plant, full spectrum hemp oils and extracts containing naturally occurring cannabinoids”

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Drug Testing What does all this mean? • SAMHSA (Substance Abuse and Mental Health Services Administration) guidelines. • Drug tested through urine for THC. • THC is responsible for marijuana’s psychoactivity and euphoria. • A consumer who uses a high-quality, scientifically vetted hemp-based product at the standard serving size is highly unlikely to test positive for THC. • Extremely high doses may result in a positive urine screen. • Consumers need to be fully informed of the specific regulations posed by their employers.

www.DrJeffreyTucker.com

CVS in the CBD business

• More than 800 stores in Alabama, California, Colorado, Illinois, Indiana, Kentucky, Maryland, and Tennessee now offer CBD products.

• “These products include topicals such as creams, sprays, roll-ons, lotions and salves. We are not selling any CBD-containing supplements or food additives. We have partnered with CBD product manufacturers that are complying with applicable laws and that meet CVS’s high standards for quality,” CVS statement.

www.DrJeffreyTucker.com

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Introduction-The Pharmacology Basics of THC and CBD

• Cannabis contains a number over 100 active compounds.

• Two of the most abundant and best studied are tetrahydrocannabinol (THC) and cannabidiol (CBD). • You can not talk about CBD without talking about THC.

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Introduction

• In combination, THC and CBD probably account for most of cannabis’ known effects.

• They have very different physiological and pharmacological properties.

• Both suppress seizures, perhaps by different mechanisms.

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Psychoactive (Personal) vs Non-Psychoactive( Medical)

Cannabinoids

Delta-9-THC CBD “PSYCHOACTIVE” “NOT PSYCHO ACTIVE”

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•THC • Delta 9 Tetrahydrocannabinol

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Source: NIDA

THC - Structure

• Converted from THCa by drying, heating.

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With Anandamide: With Marijuana: Dopamine release Dopamine release

THC – Actions

• THC has a wide number of pharmacological actions, some of which have been known since antiquity.

• Anxiolytic / Sedative (CB1) • Analgesic (CB1) • Anticonvulsant (CB1) • Appetite Stimulant (CB1) • Anti-emetic (CB1) • Anti-inflammatory / Immune Suppressant (CB2) • ETC.

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THC vs. Anandamide

• Both dial down neuron activity to change neurotransmitter release • THC has a MUCH STRONGER, LONGER effect than anandamide on brain cells • THC interferes with cell function and growth

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THC Receptors

• Most of THC’s actions are mediated through two main receptors.

• CB1 – mostly found on neurons (CNS and PNS) – g linked • (small amounts: kidney, liver, lungs)

• CB2 – found in the immune system and microglia – g linked

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Cannabinoid Receptors

• CBD can increase levels of the body’s own naturally-produced cannabinoids (known as endocannabinoids) by inhibiting the enzymes that break them down. • CB1, CB2 • Ananadamide, FAAH

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THC Binding Sites

Front Back

Source: NIDA 42

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THC Receptors

• These g-linked receptors are part of the endogenous endocannabinoid system.

• To explain how THC works, it will be useful to discuss the endocannabinoid system.

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•Background for THC: •The Physiology of the Endocannabinoid System

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The Endocannabinoid System

• The endocannabinoid systems consists of endogenous cannabinoids and their receptors.

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Endocannabinoid System – Endogenous Messengers

• The are two major endogenous messengers that bind to the cannabinoid receptors:

• 2 AG (2-arachidonoylglycerol)

• anandamide (arachidonoylethanolamine or AEA)

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Endocannabinoid System – Endogenous Messengers

• Anandamide and 2 AG are eicosanoids.

• They are formed by the action of phospholipases on plasma membrane phospholipids.

• They are broken down by FAAH and other enzymes. Blockade of FAAH extends their half-lives.

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Endocannabinoid System – Endogenous Messengers

• Both bind to CB1 and CB2 receptors.

• CB1 – 2 AG is a full agonist - anandamide is a partial agonist

• CB2 – 2 AG binds with a higher affinity than anadamide

• Anandamide was discovered first, but 2 AG is perhaps the more powerful ligand.

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Endocannabinoid System - Function

• 2 AG and anandamide are “retrograde inhibitors”.

• They are released post-synapse following receptor activation.

• They then diffuse backwards to the presynaptic cell where they inhibit transmitter (CB1) or cytokine (CB2) release.

• They act by closing Ca++ channels and opening K+ channels via Gi/o.

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Endocannabinoid System

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Endocannabinoid System

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Endocannabinoid System

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Endocannabinoid System

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Endocannabinoid System - Function

• In the brain, endocannabinoid feedback reduces transmitter release in many different systems.

• These include: GABA, glutamate, DA, NE, 5HT, glycine, etc.

• In the above diagrams, post-synaptic Ca++ results from mGLUR activation. In other systems, other mechanisms would provide the Ca++.

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Endocannabinoid System - Function

• In the brain, CB1 receptors are located in many different area and affect many different transmitters.

• They are perhaps not a “system”, but rather a series of local feedback mechanisms.

• THC and congeners, however, activate these receptors all at once.

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THC Pharmacology

THC Stimulates CB1 and CB2 Receptors Actions in the brain involve CB1

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THC/CB1 Drugs

• Different Mechanisms of Actions: • THC- jet plane • CBD- piper club

• Agonists for the CB1/THC Receptor (selected)

• Plant derived – THC - partial agonist

• Synthetic – dronabinol (Marinol), nabilone (Cesamet) (partial agonists?), WIN 55, 212-2 - full agonist

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THC/CB1 Dugs

• Antagonists for the CB1 Receptor

• Cannabindiol (CBD) – described as a specific or non-specific antagonist

• Inverse Agonists for the CB1 Receptor

• Rimonabant

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THC/CB1 Drugs – Current Use

• Current Medical Uses:

• Agonists (cannabis, dronabinol, nabilone) • Anti-emetic (chemotherapy) • Appetite Stimulant (AIDs) • Analgesic (neuropathic pain, multiple sclerosis)

• Inverse Agonist (rimonabant) • Weight loss , Smoking Reduction, Addiction

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THC/CB1 Drugs – Possible Use

• Possible Medical Use:

• As AEDS

• Animal studies have shown anti-seizure effects.

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THC - Anti-Seizure Effects - Animal Studies

• THC has anti-seizure effects in most animal models – and also pro- convulsant effects in some models. These are produced via the CB1 receptor.

• THC also has sedative/ataxic (psychotoxic) effects – also via the CB1.

• THC’s psychotoxic effects limit its usefulness as an AED. CBD looks much more promising as an AED.

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Psychoactive (Personal) vs Non-Psychoactive( Medical)

Cannabinoids

Delta-9-THC CBD “PSYCHOACTIVE” “NOT PSYCHO ACTIVE”

•CBD • Cannabidiol

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CBD- Cannabidiol

• Now we know CBD as cannabidiol, an organic compound derived from the hemp and cannabis plants. We find it in health food stores and other shops. In pills and tinctures. Salves and creams. Chocolate bars, honey sticks, energy bars, sleeping masks and coffee, among many other things. And as the CBD boom continues to crest, we will encounter the substance in increasingly more products and outlets.

