For Those Of You Abusing Phenylehtylamine.

[Bravoncius Roxford]

Be warned here, PEA increases oxidative stress in the brain in two ways: first, the breakdown products of PEA are free radical hydroxyls and superoxide anions. Secondly, PEA itself increases oxidative stress by inhibiting mitochondrial complex-1. See here: https://www.google.com/url?sa=t&rct...med/23638910&usg=AOvVaw3Tn2jYKUzvBw3VuCbdSY_n This would indicate that even people taking MAO-B inhibitors are at risk. They might not be getting the free radicals from PEA breakdown, but they are still getting a massive increase in free radicals in the brain to to the greatly increased PEA that comes from MAO-B inhibition.

 

[atara]

first, the breakdown products of PEA are free radical hydroxyls and superoxide anions.

The metabolism of everything produces hydroxyl radicals and superoxide ions, what's so different about PEA?

Secondly, PEA itself increases oxidative stress by inhibiting mitochondrial complex-1.

Inhibition of mitochondrial complex 1 is a neurotoxicity risk, but it's important to remember that this is PEA inside of neurons inhibiting MC1. Usually recreational drugs act on the outside of the cell, on cell surface receptors (this is also why professional researchers consider it unlikely that sigma receptors play a significant role in most drugs' effects). Drugs do get transported into the cell to some degree, but the fact that PEA is a major mediator of natural neurodegeneration does not allow us to conclude that a certain dose of PEA will have the effects of the same amount of PEA being synthesized inside the neurons. After all, many cell signalling molecules are present in foods, because they are made of cells; if our cells simply absorbed those molecules, most food would kill us.

So, for example, dextroamphetamine likewise inhibits the mitochondrial complexes in the electron-transport chain, but it is widely regarded as being low-toxicity:

https://www.sciencedirect.com/science/article/pii/S0163725803000524

 

[Bravoncius Roxford]

The metabolism of everything produces hydroxyl radicals and superoxide ions, what's so different about PEA?

Because taking a huge amount of PEA generates a much higher amount of ROS than what is normally produced by the small amount of PEA that we naturally produce. There is nothing special about PEA, but the problem is the amount.

Inhibition of mitochondrial complex 1 is a neurotoxicity risk, but it's important to remember that this is PEA inside of neurons inhibiting MC1. Usually recreational drugs act on the outside of the cell, on cell surface receptors (this is also why professional researchers consider it unlikely that sigma receptors play a significant role in most drugs' effects). Drugs do get transported into the cell to some degree, but the fact that PEA is a major mediator of natural neurodegeneration does not allow us to conclude that a certain dose of PEA will have the effects of the same amount of PEA being synthesized inside the neurons. After all, many cell signalling molecules are present in foods, because they are made of cells; if our cells simply absorbed those molecules, most food would kill us.

You make a good point, but remember that we were never designed to ingest grams of purified PEA. The small amount of PEA in food is not a problem, but an amount of PEA equivalent to 20 kilograms of cacao beans ingested at once might be a problem. Let me give you an example to illustrate the point. Consider vitamin B12. Usually, oral absorption is problematic because the absorption is carefully regulated by several intrinsec factors. This ensures that it is impossible to achieve Cobalt poisoning from B12 in foods. However, oral supplementation of B12 at mega doses of 1,000 mcg or more has been proven effective to reverse pernicious anemia completely. Why? Because at these gigantic, abnormal doses, the vitamin gets absorbed through the intestinal walls by diffusion. So despite the extremely poor oral bioavailability of B12 from foods, a dose of B12 hundreds or thousands of times greater than what you get from a normal diet reverses B12 deficiency because it simply overwhelms the body's ability to control absorption. I can give you another example: consider glutamate. Glutamate is a potent neurotoxin. However, glutamate from foods is not toxic at all because the blood-brain barrier simply blocks glutamate from entrance into the brain. Also, extremely tiny amounts of glutamate in the nano gram range are not harmful, so even if the blood-brain barrier is not perfect, the minuscule amount of glutamate that goes through is irrelevant and simply take up by normal cellular metabolism. But now consider someone who eats monosodium glutamate in large amounts every day. MSG is proven to damage the optic nerve, which is not protected by the BBB at all. And there is evidence that glutamate in multi-gram doses might overwhelm the BBB barrier and penetrate the brain. Diets rich in MSG are implicated in a greater risk of dementia in old age. If the BBB can block 99.999% of all glutamate in the diet from entering the brain, that makes the small amounts of glutamate in things like Parmesan cheese and shitake perfectly safe. But blocking 99.999% of all glutamate from a multi-gram dose means that a lot more glutamate would enter the brain than from a normal diet. You would need to eat 50 kilograms of shitake mushrooms in the soasse of 30 minutes to ingest an amount of glutamate from a yakisoba drenched in MSG from some Asian restaurants. So the problem here is dose. Small amounts of potential neurotoxins from food are fine, but we never developed defenses against doses hundreds or even thousands of times greater than what you get from normal food.

