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If you want to read 100+ detailed articles (some are 70 pages long) with real scientific resources on topic such as gut health, hormonal health, brain health, supplements, peptides, fatigue, skin health, hair health, autoimmune conditions etc
Go here:
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The more effortless stimulation you expose yourself to, the less satisfying your life will be.
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"Bro does this work? You've only cited 20 studies that i haven't read".
Try it if the risk and cost are low.
Just try it.
Stop procrastinating by looking for guarantees.
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The primary cellular mechanism underlying memory formation, storage and updating, is synaptic plasticity.
This is the brain’s ability to strengthen or weaken the connections between neurons in response to activity patterns.
When two neurons are active at the same time (especially repeatedly) the synapse (a tiny gap where the presynaptic neuron releases neurotransmitters that bind to receptors on the postsynaptic neuron) between them becomes more efficient.
This makes it easier for the presynaptic neuron (*) to trigger the postsynaptic neuron (**) in the future.
(*) The sender.
(**) The receiver.
Conversely, if they fire out of sync or one is inactive while the other fires, the connection can weaken.
So this bidirectional change is what allows the brain to encode specific experiences as unique patterns of connections.
What happens at the synaptic level is that high-frequency or coincident activity (imagine learning the piano, a foreign language or something similar) causes strong depolarization of the postsynaptic neuron.
This unblocks NMDA receptors.
Then calcium ions rush in, triggering the following cascade:
-Activation of CaMKII which phosphorylates and inserts more AMPA receptors into the membrane (making the neuron more responsive).
-Structural changes such as larger dendritic spines, more receptors, and sometimes new synapses.
-Gene transcription via CREB, new protein synthesis such as BDNF etc.
That was long-term potentiation (LTP) in a nutshell.
*If all these sound gibberish, check the three previous articles, threads etc.
Now early LTP is protein-synthesis independent and shorter while late LTP involves lasting structural and molecular changes.
We also have to talk about long-term depression (LTD) (think of this as weakening (LTP and LTD often occur together in the same circuits, sculpting precise engrams)).
Low-frequency or asynchronous activity leads to modest calcium influx, activating different pathways that remove AMPA receptors or shrink spines.
LTD prevents synaptic saturation, refines memories, supports pattern separation (distinguishing similar experiences), and enables forgetting or updating.
So as you might be able to tell, a memory isn’t stored in one neuron but in a sparse network of neurons called an engram (or “memory trace”).
During an experience:
-Specific neurons activate together.
-Synaptic plasticity strengthens connections within this ensemble and between related ensembles.
-Later, partial cues reactivate the same pattern → you recall the memory.
Here’s a practical example.
Imagine that you go out for dinner with close friends to celebrate a birthday.
Phase 1: Encoding phase.
In this phase sensory information (sights, sounds, etc) from the environment is gathered and translated into a neural format.
This initially relies on short-term/sensory memory systems.
For example, glutamate release triggers NMDA receptors, calcium influx activates CaMKII and CREB, kicking off early LTP (long-term potentiation).
The amygdala also “tags” the event emotionally, making it more salient.
Phase 2: Consolidation phase.
Later that night, during deep slow-wave sleep and REM, your hippocampus “replays” the neural patterns at high speed.
This replay strengthens synapses and gradually transfers the memory to neocortical networks.
Over days/weeks, the full episode becomes a stable, detailed long-term memory you can vividly recall years later.
So in this phase, short-term memories are stabilized into longer-lasting ones.
This heavily involves the hippocampus (in the medial temporal lobe), which helps transfer information to cortical areas for long-term storage.
Phase 3: Storage.
Here, memories are distributed across brain regions.
The hippocampus is key for forming new declarative (facts/events) memories, while the prefrontal cortex, basal ganglia, cerebellum, and amygdala handle aspects like working memory, skills, and emotional tagging.
Long-term memories become less hippocampus-dependent over time.
Over time (hours to years, via replay during sleep), they transfer to neocortical networks for stable storage.
Phase 4: Retrieval.
Reactivating the specific neuron ensemble by cues or context.
Stronger synaptic connections make this easier.
Now here are some studies showing that tech can in fact interfere with these:
-Heavy media multitaskers show poorer working memory (WM) capacity, sustained attention, and long-term memory (LTM) discriminability.
They allocate attention more broadly (scattered mode), struggling to filter irrelevancies, leading to shallower encoding and weaker LTP induction.
-Even the mere presence of a phone reduces cognitive resources (brain drain hypothesis).
-Heavy users exhibit lower recall accuracy and altered prefrontal/hippocampal activity.
-Prospective memory (remembering future intentions) and episodic memory suffer due to attention lapses just before encoding events.
-Taking photos/videos reduces personal encoding because the brain offloads to the device.
-Participants remember fewer details of museum objects or events when photographing vs. observing.This weakens hippocampal-dependent consolidation; deeper engagement (not just snapping) mitigates it somewhat.
-Reliance on search/GPS similarly atrophies spatial memory circuits
-Blue light from screens suppresses melatonin, delays sleep onset, reduces slow-wave sleep (SWS) and REM (critical for hippocampal replay, synaptic downscaling (homeostasis), and transferring memories to cortex).
