![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 19 of 19. This is the beginning of the thread.
Posted by JohnX2 on November 17, 2001, at 21:20:09
I thought this was an interesting article
discussing the means for development of amphetamine
sensitization/tolerance. Interesting conclusion
regarding serotonin being the culprit.http://www.ucsf.edu/cnba/Center/JournalClub/Articles/9780.pdf
Posted by Hattree on November 18, 2001, at 19:55:02
In reply to amphetamine sensitization article, posted by JohnX2 on November 17, 2001, at 21:20:09
Looks interesting but I'm too attention deficited to read it--what is the practical implication?
>
> I thought this was an interesting article
> discussing the means for development of amphetamine
> sensitization/tolerance. Interesting conclusion
> regarding serotonin being the culprit.
>
> http://www.ucsf.edu/cnba/Center/JournalClub/Articles/9780.pdf
Posted by JohnX2 on November 18, 2001, at 22:54:13
In reply to Re: amphetamine sensitization article » JohnX2, posted by Hattree on November 18, 2001, at 19:55:02
The practical implicaition is to understand the
underlying mechanism so that we can treat
addiction, tolerance, and sensitization to the
medication (in this case amphetamine).Sorry, it is extremely technical, but it is an
area I have been researching greatly because I
have a medication poop-out problem; this cruel
trick where a stimulant or anti-depressant works
for a few hours and then stops. I believe that
understand the addiction pathway and how to
alleviate it will counterattack my cruel friend
mr. dysthymia.And yes ironically
if you need amphetamines for ADD then
probably the article is a tough read!Are you ADD or was that just a simple statement
that the article is a bit boring and complex?If you are ADD do you take stimulants? Do they
always work at the same dose over time?regards,
-john
> Looks interesting but I'm too attention deficited to read it--what is the practical implication?
> >
> > I thought this was an interesting article
> > discussing the means for development of amphetamine
> > sensitization/tolerance. Interesting conclusion
> > regarding serotonin being the culprit.
> >
> > http://www.ucsf.edu/cnba/Center/JournalClub/Articles/9780.pdf
Posted by Lindsey3 on November 19, 2001, at 1:23:22
In reply to amphetamine sensitization article, posted by JohnX2 on November 17, 2001, at 21:20:09
Johnx2,
Good article. Lots of new research coming out. This is the stuff that can lead to the discovery of the cause of high comorbidity rates with depression/manic-depr./schizo./adhd,etc. and drug use. If you're meds "poop out" after a while, there are extended release forms that can work just as effectively. (Ritalin SR, Dexedrine Spansules, Prozac Weekly...). I take Adderall 10mg QID. Short enough time in between to not go thru the 'rebound'. --Lindsey
Posted by Hattree on November 19, 2001, at 8:35:37
In reply to Re: amphetamine sensitization article » Hattree, posted by JohnX2 on November 18, 2001, at 22:54:13
I have been diagnosed as ADD inattentive type (distinctly not hyperactive), along with dysthymia.
Stimulants help for both, but I too struggle with the poop out.I try to deal with it by switching back and forth between different stimulants and taking holidays (not easy--I have two little kids).
Now that I take lamictal, I can go days without the poop out and don't get as much anxiety (also the dysthymia is much better), but stimulant management is still a constant issue. I just got some L-tyrosine to try. Any experience with that?And yes, I have had to increase the dose over time, but I'm a small doses person, so that only means I'm up to about 7.5 mg/day of dextrostat, taken all at once. I supplement with a cup of coffee in the late afternoon.
>
> The practical implicaition is to understand the
> underlying mechanism so that we can treat
> addiction, tolerance, and sensitization to the
> medication (in this case amphetamine).
>
> Sorry, it is extremely technical, but it is an
> area I have been researching greatly because I
> have a medication poop-out problem; this cruel
> trick where a stimulant or anti-depressant works
> for a few hours and then stops. I believe that
> understand the addiction pathway and how to
> alleviate it will counterattack my cruel friend
> mr. dysthymia.
>
> And yes ironically
> if you need amphetamines for ADD then
> probably the article is a tough read!
>
> Are you ADD or was that just a simple statement
> that the article is a bit boring and complex?
>
> If you are ADD do you take stimulants? Do they
> always work at the same dose over time?
>
> regards,
> -john
>
>
> > Looks interesting but I'm too attention deficited to read it--what is the practical implication?
> > >
> > > I thought this was an interesting article
> > > discussing the means for development of amphetamine
> > > sensitization/tolerance. Interesting conclusion
> > > regarding serotonin being the culprit.
> > >
> > > http://www.ucsf.edu/cnba/Center/JournalClub/Articles/9780.pdf
Posted by JohnX2 on November 19, 2001, at 13:09:11
In reply to Re: amphetamine sensitization article, posted by Hattree on November 19, 2001, at 8:35:37
I've tried tyrosine supplement but generally
they only give a short lived response. The problem
is that tyrosine (the precursor to dopamine and
noradrenaline) is generally not the bottleneck
in producing those chemicals. The bottleneck
is something called tyrose hydroxylase, which
could be a target for anti-depressants in the
future.I think there is a good chance that meds will
come out that prevent "poop-out". At least
that is what I am experimenting with. A few
people on this group reported success with
memantine (available in germany, in phase III
clinical trials in the US) preventing
stimulant poop-out.-john
> I have been diagnosed as ADD inattentive type (distinctly not hyperactive), along with dysthymia.
> Stimulants help for both, but I too struggle with the poop out.
>
> I try to deal with it by switching back and forth between different stimulants and taking holidays (not easy--I have two little kids).
> Now that I take lamictal, I can go days without the poop out and don't get as much anxiety (also the dysthymia is much better), but stimulant management is still a constant issue. I just got some L-tyrosine to try. Any experience with that?
