Tobacco's History and the Rise of E-Cigarettes

1. NHOLU 2015 A Lot Remains, “Up in the Air” Smokers, Tokers, and Vapers “Different smokes for often Different folks” February 17, 2015 Bruce W. Henricks, M.D. FACP Mutual of Omaha Companies,

2. Tobacco’s history • Tobacco grows natively in the Americas • Believed to have been grown since 6,000 B.C. • Native Americans have used tobacco for 3000 years • In religious and medicinal practices • Believed to be a “cure-all” to dress wounds, and as an analgesic • Historical points • October 1492, offered as a gift from native Americans to Christopher Columbus • Taken back to Europe and grown widely across the continent • Broadly accepted as a “healing product”

3. Tobacco’s history • Historical points • Very popular by the 1600’s, widely used as money • 1610 Sir Francis Bacon • Observes that trying to quit the bad habit was very difficult • 1760 in NYC, Pierre Lorillard • Forms company to process tobacco, oldest in the US • In 1776, tobacco helped finance the Revolutionary War • Used as collateral for loans from France • During WWI the use of cigarettes explodes • In WWII cigarette sales reach an all time high • Included in the soldier’s C-rations

4. Combustible tobacco’s history • Historical points • 1954, RJ Reynolds introduces first filtered Winston brand • 1964, Surgeon General’s “Smoking and Health” report • 50th anniversary in 2014 • 1965, TV commercials banned in Great Britain • 1971, US finally takes cigarette ads off television • Smoking rates in the U.S. • 43% in 1965, to about 19% today • Nearly 50 million Americans continue to use tobacco • 85% use cigarettes

5. Impact of Combustible tobacco • Smoking prevalence • Higher rates of cigarette use among: • The poor, and mentally ill • Alcohol and illicit-substance abusers • Native Americans • LGBT community • 78% of smokers smoke every day • 40% of those are repetitively attempting to “quit” • Almost every adult smoker started by age 18 • 3000 adolescents begin smoking each day

6. Global mortality concerns • 98% of tobacco-related deaths are related to combustible tobacco products • Up to 50% of users can be expected to die from tobacco-related causes • 30% of cancers in the U.S. are tobacco-related • A global pandemic, affecting 1.2 billion • Nearly 6 million tobacco-related deaths annually • Over 440,000 in the U.S. • 10% of those die from second hand smoke

7. Global mortality concerns • Smoking is the single most important cause of premature mortality in the world • Deaths primarily from • Lung cancer • Coronary artery disease / stroke • COPD

8. Electronic Cigarettes- ( e-cigs) • Earliest patent in 1963 • 2003, the modern e-cig was invented in China • Marketed in 2004 by the Chinese • E-cigs in the U.S. since 2006 • Currently over 200 companies in the U.S. • Over 400 varied products on the market • All are proprietary • So there is no data on safety available

9. E-cig mechanism and delivery Heating cell element boils the e-liquid and creates the vapor

10. E-cig mechanism and delivery • Battery-powered electronic nicotine-delivery device resembling a cigarette • Provides an inhaled dose of nicotine by way of a vaporized solution to the respiratory system • Nosmoke or combustion is involved • Comes in assorted flavors ( > 250) and the physical sensation similar to that of inhaled cigarette smoke

11. Influences upon e-cig popularity • E-cigs are bought to • Be an aid to reduce or stop smoking • Increasingly used by the general population • As a result of internet advertising and sales, or “Vaping” shops • Retail vaping shops now commonplace, commercials on TV • No more effective than currently available FDA approved methods (Nicotine replacement, or prescription aids) • Help relieve nicotine withdrawal symptoms • Related to workplace or public venue restrictions on smoking

12. Influences upon e-cig popularity • They are less costly than cigarettes • Only 1/5 to 1/3 the cost of smoking popular cigarettes • A disposable e-cig ( at $7) can equal 2-3 packs of cigarettes at $5 to $10 / pack • 10 nicotine cartridges = about 10 packs of cigarettes and cost < $20 • Starter kits……….creative capitalism • An e-cig, car charger, 2 batteries, and 10 cartridges, for $50 • Individual e-cigarette device depending upon style, and features costs from near $25 to $250+ • Once purchased then cartridge costs the only variable

