12 replies to this topic

[johnmk]

I've seen reference many times to the real or potential neurotoxic effect of dextroamphetamine. I'm not sure one way or another, 100%, if this holds true at therapeutic doses. Could someone provide insight into the proposed mechanism of action of neurotoxicity from this substance, and would the effect be severe over 50 years of use and a relatively healthy diet well-supplemented?

[ozone]

I've seen reference many times to the real or potential neurotoxic effect of dextroamphetamine. I'm not sure one way or another, 100%, if this holds true at therapeutic doses. Could someone provide insight into the proposed mechanism of action of neurotoxicity from this substance, and would the effect be severe over 50 years of use and a relatively healthy diet well-supplemented?

I think the whole toxicity issue goes something like this... (I posted this on another forum, so I'm copy-pasting).

Our brains have neurons in them. These neurons communicate with each-other through electrical impulses. When the electrical impulse occurs, a vesicle opens and releases a neurotransmitter. After the release, the neurotransmitter is broken down at the synaptic cleft into enzymes. Okay, now here is where the neurotoxicity occurs. This stimluation and release of the nerutransmitter followed by breakdown uses a lot of energy. And because of this, the neuron is vulnerable to oxidative stress. In order to produce energy, nerve cells have a large number of mitochondria. Energy production produces free radicals, which can damage the DNA within cells. Adderall is an amphetamine and amphetamines release Norephinephrine which is a neurotransmitter. So by increasing the neurotransmitter quantity in our brain we also increase the resulting oxidative stress upon our neurons. This is why many Ectasy and Cocaine users eventually get "dumb" (every time they use the drug they are inflicting massive amounts of oxidative stress on their neurons).

While in this post I was speaking of amphetamines, I don't see why dextroamp's would be any different. Again, this is my theory on it.

[johnmk]

I understand this conceivable mechanism of toxicity. Thank you for your help. Are there mechanisms of toxicity?

[velocidex]

The exact mechanism has not been discovered. Ozone is partially correct, in that it does appear to involve oxidative stress. Dopamine catabolism by MAO-B produces free radicals; higher dopamine levels produce higher oxidative stress mechanisms. The catabolism of norepinephrine and serotonin do not produce free radicals.

The real story is rather complicated.... it involves lipid peroxidation, possibly apoptosis, etc... but at its core it involves oxidative stress.

Ozone -- neurotransmitters are broken down WITH enzyme, not INTO enzymes.

For example., dopamine is catabolised by monoamine oxidase-B. It's not just in the synaptic cleft that dopamine is metabolised, but in the intracellular space too. MAO inhibitors not only increase the free monoamine levels but also increase the intracellular ones too, meaning that each vesicle has a larger amount of the relevant monoamine.

[johnmk]

OK then I guess it's a good thing that I take my deprenyl daily with my dextroamphetamine. However . . . velocidex, are you aware that MAO-A also breaks down dopamine as well, and may in fact be more responsible for its break down in most areas of the brain than MAO-B? As far as I know, MAO-B is present mostly in glial cells.

If higher neurotransmitter level and associated break down result in oxidative stress, then I suppose being interested in something and pursuing it with passion, etc., must be pro-oxidative. I know there are states of emotional arousal that elevate dopamine levels, not just drugs.

[jpars82]

This may be some useful information.

Methamphetamine (METH)-induced neurotoxicity is characterized by a long-lasting depletion of striatal dopamine (DA) and serotonin as well as damage to striatal dopaminergic and serotonergic nerve terminals. Several hypotheses regarding the mechanism underlying METH-induced neurotoxicity have been proposed. In particular, it is thought that endogenous DA in the striatum may play an important role in mediating METH-induced neuronal damage. This hypothesis is based on the observation of free radical formation and oxidative stress produced by auto-oxidation of DA consequent to its displacement from synaptic vesicles to cytoplasm. In addition, METH-induced neurotoxicity may be linked to the glutamate and nitric oxide systems within the striatum. Moreover, using knockout mice lacking the DA transporter, the vesicular monoamine transporter 2, c-fos, or nitric oxide synthetase, it was determined that these factors may be connected in some way to METH-induced neurotoxicity. Finally a role for apoptosis in METH-induced neurotoxicity has also been established including evidence of protection of bcl-2, expression of p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), activity of caspase-3. The neuronal damage induced by METH may reflect neurological disorders such as autism and Parkinson's disease.

