By: Andrew Novick

A Walk On The (Not So)
Wild Side Of Stimulants

Caffeine seems to be the one socially acceptable stimulant: used by and marketed to people of all ages without a prescription.

My Discoveries?

Beyond a few cups of green tea, I tend to get a bit anxious. But despite how caffeine affects my individual biochemistry, I find its widespread use fascinating.

Besides a unique pharmacology, caffeine has many benefits. It's energizing. It can help aid in focus, cognition, fat loss, and athletic performance.

Most of all, tasty beverages everywhere contain caffeine! Cautiously eager singles even use caffeine consumption as an excuse to go out on dates. I admit: I've used the line myself.

Eyes glued to the ground (in an attempt to not stare at her breasts), I'd utter the magic words, "So you wanna go get a cup of coffee sometime?" Responses to this technique have varied.

So while it might not improve your game, understanding caffeine pharmacology is important. Due to its social acceptability and mass consumption, the finer points of caffeine's effects on human biochemistry are often taken for granted. To remedy this, 'Chemically Correct: Caffeine Part I' will give you the run down.

Chemistry

Caffeine (1,3,7-trimethylxanthine) is a member of the xanthine family. Xanthines are found naturally throughout the plant and animal kingdoms. Xanthine itself is a part of human metabolism.

Other naturally occurring xanthines include theobromine (found in chocolate) and theophylline (found in plants and isolated as a drug for asthma).

	Theobromine: Theobromine is the primary alkaloid found in cocoa and chocolate (Theobroma cacao is the scientific name of the cacao tree). Its presence is one of the causes for chocolate's mood-elevating effects. In chocolate, theobromine exists in doses that are safe for humans to consume in large quantities, but can be lethal for animals such as dogs and horses, as they metabolize theobromine more slowly.

Xanthines are a part of the purine family. Purines such as adenine and guanine make up the base pairs of DNA. Despite the resemblance of caffeine to aspects of our DNA, xanthines don't get mixed up in our genetic code.

	DNA Nucleobases: Nucleobases are the parts of RNA and DNA that are involved in pairing up. These include cytosine, guanine, adenine, thymine (DNA) and uracil (RNA). These are abbreviated as C, G, A, T, and U, respectively.

Rather, they are a product of purine degradation. The enzyme xanthine oxidase efficiently metabolizes xanthines

Pharmacokinetics

	What Does Pharmacokinetics Mean? The process by which a drug is absorbed, distributed, metabolized, and eliminated by the body.

Caffeine is 99% orally bioavailable. Levels tend to peak within 30-60 minutes, passing through all biological membranes including the blood brain barrier³⁶. The half-life is around 5 hours.

80% of caffeine is metabolized to paraxanthine by CYP1A2³⁷. A small percentage is converted to theophylline. Both of these metabolites are pharmacologically active and have similar half-lives to caffeine³⁸.

Only 5% of ingested caffeine remains unchanged, the majority being excreted as 1-methyluric acid³⁹.

For the same amount of caffeine ingested, plasma levels can vary by a factor of 15.9 between individuals⁴⁰. This could explain differences in individual sensitivity to caffeine.

Despite variations in human absorption and metabolism, a useful estimation is that 10mg/kg of caffeine in the rat equals out to about 250mg of caffeine in a 70kg human¹.

Pharmacology

Several direct pharmacological effects have been ascribed to caffeine. These include adenosine receptor antagonism, release of intracellular calcium, phosphodiesterase inhibition, and GABA(A) receptor antagonism.

The fact of the matter is that with the exception of adenosine antagonism, all of these effects occur at dosages that would be toxic to humans¹. Thus, only antagonism of adenosine receptors is regarded as relevant.

It is possible that caffeine has other unknown mechanisms. And some phenotypes using higher dosages might be more vulnerable than others to caffeine's "upper limit" effects such as phosphodiesterase inhibition. However, this article will concentrate on pharmacologic effects related to adenosine antagonism.

