PSYC650

Caffeine, Nicotine, and Steroids

Caffeine

• Most widely used psychoactive substance in the world; used daily by ~80 percent of adult U.S. population.

• Low doses (50–300 mg) increase alertness, energy, and ability to concentrate.

• Relaxes bronchioles, increases gastric secretions and urine output.

• Moderate consumption rarely a health risk.

• Higher doses: Produce anxiety, restlessness, insomnia and tachycardia in some sensitive people

Caffeine

Pharmacokinetics• GI absorption is 99 percent in 45 min.

(fast).• Peak plasma levels about 120 min. after

ingestion.• Half-life is ~3.5–5 hour in adult humans,

but 60–100 hours in infants.• Half-life is reduced by 30–50 percent in

smokers; doubled in women on oral contraceptives (and prolonged during last trimester of pregnancy).

• In smokers, the half-life is shortened. But, when smoking is stopped, half-life increases, and may account for some of the withdrawal discomfort (jitteriness) to cigarettes.

• Two major metabolites, theophylline and paraxanthine, behave similarly to caffeine, a third, theobromine, does not.

• Caffeine is metabolized by the CYP-1A2 subgroup of hepatic enzymes. Some SSRI-type antidepressants inhibit enzyme (fluvoxamine; Luvox), other types (e.g., venlafaxine; Effexor) do not.

Caffeine

Mechanism of action:• Adenosine is inhibitory.• Caffeine antagonizes two types of adenosine

receptors – A1 and A2a. In mice that do not have A2a receptors, caffeine only has depressant, not stimulant, effects on activity.

• Positive effect of caffeine appears to be due to the antagonism of adenosine receptors that normally act on GABA neurons to inhibit dopamine release. Removal of GABAergic inhibition increases dopamine release.

Caffeine

• Addiction and dependence:– Individuals often become dependent;

median daily intake = 360 mg and 40 percent took less than 300 mg.

• Withdrawal:– Symptoms include: Headache, tiredness, lack

of concentration, anxiety, irritability, increased muscle tension, depression, nausea/vomiting.

– Begin 12–24 hours after stopping; peak by 20–48 hours.

– Not related to the quantity of caffeine used.

Caffeine

• Cerebral blood flow is increased during withdrawal headache and decreased within 30 min. after taking caffeine.

• Reported in newborns whose mothers were heavy coffee drinkers.

• Caffeine users should be given some before any surgeries to prevent headache afterwards.

• Symptoms disappear soon after caffeine is taken; but decaf will result in headache.

Caffeine

Time course of caffeine withdrawal symptoms.

Tolerance:Some effects that became tolerant in humans:

– Blood pressure, heart rate– Adrenalin, noradrenalin levels– Anxiety, nervousness, energy

Caffeine

Some effects that did not show tolerance:– Caffeine-induced alertness and wakefulness– Cerebral energy metabolism

• “Every single exposure to caffeine is able to produce cerebral stimulant effects and this is especially true in the areas that control locomotor activity and structures involved in the sleep-wake cycle.”

Caffeine

Toxicity:• Caffeinism – At doses above 1000 mg/day, serious

effects: Delirium, excitement, ringing in ears, flashes of light, low-grade fever, chilliness, flushing, insomnia, irregular heartbeat, loss of appetite.– Looks like anxiety disorder, but does not respond to

tranquilizers.– Treatment: Get rid of caffeine.

• 6 deaths in humans; lethal dose estimated at 10 grams taken orally (about 100 cups of coffee); death is due to convulsions and respiratory collapse.

• Is caffeine safe in pregnancy? Controversial.– Moderate amounts seem to be OK. But large amounts, like

6–10 cups a day may increase risk of spontaneous abortions.

Caffeine

NicotineEpidemiology• One of the 3 most widely

used psychoactive drugs.• Most preventable cause of

disease and premature death.

• Current use fell from ~50 percent in 1965 to ~25 percent in 1998.

• Average starting age for people is declining; 9 out of 10 are addicted by age 21.

