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Home , Dronabinol, Hash oil

3/21/18

The Psychopharmacology of Substance Use Disorders:

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

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1 3/21/18

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http://www.lexisnexis.com/Communities/cfs-file.ashx/__key/ communityserver-blogs-components-weblogfiles/ 00-00-00-00-22/1641.potmap.jpg

2 3/21/18

Georgia Marijuana Act

! “Haleigh’s Hope Act” signed into law in April 2015 by Governor Nathan Cancer Deal Crohn’s disease ! Allows for possession of up to 20 Lou Gehrig’s disease ounces of oil following a Mitochondrial physician order if a patient suffers from 8 serious medical conditions disease Multiple sclerosis ! Oil must not contain more than 5% THC Parkinson’s disease ! Georgia’s medical marijuana law Seizure disorders does not legalize the production Sickle cell disease or sale of marijuana, it simply decriminalizes its possession by http://www.georgiacannabis.org/obtain-medical-marijuana/certain qualified individuals. http://www.cnn.com/2015/04/16/us/georgia-medical-marijuana-bill-signing-haleigh-cox/ http://www.ajc.com/news/news/medical-marijuana-bill-georgia-facts/nkwWM/

Legal Marijuana* *According to the Federal government

! Investigational New 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 ! (schedule III) and (schedule II) ! Treatment of nausea and vomiting associated with cancer ! Treatment of associated with weight loss in patients with acquired immune deficiency syndrome (dronabinol) ! (not FDA approved) ! Symptomatic relief of spasticity in adults with multiple sclerosis ! Symptomatic relief of in patients with MS ! Intractable cancer pain

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

3 3/21/18

Latest News Concerning Marijuana

! From the National Epidemiologic Survey on and Related Conditions (NESARC) ! Pass users of marijuana 2.2 times greater odds ratio to use prescription ; ! Users were 2.6 times greater odds of initiating Rx medication misuse, using without appropriate medical supervision or obtaining medication illegally

! http://ajp.psychiatryonline.org/doi/abs/10.1176/ appi.ajp.2017.17040413

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 increase with use and tolerance.

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

4 3/21/18

News

! More Americans are using marijuana, according to a new government report. About 8.4 percent of Americans ages 12 and older were current users of marijuana last year, up from 7.5 percent in 2013. The percentage of teens ages 12 to 17 who smoke, drink or use prescription nonmedically has fallen, Health Day reports.

New Products for 2018

5 3/21/18

The Two Tales of Marijuana: Medicine or Menace

Psychoactive (Personal) vs Non- Psychoactive( Medical)

Cannabinoids

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

6 3/21/18

" Delta-9- (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

O

Chemical constituents of

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

7 3/21/18

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

15

Cannabis Plant Anatomy

• Cannabinoid Concentration – 30,000 cannabis preparations confiscated in the U.S. between 1980 and 1997 were • Average Concentrations – 3.1% THC – 0.3% CBD – Influencing Factors • Plant sex, age/ developmental stage, environment, genetic makeup • Medical species are grown to produce similar levels of THC and CBD • Sinsemilla is derived from the unpollinated female cannabis plant – preferred for its high THC content (up to 17% THC) • Concentrations of cannabinoids in the body (parent or metabolite) are dependent use and dose

P: https://www.leafly.com/news/cannabis-101/cannabis-anatomy-the-parts-of-the-plant National Highway Traffic Safety Administration, Cannabis / Marijuana ( Δ 9 -Tetrahydrocannabinol, THC), 2012, and Human Performance Fact Sheets, http://www.nhtsa.gov/people/injury/research/job185drugs/cannabis.htm , (August 3, 2015)

