This is an archive of our old site MDMAWiki.org. Some of it will be readable, though some of the tables are in mediawiki format and will be hard to read.

To view the mediawiki tables, find a wikipedia page, click edit on the wikipedia page, and then select all the code in the editing area and delete it, and then paste the mediawiki table code from this page into the editing box, and then hit preview. Don’t hit save, just use it to preview the table.

MDMA Dosage

Optimal MDMA Dosage for Safety and Enjoyment

Dose less than or equal to 125mg for safety and enjoyment. Re-dosing or taking a booster dose increases the risk.

A study found that MDMA desirable effects are maximized, and undesirable effects minimized, at doses between 81-100 mg. (1)

If this sounds low to you, ask yourself: how certain are you of the purity levels, not just MDMA presence, of your MDMA? How do you know?

MAPS’ MDMA research protocol involves 120 mg or 80 mg doses, followed by a 60 or 40 mg booster respectively around ~2.5 h after ingesting the first dose. (2)

From MDMA researcher Matthew Baggott:

“I trained in an MDMA neurotoxicity lab (Lewis Seiden’s) and then went on to do human studies (giving MDMA to volunteers to understand its emotional effects). I think MDMA may well be neurotoxic at the higher end of recreational doses. I wouldn’t personally take/give more than 1.5-1.7 mg/kg and would never take/give a booster dose, unless there was strong reason to think the person would have some clear benefit (as in MDMA-assisted psychotherapy) to offset the added risks. Just my opinion.”

“To the best of my understanding, doses around 1.5-1.7 mg/kg MDMA (roughly 100 to 125 mg MDMA) are unlikely to cause long-lasting serotonin changes. Studies by MAPS have looked for changes in mental abilities after people participated in their studies, with some participants receiving 125 mg followed by 62.5 mg, and have not found any changes.”

Also from Baggott

In studies such as this, we sometimes see bigger effects on heart rate than I would want and people frequently say they feel close to maximal effects. As a result, I tend to think 1.5 mg/kg is high enough and I would worry that 120 mg is too high for many smaller people.

I do agree there are limits to mg/kg scaling. Mg/kg is correcting for the volume in your body that the drug dissolves into, with the idea that people will get similar blood (and then brain) concentrations. However, this volume doesn’t scale with weight perfectly because peoples’ bodies are different on the high and low ends of weight. So I would personally suggest 1.5 mg/mg up to a maximum of 120 mg. I don’t have strong evidence for a minimal dose from my studies, but if forced to choose I might use a minimum dose of 75mg.

Interestingly, MAPS is seeing preliminary evidence that lower doses might be more therapeutic, which is consistent with observations by therapist Leo Zeff that people want higher doses than they need.

Excerpt from Rollsafe.org

MAOIs, SSRIs and MDMA

__TOC__

MAOIs

You should wait 3 weeks after the last time you took an MAOI before taking MDMA. This is very important.

Common MAOIs

Isocarboxazid (Marplan) Phenelzine (Nardil) Selegiline (Emsam) Tranylcypromine (Parnate) [1]

MAPS Research Guidance

“Fatalities have occurred apparently as a result of combining MAOI medications with MDMA [133, 134]. For this reason, MAOI medications are tapered for at least five half lives of the medication and active metabolites, plus 1 week for symptom stabilization in sponsor-supported studies.” – MAPS 2016 Brochure

SSRIs

SSRIs will reduce or eliminate the subjective effects of MDMA, so you’ll want to wait until you feel back to ‘normal’ after tapering down SSRI use.

See this guide and this guide for SSRI tapering information.

Common SSRIs

• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Paroxetine (Paxil, Pexeva)
• Sertraline (Zoloft)
• Vilazodone (Viibryd) [2]

MAPS Research Guidance

“Co-administration with an SSRI may eliminate or greatly attenuate the effects of MDMA, and these medications should be tapered in line with the investigator’s clinical judgment and an approved study protocol.” – MAPS 2016 Brochure

References

1. http://www.mayoclinic.org/diseases-conditions/depression/in-depth/maois/art-20043992
2. http://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825

MDMA Research Exclusion Criteria

Information for MDMA researchers

Things researchers studying MDMA should know

“I’m frustrated — I read studies, then hit the dosing section, and then think to myself how do they not know how to properly dose rats for MDMA in 2017?”

Researchers would know how to properly dose MDMA if they read these:

• Table 1: Pharmacokinetic Constants for Plasma MDMA After Various Routes of Administration to Humans or Animals
• Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

Answers to the question “What do you wish MDMA researchers tracked?”

• Temperature. Especially if someone is studying supplements for MDMA neurotoxicity reduction, it would useful for them to track body temperature.

MDMA research wishlist

• “One of the oddities re human studies versus human use “in the wild” is that (most) studies are conducted during daylight hours, and the drug is administered in the morning. That’s also when we administer it in our therapy studies. However, people self-administering “Ecstasy” generally do so in the evening or even the middle of the night. And we don’t know whether diurnal variations in neurochemistry affect the experience. There is a single pair of studies involving administration of MDMA at night, and in two doses (Bosker et al. 2010, and I believe a study by Kuypers et al.). What I wish we tracked is whether there are, in fact, differences in effects owing to circadian rhythm.” — L (Ilsa) Jerome, Ph.D., Research and Information Specialist (MPBC / MAPS Public Benefit Corporation)

Neuroprotective Antioxidants Can Reduce MDMA Tolerance in Rats

Why is this interesting?

If tolerance is correlated to “losing the magic”, then using neuroprotective measures (limiting dose amount and pre-loading with supplements) may prevent or reduce the risk of “losing the magic”.

Am I at risk of “losing the magic”?

We don’t have conclusive evidence. The below quote from Ann Shulgin (“American author and the widow of chemist Alexander Shulgin”, Alexander Shulgin “is credited with introducing MDMA (ecstasy) to psychologists in the late 1970s”) provides anecdotal information.

Ann Shulgin:

The only thing that has happened with everyone I know who has used MDMA a great deal is that if they used it more than 4 times a year, they developed a tolerance, and after a few years, it begins to not work for them.

Why is avoiding “losing the magic” important?

By 2021 MAPS hopes to have MDMA approved by the FDA for treatment of PTSD. After that, you may one day step into a couples counseling session and take MDMA with your partner to strengthen your marriage, or to repair a relationship with your child.

If you’ve “lost the magic” of MDMA by then you may be forever unable to use a vital treatment method.

Ascorbic acid (vitamin C) prevents MDMA tolerance in rats

Key takeaway:

“The concomitant administration of ascorbic acid with the neurotoxic regimen of MDMA prevented the diminished neurochemical and behavioral responses to a subsequent injection of MDMA.”

Method:

“Rats were housed two per cage at 22–24°C and randomly assigned to one of four groups that received either vehicle, ascorbic acid (100 mg/kg, i.p. every 2 h for a total of 5 injections), MDMA (10 mg/kg, i.p. every 2 h for a total of 4 injections), or a combination of both MDMA and ascorbic acid, in which ascorbic acid was given 1 h before each MDMA injection and 1 h after the last MDMA injection. The neurochemical, behavioral, and thermal responses to a subsequent injection of MDMA were assessed in separate groups of rats 1 week after drug treatment.”

Ascorbic Acid Prevents 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Hydroxyl Radical Formation and the Behavioral and Neurochemical Consequences of the Depletion of Brain 5-HT (2001)

The MDMA 3 Month Rule

User friendly

Am I doing damage by rolling too often? What damage? Is the 3 month rule real? How often should I wait?

Anecdotal reports suggest that rolling more often can lead to a loss of the “magic” — where much of the positive effects are lost. There are also good reasons to wait between rolls: see this post by MDMA researcher Matthew Baggott.

Two people I talked with who lost the “magic” found that after losing the magic, even waiting ~10 years was only enough to get them one more decent roll before MDMA returned to “magic-less” again.

Avoid increasing dosage to make up for weaker effects

Anecdotally, people who use MDMA frequently seem to use high dosages. In the same way that alcohol harm is proportional to dosage, any MDMA neurotoxicity concerns are proportional to dosage.

Studies in primates suggest that repeated (inappropriately) high MDMA dosages can induce neurotoxicity, though MAPS believes that the 80 mg and 120 mg doses used in research are likely safe and effective.

To reduce any neurotoxicity risk, stick to dosages that are as low as possible, ideally between 80 and 120 mg.

Consider taking supplements, as there’s some evidence that certain supplements can reduce MDMA tolerance and that “neuroprotective measures (limiting dose amount and pre-loading with supplements) may prevent or reduce the risk of”losing the magic”.”

Why is waiting between MDMA sessions advisable

See the bottom of this post by MDMA researcher Matthew Baggott.

Potential damage of heavy use

“In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings—including our own—and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users.”

Though we’re not really sure.

Residual Neurocognitive Features of Long-Term Ecstasy Users With Minimal Exposure to Other Drugs

Origin of the 3 month rule

The origin of the three month rule is a quote from Ann Shulgin, widow of chemist Alexander Shulgin: “Now I would advise anyone who wants to use MDMA not to take it more than 4 times a year if you want to continue to get the best effects from it, otherwise you risk losing its effects entirely and permanently.”

Research on optimal MDMA break length

There isn’t really any high-quality research to tell us what we should do. This paper and this paper show brain changes that lasted ~3 weeks after use, but we don’t know if those changes are relevant to harm reduction.

The medical research group MAPS uses two or three MDMA doses, spaced 3 - 5 weeks apart. A minimum break is then perhaps 3-5 weeks if you’re taking less than or equal to 120 mg and with no more than 3 sessions — it may be smart to increase the delay if you plan on more than 3 sessions in your life, but we don’t really know.

Why care?

As Matthew Baggot wrote, “In ten years from now, MDMA may be legally available and used in therapy. You don’t want to be unable to save your marriage or fail to come to terms with trauma because you rolled too much in your youth and now can’t feel MDMA.”

Details

The origin of the “three month rule”

Ann Shulgin is thought to be the origin of the three month rule:

The only thing that has happened with everyone I know who has used MDMA a great deal is that if they used it more than 4 times a year, they developed a tolerance, and after a few years, it begins to not work for them. They want to get back the magic of the first experience, and that is a mistake, because - as Sasha likes to say – “You never step into the same river water twice. ” I found out, for myself, that using MDMA more often than four times a year was not wise. I used MDMA as a writing drug for about a year. Once a week, I would do a great deal of writing using MDMA; it was a wonderful experience for me to use it that way, but I discovered after that kind of use that I had to go up in dosage to get an effect, and the effect became less and less the magical insight; it was more and more the stimulant effects, and for many years now, I have been totally unable to use it. Not only because now it is illegal, but because I used it once a week, and that was too often. Nobody knew that, then, but now I would advise anyone who wants to use MDMA not to take it more than 4 times a year if you want to continue to get the best effects from it, otherwise you risk losing its effects entirely and permanently.

Science and research supporting MDMA breaks

Effect of ecstasy (MDMA) on cerebral blood flow: a co-registered SPECT and MRI study.

“However, within 3 weeks after MDMA administration, rCBF remained decreased in the visual cortex, the caudate, the superior parietal and dorsolateral frontal regions compared to baseline rCBF. The decreased rCBF tended to be more pronounced in subjects who received the higher dosage of MDMA. Two subjects who were scanned at 2 3 months after MDMA administration showed increased rather than decreased rCBF.” “Our study also found that regional hypoperfusion may be observed for 2 3 weeks after administration of MDMA, especially with the higher dosages.”

