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Characterized based on CNS Effects:
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Over-the-Counter Stimulants
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Increased energy, mental alertness
Positive hedonic effects, euphoria
Reduced fatigue, decreased sleepiness
Casually referred to as “uppers”
Toxicities associated with excessive CNS
stimulation: e.g., seizures, cardiac and
respiratory failure
Nicotine, Caffeine, Theophylline,
Theobromine, Ephedrine
Legally Restricted Stimulants
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Cocaine, Amphetamine, Methamphetamine
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Early Medicinal Uses
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Europe
New World
The spread of tobacco use
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Tobacco production
Nicotiana tobacum
 Spanish monopoly on sales to Europe
 Tobacco colony in Virginia
 Popularity of snuff in England
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Snuff
Chewing tobacco
Cigars
Cigarettes
Nicotine Replacement
Treatments

Chewing gum, lozenge, inhaler,
patch
Trends in cigarette sales since 1945
(Ksir et al., 2006. McGraw Hill)
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Males more likely than females
Recent downward trends in use among high school seniors
 36% in 1997; 22% (F), 26% (M) in 2003
Among 18- to 25-year olds
 44% of males, 36% of females (2002 survey data)
 College students less likely to smoke than non-students in
this age range.
Current smokers are more likely to also be heavy drinkers
and/or illicit drug users.
Higher smoking prevalence among people with psychiatric
diagnosis (consume 70% of cigarettes in U.S.)
Smoking more common among lower socioeconomic classes
 e.g., Smoking prevalence among Medicaid recipients 40%
greater than that in overall U.S. adult population.
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Colorless, highly volatile liquid alkaloid
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Highly toxic in pure form
Diluted concentrations when administered through tobacco
use
Nicotine is only one of ~4000 compounds in tobacco smoke
 cardiovascular, pulmonary, & carcinogenic effects
related to multiple chemicals in tobacco
Absorption
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Weak base, pKa ~ 8, poorly absorbed in digestive system
Smoked: rapid absorption into the bloodstream
 90% of inhaled nicotine is absorbed
Chewed or dipped: absorbed through the mucus lining of
the mouth
Pipe/Cigar tobacco
 air-cured, more alkaline smoke (pH 8.5), absorption in
mouth, inhalation not required
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Distribution
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Depends on route and time since administration
High concentration achieved in brain
Crosses most barriers, including placenta
Metabolism/Elimination
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Liver metabolizes 80-90% before excretion
 Two metabolic pathways
 Metabolites: cotinine, nicotine-l’-N-oxide
Excretion by kidneys depends on urine pH
 Reduced ionization in alkaline pH increases reabsorption
Half-life ~ 30 minutes
 Rapid elimination, no day-to-day accumulation
Individual Differences in Elimination
 Smokers metabolize faster
 Gender differences in nicotine metabolism
 Genetic differences
 16-25% of population with genetic “defect” in ability to metabolize
nicotine.
 May protect against becoming a smoker
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Physiological Effects
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Low-level nicotine poisoning causes nausea,
dizziness, and a general weakness
Low doses stimulate respiration, high doses
paralyze respiratory muscles (acute toxicity)
Mechanisms of Action
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Mimics and Blocks ACh
Facilitates Adrenalin Release
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Subjective Effects
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Acute Effects vs. Chronic Effects
Nesbitt’s Paradox (Arousal or Calming Effect?)
 influenced by smoker’s history
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Effects on Performance
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Inconsistent findings
Dependent on Smoking history
Enhanced Concentration and Attention
 Sustains performance on monotonous tasks,
improves speed and accuracy
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Memory Enhancement
 Improved cognitive functioning in Alzheimer’s
patients
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Unconditioned Behavior
Spontaneous motor activity initially depressed by
0.8 mg/kg, probably due to initial effects on ACh
transmission in brain.
 With repeated testing, tolerance develops and SMA
is increased, likely due to effects on epinephrine.
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Conditioned Behavior
Effects of nicotine on operant behavior (positively
and aversively motivated) are similar to those of
amphetamine
 Similarities likely related to nicotine’s indirect
actions on catecholamine release
 Effects blocked by nicotinic antagonist,
mecamylamine
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Drug Discrimination Studies
Nicotine is discriminated by rodents at 0.2
mg/kg
 NO generalization to caffeine or to any CNS
depressants, hallucinogens, or opioids
 Some evidence for partial generalization
between nicotine and amphetamine or
cocaine.
 Nicotine discrimination blocked by nicotinic
antagonists.
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Drug Self-Administration Studies
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It is surprisingly difficult to establish nicotine as a
positive reinforcer in nonhumans.
 Monkeys have been trained to inhale cigarette smoke,
following initial period of forced consumption and
reinforcing smoke inhalation with water or juice access.
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Some reports of intravenous nicotine self-administration
in nonhumans
 Response rates low and patterns of responding inconsistent
 Stimuli associated with nicotine delivery contribute to its
reinforcing efficacy.
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Conditions that support nicotine self-administration
include:
 a period of forced consumption of nicotine
 stimuli paired with the nicotine infusion
 FI schedule or a second order schedule that imposes a
period of abstinence between self-administration
opportunities
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Withdrawal Syndrome
Intensity varies among individuals
Symptoms include: decreased heart rate, concentration
difficulties, poor sleep, anxiety, irritability, anger and
aggression, increased eating and weight gain.
 For most, symptoms subside within a month, but may
persist for several months, and craving may continue
for several years.
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Quitting Smoking
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“Cold turkey”
Behavior Modification
Pharmacological Treatments for Dependence
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Nicotine gum
Nicotine patches
Nicotine nasal spray
Nicotine inhalers
Wellbutrin (buproprion: DA reuptake blocker)
Chantix (varenicline: partial nicotinic agonist)
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Tobacco presents a greater public health
threat than all other drugs combined,
including alcohol
Adverse Health Effects
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Emphysema & Bronchitis
Cardiovascular Disease
 Smoking accounts for 30% of CV disease related deaths
 ~150,000 premature deaths per year
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Cancer
 85% of lung cancers occur in smokers
 Smoking accounts for 30% of all cancers
 ~150,000 premature deaths per year
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Chronic Obstructive Pulmonary Disease
 ~80,000 premature deaths per year
Mortality ratios (total death, mean age 55 to 64) as a
function of the age at which smoking started and the
number of cigarettes smoked per day.
(Ksir et al., 2006. McGraw Hill)
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Smoking and Pregnancy
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higher miscarriage rates
lower birth weight
Some evidence for long-lasting intellectual
and physical effects in children of mother’s
who smoked during pregnancy
 e.g., lower IQ, increased prevalence of ADHD
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Sudden Infant Death Syndrome (SIDS)
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Passive Smoke Health Risks
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Exhaled Mainstream Smoke - smoke exhaled by the
smoker
Side stream smoke - smoke released from burning
end of a cigarette
Environmental tobacco smoke – mixture of side
stream smoke and exhaled mainstream smoke
U.S. Dept of Health and Human Services Data

