Adenosine on the common path of rapid antidepressant action: The coffee paradox | Hacker News Reader

Adenosine on the common path of rapid antidepressant action: The coffee paradox

genomicpress.kglmeridian.com

203 pointsPaulHoule159 comments

On chronic coffee consumption: "One meta-analysis found that RR coffee 0.757, RR caffeine 0.721 (12). Another one found RR 0.76, with an optimal protective effect at ∼400 mL/day (13). In comparison to many drug treatments that have an effect size in this range, this is not a small effect size. A risk reduction of 20 to 25% is quite impressive."

As if I needed another reason to drink coffee.

One thing I've learned over the years is that specifically setting out to enjoy and appreciate something on a daily basis is beneficial to overall satisfaction with life. And for me, that's my morning cuppa before the rest of the house wakes up. Is it (just) the coffee or is it (also) the rituals surrounding coffee?

It’s 100% the addiction.

It’s ok, me too. At home I’m a 4-6 cup a day drinker. On the go 2-3 Starbucks. I have a serious problem.

That was me too. Turns out I was just self-medicating for adhd. I still skip the meds on the weekend so I can enjoy larger quantities of coffee.

I'm not gonna lie, double espresso with ritalin before work is pretty good too. It's the T+2 date which is uncool.

That’s the ritalin. Find a healthier alternative like an energy bar with that double espresso. I find if I stack too much at once, I crash. One cup in the morning when I wake up. One before work right before the meetings. One in the afternoon to keep me fueled until dinner where I let myself gorge on protein and sugars until I crash.

suggest many many cups of 1/3 caffeinated and 2/3 decaf. There are some observed health benefits to even decaf coffee... and its got potassium besides. I drink around 10 of these. lower longer peak. Joy!

Ritalin is a highly addictive substance that wrecks you, your life and the life of everyone around. Unfortunate that we have one in family.

As a parent, tell me more. I have not yet heard this side of the coin.

Ritalin is a chemical relative of amphetamine. In prescribed amounts it's often an effective treatment. In recreational amounts, ask your doctor about ΔFosB:

https://en.wikipedia.org/wiki/FOSB#DeltaFosB

I was unaware that Ritalin is used as a recreational drug.

It's a drug that is often diverted by people who have a prescription in order to make money.

Well, I'd say lots of words for how horrible and terrible it is to have Mr. Jekyll and Hyde around. Any specific questions?

I don't know enough to ask specific questions. I could consult with an LLM, but if there is some risk or side effect that doctors do not typically mention, I'm all ears.

In that case I guess I could caution this: if you have any kind of OCB, our experience is that prolonged exposure to Ritalin will multiply it by at least 10.

Same. During the week on meds I find that drinking more than half a litre just provokes unpleasant sweating and makes me feel frantic, some amount of brain fog and occasionally a mild headache, especially if I haven't been chugging water, which I guess is probably what most normal people get from coffee

Well, that's a bit of an unfair projection; I'm fairly fastidious about keeping my consumption around 2-3 cups a day before 11am and taking occasional tolerance breaks without consequence. But if you feel like your coffee intake is a problem that you have trouble controlling, maybe cut back.

It’s my wallet that is angry, my brain still wants more.

I switched to the cheap stuff and now my palate is angry...

People act like addiction is a word with an inherent negative connotation, but that's not the case, you can totally be addicted to healthy behaviours

You're confused about the definition of addiction... breathing is an addiction too by your logic

don't be silly. next stop is to reduce pooping.

but yeah, exercising can be an addiction? as sex. now doing these daily is fine. it turns into addiction when you can't stop or interfere negatively with your routine

Seems to fall into the difference between "addiction" when used as a common, everyday word, and the alternative medical meaning.

Ah, I am a bit biased to the medical meaning

Not necessarily. I only have one cup in the morning, that's it, but I enjoy it just the same so long as the beans are good and it's done right.

Addiction to any given substance is highly variable from person to person, and there's a lot of data to back that up.

I recall a friend describing their struggle to quit caffeine, which I mocked at first, until I realized it sounded exactly like my brutal struggle to quit nicotine. Yet, plenty of people quit cigarettes effortlessly. Nicotine is one of the most variable, but caffeine, alcohol and cocaine vary widely too. I imagine we'd find this is the case for most substances if we had the data. In a sane world, we'd give every kid their addiction predisposition profile when they turn 13.

The hardest part of quitting anything is changing the behavioral habits that came with it.

For smoking, I bet you have the urge after a meal to smoke. Maybe you’re triggered when you drive long distances to “calm the nerves”. The issue is those triggers, those behaviors, need to be unlearned before you can attempt to quit. That’s why it’s easy for people who haven’t developed those behavioral habits and hard a hell for those who have. Former smoker myself so I totally get it. I can give that up, but caffeine - coffee? I’ll die with a cup on the counter half full.

The literature on this is clear cut. People absorb, metabolize and experience drugs differently, which has a big impact on how addiction takes hold. It's obviously not the only factor! But it's a big one and somewhat quantifiable.