So the issue is dosage. As the saying goes, dosage makes either the poison or the medicine. Now, consider that potent MAO-B inhibitors like selegiline and rasagiline might increase brains levels of PEA by up to a thousand fold. How is this not neurotoxic? And in the case of people eating PEA like candy, it is even worse because the normal metabolism of PEA by MAO-B generates massive amounts of free radicals. People taking MAO-B inhibitors only have to deal with the increased free radicals from MC-1 inhibtion, while people swallowing PEA by the buckets also have to deal with the free radicals that result from all that PEA getting broken up. They get a "double whammy" of free radicals.

"So, for example, dextroamphetamine likewise inhibits the mitochondrial complexes in the electron-transport chain, but it is widely regarded as being low-toxicity:"

Hmmm...but amphetamine is notorious for increasing oxidative stress.

https://www.sciencedirect.com/science/article/pii/S0163725803000524

 

[AlphaMethylPhenyl]

Just for the sake of info, oxidative stress has utility or lack thereof depending on where it occurs.

 

[atara]

Because taking a huge amount of PEA generates a much higher amount of ROS than what is normally produced by the small amount of PEA that we naturally produce.

You haven't demonstrated that.

Let me give you an example to illustrate the point. Consider vitamin B12. Usually, oral absorption is problematic because the absorption is carefully regulated by several intrinsec factors. This ensures that it is impossible to achieve Cobalt poisoning from B12 in foods. However, oral supplementation of B12 at mega doses of 1,000 mcg or more has been proven effective to reverse pernicious anemia completely. Why? Because at these gigantic, abnormal doses, the vitamin gets absorbed through the intestinal walls by diffusion. So despite the extremely poor oral bioavailability of B12 from foods, a dose of B12 hundreds or thousands of times greater than what you get from a normal diet reverses B12 deficiency because it simply overwhelms the body's ability to control absorption.

I'm not going to check this (I suspect it's carious) but you seem to have missed the implication that in the end, the patient does not get cobalt poisoning -- just as exogenous PEA does not in fact deliver thousands of times the normal levels of PEA to the cytoplasm.

Hmmm...but amphetamine is notorious for increasing oxidative stress.

Some, certainly, yes. But I'm merely arguing that PEA should not be considered significantly more neurotoxic than amphetamine, at least not based on these data. It would be very foolish for anyone to assume PEA would be dramatically less toxic than amphetamine, considering the strong similarity in structure and MoA.

 

[Bravoncius Roxford]

You haven't demonstrated that.

And you haven't proved otherwise...if you read what I wrote, I proved that PEA is a neurotoxin, and implied that increasing it by hundreds or thousands of times above normal physiological levels might be a bad idea. Nowhere do I state that I have "definitive" proof that this is the case.

I'm not going to check this (I suspect it's carious) but you seem to have missed the implication that in the end, the patient does not get cobalt poisoning

That is because the amount of B12 that gets absorbed by diffusion is only 1%. Remember, this is not a normal physiological absorption process of B12. So even if you take 1,000 mcg, no Cobalt pisoning will happen. But trust me, if you ingest, say, a gram of B12 you will get Cobalt poisoning.

just as exogenous PEA does not in fact deliver thousands of times the normal levels of PEA to the cytoplasm.