In 2005, exposure to second hand smoke responsible
for the following deaths:
 3000 adults due to lung cancer
 46,000 adults due to coronary artery disease
 430 newborns due to SIDS
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More than 50 cancer-causing chemicals are
found in secondhand smoke including:
Polynuclear aromatic hydrocarbons (PAHs) (such as
Benzo[a]pyrene)
 N-Nitrosamines (such as tobacco-specific nitrosamines)
 Aromatic amines (such as 4-aminobiphenyl)
 Aldehydes (such as formaldehyde)
 Miscellaneous organic chemicals (such as benzene and vinyl
chloride) and
 Inorganic compounds (such as those containing metals like
arsenic, beryllium, cadmium, lead, nickel and radioactive
polonium-210).
Source: Office of the Surgeon General
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http://www.surgeongeneral.gov/library/secondhandsmoke/factsheets/factsheet9.html
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Economic Impact of Tobacco Sales
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Total annual sales almost $50 billion
Advertising funding for newspapers and
magazines
The federal government collects $6 billion and
states collect $7.5 billion annually in taxes
Health Care and Productivity Losses
Related to Tobacco
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$75 billion medical costs
$82 billion lost productivity
Caffeine, Theophylline, Theobromine
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Caffeine is the most frequently consumed
stimulant in the world
Chemical classification: methylxanthine
 Multiple Products Widely Available
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 Coffee
 Tea and Chocolate (also contain other methylxanthines)
 Soft drinks and Energy drinks
 Over the Counter Products
 Analgesics (aspirin/caffeine combinations)
 Stimulants (Caffeine is the only FDA-approved OTC
“stimulant”)
 Diuretics (weight loss products)
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In the U.S., average daily caffeine intake
equivalent to 2 cups of coffee (approx. 200 mg)
Beverage
Caffeine Content (mg)/cup
Brewed coffee
90-125
Instant coffee
35-164
Decaffeinated coffee
1-6
Tea
25-125
Cocoa
5-25
Coca-Cola
45
Pepsi-Cola
38
Mountain Dew
54
Chocolate bar
1-35
Amount
5 oz.
5 oz.
5 oz.
5 oz.
5 oz.
12 oz.
12 oz.
12 oz.
1 oz.
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Arabian goatherd legend
“The women’s petition against coffee”
British Tax Act
Coffee consumption increased during
prohibition
Commercial roasting began in 1790, NYC
First commercial blend in 1892, Maxwell
House
Recent popularity of specialty coffee shops
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From ~200 in 1989 to 15,000 in 2004
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First reliable report was in a Chinese
document, dated 350 AD
First European record of Tea, 1559
English East India Company
Popular in new colonies
Boston Tea Party
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Caffeine main methylxanthine in tea
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Amount varies, ~ 40-60 mg per 5 oz cup
Theophylline in small amounts
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Theophylline is a potent respiratory stimulant,
widely used to treat asthma
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Cocoa: Aztec and Mayan origins
17th century spread to wealthy in Europe
Drinks and Coffee Houses
First chocolate bar, 1847
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Milk chocolate invented by Swiss, 1876 (sold
under Nestle label)
Theobromine main methylxanthine in
chocolate (200 mg; 4 mg caffeine)
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Methylxanthines are alkaloids
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Slightly soluble in water
Absorption of Caffeine
Rapid, peak blood levels within 30 min.
 Maximum CNS effects ~ 2 hours
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Metabolism and Elimination
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Half-life ~3 hours
< 10% excreted unchanged
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Mechanism of Action
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Adenosine Antagonism
Adenosine is a neuromodulator which inhibits
release of a variety of neurotransmitters.
CNS effects of adenosine include behavioral
sedation.
Caffeine exerts its actions by inhibiting these
effects of adenosine.
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Mild CNS effects with low to moderate doses
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Enhance alertness, cause arousal, diminish fatigue
Potential adverse CNS effects with high doses
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Insomnia, increase in tension, anxiety, and
initiation of muscle twitches
Over 500 milligrams - panic sensations, chills,
nausea, clumsiness
Extreme high doses (5 to 10 grams) - seizures,
respiratory failure, and death
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Cardiovascular system
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Low doses - heart activity increases, decreases, or
do nothing
High doses - rate of contraction of the heart
increases, minor vasodilation in most of the body,
cerebral blood vessels are vasoconstricted
Respiratory system
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Opens airways and facilitates breathing
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Unconditioned Behavior
Caffeine increases spontaneous motor activity in mice
at 20-40 mg/kg. 80 mg/kg decreases activity.
 LD50 in rodents ~250 mg/kg (i.p.)
 Automutilation has observed following chronic high
dose administration.
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Conditioned Behavior
Pavlov (1927) first to show caffeine can disrupt
conditioned discriminations (i.e., increased
responding to CS-).
 Effects on operant behavior similar, but not identical
to those of psychomotor stimulants, like the
amphetamines.
 Caffeine increases avoidance responding (indicative
of anxiogenic effects).
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Drug Discrimination Studies
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Rats can be trained to discriminate 32 mg/kg
caffeine.
Generalization to other methylxanthines
NO generalization to nicotine
Some evidence for partial generalization between
low dose caffeine and amphetamine or cocaine
DA antagonists block discrimination of low doses
caffeine, but not high doses.
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Drug Self-Administration Studies