Cannabis and Cannabinoids

• Highly concentrated THC or cannabidiol (CBD) oil extracts are being illegally promoted as potential cancer cures. These oils have not been evaluated in any clinical trials for anticancer activity or safety. • Because CBD is a potential inhibitor of certain cytochrome p450 enzymes, highly concentrated CBD oils used concurrently with conventional therapies that are metabolized by these enzymes could potentially increase toxicity or decrease the effectiveness of these therapies. • “Cannabis and Cannabinoids (PDQ®)–Health Professional Version was originally published by the National Cancee Institute.” (2018) • Cannabis and Cannabinoids (PDQ®)—Health Professional Version... https://www.cancer.gov/about- cancer/treatment/cam/hp/cannabis-... • 16

CBD Structure

• Converted from CBDa by heating.

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CBD – Pharmacological Actions

• Well Documented:

• Anti-seizure effects

• Suggested:

• Analgesic (acute and chronic pain) • Antipsychotic • Anxiolytic • Anti-cancer • Anti-inflammatory

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CBD Physiology

• CBD does act via the endocannabinoid system as usually defined.

• It does not activate CB1 or CB2 receptors - or mimic 2AG, anandamide or any known endocannabinoid.

• It may interact with the endocannabinoid system indirectly, e.g. antagonizes CBD1 receptors and inhibits FAAH (?).

• What receptors does it bind to?

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CBD – Receptors?

• A very confused field. It has been reported to act on: • CBD does NOT act on the CB1 or CB2 rceptors • Instead it acts on the following:

• 5 HT 1A – partial agonist (anxiolytic? antidepressant?) • Adenosine receptors – agonist (anxiolytic?) • TRPV1 - weak agonist, desensitizes (analgesia?) • Mu and delta opiate receptors – allosteric modulator (analgesic?) • PPAR – agonist (anticancer?) • GPR55 – antagonist (effect?) • ETC, ETC

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CBD Endogenous Ligand?

• Effects of CBD are said to be “pleotropic”. It acts on many different receptors.

• Unclear whether there is an endogenous ligand.

• Except for the chemical messengers related to its various receptors (5 HT, opioids, etc.)

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CBD – Drugs?

• Not much pharmacology.

• CBD appears to be the only clear agonist in its class.

• Although other cannabinoid extracts may have similar properties: e.g., cannabidivarin.

• There don’t seem to be any antagonists.

• But it does have anti-seizure effects in animals.

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CBD’s Anti-Seizure Effects – Animal Studies

• NIH has recently tested CBD in the standard mouse seizure models.

• It is active in the MES, MET and 6Hz ECS models.

• It is active at doses that don’t cause sedation/ataxia.

• Although sedation/ataxia does occur at higher doses.

• We are in the process of testing it in the amygdala kindling model.

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CBD as an Anti-epileptic – Animal Studies

ED50’s from the NIH Study – Broad Spectrum

MES – 83.5 mg/kg

6 Hz ECS – 164 mg/kg

s.c. MET – 159 mg/kg

TD50 from the NIH Study (Rotarod) – Non-toxic

> 400 mg/kg

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CBD as an Anti-epileptic – Animal Studies

• The receptor(s) that mediates CBD’s anti-seizure effects is currently unknown.

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Endocannabinoid Synthesis

• Anandamide (arachidonoyletholamine; AEA)

• Synthesis • Arachidonic acid (from phospholipids) + phosphatidyletholamine > N anachidonyl phosphatyletholomine (NAPE)>anandamide

• Enzymes: (first step) N acetyltransferase; (last step): PLA2, PLC, NAPE-PLD

• Degradation (very rapid – levels kept low) • Anandamide > arachidonic acid + ethanolamine

Enzyme: FAAH (fatty acid amide hydrolase)

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Endocannabinoid Synthesis

• 2 AG (2 arachidonoylglycerol)

• Synthesis (one pathway)(calcium dependent) • Phospholipids > diacylglycerol > 2 AG

• Enzyme: (first step) PLC; (last step) DAG lipase

• Degradation (levels not kept low) • 2 AG > arachidonic acid and glycerol

Enzymes: MAGL (monoacylglycerol lipase), FAAH (fatty acid amide hydrolase) and others

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Anandamide Synthesis and Degradation

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Actions at the Nerve Terminal

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Other Cannabinoids

• Canabinol – weakly anti-seizure but ataxia

• Cannabidivarin - anticonvulsant

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THC – Suggested Sites of Action

• THC partially activates the CB1 Receptors all over the brain.

• It would increase excitation/inhibition in many areas.

• Some Possible Sites of Action • Hippocampus – memory impairment • Nucleus Accumbens – reward (increased DA release) • Hypothalamus – stimulation of appetite • Pain System - analgesia

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THC – Mechanism of Action – Immune Suppression

• THC also activates CB2 receptors.

• CB2 receptors also provide negative feedback in the immunological system.

• They inhibit the release of cytokines.

• This is the basis of THC’s anti-inflammatory/ immune suppressive effects.

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Priyamvada Sharma, Pratima Murthy, M.M Srinivas Bharath. “Chemisty, Metabolism, and Toxicology of Cannabis: Clinical Implications”. Iranian Journal of Psychiatry. October 1, 2012. pg. 149 http://eds.b.ebscohost.com/eds/pdfviewer/pdfviewer?sid=14587b3e-f585-4dce-af43-007de0074755%40sessionmgr110&vid=16&hid=104 82

Legal Marijuana*

*According to the Federal government

§ Investigational New Drug Program – closed in 1992 § 12 patients allowed to continue; two patients remain in the program § Federally approved source of research-grade cannabis at a farm at the University of Mississippi § Cannabis-derived pharmaceuticals • Dronabinol (schedule III) and Nabilone (schedule II) § Treatment of nausea and vomiting associated with cancer § Treatment of anorexia associated with weight loss in patients with acquired immune deficiency syndrome (dronabinol) § Nabiximols (not FDA approved) § Symptomatic relief of spasticity in adults with multiple sclerosis § Symptomatic relief of neuropathic pain in patients with MS § Intractable cancer pain

Baron EP. Headache. June 2015 Lexicomp. “Dronabinol”. Accessed October 13, 2015. Lexicomp. “Nabilone”. Accessed October 13, 2015

Latest News About Marijuana

• Marijuana use associated with higher incidence with SUDs; • Use of marijuana may increase risk of psychiatric disorders but research inclusive with the worsening of those conditions; • Social anxiety was identified as worsening with marijuana use; • An increase dosage consumption was noticed with regular use of marijuana; • Long term outcomes are not available but the development of cannabis use disorder increase with use and tolerance.

• http://archpsyc.jamanetwork.com/article.aspx?articleid=2491944

How Do Cannabinoids Effect The CNS?

