MDMA (3,4-methylenedioxymethamphetamine) is thought to be potentially neurotoxic due to free radicals (atoms or molecules which have an unpaired electron) created as a result of the neurological actions of MDMA. The neurotoxicity of MDMA is still being debated. There are many studies which conclude that MDMA is neurotoxic (the extent of which is determined by dose, rate of use, and other factors), and there are probably just as many studies which conclude that it is not. The neurotoxicity of MDMA is still a theory, as exactly how MDMA works is also not known. Until a legitimately conclusive study is published, users must decide for themselves. Either way, because there is strong evidence that MDMA is potentially neurotoxic, it is a good idea to practice some sort of harm reduction. A great technique to combat possible unwanted acute and chronic neurological, emotional, and/or physical detoriation of the mind and body is called loading. Loading in the context of MDMA use is the practice of taking natural or synthetic supplements before (pre-loading), during, and/or after (post-loading) an MDMA session in order to better prepare your mind and body for the experience. The most widely accepted theory for MDMA-induced neurotoxicity concerns damage caused by dopamine, a neurotransmitter which plays a huge part in attention, motor function, and pleasure, among many others. The euphoria experienced during an MDMA session is caused by an increase in the release of serotonin, another neurotransmitter involved in the regulation of mood, appetite, sleep cycles, and more. MDMA's mechanism of action is complicated to anyone unfamiliar with general neuroscience, and again is not fully understood, but the end result of ingesting MDMA causes an increased concentration of serotonin in synapses (spaces between nerve cells). This results in the characteristic euphoria, empathy, and general love that most users experience. The brain is not built to deal with MDMA. Normally, serotonin concentrations inside and outside of a nerve cell are relatively constant. MDMA causes a depletion of serotonin. This is where the neurotoxicity begins. After serotonin is depleted, serotonin transporters, which normally bring serotonin back into the nerve cell after it has done its job, are empty. As a result, somehow dopamine gets brought into the cell by the transporters. Dopamine alone is toxic to serotonin cells. More importantly, the breakdown of dopamine inside the cells is what causes the toxicity. Normally when serotonin is taken back (reuptake) into the cell from the synapse, it is metabolized (broken down) into smaller molecules and recycled to make new serotonin. When dopamine enters the serotonin cell, it too is metabolized. These metabolites, however are toxic to the cells. Dopamine is broken down into hydrogen peroxide, a free radical, which oxidizes (combines with oxygen) parts of the cell which aren't meant to be oxidized. This produces oxidative stress. The brain, like every other thing on the planet, likes equilibrium (balance). This increase in oxidation causes problems, in MDMA's case perhaps cell death. A large part of loading concerns the ingestion of anti-oxidants, which are exactly what they sound like. Anti-oxidants work to inhibit oxidation. The theory behind this is that taking anti-oxidant supplements can decrease or even eliminate the excess oxidation caused by MDMA, providing neuroprotection (protecting the nerve cells from toxicity). Another theory is that some MDMA metabolites may be toxic... but that is a whole different story. That is a lot to take in. Hopefully it makes sense, there is a lot of science but I tried to clarify anything which probably is unfamiliar to most people. On to the real deal. Pre-loading The idea behind pre-loading is to elevate the level of antioxidants available to the brain before MDMA causes increased oxidation, hopefully combatting it before it even begins to hapen. In addition to antioxidants, it is a good idea to take some other supplements to combat the less dangerous but still harmful side effects of MDMA. Here is a list of common supplements used during pre-loading: Antioxidants Vitamin C (ascorbic acid) Sources: Countless generic Vitamin C pills or multivitamins, many fresh fruits and vegetables Recommended dose: 500mg-2000mg How it works: an antioxidant, will help reduce oxidation. Thought to recycle unused Vitamin E. Notes: a water-soluble vitamin, any excess will be excreted in the urine. However this means it doesn't stay in the body very long. Most of it is gone after 