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Re: amphetamine sensitization article(REBUTTLE)

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:
> >
> >
> > "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 (4C) 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?




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