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Douglas E. Masini, EdD, RPFT, RRT-ACCS, CSE (BRPT), AE-C, FAARC, FCCP

Chair, Diagnostic and Therapeutic Sciences

Professor and Program Coordinator, Respiratory Therapy

Armstrong State University

Clinical Assistant Professor, Internal Medicine,

Mercer University College of Medicine

Savannah, Georgia

2017 Focus Conference Poughkeepsie, NY

A JOINT EFFORT: MEDICAL PROFESSIONALS AND CITIZENS CONFRONT

LEGALIZED MEDICAL MARIJUANA.

The opinions expressed in this presentation are Doug Masini’s and do not represent the policies or opinions of Armstrong State University or Mercer

University College of Medicine. Product brand/generic names are used to illustrate a point and are not an endorsement.

Dr. Masini declares no conflict of interest.

WARNING! This presentation discusses medicalmarijuana across the United States. Any use ofherbal marijuana or cannabinoids is a Federalcrime. Marijuana is a federal schedule 1 drug,illegal in all or most interpretations of the law.Possession of 1 ounce or more is a felony andcarries a strict penalty. This talk looks at thepresent state of research and discusses theliterature, positive and otherwise, on use ofcannabinoids in patient care. Patients mustdiscuss this information with their physician andhealthcare provider, as there are many side-effects and hazards of unsupervised use ofmedical marijuana.

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Medical marijuana gone awry.

The medical application of cannibas sativa has 5,000 years of history in folk-remedy, traditional medicine, and in the annals of complementary / alternative therapy.

My interest: 1994, adolescents who had a variety of diseases, to include autoimmune diseases such as sarcoidosis, systemic lupus, and cancer. Treatments and empirical therapy seemed to worsen or induce nausea and suppress the appetite of our young patients.

SOAPe - Anorexia, pain, weight-loss were prominent.

What is ‘medical marijuana’?The number of states studying or passing medical marijuana legislation inspired me to objectively look at what the newest literature says about many of the new cannabinoid baseddrugs and the potential impact of medical marijuana.

CASE STUDY: One of our patients was taking the cannabinoid Dronabinol® PO tablets, 2.5 mg., BID/prn, a synthetic form of the active marijuana constituent delta-9-tetrahydrocannabinol (THC) which is available by prescription and used for appetite and antiemetic. Parents and the youth self-report:Dronabinol “improved his appetite and general state-of-mind”, the drug also allowed him to bear the severe pain from his diagnosis without using daily opiates, which he felt “clouded his judgments and made him more miserable”. His improvement was carefully measured on a pain scale, and psychological well-being, in particular his self-report of his quality of life (QOL). In short, his improvement was remarkable.

How do natural and artificial cannabinoids work?

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Physiologic receptors

CB1 receptors are found primarily in the brain, specifically in basal

ganglia, limbic system (including the hippocampus), cerebellum, and in both male and female reproductive systems. CB1 receptors

essentially absent in medulla oblongata, the part of the brain stem

that is responsible for respiratory and cardiovascular functions,

with low/no risk of respiratory or cardiovascular failure.

CB1 receptors found in highest concentration in brain neurons,

coupled via G proteins, and modulate adenylate cyclase and ion channels. CB1 receptors appear to be responsible for the euphoric

