Protecting the brain and body while on amphetamines

[MyDoorsAreOpen]

Good point. The kind of vasodilators I had in mind are gingko and vincopetine which are believed to produce their nootropic effects, in part by enhancing blood flow to the brain. I need to research this more.

Ah, I see what you're saying. I don't know a whole lot about their mechanisms of action, but I have heard this said about a lot of substances used as nootropics. If you read more about what precise hematological changes ginkgo and others cause, definitely let me know!

From what I read, its caused by the GABA_a antagonism induced by fluoroquinolones. All the reports of this I've heard, were with ciprofloxacin. I don't know whether its caused by glutamate excitotoxicity, or damage to the GABA neurons or what. BTW I meant to say taking a GABA_a direct agonist should help prevent this problem. Benzos on the other hand might make it worse, but I'm not sure. BZ agonists are positive allosteric modulators of the GABA_a receptor, so I wonder if that means they'd allow GABA_a antagonists to bind even more effectively to the GABA_a receptor.

GABA antagonism is seldom a good thing, because one of the major roles of GABAergic pathways is a safety valve for neurons firing too much and burning out. I've never given anyone flumazenil, and hope to never have to.

What you describe is not exactly what "allosteric binding" means. What it means is that the molecule has an affinity for a different spot on the receptor than the endogenous ligand our body produces to press that receptor, but sets off the same downstream cascade nonetheless. Believe it or not, benzos, barbituates, and ethanol all stick to different spots on the GABA receptor, and none of these are the same spot that GABA sticks to. So your answer your question, if a GABA antagonist's mode of action was to block GABA from binding to its receptor, then the presence of an allosteric ligand would have no bearing on the antagonist's binding affinity. However (and I suspect this is what you're driving at), so long as the shape and the way the antagonist adhered didn't block the benzodiazepine binding site also, then benzos would effectively protect against the damaging effects of unwanted GABA antagonism, so long serum levels were maintained until the antagonist was pretty much entirely out of the system.

I can't be bothered to look up the Ki of ciprofloxacin to the GABA-a receptor, but I can't imagine the binding affinity is very strong in most people, or this drug would never have made it to clinical trials, never mind to market. If there are some people who possess mutations in the genes for GABA-a receptors that allow them to bind cipro much more readily, it would be a worthwhile research project to identify these people. Their medical charts could be marked as people who should ideally never get this drug, or if they ever absolutely need it, must be given benzos concurrently. These little micro-differences in cell surface proteins are the future of medicine regimens tailored specifically to you.

 

[ebola?]

However (and I suspect this is what you're driving at), so long as the shape and the way the antagonist adhered didn't block the benzodiazepine binding site also, then benzos would effectively protect against the damaging effects of unwanted GABA antagonism, so long serum levels were maintained until the antagonist was pretty much entirely out of the system.

I'm not exactly sure whether this follows. Just looking at singular receptors, wouldn't effective direct GABAnergic antagonism preclude efficacy of positive allosteric modulation? I guess depending on relative affinities and concentrations, receptors with just one of the two ligands bound but not both could 'even out' in sum effect. . .

From what I read, its caused by the GABA_a antagonism induced by fluoroquinolones. All the reports of this I've heard, were with ciprofloxacin.

From what I've gathered, these compounds' mechanism of GABA antagonism isn't yet known, so it's unclear how they'd interact with GABAnergic positive allosteric modulators (but the site I use to pirate articles is malfunctioning today :/)
...
Thanks for the tidbit about the allosteric site for ethanol being distinct from those of benzos or barbs. From what I've gathered, ethanol's modulating action is more barb-like than benzo like, but this is just from secondary sources.

ebola

 

[tyrael]

What an amazing thread! Definitely a keeper!

A few small comments ill like to add; the consumption of CoQ10 does not have the desired effects (those results spouted by CAM proponents in assistance with metabolism [weight loss] and as an anti-oxidant [anti-aging]) often raved about. There is no pathway of absorption often through consumption, through the GI tract, hepatic portal system, through the phospholipid bilayer of all the cells, navigating through the cytosol, finding the mitochondria and sitting itself perfectly in the ETC. lol, doesn't happen.

Second to this, there is (typically in the CAM/advertising industry) way too much emphases on anti-oxidants! Not only are they a definite necessity for life ( as you'd know oxidative process(es) are used extensively throughout the body ) but again normal OTC products wouldn't supply sufficient quantities to cause an issue(effect) (that is unless one goes "anti-oxidant crazy" and does consume large quantities).

