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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 7 to 31 of 34. Go back in thread:
Posted by Philidor on August 22, 2004, at 18:19:00
In reply to The *Real* Truth about Stimulant Tolerance, posted by Ame Sans Vie on August 22, 2004, at 6:18:17
Ame,
First of all WHO TOLD YOU ABOUT MY PANTIES?Second, I left a post to you the other day, which I guess you never read:
http://www.dr-bob.org/babble/20040817/msgs/379462.htmlAnyhow, pleased to meet you.
A couple of things about what you say above. I congratulate you on your not developing any tolerance to Adderall, but then a lot of people NEVER develop tolerance, or not much, to stimulants even after years of use.
So the question is, Have you EVER had to take much more Add than 30mg a day because it stopped working? If so, how much were you taking ?
If not, what makes you think your non-tolerance is because of the DXM, and not just God-given?
Reminds me of that joke about the guy who sees his friend applying this really smelly ointment to himself.
"PEEE-YEW!", says his friend, "What IS that awful stuff you're putting on?"
"It's tsetsefly repellent. I don't want to get sleeping sickness!" say the guy.
"But, you fool," says his friend, "there are no tsetse flies on the whole continent?"
"I know," says the guy, "the stuff really works!"
And I don't care how powerful the drug companies are, if somebody found that drinking Robitussin could prevent or reverse drug tolerance, it would be all over the street and the internet and Rush Limbaugh, for example, would not have developed his addiction nor would many other people who find they need higher and higher doses of opiates to relieve their pain.
And yes, I do read the studies, which interest me far more than the brilliant theorizing: the proof of the pudding is in the eating. An yeah, I've heard of Mophidex.
The latest testing indicates that DMX enhances the effects of smaller doses of morphine but actually LESSENS the potency of high-doses of morphine. Go figure.
But this has nothing to do with "tolerance" per se.
HOWEVER, A study done a couple of years ago came to the fascinating conclusion that DMX in MICRO-DOSES actually DOES reverse tolerance to opioids. For that see my earlier posts:
http://www.dr-bob.org/babble/20040817/msgs/379176.html
...and the post just before it, in which I offer the very hypothesis you do, that if DMX works for opioid tolerance might it possibly work for stimulant tolerance? But all of this remains
speculative.It is far from PROVEN as you seem to think.
The whole business of drug tolerance is fascinating and incredibly complex. For a brief but intensely interesting take on theject by a pioneer in Ritalin use for ADHD, I invite readers to check out:
http://www.adders.org/info28.htm
Phil
Posted by elleff on August 23, 2004, at 0:50:27
In reply to The Truth about Stimulant Tolerance, posted by Philidor on August 21, 2004, at 19:51:35
Dear Philidor
This may be of no use nor benefit, but I post this link because I happened to come across this old paper recently:
"Inhibition of Amphetamine Tolerance and Metabolism by Propranolol" - Shoeman DW, Sirtori CR, & Ararnoff DL, Journal of Pharmacology and Experimental Therapeutics (1974) v191 (1):68 - 71.
This reports studies on the pharmacokinetics and anorectic effect of amphetamine on laboratory rats, which showed, from my amatuer reading, an inhibition of amphetamine breakdown rather than any alteration in pharmacodynamics.
I haven't seen nor heard any references to similar effects on humans on this board or elsewhere however.
regards
elleff
Posted by elleff on August 23, 2004, at 0:54:56
In reply to Re: The Truth about Stimulant Tolerance, posted by elleff on August 23, 2004, at 0:50:27
> Dear Philidor
>
> This may be of no use nor benefit, but I post this link because I happened to come across this old paper recently:
>
> "Inhibition of Amphetamine Tolerance and Metabolism by Propranolol" - Shoeman DW, Sirtori CR, & Ararnoff DL, Journal of Pharmacology and Experimental Therapeutics (1974) v191 (1):68 - 71.
>
> This reports studies on the pharmacokinetics and anorectic effect of amphetamine on laboratory rats, which showed, from my amatuer reading, an inhibition of amphetamine breakdown rather than any alteration in pharmacodynamics.
>
> I haven't seen nor heard any references to similar effects on humans on this board or elsewhere however.
