rachamim
Bluelighter
Mipet: "Nu2 for breathing, Mu1 for euphoria.": Both play into it synergystically. Mu1 is the only rectpr believed to mediate rush although as you probablly know the full physioloigcal mechansim for it is not comepltely understood. To date though, nothing on Mu2 points to it.
On euphoria, a different mechanism, there is whole range of interacting components. Some substances that do not have the whole facet of the crucial axiom have enough of the mechanism to be effective with what is accepted to be an overcompensation via one of the many other corresponding mechanisms...cAMP for example, and so on. However, methadone has no compensatory attributes. It would, if it could, need to rely on that crucial ommision, that flaw (if you will) in its structure.
"Limpet can testify that it foes have euphoria.": Limpet, is it not clear yet? IF your feelings are going to be the deciding factor, then mine have just as much right. This is why scientists rely instead on blind trials, etc., etc.
"Limpet believes the 'Morphine Rule' is more of a 'Morphine Guide'.": Itis in a manner of speaking. It is used to evaluate substances and those that conform in 3 out of 4 mjor axioms are then judged to be morphine class opiates/opioids and are evaluated per se. Certainly you recognise that even substances who have less than 3 axioms like the Fentanyls (as I like to call them) are STILL compared to morphine! Ever notice that EVERY opiate/opioid (NO EXCEPTIONS) is cimpared to morphine in terms of potency, onset, duration, analgesia, and so on?
However, it is not a "Guide" in the sense that you are trying to suggest. Something becomes Accepted (close enough to be considered factual in most cases or actually factual in others) when a majority of specialists in a genre concur on the finding. The Morphine Rule is THE Gold Standard. Even if you end up gaining a degree in a relvant genre, and publish a peer reviwed finding pointing in the diameritcally opposed direction, it is not going to matter UNLESS the majority sees it your way.
Now, I will be the first to point out the inherent problem with this process. Simply examine the field of Physics and Faraday...Even Einstein was considered a quack for the better portion of his professional life. However, these are men who trained in their respective disciplines for years. In addition, they provided theories that ended up changing the face of the planet by empirical research.
Are you degrees in pharmokineticks? Pharmocology? Physiology? Peer Reviewed? I am not calling you out or even angry with you, I am trying to illustrate that your seeing it one way is not going to change an accepted scientific certainty, and in this particular case an actually proven fact.
Look, in the end all that should matter to you with regards to the substance is the worth you believe you receive. What a million researchers say is not soemthing that should matter in whether or not you find it a worthwhile thing.
"Since Fentanyls, et al do not conform to the Rule, they render the Rule moot, obsolete.": No offence, but you are not understanding the Rule. I explained a bit earlier that there is a specific manner in which substances are avaulated with regard to the Rule. Obsolete? Yeah, tell me about it when the first attribute mentioned in any of the substances in the entire chain as well as any other opiate/opioid/or even possible class member when it is investigated. THEY ARE COMPARED TO MORPINE.
1500x, 0.01x, and so on. Since, as we both agree, both classes you just mentioned do NOT conform to the Rule, why make the comparison? Why make it before all else? MORPHINE IS THE GOLD STANDARD.
Fast: Euphoria with 10 mg oral? Yikes hahaha but at least you feel that it is worthwhile and in the end, as I have stated, that should be what indifviduals care about. However, if we measure your shphincter hahahahahaha. Or your GI motility...The tail twitching? Hahahaha.
Fast....Say is ain't so! You ,telling us how you feel? You, the mind of reason?
Snowbear: "Does anyone besides Rachamim doubt methadone's ability to provide euphoria?": Uh, the entire Scientific Community. This is exactly why methadone is the DOC for OST. Please research it, as I asked all people to od way back in the beginning of the thread.
"Euphoria is the most subjective...": That is why scientists quantify it instead of relying on 100 people describing the colour blue.
If you had to describe the coulr teal to a person blind form birth? You could HOWEVER explain it in scientific and quantifiable terms. Does that help you to see it a bit differently?
Since 100 people will tell you a 100 different things, it is completely worthless. If you have consistent scientific findings though, using time proven investigavtive protocols, it becomes alot easier to develop a view. Yes?
