Neurobiology of Tobacco Dependence

Richard D. Hurt, M.D. Professor of Medicine Director, Nicotine Dependence Center Mayo Clinic http://ndc.mayo.edu

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Cigarettes and Tobacco Dependence • Cigarette smoke – complex mixture of 7,000 chemicals with >60 known carcinogens • Most efficient delivery device for nicotine that exists- better than I.V. • Cigarette manufacturers modified cigarettes over the past decades to maximize nicotine delivery to the brain

• High doses of arterial nicotine → upregulation of the nicotinic acetylcholine receptors • Genetic factors influence tobacco dependence • Left untreated 60% of smokers die from a tobacco-caused disease

Cigarette Smokers in the US

• 88% of adult smokers began before age 18 • Each day >3800 teens have their 1st cigarette and >1000 become daily smokers • Causal relationship between tobacco company advertising and promotion and the initiation and progression of tobacco use in young people • In 2008 cigarette companies spent $9.8 billion on advertising and promotion which is 48% higher than in 1998 • 44% of adult smokers try to stop each year but <5% achieve long-term smoking abstinence

Source: Gogtay, Nitin et al. (2004) Proc. Natl. Acad. Sci. USA 101, 8174-8179 Copyright ©2004 by the National Academy of Sciences © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Maturation starts at the back of the brain ... and moves to the front

Physical coordination, sensory processing Amygdala Motivation

Cerebellum Emotion Nucleus Accumbens Judgment

Notice: Judgment is last to develop! Prefrontal Cortex © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED • Why would anyone smoke with this hanging over their head? • It is in the brain!

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Nicotine • Not a carcinogen • Liquid in its native state • Distilled from burning tobacco and carried on tar droplets • Liquid nicotine plus entrained gas phase free nicotine • Only free (unprotonated) nicotine crosses biological membranes • Inhalation → peak arterial concentrations 2-4 X venous concentrations • Half-life 120 minutes

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Nicotinic Acetylcholine Receptors Unique in Biology • Up-regulated by high arterial doses of nicotine • Nicotine resets sensitivity of brain reward systems to ↑’d levels • Indelible “memory” of its effect on reward systems • Down-regulation takes months of smoking abstinence • This indelible “memory” evoked by external cues → craving

Kenny, PJ and© 2013 Markou MAYO FOUNDATION A, Neuropsychopharm FOR MEDICAL EDUCATION AND RESEARCH. 31:1203, ALL RIGHTS 2005 RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Perry, DC, et al. ©J 2013 Pharmacol MAYO FOUNDATION Exp FOR Ther MEDICAL, 289:1545, EDUCATION AND 1999 RESEARCH. ALL RIGHTS RESERVED

Nicotine Withdrawal DSM-IV • Dysphoric or depressed mood • Insomnia • Irritability, frustration, or anger • Anxiety • Difficulty concentrating • Restlessness • Decreased heart rate • Increased appetite or weight gain © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Smoking Saturates Nicotinic Receptors

• Radioligand allows for visualization of α4β2 nAChRs • Position Emission Tomography (PET) Scans • 11 smokers had 14 PET scan sessions • Smoked: none, 1 puff, 3 puffs, 1 cigarette or 2-3 cigarettes (satiety)

MRI

kBq/mL 9

0.0 Cigarette 0.1 Cigarette 0.3 Cigarette 1.0 Cigarette 3.0 Cigarette Nondisplaceable

• 11 smokers and 13 nonsmokers: 1 hour SHS exposure in passenger seat of car • Smoker smoked mean 3.7 cigarettes during the hour • PET scans before and after SHS exposure • 19% occupancy of α4 β2 nAChR’s in smokers and nonsmokers • 23% ↑ craving in smokers after SHS exposure

Brody AL.© et2013 alMAYO Arch FOUNDATION Gen FOR Psychiatry, MEDICAL EDUCATION May AND RESEARCH. 2011 ALL RIGHTS RESERVED One hour of moderate secondhand smoke (SHS) exposure leads to significant decreases in 2- [18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (also known as 2-[18F]fluoro-A-85380, or 2-FA) receptor binding in brain

Brody, A. L. et al. Arch Gen Psychiatry 2011;0:archgenpsychiatry.2011.51v1-9.

We accept an interest in people’s health as a basic responsibility, paramount to every other consideration in our business. We always have and always will cooperate closely with those whose task it is to safeguard the public health.

-- creating doubt about the health charge without actually denying it

What we want to do this morning is to take a summary look at the smoking and health question and then make a proposal to you for a B&W project to counter the anti-cigarette forces.

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Doubt is our product since it is the best means of competing with the “body of fact” that exists in the mind of the general public.

Think of the cigarette pack as a storage container for a day’s supply of nicotine: Think of the cigarette as a dispenser for a dose unit of nicotine:

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED We believe that we have found possible reasonsExperiments for addiction have so farin two only other been phenomena carried out thatwith accompanyrats, but with steady these absorption it is found ofthat nicotine. certain rats become tolerant to repeated doses and after a while show the usual nicotine reactions but only on a very diminished scale.

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED There seems no doubt that the “kick” of a cigarette is due to the concentration of nicotine in the blood-stream…and this is a product of the quantityNicotine of is nicotinein the smoke in the in smoke two forms and the as freespeed nicotineof transfer base of (thinkthat nicotine of ammonia) from the and smoke as a to the nicotineblood-stream. salt (think of ammonium chloride) and it is almost certain that the free nicotine base is absorbed faster into the blood-stream.

