Summary: The Influence explores the risks and benefits of MDMA, the importance of harm reduction at festivals, and how the enzyme CYP2D6 could affect the metabolization of MDMA in some people. "There are other metabolic pathways for MDMA," explains MAPS Founder Rick Doblin, "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."
Originally appearing here.
“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.”