The theory about why amphetamine causes neurotoxicity is that dopamine is supposedly a relatively reactive molecule. It gets auto-oxidised into a reactive metabolite which then causes oxidative damage to the pre synaptic terminals of dopaminergic neurons. Unlike Parkinsons disease, the dopamine cell bodies don't actually die, but without the terminals, they can no longer release dopamine.
Lots of studies have been done on methods of inhibiting the cytotoxic effects of 6-hydroxydopamine (6-OHDA), and this is directly relevent to amphetamine toxicity because the mechanism of 6-OHDAs neurotoxicity is the same as the one proposed for amphetamine. Actually there are two mechanisms behind 6-OHDAs neurotoxicity, heres an abstract:
The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) has recently been found to be formed endogenously in patients suffering from Parkinson's disease. In this article, we highlight the latest findings on the biochemical mechanism of 6-OHDA toxicity. 6-OHDA has two ways of action: it easily forms free radicals and it is a potent inhibitor of the mitochondrial respiratory chain complexes I and IV. The inhibition of respiratory enzymes by 6-OHDA is reversible and insensitive towards radical scavengers and iron chelators with the exception of desferrioxamine. We conclude that free radicals are not involved in the interaction between 6-OHDA and the respiratory chain and that the two mechanisms are biochemically independent, although they may act synergistically in vivo.
So one of the two reasons that 6-OHDA kills dopamine neurons is that it is easily converted into a free radical. I have posted studies on various substances which have been shown to prevent 6-OHDA neurotoxicity, so one can consider those studies to apply directly to amphetamine too.
Whether this is true or not, theres no harm in taking preventative measures. Here are some ways to protect against this type of neurotoxicity, as well as other forms of neurotoxicity and damage to other areas of the body such as the liver:
First and foremost, antioxidants will protect the brain cells against oxidative damage. Antioxidants also protect other organs such as the liver. This means that antioxidants that antioxidants prevent amphetamine induced neurotoxicity, assuming that the theory mentioned above is actually valid. This is the main part of this article since most of the damage caused by amphetamines boils down to free radical damage.
Firstly, a bit about antioxidants. Antioxidants protect cells in the body by neutralizing toxic free radicals. Its necessary to take a mixture of antioxidants because different types of antioxidants protect different parts of the body. Some anti-oxidants are water soluble, some fat soluble. Some anti-oxidants can penetrate membranes easily, some can't. Some anti-oxidants can readily cross the blood brain barrier, others can't.
Vitamin C is a water soluble antioxidant so it neutralises free radicals in the blood and aqueous areas surrounding the cells. Vitamin E on the other hand is a fat soluble antioxidant, so it protects fatty areas of the body such as the walls of the blood vessels. As a result, it prevents the hardening of arteries. Some antioxidants are soluble in both water and fat. Examples are alpha lipoic acid (ALA) and melotonin. Then there are antioxidants which are present inside the cells, and thus protect the cells from the inside. Glutathione is the bodies main endogenous antioxidant which protects the inside of cells. Unfortunately it doesn't get absorbed very well so ingesting glutathione doesn't work. Alpha lipoic acid is an analogue of glutathione which can penetrate cells and thus, protect the cell membrane and inner cell.
Co-enzyme Q10, also known as ubiquinone is a powerful fat soluble antioxidant, and because of its role in cellular respiration, it gets transported to the inner wall of the mitochondria, this gives it the unusual property of protecting the inner mitochondria (an area where protection is greatly needed) from free radical damage. Since the body uses energy from the mitochondria to produce its own endogenous antioxidants such as glutathione, protecting the mitochondria enables the body to produce adequate levels of these endogenous antioxidants. Another antioxidant which protects the inner mitochondria is beta-carotene. Co-enzyme Q10 also protects cholestrol against oxidation. Another powerful antioxidant used in the cellular respiration process is acetyl-L-carnitine (ALCAR). ALCAR protects the outer walls of the mitochondria.
In order to prevent amphetamine neurotoxicity, its essential to take anti-oxidants which can cross the blood brain barrier, and thus enter the brain where amphetamines act. Some powerful anti-oxidants which can readily cross the BBB are acetylcarnitine, alpha lipoic acid and melotonin.
The first antioxidant one should stock up on is vitamin C, because many other antioxidants rely on it in order to function properly. When many antioxidants such as vitamin E neutralise a toxic free radical, they themselves get converted into toxic free radicals, which if left unchecked, would go on to harm cells. Vitamin C on the other hand gets converted into a stable (non toxic) free radical so when an oxidized Vitamin E molecule comes into collides with a Vitamin C molecule, the oxidation chain comes to an end. Curcumin is a wonder substance when it comes to amphetamine use. Not only is it a powerful antioxidant which has been proven to protect against 6-OHDA damage, it also blocks CREB , which is one of the major pathways for tolerance to various drugs. CREB alters ones genes and is believed to play a role in long term changes caused by long term drug use. PQQ is a powerful antioxidant which has been proven to protect against 6-hydroxydopa neurotoxicity.