Pharmacokinetics• 1828: Nicotine separated out from tobacco

(1 of ~4,000 compounds released by burning).• Colorless, volatile, liquid alkaloid; not well absorbed from

digestive tract (although number of children poison themselves each year from eating tobacco… exposure to pesticides).

• But amount actually delivered depends on how the cigarette is smoked.

– Nicotine is metabolized by the hepatic enzyme CYP2A6 (which may be inhibited by SSRI antidepressants).

Nicotine

Nicotine

• Lethal dose = ~60 mg (40 mg has been deadly).• Symptoms: Abdominal pain, nausea, vomiting,

diarrhea, headaches, decrease in blood pressure, death from suppression of breathing.

• Absorbed from every site on, or in, the body.• Cigarettes: Flue-cured tobacco makes acidic smoke

that reduces absorption from mouth, so nicotine must be inhaled from lungs where pH has no effect on absorption. – Nicotine is suspended in cigarette smoke in form of minute

particles (tars); is quickly absorbed into bloodstream from lungs.      

• Pipe and cigar tobacco are air-cured; makes alkaline smoke so nicotine is absorbed from the mouth and does not need to be inhaled.

Nicotine

• Nicotine is quickly and thoroughly distributed in the body, to brain, placenta, all body fluids (including breast milk).

• Liver metabolizes 80–90 percent before excretion by kidneys.

• Elimination half-life is ~2 hours. The major metabolite of nicotine is cotinine, which is basis for tests.

Nicotine

• Mechanism of action: Indirect activation of the sympathetic system.– Occupies and activates nicotinic cholinergic

sites.– Low doses stimulate the receptors.– High doses block the receptors.– Causes release of:

• Dopamine (reinforcement?)

• Acetylcholine and glutamate (memory?)

– Would nicotine-derived drugs help treat dementia?

Nicotine

Pharmacological effects

• Initially causes nausea and vomiting by stimulating vomiting center in brain stem and sensory endings in stomach. This becomes tolerant.

• Stimulates hypothalamus to produce antidiuretic hormone, causing fluid retention.

• Reduces activity coming in from muscles, producing relaxation.

• Increases heart rate, blood pressure and contractility; but carbon monoxide in smoke combines with oxygen better than hemoglobin, so it decreases oxygen carrying capacity (suffocates cells).

Nicotine

• Constricts blood vessels in skin, producing cold, thin, wrinkles (faster aging).

• Inhibits stomach secretions, stimulates bowel (laxative in nontolerant person).

• May increase metabolism of fat; dull taste buds.• Slows stomach contractions; increases blood

sugar.• May improve attention/memory; although high

doses may increase nervousness, tremors, seizures, panic attack.

• May have an antidepressant effect (i.e., are smokers self-medicating?).

Nicotine

Nesbitt’s paradox: Nicotine causes arousal and a release of epinephrine, yet most people say it relaxes them. This may be relevant to the reason people smoke.

Is it simply relief from withdrawal? Does it depend on the stress of the situation? (Relaxation with high stress, stimulation with low?)

Smokers report positive subjective effects if nicotine is given by smoking or intravenously, but nonsmokers do not like it.

Nicotine

Toxic effects• Heart disease: Nicotine increases

workload; carbon monoxide decreases oxygen supply (reduce lungs ability to get oxygen, which makes heart work harder); increases arteriosclerosis (blocking) and thrombosis (clotting) in coronary arteries.– Greatly increased risk with contraceptives.

• Lung disease: Ash and tars are deposited on moist membranes of lung; smoking reduces actions of the cilia and phagocytes that would normally clean the tissues.

Nicotine

• Increased risk of cancer of lungs, mouth and bladder; greatly increased by alcohol (less than 10 percent of nonsmokers get lung cancer).

• Reproduction: Cigarette smoking reduces oxygen delivery to the fetus; decreases fertility; produces smaller babies, more stillbirths, premature babies and sick babies; may increase SIDS (sudden infant death syndrome).

Healthy lung Diseased lung

Your Lung on Nicotine

Tolerance / dependence• Little biological tolerance; smokers usually dose themselves

with consistent amounts (30–40 ng/ml of blood).