Personally, I wasn't a "trigger" smoker, I was an "every chance I got smoker". I assume my nicotine metabolism is higher than average, which is linked to frequency of consumption and hence propensity for addiction. I also assume I have fast caffeine metabolism since I consume it at all hours with no consequence, but unlike nicotine that's linked to a lower propensity for addiction, which matches my experience.

Caffeine is not chemically addictive. It can lead to depedency but that is not addiction. Motivation and wanting are not altered but unpleasant withdrawl effects can occur.

How do you explain the headaches and exhaustion durring withdrawal then?

That's just how life feels without caffeine, not a withdrawal effect.

That's called chemical dependence and it's the point I'm trying to make. Dependence is not addiction. Addiction means wanting is hijacked, not that stopping is aversive.

Addiction and dependence have real medical meanings and in the context of this discussion and we shouldn't mix them up. See this very short and to the point lancet medical journal summary, https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0...

>Addiction (synonymous with substance use disorder), as defined by the DSM-5, entails compulsive use, craving, and impaired control over drug taking in addition to physical dependence. The vast majority of patients taking medications such as opioids and benzodiazepines are doing so as prescribed by clinicians, with only 1·5% of people taking benzodiazepine being addicted, for example. Physical dependence is much more common than addiction. Importantly, withdrawal effects occur irrespective of whether these drugs are taken as prescribed or misused.

>Failure to distinguish between addiction and physical dependence can have real-life consequences. People who have difficulty stopping their medications because of withdrawal effects can be accused of addiction or misuse. Misdiagnosis of physical dependence as addiction can also lead to inappropriate management, including referral to 12-step addiction-based detoxification and rehabilitation centres, focusing on psychological aspects of harmful use rather than the physiology of withdrawal.

>It should be made clear that dependence is not the same as addiction. The problems with prescribed drug dependence are not restricted to the small minority who are misusing or addicted to these drugs, but to the wider population who are physically dependent on and might not be able easily to stop their medications because of withdrawal effects. Antidepressants (superkuh note: and caffeine) should be categorised with other drugs that cause withdrawal syndromes as dependence-forming medications, while noting that they do not cause addiction.

Caffeine withdrawal takes 2 days.

The explanation for the headaches is that coffee raises blood pressure short term, and the blood vessels in the brain prepare for the predicted caffeine ingestion, and if it doesn't come there will be a mismatch.

What triggers the blood vessel constriction on the brain? Will avoiding e.g. certain places at certain hours also avoid the preemptive blood vessel constriction and associated headache?

Habit. No other outside stimuli. Just you and your habit.

Classical conditioning, like Pavlov's dogs?

What’s the point of this distinction, what does it mean that it’s not chemically addictive? It causes withdrawals, dependence, it definitely acts on brain chemistry.

"Addiction and physical dependence are not the same thing" https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0...

That lancet article very well refutes the point you are trying to make. The term “chemical addiction” is not really used anymore because it really just refers to mechanisms of chemical dependence, which are neither necessary or sufficient to cause addiction on their own.

There has been a major shift in how addiction is understood in modern research, but you have it backwards- your perspective of chemical addiction or direct chemical mechanism being important is the old discredited concept, not the new one, which sees it as a psychological process that requires no direct chemical mechanism at all.

The chemical dependence is quite a factor in the psychological process you refer to. It nudges and reinforces this psychological behaviour. You can broaden the definition to include addiction without chemical dependence, but it does not mean you can omit the chemical dependence factor from the equation.

This chemical dependence is often the number one reason people cannot physically stop their psychological process. Potential effects from quitting include simply dying, or with less strong chemical dependence, feeling anxiety or generally ill.

Yes this is absolutely true, it is a factor in addiction- I initially mentioned this in my comment but deleted it because I felt I was making it too complicated.

This chemical dependence is learned behavior in some cases, chemically induced in others.

I get what you’re saying. Dopamine withdrawal is real though and if you no longer get dopamine from an action or you physically prevent yourself from receiving that dopamine, it can be just as debilitating as cigarette withdrawal or kicking a (soft) drug habit.

Then there’s the opioids…

> Dopamine withdrawal is real though and if you no longer get dopamine from an action or you physically prevent yourself from receiving that dopamine

Exactly, this is why the idea of addiction is more appropriately focused around the actual real world impacts rather than specific chemical mechanisms- the difficulty quitting and the negative impacts on your life. If it's strong enough to overpower your will and destroy your life, that is sufficient, it doesn't matter exactly how.

When it comes down to it, something like an amphetamine drug or other stimulants that directly increase synaptic dopamine, vs a behavior like gambling addiction that exploits the brains instincts and wiring in other ways to still cause the increase in synaptic dopamine are not fundamentally, categorically different in a way that one or the other shouldn't be taken seriously and considered a "real addiction." Either can completely destroy some peoples life, and for other people can be easily controlled and used in moderation.

>That lancet article very well refutes the point you are trying to make.

No. That lancet article very well refutes the point you are trying to make. I'm flabberghasted by your interpretation. Could you please try to support this interpretation with quotes? I can't even begin to understand how to converse with this point of view since such a POV does not exist in the lancet article. I've read it a handful of times and now once again trying to understand you. But it's not there. I recommend you re-read the article.

