Tolerance Builds To Caffeine-Induced Anxiety

[DaveFoster]

The first of the following two studies was done on rats, and the second on humans. It seems that after about 2 weeks, the anxiogenic effects of caffeine diminishes completely as tolerance develops. Coincidentally, this is the time that it takes adenosine receptors to fully upregulate to caffeine's antagonism. It seems that a gradual increase in caffeine dosage, and maybe co-administration with a benzodiazepine during the 14-day period will completely eliminate any side effects from caffeine.

Haidut has mentioned that the liver is the primary regulator of caffeine's anxiogenic effects, and that a benzodiazepine drug does not work in these cases. While that may be true, in the absence of a fatty liver, caffeine triggers anxiety, and a benzodiazepine-like drug like niacinamide or l-theanine can probably help.

Anxiogenic action of caffeine: an experimental study in rats. - PubMed - NCBI

The anxiogenic action of caffeine (10, 25 and 50 mg/kg, i.p.) was investigated in rats and compared with that of yohimbine (2 mg/kg, i.p.). The experimental methods used were the open-field, elevated plus-maze, social interaction and novelty-suppressed feeding latency tests. Caffeine produced a dose-related profile of behavioural changes, which were qualitatively similar to those induced by yohimbine and which indicate an anxiogenic activity in rodents. Thus, both the drugs reduced ambulation and rears, and increased immobility and defaecation in the open-field test. They decreased the number of entries and time spent on the open arms of the elevated-plus maze, reduced social interaction in paired rats and increased the feeding latency in an unfamiliar environment in 48-h food-deprived rats. Lorazepam, a well known benzodiazepine anxiolytic agent, attenuated the anxiogenic effects of caffeine and yohimbine. Subchronic administration of caffeine (50 mg/kg, i.p.) for 21 days, in different groups of animals, induced a significant degree of tolerance in the elevated plus-maze test, which was statistically significant after 14 and 21 days' treatment. Yohimbine, however, did not induce similar tolerance. When caffeine (50 mg/kg, i.p.) was withdrawn after 21 days' administration, to a separate group of rats, significant withdrawal anxiety was observed 48 h later as noted in the elevated plus-maze test. The investigations support clinical evidence of caffeine-induced anxiety, tolerance to anxiety on continued use, and withdrawal anxiety in chronic caffeine-containing beverage users.

Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption

Caffeine, a widely consumed adenosine A1 and A2A receptor antagonist, is valued as a psychostimulant, but it is also anxiogenic. An association between a variant within the ADORA2A gene (rs5751876) and caffeine-induced anxiety has been reported for individuals who habitually consume little caffeine. This study investigated whether this single nucleotide polymorphism (SNP) might also affect habitual caffeine intake, and whether habitual intake might moderate the anxiogenic effect of caffeine. Participants were 162 non-/low (NL) and 217 medium/high (MH) caffeine consumers. In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions. Caffeine intake was prohibited for 16 h before the first dose of caffeine/placebo. Results showed greater susceptibility to caffeine-induced anxiety, but not lower habitual caffeine intake (indeed coffee intake was higher), in the rs5751876 TT genotype group, and a reduced anxiety response in MH vs NL participants irrespective of genotype. Apart from the almost completely linked ADORA2A SNP rs3761422, no other of eight ADORA2A and seven ADORA1 SNPs studied were found to be clearly associated with effects of caffeine on anxiety, alertness, or headache. Placebo administration in MH participants decreased alertness and increased headache. Caffeine did not increase alertness in NL participants. With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.

 

[ecstatichamster]

Thanks Dave. Excellent finds.

 

[What-a-Riot]

im curious about the mechanism of caffeine withdrawal induced anxiety

 

[DaveFoster]

Thanks hamster. Taking a 200 mg caffeine pill makes me feel good for a narrow window of time, but then it triggers some feelings of panic. Niacinamide, bag breathing, red light, and aspirin seem to reduce this effect.

Again, I think the caffeine is deactivating the sympathetic nervous system at this dosage, which in turn accentuates the hypothyroid state. For example, I returned home an anxious mess, and my pulse was 75! I took 250 mg of additional caffeine, niacinamide, and bag breathing, and my pulse rose to 80, and I feel much better.

@What-a-Riot I'd think the mechanism is similar to how low-doses of caffeine can be anxiogenic, as can high doses, but there exists a sweet spot. The upregulation in adenosine may downregulate the sympathetic response, and without the stimulant of caffeine, it will result in a nervous system response to this gap.

I think @Gl;itch.e has mentioned that he gets anxiety if he doesn't drink enough coffee.

@haidut Did you experience any anxiogenesis from lower doses of caffeine versus higher doses? I know you say the higher ones make you sleepy.