Repeated administration of MDMA causes transient down-regulation of serotonin 5-HT2 receptors.

“Twenty-one days after administration of MDMA however, the number of binding sites for [125I]MIL was back to control levels.”

The Acute and Chronic Effects of MDMA (“Ecstasy”) on Cortical 5-HT2A Receptors in Rat and Human Brain

“Also, the ex-MDMA users were studied after a relatively long MDMA-free period (on average 18 weeks) compared with the MDMA-treated rats (after 30 days).” “A significant positive correlation was observed between cortical 5-HT2A receptor binding (mean binding ratios of the three brain regions studied) and duration of abstinence from MDMA (0.57, p .01) but not between extent of previous MDMA (0.10, p .66).”

Matthew Baggott’s comments

Matthew Baggott is an MDMA researcher.

Baggott in 2015: ”Much of the advice available online comes from people with only a few years of experience with MDMA. Studies of MDMA users suggest that many people use MDMA heavily for a few years, find that the positives decrease and the negatives increase, and then quit. People with this common experience are probably less likely to be giving advice on reddit, so it can be hard to appreciate how common it is to burn out on MDMA.

Many of the experienced psychonauts who were using pure MDMA in the 1970s —people like Ann Shulgin and Debby Harlow— noticed diminishing returns from MDMA. Ann Shulgin used MDMA weekly to overcome writer’s block and found it stopped working for her. Based on that and observations of other people, Ann suggested people use MDMA no more than 4 times per year. Debby Harlow noticed that many people seemed to get only about 10 special rolls and after that the experience was merely pleasant, but not magic. These numbers may not be exactly correct for everyone, but the general experience is common: most people eventually lose the magic of MDMA with repeated, frequent use.

So my advice is treat it like you won’t always have it. Try to learn from the experience and grow your skills at recreating without drugs some of the freedoms MDMA offers. Taking MDMA before going out is not a sustainable way to deal with social anxiety. In the long run you’re much better off working to achieve personal growth.

And consider saving some of the drug’s magic for later in life. In ten years from now, MDMA may be legally available and used in therapy. You don’t want to be unable to save your marriage or fail to come to terms with trauma because you rolled too much in your youth and now can’t feel MDMA.”

Baggott in 2015: ”Beyond the anecdotal observations that higher frequency leads to loss of magic, no one really knows. All the theories about replenishing serotonin are untested ideas. It is not even known if loss of magic is associated with depleted serotonin or with brain damage or with some other mechanism like simple learning.”

Heart valve risks from MDMA

Notes

Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease.

Valvular heart disease, inducing valvular regurgitation, has been described in users of drugs such as anorectic agents and ergot derivates. 3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”) also leads in vitro to the proliferation of cardiac valvular interstitial cells by activation of the 5-hydroxytryptamine 2B receptor. The aim of this study was to determine the occurrence of valvulopathy in young adults taking MDMA. Twenty-nine subjects using or having used MDMA and 29 gender- and age-matched controls were blindly evaluated with echocardiography. Eight subjects (28%) who took MDMA had abnormal echocardiographic results using the United States Food and Drug Administration’s criteria for appetite suppressant-induced valvular heart disease, compared with none in the control group (p = 0.0045). Six (21%) subjects had mitral regurgitation of ¹⁄₄ and 4 (14%) of > or =²⁄₄, compared with none in the control group (p = 0.002). The mean mitral regurgitant area ratios (jet/atrium) were 12 +/- 9.8% and 5 +/- 1.3%, respectively (p = 0.007). Tricuspid regurgitation > or =²⁄₄ was present in 13 MDMA users (45%) and absent in controls (p <0.001). The mean tricuspid regurgitant area ratios were 19 +/- 9.5% and 9 +/- 4.5%, respectively (p <0.001). Four MDMA users (14%) had mild aortic regurgitation (p = 0.11). Valvular “strands” were present in 6 MDMA users (21%) and in none of the controls (p = 0.02). In conclusion, MDMA may lead to mild to moderate valvular heart disease and valvular strands.

The above study had participants who had taken an average of 3.6 tablets per week over 6.1 years.

May also be a concern with LSD, psilocybin

Cardiovascular toxicity of novel psychoactive drugs: Lessons from the past

Serotonin Receptors and Heart Valve Disease – it was meant 2B

3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro

Valvular heart disease in a patient taking 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’)

Possible Association Between 3,4-Methylenedioxymethamphetamine Abuse and Valvular Heart Disease

Is MDMA Neurotoxic?

This page will quote heavily from the MAPS MDMA brochure. This is the best source on evidence backed information on MDMA.

MAPS MDMA Brochure Key Excerpts

Source: The MAPS MDMA Investigator’s Brochure

What is MAPS?

“Founded in 1986, the Multidisciplinary Association for Psychedelic Studies (MAPS) is a 501©(3) non-profit research and educational organization that develops medical, legal, and cultural contexts for people to benefit from the careful uses of psychedelics and marijuana.”

Why do they summarize MDMA research?

MAPS is the main sponsor behind the recent FDA Phase 3 trial approval for MDMA.

As part of their work on MDMA for PTSD, MAPS has spent lots of money and time doing literature reviews on MDMA. MAPS is the best source for literature overviews on most MDMA related topics.

Why is there so much confusion and false information surrounding MDMA?

This letter by Rick Doblin should be informative regarding why there is so much propaganda. This letter was written back in 2004, and sadly it is still relevant in 2017.

See also

DanceSafe’s page has great information and an easier to read format.

4.0 Nonclinical Studies

4.4.10 Neurotoxicity

Repeated very high doses of MDMA in animals reduce total serotonin levels in the brain, impair transport of serotonin, and cause psychobehavioral changes such as increased anxiety [124, 226, 391-393]. In combination with other drugs or in high dose binge administration studies, MDMA may provoke serotonin syndrome. For example, rodents respond to high doses of MDMA by exhibiting flat body posture, forepaw treading and an erect tail (“Straub tail”) [393]. These behaviors are considered indicators of serotonin syndrome. Doses used in most preclinical studies of neurotoxicity are at least five times the amount used in clinical trials or nonmedical settings, and can be as high as 20 times that amount. Studies in rodents and primates suggest that repeated high doses of MDMA could reduce regional serotonin, damage serotonin axons and cause neurotoxicity [124, 135, 394-397] and promote apoptosis in the hippocampus after 5 or 10 mg/kg MDMA given daily for 1 week [214]. However, the majority of these studies employed large doses of MDMA that overestimated human-equivalent doses, with findings now clearly indicating that doses used in nearly all rat and most primate studies are inappropriately high for comparison to use in clinical settings and are more pertinent toxicological effects of MDMA [78, 114, 119]. Most studies suggested that heavy but not moderate Ecstasy users had impaired verbal memory and lower numbers of estimated SERT sites, assessed via imaging with radioactively labeled ligands in positron emission tomography (PET) or single photon emission tomography (SPECT), with heavy use often defined as 50 or more times or tablets. Taken together, findings from these studies suggest there is some risk of long-term effects in heavy Ecstasy users with respect to number of estimated SERT sites in specific brain areas and performance on measures of memory. However, interpreting findings of changes in serotonin receptors or cognitive function after repeated Ecstasy use are complicated by the possible impact of polydrug use and other potential pre-existing factors in retrospective reports, and the findings are not readily transferrable to use of MDMA in a therapeutic or research context.

Many investigations have examined cognitive function in Ecstasy users with the goal of demonstrating long-term effects of purported neurotoxicity of Ecstasy. Rogers and colleagues performed a meta-analysis on a large number of retrospective studies of Ecstasy users and various cognitive functions. Given methodological flaws in this type of analysis, the investigators cautiously concluded that there might be a significant effect of Ecstasy use on verbal memory, and a lesser effect on visual memory [53]. Retrospective designs and inappropriately matched samples continue to appear in the literature [398-400], even when using multiple control groups. Two meta-analyses of memory in Ecstasy users arrived at somewhat contradictory conclusions [401, 402]. Both detected an association between Ecstasy use and impaired performance on at least some measures of memory. However, one reported that this association had a medium to large effect size with no effect of Ecstasy dose [401], while the other reported that the association had a small to medium effect size with an Ecstasy dose effect, and that polydrug use itself contributed to impaired cognitive function [402]. A meta-analysis comparing current Ecstasy users and drug-using controls on visuospatial skills reported that current users performed less well on measures of visual recall, recognition and item production than controls [403], but found no significant relationship between lifetime Ecstasy use and visuospatial task performance. A longitudinal study comparing people who continued to use Ecstasy with those who did not do so detected lower performance on immediate and delayed visual memory [404]. In a second follow- up in the same sample reported lower scores in visual memory, at marginal significance and no further impairment [405]. An examination of the relationship between elements of Ecstasy use history and verbal memory reported that use in the past year, especially in men, was associated with impaired verbal memory [406]. The authors suggest that gender differences in polydrug use may be involved. A study comparing performance on a test of verbal memory in 65 ecstasy users enrolled in clinical trials of MDMA and an equal number of age and gender matched non-drug using controls from other trials failed to detect significant differences between the two groups [407]. This study employed a pre-determined measure of clinical significance, 1.5 times the average standard deviation of the healthy controls, and used a Bayesian statistical test suited for assessing a null hypothesis. It is notable that none of the subjects were enrolled in studies designed to compare cognitive function in ecstasy users, which may have reduced anxiety and potential risk of “stereotype threat” that may be faced by substance users completing assessments of cognitive function, which was done to reduce expectancy in the study [408].

The nature and strength of the association between regular Ecstasy use and any impairments in executive function remains inconclusive, with studies reporting conflicting results [5, 258, 259, 409, 410]. Findings from a study published in 2014 did not find differences in multitasking [301]. A meta-analysis comparing executive function in Ecstasy users and non-Ecstasy using controls found a significant effect of Ecstasy use on one component of executive function (updating), no effect on another (shifting) and mixed results when looking at other components (response inhibition and access to long-term memory) [411]. Polydrug use likely contributes to findings of impaired executive function seen in Ecstasy users [292, 412]. Current research has not settled the question.

Psychiatric problems after uncontrolled, non-medical Ecstasy use were reported in 22.1% of 199 case reports from the early 1990s to 2001, and are the most common reason for appearance at an emergency department [52, 55]. Psychiatric symptoms included affective responses, such as dysphoria, anxiety, panic, and psychotic response, as well as cases with mixed psychotic and affective features. The most common problem reported included panic, restlessness and psychotic response, as seen a systematic review and several epidemiological case series [53, 413]. The mechanisms behind Ecstasy-associated psychiatric problems remain unclear, but are likely the result of an interaction between pharmacology and individual susceptibility. The difficulty of assessing the frequency of these events is increased given that pre-existing psychiatric problems occur in people who choose to use Ecstasy [414] and findings of an association between use of Ecstasy and other drugs and self-reported symptoms of anxiety and depression. As described earlier, most cases of psychological distress after Ecstasy use resolved after supportive care [52, 55].

Anxiety responses associated with MDMA administration reported in controlled trials have resolved over time, usually either during the period of acute drug effect or with the waning of drug effects.