I have quoted the appropriate bits supporting my, and the articles very title's, claims already in the other comment in this thread and you may refer to it.

> I'm flabberghasted by your interpretation. Could you please try to support this interpretation with quotes? I can't even begin to understand how to converse with this point of view since such a POV does not exist in the lancet article.

It's hard for me to know where to start, because I feel similarly confused about where you might be coming from, and I don't know your level of background in reading and interpreting biomedical papers. However, I can elaborate a bit on my thinking and mention that I am an academic biomedical researcher that reads, publishes, and peer reviews biomedical papers - but I am not a psychiatrist or medical doctor. This is not my field of expertise, I'm not trying to argue from authority, just mentioning where I'm coming from.

First, for context, this correspondence article is in The Lancet Psychiatry, so is targeted at psychiatrists, and is able to avoid a lot of background that they can safely assume the reader already has, like the diagnostic criteria for common conditions.

You are using the term "chemically addictive," which is not used in the article, and which is a term that simultaneously implies both "physical dependence" or "substance dependence" and "addiction" from back when the two were mistakenly assumed to be one in the same. This article is emphasizing the fact that they aren't the same thing, and both can exist independently of one another. Since that is really the only singular point in the article, and is really hammered home over and over, I cannot see how pulling out quotes would help. I think our disagreement comes from the surrounding context not mentioned, not the contents of the article itself.

The article describes that as of the DSM-5 they directly address the confusion between the two, and separate them into two entirely different things. While not explained in the article, it is important to realize that the DSM-5 now includes behavioral addictions together with drug addictions, and considers physical dependence and/or other types of direct chemical modulation of the reward system to be a contributing factor in many cases, but not essential, for addiction.

This distinction is extremely important, because it allows for addiction without substance dependence to be taken just as seriously, and properly treated and addressed clinically or by other means.

Previously, because of the history of this mistaken connection, psychiatrists and patients would wrongly dismiss (as you are with caffeine) the possibility of serious addiction without a direct chemical dependence mechanism. This left people whose lives were being destroyed by things like gambling and sex addictions to be dismissed as not serious, and not allow them to get real help. On the flip side, it also made doctors wrongly afraid to administer drugs that caused chemical dependence but not addiction, for fear that it would lead to addiction in patients.

However, I would argue that while addictive, the level of addiction potential from caffeine is pretty limited because of the fact that it has pretty severe adverse/toxic effects if you take too much, and the enjoyable aspect saturates out pretty quick. Taking a lot more than a normal amount, enough to damage your health, feels awful, so people aren't likely to become addicted to doing so. Counter-intuitively, the most addictive drugs have low acute toxicity and so you can take increasingly huge doses of them and it continues to feel good rather than just make you uncomfortable and sick like a high dose of caffeine.

>This distinction is extremely important, because it allows for addiction without substance dependence to be taken just as seriously, and properly treated and addressed clinically or by other means.

Here's where you seem confused. The article is not saying this. It is explicitly saying that medications which one builds up a tolerance to and experiences withdrawal symptoms from are not addictive.

>The DSM-5 referred to the confusion over this issue, stating that “’Dependence’ has been easily confused with the term ‘addiction’ when, in fact, the tolerance and withdrawal that previously defined dependence are actually very normal responses to prescribed medications that affect the central nervous system and do not necessarily indicate the presence of an addiction.” Public Health England makes the same distinction.

You are claiming the article's distinction between addiction and dependence is discussed in order to make a claim about substance abuse and addiction without dependence. This is not in the text at all. What the heck?

I have the decades of domain specific knowledge and time spent reading neuroscience journal articles to know that I don't have to read between the lines of the article here. It's not an opaque or jargon hidden meaning. It's quite plain: dependence is not addiction. Not, "addiction can happen without dependence" which is not addressed or relevant to the paper or this HN discussion about caffeine.

I completely agree that the article only makes one very specific and narrow point, that dependence and addiction are separate things. The rest of what I wrote is, like you said, not in the article at all, but is context I am adding in attempt to explain my point.

It seems like we’re talking past each other somehow, perhaps one or the other of us misunderstood what the other is saying, but I don't see any value in continuing further.

I still don’t understand the significance of the distinction, maybe because we are talking about caffeine in particular. Caffeine alters mood and causes euphoria. Is that not a chemical component of addiction?

What’s the significance of the chemical component of addiction anyway, when people can struggle with addiction to things which have clearly no chemical component like gambling?

>Caffeine alters mood and causes euphoria.

It alters mood. It does not cause euphoria. But even if it did an addiction does not come from liking/enjoying something. Addiction comes from wanting something. Caffeine does not directly chemically alter the mechanisms of wanting (incentive salience) in the mammal brain. Drugs that directly manipulate wanting are the addictive ones.

Caffeine's mechanism of action is simply blocking the measurement of metabolic product build-up in the brain (adenosine) which is used internally for determining how tired one should be.

A lot of substances cause withdrawals/dependence and act of brain chemistry, e.g., the vast array of psychiatric drugs. However, I have never seen the word addiction used in the context of antidepressants, mood stabilizers, etc..