and anticonvulsive effects of cannabis.

~~~~~~

CB2 receptors are found in cells of the immune system, are

coupled via G proteins, inhibit adenylate cyclase.~~~~~~

CBn receptors, characterized short isoform, CB1A. The CB1A

receptor is present in amounts of up to 20% that of CB1 and has

been shown to exhibit all the known properties of CB1 to a slightly

attenuated extent

Endogenous cannabinoid -The two known endogenous cannabinoids, anandamide

AEA (N-arachidonoylethanolamine) and 2-AG (2-arachi donoylglycerol) affect mood, appetite, pain sensation, inflammation response, and memory. Pharmaceutical industry trying to find ways of regulating AEA and 2-AG activities in order to treat mood disorders, obesity, and chronic pain.Exogenous cannabinoids -Primarily phytocannabinoids, also called natural or herbal / classical cannabinoids, occur naturally in the cannabis plant; concentrated in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odor of the cannabis plant.

http://endo.endojournals.org/content/145/12/5429/F1.expansion.html

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66 cannabinoids isolated from the cannabis plant. All classes derive from cannabigerol - type compounds and differ mainly in the way this precursor is cyclized. Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common ones are: CBG Cannabigerol CBC CannabichromeneCBL CannabicyclolCBV CannabivarinTHCV TetrahydrocannabivarinCBDV CannabidivarinCBCV CannabichromevarinCBGV CannabigerovarinCBGM Cannabigerol Monoethyl Ether tetrahydrocannabinol (THC)

cannabidiol (CBD) dronabinol (Marinol)

There are several drugs on the market that are cannabis based, along with herbal ‘medical’ marijuana. Nabilone ® is an artificial cannabinoid, similar to dronabinol, and is available in Canada, the United States, the United Kingdom and Mexico, and marketed as Cesamet ®; has similar effects of dronabinol and has been used for fibromyalgia, nightmares of post-traumatic stress disorder (PTSD), and multiple sclerosis.

Sativex ® is an oral spray composed of two cannabinoids; tetrahydrocannabinol(THC) and cannabidiol (CBD). The product is formulated as an oromucosal spray which is administered by spraying into the mouth. Each spray delivers a fixed dose of 2.7mg THC and 2.5mg CBD.

Dr. Donald Abrams, a physician and researcher at the University of California San Francisco School of Medicine, strongly believes in herbal marijuana therapy, and noted that some of the effectiveness of smoked herbal marijuana arises from themultiple cannabinoids that are liberated during combustion and made available for pulmonary deposition and absorption into the pulmonary vascular circulation after inhalation and a coached, sustained maximal inspiration (SMI).

Several study also state that cannabinoids such as dronabinol may not be as effective as inhaled herbal marijuana because it contains one isolated cannabinoid, delta-9-tetrahydrocannabinol (THC); likewise Sativex has only two cannabinoids (both THC and CBD).

CASE STUDY continued….. My primary concern at that time was that our young patient was driving, and I was concerned about the possibility of him getting a ‘driving under the influence’ (DUI) charge if he was impaired, and the proper documentation of the medical orders and appropriateness of the prescription was not apparent to the officer at the time of the infraction. My second concern was the next day when he called our home and said he

would be “…driving over to pick up

my daughter.”Goal of this talk was to investigate the legal issues of cannabis-based drugs and their therapeutic value as well as their Influence on thinking, reasoning, motor skills, and in particular, driving skills….and…I drove them to the movies.

1001309

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IMPLICATIONS OF

POSSESSION OF

MARIJUANA

State Year Passed

How Passed (Yes Vote)

Fee Possession Limit Accepts other states' registry ID cards?

1. Alaska 1998 Ballot Measure 8 (58%) $25/$20 1 oz usable; 6 plants (3 mature, 3 immature) unknown1

2. Arizona 2010 Proposition 203 (50.13%) $150/$75 2.5 oz usable; 0-12 plants2 Yes3

3. California 1996 Proposition 215 (56%) $66/$33 8 oz usable; 6 mature or 12 immature plants4 No

4. Colorado 2000 Ballot Amendment 20 (54%) $90 2 oz usable; 6 plants (3 mature, 3 immature) No

5. DC 2010Amendment Act B18-622 (13-

0 vote)* 2 oz dried; limits on other forms to be determined unknown

6. Delaware 2011Senate Bill 17 (27-14 House,

17-4 Senate)** 6 oz usable Yes5

7. Hawaii 2000 Senate Bill 862 (32-18 House; 13-12 Senate)

$25 3 oz usable; 7 plants (3 mature, 4 immature) No

8. Maine 1999 Ballot Question 2 (61%) $100/$75 2.5 oz usable; 6 plantsYes6