 

[Gl;itch.e]

I think @Gl;itch.e has mentioned that he gets anxiety if he doesn't drink enough coffee.

Only because I love it so much! (;

 

[sladerunner69]

Yes. From personal experience I surmised that tolerance to caffiene, in terms of anxiety, was highly dependent upon the status and ability of the liver to process it. After I had crashed on propecia I was feeling terrible, low androgens, low allopregnenlone, no 5ar enzyme, in a few weeks I could tell I was having serious digestive problems and poor liver function as well. I knew this because I caould abrely handle even the slightest amount of liquor, although I sitll managed to drown myself in it occasionally and feel just morbidly, out-of-this world terrible. I learned to not attempt to escape my misery to alcohol in a very short time, my body just couldn't handle it at all. Feeling tired, very depressed, adn brain fogged upon waking, I tried some caffiene to liven things up. Now even before crashing I was a heavy caffeine abuser because I found out that high doses of caffiene 300mg+, along witha litany of other stimulants and NO boosters would result in really awesome work outs and massive pump. I was consumed with the pump and bodybuilding when I was 18/19 and caffiene was the way to go, although at this time I considerred it a vice because I had not heard of Ray Peat yet. So anyways after my tragic propecia crash I would drink a small cup of coffee, feel a bit better for 20-30 minutes, and then feel uncontrollably anxious. Just so anxious that I couldnt think straight, couldnt talk to anyone, just wanted to hide and cry.

So I couldnt handle caffiene at all for a couple years, until I eventually came upon Danny Roddy, discovered peating, slowly built up my metabolism through diet, and brought in coffee. I hit it too hard to fast though and was soon hooked on many cups every day, too much for me at this point where my liver was only semi funcitonal. One day I had far too much coffee, probably veyr low gaba, and was so anxious I couldnt fall asleep. So I brewed a pot of coffee and went on the computer, and by the next morning I was seriously sleep deprived and anxious, and I ended up having a giant panic attack and my mom admitted me to the hospital where for some reason they decided I had schizophrenia and brought me to some mental health/substance abuse center. That place was dreary, miserable, and totally dumb and I was stuck there with those mostly vile and unpleasant people for around a month. They didnt let me go because I wasn't in agreement with any of their instructions about drug addiciton, worldview, society, etc etc. But eventually I played very nice and they let me go free.

 

[InChristAlone]

Anxiogenic effects never wear off for me because I think my panic attacks are caused by huge BG drops. I am finally after 3+ months off all caffeine not getting any BG drops. Its heaven.

 

[AJC]

Anxiety from coffee was a problem for me as well. I've been drinking it with no problems for a couple weeks now and I'll just share what I discovered: capppucino's are completely fine, and actually make me feel relaxed. Dark roasts are mostly fine. Anything that's light or medium roast is terrible and I stay away from it. I also sometimes will take a manganese/molybdenum combination when I drink coffee that helps the liver process it and this helps somewhat. But the biggest thing is just to drink cappucino's instead of regular coffee. I think because it has less of coffee's other xanthine constituents (if I drink a medium or light roast coffee my urine will smell like coffee--indicating my liver is not doing a good job metabolizing it...with the cappucinos this is rarely a problem).

 

[madbored]

Why is it that I experience anxiety from both regular coffee and cold brew (to a lesser extent), but do not experience these effects using the equivalent dosage of caffeine in pill form?

 

[AJC]

From my experience I'd say you may have trouble metabolizing some of the extra constituents in the coffee besides the caffeine.

 

[thyrulian]

Anxiety from coffee was a problem for me as well. I've been drinking it with no problems for a couple weeks now and I'll just share what I discovered: capppucino's are completely fine, and actually make me feel relaxed. Dark roasts are mostly fine. Anything that's light or medium roast is terrible and I stay away from it. I also sometimes will take a manganese/molybdenum combination when I drink coffee that helps the liver process it and this helps somewhat. But the biggest thing is just to drink cappucino's instead of regular coffee. I think because it has less of coffee's other xanthine constituents (if I drink a medium or light roast coffee my urine will smell like coffee--indicating my liver is not doing a good job metabolizing it...with the cappucinos this is rarely a problem).

Interesting!

Decaf seems to give me a special sort of anxiety.

 

[WestCoaster]

The interesting thing about anxiety (barring some crazy disease), is it's a low Testosterone issue. Just like irritability and depression. Low Testosterone will always equal high(er) circulating insulin levels. Insulin blocks T production, so high circulating blood sugar levels will stimulate insulin equates to suppression of Testosterone which brings on varying symptoms, but in this case, anxiety as that is what we're talking about. As many of you know, coffee or specifically caffeine stimulates the adrenals which stimulate an acute cortisol spike which drags up blood sugar, which ultimately drags up insulin. So for those of you who suffer anxiety from not getting enough coffee, that's a blood sugar issue; too low blood sugar, not adapted to burning fat, body has no energy source when BG drops, cortisol spikes, muscle breaks down, drags up insulin, Testosterone lowers, anxiety ensues.

