Misc Does the tolerance to drug can be permanent ?

[neversickanymore]

I agree with some of your conclusion about the alcohol.. but it doesn’t quite fit as the effects take hold before the alc is even consumed in some cases.

where is your evidence?

 

[neversickanymore]

You absolutely didn't even read the definition of tolerance in your cited article:

"Tolerance is defined as the diminished response to alcohol or other drugs over the course of repeated or prolonged exposure"

Scientists, people that are in the scientific community take that definition to exclude damage to the organism.

It also excludes diminished response caused by deterioration in the neurotransmitter system responsible for subjective effects related to that substance In other words aging.

It also excludes diminished response caused by substances that interfere with related neurotransmitter systems.

As an example, psychostimulants have a higher subjective effect for the same dose in women for the two weeks before their menses, than during their menstrual cycle.

This is documented. I posted it in another thread, but it's absolutely documented that psychostimulant substances have a higher level of subjective effect during the follicular stage than the luteal stage.

So if you know a woman who says she doesn't roll as hard when she's on the rag, She's absolutely right.

your arguing my point.. look at the first post you made that i commented on.

enjoy your day.. i have to fire mine off right now.

 

[brokedownpalace10]

No, I'm actually asking, do you have any scientific evidence that proves the physiological response to a substance after abstinence more quickly reaches the same level of reduced effect. Then it did when a subject initially started abusing a drug.

It's easy to overlook the nuances of the subjective feelings of being high on a substance.

One can easily overlook things because they've gotten high so many times.

I've taken between 500 and 1,000 pills of ecstasy and many many grams of MDMA and associated comparable research chemicals.

I Have never lost the magic. I understand that taking any substance multiple days in a row will lead to what's called tachyphilaxis and also tolerance. It's well described in the literature.

However, after a period of abstinence and careful examination of the subjective effects of rolling, I had to conclude that given 2 weeks to a month, there was no appreciable difference between subjective effects from the same dose of verified pure MDMA the first time I took it and after I took it when I had been rolling for 3 years but a three-week break.

Most people are lazy with everything they do and it's very easy to overlook subjective effects when you're getting high and say oh it doesn't get me as high as it used to.

I do understand what you are asking, sir. I think maybe you just enjoy a good argument, and I don't feel like one today.

Let me ask you this. If a person has much more severe withdrawal symptoms after redeveloping an addiction, would it not make sense that their addiction, and thus their tolerance is developing more quickly? A cursory reading of the sites you are referring to shows kindling as being the brain being much more sensitive to addiction. Kinda semantics at this point.

Many, many people on this site and others have experienced tolerance coming back more quickly. I have as well. It's obviously a real phenomenon.
If you want to say that effect is psychological and not due to physical changes, I don't give a shit. The effect is the same.
I was just trying to throw a little light on the original question. Argue with someone else.

 

[snmfmy]

I agree with some of your conclusion about the alcohol.. but it doesn’t quite fit as the effects take hold before the alc is even consumed in some cases.

where is your evidence?

That doesn't make any sense, how can effects from alcohol tolerance or hypo tolerance as you call it take hold before the alcohol is even consumed?

Psychosomatic responses have nothing to do with tolerance.

 

[snmfmy]

I do understand what you are asking, sir. I think maybe you just enjoy a good argument, and I don't feel like one today.

Let me ask you this. If a person has much more severe withdrawal symptoms after redeveloping an addiction, would it not make sense that their addiction, and thus their tolerance is developing more quickly? A cursory reading of the sites you are referring to shows kindling as being the brain being much more sensitive to addiction. Kinda semantics at this point.

Many, many people on this site and others have experienced tolerance coming back more quickly. I have as well. It's obviously a real phenomenon.
If you want to say that effect is psychological and not due to physical changes, I don't give a shit. The effect is the same.
I was just trying to throw a little light on the original question. Argue with someone else.

No that's not what's happening and it's not reasonable to assume that.