>
> And yes, I have had to increase the dose over time, but I'm a small doses person, so that only means I'm up to about 7.5 mg/day of dextrostat, taken all at once. I supplement with a cup of coffee in the late afternoon.
>
> >
> > The practical implicaition is to understand the
> > underlying mechanism so that we can treat
> > addiction, tolerance, and sensitization to the
> > medication (in this case amphetamine).
> >
> > Sorry, it is extremely technical, but it is an
> > area I have been researching greatly because I
> > have a medication poop-out problem; this cruel
> > trick where a stimulant or anti-depressant works
> > for a few hours and then stops. I believe that
> > understand the addiction pathway and how to
> > alleviate it will counterattack my cruel friend
> > mr. dysthymia.
> >
> > And yes ironically
> > if you need amphetamines for ADD then
> > probably the article is a tough read!
> >
> > Are you ADD or was that just a simple statement
> > that the article is a bit boring and complex?
> >
> > If you are ADD do you take stimulants? Do they
> > always work at the same dose over time?
> >
> > regards,
> > -john
> >
> >
> > > Looks interesting but I'm too attention deficited to read it--what is the practical implication?
> > > >
> > > > I thought this was an interesting article
> > > > discussing the means for development of amphetamine
> > > > sensitization/tolerance. Interesting conclusion
> > > > regarding serotonin being the culprit.
> > > >
> > > > http://www.ucsf.edu/cnba/Center/JournalClub/Articles/9780.pdf
Posted by JGalt on November 19, 2001, at 15:51:14
In reply to Re: amphetamine sensitization article » Hattree, posted by JohnX2 on November 19, 2001, at 13:09:11
John, did you ever read that web page that I sent you regarding amphetamine tolerance and neurotoxicity?
Here's an interesting excerpt from it:
http://www.acnp.org/g4/gn401000166/ch162.htm
"Methamphetamine toxicity is inhibited by a variety of drug treatments, including: 1) DA synthesis inhibitor alpha-methyl-para-tyrosine; 2) DA receptor antagonists; 3) NMDA receptor antagonists, e.g., MK-801; 4) DA and serotonergic reuptake inhibitors protecting against DA and serotonin toxicity respectively (195). Even though most studies have found that serotonergic and DA reuptake inhibitors specifically protect these two sites, certain reuptake blockers (such as benztropine) do not (195). On the other hand, mazindol, a non-specific blocker, protects against both DA and serotonergic neurotoxicity. Ali et al. (1994) have further demonstrated in mice that a major factor for neurotoxicity is hyperthermia which is highly correlated with the degree of long-term DA depletion (21). Furthermore, haloperidol, diazepam and MK-801, all of which can reduce methamphetamine-induced hyperthermia, protect rats against DA depletion (4). They also demonstrated that reducing the ambient temperature (4°C) reduced neurotoxicity to the same levels found when phenobarbital, diazepam and MK-801 were present to protect the cell. Tolerance to methamphetamine induced by increasing doses also reduces the hyperthermic response and as well protects against neurotoxicity (89, 188).
An important caveat is that not all protective mechanisms act by preventing the hyperthermic effect; the monoamine uptake blockers inhibit neurotoxicity in the absence of inhibition of hyperthermia, e.g., fluoxetine blocks methamphetamine serotonin toxicity without reducing temperature (140). The monoamine protection from neurotoxicity by reuptake inhibition is emphasized by the unexpected discovery that even massive and 24-hour continuous dosing of cocaine, e.g., 100 mg/kg/day, does not result in DA system neurotoxicity (119, 182, 183). Hyperthermia has been well documented to increase amphetamine stereotypy (93, 220). Hyperthermia alone is well known to result in neuronal chromatolysis and has been previously proposed as a significant contributor to amphetamine-induced DA depletion and neuronal damage in clinical as well as experimental animal histopathology (52). Hyperthermia may have been one of the factors resulting in deaths among athletes taking moderate doses of amphetamine in the 1960s and 70s (145). Even in mild hyperthermia, increased body temperature induces a linear decrease in the inhibitory feedback of stimulants on somatodendritic autoreceptors (130). Thus, body temperature changes induced by amphetamine should be considered as one of the contributors to toxicity. "I've read on this board ppl saying that Prozac+adderal doesn't poop out much...and this mazindol might even be a better idea. What do you think?
Posted by Hattree on November 19, 2001, at 20:58:17
In reply to Re: amphetamine sensitization article » Hattree, posted by JohnX2 on November 19, 2001, at 13:09:11
> I've tried tyrosine supplement but generally
> they only give a short lived response.what response was that, by the way?
Posted by JohnX2 on November 19, 2001, at 22:20:52
In reply to Re: amphetamine sensitization article » JohnX2, posted by Hattree on November 19, 2001, at 20:58:17
For about 2 weeks, I took 1-2 g tyrosine with
b vitamins. I would get about a 4 hr relief
from depression followed by poop-out. After
the 2 weeks it stopped working. I suspect
my body adapted to the excess amino acid.What was your experience?
-john
>
> > I've tried tyrosine supplement but generally
> > they only give a short lived response.
>
> what response was that, by the way?