-Heavy use is linked to reduced gray matter in hippocampus (memory), anterior cingulate (attention/control), prefrontal cortex (executive function), and amygdala (emotion).
-Lower hippocampal volume/activity impairs LTP/LTD balance.
-Dopamine-driven reward loops (likes, notifications) promote addiction-like behavior, increasing impulsivity and reducing deep processing needed for strong engrams.
-Increasing social media use in early adolescence predicts lower verbal memory (RAVLT), visuospatial attention, and overall cognitive scores.
In summary, tech fragments the sustained, focused neural firing and offline replay required for robust synaptic changes (LTP/LTD), protein synthesis, and systems-level transfer.
The effects are indeed dose-dependent and bidirectional (pre-existing traits may amplify use), but experimental and correlational evidence consistently links heavy habitual patterns to measurable deficits in attention, encoding, and consolidation.
Do these results make sense?
Of course.
With the amount of notifications that are available for example, your attention fragments every few seconds.
Each notification or urge to check triggers “brain drain” aka your prefrontal cortex uses resources just to suppress the impulse.
This prevents the sustained, high-frequency neural firing needed for robust LTP.
Instead of deep processing, you get shallow encoding and will struggle with pattern separation in the hippocampus.
Or when sleep onset is delayed, and deep sleep/REM is reduced, hippocampal replay will become weaker and less effective so there’s no strong protein synthesis or synaptic tagging to stabilize the memory.
AND all these without even mentioning the impact that tech can have when it comes to anxiety, depression, critical thinking/exposure to misinformation, lack of privacy etc etc.
“So what should i do?”
Here are 3 practical steps that might help you.
Step 1: Never check any device in the first or last hour of the day.
Step 2: Identify “optional technologies” (social media, YouTube, Instagram, Reddit, games, non-essential news/apps).
Step 3: Take a full 30-day break from the optional stuff. Delete apps, log out of accounts, or use blockers.
Brain max here: fitandball.gumroad.com/l/bra…
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You grow what you focus on.
“Sit down kid, tell me everything that you have in your life that someone else does not for the next hour”.
“No I do not care what’s going wrong. Ignore max”.
fitandball.gumroad.com/l/bra…
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Vitamin D levels were positively associated with verbal fluency as well
Almost 20% of American adults struggle with depression and 2/3 of them have insufficient vitamin D levels.
Yet there is a relationship between vitamin D and depression.
Now the question is: are supplements the answer? Well.
Yes. No. It's better than nothing.
Let me explain.
Almost 20% of American adults struggle with depression and 2/3 of them have insufficient vitamin D levels.
Yet there is a relationship between vitamin D and depression.
Now the question is: are supplements the answer?
Well.
Yes. No. It’s better than nothing.
Let me explain.
Supplementation has been shown to help but the idea that increasing vitamin D levels through supplements is the same as increasing them through sunlight is still quite common but profoundly false.
Here are three studies as an example:
1. Increasing vitamin D levels through sunlight led to a decrease in LDL-C, HDL-C, TC but supplements did NOT lower LDL-C.
2. 48.8% of acne patients had vitamin D deficiency (control had 22.5%), and supplementing vitamin D didn’t do almost anything.
3. Low vitamin D can negatively affect your libido but supplements don’t really work for resolving this.
Also, our body tightly regulates vitamin D synthesis from UVB exposure.
This is not the case with pills.
There’s a limit to how much vitamin D we can produce. Once we make 10-20KIUs from sunlight, extra UVB breaks down the excess previtamin D3 into inactive stuff like lumisterol and tachysterol
Now overall this is an important topic since vitamin D is a hormone-like vitamin that controls about 3% of your entire genome (roughly 1,000 genes), is a cellular multitasker that affects everything from detoxing xenobiotics, insulin, leptin, testosterone, progesterone, skin health and gut health all the way to bone health, muscle building, heart health, brain health, our blood pressure, fertility and immunity.
It does this by greatly affecting calcium absorption (without enough vitamin D, you’d only absorb 10-15% of dietary calcium), the renin-angiotensin system, beta cells in the pancreas, the parathyroid hormone (PTH), dopaminergic neurogenesis and differentiation, osteoblasts and steoclasts, aids in the production of antimicrobial peptides like cathelicidin and defensins, the CYP2R1, CYP27B1 and CYP24A1 enzymes, affects claudin 2, 5 , 12 and 15, it lowers pro-inflammatory signals (like IL-6 and TNF-alpha) and boosting anti-inflammatory ones (like IL-10).
So let’s say that you don’t get enough vitamin D and this negatively affects claudin 2, then this alone can negatively impact all types of IBD for example.
In order to put in perspective how bad a vitamin D deficiency is since it is quite likely that you’ve experienced a vitamin or mineral deficiency, whether it was magnesium or vitamin B12, i’d like you to remember the consequences that this had on you and i’d like you to 2-3-5-or even-10X them in the case of a vitamin D deficiency.
A vitamin D deficiency is that dangerous.
Now we can get vitamin D through UVB light or dietary means (food and supplements). Here’s how vitamin D is created when the sun hits our skin.
