1. It's quite well known that stimulants and anything that boosts metabolism or neural activity will cause generation of free radicals.
Antioxidants quench free-radicals. Its very OBVIOUS to anyone with half a brain that taking antioxidants before ANY sort of phenethylamines is a VERY WISE move.
Take them with a small amount of food ONE HOUR prior to dosing.
Culpepper you do not have any idea what you are talking about... what, you think taking antioxidants will HURT you??? You think it will not help block neurotoxicity which it has been demonstrated is CAUSED by free-radicals? Well there is research proving EXACTLY this... one step at a time...
This page which was there a couple days ago and is supposed to point to a 1993 iissue of their journal now points to a 2010 issue... I will contact them about where this issue and article went, but it was in fact VERY well researched and referenced. Culpepper's claims that it "did not seem credible" are absurd, totally invented off the top of his ill-informed head, to make himself seem "smart" I suppose:
Phenethylamines, Free Radicals, and Antioxidants
Brian Leibovitz, Ph.D.
http://www.maps.org/news-letters/v04n1/04134pea.html
Here are the suggestions without the full article or references (the notes are from me):
Leibovitz (1993) believes that users can block phenethylamine (MDMA) damage caused by free radicals by taking the supplements in the table below (to be taken a few hours before the experience):
Nutrient Preventive Dose Therapeutic Dose Form
b-Carotene 5 mg 15 mg Consider supplements of other carotenoids (e.g., lycopene) as they become available
NOTE: RESEARCH HAS SHOWN THAT IN GENERAL *MIXED* CAROTENOIDS OUGHT TO BE USED NOT ISOLATED b_CAROTENE (which might create imbalances in the carotenoid system in the body)
Bioflavonoids 2 grams 6 grams Mixed bioflavonoids from a variety of sources
Coenzyme Q10 100 mg 300 mg Only one form available
(NOTE: THERE ARE NOW MULTIPLE FORMS OF CO-Q10 AVAILABLE, SOME CLAIMING IMPROVED ABSORPTION.... "Q-SORB" FORM OF THE STANDARD TYPE IS MIXED WITH OIL TO HELP IT ABSORB AND IS PROBABLY PLENTY ACTIVE)
L-Ascorbic acid 2-4 grams 6-12 grams Free acid or calcium, magnesium salt
(NOTE: "Ester C" IS A FORM THAT RESEARCH SHOWS IS BETTER ABSORBED AND RETAINED IN CELLS FOR LONGER, ALSO SOME BRANDS INCLUDE A GOOD DOSE OF BIOFLAVONOIDS}
L-Carnitine 1 gram 3 grams L-carnitine HCl or, if possible, less hygroscopic salts (e.g., L-carnitine magnesium citrate)
(ACETYL-L-CARNITINE IS EVEN BETTER... 500mg - 2g)
N-Acetylcysteine (NAC) 2 grams 6 grams Only one form available; do not use L- cysteine
(NOTE: 600mg - 1200 IS A MORE REASONABLE DOSE)
Selenium 250 mcg 500 mcg Form not critical -- inorganic (e.g., selenite) as effective, and less expensive, than organic forms (e.g., selenomethionine)
Vitamin E 1,000 IU 3,000 IU Available data indicate that form is not critical
(NOTE: CURRENT RESEARCH INDICATES THAT "MIXED ISOMERS" OF VITAMIN E IS BETTER THAN THE CLASSIC FORM)
* From Phenethylamines, Free Radicals, and Antioxidants by Brian Leibovitz, Ph.D.
ALSO: There is THIS article addressing similar concerns, lots of references:
http://www.erowid.org/chemicals/mdma/mdma_article3.shtml
Here are a couple excerpts:
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
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 effects and are difficult to come by. More recent research has shown that common antioxidants may prevent neurotoxicity without blocking the primary therapeutic effects of MDMA.
But the most important discovery has been that high levels of oxidative radicals are formed in the hours after administration of MDMA to rats5 and that antioxidants given to rats before or with MDMA administration reduce or eliminate the long term damage.6,7 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.
In the case of MDMA, reseach has shown that MDMA causes oxidation of certain enzymes and increases levels of certain oxidative radicals.26,5,1,6,9 Researchers Shankaran1 and Colado6,9 have 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.
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 Aguierre et al. in 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.1,3,6,7
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. Gudelsky7 found that rats given extreme doses of MDMA (20mg/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 (250mg/kg injected) showed no sign of serotonin damage.
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.24,25 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 (100-150mg) overwhelm some enzymes that metabolize MDMA.14
Which Antioxidants?
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.17,1819
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.20,2122 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, 50-100mg 5-HTP, 5000 IU vitamin A, 400 IU vitamin E, 5-50mg 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.
Summary
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.
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
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.
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.
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HERE are the main references to medical research validating the idea that antioxidants block neurological damage from MDMA/Phenethylamines:
Synapse. 2001 Apr;40(1):55-64.
Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT.
Shankaran M, Yamamoto BK, Gudelsky GA.
http://www.ncbi.nlm.nih.gov/pubmed/11170222?dopt=Abstract
J Neural Transm. 1996;103(12):1397-404.
Effect of ascorbate and cysteine on the 3,4-methylenedioxymethamphetamine-induced depletion of brain serotonin.
http://www.ncbi.nlm.nih.gov/pubmed/9029406?dopt=Abstract
Neuroreport. 1999 Nov 26;10(17):3675-80.
Alpha-lipoic acid prevents 3,4-methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity
http://www.ncbi.nlm.nih.gov/pubmed/10619665?dopt=Abstract
