Calcium channel blockers for reduction of tolerance to Amphetamines & addiction

[knockout]

I know what I am going to tell, that will be a little offtopic.
But I think, if Ca-channel blockers then should be mentioned the male infertility.
I know this is not tottaly confirmed/accepted, but some experiment was in this field.
Links:
http://www.ncbi.nlm.nih.gov/pubmed/8062958
http://www.ncbi.nlm.nih.gov/pubmed/7782439
I know this is thoretical/not sure, but methinks not hurt little bit careful be.

 

[ebola?]

but not initially. If that is what you were suggesting, I don't believe it. I'd have to see studies before I believed that Ethanol tolerance could exist before administration had occurred.

Good lord! People vary a lot in severity of initial response to ethanol, and genetics affecting neurology plays a large role in the matter. Otherwise, we could calculate precisely how ethanol would affect someone using only their mass, body fat percentage, and gender.

ebola

 

[Lightning-Nl]

Good lord! People vary a lot in severity of initial response to ethanol, and genetics affecting neurology plays a large role in the matter. Otherwise, we could calculate precisely how ethanol would affect someone using only their mass, body fat percentage, and gender.

ebola

I guess I didn't quite understand the point, so I do understand what you mean now. Yeah, everyone will have a different reaction to a drug. I took that into account, but I didn't think about initial threshold. Putting aside the fact that weight effects the distribution of drugs, it is possible one person could require more ethanol to get intoxicated than another person (level of intoxication is hard to measure though. I know they measure BAC levels, but that's not necessarily the same as how intoxicated someone is).

What I did mean though is, I don't believe someone could lower there tolerance below their initial threshold. I don't believe that by taking an NDMA antagonist you could make yourself less tolerant to Ethanol before you've ever had it administered before.

 

[MagickalKat777]

What I did mean though is, I don't believe someone could lower there tolerance below their initial threshold. I don't believe that by taking an NDMA antagonist you could make yourself less tolerant to Ethanol before you've ever had it administered before.

This is quite possible. Even when starting out, I was never one to watch consumption levels. My first time getting trashed involved a 12 ounce glass, a 4 ounce container of Tropicana orange juice, a bottle of vodka, and knowledge that a "screw driver" was vodka and orange juice... That glass ended up full and chugged so quickly that I didn't even taste the cheap vodka until I set the glass down so I'm sure you can imagine what happened after that.

I do know that I had at least one drunk incident as a child that was on account of stealing drinks of my mother's beer but I don't remember back that far.

It may very well be that I never established an initial threshold for alcohol because I jumped right in to getting smashed my first time drinking. It doesn't account for a reason as to why my tolerance crashed so quickly though. I had previous periods of short-term abstinence from alcohol and never saw a tolerance crash like that. I got into beer when I became of legal drinking age and I never had a period where one beer gave me any sort of a buzz.

 

[atara]

There has been a lot of success using NMDA antagonists after cessation of use to rapidly reduce tolerance though. Do you have any explanations for this? Its a curious thing. I've had it happen to me with both memantine and DXM in regards to alcohol tolerance (abolished to the point that after two weeks of abstinence, a single beer gave a mild buzz - previously this effect would not be achieved until at least 6 beers had been consumed) and memantine reset MDMA and phenethylamine tolerance as well.

Upon cessation of the antagonist, tolerance development starts building again but it seems to stay low as long as a maintenance dose of the antagonist is taken.

If I could stomach the idea of full-blown benzo withdrawal, I would stop taking my Valium and run tests to see if Delsym rapidly dropped benzo tolerance as well. I am currently using it rather successfully to taper without any of the common physical symptoms though and it also curiously abolished any and all alcohol and tobacco cravings.