•People who use cannabis products enjoy the experience due to the “soothing effect of cannabis”. When THC is in high concentrations vs CBD-this effect will occur. •So here is a brief explanation of how that may happen:

Neuronal Anatomy

Axonal process Axon

Myelin sheath Dendrites (insulation) Unmyelinated “Node of Ranvier” Processes connect to dendrites at Synapses

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How Nerves Fire

At rest, pumps keep the sodium ion (Na+) concentration inside neurons low, and the potassium (K+) ion concentration higher than outside

• When stimulated, Na+ channels in the node open followed by K+ channels, causing a “pulse” of charge to enter then exit the neuron. • This pulse of charge is called an “Action Potential” (AP)

+10mV Na+ in Action Potential K+ out -70mV

The Na+ induced voltage “spike” causes K+ channels to open and allow K+ out

Signal Transmission

Na+

K+

Charge moves down an axon like a “chasing light” (not like electrons in a At Synapses, chemical wire) neurotransmitters propagate the signal to the post synaptic neuron

Signal Transmission

Na+

K+

Charge moves down an axon like a “chasing light” At Synapses, chemical (not like electrons in a neurotransmitters propagate wire) the signal to the post synaptic neuron

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Neurotransmission at Synapses

At the presynapse, the AP stimulates calcium (Ca2+) Ca2+ influx influx through voltage signals release of sensitive channels neurotransmitter vesicles

Neurotransmitters This influx of charge re- activate post-synaptic receptors to allow Na+ initiates the AP on the and Ca2+ in. post-synapse

Endocannabinoids-The Brain’s Braking System

If too many APs occur, excess neurotransmitter spills outside the synapse

Receptors outside of the synapse detect this excess and synthesize the endocannabinoid 2-arachidonyl-glycerol (2AG)

2-arachidonyl glycerol (2-AG)

Volkow, N.D., Hampson, A.J., and Baler, R.D. (2017). Don't Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward. Annual review of pharmacology and toxicology 57, 285-308

Endocannabinoids Regulate Neurotransmission- The Brain’s Reset Button

CB1 releases subunits which inhibit calcium channels and reduce neurotransmission

The enzyme MAGL breaks down 2-AG and so restores neurotransmission that inhibit the calcium channels 2-AG migrates backwards across the synapse to activate pre-synaptic Cannabinoid receptors (CB1)

2-AG modulates neurotransmission where and when needed (unlike THC)

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PhytoCannabinoids

Cannabinoid Precursor

Cannabigerolic acid THCA CBDA Synthase Synthase High in marijuana 1 High in Hemp Heat, Light

THC CBD

THC / CBD absorption and metabolism: smoking vs eating

Free and Glucuronide Whole Blood Cannabinoids' Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake. Newmeye et al. Clin Chem. 2016 62(12):1579-1592

Drug Ingestion via Lungs or Stomach

Inhaled THC is rapidly distributed to all organs

All blood from the digestive system, is filtered by the liver (site of most metabolism) before reaching other organs.

This is called “First Pass Metabolism”

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THC Pharmacokinetics Comparison of THC absorption from cannabis (56 mg THC) /L ug

11-OH THC: a marker Oral administration results in of liver metabolism. more first pass metabolism /L ug

Latest Medical Cannabinols Efficacy Research

• Cannabis use was common in people with chronic non-cancer pain who had been prescribed opioids, but we found no evidence that cannabis use improved patient outcomes. People who used cannabis had greater pain and lower self-efficacy in managing pain, and there was no evidence that cannabis use reduced pain severity or interference or exerted an opioid- sparing effect. As cannabis use for medicinal purposes increases globally, it that large well designed clinical trials, which include people with complex comorbidities, are conducted to determine the efficacy of cannabis for chronic non-cancer pain. • Campbell,G et al: Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study; www.thelancet.com/public-health Vol 3 July 2018

Latest Medical Cannabinols Efficacy Research

• One meta-analysis of 119 patients in 9 pain trials, 5 of which were exclusive to cancer pain, found that tetrahydrocannabinol (THC) had an e!ect approximately equivalent to codeine, but dose-related and dose- limiting central nervous system (CNS) adverse events were common. • A more recent meta-analysis of 11 randomized controlled trials in chronic neuropathic pain demonstrated an insignificant overall change in pain scores, resulting in a weak recommendation for the use of cannabinoids. • A meta-analysis of the e!ects of cannabinoids on cancer pain in 43 randomized controlled trials revealed a beneficial effect in favor of cannabinoids, but patients were highly likely to experience significant CNS and gastrointestinal side effects. • Cannabinoids for Cancer Pain - The ASCO Post; August 25, 2018

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Latest Medical Cannabinols Efficacy Research-ADES • Twenty-eight (13%) patients (N= 218) in the cannabis group reported at least 1 SAE, compared with 42 (19%) in the control group. • Despite these limitations, this study improves our knowledge about the safety of medical cannabis. Caution should be exercised in interpreting these results for all medical cannabis use as patients in this study used a standardized, quality-controlled herbal cannabis product with a reliable THC potency of 12.5%. • This study suggests that the AEs of medical cannabis are modest and comparable quantitatively and qualitatively with prescription cannabinoids.The results suggest that cannabis at average doses of 2.5 g/d in current cannabis users may be safe as part of a carefully monitored pain management program when conventional treatments have been considered medically inappropriate or inadequate. • Ware, M et al; Cannabis for the management of pain(COMPASS) http://dx.doi.org/10.1016/j.jpain.2015.07.014.

Effect of Food on CB Absorption

• A fatty meal improves THC / CBD absorption by 200-300%* • THC/CBD is incorporated into fat droplets, absorbed by intestinal cells

• The fat droplets are directed to the lymphatic system, and so bypass the liver#

*A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray. Stott, C.G et al (2013). European journal of clinical pharmacology 69, 825-834. #Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines Atheer Zgair et al (2016) Am J Transl Res. 8: 3448–3459

A Tale of Two Drugs

• There are many different cannabinoids but the two most studied so far are tetrahydrocannabinol delta-9 (THC) and cannabidiol (CBD) • THC docks at the brains cannabinoid receptors and main psychoactive effect is inebriation or high • CBD behaves differently in the brain, has different psychoactive effects- sedation or anxiolytic (though effects less clear than THC) without inebriation • Growers have become skilled at growing plants with very high resin content, and differing THC to CBD ratios • Purveyors have become skilled at concentrating and isolating these chemicals, crystal THC-a and crystal CBD

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Terpenes and the Entourage Effect

• Terpenes are major components of resin (besides cannabinoids) • Terpenes can affect the brain and body themselves, but also seem to interact with THC and CBD • Entourage effect: interactions of THC and CBD in different ratios, and terpenes

Resin, Isolates, and Extractions

• Cannabis plants are being bred with ever higher resin percentages • Charlotte’s Web 20% CBD,.o5% THC • Sour Tsunami 11% CBD, 10% THC • Gorilla Glue .05% CBD, 25%THC • Cf. Finola (industrial hemp) 2%CBD, .24% THC • Extraction technologies concentrate resins, purify and isolate THC and CBD • Potent! Smaller amounts of bud/concentrate have ever more “doses” of these drugs

What’s in a Dose?

