MDMA Safety Enhancement and Enjoyment Amplification using Supplements and Other Methods

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What is this[edit]

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[edit]

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)[edit]

Related page: Is MDMA Neurotoxic?

Level of high quality evidence Substance Recommendation Possible outcome Research Notes
1+ Rat study Alpha Lipoic Acid (ALA) Strongly recommended Reduced risk Alpha-lipoic acid prevents MDMA-induced neurotoxicity. "ALA is recommended vs Na-RALA (RALA) because it is more cost effective." from the MDMA Supplement Recommendations Page
1+ Rat study Acetyl-L-carnitine (ALCAR) Strongly recommended Reduced risk 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 (Nagesh Babu, Kumar, & Singh, 2010; Hagen et al., 2002).
1+ Rat study No redose Strongly recommended Reduced risk 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.

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 Strongly recommended Reduced risk 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 Strongly recommended Reduced risk Reduced N-acetylaspartate levels in the frontal cortex of MDMA users: preliminary results.

Positron emission tomographic evidence of toxic effect of MDMA on brain serotonin neurons in human beings.

"Decreases in 5-HT transporter binding positively correlated with the extent of previous MDMA use."
1+ Rat study Ubiquinone (Co-Q10) Encouraged Reduced risk 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.[27]”

1+ Rat study Nicotinamide Encouraged Reduced risk Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT. -
1+ Rat study Vitamin E Encouraged Reduced risk d-MDMA during vitamin E deficiency: effects on dopaminergic neurotoxicity and hepatotoxicity. -
1+ Rat study Ascorbate (Vitamin C) Encouraged Reduced risk 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" 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 - Reduced risk Memantine prevents MDMA-induced neurotoxicity

Memantine prevents the cognitive impairment induced by MDMA in rats

Memantine has been given to humans in combination with MDMA (not to test for neuroprotection, but still good to see).

Hypothetical Gastrointestinal or urinary acidifying agents - Reduced risk - From the 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 - 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) - Reduced risk 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 (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 Erowid.

1+ Rat study SSRIs (e.g. Citalopram/Celexa) - Reduced risk The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of MDMA in healthy volunteers.

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 - Reduced risk Metformin Prevented Dopaminergic Neurotoxicity Induced by MDMA Administration (2016). -
1+ Rat study Cysteine - Reduced risk Effect of ascorbate and cysteine on the MDMA-induced depletion of brain serotonin (1996).

The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine (2004).

Neurotoxicity of "ecstasy" and its metabolites in human dopaminergic differentiated SH-SY5Y cells (2013).

Attenuation of ecstasy-induced neurotoxicity by N-acetylcysteine (2015).

Few human studies on cysteine.

Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity (1999).

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 Inadvisable during pre-load It depends Attenuation of MDMA induced neurotoxicity with the serotonin precursors tryptophan and 5-hydroxytryptophan 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) Inadvisable It depends 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 (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 Inadvisable for MDMA self-control Mostly unchanged The effect of alcohol consumption on the circadian control of human core body temperature is time dependent.

Effects of alcohol on thermoregulation during mild heat exposure in humans.

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 "co-administration of ethanol and MDMA did not exacerbate physiologic effects".

1+ Rat study THC (Cannabis) Inadvisable Conflicting Cannabis Coadministration Potentiates the Effects of “Ecstasy” on Heart Rate and Temperature in Humans

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. 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 Inadvisable 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 the only study of CYP3A and MDMA neurotoxicity I know of. Similarly, selective CY3A inhibition did not protect against MDMA-induced cell death in rat livers. And it’s not even clear that CYP3A is important for MDA formation. 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) Inadvisable Increased risk 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) Inadvisable Increased risk For caffeine:

Caffeine induces a profound and persistent tachycardia in response to MDMA administration

Caffeine promotes dopamine D1 receptor-mediated body temperature, heart rate and behavioural responses to MDMA

Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA and MDA

Association of caffeine to MDMA does not increase antinociception but potentiates adverse effects of this recreational drug

Amphetamines and 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 Inadvisable Increased risk 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).”

Pharmaceutical examples include entacapone, tolcapone, and nitecapone.

1+ Rat study High body temperatures and hot environments Inadvisable Increased risk The relationship between core body temperature and MDMA metabolism in rats: implications for neurotoxicity.

Small changes in ambient temperature cause large changes in MDMA-induced serotonin neurotoxicity and core body temperature in the rat.

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.

