15: Short-term effects after ecstasy is gone from the body

Ecstasy is an unusual drug because it has effects on the brain that develop and persist for a short time after the drug is eliminated from the body. These often include the development of depression-like feelings, anxiety, restlessness, irritability, and sleep disturbances. These "after effects" occur because of a chemical change that takes place at the serotonin synapse. To illustrate how this occurs, this image shows the serotonin synapse during and after taking ecstasy. Three conditions are illustrated: on the left, neurons normally release serotonin in response to electrical impulses (basically the release is in "spurts"). This results in the normal activation of serotonin receptors, which keeps our psychological and physiological function on an even keel. So, for example, we have a normal mood and we are calm. In the middle, ecstasy causes a sustained increase in the amount of serotonin in the synaptic space, leading to sustained activation of more serotonin receptors. This can produce an elevated mood (or euphoria). Eventually, the serotonin neurons can't make serotonin fast enough to replace that which was lost, so once Ecstasy is gone from the body (on the right), less serotonin is released with each electrical impulse and fewer serotonin receptors are activated, producing depression-like feelings and anxiety. Another important effect that may emerge after taking ecstasy is memory disruption. (Ask students if they can figure out which area of the brain is affected here; the answer should include the cerebral cortex and the hippocampus). This is an adverse effect that may persist with repeated or long-term use of ecstasy. Indicate to students that there is some evidence for this obtained from human studies.

16: Long-term effects of ecstasy: neurotoxic?

When people use Ecstasy repeatedly or long term, there may be changes in their brain chemistry that suggest that the serotonin neurons are damaged. One major clue is that serotonin itself and its metabolites (remind students that serotonin that is taken back up into the terminal is metabolized by enzymes) are diminished in the brains of animals treated with ecstasy. Moreover, the best evidence that we have so far is that even seven years after a brief exposure to ecstasy, serotonin levels in monkey brains have not fully returned to normal. This is described in the next image.

17: Long-term effects in monkeys

A very important experiment was performed in monkeys to determine if ecstasy can actually damage neurons. Monkeys were given ecstasy twice a day for four days (control monkeys were given saline). One group of monkeys' brains were removed two weeks later for analysis and another group of monkeys lived for an additional seven years before their brains were removed. Scientists examined the brains for the presence of serotonin. This image shows the presence of serotonin in neurons of the neocortex from three typical monkeys. On the left, the monkey who did not receive any ecstasy had a lot of serotonin (in pink) in the neocortex. Two weeks after a monkey received ecstasy, most of the serotonin was gone (point to the middle panel), suggesting that the serotonin neuron terminals were destroyed (there was no destruction of the serotonin cell bodies arising back in the brainstem). Point to the right-hand panel and show students that this damage appeared to be long-term because seven years later there was some recovery, but it was not complete. Scientists found similar changes in limbic areas of the brain such as the hippocampus and amygdala. The monkey experiments are an important reminder that humans may suffer the same fate, although this still remains to be demonstrated. Tell the students how difficult it is to do this same kind of experiment in humans, because it requires removing pieces of the brain to look for the loss of the serotonin neurons.

Image courtesy of Dr. GA Ricaurte, Johns Hopkins University School of Medicine.

18: Ecstasy causes degeneration of serotonin nerve terminals

This image illustrates the degeneration of serotonin nerve terminals after long-term or repeated use of ecstasy (you can refer back to image 9 to compare this degenerating terminal to a healthy terminal). Remind students that we have several pieces of evidence that support this effect of ecstasy. Experiments in animals given ecstasy indicate that this kind of degeneration occurs. Moreover, some studies of human ecstasy users report less serotonin and serotonin metabolites in the cerebrospinal fluid (which surrounds and bathes the brain and spinal cord) compared with nonusers. In contrast, the animal studies indicate that the serotonin cell bodies are still intact but the genetic instructions from the nucleus for any regrowth of the terminals may be abnormal.

Although scientists do not yet know for certain how ecstasy damages the serotonin terminals in these animal studies, some progress has been made in understanding this process. One mechanism is damage that involves the production of oxygen radicals (unstable forms of oxygen), which are very destructive to proteins, lipids, and DNA. The rich supply of mitochondria (which are a major source of oxygen radical formation) found in the terminals may cause the terminals to be especially sensitive to drugs like ecstasy.

19: Long-term ecstasy use may impair memory

It is not possible to look directly at damaged serotonin terminals in living humans. The best evidence for damage to serotonin neurons after long-term or repeated Ecstasy use in humans is the association between the neurochemical and behavioral changes. Although many behavioral measures have been assessed in Ecstasy users (the list is extensive), the most consistent findings are that some chronic Ecstasy users have verbal and visual memory impairments. Research is ongoing to determine if thinking ability is disrupted as well. However, it is important to keep in mind that many users of Ecstasy may unknowingly be taking other drugs that are sold as Ecstasy, and/or they may intentionally use other drugs, such as marijuana, which may contribute to the observed deficits in memory. Additionally, most studies in people do not have measures of memory ability in Ecstasy users before they began taking drugs. Therefore, it is difficult to rule out pre-existing memory deficits in Ecstasy users compared to nonusers. Nevertheless, in some studies Ecstasy users who had memory impairments also had less serotonin metabolites or changes in other markers of serotonin function. In fact, several studies have shown that the degree of impairment or the changes in markers of serotonin function were related to the extent of Ecstasy use over the lifetime. On the image, point to the brain areas that are involved in the memory impairment - the neocortex (yellow) and the hippocampus (blue). [As an aside, you can tell students an interesting link between low serotonin and memory impairment: normal people who are fed a diet that causes them to synthesize less serotonin also have memory impairment.]