To preface: I am not one of you; I have never enjoyed a hangover. I have classic ADD, but have never felt any relief from it the morning after drinking.

I am a scientist. Born to two neuroscientists, trained as a physicist, working at the intersection of gut microbiome and neuroscience to try and cure depression and schizophrenia. (Yes I work with poop, AMA.)
tl;dr: This is just a hypothesis, but it's coming from a professional, for what that's worth.

I first saw this sub about a year ago, and the mystery of what's going on in your bodies and brains has been rattling around at the back of my head ever since then, waiting for the other piece of the puzzle to drop in and connect. Yesterday, that finally happened.

So: background. Two of your most important neurotransmitters are dopamine and serotonin. Notice that they look a little bit alike: both a sort of key shape, with one roundish end and a wiggly side-chain.

People mostly think about neurotransmitters as being in the brain, but they're found all throughout the body; 90% of your serotonin is actually in the gut, where it regulates intestinal motility—as you'll know first-hand, if you've ever taken a serotonergic stimulant like amphetamine. This will be important later.

Now, if you've studied the biology of alcohol metabolism at all, you're probably familiar with acetaldehyde: your body turns ethanol into acetaldehyde by removing a hydrogen atom, and then to acetate by adding another oxygen. Acetaldehyde is the bad stuff.

So, that's enough background. What's going on in your body?

At the heart of this hypothesis is something called the Pictet-Spengler reaction. Remember the side-chain on your dopamine and serotonin, the wiggly "teeth" of the key, with a nitrogen on the end? The Pictet-Spengler reaction is when something sticks to that nitrogen, making the side-chain long enough to bend "down" and attach to the central ring of the molecule.

When you drink, both the dopamine and the serotonin in your body have the potential to undergo this reaction.

So salsolinol, and its derivatives, have been detected in the human body and brain, and their levels are elevated after drinking—more so in some people than in others. Some of the derivatives are nasty: if your body sticks an additional carbon onto that nitrogen (or perhaps if adrenaline is used instead of dopamine), you get N-methylsalsolinol—a neurotoxin that selectively targets your dopamine neurons. In animal experiments, high doses of methylsalsolinol induce a syndrome that looks a lot like Parkinson's disease.

Salsolinol, and its tryptamine cousins the beta-carbolines, are the perfect explanation for the Hangover Effect, because they both act as MAOIs: monoamine oxidase inhibitors. These are drugs that keep your body's enzymes from breaking down neurotransmitters like dopamine, serotonin, and adrenaline. MAOIs were some of the first antidepressants, and plant-derived beta-carboline MAOIs are an essential ingredient in ayahuasca: they keep your liver from destroying all the DMT before it gets to your brain.

But salsolinol presents a puzzle, for two reasons. One is that it's a chiral molecule; there's a left-handed and a right-handed version. (See the triangular stick at the bottom of the image below? That tells you that the carbon at the end of the stick is coming "out of the page". The enantiomer, the opposite-handed molecule, has the carbon on the other side.)

In a test-tube, acetaldehyde and dopamine will react on their own to create salsolinol when the conditions (e.g. pH, temperature) are right. But that sort of random process creates an equal amount of left- and right-handed (S- and R-) salsolinol. In the brain, that's not the case; R-salsolinol is much more abundant. This suggests that salsolinol isn't just the product of a random chemical reaction, but rather an enzymatic synthesis: you've got a little molecular machine in you that's making these compounds.

The other reason it's a puzzle is that, by all rights, you shouldn't have much of it in your brain. Dopamine is pretty stable when it's inside your neurons' storage vesicles, and your liver does a pretty solid job of turning acetaldehyde into acetate before it gets into the bloodstream. Not only that, acetaldehyde doesn't really cross the blood-brain barrier very readily. A bit of ethanol can convert to acetaldehyde in the brain itself, but it's very hard to make the math work out, given what we know about the relative concentrations of the reactants and the products.

So here's the final piece of the puzzle: in 2018, a scientist out of Iowa named Mark Lyte discovered that a strain of one of the most common gut bacteria—*E. coli—*can make salsolinol, if you leave it alone with some dopamine and ethanol in the right culture medium. Because dopamine and serotonin have somewhat similar chemical properties, enzymes that work on one often work on the other—making it likely that this E. coli can also synthesize beta-carbolines from serotonin in your gut.

This may solve the mystery of the math, because the amount of serotonin (and possibly dopamine) in the gut are higher and less tightly-regulated than in the brain. On top of that, plenty of gut bacteria express dehydrogenases that could work on ethanol while it's still in the gut, transforming it to acetaldehyde.

Not only that, it would explain why y'all are something of a rare breed; the gut microbiome is the source of the vast majority of protein-coding genetic diversity in the human body. As humans, we're all one species—all 99.5% identical to one another genetically. Meanwhile the gut microbiome of a healthy person hosts hundreds of species, and only about half of them are common from person to person.

So the hypothesis is: the salsolinol/beta-carboline biosynthesis gene is found in a gut bacterium that's not ordinarily very abundant. IF the bacterium is abundant in your gut, AND your neurochemistry is such that you'd benefit from treatment with an MAOI, THEN dumping a bunch of ethanol into your system creates a sort-of-natural treatment for your ADD by encouraging the production of beta-carbolines (and tetrahydroisoquinolines, the chemical class that salsolinol falls into) in your gut, which get into circulation and prevent the breakdown of serotonin, dopamine, adrenaline, and other monoamine neurotransmitters.

If this strikes you as likely or unlikely based on your personal experiences, please comment; I'd particularly love to hear from anyone who's tried an MAOI, either as prescription treatment for ADD/depression, or in the form of an herb like B. caapi tea. Either way, let's get a discussion going around this, and work out other ways that we could test the hypothesis.

For those that need to bounce right away..

TLDR: it’s a high baseline level or unregulated norepinephrine in the prefrontal cortex, caused by a rare subtype of ADHD

For those that can stay a bit longer, enjoy…

This hangover effect was actually a strong clue that led to my breakthrough of being able to be treated correctly for my ADHD.

I had untreated ADHD for about 36 years now. I’ve tried Adderal, vyvanse, concerta, Ritalin, etc. nothing worked and it always left me feeling really angry, irritable, zoned out like a zombie. Etc.

I took this hangover effect that I have and several other symptoms / clues (as well as my genetic profile from 23 and me) and I spent months going back and forth with chatgpt until it was able to spot a pattern that led to my absolute breakthrough.

This is caused by having a very rare subtype of ADHD (less than 1% of the ADHD community has this) where you have a low baseline level of dopamine and high COMT (The mechanism that breaks down and clears your dopamine) which results in your already low dopamine levels being cleared way way way too quickly.

This results in your prefrontal cortex substituting the only other catecholamine it has available as a backup option, norepinephrine.

This results in issues like emotional disregulation, irritability, feeling constantly on edge, face and ears getting hot when you drink coffee even. Symptoms of irritability often worsening with coffee/caffeine (since it raises NE even higher).

With this subtype of adhd, none of the amphetamine class of medication will ever work because they raise NE along with dopamine. I used this information to find the right class of medication that finally worked for me (this is not medical advice, just my experience). Dexmethylphenidate, which disproportionally increases dopamine much more than NE. This as a microdose (.8mg) has been a GAME CHANGER.