Adenosine & Adenosine Receptors:

Adenosine. You've heard of it before. It's the "A" in ATP. Since adenosine is a main component of THE energy substrate, it should come as no surprise that adenosine receptors concern themselves with functions like sleep, CNS stimulation, and metabolism.

	What Does CNS Mean? CNS stands for Central Nervous Systtem.

When lots of ATP is being consumed and not much being produced, adenosine levels rise. This would most likely occur during exercise or prolonged wakefulness. Adenosine accumulates the longer we've been awake, and returns to normal during sleep².

RELATED ARTICLE

ATP: Energy's Currency! If one has ever wondered just how we are able to summons the energy to perform a number of activities under a variety of conditions, the answer, in large part, is ATP. Without ATP, ones body would simply fail to function. Learn why... [ Click here to learn more. ]

Stimulation or antagonism of adenosine receptors indirectly affects other neurotransmitter systems. This is similar to the way nicotine utilizes acetylcholine receptors to induce dopaminergic and serotonergic effects.

There are 4 types of adenosine receptors:

• A1
• A2A
• A2B
• A3

It appears that normal adenosine levels as well as human caffeine consumption only affect A1 and A2A receptors¹.

The A1 receptor when agonized produces a sedative effect through the inhibition of neurotransmitter release. This inhibition is specific, as the A1 receptor will inhibit stimulatory neurotransmitters more than inhibitory ones like GABA³.

A2A receptors are relevant to dopamine function. They are concentrated in dopamine rich regions of the brain and are co-localized with D2 receptors⁴, which brings us to our discussion of caffeine and dopamine.

Dopamine:

Intact dopamine transmission is necessary for caffeine's stimulating effects⁵. At lower caffeine doses, the blockade of A2a receptors (rather than A1) appears to play the more important role in activating dopamine and producing stimulation⁶. A2A blockade and subsequent dopaminergic enhancement can occur at doses as low as 35mg in humans⁷.

How does A2A blockade increase dopamine activity? Adenosine action at A2A receptors decreases the affinity of dopamine binding to D2 receptors in the striatum¹⁵.

Caffeine reverses this effect, allowing dopamine to hit D2 receptors with greater ease. It's important to note that A2A blockade increases dopamine function in the striatum rather than the nucleus accumbens.

Higher doses of caffeine (above 250mg) which correspond to both A2A and A1 receptor blockade will increase dopamine activity in the nucleus accumbens.

There is a qualitative difference between increasing dopamine in the striatum (caffeine) as opposed to the nucleus accumbens (amphetamine). In more common language, caffeine can give you the "jitters" while amphetamines leave you "tweaked."

CAFFEINE INTAKE CALCULATOR

To find out your daily caffeine intake41 (in milligrams), fill in how many servings you consume per day for each of these items:

Dopamine in the striatum aids in motor control and mild increases in energy while dopamine in the nucleus accumbens produces that reinforcing pleasure and euphoria (think 10mg of l-deprenyl vs. 10mg of d-amphetamine).

Nucleus accumbens dopamine also plays a role in the cost-benefit analysis of potential rewards. If a reward requires extended effort, rats with low accumbens dopamine levels will give up and instead choose lower effort activities for smaller rewards^8,9. This can be extrapolated to the snowball effect in some forms of clinical depression.

While caffeine's action at A2A receptors increases binding to D2 receptors, it is the blockade of the A1 receptor that is responsible for actual increases in dopamine concentrations¹⁶. A1 receptors are sometimes co-localized with D1 receptors¹⁰. A1 activation will block the stimulatory effect of D1 agonists, while caffeine enhances it¹³.

There's also an interesting feedback relationship between D1 receptors, NMDA, and adenosine. Combined, D1 and NMDA stimulation (which occurs with many stimulants) triggers the release of adenosine, which in turn slows things down¹⁴. Ever wondered about the mechanism behind "I just took 30mg of Dexedrine and I'm already tired"? Now you know. Ahh, the beauty of homeostasis.