Our skin in the epidermis (the upper layer of the skin and specifically the stratum spinosum and stratum basale) has a cholesterol derivative that is called 7-dehydrocholesterol.
When wavelengths between 290 and 315 nanometers hit our skin, they break a chemical bond in it (the B ring), turning it into previtamin D3.
This is called photolysis.
But previtamin D3 is thermally unstable and has to undergo a rearrangement where a double bond shifts to a trans configuration and forms cholecalciferol. This conversion takes 8-24 hours.
Then, two hydroxylations happen: -One in the liver on carbon 25 in order to get 25-hydroxyvitamin D (25(OH)D), or calcidiol (this is the circulating form measured in blood tests).
The enzyme 25-hydroxylase (primarily CYP2R1) adds a hydroxyl group (-OH) to carbon 25 of cholecalciferol, forming 25-hydroxyvitamin D (25(OH)D), or calcidiol.
-One in the kidneys on carbon 1 in order to get 1,25-dihydroxyvitamin D (1,25(OH)2D), or calcitriol, the active hormonal form that binds to the vitamin D receptor (VDR).
1-alpha-hydroxylase (CYP27B1) adds another hydroxyl group to carbon 1 of 25(OH)D, producing 1,25-dihydroxyvitamin D (1,25(OH)2D).
Note 1: If you are wondering how vitamin D goes from the skin to the blood, this is done through vitamin D-binding protein (DBP).
A protein that is produced mainly in the liver and does exactly this (takes cholecalciferol and carries it through your blood).
Genetics variants in it like rs2282679 and rs7041 can dial down your 25(OH)D.
Note 2: The vast majority of vitamin D’s effects are mediated through the vitamin D receptor (VDR) (once calcitriol is ready, it binds to VDR to do its job).
The Vitamin D Receptor (VDR) is a nuclear receptor (a type of protein inside the cell (mostly in the nucleus)) that binds 1,25-dihydroxyvitamin D (1,25(OH)2D3), or calcitriol (the active form of vitamin D) and found in almost every cell type from osteoblasts, the kidneys, neurons, skeletal muscle cells, glial cells, keranocitees, blood vessels, epithelial cells and immune cells.
Now as one more side note, one reason why we must create the perfect balance between vitamin D and A is that once activated, the VDR pairs with the retinoid X receptor (RXR) and together, they go to vitamin D response elements (VDREs) and turn on genes like CALB1 that affect calcium transport for example (one reason why too much vitamin A and not enough vitamin D can create bone issues), or cathelicidin and defensins in macrophages in order to kill germs.
Now there are certain genetic variations in the VDR that make it less efficient that you should be aware of:
-rs1544410
-rs2228570
-rs731236
Note 3: Variants in CYP2R1 or CYP27B1 like rs2060793 or rs28934607 can also slow the conversion steps.
Note 4: When measuring 25(OH)D you want a 45+ ng/mL ideally.
Below 20 ng/mL is a serious deficiency.
Between 20-30 ng/mL is nsufficient.
Between 30-45S ng/mL is decent, and between 45-75/ng/mL is great and anything past that is just excessive (and wrong) supplementation or signals that you live in a place were you are not designed to (a Swedish person living in Brazil for example).
Now, here’s how you can increase your vitamin D levels. Number 1: First and foremost, get bloodwork done (serum 25D).
Number 2: If your levels are low tackle the most common causes of a vitamin D deficiency, such as:
-Overconsuming caffeine
-Not spending time outside
-Not getting enough magnesium
-Low fat and low cholesterol diets
-Very high fiber diets
-No resistant starch or things that feed parabacteroides.
-Wearing sunscreens with high SPF (>30)
-Things that harm the VDR such as sodium fluoride, BPA, heavy metals and being overweight (boron and curcumin help with this)
Number 3: If your levels are still low after implementing these for 2 months, get a vitamin D lamp.
Also consider urolithin A that enhances vitamin D receptor signaling.
Number 4: If you want to supplement for whatever reason :
-Make sure that your kidneys work fine
-Get one in oil form
-Consume it at noon(-ish) (vitamin D opposes melatonin)
-Test again after just 1 month of supplementing
-Consume it with a retinol-rich meal for breakfast (eggs for example)
-Supplement with vitamin K2 and magnesium as well
We can go on and on when it comes to why a pill won’t be able to replace the benefits of the sun.
Another reason why pills will never be able to replace sunlight is that pills don’t regulate POMC for example.
Another reason is that a pill can’t regulate our CR/provide zeitgebers.
Blue light (460–480 nm) for example activates melanopsin in intrinsically photosensitive retinal ganglion cells (ipRGCs).
This is why exposure to artificial light at night can desynchronize the SCN, leading to circadian misalignment with some studies suggesting that even low-intensity light (~100 lux) at night can suppress melatonin by up to 50%.
Another reason is that.....sunlight is free.
There are of course plenty of studies that have studied the impact of full-spectrum sunlight vs vitamin D pills on certain organs/markers as well (tap in the pics).
You get the idea by now.
For more about the brain go here: fitandball.gumroad.com/l/bra…
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Almost 20% of American adults struggle with depression and 2/3 of them have insufficient vitamin D levels.