You keep repeating this...where are the sources?

Some, certainly, yes.

Actually, good ol' amphetamine, you know, C9H13N, markedly increases ROS in the brain.

But I'm merely arguing that PEA should not be considered significantly more neurotoxic than amphetamine, at least not based on these data. It would be very foolish for anyone to assume PEA would be dramatically less toxic than amphetamine,considering the strong similarity in structure and MoA.

Whoa there, buddy, calling me fool. PEA doesen't need to be "more" toxic than amphetamine to be problematic, since amphetamine is toxic enough. Even 5 mg of amphetamine can increase oxidative stress in the brain. So how is arguing that PEA is just as bad am amphetamine make PEA any less pro-oxidant?

 

[novaveritas]

Be warned here, PEA increases oxidative stress in the brain in two ways: first, the breakdown products of PEA are free radical hydroxyls and superoxide anions. Secondly, PEA itself increases oxidative stress by inhibiting mitochondrial complex-1. See here: https://www.google.com/url?sa=t&rct...med/23638910&usg=AOvVaw3Tn2jYKUzvBw3VuCbdSY_n This would indicate that even people taking MAO-B inhibitors are at risk. They might not be getting the free radicals from PEA breakdown, but they are still getting a massive increase in free radicals in the brain to to the greatly increased PEA that comes from MAO-B inhibition.

The link is to an in silico docking study, How about you find some real evidence of mitochondrial inhibition, in real cells at physiological concentrations rather than Indian computer modelling.

Three-dimensional structures of mitochondrial complexes and DT-diaphorase and their ligands were downloaded from the respective data banks, and free energy of binding (docking scores) were determined.

 

[atara]

You keep repeating this...where are the sources?

My "source" for this claim is the fact that the people who take PEA don't suddenly die.

...a 1000-fold increase [in brain phenethylamine concentration] was measured after MAOI [...] in agreement with results obtained with exogenous labeled PEA...

Yet MAO-B inhibitors are used in medicine. Explain.

That is because the amount of B12 that gets absorbed by diffusion is only 1%. Remember, this is not a normal physiological absorption process of B12. So even if you take 1,000 mcg, no Cobalt pisoning will happen. But trust me, if you ingest, say, a gram of B12 you will get Cobalt poisoning.

Are you arguing that, say, recreational PEA abuse delivers 200000 times the normal concentration of PEA to the brain? Because that is false.

Actually, good ol' amphetamine, you know, C9H13N, markedly increases ROS in the brain.

If you're conceding the point about amphetamine you've given up the whole argument. As to why amphetamine isn't terrifyingly neurotoxic, I refer you to the established literature on the medical use of amphetamines.

 

[Bravoncius Roxford]

My "source" for this claim is the fact that the people who take PEA don't suddenly die.

People that accidently ingested MPTP, which is a potent mitochondrial complex-1 inhibitor, don't die either. They just develop Parkinson's. Mitochondrial-1 complex inhibitors are not equally cytotoxic to all cells in the body. They are more potent at certain cells than others. And just to make it clear, I am not saying that PEA is just as toxic as MPTP. I am just giving an example.

Yet MAO-B inhibitors are used in medicine. Explain.

Cost-benefit. If you have severe Parkson's Disease, a little mitochondrial poisoning might not be a big deal as long as it is not so extreme as to make the cell stop functioning entirely. Likewise, HIV medications like protease inhibitors are extremely bad for the body and have terrible side effects. Yet, it is used in medicine because the alternative is worse: you die in 2-4 years from HIV infection if left untreated. Medical doctors don't give a shit about a drug fucking your body as long as the benefit it gives you is greater than the cost of leaving the problem untreated. Amiodarane can cause severe pulmonary fibrosis, and yet it is used in medicine because there is no better antiarrytmic. Talidomide is still used in medicine despite it causing fetus malformation and potential liver failure because it is damned effective. The use is restricted, just like rasagiline and selegiline is restricted, but it is allowed.

Are you arguing that, say, recreational PEA abuse delivers 200000 times the normal concentration of PEA to the brain? Because that is false.