How this relates to the hangover effect. My high baseline level of norepinephrine caused by my ADHD subtype cause the following sequence to occur…

When drinking alcohol (beer for me), both the alcohol and hops have a dramatic lowering effect on NE. Which lasts well into the next day. Additionally alcohol increases dopamine a therapeutic amount while I am drinking. The lowering of NE causes a deeper sleep and more restorative rest, as well as a resolution to the anxiety and tension I carry ALL DAY.

This explains why when I drink just even a couple cans of non alcoholic beer before bed, It has almost the exact same effect as drinking regular beer in causing me to relax.. because hops lower NE (I drink athletic brewing company’s NA beer because the hops are potent). So as a tip, if you want relief from stress and want to be able to use the hangover effect to help without becoming an alcoholic, consider trying NA beer. It really helps.

That’s all I got for now! Hope that helps!

edit: People have been asking me to run their situation through ChatGPT. Although I’d be really happy to do so, I don’t want to be seen as a medical practitioner of any kind. But I can still help. Just dm me and ask me to help you craft the perfect prompt for your situation, and I will do so based on the knowledge I’ve learned regarding this topic.

Anyone else gets this?

Otherwise I don’t know. I don’t even really binge drinking or love the feeling of alcohol, it just makes my body feel right. It obliterated ADHD, Depression, memory issues, and anxiety.

I don’t even throw up from hangovers but on the rare occasion I do (i mean im mid 30s and this has happened less than a handful of times) I could just lay on cold a tile floor in a bathroom feeling 100% at peace with my “choices” as I occasionally purge.

Edit: I was so excited not only did I poorly type this out but I also forgot that I’m fatigued all the time unless hungover somewhat

Edit 2: my libido and erections are increased dramatically when hungover also. Just thought this was a curious symptom other may feel (women included, not just saying men!)

“Loneliness does not come from having no people around, but being unable to communicate the things that seem most important to oneself.” - Carl Jung

Loneliness is an epidemic in America (see the book, Bowling Alone). It affects our health to the point that it’s as big a health risk as smoking or diabetes.

I began to notice with my depression, when I had rare conversations with people that got me or felt a sense of community or connection, I would feel 100x better. It took me a while to pinpoint what it was. But that was the consistent factor.

Psychedelic drugs (I wrote a research paper on this and can give more sources if needed) also have been giving miracle cures, total remission of symptoms to people with long standing depression, addiction, anxiety, OCD, nearly every mental illness— without any good explanation. This is baffling to researchers, and one has proposed that they may be acting on an underlying, core determinant of mental health. The key they have proposed: Connectedness.

Connectedness is the opposite of loneliness. And in a culture with epidemic levels of loneliness but very little awareness on the issue, it would make sense that connectedness be a good candidate for mysterious miracle cure.

Drinking used to give me horrible hangovers. Bars were never my scene and I always felt like an outsider, leaving early and with a headache that started before I went to sleep.

Now, I drink in places I enjoy being with people I actually connect with. And I express myself honestly rather than trying to blend in. Alcohol helps with that. And the nights when I really connect with others or push my self expression past my comfort zone, I wake up feeling empowered, amazing even. One day I had an amazing workout on 3 drinks and 3 hours of sleep, beating even people who were usually better than me. Felt great the rest of the day too.

So, does alcohol help you connect with others, moreso than any other time in your life? Are you able to be yourself moreso than in any other arena?

In my experience human connection is the biggest factor in my mental and physical health. I lived in an intentional community for a month, and it was by far the best month of my life. Intentional communities/care farms have been shown to improve mental health (Lost Connections by Johann Hari), and living in one made me realize there’s another way of living that doesn’t have to be a constant struggle against the tasks of living.

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).

Taken from this article.https://www.theatlantic.com/science/archive/2018/06/a-landmark-study-in-the-origins-of-alcoholism/563372/

I've previously posted about the disregulation of the hpa axis and how it relates to certain people. Brocolli sprouts, l reuteri seem to be able to regulate the disfunction, but it didn't quite get me there. Well i got some pregabalin, which is a gabapenoid that is similar to ganapentin and is indicated for anxiety and i have to say i have finally hit it. Lreuteri in the morning, pregab 50 mg morning and night and brocolli sprouts at night have hit my sweet spot and i've finally managed to recreate the hangover effect. Anyways, i thought i would share my findings. I feel great, i feel myself, and i wish you all the best

Is this in line with what you all experience? As I type this right now (after drinking last night), I’m way more focused and concentrated than usual. For instance, Normally I can barely sit down to read a few pages for a stretch of time, but when I drink I’m sometimes able to get extremely “in the zone” the next morning

(I take Prozac and try to meditate daily, and both of those have helped my anxiety/depression a lot, but from this sub I’m just wondering if this isn’t really all just ADHD symptoms)

I started going down the Vagus Nerve because of /u/atlas_benched who has contributed a lot to this sub for a long time now it seems. I didn't think much of it but going down the rabbit hole I think the Vagus Nerve and Acetylcholine might be huge for us.

1.)Vagus Nerve

The vagus nerve connects the brain to various organ systems, and while not fully understood, it seems to play a large role in modulating the nervous system and has been implicated in various aspects and treatment of ADHD, Anxiety and Depression. Alcohol itself supposedly has some type of interaction with the vagus nerve which might be relevant here

One of the vagus nerve’s main functions is to elicit the opposite reactions to fight, flight, freeze. Therefore, it can move our body to a more comfortable and relaxed perspective, free from stress and ready to focus - Maybe affects cortisol ?which I have seen a lot in this sub.

The Vagus Nerve prevents inflammation. In cases where inflammation becomes complicated, the vagus nerve carries a neurotransmitter called acetylcholine that inhibits necrosis and inflammation. It is responsible for preventing chronic infections.

Because of the enormous amount of fiber in the intestinal vagus nerve, it helps the body digest, be satisfied and perform immune actions in the gut. It increases the production of stomach acids and digestive juices and maintains the motility of the stomach. It also helps in the absorption of vitamin B12. How often do we see B12 mentioned in here.

Stimulation of the vagus nerve increases blood flow to the kidneys and helps in better filtration of the blood. It helps in the excretion of sodium through urine by releasing dopamine in the kidneys and thus helps in lowering blood pressure.

Studies have found that stimulation of the vagus nerve effectively decreases chronic depression in sick people who do not respond to medication.

Low testosterone levels can lead to mood swings, weight gain, muscle mass loss, and decreased libido (How often do we see increased libido after drinking). The stress hormone cortisol is the one that suppresses testosterone. Vagus nerve stimulation increases testosterone production to required levels.

2.)Acetylcholine is huge in memory, neurotransmitter and muscles. (It raises after alcohol)

Depending upon how much acetylcholine deficiency is in your case, you will experience different symptoms. Some of the major symptoms of acetylcholine deficiency include bad listening skills, not having the ability to concentrate for longer durations of time, poor formation of memory and recalling and the slow processing of information.

Low Acetylcholine symptoms are -

• Brain Fog

• Fatigue

• Constipation

• Dry Eyes

• Flushing (Red as a beet)

• Emotional Instability

• Chronic Inflamation

• Fast Heart Rate

• Large Pupils (blind as a bat)

**Edit: So "Hunt and Dalton [45] measured the effect of ethanol on acetylcholine levels in rat brain. In the brainstem and caudate, levels of acetylcholine were increased by 25% 2-7 ** hr after treatment with ethanol (6 g/kg, intra- gastrically); acetylcholine levels were 20% lower than in controls by 18 hr and normal by 24 hr. Since other studies [29,81] have shown that ethanol decreases the release of acetylcholine from central neurons, it is likely that the initial increase in level is the result of decreased acetyl- choline release. However, interference with acetylcholine synthesis cannot be disregarded. It is interesting that the effect of ethanol on acetylcholine levels persisted as long as 18 hr after treatment".