Yet there is a relationship between vitamin D and depression.
Now the question is: are supplements the answer? Well.
Yes. No. It's better than nothing.
Let me explain.
Almost 20% of American adults struggle with depression and 2/3 of them have insufficient vitamin D levels.
Yet there is a relationship between vitamin D and depression.
Now the question is: are supplements the answer?
Well.
Yes. No. It’s better than nothing.
Let me explain.
Supplementation has been shown to help but the idea that increasing vitamin D levels through supplements is the same as increasing them through sunlight is still quite common but profoundly false.
Here are three studies as an example:
1. Increasing vitamin D levels through sunlight led to a decrease in LDL-C, HDL-C, TC but supplements did NOT lower LDL-C.
2. 48.8% of acne patients had vitamin D deficiency (control had 22.5%), and supplementing vitamin D didn’t do almost anything.
3. Low vitamin D can negatively affect your libido but supplements don’t really work for resolving this.
Also, our body tightly regulates vitamin D synthesis from UVB exposure.
This is not the case with pills.
There’s a limit to how much vitamin D we can produce. Once we make 10-20KIUs from sunlight, extra UVB breaks down the excess previtamin D3 into inactive stuff like lumisterol and tachysterol
Now overall this is an important topic since vitamin D is a hormone-like vitamin that controls about 3% of your entire genome (roughly 1,000 genes), is a cellular multitasker that affects everything from detoxing xenobiotics, insulin, leptin, testosterone, progesterone, skin health and gut health all the way to bone health, muscle building, heart health, brain health, our blood pressure, fertility and immunity.
It does this by greatly affecting calcium absorption (without enough vitamin D, you’d only absorb 10-15% of dietary calcium), the renin-angiotensin system, beta cells in the pancreas, the parathyroid hormone (PTH), dopaminergic neurogenesis and differentiation, osteoblasts and steoclasts, aids in the production of antimicrobial peptides like cathelicidin and defensins, the CYP2R1, CYP27B1 and CYP24A1 enzymes, affects claudin 2, 5 , 12 and 15, it lowers pro-inflammatory signals (like IL-6 and TNF-alpha) and boosting anti-inflammatory ones (like IL-10).
So let’s say that you don’t get enough vitamin D and this negatively affects claudin 2, then this alone can negatively impact all types of IBD for example.
In order to put in perspective how bad a vitamin D deficiency is since it is quite likely that you’ve experienced a vitamin or mineral deficiency, whether it was magnesium or vitamin B12, i’d like you to remember the consequences that this had on you and i’d like you to 2-3-5-or even-10X them in the case of a vitamin D deficiency.
A vitamin D deficiency is that dangerous.
Now we can get vitamin D through UVB light or dietary means (food and supplements). Here’s how vitamin D is created when the sun hits our skin.
Our skin in the epidermis (the upper layer of the skin and specifically the stratum spinosum and stratum basale) has a cholesterol derivative that is called 7-dehydrocholesterol.
When wavelengths between 290 and 315 nanometers hit our skin, they break a chemical bond in it (the B ring), turning it into previtamin D3.
This is called photolysis.
But previtamin D3 is thermally unstable and has to undergo a rearrangement where a double bond shifts to a trans configuration and forms cholecalciferol. This conversion takes 8-24 hours.
Then, two hydroxylations happen: -One in the liver on carbon 25 in order to get 25-hydroxyvitamin D (25(OH)D), or calcidiol (this is the circulating form measured in blood tests).
The enzyme 25-hydroxylase (primarily CYP2R1) adds a hydroxyl group (-OH) to carbon 25 of cholecalciferol, forming 25-hydroxyvitamin D (25(OH)D), or calcidiol.
-One in the kidneys on carbon 1 in order to get 1,25-dihydroxyvitamin D (1,25(OH)2D), or calcitriol, the active hormonal form that binds to the vitamin D receptor (VDR).
1-alpha-hydroxylase (CYP27B1) adds another hydroxyl group to carbon 1 of 25(OH)D, producing 1,25-dihydroxyvitamin D (1,25(OH)2D).
Note 1: If you are wondering how vitamin D goes from the skin to the blood, this is done through vitamin D-binding protein (DBP).
A protein that is produced mainly in the liver and does exactly this (takes cholecalciferol and carries it through your blood).
Genetics variants in it like rs2282679 and rs7041 can dial down your 25(OH)D.
Note 2: The vast majority of vitamin D’s effects are mediated through the vitamin D receptor (VDR) (once calcitriol is ready, it binds to VDR to do its job).
The Vitamin D Receptor (VDR) is a nuclear receptor (a type of protein inside the cell (mostly in the nucleus)) that binds 1,25-dihydroxyvitamin D (1,25(OH)2D3), or calcitriol (the active form of vitamin D) and found in almost every cell type from osteoblasts, the kidneys, neurons, skeletal muscle cells, glial cells, keranocitees, blood vessels, epithelial cells and immune cells.
