Should We Buy the Idea of an "Allergy" to MDMA?

Mar 15 2016

Should We Buy the Idea of an “Allergy” to MDMA?

“Molly” and high-profile molly-related deaths have generated much media attention in recent years, raising questions about the safety of the drug and the substances often sold in its name (never assume molly is MDMA).

But the small number of deaths compared to the swaths of young people ingesting the drugs at festivals and clubs suggests it’s not quite as dangerous as headlines make it sound. As with all psychoactive substances, the vast majority of users get high with no significant health problems. Still, for a few, a night intended for dancing can end up deadly.

We know that the mechanism of most MDMA-related deaths is similar to overheating (which is exacerbated by hot club or festival environments), and that a small dose is a safer dose. But the significant overlap of recreational and fatally toxic doses—in addition to the survival of peers who take molly in the same environment as friends who end up sick—makes it difficult to determine why some people have such adverse reactions when others seem fine.

The idea that some people die from an “MDMA allergy” has arisen as a potential explanation.

To account for unexplained MDMA-related deaths, some have proposed the theory that an enzyme deficiency, sometimes described as an “allergy” leaves certain individuals unable to metabolize the drug, and more susceptible to its toxicity. Most comprehensive texts on MDMA, like Julie Holland’s 2001 book Ecstasy: The Complete Guide: A Comprehensive Look at the Risks and Benefits of MDMA and research summarizing the literature on MDMA toxicity, note the theory, without necessarily endorsing it.

Others, however, have taken to the theory with more confidence. The International Drug Policy Consortium, for example, recommends in a 2015 guide to MDMA harm reduction that first-time users take a “quarter dose” of around 20-30mg, “sometimes called an ‘allergy test’” because “a portion of the population has a deficiency in a liver enzyme [CYP2D6] involved in processing MDMA and other drugs.” The IDCP links this deficiency to “fatty liver disease,” as does the harm reduction group DanceSafe. A 2014 article on DanceSafe’s page warns that “You Could Be a ‘Poor Metabolizer’ of MDMA,” following up advice on how to test for the enzyme deficiency with a report about a British teen with a liver disease, who died after taking the drug.

The theory was first proposed in the 1990s; one 1995 study described the hypothesis as asserting “persons deficient in CYP2D6 and who metabolize the drug more slowly (poor metabolizers or PM phenotypes) might have an exaggerated hyperthermic response.”

About 5 to 10 percent of the population is deficient in the enzyme CYP2D6. And because CYP2D6 has been linked to the poor metabolism and adverse health risks of many drugs, it would seem to make sense if the same could be said for MDMA. A 2005 study in The Pharmacogenomics Journal explained that CYP2D6 is crucial to the metabolism of about 20 to 25 percent of clinically used drugs. It concluded: “The enzyme appears also to be one of the most important polymorphic drug-metabolizing enzymes in causing adverse drug reactions.”

Early research into the theory postulated that people with a certain genetic makeup may experience deficiency in CYP2D6, leading to greater risk for “drug abuse” and toxicity, particularly regarding methamphetamine, a drug often assessed in the same studies as MDMA.

As a 2012 study on MDMA and “interindividual differences due to polymorphisms and drug–drug interactions” explained, prior research “suggested that CYP2D6 [poor metabolizers] are more susceptible to the acute effects of MDMA (Tucker et al., 1994), since a deficiency in this enzyme could substantially impair elimination of MDMA, leading to higher and sustained concentrations of MDMA in the body. This could subsequently increase the risk of clinical symptoms including hyperthermia, hypertension, tachycardia, seizures, serotonin syndrome and rhabdomyolysis.”

Most researchers have since been unable to prove the theory. Recently, many are instead ditching it for more complex descriptions of how enzymes may affect MDMA toxicity.

A 2012 review of the literature, authored by Rafael de la Torre, the lead researcher on several articles laying out the theory, concluded that the enzyme “may have less impact on the risk of acute toxicity than previously thought.” That study did say that one “bias worth taking into account is that the research involves small sample sizes, and within them, “poor metabolizers” are underrepresented (“perhaps due to the ‘acute effects experienced’”).

Still, as this and other studies note, robust research into the enzyme theory has found that MDMA toxicity is too complicated to explain so simply. One 2002 study concluded that “Ecstasy-related deaths are rare and complex events, which have so far defied adequate explanation,” adding “There appear to be other metabolic mechanisms which compensate for the poor metabolism of these drugs by CYP2D6.”

The notion of an enzyme deficiency that manifests as somewhat of an “allergy” to MDMA—or predisposition to health risks—has remained folklore nonetheless. On the internet and the party scene, the enzyme theory serves as a stand-in for some of the mysteries around MDMA-related deaths that scientists have yet been able to fully explain. Looking to the science, though, it’s not a useful harm reduction philosophy to promote.

“There are other metabolic pathways for MDMA,” Rick Doblin, the founder and executive director of the Multidisciplinary Association for Psychedelic Studies (MAPS), a group currently studying MDMA-assisted psychotherapy for treatment-resistant PTSD, tells The Influence.

“We don’t think CYP2D6 deficiency really matters. About 10 percent of the US population are CYP2D6-deficient and there aren’t 10 percent of users showing any consistent problems.”