If they have a much more severe withdrawal response, it's because of morphological changes to their neurotransmitters not because of tolerance.

Let's take the specific example of alcohol withdrawal. Kindling occurs because glutamate receptors, which are constantly upregulated during alcohol abuse to counteract the effects of gaba and other neurotransmitter agonization from alcohol, begin to react in a much more robust manner after multiple episodes of withdrawal.

This is called kindling. It is not related to tolerance. In fact, the two are decoupled because an alcoholic who has been in withdrawal many times and is kindling could have two drinks and be completely drunk because they have no tolerance, yet. Once the alcohol is out of their system, have a seizure from the kindling.

What effect is the same? You say tolerance but what exactly has diminished?

Is there less euphoria, is there less sympathomimetic response (That means blood pressure, heart rate, etc) Is there less psycho motor activity, is there less psycho motor impairment?

These are all metrics of the effects of a substance and I haven't heard you define what you say is less tolerance and you reach tolerance more quickly.

I think if you replicated the exact same dosing schedule that led to the initial level of tolerance after a period of abstinence tolerance would be reached at the same time.

Most people however don't stick to the same doses that they did when they first started out and that's why they actually reached tolerance quicker.

 

[brokedownpalace10]

I knew you'd do that.

Let's take the specific example of alcohol withdrawal. Kindling occurs because glutamate receptors, which are constantly upregulated during alcohol abuse to counteract the effects of gaba and other neurotransmitter agonization from alcohol, begin to react in a much more robust manner after multiple episodes of withdrawal.

Umm, and that would not be a form of residual tolerance? Them acting more robustly?

I think if you replicated the exact same dosing schedule that led to the initial level of tolerance after a period of abstinence tolerance would be reached at the same time.

Most people however don't stick to the same doses that they did when they first started out and that's why they actually reached tolerance quicker.

That's kind of a "duh" thing though, isn't it? Of course they would develop that tolerance at previous rates if they kept the dosing schedule the same. But they don't, do they?
They don't because they feel a need for more. I suppose you could say that's not tolerance, but is does kinda walk like a duck, no?.
The more robust glutamate receptors is as good a theory for the mechanism as any. Say it's all psychological if that makes you happy. I called that, "old usage habits kicking back in" as I remember. It's right up there. ^^^^^

I have myself, and I have seen many other alcoholics, quit drinking and then, after a period of abstinence be back to a fifth a day within a few weeks. That would be physically hard for a non alcoholic to do. so there's that.

 

[snmfmy]

I knew you'd do that.



Umm, and that would not be a form of residual tolerance? Them acting more robustly?


That's kind of a "duh" thing though, isn't it? Of course they would develop that tolerance at previous rates if they kept the dosing schedule the same. But they don't, do they?
They don't because they feel a need for more. I suppose you could say that's not tolerance, but is does kinda walk like a duck, no?.
The more robust glutamate receptors is as good a theory for the mechanism as any. Say it's all psychological if that makes you happy. I called that, "old usage habits kicking back in" as I remember. It's right up there. ^^^^^

I have myself, and I have seen many other alcoholics, quit drinking and then, after a period of abstinence be back to a fifth a day within a few weeks. That would be physically hard for a non alcoholic to do. so there's that.

No, it's not a form of residual tolerance.

Glutamate up regulation has nothing to do with tolerance. It has to do with homeostatic response which is not tolerance. Glutamate receptors are upregulated because the body tries to balance glutamine and gaba effects. Because alcohol agonizes Gabba, receptors and sedates the central nervous system. The body responds by increasing glutamate an excitatory neurotransmitter.

This has nothing to do with tolerance.

Thank you for admitting that people get back to the same level of tolerance more quickly than before abstinence not because of some sort of tolerance related mechanism, but because they use a lot more substance in a shorter period of time.

Using more substance in a shorter period of time is not caused by tolerance. It's caused by being stupid.