Now as one more side note, one reason why we must create the perfect balance between vitamin D and A is that once activated, the VDR pairs with the retinoid X receptor (RXR) and together, they go to vitamin D response elements (VDREs) and turn on genes like CALB1 that affect calcium transport for example (one reason why too much vitamin A and not enough vitamin D can create bone issues), or cathelicidin and defensins in macrophages in order to kill germs.
Now there are certain genetic variations in the VDR that make it less efficient that you should be aware of:
-rs1544410
-rs2228570
-rs731236
Note 3: Variants in CYP2R1 or CYP27B1 like rs2060793 or rs28934607 can also slow the conversion steps.
Note 4: When measuring 25(OH)D you want a 45+ ng/mL ideally.
Below 20 ng/mL is a serious deficiency.
Between 20-30 ng/mL is nsufficient.
Between 30-45S ng/mL is decent, and between 45-75/ng/mL is great and anything past that is just excessive (and wrong) supplementation or signals that you live in a place were you are not designed to (a Swedish person living in Brazil for example).
Now, here’s how you can increase your vitamin D levels. Number 1: First and foremost, get bloodwork done (serum 25D).
Number 2: If your levels are low tackle the most common causes of a vitamin D deficiency, such as:
-Overconsuming caffeine
-Not spending time outside
-Not getting enough magnesium
-Low fat and low cholesterol diets
-Very high fiber diets
-No resistant starch or things that feed parabacteroides.
-Wearing sunscreens with high SPF (>30)
-Things that harm the VDR such as sodium fluoride, BPA, heavy metals and being overweight (boron and curcumin help with this)
Number 3: If your levels are still low after implementing these for 2 months, get a vitamin D lamp.
Also consider urolithin A that enhances vitamin D receptor signaling.
Number 4: If you want to supplement for whatever reason :
-Make sure that your kidneys work fine
-Get one in oil form
-Consume it at noon(-ish) (vitamin D opposes melatonin)
-Test again after just 1 month of supplementing
-Consume it with a retinol-rich meal for breakfast (eggs for example)
-Supplement with vitamin K2 and magnesium as well
We can go on and on when it comes to why a pill won’t be able to replace the benefits of the sun.
Another reason why pills will never be able to replace sunlight is that pills don’t regulate POMC for example.
Another reason is that a pill can’t regulate our CR/provide zeitgebers.
Blue light (460–480 nm) for example activates melanopsin in intrinsically photosensitive retinal ganglion cells (ipRGCs).
This is why exposure to artificial light at night can desynchronize the SCN, leading to circadian misalignment with some studies suggesting that even low-intensity light (~100 lux) at night can suppress melatonin by up to 50%.
Another reason is that.....sunlight is free.
There are of course plenty of studies that have studied the impact of full-spectrum sunlight vs vitamin D pills on certain organs/markers as well (tap in the pics).
You get the idea by now.
For more about the brain go here: fitandball.gumroad.com/l/bra…
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Infants with eczema were found to have had less UV light exposure compared with those without eczema.
*Common sense disclaimer: Do not be dumb and sunburn your kids.
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Lipid peroxidation is elevated in several psychiatric disorders.
Oxidative stress is widely recognized as a major driving factor in the development and progression of almost all major brain-related pathologies, whether that's called depression, schizophrenia, ALS, Parkinson's, Alzheimer's or ASD.
Here's what you need to know.
Thread🧵
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George Ferman retweeted
"But they help my mood so much".
If you experience significant, robust and consistent mood elevation from thing such as coffee, nicotine, methylene blue, curcumin and fenugreek, it's time to look deeper into MAO enzymes.
Monoamine oxidase enzymes are mitochondrial enzymes that catalyze the oxidative deamination of amines (including neurotransmitters and dietary xenobiotics) converting them into aldehydes, ammonia (NH₃), and hydrogen peroxide (H₂O₂).
For example, they convert tyramine into p-hydroxyphenylacetaldehyde and they also use FAD as a cofactor and molecular oxygen as an electron acceptor.
The primary MAO isoforms include:
-MAO-A that metabolizes polar amines (serotonin, norepinephrine, epinephrine, melatonin) and dietary amines (tyramine).
-MAO-B that metabolizes non-polar amines like dopamine, phenylethylamine and xenobiotics.
So high activity of these can lead to inadequate flow of all these which can of course cause a variety of side effects ranging from low libido, depression and anxiety all the way to neurodegeneration.
There's plenty of research for example that indicates that MAO-A levels are up to 34% higher in depressed individuals.
Now the three main factors that can increase their activity quite a lot are: stress, environmental toxins and certain SNPs.
In the case of chronic stress, it significantly upregulates MAO-A activity by activating SIRT1 (a protein that enhances MAO-A expression in the brain) and in rats, the steroid dexamethasone (a cortisol mimic) increased MAO-A density by 300%.
When it comes to MAO polymorphisms, for MAO-A we have:
-High-activity alleles (3.5R, 4R, 5R) that lead to higher MAO-A gene transcription and thus increased MAO-A enzyme which can predispose these people to mood disorders like depression.
-Low-activity alleles (2R, 3R) that lead to lower MAOA transcription and thus reduced MAO-A activity which can predispose certain people to more impulsive and aggressive behaviors.
