Ilsa Jerome

After my initial post on the research that generated the initial post, I had a chance to read the paper more thoroughly and even discuss it with people more informed than I about matters relating to DNA damage.

Late in 2003, a news report surfaced claiming that an Italian team had shown that "MDMA and cocaine cause DNA mutations." (see Cocaine And Ecstasy Cause DNA Mutation, Study Says". Friends and family (at least one individual) heard these alarming findings announced on TV, though little explanation was given as to the nature of these findings. At the time the news report appeared, a search of PubMed failed to find any papers reporting findings relating to MDMA and "DNA mutations," either published by Italian researchers or by researchers from any other country. I knew of only one major Italian team working in the area of MDMA research, the team of Fornai and colleagues, and most of their work to date focused on MDMA neurotoxicity in mice.

Late in 2003, an electronic publication by Fornai et al. in the journal Psychopharmacology appeared, and its title referred to "DNA damage."

However, a cursory reading of the paper suggested that it was in fact an MDMA neurotoxicity paper that fit well within the Italian team's program of research, and not an examination of DNA damage. On further reading, I found that researchers had studied DNA damage-in mouse dopamine neurons. Though I stand corrected on my original assertion in a MAPS forum posting that DNA damage was not measured, my conviction that it was an "MDMA neurotoxicity paper in disguise" stand confirmed.

Specifically, the research reported by Fornai and colleagues looked at neurons in the substantia nigra and striatum of mice given 4 injections of 5 mg/kg MDMA (about 0.15 mg) every 2 hours. These brain areas contain mostly dopamine neurons, and repeated doses of MDMA reduces brain dopamine in mice. The study was unusual in the number of neurotransmitters, neurotransmitter transporters, proteins, and other variables assessed. DNA fragmentation was one of these markers, the assumption being that DNA fragmentation could serve as a sign of oxidative stress and neurotoxicity. To measure DNA fragmentation, the researchers used a measure intended to detect breaks in cellular DNA where one strand has come away from the other strand.

What Fornai and colleagues did not find were "mutations." Instead, they found changes associated with axonal damage (such as reduced VMAT-2, reduced neurotransmitters), signs of oxidative stress (such as clustering of heat shock protein, and the by now famous "DNA fragmentation." They also watched what happened when rat tumor cells (possibly embryonic and from the "neural crest") were incubated with about 0.193 mg MDMA (100 micromoles) for seven days, finding "ubiquitin-positive inclusions" that were associated with increased HSP70. Fornai and colleagues say that they saw no signs of cell death in slices of striatum or substantia nigra. In short, the study offers some strong, but not incontestable, evidence of neurotoxicity to dopamine (and perhaps serotonin) axons, but not cell bodies, in mice given repeated injections of MDMA. It does not show that MDMA causes cancer or mutations.

Incidentally, no papers have appeared explaining any findings related to cocaine, leading one MAPS forum member to speculate the journalist responsible for the news report gathered his or her information from a conference presentation.

Fornai and colleagues chose a misleading title for their report. It is not only misleading because the report focused on detecting MDMA neurotoxicity rather than assessing mutagenicity (ability to cause mutations), but because the phrase "DNA damage" is liable to be misconstrued by the public as referring to evidence of "mutations," as apparently was the case for the Reuters journalist. In fact, the journalist quotes someone as saying that MDMA might harm "hereditary" [find quote] material, displaying such a great misunderstanding of biology that I conclude it must have been a misquote. The only kind of DNA damage that can cause genetic mutations that can be passed on to one's children are mutations in reproductive cells (as sperm and eggs). Since Fornai and colleagues only looked at neurons, the findings lend no support whatsoever to claims of damage to "hereditary" material.

As for concerns that MDMA could cause cancer because it damages DNA, finding signs of DNA damage is not equivalent to finding evidence that a chemical causes cancer. Rather, most DNA damage is either repaired by the affected cell or leads it to commit suicide (apoptosis), and since cell death was not seen in this study, repair seems the more likely option. In any case, Fornai and colleagues did not look for signs of cancer in the mice they studied, so the paper does not and cannot support claims that "MDMA could cause cancer."

It is not surprising that such a paper would lead to the sensationalistic and uninformed coverage that it did, especially when there is a tendency to highlight any findings of negative effects of illicit drugs. It is a little more surprising that the authors chose such a poor title for their paper. I hope it is clear now that there still is no evidence for "DNA mutations," caused by MDMA, even if researchers did detect "DNA damage" after MDMA.

The full-text of the report (in PDF format) is now available. Those interested in following Fornai's papers can find also this paper, and others, listed in the MAPS MDMA bibliography (www.maps.org/wwwpb). I have written summaries of many of these papers (see the MDMA Literature Updates, under "Non-human and In Vitro Studies.")

I offer heartfelt thanks to a pair of anonymous member of the MAPS Forum who e-mailed me excellent explanations and information pertaining to DNA damage and its significance, and units of measurement. However, all errors or confusions in the writing above are my own.

The paper in question:

Fornai F, Lenzi P, Frenzilli G, Gesi M, Ferrucci M, Lazzeri G, Biagioni F, Nigro M, Falleni A, Giusiani M, Pellegrini A, Blandini F, Ruggieri S, Paparelli A. (2003) DNA damage and ubiquitinated neuronal inclusions in the substantia nigra and striatum of mice following MDMA (ecstasy). Psychopharmacology (Berl). 2003 Dec 13 [Epub ahead of print]

Full Text in PDF Format