Posted by JGalt on November 20, 2001, at 11:46:11
In reply to Re: amphetamine sensitization article » Hattree, posted by JohnX2 on November 19, 2001, at 22:20:52
John, I believe folic acid and Vitamin C are also needed for the conversion to neurotransmitters. Also note that these must be taken on an empty stomach (sugar is okay, no protein though), and no food for at least a half hour. I think N-acetyl-tyrosine works quite a bit better, as does DL-Phenylaline, but both seem to fade out after a while...I still get a moderate lift from them because I'm on selegiline, but its no where near what it was when I started. Perhaps the enzymes that convert these amino acids to neurotransmitters start to die off after being overloaded with the amino's too long? I don't know, though I do know that if I take a few days off the amino's and then start them up again I get a very noticeable lift. I believe the solution to this problem would be to take PEA (phenylethylamine) with selegiline, as pea doesn't require any conversion to be active. I don't think this would poop out as fast, but unfortunately pea is rather hard to get...too easy to convert it into methamphetamine or related compounds. If you do a search on the web though, some doctor has a patent on this method of relieving depression, PEA+selegiline, trying to sell it...don't know how you can do that, but its out there.
Posted by SLS on November 20, 2001, at 15:24:46
In reply to Re: amphetamine sensitization article, posted by JGalt on November 19, 2001, at 15:51:14
Hi.
> I've read on this board ppl saying that Prozac+adderal doesn't poop out much...and this mazindol might even be a better idea. What do you think?I have been interested in mazindol for quite some time. I believe it was initially investigated as an antidepressant. An anologue, ciclazindol, was also being developed as an antidepressant (by Wyeth, I think), but was dropped - probably for lack of efficacy.
Mazindol is a very selective ligand for the dopamine uptake transporter and is often used in assays. However, I am not sure if it actually inhibits the reuptake of dopamine.
Does anyone know?
If it is, it might be interesting to see if it has utility as an adjunct to antidepressants or to low-dosage neuroleptic strategies.
- Scott
Posted by Andy123 on November 23, 2001, at 10:27:34
In reply to Re: amphetamine sensitization article, posted by JGalt on November 19, 2001, at 15:51:14
This article is very alarming in that it indicates sensitization can occur at the very low therapuetic amphetamine doses used for ADD. I wish I'd read it a long time ago. I'm giving up d-amphetamine (even though I use it at a very low dose of 20mg/day.)
-Andy
> John, did you ever read that web page that I sent you regarding amphetamine tolerance and neurotoxicity?
>
> Here's an interesting excerpt from it:
>
> http://www.acnp.org/g4/gn401000166/ch162.htm
> "Methamphetamine toxicity is inhibited by a variety of drug treatments, including: 1) DA synthesis inhibitor alpha-methyl-para-tyrosine; 2) DA receptor antagonists; 3) NMDA receptor antagonists, e.g., MK-801; 4) DA and serotonergic reuptake inhibitors protecting against DA and serotonin toxicity respectively (195). Even though most studies have found that serotonergic and DA reuptake inhibitors specifically protect these two sites, certain reuptake blockers (such as benztropine) do not (195). On the other hand, mazindol, a non-specific blocker, protects against both DA and serotonergic neurotoxicity. Ali et al. (1994) have further demonstrated in mice that a major factor for neurotoxicity is hyperthermia which is highly correlated with the degree of long-term DA depletion (21). Furthermore, haloperidol, diazepam and MK-801, all of which can reduce methamphetamine-induced hyperthermia, protect rats against DA depletion (4). They also demonstrated that reducing the ambient temperature (4°C) reduced neurotoxicity to the same levels found when phenobarbital, diazepam and MK-801 were present to protect the cell. Tolerance to methamphetamine induced by increasing doses also reduces the hyperthermic response and as well protects against neurotoxicity (89, 188).
> An important caveat is that not all protective mechanisms act by preventing the hyperthermic effect; the monoamine uptake blockers inhibit neurotoxicity in the absence of inhibition of hyperthermia, e.g., fluoxetine blocks methamphetamine serotonin toxicity without reducing temperature (140). The monoamine protection from neurotoxicity by reuptake inhibition is emphasized by the unexpected discovery that even massive and 24-hour continuous dosing of cocaine, e.g., 100 mg/kg/day, does not result in DA system neurotoxicity (119, 182, 183). Hyperthermia has been well documented to increase amphetamine stereotypy (93, 220). Hyperthermia alone is well known to result in neuronal chromatolysis and has been previously proposed as a significant contributor to amphetamine-induced DA depletion and neuronal damage in clinical as well as experimental animal histopathology (52). Hyperthermia may have been one of the factors resulting in deaths among athletes taking moderate doses of amphetamine in the 1960s and 70s (145). Even in mild hyperthermia, increased body temperature induces a linear decrease in the inhibitory feedback of stimulants on somatodendritic autoreceptors (130). Thus, body temperature changes induced by amphetamine should be considered as one of the contributors to toxicity. "
>
> I've read on this board ppl saying that Prozac+adderal doesn't poop out much...and this mazindol might even be a better idea. What do you think?
Posted by SLS on November 23, 2001, at 16:46:29
In reply to Re: amphetamine sensitization article, posted by Andy123 on November 23, 2001, at 10:27:34
> This article is very alarming in that it indicates sensitization can occur at the very low therapuetic amphetamine doses used for ADD. I wish I'd read it a long time ago. I'm giving up d-amphetamine (even though I use it at a very low dose of 20mg/day.)
> -Andy
Hi Andy.What things in the article do you find alarming?
Why do you feel that these things would make it advisable for you to discontinue your medication?
Is your medication still helping you?
Thanks.
- Scott
Posted by nightlight on November 24, 2001, at 13:31:52
In reply to Re: amphetamine sensitization article, posted by Andy123 on November 23, 2001, at 10:27:34
> This article is very alarming in that it indicates sensitization can occur at the very low therapuetic amphetamine doses used for ADD. I wish I'd read it a long time ago. I'm giving up d-amphetamine (even though I use it at a very low dose of 20mg/day.)
> -AndyHi Andy,
I, too, read the article with great interest, as I have recently been prescibed stimulants and have been trying to find out as much about them as possible.
