NICOTINE ADDICTION

U.S. Surgeon General’s Report

 Cigarettes and other forms of tobacco are addicting.
NICOTINE PHARMACOLOGY and
 Nicotine is the drug in tobacco that causes addiction.
PRINCIPLES of ADDICTION
 The pharmacologic and behavioral processes that
determine tobacco addiction are similar to those that
determine addiction to drugs such as heroin and
cocaine.

U.S. Department of Health and Human Services. (1988). The Health Consequences of Smoking: Nicotine
Addiction. A Report of the Surgeon General.

CHEMISTRY of NICOTINE PHARMACOLOGY

Pharmacokinetics
Pyrrolidine ring
H
Effects of the body on the drug
Pyridine ring
N  Absorption
N CH3  Distribution
 Metabolism
Nicotiana tabacum  Excretion
Natural liquid alkaloid Pharmacodynamics
Colorless, volatile base pKa = 8.0 Effects of the drug on the body

NICOTINE ABSORPTION:
NICOTINE ABSORPTION BUCCAL (ORAL) MUCOSA
Absorption is pH‐dependent The pH inside the mouth is 7.0.
 In acidic media Acidic media Alkaline media
 Ionized  poorly absorbed across membranes (limited absorption) (significant absorption)
 In alkaline media Cigarettes Pipes, cigars,
 Nonionized  well absorbed across membranes spit tobacco,
 At physiologic pH (7.4), ~31% of nicotine is nonionized oral nicotine products

At physiologic pH, nicotine is readily absorbed. Beverages can alter pH, affect absorption.

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1
 NICOTINE ABSORPTION: SKIN and
GASTROINTESTINAL TRACT NICOTINE ABSORPTION: LUNG
 Nicotine is readily absorbed through intact skin.  Nicotine is “distilled” from burning tobacco
 Carried in tar droplets to the lungs
 Nicotine is well absorbed in the small intestine  Nicotine is rapidly absorbed across respiratory epithelium
 Low bioavailability (20‐45%) due to first‐pass  Lung pH = 7.4
hepatic metabolism.  Large alveolar surface area
 Extensive capillary system
 Approximately 1‐2 mg of nicotine is absorbed from each cigarette

NICOTINE DISTRIBUTION NICOTINE METABOLISM

80 H
Arterial 10–20%
Plasma nicotine (ng/ml)

N excreted
60
unchanged
N CH3 in urine
40
Venous
20 70–80% ~ 10% other
cotinine metabolites
0
0 1 2 3 4 5 6 7 8 9 10
Minutes after light‐up of cigarette Metabolized
and excreted
Nicotine reaches the brain within 10–20 seconds. in urine
Henningfield et al. (1993). Drug Alcohol Depend 33:23–29. Adapted and reprinted with permission. Benowitz et al. (1994). J Pharmacol Exp Ther 268:296–303.

NICOTINE EXCRETION NICOTINE PHARMACODYNAMICS

 Half‐life Nicotine binds to receptors
in the brain and other
 Nicotine t½ = 2 hr Central nervous system
sites throughout the body.
 Cotinine t½ = 16 hr Cardiovascular system
Exocrine glands

 Excretion Gastrointestinal system

Adrenal medulla
 Occurs through kidneys (pH dependent;
Other:
 with acidic pH) Neuromuscular junction
Peripheral nervous system
 Through breast milk Sensory receptors
Other organs

Nicotine has predominantly stimulatory effects.

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 NEUROCHEMICAL and RELATED
NICOTINE PHARMACODYNAMICS (cont’d) EFFECTS of NICOTINE
N  Dopamine  Pleasure, appetite suppression
Central nervous system Cardiovascular system
 Pleasure   Heart rate I  Norepinephrine  Arousal, appetite suppression
 Arousal, enhanced vigilance   Cardiac output C  Acetylcholine  Arousal, cognitive enhancement
 Improved task performance   Blood pressure O
 Anxiety relief  Coronary vasoconstriction  Glutamate  Learning, memory enhancement
T
 Cutaneous vasoconstriction  Serotonin  Mood modulation, appetite suppression
Other I
 ‐Endorphin  Reduction of anxiety and tension
 Appetite suppression N
 Increased metabolic rate  GABA  Reduction of anxiety and tension
E
 Skeletal muscle relaxation Benowitz. (2008). Clin Pharmacol Ther 83:531–541.