8 3/21/18

Typical Marijuana Preparations

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

9 3/21/18

Cannabinoids

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

Cannabinoids • THC – psychoactive, , increased reaction time, loss of memory/ cognitive functioning decreases, clearance half-life of less than 30 minutes and is not detectable in urine • CBN – Pain relief, Anti-insomnia, Promotes growth of bone cells, Antibacterial, Anti-inflammatory, Anti-convulsive, Appetite • CBD – may modify THC effects, inhibits conversion of THC to 11-OH- THC (CYP450), formation of CBD from THC does not occur by heat from smoking nor by human metabolism, blocks anxiety and psychological side effects produced by THC intake • THC-COOH – Lipid soluble component (metabolite), can be stored in cells for weeks to months, found in blood and urine, typically appears in the urine within 60 minutes, but can take as long as 4 hours, presence of the major THC-COOH >LOQ indicates exposure to THC within 3 days after a single use, to approximately 30 days in Marijuana Δ9-Tetrahydrocannabinolheavy chronic (THC), 2015, users Mayo Clinic: Drugs of Abuse Testing, http:// www.mayomedicallaboratories.com/test-info/drug-book/marijuana.html (August 10, 2015) Huestis, M. 2009, Human Cannabinoid Pharmacokinetics, National Institute of Health: Chem Biodivers, v. 4(8), p. 1770-1804.

10 3/21/18

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

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 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

11 3/21/18

THC-Pharmacokinetics Body to Drug – Absorption A. Inhalation/Smoking

90% of THC in blood circulates in plasma and rests in RBCs

Delta-9-THC is detectable in plasma within seconds after the first puff

Peak plasma concentration attained within 3 – 10 minutes

Bioavailability varies according to depth of inhalation, puff duration, and breath-hold

systemic bioavailability is ~23 – 27% for heavy users and 10 – 14% for occasional users

Maximum THC plasma concentration is observed 8 minutes after onset of smoking

Delta-9-THC plasma concentration rapidly decreases to 1 – 4ng/mL within 3 – 4 hours

THC: Pharmacokinetics – Absorption

B. Oral Ingestion

relatively slower systemic absorption: 1 to 2 hours but can be delayed by a few hours

extensive liver metabolism reduces oral bioavailability of THC by 4 – 12%

maximum THC plasma concentration 4.4011ng/mL for 20mg and 2.7 – 6.3ng/mL for 15mg

12 3/21/18

**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

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 from irritation • What – Honey Oil, Wax, • How – Using burning techniques and to rid plant and plant resins of CBD – pure THC preparations may be the presence of residual solvents (e.g., ) 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)

13 3/21/18

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/

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 28 Assistant

14 3/21/18

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 29 Assistant

Medical Marijuana Standards

15 3/21/18

What is in ?

www.fullspectrumlabs.com Accessed 07/18/2011

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 disease Dystonia Nabilone No effect Dyskinesia Nabilone ↓ Dyskinesia Tremor Δ9-THC No effect Cancer Pain Sublingual THC, CBD Phase III trial in progress Postoperative pain Pain IM ↓ pain, but less effective than existing therapies

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

16 3/21/18

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 ↓ 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)

Pharmacology

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Drug Interactions • – , , etc • increased hypertension • tachycardia • cardiotoxicity. • – 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)

18 3/21/18

Cannabidiol : CBD

Cannabinoids

Delta-9-THC “ACTIVE” CBD “INACTIVE

Charlotte

! Charlotte is a little girl from with Dravet syndrome

! Frequent bouts of febrile and afebrile status epilepticus

! Failed multiple medications: ◦ Levetiracetam, , topiramate, zonisamide, , 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/

19 3/21/18

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

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

Parental reporting of response to oral cannabis 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

20 3/21/18

Pharmacology(2018)

• 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.

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, , anti- nausea, anti-emetic, anti-psychotic, anti- ischemic, anxiolytic, and anti-epileptiform effects.

21 3/21/18

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

22 3/21/18

Cannabidiol (CBD) Absorption

• Smoked/inhaled • Average Bioavailability: 31.13% • Intravenous Administration (up to 72 hours post dosing) – Plasma Clearance: 960−1560 ml/min • Oral Application (40mg of CBD) – Blood Concentration: 1.1−11 ng/ml • 1 h after dose chocolate cookies – CBD concentrations of 0.30−2.57 ng/ml • 1 h after oral intake of 5.4 mg of CBD , remained detectable for 3−4 h after • Following administration of equivalent amounts of THC and CBD, lower plasma concentrations of CBD were always observed • Studies suggest: – Identification and quantification of CBD could be an additional proof of cannabis exposure – Could improve interpretation of THC effects considering the potential ability of CBD to modify THC effects