5.0 Effects in Humans in Clinical Settings

5.3.7 Neurobiological Effects

Ten Ecstasy user subjects receiving a minimum of two doses of 1 to 1.25 mg/kg or 2.25 to 2.5 mg/kg MDMA exhibited signal decreases in bilateral visual cortex, caudate, superior parietal, and dorsolateral frontal regions 10 to 21 days later, with increased rCBF measured in two subjects at a later time point. However, a comparison between heavy Ecstasy users and non-user controls failed to find differences in baseline rCBF [593], and a report assessing changes before and after initial Ecstasy use found increased rCBF in only one area of the prefrontal cortex [266], suggesting that the changes seen by Chang and colleagues are a transient effect.

5.3.8.1 Cognitive Function

In MP-1, no significant differences in cognitive function were detected at the 2-month follow-up between subjects who received two sessions with 125 mg of MDMA compared to subjects who received placebo, as measured by RBANS and PASAT [41]. These findings suggest that MDMA did not impair cognitive function in this sample or that the effect was too small to attain statistical significance in this small pilot study. Two ongoing studies (MP-12 and MP-4) include these measures to assess reproducibility of this finding. Since both MP-4 and MP-12 were ongoing as of the data cut-off, available data pooled across studies are presented below by dose.

On average, RBANS scores trend towards improvement after treatment with placebo and 40 mg to 100 mg initial dose of MDMA, whereas scores stay the same after treatment with 125 mg initial dose of MDMA. The trend towards improvement could be a practice effect from repeated assessments, although stimuli were varied across these, or could possibly be correlated with PTSD symptom reduction. One to three additional treatments with open-label active dose MDMA do not appear to worsen cognitive function based on preliminary End of Stage 1 and End of Stage 2 results. The significance of these pooled findings is yet to be determined.

On average, PASAT scores stay about the same after treatment with placebo and 100 mg initial dose of MDMA and trend towards improvement after treatment with 40 and 125 mg initial dose of MDMA. The trend towards improvement could be a practice effect from repeated assessments or could be correlated with PTSD symptom reduction. One to three additional treatments with open-label active dose MDMA do not appear to worsen cognitive function and continued to trend towards improvement on average based on preliminary End of Stage 1 and End of Stage 2 results. Cognitive function tests such as the PASAT are also known to be subject to individual variability, as they require basic proficiency with mathematical skills that are influenced by education level. The significance of these pooled findings is yet to be determined, but it does not appear that MDMA-assisted psychotherapy is negatively impacting cognitive function.

Matthew Baggott, MDMA researcher

“To the best of my understanding, doses around 1.5-1.7 mg/kg MDMA (roughly 100 to 125 mg MDMA) are unlikely to cause long-lasting serotonin changes. Studies by MAPS have looked for changes in mental abilities after people participated in their studies, with some participants receiving 125 mg followed by 62.5 mg, and have not found any changes. I looked for changes in mental abilities and mood in about the first 25 people I gave 1.5 mg/kg MDMA to and did not see any changes.“ Via.

Other

Neuroimaging in moderate MDMA use: A systematic review

There is no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures. The lack of significant results was associated with high methodological heterogeneity in terms of dosages and co-consumption of other drugs, low quality of studies and small sample sizes.

Moderate in this study refers to <50 lifetime MDMA sessions / <100 lifetime MDMA tablets

MDMA Safety Enhancement and Enjoyment Amplification using Supplements and Other Methods

What is this

This is an evidence-table for MDMA safety recommendations.

This page details the best methods to our knowledge for a) reducing the risk of MDMA neurotoxicity, b) reducing the risk of MDMA serious adverse-effects, and c) amplifying the positive effects of MDMA.

None of these things have been tested in a controlled fashion with humans for reducing adverse effects so it is hard to make clear recommendations.

FAQ

Why does this page exist?

“Although first synthesized 100 years ago, [MDMA] came into unofficial therapeutic use in the 1970s. Originally known as ‘empathy’, it was used in the United States as an adjunct to psychotherapy owing to its ability to facilitate interpersonal communication. Before the neuroscientific mechanisms of this property could be investigated, it entered youth culture in the dance/rave scene, where dealers changed the name to ‘ecstasy’ (Nutt, King and Nichols, 2013).”

MDMA was made Schedule I in the US soon after, massively limiting research on therapeutic potential.

Now MDMA is entering a golden age. MDMA has been approved for FDA Phase 3 trials in the USA, and MAPS believe MDMA will be made into a prescription medicine by 2021.

This wiki needs to exist because millions of people still use MDMA each year, and so we should do everything we can to help these people get maximum therapeutic/personal benefit from MDMA, as well as helping them experience minimal downsides.

How can I best help others?

Correct mis-information. If someone tells you mis-information, look at this table, find the relevant scientific evidence, and then give that evidence to the person in question so they have up to date information.

e.g. if you see someone talking about taking hot showers or using a hot tub while on MDMA, you can point them to information on body temperature to make sure they have all the information they need to be as safe as possible.

Is MDMA Neurotoxic?

Read this page.

Do I need to take supplements with MDMA for neurotoxicity mitigation?

No. However, I would advise any family members of mine who were planning on taking MDMA to use supplements each time, and to follow the other harm reduction methods below.

“If supplements can protect against MDMA damage (if it happens) at a low cost, then the cost-benefit ratio for supplements is excellent.

I believe the best rationale for taking supplements with MDMA is that supplements may reduce the risk of or prevent “losing the magic” with MDMA use over time. This is hypothetical. We do know supplements can prevent MDMA tolerance in rats.”

Mostly interested in supplements?

MDMA Supplements: This page covers the most scientifically supported supplements for MDMA neuroprotection.

Outcome: Reduced Neurotoxicity Risk (Harm Reduction)

{| class=“wikitable” ! Level of high quality evidence || Substance || Recommendation || Possible outcome || Research || Notes |- | 1+ Rat study || Alpha Lipoic Acid (ALA) || class=“reduced-risk” | Strongly recommended || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/10619665 Alpha-lipoic acid prevents MDMA-induced neurotoxicity.] || “ALA is recommended vs Na-RALA (RALA) because it is more cost effective.” from the [https://rollsafe.org/mdma-wiki/ MDMA Supplement Recommendations Page] |- | 1+ Rat study || Acetyl-L-carnitine (ALCAR) || class=“reduced-risk” | Strongly recommended || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/10619665 Acetyl-L-carnitine provides effective in vivo neuroprotection over MDMA-induced mitochondrial neurotoxicity in the adolescent rat brain.] || In these studies seems to work well with Alpha Lipoic Acid ([http://link.springer.com/article/10.1007/s12640-010-9165-3 Nagesh Babu, Kumar, & Singh, 2010]; [http://www.pnas.org/content/99/4/1870.short Hagen et al., 2002]). |- | 1+ Rat study || No redose || class=“reduced-risk” | Strongly recommended || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/15358986 Effect of repeated (‘binge’) dosing of MDMA to rats housed at normal and high temperature on neurotoxic damage to cerebral 5-HT and dopamine neurones.]

[https://www.ncbi.nlm.nih.gov/pubmed/26073279 Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart.] || Taking more MDMA when nearing the end of the effects is inadvisable from a neurotoxicity standpoint. 

Much of the therapeutic research with MDMA uses a booster dose of 50% of the first dose taken 1.5-2.5 hours after ingesting the first dose. For this site, “redosing” refers to taking another dose as you are “coming down” from a prior dose, and “booster dose” refers to taking a smaller sized dose roughly when you are experiencing peak effects from the first dose to extend the length of the roll. Using a small “booster dose” is likely a lower risk than redosing at the end of the roll. However, the lowest risk option is to take a reasonable dose at t=0 and to not use a booster dose or a redose. |- | Hypothetical || Dose <=125mg || class=“reduced-risk” | Strongly recommended || class=“reduced-risk” | Reduced risk || [https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/mdma/MDMA_IB_FINAL_30Mar2016_Linked.pdf MAPS Investigator’s Brochure 8th Edition Section 4.4.10] || “Studies in rodents and primates suggest that repeated high doses of MDMA could reduce regional serotonin, damage serotonin axons and cause neurotoxicity [124, 135, 394-397] and promote apoptosis in the hippocampus after 5 or 10 mg/kg MDMA given daily for 1 week [214]. However, the majority of these studies employed large doses of MDMA that overestimated human-equivalent doses, with findings now clearly indicating that doses used in nearly all rat and most primate studies are inappropriately high for comparison to use in clinical settings and are more pertinent toxicological effects of MDMA [78, 114, 119].” High doses cause neurotoxicity in animals. We don’t know what the dose risk/reward curve looks like, but from a harm reduction perspective using the same or lower MDMA dose as used in clinical research is both highly accessible for all users and is advisable for reduced neurotoxicity risk.

Baggott: “I trained in an MDMA neurotoxicity lab (Lewis Seiden’s) and then went on to do human studies (giving MDMA to volunteers to understand its emotional effects). I think MDMA may well be neurotoxic at the higher end of recreational doses. I wouldn’t personally take/give more than 1.5-1.7 mg/kg and would never take/give a booster dose, unless there was strong reason to think the person would have some clear benefit (as in MDMA-assisted psychotherapy) to offset the added risks. Just my opinion.” |- | 1+ Human correlational study || Less frequent dosing || class=“reduced-risk” | Strongly recommended || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/11847047 Reduced N-acetylaspartate levels in the frontal cortex of MDMA users: preliminary results.]

[https://www.ncbi.nlm.nih.gov/pubmed/9807990/ Positron emission tomographic evidence of toxic effect of MDMA on brain serotonin neurons in human beings.] || [https://www.ncbi.nlm.nih.gov/pubmed/9807990/ “Decreases in 5-HT transporter binding positively correlated with the extent of previous MDMA use.”] |- | 1+ Rat study || Ubiquinone (Co-Q10) || class=“reduced-risk” | Encouraged || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/16098955 Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT.] || Co-Q10 is generally not absorbed well, in rat studies for MDMA has been locally perfused.

“CoQ10 is lipophilic or fat-soluble and should be supplemented with some form of dietary fat or lipophilic transport.[https://examine.com/supplements/coenzyme-q10/#ref27 [27]]” |- | 1+ Rat study || Nicotinamide || class=“reduced-risk” | Encouraged || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/16098955 Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT.] || - |- | 1+ Rat study || Vitamin E || class=“reduced-risk” | Encouraged || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/11931860 d-MDMA during vitamin E deficiency: effects on dopaminergic neurotoxicity and hepatotoxicity.] || - |- | 1+ Rat study || Ascorbate (Vitamin C) || class=“reduced-risk” | Encouraged || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/11170222 Ascorbic acid prevents MDMA-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT.] || See: [[Will Vitamin C or orange juice decrease the effects of MDMA?]] |- | Hypothetical, debated || Magnesium || Use if you experience “gurning” || class=“reduced-risk” | Reduced risk || - || Baggott: “There is no evidence I know of that magnesium has any effects on safety. Someone here on reddit has a theory that MDMA might cause excitotoxicity and magnesium might prevent it, but that’s speculation. There’s maybe one scientific paper that speculates MDMA might cause excitotoxicity. If this really happens, it would be unrelated to the serotonergic changes that most of these supplements are trying to protect against. Magnesium does, anecdotally, seem to reduce muscle tension and twitching (including “jaw gurning”).”

