Increasing bioavailability of benzo's

[Rafterman]

RM - Thought you might find this interesting:

Abstract

Cimetidine has been shown to inhibit the liver microsomal metabolism of the benzodiazepines diazepam and chlordiazepoxide, resulting in an increase in half-life and decrease in the clearance of these two drugs. Patients receiving the combination of diazepam and cimetidine have been noted to be more sedated than when given an equal dose of diazepam alone. Many benzodiazepines undergo N-dealkylation and hydroxylation via the cytochrome P450 oxidase system. Cimetidine is thought to bind to cytochrome P450 oxidase and to interfere with many drugs using this path way. Oxazepam and lorazepam are two benzodiazepines not oxidatively metabolized by cytochrome P450, but are glucuronidated by glucuronyl transferase and are, therefore, not subject to metabolic inhibition by cimetidine. Thus, when clinically indicated, oxazepam and lorazepam may be the benzodiazepines of choice to use in combination with cimetidine to eliminate the clinically significant drug interaction seen with diazepam and chlordiazepoxide.

Link: xxxxx://www.ncbi.nlm.nih.gov/pubmed/6116285 (replace xxxxx with https, of course.

Thanks for this, O. I have seen studies like these. In fact, about 10 years ago I was really psyched by the idea that Tagamet might indeed revolutionize my experience with benzo's (and opioids). I have been in the market for a true potentiator of both for decades. I know that grapefruit juice is a legit potentiator, but I cannot have that because I take the medication Digoxin. So I began trying Tagamet. I must say that I did not notice a different but that's just me. Everyone else seems to note a difference. I have a weird make up. For instance, I noticed that 400mg's of magnesium, taken an hour before a dose of oxy or hydro, definitely improves the experience somewhat. No one else seems to think that. Are you going to try the Tagamet? You are making me feel like giving it another run. Walgreen's used to have a trial size. Not sure if they still do. Otherwise, Amazon is probably your best bet. Let me know. I'll probably do it with you.  RM

[OldBoy]

RM - Thought you might find this interesting:

Abstract

Cimetidine has been shown to inhibit the liver microsomal metabolism of the benzodiazepines diazepam and chlordiazepoxide, resulting in an increase in half-life and decrease in the clearance of these two drugs. Patients receiving the combination of diazepam and cimetidine have been noted to be more sedated than when given an equal dose of diazepam alone. Many benzodiazepines undergo N-dealkylation and hydroxylation via the cytochrome P450 oxidase system. Cimetidine is thought to bind to cytochrome P450 oxidase and to interfere with many drugs using this path way. Oxazepam and lorazepam are two benzodiazepines not oxidatively metabolized by cytochrome P450, but are glucuronidated by glucuronyl transferase and are, therefore, not subject to metabolic inhibition by cimetidine. Thus, when clinically indicated, oxazepam and lorazepam may be the benzodiazepines of choice to use in combination with cimetidine to eliminate the clinically significant drug interaction seen with diazepam and chlordiazepoxide.

Link: xxxxx://www.ncbi.nlm.nih.gov/pubmed/6116285 (replace xxxxx with https, of course.

Thanks for this, O. I have seen studies like these. In fact, about 10 years ago I was really psyched by the idea that Tagamet might indeed revolutionize my experience with benzo's (and opioids). I have been in the market for a true potentiator of both for decades. I know that grapefruit juice is a legit potentiator, but I cannot have that because I take the medication Digoxin. So I began trying Tagamet. I must say that I did not notice a different but that's just me. Everyone else seems to note a difference. I have a weird make up. For instance, I noticed that 400mg's of magnesium, taken an hour before a dose of oxy or hydro, definitely improves the experience somewhat. No one else seems to think that. Are you going to try the Tagamet? You are making me feel like giving it another run. Walgreen's used to have a trial size. Not sure if they still do. Otherwise, Amazon is probably your best bet. Let me know. I'll probably do it with you.  RM

Hi RM,

I'm a bit ahead of you - Received 4 bottles of generic (Equate) brand Cimetidine from Amazon on Monday, and tried the following:

1. Cimetidine after a meal, then di@z
2. Cimetidine on an empty stomach, then di@z
3. Cimetidine on an empty stomach, followed by a 15-minute wait, then di@z

Of the three, the third method has a definite effect as a potentiatior - In terms of how quickly the di@z kicks in, it's perceived strength, and the duration of effect.  It seems to increase the properties of the di@z by about 1/3, which is fantastic.


Of course, now to see if the effect is consistent, or if I need to take a break from the Cimetidine every now and then ;-)

Have a great weekend!

[Rafterman]

RM - Thought you might find this interesting:

Abstract

Cimetidine has been shown to inhibit the liver microsomal metabolism of the benzodiazepines diazepam and chlordiazepoxide, resulting in an increase in half-life and decrease in the clearance of these two drugs. Patients receiving the combination of diazepam and cimetidine have been noted to be more sedated than when given an equal dose of diazepam alone. Many benzodiazepines undergo N-dealkylation and hydroxylation via the cytochrome P450 oxidase system. Cimetidine is thought to bind to cytochrome P450 oxidase and to interfere with many drugs using this path way. Oxazepam and lorazepam are two benzodiazepines not oxidatively metabolized by cytochrome P450, but are glucuronidated by glucuronyl transferase and are, therefore, not subject to metabolic inhibition by cimetidine. Thus, when clinically indicated, oxazepam and lorazepam may be the benzodiazepines of choice to use in combination with cimetidine to eliminate the clinically significant drug interaction seen with diazepam and chlordiazepoxide.