Caffeine dosages that antagonize A1 and A2A receptors cause a multi-receptor dopaminergic response. However, chronic caffeine ingestion only produces tolerance to a D1 or D2 agonist, but not their combination¹⁷. Indirect dopamine agonism (such as that from increased release or re-uptake inhibition) might be a requirement for the reinforcement and pleasure seen from cocaine and amphetamine.

It just seems that a certain phenomenon happens when you hit every type of dopamine receptor at once. It's what separates the subjective effects of bromocriptine from cocaine. The above research also suggests that those utilizing caffeine consistently will not develop a tolerance to the effects of cocaine or amphetamine.

Subjective Effects

Caffeine is associated with many positive subjective effects. Fredholm et al. reported that users consuming caffeine in a work environment felt "energetic, imaginative, efficient, self-confident, and alert, able to concentrate and were motivated to work but also had the desire to socialize" ¹.

However, in attempting to reap these effects from caffeine, two things should be taken into account.

• The first is baseline.

• The second is the omnipotence and omnipresence of the inverted U-shaped curve.

Baseline:

As for baseline, Smith et al. found that when people with the common cold consumed caffeine, they performed better and felt more alert. The subjects failed to have such a positive response with caffeine when feeling well¹⁸.

This probably goes for most substances. Before we buy into the claim that something has a substantial mind-altering effect, we have to consider where the person was mentally, physically, etc before taking the substance.

I would often get frustrated when some of my more "normal" friends failed to get any response from things like Phenibut or 5-HTP. Mild anxiolytics work best when one is feeling anxious.

With caffeine, if one is already feeling "energized" and "efficient", it is unlikely that a mild stimulant will have much subjective effect.

Inverted U-Shaped:

The inverted U-shaped curve phenomenon occurs with all sorts of substances. It demonstrates that there is an optimal dosage for a beneficial effect, with more leading to diminishing returns. Caffeine is on an inverted U-shaped curve for several of its effects.

At A Certain Dosage One Receives The Most Benefits.
From Then On The Benefits Begin To Drop Off.

With respect to locomotor stimulation¹⁹, the threshold effect is 1-3mg/kg in mice (about 20mg-70mg for a 70kg human), and the peak effect is 10-40mg/kg (about 230mg-930mg for a 70kg human).

For those who prefer more anecdotal evidence, at age 16, I vividly remember taking 8 vivarins (1600mg) as a pre-workout boost. It wasn't pleasant or stimulating.

This brings up a big a big difference between caffeine and cocaine. With cocaine, positive reinforcement is correlated with locomotor stimulation ²⁰.

The more revved up a rat (or person) gets on cocaine, the more cocaine they usually want. But as most can attest to, when the jitters really set in with a high dose of caffeine, more caffeine is usually the last thing on our mind.

Performance Enhancement & Arousal

Performance enhancing effects of caffeine with regards to cognition also follow the inverted U, with performance decreases being observed past 500mg²¹. This is probably because caffeine enhances performance mainly by promoting arousal²².

The right amount of arousal will "suppress background noise while enhancing cortical neural response to a stimulus, thereby focusing neural activity to brain structures specific for the processing of particular information."¹².

In other words, the right amount of CNS arousal helps you focus on what you want to focus on! And in our ADHD society that ambushes us with stimulation from every direction, FOCUS is an essential ability.

The most famous guys to look into the effects of arousal on performance and cognition were Yerkes and Dodson. They discovered two things.

Inverted_U:

First, arousal and performance follow that inverted-U shaped curve again. More isn't always better.

There's an optimal amount of arousal before its starts to inhibit performance.

Different Levels:

Second, different types of tasks require different levels of arousal. Arousal can be detrimental for difficult tasks utilizing working memory and multiple sources of information.

A calm and flexible sort of concentration is more important in these situations. This explains why beta-blockers and benzodiazepines (two drug classes that prevent over-arousal) are prohibited in sports like chess.