Maybe not that much because most PEA is broken down by MAO-B in the gut. But it is certainly not healthy. The real danger might actually come from using potent MAO-B inhibitors. Rasagiline, for instance, can increase PEA in the brain up to 1,000 times! Things like catechin, which also is a MAO-B inhibitor is not of a concern because catechin is really weak and the oral bioavailability is so incredibly poor. You could take grams of the stuff and there wouldn't be a problem. But something like rasagiline is orally bioavailable and literally 10,000 X more potent than catechin, and that is where the real danger is.

If you're conceding the point about amphetamine you've given up the whole argument. As to why amphetamine isn't terrifyingly neurotoxic,

How am I conceding the whole argument? I don't use amphetamine exactly because I believe that is harmful to the brain.

I refer you to the established literature on the medical use of amphetamines.

Medical use doesen't mean anything. Doctors couldn't care less about a risk of oxidative stress in the brain from amphetamine. What they care about is treating ADHD or narcolepsy. Doctors couldn't care less about potential damage to the brain 10 years down the line from increased ROS in the brain. Also, "medical use", and pharmacological studies are two different things. Doctors won't stop using a drug because in vitro studies shows that the drug in question is pro-oxidant.

 

[Bravoncius Roxford]

The link is to an in silico docking study, How about you find some real evidence of mitochondrial inhibition, in real cells at physiological concentrations rather than Indian computer modelling.

But we are not talking about physiological concentrations here. We are talking about hundreds or thousands of times the normal physiological concentration from ingesting massive amounts of pure PEA or taking MAO-B inhibitors. How about you prove that massive amounts of PEA from huge ingested doses or from taking MAO-B inhibitors does not increase oxidative stress in the brain?

 

[AlphaMethylPhenyl]

In the absence of an MAOI, phenylethylamine breaks down too fast to be significantly psychoactive.

 

[Seppi]

Medical use doesen't mean anything. Doctors couldn't care less about a risk of oxidative stress in the brain from amphetamine. What they care about is treating ADHD or narcolepsy. Doctors couldn't care less about potential damage to the brain 10 years down the line from increased ROS in the brain. Also, "medical use", and pharmacological studies are two different things. Doctors won't stop using a drug because in vitro studies shows that the drug in question is pro-oxidant.

That's probably because doctors realize that oxidative stress is not pathological (i.e., a cause of any human disease); similarly, antioxidants don't prevent or treat any disease (as in, the antioxidative biological function of an arbitrary antioxidant; I would facepalm if someone argued something like vitamin C prevents/treats scurvy since that's due to its action as an enzyme cofactor).

 

[Bravoncius Roxford]

That's probably because doctors realize that oxidative stress is not pathological (i.e., a cause of any human disease);

Actually, increased oxidative stress is at the root of several degenerative diseases like asthma, arthritis and Parkinson's disease. Thee is a reason why are body produces antioxidant enzymes like catalase and superoxide dismutase: because reactive oxygen species are fucking harmful to all the cells of the body, especially to the mitochondria. Oxidative stress is also one of the three mains processes driving ageing, the other two being cellular senescence and glycation(cellular cross-linking)

similarly, antioxidants don't prevent or treat any disease"

That's because antioxidants from the diet, like vitamins C and E are not very bioavailable. Furthermore, vitamin E can actually be pro-oxidant in some situations or in excess. It is a very long way from your mouth to the cellular mitochondria where the oxidative damage happens. But this does not change the fact that our bodies produce antioxidants for defense, which indicates that ROS are harmful to cells, otherwise the body wouldn't bother. Superoxide dismutase is roughly 10,000 X more potent than vitamin C by molar concentration, and it is directly located at cellular membranes for increased efficiency. A large part of the benefit of caloric restriction in decreasing inflammation and tissue degeneration comes from increased SOD levels in cells. ​

I would facepalm if someone argued something like vitamin C prevents/treats scurvy since that's due to its action as an enzyme cofactor).

I am not sure what you are trying to argue here. Vitamin C deficiency is the cause of scurvy, and it is treated by vitamin C. Sailors used to get scurvy all the time, until they started to dress their fish with lemon juice and then they no longer get scurvy. Vitamin C is not a very effective antioxidant "in vivo" but it's deficiency is the cause of scurvy. I am sorry, but I really didn't understand your point here.