To some degree drug tolerance and addiction is suspected to be dependent on long-term potentiation. NMDA receptors are important in long-term potentiation, so some have suggested that PCP site antagonists may weaken LTP and thereby lower tolerance, and in a similar way break the "vicious cycle" of depression. This is all really beyond the scope of my understanding, so have a link:

http://www.bluelight.ru/vb/threads/467887-NMDA-antagonists-and-synaptic-plasticity

Related is the effect of NMDA antagonists in treating phantom limb pain and similar extra-sensory perceptual disorders. In short it seems like methoxetamine is actually able to make the brain forget its old limb. But let's make this all more general:

We've learned -- from treating depression to reducing tolerance to strange week-long afterglows of powerful dissociative experiences -- that PCP site antagonists have "lingering effects" that persist for up to several weeks after the drug has been cleared from the system. The apparent tolerance reduction appears to be part of the lingering effects, especially since it dissipates after the dissociative is discontinued.

I'd be very very cautious about trying to use this for hedonistic ends for any long period of time. The bottom line is that we really don't know what's going on. I'm usually suspicious of "tolerance-lowering" efforts regardless of method: the goal seems to be to reinforce reckless behavior.

Incidentally, the fashionable term has gone from "non-competitive antagonist" to "uncompetitive antagonist" to "uncompetitive pore-blocker" and the receptor is either the NMDA glutamate receptor or the NMDA glutamate/glycine-linked ion channel, and, frankly, this is all a bit annoying, so I say PCP site antagonist, which is short and obvious.

 

[MagickalKat777]

To some degree drug tolerance and addiction is suspected to be dependent on long-term potentiation. NMDA receptors are important in long-term potentiation, so some have suggested that PCP site antagonists may weaken LTP and thereby lower tolerance, and in a similar way break the "vicious cycle" of depression. This is all really beyond the scope of my understanding, so have a link:

http://www.bluelight.ru/vb/threads/467887-NMDA-antagonists-and-synaptic-plasticity

Related is the effect of NMDA antagonists in treating phantom limb pain and similar extra-sensory perceptual disorders. In short it seems like methoxetamine is actually able to make the brain forget its old limb. But let's make this all more general:

We've learned -- from treating depression to reducing tolerance to strange week-long afterglows of powerful dissociative experiences -- that PCP site antagonists have "lingering effects" that persist for up to several weeks after the drug has been cleared from the system. The apparent tolerance reduction appears to be part of the lingering effects, especially since it dissipates after the dissociative is discontinued.

I'd be very very cautious about trying to use this for hedonistic ends for any long period of time. The bottom line is that we really don't know what's going on. I'm usually suspicious of "tolerance-lowering" efforts regardless of method: the goal seems to be to reinforce reckless behavior.

Incidentally, the fashionable term has gone from "non-competitive antagonist" to "uncompetitive antagonist" to "uncompetitive pore-blocker" and the receptor is either the NMDA glutamate receptor or the NMDA glutamate/glycine-linked ion channel, and, frankly, this is all a bit annoying, so I say PCP site antagonist, which is short and obvious.

I did go ahead and read part of that thread. Way beyond my scope of understanding as well and far more than I wish to get into, however, the bold part is of interest to me.

I am by no means saying that this is useful for a long period of time nor recommending it for a long period of time. Considering that I hit that magical "50 trip" wall with DXM years ago, I find it amazing that it has any effect on me at all. I also keep the doses very low. I've been keeping a chart since the beginning of my doses and I've recently settled on 5mL twice a day of Delsym as being optimal for me.

I'm using it while I taper (I am tapering at a rate of 6.25% a week but thinking about bumping that to 12.5%, currently mulling over whether or not it is worth it to me as either way I have two more Valium refills and 90 days worth of Delsym) and then I'm going to remain on it for another 30 days post-taper to make sure I don't have any rebound issues and then discontinue it.

There are some effects that I hope are more than lingering - like kicking smoking and not having constant alcohol cravings.

But yeah I don't think that any NMDA antagonist should be used as a long term thing. Once my brain is functioning properly between GABA and NMDA, I'm not going to mess that up.

One of my big hopes though is that using DXM this whole time will help reset my receptors so I don't have a post-acute reaction down the line. It is ridiculous what little it takes to trigger one - I've heard of a single beer causing it or even something as supposedly benign as tylenol.