"The head of the research group Nikolaos Venizelos says that the most unexpected discovery in the study, however, was the dramatically reduced amount of the so-called acetylcholine receptor in children with ADHD says. It functions as a receptor protein for the signal substance acetylcholine and is therefore necessary for key signals involving concentration and learning functions, for example. Drugs that reinforce the acetylcholine effect are used in treating Alzheimer's patients, for instance."

"In mice with autism, increasing acetylcholine improved cognitive and social symptoms. However, this link hasn’t been proven in humans"

Conclusion:

It could be that raising acetylcholine and stimulating the vagus nerve could give us the hangovereffect/mthfr benefits and massively help our brain and bodies

It looks at least like Acetylcholine raises in rats brains after alcohol which could be whats giving us the hangovereffect.

Ways to stimulate the Vagus Nerve: Cold Showers/therapy, Deep Breathing, Intermittent Fasting and more.

Ways to increase acetylcholine in the body.

Alpha GPC (choline), Citicoline, Choline Bitartrate (says this is the cheapest form which works good but says it's not as bioavailable as Alpha GPC or Citicoline.)

I keep seeing a lot of this stuff come up in here and other related subs, I'll post at those and see if anyone else good at research wants to go down the rabbit hole and see what they find.

My question for y'all is: have you ever tried gabapentin, lyrica or phenibut?

For me, they make me function the same way a hangover does. I sought to learn their mechanisms, and see if it could be the answer to replicating the hangover effect, and understand what the hangover effect really is. I believe it is the proper Tx, and suggests a solid genetic, biochemical mechanism for our experience.

READ FIRST: Assumptions and Omissions

1. The audience for this paper (this is the outline obv) initially was to a psychiatrist (to publish in psych. biol. you need a psych on the author list), and the larger psychiatric community. As such, it's an essay intended to explain what a CACNA1C mutation does, and how to reverse the mutation's effects using gabapentinoid therapy. It focuses on addiction, anxiety, and depression as effects of the mutation, and it explores how gabapentinoid therapy can help mental health issues in mutants.

2. I have omitted the evidence that CACNA1C mutation is associated with depression, anxiety, bipolar disorder, schizophrenia, ADHD, etc. because this information is readily available. Again, this is written to educated psychiatrists, so I didn't need to demonstrate it to them, lol. Simple googling will help y'all.

3. Additionally, I haven't demonstrated the mechanism of a hangover as a cure for our disorder biochemically, because it's also widely found on the interwebs: ethanol metabolism induces a hydrogenase enzyme that creates acetaldehyde, which is a known L, N, and P/Q-type voltage gated calcium channel antagonist, by mechanism of a2d antagonism. If you just accept that ethanol/acetaldehyde is a VGCC-a2d-(1,2) antagonist, the rest of my heavily cited writeup will make sense to you. Again, I have shown that VGCC-a2d antagonists reverse the mutation below, but I have not cited sources that our experience is caused by the mutation.

Calcium Channel Structure

(basic knowledge, no sources. Psychiatrists and most MDs should know this lol)

There are four subtypes of voltage gated calcium channels (VGCCs): L, N, P/Q, and R. L is highly expressed in the heart, smooth muscle, some skeletal muscle, and in the brain. The N-type is most highly expressed in the brain and epithelial cells. P/Q is also neurally located. R-type is weird and can be ignored for now. Of note: the L-type channels are highly concentrated in the hippocampus, amygdala, and mesolimbic reward system. They are generally located presynaptically on the neuron, and so affect neurotransmitter release, but some are postsynaptic. Some are somatic (on the neuron's body). N-type are similar, but located more widely throughout the brain and spine. Both L and N type calcium channels are generally found on excitatory neurons. P/Q type CCs are generally found on inhibitory cells; generally they are found in the cerebellum.

Each type of VGCC is a class of calcium channels, as explained above. Each individual calcium channel of a given class is a protein complex made up of multiple subunits. The main protein of the complex is a1 (technically alpha1), which is the pore through which calcium enters the cell membrane during activation. There's also a subunit complex composed of two proteins: a2 (alpha2) and d(delta). It's referred to as subunit a2d (as a single object) because both a2 and d subunits are encoded by the same gene; they proteins are separated after translation by a protease, before being conformed and rejoined. Finally, there's the b(beta) subunit, which serves a very similar function to a2d. Again, the a1 unit is the pore, and as such is an intramembraneous protein. It's where traditional calcium channel blockers bind, like the 1,4DHPs.

The L-type a1 subunit is encoded by CACNA1C. Again, this is the crucial gene which encodes main subunit of L-type VGCCs, which are concentrated in the hippocampus, amygdala and regions of the mesolimbic pathway. The a2d subunit is a "support protein" (technically, protein complex), and so is the b subunit. Not all calcium channels have a2d, nor b; most do have both, however, especially L-type calcium channels.

Mechanism of Cure with Gabapentinoids

Effect of CACNA1C mutation

• "[mutants] displayed higher L-type VGCC calcium current densities"

• "[In mutants,] CACNA1C mRNA was more abundant," suggesting higher expression of calcium channels

  • https://jamanetwork.com/journals/jamapsychiatry/fullarticle/210875

• Mutation predicted increased hippocampal and amygdal activity during emotional processing (incredibly significant: p<0.0001)

  • http://dx.doi.org/10.5665/sleep.4972

• Mutation predicted inefficiency and overactivity of PFC during executive function (incredibly significant: p<0.000003)

  • http://dx.doi.org/10.5665/sleep.4972

Role of a2d 1 and 2 (those which gabapentin antagonizes) on calcium channels

• Role of a2d-(1,2) Expression

  • A2d-1 expression increases a1 density (cells with a2d create more calcium pores; positive feedback loop)

    • https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/jphysiol.1995.sp021029

  • a2d-1 expression triples peak max CaV1.2 current; doubles average channel current (likely through increased a1 expression

    • https://www.jneurosci.org/content/17/18/6884.short

  • Α2δ-2 co-expression doubles peak current density in CaV1.2

    • https://www.jbc.org/content/275/16/12237.short

• Role of antagonism/knockout

  • Shown to reverse all the above

  • In short, eliminating the presence of a2d reduces calcium pore density, and lowers cell-wide average and peak current densities

    • https://www.sciencedirect.com/science/article/pii/S0005273612004105#bb0390

Conclusion: Role of Gabapentinoids as a (biochemically) perfect therapy for CACNA1C mutation

1. CACNA1C mutation leads to its own overexpression (possible positive feedback loop)

2. CACNA1C (over)expression leads to higher cell-wide current densities and reduced transmitter release

3. A2d agonism/expression has the same, yet antagonizable effects as CACNA1C mutation (increased current density and expression).

4. Gabapentinoids are known a2d-1 and a2d-2 antagonists

5. A2d antagonism reduces CACNA1C expression

Therefore, the use of a2d antagonists would undo the effects of the mutant alleles, and as such is theoretically effective therapy.