TChort: "Alkalinity in relation to renal evacutaion/metabolism.": Only in a very marginal and indiscernible way.
First, as I pointed out to the OP bacmk in the beginning, you are talking about a substance with an oral bio of between 80 and 87% depending on the trial we examine. This is one of the highest oral bios in existence. Inefficent itis not. However, of course 13 to 20 points is alot of room for improvement
BUT, when you examine renal function and plasma levels, which is what you are referring to, you have to realise that substances need to be examined via their constituent metabolites. So, would there be any improvement? I offer thaty it would not be any you would ever notice.
"Grapefruit.": No, you are wrong on that one. I explained in a thread that must be archived, I believe it was this year, in OD if you care to dig for it. I will summarise quickly though, for the sake of brevity; Well, better just save the time and point you to the Refs and let them explain,
I) "The Effects of Inhibting Cytochrome p450,3A P-glycoprotein and Gastric Acids" by Kukanich, et al in "Journal of Vetenarian Pharmocology and Therapeutics" 10/2005 Vol. 28, Issue#5, pp 461-466
and
II) " Role of Hepatic and Intestinal Cytochrome p450, 3A and 2B6 In the Metabolism and Disposition and Miotic Effects of Methadone" by Kharasc, et al in "Clincial Pharmacological Therapy: 9/2004 Volume 76, Issue# 3 pp 250-269.
There is discernible difference whatsoever and in one of the studies there was even a decreased bio! The issue, and I will summarise it very simply, has to do with the location of the relevant 3A substrate, it is in the lower intestine not the stomach.
On your question regarding SSRIs, in a nutshell no go. The issue with methadone is more towards substances that decrese its efficny, not increase it in any discernible way. There is at least one that DOES have a charted efect but it would not be in any kind of nitceable increment...although one should NEVER discount the Placebo Effect provided by the psychological knowledge that it is charted as such.
This is the thing with potentiation: Look for the most highly utilised substrate, then find a relatively innocuous substance that has nearly (or even more) efficeny via the same substrate. People over generalise and say all p450 wiill poentiate one another and on paper it usually seems like it but you need to examine the work very carefully.
On euphoria, a different mechanism, there is whole range of interacting components. Some substances that do not have the whole facet of the crucial axiom have enough of the mechanism to be effective with what is accepted to be an overcompensation via one of the many other corresponding mechanisms...cAMP for example, and so on. However, methadone has no compensatory attributes. It would, if it could, need to rely on that crucial ommision, that flaw (if you will) in its structure.
"Limpet can testify that it foes have euphoria.": Limpet, is it not clear yet? IF your feelings are going to be the deciding factor, then mine have just as much right. This is why scientists rely instead on blind trials, etc., etc.
"Limpet believes the 'Morphine Rule' is more of a 'Morphine Guide'.": Itis in a manner of speaking. It is used to evaluate substances and those that conform in 3 out of 4 mjor axioms are then judged to be morphine class opiates/opioids and are evaluated per se. Certainly you recognise that even substances who have less than 3 axioms like the Fentanyls (as I like to call them) are STILL compared to morphine! Ever notice that EVERY opiate/opioid (NO EXCEPTIONS) is cimpared to morphine in terms of potency, onset, duration, analgesia, and so on?
However, it is not a "Guide" in the sense that you are trying to suggest. Something becomes Accepted (close enough to be considered factual in most cases or actually factual in others) when a majority of specialists in a genre concur on the finding. The Morphine Rule is THE Gold Standard. Even if you end up gaining a degree in a relvant genre, and publish a peer reviwed finding pointing in the diameritcally opposed direction, it is not going to matter UNLESS the majority sees it your way.
Now, I will be the first to point out the inherent problem with this process. Simply examine the field of Physics and Faraday...Even Einstein was considered a quack for the better portion of his professional life. However, these are men who trained in their respective disciplines for years. In addition, they provided theories that ended up changing the face of the planet by empirical research.