I won't go into all of my DXM experience but let's just say that I'm familiar with NMDA antagonists being able to make the brain forget things. That's the main reason I believe that keeping my brain busy with NMDA antagonism during my withdrawal could trigger my brain to forget the benzos were ever there. It certainly seems to be working thus far. I couldn't budge on my benzo dose before without extreme discomfort and I always gave in and went back on my full dose or indulged in something else to replace the lost dose... It was a failure every attempt. This is the closest I've ever gotten and it will be 2 months in on the 13th.

 

[sekio]

What I did mean though is, I don't believe someone could lower there tolerance below their initial threshold. I don't believe that by taking an NDMA antagonist you could make yourself less tolerant to Ethanol before you've ever had it administered before.

Fun fact: This is a real phenomenon called sensitization. It is actually observed in some cases like with amphetamines and nicotine in mice/rats (but not, unfortunately, in humans** - so that's not the explanation in this case)

A more likely explanation though, is variation in set and setting. A lot of people ignore those; they play a huge role in the effects of even drugs like alcohol. Diet, time of day, what's in your stoach, what's in your drink, environment, social atmosphere, and stress levels can all play a role in how intoxicated you might feel. Especially intent - if you drink a beverage intending to get drunk, it will act differently than if you were consuming it, thinking it to be non-alcoholic.

** Some people argue that e.g. cannabis, opioids, salvia and the like have "reverse tolerance" initially, but there's not much evidence for that beyond anecdote.

 

[endotropic]

Fun fact: This is a real phenomenon called sensitization. It is actually observed in some cases like with amphetamines and nicotine in mice/rats (but not, unfortunately, in humans** - so that's not the explanation in this case)

A more likely explanation though, is variation in set and setting. A lot of people ignore those; they play a huge role in the effects of even drugs like alcohol. Diet, time of day, what's in your stoach, what's in your drink, environment, social atmosphere, and stress levels can all play a role in how intoxicated you might feel. Especially intent - if you drink a beverage intending to get drunk, it will act differently than if you were consuming it, thinking it to be non-alcoholic.

** Some people argue that e.g. cannabis, opioids, salvia and the like have "reverse tolerance" initially, but there's not much evidence for that beyond anecdote.

What makes you think that sensitization to stimulants doesn't occur in humans? From what I've read it does occur in people, depending on the pattern of use. Heavy use followed by long breaks seems to cause it the most. Here's one clinical trial that found evidence for sensitization:

Enhanced response to repeated d-amphetamine challenge: Evidence for behavioral sensitization in humans

 

[sekio]

http://www.sciencedirect.com/science/article/pii/S0149763499000615

The clinical pharmacokinetics and pharmacodynamics of d-amphetamine (d-AMP) and methylphenidate (MPH) have been well-studied. The plasma half-life of these compounds in children is approximately 5 h, with an onset of therapeutic action within a half-hour, and peak action at 1–3 h. The effective dose range for d-AMP in children is 0.2–0.5 mg/kg, and for MPH 0.3–1.0 mg/kg. In humans, psychostimulants bring about reductions in activity level and impulsivity, and improvement in attention span. Enhancement of executive processes mediated in the pre-frontal cortex in humans (especially tolerance for delay) is believed to mediate these therapeutic effects. There are no long-term remedial effects of the drug on behavior—i.e. symptoms return when the drugs are withdrawn. When used in the therapeutic dose range, there is no evidence of the development of significant tolerance or sensitization.

Among other papers. Of course, now that I think about it, I see no reason humans couldn't exhibit a similar pattern...

 

[endotropic]

http://www.sciencedirect.com/science/article/pii/S0149763499000615


Among other papers. Of course, now that I think about it, I see no reason humans couldn't exhibit a similar pattern...

I think the key there is "When used in the therapeutic dose range", and presumably also when used as prescribed, as opposed to a binge and break pattern.

 

[ebola?]