>
> regards
>
> elleffPS sorry, forgot to include the link (but it's not much use because no abstract available):
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=4418151
Posted by sb417 on August 23, 2004, at 1:01:22
In reply to Re: The Truth about Stimulant Tolerance, posted by elleff on August 23, 2004, at 0:50:27
>> > This reports studies on the pharmacokinetics and anorectic effect of amphetamine on laboratory rats, which showed, from my amatuer reading, an inhibition of amphetamine breakdown rather than any alteration in pharmacodynamics.> > regards
> > elleffHello elleff. Your interpretation makes sense. Propranolol mildly inhibitis the enzyme, cytochrome P450 2D6. Amphetamines are substrates of that same enzyme, so if that enzyme is inhibited, there may not be enough available to thoroughly metabolize amphetamine.
Posted by Philidor on August 23, 2004, at 11:15:03
In reply to Re: The Truth about Stimulant Tolerance, posted by elleff on August 23, 2004, at 0:54:56
> > Dear Philidor
> >
> > This may be of no use nor benefit, but I post this link because I happened to come across this old paper recently:
> >
> > "Inhibition of Amphetamine Tolerance and Metabolism by Propranolol" - Shoeman DW, Sirtori CR, & Ararnoff DL, Journal of Pharmacology and Experimental Therapeutics (1974) v191 (1):68 - 71.
> >
> > This reports studies on the pharmacokinetics and anorectic effect of amphetamine on laboratory rats, which showed, from my amatuer reading, an inhibition of amphetamine breakdown rather than any alteration in pharmacodynamics.
> >
> > I haven't seen nor heard any references to similar effects on humans on this board or elsewhere however.
> >
> > regards
> >
> > elleff
>
> PS sorry, forgot to include the link (but it's not much use because no abstract available):
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=4418151
>
Greetings elleff, thanks for that link.My only comment on the study---since I'm unable to read it, is that it's 30 YEARS OLD! If proprananol, a beta-blocker that is used all the time by doctors, did indeed prevent tolerance developing to stimulants in HUMANS, it would be common knowledge and routinely prescribed for just that purpose. (As a psych-med, it's still sometimes used to treat "stage fright", among other things, with mixed results.)
The fact that it is not, and that you've seen nothing further published on the subject, should tell you something.
This sort of thing happens ALL THE TIME in phamaceutical research. A single study on lab rats indicates that drug X cures or prevents disorder Y, causing initial interest, or even excitment, which quickly fades when follow-up studies fail to produce the same result.
That's why it's wise to withhold judgement until all the results are confirmed, and to ignore the impressive-sounding theorizing from so-called experts giving you lots of "scientific" reasons why melatonin, or whatever, is bound to be the answer to insomnia, (or whatever).
"Show me the money!", I say.
Best,
Phil
PS Of course,there's no harm in TRYING some of these potential remedies as long as the costs and risks are acceptable to you. You never know. Like, I've tried melatonin for insomnia myself, (and gotten the same disappointing results as most people.)
Posted by alesta on August 23, 2004, at 11:43:49
In reply to Re: The *Real* Truth about Stimulant Tolerance, posted by Philidor on August 22, 2004, at 18:19:00
hi, phil,
i enjoyed your stimulating, thought-provoking commentary. and i agree: show me the money!:)
amy :)
Posted by Dr. Bob on August 23, 2004, at 13:44:22
In reply to The *Real* Truth about Stimulant Tolerance, posted by Ame Sans Vie on August 22, 2004, at 6:18:17
> All you geniuses who claim that gulping cough syrup till you puke or taking grampa's Alzheimer's meds or whatever will make the Ritalin work again are simply full of it.
>
> Philidor> My guess is that you haven't done your research into this ... or else you wouldn't be quite so unnecessarily bitter.
>
> obviously you're not aware of the power the pharmaceutical industry holds
>
> Ame Sans ViePlease don't jump to conclusions about others or post anything that could lead others to feel accused or put down.
Anyone who has questions about this or about posting policies in general, or who is interested in alternative ways of expressing themselves, should see the FAQ:
http://www.dr-bob.org/babble/faq.html#civil
Also, follow-ups regarding these issues should be redirected to Psycho-Babble Administration.
Thanks,
Bob
Posted by Philidor on August 23, 2004, at 15:58:30
In reply to Re: please be civil » Philidor » Ame Sans Vie, posted by Dr. Bob on August 23, 2004, at 13:44:22
Dear Doc,
Your point is well taken and in the future I will honor your request.
My initial post was written in a fit of pique and was aimed at NO ONE in particular. While I stand by the point behind it, I should have made it more tactfully.