Even non-psychiatric drugs like NSAIDs, insulin, hypertension medication, etc. can have a withdrawal effect.

I might be mistaken, but I am under the impression that addiction is psychological in nature. Take gambling addiction, for example, I am not certain if there is any physical withdrawal effect, but there is definitely a psychological compulsion.

There is no real importance to the concept of “chemically addictive” and it has largely gone out of favor in psychology. Even physical behaviors like gambling and sex that obviously cannot directly, chemically act on reward system pathways, can still be just as life destroying addictive and challenging to quit as any drug. The dsm now classifies gambling disorder as an addiction.

Caffeine, unlike some drugs and alcohol, doesn't cause severe withdrawal symptoms. Because of that, experts don't label regular caffeine use as an addiction.

https://www.webmd.com/diet/caffeine-myths-and-facts

While it is a contributing factor, physical dependence- withdrawal is not anymore considered necessary or sufficient for addiction. The author there is using an outdated pre-DSM5 definition of addiction which failed to recognize that there are two separate but related phenomena here. Things like gambling and sex addiction obviously cause no withdrawal symptoms from chemical dependence at all, but can be almost impossible to quit and serious enough to destroy someone’s life.

Severity of withdrawal symptoms from caffeine also varies substantially from person to person. It’s probably not directly killing anyone, but for some people it can be brutally unpleasant and disabling for at least several days.

There’s so many layers to this. First, there’s history: Coka-cola (originally made from a Kola nut and cocaine) was told they couldn’t put cocaine in their “medicine” anymore so they just sold it as a “soft-drink” without the cocaine.

Then there’s the beverage industry who pointed out there’s caffeine in tea leaves and other plant material and that it’s not a threat: (1) US vs 40 barrels and 20 kegs of Coka-cola. Ultimately reducing the amount of caffeine in soft-drinks.

Round and round we go allowing companies to use chemicals to keep us buying their consumables.

(1) https://en.wikipedia.org/wiki/United_States_v._Forty_Barrels...

I don't want to get too deep into caffeine addiction so I drink mostly decaffeinated coffee. Am I just cheating myself?

No, there’s benefits from drinking coffee whether it’s caffeinated or not.

Ah, it’s good to know that. Unfortunately my stomach feels a bit weird after too much coffee. Wish I could drink more.

> Starbucks

By the way, why does Starbucks make such bad cappuccinos? The milk is foamy instead of creamy. There is no heart shape or any shape really. And the entire beverage is too hot.

Blame the barista. The quality has gone down significantly over the last decade. It’s either a tall in a venti cup. A flat white when it should be a white mocha. Or a mocha. In the end, it’s still a quick service restaurant. Training is an expense. Now they just press buttons. If my local cafe could deliver me coffee that would be great, until then I’m short on time and hit the drive thru.

Say this next time: “Cappuccino, whole milk, no foam” and see what they do.

Yeah, one problem is that the person who takes the order is not the person who brews the coffee.

I also enjoy my morning ritual of preparing the grinds and brewing a fresh pot. But I'll be honest, at the end of the day it doesn't really matter where I get it -- brunch at a nice restaurant, Starbucks, McDonalds, a cheap hotel buffet, lukewarm from a flight attendant ... as long as I get it. Sounds healthy, right?! ;)

I've always associated this sort of life satisfaction & ritual spectrum with Zen "no-mind" [^1]

Whether it's coffee ritual, or doing dishes there's something pretty magical about the quiet flow state of engaging with the moment

[^1]: https://en.wikipedia.org/wiki/No-mind

I used to have withdrawal symptoms when I didn't have coffee, now I don't have those. But yes, the alone time in the morning is critical for me.

My wife and I don't drink caffeine anymore but still have a swiss water decaf coffee every morning.

The caffeine aspect is completely unnecessary, but coffee still tastes good, warm drinks are still nice. It's all the ritual.

Ah yes, the Twin Peaks method

Is it the addictive substance or the ritual I created around it?

I used to think this same thing, that my enjoyment of coffee was largely the ritual. But then I switched to decaf for quite a long time and all my little rituals fell away quite quickly.

I still occasionally drank coffee when I felt like the taste, but I certainly wasn’t performing daily morning ritual.

I’ve switched to decaf full time and a my generalised anxiety basically went away. I love coffee and still drink it ritualistically. I probably drink more coffee now, at all hours of the day (caffeinated coffee after 12 really messed my sleep).

Also once per week I allow myself an espresso, and I get a nice buzz from it that lasts the entire day.

That’s cool. I’d like to quit again sometime but right now caffeine staves off migraines for me. And with a baby in the house I really don’t have the resources for that battle.

When(ever) I quit coffee, I got strong migraines after a day or so. However, they subside and go away after a few more days.

I wouldn’t claim it works the same way for everyone, but the difference between coffee being a treatment for migraines and migraines being a symptom of coffee withdrawal may be indistinguishable in immediate term.

Ah yes. I do get those, but also just get migraines (as well as hypnic headaches) which caffeine is a wonder at ameliorating.

I quit caffeine for about 2 years and the headaches never subsided (except the caffeine withdrawal ones of course).