 

[brokedownpalace10]

No, it's not a form of residual tolerance.

Glutamate up regulation has nothing to do with tolerance. It has to do with homeostatic response which is not tolerance. Glutamate receptors are upregulated because the body tries to balance glutamine and gaba effects. Because alcohol agonizes Gabba, receptors and sedates the central nervous system. The body responds by increasing glutamate an excitatory neurotransmitter.

This has nothing to do with tolerance.

Thank you for admitting that people get back to the same level of tolerance more quickly than before abstinence not because of some sort of tolerance related mechanism, but because they use a lot more substance in a shorter period of time.

Using more substance in a shorter period of time is not caused by tolerance. It's caused by being stupid.

"Thank you for admitting", huh? Thank you for proving you are just out for an argument.

Glutamate receptors are upregulated because the body tries to balance glutamine and gaba effects. Because alcohol agonizes Gabba, receptors and sedates the central nervous system. The body responds by increasing glutamate an excitatory neurotransmitter.

So, again, glutamate receptors being more easily upregulated, "acting in a more robust manner" then tolerance to alcohols sedative effects would be more easily gained.
If you want to divide that from the euphoric, etc., effects no one cares.

You said
"an alcoholic who has been in withdrawal many times and is kindling could have two drinks and be completely drunk because they have no tolerance, yet. Once the alcohol is out of their system, have a seizure from the kindling."
That's interesting. Give me a cite on that.

 

[snmfmy]

"Thank you for admitting", huh? Thank you for proving you are just out for an argument.



So, again, glutamate receptors being more easily upregulated, "acting in a more robust manner" then tolerance to alcohols sedative effects would be more easily gained.
If you want to divide that from the euphoric, etc., effects no one cares.

You said
"an alcoholic who has been in withdrawal many times and is kindling could have two drinks and be completely drunk because they have no tolerance, yet. Once the alcohol is out of their system, have a seizure from the kindling."
That's interesting. Give me a cite on that.

Glutamate up regulation has no effect on the sedative effects of alcohol.

Tolerance to alcohol is caused by the ethanol induced plasticity in GABAA receptors and sub receptor units so that ethanol actually binds less easily over time.

It should be noted that kindling does not occur without multiple episodes of withdrawal. The only stimulus in alcohol withdrawal that would support kindling is the increase in glutamate activity and the downstream effect of neuronal excitability caused by calcium influx from the glutamate action.

This repetitive process of repeated withdrawal acts in the same way that multiple repeated shocks of small electrical current over time would precipitate seizures as if the current was much higher. (You can research the basis for the kindling phenomena if you want)

Administration of benzodiazepines abolishes kindling seizure activity during withdrawal.

You asked me to find a citation for what purpose?

Kindling is associated only with withdrawal. It doesn't matter how much alcohol you're drinking, just that you're withdrawing.

It's not associated with tolerance because hardcore drinkers with the tolerance to drink a liter and a half of hard liquor a day. Don't experience kindling unless they go into withdrawal.

You don't experience kindling if you are given benzodiazepines.

I don't know what information you want when you said a citation. And I don't have one that specifically says that.

I do have my own experiences that after suffering kindling in multiple episodes of alcohol withdrawal and then only drinking two shots of alcohol a month later I experienced a. Paresthesia, tingling, irritability, and insomnia approximately 8 to 12 hours after the two drinks that continued for about 12 hours.

I don't drink regularly anymore. In fact, I maybe have a drink or two once a week.

And after about 2 months, having a drink or two didn't cause that pseudo withdrawal syndrome.

I have spoken with multiple alcoholics and ex alcoholics that have stated to me. They relapse after a period of abstinence and only have one or two drinks where they feel tipsy, they can suffer kindling from the withdrawal from those two drinks.

Is it going to result in a seizure and delirium tremens? Probably not and maybe I shouldn't have used the word drunk. I should have used the word tipsy and affected.

