• N&PD Moderators: Skorpio | thegreenhand

Calcium channel blockers for reduction of tolerance to Amphetamines & addiction

Not surprising, from what I understand amphetamine, in low doses, can increase DAT expression, so by your next dose you have a greater number of transporters running in reverse than before. But high doses, or chronic doses, have the opposite effect on DAT so it doesn't really mean much to people trying to get high or use it therapeutically. Not to mention receptor regulation could create a scenario where higher levels of dopamine would still have less of an effect.

I doubt that DAT expression has anything to do amphetamines action to be honest.

Dopamine synthesis isn't controlled by the same cells that act as "vesicles". You would have to actually increase Dopamine synthesis for all synaptic vesicles of Dopamine to "fill up" so to speak. In fact, I think increased DAT expression would actually decrease the effects of Amphetamine due to the fact that more presynaptic TAAR1 receptors have to be stimulated in order for the transporters to be reversed. That means there would insufficient levels of amphetamine to fill all synaptic vesicles of Dopamine. Plus, if the synaptic vesicles are already filled with Dopamine - less amphetamine is able to enter the cell because DAT won't be transporter any Dopamine in. Since amphetamine gains access to VMAT2 through reuptake - this would make it less likely that a lot of amphetamine could get inside the cell and phosphorylate DAT through TAAR1 agonism. Although, amphetamine diffuses directly through the membrane of synaptic vesicles (again VMAT2) which I believe pushes Dopamine out.
 
I doubt that DAT expression has anything to do amphetamines action to be honest.

What? Why?


Dopamine synthesis isn't controlled by the same cells that act as "vesicles".

No, dopamine is synthesized in those same cells that produce vesicles containing dopamine and with transporters governing its intrasynaptic concentration (though VMAT2 is probably more important than DAT in many cases). Also, it doesn't make sense to say a cell acts as a "vesicle".

I think increased DAT expression would actually decrease the effects of Amphetamine due to the fact that more presynaptic TAAR1 receptors have to be stimulated in order for the transporters to be reversed.

Activity at TAAR1 is downstream and responsible for a minority of amphetamines' effects on dopamine.

Plus, if the synaptic vesicles are already filled with Dopamine - less amphetamine is able to enter the cell because DAT won't be transporter any Dopamine in.

I actually don't really understand what you're claiming here...can you clarify (mainly ". . .DAT won't be transporter any Dopamine in")? Intracellular synthesis of dopamine and the vesicles that contain it is ongoing, and you don't see conditions where competitive agonism between DA and DA releasers at DAT or VMAT2 inhibits the transporter reversal underlying the activity of DA releasers.

Since amphetamine gains access to VMAT2 through reuptake

While diffusion into the cell is important for the activity of amps, amp acts as a ligand at VMAT2 and DAT, without competing with vesicles for binding.

Although, amphetamine diffuses directly through the membrane of synaptic vesicles (again VMAT2) which I believe pushes Dopamine out.

I strongly suggest looking at the online pharmacology-primer 'textbook' sticky-threaded in here, as some basics are key to understand all this. Namely, the differences between typical receptors triggered by ligands, transporters, vesicles, and intercellular and intracellular activity are all key to understanding the mechanics of what's going on.

ebola
 

Don't worry Ebola, I know what I'm talking about (most of the time).

Unfortunately, I pretty bad explaining my thoughts through either text or speech (common symptom of thought disorder, eh?) I do know, for the most part, what I was talking about but I don't believe I could make myself look any better by explaining it correctly.

Anyways, it was a moot point - just me wanting to be oppositional. I understand how these system works (at least, the ones I've read about) and I'm not just making blanket statements. I tend to write up entire paragraphs about nothing when I plug a larger dose of amps.
 
Whoever looks like they know what they're talking about doesn't matter; the point is to try to explore new ideas and empirical findings, so an explanation is valuable, irrespective of it making someone look good or bad.

ebola
 
In some people's view, you don't truly understand a concept until you can explain or teach it to another. It certainly goes a long way towards being 'intellectually consistent'.
 
