Ecstasy Associated With Chronic Change in Brain Function

Originally appearing at Ecstasy — the illegal “rave” drug that produces feelings of euphoria and emotional warmth — has been in the news recently as a potential therapeutic. Clinical trials are testing Ecstasy in the treatment of post-traumatic stress disorder. But headlines like one in Time magazine’s health section in February — “Ecstasy as therapy: have some of its negative effects been overblown?” — concern Ronald Cowan, M.D., Ph.D., associate professor of Psychiatry. His team reports in the May issue of Neuropsychopharmacology that recreational Ecstasy use is associated with a chronic change in brain function. “There’s tension in the fields of psychiatry and psychotherapy between those who think Ecstasy could be a valuable therapeutic that’s not being tested because of overblown fears, and those who are concerned about the drug’s potentially harmful effects,” Cowan said. “We’re not on one side or the other; we’re just trying to find out what’s going on in the brain — is there any evidence for long-lasting changes in the brain?” The message in news reports needs to be accurate, Cowan said. His team’s studies suggest that the current message should be: “If you use Ecstasy recreationally, the more you use, the more brain changes you get.” Cowan and his colleagues examined brain activation during visual stimulation, using functional magnetic resonance imaging (fMRI), in subjects who had previously used Ecstasy (but not in the two weeks prior to imaging) and in subjects who had not previously used Ecstasy. They found increased brain activation in three brain areas associated with visual processing in Ecstasy users with the highest lifetime exposure to the drug. The findings were consistent with the investigators’ predictions based on results from animal models: that Ecstasy use is associated with a loss of serotonin signaling, which leads to hyper-excitability (increased activation) in the brain. The hyper-excitability suggests a loss in brain efficiency, Cowan said, “meaning that it takes more brain area to process information or perform a task.” The investigators found that this shift in brain excitability did not return to normal in subjects who had not used Ecstasy in more than a year. “We think this shift in cortical excitability may be chronic, long-lasting, and even permanent, which is a real worry,” Cowan said, noting that the Ecstasy users in the study are young (18 to 35 years old). “The question is what will happen to their brains as they age over the next 60 years.” Cowan said that the pattern of hyper-excitability is similar to that observed in fMRI studies of individuals at risk for, or with early, Alzheimer’s disease. “I’m not saying that these people are at increased risk for dementia, but that there’s a loss of brain efficiency in both recreational Ecstasy use and early Alzheimer’s.” The findings suggest that brain hyper-excitability (increased activation in fMRI scans) may be a useful biomarker for Ecstasy-induced neurotoxicity, which the investigators will continue to study. “Our goal is to be able to let people know whether or not the drug is causing long-term brain damage,” Cowan said. “That’s really critical because millions of people are using it.” The 2009 National Survey on Drug Use and Health estimated that 14.2 million individuals 12 years or older in the United States had used Ecstasy in their lifetime; 760,000 people had used Ecstasy in the month prior to being surveyed. Cowan is also interested in determining the doses of Ecstasy that are toxic, and whether there are genetic vulnerabilities to toxicity. If clinical trials show that the drug has therapeutic benefits, it’s critical to know the risks, he said. The research was supported by the National Science Foundation, the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Center for Research Resources. Story Source: The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Vanderbilt University Medical Center, via EurekAlert!, a service of AAAS. Journal Reference: 1. Amy L Bauernfeind, Mary S Dietrich, Jennifer U Blackford, Evonne J Charboneau, James G Lillevig, Christopher J Cannistraci, Neil D Woodward, Aize Cao, Tristan Watkins, Christina R Di Iorio, Carissa Cascio, Ronald M Salomon, Ronald L Cowan. Human Ecstasy Use is Associated with Increased Cortical Excitability: An fMRI Study. Neuropsychopharmacology, 2011; 36 (6): 1127 DOI: 10.1038/npp.2010.244.

A recent study by a Vanderbilt psychiatrist finds long-term differences in brain function between recreational Ecstasy users and non-users. This ScienceDaily article wonders whether these possible risks extend to those who are administered MDMA in therapeutic contexts.

The researchers performed fMRI scans on 20 ecstasy users, men and women reporting a lifetime of 33.25 +/- 37.79 occasions of use on average, range = 3-155), and 20 non-user controls. Generally speaking, a greater number of ecstasy users had experience with nearly every other substance listed, except alcohol, and including cannabis, stimulants, psychedelics, sedatives, opiates. The researchers imaged the brain while people watched either red or blue light, shown at three levels of brightness, and then measured brain activation. The researchers found no significant difference in brain activation between ecstasy user and non-ecstasy user controls. the researchers then correlated lifetime exposure to ecstasy to brain activation, finding a relationship between lifetime exposure and degree of cortical excitability in primary visual cortex, an area of brain involved in visual processing. The researchers also split the sample of ecstasy users on the basis of median (the value in the exact middle of the sample) lifetime ecstasy use, finding greater excitability in “heavy” versus “light” ecstasy users. Though adding lifetime exposure to methamphetamine slightly lowered the strength of this relationship between lifetime drug use and cortical excitability overall, it increased the strength of relationship in specific areas, suggesting a role of methamphetamine use. The researchers do not cite any relationship between cortical excitability in this area and any type of dementia. Instead, they discuss its relationship with neurons that receive input from the serotonin system.

The same team of researchers first reported increased activation in the visual cortex in 2006 (Cowan et al. 2006).

The sole paper that attempts to address the effects age and ecstasy use examined cognitive function in people aged 39-55 reporting repeated ecstasy use and comparing them with polydrug users, including some light ecstasy users (Schilt et al. 2010). This report reported that older ecstasy users and younger ecstasy users (from another study) had similar test scores.

As ScienceDaily puts it, “The message in news reports needs to be accurate.” Misleadingly, neither Cowan nor ScienceDaily acknowledge that illegally purchased Ecstasy used recreationally may or may not contain MDMA, and often contains methamphetamine, ketamine, BZP, caffeine, or other narcotics and stimulants. Besides, there is no reason to assume that the effects of regular recreational Ecstasy use–even if it was just MDMA–extend to those of MDMA administered only a few times in therapeutic settings. The article also fails to point out that users of Ecstasy also tend to use other drugs as well. In other words, there’s no way to know whether the observed effects were due to Ecstasy, to another drug, or to something else entirely.

Journalists reporting on scientific results need to be careful not to overstate their implications. It is important to be cautious when taking any drug repeatedly, but there is a big diff
erence between acknowledging long-term changes in brain function after using a substance and claiming that those changes are harmful. The scientist quoted in the article implies that because both long-term Ecstasy users and Alzheimer’s patients experience changes in brain function, somehow Ecstasy use causes Alzheimers. This is so misleading as to be dishonest; people have been using Ecstasy recreationally for over 30 years, and not a single study has shown a link between long-term recreational Ecstasy use and Alzheimer’s. To claim that there is a link is pure conjecture.

And there are reasons to believe that the benefits of MDMA used in therapy may outweigh its risks. According to MAPS Executive Director Rick Doblin, Ph.D., “The dosing [of MDMA] MAPS is using doesn’t cause any negative functional consequences in neurocognitive tests. There have been no reports of persisting problems in brain function or mood in any of our US PTSD subjects after an average of 41 months.”