DarkGhost101
Greenlighter
- Joined
- Oct 14, 2014
- Messages
- 5
Hello all,
As obvious to all of us, long term drug use has an effect on receptors in the brain, which is the cause for tolerance and dependence.
For example, let's take Xanax. Xanax is a benzodiazepine drug, which acts as an agonist (or if being more accurate, positive modulator, but it's almost the same thing) on GABA receptors in the brain.
The result is a calming effect, followed by muscle relaxation and drowsiness.
After long-term use of Xanax, the brain starts downregulating (temporarily shutting down) GABA receptors and lower the sensitivity of the remaining ones, in order to restore balance in the brain (Homeostasis).
The immediate result of GABA downregulation is tolerance to benzodiazepines. Not only that the Xanax has more receptors to act on, the remaining ones also have reduced sensitivity to the Xanax, requiring a higher dosage to activate them from usual. And when the usage is stopped, a life-threatening withdrawal syndrome appears - that's because the neurotransmitter GABA is inhibitory, and with a low amount of GABA during withdrawal, neurons fire easily and quickly (there is not enough GABA to reduce their firing), posing a great risk for grand mal seizures. Eventually the GABA receptors upregulate after quitting, and that ends the withdrawal.
But even after the withdrawal syndrome is over, some people experience a few mild withdrawal symptoms for years after quitting (sometimes even 10-20 years), and many times it's even permanent (these withdrawal symptoms are usually weak memory and clouded thinking, and they are not life-threatening). Why is that? Sadly, long-term drug use (and not only benzodiazepines) permanently changes the receptors affected by the certain drug to some extent. In our example, long-term use of benzodiazepines will permanently reduce the sensitivity of GABA receptors in the brain, and even after years of quitting them, the GABA receptors will still not be as sensitive as they have been before the Xanax use.
Also, look at tolerance. When people build tolerance, they take long tolerance breaks to reset their tolerance. When they return to the drug, they see that their tolerance has gone down significantly, but the tolerance will return to what it used to be only 1 or 2 days after returning the drug. In other words, the receptors in the brain remember the past drug use, and just one use after quitting, even for years, will return them back to their previous state of tolerance.
But here's something interesting. There are a few researches that have used Flumazenil (a GABA antagonist) as an experiment to treat people with protracted withdrawal symptoms from benzodiazepines. The result was a sucess - the withdrawal symptoms went away totally after a few doses, and the researchers hypothesized it might be because using a GABA antagonist "resets" the GABA receptors to their normal state, something that can't happen naturally at the brain after long-term use of benzodiazepines. Also, in opioid dependence, a few doses of opioid antagonists (usually naltrexone or naloxone) are being used to stop withdrawal and greatly reduce, if not totally reset, opiate tolerance.
So would it work for every drug, in your opinion? Think about it - Xanax is a GABA agonist, and agonists always cause downregulation after long-term use. But antagonists, which block the receptor without activating it, would always cause receptor upregulation - the complete opposite of an agonist. And think of that - if downregulation by agonists mean loss of effect and dependence, couldn't it be solved by using antagonists to cause upregulation? (Antagonists cause upregulation by blocking the receptors, and the receptors upregulate as an attempt to restore natural levels of neurotransmitter binding). Withdrawals from agonist drugs ends after a few weeks or months when the receptors have upregulated themselves to the normal level - so couldn't you speed up the process by adding an antagonist, forcing the receptors to upregulate more quickly?
These are the 2 studies I were talking about:
A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal:
http://www.bcnc.org.uk/flumazenil.html
Effects of flumazenil in the treatment of benzodiazepine withdrawal – a double-blind pilot study:
http://www.springerlink.com/content/2vpf562teffglej5/fulltext.pdf ( http://www.springerlink.com/content/2vpf562teffglej5/fulltext.pdf )
So what is your opinion? Would using antagonists always work to reduce tolerance caused by agonists?
Please share your opinion, and if you have personal experience, please share it too.
If you have any questions, ask them and we can discuss the answers here.