Are you degrees in pharmokineticks? Pharmocology? Physiology? Peer Reviewed? I am not calling you out or even angry with you, I am trying to illustrate that your seeing it one way is not going to change an accepted scientific certainty, and in this particular case an actually proven fact.
Look, in the end all that should matter to you with regards to the substance is the worth you believe you receive. What a million researchers say is not soemthing that should matter in whether or not you find it a worthwhile thing.
"Since Fentanyls, et al do not conform to the Rule, they render the Rule moot, obsolete.": No offence, but you are not understanding the Rule. I explained a bit earlier that there is a specific manner in which substances are avaulated with regard to the Rule. Obsolete? Yeah, tell me about it when the first attribute mentioned in any of the substances in the entire chain as well as any other opiate/opioid/or even possible class member when it is investigated. THEY ARE COMPARED TO MORPINE.
1500x, 0.01x, and so on. Since, as we both agree, both classes you just mentioned do NOT conform to the Rule, why make the comparison? Why make it before all else? MORPHINE IS THE GOLD STANDARD.
Fast: Euphoria with 10 mg oral? Yikes hahaha but at least you feel that it is worthwhile and in the end, as I have stated, that should be what indifviduals care about. However, if we measure your shphincter hahahahahaha. Or your GI motility...The tail twitching? Hahahaha.
Fast....Say is ain't so! You ,telling us how you feel? You, the mind of reason?
Snowbear: "Does anyone besides Rachamim doubt methadone's ability to provide euphoria?": Uh, the entire Scientific Community. This is exactly why methadone is the DOC for OST. Please research it, as I asked all people to od way back in the beginning of the thread.
"Euphoria is the most subjective...": That is why scientists quantify it instead of relying on 100 people describing the colour blue.
If you had to describe the coulr teal to a person blind form birth? You could HOWEVER explain it in scientific and quantifiable terms. Does that help you to see it a bit differently?
Since 100 people will tell you a 100 different things, it is completely worthless. If you have consistent scientific findings though, using time proven investigavtive protocols, it becomes alot easier to develop a view. Yes?
TChort: "Alkalinity in relation to renal evacutaion/metabolism.": Only in a very marginal and indiscernible way.
First, as I pointed out to the OP bacmk in the beginning, you are talking about a substance with an oral bio of between 80 and 87% depending on the trial we examine. This is one of the highest oral bios in existence. Inefficent itis not. However, of course 13 to 20 points is alot of room for improvement
BUT, when you examine renal function and plasma levels, which is what you are referring to, you have to realise that substances need to be examined via their constituent metabolites. So, would there be any improvement? I offer thaty it would not be any you would ever notice.
"Grapefruit.": No, you are wrong on that one. I explained in a thread that must be archived, I believe it was this year, in OD if you care to dig for it. I will summarise quickly though, for the sake of brevity; Well, better just save the time and point you to the Refs and let them explain,
I) "The Effects of Inhibting Cytochrome p450,3A P-glycoprotein and Gastric Acids" by Kukanich, et al in "Journal of Vetenarian Pharmocology and Therapeutics" 10/2005 Vol. 28, Issue#5, pp 461-466
and
II) " Role of Hepatic and Intestinal Cytochrome p450, 3A and 2B6 In the Metabolism and Disposition and Miotic Effects of Methadone" by Kharasc, et al in "Clincial Pharmacological Therapy: 9/2004 Volume 76, Issue# 3 pp 250-269.
There is discernible difference whatsoever and in one of the studies there was even a decreased bio! The issue, and I will summarise it very simply, has to do with the location of the relevant 3A substrate, it is in the lower intestine not the stomach.
On your question regarding SSRIs, in a nutshell no go. The issue with methadone is more towards substances that decrese its efficny, not increase it in any discernible way. There is at least one that DOES have a charted efect but it would not be in any kind of nitceable increment...although one should NEVER discount the Placebo Effect provided by the psychological knowledge that it is charted as such.
This is the thing with potentiation: Look for the most highly utilised substrate, then find a relatively innocuous substance that has nearly (or even more) efficeny via the same substrate. People over generalise and say all p450 wiill poentiate one another and on paper it usually seems like it but you need to examine the work very carefully.
)