Edit: regarding alcohol, barbs and benzo binding sites - GABAa is (its general construct) an inotropic, pentameric complex constructed of 5 allosteric binding sub-units (2 α-, 2 β- and 1 γ- subunits [with sub-subunits again distinguished]), 2 GABA binding sites, 1 BZD site and a central ion pore (alternate GABA receptors are composed of any combination of α1–6, β1–3, γ1–3, δ, ε, θ, and π).

* GABA binds to the α-
* Benzodiazepines predominately bind to the BZD site (a combination of α- and γ-subunits)
* Barbiturates to the β-and γ-subunits
* Ethanol it seems potentiation is dependant on which combination of subunits are in the receptor. Although the δ-subunit seems to be common*

All of which are obviously positive allosteric modulators. (And of course this doesn't mention each of their owns additional MOA).


* An excerpt from a paper I was reading....

However, there are also many reports showing no effect of moderate or even large concentrations of ethanol in vivo and in vitro. Thus, a key question is whether there are specific GABA receptor subunits that are sensitive to low concentrations of ethanol in vivo and in vitro. Another possibility (for which there is also evidence — Weiner and Valenzuela, 2006) is that ethanol acts presynaptically to increase the release of GABA, and certain receptors (e.g., extrasynaptic) are particularly sensitive to this spillover of GABA resulting in enhanced GABAergic function.

-- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574824/

 

[tyrael]

.... So your answer your question, if a GABA antagonist's mode of action was to block GABA from binding to its receptor, then the presence of an allosteric ligand would have no bearing on the antagonist's binding affinity......

However what about, in the instance of a GABA antagonists as you described, could the allosteric ligand (if it's MOA work as this) not still cause the ion channel to open. Irrespective of any GABA binding. Still providing an open Ca^- channel?

I'm not exactly sure whether this follows. Just looking at singular receptors, wouldn't effective direct GABAnergic antagonism preclude efficacy of positive allosteric modulation?...

It would be dependant on specifically how the drug achieved it's antagonistic effect - a conformational change? physical occlusion?

We have Flumazenil's MOA - an antagonist for only benzodiazepines and Z-drugs due to the nature of its binding sites. The Flumazenil recognition site sits neatly between the GABA/benzo receptor and GABA/Z-drugs (Zolpidem, Zopiclone) receptor however no where near the site of action for barbiturates.

....Thanks for the tidbit about the allosteric site for ethanol being distinct from those of benzos or barbs. From what I've gathered, ethanol's modulating action is more barb-like than benzo like, but this is just from secondary sources....

All three act similarly, via binding to (and assuming causing a conformational changes to the receptor complex) GABA_A subunit binding sites (described above).

Check out this image of the GABA_A receptor, a transverse cut and subunit composition....

 

[FrogWarrior]

However what about, in the instance of a GABA antagonists as you described, could the allosteric ligand (if it's MOA work as this) not still cause the ion channel to open. Irrespective of any GABA binding. Still providing an open Ca^- channel?

It would be dependant on specifically how the drug achieved it's antagonistic effect - a conformational change? physical occlusion?

We have Flumazenil's MOA - an antagonist for only benzodiazepines and Z-drugs due to the nature of its binding sites. The Flumazenil recognition site sits neatly between the GABA/benzo receptor and GABA/Z-drugs (Zolpidem, Zopiclone) receptor however no where near the site of action for barbiturates.

In the case of BZ site modulators (as well as barbiturates I believe), I believe the positive modulation is achieved by changing the active site to a more active conformation. More active in the sense that GABA will have greater affinity for it. I don't know if that will mean that a competitive GABA_a antagonist will also have greater affinity for it too, I suppose that depends on the structure of the antagonist. That whole area where benzos, flumazenil and z-drugs bind is the BZ site. I don't know if they ever discovered an endogenous ligand for it. I'm guessing those lines (connecting GABA to the Cl- channel) mean that its only the active site that can directly open the chloride channel. Picrotoxin and bicuculne work by clogging up the Cl- channel, I wonder if there are compounds which do the opposite.

 

[mardybum]

Sorry if I'm bumping an old thread but that was a brilliant summary of some very helpful information to those using stimulant medications. Thanks so much for putting the time in and sharing this with us!