Beneficial for side-effect reduction (“jaw gurning”). See the side-effect reduction section. |- | 1+ Rat study || Memantine || - || class=“reduced-risk” | Reduced risk || [http://www.sciencedirect.com/science/article/pii/S0161813X07001842 Memantine prevents MDMA-induced neurotoxicity]

[http://www.sciencedirect.com/science/article/pii/S0014299908005220 Memantine prevents the cognitive impairment induced by MDMA in rats] || Memantine has been https://www.researchgate.net/profile/Magi_Farre/publication/261102281_Memory_and_mood_during_MDMA_intoxication_with_and_without_memantine_pretreatment/links/55b64c9c08ae092e9655d68e.pdf given to humans in combination with MDMA. |- | Hypothetical || Gastrointestinal or urinary acidifying agents || - || class=“reduced-risk” | Reduced risk || - || From the [http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021303s031lbl.pdf Adderall XR 2015 FDA info sheet], this seems undesirable during MDMA’s absorption: “Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) lower absorption of amphetamines. Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines.” |- | Hypothetical || Other antioxidants || - || class=“reduced-risk” | Reduced risk || - || Baggott: “Theoretically, one would guess that other antioxidants could be helpful. But we should keep in mind that antioxidant extracts from plants often have multiple effects in the body, so these may have unexpected negative effects.” |- | 1+ Rat study || Sildenafil (Viagra) || - || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/21948520 Long-lasting neuroprotective effect of sildenafil against MDMA-induced 5-hydroxytryptamine deficits in the rat brain.] || “Sildenafil at recommended doses has no effect in the absence of sexual stimulation ([https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020895s033lbl.pdf FDA, 2010]).” Viagra doesn’t cause erections unless you’re sexually stimulated.

Some anecdotal reports of unpleasant experience, some of good experiences e.g. see [https://erowid.org/experiences/exp.php?ID=27174 Erowid]. |- | 1+ Rat study || SSRIs (e.g. Citalopram/Celexa) || - || class=“reduced-risk” | Reduced risk || [http://www.nature.com/npp/journal/v22/n5/full/1395472a.html The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of MDMA in healthy volunteers.]

[http://www.maps.org/images/pdf/1987_schmidt_1.pdf Neurotoxicity of the psychedelic amphetamine, MDMA.] || Baggott: “A more common rationale is that the long-term serotonergic effects of MDMA are caused by MDMA and/or another toxic molecule (a metabolite or dopamine) entering the serotonergic neuron through the serotonin transporter and MDMA causing sustained high metabolic activity inside the neuron until the neuron runs out of energy and cannot protect itself from the metabolic byproducts of its activity. It’s hard to say how long this activity can go on for before you start to get long term serotonergic consequences. From rat studies, it seems to be a few hours. However, those studies produce brain concentrations of MDMA that are likely a bit higher than typically achieved by 100-125 mg in humans. Thus, it may take longer in humans.

Taking an SSRI prevents MDMA (and other substrates) from entering through the serotonin transporter. This terminates MDMA’s psychoactive effects and prevents neurotoxic effects from developing.

Timing the SSRI for about 3 hours after MDMA means you won’t really shorten the (non-redosed) MDMA experience since it takes an hour or so for the SSRI to be absorbed and start showing up in the brain. The exact timing of absorption will depend on the SSRI formulation.

There isn’t really any research on the optimal dose. 20 mg oral citalopram seems adequate. Swiss studies have used 40 mg IV citalopram with MDMA in humans.*” |- | 1+ Rat study || Metformin || - || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/27251371 Metformin Prevented Dopaminergic Neurotoxicity Induced by MDMA Administration (2016).] || - |- | 1+ Rat study || Cysteine || - || class=“reduced-risk” | Reduced risk || [https://www.ncbi.nlm.nih.gov/pubmed/9029406 Effect of ascorbate and cysteine on the MDMA-induced depletion of brain serotonin (1996).]

[https://www.ncbi.nlm.nih.gov/pubmed/15212815 The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine (2004).]

[https://www.ncbi.nlm.nih.gov/pubmed/23194825 Neurotoxicity of “ecstasy” and its metabolites in human dopaminergic differentiated SH-SY5Y cells (2013).]

[https://www.ncbi.nlm.nih.gov/pubmed/25096201 Attenuation of ecstasy-induced neurotoxicity by N-acetylcysteine (2015).]

|| Few human studies on cysteine.

[https://www.ncbi.nlm.nih.gov/pubmed/10604863 Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity (1999).]

[https://www.ncbi.nlm.nih.gov/pubmed/15634943 Serotonergic neurotoxic metabolites of ecstasy identified in rat brain (2005).]

From the 2015 study, I wonder how this impacts subjective MDMA effects: “These data have suggested that NAC could protect against behavioral changes” |- | 1+ Rat study || 5-HTP || class=“conflicting-research” | Inadvisable during pre-load || class=“conflicting-research” | It depends || [http://www.sciencedirect.com/science/article/pii/002432059400658X Attenuation of MDMA induced neurotoxicity with the serotonin precursors tryptophan and 5-hydroxytryptophan] || [https://erowid.org/experiences/exp.php?ID=43077 Anecdotal] and hypothetical concerns around serotonin syndrome if co-administered. No literature, but the cautious method would be to avoid taking 5-HTP perhaps 24 hours before or after taking MDMA. |- | 1+ Rat study || L-deprenyl (Selegiline) || class=“conflicting-research” | Inadvisable || class=“conflicting-research” | It depends || [http://link.springer.com/article/10.1007/BF02245967 Inhibition of MAO-B protects against MDMA-induced neurotoxicity in the striatum] || Exercise caution. If talking to a family member I would advise they steer clear. L-deprenyl is a MAO-A inhibitor at higher doses which is very dangerous with MDMA. Also substantially potentiated by oral contraceptives which many people take ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014223/ Laine, Anttila, Helminen, Karnani, & Huupponen, 2001]).

“There is no human literature on MAO-B antagonism with MDMA in humans, so we just have to guess about the combination.” “If I were trying it, I would probably start lower than the prescription dosage for parkinsons or depression. Truthfully, if I were trying it, I’d probably want to see more information on long term effects.” (Private conversation, 2013)."

Theoretically, selegiline at a low dose should be MAO-B selective and therefore neuroprotective however currently the risk-benefit ratio is not high enough to recommend this. |- | Hypothetical || Alcohol || class=“conflicting-research” | Inadvisable for MDMA self-control || class=“conflicting-research” | Mostly unchanged || [https://www.ncbi.nlm.nih.gov/pubmed/11404278 The effect of alcohol consumption on the circadian control of human core body temperature is time dependent.]

[https://www.ncbi.nlm.nih.gov/pubmed/16377461 Effects of alcohol on thermoregulation during mild heat exposure in humans.]

[https://www.ncbi.nlm.nih.gov/pubmed/19074534 Ethanol co-administration moderates MDMA effects on human physiology.] || Alcohol can interfere with your ability to regulate body temperature. Body temperature is a factor for MDMA neurotoxicity and adverse effects. Anecdotally alcohol may also interfere with your ability to moderate MDMA dosage.

In humans [https://www.ncbi.nlm.nih.gov/pubmed/19074534 “co-administration of ethanol and MDMA did not exacerbate physiologic effects”.] |- | 1+ Rat study || THC (Cannabis) || class=“conflicting-research” | Inadvisable || class=“conflicting-research” | Conflicting || [https://www.ncbi.nlm.nih.gov/pubmed/19440186 Cannabis Coadministration Potentiates the Effects of “Ecstasy” on Heart Rate and Temperature in Humans]

[http://www.sciencedirect.com/science/article/pii/S0028390804000127 Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA in rats] || In the human study, THC “prolonged the duration of temperature elevation”.

Someone much more well informed on MDMA than me noted that they wouldn’t cite mice studies for humans (e.g. [https://www.ncbi.nlm.nih.gov/pubmed/20174577 this THC mouse study]) since neurotoxicity from MDMA for mice is DAergic (dopaminergic) not 5HTergic (serotonergic). This means it is less certain that the mice MDMA neurotoxicity studies are relevant to humans. |- | Hypothetical, debated || Grapefruit juice || class=“conflicting-research” | Inadvisable || class=“conflicting-research” | Conflicting || - || J: “It makes sense that grapefruit could counter CYP3A4 conversion to MDA, thereby allowing more metabolism to occur via CYP2D6 route, but I think the effects would need to be tested in living organisms to be sure. If the CYP2D6 system is maxed out, then blocking CYP3A4 could lead to the parent drug and metabolites to be in the system for too long. My biggest concern with grapefruit juice is that people vary widely in their response to it, given their general level of CYP2D6 and CYP3A4 activity. If someone had low activity on both systems, blocking the metabolism further with grapefruit could be toxic. There are, I believe, genetic tests to determine if someone has abnormal metabolism, and there are certain races that have much higher incidence of impaired metabolism in those systems. Bottom line, I understand the argument and think it could help in some people. But if it was someone close to me, I’d probably recommend they skip the grapefruit juice.”

Baggott: “The argument for decreasing MDA formation using grapefruit juice is purely theoretical. No study has shown it is protective. Based on a reddit posting, people sometimes take grapefruit juice to inhibit CYP3A4 and, they hope, MDA formation. However, inhibiting CYP3A and a bunch of other enzymes was not found to protect against MDMA neurotoxicity in rats in [http://www.ncbi.nlm.nih.gov/pubmed/7582557 the only study of CYP3A and MDMA neurotoxicity I know of]. Similarly, selective CY3A inhibition [http://www.ncbi.nlm.nih.gov/pubmed/20170704 did not protect against MDMA-induced cell death in rat livers]. And it’s not even clear that CYP3A is important for MDA formation. [http://www.ncbi.nlm.nih.gov/pubmed/18725511 MDA formation might not be via CYP3A4 but instead thru 2B6 and 1A2] so inhibiting 3A4 might not alter MDA formation. Finally, the amount of MDA formed is small and late, so it is unclear if it has any effects. To be clear, I don’t know of evidence that grapefruit juice is harmful; I only know there is no evidence it is helpful.” |- | 1+ Rat study || LSD (and other psychedelics) || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [http://onlinelibrary.wiley.com/doi/10.1002/nrc.20023/abstract Potentiation of MDMA-induced toxicity by the serotonin 2A receptior partial agonist LSD, and the protection of same by the serotonin 2A/2C receptor antagonist MDL 11,939] || Psilocybin (shrooms) and other psychedelics expected to have the same effect. |- | Hypothetical || Stimulants (Adderall, methamphetamine/other amphetamines, caffeine, ephedrine, cocaine) || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || For caffeine:

[http://www.sciencedirect.com/science/article/pii/S0014299906012490 Caffeine induces a profound and persistent tachycardia in response to MDMA administration]

[http://link.springer.com/article/10.1007/s00213-010-1864-1 Caffeine promotes dopamine D1 receptor-mediated body temperature, heart rate and behavioural responses to MDMA]

[http://www.sciencedirect.com/science/article/pii/S0028390805003114 Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA and MDA]

[http://www.sciencedirect.com/science/article/pii/S0006899306019937 Association of caffeine to MDMA does not increase antinociception but potentiates adverse effects of this recreational drug] || [https://www.drugabuse.gov/publications/drugfacts/stimulant-adhd-medications-methylphenidate-amphetamines Amphetamines] and [https://www.drugabuse.gov/publications/drugfacts/cocaine cocaine can increase body temperature or otherwise interfere with your thermoregulation.] Body temperature is a factor for MDMA neurotoxicity and adverse effects. |- | 1+ Rat study || Catechol-O-methyltransferase inhibitors || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [https://www.ncbi.nlm.nih.gov/pubmed/18074122 The relationship between core body temperature and MDMA metabolism in rats: implications for neurotoxicity.] || “Furthermore, interfering in MDMA metabolism using the catechol-O-methyltransferase inhibitor entacapone potentiated the neurotoxicity of MDMA, indicating that metabolites that are substrates for this enzyme may contribute to neurotoxicity (Goni-Allo, et al., 2007).”