The article is quite long, as thorough as possible, given certain restrictions on long-term testing of some pertinent groups, but, the overall conclusion, for those *human* patients who take therapeutic doses of amphetamines/ritalin is positive and fairly benign.
But, you have to get to the last section or so, before this is made clear. (There is a great deal of discussion about animal studies and the effects of stimulants on schizophrenics and seasoned meth abusers which can mislead the layman, like me, unless the entire article is studied). Amphetamine psychosis is quite rare among those who take prescribed dosages, and current scientific data suggests that the use of stimulants in childhood and adolescence probably *reduces* substance abuse in the patient who was properly diagnosed and treated for ADHD/ADD.I thought the article was pretty good for allaying some of my fears, although it did remind me that one does not want to consider the taking of any psychotropic med lightly.
I echo Scott in wondering what you found so disturbing about the article. I did simply scan some of it (mostly the stereotypical animal behaviour studies towards the end). So, maybe I missed something???
sincerely~nightlight
>
> > John, did you ever read that web page that I sent you regarding amphetamine tolerance and neurotoxicity?
> >
> > Here's an interesting excerpt from it:
> >
> > http://www.acnp.org/g4/gn401000166/ch162.htm
> > "Methamphetamine toxicity is inhibited by a variety of drug treatments, including: 1) DA synthesis inhibitor alpha-methyl-para-tyrosine; 2) DA receptor antagonists; 3) NMDA receptor antagonists, e.g., MK-801; 4) DA and serotonergic reuptake inhibitors protecting against DA and serotonin toxicity respectively (195). Even though most studies have found that serotonergic and DA reuptake inhibitors specifically protect these two sites, certain reuptake blockers (such as benztropine) do not (195). On the other hand, mazindol, a non-specific blocker, protects against both DA and serotonergic neurotoxicity. Ali et al. (1994) have further demonstrated in mice that a major factor for neurotoxicity is hyperthermia which is highly correlated with the degree of long-term DA depletion (21). Furthermore, haloperidol, diazepam and MK-801, all of which can reduce methamphetamine-induced hyperthermia, protect rats against DA depletion (4). They also demonstrated that reducing the ambient temperature (4°C) reduced neurotoxicity to the same levels found when phenobarbital, diazepam and MK-801 were present to protect the cell. Tolerance to methamphetamine induced by increasing doses also reduces the hyperthermic response and as well protects against neurotoxicity (89, 188).
> > An important caveat is that not all protective mechanisms act by preventing the hyperthermic effect; the monoamine uptake blockers inhibit neurotoxicity in the absence of inhibition of hyperthermia, e.g., fluoxetine blocks methamphetamine serotonin toxicity without reducing temperature (140). The monoamine protection from neurotoxicity by reuptake inhibition is emphasized by the unexpected discovery that even massive and 24-hour continuous dosing of cocaine, e.g., 100 mg/kg/day, does not result in DA system neurotoxicity (119, 182, 183). Hyperthermia has been well documented to increase amphetamine stereotypy (93, 220). Hyperthermia alone is well known to result in neuronal chromatolysis and has been previously proposed as a significant contributor to amphetamine-induced DA depletion and neuronal damage in clinical as well as experimental animal histopathology (52). Hyperthermia may have been one of the factors resulting in deaths among athletes taking moderate doses of amphetamine in the 1960s and 70s (145). Even in mild hyperthermia, increased body temperature induces a linear decrease in the inhibitory feedback of stimulants on somatodendritic autoreceptors (130). Thus, body temperature changes induced by amphetamine should be considered as one of the contributors to toxicity. "
> >
> > I've read on this board ppl saying that Prozac+adderal doesn't poop out much...and this mazindol might even be a better idea. What do you think?
Posted by Andy123 on November 24, 2001, at 18:17:37
In reply to Re: amphetamine sensitization article » Andy123, posted by nightlight on November 24, 2001, at 13:31:52
I had noted some of these behaviors while using the drug:
"The stimulant-induced hyper-reactivity is characterized by a short
period of stereotypy followed by repetitive hyper-reactive behaviors. The hyper-reactive behaviors include 1) hyper-startle responses; 2) jerking or reactive orienting movements to unseen stimuli; 3) hyper-reactive movement to the animals own bodily functions such as salivation; 4) hyper-reactive side-to-side looking movements; "The first physician who prescribed a stimulant to me had indicated that some of these hyper-reactive behaviors are a relatively common side effect of the drug. I had always chalked it up to anxiety.
What I didn't say in my previous post was that I had been taking a low dose of a TCA to even out response. Taking both together is known to increase the amount of amphetamine that ends up in brain tissue. I'm not sure, but this might have put me in some amount of danger of initiating the cascading events that lead to hypersensitivity and then to psychosis.I think this was also relevant:
"That behavioral tolerance develops to both cocaine and amphetamine provides evidence that tolerance and neurotoxicity are separable phenomena, since very high doses of cocaine do not induce neuronal damage (119, 183)"In the text before this quote, the author had been focusing on reverse sensitization. The dosages that cause histologically discernable damage are much higher than those that cause reverse sensitivity. So reverse sensitivity is the thing that bothers me. I don't want to have a psychotic break anytime soon :) Really, though I was doing fine with the dosaging regimen of 20 mg + low dose TCA, but on Thursday I kind of went into a "catatonic stupor." [At least that is what it would have appeared to someone observing me. I just sat around and contemplated things for about 1.5 days and I was extremely dysphoric.] At that time, I was thinking that I was causing this difficulty by taking stimulants with the TCA.