9. Michigan 2008 Proposal 1 (63%) $100/$25 2.5 oz usable; 12 plants Yes

10. Montana 2004 Initiative 148 (62%) $25/$10 1 oz usable; 4 plants (mature); 12 seedlings No

11. Nevada 2000 Ballot Question 9 (65%) $150+ 1 oz usable; 7 plants (3 mature, 4 immature) No

12. New Jersey 2010 Senate Bill 119 (48-14 House; 25-13 Senate)

$200/$20 2 oz usable unknown

13. New Mexico 2007Senate Bill 523 (36-31 House; 32-3 Senate)

$0 6 oz usable; 16 plants (4 mature, 12 immature) No

14. Oregon 1998 Ballot Measure 67 (55%) $100/$20 24 oz usable; 24 plants (6 mature, 18 immature) No

15. Rhode Island 2006 Senate Bill 0710 (52-10 House; 33-1 Senate)

$75/$10 2.5 oz usable; 12 plants Yes

16. Vermont 2004 Senate Bill 76 (22-7) HB 645 (82-59)

$50 2 oz usable; 9 plants (2 mature, 7 immature) No

17. Washington 1998 Initiative 692 (59%) *** 24 oz usable; 15 plants No

Medical marijuane statutes or bills…

U.S. LEGAL AND

‘DECRIMINALIZED’ MEDICAL

MARIJUANA(WHAT A DIFFERENCE TIME

MAKES!)

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Medical marijuana laws currently exist in 16 states and the District of Columbia, and require a physician’s supervision, recommendation or prescription, and an established diagnosis and medical necessity in order to legally use herbal marijuana as a therapeutic agent. Requirements

differ widely in all states, and require a physicians order, documentation, and in most cases, a user identification card that

requires a fee. Five states allow participants from other states to have marijuana reciprocity in that state.

Diagnoses and symptoms generally considered appropriate for treatment include debilitating medical conditions, cancer, glaucoma, HIV/AIDS,

hepatitis C, amyotrophic lateral sclerosis, Crohn's disease, agitation

of Alzheimer's disease, musculoskeletal, cachexia or wasting syndrome, severe and chronic pain, severe nausea, seizures,

epilepsy, muscle spasms, and multiple sclerosis, and many others diagnosis that vary state-to-state.

Decriminalization statutes Two states, Arizona and Maryland, did not

legalize marijuana but enacted language that allows someone, supervised by a physician, to possess and use it; however, in Maryland, legal actions and fines can be levied for infractions committed by users, even if medical necessity was determined.

16 States with Pending Legislation to Legalize Medical Marijuana, Jan. 25, 2012 (All or most of these states carried over legislative consideration to 2013 calendar.)

1. Alabama 2. Idaho 3. Illinois 4. Indiana

5. Iowa 6. Kansas 7. Maryland 8. Massachusetts

9. Missouri10. New Hampshire

11. New York 12. Ohio

13. Oklahoma 14. Pennsylvania 15. West Virginia 16. Wisconsin

In 2011-2013, Legislation FAILED (or died in committee) in…

Connecticut

New York Texas

Delaware

North Carolina Florida

Tennessee

Idaho Mississippi

Status of Legitimacy of Medical Use in February 2013“Modern medical research has discovered beneficial uses for cannabis in 13 treating or alleviating pain, nausea, and other symptoms associated with 14 certain debilitating medical conditions, as found by the National Academy of 15 Sciences' Institute of Medicine in March 1999.”- Medical use of marijuana is allowed in Alaska, Arizona, California, Colorado, Connecticut, the District of Columbia, Delaware, Hawaii, Maine, Massachusetts, Michigan, Montana, Nevada, New Jersey, New Mexico, Oregon, Rhode Island, Vermont and Washington.- Patients who receive a doctor's permission to possess not more than 24 ounces in a form usable for medical purposes.- A patient would also be allowed to have garden to grow cannabis that is not larger than 250 square feet.- Primary sponsors of the legislation are listed as North Carolina representatives Kelly Alexander (D-Raleigh) and Pricey Harrison (D-Greensboro).

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WHO IS CONSIDERING MEDICAL MARIJUANA…..2013 LEGISLATION AND RELATED NEWLY ENACTED LAWS:Colorado – HB 1317, HB 1318 Summary: Establishes regulations regarding the commercial production and retail sales of cannabis to those over age 21; proposes excise tax and sales tax rates for commercial production and retail sales of cannabis; tax rates must be approved by voters Status: Both measures signed into law on May 28 Kentucky – SB 50 Summary: Encourages state-sponsored hemp research; establishes regulations regarding the licensed production of hemp as an agricultural commodity Status: Became law without the Governor’s signature on April 5 Maryland – HB 1011 Summary: Establishes an independent, 12-member medical marijuana commission within the state Department of Health; the commission will