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED All evidence indicates that the relatively high smoke pH (high alkalinity) shown by Marlboro (and other Philip Morris brands) and Kool is deliberate and controlled.

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Methods which may be used to increase smoke pH and/or nicotine “kick” include:…(3) use of alkaline additives, usually ammonia compounds, to the blend.

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED AT is the key to competing in smoke quality with PM worldwide.

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “All work in this area should be directed towards providing consumer reassurance about cigarettes and the smoking habit.” “This can be provided in different ways, e.g., by claimed low deliveries, by the perception of low deliveries and by the perception of ‘mildness.’”

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “People believe that cigarettes low in tar and nicotine have different ‘tobacco’ ingredients and different kinds of filters than other cigarettes.” “the tobacco is milder or a special mild blend, perhaps treated to remove tar and nicotine...” “Those who smoke low tar and nicotine cigarettes generally do so because they believe such cigarettes are ‘better for you.’” © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “It appears that we have sufficient expertise available to ‘build’ a lowered mg tar cigarette which will deliver as much ‘free nicotine’ as a Marlboro, Winston or Kent without increasing the total nicotine delivery above that of a ‘Light’ product.” “There are products already being marketed which deliver high percentage ‘free nicotine’ levels in smoke, i.e., Merit, Now.” © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “The smoker profile data reported earlier indicated that Marlboro Lights cigarettes were not smoked like regular Marlboros…”

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “In effect, the Marlboro 85 smokers in this study did not achieve any reduction in the smoke intake by smoking a cigarette (Marlboro Lights) normally considered lower in delivery.”

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “Low Tar Low Nicotine” Cigarettes FTC Method • Determines relative yield of individual cigarettes by a smoking machine • Machine draws 35ml puff of 2 seconds duration every minute until cigarette smoked down to 23mm butt length • Cambridge filter collects the particulate matter • Does not measure the gas phase “free nicotine” • 2008 no longer used and as of June 2010 no longer can use “light” or low tar

• Ventilation holes key technology to manipulate tar and nicotine yields • Electrostatic or laser perforations in the filter tipping paper • Ventilation holes not visible in most brands • 2/3’s of U.S. smokers are unaware of ventilation holes • Smokers block (consciously or not) the ventilation holes with their lips on fingers increasing tar/nicotine yields

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Smokers vs. Machines

Nicotine Yield FTC ≤0.8 mg 0.9-1.2 mg Protocol

Puff volume (ml) 48.6 44.1 35

Puff duration (sec) 1.5 1.5 2

Puff no. 12.7 12.1 8-10

Djordjevic MV,© 2013 et MAYO al. FOUNDATIONJ Natl Cancer FOR MEDICAL Inst EDUCATION 92:106, AND 2000RESEARCH. ALL RIGHTS RESERVED Benowitz, NL et© al2013 NEJM MAYO FOUNDATION 309:139, FOR 1983MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Carcinogens Excreted by Smokers of Regular or “Light” Cigarettes • 150 smokers of regular or “light” cigarettes • Serum cotinine and urine NNAL and 4 aminobiphenyl hemoglobin adducts. • Essentially the same concentrations of NNAL & 4-ABP were present in “light” or regular cigarette smokers.

Bernert J.T., et. al. Nic & Tob Res 7:729, 2005

Cigarettepedia.com

New Brand Line

Sample Note from online retailer: Formerly known as Light, Pall Mall has changed the name to Blue. These are the same cigarettes. http://www.agoodcigarette.com/index.php?main_page=product_info&cPath=&products_id=3349 © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Camel Turkish Line – Manufactured by RJ Reynolds No Light or Ultra Light Descriptors on package Product: Camel Turkish Gold Package Descriptors: Smooth & Mellow Package Color: GOLD Website Descriptors: Outstanding mellow flavor & smoothness Nicotine (FTC method): 0.7mg Nicotine (MA Method Nicotine/Cigarette): 12.5mg Nicotine per gram (mg/g): 18.6 mg/g Ventilation: 31.8%

Product: Camel Turkish Royal Package Descriptors: Rich & Mellow Package Color: BLUE Website Descriptors: Undeniably Rich & Mellow taste Nicotine (FTC method): 1.0mg Nicotine per gram (mg/g): 20.0 mg/g Ventilation: 22.5%

Product: Camel Turkish Silver Package Descriptors: Extra Smooth & Mellow Package Color: SILVER Website Descriptors: Exceptionally Mellow flavor and extraordinary smoothness Nicotine (FTC method): 0.7mg Nicotine per gram (mg/g): 19.1 mg/g Ventilation: 35.2%

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION ANDSource: RESEARCH. MDPH ALLNicotine RIGHTS Disclosures RESERVED SALEM – Manufactured by RJ Reynolds Old Brand Line Regular Full Flavor Lights Ultra Lights

Cigarettepedia.com

New Brand Line

• MDPH tested 116 brands → no difference in total nicotine content. • Larger puff volume, shorter interval between puffs and 50% coverage of ventilation holes. • Nicotine yield ↑ 1.72 mg (1998) → 1.89 mg (2004). • 84% cigarettes tested(1998) as “high yield” nicotine vs. 93% (2004).

© 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “In short defendants have marketed and sold their lethal product with zeal, with deception, with the Racketeers single-minded focus on their financial success , and without regard for the human tragedy or social costs that success exacted.” United States et.al. v. Philip Morris et. al. (2006)

No matter how innocent they appear, the tobacco industry CANNOT BE TRUSTED!