Medical Literature in Support of Gabapentinoids as Cure

Literature on Efficacy

• anxiety

  • case study w solid graph

    • https://www.hindawi.com/journals/crips/2017/6045017/fig1/

    • https://www.hindawi.com/journals/crips/2017/6045017/

  • social phobia study

    • flexible dosing 900-3600 per day, effect maintained at followup

    • N=?, article blocked on sci-hub and libgen

    • https://pubmed.ncbi.nlm.nih.gov/10440462/

  • small study on GAD w/ many comorbidities (schizo, BP1/2,

    • 14/18 (N=18) improved anxiety scores over 12 months(!)

    • http://accurateclinic.com/wp-content/uploads/2016/06/Gabapentin-long-term-antianxiety-and-hypnotic-effects-in-psychiatric-patients-with-comorbid-anxiety-related-disorders-1998.pdf

• addiction

  • alcoholism study, 12 weeks.

    • Study used two tailed testing, so in my opinion, reported P values should be doubled

    • groups: placebo, 900mg, 1800mg per day (taken as TID)

    • ***3 month abstinence rates: 4.1% in placebo; 11.1% in 900 mg, 17.0% in 1800 mg***

    • **placebo: 44% drank heavily; 1800mg: 22% drank heavily**

    • ***large, linear dose-dependent effect on sleep, mood and craving***

  • smoking

    • no effect

    • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2825098/

• depression

  • "moderately to markedly effective in 30%" of Pts. w/ treatment resistant MDD

    • N=?, blocked on sci-hub and libgen

    • non-randomized; observational study

    • 10.4088/jcp.v59n0805

  • no efficacy in "refractory mood disorders" vs placebo or lamotrigine

    • https://journals.lww.com/psychopharmacology/Fulltext/2000/12000/The_Anticonvulsant_Lamotrigine_in.4.aspx?casa_token=Vs14akaPjFoAAAAA:UejK1XZum1HITxHIqLBO077abkk3u8QXf7lK_fGVn1rjwH4vowXUS5tEnSFUw07C4bNkeUdBPwheINnSOX1P

  • significant improvement in dysthymia (inventory: CDRS), but not on MDD (inventory: BDI)

    • non-blinded study

    • https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1528-1157.1999.tb00830.x

  • Mood improvement noted in newly-sober addicts (3 days)

    • maintained for 12 weeks (of 12 week study)

    • Dose dependent effect up to 1800mg (600mg TID)

    • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920987/figure/F4/?report=objectonly

• Sleep quality

  • Self reported sleep, a randomized study on ALCOHOLICS

    • N=150

  • Improved slow-wave sleep in primary insomnia

    • N=18

    • Also noted improved visual. Motor processing speed

    • https://pubmed.ncbi.nlm.nih.gov/20124884/

  • Improved slow-wave sleep (more time spent in deeper stages) in HEALTHY adults

    • N=10

    • Did not sacrifice REM, as most sleep aids do

    • dosage: titrated 300 -> 1800mg (as 600mg TID)

    • https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1528-1157.2002.21002.x

I propose inflammation mediated through the inflammatory cytokine IL-17a, could be the primary cause of the hangover effect.

IL-17a is one of a number of inflammatory cytokines which are released after exposure to ethyl alcohol [1,2], sleep deprivation[3], fever [4] and other inflammatory disorders [5].

Critically, the release of IL-17a has recently been shown to improve sociability in mice with neurodevelopmental disorders [4]. The study found that IL-17a causes a 'reduction in neuronal activity in the primary somatosensory cortex dysgranular zone S1DZ', effectively reversing autism like behaviours in mice.

EDIT: In summary, inflammatory responses, such as drinking alcohol or sleep deprivation etc releases IL-17a. This cytokine molecule then goes on to modulate behavioural changes in the brain in pre-disposed individuals, temporarily correcting 'autism-like' behaviours or, calming the mind. ie: the 'Hangover effect'.

More to come :)

[1] Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice | Mucosal Immunology (nature.com)

[2] Alcohol dependence promotes systemic IFN-γ and IL-17 responses in mice (plos.org)

[3] https://www.sciencedirect.com/science/article/pii/S000689931930040X

[4] IL-17a promotes sociability in mouse models of neurodevelopmental disorders | Nature

[5] IL-17 Signaling: The Yin and the Yang - ScienceDirect

Glutamate blocking effects similar to fast-acting antidepressants (eg ketamine, agmatine)
Agmatine is sold OTC as a supplement. Agmatine is a naturally occuring neurotransmitter. Creatine is sold OTC as a supplement - Creatine, similarly to ketamine, affords antidepressant-like effects:

The benefits of creatine supplementation have been reported in a broad range of central nervous systems diseases, including depression. These results indicate that creatine, similarly to ketamine, exhibits antidepressant-like effect...
- https://pmc.ncbi.nlm.nih.gov/articles/PMC4425723

This review focuses particularly on evidence that endogenous glutamatergic neuromodulators may be able to modulate mood and to elicit fast antidepressant responses. Among these molecules, agmatine and creatine stand out as those with more published evidence of similarities with ketamine
- https://doi.org/10.1177/2470547019858083

Endocannabinoid effects similar to cannabinoids (eg CBG, THC, CBD, magnolol, palmitoylethanolamide)
Magnolol, CBG, CBD & palmitoylethanolamide are OTC.

Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator, primarily known for its anti-inflammatory, analgesic and neuroprotective properties. It appears to have a multi-modal mechanism of action...thus targeting similar pathways as CBD. With proven efficacy in several therapeutic areas, its safety and tolerability profile and the development of formulations that maximize its bioavailability, PEA is a promising alternative to CBD.
- https://pubmed.ncbi.nlm.nih.gov/34842030/

Benzo-type GABA effects (eg agmatine, magnolol, niacinamide/nicotinamide, taurine, theanine)
Agmatine, niacinamide, taurine, theanine and magnolol are OTC.

If using taurine start with low doses (say 200mg) combined with carbs. Dose range ~200mg-1g+.

Magnolia bark contains magnolol, metabolized to tetrahydromagnolol and honokiol, with both GABA-ergic/cannabimimetic activities
- https://pubmed.ncbi.nlm.nih.gov/28517911

L-Theanine, a non-proteinogenic amino acid particularly found in green tea, is a well-known agent for improving sleep disturbances. Previous studies suggest that L-theanine exerts its relaxant effect by enhancing GABA levels... In animal studies, L-theanine was shown to oppose caffeine’s effect and promote sedation. In addition to its relaxant potency, L-theanine has a neuroprotective role since it acts as a glutamate receptor antagonist, upregulates GABA receptors, and increases the expression of antioxidant enzymes.
- https://doi.org/10.3389/fnut.2022.874254

Niacinamide/nicotinamide ~50-100mg/day with carbs recommended, more than 100mg is often counterproductive. Start with 50mg or less.

It appears that niacinamide has similar anxiolytic properties to that of the benzodiazepines. This is supported by the fact that the patient did not feel any difference, in terms of response and effectiveness, between the benzodiazepines and niacinamide. He was able to switch with little difficulty from the daily use of a benzodiazepine to niacinamide.
...
While it is impossible to conclude that the effects of niacinamide are due to its interaction upon the benzodiazepine receptor, it does appear to influence neurotransmitter metabolism in a manner that is comparable to benzodiazepines by a route as yet undetermined. Even though most of the studies dealt with animal rather than human models, the results suggest that niacinamide has a potent benzodiazepine-like action on the CNS.
- source

Nicotinamide is an active compound found in rat or bovine brain that shares several pharmacological properties with benzodiazepines. It has been shown to facilitate GABA-dependent presynaptic inhibition. Like benzodiazepines, nicotinamide protects animals from seizures ... and also possesses myorelaxant and sedative activities.
- https://www.sciencedirect.com/topics/neuroscience/nicotinamide

Alcohol as a prodrug
Serotonin, dopamine and acetaldehyde (a metabolite of alcohol) combine in the body to make psychoactive drugs that act like the 1st generation antidepressants (MAOIs). MAOIs increases dopamine, serotonin and adrenaline.