request applications from Maryland academic medical centers to operate ‘medical marijuana compassionate use programs’. Status: Signed into law on May 2 LEGISLATION APPROVED BUT PENDING GOVERNOR’S SIGNATUREColorado – SB 241 Summary: Creates a program within the Department of Agriculture to regulate the commercial production of industrial hemp Status: pending Governor’s signature Hawaii – HB 668, SB 642 Summary: Transfers the administration of the state’s medicinal cannabis program from the Department of Public Safety to the Department of Public Health; increases the quantity of medical cannabis that may be possessed by qualified patients from three ounces to four ounces; increases the number of mature plants that a patient may cultivate from 3 to 7 Status: Pending signature Illinois – HB 01 Summary: Establishes a pilot program regulating the state-licensed production and dispensing of therapeutic cannabis to qualified patients. Status: Pending Governor’s signature Nevada – SB 374 Summary: Establishes rules and regulations for the establishment of up to 66 not-for-profit medical marijuana dispensaries Status: Pending Governor’s signature Oregon – SB 281 Summary: Expands the state’s existing medical marijuana program to include post-traumatic stress as a state-qualified illness Status: pending Governor’s signature Vermont – HB 200 Summary: Amends the penalty for the possession of one ounce of marijuana by a person 21 years of age or older from a criminal misdemeanor to a civil fine. Status: Pending Governor’s signatureIN CONFERENCENew Hampshire – HB 573 Summary: Establishes a statewide medical marijuana program and state-licensed dispensary systemStatus: Awaits action in Conference CommitteePENDINGHawaii – SB 472 Summary: Amends the penalty for the possession of one ounce of marijuana by a person 21 years of age or older from a criminal misdemeanor to a civil fine. Status: Approved by Senate; Voted ‘recommit’ by House; pending further action in 2014Maine – LD 1229 Summary: Asks for a statewide referendum on legalizing marijuana for adults Status: Pending House floor vote this week New Jersey – A. 1465 Summary: Amends the penalty for the possession of 15 grams of marijuana by a person 21 years of age or older from a criminal misdemeanor to a civil fine Status: Approved by state Assembly; awaits Senate action New York – A. 6716-A Summary: Equalizes marijuana possession penalties to a civil offense Status: Approved by state Assembly; awaits Senate action New York – A. 6357 Summary: Establishes a statewide medical marijuana program and state-licensed dispensary system Status: Approved by state assembly; awaits Senate action Louisiana – HB 103 Summary: Significantly reduces penalties for repeat marijuana possession offenders Status: Approved by House, awaiting Senate floor vote this week

NIDA statistics… Effects and affectShort-term effects of marijuana use include euphoria, distorted perceptions, memory impairment, and difficulty thinking and solving problems.

Statistics and Trends

In 2009, 28.5 million Americans age 12 and older had abused marijuana at least once in the year prior to being surveyed. Source: National Survey on Drug Use and Health Substance Abuse and

Mental Health Administration.

The NIDA-funded 2010 Monitoring the Future Study showed that 13.7% of 8th graders, 27.5% of 10th graders, and 34.8% of 12th graders had used / abused marijuana at least once in the year prior to being surveyed. Source: Monitoring the Future University of Michigan.

The use of ‘smoked herbal’ medical marijuana was encouraged by many sources, in spite of the fact that it is still considered a schedule I drug and violates the Controlled Substances Act of 1970. In situations covered by compassionate investigational new drug rules or state laws, the federal laws may not be enforced at that state level.

Zuurman and associates eliminated ignition and combustion, and prepared marijuana for inhalation by vaporizing the plants; they found its potency, particle size, and the potential

for pulmonary deposition to be greatly enhanced for inhalation and other therapeutic applications.

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Georgia - 1976, ex-Gov. Carter campaigns on decriminalization. Medical Marijuana Necessities Act (Controlled Substances Therapeutic Research Act), 1981; trials defunded. 2011, Georgia Medical Composite Board recruiting 5 physicians, 1 pharmacist for Patient Qualification

Review Board. No action, February, 2012.

South Carolina - South Carolina ‘Controlled Substances Therapeutic

Research Act’ of 1980. S220 medical marijuana legislation for seriously ill South Carolinians, 2007. No action, February, 2012.