Link: xxxxx://www.ncbi.nlm.nih.gov/pubmed/6116285 (replace xxxxx with https, of course.

Thanks for this, O. I have seen studies like these. In fact, about 10 years ago I was really psyched by the idea that Tagamet might indeed revolutionize my experience with benzo's (and opioids). I have been in the market for a true potentiator of both for decades. I know that grapefruit juice is a legit potentiator, but I cannot have that because I take the medication Digoxin. So I began trying Tagamet. I must say that I did not notice a different but that's just me. Everyone else seems to note a difference. I have a weird make up. For instance, I noticed that 400mg's of magnesium, taken an hour before a dose of oxy or hydro, definitely improves the experience somewhat. No one else seems to think that. Are you going to try the Tagamet? You are making me feel like giving it another run. Walgreen's used to have a trial size. Not sure if they still do. Otherwise, Amazon is probably your best bet. Let me know. I'll probably do it with you.  RM

Hi RM,

I'm a bit ahead of you - Received 4 bottles of generic (Equate) brand Cimetidine from Amazon on Monday, and tried the following:

1. Cimetidine after a meal, then di@z
2. Cimetidine on an empty stomach, then di@z
3. Cimetidine on an empty stomach, followed by a 15-minute wait, then di@z

Of the three, the third method has a definite effect as a potentiatior - In terms of how quickly the di@z kicks in, it's perceived strength, and the duration of effect.  It seems to increase the properties of the di@z by about 1/3, which is fantastic.


Of course, now to see if the effect is consistent, or if I need to take a break from the Cimetidine every now and then ;-)

Have a great weekend!

Wow! That is phenomenal, O. Now I am certain that I will dive back in and give it another try. I can't say for certain that I used your Method #3, which makes having another go at it even more exciting. Are you thinking of going even further in your studies of this? Say, like waiting an hour after taking the Cimeditine? Or increasing the dose of the Cimeditine? BTW, please tell me again the dose of the C that you were using. Thanks. I am going to grab a trial size at the local Walgreens. Might be a couple of days from now, as I am under the weather. I will definitely let you know what happens. Thanks for all the great info. I hope that you are enjoying your weekend!  RM

[I-carus8045]

This isnt exactly a method for increasing availability, but it effectively works at slowing down metabolisation and allowing more of the benzo to process into your sytem but it only works on some very specific benzos for very specific reasons.

I remember studying this a few years back because I find the whole area of enzymes, metabolisation and potentiation extremely interesting and compelling to learn about.

In the interest of health and safety however I think it is worth mentioning that personally I will not potentiate O{IATES using this method as it can be highly unpredictable depending an individuals metabolisation and strength of their enzymes and genetics and all sorts of other variables. Benzos are alot harder to overdose one, but when it comes to the main benzo this process applies to i still would NOT recommend it.

However we are all adults, and the OP asked if there is a way and there kinda sorta is a way. So after seeing the OP i spent a little bit of time tracking down some of the more easily digestable quotes on the subject as sourced from wiki and erowid. just the basics you know so its easy to understand.

So for starters

How grapefruit juice affects opiate/opiod metabolism:
"The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids). These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells." - https://en.wikipedia.org/wiki/Grapefruit...teractions

and next up the following are the benz0diazepines MOSTLY catalyzed by this enzyme:
@lpraz0lam, triaz0lam, br0tiz0lam and midaz0lam are mainly metabolished by CYP3A4. Infact for those of you who arent aware pretty much all of the effects felt from Midaz0lam are caused by this process. https://www.ncbi.nlm.nih.gov/pubmed/012875231

Why is this??:
". Midaz0lam is poorly absorbed orally, with only 50 percent of the drug reaching the bloodstream.[6] Midaz0lam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midaz0lam are due to its effects on the GABAA receptors; midaz0lam does not activate GABAA receptors directly but, as with other benz0diazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benz0diazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects". https://en.wikipedia.org/wiki/Midazolam#Pharmacology

Regardless of how Midaz does or doesnt work however the information, studies and scientific researches do exist to prove that grapefruit juice is an effective potentiater for some of the most commonly abused benz0s in the world.

Infact most other benz0s that arent MOSTLY catalyzed in this process are still PARTLY catalyzed by this process:
Qu@zepam, di@zepam and flun1trazepam being some of the more well known ones. - https://www.ncbi.nlm.nih.gov/pubmed/012875231

I guess from seeing it laid out in this format we can speculate that it is mostly triaz0lobenz0diazepines that are MOSTLY catalyzed in this manner.

Anyway here is the kinda tricky part, attempting to potentiate or enhance using this method with the grapefruit juice can be a double edged sword and have an OPPOSITE effect of what is trying to be achieved

Here is the quotes on that:
"Inhibition of enzymes can have two different effects, depending on whether the drug is either:
(A) - metabolized by the enzyme to an inactive metabolite, or
(B) - activated by the enzyme to an active metabolite.
If the active drug is metabolized by the inhibited enzyme, then the fruit will stop the drug being metabolized, leaving elevated concentrations of the medication in the body, which can cause adverse effects. Conversely, if the medication is a prodrug, it needs to be metabolised to be converted to the active drug. Compromising its metabolism lowers concentrations of the active drug, reducing its therapeutic effect, and risking therapeutic failure." https://en.wikipedia.org/wiki/Grapefruit...teractions

So there you go. It was fun tracking all this info down again so you could enjoy reading. I hope you enjoy ingesting this knowledge as much as I enjoyed typing it up.

Also some interesting general info on an erowid article https://erowid.org/chemicals/opiates/opi...nfo3.shtml