Melotonin like alpha lipoic acid, is a multipurpose antioxidant which is both water and fat soluble, penetrates cells, and readily crosses the blood brain barrier. Melotonin is a sleep inducing hormone, and can thus help counter amphetamine induced insomnia if taken at night time. Additionally, melotonin has been shown to protect the liver and even help repair liver damage. Melotonin is produced by the pineal gland in the absence of light hitting the retina, so its a good idea to use a blind fold for sleeping in order to maximize melotonin production in the brain.
Aspirin is a good antioxidant which has been shown to protect the brain against amphetamine related damage. It is also an anticoagulant so it helps counteract hypertension (a side effect of amphetamine) and prevents strokes and heart attacks etc. Thats why I always take aspirin along with dexedrine. Baby aspirin is all you need (higher doses are hard on the stomach).
Plant extracts such as grape seed extract and green tea extract are good because they contain a wide range of different anti-oxidants and classes essential nutrients such as flavonoids (nutrients with antioxidant and anti-inflammatory properties), isoflavones, carotenoids, essential fatty acids etc.
One should also know a bit about the bodies own endogenous anti-oxidants in order to know how to keep them at optimum levels. On top of protecting the mitochondria (explained above), another way to boost glutathione is by taking precursors such as acetylcysteine. The bodies antioxidant enzymes use zinc, copper, selenium and manganese so its a good idea to make sure one has enough of these trace elements in their body.
Another cause of brain damage is glutamate cytotoxicity. This happens when you have a surplus of glutamate in the brain, the glutamate overactivates the glutamate receptors and damages them. The 3 types of glutamate receptors are NMDA, AMPA and kainate.
NMDA antagonists protect the brain against this kind of damage and on top of that, they counteract tolerance to amphetamine. Magnesium is a partial NMDA antagonist so its a good idea to take a magnesium supplement every day. Full NMDA antagonist drugs like ketamine or DXM can of course be dangerous so shouldn't be combined with other drugs unless you know exactly what you are doing. Memantine is a safer option since it is a partial NMDA antagonist.
NMDA induced neurotoxicity seems to be caused, ultimately by the conversion of nitric oxide (a neurotransmitter released after the NMDA receptor is activated), therefore this kind of neurotoxicity can be prevented by blocking steps further down the cascade. For example, nitric oxide synthase (NOS) inhibitors such as methylene blue prevent NMDA excitotoxicity by inhibiting the cells ability to produce nitric oxide. NOS inhibitors also prevent tolerance to amphetamines. Note: methylene blue is also an MAOI, so it may not be safe to use in conjunction with amphetamines. The best way to block this damage, without interfering with the activity of glutamate receptors would be to block the action of superoxide itself. Co-Enzyme Q10 helps boost levels of superoxide dismutase, a class of enzymes which break down superoxide.
Protecting the Heart and Brain:
Amphetamine use causes some cardiovascular issues, and this can indirectly cause harm to the brain since its the cardiovascular system which carries the oxygen and other compounds needed to keep the brain cells alive and healthy. Thus, it is a good idea to take measures to prevent the risk of heart attack or stroke, and maintain a healthy cardiovascular system. Firstly, as mentioned in the anti-oxidant section, taking the right combination of anti-oxidants will protect the blood vessels. One factor which causes heart problems is oxidation of the arterial walls. Fat soluble antioxidants like vitamin E prevent this.
Oxidised LDL cholestrol also attacks artery walls so taking anti-oxidants like Co-Enzyme Q10 prevents this by shielding the cholestrol. Most people over 20 already have significant amounts of oxidized LDL cholestrol in the arteries, so another class of antioxidant called flavanoids can be used to reverse that. Flavonoids enter the blood vessel walls and dampen down the inflammation. A good flavonoid is quercetin.
Taking vasodilators may be a good idea in order to counteracting amphetamine induced vasoconstriction Gingko biloba is a decent vasodilator, which also contains powerful anti-oxidants. GABA activity induces vasodilation so boosting GABA levels is a good idea. GABA itself doesn't cross the blood brain barrier very well, but its picamilon can readily cross the BBB and boost GABA levels in the brain. Picamilon is basically a molecule of GABA binded to a molecule of niacin, which gets metabolised into GABA and niacin in the brain, so it can be considered a GABA and vitamin B3 supplement. It is an effective vasodilator. Boosting GABA levels will also help prevent glutamate excitotoxicity since GABA and glutamate balance each other out.
Anticoagulents such as aspirin help prevent blood clotting, and thus lower the risk of heart attack or stroke. One should be careful with stronger anticoagulents such as warfarin as they have a greater tendency to interact with drugs.
There are also substances which directly protect the brain against hypoxia induced damage. Racetams such as piracetam and related nootropics protect the brain by enhancing the bioavailability of oxygen to neurons in the brain. Piracetam has been shown to drastically reduce the brain damage incurred by stroke victims, if administered shortly after the stroke. There is also some anecdotal evidence that piracetam counteracts amphetamine tolerance.
