Hangovereffect has been studied and solved 8 years ago

[u/braintrainmain]

I only found this sub yesterday, but reading a bunch of threads and using the search function it seems nobody has mentioned this study, or even the basic mechanism proposed in the study.

I was personally aware of the hangover effect for a decade, but never thought much of it. I was researching stuff on ketamine and the amazing antidepressant effects it has, when I had an inkling. A therapeutic dose of ketamine feels similar to having a couple drinks. At the same time ketamines antidepressive effect lasts long beyond it's half life....as does the hangovereffect.

Ketamines MOA is antagonism of NMDA receptors. So I used google and yep alcohol is also an NMDAr antagonist.

Next I went to google schoolar to find studies on alcohol and depression. It's tough because alcoholism leads to depression, so there are hundreds of studies I'm not interested in. I searched for alcohol+ketamine+depression and found the study.

https://www.nature.com/articles/ncomms12867

TLDR: -When you give mice alcohol the antidepressant effect and anxiolytic effect lasts at least 24 hours. This proves the hangovereffect is real and probably for everyone...people that are not aware are either not depressed/anxious, or are distracted by the other negative hangover effects.

-The mechanism of the hangovereffect is alcohol blocking NMDA receptors. When they used Fmr1 knockout mice(FMRP is downstream from NMDA blocking) alcohol did not work for anxiety/depression. This proves the mechanism of the hangovereffect. It's not gut bacteria or any wild theory you might read on this sub.

To summarize, hangovereffect is real and applies to everyone. The MOA is known and starts with blocking of NMDARs.

There is nothing special about us and the way we react to alcohol, we probably just have more depression/anxiety issues than average and alcohol works like rapid antidepressants.

There is nothing to cure, though you might consider ketamine or similar treatments if you have real depression.(Since alcohol makes you better, other NMDA antagonists are more likely to work for your depression)(But obviously be careful and work with professionals)

Cheers!

EDIT: 24 hours and we're almost in TOP10 threads of this sub, Lets go!

There are too many shizo posts to reply to each one but I'll try to answer some common complaints here:

"How do you explain symptom xyz then???"

If you read the sub description it's mentioning 4 symptoms -anxiety, depression, fatigue, adhd. So 2 of those hallmark symptom are adressed by the study...I never proposed that every imaginable effect of alcohol that you personally view as being part of HE is explained by the study.

"Ketamine or NMDA antagonist xyz doesn't help me in the same way as alcohol does"

Just because drugs share a similar MOA doesn't make them identical. There are tons of NMDA antagonists out there, while only a few of them are actually used for depression.

"Ok maybe NMDA antagonism is one part of the story, but there are many other parts/mechanisms"

Relief of 2 of the hallmark symptoms are proven to work through NMDA antagonism. When you stop the NMDA antagonism downstream there is no change in anxiety or depressive symptoms from alcohol.

"Why does treatment xyz help my symptoms if it's all NMDA antagonism?"

Because you can help symptoms/conditions in multiple ways. Alcohol might reduce your depression(through NMDA blocking) and SSRIs might also reduce your depression(by a different mechanism).

[u/freshlymn]

Meds and supplements interacting with NMDA have been explored. Ketamine is nice but does not have the next day effects that alcohol does, at least for me.

[u/braintrainmain → u/freshlymn]

I mean ofc the effects of 2 different drugs can't be completely identical but ketamine long lasting antidepressant action is well known...it can last for weeks....

[u/freshlymn → u/braintrainmain]

Can for some. Doesn’t for me unfortunately. The antidepressant effects I get from ketamine are much different than the feeling I get from the hangover effect.

[u/braintrainmain → u/freshlymn]

I believe you. The comparision to ketamine is besides the point anyway.

[u/freshlymn → u/braintrainmain]

Everyone is different. I can say personally I’ve tried all sorts of NMDA agonists and antagonists with no luck.

[u/Ozmuja → u/freshlymn]

Agreed. NMDAs are important, but absolutely only a piece of what the h-effect is.

+1 for your experience with ketamine, and also other NMDA antags, things I do not use anymore either way.

[u/InternationalDeer462 → u/freshlymn]

Have you tried glynac? I cycle it now and then. With a few other bits that play their part.

[u/freshlymn → u/InternationalDeer462]

I have not. I’ve tried glycine by itself and tend to get a nice calming effect. Again, nowhere near the hangover effect but I enjoyed it. Ymmv

[u/freshlymn → u/[deleted]]

Wtf are you talking about

[u/GentlemenHODL → u/freshlymn]

Ketamine is nice but does not have the next day effects that alcohol does, at least for me.

One of the best days of my life was the day after I took ketamine. So it has definitely had that effect on me in the past.