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

Cannabidiol (CBD) Metabolism • Significant first-pass effect – Unlike THC, a large proportion is excreted unchanged in the feces • Co-administration of CBD with THC did not significantly impact THC or THC metabolite kinetics, including: – the total clearance, – volume of distribution – terminal elimination half-lives • CBD only partially inhibited the hydroxylation of THC to 11-OH-THC catalyzed by CYP 2C – Study based on concentration vs time curves, ratios of max. average concentrations, and AUC values of: • 11-OH-THC/THC • THC-COOH/THC • THC-COOH/11-OH-THC

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

23 3/21/18

Different Routes of Administration and the Effect on Plasma Concentrations

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

Intravenous Route- Research primarily How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆9- Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to Paranoia Daniel 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+

24 3/21/18

Edibles

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 50 Assistant

25 3/21/18

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 , toluene, and naphthalene, which are generated when marijuana is smoked – vaporizer to inhale some form of pure THC (likely dissolved in alcohol or another )

Hazekamp, A., Ware, M., Muller-Vahl, K., Abrams, 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

26 3/21/18

Dabbing

Inhalation of a concentrated tetrahydrocannabinol (THC) product created through 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%

New Types of Concentrates

• • Hash • CO2 Oil • Butane Hash Oil (BHO) •

27 3/21/18

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.

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)

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.

28 3/21/18

Concentrates of CO2 Oil

• This variety of extract is created using 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.

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.

29 3/21/18

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.

30 3/21/18

Other Administrations • Routes – Oromucosal • Sativex® is administered sublingually to avoid first-pass metabolism by the liver. Sativex® is approved in for the treatment of neuropathic pain associated with multiple sclerosis, and in three European countries for a number of indications. – Rectal • THC-hemisuccinate provided the highest bioavailability of 13.5% (Marinol suppository) • bioavailability of the rectal route was approximately twice that of the oral route • THC did not accumulate in the blood following 10−15 mg daily doses • administration of 2.5−5 mg of THC produced maximum plasma concentrations of 1.1−4.1 ng/ml within 2−8 h. – Transcutaneous • mean steady-state plasma concentration of Δ8-THC was 4.4 ng/ml within 1.4 h, and was maintained for at least 48 h • Permeabilities of CBD and CBN were found to be 10-fold higher than for Δ8-THC • Low abuse potential due to slow delivery of THC to the brain – Intravenous • THC produced schizophrenia-like positive and negative symptoms and euphoria, and altered aspects of cognitive function – Acute paranoia, panic, hypotension, withdrawal, behavior and cognitive defects (endogenous psychosis)

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

Adverse Drug Effects( ADES)

Dr. Merrill Norton,Pharm.D., D.Ph., ICCDP-D and Caitlin Payne, Research 62 Assistant

31 3/21/18

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

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

32 3/21/18

COLORADO STANDS OUT AS THE ONLY STATE THAT IS A TOP CONSUMER OF ALL FOUR SUBSTANCES.

MORE DEATHS IN CO FROM DRUG OVERDO SES THAN FROM AUTO CRASHES !

MARIJUANA

" (also ) " Plant material - stems and leaves " Trichomes - resin glands on leaves and buds " Buds – represent the flowering stage " Covered with trichomes " Contain the most drug

33 3/21/18

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 6 4.9 PERCENT PERCENT 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 ElSohly, et al. Biological Psychiatry 79:613 (2016) ElSohly, et al., Journ of Forensic Sci 45:24 (2000)

AS ADVERTISED IN CANNAPAGES COUPON BOOK

34 3/21/18

MARIJUANA IS NATURAL; THEREFORE INHERENTLY GOOD!

NOT SO FAST!!

