and



- - Shankaran et al. 2001 "The MDMA-induced depletion of brain 5-HT and the functional consequences thereof appeared to involve the induction of oxidative stress resulting from an increased generation of free radicals and diminished antioxidant capacity of the brain."



- - McKersie 1996 "The role of the hydroxyl radical is analogous to a ‘spark' that starts a fire."



- - O'Shea et al. 1998 "Damage occurs when endogenous free radical scavenging mechanisms become overwhelmed or exhausted."

TERMINOLOGY

5-HT – Serotonin, 5-hydroxy-tryptamine.

Axon – The extension of a neuron's cell body along which signals are transmitted.

DA – Dopamine, 3,4-dihydroxy-phenethylamine.

Half-life – The time required to reduce blood levels of a chemical to half their peak level.

Neurotoxicity – A broad definition of long lasting damage to brain cells which impairs their function or kills them.

SSRI – Selective serotonin reuptake inhibitor, a chemical which blocks the serotonin reuptake transporter.

Transporter – Protein embedded in a neuron's cell wall which ‘transports' chemicals across the cell wall.



ROUTES OF ADMINISTRATION

IM - Intramuscular -- Injected into a muscle

IP - Intraperitoneal -- Injected into the abdomen

IV - Intravenous -- Injected into a vein

PO - Oral -- Swallowed or eaten

SC - Subcutaneous-- Injected under the skin



Effects of Vitamin C on Free Radical Levels

After Single MDMA Administration



Figure 1. Effects of MDMA on the extracellular concentration of the free radical 2,3-DHBA in rats. The upper line shows that levels of 2,3-DHBA are highest in rats given MDMA without Vitamin C. In comparison, the line with the downward pointing triangles shows levels of 2,3-DHBA in rats given both vitamin C and MDMA. Lines marked with circles and squares show levels in control rats not given MDMA. (graph from Shankaran 2001)

Equivalency of Dosages

Effects of Vitamin C on Serotonin Levels

After Multiple MDMA Administrations



Figure 2. Effects of MDMA on serotonin levels in rats. The bottom line shows that levels are lowest in rats given MDMA without Vitamin C one week earlier. In comparison, the line with downward pointing triangles shows levels of serotonin in rats given both Vitamin C and MDMA one week earlier. Lines marked with circles and squares show levels in control rats not given MDMA the week before. (graph from Shankaran 2001)

Exaggerating To Find Subtleties

Injected vs Oral

Remaining Questions

Do the supplements already in use reduce unwanted side effects or hangover?

What is the minimum effective dose of antioxidants which will block neurotoxicity in rats?

Do 5-HTP or other supplements increase any medical risks in combination with MDMA?

Are combinations of supplements more effective at lower doses than single chemicals in decreasing recovery time?

Can oral antioxidants reach levels necessary to block neurotoxicity? Several questions must still be answered before we know how useful this research is for humans.

Supplement Regimens Reported Effective by MDMA Users Regimen 1

One dose just prior to use, one as effects wear off, and a third at 10-12 hours



5-HTP = 100 mg

Vitamin C = 1000 mg

Alpha Lipoic Acid = 250 mg



Regimen 2

One dose just prior to use and one dose as effects wear off.



5-HTP = 100 mg

Magnesium = 500 mg

Vitamin C = 1000 mg

Vitamin B6 = 100 mg

L-Tyrosine = 1000 mg

DLPA = 400 mg

One dose just prior to use, one as effects wear off, and a third at 10-12 hours5-HTP = 100 mgVitamin C = 1000 mgAlpha Lipoic Acid = 250 mgOne dose just prior to use and one dose as effects wear off.5-HTP = 100 mgMagnesium = 500 mgVitamin C = 1000 mgVitamin B6 = 100 mgL-Tyrosine = 1000 mgDLPA = 400 mg Please note that both regimens include 5- HTP. While 5-HTP is an anti-oxidant, it is also a direct precursor of serotonin. It's quite possible that the effectiveness of the regimens are the result of 5-HTP as a serotonin precursor.



