 most commonly consumed psychoactive drug in the world ◦ in US – consumed by 80% adult population ◦ found in coffee, tea, cola, chocolate and cocoa ◦ also found in many prescription and OTC medications  (FDA estimates ~1000 prescription and 2000 OTC contain caffeine)  safe and can be added to just about anything that we can swallow!

200 mg in 4 ounces!!!! “

 commodity traded most extensively in the world is oil (wars fought over oil)  Next most widely traded commodity ◦ caffeine  raw material includes coffee beans, tea leaves, cola nuts  estimates ~ 120,000 tons/year; employs more than 20,000,000 people

 Chinese claim to have discovered tea around 2700 BCE  At least ½ the world drinks tea  England and China – fed each others addictions ◦ China provided tea for England and England (from their British Colonies close to India) provided China with Opium

Cutty Sark - renovated Tea- clipper last survivor - mid 1800’s now in Greenwich England called “Clipper ships” - very fast sailing ships built to cut the time needed to get tea from India and China back to Europe

 absorption – oral caffeine is rapidly and completely absorbed ◦ significant blood levels within 30 – 45 min; completely absorption over next 90 min ◦ freely and equally distributed throughout the body ◦ crosses placenta to fetus  breast milk = or exceeds level in maternal plasma

Pharmacokinetics:  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).

 metabolized by liver before excretion ◦ main metabolites; theophylline, theobromine ◦ CYP1A2 enzyme  certain SSRI antidepressants (flovoxamine) are potent CYP1A2 inhibitors – caution needed…..

Tolerance: Some effects that became tolerant in humans: ◦ Blood pressure, heart rate ◦ Adrenalin, noradrenalin levels ◦ Anxiety, nervousness, energy

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

Sleep is the physiological function most sensitive to the effects of caffeine. ◦ Caffeine increases the time it takes to go to sleep and the total duration, but does not disturb the phases. ◦ Some tolerance develops to sleep disturbance. EFFECT OF AN ADENOSINE ANTAGONIST (CAFFEINE) ON SLEEP IN A NORMAL SUBJECT

Reinforcement:  not a powerful reinforcer in animals self- administering intravenously.  Reinforcement varies with dose – ◦ does not directly increase DA in mesolimbic regions – maybe prefrontal cortex Discrimination  Human subjects can discriminate caffeine from placebo, in coffee or capsules  Doses of 300 mg or more are most reliably detected, but some people can detect much lower doses

 ingestion of 85 – 250 mg caffeine (1 -3 cups of coffee) increases capacity for sustained attention and decreased reaction time  fine or delicate muscular coordination or timing…..

 mg a day of caffeine probably will NOT make someone feel very well

Toxicity:  Caffeinism – (typically above 1000 mg/kg  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

3 types of related alkaloids from plants 1. theophylline 2. caffeine 3. theobromine

1. relax smooth muscle (notably bronchial muscles) 2. stimulate CNS and cardiac muscle theophylline and caffeine more than theobromine 3. produce diuresis in kidneys

 therapeutically- used to treat a variety of disorders ◦ asthma (theophylline mostly to relax respiratory muscles) ◦ narcolepsy (to maintain daytime wakefulness) ◦ migraine ◦ adjunct to treat headache and other pain syndromes

 Caffeine – effective psychostimulant  heavy consumption (12 or more cups/day or 1.5 g caffeine) ◦ agitation, anxiety, tremors, rapid breathing, insomnia  lethal dose – 10 g (100 cups of coffee)  people with anxiety disorders – especially sensitive to caffeine

 anxiety disorders  tremors  possible dehydration

 caffeine exerts variety of effects in CNS at different doses ◦ most likely – blockade of adenosine receptors ◦ so adenosine antagonist! ◦ represents major site of action  Adenosine – ◦ neuromodulator of several nt in CNS ◦ majority of adenosine effects are sedating, depressing, and anticonvulsant