Some of the damage to the CNS that is observed following amphetamine and methamphetamine (METH) administration is known to be linked to increased formation of free radicals. This increase could be, in part, related to mitochondrial dysfunction and/or cause damage to the mitochondria, thereby leading to a failure of cellular energy metabolism and an increase in secondary excitotoxicity. The actual neuronal damage that occurs with METH-induced toxicity seems to affect dopaminergic cells in particular. METH-induced toxicity is related to an increase in the generation of both reactive oxygen (hydroxyl, superoxide, peroxide) and nitrogen (nitric oxide) species. Peroxynitrite (ONOO(-)), which is a reaction product of either superoxide or nitric oxide, is the most damaging radical. It can be reduced by antioxidants such as selenium, melatonin, and the selective nNOS inhibitor, 7-nitroindazole. METH-induced toxicity has been previously shown to increase production of the peroxynitrite stress marker, 3-nitrotyrosine (3-NT), in vitro, in cultured PC12 cells, and also in vivo, in the striatum of adult male mice. Pre- and post-treatment of mice with l-carnitine (LC) significantly attenuated the production of 3-NT in the striatum after METH exposure. LC is a mitochondriotropic compound in that it carries long-chain fatty acyl groups into mitochondria for beta-oxidation. It was shown also to play a protective role against various mitochondrial toxins, such as 3-nitropropionic acid. The protective effects of LC against METH-induced toxicity could be related to its prevention of possible metabolic compromise produced by METH and the resulting energy deficits. In particular, LC may be maintaining the mitochondrial permeability transition (MPT) and modulating the activation of the mitochondrial permeability transition pores (mPTP), especially the cyclosporin-dependent mPTP. The possible neuroprotective mechanism of LC against METH-toxicity and the role of the mitochondrial respiratory chain and the generation of free radicals and their subsequent action on the MPT and mPTP are also being examined using an in vitro model of NGF-differentiated pheochromocytoma cells (PC12). In preliminary experiments, the pretreatment of PC12 cells with LC (5 mM), added 10 min before METH (500 micro M), indicated that LC enhances METH-induced DA depletion. The role of LC in attenuating METH-evoked toxicity is still under investigation and promises to reveal information regarding the underlying mechanisms and role of mitochondria in the triggering of cell death.

Amphetamine-like psychostimulants are associated with long-term decreases in markers for monoaminergic neurons, suggesting neuronal loss and/or damage within the brain. This long-term "toxicity" results from formation of free radicals, particularly reactive oxygen species (ROS) and reactive nitrogen species (RNS), although the mechanism(s) of ROS and RNS formation are unclear. Mitochondria are a major source of ROS and mitochondrial dysfunction has been linked to some neurodegenerative disorders. Amphetamines also inhibit mitochondrial function, although the mechanism involved in the inhibition is uncertain. This review coordinates findings on the multiple pathways for ROS and RNS and describes a hypothesis involving mitochondrial inhibition in the initiation of amphetamine-induced cellular necrosis.

There is growing evidence that suggests that brain injury after amphetamine and methamphetamine (METH) administration is due to an increase in free radical formation and mitochondrial damage, which leads to a failure of cellular energy metabolism followed by a secondary excitotoxicity. Neuronal degeneration caused by drugs of abuse is also associated with decreased ATP synthesis. Defective mitochondrial oxidative phosphorylation and metabolic compromise also play an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging. The energy deficits in the central nervous system can lead to the generation of reactive oxygen and nitrogen species as indicated by increased activity of the free radical scavenging enzymes like catalase and superoxide dismutase. The METH-induced dopaminergic neurotoxicity may be mediated by the generation of peroxynitrite and can be protected by antioxidants selenium, melatonin, and selective nNOS inhibitor, 7-nitroindazole. L-Carnitine (LC) is well known to carry long-chain fatty acyl groups into mitochondria for beta-oxidation. It also plays a protective role in 3-nitropropioinc acid (3-NPA)-induced neurotoxicity as demonstrated in vitro and in vivo. LC has also been utilized in detoxification efforts in fatty acid-related metabolic disorders. In this study we have tested the hypothesis that enhancement of mitochondrial energy metabolism by LC could prevent the generation of peroxynitrite and free radicals produced by METH. Adult male C57BL/6N mice were divided into four groups. Group I served as control. Groups III and IV received LC (100 mg/kg, orally) for one week. Groups II and IV received 4 x 10 mg/kg METH i.p. at 2-h intervals after one week of LC administration. LC treatment continued for one more week to groups III and IV. One week after METH administration, mice were sacrificed by decapitation, and striatum was dissected to measure the formation of 3-nitrotyrosine (3-NT) by HPLC/Coularry system. METH treatment produced significant formation of 3-NT, a marker of peroxynitrite generation, in mice striatum. The pre- and post-treatment of mice with LC significantly attenuated the production of 3-NT in the striatum resulting from METH treatment. The protective effects by the compound LC in this study could be related to the prevention of the possible metabolic compromise by METH and the resulting energy deficits that lead to the generation of reactive oxygen and nitrogen species. These data further confirm our hypothesis that METH-induced neurotoxicity is mediated by the production of peroxynitrite, and LC may reduce the peroxynitrite levels and protect against the underlying mechanism of METH toxicity, which are models for several neurodegenerative disorders like Parkinson's disease.