Both L-Tyrosine and DLPA are dopamine precursors. Dopamine has been implicated in MDMA neurotoxicity and there are some concerns that they may do more harm than good.



It is also important to note that we have received many reports of ineffective supplement use. Given the current dataset, it's impossible to know what factors are responsible for differing reactions to MDMA and supplements.

Some very interesting research has been published in the last few years showing that common, over-the-counter antioxidants such as vitamin C, vitamin E, beta carotene, and selenium, can not only substantially reduce or entirely block MDMA neurotoxicity in rats, but can actually reduce tolerance between doses. 1 While the controversy around MDMA neurotoxicity is too complex to be covered here, it is well established that MDMA causes long lasting changes in the serotonin system of rats at dosages and frequencies similar to those used recreationally by some people. Furthermore, there is strong evidence that some high-dose and/or frequent users of MDMA also show signs of these reductions. There is also concerning, but still controversial, data showing subtle memory disruptions in heavy users as well as some indications of long term pharmacological blunting of physiological response to MDMA (loss of magic).Although many people are jaded to the continual barrage of cautionary and negative information about ecstasy's future impact on their lives, there have been some significant advances in research into methods of reducing the risk of long term serotonergic damage, reducing hangover effects, and decreasing tolerance. Over the last 15 years, research has explored several different methods for reducing the neurotoxic effects of MDMA, but some of them (like the use of fluoxetine / Prozac) can also reduce the therapeutic effectsare difficult to come by. More recent research has shown that common antioxidants may prevent neurotoxicity without blocking the primary therapeutic effects of MDMA. This article is an introduction to the possibility of antioxidants being used to prevent MDMA related neurotoxicity and side effects.In the mid-1980s, it was discovered that some amphetamines damage dopamine neurons through a process called "oxidative stress". The research also showed that administering antioxidants blocked or reduced this dopamine neuron damage in the brains of rats. 2 In the late 1980s, MDMA was found to be neurotoxic, although it causes reductions in serotonin (5-HT) rather than dopamine (DA). Over the next ten years, a great deal was learned about the mechanism by which MDMA damages serotonin cells. It was discovered that serotonin reuptake transporters are key to the long-term damage 3 and that dopamine may also be involved in the process. 4 But the most important discovery has been that high levels of oxidative radicals are formed in the hours after administration of MDMA to rats 5 and that antioxidants given to rats before or with MDMA administration reduce or eliminate the long term damage.While there are competing theories for the exact metabolic process which creates these oxidative radicals, it is now widely accepted that oxidative stress is a primary component of MDMA's neurotoxicity.Oxidation is a normal metabolic chemical process in the body. As cells transfer and use energy, metabolize proteins and nutritive chemicals, break up larger molecules into smaller molecules with enzymes, and go about their general functioning, by-products called "oxidative radicals" (also called "free radicals" or "reactive oxygen species") are created. Oxidative radicals are highly reactive molecules which have unpaired electrons. They pull strongly on the electrons of other molecules, causing damage by destabilizing the molecule's electrical balance. This destabilization can cause molecules to break apart, sometimes initiating chain-reactions of oxidative radical formation, thus a single hydroxyl radical can damage several other molecules. 8 Under normal conditions, cells balance the ongoing creation of oxidative radicals with reserves of "antioxidant" molecules present in cell fluids and walls. Antioxidants, sometimes called "free radical scavengers", are chemicals having "extra", weakly attached electrons which they can donate to a free radical without themselves becoming unstable. Oxidative stress begins to cause problems when free radicals become too plentiful, overwhelming the ability of the system to keep up with them and the cell runs out of antioxidant reserves. As oxidative stress increases, it can damage cell walls, reduce the flexibility of blood vessels, destroy necessary enzymes, and damage many other proteins and molecules.In the case of MDMA, reseach has shown that MDMA causes oxidation of certain enzymes and increases levels of certain oxidative radicals.Researchers Shankaran1 and Coladohave directly measured a steep increase in oxidative radicals in the first few hours after MDMA