Those of you who suffer anxiety from drinking coffee or too much coffee, again it's a blood sugar and insulin dis-regulation combined with too much cortisol (usually because one is glucose and/or sugar dependent). Cortisol already semi-high, coffee is consumed, cortisol elevates even higher, blood sugar goes much higher, and insulin comes out to deal with it, Testosterone is kicked to the curb, anxiety ensues, and the feeling of calm and relaxed is a distant memory. Testosterone has a calming effect on the body.

What this ultimately means is, coffee isn't bad per-say but if one is highly sugar and glucose dependent, they probably shouldn't be taking in any type of caffeine at all. They best be somewhat fat adapted so your body has some sort of energy source to draw on once once the BG plummets when the caffeine has ran it's course. In a nutshell I guess what this means is, if someone is suffering from some sort of ill effects from coffee/caffeine, it's an insulin issue because it's blocking Testosterone production, leading to the symptoms. Work on lowering both your fasting insulin and insulin levels after food consumption, and that is not done through sugar and glucose, as it will amplify the problems.

 

[InChristAlone]

The interesting thing about anxiety (barring some crazy disease), is it's a low Testosterone issue. Just like irritability and depression. Low Testosterone will always equal high(er) circulating insulin levels. Insulin blocks T production, so high circulating blood sugar levels will stimulate insulin equates to suppression of Testosterone which brings on varying symptoms, but in this case, anxiety as that is what we're talking about. As many of you know, coffee or specifically caffeine stimulates the adrenals which stimulate an acute cortisol spike which drags up blood sugar, which ultimately drags up insulin. So for those of you who suffer anxiety from not getting enough coffee, that's a blood sugar issue; too low blood sugar, not adapted to burning fat, body has no energy source when BG drops, cortisol spikes, muscle breaks down, drags up insulin, Testosterone lowers, anxiety ensues.

Those of you who suffer anxiety from drinking coffee or too much coffee, again it's a blood sugar and insulin dis-regulation combined with too much cortisol (usually because one is glucose and/or sugar dependent). Cortisol already semi-high, coffee is consumed, cortisol elevates even higher, blood sugar goes much higher, and insulin comes out to deal with it, Testosterone is kicked to the curb, anxiety ensues, and the feeling of calm and relaxed is a distant memory. Testosterone has a calming effect on the body.

What this ultimately means is, coffee isn't bad per-say but if one is highly sugar and glucose dependent, they probably shouldn't be taking in any type of caffeine at all. They best be somewhat fat adapted so your body has some sort of energy source to draw on once once the BG plummets when the caffeine has ran it's course. In a nutshell I guess what this means is, if someone is suffering from some sort of ill effects from coffee/caffeine, it's an insulin issue because it's blocking Testosterone production, leading to the symptoms. Work on lowering both your fasting insulin and insulin levels after food consumption, and that is not done through sugar and glucose, as it will amplify the problems.

What?? No, just no. We should be dependent on glucose. Our brain runs on glucose not fat!

 

[DaveFoster]

Yes. From personal experience I surmised that tolerance to caffiene, in terms of anxiety, was highly dependent upon the status and ability of the liver to process it. After I had crashed on propecia I was feeling terrible, low androgens, low allopregnenlone, no 5ar enzyme, in a few weeks I could tell I was having serious digestive problems and poor liver function as well. I knew this because I caould abrely handle even the slightest amount of liquor, although I sitll managed to drown myself in it occasionally and feel just morbidly, out-of-this world terrible. I learned to not attempt to escape my misery to alcohol in a very short time, my body just couldn't handle it at all. Feeling tired, very depressed, adn brain fogged upon waking, I tried some caffiene to liven things up. Now even before crashing I was a heavy caffeine abuser because I found out that high doses of caffiene 300mg+, along witha litany of other stimulants and NO boosters would result in really awesome work outs and massive pump. I was consumed with the pump and bodybuilding when I was 18/19 and caffiene was the way to go, although at this time I considerred it a vice because I had not heard of Ray Peat yet. So anyways after my tragic propecia crash I would drink a small cup of coffee, feel a bit better for 20-30 minutes, and then feel uncontrollably anxious. Just so anxious that I couldnt think straight, couldnt talk to anyone, just wanted to hide and cry.

