• N&PD Moderators: Skorpio | thegreenhand

Valproic Acid seems IDEAL for Amphetamine issues!

Built240

Bluelighter
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Jun 24, 2016
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So many of us are always trying to figure out ways to help with amphetamine sensitization, preventatives, tolerance,etc.. I wonder why valproic acid(VP) hasn?t been talked about more. I read a study about how vp is prescribed for tardive dyskinesia which led me to think it must have a positive affect on dopamine as tardive dyskinesia comes from lack of dopamine. Then I was reading some research on how the GABA system plays a huge role in amphetamines and it?s not just dopamine like most people think. Then newer research points to the inhibition of HDAC potentiating and regulating amphetamines.

Valproic Acid(Depakote) is GABAergic:

https://en.m.wikipedia.org/wiki/Valproate


Valproic Acid is an HDAC inhibitor:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC125788/

Which in turn regulates DeltafosB:
https://www.ncbi.nlm.nih.gov/pubmed/18848971/


Valproic Acid is an NMDA antagonist:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564799/

Valproic Acid upregulates Tyrosine Hydroxylase which gets depleted with long term amp use:
https://www.ncbi.nlm.nih.gov/pubmed/26512932/

https://www.ncbi.nlm.nih.gov/pubmed/10633488/

Valproic Acid reduces cortisol which is greatly elevated from amphetamines:
https://www.ncbi.nlm.nih.gov/pubmed/3129907/

Valproic Acid regulates dopamine and is an MOAI:
https://www.ncbi.nlm.nih.gov/pubmed/21200377/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3454414/

I believe Valproic Acid also can play a role in rho kinase and Calcium/calmodulin‐dependent protein kinase II (CaMKII) which I believe play a role in amphetamines but I haven?t had the time to research this yet.

Im curious of your thoughts on Valproic Acid being a novel drug to help with amphetamine sensitization,tolerance, withdrawal,etc..?
 
This could have to do with the (side) effects of Valproic acid. No matter how ideal not a single hair on my head would consider taking a medical dose of that garbage again. Btw I am not even close to being bold.

This was prescribed to me when dr's thought I had Bipolar, which I haven't just manic Ad(h)d-episodes that I learned from a dr further on that existed This medication created the most zombie like effect I ever encountered. And it creeps up. Feels nothing remotely Gaba-ergic, only the first day I thought it had something Gaba like which I contribute to wishfull thinking on my part.

Count up the hepatoxicity. Periodic Liver tests are necessary when on Depakote, something the proffessials eassiuly forget about but imo is a concern when taking Valproic acid. Especially when for non intended use. I would advise no but lets see what other have chime in.
 
This could be a thing, sure. I'm going to move it over to Neuroscience though as I wouldn't consider it a matter of emergent need and I feel that those folks will be able to answer your questions with more of an academic authority than I feel confident implying.
 
As this about Amphetamine essentially. When I was on Valproic acid I actually requested my dr. if he could reinstate Dexamphetamin. The brain fog of 1000mg with the absolute unwillingness to do anything that would normaly excite me. Please tell me its only a fraction of the ammount or a one time dose that does what you are aiming for.

And I learned the hard way, Wikipedia is wrong at times so you are taking a chance listing it as a source built240


Some of the antiseizure effcts could have to do with the GHB receptor. from 2002
https://www.ncbi.nlm.nih.gov/pubmed/12269861
 
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Valproic acid may raise the seizure threshold, but for off label uses, it is TOTAL PLACEBO GARBAGE, kind of like gabapentin but even more useless.
 
^^^And I shall acquiesce!

I don't know where you got some of this information, OP. Yes, it's GABAergic. It functions as a reuptake inhibitor and slows the activity of GABA-transaminase (which breaks down GABA). It may have other pro-GABAergic effects. It's a mood-stabliizer, known for being more useful in mania than in depression. It's also used for epilepsy.

Lots of medications are GABAergic.