13. Influences upon e-cig popularity • Wide assortment of vapor flavors, over 250 • Mint, dessert flavors, fruits, chocolate,…. etc., etc…. • Mimic popular cigarettes- Camel, Marlboro etc. • Flavor combinations with variable concentrations of nicotine • Vaping avoids the stigma of smoking • You are “vaping” not smoking which is perverse in our society • Attractive to younger individuals • In 2012, 7% of adolescents 12 and older were vaping

14. The economics of e-cigs • Sales exceeded $2.2 billion in 2014 • Vaping forecast to soon be > a $10 billion market • Dwarfed by the $85 billion spent on combustible tobacco • “Big Tobacco” already heavily invested in e-cigs • Lorillard, 3rd largest cigarette producer (founded in 1760) • Owns “Blu e-cigs, will spend $40+ million this year on advertising and celebrity endorsements • Multinational companies have the intellectual property allowing inhalation products to achieve alveolar deposition and thus the arterial delivery of nicotine that drives addiction

15. Marketing e-cigs and Vaping E-cig reservoirs for mixing and groups

16. Vapor composition concerns Vapor Combustible tobacco 3500+ chemicals plus 60+ known carcinogens Nicotine Vapor contains Ethylene or propylene glycol Glycerin Nicotine Flavoring Nitrosamines and diethylene glycol (both carcinogens) are found in e-cig vapor

17. Formaldehyde in Vapor • Formaldehyde is a degradation product of propylene glycol ( NEJM 1-22-15 ) • A group 1 carcinogen • International Agency for Research on Cancer • NMR spectroscopy can detect hemiacetals • Degradation products of the “vaping” process • The average e-cig vaper using 3 ml of e-liquid/ day has a lifetime cancer risk 5 times higher than the one pack/day use of conventional cigarettes

18. Nicotine, a Gateway Drug • Epidemiologic studies have shown nicotine use is a gateway to the use of marijuana in humans • A molecular basis impacting gene transcription • Cyclic AMP response-element binding protein (CREB) • Acts as a “switch” converting short-term memory to long-term • Memory is developed and “learned” from a sequence of reactions in cellular biology • CREB activation by nicotine influences target gene transcription and “primes” the brain’s potential for a developmental sequence of drug use (nicotine to marijuana to cocaine)

19. The pharmacology of Nicotine • Nicotine • A naturally-occurring alkaloid found primarily in tobacco • Acts upon nicotinic cholinergic receptor genes with 5 subunits • Alpha 4 and beta 2 subunits mediate nicotine addiction • Alpha 3 and beta 4 containing receptors influence nicotine’s cardiovascular effects • Specific cholinergic nicotinic receptor (CHRN) genes • Influence not only addiction, but the potential for smoking-related diseases (COPD, Lung cancer, and vascular disease) • Reinforces the molecular basis for both behavior and disease

20. The Pharmacology of Nicotine • Nicotine • A ganglionic and CNS stimulant • Nicotinic receptors are located in the brain, autonomic ganglia, the adrenal glands, and at neuromuscular junctions • A sympathomimetic substance that releases • Adrenal neurotransmitters (catecholamines) • Epinephrine, norepinephrine, • Dopamine, vasopressin • Nitric oxide, serotonin, acetylcholine

21. The Pharmacology of Nicotine • Physiologic effects of the catecholamines • Increases myocardial work by elevating BP, HR and cardiac contractility • Causes coronary vasoconstriction • Promotes a hyper-coaguable state • Reduce insulin sensitivity • Diabetogenic • Play a role in endothelial dysfunction-integral in atherosclerosis • Have an adverse effect on lipid metabolism • Collectively impose a multi-faceted burden on our cardiovascular system

22. The Pharmacology of Nicotine • Psychoactive effect • Fulfils all the criteria of an addictive substance • Rooted in cellular biology and gene transcription • Psychoactive properties • Beneficial effect on concentration, attention and mood • Has both euphoriant, and sedative properties • Fosters drug-reinforced behavior • Withdrawal occurs • The biology of memory • Promotes physical tolerance and dependence

23. E-cigs and Vaping Risks • Very little is known about • Long-term health effects from vaping or second hand vapor inhalation • Propylene glycol known to impede lung function • May exacerbate asthma or chronic bronchitis • Known carcinogens/hemiacetals in vapor without proper long-term study • Vapor toxicology • Lack of combustion reduces carcinogens and toxins significantly, however many remain and are not fully appreciated by credible data