But higher arousal can improve performance when the task requires selective attention to few sources of information and when there are time constraints (taking notes in class or even the reading comprehension section of a standardized test).

Take Home Message:

Here's the take-home message with regard to cognitive enhancement and caffeine. High dosages can come in handy when the task is relatively simple, boring, and repetitive, requiring sustained, selective attention. Lower doses or no caffeine at all should be utilized when attempting more complex tasks.

However, there's also the issue of state-dependent learning. So, if you are the type of person who's used to doing calculus problems with back to back espressos, it would be unwise to stop this habit for a test.

Because of caffeine's ability to increase arousal rather than complex concentration, it is probably best labeled a "psychomotor performance enhancer" rather than "cognitive performance enhancer"²³.

Activity

The diminishing effects on performance from higher doses of caffeine might have to do with anxiety. In 1974, Greden was the first to publish the observation that psychiatric patients consuming more than 1000mg of caffeine a day demonstrated symptoms of generalized anxiety²⁴. Coining the term "Caffeinism" to describe his anxious, caffeinated patients, his diagnosis was eventually added to the DSM-IV.

Later studies corroborated the anxiogenic effects of caffeine. 300mg (but not 100mg) can produce anxiety in healthy humans²⁵. Individuals with pre-existing anxiety are more likely to experience caffeine's anxiogenic effects and tend to prefer lower doses^{26, 27}.

The neurochemical basis behind caffeine induced anxiety might have to do with an indirect effect on GABA(A) receptor activity²⁸. It's also been shown that A2A knockout mice showing increased anxiety²⁹.

But just like caffeine's stimulatory mechanism differs from typical stimulants, its anxiogenic mechanism differs from the typical anxiogenic, yohimbine. In animal models, the combination of caffeine and yohimbine can actually reduce anxiety!³⁰

Sleep & Sleep Deprivation

It's common knowledge that caffeine intake can disrupt sleep. The finer details and mechanisms (as well as possible solutions) are less well known. 100mg taken at bed-time increases the time to get to sleep and decreases delta-wave deep sleep³¹.

RELATED ARTICLE

How Can Someone Improve Their Sleep For Maximum Results? How can someone improve their sleep for maximum results? Find out what other people from the message boards think... [ Learn More ]

Decreases in deep sleep can even occur from a dose of 200mg taken in the morning³². A disruption in deep sleep reduces the restorative benefits of sleep³³.

In other words, without deep sleep, we tend not to feel as refreshed. For those looking to remedy caffeine-related sleep difficulties, a combination of valerian root and hops has been found effective³⁵.

Caffeine does have restorative effects when used during sleep deprivation. It is effective at restoring positive mood and vigor in subjects who have been awake for 48h³⁴.

On the other side of this research is the common claim that many individuals consume a caffeinated beverage before bed without any ill effect.

Some even claim that it helps their sleep. Fredholm et al. explained this with the possibility that caffeine interferes with less fundamental aspects of sleep neurochemistry.

Adenosine is a transient signal to go to sleep, rather than a sleep-promoting substance itself^1,2. This also speaks to the fact that regular sleep rituals tend to trump mild neurochemical manipulation.

Part II

In part II, we'll continue reviewing caffeine's influence on other neurotransmitter systems, including:

• Acetylcholine
• Norepinephrine
• Serotonin
• GABA

  To Be Notified Of Updates Click Here.