• Calculated doses based on Colorado’s “Medical Equivalency in Portion and Dosage.” • For one ounce of flower/bud with 17.1% THC content you can get more than 425 doses of 10 mg each. This would be 1,063 doses per 2.5 ounces, and 2,126 doses per 5 ounces - which a QP can purchase in a month (under PL 2017, Ch. 452 [LD 1539]it will be 8 pounds in any form of harvested marijuana). • That is 6,800 doses per pound so potentially 54,400 doses from 8 pounds of harvested marijuana; or 1,360,000 doses per 200 pounds that Tier 2 manufacturing licensees could possess at one time.

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Amounts

• For a long time the usual amount of medical marijuana for a year was 1 pound of bud/leaf • More recent averages for medical marijuana users is around 1-2 ounces per month • Colorado considers 10mg THC a dose • Cf. starting dose of Dronabinol (synthetic THC) would be about 5 mgs to help with nausea • Amounts allowed under various laws for cultivation and possession have been overly generous for many patients

CBD & Industrial Hemp

• CBD oil meets the definite of marijuana under the Controlled Substances Act (“CSA”) because it is derived from the resin of the plant. “Marihuana" means all parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant… Such term does not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination.” 21 USC §802(16).

Low THC

• “Industrial hemp” is the subject of a federal program under the Agriculture Act (“Farm Bill”) of 2014 at Section 7606(b)(2). Section 7606 protects certain entities who grow and use industrial hemp (with <.3% THC by dry weight). for research projects. Industrial hemp may only be grown by an institution of higher education or a state department of agriculture for purposes of research conducted under an agricultural pilot program or other agricultural or academic research, and if the growing or cultivating of industrial hemp is allowed under the laws of the state where the cultivation or research occurs. • Maine has a program for “industrial hemp” growers, but it does not meet the requirements of the federal program in the Farm Bill and so does not provide much protection against the federal CSA. 7 MRS §2231.

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CBD is not Industrial Hemp

• CBD Oil can be extracted from industrial hemp strains that have less than .3% THC because these hemp varieties usually have some CBD but it is also usually low, at 1- 3% or so. • To add to the confusion there are high resin, high CBD strains that have <.3% THC). • More importantly “industrial hemp” covers only that which is used for industrial purposes (fiber and seed). Products from industrial hemp may be sold for purposes of marketing research by institutes of higher education or state departments of agriculture, but not for purposes of general commercial activity. US Secretary of Agriculture, July 25, 2016, Federal Register, Vol. 81, No. 156 p.53395-53396.

CBD is a now a prescription drug approved by the FDA.. more on this later

• 1980 studies in Israel, Dr. Raphael Mechoulam • Patients with epilepsy suffered fewer seizures • June 2018, Epidiolex approved by US FDA for Dravet Syndrome and Lennox- Gastaut Syndrome • Prescription drug, not OTC • Botanical drug not chemical copycat • Because FDA approved it as a prescription drug it meets the requirement of having a currently acceptable medical use in the US • Before it can be prescribed and sold in US DEA will have to reschedule at least part of marijuana (CBD)

New Products for 2019

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The Two Tales of Marijuana: Medicine or Menace

Cannabinoid Solubility Compared with Caffeine

Caffeine formulation* mg/dose Cannabinoid oral dose mg/dose

Starbucks Latte THC Low Dose 5-15 150 (16oz/0.5L) THC Medium Dose 15-30 Diet Coke (12oz/0.35L) 46 THC High Dose 40-100 Red Bull (8oz/0.25L) 80 CBD anxiolytic dose 300 CBD antiseizure dose ~1000-1500

Caffeine Solubility Cannabinoid Solubility Cold Water 20,000 mg/L Water (CBD/THC) 2.8 mg/L# Hot Water 60,000 mg/L CBD Pure Alcohol 24,000 mg/L$

*Center for Science in the Public Interest # Physiochemical properties, solubility, and protein binding of delta9-tetrahydrocannabinol. Garrett ER, Hunt CA. (1974) J Pharm Sci. 63(7):1056-64. $WHO Expert Committee on Drug Dependence, 39th Meeting Geneva 2017

Public Health Dangers of Cannabis Use

• Effects of THC include poor motor coordination, somnolence, cognitive impairment (learning, judgement and memory impairment)

• Most problematic in developing brains (teenagers), developmental cognitive concerns

• Associations with ADHD, Anxiety and Depression – Causative? • Potential precipitation of psychotic episode in those predisposed. Synthetic CBs cause psychotic episodes • THC use results in reduced ability to quit smoking and smoking impairs ability to quit cannabis

• Hyperemesis syndrome is becoming more commonly recognized in heavy users. There is no current treatment • Cannabis somewhat increases the risk of opioid-induced respiratory depression (RD). The effect may be less intense than opioid plus alcohol or sleeping pill combinations

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But What About the Current FDA Approved Cannabinols???

• Dronabinol( Marinol, Syndros) 1985, 2017 • Nabilone (Cesamet) 1985 • Cannabidiol (Epidiolex) 2018

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Dronabinol (Marinol)

• Dronabinol is a light yellow, sticky resinous oil formulated in sesame oil. It is insoluble in water and, therefore, only a fraction of the orally ingested compound reaches the patient’s circulation. This amount is further reduced by the action of the liver, which recognizes dronabinol as a contaminant, and removes it from the bloodstream. As a result, researchers have estimated that only 10 to 20 percent of the dronabinol in each capsule actually reaches its target in the body.

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Dronabinol (Syndros)

• Last year, the FDA approved a new liquid formulation of dronabinol. The new version of the drug is made by DPT Lakewood LLC for Insys Therapeutics and is marketed under the brand name Syndros. • Indications are the same for Syndros as they are for Marinol: anorexia associated with weight loss in patients with AIDS, and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional treatment

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Nabilone (Cesamet)

• Cesamet (SES-uh-met) is the brand name for nabilone. Cesamet is a purely man-made synthetic drug that claims to activate the cannabinoid receptor CB1, which reduces proemetic signaling in the vomit center and thus inhibits nausea and vomiting. Cesamet claims it replicates the healing properties of delta-9- tetrahydrocannabinol (THC), but does not actually contain any of the constituents found in the Cannabis plant and thus, lacks the ability to tap into the entourage effect produced by whole plant cannabis medicines. • Cesamet is classified as an antiemetic. Antiemetics are medicines that help prevent or treat chemotherapy-induced nausea and vomiting (CINV). Cesamet is to be prescribed to people who continue to experience these symptoms after trying other traditional medications, specifically antiemetics, to find relief.