Phil
Posted by zeugma on August 23, 2004, at 18:58:31
In reply to Re: The *Real* Truth - zeugma too, posted by KaraS on August 22, 2004, at 15:24:00
hi kara,
i can do little other than post the results of my own experiments in reducing stim tolerance- see my post in reply to alesta further down. It puzzles me about NMDA antagonists being potentially useful- my understanding of the function of NMDA receptors, based on the textbook i have quoted extensively from, is that NMDA receptors facilitate synaptic plasticity, which would seem to be a good thing, and i had always thought that PCP, a powerful dissociative agent, was a NMDA antagonist. I can only surmise that neuroadaptation to stimulant effects is responsible for tolerance, and that by blocking this adaptation, the mind remains in an artificially 'drug-naive' state. That's my guess from poring over my dubiously accurate textbook, which does not, of course, address the problem of stimulant tolerance at all. Shame- he should do better next time. (And maybe the next edition will contain glowing accounts of the antidepressive effects of noradrenergic neurotransmission, in the wake of Cymbalta's dazzling success. One can only hope.)
-z
-z
Posted by KaraS on August 23, 2004, at 20:57:48
In reply to Re: The *Real* Truth - zeugma too » KaraS, posted by zeugma on August 23, 2004, at 18:58:31
> hi kara,
>
> i can do little other than post the results of my own experiments in reducing stim tolerance- see my post in reply to alesta further down. It puzzles me about NMDA antagonists being potentially useful- my understanding of the function of NMDA receptors, based on the textbook i have quoted extensively from, is that NMDA receptors facilitate synaptic plasticity, which would seem to be a good thing, and i had always thought that PCP, a powerful dissociative agent, was a NMDA antagonist. I can only surmise that neuroadaptation to stimulant effects is responsible for tolerance, and that by blocking this adaptation, the mind remains in an artificially 'drug-naive' state. That's my guess from poring over my dubiously accurate textbook, which does not, of course, address the problem of stimulant tolerance at all. Shame- he should do better next time. (And maybe the next edition will contain glowing accounts of the antidepressive effects of noradrenergic neurotransmission, in the wake of Cymbalta's dazzling success. One can only hope.)
>
> -z
>
> -z
>
>
Thanks. Absolutely on the Cymbalta. Are you thinking of trying it or are you just saying that for everyone else?
Posted by zeugma on August 23, 2004, at 21:09:28
In reply to Re: The *Real* Truth - zeugma too » zeugma, posted by KaraS on August 23, 2004, at 20:57:48
I'm saying it for everyone else. Nortriptyline is working, although it has its inconveniences. But I am positive that Cymbalta is going to help many, many people.Do you plan to try it soon?
-z
Posted by KaraS on August 23, 2004, at 22:15:05
In reply to Re: The *Real* Truth - zeugma too » KaraS, posted by zeugma on August 23, 2004, at 21:09:28
> I'm saying it for everyone else. Nortriptyline is working, although it has its inconveniences. But I am positive that Cymbalta is going to help many, many people.Do you plan to try it soon?
>
> -z
>
>
z,
I have a really good feeling about Cymbalta as well. I'm not planning on trying it right away though. I have a couple of other things I'll try first but I'll probably end up trying it down the road. I'm watching all of the reports and keeping my fingers crossed for those who are tyring it now.Kara
Posted by zeugma on August 24, 2004, at 4:30:38
In reply to Re: The *Real* Truth - zeugma too » zeugma, posted by KaraS on August 23, 2004, at 22:15:05
Posted by Terry on August 24, 2004, at 10:06:42
In reply to The *Real* Truth about Stimulant Tolerance, posted by Ame Sans Vie on August 22, 2004, at 6:18:17
>
> ~Michael
> (14 months using Adderall for depression with NO development of tolerance to euphorigenic or antianergic effects, thanks to DXM)
What is DXM?Terry
Posted by Philidor on August 24, 2004, at 11:42:14
In reply to Re: The *Real* Truth - zeugma too » KaraS, posted by zeugma on August 23, 2004, at 18:58:31
To Zeugma:
"i can do little other than post the results of my own experiments in reducing stim tolerance- see my post in reply to alesta further down."Well, where the heck IS that post? I'd like to see those results.