The 3R allele is often referred to as the “warrior gene” as well (not something to be proud of though just because of the name since in most cases this gene is associated with wildly antisocial behaviors).
-rs6323 (T941G) that is associated with higher MAO-A activity.
-rs1137070 that also affects MAO-A expression and is implicated in anxiety disorders and stress response.
When it comes to MAO-B polymorphisms we have:
-rs1799836 (A/G in intron 13) where the A allele is associated with higher MAO-B activity and the G allele correlates with lower activity.
Increased MAO-B activity accelerates dopamine and phenethylamine breakdown, contributing to dopamine depletion while reduced MAO-B activity may increase dopamine availability, potentially enhancing reward sensitivity but also raising addiction risk.
-rs6651806 that could contribute to mood disorders and neurodegeneration.
Now other inducers include diets low in antioxidants which are correlated with higher MAO-B activity and chronic alcohol consumption which also increases MAO-B expression.
*Candida albicans and mycotoxin exposure could also elevate it through acetaldehyde in theory.
Now when it comes to inhibitors (MAOIs) we have:
-Non selective (these inhibit both MAO-A and MAO-B) such as phenelzine, fenugreek, coffee, tranylcypromine and isocarboxazid, passion flower, chamomile and rhodiola.
We also have ginkgo biloba but the main studies were done in rats and human ones it didn’t really do much.
-Selective MAO-A inhibitors such as methylene blue, pirlindole, St. John’s Wort, quercetin and mocobemide.
-Selective MAO-B inhibitors such as safinamide, resveratrol, EGCG and rasagiline.
That was it.
These were the absolute basics.
More about the brain: fitandball.gumroad.com/l/bra…
Stimulant use has partly become so popular because it can make every boring activity, well, less boring by increasing dopamine in the short run.
Yet, do it for long enough and you will need 3 shots of espresso just to put your pants on in the morning.
It's very common for someone these days to need 400mg of caffeine and 12 mg of nicotine just to barely function.
This is of course not normal and a sign that this person has to pay attention to their overall health instead of creating more issues down the line since let's not forget that stimulants deplete B vitamins and minerals such as magnesium for example.
And this is without mentioning the negative impact that they can have on our hormones and neurotransmitters.
"But i like coffee" someone might say.
That's fine, i like coffee as well.
But do you pathologically need coffee? If the answer is yes then there might be a problem.
Now here's some food for thought when it comes to coffee/caffeine for example.
First, here's who should NOT consume coffee on a regular basis (1+/week):
-If you have issues with mold toxicity, do not have coffee since CYP1A2 is the primary enzyme responsible for metabolizing caffeine in the liver.
-If you have gut issues that are unrelated to fat malabsorption do not have caffeine (this does not mean that caffeine will be helpful in case you do have them, it's just not that big of an issue and that coffee can help through the bitter taste receptors).
–If you have fried adenosine receptors / chronic insomnia, do not have it.
-If you have polymorphisms in the ADA gene (think rs73598374) or CYP1A2 enzyme do not have coffee.
-If you have issues with low GABA, do not have caffeine.
-If you are struggling with issues such as bipolar disorders, do not have caffeine.
-If you have issues with histamine intolerance / MCAS, do not have caffeine.
ncbi.nlm.nih.gov/pmc/article…
ncbi.nlm.nih.gov/pubmed/1945…
Now if you do not have these and can accept the usage of coffee/caffeine as a tool, here are some of its potential benefits.
For starters, in my opinion, picking a light roast with quality beans is a good first step.
pubmed.ncbi.nlm.nih.gov/2858…
https://pubmed.ncbi.nlm.nih.gov58/
pubmed.ncbi.nlm.nih.gov/2807…
pubmed.ncbi.nlm.nih.gov/2926…
Now some of the benefits of coffee include (most of them are minor):
-Ergogenic effects
-Increasing eNOS
-Increased metabolic rate
-Increasing D2 and D3 (a lot of the brain benefits seem to circle back to this) and can thus help with unipolar depression
-Inhibiting iron and heavy metal absorption from certain foods
That's all.
Learn how to upgrade your brain:
fitandball.gumroad.com/l/bra…
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Based on over 30,000 clinically depressed patients, Dr. Walsh categorized clinical depression into five distinct chemical imbalances:
-Undermethylation (38%).
Characterized by low activity at serotonin receptors, high inner tension, and strong-willed or perfectionistic traits.
-Folate deficiency / overmethylation (20%).
Characterized by high anxiety, low energy, and a high sensitivity to food or chemicals.
-Copper toxicity
Found predominantly in women, leading to high anxiety and mood volatility.
-Pyrrole disorder / Pyroluria (15%)
Caused by a severe genetic or stress-induced deficiency in zinc and vitamin B6, manifesting as major mood swings and sensory overload.
-Toxin/toxic metal overload (5%)
Linked to high levels of heavy metals like lead, mercury, or environmental toxins.
-Other (5%): Encompasses minor lifestyle or clinical factors (like severe gut dysbiosis or specific nutrient absorption limitations).
The reality now is that, these specific percentages and "biotypes" are not legitimate so these posts are only good for e-girls.