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Cannabinoids as Therapeutics

Palliative Effects of Cannabinoids (Nausea and Analgesia)

Systematic Review and Meta-Analysis of Cannabinoids in Palliative Medicine. Mücke M et al 2018 J.Cachexia Sarcopenia Muscle, 9:220-234 • The quality of evidence was low / very low mainly because of inadequate sample size and high number of non- completers

• In HIV patients, cannabinoids were superior to placebo for both weight gain and appetite (mod effect size), but not for nausea/vomiting. There was a significant increase in mental health symptoms, but effect size was low

• In cancer patients, No difference between cannabis and placebo for improving caloric intake, appetite or nausea/vomiting, sleep problems or the number of patients with a >30% reduction in pain. No difference in side effects (dizziness or mental health).

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Opioid Sparing in Pain Patients How well cannabinoids can reduce the dose of opioid needed for pain relief. Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis. Nielsen et al 2017 Neuropsychopharmacology.;42(9):1752-1765. This was a systematic review of available pre-clinical (animal) and clinical studies • 17 of 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co- administration. • The median effective dose (ED50) of morphine in animals is 3.6 times lower when administered with delta-9-tetrahydrocannabinol

• The 10 Clinical studies were of varying quality, half provided moderate to high quality evidence, and half were low or very low quality evidence quality evidence.

• Only the v low quality (n=3) study showed opioid sparing effect. • Two low quality studies (no placebo) showed some improved pain, and improved sleep and overall functioning. • None of the 3 high quality, placebo controlled trials showed improved pain or opioid sparing

FDA approves first drug derived from marijuana (Cannabidiol) to treat rare, severe forms of epilepsy

• Epidiolex was approved to treat Dravet’s and Lennox-Gastaut syndromes by FDA on June 25th 2018.

• On 27th Sept. 2018 Epidiolex was scheduled by DEA as CV(5) – the lowest risk category of the Controlled Substances Act.

• Currently other CBD formulations of CBD remain CI(1).

Epidiolex (Cannabidiol 100mg/ml Oral Solution)

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Epidiolex In Dravet’s Syndrome (Clinical trials.gov ref= NCT02091375) Dravet’s is a rare genetic condition starting in the first year of life. • Initially frequent fever-related seizures. • Later, other seizure types develop; myoclonic seizures (involuntary muscle spasms) and status epilepticus, (life-threatening, continuous seizures requiring emergency medical care). • High drug-resistance and mortality rate.

STUDY: 120 drug-resistant children and young adults received placebo or 20mg/kg CBD added to existing treatment regimen. (Note high dose) RESULTS • Mean convulsive seizure frequency reduced by 23%, with median # decreasing from 12.4 to 5.9 in CBD group. • 43% of CBD patients and 27% of placebo had >50% reduction in convulsive-seizure frequency

• Adverse events included diarrhea, vomiting, fatigue, fever, somnolence, and elevated markers of liver impairment.

• Drug interactions with Clobazam (a valium type antiseizure drug) were observed

*Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. Devinsky et al N Engl J Med. 2017 May 25;376(21):2011-2020. (NCT02091375)

Epidiolex and Lennox-Gastaut Syndrome (Clinical trials.gov ref= NCT02224560) Syndrome with frequent seizures starting between ages 3 and 5. • 75% have tonic seizures, (uncontrollable muscle contraction). Absence and atonic (drop) seizures also common • Almost all children have learning problems and intellectual disability. Many have delayed motor skills development.

STUDY: 30 site double-blind, randomized, 225 patients (2 to 55 years) with two or more drop seizures / week • Treated with placebo, or Epidiolex; 5mg or 10 mg/kg x2/day for 14 weeks.

RESULTS • drop seizures averaged 85/28 day baseline period. • 37% frequency reduction in 5 mg/kg group, 42% in 10mg/kg group

• Common dose-related adverse events were somnolence, decreased appetite, and diarrhea and elevated liver enzymes

• FDA has required post-marketing vigilance for liver injury, long term carcinogenicity and kidney function over next 2 years

Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. Devinsky et al N Engl J Med. 2018 May 17;378(20):1888-1897.

A Review

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Ë Delta-9-tetrahydrocannabinol (THC) is the active ingredient of marijuana

major metabolites OH-THC (11-delta-9-THC) and THC-COOH (11-nor-delta-9-THC- carboxylic acid, inactive) Levo is the more active isomer

THC 11-OH-THC (active) OH

Chemical Constituents of Cannabis Chemical classes Cannabinoids (66) Nitrogenous compounds (27) Amino acids(18) Proteins/ enzymes (11) Sugars (34) Hydrocarbons (50) Simple alcohols (7) Simple aldehydes (12) Simple ketones (13) Simple acids (21) Fatty acids (22) Simple esters/lactones (13) Steroids (11) Terpenes (20) Non-cannabinoid phenols (25) Flavoroids (21) Vitamins (1) Pigments (2) Elements (9) Total known compounds (483)

The Ubiquitous CB1

• Endogenous CBs are a major class of neuromodulators, acting through receptors, CB1 and CB2 • CB1 receptors are primarily located on CNS neurons • Levels exceed those of nearly all neurotransmitter receptors • Exogenous CBs exert their effects by driving this innate system, often mimicking and enhancing its natural functions

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Cannabinoids

Huestis, M. 2009, Human Cannabinoid Pharmacokinetics, National Institute of Health: Chem Biodivers, v. 4(8), p. 1770-1804.

THC: Pharmacodynamics Drug to Body

• Causes disinhibition of dopamine (DA) neurons by presynaptic inhibition of GABA neurons in the VTA • Causes euphoria and relaxation • Feelings of well-being, grandiosity, and altered perception of passage of time • Dose-dependent perceptual changes, drowsiness, diminished coordination, and memory impairment • Hash (concentrated THC) may result in visual hallucinations, depersonalization, and frank psychotic episodes

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THC: Pharmacodynamics

• a partial agonist at both CB1 & 2 receptors, has activity at non-CB receptors and other targets, and is responsible for the psychoactive effects of cannabis through its actions at the CB1 receptor.

• smoking route or by vaporization: central nervous system and physiological effects occur within minutes

• The psychotropic effect or "high" occurs much more quickly by the smoking than by the oral route

• Physiological effects include rapid changes in heart rate and diastolic blood pressure, conjunctival suffusion, dry mouth and throat, vasodilatation, and decreased respiratory rate

**THC: Pharmacokinetics – Metabolism

Active, Psychoactive component Inactive; Diagnostic

Peak 3-8 Peak 15- 81 Peaks 81-240 minutes minutes minutes

*THC is metabolized in the liver by cytochrome P450s – 2C9, 2C19, and 3A

http://eds.b.ebscohost.com/eds/pdfviewer/pdfviewer?sid=14587b3e-f585-4dce-af43-007de0074755%40sessionmgr110&vid =16&hid=104

How much should a person use to get 25 mg of THC? • 20% THC • Single serving 50 mg • Net weight 1/8 oz or 3.5 gm

http://bothcollective.com/page/6/?app-download=windowsphone

http://onehumanbeing.com/the_mmj_project/2009/03/granddaddy-purple-at-cclb/

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Modifying Concentrations • Why • Seeking better high • More THC and less CBD • CBD limts psychoactive effects of THC • terpenes, delay or modulate the onset of effects of cannabinoids • anti-inflammatory terpenes that protect the lungs from irritation • What • Honey Oil, Wax, Hash Oil • How • Using burning techniques and solvents to rid plant and plant resins of CBD • pure THC preparations may be the presence of residual solvents (e.g., ethanol) that are needed to solubilize the sticky pure THC

De Backer, B., Maebe, K., Verstraete, A., Charlier, C., 2012, Evolution of the Content of THC and Other Major Cannabinoids in Drug-Type Cannabis Cuttings and Seedlings During Growth of Plants, Journal of Forensic Sciences, v. 57(4) National Highway Traffic Safety Administration, Cannabis / Marijuana ( Δ 9 -Tetrahydrocannabinol, THC), 2012, Drugs and Human Performance Fact Sheets, http://www.nhtsa.gov/people/injury/research/job185drugs/cannabis.htm , (August 3, 2015)

But Is THC Toxic???

