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

2. The Problem

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

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

5. 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)

6. CRITERIA FOR ADDICTION: 1988 SURGEON GENERAL’S REPORT

7. 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.”

9. 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.”

10. 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.

11. 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)

12. 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)

13. 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 ± 30 minutes ± 60 minutes After 60 minutes 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 Which cigarette would you hate most to give up? The first one in the morning All others How many cigarettes/day do you smoke?* 10 or less ± ± or more Do you smoke more frequently during the first hours after waking than Yes 1 during the rest of the day? No Do you smoke when your are so ill that you are in bed most of the day? Yes No 0 *HSI items.

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

16. Nicotine Receptors and Neurochemistry

18. 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.

19. 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

20. 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

21. 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

22. 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:S
Changeux JP, Bertrand D, Corringer P, et al. Brain Nicotinic receptors: structure and regulation, role in learning and reinforcement. Brain Research Reviews 1998; 26:
Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: An 4β2 nicotinic receptor partial agonist for smoking cessation. J. Med Chem. 2005;48:

23. The Cigarette as a Drug Delivery System

26. Neuroadaptation

27. 27

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

29. NICOTINIC RECEPTOR UPREGULATION IN SMOKERS

30. 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

31. 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

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

33. Is Tobacco Addiction Only Due to Nicotine? Monoamine Oxidase

34. MAO A Activity
Figure

35. 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

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

37. Tobacco Smoking & Co-morbidity

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

39. 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

40. Smoking and Conditioned Behavior

41. 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

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

44. 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.

45. COMPARISON OF NICOTINE DEPENDENCE AND DEPENDENCE ON OTHER DRUGS OF ABUSE

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

48. FTC Machine Test Method

49. 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.

50. “FREE CHOICE” TO SMOKE OR NOT TO SMOKE

51. 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.”

52. 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.

53. 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