The other odd thing is that I took about 4 grams of vitamin C to help remove the drug from my system [lowers urine pH] and of course I started to feel terrible. Today, however, I haven't taken any stimulant and but I am not having my usual withdrawal. Usually when i don't take the stimulant I get very lethargic. Today I have as much energy as I would if I were taking the medicine, although my concentration isn't as good.
So really I should have qualified my comments to say that the decision to stop taking stimulants (for now) was because I had possibly overdone it with the TCA + dexedrine mixture.
Sorry if any of this seems incoherent :)
-Andy
Posted by benzapp on November 25, 2001, at 20:59:21
In reply to Re: amphetamine sensitization article, posted by Andy123 on November 23, 2001, at 10:27:34
I don't agree. The study deals with methamphetamine toxicity, particularly to seratonine and dopamine receptors. Due to some alarming errors that should be evident to many people, I question its accuracy. Stimulants are stimulants because they affect the adrenal system or mimic its function. The end result of any stimulant, cocaine, amphetamine or epinephrine released by your adrenal gland due to stress will raise your body temperature. Stimulants affect metabolic rate, that is your body's utilization of stored energy. Stimulants cause weight loss by increasing the metabolic rate, utilizing more stored energy (fat). 100mg/kg? Thats insane. Maybe with a rat. But I dare you to eat 30 grams of cocaine, hyperthermia will be the least of your problems. Also, with cocaine, the dopamine reuptake affect is a THEORY, and a highly unproven one at that. Its stimulant effect actually seems to be caused due to inducing cortisol release, which causes epinephrine to be released.
The drugs mentioned that supposedly protect against neuron damage and hyperthermia due so because they suppress the stress response induced by these drugs. Without getting into the physiology, natural stimulant reactions occur due to the following: antagonised GABA-A receptors cause the anterior pitutary gland in the brain to release the Adrenocorticotropic hormone, which in turn causes the adrenal gland to release corisol and epinephrine. Basically, the drugs are GABA-A antagonists, and interfere with the entire stress response. Hyperthermia doesn't occur because the body no longer thinks it needs to prepare for a life threatening battle. For the Opiate advocates out there, endorphins mediated by the hypothalamus potentiate endogenous GABA-A agonist production. Of course, cooling the ambient temperature to a level that makes it impossible for your body to increase in temperature will have the same effect. So, the article spend a great deal of time talking about how to counter act hyperthermia induced by the stress response.
The primary question is this, does hyperthermia cause dopamine axon damage in general, or only when present with amphetamine? The suggestion that cocaine is not damaging to dopamine axon terminals seems to suggest this, but this distinction is not made. Of course, if the former is true it would mean every time you have a fever you are killing brain cells.
Since the author believes cocaine does not damage dopamine axons versus amphetamine we need to determine what the difference is. Its not hyperthermia. I would argue that cocaine causes greater hyperthermia. But how does amphetamine work? Amphetamine works because it binds to adrenal receptors in the brain just like endogenous epinephrine does. Look at the structure of epinephrine and methamphetamine, and you will see some striking similarity. The primary difference is the lack of certain amines, similiar to DHEA.
The adrenal gland produces DHEA, a hormone necessary for DNA replication. Other hormones are site specific DHEA, that is they focus on growth of specific cells. Testoserone for instance is male sex specific DHEA, that causes growth in muscles and the gonads. I believe epinephrine does the same thing, but its DHEA is intended for the brain.
Damage to neuron axons seems to occur when the axon is unoccupied for extended periods of time, allowing free radicals to damage it. When you take amphetamine, it affects your brain like epinephrine, activating the same receptors, but amphetamine does not containe the necessary hormone utilized by DNA transcriptase. So while the brain wants to produce more dopamine, it lacks the ability to read a DNA strand and thus is unable to produce the proper proteins. If any neurotoxicity results, it is due to your brain using up dopamine thinking more will be made, which never happens. The exposed axons are vacated when dopamine runs out and are damaged by free radicals.
Cocaine probably doesn't cause dopamine axon damage because cocaine stimulates the release of natural epinephrine, which allows the further production of dopamine and thus the neurons are not as vacant.
Just to let you know, increased body temperature occurs due to increased energy utilization, either for locomotion or cellular activity. The reason you get a fever when you are sick is not to kill invading bacteria, but because your body is producing so many new cells at a rapid rate. The stress response is a combination of factors. Think cortisol is for repairing and mitigating damage to the body like what would occur in a fight, and epinephrine is for increasing respiration and mental accuity to deal with the perceived threat.
Lowering the metabolic rate by interfering with the endocrine system or by directly lowering the persons temperature only means that less cellular division will be taking place, meaning less activity in general will be taking place and dopamine won't be overutilized.
Now this is only a theory, the best I can do with this article. For someone who does not take amphetamine on a regular basis, and takes a high dose I would say this is more of a problem. In fact, I would venture to say that people who experience the scenario I described above probably took massive doses of methamphetamine.
But for people who take low doses of amphetamine on a daily basis, this does not happen. I take 40mg of Adderall every day, and my body temperature only exceeds 98.6 degrees when I am sick, or when I am working out. Again, the article here is about amphetamine TOXICITY, not amphetamine in general. Everything is toxic, the only question is how? If you are taking any amphetamine as prescribed, I highly doubt you have anything to worry about. I just don't see any connection between the facts presented and the toxicity of 20mg of dextroamphetamine. Further, I don't see any logical explanation on why this would even occur. The articles failure to address the significance of hyperthermia is also troubling. Did it not occur to the people conducting this study that hyperthermia has a biological purpose? Did they honestly think "Hmm, high body temperature must cause them dopamine axon terminals to burn up!"? I certainly hope not. I almost guarantee this study was intended to further the DEA agenda. Anti-drug folks tend to completely ignore the physiology of drugs, and rely on simple empirical observation like this. The 100mg/kg bit seems to further this. The government spent billions demonizing cocaine. Might as well make amphetamine even worse!