• Many herbals are very toxic – Castor Bean - produces ricin (ricin equivalent to a few grains of salt will kill a person) – Poison oak – Poison Ivy – Fox glove – Oleander – Rhubarb Leaves – Hemlock

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Industrial and the Agricultural Act of 2014 • Industrial hemp - variety of the cannabis plant for industrial purposes (e.g., fiber and seed). THC less than 0.3 % dry weight • Federal law applies to activities associated with industrial hemp. • Pilot programs allowed if sanctioned by a State Agency – Must be registered – Certification of site – Persons authorized to conduct research or institution of higher education • The 2014 Act did not remove industrial hemp from the list of controlled substances. • Federal Food, Drug, and Cosmetic Act and the CSA continue to apply to industrial hemp-related activities. • No transport across state lines

Federal Register, Vol. 81, No. 156, 53395. August 12, 2016

CANNABIMIMETICS () • Some mimic the effects of THC – others are just toxic • Sold over the counter in some markets as – Spice – K2 – Incense • Youth think they are harmless because of availability – NOT the case! • Hundreds have been made by pharmaceutical scientists looking for cannabinoid medicines e.g., Dr. J.W. Huffman of Clemson University – published syntheses of many cannabimimetics

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CANNABIMIMETICS

• All cannabinoid-like synthetics are DEA Schedule I if they bind to the CB1 receptor in brain • Cannabimimetics are defined by this interaction with the brain receptor • This classification of a group of drugs by their effect is unusual for DEA • These drugs won’t be discussed other than to say they are generally toxic with adverse effects

USE OF CANNABIS

• 1960’s use – low THC percent (a few percent) – Generally Smoked – Some use of – containing concentrated drug (trichomes) • Today! (Gallup Poll, July 2016) – 2013 -- 7 % of U.S. Adults current users – 2016 -- 13 % of U.S. adults current users – More than 40 % have tried – About 19 % of young adults are currently using – Using stronger marijuana and different delivery methods – Past month use 18 – 25 Year Olds • Colorado 31.24 % • National Average 19.3 % (SAMHSA – National Survey on Drug Use and Health)

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THC – PREPARATION AND PRODUCTS • Each grower has variations in potency and content • The effect and metabolism of marijuana varies with the method of use – Inhalation • Smoked • Vaped • Dabs – Edibles (oral) • Edibles have drug effects and metabolism VERY different than THC by inhalation • Generally, in non-tolerant individuals, doses of 25mg THC and higher cause substantial drug effects and cognitive impairment

SMOKING OF MARIJUANA

• Marijuana smoke contains same carcinogens and toxins as (Albertson, FP Essent 2016 Feb;441:11-7) • Fewer marijuana cigarettes per day may reduce risk of cancer • Respiratory studies – Chronic cough and bronchitis – Airway obstruction – Cellular inflammation • Cancer studies have mixed results • CA classifies marijuana smoke as carcinogen • A recent animal study shows significant cardiovascular effects of second hand smoke from marijuana – but not due to the THC (J Amer Heart Assoc. 2016)

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THC VS. TOBACCO THE NEXT “BIG TOBACCO” • Cigarette smoking is the leading cause of preventable disease and death in the , accounting for more than 480,000 deaths every year, or 1 of every 5 deaths

• More than 16 million Americans live with a smoking-related disease

• Current smoking has declined from nearly 21 of every 100 adults (20.9%) in 2005 to about 17 of every 100 adults (16.8%) in 2014

• Marijuana use is approaching tobacco use (19 % of young adults)

*Current smokers - persons who reported smoking at least 100 cigarettes during their lifetime and who, at the time of survey, reported smoking every day or some days. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/

VAPING – Recent Trend In Smoking • E-CIGS (vaping) - alternatives to traditional cigarettes – delivery device for other licit or illicit drugs – Reduces odor, hard to tell what is being smoked – Heats liquid to around 200 degrees C. • E-LIQUIDS CONTAIN: , water, propylene glycol, glycerin, flavoring and coloring agents, and preservatives (benzaldehyde) • THC – Most common illicit substance used as e-liquid – also meth, synthetic cannabinoids, and I suspect opiates • Long term toxicity NOT known! Many Health concerns • Fires, explosions and burns have resulted from e-cig use • December 2015 – 47 states banned sales to minors, – 8 regulated the sales of e-liquids – 7 banned in public places.