They are just a fact of my life I’m afraid.

As much as I’d like to get off of caffeine I am very grateful to have is as a remedy.

My gf has a migraine head and she’s tried going decaf but it just doesn’t work. Apparently caffeine does a lot to reduce the risk of migraines? So I’d probably just try to lower the dose until you find what works for you.

I love the term “migraine head”. I’ve never seen that before. It’s gets across the idea that it’s just the way one’s head is quite nicely!

This hits home. For me stopping coffee (and caffeine) consumption was also one building block of taking care of my generalised anxiety disorder. I enjoyed the morning ritual, but it stopped with quitting drinking coffee. Maybe I should give decaf a shot, but I also miss just grabbing a coffee when out with friends (usually tea does not scratch the same itch and is not worth it when everyone else around you is enjoying a great smelling coffee). All I want to say is “Thanks for sharing” I guess. I was able to connect with what you said.

I went to the US recently and was fully prepared to drink caffeine on the trip because of all the cool coffee shops and roasters. But I was amazed that decaf was basically a first-class citizen there. The hotel breakfast had one giant brewer for regular and the same giant brewer for decaf. It was amazing.

And it’s pretty important to realize that well-made decaf doesn’t have to taste worse than regular coffee. James Hoffmanns decaf project proved this for me, and his video about decaf sold me on the idea: decaf drinkers are the OG coffee drinker, drinking it purely for the taste, even without the drug-induced high that caffeine gives you.

https://youtu.be/yYTSdlOdkn0?si=V0xKFGCZR1-YgGmO

It's both. In stronger drug addictions, the ritual itself is rewarding even if there are no drugs present in your system yet.

Add that to conditioned place preference and you have your rewarding coffee ritual.

Yes, my morning coffee and cigarette breakfast was the most rewarding ritual. I basically couldn’t start my day without it!

Even though I quite smoking over 10 years ago I still remember it with the fondness of an old friend.

There is an absolutely huge ritual part to it because I have been trying swap out coffee and just take caffeine pills in the morning to be more exact in my caffeine consumption.

I just can not do it. It is just not the same sitting here without the taste, smell and sensory experience completely divorced from the actual caffeine. That is with even taking more caffeine than I would get from my brew coffee.

It could also be that the decaf wasn't good? A lot of decaf is poorly roasted and tastes wrong.

Father of three here. I also enjoy very much this moment of the day, the calm before the storm. It was a real motivation to wake up a bit earlier.

One day, I decided to stop coffee for some weeks. My motivation to wake up before my kids vanished in a few days. I was quite surprised since it used to be a real pleasure. I guess the ritual part was much less important than the coffee chemical role.

I got back to coffe quite rapidly.

For me, it’s the reward after the storm – once everyone has gone I sit there and enjoy my coffee.

Did you just remove the warm drink part of the ritual or did you replace the coffee with another warm drink? This could be the big difference you were missing.

This is the big question in this comment indeed

One could say the same about any drug. :D

I try to not let taste or smell overrule other decisions made by my brain. Of course it is so visceral that one can not escape it; some stinky fish challenges show how powerful smell is. Some people can not control their body's reactions to bad smell.

>enjoy and appreciate something on a daily basis is beneficial to overall satisfaction with life.

I'll couch this in a warning that you need to have the money for it, but for me an espresso machine and good grinder was such a great investment.

It's this thing I appreciate a lot every day.

If you're a drip coffee person I guess this won't apply and you can save a few thousand. Although I'd still recommend getting a grinder (not necessarily an expensive espresso worthy one) and good beans then.

Drip coffee is amazing: A consistent grinder; fresh, light or medium roasted beans protected from oxidation; and a machine that heats the water to the correct brew temperature (190-195 F)is all you need.

The flavor profiles are akin to wines; no decanting required.

Extremely enjoyable in the early morning moments.

Espresso is my soft spot given my origins, but a good drip on paper filters (to remove some oils and cholesterol) is akin to good tea, full of aromatics. I disagree with the temperature, for me a blonde roast calls for 72 degrees Celsius (162F).

To be accurate, I should qualify that for me it’s “light/medium” and not a true blonde roast.

I haven’t had the pleasure of trying to brew my own blonde roast yet.

But I was amazed when I first tried a black coffee brewed properly, and it took me far longer than I want to admit to learn the basic nuances; it was a very fun journey though.

Exactly, and a lot of people that don't like black coffee never had a solid experience: a cup full of aromatics — like tea — instead of just burnt, bitter, over-heated slurry.

I'm a hater of drip coffee as it almost always contains under-extracted (outside of cone) and over-extracted (middle of cone) coffee. You're correct about the importance of brew temperature, although I take issue with the strange units you use.

For me, full immersion brewing is the best as it's far easier to control than expresso - you can fine-tune the water temperature, the grind size and the brew time until you get coffee that astonishes people. Personally, I'm a big Aeropress fan, though I don't know why so many people make horrible coffee using french presses. I think most french press coffee I've drunk has had far too little coffee or too much water in the brew.

If you mean the temperature is slightly too low, then yes. I was going by memory, then subtracted by five second-guessing myself.