3 or 4 hours. This is why it should be taken multiple times during an MDMA session. However, as an acid, too much can cause stomach problems (ie diarrhea, indigestion, heartburn). An overdose is extremely unlikely, but too much can cause side effects which will make the experience less enjoyable. A good idea is to pre-load with 1000mg and post-load with the same, although some users find it produces nausea if taken during post-load. Know how your body will react before supplementing during an actual session. In addition, ascorbic acid is obviously acidic, and a more acidic environment is not conducive to MDMA absorption. However, my dog has never noticed the slightest decrease in MDMA awesomeness due to taking this supplement. Vitamin E (tocopherol) Sources: supplements, some foods such as eggs, avocado, spinach, some nuts Recommended dose: 200-400 IU How it works: an anti-oxidant, will prevent oxidation. Notes: a fat-soluble vitamin, it leaves the body much more slowly than a water-soluble vitamin (ie ascorbic acid). Risk of overdose is higher, especially since supplementing usually involves taking more than the recommended dosage. It is probably quite safe to go to at least 1000 IU a day, and the risk of overdose is significantly decreased if the vitamin is only taken for one day (ie for one MDMA session and not as a continued high-dose supplement). Too much Vitamin E can cause stomach problems, fatigue, and headache. Again, test yourself before experimenting during an actual session. Grape seed extract Sources: grapes (duh), supplements Recommended dose: 50-100mg How it works: contains antioxidants, will reduce oxidation. Notes: Grape seed extract is a very long lasting antioxidant, a half life (how long until half of it is broken down or out of the body) of about 7 hours. Therefore it is really only necessary to take this during pre-loading as an MDMA session usually only lasts about 6 hours. Side effects (quite uncommon): headache, nausea, stomach pain. Theoretically could increase the risk of internal bleeding, so be careful if you have any health issues such as a bleeding disorder. ALA (alpha-lipoic acid) Sources: red meats*, yeast, supplements Recommended dose: 600mg-3000mg How it works: an antioxidant, will reduce oxidation. Notes: water and fat soluble, a very strong antioxidant as it can work pretty much everywhere. Short half life. Coenzyme Q10 Sources: some fish, ie mackerel, sardines, salmon, tuna; supplements Recommended dose: 50mg-300mg How it works: an antioxidant, will reduce oxidation. Necessary for healthy mitochondrial (mitochondria are a cell's source of energy) functioning. Notes: fat soluble, half life of over a day, therefore only necessary to take during pre-loading. At higher doses, effectiveness decreases as dosage increases. Other supplements Magnesium Source: green vegetables, some legumes, nuts, and whole grains; supplements Recommended dose: 400-1000mg How it works: A common side effect of stimulants (including MDMA) is bruxism (jaw-clenching). Magnesium helps relax muscles. Notes: Be careful with dosing this one. Excess magnesium can cause diarrhea and abdominal cramping. Couple with dehydration this can make for some nasty side effects. Again, determine what an acceptable dose is for yourself before mixing with MDMA. No one wants to have to sit on the toilet all night when they could be out on the dance floor. 5-HTP (5-hydroxytryptophan)/trytophan Sources: 5-HTP can only really be found in supplements. It is the precursor (the chemical involved in the reaction which produces another chemical, ie serotonin) to serotonin. Tryptophan, the immediate precursor to 5-HTP, can be found in turkey, dairy products, eggs, nuts, and some fruits (notably bananas, which are delicious). Recommended dose: Tryptophan supplementation is much less common than 5-HTP supplementation, so that is what will be discussed. Why supplement with the precursor to the precursor when you can skip a step and make it easier for your body? As stated previously, 5-HTP is the precursor to serotonin. Therefore it needs to be converted to serotonin by the body before it has any effect. It takes a few hours for this conversion to happen, and only taking it during preloading the day of a session won't have a significant effect. 