Sigh. I didn't want to respond earlier since explaining this is a like writing an essay and hence a pain in the ass, but whatever. Might as well do it now. Also, fair warning, I didn't bother to proofread this reply for butchered sentence fragments or typos before posting it.
Re:
Carnitine isn't an antioxidant. It's a compound which binds to fatty acids (e.g., "isovaleryl-carnitine", "hydroxyisovaleryl-carnitine", "pickYourFavoriteFattyAcid
yl-carnitine") and facilitates their transport into and out of mitochondria via carnitine-specific transporters. The reason carnitine in animal models
might mitigate methamphetamine-induced neurotoxicity is likely just due to the fact that amphetamine and methamphetamine
weakly competitively inhibit the human carnitine transporter
SLC22A5 and therefore impair carnitine transport at high doses (I have no clue whether or not these compounds inhibit SLC22A5 in rodents). Increasing the prevalence of carnitine in cells would therefore strongly mitigate the relatively weak competitive inhibitory effect of these drugs on carnitine-bound fatty acid transport via those transporters, in turn preventing toxicity arising from the buildup of oxidized fatty acids in mitochondria.
Re:
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.
The redox system in animals simply serves to manage oxidation reactions that occur via oxidative phosphorylation (OXPHOS) in mitochochondria. Oxidative reactions are not pathogenic. The reason I say oxidative stress is not pathogenic is that many physiological activities induce oxidative stress. Case in point, the most health-promoting activity of which I know, aerobic exercise, induces a
massive amount of OXPHOS activitiy for very obvious reasons, in turn causing
oxidative stress. This is entirely
physiological, not
pathological, and therefore this contradicts the notion that oxidative stress is inherently pathological. Moreover, I've read several studies about oxidative stress having a beneficial and/or an adaptive effect on cells on the organism as a whole, thereby facilitating environmental fitness. That said, when cellular systems are highly dysregulated, cells die: very high levels of oxidative stress can cause apoptosis and in the case of poisoning by ionizing radiation, necrosis can even occur.
This is not the case with phenethylamine, amphetamine, or methamphetamine as these substances do not cause neuronal apoptosis (solely) via dysregulated redox systems at excessively high doses
(for context, read this review, which is one of the most comprehensive and damning reviews on methamphetamine neurotoxicity that I've read; it suggests that oxidative stress might be involved, not is involved, in methamphetamine-induced neuronal apoptosis). I can't even remember how many review articles I've read about neurotoxicity associated with these substances in non-human animals (specifically, amphetamine and methamphetamine) and in humans (specifically, methamphetamine; I have yet to find any articles that identified markers of amphetamine neurotoxicity in humans either
in vivo or post-mortem); however, you can read a summary of the reviews I've read on amphetamine
here and on methamphetamine
here (as shown here, here, and here, I wrote the vast majority of these Wikipedia articles and uploaded the diagram on methamphetamine-induced neurotoxicity, so I'm not talking out of my ass). What is likely the most important factor that mediates neurotoxicity from markedly overdosing on either of these drugs is
cerebral hyperpyrexia, which impairs a multitude of biological processes in cells through diverse mechanisms (e.g., it alters enzyme kinetics, impairs the redox system, and increases the permeability of various biofluid-brain barriers, among other things). The notion that oxidative stress alone is responsible for phenethylamine/amphetamine/methamphetamine-induced neurotoxicity is sophomoric, as it completely ignores the fact that biological systems, and the redox system in particular, are adaptive and dynamic (re: the paragraph immediately above).
Re the part I've bolded below:
And BTW, just because something does not treat diseases it does not mean that it does not prevent diseases. For instance, a low sugar diet does not cure diabetes, but it can prevent you from becoming diabetic in the first place. Eating lots of produce and fruits does not treat cancer, but it might stop you from developing câncer in the first place.(especially intestinal câncer). While the phytohemicals in plants have extremely poor bioavailability, the metabolism generates uric acid which does have antioxidante properties on many cells. The lower rate of cancer among vegetarians that eat lots of produce indicates that antioxidants might be valuable in preventing diseases.
That fact does not demonstrate that antioxidants are prophylactic (i.e., "prevent disease"). I've never come across a study that has shown that the free radical scavenging property of any antioxidant is prophylactic; keep in mind that any study demonstrating such an effect would necessarily have to be
in vivo (i.e., a clinical trial).
Lastly, and I really can't emphasize this point enough: since phenethylamine, amphetamine, and methamphetamine bind to different "off-target" receptors in humans vs non-human animals (e.g., postsynaptic DA, 5-HT, NE, and intracellular sigma receptors to name a few), the "on-target" receptor (TAAR1) that they bind to in both humans and non-human animals is not highly homologous, and the metabolism of these drugs (including what metabolites are produced) varies extremely widely across species, one should take animal studies involving phenethylamine, amphetamine, and methamphetamine with a
full pound -
not a grain -
of salt.
Animal studies involving amphetamine in particular generally do not translate well to humans; the most notable example of this lack of animal research translation is covered in the first paragraph of
this section.
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Also, I'm going off on a tangent here, but the reason the redox system is adaptive and dynamic is that the expression of all virtually human redox proteins is controlled by a master regulator (i.e., a transcription factor that regulates all components of a cellular system or process) known as
Nrf2. It's sometimes called the "master regulator of oxidative stress" because it regulates the expression of over 1000 genes in mice and all human genes that encode redox system proteins - i.e., enzymes like SOD, catalase, GST, thioredoxin, sulfiredoxin, and countless other oxidoreductases, among other proteins. That transcription factor is an oxidant sensor which is highly responsive to oxidative stress; i.e., oxidative stress activates Nrf2, which then upregulates the expression of redox system proteins and downregulates ROS production by modulating the expression of proteins that mediate OXPHOS, thereby adapting the cell to heightened oxidative conditions and ameliorating oxidative damage.
For reference, see
this entire textbook on Nrf2 and/or
this comparatively shorter review article on its role in oxidative stress.
maybe later..