Concerning NMDA antagonists, you are quite right in saying that, NMDA antagonists (such as dextromethorphan (DMX)), should be worthless at best for inhibiting tolerance to morphine. But in one study it not only did, but REVERSED tolerance in human patients. Incredible? Well, the researchers who did the study thought so too:
"When we received the results from the first experiment, I couldn't believe it. Everything we knew up to that point indicated that it shouldn't work - but it did!" (said Dr.)Jhamandas."
http://opioids.com/tolerance/paincontrol.html
Apparently, DXM's biochemical action is dose-related. In micro-doses, it seems to work in reverse and becomes an NMDA agonist!
But this is just one study, and needs furthur investigation.
Phil
Posted by SLS on August 24, 2004, at 14:16:35
In reply to Re: The *Real* Truth - zeugma too, posted by Philidor on August 24, 2004, at 11:42:14
> "i can do little other than post the results of my own experiments in reducing stim tolerance- see my post in reply to alesta further down."
>
> Well, where the heck IS that post? I'd like to see those results.You might want to do a search here on Psycho-Babble for posts submitted by AndrewB. He was an excellent reporter of his experiences with various drug trials. His posts describing his success with memantine potentiating the psychostimulant and anti-social anxiety effects of Adderall are compelling. He later switched from memantine (Namenda), an uncompetitive NMDA receptor antagonist to acamprosate (Campral), a glutamate release inhibitor, a drug recently approved in the US for the treatment of alcoholism. He preferred the acamprosate, but I can't remember why.
- Scott
Posted by zeugma on August 24, 2004, at 17:41:34
In reply to Re: The *Real* Truth - zeugma too, posted by Philidor on August 24, 2004, at 11:42:14
My plan to address stimulant tolerance is very simple, and grows kind of naturally out of my circumstances. I had a prescription for Provigil and for Ritalin, with instructions to try them both. I tried Provigil first, which was my dr.s preference. It worked, but certain undesirable side effects- insomnia, GI distress- made it difficult to get up to 100 mg/day, let alone the 200 mg/day that is the target dosage. I tried the Ritalin next, in 10 mg LA capsules. That one worked with no s/e, so I stayed with that one for a while. Because I am also taking a TCA, and Ritalin can have cardio- s/e, I haven't wanted to push the dose any higher without consulting my dr. in person, but 10 mg is not enough. So I added 50 mg Provigil and it seems to have an augmentive effect. The two drugs work in different parts of the brain- see http://www.pnas.org/cgi/content/full/93/24/14128 -
so i'm not worried about redundancy, but of course no one has a clear idea of what modafinil does. I'll post later on what effect I think Provigil has on me, but that will be the topic for a separate thread.-z
Posted by Dr. Bob on August 24, 2004, at 19:35:02
In reply to Re: please be civil, posted by Philidor on August 23, 2004, at 15:58:30
Posted by Dave001 on August 24, 2004, at 20:30:52
In reply to Re: The *Real* Truth - zeugma too » Philidor, posted by zeugma on August 24, 2004, at 17:41:34
> My plan to address stimulant tolerance is very simple, and grows kind of naturally out of my circumstances. I had a prescription for Provigil and for Ritalin, with instructions to try them both. I tried Provigil first, which was my dr.s preference. It worked, but certain undesirable side effects- insomnia, GI distress- made it difficult to get up to 100 mg/day, let alone the 200 mg/day that is the target dosage. I tried the Ritalin next, in 10 mg LA capsules. That one worked with no s/e, so I stayed with that one for a while. Because I am also taking a TCA, and Ritalin can have cardio- s/e, I haven't wanted to push the dose any higher without consulting my dr. in person, but 10 mg is not enough. So I added 50 mg Provigil and it seems to have an augmentive effect. The two drugs work in different parts of the brain- see http://www.pnas.org/cgi/content/full/93/24/14128 -
> so i'm not worried about redundancy, but of course no one has a clear idea of what modafinil does. I'll post later on what effect I think Provigil has on me, but that will be the topic for a separate thread.
>Note that modafinil also causes significant induction of the CYP3A4/5 enzymes, and is an inducer of its own metabolism.
Dave
Posted by zeugma on August 25, 2004, at 5:32:44
In reply to Re: The *Real* Truth - zeugma too » zeugma, posted by Dave001 on August 24, 2004, at 20:30:52
Note that modafinil also causes significant induction of the CYP3A4/5 enzymes, and is an inducer of its own metabolism.