So insofar a HDAC inhibitor, from a quick look, it seems that it serves to decrease the aggregate genetic proclivity for sympathomimetic nature. In other words, it alters the DNA of a neuron to reduce how much stimulation it could cause. Maybe in addition it cleanly kills neurons that produce sympathomimetic neurotransmitters, or reduces the strength of neuronal communications between neurons that release excitatory nt's, which could lead to cell death secondarily (as lack of activity leads to a less-strong relation, or even cell death). Otherwise, it may be effective against malignant tumors...yay.

From what I know, deltafosb, guessing that it's a transcription factor, could be good if activity reduces depending on the larger climate of one's CNS. It's not good entirely in itself. I can't say more on this.

So it's the acute NMDA-antagonism that leads to the euphoria and dissociative effects. They reduce depression in acute doses, but ketamine does so for longer (as it has some additive function, likely an AMPA agonist as a metabolite). But we're looking at chronic NMDA-antagonism here. As we understand that glutamate is the most prominent excitatory nt in the CNS, it would follow that valproate (and such) would reduce such activity. So it would make sense to decrease the depolarization by blocking EPSPs so that action potential of glutamatergic neurons is reached less often/frequently so that these type of neurons wouldn't work as much. However you could find the same thing with any GABAergic, essentially. This isn't that special. It's fairly obvious.

Interesting about the TH. That said, there are other agents that must be present to convert it into tyramine and dopamine, even if it's just something like ATP (energy). Rather it would be an enzyme to convert. One could imagine that this enzyme gets depleted over time though, even to pre-treatment levels, which more goes with valproate as an anti-manic agent.

Again, GABAergics, barring some paradoxical effects, reduce excitatory nt's and hormones, of which cortisol is one. It must lower the HPA Axis activity. No surprise there. And no surprise that amp, the gold standard of stimulants, increases cortisol. But with that might come a lowering of the therapuetic effects of both.

As an MAOI, you do see that it works in this manner to the smallest extent of the 10-20 medications considered in the study.

I couldn't really speak to the last study.

I mean, in honesty, mood stabilizers help people look normal on the outside, but antipsychotics are more about also calming oneself down inside, as well.

Please anyone correct my newbness
 
^^^And I shall acquiesce!

I don't know where you got some of this information, OP. Yes, it's GABAergic. It functions as a reuptake inhibitor and slows the activity of GABA-transaminase (which breaks down GABA). It may have other pro-GABAergic effects. It's a mood-stabliizer, known for being more useful in mania than in depression. It's also used for epilepsy.

............

I was on 1500mg Valproic acid for over 8 years for epilepsy. This dosage is about 40% higher than a standard dose for my weight as my liver apparently superduper and does not finds this med hard enough to warrant an increase in enzymes.
It will limit your emotional range, meaning highs will be not so high and lows not so low, this effect slowly creeps in and it caused a part of my personality to lag behind, as I realized it was very hard to control my emotions after quitting this.
Taking it for extended periods of time requires you to taper off or run the risk of seizures.
If it works for upregulating TH in Amphetamine (ab)users, great, but I would not call this ideal by any means.
 
Not going to comment on using VPA in cases where an individual is not addicted to amphetamine or meth, but in cases where a person is, class I HDAC inhibitors like VPA should never be used on the same day that either of those drugs is taken.

The effects of HDACis in addicted individuals varies by context, location, and timing relative to the use of the addictive drug. Depending on those factors, the acute effects of using an HDACi can exacerbate symptoms or alleviate them. Wikipedia's addiction article mentions/references these facts; I don't remember which section I added that in though.
 

Newbness, yeah right. I will try to reread tomorroiw, probably way beyond, at least atm.

Took that VPA for a while and thought it was not so good for the mind. That DNA alteration doesn't sound right either btw. For Cortisol and NMDA there are certainly better option's.

OP opt's it for Amphetamin. I have taken it daily for a while therapeutically and would advise against it at those dosages. It would fight the purpose Built240.
 
What exactly is the problem with HDAC inhibition, I've read that it is something deeply coupled with learning / memory formation and that VPA is able to re-open critical period window for things like perfect pitch. Could it hard-code tolerance, so to speak?

A bit off-topic but might this mechanism help with overcoming (social) anxiety resulting from childhood trauma?