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USE OF THC

• THC does not dissolve well in water • THC needs to be activated by heat – Eating raw plant materials has little effect • A baked or cooked edible will produce effect; however, delayed - not immediate high • Smoking, vaping, dabs all get THC directly to lungs – very quickly – and immediately into blood stream • Effect based on dose taken and experience of user • CBD is generally taken as a solution – dissolved in oil or a solution of some type.

EXTRACTS • This is made especially to extract in home or apartment – Wax – BHO (Butane Honey Oil) • Results in extraction lab explosions – homes, apts • Can destroy homes and cause personal injury • In the first half of 2014 there were 27 injuries.

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EXTRACTS

RESULTS

For users that do not want to pay the $400 plus per ounce for shatter – they go their own way!

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APEKS SUPERCRITICAL CO2 EXTRACTION

Company Advertisement On Youtube Shows How To Get A 99% THC Product!!! (Glass Shatter)

This is the SAFE, but expensive, way to do an extract.

THC and CBD

• THC – Stored in fat tissue in body. Release from fat determines elimination from body • THC – metabolizes to 11-hydroxy-THC and then to THC acid (used to clear from body) • THC and 11-hydroxy-THC - psychoactive – produce euphoria and cardiovascular effects • CBD – Not psychoactive. Currently being illegally produced and marketed. Actual content uncertain. Not approved as drug for human administration

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Cannabidiol (CBD)

• Not Listed on DEA Schedule • Treated as Schedule 1 because CBD is naturally occurring constituent of marijuana • No currently accepted medical use in U.S. • Charlotte’s Web Oil – currently being used by parents to treat children with intractable seizures – Controlled studies must be completed with known composition of drug, dose, purity, type of seizure being treated and control for placebo effect • Label accuracy in edible products is poor (Vandrey et al., JAMA, Research Letter, June 23 2015)

HOW THC AND CBD WORK

• THC – CB1 – Euphoria CB2 – Psychoactive – Analgesic – Reduces muscle spasms – Reduces nausea – Stimulates appetite • CBD – Anticonvulsant CB1 – Analgesic CB2 – Anti-inflammatory – Neuroprotective – Immune modulation

• Effects of both are through binding to receptor sites in the brain

• There are certainly proposed beneficial effects of THC and CBD as pharmaceutical medications

Cascio and Pertwee (2014); Pertwee and Cascio (2014); Friedman and Devinsky (2014); Blair et al. (2015)

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MEDICAL MARIJUANA

• 8/12/2016 DEA published decision to retain Marijuana as Schedule I (no approved medical use.)

• Medical Marijuana – use of the unprocessed plant or extract as a medication.

• DEA did very comprehensive review of science! – Marijuana has a high potential for abuse – Marijuana has no currently accepted medical use in treatment in the U.S. – Marijuana lacks accepted safety for use under medical supervision

• Medical marijuana is not medications from Cannabis

Federal Register /Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 53689

IS MARIJUANA MEDICINE?

• Drug chemistry must be known and reproducible • Must have adequate safety studies • Must prove efficacy with well controlled studies • Must be accepted by qualified experts • Scientific evidence must be widely available

• Marijuana does not meet any of the five requirements

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CANNABIS MEDICINES • Marinol (Dronabinol) – actual THC; approved – Used to treat nausea and increase appetite • Sativex (THC and CBD) – UK; being studied for treatment of MS • Epidiolex (CBD) – UK; 2014 granted fast track status for studies on Childhood epilepsy in U.S. • Cesamet (Nabilone) – similar to THC but not identical; approved (actually cannabimimetic) – Used for nausea and vomiting following chemotherapy • How many of you would choose a medication made by your neighbor in a garage over that made and tested by a pharmaceutical company?

MEDICAL RESEARCH

• Marijuana is available for research • A quick search for “marijuana” through PUBMED produced over 24,000 medical/ scientific citations • Controlled Substances Act allows for bona fide research – FDA approves the study – DEA ensures appropriate protections are in place to meet the CSA. • Research has been ongoing for 50 years

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FEDERAL MARIJUANA GROW FACILITY (For Research Purposes)

For the past 40 years, Dr. ElSohly of the University of Mississippi has provided a sufficient supply of marijuana to support research efforts.