Tennessee - House Bill 294 Rep. Jeanne Richardson (D-Memphis), sponsor of the Safe Access to Medical Cannabis Act, withdrew the bill after testimony on behalf of the legislation in the House Health and Human Resources Committee. Richardson agreed to withdraw the bill, and it’s companion, Senate Bill 251. The bill would have created the toughest access standards among medical marijuana states, and set up

a licensing and enrollment program for the production, distribution and dispensing of marijuana for qualifying medical conditions.

University of Mississippi, NIDA FarmIrv Rosenfeld one of last surviving legal users (enrolled in

NIDA study in 1982, continues to receive 300 cigarettes listed as a compassionate investigational new drug , IND)

http://www.youtube.com/watch?v=B1NggzEkltM&feature=player_embedded

IS SMOKING

HERBAL MARIJUANA AN ISSUE?

Cochrane studies: No conclusive studies of anydose of cannabis or medical marijuana as therapy

for any disease.

National Institute of Health, Institute of Medicine:Marijuana’s future as medicine does not involve smoking it. If

there is any future for marijuana as medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives.

There is no compelling evidence that marijuana should be used to treat glaucoma, and little evidence for treating migraine headaches.

Medical marijuana should be tried only when there is failure of all approved medications to provide relief and always under medical supervision.

Medical marijuana should be used only in short-term (<6 months’ duration) trials (with evaluation and measurement of outcomes, good and bad)(Schwartz, 2002).

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DRUG % who get addicted

after trying

Tobacco 31.9

Heroin 23.1

Cocaine 16.7

Alcohol 15.4

http://www.tobaccofreedom.org/issues/addiction

“arterialization”

Pulmonary arterialblood to pulmonary arteriole

alveoli

Alveolar-capillary membrane

Blood from right ventricle

Combustion allows for vaporization and production of stableaerosols < 1 µ

Russell MA; Jarvis M; Iyer R; Feyerabend C. Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers. Br Med J. 1980; 280(6219):972-6Pain Management from the Other Side of the mountain. ASA Journal. Available at: http://www.asahq.org/Newsletters/1997/08_97/PainMgmt_0897.htmlhttp://www.hawaii.edu/hivandaids/Cocaine_and_Tobacco_Use_and_the_Risk_of_Spontaneous_Abortion.pdf#search='cigarette%20smoking%20is%20like%20crack%20cocaine%20%20NEJMSRNT Newsletter on world tobacco research http://www.srnt.org/pubs/SRNT%20V1N3.html

To left heart and aorta

THC and products of combustion.

Cannabinoid uptake in the lungs – consider the rich vascular bed available for absorption.

To brain and systemic circulation

15th - 25th generation

Pulmonary veins

Smoked cannabis for chronic neuropathic pain: a randomized

controlled trial. Ware, MA, etal. CMAJ182(14) doi:10.1503/cmaj

Methods: Adults with post-traumatic or postsurgical neuropathic pain were randomly assigned to receive cannabis at four potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabinol) over four 14-day periods in a crossover trial. Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle, followed by a nine-day washout period. Daily average pain intensity was measured using an 11-point numeric rating scale. We recorded effects on mood, sleep and quality of life, as well as adverse events.Results: 23 participants (mean age 45.4 [standard deviation 12.3] years, 12 women [52%]); 21 completed the trial.Participants receiving 9.4% tetrahydrocannabinol reported improved ability to fall asleep (easier, p = 0.001; faster, p < 0.001; more drowsy, p = 0.003) and improved quality of sleep (less wakefulness, p = 0.01) relative to 0% tetrahydrocannabinol. We found no differences in mood or quality of life. The most common drug-related adverse events during the period when participants received 9.4% tetrahydrocannabinol were headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness and cough.

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20-Year-Long Study Finds No Decline in Lung Function for Occasional Pot Smokers By Brenda Goodman, MA, Reviewed by Laura J. Martin, MD (1-10-12)

STUDY: 5,000 young adults in four cities, for more than two decades. More than half of the people in the study reported smoking tobacco, marijuana, or both. Measured FVC and FEV1, to help doctors diagnose chronic, irreversible breathing problems like chronic obstructive pulmonary disease (COPD).RESULTS: Found no harmful effect on lung function (1 joint a day); marijuana and cigarette smokers in the study saw their lung function drop significantly over 20 years. Heavy, habitual marijuana smokers - people who smoked the equivalent of a joint a day for 50 years - found no harmful effect on lung function, but it was linked to some short-term irritation. LIMITATIONS: Study didn’t look at other possible dangers like lung cancer. Some evidence that very heavy users -- those who smoked the equivalent of a joint a day for 40 years or lit up more than 25 times a month -- might lose lung function.

