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Action of caffeine (and other wake promoting agents)


mccoy
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This is an interesting topic, since sometimes it occurs the necessity to be fully awake, in lack of, or notwithstanding sufficient sleep time.

I've been listening to podcasts (for example, Pete Attia's the drive) where the effect of caffeine has been related to it's properties to bind to the adenosine receptors, adenosine being a neurotransmitter linked to the homeostatic sleep drive. In a few words, caffeine is an antagonist of adenosine. It binds to adenosine receptors, effectively counteracting, according to its concentration, the effect of sleep-inducing adenosine where such receptors are blocked. 

But, as I realized, the above explanation is not complete. The final result is actually related to an increased dopamine flow thru the following effect (source: Stahl's essential psychofarmacology). In a few words, adenosine can heterodimerize D2 receptors, reducing the affinity of D2 receptors for dopamine, hence blocking 'by proxy' the flow of this neurotransmitter.

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Posted (edited)

Another couple of powerful ergogenic and wake-promoting compounds are the amphetamines and methylphenidate. Their final effect is dopaminergic and adrenergic, as dopamine and norepinephrine reuptake inhibitors (they inhibit the reuptake of such neurotransmitters, which is a sparing mechanism but also decreases their availability) and as inhibitor of another transporter, VMAT2. Such compounds can have detrimental side effects and can be addicting.

The following excerpt is always from Stahl's essential psychopharmacology

 

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Edited by mccoy
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My experience with caffeine with quite a bit of experimentation is that I sleep better with it than without it. I drink green tea and regular coffee along with some decaf. Comes out to about 250-300 milligrams. I never drink it later than 3 PM. GAve it up several times for a month and my sleep was worse. William Dement the Giant of sleep physiology claimed a morning coffee was cool because it helps set one’s circadian rhythm’s. But he did suggest only drinking one cup in the morning.

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Mike, what I know is that the half-life of caffeine is on the average 6 hours but there is an individual variability in the time it's metabolized, as in all other things metabolic.

So you might be a fast metabolizer and your 250-300 mg (which is a really large quantity) may be the equivalent of 90-150 for the average individual.

On the side of the neurotransmitters receptors  I don't know, but again, individual variability in the brain setup is very high as well. In psychopharmacology it is not a mystery that the response to a drug may be wildly different in different people. I may add, in my own observations, that the response may be totally different even in the same individual a few years later.

This is the reason why psychiatrists often employ the trial and error method, even though based on literature and previous experience. 

Edited by mccoy
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Modafinil (together with its enantiomer armodafinil) is a drug which is replacing amphetamines in some environments as a wake promoting agent (even in the special forces of some countries). I confess I've been tempted to try it in periods of very poor sleep. Not yet using it though. It is a dopamine transporter (DAT) inhibitor , which increases the flow of dopamine. After blockade of DAT, increased synaptic dopamine results in increased tonic firing and downstream effect on neurotransmitters involved in wakefulness, among which hystamine and Orexin/hypocretin.

 

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On 8/21/2022 at 6:15 AM, mccoy said:

Mike, what I know is that the half-life of caffeine is on the average 6 hours but there is an individual variability in the time it's metabolized, as in all other things metabolic.

So you might be a fast metabolizer and your 250-300 mg (which is a really large quantity) may be the equivalent of 90-150 for the average individual.

On the side of the neurotransmitters receptors  I don't know, but again, individual variability in the brain setup is very high as well. In psychopharmacology it is not a mystery that the response to a drug may be wildly different in different people. I may add, in my own observations, that the response may be totally different even in the same individual a few years later.

This is the reason why psychiatrists often employ the trial and error method, even though based on literature and previous experience. 

I totally agree! With caffeine I guess it’s a matter of self experimentation. My mother always drank coffee in the afternoon still does and she’s 93!! But the thing I find interesting is that after literally years of playing around with caffeine I definitely find it is useless to cut back or quit in fact counterproductive. What I think might be going on is circadian rhythms factors. I know all about adenosine, but one has to consider the waking factor of caffeine may play a role in circadian factors. I, for instance, tend to get sleepy in the afternoon whether I drink caffeine or not, but I can moderate it quite a bit with my afternoon caffeine. Also in the morning caffeine sends a pulse of awakening factors which could indeed reinforce circadian rhythms. Even the great sleep expert William Deming claimed a cup of coffee in the morning could help with our sleep by waking us up more.

Edited by Mike41
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