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Ecstasy, a popular street drug used to create a sense of euphoria, has unexpectedly given scientists a better understanding of how much genetics can influence our reaction to medications.

Although news reports usually focus on the dangers of Ecstasy overdose, the amphetamine derivative is highly addictive and has other problems associated with long-term use, such as depression. Some studies report up to a 33% incidence of depression in long term users of Ecstasy. Although the way that the drug creates a euphoric feeling has been known for some time, we have not known why some users develop severe depression. Genetics may be the answer.

Ecstasy creates a euphoric sensation by changing the concentration of a chemical messenger in the brain called serotonin. Serotonin is an important brain chemical involved in the control of mood and emotion. Many antidepressant drugs, especially the SSRIs, or selective serotonin reuptake inhibitors (including Lexapro, Prozac, Zoloft and others), take advantage of serotonin's action in the brain to treat the disorder. They increase the amount of serotonin action in the brain by blocking the uptake and storage of serotonin back into brain cells. This is a slow, controlled process that keeps more serotonin molecules free to act on mood stimulation receptors.

Ecstasy not only blocks this uptake and storage, but it causes a massive release of serotonin that has built up inside storage sites. This massive release of serotonin is responsible for the short-lived, euphoric effects of the drug.

The serotonin storage system is different from person to person, in large part based upon the type of serotonin transporter genes that you inherited. Researchers have identified what they call a long and a short transporter gene. Because one transporter gene is inherited from each parent, you could have two long forms, two short forms or one of each, depending upon which ones ended up in the sperm and the egg that got you started.

To see how the different transporter genes correlate with depression in Ecstasy users, researchers recently studied the frequency of depression among 66 heavy users of Ecstasy, 30 users of marijuana and 28 people who did not use any drugs. The participants completed two standard questionnaires for diagnosing depression. Then, the researchers compared the depression test results with the patterns of serotonin transporter genes. Here’s what they found:

Heavy users of Ecstasy who had the two short transporter genes were more likely to have depression than those with either two long genes or one long and one short gene.
People who had two short versions of the transporter gene who do not use Ecstasy did not have any increased risk of depression.

Studies looking at people with depression who have less than optimal responses to SSRI drugs show a similar pattern. They are more likely to have inherited two short serotonin transporter genes rather than two longs or one of each.

This is just one example of what to expect in the future. Genetic testing to predict how effective a drug will be for a specific patient will become even more common in the next few years.

Harold J. DeMonaco, M.S. is senior clinical associate in the Decision Support and Quality Management Unit at the Massachusetts General Hospital and is currently a Visiting Scholar at the MIT Sloan School of Management. He is author of over 20 publications in the pharmacy and medical literature and routinely reviews manuscript submissions for eight medical journals.

Depression, Genetics and the Drug Ecstasy