is given which slowly returns to normal as MDMA is cleared from the body (taking about 24-36 hours). Initially, the body's resources are able to handle the increased oxidative load, but the data suggest that within a few hours, antioxidant reserves become depleted and damage to the serotonin axons begins. With a metabolic half-life of around 9 hours in human, MDMA can continue causing oxidative stress for more than 24 hours after a single dose.The oxidative stress caused by MDMA may also affect other systems, even at levels far below those necessary to cause detectable neurotoxicity. One of the essential enzymes in the production of serotonin is Tryptophan Hydroxylase (TPH) which converts Tryptophan to 5-HTP. Since MDMA causes a huge release of serotonin (and much of this serotonin is metabolized and excreted), TPH is important to replenishing the brain's serotonin reserves after use. Both serotonin and TPH levels are much lower than normal after MDMA administration and it is speculated that some of the day-after effects of MDMA are the result of these lower levels of serotonin.TPH is the rate-limiting step in the production of serotonin, meaning that even when there are enough building blocks (tryptophan) for more serotonin, it is the amount of TPH which determines how quickly serotonin can be restored. Researchers have shown that TPH is inactivated by oxidative radicals and it is possible that protecting this enzyme from oxidation may increase the speed with which the brain is able to recover normal levels of serotonin. Even if MDMA never reaches neurotoxic levels, antioxidants may help the brain and body recover more quickly after the effects subside.One of the most important recent findings about MDMA neurotoxicity is the fact that damage to the serotonin system appears to be entirely separable from the primary experiential effects. More than a decade ago, several papers documented that SSRIs such as fluoxetine block MDMA neurotoxicity, but some users have understandable discomfort about mixing two strong psychoactives, not to mention that SSRIs are expensive, can be difficult to get, and reduce desirable effects if taken before MDMA. There are also some theoretical concerns about possible dangerous interactions between MDMA and SSRIs, although these are not borne out by case reports and a research suggests that SSRIs reduce MDMA's overall physiological effects. 10 Despite these issues, there is good reason to believe that SSRIs are effective at reducing risk of neurotoxicity.Antioxidants could be more promising than SSRIs for widespready use in reducing MDMA neurotoxicity. Since the damage appears to be caused by oxidative stress, one way to reduce might be to simply increase the amount of antioxidants available to the cells. Some very compelling papers have been published showing that antioxidants alone can prevent neurotoxicity caused by enormous doses of MDMA. In a paper published by Aguierrein 1999, researchers administered 4 high doses of alpha lipoic acid by injection to rats during the 2 days preceding a single neurotoxic dose of MDMA (20 mg / kg, also injected) and found that alpha lipoic acid "completely prevents the loss of 5-HT [serotonin] content and the decrease of ... 5-HT transporters in the frontal cortex, hippocampus and in the striatum and also abolishes the increases in the glial response [another marker of neurotoxicity] observed in the hippocampus 7 days after MDMA." 11 Several additional labs have reproduced and confirmed that high-dose, injected antioxidants block MDMA neurotoxicity in rats.But perhaps even more interesting is work done with cheap, well tolerated, and universally available antioxidants such as ascorbic acid (vitamin C) showing similar protection. In the first paper to demonstrate this, G.A. Gudelsky 7 found that rats given extreme doses of MDMA (20 mg/kg injected under the skin) had lasting damage to their serotonin system, but that rats given this same dose of MDMA with a very high dose of ascorbic acid (250 mg/kg injected) showed no sign of serotonin damage.As with humans, rats given two doses of MDMA within a short period of time experience substantially reduced experiential effects from the second administration. In rats, this occurs even when the doses are spread a week apart. Because a rat's metabolism is much faster than that of a human, one week may represent an even longer recovery period in humans.A paper published in early 2001 by Shankaran, Yamamoto, and Gudelsky not only confirmed the previous work showing that antioxidants prevent serotonin depletion, but found that rats given ascorbic acid (vitamin C) with their MDMA and then given another dose of MDMA a week later had stronger effects during the second experience than rats who did not receive ascorbic acid the first week. This means that antioxidants administered with MDMA may not only reduce neurotoxicity, but may also decrease the reduction in effects