By itself, caffeine is a relatively weak positive
reinforcer.
 Caffeine maintains low and inconsistent patterns of
responding, but generally higher responding
compared to vehicle.
 Initial forced consumption is usually required to
establish caffeine as a reinforcer in nonhumans.
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Caffeine has been shown to potentiate reinforcing
effects of low cocaine doses.
Caffeine has been shown to prime reinstatement of
previously extinguished cocaine self-administration.
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Potential Health Risks of Caffeine Use

Increased risk of pancreatic cancer ?
 Original research criticized for methodological flaws
 Currently no support for this putative link

Other research shows a relationship with:
 cancers of the bladder, ovaries, colon, and kidneys
 women - fibrous cysts in breasts
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Reproductive Effects
 High daily doses (> 300 mg/day) may inhibit pregnancy,
promote miscarriage, and slow fetal growth
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Heart Disease
 Some retrospective studies report the incidence of nonfatal
heart attacks in men under 55 directly related to amount of
coffee consumed
 A prospective study showed that men who consume 5 or
more cups of coffee daily are 2.5 x more likely to suffer
from coronary artery disease.
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Caffeine Intoxication
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Caffeinism: restlessness, nervousness,
excitement, insomnia, flushed face, diuresis,
muscle twitching, rambling thoughts and
speech, stomach complaints
Caffeine Dependence
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Primary withdrawal symptom: headache ~18
hours after last use
Other symptoms include increased fatigue,
reduced energy evident within first two days,
with decreased symptoms over 5-6 days.