Again, kindling is independent of tolerance and is only associated with withdrawal.

In fact, kindling is absent in alcoholics that have not had extremely bad withdrawal symptoms.

 

[brokedownpalace10]

Glutamate up regulation has no effect on the sedative effects of alcohol.

Glutamate upregulation becoming more robust more quickly would increase neuronal excitability which would counteract some of the sedative effects of alcohol. I shouldn't have called it "tolerance". You seem to be very fixated on that word. An addict would need more to get the same sedative effects more quickly if that's better.

You asked me to find a citation for what purpose?

Because your statement was rather excessive. You've backpedaled a bit, so all good. Ya any addict is going to notice and experience more rebound effects and/or mild withdrawal after one use.

 

[snmfmy]

Glutamate upregulation becoming more robust more quickly would increase neuronal excitability which would counteract some of the sedative effects of alcohol. I shouldn't have called it "tolerance". You seem to be very fixated on that word. An addict would need more to get the same sedative effects more quickly if that's better.


Because your statement was rather excessive. You've backpedaled a bit, so all good. Ya any addict is going to notice and experience more rebound effects and/or mild withdrawal after one use.

The increased neuronal excitability that happens because of increased glutamate release, transport, up regulation occurs after some time period of ethanol consumption.

Doesn't happen in advance of alcohol consumption.

There's no mechanism whereby the glutamate system is upregulated in anticipation of more alcohol drinking.

So no, the adaptations of the glutaminergic system due to alcohol consumption will never preemptively counteract the effects of ethanol consumption causing less sedation because it's an after the fact adaptation..

Alcohol abusers need more ethanol to get the same subjective effects and sedation because of the morphological changes that occur to the GABA receptor complex that result in less positive allosteric modulation of the GABA receptor after repeated use.

There is also something called the BK channel which is a potassium channel that's modulated by calcium and voltage and it's also controlled by alcohol exposure. The BK channel is responsible for neurotransmitter release. Changes to the function and phosphorylation of the BK channel and the gaba A receptor complex are the mechanisms by which tolerance develops.

Of interest is that lowered receptor expression and density of the alpha 1 subunit on GABA receptors has been seen after chronic ethanol exposure.

The fact that the alpha 1 subunit is also a target for benzodiazepines and that tolerance alcohol also causes tolerance to benzodiazepines lends much evidentiary support that morphological changes in the GABA. A receptor complex are a major reason for the development of tolerance from ethanol exposure.

 

[brokedownpalace10]

The increased neuronal excitability that happens because of increased glutamate release, transport, up regulation occurs after some time period of ethanol consumption.

Doesn't happen in advance of alcohol consumption.

the GABA. A receptor complex are a major reason for the development of tolerance from ethanol exposure.

Huh? No one said anything about anything happening in advance. The glutamate upregulation becoming more robust more quickly would counteract the sedative effects upon next consumption, thus adding to habits of use in making the user increase dosage more quickly.

You know, in all the sites where you have maybe read about kindling it has been studied in relation to addiction and addiction counseling. Proving one thing does not rule out another.

Look. I'm getting tired of explaining this concept. You know what? You're right. In the technical mechanisms of tolerance, alcohol tolerance does not quickly return. No need for any more posts to impress everybody with your esteemed knowledge of pharmacology.

 

[snmfmy]

Huh? No one said anything about anything happening in advance. The glutamate upregulation becoming more robust more quickly would counteract the sedative effects upon next consumption, thus adding to habits of use in making the user increase dosage, and thus tolerance, more quickly.

You know, in all the sites where you have maybe read about kindling it has been studied in relation to addiction and addiction counseling. Proving one thing does not rule out another.

Look. I'm getting tired of explaining this concept. You know what? You're right. In the technical mechanisms of tolerance, alcohol tolerance does not quickly return. No need for any more posts to impress everybody with your esteemed knowledge of pharmacology.

