 2007 Johns Hopkins Bloomberg School of Public Health Tobacco Addiction Jack E. Henningfield, PhD Johns Hopkins School of Medicine Pinney Associates

 2007 Johns Hopkins Bloomberg School of Public Health 2 Addiction Terminology Addiction: common term applied to maladaptive drug-seeking behavior  Equivalent to American Psychiatric Association (APA)/World Health Organization (WHO) “dependence” Dependence: APA refers to “nicotine,” while WHO refers to “tobacco” amount delivered to the person

 2007 Johns Hopkins Bloomberg School of Public Health 3 Addiction Terminology Withdrawal: transient symptoms following abstinence when physical dependence is present (i.e., neuroadaptation) Tolerance: decreased response to repeated doses Dependence, withdrawal, and tolerance can occur independently Withdrawal and tolerance are neither necessary nor sufficient for dependence

 2007 Johns Hopkins Bloomberg School of Public Health 4 Cigarettes Are among the Most Addictive Drugs Addiction risk following use and addiction in current users:  Cigarettes > Cocaine > Opioids > Alcohol Image source: adapted by CTLT from U.S. National Academy of Science, Institution of Medicine. (1999).

 2007 Johns Hopkins Bloomberg School of Public Health 5 Trajectory of Tobacco Use

 2007 Johns Hopkins Bloomberg School of Public Health 6 Tobacco Related Deaths Image source: Jack Henningfield.

 2007 Johns Hopkins Bloomberg School of Public Health 7 Smoke for Nicotine; Die from Smoke “Smoke for nicotine; die from smoke”—Michael A.H. Russell Image source: Jack Henningfield.

 2007 Johns Hopkins Bloomberg School of Public Health 8 All Tobacco Products Are Deadly and Addictive Image source: Institute for Global Tobacco Control.

 2007 Johns Hopkins Bloomberg School of Public Health 9 Up in Tobacco Smoke Most cigarettes contain about 10 mg nicotine Bioavailability: 10–40% typical dose is 1–3 mg nicotine per cigarette, regardless of whether it is advertised as “light” or “regular” Tar (or TPM) comes from the burning (pyrolysis) of tobacco; the particles in smoke are in the size range (< one micron) that enters the lung CO is a pyrolysis product; its half life varies with respiratory rate but it is typically four to seven hours in expired air or COHb tests

 2007 Johns Hopkins Bloomberg School of Public Health 10 Quotes “Free nicotine is absorbed more rapidly by the smoker than is bound nicotine”  RJR, Rodgman (1980) “As the pH increases, the nicotine changes its chemical form so that it is more rapidly absorbed by the body and more quickly gives a ‘kick’ to the smoker”  McKenzie (1976); Minn. Trial Exhibit 12,270 “AT [ammonia technology] is the key to competing in smoke quality with PM [Philip Morris] world-wide”  B&W, Johnson (1989)

 2007 Johns Hopkins Bloomberg School of Public Health 11 Quotes Low tar cigarettes  “Provide smokers with a choice and a reason not to quit”— Brown & Williamson (1979)  “... the effect of switching to low tar cigarettes may be to increase, not decrease, the risks of smoking”— BAT, Lee (1979)

 2007 Johns Hopkins Bloomberg School of Public Health 12 Light Cigarettes “Light” cigarettes are more ventilated and more readily enable compensatory smoking Ventilation holes

 2007 Johns Hopkins Bloomberg School of Public Health 13 Menthol Light Cigarettes Product design and ingredients (menthol) converge to produce cooler, smoother smoke This is a deadly and deceptive marketing ploy because the cigarettes are as toxic as “full flavor” cigarettes Image source: Tobacco Documents Online. Permission granted for educational use.