 

[Seppi]

Actually, increased oxidative stress is at the root of several degenerative diseases like asthma, arthritis and Parkinson's disease. Thee is a reason why are body produces antioxidant enzymes like catalase and superoxide dismutase: because reactive oxygen species are fucking harmful to all the cells of the body, especially to the mitochondria. Oxidative stress is also one of the three mains processes driving ageing, the other two being cellular senescence and glycation(cellular cross-linking)

That's because antioxidants from the diet, like vitamins C and E are not very bioavailable. Furthermore, vitamin E can actually be pro-oxidant in some situations or in excess. It is a very long way from your mouth to the cellular mitochondria where the oxidative damage happens. But this does not change the fact that our bodies produce antioxidants for defense, which indicates that ROS are harmful to cells, otherwise the body wouldn't bother. Superoxide dismutase is roughly 10,000 X more potent than vitamin C by molar concentration, and it is directly located at cellular membranes for increased efficiency. A large part of the benefit of caloric restriction in decreasing inflammation and tissue degeneration comes from increased SOD levels in cells. ​

I am not sure what you are trying to argue here. Vitamin C deficiency is the cause of scurvy, and it is treated by vitamin C. Sailors used to get scurvy all the time, until they started to dress their fish with lemon juice and then they no longer get scurvy. Vitamin C is not a very effective antioxidant "in vivo" but it's deficiency is the cause of scurvy. I am sorry, but I really didn't understand your point here.

Cite a reliable secondary medical source that actually backs up your assertion that antioxidants treat any disease. That's utter bullshit.

You completely missed my point re:your third paragraph because you don't understand the molecular biology of vitamin C in the human body. Look up a list of enzymes that it functions as a cofactor for, look at the functions of those enzymes, and compare that to the symptoms of scruvy and it should be abundantly clear that scurvy is not due to oxidative stress, but rather impaired collagen synthesis and immune function.

 

[Beenhead]

This is why you need to think critically about the problems associated with any in vitro experiment.

A lot, if not, most of these types of studies are in vitro.

 

[Bravoncius Roxford]

Cite a reliable secondary medical source that actually backs up your assertion that antioxidants treat any disease. That's utter bullshit.

You completely missed my point re:your third paragraph because you don't understand the molecular biology of vitamin C in the human body. Look up a list of enzymes that it functions as a cofactor for, look at the functions of those enzymes, and compare that to the symptoms of scruvy and it should be abundantly clear that scurvy is not due to oxidative stress, but rather impaired collagen synthesis and immune function.

I think you just be high. When have I ever stated that scurvy is caused by oxidative stress?

Cite a reliable secondary medical source that actually backs up your assertion that antioxidants treat any disease. That's utter bullshit.

.

You seem to have a love for straw mans. Where have I stated that antioxidants treat diseases? I went as far as saying that some antioxidant like vitamin E can be pro-oxidant in excess, or when combined with Iron.

Antioxidants do not directly fight diseases, but they do help to protect the body from diseases; otherwise, the body wouldn't bother making them. Why do we have catalase? Or superoxide dismutase? Elucidate this please.

 

[Dresden]

This title might as well be titled, "For Those Of You Eating Chocolate."

 

[negrogesic]

I know an individual who took obscene amounts of PEA (in concert with l-deprenyl) for years, and from what I gather can still tie her own shoes.

 

[sekio]

Why do we have catalase? Or superoxide dismutase? Elucidate this please.

because H₂O₂ is a side product of many oxidase enzymes that use O₂ as an oxidant...

antioxidants do not treat disease, otherwise you'd see people prescribing e.g. methylene blue for viral/bacterial infections

 

[Xorkoth]

In the absence of an MAOI, phenylethylamine breaks down too fast to be significantly psychoactive.

Although most of it is certainly broken down before an effect can be reached, if you take like 3 grams at once you certainly get high, without an MAOI. It only lasts like 20 minutes but it's a pretty strong rush that reminds me a little of a rush of amphetamine or MDMA. And then after the come-up it disappears.