Low-Dose Ecstasy Use Linked to Decline in Verbal Memory

AMSTERDAM, The Netherlands, June 4 -- New users who took the street drug Ecstasy for a mean 1.6 months at low cumulative doses showed a decline in verbal recall and recognition.

There is growing evidence that Ecstasy, the street name for -3,4-methylenedioxy-methamphetamine (MDMA), is potentially neurotoxic in human beings, wrote Thelma Schildt, M.Sc., of the University of Amsterdam, and colleagues in the June issue of the Archives of General Psychiatry.

However, they said, most studies have been done on frequent Ecstasy users and there have been no human data regarding the sustained neurocognitive effects of a single or low dosage use of the drug among novice users.

To examine that question, the researchers conducted a prospective cohort study, part of the Netherlands XTC Toxicity study. The original sample consisted of 188 healthy, Ecstasy-naive volunteers (mean age, 22) who said they had considered starting to use Ecstasy in the near future.

The initial enrollment took place from April 10, 2002 to April 28, 2004, with a follow-up within three years.

Of the original 188 subjects, 58 started using Ecstasy (mean cumulative dose, 3.2 tablets; median cumulative dose 1.5 tablets in a mean period of 1.6 months). The average follow-up was over 11.1 months.

They were compared with 60 subjects who had never used Ecstasy and were matched for age, sex, intelligence, and use of substances other than Ecstasy.

Subjects were paid for their participation, depending on the number of assessment sessions. Differences in cognition between Ecstasy users and non-users were adjusted for differences in use of cannabis and other recreational drugs.

At the initial examination, the two groups showed no statistically significant differences in any of the neuropsychological test scores, the researchers said.

At follow-up, however, scores for change on immediate and delayed verbal recall and verbal recognition were significantly lower in those who'd taken Ecstasy compared with the non-users. The changes, the researchers noted, were still within the normal range.

For example, on the Rey Auditory Verbal Learning Test (RAVLT), which tests the immediate recognition of words, the change score for the Ecstasy users was 0.86, compared with 3.90 for the nonusers.

The mean recognition of words score at the initial examination for the Ecstasy users was 29.95 (SD 0.2) and 29.66 at follow-up, with 22.4% of subjects showing a decline.

The initial score for the non-users was 29.88 and at follow-up 29.93, with 6.7% of subjects showing a decline (P=0.02).

There were no significant differences on other test scores, the researchers reported. At follow-up, the Ecstasy users reported to have used a mean of 3.2 tablets (range 0.5-50 tablets; median 1.5 tablets) in a mean period of 1.6 months during the average follow-up of 11.1 months. Mean follow-up for the non-users was 19.1 months.

The assessment took place on average 11.8 weeks after the last Ecstasy use, unlike the much shorter durations in other studies, the researcher noted.

At follow-up, the Ecstasy users also reported having used more cannabis and cocaine in the previous year than the non-Ecstasy users. The non-users also drank less alcohol at follow-up, the researchers reported.

The current findings are consistent with numerous previous studies that reported a specific negative effect of Ecstasy use on verbal memory, the researchers said.

In this study, they noted, the association between Ecstasy dose and verbal memory performance was rather weak. This was not surprising, they said, given the relatively low doses that were used and the short duration of Ecstasy use.

No differences between the two groups were observed on other neurocognitive tests, nor was sex a factor, the researchers said. Some explanations include a possible combined effect with cannabis, a possibility that cannot be excluded.

Another possible confounding effect might have been depression, leading to higher levels of sensation-seeking. Yet, this would not explain why only verbal memory test scores were affected, whereas scores on other highly demanding tests were not affected, the investigators wrote.

It can be hypothesized, they said, that the medial temporal lobes, particularly the hippocampal area, are specifically vulnerable to Ecstasy. It is possible, they said, that the main underlying factor is depletion of serotonin, involved in several cognitive functions, but possibly especially relevant to learning and memory, while attention remains unaffected.

The researchers acknowledged several limitations of the study, including the prospective design, which limited evidence of causality. There was also a potential confounding of lifestyle differences, the pattern of drug use and its environment, and the lack of control of the purity of the amount of MDMA in the tablets.

Moreover, they said, the sample was not representative of the general population of young adults, which might limit the generalizability of the results.

A final limitation, the researchers said, is that the study did not answer the question of whether the observed short-term effects will remain after quitting the drug. Monitoring this cohort would be worthwhile, they said.

Although the performance of the group of Ecstasy users was still within the normal range and the immediate clinical relevance of the observed deficits is limited, the researchers concluded, the long-term consequences cannot be excluded.