University of California San Francisco NICOTINE ADDICTION Neal L. Benowitz, MD University of California San Francisco February 8, 2017

The Problem

WHAT IS DRUG ADDICTION? The essence is loss of control of drug use.

WHAT IS DRUG ADDICTION? The essence is loss of control of drug use. A disease of brain reward centers (Dackis and O’Brien, 2005)

DEFINITION OF A DRUG “…Articles other than food intended to affect the structure or any function of the body of man…” (F.D.A., 1938)

CRITERIA FOR ADDICTION: 1988 SURGEON GENERAL’S REPORT

CRITERIA FOR ADDICTION: WORLD HEALTH ORGANIZATION “A behavioral pattern in which the use of a given psychoactive drug is given a sharply higher priority over other behaviors which once had a significantly higher value.”

SFGH Cardiac Clinic - May 1, 1996 57 yo smoker with coronary heart disease, recent bypass surgery, and severe hypertension, on multiple antihypertensive medications. Compliant with medications and office visits, but… “If I don’t have a cigarette, I can’t think, I can’t read, I become disoriented… If I can’t smoke, I don’t care if I live or die.”

DIAGNOSING TOBACCO ADDICTION: DSM-V (Tobacco Use Disorder) A problematic pattern of tobacco use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: Tobacco is often taken in larger amounts or over a longer period than was intended. There is a persistent desire or unsuccessful efforts to cut down or control tobacco use. A great deal of time is spent in activities necessary to obtain or use tobacco. Craving, or a strong desire or urge to use tobacco. Recurrent tobacco use resulting in a failure to fulfill major role obligations at work, school or home (e.g., interference with work). Continued tobacco use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of tobacco (e.g., arguments with others about tobacco use.

exacerbated by tobacco. Important social, occupational, or recreational activities are given up or reduced because of tobacco use. Recurrent tobacco use in situations in which it is physically hazardous (e.g., smoking in bed). Tobacco use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by tobacco. Tolerance, as defined by either of the following: A need for markedly increased amounts of tobacco to achieve the desired effect. A markedly diminished effect with continued use of the same amount of tobacco. Withdrawal, as manifested by either of the following: The characteristic withdrawal syndrome for tobacco (refer to Criteria A and B of the criteria set for tobacco withdrawal). Tobacco (or a closely related substance, such as nicotine) is taken to relieve or avoid withdrawal symptoms. Data from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-V)

DIAGNOSING TOBACCO WITHDRAWAL: DSM-V (Tobacco Use Disorder) Daily use of tobacco for at least several weeks Abrupt cessation of tobacco use, or reduction in the amount of tobacco used, followed within 24 hours by four (or more) of the following signs or symptoms. Irritability, frustration, or anger Anxiety Difficulty concentrating Increased appetite Restlessness Depressed mood Insomnia. The signs of symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The signs or symptoms are not attributed to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance. Data from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-V)

SEVERITY OF ADDICTION: FAGERSTROM TEST FOR CIGARETTE DEPENDENCE Items Response options Points 1. How soon after you wake up do you smoke your first cigarette?* Within 5 minutes 3 6± 30 minutes 2 31± 60 minutes 1 After 60 minutes 0 2. Do you find it difficult to refrain from smoking in places where it is Yes 1 forbidden, e.g. in a church, at the library, in cinema, etc.? No 0 3. Which cigarette would you hate most to give up? The first one in the morning 1 All others 0 4. How many cigarettes/day do you smoke?* 10 or less 0 11± 20 1 21± 30 2 31 or more 3 5. Do you smoke more frequently during the first hours after waking than Yes 1 during the rest of the day? No 0 6. Do you smoke when your are so ill that you are in bed most of the day? Yes 1 No 0 *HSI items.

Neuroscience of Nicotine Addiction Nicotinic Receptors in Brain Neurochemical Effects The Cigarette as a Drug Delivery System Neuroadaptation Conditioned Behavior Genetics of Nicotine Addiction

Nicotine Receptors and Neurochemistry

Structure of Nicotinic ACh Receptors ion acetylcholine pore      muscle type nicotinic receptor x y neuronal type nicotinic receptors z Picciotto M. Emerging neuronal nicotinic receptor targets. SRNT 9th Annual Meeting; February 2003; New Orleans, La.

Nicotinic Receptors in the Brain 11 subunits (α2 – α9 and β2 – β4) Α4β2 – high affinity, most prevalent, linked to addiction α3β4 - cardiovascular α7 homomeric – rapid synaptic transmission; learning, sensory gating

Genetic Studies of Nicotinic Receptor Subtypes β2 – Dopamine release, self-administration (Picciotto) α4 – Nicotine sensitivity (Tapper) α5, α6– Combine with α4 and β2; associated with human dependence

NICOTINE DOPAMINE Pleasure, Appetite Suppression NOREPINEPHRINE Arousal, Appetite Suppression ACETYLCHOLINE Arousal, Cognitive Enhancement GLUTAMATE Learning, Memory Enhancement SEROTONIN Mood Modulation, Appetite Suppression BETA-ENDORPHIN Reduction of Anxiety and Tension GABA Reduction of Anxiety and Tension NICOTINE

Nicotine Addiction: Reinforcing Behavior 4b2 nAChR Ref1/Picciotto/ S123/2/3/1-6 Ref2/Changeux/ 200/1/2/7-12 Ref3/Coe/ 3474/2/1/1-7 After inhalation, nicotine predominantly binds to the nicotinic aceylcholine (nACh) receptors located in the mesolimbic-dopamine system of the brain within a matter of seconds. Nicotine specifically activates 4β2 nicotinic receptors in the Ventral Tegmental Area (VTA) causing an immediate dopamine release at the Nucleus Accumbens1 (nAcc). The dopamine release is believed to be a key component of the reward circuitry associated with cigarette smoking1. Dopamine GLU GABA nicotine Nicotine activates nAChRs on DA and GABA neurons (VTA) and Glu neurons Net result of stimulatory and inhibitory effects and differential desensitization of nAChRs is enhanced DA release in the n. accumbens Studies in transgenic mice: crucial role of a4 and b2 nAChR subunits - courtesy of H. Rollema, Pfizer References Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S121-125. Changeux JP, Bertrand D, Corringer P, et al. Brain Nicotinic receptors: structure and regulation, role in learning and reinforcement. Brain Research Reviews 1998; 26:198-216. Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: An 4β2 nicotinic receptor partial agonist for smoking cessation. J. Med Chem. 2005;48:3474-3477.