• 2009 study from American Scientist on the relative toxicity of recreational drugs showed that using only 10 times the "effective" dose of alcohol could be fatal, whereas more than 1,000 times the effective dose of marijuana would have to be used to be possibly fatal. • The toxic dose of THC in a 65kg adult would be 8.45kg.

Dr. Merrill Norton,Pharm.D., D.Ph., ICCDP-D and Caitlin Payne, Research Assistant 138

But is THC Toxic???

• The tachycardia almost invariably produced in acute intoxication, combined with the sensory alterations and increased tremor commonly reported, probably contribute to the affective components of these reactions. CNS and respiratory depression are noted with high doses, which in severe overdose may be life-threatening (Rosencrantz, 1983). These effects are, of course, more dangerous to those with pre-existing cardiac irregularities. Because of the large effective to lethal dose ratio in humans (probably in excess of 1:1000 in non-tolerant users) the risk of experiencing severe toxic effects of cannabis is limited by the aversive psychotropic effects of high doses, which usually lead to cessation of use before the onset of dangerous physical consequences.

Dr. Merrill Norton,Pharm.D., D.Ph., ICCDP-D and Caitlin Payne, Research Assistant 139

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Medical Marijuana Standards

Pharmacology

https://cbdbrothers.com/wp- content/uploads/2014/05/tumblr_mmt475oMxO1s85ojqo1_500.png

What is in medical cannabis?

www.fullspectrumlabs.com Accessed 07/18/2011

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Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders

Disorder Target Symptoms Therapeutic Clinical Outcome Cannabinoid Multiple Sclerosis Spasticity Oral THC, CBD In progress Neurogenic pain Sublingual THC, CBD Phase II trial in progress Bladder dysfunction Sublingual THC, CBD Phase II trial in progress Parkinsons’s Dystonia Nabilone No effect disease Dyskinesia Nabilone ¯ Dyskinesia Tremor D9-THC No effect Cancer Pain Sublingual THC, CBD Phase III trial in progress Postoperative pain Pain IM levonantradol ¯ pain, but less effective than existing therapies

CBD = cannabidiol Croxford, JL. CNS Drugs 2003; 17(3) THC = tetrahydrocannabinol

Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders (cont’d)

Disorder Target Symptoms Therapeutic Clinical Outcome Cannabinoid Spinal cord injury Pain Sublingual THC, Phase II trial in progress CBD GI tract pain Pain THC ¯ Morphine requirement

Traumatic Brain Neurodegeneration IV dexanabinol ¯Intracranial pressure, Injury / Stroke (HU-211) ¯ mortality, phase III trial in progress Neurodegeneration CBD In progress

HIV wasting Appetite loss, nausea Smoked cannabis In progress syndrome Appetite loss, nausea Dronabinol appetite, ¯ nausea

Tourette’s syndrome Behavioural disorders THC undetermined

Croxford, JL. CNS Drugs 2003; 17(3)

http://steephilllab.com/wp-content/uploads/2014/01/Understanding-Medical-Cannabis-2.jpg

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Drug Interactions • Stimulants • Cocaine, Amphetamines, etc • increased hypertension • tachycardia • cardiotoxicity. • Depressants • Benzodiazepines, Barbiturates, Ethanol, Opioids, Antihistamines, muscle relaxants, etc. • increase drowsiness • CNS depression • Alcohol • greater impairment • decreases in function • less likely to react appropriately • increased reaction times

National Highway Traffic Safety Administration, Cannabis / Marijuana ( Δ 9 -Tetrahydrocannabinol, THC), 2012, Drugs and Human Performance Fact Sheets, http://www.nhtsa.gov/people/injury/research/job185drugs/cannabis.htm , (August 3, 2015)

Cannabidiol : CBD Cannabinoids

Delta-9-THC “ACTIVE” CBD “INACTIVE

Charlotte

§ Charlotte is a little girl from Colorado with Dravet syndrome § Frequent bouts of febrile and afebrile status epilepticus § Failed multiple medications: • Levetiracetam, oxcarbazepine, topiramate, zonisamide, valproate, clobazam, clonazepam, and diazepam § At 5 years of age, had significant cognitive and motor delays, required a feeding tube, and needed full assistance with activities of daily living § 50 generalized tonic-clonic seizures per day

http://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/

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Charlotte’s Web

• A high concentration CBD/THC strain of cannabis produced by a medical marijuana group in Colorado • Charlotte’s Web, supplied by Realm of Caring, is based out of Colorado and parents and families are moving there to attempt treatment

Month 20: 2-3 Parents began Month 3: >90% nocturnal generalized giving Charlotte reduction in tonic-clonic seizures per low doses of month, feeds and drinks plant extract and generalized tonic- clonic seizures and by mouth by herself and slowly increased weaned from other autistic behaviors have the dose over AEDs improvement, walking time and talking

http://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/

Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy

Methods:

• Retrospective chart review of children and adolescents who were given oral cannabis extracts (OCE) for treatment of their epilepsy • Seizure response was based on parental report of total seizure frequency prior to initiating OCE treatment • Deemed a responder if parental report of >50% reduction in seizure frequency

Patients:

• 75 patients (45.3% male) • Mean age 7.33; range 0.5 – 18.25

Results

• 43/75 (57%) of parents reported some improvement • 25/75 (33%) reported to have >50% reduction in seizures • 2/75 (0.3%) reported to be seizure free by their last follow up • No difference in response rate between different types of oral cannabis extract (CBD, CBD+other OCE, THC only, other)

Press CA et al. Epilepsy and Behavior 45 (2015) 49-52

Pharmacology (2019)

• Cultivation methods have been developed to reproducibly produce plants with defined THC or CBD concentrations. GW Pharmaceuticals has produced two standardized extract preparations, Tetranabinex®, which is high in THC, and Nabidiolex®, which is high in CBD. Sativex® contains equal proportions of Tetranabinex® and Nabidiolex®, and, hence, almost equal amounts of THC and CBD

Huestis, M. 2009, Human Cannabinoid Pharmacokinetics, National Institute of Health: Chem Biodivers, v. 4(8), p. 1770-1804.