• Withdrawal symptoms: Irritability, anxiety, anger, difficulty in concentrating, restlessness, weight gain, insomnia

Nicotine

Within 20 minutes: Blood pressure returns tonormal and heartbeat stabilizes

Within 3 months: Circulation improves Immune system improves

Within 8 hours: Oxygen level in blood increases Mucus begins to clear out of your lungs making breathing easier

Within 9 months: Sinus congestion, wheezing, shortness of breath and phlegm production decrease Lung function improves

Within 48 hours: Senses of smell and taste improve Chances of heart attack decrease

1 Year: Risk of dying of a heart attack is cut in half

  5 Years: Stroke risk reduced to that of a non-smoker

  10 Years: Chances of getting lung cancer is cut in half

Nicotine

When you stop, your body begins to repair itself immediately:

Therapy• Low nicotine content cigarettes not useful,

people just smoke more.• Substitution/replacement: Nicorette gum,

nicotine patches, nasal sprays and inhalers.• Efforts to reduce the craving,

(i.e., antidepressants, bupropion; Zyban = Wellbutrin).

• All replacement methods are equally effective, approximately doubling the quit rate of smokers without help.

Nicotine

• Factors that create the addiction: 10–15 percent of current alcohol drinkers are considered problem drinkers, but 85–90 percent of cigarette smokers consider themselves addicted to nicotine.

– Rapid and frequent reinforcement (200 times a pack).– Rapid metabolism (clearance allows frequent and

repeated use), plus rapid onset of withdrawal.– Complex direct pharmacological effects.– Social rewards of peer group– Smoking conditioned to other activities (e.g., eating,

drinking, driving).

Nicotine

– No performance impairment; might even be improvement in alertness, reaction time.

– Relatively inexpensive (?)– No equipment other than match– Readily available (?)– Portable, easy to store– Legal for 18 and up

Can you hold out for 18 minutes?

Factors promoting addiction (cont.)

Treatment of Nicotine Dependency

• Nicotine replacememt therapy– Gums, patches, inhaler, etc.

• Bupropion (Wellbutrin, Zyban)• Partial nicotinic receptor agonist

– Varenicline (Chantix)

• Nicotine vaccines (investigational)

Nicotine Dependence

• Treatment commonly uses pharmacotherapies.

• A specific ‘quit date’ is set.• No substantial social/occupational

dysfunction• Less need for family involvement• Effective OTC treatments available.

Nicotine Patch

• Begin with high dose patch (21 or 22 mg).• But, <15 cigarettes, start with 11 or 14 mg

patch.• Can use either 24 hour or 16 hour patch.

– 24 hour patch relieves AM craving but may cause insomnia.

• Skin irritation, nausea, vivid dreams• Duration = 6–12 weeks with tapering.

Nicotine Gum/Lozenge

• Dose: One 2 mg lozenge or piece of gum every hour (or 4 mg dose for heavy smokers, >25 cigarettes/day).

• Dose tapered over 6–12 weeks by decreasing dose or increasing time between doses.

• For gum: Chew slowly until slight tingling, then park gum until tingling subsides, then repeat over 30 minutes.

• For lozenge: Suck, not chew.

Side Effects

• Lozenge– Nausea, heartburn, mild throat/mouth

irritation– Contains phenylalanine; do not use with PKU.

• Gum– Jaw soreness– Canker sores

Nasal Spray/Inhalers

• Nasal Spray– Droplets average 1 mg per administration.– Apply spray to each nostril every 1 to 2

hours.

• Vapor inhalers– Cartridges of nicotine in tube– Nicotine vapor (0.013 mg/puff)– Dose = 6–16 cartridges daily; used ad lib

for about 12 weeks.

Side Effects

• Nasal spray– Nasal and throat irritation, rhinitis,

sneezing, coughing, watering of eyes (75 percent)

• Inhaler– Throat irritation or coughing (50 percent)

Bupropion (Zyban/Wellbutrin)

• Can be used as 1st line treatment.• Target dose = 300 mg/day.

– Start at 150 mg/day, 7 days prior to quit date; after 3 to 4 days increase dose to 300 mg (150 mg bid).

