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bicep curlby: Andrew Novick

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).

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

Pharmacokinetics

Caffeine is 99% orally bioavailable. Levels tend to peak within 30-60 minutes, passing through all biological membranes including the blood brain barrier (36). The half-life is around 5 hours. 80% of caffeine is metabolized to paraxanthine by CYP1A2 (37). A small percentage is converted to theophylline. Both of these metabolites are pharmacologically active and have similar half-lives to caffeine (38). Only 5% of ingested caffeine remains unchanged, the majority being excreted as 1-methyluric acid (39).

For the same amount of caffeine ingested, plasma levels can vary by a factor of 15.9 between individuals (40). 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 human (1).

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 humans (1). 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 and 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.

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 sleep (2).

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, and A3. It appears that normal adenosine levels as well as human caffeine consumption only affect A1 and A2A receptors (1). 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 GABA (3). A2A receptors are relevant to dopamine function. They are concentrated in dopamine rich regions of the brain and are co-localized with D2 receptors (4), which brings us to our discussion of caffeine and dopamine.

Dopamine

Intact dopamine transmission is necessary for caffeine’s stimulating effects (5). At lower caffeine doses, the blockade of A2a receptors (rather than A1) appears to play the more important role in activating dopamine and producing stimulation (6). A2A blockade and subsequent dopaminergic enhancement can occur at doses as low as 35mg in humans (7).

How does A2A blockade increase dopamine activity? Adenosine action at A2A receptors decreases the affinity of dopamine binding to D2 receptors in the striatum (15). 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.” 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: lack of motivation to pursue reward à lack of reward à decreased dopamine in the nucleus accumbens à further lack of motivation to pursue reward.

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 concentrations (16). A1 receptors are sometimes co-localized with D1 receptors (10). A1 activation will block the stimulatory effect of D1 agonists, while caffeine enhances it (13). 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 down (14).

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 combination (17). 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.

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 well (18). This probably goes for most substances. With caffeine, if one is already feeling “energized” and “efficient”, it is unlikely that a mild stimulant will have much subjective effect.

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. With respect to locomotor stimulation (19), 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.

Performence Enhancement and Arousal

Performance enhancing effects of caffeine with regards to cognition also follow the inverted U, with performance decreases being observed past 500mg (21). This is probably because caffeine enhances performance mainly by promoting arousal (22). 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. 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. 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).

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 anxiety (24). 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 humans (25). 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 activity (28). It’s also been shown that A2A knockout mice show increased anxiety (29). 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 and 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 sleep (31). Decreases in deep sleep can even occur from a dose of 200mg taken in the morning (32). A disruption in deep sleep reduces the restorative benefits of sleep (33). 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 effective (35).

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 48h (34).

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.

References

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