So I couldnt handle caffiene at all for a couple years, until I eventually came upon Danny Roddy, discovered peating, slowly built up my metabolism through diet, and brought in coffee. I hit it too hard to fast though and was soon hooked on many cups every day, too much for me at this point where my liver was only semi funcitonal. One day I had far too much coffee, probably veyr low gaba, and was so anxious I couldnt fall asleep. So I brewed a pot of coffee and went on the computer, and by the next morning I was seriously sleep deprived and anxious, and I ended up having a giant panic attack and my mom admitted me to the hospital where for some reason they decided I had schizophrenia and brought me to some mental health/substance abuse center. That place was dreary, miserable, and totally dumb and I was stuck there with those mostly vile and unpleasant people for around a month. They didnt let me go because I wasn't in agreement with any of their instructions about drug addiciton, worldview, society, etc etc. But eventually I played very nice and they let me go free.

Sorry about that, slade. That sound ridiculously rough. Caffeine often gives me extended periods of extreme anxiety. Just very bad, and it comes and goes. I'd like to find out how to prevent this. I'm going to try l-theanine.

 

[Wagner83]

I'm not sure what changed , but as of late coffee has often had very relaxing effects, I take a good amount of it with half the volume as milk, I add white sugar and usually take it on a well fed stomach . I started taking energin but can't remember if this was at the same time when coffee became relaxing. I don't think so, I've just been drinking more of it for some time.

 

[haidut]

Thanks hamster. Taking a 200 mg caffeine pill makes me feel good for a narrow window of time, but then it triggers some feelings of panic. Niacinamide, bag breathing, red light, and aspirin seem to reduce this effect.

Again, I think the caffeine is deactivating the sympathetic nervous system at this dosage, which in turn accentuates the hypothyroid state. For example, I returned home an anxious mess, and my pulse was 75! I took 250 mg of additional caffeine, niacinamide, and bag breathing, and my pulse rose to 80, and I feel much better.

@What-a-Riot I'd think the mechanism is similar to how low-doses of caffeine can be anxiogenic, as can high doses, but there exists a sweet spot. The upregulation in adenosine may downregulate the sympathetic response, and without the stimulant of caffeine, it will result in a nervous system response to this gap.

I think @Gl;itch.e has mentioned that he gets anxiety if he doesn't drink enough coffee.

@haidut Did you experience any anxiogenesis from lower doses of caffeine versus higher doses? I know you say the higher ones make you sleepy.

Yep, I do get bad anxiety from caffeine sometimes at doses in the 200mg - 400mg range. Caffeine can raise lactate if the dose is not right based on glycogen stores and lipoysis state. I would take caffeine with niacinamide if possible to avoid the potential side effects. Actually, caffeine and inosine (with or without addede niacinamdie) can completely eliminate the anxiety from caffeine, which suggests the anxiety is due to some kind of GABA antagonism by caffeine, at least in the lower doses.

 

[DaveFoster]

Yep, I do get bad anxiety from caffeine sometimes at doses in the 200mg - 400mg range. Caffeine can raise lactate if the dose is not right based on glycogen stores and lipoysis state. I would take caffeine with niacinamide if possible to avoid the potential side effects. Actually, caffeine and inosine (with or without addede niacinamdie) can completely eliminate the anxiety from caffeine, which suggests the anxiety is due to some kind of GABA antagonism by caffeine, at least in the lower doses.

Very helpful post; I will definitely look into inosine. The niacinamide dose needed is quite large in my experience (1g or more) for each higher dose of caffeine to halt anxiogenesis. I'll get some inosine and report back.

 

[kaybb]

Hadut told me about using taurine and L-theanine with caffine. Taurine has helped with rapid heart beating after caffine, and L-theanine helps with relaxation. I think I need something more also, because urine smells like coffee continually. What causes that?

 

[chispas]

A weird thing happened to me recently, where I moved cities and experienced some stress during the move, and this ultimately disturbed my diet routine. Before the interruption, I was easily consuming a couple of triple-espressos per day (each day) with not a whim of concern for the caffeine kick - it made me feel happy, elated and well. Then all of a sudden, post-transition to the new city, a simple cup of instant would give me the worst woozy/dizzy/anxious-like feelings, where I became highly sensitive to light, and would have to lie down for an hour, have something salty/sugary to recover. I couldn't believe a weak cup of instant would knock me about so severely.

What I noticed, is that I simply wasn't eating my usual quantity of calcium foods. Once I built up my calcium intake from cheese and milk, suddenly I could cope with caffeine again. I have tested this on myself reluctantly to confirm the effect, but if I go a day or two without enough cheese and milk, I'm back to the bad feelings post-coffee.

I don't know what the relationship is unfortunately. I do note that certain Scandanavians like cheese in their coffee. I now wonder if this is a coincidence.

 

[Parsifal]

I had this issue when trying to replace caffeine (I'm taking 100mg/day) with a low dose of theacrine (60mg). Got a massive panic attack on theacrine so decided to not try it anymore. That's funny because normally my liver should be healthier thanks to caffeine since I'm handling it better.