• Side effects:– H/A, jitteriness, insomnia and GI

symptoms– Seizures– Don’t use in those with eating disorders.

Varenicline (Chantix)

• Approved: May 2006• Unique MOA: Partial agonist at

nicotinic ACh receptors• Blocks ability of nicotine to stimulate

ACh receptors, thus blocking activation of DA system (reward system).

• Elimination half-life = 24 hours.– Renal route

Varenicline (Chantix)

• Dosing:– After meals and a full glass of water

• Recommended dose of CHANTIX = 1 mg twice daily following a 1-week titration as follows:– Days 1–3: 0.5 mg/daily– Days 4–7: 0.5 mg bid– Days 8–end: 1.0 mg bid

• Course of treatment = 12 weeks + 12 weeks if abstinent.

• Most common side effect = nausea.

Figure 1: Continuous Abstinence, Weeks 9 through 12

Figure 2: Continuous Abstinence, Weeks 9 through 52

Figure 3: Continuous Abstinence Rate during nontreatment follow-up

Anabolic Steroids

• Anabolic, or anabolic-androgenic steroids: Synthetic substances related to testosterone (naturally-occurring male sex hormone).

• Have both muscle-building and masculinizing effects.

Anabolic Steroids

• Use is surprisingly common…– 55 percent of 27-yr-old male bodybuilders– 10 percent of 24-yr-old female

bodybuilders– 20 percent of college athletes– 6 percent of male and 2.5 percent of

female high school athletes– Lifetime use is 4.9 percent for males and

2.4 percent for females

… and increasing!

Anabolic Steroids

• Promote increased muscle mass and enhanced physical strength, endurance, physical appearance, athletic performance.

• Androstenione: Testosterone precursor admittedly used by MLB home run record-holder Mark McGwire.– Made illegal in 2004.– Now testable in urine.

Anabolic Steroids

• Well-recognized uses in prescription.– Treatment of delayed puberty.– Prevention of weight loss in patients

undergoing hemodialysis and in males with HIV.

Anabolic Steroids

• Mechanism of action:– Steroids differ not so much in structure but

in resistance to metabolism by liver enzymes.– Oral administration; effectively absorbed by

intestine, quickly metabolized in liver.– Injection; first-pass metabolism is blunted.– Structural modification can alter metabolic

processes and increase efficacy.

Anabolic Steroids

• Effects on athletic performance:– Increase fat-free mass, muscle size,

strength in men even in the absence of exercise.• Effects of steroids and exercise on strength

are therefore additive.

– No positive effects on aerobic performance.

– Amounts commonly used by athletes are 10 to 200 times therapeutic dose for testosterone deficiency.

Anabolic Steroids

• Anticatabolic effect:– Block action of natural cortisone, which

makes energy available by breaking down proteins.

– This is how steroids increase body mass.

• Anabolic effect:– Synthesis of new protein in muscle cells;

promote release of endogenous growth hormone.

Anabolic Steroids

• Female athletes:– Same anticatabolic and anabolic effects

as male athletes.– Also induce female masculinizing and

related effects.• Increased body and facial hair• Lowered voice• Enlarged clitoris• Coarser skin• Menstrual cycle cessation or irregularity

Anabolic Steroids

• Effects in Middle-Aged and Elderly Men:– Testosterone naturally declines with age,

leading to loss of muscle mass and increase in body fat.• Steroids can inhibit these changes.

– Side effects: Dangerously increased hemoglobin levels, leg edema, kidney problems, prostate cancer

– Steroids can induce meaningful improvements in physically impaired aging men.• Should we use steroids as an “antiaging” cure?

Anabolic Steroids

• Psychological side effects:– Aggressive personality (“roid rage”)

• Anger• Violent feelings• Irritability• Distractibility• Forgetfulness• Increased aggression reported by 60

percent of users

– Mild hypomania or mania

Which of the following is a partial

nicotinic agonist?

Zyb

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Chan

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25% 25%25%25%1. To aid in the efficacy of chemotherapy

2. To increase weight mass in men with HIV

3. To improve athletic performance

4. To counter pathological passivity 1010

Questions? Thoughts?