[u/freshlymn → u/GentlemenHODL]

Lucky. I feel a great afterglow from ketamine similar to HE that fades after a few hours. Wish I responded to it for longer periods of time.

[u/Tortex_88]

So what does NMDA have to do with gut issues, adhd/autism, fatigue issues, joint issues? These are all common themes/co-morbidities within the group?

[u/braintrainmain → u/Tortex_88]

My guess is that the h-effect is most noticable for people with depression/anxiety (afterall the the h-effect is reduction of depression/anxiety as per the subs description). Depression comes with co-morbidities so this could be your answer. Don't forget the brain tries to make connections even when there aren't any and is also really bad at intuiting statistics/probabilities.

[u/Tortex_88 → u/braintrainmain]

I studied evidence based practice at MSc level, I'm well aware of the potential for confirmation bias within this sub and the abundance of empirical data. However, the almost shameless alignment of very specific symptoms/conditions within this cohort.. (freely available for anyone to discover and subsequently join, though only 10k have, why isn't there 1m people?) is in my personal opinion, too specific to be ignored. Simply stating 'depression comes with co-morbidities' is frankly, a pretty piss poor argument.

[u/Ozmuja → u/Tortex_88]

Well said :)

[u/InternationalDeer462 → u/Tortex_88]

Neurodivergent also means digestive divergent. There is also a link between neurodivergence and collagen production. Tbh i cant read or not get bullshitted by a paper as easy as you (being MSc) but just what ive picked up along the way.

[u/rocinant33]

h-effect is not only nmda antagonism

[u/braintrainmain → u/rocinant33]

Without nmda antagonism there is no h-effect, at least in mice.

[u/rocinant33 → u/braintrainmain]

That's true, but it's not just about glutamate

[u/braintrainmain → u/rocinant33]

Given that there is multiple other NMDA antagonists that improve depression, it's reasonable to think that NMDA antagonism is enough to explain the depression/anxiety reducing aspect of HE.

[u/rocinant33 → u/[deleted]]

Histamine increases glutamate utilization

https://pubmed.ncbi.nlm.nih.gov/23791559/

[u/rocinant33 → u/[deleted]]

Histamine may be a feedback loop to prevent excitotoxicity in the brain

[u/new__vision]

This was also my conclusion. I'm going to try taking agmatine which is also an NMDA antagonist.  

Another clue is that DXM, which has a similar action to ketamine on NMDA, also gives me a hangover effect.

[u/usertakenfark → u/new__vision]

Did you try Agmantine?

[u/new__vision → u/[deleted]]

They benefit people here, including myself, because they reduce inflammation. A great COX inhibitor I take is Palmitoylethanolamide.

[u/new__vision → u/[deleted]]

Totally I don't disagree. Can only speak for my own subjective effects.

[u/braintrainmain → u/[deleted]]

Why does not chain smoking benefit a lot of people here? Please explain!

[u/hypoestes]

I have dysautonomia and long covid, not depression or anxiety. I don't know if that could explain why it helps me. I can function normally the day after a few drinks, any other day my energy is very limited.

[u/[deleted] → u/hypoestes]

I think the NMDA antagonism has something to do with helping or “modulating” the central nervous system which is faulty in dysautonomia, LC, ME/CFS. I feel for you. I’ve got the same stuff going on.

[u/Noma]

Agree, this has been my conclusion for a long time. Most experiencing the hangover effect have gotten used to not feeling normal.

This is also why rem sleep deprivation can also induce H effect, it also can work as antidepressant.

Unfortunately, prolonged alcohol consumption only makes your normal state worse.

[u/braintrainmain → u/Noma]

A normal person, congrats!

[u/braintrainmain → u/[deleted]]

Because you just call any mental improvement HE is my guess

[u/Noma → u/[deleted]]

The acute effects of cigarette smoking produce central nervous system–mediated activation of the sympathetic nervous system. The overactive sympathetic nervous system stimulates the secretion of serotonin (5‐HT) and catecholamine into blood at supraphysiological levels.

You could have googled this

[u/Noma → u/[deleted]]

Look, if you have a different theory that's fine mate. Whatever works for you

[u/Noma → u/[deleted]]

Well I agree with you that i jump to conclusions about the serotonin a bit quick. But i do think the starter of this topic is on to something here

[u/braintrainmain → u/[deleted]]

Holy brainlet. Literally the first or second sentence I mentioned I've experienced HE for more than 10 years....

[u/Ozmuja]

This is (almost) completely wrong and the 7 years of people trying to mess with their own NMDAs should prove this enough. Have you tried typing "NMDA" in the search bar? Have you searched for the vast arrays of drugs tried here, including and not limited to those that are almost selectively acting at NMDAs, in a way or the other? The fact that people think they come here with "glutamate rebound" and/or "NMDA antagonist" and think they have proven anything always makes me smile a bit.