“[https://en.wikipedia.org/wiki/COMT_inhibitor Pharmaceutical examples include entacapone, tolcapone, and nitecapone.]” |- | 1+ Rat study || High body temperatures and hot environments || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [https://www.ncbi.nlm.nih.gov/pubmed/18074122 The relationship between core body temperature and MDMA metabolism in rats: implications for neurotoxicity.]

[https://www.ncbi.nlm.nih.gov/pubmed/9634574 Small changes in ambient temperature cause large changes in MDMA-induced serotonin neurotoxicity and core body temperature in the rat.]

[https://www.ncbi.nlm.nih.gov/pubmed/14726996 Effect of ambient temperature and a prior neurotoxic dose of MDMA on the hyperthermic response of rats to a single or repeated (‘binge’ ingestion) low dose of MDMA.]

[http://jpet.aspetjournals.org/content/278/1/258.short Co-administration of MDMA with drugs that protect against MDMA neurotoxicity produces different effects on body temperature in the rat.] || Baggott: “I think the jury is out on the role of elevated body temperature in MDMA-induced neurotoxicity in non-rodents. We know it is important for rat toxicity, but it might not be for humans. So I don’t think I have a strong basis for a recommendation either way.”

Baggott: “If there’s brain damage, it’s not usually directly from overheating or blood pressure. Overheating increases the oxidative stress from MDMA, which is the real concern. (There’s also a little evidence that big increases in blood pressure can damage the blood-brain barrier and let more stuff into the brain than normal.)”

If temperature is important in humans, from rat studies I might suggest an ambient temperature below 24C/75F. |}

Outcome: Reduced Serious Adverse Effect Risk (Harm Reduction)

{| class=“wikitable” ! Level of high quality evidence || Substance/method || Recommendation || Possible outcome || Research || Notes |- | 1+ Human correlational study || Dose <=125mg || class=“reduced-risk” | Strongly recommended || class=“reduced-risk” | Reduced risk || [https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/mdma/MDMA_IB_FINAL_30Mar2016_Linked.pdf MAPS Investigator’s Brochure 8th Edition Section 5.3]

[http://link.springer.com/article/10.1007/s00213-011-2529-4 Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users] [[http://www.biblioteca.cij.gob.mx/Archivos/Materiales_de_consulta/Drogas_de_Abuso/Articulos/73823403.pdf Full text PDF]]

[https://www.ncbi.nlm.nih.gov/pubmed/15358986 Effect of repeated (‘binge’) dosing of MDMA to rats housed at normal and high temperature on neurotoxic damage to cerebral 5-HT and dopamine neurones.] || “An individual with substantial experience giving MDMA to humans in clinical research noted to us they believe it is psuedoscience to dose by weight” (Private conversation, 2016).

Another researcher we talked with noted that they would recommend <120mg, perhaps 150mg if someone was going to try MDMA only once in their life, and for small females they would advise <100mg due to stimulant effects (Private conversation, 2016).

It’s quite possible there is some variation by weight, it just seems to not be large enough to recommend larger doses for larger people (though reducing for small females due to stimulant effects seems reasonable).

MAPS Phase 3 MDMA trials are using “80 or 120mg MDMA (plus supplemental half dose of 40 or 60mg unless contraindicated)” ([http://www.maps.org/news/bulletin/articles/410-bulletin-winter-2016/6400-mdma-ptsd-2016 MAPS 2016]). The supplemental dose is taken 1.5 to 2.5 hours after the initial dose is taken ([https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/mdma/MDMA_IB_FINAL_30Mar2016_Linked.pdf MAPS 2016]). MAPS’ studies have not adjusted dose by weight, they have randomly assigned people to active dose groups ([http://www.maps.org/research-archive/mdma/MP12_FINAL_Protocol_Amendment_5_Version_1_19Aug14_web.pdf MAPS 2014]). Given MAPS’ work with the FDA, this likely means that thus far the FDA agrees with weight independent dosing.

81-100mg seems to be an optimal dose for maximal enjoyment ([http://www.biblioteca.cij.gob.mx/Archivos/Materiales_de_consulta/Drogas_de_Abuso/Articulos/73823403.pdf Brunt, Koeter, Niesink, & van den Brink, 2011]). |- | Hypothetical || Taking only pure MDMA, and not assuming that MDMA presence means pure || class=“reduced-risk” | Strongly recommended || class=“reduced-risk” | Reduced risk || [http://onlinelibrary.wiley.com/doi/10.1046/j.1360-0443.2001.96811397.x/full Ecstasy pill testing: harm minimization gone too far?]

[http://pubs.rsc.org/is/content/articlehtml/2016/ay/c5ay02924d Forensic electrochemistry: simultaneous voltammetric detection of MDMA and its fatal counterpart “Dr Death” (PMA)]

[http://www.sciencedirect.com/science/article/pii/S0376871605003716 Tanner-Smith, E. E. (2006). Pharmacological content of tablets sold as “ecstasy”: Results from an online testing service. Drug and Alcohol Dependence, 83(3), 247–254. doi:10.1016/j.drugalcdep.2005.11.016] || Brief [http://www.drugscience.org.uk/drugs/stimulants/mdma/pma information on PMA here.] |- | 1+ Human study || Appropriate (i.e. limited) water intake/hydration, and ensure appropriate electrolyte intake (applies both in non-active locations like a home, and in active ones like a nightclub) || class=“reduced-risk” | Strongly recommended || class=“reduced-risk” | Reduced hyponatremia risk, particularly important for females || [http://biorxiv.org/content/early/2015/06/18/021113.short MDMA impairs response to water intake in healthy volunteers]

[https://www.ncbi.nlm.nih.gov/pubmed/21715530 Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects.] || The [http://www.maps.org/research-archive/mdma/MP12_FINAL_Protocol_Amendment_5_Version_1_19Aug14_web.pdf MAPS MDMA Phase 3 study in Boulder, CO] limits fluid intake to 3L during the session.

From [https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/mdma/MDMA_IB_FINAL_30Mar2016_Linked.pdf MAPS’ 2016 investigator’s brochure]: “Prevention of hyponatremia with limited consumption of electrolyte containing fluids and controlled ambient temperatures are required to preserve the body’s homeostatic maintenance of fluid balance.”

Baggott: “MDMA does not dehydrate you. If you weren’t dancing or in a hot environment, you wouldn’t need to think about hydration. It is a good idea to start out well hydrated, however, especially if you will be dancing.” “Under hydration is only a concern if you are in a hot environment like a club or are exercising or have lost fluids otherwise (vomiting). On the other hand, overhydration is ALWAYS a concern for female MDMA users. Overhydration (hyponatremia) can be deadly in women and the symptoms of overhydration (headache, nausea) are hard to tell from those of dehydration.”

Sugar-free gatorade, Propel water (from the same people as Gatorade), or Propel powder packs (sugar free and appears to have good electrolyte quantities) seem ideal.

[http://ajprenal.physiology.org/content/274/5/F868 This paper] in combination with Baggott’s paper is interesting in terms of figuring out how much sodium/electrolytes to consume. You could try ~30mg/sodium/hour. |- | Hypothetical || If you have: “pre-existing uncontrolled hypertension or known cardiovascular or cerebrovascular disease” || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/DSURAnnualReportMdma04JAN2016.pdf MAPS Investigator’s Brochure 8th Edition (2016)] || Newer MDMA research allows participants with some exclusionary conditions from Greer’s 1986 paper. Still, exercise caution in non-research/controlled environments. New MDMA research still excludes people with “pre-existing uncontrolled hypertension or known cardiovascular or cerebrovascular disease,” so if you fall into this category, avoid using MDMA.

The [https://medlineplus.gov/druginfo/meds/a601234.html NIH’s guidelines on Adderall] will be decently applicable here: “tell your doctor if anyone in your family has or has ever had an irregular heartbeat or has died suddenly. Also tell your doctor if you have recently had a heart attack and if you have or have ever had a heart defect, high blood pressure, an irregular heartbeat, hardening of the arteries, heart or blood vessel disease, or other heart problems. Your doctor will examine you to see if your heart and blood vessels are healthy. Your doctor will probably tell you not to take dextroamphetamine and amphetamine if you have a heart condition or if there is a high risk that you may develop a heart condition.” |- | 1+ Rat study || MAOIs (e.g. Nardil, Parnate, Marplan) || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [http://onlinelibrary.wiley.com/doi/10.1111/j.1369-1600.2008.00143.x/full PRECLINICAL STUDY: Ecstasy-induced oxidative stress to adolescent rat brain mitochondria in vivo: influence of monoamine oxidase type A] || The [https://medlineplus.gov/druginfo/meds/a601234.html NIH’s guidelines on Adderall] are decently applicable: “tell your doctor if you are taking monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate), or if you have stopped taking them during the past 14 days. Your doctor will probably tell you not to take dextroamphetamine and amphetamine until at least 14 days have passed since you last took an MAO inhibitor.”

Also [https://en.wikipedia.org/wiki/Monoamine_oxidase_inhibitor#List_of_MAO_inhibiting_drugs nialamide (Niamid) and others.]

Worth exercising caution around other drugs or supplements that might have MAO effects. For example, Ayahuasca contains MAOIs, Rhodiola Rosea may have an impact though [https://examine.com/supplements/rhodiola-rosea/ there are questions around whether it would have this effect when taken orally.][https://www.ncbi.nlm.nih.gov/pubmed/15582589 Tobacco smoke is also an MAOI], and I’m not sure how strong this MAO inhibition effect is relative to other MAOIS.

From the [https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/mdma/MDMA_IB_FINAL_30Mar2016_Linked.pdf 2016 MAPS MDMA Investigator’s Brochure]: “Fatalities have occurred apparently as a result of combining MAOI medications with MDMA [133, 134]. For this reason, MAOI medications are tapered for at least five half lives of the medication and active metabolites, plus 1 week for symptom stabilization in sponsor-supported studies.” |- | 1+ Mouse study || High body temperatures and hot environments || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased hyperthermia risk || - || From [https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/mdma/MDMA_IB_FINAL_30Mar2016_Linked.pdf MAPS’ 2016 investigator’s brochure]:

“Reducing ambient temperature and administering the 5HT2A antagonist ketanserin reduced lethality, suggesting that amplified elevation in body temperature and activity at serotonin receptors may promote lethality in group-housed mice given MDMA [189].”

“Unlike rodents given MDMA at higher mg/kg doses, humans do not exhibit reduced temperature when MDMA is given in a cold environment, and they do not exhibit significant hyperthermia in a warm environment.”