If you want to "categorize" depression, they have successfully identified six biological subtypes of depression.
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If you are an entrepreneur, trader, or executive, you understand the concept of asymmetric risk.
You look for investments where the downside is strictly capped, but the upside is virtually limitless.
Now, let's apply that exact math to your primary wealth-generating asset: your mind.
Think about your last major mental mistake.
Maybe it was a bad trade executed during a mid-afternoon energy crash.
Maybe it was a critical client email you put off.
What did that single moment of cognitive fatigue actually cost you?
For some people in high-stakes industries, a single foggy day can cost tens of thousands in lost revenue or missed opportunities.
That is the hidden tax of poor brain health.
So you aren't losing because you lack talent.
You are losing because your biological infrastructure is facing an energy crisis.
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Glutathione levels are significantly reduced in the occipital cortex of patients with major depressive disorder (MDD).
"So, supplementing with glutathione helps depression?"
It's not that simple.
In general in case you have no idea what glutathione is, it is quite a potent water-soluble (hydrophilic (it cannot dissolve in or protect lipid-rich environments (think lipid membranes or LDL particles directly) so it cannot directly stop lipid peroxidation in cell membranes (this is why the body places vitamin E right in the membranes and uses glutathione with vitamin C to regenerate it))) antioxidant.
It is synthesized in virtually every cell that has a nucleus, but its concentration differs dramatically between organs and cell types, depending on where the body most urgently needs protection from oxidative stress for example.
When it comes to its structure, it’s a tripeptide composed of three amino acids:
-Glutamic acid
-Cysteine
-Glycine
which is why its full name is: gamma-L-Glutamyl-L-Cysteinyl-Glycine.
Glutamate + Cysteine give us gamma-Glutamylcysteine with the help of the enzyem Glutamate-Cysteine Ligase (GCL) and then gamma-Glutamylcysteine + Glycine give us Glutathione with the help of glutathione synthetase.
What makes it unique is not just that it contains three common amino acids but how they are linked.
Here's an example.
Plenty of proteins/peptides use alpha-peptide bonds, in glutathione, glutamate is attached to cysteine through its gamma carboxyl group instead of the usual alpha carboxyl.
This linkage is extremely rare and what gives glutathione its biological stability and resistance to breakdown by most peptidases in the gut and blood.
"GEORGE, THESE ARE WAY TOO NERDY".
Fine, let's use this basic boring fact in order to understand why most glutathione supplements but also plenty of discussions about "dietary glutathione" are also false.
Because of this bond that we just talked about, dietary glutathione is mostly destroyed when taken orally UNLESS it's somehow protected (think liposomal or S-acetyl forms).
But still, ideally, you want to pin/inject it if you want to fully utilize its benefits.
This is why precursors like NAC are more effective at raising glutathione levels plenty of times (BUT, NAC can have its own downsides and injecting glutathione can be better in cases of a viral infection, liver disease and so on).
Then of course when it comes to its structure we can also talk about the thiol (-SH) group on cysteine that:
-Donates electrons → neutralizes free radicals
-Easily oxidized → forms disulfide bonds (GS-SG)
-Binds directly to toxic metals (mercury, lead, cadmium) and electrophilic xenobiotics
Glutathione can be found in two "forms" in the body:
-Reduced GSH (active)
-Oxidized GSSG (inactive (high levels indicate oxidative stress)
The body keeps the vast majority (98–99%) as GSH and only 1–2% as GSSG under healthy conditions.
Low GSH is found in almost every chronic disease from Alzheimer’s all the way to liver disease and heart disease.
The main functions in the body include:
1. Antioxidant defense
It neutralizes harmful reactive oxygen species such as superoxide, hydrogen peroxide, hydroxyl radical, and peroxynitrite.
When GSH neutralizes a free radical, two GSH molecules combine to form one GSSG.
As a side note, the ratio GSH:GSSG is a key marker of cellular redox status.
A healthy cell has a ratio > 100:1; in oxidative stress or disease, it can drop below 10:1.
2. Detoxification (Phase II)
Glutathione conjugates certain toxins so they become water-soluble and can be excreted in bile or urine.
This is called glutathione S-transferase (GST) reaction.
Examples of substances detoxified:
-Heavy metals (mercury, lead, cadmium, arsenic)
-Xenobiotics (pesticides, BPA, phthalates)
-Aflatoxins
-Acetaminophen/Tylenol
-Chemotherapy drugs
3. Immune system support
Required for T-cell proliferation and function (especially cytotoxic T-cells and NK cells).
Determines whether immune cells shift toward Th1 (anti-viral, anti-cancer) or Th2 (anti-parasite, allergy-prone) responses.
4. Regeneration of other antioxidants
Glutathione can recycle (reduce) oxidized vitamin C (dehydroascorbate) back to active vitamin C.
Vitamin C then recycles oxidized vitamin E (tocopheryl radical) back to active vitamin E.
5. DNA and protein synthesis / repair
Protects DNA from oxidative damage during cell division.
Low GSH increases 8-OHdG (a marker of DNA oxidation) → higher mutation rate → higher cancer risk.
Maintains proper protein folding by regulating disulfide bonds (critical in the endoplasmic reticulum).
