Characterized based on CNS Effects: 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

Over-the-Counter Stimulants Nicotine, Caffeine, Theophylline,

Theobromine, Ephedrine Legally Restricted Stimulants

Cocaine, Amphetamine, Methamphetamine

Early Medicinal Uses Europe New World

The spread of tobacco use Tobacco production Nicotiana tobacum

Spanish monopoly on sales to Europe Tobacco colony in Virginia Popularity of snuff in England

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)

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.

Colorless, highly volatile liquid alkaloid 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 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

Distribution Depends on route and time since administration High concentration achieved in brain Crosses most barriers, including placenta

Metabolism/Elimination 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

Physiological Effects 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

Mimics and Blocks ACh Facilitates Adrenalin Release

Subjective Effects Acute Effects vs. Chronic Effects Nesbitt’s Paradox (Arousal or Calming

Effect?) influenced by smoker’s history

Effects on Performance Inconsistent findings Dependent on Smoking history Enhanced Concentration and Attention

Sustains performance on monotonous tasks, improves speed and accuracy

Memory Enhancement Improved cognitive functioning in Alzheimer’s

patients

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.

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

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.

Drug Self-Administration Studies 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.

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. 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

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.

Quitting Smoking “Cold turkey” Behavior Modification Pharmacological Treatments for Dependence

Nicotine gum Nicotine patches Nicotine nasal spray Nicotine inhalers Wellbutrin (buproprion: DA reuptake blocker) Chantix (varenicline: partial nicotinic agonist)

Tobacco presents a greater public health threat than all other drugs combined, including alcohol

Adverse Health Effects Emphysema & Bronchitis Cardiovascular Disease

Smoking accounts for 30% of CV disease related deaths

~150,000 premature deaths per year Cancer

85% of lung cancers occur in smokers Smoking accounts for 30% of all cancers ~150,000 premature deaths per year

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)

Smoking and Pregnancy 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

Sudden Infant Death Syndrome (SIDS)

Passive Smoke Health Risks 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

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 Generalhttp://www.surgeongeneral.gov/library/secondhandsmoke/factsheets/factsheet9.html

Economic Impact of Tobacco Sales 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 $75 billion medical costs $82 billion lost productivity

Caffeine, Theophylline, Theobromine

Caffeine is the most frequently consumed stimulant in the world Chemical classification: methylxanthine Multiple Products Widely Available

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)

In the U.S., average daily caffeine intake equivalent to 2 cups of coffee (approx. 200 mg)

Beverage Caffeine Content (mg)/cup Amount

Brewed coffee 90-125 5 oz.Instant coffee 35-164 5 oz.Decaffeinated coffee 1-6 5 oz.Tea 25-125 5 oz.Cocoa 5-25 5 oz.Coca-Cola 45 12 oz.Pepsi-Cola 38 12 oz.Mountain Dew 54 12 oz.Chocolate bar 1-35 1 oz.

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 From ~200 in 1989 to 15,000 in 2004

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

Caffeine main methylxanthine in tea Amount varies, ~ 40-60 mg per 5 oz cup

Theophylline in small amounts Theophylline is a potent respiratory

stimulant, widely used to treat asthma

Cocoa: Aztec and Mayan origins 17th century spread to wealthy in

Europe Drinks and Coffee Houses First chocolate bar, 1847

Milk chocolate invented by Swiss, 1876 (sold under Nestle label)

Theobromine main methylxanthine in chocolate (200 mg; 4 mg caffeine)

Methylxanthines are alkaloids Slightly soluble in water

Absorption of Caffeine Rapid, peak blood levels within 30 min. Maximum CNS effects ~ 2 hours

Metabolism and Elimination Half-life ~3 hours < 10% excreted unchanged

Mechanism of Action 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.

Mild CNS effects with low to moderate doses Enhance alertness, cause arousal, diminish fatigue

Potential adverse CNS effects with high doses 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

Cardiovascular system 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 Opens airways and facilitates breathing

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. 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).

Drug Discrimination Studies 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.

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.

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.

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

Reproductive Effects High daily doses (> 300 mg/day) may inhibit

pregnancy, promote miscarriage, and slow fetal growth

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.

Caffeine Intoxication Caffeinism: restlessness, nervousness,

excitement, insomnia, flushed face, diuresis, muscle twitching, rambling thoughts and speech, stomach complaints

Caffeine Dependence 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.