It doesn't become more robust more quickly in a vacuum, it only happens if you're drinking more alcohol quicker than before.

What don't you understand about the fact that glutaminergic upregulation happens after increases in ethanol consumption. Because alcohol inhibits glutamate receptor function.

Glutamate does not inhibit gaba receptor function.

Glutamate reuptake inhibitors Do not reduce the subjective effects of alcohol.

In fact, it seems that glutamate in some cases may actually potentiate the action of GABA receptors.

Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain

Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor (GABA[A] R) mediated inhibition is essential for brain functioning; and its imbalance contributes to the pathogenesis of many brain ...

www.ncbi.nlm.nih.gov

 

[brokedownpalace10]

It doesn't become more robust more quickly in a vacuum, it only happens if you're drinking more alcohol quicker than before.

What don't you understand about the fact that glutaminergic upregulation happens after increases in ethanol consumption. Because alcohol inhibits glutamate receptor function.

Glutamate does not inhibit gaba receptor function.

Glutamate reuptake inhibitors Do not reduce the subjective effects of alcohol.

In fact, it seems that glutamate in some cases may actually potentiate the action of GABA receptors.

Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain

Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor (GABA[A] R) mediated inhibition is essential for brain functioning; and its imbalance contributes to the pathogenesis of many brain ...

www.ncbi.nlm.nih.gov

Yes* each* consumption* is* going* to* make* it* a* little* more* robust* affecting* the* next* consumption*

 

[snmfmy]

Yes* each* consumption* is* going* to* make* it* a* little* more* robust* affecting* the* next* consumption*

No, each consumption is going to make the glutamate receptor more impaired. That means it has to become more sensitive to glutamate in order to function the same way.

Glutamate upregulation does not counteract the sedative effects of ethanol in any way because it doesn't affect the gaba receptor in any way except glutamate the neurotransmitter may possibly potentiate its actions in certain cases.

 

[snmfmy]

Yes* each* consumption* is* going* to* make* it* a* little* more* robust* affecting* the* next* consumption*

I think you're operating under the assumption that glutamate up regulation means more production of glutamate and that's not the case.

It means that the sensitivity of the neuron- glutamate receptor complex to glutamate becomes upregulated either through a higher action from binding or from a higher number of receptors on the neuron. Or from greater receptor density. There's a subtle difference between increased receptor density and increased expression of receptors.

Regardless, there's no mechanism for NMDA/AMPA/Kainate receptor upregulation to reduce ethanol sedation.

 

[brokedownpalace10]

Kindling occurs because glutamate receptors, which are constantly upregulated during alcohol abuse to counteract the effects of gaba and other neurotransmitter agonization from alcohol, begin to react in a much more robust manner after multiple episodes of withdrawal.

 

[snmfmy]

Yes, I said that. What's your point?

Glutamate up regulation in the absence of GABA agonism by ethanol leads to a downstream cascade of catecholamine release that includes serotonin, dopamine and high levels of norepinephrine. This contributes to what's called the alcohol withdrawal syndrome

In the presence of Gabba agonists either alcohol or benzodiazepines, this downstream cascade from over activity of the glutamate receptor doesn't occur.

What part of Gabba agonism and the GABA neurotransmitter itself impairs the function of glutamate receptors, but the converse is not true Do you not understand?

Kindling has nothing to do with tolerance.

 

[brokedownpalace10]

In the presence of Gabba agonists either alcohol or benzodiazepines, this downstream cascade from over activity of the glutamate receptor doesn't occur.

So, drinking more alcohol would alleviate it?

 

[snmfmy]

So, drinking more alcohol would alleviate it?

Yes, in the absence of benzodiazepines, ethanol is given as a rescue treatment for alcohol withdrawal. Any amount of alcohol will reduce the withdrawal syndrome.

It doesn't necessarily work if the alcohol withdrawal has turned into delirium tremens, but benzodiazepines don't always work then either.