• N&PD Moderators: Skorpio | thegreenhand

Basic guide to amphetamines in neurology

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https://books.google.ca/books?id=VNAQCyiDgb0C&pg=PT14&lpg=PT14&dq=does+the+chemical+structure+of+dexedrine+have+a+Benzene+ring&source=bl&ots=RgOrvNFn0M&sig=ACfU3U1n53EzdBTirticYL7UGwA7JkY7vw&hl=en&sa=X&ved=2ahUKEwjGpauvo5fmAhXWo54KHWreC5QQ6AEwDHoECAoQAQ#v=onepage&q



I read up to the last available page and found it quite enlightening. As for my own previous experiences with amphetamines and related molecules, this all rings very true and also sheds a good deal of light on some of the theory behind what is going on in the brain when under the influence of various nootropic drugs. It would be interesting to see similar literature on dopaminergic drugs that are not phenethlamines or amphetamines.

Having tried 9-methyl-β-carboline and Bromantane (simultaneously among others), the bell shaped curve relating to productivity enhancement really helped me connect some concepts, as simultaneously administering these two gradually produced such a strong dopamine accumulation (and presumably norepinephrine) that I did in fact have a hard time concentrating during days 7 to 10 of the experiment, pointing to over production and or accumulation of these related amines, which would be very intense for a number of hours, and fall to a manageable level where I could function at a good level at about the 4th hour after administration.

The thread for that experience is called;
"9-methyl-β-carboline + others" if anyone is interested in the endless anecdotes I seemed compelled to share during the experience. It's a long read. It was interesting to also note that my blood pressure was very steady and in a healthy range during the whole experiment. And I have a history of struggling to get the parameters in the 120 / 80 range. My average during the experiment was 125 over 75 RHR of 50.

Also, it is interesting to note that the subtypes of dopamine receptors seem to have a significant role in how the stimulus is perceived and thus effects the user, as does genetic factors.

This mass flood of dopamine could point to some of the marked effects of exess acute Flakka administration, causing the repeat, pointless movements that are characteristic of heavy users of the drug, and also people who use high doses of amphetamines. Flakka possibly having an even greater affinity for certain receptors in the brain, and this affinity facilitating the severe physiological and psychological effects of a dose that is way above ideal.

This is a very interesting topic for anyone who is interested in performance enhancement, treatment of depression, experiencing accidental damage of their own brain due to overuse and misuse of dopaminergic and sypmathomimetic substances.

Anyone with relevant scholastic or anecdotal imput, is encouraged to post links in this thread and share ideas, thoughts and experiences.

For science.

Just as a side note, I had been prescribed D-amph for many years and very much perfer nootropics for the subjective reduction in heartrate and blood pressure deviation that I commonly experienced with amphetamines. I still use them on occasion at a dose of 10 mg, but still find the effect of say, 135 mg phenylpiracetam and 2 cups of coffee, much more productive and less forceful than D-amph.

Other nootropic experiences are being done on myself, and I will update my findings as they occur in follow up threads.
 
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Another good article on the effects of amphetamine in the CNS and peripheral NS
 

Another good article on the effects of amphetamine in the CNS and peripheral NS
I don’t tend to read reviews on this topic that don’t contain “TAAR1” in the article, like this one, because they’re rather low-quality. E.g., the diagram in that paper is simply incorrect.

This is the 2nd 2019 review I’ve come across which describes amphetamine’s pharmacology incorrectly.
 
Well if you would, please enlighten us and attach a relavent article so we may be educated
 
Thank you for this!

I am facing treatment with stimulants for narcolepsy and I am researching them so I understand and am educated.
I need to make educated and informed decisions.
I don’t want to end up getting myself into a worse situation!

Really appreciate this information.
If anyone has anything else to add, that would really help me out.
Nothing beats experience. I need all the advise I can get!

Thanks again!
 
Missed this thread.
Seppi does like his wikipedia contribution, as you can see by his nice figures in the article, among other things. References in wiki can be decent starting points.

Various links for articles:

Newer Mol Psych article - references contained can be good points for further evaluation.

Interesting cycle view to consider

One of the reviews I'm guessing not covered. Interesting viewpoint on monoamine receptor selectivity with agents.

Decent reviews, doesn't mention TAAR
" with methylphenidate

TAAR 2011 review mentioning amp.

Newer TAAr


A middling neurotoxicity ref

JAMA psych paper review of DA alterations with stimulant use.


Nature DAT structural paper with agents

Cochrane review adult adhd - decent clinical perspective review

Random nicotinergic paper from amp
 
This is the first review article I think I've seen on the effect of zinc ions on amphetamine-induced dopamine reuptake and dopamine efflux; it's been covered in the Wikipedia article for years, but I think I might cite this review instead of the primary sources that the article currently cites. Thanks for linking that.
 
Hmm. I take 100mg daily (NB: I've taken doses as high as 1 gram/day when I've been sick due to the immediate immunomodulatory effects of plasma zinc on cytokine expression and antiviral effect against the human rhinovirus), which has a noticeable psychoactive effect when taken concurrently with amphetamine but not when I take it alone. Not sure what it will do when taken with methylphenidate, but it presumably could potentiate methylpheniate's effect on hDAT-mediated reuptake inhibition.