5-HTP has been shown to increase serotonin levels in mice, and presumably this would help with depression... but depression is (most likely) a result of constant low levels of serotonin, therefore 5-HTP should be doses continuously also. It is recommended to take 100-200mg a day for at least a few days prior to the experience. How it works: Basically provides more raw material for the production of serotonin. Notes: Artificially increasing serotonin levels may put a user at risk of developing serotonin syndrome (basically a serotonin overdose- NOT a good thing) when combined with MDMA. There is really only anecdotal evidence concerning this supplement. Many users have reported no effects, others have reported ill effects, and some stand by the claim that it definitely contributes to the MDMA experience. Only you can decide. Personally, my dog would not recommend bothering with this one at all during pre-loading to be safe... definitely go for it during post-loading though, no risk of potentially fatal side effects. One study (http://www.ncbi.nlm.nih.gov/pubmed/7934616), showed neuroprotective effects, but this is about the only publication my dog could find. Antacids (ie Tums, Rolaids) Sources: Don't bother with trying to eat foods which have anti-acidic properties. Just buy some Tums. Recommended dose: 400-2000mg (perhaps 2 or 3 Tums is a good choice) How it works: This is tricky. Acidity inhibits the absorption of amphetamines. The point of taking antacids is to reduce the acidity of the stomach, increasing absorption of the MDMA. Tums and Rolaids both contain the compound CaCO3, which (my dog believes) breaks down into Ca+2 and CO3-2 (a weak base) in the stomach. However, like the brain, the stomach also works hard to maintain equilibrium (in this case a very acidic environment), therefore if one eats a bunch of basic (opposite of acidic) substances, the stomach will work harder to bring the acidity level back to normal, perhaps actually momentarily increasing stomach acidity. Antacids containing carbonate (ie the CO3 in Tums and Rolaids) usually take about 30 minutes to begin doing their duty, therefore it is recommended to take them with the MDMA rather than a small time before. My dog hasn't had enough experience with MDMA to conclude whether this has any real effect or not, but perhaps other users can offer some input. Grapefruit juice Sources: grapefruits... or grapefruits in juice form. Recommended dose: A big tall glass. How it works: It is generally accepted that grapefruit inhibits an enzyme (a substance which helps a reaction take place) which breaks down many recreational drugs, ie MDMA... but this is wrong. Grapefruit juice does potentiate MDMA (among many other drugs), but by a different mechanism. My dog won't get into the details as it would twist many people brains, but here is a great thread Paracelsus posted about the subject if one would like to delve further into it: https://drugs-forum.com/threads/32404&highlight=grapefruit+juice Notes: While grapefruit juice can definitely increase MDMA bioavailability (a measure of the amount of a drug which actually contributes to a physiological response), it may be counteracted by the fact that grapefruit juice is very acidic (about a pH of 3 on a scale of 1-14, 1 being the most acidic). My dog hasn't read anything specific about this dilemma, and he hasn't had enough experience to make a conclusion. Again, who knows what's best for you? You do! Be the guinea pig. Piracetam Sources: supplements Recommended dose: 1000mg-4000mg a day for days or weeks before an MDMA session How it works: The exact mechanism of action of piracetam, a drug originally developed to slow the progression of such mentally deteriorating diseases as Alzheimer's or alcoholism, is not completely known. It is thought to enhance cognition and memory, as well as increase blood flow in the brain. Many experiences posted on Erowid champion the use of this drug, claiming it enhances the experience, perhaps reduces tolerance. My dog couldn't find any publications on this subject and doesn't expect to... piracetam is a relatively new and understudied drug, most people have never even heard of it. My dog says that he has personally tried this (dosing for 4 or 5 days before an MDMA experience) and can say his third roll was just as good if not better than his first, both were similar doses. He has only had three though so cannot give a real conclusion. ONLY YOU HOLD THE POWER TO DECIDE. There are MANY more possible supplements. This is merely a list of the most common, perhaps most effective ones. Any combination of supplements can be taken. Perhaps one is sensitive to magnesium but always has a sore jaw after an experience... look for another supplement which can induce muscle relaxation, or simply bring a pacifier (if you're into that... my dog thinks these