Health, Education and Welfare Secretary Joseph Califano was quoted in a 1978 Time Magazine saying: "If an individual smokes three to five heavily contaminated marijuana cigarettes each day for several months, irreversible lung damage will result." He added that there is also a "risk of lung damage for individuals who use marijuana less often or in smaller amounts."

ELIMINATION OF TAR, BYPRODUCTS OF COMBUSTION AND

CARBON MONOXIDE. Donald I. Abrams, MD, UCSF professor of clinical medicine.18 individuals were enrolled as inpatients for six days under

supervision in the General Clinical Research Center at San Francisco General Hospital Medical Center.

Under the study protocol, the participants received (on different

days) three different strengths of cannabis by two delivery

methods - smoking or vaporization - three times a day.

Plasma concentrations of THC were measured along with the

exhaled levels of carbon monoxide, or CO. A toxic gas, CO served as a marker for the many other combustion-generated toxins

inhaled when smoking. The plasma concentrations of THC were

comparable at all strengths of cannabis between smoking and

vaporization. Smoking increased CO levels as expected, but there

was little or no increase in CO levels after inhaling from the

vaporizer, according to Abrams. Clinical Pharmacology and Therapeutics.

Vaporization without combustion: CBD 206.3°C (403°F), CBN 212.7°C (414°F), and

THC 149.3°C (300°F)

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Vaporizers

ISSUES WITH

CANNABINOIDS

Side effects/cautions:

- Syncope, hypotension; used with caution in pregnant patients, nursing mothers, or pediatric patients. - Potential for additive central nervous system depression if used concomitantly with alcohol or other

CNS depressants such as benzodiazepines and barbiturates. - Specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely. - Possible changes in mood and other adverse behavioral effects; should be used with caution in patients

with cardiac disorders because of occasional

hypotension, possible hypertension, syncope, or tachycardia.

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- Used with caution in patients with a history of substance abuse,

including alcohol abuse or dependence, because they may be more prone to abuse. Multiple substance abuse is common and marijuana, which

contains the same active compound, is a frequently abused substance. - Caution and careful psychiatric monitoring in patients with mania, depression, or schizophrenia, may exacerbate these illnesses. -Used with caution in patients receiving concomitant therapy with sedatives,

hypnotics or other psychoactive drugs because of potential for additive or synergistic CNS effects.

Patients also reported:

- hallucinations (seeing or hearing things that are not there);- paranoia, extreme fear;- fast heart rate;- feeling light-headed, fainting; or- unusual thoughts or behavior.Talk with your doctor if you have any of these less serious side effects:

- dizziness, drowsiness;- feeling "high";- weakness, lack of coordination;- depression, anxiety, confusion;- dry mouth;- headache, trouble concentrating; or sleep problems (insomnia).

A hazard of medical marijuana, a target for thieves in California

I will inject here that some practitioners strongly disagree with providing smoked, herbal marijuana as a therapy. As licensed practitioners, it is important to understand protection of ‘rights of

conscious’ laws and statutes in all states (excluding Alabama, New Hampshire, and

Vermont) that protect us from providing therapeutic care or medicine found to be

objectionable.

Practitioners who disagree with the provision of medical marijuana as a part of a therapeutic regimen should not fear reprisal.

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THANK YOU…QUESTIONS???

References:- Schwartz, RH Marijuana: A decade and a half later, still a crude drug with underappreciated toxicity. PEDIATRICS (109), 2 February 2002, pp. 284-289. http://pediatrics.aappublications.org/cgi/content/full/109/2/284- Medical Marijuana AMA http://www.ama-assn.org/ama/no-index/about-ama/13625.shtml- Sutter Health http://www.cpmc.org/advanced/pediatrics/physicians/pedpage-706marijuana.html- Von Sydow, K et al “The natural course of cannabis use, abuse and dependence over four years: a longitudinal community study of adolescents and young adults.” Drug and Alcohol Dependence 2001 Nov;64(3):347-61- Wu, T.C. Pulmonary Hazards Of Smoking Marijuana As Compared To Tobacco.” NEJM 1998 Feb; 318(6):347-51