 

[PlayDoughBrain]

follow up

I echo mardybums thoughts here... I realize there is another forum for amphetamine protection but I just wanted to add that if you want to work downstream from potentially memory impairing glutamate receptors, calcium channel inhibitors (high dose) might be ideal. They prevent the release of NOS which starts the overexictitation feedback cycle which inevitably leads to the surfacing of more and more AMPA receptors which are the real culprit for tolerance and addiction/withdrawal.

As far as I understand when the synapse surfaces more and more AMPA receptors of all types it requires more and more excitation to feel the action potential.
I have also read that agonizing AMPA receptors eventually causes a downregulation to occur. The inverse is true as well, antagonizing them causes upregulation to occur. One unknown is the time period required for these adaptations. Obviously it can be quite time consuming as sufferers of Post Acute benzo/addictive drug withdrawal can attest to. Another unknown is whether or not after a cold turkey withdrawal the AMPA receptors are hit so hard that they are now in a downregulated steady state or an upregulated steady state. This applies to amphetamines as well.

I can verify Tianeptine, a known AMPA/NMDA modulator had a profound effect on me about 2 months post withdrawal, only reason I have been able to function as of late. However, whether or not it agonizes or antagonizes AMPA is cryptic and I haven't found a straightforward answer.

I was on Alprazolam 2mg a day (maybe more because of its interaction with fluvoxamine which I was also taking) in addition to methylphenidate. I was even continuing methylphenidate during the withdrawal because as uneducated as I was I thought the alprazolam was the only cause of the methylphenidate tolerance I got. (Side note, for me methylphenidate is the devil. Straight up addictive poison, the highway to hell. Right there with ssri's as the two most awful substances I have encountered)

Here is some literature:

This supports the theory that chronic benzo use is similar to amphetamine use in that it activates excessive calcium channel currents:
http://jpet.aspetjournals.org/content/327/3/872.full

This is a straight forward study that shows how a calcium channel inhibitor completely attenuates benzo withdrawal in an animal model:
http://www.ncbi.nlm.nih.gov/pubmed/8707372

AMPA agonist induced downregulation
http://www.ncbi.nlm.nih.gov/pubmed/15202775

Id be interested if anyone has experience with this or just thoughts in general. Im considering going the AMPA agonist route and either getting a script for modafinil or ordering some adrafinil and hoping it balances out in the end.

 

[DataMatrix]

Glutathione is the bodies main endogenous antioxidant which protects the inside of cells. Unfortunately it doesn't get absorbed very well so ingesting glutathione doesn't work.

You know you can take N-Acetylcysteine to boost glutathione levels because cysteine is a precursor to glutathione. Cysteine + glycine + glutamate = glutathione. They use it in paracetamol overdoses because it boosts glutathione levels to bind to toxic paracetamol metabolites. It also activates the cysteine-glutamate antiporter which will regulate extracellular glutamate levels, thus stimulating mGlu2 and preventing over-excitation.

You can also take methionine, betaine or citicoline. All are precursors to glutathione.
http://www.nature.com/nrc/journal/v2/n6/fig_tab/nrc819_F3.html
https://www.dovepress.com/cr_data/article_fulltext/s87000/87886/img/CIA-87886-F02.jpg
http://www.nature.com/nrc/journal/v11/n12/fig_tab/nrc3162_F2.html
https://en.wikipedia.org/wiki/Choline#/media/File:Choline_metabolism-en.svg

You should also take B12 and B6 with this, as these are requirements to process these amino acids. B9 wouldn't go amiss either.

These also boost membrane lipid production, such as phosphatidylcholine while spares it from being broken down for choline catabolism. These supplements also spare cardiolipin and sphingomyelin.

 

[FrogWarrior]

MODS: Can you delete this thread please. I'm going to host this as an article on my new site.

 

[aced126]

Keep it, it's quite informative. What's your site called?

 

[Seppi]

For the love of god... amphetamine is not a neurotoxin and there is no point in trying to "protect the heart" from its cardiovascular effects unless one has a structural heart defect. In healthy people, amphetamine use has no relationship with serious adverse cardiovascular events (e.g., stroke, sudden cardiac death, heart attack); in people with a structural heart defect, amphetamine could be lethal, which is why this subclass of heart disease is an absolute contraindication for the drug.