Pyramiding the grind works-around the problem well-enough for me, however.

I wasn't complaining about the actual temperature (I tend to 80°C water for my Aeropress brews), but the use of freedom units.

I'm sure there's ways to make quality drip coffee, but all the drip coffee that I've had has been very poor. I've also lost count of the number of times that I see people using boiling water for making coffee.

To my mind, it's easy to get obsessive over making good coffee, but what I'd like to see is just more people knowing how to not make bad coffee. If you're thinking about water temperature and pyramiding the grounds, then you're likely making great coffee.

Coffee in the morning is especially good because it induces bowel movements.

https://www.nytimes.com/2021/11/30/well/eat/why-does-coffee-...

It's the only time of the day that's mine. Morning coffee and me. Silence, taste, and treasured bouquet. Sanctuary.

The last 20th century vice. It's mine.

The problem is, most Americans don't drink coffee, they drink sugary mix with coffee flavor

One thing you learn from reading depression papers is that there are a lot of things that supposedly have significant effects on depression according to some papers, but then fail to work when people try them or they’re tested in trials.

The linked paper is pretty obvious AI paper mill content, so I wouldn’t take anything it says as directly true without checking citations. The citation is a meta-analysis so you’d have to check the criteria and the studies.

The most common explanation for the “everything treats depression” result is inclusion of studies that have no control group. The placebo response rate in depression studies is very high as many patients revert to the mean of being not-super-depressed after they are so depressed that they enroll in a study for depression treatments. Paper writers seeking a positive result will abuse this to their benefit by omitting the control group. They’ll collect depressed patients, give them some treatment, and when the average improves they’ll publish a paper saying that the treatment has positive effects in depression. So after reading a lot of papers about depression, you start dismissing claims by default unless you can confirm they came from a properly powered, placebo-controlled, double-blind study.

But hey, if you’re already drinking coffee and enjoying it, continue to enjoy it!

I don’t have hard data, but I think this optimal value is very closely approximated by coffee drinkers’ daily average. 400 ml is about 1.75 cups, and i think the normal distribution of coffee cups among drinkers is centered at ~2 cups. Makes me wonder if we’re all self medicating and accidentally finding the sweet spot.

Well, that's the hardest data of all!

OR it could be that we find the sweet spot because it's the spot we feel the best.

Hmm to feel a bit elevated makes sense. I also have that with one glass of alcohol at certain times. Heart rate goes up, things get a bit more intense. It's a nice vibe if you're open to it. It's also a bit subtle.

For me what I've noticed: 2 cups hits the spot, but I always tend to drink more, around 4 cups. On the 3rd cup my mind gets jittery. It's not so much my body or anything and I don't experience the jitters strongly but at the same time I feel a stronger focus while noticing that stronger focus isn't getting anything extra done. Hence I call it mind jitters.

But I can imagine that at 2 cups people are genuinely just a bit elevated in certain ways.

How about a reason to cycle your coffee :)

https://rouvy.com/blog/caffeine-in-cycling

Caffeine periodization in cycling: the science behind performance (2025)

IMHO Coffee is way too strong for most of us. Sipping green tea gives a smooth subtle high all day. And you can sleep at night. And not be an angry/anxious bastard.

I love coffee, I take 100mg L-theanin daily so my body tolerates it. Basically best of both worlds.

Yea high quality Japanese green tea has been my go to. Unfortunately, I'm addicted to coffee. Thank god I'm also lightly addicted to living frugally and that is currently winning out. Black tea for 20 bags for 35 cents it is.

Decaf beans improved significantly in the past few years.

> As if I needed another reason to drink coffee.

I tried it but coffee to me just tastes horribly bad. Chocolate on the other hand can be quite great (there is also a lot of horrible chocolate, but good chocolate has a better taste to me than coffee.)

How were you drinking it? Espresso with steamed milk, sugar, and flavored syrup is quite a treat.

Drip, black, is going to be quite... utilitarian.

If by utilitarian you mean delicious, yes

An espresso is about 30 ml of liquid... I am not sure this mixture of milk and sugar (and more sugar!) into 30 ml can still be called a "coffee" , but i'm sure it is a delicious beverage!

Milk, sugar, syrup, and additional flavour?

Might as well have a cake if you need to mask the flavour so much :)

I like espresso-style coffee. Over the years i discovered that the very best espresso shots do have a rather strong chocolate note. No acidity, no bitterness.

Unfortunately I also found out that it is basically impossible to get that kind of quality from coffee shops. You must make it yourself, have the right equipment (the grinder is the most important one) and a lot of practice. Then you might have one in 10 god shots... but you taste it... you immediately recognize it.

You can achieve near 100% great shots. I have a decent grinder, Robot Cafelat manual machine, and found the beans and roasting level I enjoy form a local roaster. Total under 900CAD.

Agree about not being able to enjoy any other coffee anymore.

Wholly anecdotal, but as a 52 year old nearly-lifelong caffeine (ab)user I quit this year and the withdrawal period was horrendous -- not for the headaches everyone knows about (they were bad but only lasted a couple of days) but for the somewhat extended depression/anhedonia which I had never really experienced before.