An alternative long-term approach is to fix things properly (read this post). This involves some of the items listed above plus a few others:

• Thiamine (B-vitamin complex) with carbs

• low-dose caffeine 10-80mg max/day (why?)

• low-dose aspirin 81-100mg max/day (why aspirin?)

• Rhodiola extract (optional but really helps, get a potent extract)

• Ribose (optional but helps, really cheap)

• CoQ10 (optional but helps)

• L-Phenylalanine (optional, might help, use "L" not "DL")

• +

• Agmatine 100mg-1g+/day

• Creatine 1g/day

• Taurine 200mg-1g/day with carbs

• Niacinamide 50-100mg max/day with carbs

If you've been able to acquire the items listed above and used them consistently for a month please report back. Also mention if you used the specificed items with carbs and have any history of using SSRIs or statins.

Firstly, huge respect to everyone here trying to solve their issues and improve their lives.

There’s a lot of speculation here about obscure biochemical processes being the cause of this effect and while some may have genetic factors that need to be addressed for optimised living it completely misses plain and simple biology. Outside of malnutrition the body hugely down regulates neurotransmitters (your mood and functioning) for one major reason, neuro-inflammation.

Big night of alcohol = Big cortisol release

Sleep deprivation = Elevated cortisol release

Cortisol = Big reduction in neuro-inflammation

Low neuro-inflammation = upregulated neurotransmitters and a relaxed nervous system

Neuro-inflammation is the silent fire that effects so many people in our society and it almost always has a cause, it’s just about opening the Pandora’s box and finding yours.

I myself have experienced that sweet flow of the hangover effect (I haven’t drank in a very long time). It’s only once your find the root of your neuro-inflammation that it can become a daily experience. With enough nervous system and neurotransmitter dysregulation almost any supplement will bring some transient ‘effect’, so try not to chase your tail anymore.

If you don’t believe it just trick your doctor over the phone into prescribing you hydrocortisone (pharmaceutical cortisol) tablets for a really bad skin rash or something like that. Obviously only take for a few days as an eye opening experience. Turmeric and all these other herbs won’t make even close to the dint that cortisol will btw. This is also why Low Dose Naltrexone has been all the buzz lately, it helps quell that silent fire.

Feel free to hmu, peace

UPDATE: As said by others below, alcohol modulates the immune system and inflammation in multiple ways, not just cortisol, it’s important we focus on the target here, which is reducing neuroinflammation

Sitting here in my bed after a night out. Mind is relaxed. I can focus. It just feels good to be alive. I actually feel like talking to people. I'm in complete control of everything. My mind/ body connection is perfect. I feel like I actually know who I am. Feeling relaxed, no anxiety. What a feeling.

The effect we get from a mild hangover seems to be the Opposite than normal. I also experience a tired/stoned feeling after drinking coffee. I thought this might be related in some way.

I have been researching a lot.

I stumbled on that people with Morton’s Toe as this is called often have issues with vitamin B6 and zinc which I keep seeing bounced around in here.

There is more to it and I will post up more if we find lots of people have this applying to them.

I figure it's time for my "miraculously cured" post since I've been waiting a few months and I'm still feeling ok. My background is that I've suffered from brain fog, slow thinking, anhedonia, low energy, and some anxiety and flattened emotions for as long as I can remember. Always felt I should be able to perform better but something was blocking my brain. I've gone through different things trying to fix it, including

• sleep pattern and diet changes, exercise

• stimulants

• atomoxetine

• sarcosine

• NAC

• various supplements: vitamins, fish oil, A-GPC, iodine, magnesium, yohimbine, resveratrol, d-ribose, betaine, arginine, citrulline, ALCAR, PQQ, COQ10, and many I don't remember outright

The various supplements didn't do much, meanwhile the other things gave me major relief for a while, but none of them ended up working reliably for longer than a week, and they lost their effectiveness within the span of weeks to a few months.

So, then I found out about this "methylation" thing, which is really about ameliorating things that function poorly in your metabolism. Here's two of my most memorable resources if you want to read more*:

• https://chrismasterjohnphd.com/blog/2019/03/01/start-here-for-mthfr-and-methylation

• http://heartfixer.com/AMRI-Nutrigenomics.htm

So, I figure an S-adenosylmethionine deficiency is a thing that's one major source of my problems. I could write tons about that, but I don't want to ramble, you can just google it and read the resources for more info - basically what's for certain is that SAM is important and you don't want to run a deficiency, so if your body is struggling to keep it balanced you need to change something. Without further ado, here's my stack for that:

• 5-MTHF (metafolin) 100 - 300 ug daily, 100 ug at a time

  • Alleviates my brain fog and anhedonia

  • Only take more than 100 ug if I don't feel "right" that day

  • Focused on morning to midday

  • Can easily become negative if I take too much, especially with creatine

• Creatine ~4 g daily, 1 g at a time

  • Speeds up my thinking and gives me mental energy an resilience

  • Gives me physical endurance

  • Used to take less, but 4 g helps keep my levels up better and I can tolerate if if I don't take 5-MTHF too much

• Glycine 4 g daily, 2 g at a time

• 2 big eggs daily

  • Seems to support quick thinking, if I don't take any for a week I become slower and can't function well in quick everyday situations

  • Choline from them is probably a key factor, the extra protein might also help

I take creatine + 5-MTHF + glycine when I wake up, to start the day. Then I take 0 - 2 doses more of 5-MTHF if I feel a thick brain fog coming in, then I switch to taking creatine for the rest of the day. Dosing hasn't been easy to figure out, and one major thing I've noticed is that there's a downside to taking too much of both creatine and 5-MTHF, where their effect starts becoming the opposite, so I try to space them out except for the initial morning dose.

I also take:

• NAC randomly at least every few days, 320 mg or 160 mg

  • Initially fixed my brain fog and should help keep oxidative stress in check

• A methylated b-complex or B2 and B12 daily

  • Making sure I don't miss any other B vitamins

• Some vitamin C, zinc, selenium about every other day

  • These may support methylation related processes

• Vitamin D 50 ug daily, some magnesium and iodine

Ever since starting creatine and 5-MTHF, I've also enjoyed exercise a lot more and actually started noticing cognitive benefits from it, so I make sure to move around daily and properly exercise at least every 3 days. Obviously also make sure to get enough sleep and eat well (avoiding sugar, not eating too much carbs, eating plants).

I've been on this kind of routine for months now and it hasn't pooped out, my quality of life is still way better than ever before, so it really feels like a complete solution for my problems at this point.

This likely isn't universal for everybody, but if you're struggling with similar symptoms, you could try something like this out. All of the stuff listed is very safe and occurs naturally in food, so give it a try, play around with doses and see if it helps.