> This article is very alarming in that it indicates sensitization can occur at the very low therapuetic amphetamine doses used for ADD. I wish I'd read it a long time ago. I'm giving up d-amphetamine (even though I use it at a very low dose of 20mg/day.)
> -Andy
>
>
> > John, did you ever read that web page that I sent you regarding amphetamine tolerance and neurotoxicity?
> >
> > Here's an interesting excerpt from it:
> >
> > http://www.acnp.org/g4/gn401000166/ch162.htm
> > "Methamphetamine toxicity is inhibited by a variety of drug treatments, including: 1) DA synthesis inhibitor alpha-methyl-para-tyrosine; 2) DA receptor antagonists; 3) NMDA receptor antagonists, e.g., MK-801; 4) DA and serotonergic reuptake inhibitors protecting against DA and serotonin toxicity respectively (195). Even though most studies have found that serotonergic and DA reuptake inhibitors specifically protect these two sites, certain reuptake blockers (such as benztropine) do not (195). On the other hand, mazindol, a non-specific blocker, protects against both DA and serotonergic neurotoxicity. Ali et al. (1994) have further demonstrated in mice that a major factor for neurotoxicity is hyperthermia which is highly correlated with the degree of long-term DA depletion (21). Furthermore, haloperidol, diazepam and MK-801, all of which can reduce methamphetamine-induced hyperthermia, protect rats against DA depletion (4). They also demonstrated that reducing the ambient temperature (4°C) reduced neurotoxicity to the same levels found when phenobarbital, diazepam and MK-801 were present to protect the cell. Tolerance to methamphetamine induced by increasing doses also reduces the hyperthermic response and as well protects against neurotoxicity (89, 188).
> > An important caveat is that not all protective mechanisms act by preventing the hyperthermic effect; the monoamine uptake blockers inhibit neurotoxicity in the absence of inhibition of hyperthermia, e.g., fluoxetine blocks methamphetamine serotonin toxicity without reducing temperature (140). The monoamine protection from neurotoxicity by reuptake inhibition is emphasized by the unexpected discovery that even massive and 24-hour continuous dosing of cocaine, e.g., 100 mg/kg/day, does not result in DA system neurotoxicity (119, 182, 183). Hyperthermia has been well documented to increase amphetamine stereotypy (93, 220). Hyperthermia alone is well known to result in neuronal chromatolysis and has been previously proposed as a significant contributor to amphetamine-induced DA depletion and neuronal damage in clinical as well as experimental animal histopathology (52). Hyperthermia may have been one of the factors resulting in deaths among athletes taking moderate doses of amphetamine in the 1960s and 70s (145). Even in mild hyperthermia, increased body temperature induces a linear decrease in the inhibitory feedback of stimulants on somatodendritic autoreceptors (130). Thus, body temperature changes induced by amphetamine should be considered as one of the contributors to toxicity. "
> >
> > I've read on this board ppl saying that Prozac+adderal doesn't poop out much...and this mazindol might even be a better idea. What do you think?
Posted by benzapp on November 25, 2001, at 21:10:02
In reply to Re: amphetamine sensitization article, posted by Andy123 on November 23, 2001, at 10:27:34
I wasn't able to access the link before, but as I said, who sponsored this study? The National Institute of Drug Abuse. Of course, they are authority on neuropharmacology. The NIDA only reports studies that further their agenda, rarely require peer review, and never acknowledge contradictory studies. To be fair, the study does say therapeutic doses of amphetamines are safe, contrary to the previous poster. Of course, this is in stark contrast to a previous statement that frequent regimes of amphetamine causes sensitization (requiring increasing doses). The rate increase was fairly high I seem to recall. Again, were their subjects the 1 million kids taking Adderall? No. Check out the acknowledgements...
Preparation of the manuscript was supported by a NIDA FIRST Award, 1R29-08899, G.R. King, P.I.; Grant No. DA 06519, T.H. Lee, P.I. and Grant No. DA 10327, E.H. Ellinwood, P.I. Reprint requests should be addressed to E.H. Ellinwood, Box 3870, Duke University Medical Center, Durham, NC 27710.> This article is very alarming in that it indicates sensitization can occur at the very low therapuetic amphetamine doses used for ADD. I wish I'd read it a long time ago. I'm giving up d-amphetamine (even though I use it at a very low dose of 20mg/day.)
> -Andy
>
>
> > John, did you ever read that web page that I sent you regarding amphetamine tolerance and neurotoxicity?
> >
> > Here's an interesting excerpt from it:
> >
> > http://www.acnp.org/g4/gn401000166/ch162.htm
> > "Methamphetamine toxicity is inhibited by a variety of drug treatments, including: 1) DA synthesis inhibitor alpha-methyl-para-tyrosine; 2) DA receptor antagonists; 3) NMDA receptor antagonists, e.g., MK-801; 4) DA and serotonergic reuptake inhibitors protecting against DA and serotonin toxicity respectively (195). Even though most studies have found that serotonergic and DA reuptake inhibitors specifically protect these two sites, certain reuptake blockers (such as benztropine) do not (195). On the other hand, mazindol, a non-specific blocker, protects against both DA and serotonergic neurotoxicity. Ali et al. (1994) have further demonstrated in mice that a major factor for neurotoxicity is hyperthermia which is highly correlated with the degree of long-term DA depletion (21). Furthermore, haloperidol, diazepam and MK-801, all of which can reduce methamphetamine-induced hyperthermia, protect rats against DA depletion (4). They also demonstrated that reducing the ambient temperature (4°C) reduced neurotoxicity to the same levels found when phenobarbital, diazepam and MK-801 were present to protect the cell. Tolerance to methamphetamine induced by increasing doses also reduces the hyperthermic response and as well protects against neurotoxicity (89, 188).