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CBD Anxiolytic Effects • Most current anxiolytics are “Valium™”-type or “Prozac™ / Cymbalta™ type antidepressants. • CBD-induced anxiolysis appears to be mediated by serotonin receptor 1a. • Mostly preclinical studies (to date)

Elevated Maze Model

Chronic Unpredictable Stress Model

1. Food restriction 4. Substitution of sawdust with 37C water 2. Restraint (2h) 5. Forced swim (10 min) 3. Reversal light/dark cycle 6. Removal of sawdust (24 h) 7. Light to dark shifts (four shifts of 30 min)

The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system Campos AC, et al. Int J Neuropsychopharmacol. 2013 16(6):1407-19.

Effect of CBD in Healthy Subjects Simulated Public Speaking Test- More is NOT Better

Basal Pretest Speech F Post speech

Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. Zuardi et al (2017) Front Pharmacol. 2017 11;8:259

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CBD: Pharmacodynamics

• Lacks detectable psychoactivity and does not appear to bind to either CB1 or CB2 receptors at physiologically meaningful concentrations. • Affects the activity of a significant number of other targets including ion channels, receptors, and enzymes. • May have anti-inflammatory, analgesic, anti-nausea, anti-emetic, antipsychotic, anti-ischemic, anxiolytic, and anti-epileptiform effects.

CBD: Pharmacokinetics

Absorption • Oral Bioavailability: 13 – 19% due to marked first pass effect • IV preferable

Distribution • Like THC, it is highly lipophilic – rapidly distributed and easily passes the blood brain barrier (BBB)

CBD: Pharmacokinetics

Metabolism • undergoes multiple hydroxylations, oxidations to carboxylic acids, beta-oxidation, conjugation, and epoxidataion

Excretion / Elimination • prolonged due to lipophilicity (stays in system longer) • excreted from urine, both in free state and as its glucuronide • ****Half life = 9 hours

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Different Routes of Administration and the Effect on Plasma Concentrations

A. Intravenous Route B. Oral Route C. Vaporization/ Inhalation D. Dabbing E. Transdermal

• Intravenous Route- Research primarily • How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆9- Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to ParanoiaDaniel Freeman*,1, Graham Dunn2, Robin M. Murray3, Nicole Evans1, Rachel Lister1, Angus Antley1, Mel Slater4,5, Beata Godlewska1, Robert Cornish6, Jonathan Williams7, Martina Di Simplicio8, Artemis Igoumenou9, Rudolf Brenneisen10, Elizabeth M. Tunbridge1, Paul J. Harrison1, Catherine J. Harmer1, Philip Cowen1 and Paul D. Morrison3+

Edibles

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Edibles

• Gelatin capsules, glycocholate, sesame oil: improved bioavailability • Considerable variations in peak concentrations and rates of absorption • Occurred even when administer in the same vehicle more than once • Sesame Oil based Administration • Oral THC bioavailability: 10-20% • Men ingested 20 mg • Women ingested 15 mg • Plasma Peak at 4-6 hours, but were considered over estimated because of radioactive labeling not being subject to only THC and extending to its metabolites

Dr. Merrill Norton,Pharm.D., D.Ph., ICCDP-D and Caitlin Payne, Research Assistant 161

Vaping

• Absorption • vaporizers reported the onset of effects more rapidly with pure THC (mean 2.5 min) than herbal cannabis (mean 6.5 min) • vaporizer resulted in higher plasma concentrations of THC compared to smoked marijuana at 30 and 60 min at each strength • Technique • heating cannabis to a temperature between 180 and 2001C, it is possible to vaporize the cannabinoids that reside on the trichomes on the surface of cannabis flowers and leaves, while avoiding combustion • Thought on safety/delivery • volatizes components such as THC, CBD, and terpenes, but with significant reduction of pyrolytic byproducts • release substantial • amounts of the THC while producing no measurable amounts of the benzene, toluene, and naphthalene, which are generated when marijuana is smoked • vaporizer to inhale some form of pure THC (likely dissolved in alcohol or another solvent)

Hazekamp, A., W are, M ., M uller-Vahl, K., Abram s, D., Grotenhermen, F., 2013, The medicinal use of cannabis and cannabinoids--an international cross-sectional survey on administration forms, Journal of Psychoactive Drugs, 45(3), p. 199-210

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Dabbing

• Inhalation of a concentrated tetrahydrocannabinol (THC) product created through butane extraction • Blasting - pass butane through a steel or glass tube packed with dried cannabis trimmings - THC and other hydrophobic compounds in the plant’s trichomes dissolve into the butane - butane-THC solution leaves the tube through filter and is collected in a dish or tray - butane evaporates and leaves resins that can have THC concentration up to 80%

Transdermal Drug Delivery

Human Skin Structure

Waterproof “horny” outer layer, enriched in ceramides, so only fat soluble drugs penetrate Needs to be somewhat water soluble to penetrate the water-rich dermis and blood vessels Drug Penetration Depends on “Greasiness” lidocaine Efficient trans-dermal testosterone absorption generally hydrocortisone requires a Log P of 1.5-4 nicotine THC/CBD Log P ~ 5.5

(a measure of greasiness)

New Types of Concentrates

• Kief • Water Hash • CO2 Oil • Butane Hash Oil (BHO) • Rosin

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Concentration: Kief

• Also known as dry sieve (sometimes “dry sift”) hash, kief is the simplest of concentrates. Kief is composed of the trichomes (the crystalline structures coating the outside surface of the flowers) broken away from the dried plant material, usually via specialized filtering screens and a little elbow grease. Kief is generally considered a lower-quality extract, but some top-flight extractors can produce an extremely clean and flavorful product using this method. THC content can range from 20 percent to 60 percent. This process at its highest level yields nothing but the largest, most perfect trichome gland heads and none of the gland stems, plant matter, etc. that generally clouds the quicker, lower-quality kief extractions. While it is certainly available in Colorado dispensaries, compared to three years ago, it is much harder to find because of the prevalence of solvent extracts and the low return that it provides to commercial growers.

Concentrates of Water Hash

• There are various techniques used in the production of water hash, and the resulting products have many forms (bubble hash, solventless wax, ice wax, among others). The basic principle is this: plant material (either dry or fresh- frozen generally) is mixed with cold water and ice, then agitated manually or mechanically in order to break off the now-brittle trichome heads. This solution is then filtered through specifically-sized screens to remove anything undesirable, leaving behind a relatively pure finished product that typically tests between 50 percent and 80 percent THC. The most common way that water hash is extracted is using a series of microscreen fabric bags (generally referred to as “bubble bags”) which remove various grades of product according to the size of particles they allow through.

Concentrates of CO2 Oil

• This variety of extract is created using carbon dioxide compressed at high pressures until it becomes what is known as a “supercritical fluid,” which then is able to strip the essential oils of the cannabis plant much like hydrocarbon solvents. CO2 oil is generally a loose, orange-tinted oil that can be either clear or opaque depending upon the finishing processes used after extraction, and THC content tests between 50 percent and 75 percent. The appeal of this method for many is that it is non-flammable and contains no chemical solvents. The machines required to do CO2 extractions at any kind of commercial scale can cost hundreds of thousands of dollars.