 2007 Johns Hopkins Bloomberg School of Public Health 14 The “Ultimate” Chemical Cocktail Tobacco-delivered nicotine  Most addictive  Most toxic  Explosively fast delivery  Optimal particle size to deposit in the lung  pH controlled  Sensory “optimization”  Chemical cocktail designed to addict  Ammonia increases dose  Acetaldehyde synergy  “Smoothing” menthol  MAO (monoamine oxidase) inhibiting effects

 2007 Johns Hopkins Bloomberg School of Public Health 15 Neurobiology of Nicotine and Other Drugs Like other abused drugs, nicotine stimulates brain reward pathways and increases dopamine in the nucleus accumbens in the brain Effects in the brain reinforce behavior, alter mood, and create a need that did not exist prior to drug exposure

 2007 Johns Hopkins Bloomberg School of Public Health 16 Other Effects Contribute to Tobacco Use Reduces anxiety and relieves stress and boredom Improves performance and attention or at least reverses withdrawal deficits Decreases appetite Helps start car and answer phone? The ubiquitous association of smoking with daily living leads to powerful behavioral conditioning

 2007 Johns Hopkins Bloomberg School of Public Health 17 Blood Nicotine Concentration Nicotine levels fluctuate widely, beginning at low levels after sleeping and rising throughout the day Waking is accompanied by early signs of withdrawal—with stronger cravings in more dependent smokers Image source: Jack Henningfield.

 2007 Johns Hopkins Bloomberg School of Public Health 18 Damaging Effects of Tobacco Nicotine in the brain leads to addiction Image source: Jack Henningfield.

 2007 Johns Hopkins Bloomberg School of Public Health 19 Effects of Four Drugs on Dopamine Levels Image sources: adapted by CTLT from (top left to bottom right) Ponberi, F. E., et al. (1996); Melega et al. (1995); Tanda et al. (1997).

 2007 Johns Hopkins Bloomberg School of Public Health 20 Nicotine Receptor Modulation Image source: Jack Henningfield. Nicotine receptor modulation produces cascading effects via neurohormones

 2007 Johns Hopkins Bloomberg School of Public Health 21 Nicotine Receptors Upregulate Nicotine receptors upregulate: reversibility in chronic smokers unclear Image source: Jack Henningfield.

 2007 Johns Hopkins Bloomberg School of Public Health 22 Increased receptors associated with tolerance and dependence Increased Receptors Image source: Jack Henningfield.

 2007 Johns Hopkins Bloomberg School of Public Health 23 Brain of Nonsmoker Versus Brain of Smoker Autopsy studies comparing smokers to nonsmokers reveal up to 400% increases in brain nicotine receptors Reversibility extent, time course, and variability is unclear Text source: Perry, D., et al. (1999); Image source: Journal of Pharmacology and Experimental Therapeutics. (1999). Temporal cortex Prefrontal cortex Hippocampus Nonsmoker Smoker

 2007 Johns Hopkins Bloomberg School of Public Health 24 Nicotine Withdrawal and Dysfunction of the Brain Nicotine withdrawal is associated with dysfunction of the brain and performance, but it can be treated Nicotine replacement and other therapies are available

 2007 Johns Hopkins Bloomberg School of Public Health 25 Withdrawal Can Be Treated Source: adapted by CTLT from Synder, F. and Henningfield, J. (1998).

 2007 Johns Hopkins Bloomberg School of Public Health 26 Medications (2006) NRTs  Gum  Lozenge  Patch (several types)  Nasal  Oral “inhaler” Nicotinic  Varenicline

 2007 Johns Hopkins Bloomberg School of Public Health 27 Medications (2006) In development  Rimonabant  Vaccines  New nicotine replacement therapies (NRTs)  New medications

 2007 Johns Hopkins Bloomberg School of Public Health 28 Advertisement Image source: Tobacco Documents Online (TobaccoDocuments.org). Permission granted for educational use.

 2007 Johns Hopkins Bloomberg School of Public Health 29 Regional cerebral blood flow (rCBF) fMRI: BOLD STUDY: Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery. Psychopharmacology. Brain Imaging Studies Smoking, withdrawal, and evoked cravings affect brain function as assessed by imaging techniques including PET and fMRI Image source: Zubieta, et al. (2005); Smolka, et al. (2005). No permission granted.

 2007 Johns Hopkins Bloomberg School of Public Health 30 Summary Nicotine is highly addictive, and it is most addictive when delivered in the form of tobacco products Nicotine affects receptors in the brain and causes addiction People who try to give up tobacco are fighting biology Health professionals need to address the physical side of addiction Treatment of addiction and prevention of smoking should go hand in hand