> > An important caveat is that not all protective mechanisms act by preventing the hyperthermic effect; the monoamine uptake blockers inhibit neurotoxicity in the absence of inhibition of hyperthermia, e.g., fluoxetine blocks methamphetamine serotonin toxicity without reducing temperature (140). The monoamine protection from neurotoxicity by reuptake inhibition is emphasized by the unexpected discovery that even massive and 24-hour continuous dosing of cocaine, e.g., 100 mg/kg/day, does not result in DA system neurotoxicity (119, 182, 183). Hyperthermia has been well documented to increase amphetamine stereotypy (93, 220). Hyperthermia alone is well known to result in neuronal chromatolysis and has been previously proposed as a significant contributor to amphetamine-induced DA depletion and neuronal damage in clinical as well as experimental animal histopathology (52). Hyperthermia may have been one of the factors resulting in deaths among athletes taking moderate doses of amphetamine in the 1960s and 70s (145). Even in mild hyperthermia, increased body temperature induces a linear decrease in the inhibitory feedback of stimulants on somatodendritic autoreceptors (130). Thus, body temperature changes induced by amphetamine should be considered as one of the contributors to toxicity. "
> >
> > I've read on this board ppl saying that Prozac+adderal doesn't poop out much...and this mazindol might even be a better idea. What do you think?
Posted by JGalt on November 28, 2001, at 18:20:59
In reply to Re: amphetamine sensitization article(REBUTTLE) , posted by benzapp on November 25, 2001, at 20:59:21
You're certainly right on the fact that it was produced by the NIDA w/ their own agenda that by no means has any correlation with the truth. I was worried about that too... anyway, I think you misunderstood one thing, that is that sensitization means to be sensitized, which means that at least some of the effects (usually the undesireable ones) become more potent with time (especially during intermittant dosing).
>Stimulants are stimulants because they affect the adrenal system or mimic its function.
For some stimulants, yes, but what about those that act primarily on the reward system? I could be wrong on this, but as far as I know amphetamine goes into the brain, and then forces some of the presynaptic vesicles to release their dopamine, and of course also it has some effect on serotonin and increasing adrenaline...the increase in adrenaline surely must be small compared to the increase in dopamine (for amphetamine).
< < The end result of any stimulant, cocaine, amphetamine or epinephrine released by your adrenal gland due to stress will raise your body temperature. Stimulants affect metabolic rate, that is your body's utilization of stored energy. Stimulants cause weight loss by increasing the metabolic rate, utilizing more stored energy (fat). > >
Actually most stimulants cause weight loss primarily by decreasing appetite. The actual effect on metabolism rarely ever exceeds 10% by stimulants. High increases in metabolism are not possible without DNP (up to 70% increase) or perhaps high doses of thyroid hormone.
> >100mg/kg? Thats insane. Maybe with a rat. But I dare you to eat 30 grams of cocaine, hyperthermia will be the least of your problems. Also, with cocaine, the dopamine reuptake affect is a THEORY, and a highly unproven one at that. Its stimulant effect actually seems to be caused due to inducing cortisol release, which causes epinephrine to be released. > >Surely you realize that the mg/kg amounts for rats are much higher than for us. Granted that's still a much higher dose than we are using for psychiatry even when you do take into account the rat-human differences...
> The drugs mentioned that supposedly protect against neuron damage and hyperthermia due so because they suppress the stress response induced by these drugs. Without getting into the physiology, natural stimulant reactions occur due to the following: antagonised GABA-A receptors cause the anterior pitutary gland in the brain to release the Adrenocorticotropic hormone, which in turn causes the adrenal gland to release corisol and epinephrine. Basically, the drugs are GABA-A antagonists, and interfere with the entire stress response. Hyperthermia doesn't occur because the body no longer thinks it needs to prepare for a life threatening battle. For the Opiate advocates out there, endorphins mediated by the hypothalamus potentiate endogenous GABA-A agonist production. Of course, cooling the ambient temperature to a level that makes it impossible for your body to increase in temperature will have the same effect. So, the article spend a great deal of time talking about how to counter act hyperthermia induced by the stress response.
>I'm sorry, I guess I don't understand where you're getting this from. If what you say is true, then it would seem all one would have to do would be to take a benzo (such as clonazepam) and we would be free of amphetamine neurotoxicity. But where you're getting that all these drugs act as GABA agonists, if that is what you're saying, I do not see...their actions on DA seem much more relevant to me.
> The primary question is this, does hyperthermia cause dopamine axon damage in general, or only when present with amphetamine? The suggestion that cocaine is not damaging to dopamine axon terminals seems to suggest this, but this distinction is not made. Of course, if the former is true it would mean every time you have a fever you are killing brain cells.
>Well obviously you are right there that it is hyperthermia from amphetamine that causes the damage. The drugs they used to counteract it seemed mostly there to prevent DA from being released in too great of quantities (with the exception of the reuptake blockers).
> Damage to neuron axons seems to occur when the axon is unoccupied for extended periods of time, allowing free radicals to damage it. When you take amphetamine, it affects your brain like epinephrine, activating the same receptors, but amphetamine does not containe the necessary hormone utilized by DNA transcriptase. So while the brain wants to produce more dopamine, it lacks the ability to read a DNA strand and thus is unable to produce the proper proteins. If any neurotoxicity results, it is due to your brain using up dopamine thinking more will be made, which never happens. The exposed axons are vacated when dopamine runs out and are damaged by free radicals.
>This is an interesting theory for sure... However, I hardly feel euphoric by taking something that causes epinephrine release, unlike AMPH which from my reading has more direct effect on dopamine release.