“It is notable that subjects in studies in a clinical setting have not engaged in vigorous exercise and have remained either sitting or lying down throughout duration of drug effects. It may be the case that heat dissipation impaired by a hot environment, heat generation increased by exertion, interactions of serotonergic drugs, and potential disturbance of central heat regulation mechanisms contribute to the occurrence of hyperprexia (body temperatures >41°C) in people ingesting Ecstasy in uncontrolled settings.”

“In research settings, the risk of hyperthermia is limited by controlling ambient temperature, conducting treatment sessions in relaxed, private environments, and generally limiting permissive factors.”

Safest bet would be to avoid hot environments. If you want to take extra prevention methods, feel free to try a fan or a cold shower ([https://www.ncbi.nlm.nih.gov/pubmed/21924843 fans and ice baths are used for moderate hyperthermia]). If you have serious hyperthermia, seek emergency assistance as soon as possible. |- | Hypothetical || If you have: “hypertension, heart disease, hyperthyroidism, diabetes mellitus, hypoglycemia, seizure disorder, diminished liver function, actual or possible pregnancy” || class=“conflicting-research” | Inadvisable in non-clinical setting || class=“increased-risk” | Increased risk || [http://www.maps.org/images/pdf/1986_greer_1.pdf Subjective Reports of the Effects of MDMA in a Clinical Setting (1986)] || From [https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/mdma/MDMA_IB_FINAL_30Mar2016_Linked.pdf MAPS’ 2016 investigator’s brochure]:

Cardiovascular: “Risks posed by elevated blood pressure are addressed by excluding candidates with a history of cardiovascular, cerebrovascular disease, or with pre-existing uncontrolled hypertension and by regularly monitoring blood pressure and pulse throughout experimental sessions.”

Pregnancy: “Risks posed to pregnant women by MDMA are not known. Two of three studies of Ecstasy users suggest that use of Ecstasy and other drugs during pregnancy may be associated with some abnormalities at birth, delays in mental and motor development, but not language or emotional development.”

Hyperthyroidism: “A case report and some findings in rodents suggest that hyperthyroidism or thyroid dysregulation may play a role in MDMA-related hyperthermia in humans [245, 246].”

Newer MDMA research allows participants with some exclusionary conditions from Greer’s 1986 paper. Still, exercise caution in non-research/controlled environments. |- | Hypothetical || If you cannot sustain moderate exercise || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || - || - |- | Hypothetical || If you have: “a history of a socially or vocationally disabling psychological condition” || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [http://www.maps.org/images/pdf/1986_greer_1.pdf Subjective Reports of the Effects of MDMA in a Clinical Setting (1986)] || - |- | Hypothetical || If you have sensitivity to heatstroke (e.g. Central core disease) || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || - || - |- | Hypothetical || If you have lung disease or asthma || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || - || - |- | Hypothetical || Urinary or gastrointestinal alkalinizing agents || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || - || From the [http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021303s031lbl.pdf Adderall XR 2015 FDA info sheet]: “Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) increase absorption of amphetamines. Co-administration of ADDERALL XR and gastrointestinal alkalinizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines.”

Common gastroinstestinal alkalinizing agent: antacids. |- | Hypothetical || Sympathomimetic medicines (e.g. cocaine, salbutamol/Ventolin, psuedoephedrine/Sudafed, amphetamine/Adderall) or other drugs that increase heart rate, blood pressure, or body temperature || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [https://www.ncbi.nlm.nih.gov/pubmed/16087815 Effect of oral pseudoephedrine on blood pressure and heart rate: a meta-analysis.] || Caution especially around large amounts. Not medical advice, but certainly if a family member called me while using MDMA and needed to use their asthma inhaler, I would tell them to use their inhaler if they need it.

Hypothetically, the stronger the sympathomimetic effect, the higher the risk. Common sympathomimetic substances: amphetamines (Adderall, speed), methamphetamine, cocaine. [https://thedea.org/mdma-risks-science-and-statistics-technical-faq/mdma-molly-ecstasy-use-and-death-rate-statistics/ Many MDMA deaths have also involved cocaine.] |- | Anecdotal || DXM (found in some cough syrup) || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || - || https://dancesafe.org/dxm/ |- | Hypothetical || Proton Pump Inhibitors or H2 antagonists || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || - || PPIs or H2 antagonists are commonly used to treat peptic ulcer disease and gastroesophageal reflux disease. Example H2 antagonists: Cimetidine, Famotidine, Nizatidine and Ranitidine. Example PPIs: Omeprazole, Lansoprazole.

From the [http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021303s031lbl.pdf Adderall XR 2015 FDA info sheet]: “PPIs act on proton pumps by blocking acid production, thereby reducing gastric acidity. When ADDERALL XR (20 mg single-dose) was administered concomitantly with the proton pump inhibitor, omeprazole (40 mg once daily for 14 days), the median Tmax of d-amphetamine was decreased by 1.25 hours (from 4 to 2.75 hours), and the median Tmax of l-amphetamine was decreased by 2.5 hours (from 5.5 to 3 hours), compared to ADDERALL XR administered alone. The AUC and Cmax of each moiety were unaffected. Therefore, co-administration of ADDERALL XR and proton pump inhibitors should be monitored for changes in clinical effect.”

This [https://www.researchgate.net/post/how_long_do_proton_pump_inhibitors_affect_the_gastric_mucosa_after_discontinued_use thread on ResearchGate] indicates that you should wait 2 weeks after discontinuing PPIs, as stomach acid may rebound, therefore reducing MDMA’s effects. |- | Hypothetical || CYP2D6 drugs (e.g. bupropion/Wellbutrin, ritonavir/Norvir) || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495276/ MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?]

[http://journals.sagepub.com/doi/abs/10.1177/0269881106065907 Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA]

[https://www.ncbi.nlm.nih.gov/pubmed/10527300 Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate.] || See the [http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table3-2 FDA’s table of strong, moderate and weak CYP2D6 inhibitors].

[https://erowid.org/chemicals/mdma/mdma_info1.shtml One death involving MDMA and ritonavir], with CYP2D6 inhibition possibly playing a role, but possibly not. |- | Anecdotal || 5-HTP || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased serotonin syndrome risk if co-administered || - || [https://erowid.org/experiences/exp.php?ID=43077 Anecdotal] and hypothetical concerns around serotonin syndrome if co-administered. No literature, but the cautious method would be to avoid taking 5-HTP perhaps 24 hours before or after taking MDMA. |- | Hypothetical || Sedatives (e.g. alcohol, opioids like codeine or hydrocodone) || class=“conflicting-research” | Inadvisable || class=“increased-risk” | Increased risk || [https://www.ncbi.nlm.nih.gov/pubmed/11404278 The effect of alcohol consumption on the circadian control of human core body temperature is time dependent.]

[https://www.ncbi.nlm.nih.gov/pubmed/16377461 Effects of alcohol on thermoregulation during mild heat exposure in humans.]

[https://www.ncbi.nlm.nih.gov/pubmed/19074534 Ethanol co-administration moderates MDMA effects on human physiology.] || Alcohol can interfere with your ability to regulate body temperature. Body temperature is a factor for MDMA neurotoxicity and adverse effects. In humans [https://www.ncbi.nlm.nih.gov/pubmed/19074534 “co-administration of ethanol and MDMA did not exacerbate physiologic effects”.]

[https://thedea.org/mdma-risks-science-and-statistics-technical-faq/mdma-molly-ecstasy-use-and-death-rate-statistics/ Many MDMA deaths have involved alcohol and opioid co-administration.]

Recommendation: avoid if possible, if you’re set on combining MDMA and a sedative exercise caution and moderation of both substances. |- | 1+ Rat study || Caffeine || class=“conflicting-research” | Caution || class=“conflicting-research” | Increased risks in caffeine-naive rodents || [http://www.sciencedirect.com/science/article/pii/S0014299906012490 Caffeine induces a profound and persistent tachycardia in response to MDMA (“Ecstasy”) administration]

[http://link.springer.com/article/10.1007/s00213-010-1864-1 Caffeine promotes dopamine D1 receptor-mediated body temperature, heart rate and behavioural responses to MDMA (‘ecstasy’)]

[http://www.sciencedirect.com/science/article/pii/S0028390805003114 Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA (“Ecstasy”) and MDA (“Love”)]

[http://www.sciencedirect.com/science/article/pii/S0006899306019937 Association of caffeine to MDMA does not increase antinociception but potentiates adverse effects of this recreational drug] || The Caffeine-MDMA combination may increase the risk of hyperthermia, long term neurotoxicity, cardiovascular issues.

Someone much more knowledgable on MDMA than me noted that the animal caffeine studies usually use caffeine-naive (i.e. limited prior caffeine exposure) animals and high caffeine doses. This means the caffeine+MDMA effects are more extreme in these studies, and likely don’t reflect the effects in typical human caffeine users. |}

Outcome: Enjoyment Amplification / Side-effect Reduction

{| class=“wikitable” ! Level of high quality evidence || Substance/method || Recommendation || Outcome || Category || Research || Notes |- | 1+ Study based on user reports || Dosage between 81-100mg || class=“reduced-risk” | Strongly recommended || Reduced side-effects, maximized positive effects || Dosing || [http://link.springer.com/article/10.1007/s00213-011-2529-4 Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users] || [[File:MDMA-best-dosage-maximized-desirable-effects.png|thumb|250px]] |- | Anecdotal || Magnesium || class=“reduced-risk” | Use if you experience “gurning” || Reduced jaw activation || Supplement || - || Over time jaw activation can wear down teeth. Not everyone gets jaw activation from MDMA, but for those that do this would be a helpful addition.

Anecdotally magnesium glycinate seems to be preferred for good bioavailability and minimal GI upset. |- | Anecdotal || Less frequent dosing || class=“reduced-risk” | Strongly recommended || Preventing loss of the “magic” || Dosing || [https://www.ncbi.nlm.nih.gov/pubmed/10708923 Effect of ecstasy (MDMA) on cerebral blood flow: a co-registered SPECT and MRI study.] “However, within 3 weeks after MDMA administration, rCBF remained decreased in the visual cortex, the caudate, the superior parietal and dorsolateral frontal regions compared to baseline rCBF. The decreased rCBF tended to be more pronounced in subjects who received the higher dosage of MDMA. Two subjects who were scanned at 2 3 months after MDMA administration showed increased rather than decreased rCBF.” “Our study also found that regional hypoperfusion may be observed for 2 3 weeks after administration of MDMA, especially with the higher dosages.”

[https://www.ncbi.nlm.nih.gov/pubmed/1359444 Repeated administration of MDMA causes transient down-regulation of serotonin 5-HT2 receptors.] “Twenty-one days after administration of MDMA however, the number of binding sites for [125I]MIL was back to control levels.”

[http://www.sciencedirect.com/science/article/pii/S0893133X01003669 The Acute and Chronic Effects of MDMA (“Ecstasy”) on Cortical 5-HT2A Receptors in Rat and Human Brain] “Also, the ex-MDMA users were studied after a relatively long MDMA-free period (on average 18 weeks) compared with the MDMA-treated rats (after 30 days).” “A significant positive correlation was observed between cortical 5-HT2A receptor binding (mean binding ratios of the three brain regions studied) and duration of abstinence from MDMA (0.57, p .01) but not between extent of previous MDMA (0.10, p .66).” || [https://www.reddit.com/r/MDMA/comments/3r09sg/thoughts_on_taking_supplements_with_mdma/ Baggott in 2015:] “Much of the advice available online comes from people with only a few years of experience with MDMA. Studies of MDMA users suggest that many people use MDMA heavily for a few years, find that the positives decrease and the negatives increase, and then quit. People with this common experience are probably less likely to be giving advice on reddit, so it can be hard to appreciate how common it is to burn out on MDMA.

