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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,

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”

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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

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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

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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

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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

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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

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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

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E-cig mechanism and delivery

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Heating cell element boils the e-liquid and creates the vapor

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

• No smoke or combustion is involved

• Comes in assorted flavors ( > 250) and the physical sensation similar to that of inhaled cigarette smoke

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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 smoking11

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

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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

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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

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Marketing e-cigs and Vaping

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E-cig reservoirs for mixing and groups

Vapor composition concerns

Vapor Combustible tobacco

16Nitrosamines and diethylene glycol (both carcinogens) are found in e-cig vapor

Vapor contains Ethylene or propylene glycol Glycerin Nicotine Flavoring

3500+ chemicals plus 60+ known carcinogens

Nicotine

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

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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)

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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

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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

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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

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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

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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

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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-cigs24

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

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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

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Hookah or Water pipes

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Head

Mouthpiece

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

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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

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Cannabis sativa

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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 use31

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

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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

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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

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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 taxing35

Marijuana, the “cash crop”

36$4700 of revenue per plant every 6 weeks

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

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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

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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)

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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

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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

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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

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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 43

Marijuana effects on the brain

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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

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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

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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 months47

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

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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 many49

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

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Adverse physiologic effects of MJ

•Pulmonary• Increases carboxyhemoglobin levels- 5 fold

• Contributory to its negative vascular effect

• Acute short term use may lead to bronchodilation

• Potential use in asthma

• Chronic use associated with bronchial inflammation

• Chronic bronchitis a legitimate concern

• Emphysema risk appears to be un-effected51

Adverse physiologic effects of MJ

• Lung cancer risk

• 50-70% more carcinogens than combustible tobacco• MJ contains 3 times more tar than tobacco

• 1/3 more tar retention in lungs

• 1 joint per day is nearly equivalent to 1 pack of cigarettes per day in terms of lung cancer risk

• Studies support an increased hazard ratio for lung cancer• Increased by frequency and duration of exposure

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Adverse physiologic effects of MJ

•Psychiatric• About 60% of the likelihood of developing a MJ use disorder is

due to genetic factors

• Based upon multi-national twin studies

• Linked to regions on chromosomes 3 & 9, + possibly 4 others

• Increases risk of schizophrenia, bipolar disorder and depression

• Particularly in the developing adolescent

• May unmask risk in those predisposed

• Risk proportion to dose53

Teen Use of Marijuana

• Reported teen use of marijuana within the past month

Adverse physiologic effects of MJ

•Psychiatric, cont.• Psychosocial functioning

• Short-term outcomes• School dropout increased

• THC impact on the developing adolescent brain

• Early and frequent exposure does lower IQ and alter behaviors

• Use of other drugs in those who use MJ frequently (German data)

• Alcohol in 90%

• Nicotine in 68%

• Cocaine in 12%

• Stimulants and hallucinogens 6-9%

• Opioids 3%

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Adverse physiologic effects of MJ

• Psychosocial functioning

• Incidence of crime, New Zealand study• Direct relationship between frequency of MJ use and number of crimes, vs. non-

users

• Use < monthly committed 1.6 times more crimes

• Use at least weekly, committed 3.7 times more crimes

• Lasting adverse effects in users weekly or more• Reduced attention and processing speed

• Memory deficits

• Abnormal social behavior

• Increased susceptibility to anxiety and depression

• Known risk of poly-drug dependence

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Medical Marijuana

•Most medical MJ patients are• Heavy regular users

• Smokers of cannabis- easier to titrate the effect

•Areas of concern• Laws are vague on valid indications for medical MJ

• Most states only require a prescription

• Readily available, with minimal requirements

• No established physician relationship• $50, “ I have pain” and you are OTD-”out the door”

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MJ and driving

•Two thirds of trauma center admissions• Are from MVAs

• Nearly 60% test positive for drugs or alcohol• 12 % of Americans drive under the influence of alcohol

•Colorado data• 11% of MVAs tested + for THC

• Driving under the influence of cannabis (DUIC)• 2007, MJ the most common illicit drug with 8.6% testing +

• Increases risk of a MVA 2-4 fold• Compounded when in concert with alcohol

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Marijuana and Cotinine testing

•Mutual’s experience• Tested for THC and blood alcohol since 2004

• 2.3% of samples test + for THC • $ 68.5 million in face amount in 2014

• Consistent THC “hit” rate, a sentinel effect seen early with BAC

• 8 fold greater incidence than a + BAC (96 in 2014) on $ 29 million

• Majority are in middle class or above

• Average issue age ~ 47 years

• Median age in the U.S. is 37

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Underwriting Marijuana

• There never has been a documented death attributed directly to marijuana use

• MJ use is associated with a higher probability of risk taking behavior

• Keep the MJ risk in perspective with the “company it keeps”

• Most legitimate medical MJ use is in high risk conditions• (Pain management and glaucoma as exceptions)

• Ideally under a physicians care

• Very high risk in those under age 1860

Underwriting Marijuana

• Points of caution• Be vigilant of current or past evidence of alcohol or other substance abuse

• Current use of opioid analgesics

• Noteworthy driving criticisms

• Individuals with significant current or past history of psychiatric illnesses

• Associated medical conditions that pose higher risk

• COPD

• Tobacco-related cancers

• CAD or Cerebrovascular disease

• PMH of poorly controlled asthma

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Smokers, Tokers and Vapers

Q&A

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