> Cocaine probably doesn't cause dopamine axon damage because cocaine stimulates the release of natural epinephrine, which allows the further production of dopamine and thus the neurons are not as vacant.
>This isn't making any sense, if all amphetamine is doing is releasing epinephrine, then all I have to do is take ephedrine or anything else which causes some of its release and I'll get the same effect. Not hardly.
> Just to let you know, increased body temperature occurs due to increased energy utilization, either for locomotion or cellular activity. The reason you get a fever when you are sick is not to kill invading bacteria, but because your body is producing so many new cells at a rapid rate. >
So are you saying that if we take aleve to lower the body temperature that it will slow the rate at which new cells divide?
>
> Lowering the metabolic rate by interfering with the endocrine system or by directly lowering the persons temperature only means that less cellular division will be taking place, meaning less activity in general will be taking place and dopamine won't be overutilized.
>
> But for people who take low doses of amphetamine on a daily basis, this does not happen. I take 40mg of Adderall every day, and my body temperature only exceeds 98.6 degrees when I am sick, or when I am working out. > >Of course, even the article stated that after continual use hyperthermia, if present, would level out from lowered DA levels. There's several other mechanisms I can think of that would also account for the lowered body temp...in any case with several times-daily dosing tolerance to motivating effects of amphetamine wears out quick at a given dose.
> Again, the article here is about amphetamine TOXICITY, not amphetamine in general. Everything is toxic, the only question is how? If you are taking any amphetamine as prescribed, I highly doubt you have anything to worry about. I just don't see any connection between the facts presented and the toxicity of 20mg of dextroamphetamine. Further, I don't see any logical explanation on why this would even occur. The articles failure to address the significance of hyperthermia is also troubling > >
I agree, I doubt low doses have toxicity either. When you look at serious addicts that after years of high doses have finally amassed significant amounts of damage, it is easy to believe that small doses aren't going to cause the same problems. I am simply interested in decreasing tolerance to the mood-lifting/motivating effects of amphetamine and decreasing eventual sensitization to the irritability and anxiety type effects of it. To me, amphetamine seems like borrowed energy. If you take it one day, but not the next you'll be that much more depressed and unmotivated and unfocused...after a few days of steady dosing, tolerance sets in and the bad side effects become more predominant...the increased focusing ablitiy doesn't seem to go away, or else it would be uneffective for ADD. I just am interested in finding ways around this negative feedback mechanism...probably something to do with one or two of the particular DA autorecptors.
Posted by nightlight on November 29, 2001, at 10:17:29
In reply to Re: amphetamine sensitization article » nightlight, posted by Andy123 on November 24, 2001, at 18:17:37
Andy,
OK, I understand your qualms a bit better now. The literature on AD/HD meds usually comments on the fact that these drugs often potentiate 'tics', repetitive movements and indiosynchrasies a child (or adult, I suppose) might have.
I know I have the terrible habit of 'cracking' my joints, in my hands, but, also in various places all over my body. I do this more often when I take stimulants, and it is more difficult to control. I crack my neck and back a lot, but, some of that probably has to do w/my body being slightly more tense (sometimes) when I take a stimulant.I just call it chiropractic auto-adjustment. That and stretching exercises help me with relaxation and not becoming anxious, or over-stressed. Altho, it's not a panacea. Just helps.
By the way, what is your diagnosis, and how are you feeling now? Still off the stimulants?sincerely~nightlight
> I had noted some of these behaviors while using the drug:
>
> "The stimulant-induced hyper-reactivity is characterized by a short
> period of stereotypy followed by repetitive hyper-reactive behaviors. The hyper-reactive behaviors include 1) hyper-startle responses; 2) jerking or reactive orienting movements to unseen stimuli; 3) hyper-reactive movement to the animals own bodily functions such as salivation; 4) hyper-reactive side-to-side looking movements; "
>
> The first physician who prescribed a stimulant to me had indicated that some of these hyper-reactive behaviors are a relatively common side effect of the drug. I had always chalked it up to anxiety.
> What I didn't say in my previous post was that I had been taking a low dose of a TCA to even out response. Taking both together is known to increase the amount of amphetamine that ends up in brain tissue. I'm not sure, but this might have put me in some amount of danger of initiating the cascading events that lead to hypersensitivity and then to psychosis.
>
> I think this was also relevant:
> "That behavioral tolerance develops to both cocaine and amphetamine provides evidence that tolerance and neurotoxicity are separable phenomena, since very high doses of cocaine do not induce neuronal damage (119, 183)"
>
> In the text before this quote, the author had been focusing on reverse sensitization. The dosages that cause histologically discernable damage are much higher than those that cause reverse sensitivity. So reverse sensitivity is the thing that bothers me. I don't want to have a psychotic break anytime soon :) Really, though I was doing fine with the dosaging regimen of 20 mg + low dose TCA, but on Thursday I kind of went into a "catatonic stupor." [At least that is what it would have appeared to someone observing me. I just sat around and contemplated things for about 1.5 days and I was extremely dysphoric.] At that time, I was thinking that I was causing this difficulty by taking stimulants with the TCA.
> The other odd thing is that I took about 4 grams of vitamin C to help remove the drug from my system [lowers urine pH] and of course I started to feel terrible. Today, however, I haven't taken any stimulant and but I am not having my usual withdrawal. Usually when i don't take the stimulant I get very lethargic. Today I have as much energy as I would if I were taking the medicine, although my concentration isn't as good.
> So really I should have qualified my comments to say that the decision to stop taking stimulants (for now) was because I had possibly overdone it with the TCA + dexedrine mixture.
> Sorry if any of this seems incoherent :)
> -Andy
This is the end of the thread.
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