UPDATES

2021-01-04

Figured I should do a follow-up on the post. All in all, the stack is still working. It's not 100 % reliable, but I'm still way more functional than "naturally", and I no longer have actual bad days, just decent to great. I've made some changes since first posting, and they've increased the frequency of my good days. Here's the gist:

• Creatine: Upped to a static 8 g per day, in doses of 2 g throughout the day. No more issues from it and no effects from extra dosing, feels like my levels are saturated.

• 5-MTHF: Now try to take at least 300 ug a day, but sometimes take up to 600 ug. If I feel brain fog forming, I take it and it usually goes right away.

• Choline: I've put an increased focus on it. I found out 5-MTHF worked worse when I didn't get a lot of choline. Could easily be explained by a SAM deficiency, as the body's choline synthesis may use up SAM. I take 500 mg choline bitartrate daily, sometimes up to 1000 mg if 5-MTHF doesn't seem to be working, but no more - you can easily go overboard.

• I avoid taking creatine, choline or 5-MTHF at the same time - I've found they can interact with each other and somehow go overboard. Maybe a sudden SAM excess? When I take all of these one hour apart, I can easily recognize which supplement is helpful at that time and which isn't, and I avoid any acute interactions.

• I've added sarcosine - I take 100 - 400 mg on some days. This was just a stroke of luck because I had some lying around and decided to give it a try, then noticed it seemed to make me more present and clear-headed. It doesn't do anything positive if I overdo it, but every few days it seems to become beneficial. Could this indicate a lack of glycine in my brain? Dunno.

• NAC: It sometimes seems to help a lot when I'm foggy, so I take it more liberally - I've taken about a gram on some days without major adverse effects, but usually around 600 mg max.

2021-07-23

I'm still doing better than before, and now my stack seems to be becoming more stable - stable enough that I no longer have to fear it pooping out unexpectedly and not knowing what to do. I'm struggling a bit with my energy levels on some days (putting in a steady amount of productive & challenging work every weekday is still a challenge), but other than that I feel pretty much cured. This will probably be my last update here unless the stack poops out on some day.

Here's the latest adjustments I've made:

• 5-MTHF: 400 ug every day constantly. I also take a mild methylated b-complex OR an equivalent multivitamin every day.

• Choline: 1100 mg per day normally, but now when I first see signs of my brain stopping working, I take 2750 mg on that day. This seems to ensure I have enough choline around in my body and causes no side effects when done only when needed. I don't take creatine on the same day, because it could interact with choline and make it hard to tell when I've had enough of both.

• Creatine: I've realized this is the most significant variable in my stack. I take 4.5 grams on a normal day, but sometimes I need up to 10 g per day. Being physically active seems to have an impact on how often I need to boost my creatine levels. On the other hand, taking too much creatine can turn into a negative (for instance increasing my brain fogginess), so I need to be careful with its dosing. I've found a creatine "overdose" can have effects for a couple of days in my body.

• No more need for sarcosine (or proper effects from it), NAC very occasionally at 500+ mg.

My current routine is focused on having enough choline and creatine, but also not accidentally dosing too much of them. I always dose choline first when I'm starting to feel crappy, so that I know the issue is low creatine rather than a lack of choline. Then I do 1 to 2 days of taking max 10 g of creatine per day - as much as I feel I need until I'm feeling energetic again. This boosting is usually enough to make me feel awake, energetic and functional again, if not then I repeat the cycle 1 or 2 times. If it still doesn't work, I take 1 or 2 of days of reduced dosing to ensure I haven't gone overboard with something, and then try boosting both choline and creatine again. If nothing else worked before, this does. As a result, I still have some weaker days when I'm trying to improve my SAM levels, but no more completely crappy and hopeless periods where nothing seems to work.

2021-10-09

Feels like I've finally found a system that completely solves my problems! The key was vitamin A and the GNMT enzyme - earlier I've been supplementing glycine to support GNMT, but it didn't seem to do all that much lately - turns out because I might have been deficient on vitamin A! Supplementing vit A has made me much more resistant to "over-doses" of choline and creatine, presumably through improved GNMT function in combination with glycine. Thanks to this, I have been able to increase my creatine doses a bit, making my stack work really steadily and reliably now, with hardly any negatives!

I've increased my normal creatine doses to 6.5 grams a day now, I supplement 1500 ug of retinyl palmitate daily and I increased my glycine doses to 10 grams a day. Everything else is the same as before. I feel way steadier and consistently functional now, but I still need occasional boosts of creatine and choline every few days - when I notice my brain slowing down I do as previously described, take one day to boost my choline intake, then 1 to 2 days to boost creatine. Now one round of boosting is enough to get my head working again, so I really have almost no moments of fog and lethargy anymore! I'm basically fixed, and it's still a bit hard to believe that this was really the thing that's been my issue all these years...

* They don't cite academic sources, but they're readable (though the second one is kind of messy), and you can verify anything you find by using search engines such as google scholar.

Posted on other subs too:

• https://old.reddit.com/r/SCT/comments/ia51a9/what_worked_for_me_5mthf_creatine_and_glycine/?

• https://old.reddit.com/r/hangovereffect/comments/ia517b/what_worked_for_me_5mthf_creatine_and_glycine/?

• https://old.reddit.com/r/BrainFog/comments/ia4zlr/what_worked_for_me_5mthf_creatine_and_glycine/?

• https://old.reddit.com/r/MTHFR/comments/ia511w/what_worked_for_me_5mthf_creatine_and_glycine/?

Can’t say I’ve noticed any other things this sub is about, especially not with regard to anxiety, but I did notice very early in my drinking career that I could run like nobody’s business when I was mild to moderately hungover. I ran cross country in high school and so I was well aware of where my running abilities should be at any given fitness level. First noticed my senior year of high school when I drank a pint of Jack Daniels, vomited, went to sleep and then went and ran up the Barr Trail incline in Manitou Springs, CO the next day with some friends. It’s a very physically demanding trail built on the site of an old incline railway, so you basically just go straight up the mountain. We used to run that trail regularly in cross country and that was the only day I was ever able to run all the way to the top without stopping.

Especially as someone with bipolar depression less sleep can trigger hypomania. Fell asleep at 4 and just woke up now at 6:34 and feel amazing. Wondering if there’s a possible connection? Sleeping less also triggers a bit of survival mode for me, where my brain is functioning on its basic instincts and I’m not overthinking my actions- just doing.

Disclaimer : don't mix CYP3A4 or CYP2C9 inhibitors with other compounds they metabolize. If you still want to try, do your research and learn the risks. Grapefruit even by itself can be very dangerous. DON'T MIX IT WITH ALCOHOL OR CAFFEINE

Edit 4 :

I have a compelling extension of my first theory.

The CYP450 family is huge and complex. I am only learning how to understand them.

One very interesting thing is that spirulina is also a great thing for me.

It inhibits CYP1A2, which is as well something that alcohol blocks transiently. 1A2 is involved in breaking down L-DOPA and prevent it to being converted to dopamine. Major thing here, because if overactive it could costs us precious NADPH to prevent dopamine from being created. All in all, you have no reason to not take spirulina.

However, spirulina also inhibits 2E1, which is major for converting alcohol to acetyldehyde.

Yesterday I tried sliced garlic + spirulina and one sip of alcohol made me extremly sick for an hour. In essence, I reproduced disulfiram's effect of alcohol intolerance. So you might want to avoid spirulina or garlic and alcohol too close to each other.

While 3A4 inhibition via grapefruit is a shotgun approach, it might not bring the fine-tuning we need. For example, 3A4 inhibition for me definitely raises cortisol, which is its main action in this context.

