I began to question the “positives” of caffeine when I was reading combination therapy studies where caffeine alone was not effective but caffeine plus a therapy was more effective than the therapy alone. That raised an eyebrow for me. Perhaps it is useful to know how compounds exert their effects before we say something is good for you.

Caffeine as are most methylxanthines are potent inhibitors of respiration. There are also a number of negative hormonal side effects with the digestive system leading me to wonder e.g. if some perceived food intolerances are caused by heavy chronic coffee consumption.

When I see a compound inhibit respiration and a shift towards glycolysis I automatically think insulin. Caffeine effectively increases insulin. This would have the effect of suppressing beta-oxidation to some extent causing a stress response which would temporarily increase the RMR. Anytime respiration is suppressed acutely there is a temporary increase in the RMR to restore NAD+/NADH ratios. Caffeine probably inhibits respiration by shifting the cells towards glycolysis increasing NADH which essentially creates the Crabtree effect. It happens that the Crabtree effect causes cells to uptake calcium which eventually causes apoptosis. In cancer this would be useful. Essentially the caffeine is stressing the cell making the pharmaceutical therapy more potent.

Some people report that when they give up coffee there is a period of time where they feel excessively tired. My opinion is that when chronic stress is reduced this symptom is to be expected.

Dr. Peat mentions caffeine being an “adaptogen” he is somewhat correct in the sense that acute caffeine consumption would cause a temporary increase in RMR (stress response) causing weaker damaged cells to follow through to apoptosis. Caffeine does stimulate autophagy. Basically a sort of ripple effect through the organism i.e. a window cleaning with a squeegee. When insulin increases the thyroid hormones tend to increase as the thyroid hormones participate in degrading insulin thus restoring organization through increased beta-oxidation of fatty acids.

But chronic consumption could be maladaptive. On the surface there seems to be a loss of heavy caffeine consumers in centenarian pools. Fat, nicotine, chocolate, and alcohol (although heavy alcohol consumption does as well skew NAD+/NADH ratios) seems to be far more common with coffee consumption being a cup or two a day for those that do drink it and happen to make past their 90’s. But that observation is probably biased because I haven’t looked that hard.

Chocolate also contains methylxanthines but the stearic acid and other SFAs probably offset the negative consequences.

For those who look at metabolic rates, there are a lot of compounds that increase the metabolic rate. A lot of lethal substances are on that list. I think that it is important to look at the context when recommending chronic consumption of said substances as an adaptive stress response is something quite different then a chronically induced state of hypermetabolism. Animals that live long such as the naked mole rat have low RQs, are insulin resistant, and Vitamin D deficient. During hypoxia (e.g. altitude or underground) humans react physiologically, fatty oxidation increases and ketones increase. Fatty acids, lactate, and ketones are protective in low oxygen environments.

Then there are those who are better or worse at metabolizing caffeine and other xenobiotic compounds, I would guess this would determine tolerance to such compounds as well as what “dose” would mediate a beneficial hormetic response.

In the beginning I mentioned that I began to question the “positives” of caffeine. I want to define “positives”. Because the idea is not to recommend that you should axe coffee the idea is that just because we see good evidence of a substance with benefits doesn’t mean we turn off our brains and forget to ask why are there these benefits, how does the substance mediate its effects, how can I best use this substance without interfering in general with my enjoyment of a substance which possibly could be a double edged sword.

So having a cup or two of coffee a day is probably adaptive, but if you are drinking “50 cups of coffee per day” there is probably something extremely wrong with you.

24 Comments Caffeine

  1. Andy

    Which brand of chocolate do you prefer?

    Raw cacao is a poor choice, correct?

  2. James

    I also wondered about caffeine. It seems to pair up with sugar & supplemented thyroid, something that acts fast but short lived so the idea is to continually eat them. The biggest problem I see with this idea is what happens at night. Can’t do this while sleeping, so this channel runs out. The antioxidants would also have been excreted I think. So presumably upon wake up, the stress could be very high. That was my experience. I wonder if that alone could offset any benefits of this approach, because several hours of stress every day (or rather, night) is a lot. What kind of damage occurs during early hours? Temperature gets lower during sleep so presumably a whole lot of things don’t function well, but on the other hand there is no action so no chance of damaging a muscle for example.

  3. mitchell

    Now we are waiting/hoping to hear your fresh take on tobacco/nicotine. Interesting stuff.