References

1. Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999 Mar;51(1):83-133.
2. Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, Greene RW, McCarley RW. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science. 1997 May 23;276(5316):1265-8.
3. Fredholm BB, Dunwiddie TV. How does adenosine inhibit transmitter release? Trends Pharmacol Sci. 1988 Apr;9(4):130-4.
4. Lorist MM, Tops M. Caffeine, fatigue, and cognition. Brain Cogn. 2003 Oct;53(1):82-94.
5. Ferre S, Fuxe K, von Euler G, Johansson B, Fredholm BB. Adenosine-dopamine interactions in the brain. Neuroscience. 1992 Dec;51(3):501-12.
6. Svenningsson P, Nomikos GG, Fredholm BB. The stimulatory action and thedevelopment of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. J Neurosci. 1999 May 15;19(10):4011-22.
7. Nehlig A, Boyet S. Dose-response study of caffeine effects on cerebral functional activity with a specific focus on dependence. Brain Res. 2000 Mar 6;858(1):71-7.
8. Aberman JE, Salamone JD. Nucleus accumbens dopamine depletions make rats more sensitive to high ratio requirements but do not impair primary food reinforcement. Neuroscience. 1999;92(2):545-52.
9. Aberman JE, Ward SJ, Salamone JD. Effects of dopamine antagonists and accumbens dopamine depletions on time-constrained progressive-ratio performance. Pharmacol Biochem Behav. 1998 Dec;61(4):341-8.
10. S. Ferr, K. Fuxe, G. von Euler, B. Johansson and B.B. Fredholm, Adenosine-dopamine interactions in the brain. Neuroscience 51 (1992), pp. 501-512
11. Arnsten AF, Goldman-Rakic PS. Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry. 1998 Apr;55(4):362-8.
12. Mattay VS, Berman KF, Ostrem JL, Esposito G, Van Horn JD, Bigelow LB, Weinberger DR. Dextroamphetamine enhances "neural network-specific" physiological signals: a positron-emission tomography rCBF study. J Neurosci. 1996 Aug 1;16(15):4816-22.)
13. Ferre S, O'Connor WT, Svenningsson P, Bjorklund L, Lindberg J, Tinner B, Stromberg I, Goldstein M, Ogren SO, Ungerstedt U, Fredholm BB, Fuxe K. Dopamine D1 receptor-mediated facilitation of GABAergic neurotransmission in the rat strioentopenduncular pathway and its modulation by adenosine A1 receptor-mediated mechanisms. Eur J Neurosci. 1996 Jul;8(7):1545-53.
14. Harvey J, Lacey MG. A postsynaptic interaction between dopamine D1 and NMDA receptors promotes presynaptic inhibition in the rat nucleus accumbens via adenosine release. J Neurosci. 1997 Jul 15;17(14):5271-80.
15. Ferre S, von Euler G, Johansson B, Fredholm BB, Fuxe K. Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7238-41.
16. Okada M, Kiryu K, Kawata Y, Mizuno K, Wada K, Tasaki H, Kaneko S. Determination of the effects of caffeine and carbamazepine on striatal dopamine release by in vivo microdialysis. Eur J Pharmacol. 1997 Feb 26;321(2):181-8.
17. Garrett BE, Holtzman SG. Caffeine cross-tolerance to selective dopamine D1 and D2 receptor agonists but not to their synergistic interaction. Eur J Pharmacol. 1994 Sep 1;262(1-2):65-75.
18. Smith A, Thomas M, Perry K, Whitney H. Caffeine and the common cold. J Psychopharmacol. 1997;11(4):319-24.
19. Nikodijevic O, Jacobson KA, Daly JW. Locomotor activity in mice during chronic treatment with caffeine and withdrawal. Pharmacol Biochem Behav. 1993 Jan;44(1):199-216.
20. Bedingfield JB, King DA, Holloway FA. Cocaine and caffeine: conditioned place preference, locomotor activity, and additivity. Pharmacol Biochem Behav. 1998 Nov;61(3):291-6.
21. Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Cotreau MM, Harmatz JS, Shader RI. Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol. 1997 Aug;37(8):693-703.