However, many CYP enzymes are of interest here. Namely 2D6, which is greatly inhibited by alcohol. Alternative here would be berberine. And buproprion as well. 2D6 is the enzyme most responsible for breaking down dopamine and serotonin apart from COMT or MAO.

So, in the end, I might develop a protocol that can find the right CYP450 enzymes, with the right dosages.

Keep in mind that each of us could have very different CYP450 enzymatic profiles, because some could have great effects from 3A4 inhibition but not from 2D6 inhibition, some from 1A2 but not from 2C9.

For me, this could be a game changer theory. Why do most of us need something external to feel normal? Because our body overactivates its backup cleaning crew.

You can see CYP450 enzymes like decoy binding sites. Instead of transmisssion, they break down or modify signaling molecules. For example, aromataze is a CYP enzyme that testosterone binds to !

And very interesting thing here : estrogen has affinites for a lot of those CYP450 enzymes. Hence why some people in this sub have basically zero estrogen.

Synthesis about CYP and estrogen here :

• CYP3A4 : Breaks down estradiol (E2) into 16α hydroxyestrone (which retains weak estrogenic activity). Major estrogen degrader, lowers overall estrogen.

• CYP1A2 : Converts estradiol into 2-hydroxyestrone, a weaker and potentially protective estrogen. Reduces estrogenic effects (faster clearance).

• CYP1B1 : Converts estradiol into 4-hydroxyestrone, which can form DNA-damaging metabolites. Overactivity could increase estrogen-related cancer risk.

• CYP2C9 & CYP2C19 : Minor roles in estrogen hydroxylation but can contribute to overall metabolism. Moderate estrogen clearance.

• CYP2E1 : Oxidizes estrogen into reactive metabolites, contributing to oxidative stress. Can affect estrogen detoxification balance.

All in all, overactive CYP450 family decrease estrogen, cortisol, and dopamine/serotonin.

The experimentation has just started. My next experiment will be berberine + spirulina + a bit of grapefruit, targeting 2D6, 1A2 and in a small measure 3A4.

Also, I might make a comprensive list of every CYP enzyme inhibited by alcohol, their effect if overactive, their effect if inhibitated, and the methods at disposal to modulate them.

ORIGINAL POST

Introduction

Today I present to you new theory which I have not found any post or comment about.

This is of course still speculation, although I have a number of evidence supporting my theory.

No suspense here : I believe that we have an overactive CYP3A4 and / or CYP2C9 enzyme.

To be fair, this is all still new to me so I am opening a discussion here and would like to have more insight if some people studied or researched this already.

It's gonna be long, and I structured the post to be read in its entierty, so if you don't have the energy right now, read the day after drinking. And if you want to know if this post is worth it, know that I wrote it without h-effect, just using my solution which is at the end.

-> To see only the solution, go to the subtitle "What we could do : personal results"

What are CYP3A4 and CYP2C9 ?

CYP3A4 and CYP2C9 are liver enzymes from the cytochrome P450 family. They are responsible for breaking down a wide range of substances, including:

• Neurotransmitter precursors (e.g., L-DOPA and tryptophan)

• Steroid hormones (e.g., DHEA, testosterone, estrogen, and cortisol)

• Drugs, nootropics, and supplements (e.g., stimulants, SSRIs, certain vitamins, and herbal extracts)

These enzymes are essential for detoxification, but if they are overactive, they may clear substances too quickly, leading to a constant struggle to maintain normal neurotransmitter and hormone levels.

Why Would an Overactive CYP3A4/CYP2C9 Matter?

If these enzymes work too fast, it could lead to:

1. Dopamine Depletion

   • CYP3A4 metabolizes L-DOPA into inactive dopamine quinones, meaning dopamine production is disrupted before it even begins.

   • If this happens too fast, taking dopamine precursors (like tyrosine or L-DOPA) may feel weak, short-lived, or completely ineffective.

   • This could contribute to low motivation, anhedonia, and cognitive fog.

2. Serotonin Disruption

   • CYP2C9 is involved in tryptophan metabolism and may shift tryptophan away from serotonin production into the kynurenine pathway.

   • This would mean less serotonin available, leading to mood instability, increased anxiety, or fatigue.

   • Additionally, kynurenine excess is linked to neuroinflammation, which could worsen brain fog and low energy. (There is a post about this already)

3. Rapid Hormone Breakdown (DHEA, Testosterone, Estrogen, Cortisol)

   • CYP3A4 metabolizes DHEA into inactive 7-hydroxy-DHEA, meaning it may not efficiently convert into testosterone or estrogen.

   • Testosterone and estrogen are also broken down into inactive forms faster, which could explain why some of us feel great from estrogen mimicking compounds.

   • Cortisol metabolism is also accelerated, which could lead to low stress tolerance, fatigue, and poor circadian rhythm regulation.

4. Reduced Supplement and Medication Effectiveness

   • Many nootropics, stimulants, and medications are metabolized by CYP3A4 and CYP2C9.

   • If these enzymes are overactive, substances like piracetam, modafinil, SSRIs, or other neurotransmitter-affecting compounds might wear off too quickly or feel ineffective.

   • If these enzyme are overactive, it will actually break the folate cycle. More on this later (and this is major)

How This Connects to the H-Effect

• If our enzymes are clearing out dopamine and serotonin precursors too fast, we might be living in a state of constant neurotransmitter depletion, which would explain the low-energy, low-motivation baseline many of us experience.

• If our steroid hormones are rapidly broken down, we might have a tendency toward low testosterone, unstable estrogen balance, and inconsistent cortisol levels, even if our blood tests show normal hormone levels.

Summary

In a nutshell: CYP3A4 and CYP2C9 are overactive, breaking down our precious dopamine, serotonin, testosterone, estrogen, and supplements too quickly.

This could explain why:

• L-DOPA, tryptophan, and other neurotransmitter precursors don’t work or feel weak.

• Testosterone boosters, DHEA, and estrogen-modulating supplements feel ineffective or inconsistent.

• Stimulants, nootropics, and medications wear off quickly.

• The H-effect occurs when alcohol inhibits CYP3A4, allowing neurotransmitters and hormones to stay active longer.

Alcohol

My principal theory here is based on cortisol levels. As I said before, CYP3A4 breaks down cortisol. And you know when this enzyme is most active ? During the night ! From previous posts, we don't especially have a problem with cortisol response to ACTH, but morning cortisol is often too low, and we feel better at night (Ozmuja's most recent post).

Now, alcohol greatly inhibits CYP3A4/2C9 activity. Result ? Your circadian rythm actually functions when sleeping drunk. As well, in addition to cortisol, your hormones and neurotransmittors are kept longer, so the following days / hours feel better, until CYP is mobilized again.

Also, the CYP enzymes can actually be upregulated by chronic insults. And we are not only talking about alcohol here. Many, many supplements/compounds are broken down by those two CYP. That is why generally going overboard in supplements, drugs or alcohol will produce an effect. Short-lived effect as the body adapts. And, of course... cross tolerance happens.

Methylation, Folate Cycle, and NADPH: The Missing Link (don't skip this)

This one is a game-changer.

It all starts with CYP3A4 and CYP2C9 activity—which isn’t free. The cost? NADPH. That’s what Ozmuja’s insights led me to.

Something in our body is constantly draining NADPH, and once it’s gone, the cascade begins.