Have an awesome day,
-DarkGhost101-
As obvious to all of us, long term drug use has an effect on receptors in the brain, which is the cause for tolerance and dependence.
For example, let's take Xanax. Xanax is a benzodiazepine drug, which acts as an agonist (or if being more accurate, positive modulator, but it's almost the same thing) on GABA receptors in the brain.
The result is a calming effect, followed by muscle relaxation and drowsiness.
After long-term use of Xanax, the brain starts downregulating (temporarily shutting down) GABA receptors and lower the sensitivity of the remaining ones, in order to restore balance in the brain (Homeostasis).
The immediate result of GABA downregulation is tolerance to benzodiazepines. Not only that the Xanax has more receptors to act on, the remaining ones also have reduced sensitivity to the Xanax, requiring a higher dosage to activate them from usual. And when the usage is stopped, a life-threatening withdrawal syndrome appears - that's because the neurotransmitter GABA is inhibitory, and with a low amount of GABA during withdrawal, neurons fire easily and quickly (there is not enough GABA to reduce their firing), posing a great risk for grand mal seizures. Eventually the GABA receptors upregulate after quitting, and that ends the withdrawal.
But even after the withdrawal syndrome is over, some people experience a few mild withdrawal symptoms for years after quitting (sometimes even 10-20 years), and many times it's even permanent (these withdrawal symptoms are usually weak memory and clouded thinking, and they are not life-threatening). Why is that? Sadly, long-term drug use (and not only benzodiazepines) permanently changes the receptors affected by the certain drug to some extent. In our example, long-term use of benzodiazepines will permanently reduce the sensitivity of GABA receptors in the brain, and even after years of quitting them, the GABA receptors will still not be as sensitive as they have been before the Xanax use.
Also, look at tolerance. When people build tolerance, they take long tolerance breaks to reset their tolerance. When they return to the drug, they see that their tolerance has gone down significantly, but the tolerance will return to what it used to be only 1 or 2 days after returning the drug. In other words, the receptors in the brain remember the past drug use, and just one use after quitting, even for years, will return them back to their previous state of tolerance.
But here's something interesting. There are a few researches that have used Flumazenil (a GABA antagonist) as an experiment to treat people with protracted withdrawal symptoms from benzodiazepines. The result was a sucess - the withdrawal symptoms went away totally after a few doses, and the researchers hypothesized it might be because using a GABA antagonist "resets" the GABA receptors to their normal state, something that can't happen naturally at the brain after long-term use of benzodiazepines. Also, in opioid dependence, a few doses of opioid antagonists (usually naltrexone or naloxone) are being used to stop withdrawal and greatly reduce, if not totally reset, opiate tolerance.
So would it work for every drug, in your opinion? Think about it - Xanax is a GABA agonist, and agonists always cause downregulation after long-term use. But antagonists, which block the receptor without activating it, would always cause receptor upregulation - the complete opposite of an agonist. And think of that - if downregulation by agonists mean loss of effect and dependence, couldn't it be solved by using antagonists to cause upregulation? (Antagonists cause upregulation by blocking the receptors, and the receptors upregulate as an attempt to restore natural levels of neurotransmitter binding). Withdrawals from agonist drugs ends after a few weeks or months when the receptors have upregulated themselves to the normal level - so couldn't you speed up the process by adding an antagonist, forcing the receptors to upregulate more quickly?
These are the 2 studies I were talking about:
A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal:
http://www.bcnc.org.uk/flumazenil.html
Effects of flumazenil in the treatment of benzodiazepine withdrawal – a double-blind pilot study:
http://www.springerlink.com/content/2vpf562teffglej5/fulltext.pdf ( http://www.springerlink.com/content/2vpf562teffglej5/fulltext.pdf )
So what is your opinion? Would using antagonists always work to reduce tolerance caused by agonists?
Please share your opinion, and if you have personal experience, please share it too.
If you have any questions, ask them and we can discuss the answers here.
Have an awesome day,
-DarkGhost101-