experienced with a second dose a week later.Shankaran studied 4 groups of rats, one which received saline only, one group saline + ascorbic acid, one group saline + MDMA (10 mg/kg ip), and one group ascorbic acid (100 mg/kg ip) + MDMA (10 mg/kg ip). One week later, a few rats from each group were killed and their levels of serotonin measured. The rats who received ascorbic acid with MDMA did not have statistically different serotonin levels than the rats who received saline-only or vitamin C-only, but the rats who received MDMA+saline had serotonin levels about 40% lower than all of the other rats, suggesting neurotoxicity. At the same time, the remaining live rats were all given MDMA (10 mg / kg injected, 4 times in 8 hours) and their behavioral and biochemical reactions recorded. The results clearly demonstrated that the rats who received MDMA without ascorbic acid during their first session showed substantially attenuated effects to the second administration compared to the other 3 groups. MDMA activated release of serotonin in these rats was blunted (figure 2), body temperature was less affected, and behavioral signals (head weaving, paw treading, and body posture) all indicated significant tolerance to MDMA which none of the other rats exhibited. Ascorbic acid administered with MDMA had blocked not only damage, but also tolerance.This research re-energizes the question of whether long term experiential tolerance to MDMA may be related to neurotoxicity, but this remains an unresearched issue.What Does This Mean For Humans? Although there is no research in humans confirming that antioxidants block MDMA-specific oxidative stress, neurotoxicity, or tolerance, it is believed that the oxidative stress mechanisms for toxicity in rats are very similar to those in humans. Trying to speculate what implications this research has for humans is fraught with possible invalidating assumptions, but the research with antioxidants seems to offer a potential method for decreasing the negative effects of MDMA. The following paragraphs will attempt to describe some of the issues and questions involved in trying to extrapolate from rat data to human use.Because of differences in the metabolic systems of rats and humans, it is extremely difficult to extrapolate from the available data to practical human application. There are a number of confounding issues.1)Some researchers suggest that risk of neurotoxicity increases as "total exposure" to MDMA and its metabolites increases. 5 This means that potential neurotoxicity is affected not only by peak levels of MDMA, but also by how long the MDMA remains in the bloodstream. Total exposure is measured by something called "Area Under the Curve" (AUC). Very simply, AUC is the height of a curve multiplied by its length. Picture a chart with a curved line running from left to right.The height of the line represents the amount of MDMA in the blood and the length of the line represents time passing. As you'd expect, after a single dose of MDMA, the line would rise initially, come to a peak, and then slowly go down over time. If you imagine shading in the space below the line in the chart, the area you shaded would be the Area Under the Curve and would measure the total exposure of serotonin neurons to MDMA and its metabolites. It is easy to picture how both increasing the dose (which would cause a higher peak) or redosing during the experience (which would cause a longer curve) would increase the AUC and thus increase the amount of oxidative stress the cells are exposed to.The AUC model helps explain why the seemingly excessive dosage regimens given to rats might be reasonable. Rats metabolize MDMA 4-8 times faster than humansand thus in order to approximate the AUC for humans with a single dose in rats, a much higher single dose is required. A second way to approximate the AUC of a human is to give rats multiple doses, spaced apart in time. This method, used in the Shankaran study described above, extends duration as a way to better match human AUC and thus total exposure to oxidative stress.2)It is likely that the levels of neurotoxicity demonstrated in rats at doses of 10+ mg/kg are much worse than those experienced by any moderate recreational user of MDMA. This is a standard issue with laboratory research: exaggerated doses and contexts are created to make otherwise small changes more easily detectable.Rats are given very high doses, when measured by dose per bodyweight, in order to be able to detect what would otherwise be subtle effects. Researchers inject rats with doses of MDMA 4-20 times higher than those taken orally by humans and these doses are measurably neurotoxic. The reasoning goes that if a large dose is very neurotoxic, a small dose is a little neurotoxic. This logic is not always correct because it assumes a linear relationship between dose and damage. It is also quite possible that there are thresholds under which no damage occurs.There