Dave
yes i know that. i take buspirone (30 mg) and clonazepam (1 mg) which could be affected by this. i'm not worried about the buspirone because that drug has such a short half life, and its metabolite (which will increase as a result of enzyme induction)is an alpha 2 antagonist which probably has a therapeutic effect for me. the clonazepam is more serious but i was taking Provigil for over a month at dosages up to 100 mg/day and did not notice increases in anxiety.
the problem is that i'm also taking nortriptyline 100 mg/day and that makes 5 meds taken concurrently which could be very complicated. if anything 3A induction would lower nortriptyline levels slightly. but it's the effect of all 5 that concerns me.
-z
Posted by SLS on August 25, 2004, at 7:17:06
In reply to Re: The *Real* Truth - zeugma too » Dave001, posted by zeugma on August 25, 2004, at 5:32:44
> Note that modafinil also causes significant induction of the CYP3A4/5 enzymes, and is an inducer of its own metabolism.
>
> Dave
>
> yes i know that. i take buspirone (30 mg) and clonazepam (1 mg) which could be affected by this. i'm not worried about the buspirone because that drug has such a short half life, and its metabolite (which will increase as a result of enzyme induction)is an alpha 2 antagonist which probably has a therapeutic effect for me. the clonazepam is more serious but i was taking Provigil for over a month at dosages up to 100 mg/day and did not notice increases in anxiety.
>
> the problem is that i'm also taking nortriptyline 100 mg/day and that makes 5 meds taken concurrently which could be very complicated. if anything 3A induction would lower nortriptyline levels slightly. but it's the effect of all 5 that concerns me.Hi Z.
I see that 3A is a minor pathway for nortriptyline metabolism.
Is there a site on the Internet you use to stay current on CYP450 information?
I have an older program that can compare the interactions of multiple medications. If you list them, I can check them for you.
- Scott
Posted by zeugma on August 25, 2004, at 7:29:02
In reply to Re: The *Real* Truth - zeugma too, posted by SLS on August 25, 2004, at 7:17:06
hi Scott,
mostly i search pub med for papers on interactions and combinations. i did find this interesting pdf file: http://www.primarypsychiatry.com/pdf/art_453.pdf
which contains interesting info, but as Preskorn (one of its compilers) notes, there is limited data on a lot of possible interactions.
i currently take:
100 mg nortriptyline
30 mg buspirone
10 mg Ritalin
1 mg clonazepam
20-50 mg Provigilit's the last one that does concern me, not least because its mechanism is currently only speculative. I am going to call my dr. soon also. if you could run these through your program i would be most grateful :)
thanks,
z
Posted by SLS on August 25, 2004, at 8:07:54
In reply to Re: The *Real* Truth - zeugma too » SLS, posted by zeugma on August 25, 2004, at 7:29:02
I don't know if this will add anything to what you already know, but...
****************************************
Nortriptyline: increased slightly by methylphenidate 2D6Nortriptyline: decreased slightly by modafinil 3A
Buspirone: decreased by modafinil 3A
Methylphenidate: increased slightly by nortriptyline 2D6
Modafinil: no change
Clonazepam: decreased by modafanil 3A
Clonazepam active metabolite: increased due to induction on parent compound..... "This therapeutically active metabolite may be increased because the parent compound's metabolism is induced by a cytochrome. The effect is like opening a flood gate leading to an increased level of the metabolized drug. This is especially significant if the metabolite contributes significantly to the therapeutic effect or the metabolite is the active drug and the drug given is not pharmacologically active."
****************************************
The program was published by a group from Harvard University. I think it is important to note that these interactions are "on paper" and that each and every one has not been determined clinically.
- Scott
Posted by zeugma on August 25, 2004, at 8:45:44
In reply to Re: The *Real* Truth - zeugma too » zeugma, posted by SLS on August 25, 2004, at 8:07:54
thanks a lot Scott. It looks like the pharmacokinetic interactions are minor. I still need to call my dr., but i'm a little less anxious.
by the way i thought that clonazepam's metabolite was inactive.
-z
Posted by SLS on August 25, 2004, at 9:15:12
In reply to Re: The *Real* Truth - zeugma too » SLS, posted by zeugma on August 25, 2004, at 8:45:44
> thanks a lot Scott. It looks like the pharmacokinetic interactions are minor. I still need to call my dr., but i'm a little less anxious.
>
> by the way i thought that clonazepam's metabolite was inactive.
>
> -z
I can't find anything on the Internet describing an active metabolite either. Is there such a thing as desmethylclonazepam?
- Scott
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