- Fliegiel, et al. Tracheobronchial histpathology in habitual smokers of cocaine, marijuana, and/or tobacco. Chest 1997 Aug; 112(2): 319-326- Benson, M.K., Bentley, A.M. Lung disease Induced By Drug Addiction. Thorax 1995 Nov; 50(11): 1125-1127- Johnson, et al. Large Lung Bullae In Marijuana Smokers. Thorax 2000 April; 55(4): 340-342- Hubbard, J.R. Marijuana: Medical Implications. American Family Physician 1999 Dec; 60(9):- NHTSA Notes. Marijuana and Alcohol Combined Severely Impede Driving Performance. Annals of Emergency Medicine 2000 April; 35(4):- Dronabinol use as an anti-emetic http://www.cancerlinksusa.com/chemo/marijuana_use_in_cancer.asp- Knonoff-Cohen, H. and Lam-Kruglick, P. Maternal and Paternal Recreational Drug Use and Sudden Infant Death Syndrome.” Archives of Pediatrics and Adolescent Medicine 2001 July; 155(7):765-770- Zuurman, etal. Effect of intrapulmonary tetrahydrocannabinol administration in humans.http://jop.sagepub.com/content/22/7/707

Oz, M The endogenous cannabinoid, anandamide, inhibits dopamine transporter function by a receptor–independent mechanism J

Neurochem. 2010 March; 112(6): 1454–1464.

- NIDA website – Real teens respond to the Sara Bellum blog. http://teens.drugabuse.gov/blog/real-teens-ask-about-marijuana/

- Verena Isabell Leussink, Leila Husseini, Clemens Warnke, Erasmia Broussalis, Hans-Peter Hartung, Bernd C. KieseierSymptomatic therapy in Multiple Sclerosis: The role of cannabinoids in treating spasticity. Ther Adv Neurol Disorders. 2012;5(5):255-66.

WEBSITES:http://www.drugscience.org/States/GA/GA.pdfhttp://www.atlantaprogressivenews.com/interspire/news/2011/04/23/georgia-to-begin-medical-marijuana-research-trials.htmlhttp://www.drugs.com/sfx/marinol-side-effects.htmlhttp://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000403/http://www.psychiatrist.com/pcc/brainstorm/br591101.htm

Medications with natural or synthetic cannabinoids or cannabinoid analogs:* Dronabinol (Marinol), is ∆9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic* Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III* Sativex, a cannabinoid extract oral spray containing THC, CBD, and other cannabinoids used for neuropathic pain and spasticity in Canada and Spain. Sativex develops whole-plant cannabinoid medicines* Rimonabant (SR141716), a selective cannabinoid (CB1) receptor antagonist used as an anti-obesity drug under the proprietary name Acomplia. It is also used for smoking cessation; not available in the U.S. due to dangerous side-effects.Other notable synthetic cannabinoids include:

* CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC* Dimethylheptylpyran* HU-210, about 100 times as potent as THC* HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II.* SR144528, a CB2 receptor antagonists* WIN 55, a potent cannabinoid receptor agonist* JWH-133, a potent selective CB2 receptor agonist* Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine.Source:

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WARNING: VERY DANGEROUS artificial cannabinoids/chemicals in Spice, K2

Molecular structure: CP 47,497Molecular formula: C21H34O2

Molecular weight: 318.5 g/mol

Molecular structure: JWH-018Molecular formula: C24H23NOMolecular weight: 341.5 g/mol

Molecular structure: HU-210Molecular formula: C25H38O3

Molecular weight: 386.6 g/mol

Structure of selected synthetic cannabinoids found in ‘Spice’ products, with high affinity for cannabinoid (CB1) receptors

Molecular structure: ∆9-THC

Molecular formula: C21H30O2

Molecular weight: 314.4 g/mol

Other cannabinoid receptor agonists include substances such as oleamide —an endogenous substance that is also used in plastics manufacture — and methanandamide, both of which are structurally related to anandamide. However, the cannabinoid activity of these has been questioned. It is thought that neither methanandamide nor other arachidonyl derivatives related to anandamide would be sufficiently volatile to be smoked. Certain fluorosulfonates exhibit agonist activity at cannabinoid receptors, as does naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone, but the latter appears not to be psychoactive, at least when administered orally.

Artificial cannabinoid chemistry