[velocidex]

OK then I guess it's a good thing that I take my deprenyl daily with my dextroamphetamine. However . . . velocidex, are you aware that MAO-A also breaks down dopamine as well, and may in fact be more responsible for its break down in most areas of the brain than MAO-B? As far as I know, MAO-B is present mostly in glial cells.

If higher neurotransmitter level and associated break down result in oxidative stress, then I suppose being interested in something and pursuing it with passion, etc., must be pro-oxidative. I know there are states of emotional arousal that elevate dopamine levels, not just drugs.

Yeah I'm aware of that. MAO-B has a much higher affinity for dopamine though.... MAO-A inhibition does increase dopamine levels in the brain, but MAO-B more so (hence its choice for parkinsonism)

[johnmk]

I don't think it's clear that MAO-B inhibition increases dopamine availability more than MAO-A inhibition. I think it's just more convenient with regards to tyramine-induced hypertensive crisis to inhibit MAO-B and leave MAO-A alone. I'll try to find time tonight to research this, but I'm sure I've read it somewhere (the first sentence).

EDIT: MAO-B is primarily present only in glial cells, and MAO-B tends to only break down catecholamines dopamine and norepinephrine within glian cells. MAO-A also breaks down the catecholamines , but also breaks down serotonin and I believe other neurotransmitters. MAO-A is present in every area of the brain and blocking its action can have a much more massive effect on neurotransmitter levels than blocking MAO-B. Of course there is a risk to doing that of hypertensive crisis however. I'm not sure how this risk is influenced by the form of deprenyl you take, be it liquid or tablet.

Edited by johnmk, 13 May 2005 - 03:17 PM.

[velocidex]

Why not just moclobemide then? That's got no problems with tyramine-induced hypersensitivity...

Admittedly its reversible *shrug*

[hughbristic]

I wonder if alpha lipoic acid, cysteine, or vitamin C could help. There are studies that show these can help prevent any damage from free radicals in the brain when taking MDMA. See http://www.neurotran...matoxicity.html. By the way, this site is awesome. Check it out.

Hugh

[velocidex]

hugubristic -- check out www.thedea.org

There's an indepth article written there on neurotoxicity, and what you can do to ameliorate or prevent it

Indeed alpha lipoic acid and vitamin C can help. Steer clear of cysteine though... there's been some suggestion that glutathione adducts of MDMA MAY exaccerbate neurotoxicity. The research is kindof equivocal, but I'd steer clear of it just to be safe.

[johnmk]

What do you folks think of this?

http://www.dr-bob.or...msgs/85145.html

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!

[velocidex]

^^ A lot of this stuff is rubbish. It's well accepted that cocaine is a dopamine reuptake inhibitor, whereas amphetamine-like compounds inhibit the reuptake of monoamines as well as cause their release by reversing the relevant monoamine transporter.

All reuptake inhibitors protect against neurotoxicity, cocaine included. The problem with cocaine is that it's cardiotoxic.... and the rapid clearance rate leaves open the path to multiple rapid dosing on a short time scale, which reenforces the behaviour very quickly.

Ignore all that rubbish quoted above.