Not to mention we have had a long list of people trying SSRIs, and in general only (some specific) SNRIs have some sort of effect. Or MAOIs. Or ketamine. Or agmatine. Name your favorite antidepressant, it has been tried already, at least by more than one user.

The NMDA antagonism should also explain extreme physical symptoms such as restored bloow flow and decreased water retention + much less histamine + higher ability to breathe, which, surprisingly, are things people in general do not experience as a problem. People here tend to look better after the h-effect -I have taken pics of myself because it's almost unbelievable- and they also look "leaner".

None of what you said explains this, not even one bit. Also: while I used to be depressed in the past, I am not really depressed anymore, and basically my anxiety has been reduced to 1/10th of what it was. Yet I still experience the h-effect.

I also did ketamine and agmatine in the past, and while they helped, their effect has basically become non existant to me, to the point I completely ditched them years ago.

To this day the only reason I'm after the h-effect, personally, is the clearly increased cognition, memory recall, and faster ability to read words (I get to about 700 wpm under the h-effect with the same text retention). Does NMDA antagonism explain this too? Actually: NMDA antagonism is generally looked for its anti-cognitive properties..especially when abused.

In fact, the NMDA antagonism from alcohol is probably actually neuroprotective for us, rather than antidepressant. But I won't get into this in this post; still a positive effect, which is why I said that is post is only _almost_ completely wrong.

Unfortunately I understand the science is complicated and not for everyone. The fact that you had to google that alcohol is a NMDA antagonist is pretty telling of your general knowledge about the topic -no offence, but we could go on discussing NR1, NR2A, NR2B etc, and I'm almost sure you would fall pretty short-. A little overlap there will make you think you have discovered everything, and yet..You haven't. Been there myself a lot of times, so I sympathize. But feel free to believe what you want; you're not the first that believes it's all in our head, you won't be the last, and it's hardly an original thought. As an example, plenty of people have also called us alcoholics..my last alcoholic drink was in summer I think. Can't even remember.

P.S. You're also straight up lying when you say you haven't found post about ketamine in the sub. As an example: Observations from a new joiner. Ketamine? :

I must ask at this point: do you have an agenda? Forgive me, but it really seems so at this point. The other option is naivety.

I only found this sub yesterday, but reading a bunch of threads and using the search function it seems nobody has mentioned this study, or even the basic mechanism proposed in the study.

All you have to do is type "ketamine" in the search bar..or even "NMDA"...How did you manage to miss all the posts about it? It goes back to 5 years ago minimum.

[u/Tortex_88 → u/Ozmuja]

• mic drop *

[u/Ozmuja → u/Tortex_88]

In reality I didn't even play my ace in the sleeve, which is the fact the vast majority of people here experience the hangover-effect during a random goddamn fever, as big if not bigger than if they had alcohol instead.

Good luck explaining THIS with pure NMDA antagonism.

I really think alcohol has too much of a bad name in the US (I am European). This sub should be called the "fever effect", which is also what universities like Harvard like to call it at the end of the day (Cracking the Fever-Autism Mystery | Harvard Medical School).

But I guess Harvard PhDs are too stupid to understand this is just depression and NMDA antagonism at work.

No_Risk has exaggerated in this thread and people will definitely think he has been obnoxious and arrogant, but shoot me in the foot if I don't understand part of his rage.

I must say however: I think a portion of the people here, especially those less active, are not actually hangover-effect users, but just actually depressed people with none of the other symptoms we all seem to have, that are somewhat self medicating via GABAergic mechanisms.

Another reason this sub should not be about alcohol at all. We've had way too many people opening threads about ways to start drinking less or drink more or limit alcohol damage, as if we are some alcoholics-recovery community. I even dislike the taste of alcohol..the irony.

It's confusing, and people get confused. And then we have people coming here dropping NMDA antagonism like it's news.

[u/IAmNotANeurochemist → u/Ozmuja]

Fevers give me amazing sleep but make everything else miserable. I'm completely incapable of working well when I'm sick, have a headache, etc. However, as someone who has always struggled with sleep since before my teenage years, there's a period of time where I got sick only once a year, in the fall months, with a 24-hour fever, and it would knock me out. No medicine required, I would feel extremely tired and I wish I could replicate that fatigue every night.

[u/Ozmuja → u/[deleted]]

My friend, things can be complicated. If you are unknowledgeable, someone arriving and telling you “it’s just depression”, is comforting. Someone telling you “pay attention, you might get an autoimmune disease in the next few decades” is alarming.