are best given to babies)! Can't afford expensive anti-oxidants like ALA or grapeseed extract? Eat an orange. Guinea pigs! H2O (WATER!) This is the most important supplement of all. Drink lots of it! All the time! MDMA causes dehydration and increased heart rate (the heart is working super hard), dancing causes dehydration (and works the heart even harder), and those who drink alcohol with MDMA (which my dog hears is quite common... doesn't understand why anyone would want to cloud the experience) are dehydrating themselves even more. This can be a dangerous combination. Drink at least a 20oz bottle or so every hour, especially if a guinea pig is dancing really hard. What about too much water? Risk of hyponatremia (basically a water overdose) is quite low, but still possible. In fact, in terms of deaths associated with MDMA this is really one of the only things to worry about, aside from polydrug (more than one drug) use and dehydration. Possible hyponatremia is easily combatted by drinking something with electrolytes (ie Gatorade) which will not disturb the body's salt balance as much. Sample pre-loading regimen (my dog's ideal recipe) Every day for approximately a week or more prior to the experience: 4000mg Piracetam (2000mg 2x a day) Anywhere from 1 hr to at the time of MDMA ingestion (MDMA usually takes approximately 30-60 minutes to work its magic): 1000mg Vitamin C 400 IU Vitamin E 50 mg Co-Q10 600mg ALA 400mg magnesium (too much hurts his tummy) And finally, 2-3 tums at the time or about half an hour prior to MDMA ingestion (my dog proposes that if he takes the Tums 30 minutes before ingestion, the levels of base will be relatively high when he ingests the MDMA) Guinea pigs: see what works best for you! Theoretical knowledge is great, but experience is just as important. Post-loading There are really two "post-loads"... my dog defines the first as perhaps 3-6 hours after MDMA ingestion, and the second as the day/night (depending on when the MDMA was taken) and a few days after the experience. First post-load (about 3-6 hours after MDMA ingestion, or as soon as possible after that) Since after 3-6 hours MDMA is still potentially toxifying nerve cells, many of the supplements should still be used. Antioxidants (in the same, higher, or lower doses- YOU DECIDE) are still a good idea, just be careful with fat-solubles such as Vitamin E... chances of something terrible happening are miniscule, but it is still good to practice harm reduction of harm reduction! Some users complain of stomach cramps when post-loading with Vitamin C (talk to your guinea pig). Magnesium is also a good idea if guinea pigs think they are having jaw issues. Now, my dog thinks, is the best time for 5-HTP supplementation. As serotonin is quite depleted, giving the body more raw serotonin material can only help. Perhaps 100-200mg at this time, and more the following few days (discussed soon). If one's guinea pig has it available, perhaps think about something like Prozac (fluoxetine), or Celexa (citalopram), both SSRI's (selective-serotonin reuptake inhibitor). SSRI's have a high (ie higher than dopamine) affinity (attraction) for serotonin transporters. Since the theory behind MDMA neurotoxicity concerns the reuptake of dopamine after serotonin depletion, perhaps fluoxetine can prevent this reuptake, as when it binds to serotonin transporters it sticks and it is difficult for things to get back into the cell (hence why it is used to treat depression- it inhibits the reuptake of serotonin [which regulates mood], increasing the serotonin concentration in the synapse). DO NOT take SSRI's before using MDMA. Well, if your guinea pig wants to, go ahead. But he probably won't feel much, if anything. Most importantly, hydrate! My dog thinks MDMA and humans are a match made in heaven, but physiologically they don't really like each other. Give your heart a helping hand by replenishing it with delicious liquids. Sample first post-load regimen: (again my dog's ideal) 1000mg Vitamin C 400 IU Vitamin E 400mg magnesium if his jaw is uncontrollable 600mg ALA Second post-load (after returning to baseline and the day after) Now the experience is over. But it was awesome right? You had fun, but your body and brain didn't. Depending on what time it is and whether you have an appetite, eat a nutritious (and large) meal. Spoil yourself, but spoil yourself with classy things. Eat some fish (omega fatty acids promote brain health), a pound of salad, a fresh fruit smoothie, etc. It's not that hard to make a great tasting meal which also helps your