In some people's view, you don't truly understand a concept until you can explain or teach it to another. It certainly goes a long way towards being 'intellectually consistent'.

If you want me to explain what I meant - I can. However......ya know what. I'll just say it simply and easily, that's what my problem is...

If there are less synaptic vesicles of Dopamine, it stand to reason that there is going to be more Dopamine occupying those vesicles. If the cell is filled Dopamine - less amphetamine can diffuse into the cell and push dopamine out. If there are more vesicles, that same amount of Dopamine exists - but it's located in more vesicles. If there's more vesicles, that means there has to be more amphetamine present to agonize TAAR1 in order to effectively reverse transporters and output more dopamine and stop reuptake more effectively.

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After writing that down, I can see where the inconsistencies in that theory are. Mainly - as more amphetamine pushes dopamine out, this will systematically make room for more amphetamine inside the cell. Which more amphetamine can then diffuse into the cell (or enter it via DAT) and push even more dopamine out while effectively stopping reuptake at that cell.
 
If the cell is filled Dopamine - less amphetamine can diffuse into the cell and push dopamine out.

Not necessarily. Dopamine vesicles aren't going to crowd the cytosol that much, and amphetamine is very lipophilic, it goes right through cell membranes. You're thinking along the right track though, maybe it's desensitization of VMAT2 that helps - not necessarily more vesicles, but fewer VMAT2 receptors for every one. For instance, reserpine is apparently an effective antidepressant in low doses, and it blocks VMAT2 entirely.
 
Verapamil is an L type calcium channel blocker and since such channels are highly concentrated in the CNS it would likely affect tolerance given that Calcium influx into Neurones plays a key role in its development, but more importantly long-term tolerance maintenance. The thing I love about Verapamil and similar drugs is that they don’t have psychoactive affects of their own, so shouldn’t interfere with the drug experience apart from the physical impacts and tolerance. On a related note, I have read that verapamil can significantly extend the duration of Thiopental induced sleep in Rats and Mice, but verapamil alone had no sedative affect. Do you agree with this or do you have a different perspective. My opinion is just based on research, but since you have first hand experience your contribution is more valied.
Also, I have long wanted to try opioids but am far to scared at the moment due to my addictive personality, but your anecdote has given me some hope so thanks for sharing it. Not saying you encouraged me to take drugs, but gave me an extra bit of harm reduction information for the future.
 
Maybe there is something to this. I didn't have a long run with coke...mostly because my guy seemed like he had too many customers and was getting drunk way too much after work, where he would take orders, it was delivery service...back in 2008, usually the best stuff is delivery and the kind of structured delivery too, where you had certain hours where you could call. Anyway, the guy had the purest rock when crushed was fishscale quality, it was amazing, and not too expensive either. I had been having issues of tachycardia even before I got into the solitary habit of turning it to freebase and smoking it with baking soda or ammonia. Freebase is so amazing but I think that, although I wasted about the price of a good 4 wheel drive subaru sedan in 8 months on calling everyday and thankfully I had lived very close to him in the first place.

I think my prescription of Verapamil for quasi-high blood pressure and reduction of tachycardia and also an admission to an ER doc that I wasn't able to enjoy weed anymore and 3/4 of the time it just ended up giving me chest pain and tachycardia although I was mentally addicted so he told me, well worrying for nothing isn't good for your heart either and gave me a year's worth of verapamil, which is a calcium channel blocker. It made it so I never practically had tachycardia, even after smoking a gram a night of freebase i'd make myself off that really high quality to start with cocaine hcl, I never felt like I was gonna have a heart attack like so many people from doing this, I could smoke 3.5g in 2 days and just get the extreme euphoria, although lasting 5 minutes...it made time dilate and if I was feeling like looking for pieces of my dried freebase cook that might have fallen on the floor (which happened maybe twice in that 8 month stretch), I had a whole lot of 4mg risperdal that someone gave me and I took them in case I had some kind of psychedelic bad trip. They had been in a drawer for a very long time but I found a use for them...4mg is a large dose, I split the pill in 2 at the score line, and did that again with those 2 2mg parts and again, so I would have approximately 0.5mg risperdal which I think is the lowest dose. It worked at killing all the dopamine craving and depression one often gets after cocaine. So, let's say I was well equipped to go on a freebase 8 month rampage, it didn't damage me at all.