I was worried during that stretch of time that maybe the caffeine had been masking some underlying depression I already had, but a couple of weeks in it passed, so I think my brain just needed to rebalance itself to the new caffeine-free reality.

I'm glad I quit (less anxiety, better sleep, I'm finding it a lot easier to eat healthy while not buzzed on caffeine all the time, and the depressive episode was temporary) but going through that makes it pretty easy for me to believe caffeine can have rather powerful effects in this area.

I think a lot of the difficulty in quitting can be mitigated by slowly titrating down the dose over a month or two instead of quitting cold turkey.

But your experience mirrors mine in going cold turkey which I think demonstrates that caffeine can cause both physical chemical dependence, and psychological addiction.

This appears to be some kind of AI-slop rapid response to a piece of actual research (over at https://www.nature.com/articles/s41586-025-09755-9 ). I don't mind discussing that, but this piece should never have been published. Just look at Figure 2 if you don't believe me, or the publication timeline.

Glad I wasn't the only one to suspect AI slop. The language is too self promoting and vacuous in parts. Just doesn't feel like a human wrote it to me.

Agreed. I got further into this one than usual before I grew suspect, but something felt off.

Agreed. It even has the classic “this not that” and “from this to that” LLM tells in the headline.

I would suggest ignoring this document and reading the Nature article linked in the comment above.

“X: the Y paradox” is pretty indicative too

"The mechanism of action of ketamine primarily involves modulation of mitochondrial metabolism as opposed to NMDA receptor antagonism"

More evidence for Chris Palmer's 'Metabolic Theory of Mental Disorders'

It kinda makes sense if you consider depression to be a mechanism to get into winter hibernation. It's just we can't hibernate and even if we could, somebody has to pay them bills.

That was the funniest social critique I’ve heard in a long time.

But are we built for hibernation? Or is the capacity for depression just a biological mistake for us?

We are not build for anything. It's a legacy codebase. Some stuff stopped working, but nobody removed the surrounding utility codes and the config entry to enable it.

Damned legacy code and technical debt always ruining everything.

I never knew that “acute intermittent hypoxia” was a known treatment for depression, but I’ve found both freediving and Wim Hof breathing to be effective at treating my depression- however never the two at the same time as that is extremely dangerous.

I’ve found wim hof no more effective than laughing gas. Very short euphoric high then back to where I was plus a slight headache.

Then again, Wim Hof costs you $0 and laughing gas gets expensive.

How about just laughing without the gas? Ok you have to find something to laugh about. Nowadays turning on the news does that fairly effectively.

There is a Buddhist practice of just laughing! Force yourself to laugh and the energy from that will extend. There are videos of it on Youtube.

I suspect you’re missing something important- not surprising since Wim is a really unclear teacher. The low oxygen and/or high co2 causes your body to panic and you are supposed to use that as a stimulus to gradually train conscious control of your heart rate and stress response and calm yourself down. This is where the benefit comes from, not the short term physiological panic itself, whose symptoms you are describing. In fact, those symptoms should go away entirely when you learn to calm the panic and consciously control your autonomic nervous system. This then also primes you mentally to be able to go into ice water, which is also a large stimulus to learn to calm, plus trains your brain to more easily jump into anything difficult. All of this takes months or years of consistent practice to gradually develop a relatively permanent sense of calm and internal strength among other things, and is really just a simplified form of tantric tummo meditation.

where can I learn more?

I'm not sure. I figured out most of that from taking Wims online class, and through years of personal practice and experimentation. I found that I was able to pick up a lot more by watching Wims body language and actions in videos, that he never directly explains, but I am not sure everyone could pick those up.

Ultimately, Wim's stuff is mostly based on tummo and other Vajrayana/Tantra yoga practices, and you can find both books and in person teaching locally in most places that cover these things. Wim never even explicitly mentions this, but effectively what he is is a yoga master that has developed yet another new system of yoga. Before the 'Ice Man' stuff he had even developed and written about other yoga innovations he had come up with.

Another thing worth mentioning is that while Wim is truly a master at his own method, he tries to rationalize everything with a scientific backing, but he has absolutely zero understanding of what he is talking about, and it's all nonsense. I have a biomedical background, and have developed some of my own theories about how his stuff is actually working physiologically and psychologically, plus there is some academic research out there you can read both on his methods and Tummo itself- but ignore everything he says about that, he doesn't even understand the basics.

Also, ignore everything he says about putting breath pressure up in your head/ears- absolutely never do that, as it can cause tinnitus, and the methods work fine without it.

Completely anecdotal but I've found Ujjayi Breathing from yoga to have an enormously calming effect.

Long exhales in general with a short pause at the end, before inhaling, are also incredibly useful. I try to do this as often as I need.

Interesting… I will look into that. Part of Wim Hofs teachings include breathing with an extremely long exhale while humming which sounds related. I’ve heard of research showing that any type of breathing with longer exhales than inhales activates a parasympathetic response, calming you down.

Sounds like Indian Om chanting, 3/8th of the duration with 'O' with open mouth and 5/8th with the 'm' hum. There is also a 4 moments inhale, 4 moments hold and 4 moments exhale. We learned it as teens or young adults.