I thought that with classical stimulants in humans, sensitization is somewhat selective for anxiogenesis, movement, peripheral effects, and proneness to psychosis with overuse over other effects. I hate to say that I have a friend who I've seen lose the plot after one session (k...over many hours of periodic vaporization), with no lost sleep.

http://www.sciencedirect.com/science/article/pii/S0149763499000615

But this study suggests otherwise.

ebola

 

[Lightning-Nl]

Fun fact: This is a real phenomenon called sensitization. It is actually observed in some cases like with amphetamines and nicotine in mice/rats (but not, unfortunately, in humans** - so that's not the explanation in this case)

I don't think you meant to imply that sensitization doesn't occur at all in humans. So I'm going to assume you worded that wrong because sensitization has definitely been observed in humans. It may not occur in the same way in humans as in rodents, but it definitely occurs. Glutamate activity upregulating in response to Dopaminergic activation is a form of sensitization as it downregulates the effects of Dopamine.

Also, if that were the case, why would that be bad? It would be bad if sensitization DIDN'T occur in humans because then all of our behavior would be repetitive and we would never learn a thing. You mean, it's unfortunate because you can't prove your point?

A more likely explanation though, is variation in set and setting. A lot of people ignore those; they play a huge role in the effects of even drugs like alcohol. Diet, time of day, what's in your stoach, what's in your drink, environment, social atmosphere, and stress levels can all play a role in how intoxicated you might feel. Especially intent - if you drink a beverage intending to get drunk, it will act differently than if you were consuming it, thinking it to be non-alcoholic.

Variation and setting are everything, I agree with that. However, the perceived effects of the drug change, only because you think they will be different - meaning it's entirely placebo. It's been observed over and over again that if you think something is going to happen - it will. If you think you're going to get more drunk, you're more likely too. In fact, it's even been noted in studies that before the administration of a drug - your body actually responds by increasing levels of dopamine, or GABA or whatever even BEFORE the drug has had an effect on you.

Dopamine, for instance, is always thought to be "the" neurotransmitter that is responsible for you "feeling good" and getting a "reward" out of doing a behavior. When in reality, this is a misconception. Dopamine is released in anticipation of reward. Because a reward is perceived, or predicted, dopamine is released to "motivate" you to carry out that behavior - the actual reward, is the reward. Not the otherway around.

This is why Dopamine is so important in the role of life. Dopamine will motivate you to achieve a certain behavior that is thought to lead to an advancement in your well-being. This is why dopamine plays such a big role in learned behaviors - our entire existence is based around the advancement of our well-being, this hardwired into our brains. However, repetetive behaviors won't advance our well-being is duplicated over and over which is why certain behaviors become unpleasurable overtime. Whats happening is the dopamine neurons are adapting to that behavior so executing that action will become less enjoyable over time. This means you either have to repeat the behavior more often, or change the behavior.

But there are "errors" in this system. A great example is compulsive gambling. The likelihood of gaining money from gambling is incredibly slim, but the anticipation of the reward is what's so addicting. Especially since the the consequence and reward for gambling is so great - it's two extremes. You either win an incredible amount of money, or you lose an incredibly amount of money. It's almost like life and death. Because of this immense anticipation you keep executing the action because the possibility of such a great reward exists. If this possibility didn't exist, no one would gamble.

Interestingly enough, this is how Obsessive-Compulsive Disorder works, but instead of a great reward being anticipated, a great consequence is anticipated. In people with bad OCD this leads to false beliefs, fearing that an extremely bad situation will happen if you don't do something - "If I don't wash my hands all the time, I will get an extremely severe illness and die." another common one being "If all of my doors and windows aren't locked, someone will break into my house and steal everything I own or wait for me to come back so they can kill me. Therefore, I must make sure that my doors and windows are locked at all times."

This leads to repetitive behaviors even though the brain is supposed to stop this from happening, because the perceived consequence is death. This violates this most basic rule of all life - "I must stay alive." Therefore, this will always "override" the system that the brain has in place to stop this kind of behavior from happening.