is, however, evidence that some long term changes or damage do occur at doses used by some people and there is also evidence that doses of MDMA within the normal human range (100-150 mg) overwhelm some enzymes that metabolize MDMA. 14 The doses of antioxidants given to the rats are also very high. Injected doses of 100 mg/kg of ascorbic acid would be the equivalent of 5-10 grams (!) of vitamin C injected into humans, an extremely high dose. It is impossible, given the limited data, to know what levels of oral antioxidants might be required to reduce MDMA-related oxidative stress.Since we have no data about what doses of vitamin C areeffective at blocking MDMA neurotoxicity in rats, we don't have a lower bound from which to speculate about minimum human doses. Clearly it is unreasonable to even suggest that ecstasy users inject 5 grams of vitamin C into their abdomen, but since the neurotoxic rat doses of MDMA are also administered by injection and very high, there is reason to think the doses of antioxidants do not need to be this high to have some positive effect. Normal supplement level doses of over-the-counter antioxidants are very well tolerated and, based on the work by Aguirre, it may be helpful to take antioxidant supplements in the days both before and after each MDMA exposure.3)Injected doses of vitamins can act very differently from oral doses. When taken orally, the blood levels of vitamin C peak much lower than the levels achieved with injection. In lab research, humans given high oral doses of vitamin C never reached peak plasma levels of ascorbic acid higher than 100 umol per liter, while injected doses easily raised ascorbic acid concentrations in blood to 10 times that amount.Unfortunately oral administration is seldom studied in rats. Because of this, there is still the question of whether it is possible to reach high enough levels of antioxidants after oral use to be neuroprotective.Although research has only shown that ascorbic acid, alpha lipoic acid, l-cysteine, and some obscure free radical scavengers are effective at reducing oxidative stress caused by MDMA, there is every reason to believe that other antioxidants would also be effective. Antioxidants appear to work best in combination, interacting to make each other more effective. Vitamin E and C are some of the best studied and most common antioxidants. When the heavier vitamin E (alpha-tocopheryl-acetate) loses its electrons to a free radical, the lighter and water-soluble ascorbic acid can replace the lost electron and then be carried off as an inert waste product.Vitamins C, E, and A are all plentiful in fresh fruits and vegetables, but because MDMA acts as an appetite suppressant, it is impractical to imagine users would consume enough food sources of antioxidants during or directly after their experience. Antioxidant multivitamins include things like vitamins C and E, lipoic acid, selenium, riboflavin, zinc, carotenoids, etc which should all help reduce general oxidative stress in the body. The water soluble vitamins such as C and lipoic acid are quickly excreted from the body, so it is necessary to take them every 3-4 hours to maintain high levels in the bloodstream.Perhaps the most commonly reported supplement taken with MDMA is 5-HTP, a serotonin precursor. There are numerous anecdotal reports that taking 5-HTP alone or in combination reduces both unwanted side effects and day-after effects. One paper found that very high doses of injected 5- HTP block MDMA neurotoxicity and 5-HTP has been shown to be an antioxidant, but 5- HTP's neuroprotective effect may have nothing to do with its being a mild antioxidant.It may be that 5-HTP is particularly suited to the task of reducing MDMA's physical impact by both providing some oxidative protection and supporting the replenishing of serotonin. Unfortunately, it is also possible that 5-HTP could increase the risk of serotonin syndrome and research needs to be done to determine whether this is a practical concern.There are also an increasing number of recreational-psychoactive specific vitamin products available, with combinations of antioxidants and supplements chosen to reduce side effects and hangovers. Many MDMA users create their own combinations based on the word of friends or comments from web forums. Vitamins and supplements which are frequently mentioned by MDMA users include vitamin C, E, A (beta carotene), alpha-lipoic acid, coenzyme Q-10 ("ubiquinone", an antioxidant involved in intracellular energy systems), selenium, B-6 and other B-vitamins, magnesium (involved in cell-energy and the production of serotonin), and many others. While there are a large number of people selfexperimenting with supplements, so far there isn't much in the way of documentation of successes and failures.Because of the limitations listed above, nothing conclusive can be said about what dosage of antioxidants might be effective. However, there are a