To add something constructive:

I've used a novel nootropic which is an adenosine antagonist (KW-6356) for long-lasting energy without dopaminergic stimulation. Something I found and which is commonly reported by other users is mood-enhancing properties:

https://en.wikipedia.org/wiki/Sipagladenant

How do you know that's not frying some kind of receptor in your body? It seems there are no free lunches with antagonist drugs

The manufacturer doesn't make it clear why they axed it, but from my experience in med-tech I think this translates to "the FDA is going to balk at it"

https://www.kyowakirin.com/media_center/news_releases/2022/p...

  > How do you know that's not frying some kind of receptor in your body?

I don't. One of the things I enjoy about life is being able to experiment on my own body.

Maybe this is normal for mice but the dose of ketamine used (5-20 mg/kg) seems high? I know mice metabolism is very different but that's in the range of a gram of ketamine for a normal sized human.

The mice may not have been depressed because it's hard to be depressed when you're in a k hole

I believe drug dosage scales with body surface rather than body mass, which scales differently.

Depends on the drug, no?

Not really. There a things like the square-cube law and Kleiber's law which indicate that drugs don't scale with weight. See

http://clymer.altervista.org/minor/allometry.html

I'm not sure what a typical ketamine dosage looks like, but I have discussed it with my psychiatrist as a fallback if TMS doesn't work out, and she said that ego death is one of the primary mechanisms (alongside reintegration therapy, spending a weekend tripping balls won't fix a thing - at least perpetually).

For humans the antidepressant dose is very low - I think less than 50mg. You might feel some minor dissociative effects at that dose, but only minor, yet in some patients it can apparently produce a pronounced antidepressant effect which is interesting and suggests a non NMDA mechanism

It seems that a session like 10×100 m sprints with <90 seconds of rest produces a metabolic pattern very similar to acute intermittent hypoxia, short intense bouts with incomplete recovery. Am I thinking about this right?

Here in Finland we have the world's highest coffee consumption per capita, and also long, dark winters. Is it a coincidence? I don't think so.

I've found combination of coffee and light therapy to be quite effective against seasonal affective disorder (the kind of temporary depression where lack of sunlight is a significant cause).

This also helps explain why extremely early waking or late sleeping is common in depression.

It'd be extraordinary compelling to genuinely have a unified mechanism to explain depression treatments, but I am not qualified to make heads or tails of the research. Wondering what the take of those with relevant experience is on this?

Not an expert, but the standout thing about ketamine in particular is that it targets an entirely different neurotransmitter pathway than almost all traditional anxiety and depression meds. Traditionally, people treating serious depression or anxiety rotate through a variety of drugs that all hit same small set of neurotransmitters and settle on the one that works the best/sucks the least.

This is why people get excited about ketamine and psychedelics as therapeutics. Otherwise, we're just sitting around waiting for the next round of "new" drugs that manipulate the same pathways as all the old drugs (and carry much of the same risks).

Nice read, I've been wondeling if coffee really had an effect on mental health too

> applied GRABAdo1.0, a GPCR-based sensor for adenosine

At first the intro was:

> Using genetically encoded adenosine sensors

And I did not know what was meant with that. Lateron this became more clear - GPCR is a common motif for membrane-based receptor systems. https://en.wikipedia.org/wiki/G_protein-coupled_receptor

So, saying it is "genetically encoded" xyz, means absolutely NOTHING at all, because all the other receptors based on GPCR (see the wikipedia article) are ALSO "genetically encoded". After all some stretch of DNA yields mRNA which in turn is translated into the corresponding aminoacid sequence (= protein), if we ignore splicing and so forth to simplify this (and then transport into the membrane). This is supposed to be a scientific article though - why do they use such a strange terminology e. g. "genetically encoded"? I mean, this follows by simple logic unless it was made completely artificially. Lateron in the article it is more clear, but it is strange that they use those words in the summary-intro part. It almost seems to me as if they wanted to integrate certain keywords as buzzwords or to rank an article higher. I don't quite like that.

Contrast this to Watson and Crick from 1953:

"It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material."

It is probably one of the most famous intro lines, e. g. the "It has not escaped our notice" since it was so casual. (And they built their insights on data of others, so it wasn't just Watson and Crick to have made the discovery; not even only Franklin etc.. but several more that should have been credited with it. Watson and Crick's main achivement here was more that they built it together into a simple, cohesive overview and explanation model. If I recall correctly, Linus Pauling also came close but proposed three helices.)

> This is supposed to be a scientific article

The 'article'[1] is completely written by an LLM.

1. https://genomicpress.kglmeridian.com/view/journals/brainmed/... currently, hopefully it is changed to the actual research link which is https://www.nature.com/articles/s41586-025-09755-9

"Genetically encoded" is the appropriate term here -- it was used in the original journal article. It's a common industry term in neuroscience research. For example, GEVIs and GECIs are "genetically encoded voltage indicator" and "genetically encoded calcium indicator" respectively. "Genetically encoded adenosine sensor" here is a term of art.

TIL coffee is extra good for your brain

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