  • sferios

    I’m Emanuel Sferios, founder of DanceSafe, and one of the early proponents of the CYP-2D6 link to adverse MDMA reactions. I still believe this is true, and all studies point to it being true. The 2012 review cited above that the author claims suggests otherwise actually agrees that there is a link. Specficiallly, it concludes, “Concerning acute effects, those subject carriers of alleles with a reduced functionality are at higher risk, for both MDMA and methamphetamine, of experiencing heightened pharmacological effects. Moreover, in combination with some environmental factors this may lead to acute toxicity episodes including death.” ( ) I do not understand where the author is getting her information. It is vitally important that recreational MDMA users understand that if they are slow metabolizers of CYP-2D6, they carry an increasing risk of adverse reaction, includin gpossible death.

    • Starbrite Morning Glories this is an article about the changes post op for oxy. I found after I lost a third of my pancreas, I could no longer take MDMA because of elevated heart rate, chest/abdominal pain and high temperature. It could just be coincidence but it might be helpful for your theory.

      (NOTE: I was able to use MDMA before I had the damage)

  • Maurice Dutton

    I run a safety consultancy & we are going into Raves as we about to sign our first contract. The enzyme deficiency is about 9% for caucasians. When you combine this with a dose of varying strength as well as the heat of the dance scene & then factor in body size, my research indicates that females have a slightly higher chance of having an adverse reaction. The moot point is though that many countries now have testing at raves & this saves lives. When you couple real time testing with advanced paramedic standbys, you reduce the chance of someone dying. Also, watch how fast you drink water. About one pint an hour( 450 millileters) is the most you should consume as you may well swell your cells to explode in your skull as there is little room for expansion if you overheat. So we should agitate for real time testing as well as education & buddy up with some one you know will look after you. If you are a female & have not taken molly for a while get some one else to go first & wait. These raves go all night so you have plenty of time to party & never never have a drug consumption challenge with any one. Stay safe, play safe & stay around. cheers

    • Nick ‘Treacle’ Gilbert

      “you may well swell your cells to explode in your skull” Do you think that your choice of words is going to deter people, or just cause them to panic, when they’re coming up? That’s a good way to end up dealing with a load of people who think they’re dying, because you’ve phrased it like that. Hyponatremia is something that happens to people who don’t take MDMA, as well. Rather than scaring people, you might want to act a bit more professionally and explain why this happens. It worries me that you’re in charge of people taking drugs, seriously.

      • Maurice Dutton

        I take your point & will reply to you a little later. Off course I am open to any criticism that is fair minded. May I write an article on what my own thoughts are. They are my own as all the readers are. thanks & give me a few days.

      • Maurice Dutton

        Nick, I am never in charge of any one taking drugs. Thats a huge throw off. People need to take responsibility for their own drug taking. Now if you wish to post a site that shows that certain profiles of people are more likely to suffer Hyponatremia, which is loosely characterised by head ache, nausea, vomiting, tiredness as well as muscle spasms & seizures you are more than welcome.When you state that people also suffer Hypnatremia outside of raves can you give me some data ? I am sure they do but Raves seem to attract a huge cohort of Hypnotreamia sufferers. It is also loosely referred to as too much water in your system. But its just semantics really. The crux is if you are using drugs, play safe. Also you may wish to know the jury is still out about the relationship for the effects these liver enzymes. The problem is that Raves have a huge confounding variables to analyse people. It may well be the adulterants put into these pills that cause reactions but I stand by the majority of what I have posted. Also when you are contracted to supply safety services you write in a non judgmental easy to read format. here is a couple of sites your readers may wish to research. Also try & get insurance for when you are the safety contractor for these events. I am doing so now & my insurer is a little shaky about even wanting to go there.
        So if you would like to assist me in designing a pamphlet we can hand out at raves instead of criticising one point of many I would welcome your input.
        Here is my web page & also hello Emanuel. I am new to this but wish you well.
        have a great weekend Cheers M
        Ps hello Emanuel I am now following your work !

        • Nick ‘Treacle’ Gilbert

          ‘When you state that people also suffer Hypnatremia outside of raves can you give me some data ?’ It’s a shame you can’t spell the word, and you haven’t even read the Wikipedia page. Around 13% of marathon runners end up in such a state. Nowhere near 13% of MDMA users do.

          • Maurice Dutton

            you are splitting hairs, A typo is no big deal & using wikipedia says at lot about your research.

          • Nick ‘Treacle’ Gilbert

            I’m sorry, but anyone that knows anything about MDMA knows this. Are the medical citations on that Wikipedia article not enough to emphasise the point I was trying to make? I’m trying to inform you, that’s all…

          • Maurice Dutton

            Well why are they still dying?

          • Nick ‘Treacle’ Gilbert

            Who is ‘they’? The one in around 100,000 people that take MDMA and die? I believe this topic has already covered the reasons why people COULD die, and how it’s preventable. Dehydration, overhydration, possible sensitivities (not allergies) and undiagnosed heart/other organ conditions. I’ve taken MDMA over a thousand times, and know maybe 100 people who’ve done the same, and none of us have ever required medical attention, because we know that testing pills and paying attention to our bodies makes a massive difference. Your chances of dying from a night out on alcohol are far higher, whether that’s your fault, or someone else who is drunk.

  • newlibertarian

    I believe the jury is still out on the enzyme deficiency theory, though I tend to agree more with Rick Doblin. But unless all these tests and studies were based on users taking only pure MDMA, they are tainted – just like the majority of Ecstasy sold for the last two decades. And that, more than an enzyme ‘allergy,’ is the crux of the biscuit. Legal MDMA would be safe for almost everyone.