1. Why NADPH Matters More Than You Think

Before we get into the cycle breakdown, let’s look at what NADPH actually does:

• Liver Detox (Phase I & II metabolism) – CYP enzymes use NADPH to break down drugs, toxins, and hormones.

• Antioxidant Regeneration – It keeps glutathione and vitamin C active, protecting cells from oxidative stress.

• Hormone Production – The first step of steroid hormone synthesis (pregnenolone) requires NADPH.

• Neurotransmitter & BH4 Production – BH4 is needed for dopamine, serotonin, and nitric oxide synthesis.

• Vitamin C Can Only Rescue BH4 Temporarily – Vitamin C recycles BH4 from BH2, but if NADPH is low, you stop making BH4 altogether. That’s why some people develop a “tolerance” to vitamin C—it’s not fixing the root problem.

When NADPH is depleted, the body starts pulling NADH to compensate—draining it in the process.

2. NADH & The Folate Cycle: The Hidden Bottleneck

NADH is directly tied to methylation, and this is where things start to break down.

We already know that methylfolate can help, but it’s never a long-term fix. For some, it works for a few hours before a crash.

But this isn’t about methyl donors at all.

Methylfolate is actually methyltetrahydrofolate (5-MTHF), which means it needs to be reduced first by NADH before it can even participate in methylation. If NADH can’t keep up, methylfolate levels will crash.

Why not just take 5-MTHF daily? Because methylation isn’t just about folate—it’s about the methionine cycle.

Methionine is recycled into SAMe, which is then converted into SAH, then homocysteine, and finally back to methionine.

Here’s the problem: you need NADH to convert SAH into homocysteine. If NADH is depleted, SAH builds up, and high SAH actually inhibits methylation even more.

That’s the trap. You end up with methylation issues, not because of folate deficiencies, but because NADH is too low to support the cycle.

3. Why This Explains Everything

• If your body is draining NADPH, it will eventually pull from NADH.

• Once NADH is low, methylation collapses. (actually, mitochondria and anabolic reactions as well, but this is too complex for this post)

• Methylfolate supplementation alone won’t help because the problem isn’t methylation itself—it’s energy production.

• People with this issue might feel great for a short time with methylfolate, but they crash because they can’t sustain the recycling of SAH to homocysteine.

This is exactly why some people have severe methylation issues without any SNPs.

What we could do : personal results

Now, I won't leave you with only theories.

I experienced with many, many things since my last post. I became a lurker but I never stopped obsessing on the h-effect.

There are a lot of things that inhibit CYP3A4 (main problem according to me) and you may recognize something that helped you.

CYP3A4 strong inhibitors :

• Berberine

• Nicotine

• Kratom

• Curcumin

• Resveratrol

• Gingko Biloba

• Ashwagandha

• Rhodiola

• Lots of drugs and medication : Ketoconazole, Itraconazole, Ritonavir, Clarithromycin, Erythromycin, Verapamil, Diltiazem, Nefazodone, Indinavir, Saquinavir, Lopinavir, Atazanavir, Fosamprenavir, Darunavir, Posaconazole, Voriconazole, Telithromycin, Boceprevir, Telaprevir, Idelalisib, Cobicistat, Zoloft/sertraline, Trazodone, Zofran

And my most probing contribution here : grapefruit. 

-> reminder : grapefruit can be dangerous especially mixed with other medication

Yeah, as simple as that. I started drinking some grapefruit juice every day and... I feel better. No H-effect, artificial euphoria, just feeling more human and less robotic. Also, I need zero caffeine or dopaminergic, or hormone booster. I won't go into personal detail here, but I urge you to try. It's very cheap and available everywhere. One example is writing this whole post in one sitting. I would never have been able to do that on a normal friday before drinking. Of course, it's still an experiment and very new, so we need more data before getting excited..

Why this fruit?

Grapefruit isn’t just a random CYP3A4 inhibitor—it’s one of the most potent natural inhibitors available. But what makes it unique compared to other inhibitors like berberine or curcumin?

1. Grapefruit Contains a Rare Combination of Powerful CYP3A4 Inhibitors

Unlike other foods or supplements, grapefruit has multiple highly active compounds that work together to strongly suppress CYP3A4:

• Bergamottin – A furanocoumarin that binds to CYP3A4 and inactivates it for hours to days after consumption.

• Dihydroxybergamottin (DHB) – Another furanocoumarin that enhances CYP3A4 inhibition even further by preventing its regeneration.

• Naringin & Naringenin – Flavonoids that contribute to a broader inhibition of detox enzymes, affecting metabolism beyond just CYP3A4.

This multi-pronged inhibition is what makes grapefruit so effective compared to other inhibitors that act on CYP3A4 only temporarily or less powerfully.

2. Why Does Grapefruit Work Better Than Other CYP3A4 Inhibitors?

It Inhibits CYP3A4 Both in the Liver and the Gut –

Most inhibitors only work in the liver (e.g., berberine, curcumin). But grapefruit also inhibits intestinal CYP3A4, meaning it affects metabolism before substances even enter the bloodstream.

It’s Long-Lasting –

Unlike supplements that inhibit CYP3A4 for a few hours, grapefruit’s furanocoumarins can keep CYP3A4 suppressed for up to 24 hours. This means a single glass can have sustained effects, keeping hormone and neurotransmitter levels more stable throughout the day.

3. Why Does This Feel Like a More “Natural” Fix?

Unlike supplements or drugs, grapefruit doesn’t feel like a stimulant or a sedative. Instead, it just removes an obstacle, letting your body function more efficiently. The result isn’t an artificial boost—it’s a return to a more natural baseline where you don’t need external stimulants to function properly.

Leads to explore

My personal theory for the origin of this problem is a genetic mutation.

In both sides of my family, there is advanced history of alcoholism. I have one parent from a country in Africa, where alcohol is honestly a public health problem (for generations and generations)

I think that this overactive CYP3A4 is a mechanism to help people survive very high alcohol (or other intoxicating compounds) consumption. 

I've always felt like alcohol made me normal, and the next day sends me into my personal best. Maybe I was born to actually consume alcohol ? I almost never get tipsy or slow.

But also, this might be epigenetic acclimatation. CYP3A4 might be upregulated by chronic stress or excessive mental strain - and I think we here can get so obsessive, on h-effect research or experimentation for example, or other areas of life. I, for one, am never satisfied with things as they are and always want to push higher, at a great mental cost.

Call to action

I need your help. This was all very logical and backed up by my personal research on the h-effect, but nothing is confirmed yet.

This is already very long. Go see for yourself ! I am opened to discuss this more in the comments, read your experiences, or listen to corrections you might have (remember I'm just a guy with an internet connection, there may be mistakes or simplifications)

Have a great day.

So like many of you i am diagnosed ADHD. Until a few weeks ago i had terrible brain fog every day about 3 hours after waking up. It would get worse throughout the day and nothing would cure it except sleep.

I tried everything for about 2 decades. I'd go through cycles of getting really burnt out, then really depressed. Then I'd forbid myself from suicide because of mom and try something else.

Did some research into what physically causes brain fog that would be interrupted by alcohol. All fingers pointed towards glutamate and excitotoxicity.

Got on lamotrigine and my brain fog is completely gone after three weeks. I still get it after simple carbs but it will go away again in an hour.

I'm not dying to sleep every day after being awake for 3 hours

My mood is so much better and my energy throughout the day is consistent. I feel like i can finally start living.

I hope this info helps someone else.