Many of the experienced psychonauts who were using pure MDMA in the 1970s —people like Ann Shulgin and Debby Harlow— noticed diminishing returns from MDMA. Ann Shulgin used MDMA weekly to overcome writer’s block and found it stopped working for her. Based on that and observations of other people, Ann suggested people use MDMA no more than 4 times per year. Debby Harlow noticed that many people seemed to get only about 10 special rolls and after that the experience was merely pleasant, but not magic. These numbers may not be exactly correct for everyone, but the general experience is common: most people eventually lose the magic of MDMA with repeated, frequent use.

So my advice is treat it like you won’t always have it. Try to learn from the experience and grow your skills at recreating without drugs some of the freedoms MDMA offers. Taking MDMA before going out is not a sustainable way to deal with social anxiety. In the long run you’re much better off working to achieve personal growth.

And consider saving some of the drug’s magic for later in life. In ten years from now, MDMA may be legally available and used in therapy. You don’t want to be unable to save your marriage or fail to come to terms with trauma because you rolled too much in your youth and now can’t feel MDMA."

[https://www.reddit.com/r/MDMA/comments/3hgrsy/what_does_the_3_month_rule_actually_protect_you/cu7gwvm/ Baggott in 2015:] “Beyond the anecdotal observations that higher frequency leads to loss of magic, no one really knows. All the theories about replenishing serotonin are untested ideas. It is not even known if loss of magic is associated with depleted serotonin or with brain damage or with some other mechanism like simple learning.”

[https://www.erowid.org/culture/characters/shulgin_alexander/shulgin_alexander_interview2.shtml Ann Shulgin on the 3 month rule.]

Anecdotally the severity and length of the MDMA comedown is longer with more frequent use. We don’t know if this means more neurotoxic but it’s not a crazy assumption.

[[The MDMA 3 Month Rule]] |- | Hypothetical || Be at peace with the idea of altering your state of mind || class=“reduced-risk” | Strongly recommended || Reduced risk of panic || Preparation || - || [http://thedea.org thedea.org]: “When the world starts to look a little different and you start to feel a little different, your response should be “cool, the drug is kicking in”, not “oh my god what’s happening to me?” Once you introduce a drug into your system, it will run its course, one way or the other. Address any major reservations you have before dosing. After you’ve swallowed a pill is not the time for second thoughts…at that point you’re committed.” |- | Anecdotal || Be thoughtful around not doing things you might regret, or consider having a “buddy” || class=“reduced-risk” | Strongly recommended || Reduced risk of activities that later cause regret || Preparation || - || - |- | Anecdotal || Well rested, safe/comfortable space, people that you feel safe with, dosage and any supplements planned out ahead of time || class=“reduced-risk” | Strongly recommended || Generally improved experience || Environment || - || - |- | Hypothetical || Prevent gastrointestinal or urinary acidification (e.g. using antacids) || class=“conflicting-research” | Exercise caution || Better absorption || Medicine || - || Not sure about desirability or efficacy of this. Seems we might want to prevent acidification of urine/stomach during MDMA’s absorption, but safety concerns around potentiation through too much alkalization.

From the [http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021303s031lbl.pdf Adderall XR 2015 FDA info sheet]: “Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) increase absorption of amphetamines. Co-administration of ADDERALL XR and gastrointestinal alkalinizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines.”

Common gastroinstestinal alkalinizing agent: antacids. |- | 1+ Human RCT || SSRIs || class=“conflicting-research” | Inadvisable || Reduces MDMA’s effects || Medicine || - || [https://s3-us-west-1.amazonaws.com/mapscontent/research-archive/mdma/MDMA_IB_FINAL_30Mar2016_Linked.pdf MAPS 2016 Investigator’s Brochure]: “Pre-treatment or co-administration studies of SSRIs with MDMA appear to attenuate or eliminate most subjective, physiological and immunological effects of MDMA due to competition for binding sites on the SERT which may prevent transporter-mediated serotonin release [91, 555-558].” |- | Anecdotal || Cocaine || class=“increased-risk” | Avoid || May blunt subjective high || Drug || - || Anecdotally can make MDMA effects harder to feel. See also: Cocaine in the ‘reducing risk of serious adverse effects’ section. |- | Hypothetical || St John’s wort || class=“increased-risk” | Avoid || Potential unexpected interactions || Supplement || [https://www.ncbi.nlm.nih.gov/pubmed/19859815 Herb-drug interactions with St John’s wort (Hypericum perforatum): an update on clinical observations.]

[https://www.ncbi.nlm.nih.gov/pubmed/15049433 Drug interactions with St. John’s Wort (Hypericum perforatum): a review of the clinical evidence.] || If a family member asked I would recommend they stay away from this combination due to hypothetical concerns around SJW’s interactions with many drugs.“SJW represents a herbal medicine with a high potential for drug interactions. Some of such interactions may have serious clinical consequences (Izzo, 2004).” |- | Anecdotal || 5-HTP || Optional method, taken once a day beginning 24 h after MDMA for a few days || Eased comedown || Supplement || - || Hypothetically helps the body replenish serotonin that MDMA has depleted.

[https://erowid.org/experiences/exp.php?ID=43077 Anecdotal] and hypothetical concerns around serotonin syndrome if co-administered. No literature, but the cautious method would be to avoid taking 5-HTP perhaps 24 hours before or after taking MDMA.

Baggott: “Another theory for taking EGCG is it can inhibit an enzyme (aromatic L-amino acid decarboxylase) in the stomach that converts 5-HTP to serotonin. This might allow more 5-HTP to reach the brain. Not certain this is worth worrying about.” Anecdotally EGCG in combination with 5-HTP seems to substantially help some people, while others don’t find adding EGCG helps. |- | 1+ Human RCT || Melatonin || Optional method pre-sleep || Reduced insomnia || Supplement || [https://examine.com/supplements/melatonin/ Very high for reduced insomnia] || Anecdotally MDMA can lead to insomnia on the night of use.

[https://www.ncbi.nlm.nih.gov/pubmed/14740000 Melatonin’s antioxidant effects] may also be useful. Perhaps 10mg for these purposes.

[https://www.ncbi.nlm.nih.gov/pubmed/8127888 Melatonin also reduces body temperature], though not sure that it would be desirable to take during MDMA’s effects, and not sure that a body temperature reduction is beneficial after MDMA’s effects is worth supplementing for. |- | Anecdotal || Supplements recommended for reduced neurotoxicity risk. || Optional || Preventing loss of the “magic” || Supplement || - || Anecdotal reports that supplements also increase the positive feelings of MDMA. |- | Anecdotal || Piracetam or Noopept || Optional, potential concerns || Reversing loss of “magic” || Nootropic || Related but not a study of bringing back the magic specifically: [https://www.ncbi.nlm.nih.gov/pubmed/22607774 Could piracetam potentiate behavioural effects of psychostimulants?] || [https://www.reddit.com/r/MDMA/comments/4wyjd9/mechanisms_of_mdma_tolerance_and_loss_of_magic/d6c5lb0/ Baggott in 2015:] “Another concern is that we don’t know if potentiation increases any risks of MDMA, like hyperthermia or hyponatremia.” (Via methods like Piracetam)

Anecdotal evidence varies for piracetam or noopept. If using definitely combine with a choline source to reduce likelihood of headaches. |- | Hypothetical, debated || EGCG/diuretic during MDMA effects || - || Easier urination || Supplement || [https://www.ncbi.nlm.nih.gov/pubmed/12695345 Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by (-)-epigallocatechin gallate.]

[https://www.ncbi.nlm.nih.gov/pubmed/18074122 The relationship between core body temperature and MDMA metabolism in rats: implications for neurotoxicity.]

[https://www.ncbi.nlm.nih.gov/pubmed/16574714 Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population.] || Baggott: “Some people think diuretics helps you urinate, but the medical literature says difficulty urinating is because MDMA stimulates alpha-adrenergic receptors that tighten the muscle of the neck of the bladder.” “EGCG is also a catechol-o-methyl transferase inhibitor and these are known to increase MDMA neurotoxicity.” |- | Anecdotal || THC (cannabis) || - || May blunt subjective high || Drug/Medicine || - || Anecdotally can make MDMA effects less-MDMA like, and can be unpleasant for some and pleasant for others. See also, THC in the neurotoxicity section. |}

Thanks to all the authors and contributors on all MDMA research, to the individuals online who have put time and thought into MDMA supplementation and harm reduction (e.g. DanceSafe, MYASD, Borax), and to those who commented on and contributed to this page, Matthew Baggott, J, ES and RD.

MDMA Supplements

Background

Do I need to take supplements with MDMA?

No. However, I would advise any family members of mine who were planning on taking MDMA to use supplements each time, and to follow the other harm reduction methods on MDMA Safety Enhancement and Enjoyment Amplification using Supplements and Other Methods.

Why would you advise a family member to take supplements with MDMA?

If supplements can protect against MDMA damage (if it happens) at a low cost, then the cost-benefit ratio for supplements is excellent.

I believe the best rationale for taking supplements with MDMA is that supplements may reduce the risk of or prevent “losing the magic” with MDMA use over time. This is hypothetical. We do know supplements can prevent MDMA tolerance in rats.

“By 2021 MAPS hopes to have MDMA approved by the FDA for treatment of PTSD. After that, you may one day step into a couples counseling session and take MDMA with your partner to strengthen your marriage, or to repair a relationship with your child.

If you’ve “lost the magic” of MDMA by then you may be forever unable to use a vital treatment method.”

MDMA Supplement Table

{| class=“wikitable” ! Supplement ! Recommendation ! Purpose ! Research ! Possible schedule with MDMA ! Price per event ! Tmax ! Elimination half-life ! Dosage used in human research |- | Alpha Lipoic Acid (ALA) | class=“reduced-risk” | Strongly recommended | Neurotoxicity minimization | [https://www.ncbi.nlm.nih.gov/pubmed/10619665 Alpha-lipoic acid prevents MDMA-induced neurotoxicity.] | Rat study used 100mg/kg twice a day for 2 days.

Proposed: 300-mg ALA with MDMA dosing, then every hour after that until 7 h post dose (total 2.4-g) |

See below for Na-RALA comparison. | [https://www.ncbi.nlm.nih.gov/pubmed/10072479 1 h for 600-mg ALA], [http://www.anaturalhealingcenter.com/documents/Thorne/articles/R-Lipoic12-4.pdf 14 min for 600-mg Na-RALA] | [https://www.ncbi.nlm.nih.gov/pubmed/10072479 0.6 h for 600-mg ALA], [http://www.anaturalhealingcenter.com/documents/Thorne/articles/R-Lipoic12-4.pdf 14 min for 600-mg Na-RALA] | [https://examine.com/supplements/alpha-lipoic-acid/#how-to-take 600-mg ALA], [https://examine.com/supplements/alpha-lipoic-acid/#summary15 Up to 2400-mg/day] |- | Acetyl-L-carnitine (ALCAR) | class=“reduced-risk” | Strongly recommended | Neurotoxicity minimization | [https://www.ncbi.nlm.nih.gov/pubmed/19015003 Acetyl-L-carnitine provides effective in vivo neuroprotection over MDMA-induced mitochondrial neurotoxicity in the adolescent rat brain.] | Rat study used “a single i.p. injection of 100 mg/kg ALC.”