DOPAMINE REWARD PATHWAY

WHAT IS ADDICTION? Prefrontal
cortex
“Compulsive drug use, without medical
purpose, in the face of negative Dopamine release
consequences” Stimulation of
Alan I. Leshner, Ph.D. Nucleus
nicotine receptors
Former Director, National Institute on Drug Abuse accumbens Ventral
Nicotine enters
National Institutes of Health tegmental
area brain
Nicotine addiction is a chronic condition with a biological basis.

CHRONIC ADMINISTRATION of NICOTINE WITHDRAWAL SYMPTOMS:

NICOTINE: EFFECTS on the BRAIN Time Course*
Human smokers have increased nicotine Irritability / Frustration / Anger
receptors in the prefrontal cortex. Anxiety
Difficulty concentrating
Most symptoms manifest
Restlessness / Impatience within the first 1–2 days, peak
Depressed mood / Depression within the first week, and
Insomnia subside within 2–4 weeks.
High
Impaired task performance
Increased appetite 6 months
Weight gain
Low Cravings Can persist for months
to years after quitting
1 week 4 weeks 12 weeks

Quit Former
Nonsmoker Smoker Recent quitter
date tobacco user
Image courtesy of George Washington University / Dr. David C. Perry
Perry et al. (1999). J Pharmacol Exp Ther 289:1545–1552. *Timeline aspect of the figure is not according to scale. Data from Hughes. (2007). Nicotine Tob Res 9:315–327.

Copyright © 1999‐2025 The Regents of the University of California. All rights reserved.

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 NICOTINE ADDICTION CYCLE NICOTINE ADDICTION
 Tobacco users maintain a minimum serum nicotine
concentration in order to:
 Prevent withdrawal symptoms
 Maintain pleasure/arousal
 Modulate mood
 Users self‐titrate nicotine intake by:
 Smoking/dipping/vaping more frequently
 Smoking/vaping more intensely

Reprinted with permission. Benowitz. (1992). Med Clin N Am 2:415–437. Benowitz. (2008). Clin Pharmacol Ther 83:531–541.

ASSESSING
NICOTINE DEPENDENCE
Fagerström Test for Nicotine Dependence (FTND)
 Developed in 1978 (8 items); revised in 1991 (6 items)
 Most common research measure of nicotine dependence;
sometimes used in clinical practice
 Responses coded such that higher scores suggest higher levels
of dependence
 Scores range from 0 to 10; score of greater than 5 suggest
substantial dependence CLOSE TO HOME © 2000 John McPherson.
Reprinted with permission of UNIVERSAL PRESS SYNDICATE.
All rights reserved.
Heatherton et al. (1991). British Journal of Addiction 86:1119–1127.

FACTORS CONTRIBUTING to TOBACCO DEPENDENCE:

TOBACCO USE A 2‐PART PROBLEM
Individual Pharmacology
Tobacco Dependence
 Sociodemographics  Alleviation of withdrawal
symptoms Physiological Behavioral
 Genetic predisposition
Tobacco  Weight control
 Coexisting medical The addiction to nicotine The habit of using tobacco
 Pleasure, mood
conditions Use modulation Treatment Treatment

Environment Medications for cessation Behavior change program

 Tobacco advertising
Treatment should address the physiological
 Conditioned stimuli
and the behavioral aspects of dependence.
 Social interactions

Copyright © 1999‐2025 The Regents of the University of California. All rights reserved.

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 NICOTINE PHARMACOLOGY and
ADDICTION: SUMMARY
 Tobacco products are effective delivery systems for the drug
nicotine.
 Nicotine is a highly addictive drug that induces a constellation of
pharmacologic effects, including activation of the dopamine reward
pathway in the brain.
 Tobacco use is complex, involving the interplay of a wide range of
factors.
 Treatment of tobacco use and dependence requires a multifaceted
treatment approach.

Copyright © 1999‐2025 The Regents of the University of California. All rights reserved.