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Concentrates of Butane Hash Oil (BHO)

• Perhaps the most common type of extract on the market, BHO has a variety of names (wax, shatter, crumble, oil, errl, honeycomb, moon rock, nectar, etc.) but like water hash, the basic principles of extraction are the same across all of them, with the variations in appearance and texture mostly coming in finishing processes. To make a butane concentrate, butane is pressurized in a vessel and washed over plant material (usually dry, but sometimes fresh-frozen — more on that below), then the resulting solution is collected. The hashmaker must remove any residual solvent from this solution, so the next step generally is applying heat (butane has a low boiling point) and vacuum (which lowers the boiling point further) in order to make this process easier and faster while retaining the highest amount of flavorful terpenes and cannabinoids in the finished product. BHO generally tests between 60 percent and 90 percent THC, making it perhaps the strongest concentrate on the mainstream market.

Concentrates of Rosin

• The newest and hottest type of extract on the scene right now, rosin is extracted from either dried buds, trim, or lower-grade water hash/kief. What is unique about rosin is that it can be made with nothing more than a standard hair straightener, parchment paper and some hand-applied pressure. When the material is smashed and heated quickly between the parchment sheets, it extrudes some of the essential oils present in the plant, resulting in a golden shatter or oil-like extract that looks similar to pressed high-quality water hash or even solvent-extracted shatter. Rosin is a fairly recent development, so its availability in dispensaries is still somewhat limited, as is data about its potency; but early reports on some rosin extracts have showed numbers between 50 percent and 70 percent THC, similar to that of high-quality water hash.

Colorado Marijuana Analysis – March 2015

• Denver lab analyzed more than 600 samples of bud provided by certified growers and sellers • average THC level was 18.7%, and some retail pot contained 30% THC or more • Little or no cannabidiol (CBD) —the average CBD amount: 0.1% • Recall: CBD lacks detectable psychoactivity and instead has anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform effects – the “medical” in medical marijuana.

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Adverse Drug Effects( ADES)

Memory

•Memory • persistence of learning over time via the storage and retrieval of information

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Memory • Encoding • the processing of information into the memory system • Storage • the retention of encoded information over time • Retrieval • process of getting information out of memory

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The Modal Memory System

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Stage 3: Long Term Memory

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Canadian Study on ADEs • Canadian Medical Association • Products include Sativex, Marinol, Nabilone, and leaf Marijuana • 321 articles • N= 4779 Adverse events reports (4515 reported as non serious) and 164 reported as serious • 15 deaths reported • Not all studies reported ADEs • Serious ADEs include respiratory, renal, cardiac, infectious disease

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Withdrawal Time Course

Total Sum W ithdrawal

Cannabis

Day

NSW Drug and Alcohol Withdrawal Clinical Practice Guidelines. Mental Health and Drug & Alcohol Office, NSW Department of Health, Australia 2008 Time-course of the DSM-5 cannabis withdrawal symptoms in poly-substance abusers Hesse and Thylstrup BMC Psychiatry 2013, 13:258

Symptoms of Cannabis Withdrawal

Withdrawal symptom % (n) subjects Onset after quitting Peak intensity reporting (days) (mean [SD]) (mean [median]) Craving for cannabis 59.4% (228) 4.4 (0.9) 4.4 (5.0) Sleep difﬁculties 50.5% (194) 2.6 (4.9) 3.8 (4.0) Insomnia 48.7% (187) 2.7 (5.0) 3.8 (4.0) Feeling angry and/or aggressive and/or 45.6% (175) 3.0 (5.5) 3.9 (4.0) irritable Feeling anxious, “nervous” 38.5% (148) 3.4 (6.5) 3.6 (3.0) Change in appetite 36.4% (140) 3.7 (5.9) 3.9 (4.0) Feeling sad, depressed 34.4% (132) 4.0 (6.7) 3.7 (4.0) Feeling angry and/or aggressive 33.9% (130) 2.8 (5.4) 3.9 (4.0) Feeling irritable, “jumpy” 29.4% (113) 3.3 (6.1) 3.7 (4.0) Feeling angry 28.9% (111) 3.1 (5.7) 3.9 (4.0) Physical symptom 25.3% (97) 3.1 (5.0) 3.6 (4.0) Feeling restless 21.9% (84) 2.8 (4.4) 3.7 (4.0) Feeling aggressive 20.1% (77) 3.6 (5.6) 3.8 (4.0) Weight loss and/or decreased appetite 20.8% (80) 4.9 (8.1) 3.5 (4.0) Increased appetite 20.8% (80) 3.3 (6.1) 4.0 (4.0) Decreased appetite 17.4% (67) 4.0 (7.3) 3.6 (4.0)

*Diagnostic criteria for cannabis withdrawal syndrome. Gorelick, D.A., et al (2012). Drug and alcohol dependence 123, 141-147.

Opioid Sparing

Effect of Cannabis Use in People With Chronic Non-Cancer Pain Prescribed Opioids: Findings From a 4-year Prospective Cohort Study. Campbell et al 2018 Lancet Public Health; 3:e341-e350.

• Prospective observational study to investigate cannabis use in people with chronic pain prescribed opioids, examined reasons for use, perceived effectiveness and potential opioid-sparing effects.

• Results: Cannabis use was common (24% over 4 yr period). • Cannabis users had slightly increased risk of greater pain score • No evidence of improved patient outcomes. • No evidence of opioid sparing.

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Neuropathic Pain

Cannabis-Based Medicines for Chronic Neuropathic Pain in Adults. Mücke M et al 2018 Cochrane Database Syst Rev. Mar 7;3:CD012182

Review of 16 studies / 1750 participants. 2 to 26 weeks long, • Sativex/nabiximols (THC:CBD spray (10 studies) • nabilone ( 2 studies), • inhaled herbal cannabis (2 studies) • dronabinol (2 studies). • Modest increase in # of people achieving >30% pain relief (39% vs 33%) NNT 11, (1586 participants, 10 studies, moderate quality evidence). • Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% vs 29%) • Psychiatric disorders occurred in 17% vs 5% using placebo NNTH 3, 1304 participants, 9 studies, low-quality evidence).

Opioids and Cannabinoids: Delight or Dilemma for Chronic Pain Management Summary • Use of opioids for chronic pain syndromes are NOT recommended unless VERY close supervision is applied to patient care; • Increased dosages of opioids for cancer survivors is on the rise-close supervision required; • At the present time, the latest medical studies indicate that neither THC or CBD preparations provide adequate pain reduction for severe chronic non cancer or cancer pain; • Much more research is required before an appropriate substitution of medical cannabinols for opioids; • Most experts will support the placebo effect of cannabinols in place of opioids.

Questions???????

Dr. Merrill Norton,Pharm.D., D.Ph., ICCDP-D and Caitlin Payne, Research Assistant 184