14 ms·
Adenosine on the common path of rapid antidepressant action: The coffee paradox
- liamwire 1y agoIt'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?
- standardUser 1y agoNot 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).
- aguynamedben 1y agoTIL coffee is extra good for your brain
- gatane 1y agoNice read, I've been wondeling if coffee really had an effect on mental health too
- k1musab1 1y agoOn 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.
- boothby 1y agoOne 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?
- reactordev 1y agoIt’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.
- lanfeust6 1y agoNot 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.
- mrmincent 1y agoThat 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.
- Muromec 1y agoI'm not gonna lie, double espresso with ritalin before work is pretty good too. It's the T+2 date which is uncool.
- reactordev 1y agoThat’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.
- ipnon 1y agoThis also helps explain why extremely early waking or late sleeping is common in depression.
- XCSme 1y ago[flagged]
- ipnon 1y agoThis is also true that sleep deprivation can act as shock therapy! But it seems to still indicate that depression can be caused by chronic adenosine dysfunction. So temporary sleep deprivation will put the adenosine system in a state it isn't usually in, and alleviate symptoms.
- XCSme 1y agoWhy is downvoted? Is it wrong? It does continue to say it's just a short-term burst and bad in the long-term.
- exmadscientist 1y agoThis 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 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.
- zoom6628 1y agoGlad 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.
- ruuda 11mo agoAgreed. I got further into this one than usual before I grew suspect, but something felt off.
- Aurornis 1y agoAgreed. 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.
- nojs 11mo ago“X: the Y paradox” is pretty indicative too
- wslh 1y agoIt 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?
- MilkyWayMasta 1y ago"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'
- Muromec 1y agoIt 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.
- _yb2s 1y agoI 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.
- idontwantthis 1y agoI’ve found wim hof no more effective than laughing gas. Very short euphoric high then back to where I was plus a slight headache.
- fragmede 1y agoThen again, Wim Hof costs you $0 and laughing gas gets expensive.
- Towaway69 1y agoHow about just laughing without the gas? Ok you have to find something to laugh about. Nowadays turning on the news does that fairly effectively.
- fragmede 11mo agoThere 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.
- _yb2s 1y agoI 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.
- georgemcbay 1y agoWholly 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.
- _yb2s 1y agoI 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.
- ifwinterco 1y agoMaybe 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
- cubefox 1y agoI believe drug dosage scales with body surface rather than body mass, which scales differently.
- zamalek 11mo agoI'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).
- ifwinterco 11mo agoFor 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
- gavinray 1y agoTo 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 https://en.wikipedia.org/wiki/Sipagladenant
- candiddevmike 11mo agoHow do you know that's not frying some kind of receptor in your body? It seems there are no free lunches with antagonist drugs
- ryukoposting 11mo agoThe 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/pdf/e20220715_01.pdf https://www.kyowakirin.com/media_center/news_releases/2022/p...
- gavinray 11mo ago> 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.
- shevy-java 11mo ago> 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 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.)
- bonsai_spool 11mo ago> 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/aop/article-10.61373-bm025c.0134/article-10.61373-bm025c.0134.xml 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 https://www.nature.com/articles/s41586-025-09755-9
- nomadpenguin 11mo ago
- reeredfdfdf 11mo agoHere 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).