As for amphetamines, I had a prescription for Dexedrine 10mg spansules x 2 in the morning + 2x5mg IR at 3-4 pm for when I had a lot of homework or to get some energy to be able to handle an evening job after school. What I found really reduced a lot of the bad feelings that can be caused by amps, whether psychosomatic or real, for the time I had that prescription in the 4 years of my BSc. that I finished, well, benzos obviously helped, but otherwise, I can say that low dose inderal helped, a lot, 10mg IR as needed when I had too many PNS symptoms, yes, they still exist with pure dexamphetamine, it's a lot less crappy than with Adderal XR where I heart thought I was running a marathon due to the levo-amph. I wish we had Tenex then. I wanted to switch to Verapamil again when I read a lot of evidence like the evidence presented in this thread, but my doctor refused, saying I would need to stop Inderal point blank as you can't mix beta blockers with verapamil, whether it is because it is a calcium channel blocker or for something particular to verapamil (it seems like it doesn't mix with a lot of things) I don't know. I just wish Tenex (guanfanacine) was available here. Now it is, for mostly children with ADHD, and only as an extended release medication, Intinuvi XL...those proprietary drug names, they're starting to run out of ideas heh. And it is not covered for people over 18 unless your doctor has a lot of documentation on treating you with other stuff without success or not enough success, like for Adderal XR and Vyvanse..well that one isn't covered even for children unless other things have been tried before and your doctor fills a form to have the government medication insurance pay for it. Adderal XR 25mg was really expensive, in Canadian standards, the 2 months i paid for it then realized Dexedrine did not need any sort of government approval at the ministry of health doctor bureaucrats. When I got the letter I couldn't get "Mix of 5 amphetamine Salts"..I just printed the evidence and I learned how Dexedrine is the first line ADD medicine here when Ritalin and the extended release Biphentin or Concerta didn't work/the person doesn't tolerate MPH at all, as was my case (psychosis from 20mg of ritalin a day when I was 17...took a good 3 months to feel normal again without medication, also some kind of seizure issue that I described to a neurologist who made it official that I did not tolerate MPH and didn't use amps for a long time before giving them a go to finish once and for all university.

I can attest that Verapamil made it so that cocaine was much less of a problem than the few times when I made myself some freebase and had no more a script for it where I though I was gonna be stroking heh (and I stopped on Jan 19th 2009 to smoke it, although I doubt my guy had the shit, but levamisole tainted coke was getting big with posters here inside ER waiting rooms about it). I wonder if that ever stopped, but that's for another thread.
 
The thing I love about Verapamil and similar drugs is that they don’t have psychoactive affects of their own, so shouldn’t interfere with the drug experience apart from the physical impacts and tolerance.

I've trialed several classes of CCBs - 12 drugs in all, including verapamil - and found that (to varying degrees) they all diminish the positive effects of both amps and meth. The subsequent capacity to attenuate discriminative stimulus is one reason they've been studied as treatments for meth addiction. There are a couple of papers suggesting verapamil (specifically) can potentiate amp effects in rats, but this doesn't appear to happen in humans.
 
I wanted to switch to Verapamil again when I read a lot of evidence like the evidence presented in this thread, but my doctor refused, saying I would need to stop Inderal point blank as you can't mix beta blockers with verapamil, whether it is because it is a calcium channel blocker or for something particular to verapamil (it seems like it doesn't mix with a lot of things) I don't know.

This is because both slow the functioning of the heart's 'pacemaker', potentially causing quite severe bradycardia and in some people triggering atrial fibrillation (which can kill). Mixing a stimulant into that mix may make things worse thanks to additional alpha-adrenergic stimulation.
 
Yes, I always expected that to be. So I never went back to the verapamil and I switched to clonidine as a Dexedrine crash weakener.
 
No, I know of the dangers of that, one has to be stopped before the other for a couple weeks before even reducing the dose of the other, I wouldn't even accept taking both together, I'd ask for a better option.
 
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