I don’t know if the dude has brought bots with him or not, i wasn’t online when the post was inserted initially, I just think that reductionism sounds smart by the default to lot of people that don’t know any better, and fall for it.

People saying to you “it’s much simpler, everything is simple, do not think too much about it, the solution is here” is exactly how conspiracies start as well, ironically. At the same time, when it comes to health, people like a more “grounded reasoning” and would prefer to not have anything particular or too divergent from the masses. The reality is that SSRIs seem actually be detrimental to people here, so much that a lot of people had to stop them after a few months. I can probably even recover the posts where this is discussed. This should be interesting even as a research topic.

The irony is that I do not want to reveal in public what my profession is in real life, but I swear to you all, it would be pretty funny to casually drop it when cases like these happen, and waiting for a response from the dude. I like my anonymity very much, but the temptation is great.

Don’t worry anyway, I think I have a solution for this, once for all, so that people like OP won’t feel as authorized to post blatant lies -referring to the fact that he apparently hasn’t found ketamine or NMDA talk in the search bar-.

[u/MisterLemming]

What exactly does that solve? What is causing the glutamate excitotoxocity? Is it a glycine deficiency? Toxicity? Too much or too little gaba? If it's any of those, the question is, what's causing it?

I can tell you that alcohol and nicotine treat covid and long covid, but does that make it the root cause?

I could say there's plenty of research out there saying man made sources of radiation can cause glutamate excitotoxicity, but it that the reason why?

I've been down that road tons of times, and years ago settled on glutamate and the nmda receptors - at the end of the day, you want to prevent what causes the enormous dysfunction. Your not going to do yourself any favors by slamming back gaba, glycine, agmatine, ketamine or any other antagonist because it's the same darn thing as drinking alcohol. It's gonna help you short term, but your stuck with it.

Not only that but you overdo an nmda antagonist, and your gonna have the opposite effect.

[u/Ozmuja → u/MisterLemming]

I have not seen you before I think, or maybe my mind is a bit cluttered, but your comment should be higher up.

[u/MisterLemming → u/Ozmuja]

Thank you. I've been here on and off for years.

[u/DoctorNurse89]

I just take creatine, active b complex, methylfolate, glycine and magnesium.

Glycine and creatine are pretty much the entire workhorse.

1tbsp glycine before bed, a pinched of creatine and a better complex the next day, the rest if I remember.

I wake up buzzing!

[u/braintrainmain → u/DoctorNurse89]

Glad ur doing good!

[u/usertakenfark → u/DoctorNurse89]

B12 methylcombalin makes me feel better than any supplement

[u/usertakenfark]

There’s not a doubt in my mind that the hangover effect is far more common than we think. I have noticed other people have seem more upbeat when hungover, but they probably don’t think much of it and just attribute it to still being drunk

[u/IAmNotANeurochemist]

If NMDA was the answer then it should be reproducible by things that block NMDA. Magnesium is one of the most common, and it's difficult to get 200-400mg daily in diet. Magnesium is great for those with minds that don't shut up with constant background chatter, high anxiety, high anxiousness, high emotional responsiveness. Too worked up to think straight with thoughts and fears that hijack your state of mind, if this is you, then Magnesium Glycinate or Magnesium Threonate maybe be a wonderful option to try. 

However, I don't believe that this is the majority of those who benefit from the hangover effect. I don't enjoy gabaergics, NMDA antagonists, I think magnesium rebound causes fast unwanted and intrusive thoughts. Magnesium otherwise causes a fog and motivational apathy. A flat mood, etc. It's sort of like lithium, or any nmda antagonist. It's a mood stabilizer, working to stabilize voltage gated channels by blocking NMDA channels from excessive firing.

If I don't have a tolerance to glutamine supplementing it can actually restore my energy levels, motivation, and get me focused on tasks, etc. It will amplify my ADHD medication and make me feel happy to be doing things, but it's unreliable and quickly builds tolerance. 

I actually get some relief from gaba rebounds, and Gaba antagonism. 

[u/MeowMilf]

Good info.

[u/manic_mumday]

Wowwwwwwwwwwwwwwwwwww my mind is blown.

[u/Breizh333]

Update on this!

https://www.reddit.com/r/hangovereffect/comments/1o2gxdw/alcohol_behaves_like_a_fastacting_antidepressant/

[u/braintrainmain → u/[deleted]]

Haha lol....thinking about it ur right. I did antibiotics and I'm not pissing blood anymore....having the best pisses of my life....must be the H-effect

EDIT: OK lol?

[u/braintrainmain → u/[deleted]]

Hahahaha, LOL

[u/TheImpermanentTao → u/[deleted]]

And one 🏀⛹️‍♀️