Diet, time of day, what's in your stoach,

That is a factor certainly, but not in all drugs. You fail to take that into account. Amphetamine, for instance, has a bioavailability that is usually near 100%. Acidity can change that, but it's pretty stable and is unaffected by "how much" food there is in your stomach - unlike Gabapentin or Ethanol which is not well absorbed at all when there is other matter in the stomach. Or opioids which are better absorbed when there is food in the stomach.

 

[sekio]

That is a factor certainly, but not in all drugs. You fail to take that into account. Amphetamine, for instance, has a bioavailability that is usually near 100%.

It's not, though - it depends greatly on stomach pH and how much fat you consume. For sure the rate of absorbtion is quicker on an alkaline empty stomach than an acidic fat-filled one.

 

[Lightning-Nl]

It's not, though - it depends greatly on stomach pH and how much fat you consume. For sure the rate of absorption is quicker on an alkaline empty stomach than an acidic fat-filled one.

More actually is absorbed in alkaline conditions. This source says that amphetamine bioavailability is usually anywhere from 70%-100%, but in alkaline conditions, this standard becomes 90%-100%.

http://www.drugs.com/interactions-check.php?drug_list=843-0,2075-0

Also, you fail to address the other things in my post above. I'm not trying to dictate anything and I'm not saying anything you said is necessarily wrong, but you didn't account for everything you said.

 

[sekio]

I don't think you meant to imply that sensitization doesn't occur at all in humans. So I'm going to assume you worded that wrong because sensitization has definitely been observed in humans. [...] It would be bad if sensitization DIDN'T occur in humans because then all of our behavior would be repetitive and we would never learn a thing. You mean, it's unfortunate because you can't prove your point?

I mean it's unfortunate because typically most people don't find amphetamine gets more effective over time. But I guess I'm wrong.

 

[Lightning-Nl]

I mean it's unfortunate because typically most people don't find amphetamine gets more effective over time. But I guess I'm wrong.

Incredible. This makes Amphetamine the best drug ever invented.

I posted a while back that after the "honeymoon effect" of amphetamine was gone, all euphoria went away. But I swore that as I kept taking it, overtime, I actually experienced some of the euphoric effects of Amphetamine start to comeback. It's no where near what the honeymoon was like - which is disappointing of course. But I noticed that amphetamine started becoming "better" as I kept taking it.

I never had any clinical proof to back up what I was experiencing, and I thought it might just be pleasurable because amphetamine was increasing the overall function in my life - but this is amazing.

Thanks for the study!

EDIT: I decided this part was best for PM

 

[ebola?]

Incredible. This makes Amphetamine the best drug ever invented.

Hah...did you write this near the peak of an amphetamine experience, by any chance?

ebola

 

[issokay]

I've noticed benzos and opiates no longer affect me since being on gabapentin. Does this jive with what you're saying. It was a little over my head, I've been off the gabapentin for 7 days now after 300mg 3x/day for 5 weeks. If it takes from opiate and benzo benefits I refuse to take it and honestly I'm concerned it won't come back. This happened to me when I tried Chantix as well but it seems like it didn't take this long for my pain & anxiety meds to begin working again. It's pretty scary to be in so much pain, the gabapentin didn't touch my bad pain, only cut back on tingling which wasn't a good trade off at all.
Thx

 

[Toz]

You do know gabapentin can take up to 4 weeks before it gives it's desired effect on pain right? That's what my doctor told me at least when I was put on it.

I never noticed any tolerance reduction to anything while on gabapentin, I'd agree with above poster instead and say it just blocked the effects of most drugs quite effectively.

I've abused PCP though which usually leaves me with a riddiculous tolerance reduction to everything (I can reduce my dosages by about 2/3 with pretty much everything). This effect usually lasts about a month and then it dissipates along with the other side effects such as dizzyness. During this period I have to be careful with other drugs or I easily end up overdosing.

 

[Coolwhip]

I mean it's unfortunate because typically most people don't find amphetamine gets more effective over time. But I guess I'm wrong.

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.