Lecture 13 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Includes pharmacokinetics and pharmacodynamics.

1. Caffeine
Brian J. Piper, Ph.D.

2. Goals
• Structure of different xanthines
• Pharmacokinetics
• Psychological and Physiological
Effects
• Pharmacodynamics
http://en.wikipedia.org/wiki/Caffeine

3. Coffea aribica Coffea robusta
Botany
• Coffea aribica: grown in Brazil, 10 m tall, 7 years to
mature
• Coffea robusta (Coffea canephora): grown in Vietnam,
< 1 year to mature, 2 x caffeine
● Camellia sinensis: grown in China, 2 m tall, leaves =
4% caffeine
● Theobroma cacoa: grown in Mexico, 6 m tall, contains
theobromine, dogs 
Theobroma cacao Camellia sinensis
http://en.wikipedia.org/wiki/Camellia_sinensis
http://www.ico.org/botanical.asp

4. Structure
• Xanthine: group of mild
stimulants, Xanthine forms
backbone
• Methly Group: a Carbon & 3
Hydrogens (CH3)
• Theobromine: Xanthine + two
methyl groups (3,7)
• Theophylline: Xanthine + two
methyl groups (1,3)
• Caffeine: Xanthine + three methyl
groups (1,3,7)

5. Structure
• Caffeine: Xanthine + three methyl
groups (1,3,7)
• CYP1A2: removes methyl groups

7. Energy Drinks Serving Size Caffeine (mg)
(oz.)
Spike Shooter 8.4 300
Cocaine 8.4 280
Monster Energy 16 160
Full Throttle 16 144
Rip It, all varieties 8 100
Enviga 12 100
Tab Energy 10.5 95
SoBe 8 83
Red Bull Sugarfree 8.3 80
Rockstar Energy Drink 8 80
SoBe Adrenaline Rush 8.3 79
Amp 8.4 74
Glaceau Vitamin Water Energy Citrus 20 50
SoBe Essential Energy, Berry or Orange 8 48
http://www.cspinet.org/new/cafchart.htm Accessed 3/15/08

8. http://anrcatalog.ucdavis.edu/pdf/8265.pdf

9. Seizures?
• Rats that were genetically prone
to convulsions received different
doses (umol/kg) of
methylxanthines.
• Behavior was rated for 6 hours:
– 0 = no response
– 2 = tremor
– 4 = forelimb clonus
– 6 = falling down
– 8 = tonic-clonic seizures/death
*Clonus (Gr: violent, confused motion), large involontary movements
De Sarro et al. (1997) Naunyn-Schmiedeberg’s Arch Pharmacol, 356, 48-55.

10. Seizures?
• Rats that were genetically prone
to convulsions received different
doses (umol/kg) of
methylxanthines.
*Clonus (Gr: violent, confused motion), large involontary movements
De Sarro et al. (1997) Naunyn-Schmiedeberg’s Arch Pharmacol, 356, 48-55.

11. Sex Differences in
Caffeine PK <-women, non-smoking
• Women and men received
100 mg caffeine capsules.
• Women (open circles) had men, smoking ->
<-men, non-smoking
higher caffeine levels than
men (open-squares).
• Sex differences were
apparent in both plasma and
saliva.
• Smoking: increases CYP1A2
• Oral Contraceptives: inhibit
CYP1A2
Carrillo et al. (2000).Ther Drug Monitor, 22, 409-417.

12. Smoking Difference
in Caffeine PK <-women, non-smoking
• Smoking: increases CYP1A2
• Oral Contraceptives:
inhibit CYP1A2 men, smoking ->
<-men, non-smoking
Carrillo et al. (2000).Ther Drug Monitor, 22, 409-417.

13. Caffeine-Melatonin CYP1A2
Interaction
Caffeine increased:
Cmax 2.4
AUC 2.2
Plasma melatonin levels in humans after melatonin administer either alone (circles)
or preceeded by 3 x 200 mg or caffeine (squares).
Hartter (2003). Brit J Clin Pharmacology, 56, 679-682.