body. My dog enjoys a huge bowl of whole grain cereal and bananas, plus a plateful of veggies and some sort of protein (but he is a vegetarian and has some pretty odd eating habits). Most likely it is too late to eat/you aren't hungry. Go to sleep! Sleep well. Again, spoil yourself. It's ok to live a little, but good things come at a price... your body did all the work, now give it some rest. In the morning, keep the nutritious mindset. Eat a large breakfast, stay hydrated, and continue to be healthy for the rest of the day and the next few days. Maybe even do some exercise! The only supplement my dog would suggest for the days after an experience is 5-HTP, at the doses recommended in previous sections of this post. Sample second post-load regimen A LOT OF FOOD. Food at night, food in the morning, food all day. Drink a ton too! Perhaps start a few days of 5-HTP supplementation, especially if your guinea pig thinks he might suffer a case of the Tuesday blues. Hope this helps! Much of the information in this post was drawn from simple google searches (ie supplement sources), some is from personal and peer experience. However, much of the science is published. My dog uploaded a few articles and from which he drew conclusions, for example the theory behind MDMA neurotoxicity. WillowOne created a comprehensive week-long regimen here. Stay safe! Notes: *bLuE posted this: This is a good point, and it also reminds my dog that for the most part, supplements are recommended over many of the food sources for three reasons. First off, because it is best to eat on a relatively empty stomach to increase potential MDMA absorption and the rate at which it occurs, second, as bLuE mentioned, certain foods can interact negatively with MDMA, and third (from experience alone), it's just a lot easier to pop a few pills than plan out an organized meal. It is a mystery to my dog why anyone would want to eat a giant steak before an MDMA experience anyway... Regarding the inclusion of more information on MDMA toxicity (I assume Priapism requested this), which someone mentioned in a rep: I totally agree. However, as Dr. Satan said apparently they are close to finishing a more informative sticky which (hopefully) will have a large section on neurotoxicity. In addition, this thread was geared toward pre/postloading... yes the reason this is done is to prevent neurotoxicity, but if my dog really got into talking about it in depth then he would have to start explaining much more about biology, pharmacology, MDMA biochemistry, etc. which 1) would be difficult for many people to understand and 2) would defeat the purpose of a thread solely about pre/postloading. In addition, a bunch of the articles attached talk way more in depth about the toxicity and propose theories as to why it may be neurotoxic and how. Lastly, I say may because there is no definitive evidence that MDMA is neurotoxic, at least in the short term. There have been studies which show obvious almost irreparable breakdown of functioning in heavy, long term users, but for the most part it seems like (from what my dog has read) that they are hard pressed to prove that moderate doses spread out over time cause permanent changes. Plus, the theories behind WHY it might be neurotoxic are still only THEORIES. Just to clarify, my dog does believes that if a guinea pig takes a bunch of ecstasy too often (ie every weekend 3 or 4 pills) that this will definitely have at least semi-long term problems and the danger seems to be related to how often and how heavy the use is... but he firmly opposes the idea that taking 120mg of MDMA 2 or 3 times a year will cause any permanent damage. Links: Your brain on ecstasy (a brilliant slideshow created by DanceSafe, a harm reduction website): http://www.dancesafe.org/slideshow/ Free radicals and antioxidants: http://www.healthchecksystems.com/antioxid.htm 5-HTP and MDMA (Erowid) Piracetam (most of you have probably never heard of it): http://www.ds-health.com/pir_res.htm SSRI's: http://www.healthyplace.com/depression/antidepressants/selective-serotonin-reuptake-inhibitors-ssris/menu-id-68/ ; abstract of article about fluoxetine's neuroprotective effect (couldn't find the full article): http://www.ncbi.nlm.nih.gov/pubmed/...ed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=11 Abstract about 5-HTP supplementation and increased serotonin levels in mice: http://www.ncbi.nlm.nih.gov/pubmed/...med_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5 If anyone has access to those articles please let my dog know and he can upload them here.