  4. Andy

    Nicotine suppresses insulin, but increases blood glucose. Does this make nicotine a safer stimulant, compared to caffeine?

  5. James

    I read that nicotine speeds up caffeine elimination, apparently as a direct effect on the liver. I also read that nicotine and caffeine combined has an unusual thermogenic effect.

  6. Edward

    James, are you referring to this paper as far as caffeine elimination?

    Parsons, W. D., & Neims, A. H. (1978). Effect of smoking on caffeine clearance. Clinical Pharmacology and Therapeutics, 24(1), 40–5. Retrieved from

    The elimination of caffeine from saliva was compared in groups of healthy smokers (n = 13) and nonsmokers (n = 13). Mean caffeine t1/2 in smokers (3.5 hr) was shorter than that in the nonsmokers (6.0 hr). The body clearance of caffeine in the smokers (155 +/- 16 ml . kg-1 . hr-1) was greater than that in the nonsmokers (94 +/- 18 ml . kg-1 . hr-1) (p less than 0.05). No significant difference was noted in the apparent volume of distribution in smokers (720 +/- 67 ml . kg-1) and nonsmokers (610 +/- 80 ml . kg-1). These differences probably reflect the induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity in smokers. The increased clearance of caffeine by smokers may contribute to the higher consumption of coffee reported to occur in this group.

  7. James

    A common impression is that long lived people tend to be less stressed and more sociable. If longevity is associated with higher nicotine, alcohol, coffee and chocolate consumption, then I wonder whether the pro dopamine effect could contribute. Perhaps a combination of low dose caffeine, nicotine and alcohol is effective at increasing dopamine. Although this seems like an artificial way to promote dopamine, promoting dopamine in rats seems to be good for longevity. Maybe from an evolutionary standpoint low optimism was more useful in a threatening environment and we have not yet adapted.

  8. Matt

    Currently about 50lbs overweight [obese] after following high sugar diet for 2 yrs. I tried drinking about 3x as much coffee as I usually do the other day, and noticed a pronounced flare-up of several symptoms, most notable being peripheral neuropathy. I experienced it worse that day than I probably ever have.

  9. Matt

    Also, do you truly think cigarettes aren’t harmful, or are you just open to the possibility. I’ve become a little wary of the potential for rationalization when “addictive” substances are involved.

    That being said, in my personal experience smoking cigars is pretty awesome, and hasn’t really caused me any problems. Being a regular smoker of good cigars has given me something to contrast name-brand cigarettes against, and the difference is huge. Comparing them is like comparing a wagyu burger from a gastro-pub to a big mac from Mcdonald’s. I’m not sure I would go so far as to say that cigars have health benefits, and in reality I have no way of knowing. My gut says smoke the shit out of them, but my brain says each cigar probably contains 10 cigarettes, thanks to anti-smoking campaigns. My wallet says it doesn’t matter, because I can’t afford them anyway.

  10. James

    Re smoking: I read that Cuba has a high rate of cancer, especially lung cancer. Cubans smoke a fair bit. Cuban cigars are supposed to be good quality, at least those for export. That suggests smoking itself as a cause, rather than associations like additives or smog.

  11. Edward

    I would guess that smoking and the possible relationship to lung cancer is multifactorial. In cancer research you have what are known as tumor initiators and tumor promoters. Tumor promoters do not actually cause cancer. Tumor initiators do. And growth of a tumor is facilitated by the promoter. Typically these are completely different substances or factors. Because the Kitavans and Masai smoked like chimneys you’d expect to see elevated lung cancer rates. Then more modernly you also have the folks of the Victorian age who where quite fond of alcohol and tobacco (although cigarettes did not exist at the time), they had good health as well. Of course, nobody has really looked at this in depth because it really is an established dogma that tobacco use causes cancer. When smoking is noted typically it goes something like this: “…these follks smoked but were healthy and had low rates of CVD…”; most of the time these people are looking at CVD risks not cancer risks although native populations as well have low incidence of cancer. As well, one might even take the lack of mention to mean cancer is low and is not even worth mentioning. But that might be wishful thinking.

    Without a doubt nicotine alone is anti-inflammatory and has several systematic effects that I feel are beneficial, these systematic effects are probably due to the effect nicotine has on respiration as well as modulation of endotoxin (LPS). The delivery method probably does complicate these things a bit. But I think there are other more important factors.

