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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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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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  • 7 months later...

A recent paper with lots of references:

Mental Performance and Sport: Caffeine and Co-consumed Bioactive Ingredients  (Nov. 2022)

Discusses in detail  caffeine, coffee, cacao, green tea, guarana, ginkgo biloba, ginseng,  taurine,  l-theanine etc.

Quote

Of particular note here, caffeine and polyphenols enjoy a number of potentially additive or interactive relationship effects. These may be due to their common affinity with the same CYP450s, or alternatively caffeine’s effects on the absorption, distribution and clearance of other compounds, or caffeine’s ability to form complexes with other acidic compounds, including phenolics [34].

In line with this, research has demonstrated increased functionality or bioavailability when polyphenols [104106], or other phenolic compounds [34], are consumed alongside caffeine. As an example, a recent study in humans showed that co-administration of cocoa-flavanols alongside their naturally occurring caffeine/methylxanthines resulted in a synergistic effect on the bioavailability and cardiovascular effects of the cocoa-flavanols [104].

The interactive effects of caffeine can also be seen across the wider literature here. As an example, a meta-analysis of 15 studies showed that, whereas green tea catechins without caffeine had no effect, in combination with caffeine they decreased body weight and/or body mass index (BMI) in comparison to caffeine-matched controls [107].

These interactive effects may underpin the results from a meta-analysis of 120 controlled trials [108] that found that flavanol-rich compound interventions with caffeine (e.g., tea and cocoa extracts) were ranked higher than those without caffeine (apple extracts) in terms of beneficial effects on BMI, waist circumference, total-cholesterol, low density lipoprotein and high density lipoprotein (LDL/HDL)-cholesterol and triglycerides.

 

Edited by Sibiriak
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On 4/19/2023 at 8:19 AM, Sibiriak said:

These interactive effects may underpin the results from a meta-analysis of 120 controlled trials [108] that found that flavanol-rich compound interventions with caffeine (e.g., tea and cocoa extracts) were ranked higher than those without caffeine (apple extracts) in terms of beneficial effects on BMI, waist circumference, total-cholesterol, low density lipoprotein and high density lipoprotein (LDL/HDL)-cholesterol and triglycerides.

In the latest year I've been consuming every morning one cup of espresso coffee plus 2 tablespoons of cacao powder on average, plus often another cup of decaffeinated coffee. I'm wondering if this combination contributed significantly in improving my metabolic parameters (lipids, glucose, blood pressure). It may be lots of walnuts, it may be coffee plus cocoa, it may have been both, of course it may have been many other things, I'm also aware that values may not keep so good. 

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On 8/13/2022 at 7:55 PM, mccoy said:

...necessity to be fully awake, in lack of, or notwithstanding sufficient sleep time.

Sometimes I need to drive through a crowded city  and out  to a neighboring village.  Driving conditions can be quite dangerous--icy  roads + poor visibility + numerous reckless, non-law-abiding drivers  to contend with.

I want to be maximally alert and focused, and if  I feel I need a boost,  I use some or all of these aids:

  • Ice-cold shower  (1-3 reps/ with  energizing breathing)    Short duration/high intensity cold exposure-->long-lasting increase in dopamine and norepinephrine.   Fortunately the tap water here is extremely cold,  otherwise I’d probably go for a short ice bath.
  • Coffee+cacao (sometimes green tea, if less caffeine preferred.  Ideally I’d  stop caffeine intake 10hrs before sleep time).
  • Nicotine lozenge (occasionally, 1/2 or less)  Enhances alertness  via dopamine, acetylcholine, norepinephrine.   

 

 

Edited by Sibiriak
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Sibiriak,

 👍to ice cold showers, without which I often cannot get fully awake, their effect seems to be time limited though and the main drawback is that they should be done on an empty stomach.

 👍to coffee and cacao, which in my case though have a gain a time-limited effect and after noon will probably impair sleep quality

Nicotine lozenge I never tried and that's a good tip.

I did not try any pharmaceutical drugs because situation improved enough, but sometimes I start swerving while driving and that's the time I'll pull up and take a 2-minutes nap. 

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  • 4 weeks later...

Caffeine, by blocking the effect of adenosine, can be an effective way of achieving a state of wakefulness when sleep deprivation is a factor. It works by binding to adenosine receptors, and in doing so, counteracting the effect of adenosine, which is normally responsible for causing sleepiness. Additionally, it stimulates the release of dopamine, a neurotransmitter with wakefulness-promoting properties, thus leading to an overall increase in alertness and decreased sleepiness. While this can be beneficial in short-term situations, it is important to recognize that long-term use of caffeine can lead to dependence and other potential side effects. Building an app like Uber requires a few steps, including choosing the right technology stack, creating an efficient backend architecture, and designing a great user experience. First, you need to decide on the technology stack for building your app. This includes choosing a programming language, database, server framework, and other necessary tools. Popular options for mobile apps include Swift and Kotlin for iOS and Android, respectively. Next, you will need to create an efficient backend architecture capable of supporting your app’s features. This may include using APIs, developing a payment processing system, and setting up cloud hosting for scalability. Finally, once you have the technical foundation in place, you can begin designing the user interface of your  mlsdev.com/blog/how-to-make-an-app-like-uber

Edited by barrymilels
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