22. Anderson KJ, Revelle W. Impulsivity, caffeine, and proofreading: a test of the Easterbrook hypothesis. J Exp Psychol Hum Percept Perform. 1982 Aug;8(4):614-24.
23. Temple JG, Warm JS, Dember WN, Jones KS, LaGrange CM, Matthews G. The effects of signal salience and caffeine on performance, workload, and stress in an abbreviated vigilance task. Hum Factors. 2000 Summer;42(2):183-94.
24. Greden JF. Anxiety or caffeinism: a diagnostic dilemma. Am J Psychiatry. 1974 Oct;131(10):1089-92.
25. Stern KN, Chait LD, Johanson CE. Reinforcing and subjective effects of caffeine in normal human volunteers. Psychopharmacology (Berl). 1989;98(1):81-8.
26. Lee MA, Cameron OG, Greden JF. Anxiety and caffeine consumption in people with anxiety disorders. Psychiatry Res. 1985 Jul;15(3):211-7.
27. Griffiths RR, Woodson PP. Reinforcing properties of caffeine: studies in humans and laboratory animals. Pharmacol Biochem Behav. 1988 Feb;29(2):419-27
28. Lopez F, Miller LG, Greenblatt DJ, Kaplan GB, Shader RI. Interaction of caffeine with the GABAA receptor complex: alterations in receptor function but not ligand binding. Eur J Pharmacol. 1989 Dec 5;172(6):453-9.
29. Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, Costentin J, Heath JK, Vassart G, Parmentier M. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature. 1997 Aug 14;388(6643):674-8.
30. Baldwin HA, Johnston AL, File SE. Antagonistic effects of caffeine and yohimbine in animal tests of anxiety. Eur J Pharmacol. 1989 Jan 10;159(2):211-5.
31. Landolt HP, Dijk DJ, Gaus SE, Borbely AA. Caffeine reduces low-frequency delta activity in the human sleep EEG. Neuropsychopharmacology. 1995 May;12(3):229-38.
32. Landolt HP, Werth E, Borbely AA, Dijk DJ. Caffeine intake (200 mg) in the morning affects human sleep and EEG power spectra at night. Brain Res. 1995 Mar 27;675(1-2):67-74.
33. Bonnet MH, Arand DL. Metabolic rate and the restorative function of sleep. Physiol Behav. 1996 Apr-May;59(4-5):777-82.
34. Penetar D, McCann U, Thorne D, Kamimori G, Galinski C, Sing H, Thomas M, Belenky G. Caffeine reversal of sleep deprivation effects on alertness and mood. Psychopharmacology (Berl). 1993;112(2-3):359-65.
35. Schellenberg R, Sauer S, Abourashed EA, Koetter U, Brattstrom A. The fixed combination of valerian and hops (Ze91019) acts via a central adenosine mechanism. Planta Med. 2004 Jul;70(7):594-7.
36. Bruce M, Scott N, Lader M, Marks V. The psychopharmacological and electrophysiological effects of single doses of caffeine in healthy human subjects. Br J Clin Pharmacol. 1986 Jul;22(1):81-7.
37. Fuhr U, Rost KL, Engelhardt R, Sachs M, Liermann D, Belloc C, Beaune P, Janezic S, Grant D, Meyer UA, Staib AH. Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations.
38. Benowitz NL, Jacob P 3rd, Mayan H, Denaro C. Sympathomimetic effects of paraxanthine and caffeine in humans.
39. Bruce M, Scott N, Lader M, Marks V. The psychopharmacological and electrophysiological effects of single doses of caffeine in healthy human subjects. Br J Clin Pharmacol. 1986 Jul;22(1):81-7.
40. Birkett DJ, Miners JO. Caffeine renal clearance and urine caffeine concentrations during steady state dosing. Implications for monitoring caffeine intake during sports events. Br J Clin Pharmacol. 1991 Apr;31(4):405-8.
41. Fraser, Clarence M., et al, eds. The Merck Veterinary Manual, 7th ed. Rahway, NJ: Merck & Co., Inc. 1991. pp. 1643-44.

Andrew Novick

Recommend this article to a friend by e-mail here!

Visitor Reviews Of This Article!
Read Visitor Reviews - Write Your Own Review

Back To Par Deus' Main Page

Back To The Articles Main Page.

Related Articles
Caffeine
Chitosan
Lipoic Acid: The Super Supplement!

Avant Labs Lipoderm-Y Topical Solution Containing Yohimbine Hydrochloride! Learn More!