24. E-cigs and Vaping Risks • An unregulated industry • The FDA has no current policy • Studying a proposal to extend tobacco regulation authority to the e-cig industry • Including novel tobacco forms and new delivery systems • Recent action to limit sales to those 18 and older • Credible data deficient on safety, morbidity/mortality • The majority of data available provided by • The e-cig industry • Marketing organizations for “Big Tobacco” or e-cigs

25. E-cigs and Vaping Risks • Nicotine and e-juice components are proprietary • Lack regulation on • Manufacturing procedures • Concentrations of nicotine and e-juice components • Purity and sterility standards • The perils of nicotine • The negative cardiovascular effects • 1/3 of tobacco-related deaths are cardiac • …Nicotine very likely the key factor

26. E-cigs and Vaping Risks • The perils of nicotine, continued • Growing evidence for its role as a “Gateway” drug • Amidst an environment where marijuana is being viewed and used more liberally • Addictive • Toxic ingestion among children • E-cig cartridge overdoses a growing problem

27. Hookah or Water pipes Head Mouthpiece

28. Hookah use • Dates from ancient Persia and India • Traditional form of tobacco use in the Middle East • Emerging form of tobacco use in the U.S. • Used by as many as 22-40% of young adults • Hookah cafes popular throughout the world • Assorted tobacco “flavors” increasingly available • Hookah pens, similar to e-cigs are popular • Many hookah smokers think it is less harmful than cigarettes • In a typical hookah session the inhaled smoke may be 180 times greater than a single cigarette

29. Hookah Use • Realistically hookah smoke is at least as toxic as cigarettes • Charcoal heating of the tobacco may produce higher levels of toxins and carcinogens • Second hand smoke at least comparable to that of cigarettes • Increased risk for • Oral cancers- exposure and dose-related • Bladder and gastric cancers, beyond those with cigarettes • The dual inherent risks of nicotine • Cardiovascular • An addictive substance

30. Cannabis sativa

31. Cannabis sativa • Marijuana • U.S.-7000 try marijuana (MJ) for first time each day • About 17.5 million Americans are smokers of MJ each month • Males account for 75% of its use • 37% are both cotinine and MJ positive • Used by ~ 6% of the U.S. population • 4% worldwide (> 160 million) • Accounts for over 75% of all current illicit drug use

32. Marijuana use- 2013 NSDUH • 5.7 million used MJ 300 days or more in the past 12 months • Increasing yearly from 3.1M in 2006 • 8.1 million used MJ 20 or more days in the past month • Increasing steadily since 2007

33. Marijuana demographics • Race and ethnicity • Prevalence significantly higher in blacks than whites or Hispanics • Education • No significant association between educational attainment and lifetime prevalence of MJ use • Marital status • Lifetime use significantly higher in those separated or divorced

34. Marijuana demographics • Predictors of continued MJ use • Early onset of use • Male sex • Frequent use • Using cannabis to enhance positive feelings • Using other illegal substances • About 60% of users between ages 23 to 30, however stop using the drug

35. Marijuana historically • Used for over 5000 years • Origins of medical use- Central and Eastern Asia • Derived from the leaves, flowers and stems of MJ • Grown in nearly every country in the world • In the U.S. • 1937- Marijuana Tax Act, stops use in medical practice • 1970- Schedule I drug, no medical use, high abuse potential • 1996- CA first state to permit medical use • Now 23 states and D.C. permitting medical use • 4 states (CO, WA, OR, AK) regulating and taxing

36. Marijuana, the “cash crop” $4700 of revenue per plant every 6 weeks

37. Marijuana, the business • Colorado- first to legalize recreational sales • Month of August 2014, • 300 retail outlets- MJ sales $34.1 million • Over 500 medicinal outlets- $33.4 million • Population of 5.26 million, spending per capita = $12.83 • Raising ~ $ 4 million a month in MJ taxes • A potential $40 billion U.S. market • “Big tobacco” already involved

38. Processed MJ- 3 products • Herbal cannabis • Dried leaves and flowers- choice of North America • Hashish • A pressed resinous secretion- favored in Europe • From female MJ flower • Thick sticky dark brown, high potency substance • Oil • Hash oil • Significant fire hazard during production • Colorado experience- home fires and serious burn injuries