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)[edit]

Level of high quality evidence Substance/method Recommendation Possible outcome Research Notes
1+ Human correlational study Dose <=125mg Strongly recommended Reduced risk MAPS Investigator’s Brochure 8th Edition Section 5.3

Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users [Full text PDF]

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)” (MAPS 2016). The supplemental dose is taken 1.5 to 2.5 hours after the initial dose is taken (MAPS 2016). MAPS’ studies have not adjusted dose by weight, they have randomly assigned people to active dose groups (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 (Brunt, Koeter, Niesink, & van den Brink, 2011).

Hypothetical Taking only pure MDMA, and not assuming that MDMA presence means pure Strongly recommended Reduced risk Ecstasy pill testing: harm minimization gone too far?

Forensic electrochemistry: simultaneous voltammetric detection of MDMA and its fatal counterpart “Dr Death” (PMA)

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 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) Strongly recommended Reduced hyponatremia risk, particularly important for females MDMA impairs response to water intake in healthy volunteers

Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects.

The MAPS MDMA Phase 3 study in Boulder, CO limits fluid intake to 3L during the session.

From 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.

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" Inadvisable Increased risk 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 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) Inadvisable Increased risk PRECLINICAL STUDY: Ecstasy-induced oxidative stress to adolescent rat brain mitochondria in vivo: influence of monoamine oxidase type A The 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 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 there are questions around whether it would have this effect when taken orally.Tobacco smoke is also an MAOI, and I’m not sure how strong this MAO inhibition effect is relative to other MAOIS.

From the 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 Inadvisable Increased hyperthermia risk - From 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 (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" Inadvisable in non-clinical setting Increased risk Subjective Reports of the Effects of MDMA in a Clinical Setting (1986) From 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 Inadvisable Increased risk - -
Hypothetical If you have: "a history of a socially or vocationally disabling psychological condition" Inadvisable Increased risk Subjective Reports of the Effects of MDMA in a Clinical Setting (1986) -
Hypothetical If you have sensitivity to heatstroke (e.g. Central core disease) Inadvisable Increased risk - -
Hypothetical If you have lung disease or asthma Inadvisable Increased risk - -
Hypothetical Urinary or gastrointestinal alkalinizing agents Inadvisable Increased risk - From the 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 Inadvisable Increased risk 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. Many MDMA deaths have also involved cocaine.

Anecdotal DXM (found in some cough syrup) Inadvisable Increased risk - https://dancesafe.org/dxm/
Hypothetical Proton Pump Inhibitors or H2 antagonists Inadvisable 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 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 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) Inadvisable Increased risk MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?

Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA

Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate.

See the FDA’s table of strong, moderate and weak CYP2D6 inhibitors.

One death involving MDMA and ritonavir, with CYP2D6 inhibition possibly playing a role, but possibly not.

Anecdotal 5-HTP Inadvisable Increased serotonin syndrome risk if co-administered - 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) Inadvisable Increased risk The effect of alcohol consumption on the circadian control of human core body temperature is time dependent.

Effects of alcohol on thermoregulation during mild heat exposure in humans.

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 "co-administration of ethanol and MDMA did not exacerbate physiologic effects".

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 Caution Increased risks in caffeine-naive rodents Caffeine induces a profound and persistent tachycardia in response to MDMA (“Ecstasy”) administration

Caffeine promotes dopamine D1 receptor-mediated body temperature, heart rate and behavioural responses to MDMA (‘ecstasy’)

Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA (“Ecstasy”) and MDA (“Love”)

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[edit]

Level of high quality evidence Substance/method Recommendation Outcome Category Research Notes
1+ Study based on user reports Dosage between 81-100mg Strongly recommended Reduced side-effects, maximized positive effects Dosing Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users
MDMA-best-dosage-maximized-desirable-effects.png
Anecdotal Magnesium 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 Strongly recommended Preventing loss of the "magic" Dosing 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).”

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.”

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 Strongly recommended Reduced risk of panic Preparation - 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" 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 Strongly recommended Generally improved experience Environment - -
Hypothetical Prevent gastrointestinal or urinary acidification (e.g. using antacids) 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 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 Inadvisable Reduces MDMA's effects Medicine - 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 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 Avoid Potential unexpected interactions Supplement Herb-drug interactions with St John’s wort (Hypericum perforatum): an update on clinical observations.

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.

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 Very high for reduced insomnia Anecdotally MDMA can lead to insomnia on the night of use.

Melatonin’s antioxidant effects may also be useful. Perhaps 10mg for these purposes.

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: Could piracetam potentiate behavioural effects of psychostimulants? 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 Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by (-)-epigallocatechin gallate.

The relationship between core body temperature and MDMA metabolism in rats: implications for neurotoxicity.

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.