The Cigarette as a Drug Delivery System

Neuroadaptation

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Neuroadaptation and Nicotine Dependence Upregulation of nicotinic receptors Neuroplasticity Induction of gene products (c-Fos) Changes in protein expression Altered cell signaling

NICOTINIC RECEPTOR UPREGULATION IN SMOKERS

TOBACCO ABSTINENCE SYMPTOM CLUSTERS (Gross and Stitzer) PSYCHOLOGICAL DISTRESS: Irritability, Anger, Impatience, Anxiety DIFFICULTY CONCENTRATING: Cognitive and Performance Impairment HUNGER AND EATING: Weight Gain TOBACCO CRAVING

Hedonic Dysregulation (Koob and LeMoal, Science 278:52, 1997) Negative Affect State Common To Abstinence From All Drugs Of Abuse Dysphoria Depression Irritability Anxiety Anhedonia

MAINTAINING NICOTINE ADDICTION Positive reinforcement – Liking a drug is part of addiction Physical dependence – Avoiding withdrawal symptoms

Is Tobacco Addiction Only Due to Nicotine? Monoamine Oxidase

MAO A Activity Figure

Monoamine Oxidase and Tobacco Addiction Smoking inhibits brain MAO-A and MAO-B Effect due to benzoquinones, 2-naphylamine, harmon and other chemicals, but not nicotine MAO inhibition enhances nicotine self-administration in animals MAO inhibitors may be useful in treating nicotine addiction

Enhancement of Nicotine Self-Administration by Tranylcypromine Pre-treatment                                                                                   Fig

Tobacco Smoking & Co-morbidity

Tobacco Addiction is Frequently Co-morbid with Alcoholism Drug Abuse Depression Schizophrenia

Cigarette Smoking and Depression History of major depression more common in smokers More dependent smokers have higher rates of depression Smokers with depression history have more severe withdrawal symptoms, including severe depression symptoms

Smoking and Conditioned Behavior

URGE TO SMOKE URGE TO SMOKE NO URGE TO SMOKE OVERT BEHAVIOR SITUATIONS ASSOCIATED WITH SMOKING SMOKING STATUS COGNITIVE BEHAVIOR SMOKE CIGARETTE CURRENT SMOKER URGE TO SMOKE LAPSE OR RELAPSE MEAL COFFEE ALCOHOL PARTY TELEPHONE DRIVING FRIENDS SMOKING URGE TO SMOKE RECENTLY ABSTAINING SMOKER MAINTAINED ABSTINENCE NO URGE TO SMOKE LONG-TERM ABSTINENT SMOKER NO CIGARETTE

Things Go Better with Nicotine Nicotine increases the rewarding value of non-nicotine stimuli (such as food).

The Health Consequences of Smoking: NICOTINE ADDICTION A Report of the Surgeon General, 1988 Cigarettes and other forms of tobacco are addicting. Nicotine is the drug in tobacco that causes addiction. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine.

COMPARISON OF NICOTINE DEPENDENCE AND DEPENDENCE ON OTHER DRUGS OF ABUSE

Public Health Implications of Nicotine Addiction: The Low Yield Cigarette Story

FTC Machine Test Method

LOW YIELD CIGARETTES Smokers take in same amount of nicotine and tar as from regular cigarettes. This “compensation” behavior is a reflection of nicotine addiction. Tobacco industry advertisements imply lower risk. Industry knew but never informed consumers about compensation.

“FREE CHOICE” TO SMOKE OR NOT TO SMOKE

RATIONALIZATION AND DENIAL IN ADDICTION All drug addicts try to rationalize their behavior, including denial of health hazards of drug use in order to keep using drugs. For smokers --- -The “controversy” over health hazards. -Positive images in advertising. -Switching to low yield cigarettes. -Lesser perception of risk. -“I will quit before I get sick.”

TOBACCO INDUSTRY DOCUMENTS Nicotine is a drug and is addictive; the cigarette is a drug delivery device. Threshold levels of nicotine needed to sustain addiction. Youth smoking – initiating for social reasons, continuing to smoke for pharmacological reasons. Drug research on nicotine/admitting that nicotine is a drug would invite FDA regulation. Nicotine addiction undermines free choice. Compensation – smokers of low yield cigarettes are exposed to the same level of tobacco smoke as are smokers of regular cigarettes.

WILLIAM DUNN, RESEARCHER, PHILIP MORRIS TOBACCO, 1972 THE CIGARETTE SHOULD BE CONCEIVED NOT AS A PRODUCT BUT AS A PACKAGE. THE PRODUCT IS NICOTINE … THINK OF THE CIGARETTE PACK AS A STORAGE CONTAINER FOR A DAY’S SUPPLY OF NICOTINE… THINK OF A PUFF OF SMOKE AS THE VEHICLE OF NICOTINE AND THE CIGARETTE THE MOST OPTIMIZED DISPENSER OF SMOKE. WILLIAM DUNN, RESEARCHER, PHILIP MORRIS TOBACCO, 1972