If you regularly take doses higher than 50 mg/day (NB: doses this high may induce nausea), I'd suggest taking a copper supplement somewhat regularly since zinc competitively inhibits copper uptake in the gastrointestinal tract and clinical studies have shown that copper deficiency can occur with long-term zinc supplementation.
 
Yeah, I've seen some low grade clinical studies for zinc augmentation of methylphenidate, but I'm curious to see what occasional supplementation may do, especially when food intake may be limited. Also use it occ for colds. Definitely the balance with copper. I have family with malabsorption and gastric bypasses who have to watch out. No Wilson's disease.
 
Within the past couple hours, I learned from IUPHAR that amphetamine exhibits high nanomolar activating effects at 2 human carbonic anhydrase (CA) enzyme isoforms (it cited a 2019 paper: https://sci-hub.tw/10.1016/j.bioorg.2019.03.062); after searching for other literature, I came across https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009978/ from December 2017 which indicates that amphetamine is a low nanomolar through low micromolar (i.e., a potent) activator of 7 out of the 11 CA isoforms it assessed: hCA4 (extracellular/membrane-associated), hCA5A and hCA5B (both mitochondrial), hCA7 (cytosolic), hCA12 (transmembrane), hCA13 (cytosolic), and hCA14 (transmembrane). Its most potent activation effect is 94 nanomolar at hCA4; its weakest activation effect (below the 150 micromolar detection threshold) is 24.1 micromolar at hCA13. Some of these are highly expressed in the human brain (e.g., hCA7) or BBB endothelium (e.g., hCA4).
Per this paper:
The paper (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009978/) said:
Here, we report the first such study, showing that amphetamine, methamphetamine, phentermine, mephentermine, and chlorphenteramine, potently activate several CA isoforms, some of which are highly abundant in the brain, where they play important functions connected to cognition and memory, among others26,27. ...

Amines 59 are strong central nervous system (CNS) stimulants and were originally used as drugs, for the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, obesity, nasal congestion, and depression35–37. They interfere with the catecholamine neurotransmitters norepinephrine and dopamine metabolism, by the activation of a trace amine receptor31, which leads to an increase of monoamine and excitatory neurotransmitter activity in the brain, leading to emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, accompanied by improved cognitive control38–40. [Hey, they actually mentioned TAAR1 in this paper! Although, it's probably because they literally copy/pasted the italicized+underlined parts of this sentence from the introduction of this article revision and superficially revised them by adding the intervening clauses. It amuses me when I read my writing in academic papers, lol.]

With so many CA isoforms in the CNS it is rather difficult to ascertain their precise physiological role, but some indirect information may be drawn from the fact that positively-charged, membrane-impermeant CAAs (or CAIs) do not show central nervous system effects when administered intra-peritoneally, which may be explained by the fact that intracellular (cytosolic or mitochondrial) CA isoforms are involved in the activation/inhibition phenomena. As mentioned briefly above, CA activation in the brain leads to enhanced memory, through the activated extracellular signal-regulated kinase (ERK) pathway, which is involved in a critical step for memory formation in the cortex and the hippocampus, two brain areas known to play a crucial role in memory processing, as recently demonstrated by one of our groups27.
Methamphetamine is also a carbonic anhydrase activator per this paper.

This is actually a pretty big deal, since it's likely that carbonic anhydrase activation mediates some of the psychoactive and possibly neurotoxic effects of substituted amphetamines and might impinge upon their mechanism of action in monoamine neurons. I only wish this paper examined interactions with the non-catalytic hCA8, hCA10, and hCA11 proteins as well because all 3 are functional proteins despite lacking carbonic anhydrase catalytic activity and are highly expressed in the brain.
 
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Also, as far as I can tell, those are the only 2 papers that have examined carbonic anhydrase activation by amphetamine, so I'm not surprised I didn't notice it earlier.
 
Thank you for your contribution Seppi and Checktest! This is a wealth of detail that will take me a good few days to go through, but understanding the pharmacology of these drugs will help in connecting concepts when considering pathways and anatomy during the considerations of other related compounds.

It's a shame we don't have as much information on some of the nootropic compounds floating around out there that we love to tinker with.

I do love this community for it's educational potential. The more each person knows about the complex ballet of chemistry that occurs within one's self, the better we can all make educated and sound decisions about what, when, how and why we might expose our systems to chemical adulterants. Or purely for the love of knowing. Some doctors ought to make bluelight accounts to better understand what they may be prescribing to their patients. It is incredible how behind the average family doctor is on endocrine function, nutrition and pharmacology.
 
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This is the first review article I think I've seen on the effect of zinc ions on amphetamine-induced dopamine reuptake and dopamine efflux; it's been covered in the Wikipedia article for years, but I think I might cite this review instead of the primary sources that the article currently cites. Thanks for linking that.

NP. I've been meaning to try some low zinc again with my methylphenidate.

I ended up citing that paper. https://en.wikipedia.org/w/index.php?title=Amphetamine&type=revision&diff=933639026&oldid=933469993
 
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