Although often referred to simply as synthetic cannabinoids, many of the substances are not structurally related to the so-called ‘classical’ cannabinoids, i.e. compounds, like THC, based on dibenzopyran. The cannabinoid receptor agonists form a diverse group, but most are lipid soluble and non-polar, and consist of 22 to 26 carbon atoms; they

would therefore be expected to volatilize readily when smoked. A common structural feature is a side-chain, where optimal activity requires more than four and up to nine saturated carbon atoms. The first figure shows the structure of THC, while the others show examples of synthetic cannabinoid receptor agonists, all of which have been found in ‘Spice’ or other smoking mixtures. The synthetic cannabinoids fall into seven major structural groups:Naphthoylindoles (e.g. JWH-018, JWH-073 and JWH-398).Naphthylmethylindoles.Naphthoylpyrroles.Naphthylmethylindenes.Phenylacetylindoles (i.e. benzoylindoles, e.g. JWH-250).Cyclohexylphenols (e.g. CP 47,497 and homologues of CP 47,497).Classical cannabinoids (e.g. HU-210).

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66 cannabinoids isolated from the cannabis plant. All classes derive from cannabigerol - type compounds and differ mainly in the way this precursor is cyclized. Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common ones are: CBG Cannabigerol CBC CannabichromeneCBL CannabicyclolCBV CannabivarinTHCV TetrahydrocannabivarinCBDV CannabidivarinCBCV CannabichromevarinCBGV CannabigerovarinCBGM Cannabigerol Monoethyl Ether tetrahydrocannabinol (THC)

cannabidiol (CBD) dronabinol (Marinol)

GENERAL ASSEMBLY OF NORTH CAROLINA SESSION 2013 H 2 HOUSE BILL 813 Committee Substitute

Favorable 5/8/13 Short Title: Ban Synthetic Cannabinoids. (Public) Sponsors: Referred to: April 11, 2013 *H813-v-2*

A BILL TO BE ENTITLED 1 AN ACT TO MAKE THE MANUFACTURE, POSSESSION, SALE, USE, AND DELIVERY 2 OF ALL SYNTHETIC

CANNABINOIDS UNLAWFUL. 3 The General Assembly of North Carolina enacts: 4 SECTION 1. G.S. 90-94 reads as rewritten: 5 "§ 90-94. Schedule VI controlled substances. 6 This schedule includes the controlled substances listed or to be listed by whatever official 7 name, common or usual name, chemical name, or trade name designated. In determining that 8 such substance comes within this schedule, the Commission shall find: no currently accepted 9 medical use in the United States, or a relatively low potential for abuse in terms of risk to 10 public health and potential to produce psychic or physiological dependence liability based upon 11 present medical knowledge, or a need for further and continuing study to develop scientific 12 evidence of its pharmacological effects. 13

The following controlled substances are included in this schedule: 14 (1) Marijuana. 15 (2) Tetrahydrocannabinols. 16 (3) Synthetic cannabinoids. – Any quantity of any synthetic chemical compound 17 that (i) is a cannabinoid receptor agonist and mimics the pharmacological 18 effect of naturally occurring substances or (ii) has a stimulant, depressant, or 19 hallucinogenic effect on the central nervous system Any material, 20 compound, mixture, or preparation that is not listed as a controlled substance 21 in Schedule I through V, and is not an FDA-approved drug, drug. Synthetic 22 cannabinoids include, but are not limited to, the substances listed in sub-23 subdivisions a. through j. of this subdivision and any substance that contains 24 any quantity of the following substances, their salts, isomers (whether 25 optical, positional, or geometric), homologues, and salts of isomers and 26 homologues, unless specifically excepted, whenever the existence of these 27 salts, isomers, homologues, and salts of isomers and homologues is possible 28 within the specific chemical designation:designation. The following 29 substances are examples of synthetic cannabinoids and are

not intended to be 30 inclusive of the substances included in this Schedule: 31 … 32 j. Tetramethylcyclopropanoylindoles. Any compound containing a 33 3-tetramethylcyclopropanoylindole structure with substitution at the 34 nitrogen atom of the indole ring by an alkyl, haloalkyl, cyanoalkyl, 35 alkenyl, cycloalkylmethyl, cycloalkylethyl, 36 General Assembly Of North Carolina Session 2013

Page 2 H813 [Edition 2] ethyl-2-piperidinyl)methyl, 2-(4-morpholinyl)ethyl, 1 1-(N-methyl-2-pyrrolidinyl)methyl, 1-(N-methyl-3- 2 morpholinyl)methyl, or tetrahydropyranylmethyl group, whether or 3 not further substituted in the indole ring to any extent and whether or 4 not substituted in the tetramethylcyclopropyl ring to any extent. 5 Some trade name or other names: "XLR-11."" 6 SECTION 2. This act becomes effective July 1, 2013, and applies to offenses 7 committed on or after that date. 8