EFFECTS OF CANNABIS

• Cognitive effects – little controversy about driving impairment. • THC and alcohol results – greater effect than each drug alone. • About 9 % of users become dependent • Withdrawal include anger, aggression, anxiety, cravings, disturbed sleep. Symptoms may persist

Albertson, FP Essent 2016 Feb;441():11-7

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BRAIN ACTIVITY BY “PET”

Chang And Chronicle. Neuroscientist 13(5):422–432, 2007; (Volkow)

CANNABIS HYPEREMESIS SYNDROME • Syndrome is often un-recognized. • Features: – Current heavy cannabis use – Abdominal Pain – Recurrent nausea and intractable vomiting – Standard treatment fails to stop nausea and vomiting – Compulsive hot baths or showers for relief (very important in diagnosis) – May take weeks to resolve when cannabis stopped • ER visits for hyperemesis have doubled in CO following liberalization of marijuana use. (Kim, et al., Acad Emerg Med. 2015. 22:694-9) • Remission requires abstinence

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SPORT

• World Anti-Doping Agency prohibits all cannabinoids and cannabimimetics in-competition for Olympic sports – Safety – Decision making and inhibitions • NCAA prohibits all cannabinoids and cannabimimetics for collegiate athletes

• Professional sports prohibit marijuana. For example the NFL has two programs prohibiting substances: – Substances of Abuse (includes marijuana) – Performance enhancing substances

• Marijuana is not performance enhancing and certainly may create safety and decision risks.

• There was a recent admission by NFL player Eben Britton that he played his “best games stoned”. Suspended in 2015 – has not played since – obviously having not made sound decisions concerning career

TRUTH

• Gateway Drug - future use of other illicit drugs up 7.8 times • Increased failure rate in school - 37 % as likely to finish high school and obtain degree • Addictive – later cannabis addiction up 17 fold • Increased suicide attempts – up 6.8 times • All studies controlled and compared to those who had never used cannabis (Lancet Psychiatry Sep 2014, 1: 286-293 And JAMA Psychiatry 2016, 73:388)

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FEDERAL MANDATED DRUG TESTING • DoD started program in 1982 – Enlisted had 50 % use in last 30 days – Now a few percent have use in last 30 days • Federal interest began in January 1987 when two railroad engineers shared a – Operating three 130-ton locomotives – Missed a signal light – Collided with an Amtrak train • Three Amtrak passenger cars were destroyed • 16 people died • 174 were injured.

Addiction = Depression in 2018

BDNF

cAMP

CREB

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Memory

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

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

Stage 3: Long Term Memory

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Explicit Memory

• Explicit memory involves the processes used to remember specific information which can be declared

• Episodic memory is personal

• Semantic memory involves knowledge of facts

Implicit Memory

• Implicit memory is the pervasive process by which people show without awareness that they are remembering something

• Implicit memory does not require attention and is automatic

• Consider “procedural memory”

• Repetition priming

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Retrieval • Recall – retrieve information learned earlier • Recognition – identify items previously learned

Figure 3.1 First messengers carry information between neurons; second messengers carry the signal into the neuron

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Impact of Addiction

■ MARIJUANA:

16 y.o. Normal 2 year history of daily abuse underside surface view of prefrontal and temporal lobe activity © 2006 Amen Clinics Inc

3/21/18 Dr. Merrill Norton 108 Pharm.D.,D.Ph.,ICCDP-D

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Withdrawal According to the DSM 5

• A. Cessation of cannabis use that has been heavy and prolonged • B. 3 or more of the following develop within several days after Criterion A • 1. Irritability, anger or aggression • 2. Nervousness or anxiety • 3. Sleep difficulty (insomnia) • 4. Decreased appetite or weight loss • 5. Restlessness • 6. Depressed mood • 7. Physical symptoms causing significant discomfort: must report at least one of the following: stomach pain, shakiness/tremors, sweating, fever, chills, headache

Dr. Merrill Norton,Pharm.D., D.Ph., ICCDP-D and Caitlin Payne, Research 109 Assistant

Questions???????

Dr. Merrill Norton,Pharm.D., D.Ph., ICCDP-D and Caitlin Payne, Research 110 Assistant

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