    Nicotine alone is still debated as being addictive but the evidence is in favor of it not being addictive, whereas the delivery method could be addictive. Things that are called addictive are tricky because one can say, well I like to eat food, and when I’m hungry I have to eat food, therefore I am addicted. I try to stay away from such lines of reasoning because it can get in the way of objectivity.

    Disclaimer: I regularly smoke and am biased on this topic in the sense that I myself have noticed specific benefits in my health ever since I started 14 years ago. Am I concerned about lung cancer? Doesn’t enter my mind unless someone brings it up. Do I smoke at regular intervals? No. I smoke when it’s time to smoke. Just like I pee and poop when it is time to pee and poop. So I don’t have to have that morning smoke, nor the smoke after eating. Sometimes I don’t smoke at all for days. I’ve never really been that person who feens for things in general. Honestly, when it comes to an actual craving where I feel like life can’t go on where there is a specific goal oriented drive to obtain it, it’s always something fatty. For example, I often will get very distinct cravings for bacon at irregular intervals that make no meaningful sense to me, same with chicken, sometimes I get distinct cravings for chicken, and I love beef!

    If I recall correctly a lot of low fat people tend to crave fat after a while. I wonder if they are addicted or if there is a need? In the case of nicotine I think it is hard to look at for most people objectively including myself (it is a polarizing subject) because it blurs the line between vice and need.

    Best wishes,

  12. Matt

    Yea, I think there is a certain amount of insanity behind obsessing over the “initiators”, especially since we are surrounded by potential initiators at all times. I think for the healthy, cancer is almost impossible to initiate, whereas in the chronically unhealthy, it will inevitably form with even the slightest prodding by the environment. In other words, if an AIDS patient gets a cold, only a crazy person would blame the public transit system.

    2 other things. Another brand of bean to bar chocolate is Raaka chocolate.

    When you say you drink cream, is it pasteurized or do you get raw dairy?

  13. Isaac

    Doesn’t hurt that commercial cigarettes are bleached with chlorine and fluoride is in the water they use to water the tobacco plants, plus all those additives and the fact that they use reconstituted tobacco and stems as filler, plus Fire Safe Cigs are doused in aromatic polycarbonate or something like that. And people like to blame innocent Tobacco.

  14. Isaac

    Science seems incredibly supportive of Cannabis though, even though it has 4x more “known carcinogens” and blah blah blah:
    I saw somewhere where it said marijuana sped up fluoride metabolism or chelation or something…. Interesting… Japan’s soil is naturally low in fluoride, they smoke more than America and have half lung disease rates… Interesting…. I wonder if fluoridation of the water supply can be linked to tobacco related disease.

  15. Matt


    In regards to the health effects of nicotine, I think its worth mentioning the variable nicotine levels in different brands. After smoking nat sherman/dunhill for a few weeks, I tried a single camel crush and have to say it felt like I had smoked an entire pack of the former at once. I’m a tobacco noob but still have confidence in saying the difference was extreme. I’ve also heard of field workers being forced to handle modern tobacco leaves with gloves so as not to get high from transdermally absorbed nicotine. It seems like major tobacco companies are probably pushing tobacco as much toward drug status as they possibly can, breeding strains with unaturally high levels of nicotine to increase potential for addiction/drug-like effects of smoking.

  16. Isaac

    Idk matt, they put a lot of stems and reconstituted tobacco in modern mainstream cigarettes (I think) I think the curing process determines which areas of the leaf has higher nicotine and air curing tends to produce the most in the lamina/basically the main leaf part, and flue curing, while faster, produces more in the midrib/stems but less overall. It’s possible that air curing organic tobacco results in more nicotine plus minor alkaloids, what I wanna know is the level of minor alkaloids in various areas and processes of tobacco, vapers tend to vape a LOT of nicotine only e-liquid and get all wired and never satisfied but then they try WTA (Whole Tobacco Alkaloid) e-liquid and finally feel that satisfaction of a real cigarette. Studies need to focus on grouping nicotine with its companion alkaloids.

  17. Isaac

    Actually, it’s funny how they say that this black stuff is found “in smokers WITH EMPHYSEMA” they never really say that they found this stuff in all smokers lungs.

  18. Grasspunk

    “That raised an eyebrow for me.”

    I love it when an anomaly crops up. That’s when you learn something.

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