number of anecdotal reports from users that taking moderately high doses of antioxidants before, during, and after MDMA experiences reduces the side effects and hangover. The doses described are generally those provided in typical commercial supplements (1-2 grams of vitamin C, 50-100 mg 5-HTP, 5000 IU vitamin A, 400 IU vitamin E, 5-50 mg B-6, etc). Confusingly, we receive as many or more reports of "no effect" from those who have experimented with supplements. Although the anecdotal reports to date are hardly convincing, the issue appears worth further investigation.The most common side effect of taking vitamins is stomach discomfort. Most vitamins should be eaten with a small amount of food, such as a piece of fruit, bread, or cracker in order to reduce stomach upset and unpleasant side effects.Virtually all over-the-counter antioxidant supplements have a unique blend of vitamins in them and generally include appropriate dosage labelling. It's very important not to take overdoses of A and D vitamins which can build up in the system with successive doses and are known to cause health problems at high levels. Too much vitamin A (over 25,000 IU per day), for instance, can cause headaches, hair loss, and liver damage. Vitamin E can also build up, but there are no published case reports of serious problems resulting from overdoses. People who take blood thinners have increased risk of bleeding because vitamin E can increase the action of blood thinning medications. Overdoses of vitamin C (usually more than 1-2 grams at a time) can cause diarrhea and intestinal discomfort. Alpha-lipoic is water soluble and well tolerated, but tends to be expensive and is not as common as other antioxidants.Most people tolerate the common antioxidants well, but those with special sensitivities or health issues should be careful whenever trying a new chemical. Users should ask their doctor about the specific vitamins and dosages they plan to take. Specifically, they can ask about the use of vitamins to help during times of particularly high stress and physical activity, about possible complications, about contraindications with any other medications or supplements they are taking, about research into benefits and risks of higher doses, and about FDA guidelines. There are other theoretical risks with taking high doses of antioxidants, such as acute allergic reactions, unexpected pharmacological interactions, or potentially worsening unrelated severe adverse reactions to MDMA by lowering the pH of the blood slightly, but these risks are speculative and likely very low.MDMA causes a sharp increase in oxidative hydroxyl radicals shortly after administration. It is now believed that this rise in oxidative stress is likely involved in MDMA's neurotoxicity, and may be involved in some of its negative side effects. Very high doses of injected antioxidants have been shown in rats to dramatically reduce or block MDMA neurotoxicity as well as reduce tolerance to MDMA's effects between neurotoxic doses. Based on these findings, it is possible that common vitamin antioxidants may be effective at reducing risks of MDMA neurotoxicity, hangover effect, tolerance, and general body stress.The practical implications of rat-based laboratory research are difficult to reliably assess. However, well-tolerated, common antioxidant supplements such as vitamins C, E, alpha lipoic acid, and others certainly warrant further investigation as a simple means to reduce the negative impact of ecstasy use on the body. For MDMA users who already take antioxidants occasionally, there seem to be few downsides to making sure to take reasonable doses of antioxidants in the days before, during, and after their ecstasy use. The risks are low and the benefits may be immediately apparent.A potential side-benefit to suggesting ecstasy users take vitamin supplements may be to increase awareness that MDMA is hard on the body. Taking antioxidants before, during, and after experiences could help foster more intention around ingestion, act as a reminder that ecstasy is physically stressful, and could offer an additional way experienced users and harm reduction workers can communicate to new users about risks and precautions. Harm reduction groups could engage users in the issue of toxicity by discussing proper nutrition as a way to maintain the enjoyable effects and recover more quickly.The primary downside to suggesting antioxidants may be neuroprotective is the chance that some ecstasy users will misunderstand the information and believe that taking vitamin C will protect them from harm or that some will assume that taking antioxidants will allow them to increase their use of MDMA. Increasing MDMA dosage or frequency of use is likely to significantly increase risk of neurotoxicity. The simplest and most effective way to reduce risk of neurotoxicity is to reduce dosage, refrain from re-dosing during an experience, and reduce frequency of use.