39. How MJ is used • Smoked • In hand-rolled cigarettes (joints) • 20-50% of the THC content is absorbed by the lungs • Peak concentrations in ~ 15 minutes • Peak clinical effects in 30 minutes • Most medical users do so via smoking, ease of titration • In pipes, or water pipes (bongs) • In cigars with a mixture of MJ and tobacco (blunts)

40. How MJ is used • Ingested • Mixed in food or brewed as a tea • Oral use reduces bioavailability due to the hepatic first pass effect • Similar physiologic effects as being smoked • Slower and more erratic absorption • Peak concentrations in 1-3 hours • Lower levels than with smoking

41. MJ’s addiction potential • Potency has increased • Delta-9-tetrahydrocannabinol (THC) • 1980’s concentration about 4 % • 2012- now at 15% ….“creative/economic agronomy” • Higher concentrations directly impact addiction potential • Use and addiction potential • Occasional user- 9% become addicted • Adolescent with weekly use- 17% • Daily user- 25-50% risk

42. Marijuana pharmacology • Composition of MJ • Over 400 active chemicals, and 60 different cannabanoids • Major active ingredients • Delta 9-THC • Psychoactive • Potency varies with origin of the cannabis plant • Cannabidiol • More peripheral physiologic effects • Non-psychoactive • May a have role in seizure therapy

43. Marijuana pharmacology • THC reaches the brain within minutes following absorption • Readily crosses the blood brain barrier and binds to • Endocannabanoid system – a neural communication network • CB1 receptors in the mesolimbic dopamine system • CB1 receptors mediate the psychoactive effects of THC • THC over activates the system, causing the “high” • CB1 receptors primarily found in brain areas that influence: • Pleasure, memory, concentration and cognitive function • Sensory and time perception • Coordination

44. Marijuana effects on the brain

45. Marijuana pharmacology • CB2 receptors • Present in immune cells and low levels within the CNS • Influence • Pain perception • Host defense and immunosuppression • Anti-inflammatory effects • FDA-approved synthetic marijuana drugs • THC versions: Dronabinol ( Marinol), Nabilone (Cesamet) • Used in chemo-induced N&V, or in wasting diseases- CA or HIV • Glaucoma • Pain syndromes- migraines, neuropathic, musculoskeletal disorders • Neurologic spasticity- MS, Parkinsonism, and SCI

46. Marijuana pharmacology • In FDA trials • Cannabadiol (CBD) based • Epidiolex for childhood epilepsy • THC and CBD derivatives • Sativex, approved in the UK • Used for cancer analgesia and the spasticity of MS • NIH research with THC and CBD in • Autoimmune disease, as anti-inflammatories, analgesics • Anti-epileptics, substance abuse, psychiatric disorders

47. Marijuana testing • Urine testing for THC • Most commonly used • Positivity dependent upon cutoff used, drug absorption and frequency of use • Recent use- positive 1-3 days • As long as a month or more, in chronic users • MJ is fat soluble and is rapidly deposited in adipose tissue • Blood, oral and hair assays • Bodily fluids only + a few hours in most • Hair, can be positive up to 3 months

48. Adverse physiologic effects of MJ • Multi-systemic effects from chronic use • MJ use appears to suppress aspects of immunologic function • Does it increase the risk of infection? • Could it impede immune surveillance? • Chronic heavy use • Cannabanoid hyperemesis syndrome • Orthostatic hypotension • Compounding cardiovascular risks

49. Adverse physiologic effects of MJ • Reproductive • Men: reduces testosterone secretion impacts libido, gynecomastia, reductions in sperm motility and counts • Women: increases prolactin and risk of galactorrhea • Negatively impacts bone metabolism • Osteoporosis risk • Transitional cell carcinoma of the bladder • Chronic users, aggravated by tobacco use in many

50. Adverse physiologic effects of MJ • Cardiovascular • MJ increases sympathetic activity and reduces parasympathetic activity • Results in tachycardia- 20-100% increase in HR and cardiac output (workload) • May last up to 3 hours • Shown in some studies to increase risk of an MI 5 fold in the first hour after smoking • May similarly double the risk of stroke • Via cerebral vasospasm, and arteritis from chronic use