Prevents protein thiol groups (-SH) from irreversible oxidation → preserves enzyme function.
6. Regulation of cell growth and apoptosis
GSH levels act like a cellular “life-or-death switch”:
-High GSH → promotes cell survival and proliferation
-Mild drop in GSH → triggers normal apoptosis
Severe drop → necrosis
Cancer cells often overexpress glutathione systems to resist chemotherapy-induced apoptosis.
When it comes to its distribution:
The liver is the undisputed glutathione factory and reservoirProduces the majority of the body’s GSH and exports it (as GSH, GSSG or conjugates) to other tissues through blood or bile.
In fasting, illness or even during exercise, liver GSH can drop 50–70% within hours to supply the rest of the body.
Tissues facing the outside world or high toxin load have the highest levels
Liver → detox, lung → air, lens → UV, kidney → filtered toxins.
Cells without mitochondria or backup systems (RBCs, lens) are 100% dependent on GSH
That’s why deficiencies hit these tissues first (hemolytic anemia, early cataracts).
Immune cells keep huge stores because they weaponize oxygen
Activated neutrophils can raise intracellular GSH temporarily by 5–10×.
Brain GSH is compartmentalized
Neurons rely on astrocytes to synthesize and release GSH precursors (cysteine, cysteinyl-glycine) because neurons have low expression of the rate-limiting enzyme (glutamate-cysteine ligase).
Now should you supplement with it?
Most likely:
-Not being a vegan
-Lowering your toxin load (less GSH used for conjugation)
-Selenium
-NACET
-NAC
-R-ALA
-Milk thistle
-Some cruciferous vegetables
-Glycine
-Sauna use
-Curcumin
-Vitamin C
-Vitamin E
will increase your levels just fine.
The right pic for example, is a comprehensive meta-analysis published in PubMed that analyzed 12 randomized controlled trials (904 total patients).
It found that adjunctive NAC at doses ranging from 1,000 mg to 3,000 mg per day led to a statistically significant reduction in depressive symptoms compared to a placebo.
But of course, these are high doses and if you are not suffering from depression, using them for weeks can have side effects such as blunting your emotional reactions (both positive and negative) and learning.
Also, NAC is more consistently effective at reducing the depressive phase of bipolar disorder rather than unipolar major depressive disorder.
Go here to learn what supplements work for the brain and how to use them: fitandball.gumroad.com/l/bra…
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No amount of caffeine or meds can fix a neuron that physically lacks the energy to fire.
Working to optimize or balance your neurotransmitters is largely ineffective if your cells are not producing enough ATP.
The creation of neurotransmitters from amino acid precursors requires enzymatic steps that are ATP-dependent processes.
So without enough cellular energy, your brain cannot efficiently build these chemical messengers.
Once neurotransmitters are made, they must be actively pumped into storage sacs called vesicles.
This relies on V-ATPase, an enzyme that also requires direct ATP consumption to move neurotransmitters against their concentration gradient.
To send a signal, neurons must fire and then reset their electrical balance.
The sodium-potassium pump resets the neuron's membrane potential after an action potential.
This single process consumes roughly HALF of the total energy used by the entire brain.
Then after a neurotransmitter is released into the synaptic cleft, it needs to be cleared or recycled via reuptake transporters.
These transporters also rely on the ion gradients maintained by ATP-driven pumps.
So without sufficient ATP, your brain cells lack the basic power needed to manufacture, store, release, and clean up neurotransmitters.
To build what feels like "unlimited willpower," you must shift from viewing willpower as a moral choice or a mental muscle and start viewing it as a metabolic resource.
Read more:
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SSRIs and finasteride are probably the most common medications that can lead to ED.
In a study of 1,022 outpatients with previously NORMAL sexual function for example, they found an overall incidence (when it comes to erectile dysfunction) of 59%, with individual SSRIs ranging from about 58% (fluoxetine) to 71–73% (paroxetine and citalopram).
Why this happens is not hard to understand.
One of the functions of SSRIs is block the serotonin transporter (SERT), raising synaptic serotonin.
But serotonin has a net inhibitory effect on sexual response in several ways:
-It stimulates postsynaptic 5-HT₂ receptors (especially 5-HT₂C) that delay or block orgasm and ejaculation and can reduce desire.
-Increased serotonin tone inhibits dopamine release in mesolimbic and hypothalamic circuits (dopamine normally facilitates desire, arousal, and orgasm).
-Then some SSRIs like paroxetine can inhibit nitric oxide synthase, impairing the vascular changes needed for erection.
Or when it comes to finasteride, it reduces the conversion of testosterone to dihydrotestosterone (DHT) and these effects on androgen signaling influence AR function and related pathways.
DHT has a higher affinity for ARs than testosterone (2–10 times stronger binding) and thus by inhibiting 5α-reductase it reduces AR activation.
Since ARs regulate gene expression through binding to androgen response elements (AREs) finasteride result in decreased transcription of DHT-dependent genes.
Also, reduced DHT levels can disrupt the hypothalamic-pituitary-gonadal (HPG) axis.
More: fitandball.gumroad.com/l/bra…
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