I tried to get on VPA some months ago but had to quit the attempt after about a week because it made me very sick, nauseous without end, diarrhea, dysphoria, feelings of 'coldness' is what I remember and it was just 150-0-150mg XR when the doc wanted to start with double that dose. Might have been an interaction with the morphine XR I had, but if it was a direct interaction causing the symproms from morphine withdrawal or the VPA inducing diarrhea, washing the morphine out before it'd get absorbed, who knows.

Hoped for its emotionally stabilising / limiting effects ...
 
I was prescribed it alongside Quetiapine. I'm guessing the shrink thought I was manic/bipolar but I was just wired on stims at the time...can't say I noticed any effect from it compared to the Quetiapine which would knock me out completely.
 
What exactly is the problem with HDAC inhibition, I've read that it is something deeply coupled with learning / memory formation and that VPA is able to re-open critical period window for things like perfect pitch. Could it hard-code tolerance, so to speak?

A bit off-topic but might this mechanism help with overcoming (social) anxiety resulting from childhood trauma?

I tried to get on VPA some months ago but had to quit the attempt after about a week because it made me very sick, nauseous without end, diarrhea, dysphoria, feelings of 'coldness' is what I remember and it was just 150-0-150mg XR when the doc wanted to start with double that dose. Might have been an interaction with the morphine XR I had, but if it was a direct interaction causing the symproms from morphine withdrawal or the VPA inducing diarrhea, washing the morphine out before it'd get absorbed, who knows.

Hoped for its emotionally stabilising / limiting effects ...

Re - the bolded text: I'm going to frame my response within that context.
HDAC inhibition does indeed modulate learning/memory; operant and classical conditioning are forms of "associative learning", and HDAC inhibition impinges upon this. In other words, it also upregulates these during the drug's duration of action.
Addiction is a brain disease that can be conceptualized as a disorder of learning/memory pathways in the brain.

That said, it should now be readily apparent why taking high doses of an addictive drug and an HDAC inhibitor at the same time is a very bad idea; there's ample literature on the behavioral effects induced by those interactions in lab animals if you care to read about it.
 
Valproic acid may raise the seizure threshold, but for off label uses, it is TOTAL PLACEBO GARBAGE, kind of like gabapentin but even more useless.

I noticed unambiguous psychoactive effects when I used it off-label.
In relation to this thread's subject, 1000mg inhibited the psychostimulant effect of 60 mg Adderall and induced noticeable but not marked somnolence.
 
So GABA is a cyclic derivative of glutamate. They are tightly related in this respect.

So many people getting 60 mg Adderall..yikes.

Depending. If one is on adderall and then adds valproic acid, it will seem that the latter engulfs the effects of the former until one is used to the medication. Same vice-versa.

I couldn't tolerate depakote. AP's I can, depending on the one. But depakote is heavily relied upon for bipolar symptoms. It's supposed to be more effective for mania. Again, it increases GABA concentrations by GABA transaminase inhibition, reuptake inhibition, and more.

In order to truly temper the effects of adderall, usually an ap is required. That would create a more equal ratio of D1:D2 activity. Depakote acts mostly to reduce glutamatergic activity. It doesn't antagonize D2 as is needed (save Clozaril) for antipsychotic effects.

Seroquel is an ap, but is much more suited for bipolar than for psychotic effects because it's mainly a sedative (via various) and a 5-HT2a antagonist, which increases preforntal dopaminergic activity in the cortical region to temper mania of D2 activation in the nucleus accumbens...looking at its activity via wikipedia and it's dirty af--as is its metabolite, which is about two times as potent a 5-HT2a antagonist.

Also, didn't know this before, but its NQTP is a potent NRI! Glutamate tempered by increased NE. 5-HT1a partial, as are many ap's, adding to anxiolytic effects.

5-HT2b antagonism via its metabolite is very strong, the strongest effect apparently, does anyone know what phenomeal/neurological effect this particular mechanism has?

5-HT7 antagonist: increased concentration.

Is that adrenergic autoreceptor agonism or post-synaptic?

Muscarinic antagonism is overall quite strong, too. Time for beddy bye. Interesting chemical we have here!
 
One is metabolized into another. That's what I meant. I think I just said it in a more advanced manner.
 
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