14. Effects
• Psychological • Physiological
– Increased alertness – Constricts blood
– Improved attention vessels in brain and
– Euphoria (slight) eyes.
– Nervousness (High – Increases heart rate
Doses) – Elevates urine
production
– Increases breathing
rate

15. Cognitive Benefits
• Medical students (N=18)
completed tests of vigilance or
sleepiness at baseline, after
placebo,150 mg caffeine, or
caffeine + 2 g taurine.
• Both caffeine & caffeine +
taurine improved performance
Aggarwal et al. (2011). Brit J Surgery, 98, 1666-1672.

16. Caffeine & Reinforcement
Preference
----------------------------------
Aversion
Patkina & Zvartau Eur J Neuropsychopharm, 8, 287-291.

17. Pharmacodynamics
• Adenosine antagonist
• Increases dopamine & glutamate
• Elevates adrenaline (epinephrine)
• Blocks antidiuretic hormone
For more details about neurobiological effects of caffeine, goto:
http://images.google.com/imgres?imgurl=http://www.benbest.com/health/A_Recept.gif&imgrefurl=http://www.benbest.com/health/caffeine.html&h=288&w=429&sz=29&tbnid=yC5aX2S9XqKrbM:&tbnh=82&tbnw=123&hl=en&start=12&prev=/images%3Fq%3Dadenosi
ne%26svnum%3D10%26hl%3Den%26lr%3D%26rls%3DCNDB,CNDB:2004-15,CNDB:en%26sa%3DN

18. Adenosine
• has 24 hour rhythm

19. Neurochemistry
• Caffeine causes biphasic effects
on nucleus accumbens
neurotransmitters and behavior.
Solinas, M. (2002). et al. J. Neurosci 22, 6321-6324

20. Caffeine
Tolerance
• Caffeine abstaining humans
(N=18) lived in a lab for two-weeks
– Day 1-3: all placebo
– Day 4-10: 250 mg caffeine or placebo
– Day 11-14: placebo
Robertson et al. (1981) J Clin Invest , 67, 1111-1117.

21. Tolerance to other
Physiological Effects
<- Day 1
<- Day 7
Robertson et al. (1981) J Clin Invest , 67, 1111-1117.

22. Caffeine Tolerance
• Rats received caffeine (1.0, Dose
0.25, or 0 mg/ml drinking
water) for two-weeks.
• They were then dosed with
caffeine, adenosine
antagonists (CPT or MSX) or
amphetamine.
• Motor activity was recorded.
• How do you interpret this
data?
Caffeine in Water for 2 weeks
Karcz-Kubicha et al (2003) Neuropsychopharmacology, 28, 1281-1291.

23. Interpretation
• What information is provided by:
– A versus B
– B versus C
– D versus E versus F
– G versus H
B
D E
G F
C H
A

24. Interpretation
• In rats that were caffeine naïve, caffeine
caused hyperactivity (A vs. B).
• Rats that regularly consumed caffeine were
insensitive/tolerant to caffeine (B vs. C).
● There was no cross-
tolerance to the B
hyperactivity caused by
amphetamine(D vs. E vs. F).
D E
● Adenosine is important G F
for caffeine tolerance.
Caffeine pre-
exposed rats also showed a
blunted hyperactivity to the C H
A1 and A2A antagonists (G vs H).
A

25. Caffeine & Parkinson’s
Disease (PD)?
• Dietary habits were
obtained from middle aged
men (N=8,000) in 1965.
• Subjects were monitored
for 30 years for incidence
of PD.
• Mechanisms
– Antioxidant
– 3rd variable
Parkinson’s Symptoms (2 min):
http://www.youtube.com/watch?v=_L_WF6gv5BI
Ross, G. W. et al. (2000). JAMA, 283, 2674-2679.

26. Tri-methyl-xanthine Summary
• Pharmacokinetics (CYP1A2)
• Pharmacodynamics
– Adenosine antagonist
• Risks (seizures?)
• Benefits (Parkinson’s Disease?)

27. Self-test
• Jane drinks two large (12 oz) cups of instant
coffee with breakfast, a Starbucks cafe latte
in the afternoon, a Coke (12 oz) with dinner,
and a decaf coffee (8 oz) while studying
before bed.
• What was her total (mg) of caffeine
consumption for the day? Please show how
you reached this total using the chapter in
Buzzed.