Protecting the Liver:
The majority of drug induced liver damage boils down to oxidative damage, therefore antioxidants are the most important factor for protecting the liver. The endogenous antioxidant responsible for protecting the liver against this damage is glutathione, liver damage occurs when the bodies natural glathione reserves are depleted faster than they can regenerate. Two powerful liver protecting supplements one should know about are milk thistle and acetylcystine. Milk thistle is the most powerful liver tonic known to man. It protects the liver against damage and even helps repair the liver. It works by increasing levels of glutathione which is a compound the liver uses to metabolise drugs.
Acetylcysteine is one of the bodies precursors for glutathione so it can used to boost glutathione levels. It is also a potent antioxidant in itself.
Replenishing Neurotrasmitters: Amphetamine causes dopamine and norepinephrine to be released and as a result, it causes these neurotransmitters to get depleted at a relatively rapid rate. The obvious way to replenish them is to take neurotransmitter supplements. To make dopamine and norepinephrine, the body starts with phenylalanine, it goes:
Phenylalanine -> Tyrosine -> Dopa -> Dopamine -> Norepinephrine -> Epinephrine
I think I left out a metabolite or two but they're the ones you should know about. The most direct way to replenish your dopamine is by taking l-dopa. It gets converted to dopamine quicker than l-tyrosine does. However, amphetamine doesn't just deplete dopamine and norepinephrine, it depletes all the neurotransmitters in the metabolic pathway. It also depletes phenethylamine which is another neurotransmitter that the body synthesises from phenylalanine. With this in mind, its a good idea to take phenylalanine supplements so that you replenish the starting material.
One of the problematic long term changes amphetamine use is the downregulation of various receptors such as dopamine and adrenaline (which are binded to by both epinephrine and norepinephrine), and transporters such as DAT and VMAT. DAT which transports dopamine back into the cell and VMAT2 which is used to transport monoamines (such as dopamine) in the cells back into synaptic vesicles (the neurotransmitters have to be in these vesicles before they can be released). According to some studies methamphetamine also downregulates the enzymes tyrosine hydroxylase (used by the body to produce dopamine) and tryptophan hydroxylase (used to produce serotonin). Therefore taking substances which are known to upregulate/resensitise these receptors, transporters and enzymes may be a good idea. Long term nicotine upregulates dopamine receptors, but of course long term nicotine use may be a bad idea since it is fairly addictive.
Uridine upregulates D2 receptors. Uridine seems to be hard to obtain, an alternative is citocoline which is metabolised into uridine (and choline). Supposedly (I can only find anecdotal reports, if anyone knows of any studies, can you post them) lithium upregulates both VMAT2 and D2/D3 receptors. Lithium of course can cause its own neurotoxicity, so one has to research this in depth before deciding to take it. Lithium orotate is far safer than conventional lithium drugs because it has a very high bioavailability, meaning one can ingest lower quantities of it.
Melotonin has been shown to prevent methamphetamine induced downregulation of tyrosine hydroxylase.
Substances which prevent 6-OHDA toxicity:
As I said, 6-OHDA neurotoxicity has the same mechanism of the supposed amphetamine induced neurotoxicity, so the studies done on it applies to amphetamines.
Anandamide has been shown to counteract 6-OHDA toxicity. Anandamide is an endogenous cannabinoid so its possible that synthetic cannabinoids like THC have the same neuroprotective effect. As mentioned below, curcumin has been shown to protect against 6-OHDA damage. Selegiline protects the brain against this kind of damage.
Apoptosis is a built in self destruct mechanism for cells. Dopamine neurotoxins like 6-hydroxydopamine induce apoptosis, and according to some studies, amphetamines can do this too. So taking apoptosis inhibitors may be a good idea. According to some studies, curcumin protects the brain against 6-OHDA cytotoxicity. Curcumin also protects the brain against ischemia induced apoptosis. Resveratrol is an apoptosis inhibitor, as well as a powerful antioxidant. Red grapes and blueberries are two good sources of resveratrol.
Repairing the Brain
On top of protecting against damage occuring, its likely a good idea to take measures to reverse the damage that has already occured. Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) are two substances involved in neuroplasticity, which help the brain recover from damage. Phosphatidylserine is good for boosting NGF activity. Acetylcarnitine and alpha-glycerophosphocholine (GPC) are two other substances that upregulate NGF receptors. It also enhances dopamine release, so it is a good substance to take during amphetamine withdrawal. I personally find that taking a combination of rhodiola rosea + phosphatidylserine counteracts some of my ADHD symptoms.
Centrophenoxine has been shown to remove lipofuscin deposits from cells, and help repair synapses. Centrophenoxine is metabolised into DMAE and parachlorophenoxyacetate. DMAE also clears lipofuscin from cells and boosts brain function. Lipofuscin is a fatty acid oxidation product which accumulates in cells with age, and excessive accumulation of it has been implicated in Parkinsons disease, Alzheimers and other neurodegenerative disorders, so removing it from brain cells aids the recovery process.
Selegiline has been shown to protect against 6-OHDA toxicity. If one is responsible and cautious enough, one should be able to figure out safe doses for combining amphetamines with selegiline.