500-mg 3 h before and then every 2 h until 5 hours after dosing (2.5-g) | $23.26 for 200 x 500-mg | [https://www.ncbi.nlm.nih.gov/pubmed/15283472 3.1 h for 500-mg] | [https://www.ncbi.nlm.nih.gov/pubmed/15283472 4.2 h for 500-mg] | [https://examine.com/supplements/l-carnitine/#how-to-take 630-2,500-mg of ALCAR] |- | Electrolytes / Isotonic fluids | class=“reduced-risk” | Strongly recommended, especially important for females | Reduced hyponatremia risk | [http://biorxiv.org/content/early/2015/06/18/021113.short MDMA impairs response to water intake in healthy volunteers]

[https://www.ncbi.nlm.nih.gov/pubmed/21715530 Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects.] | Ideally we want to consume isotonic fluids (i.e. ~290 milliOsmol/L).

Perhaps ¹⁄₄ - ¹⁄₂ sodium containing electrolyte packet with 250-ml water per hour, or 250-ml electrolyte beverage per hour (Gatorade has about 110-mg sodium per 250-ml, coconut water has 25 to 50-mg per 250-ml) | $12.95 for 36 Propel Powder packets with 210-mg sodium

$1.08 for 3

Lasts for 12 sessions | | | |- | Ubiquinone (Co-Q10) | class=“reduced-risk” | Encouraged | Neurotoxicity minimization | [https://www.ncbi.nlm.nih.gov/pubmed/16098955 Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT.] | Rat study used 100-microM, roughly 300-mg/kg “perfused into the striatum beginning 2 h before the first MDMA or vehicle injection and continuing until 6 h after the last drug injection.”

800-mg 6 h before, 800-mg at same time as MDMA, and 800-mg 6 h after MDMA (2.4-g) | $13.14 for 120 x 100-mg

$2.63 for 24

Bottle of 120 lasts for 5 people/MDMA sessions | [https://www.ncbi.nlm.nih.gov/pubmed/3781673 6.5 h for 100-mg] | [https://www.ncbi.nlm.nih.gov/pubmed/3781673 33 h for 100-mg] | [https://examine.com/supplements/coenzyme-q10/#how-to-take 90-mg once daily], [https://www.ncbi.nlm.nih.gov/pubmed/20669312 up to 3,600-mg daily] |- | Nicotinamide | class=“reduced-risk” | Encouraged | Neurotoxicity minimization | [https://www.ncbi.nlm.nih.gov/pubmed/16098955 Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT.] | Rat study used 1-mM, roughly 400-mg/kg “perfused into the striatum beginning 2 h before the first MDMA or vehicle injection and continuing until 6 h after the last drug injection.”

500-mg 1 h before, 1 h after, 3 h after, 5 h after, 7 h after (2.5-g) | $26.89 for 100 x 500-mg

$1.34 for 5

Bottle of 100 lasts for 20 people/MDMA sessions | 45 min for 500-mg [http://www.inchem.org/documents/sids/sids/98920.pdf 1], [https://www.ncbi.nlm.nih.gov/pubmed/8356223 2] | ~2 h for 500-mg [http://www.inchem.org/documents/sids/sids/98920.pdf 1], [https://www.ncbi.nlm.nih.gov/pubmed/8356223 2] | [https://examine.com/supplements/vitamin-b3/#how-to-take 1 g+], [https://www.ncbi.nlm.nih.gov/pubmed/11126400 <3 g/day] |- | Vitamin E | class=“reduced-risk” | Encouraged | Neurotoxicity minimization | [https://www.ncbi.nlm.nih.gov/pubmed/11931860 d-MDMA during vitamin E deficiency: effects on dopaminergic neurotoxicity and hepatotoxicity.] | Average American intake of [https://www.ncbi.nlm.nih.gov/pubmed/21865568 6.5-mg/day from food.]

Beginning 7 days before MDMA dose, 400-IU daily, including 400-IU on the morning of MDMA dose (8 total).

If this is impractical, perhaps a single dose of 1200-IU on the morning of MDMA dose day. | $11.10 for 100 x 400-IU

89c for 8

Lasts for 12 sessions | https://www.ncbi.nlm.nih.gov/pubmed/8429120 13 h for 800-mg of α-tocopheryl | [https://www.ncbi.nlm.nih.gov/pubmed/8429120 73 h for 800-mg of α-tocopheryl] | [http://www.ncbi.nlm.nih.gov/pubmed/17330512 In this study, 320-mg/480-IU per day saw antioxidant benefits], [http://ajcn.nutrition.org/content/81/4/736.full <= 1600-IU] |- | Ascorbate (Vitamin C) | class=“reduced-risk” | Encouraged | Neurotoxicity minimization | [https://www.ncbi.nlm.nih.gov/pubmed/11170222 Ascorbic acid prevents MDMA-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT.] | In rat study: “100 mg/kg, i.p. every 2 h for a total of 5 injections” “in which ascorbic acid was given 1 h before each MDMA injection and 1 h after the last MDMA injection.” A rough human conversion might be 7-g vitamin C every 2 h, though you might experience diarrhea at this dosage (e.g. see [https://www.ncbi.nlm.nih.gov/pubmed/7321921 this] [http://www.vitamincfoundation.org/www.orthomed.com/titrate.htm paper]).

Proposed: 1-g vitamin C 6 h before MDMA dose, 5 h before, then resuming 2h after dose and hourly until 6 h post MDMA dose (total of 7-g). Dosage gap ([http://jap.physiology.org/content/92/2/427 4 h sufficient]) to prevent any gastrointestinal acidification which may hypothetically slow the speed of MDMA absorption, unclear if it would impact onset of effects though. I would recommend 7-g every 2 hours if I there wasn’t a risk of diarrhea. Perhaps you could try dosing vitamin C on a non-MDMA day to see how your body tolerates larger doses. | $13.83 for 250 x 1000-mg

39c for 7

Bottle lasts for 35 sessions/people | [https://www.ncbi.nlm.nih.gov/pubmed/15380894 4 h for 250-mg in smokers] | [https://www.ncbi.nlm.nih.gov/pubmed/15380894 24 h for 250-mg in smokers] | |- | Cysteine | - | Neurotoxicity minimization | [https://www.ncbi.nlm.nih.gov/pubmed/9029406 Effect of ascorbate and cysteine on the MDMA-induced depletion of brain serotonin (1996).] | | | | | |- | Magnesium | Use if you experience jaw clenching | Bruxism (jaw clenching) | Anecdotal | 2-4 tablets on the morning of | $15.37 for 240

26c for 4 caps

Lasts for 60 sessions | | | |- | 5-HTP | Use if you experience a come down | “Come down” reduction | Anecdotal | [https://erowid.org/experiences/exp.php?ID=43077 Anecdotal] and hypothetical concerns around serotonin syndrome if co-administered. No literature, but the cautious method would be to avoid taking 5-HTP perhaps 24 hours before or after taking MDMA. | | | | |}

Dosing regimen

During your MDMA session, consume only electrolyte containing fluids (sugar free gatorade, coconut water, Propel powder packets in water, etc). Limit fluid intake to 500-ml/hour if dancing, or 250-ml/hour if not highly active.

Try and keep your body temperature within normal range. If dancing, cool off each hour or more frequently.

See RollSafe for a more user friendly presentation of this material.

Other important notes

Don’t dose if you’ve taken any MAOIs in the past 14 days.

Don’t take 5-HTP within 24 hours of dosing.

Look over the list of cautions on this page and make sure none apply to you: MDMA Safety Enhancement and Enjoyment Amplification using Supplements and Other Methods.

Vitamin C has been left out, add in at your own tolerance (Vitamin C at high doses can upset your GI system, depending on the person).

Last minute purchasing options (grocery stores, Instacart/Amazon Prime Now)

If you’re using MDMA within a few hours and need to purchase supplements from a store, this is an option.

The simplest option would be to purchase ALA (not Na-RALA) and ALCAR. Most grocery stores or health food stores should carry both of these. The price will be higher than purchasing online.

You could use a service like Instacart or Amazon Prime Now to have the groceries delivered within a few hours if you can’t leave the house.

Look for 300-mg ALA, and get a bottle with 8 pills per person (600-mg is okay, and then you could dose half as often, however smaller, more frequent doses are hypothetically better). Look for 500-mg ALCAR, and get a bottle with 5 pills per person.

FAQ

How can we calculate human dosages from rat studies?

We don’t really know. It’s speculative. Rat studies use high supplement dosages because they want to increase the chance of a statistically significant effect.

Matthew Baggott: “I think we don’t know doses/concentrations needed to start getting protection for any of these supplements and most are more likely to helpful than harmful.”

The short answer is we cannot calculate human dosages, in supplements with no downsides we might encourage higher doses as they are more likely to help than hurt and most supplements are pretty cheap.

ALA vs Na-RALA

Data

Pharmacokinetics, Metabolism, and Renal Excretion of Alpha-Lipoic Acid and Its Metabolites in Humans [1] [2] [3]

“The bioavailability, Cmax, and AUC values were decreased by the coingestion of food (Gleiter et al., 1996).”

200-mg racemic alpha-lipoic acid AUC data: 24.6+-7.8 for R(+)-alpha-lipoic acid and 15.0+-5.4 mcg min/mL for S(-)-alpha-lipoic-acid

200-mg racemic alpha-lipoic acid AUC 46.82 +- 21.46 mcg min/mL (total ALA, not separated by isomer)

600-mg racemic alpha-lipoic acid AUC 148.08 +- 58.67 mcg min/mL (total ALA, not separated by isomer)

If we assume the R/S ratio from the 200-mg racemic mixture holds, then the 600-mg would have AUC for R(+) of ~90 mcg min/mL

The Plasma Pharmacokinetics of R-(+)-Lipoic Acid Administered as Sodium R-(+)-Lipoate to Healthy Human Subjects. [4]

600-mg oral Na-RALA total (including both R and S) AUC 441.6 mcg min/mL

Pharmacokinetics of different formulations of tioctic (alpha-lipoic) acid in healthy volunteers. [5]

600-mg oral ALA total (including both R and S) average AUC 3131.45 ng × h/g (199.16 mcg min/mL)

Based on the above limited data, 600-mg ALA seems to give a total (R & S) AUC of about 3 times lower than 600-mg Na-RALA. 600-mg ALA hypothetically gives an R(+) AUC of ~5 times lower than 600-mg Na-RALA.

$20.86 for 180 x 600-mg ALA gives a cost of 11.6c per 600-mg ALA. $16.59 for 60 x 100-mg Na-RALA gives a cost of $1.659 per 600-mg Na-RALA. This Na-RALA is 14.3x more expensive than the ALA in question.

Conclusion

Na-RALA is 14.3x more expensive in the above comparison, and the more generous comparison gives it an AUC that is ~5X higher than ALA.

ALA is recommended vs Na-RALA (RALA) because it is more cost effective.

End

This is the end of our MDMAWiki.org archive.