Biology 202
1999 Second Web Reports
On Serendip

“LITTLE PILL WHITE AND ROUND
GULP OF WATER, TURBO DOWN!
ANXIETY NOW, CAN'T STAND OR SIT,
JUST WAIT, DON'T WORRY, IT WILL HIT!
IN HALF-AN-HOUR YOU RISE INSIDE,
EVERYONE LOVES, NO HATE TO HIDE.
EVERYTHING'S GOOD, THERE IS NO
WRONG, IF THE WHOLE WORLD SWALLOWED IT,
EVERYONE WOULD GET ALONG...
WORLD PEACE I HAVE A VISION,
CANNOT BE OBTAINED THROUGH RELIGION
BUT CAN BE RESOLVED CHEMICALLY
THERE IS A GOD CALLED ECSTASY!”
- By Anonymous user of ecstasy (1).

The various account of users of a drug known as ecstasy were among the most moving and perplexing reading that I had ever encountered. It is remarkable to imagine that each of us is able “to rise inside,” overcome the barriers of all negative feelings, and to love to our outermost capacity.... with some help from the little white pill. While most of the accounts that I reviewed had an overriding theme of experience of closeness, love, and peace, the accounts were very case specific: A writer finds a years lost muse, a girl “learns” how to love herself and others, a religious man finally achieves “spiritual expansion,” a couple is able to exchange sexual roles as if having their partner’s body, and the list goes on and on (2). But there are also negative experiences associated with the use of ecstasy, although they are documented much less. For example, a user describes his state after a trip on ecstasy: “for the next couple of days afterwards I was an emotional wreck, paranoid as hell, shaking, involuntary muscle spasms, and my tonsillitis came back” (3). After a similar negative experience, another user who actually had to stop taking ecstasy because of the detrimental side effects it produced, comments: “It’s just a pity that people can’t feel like they do on Ecstasy, naturally” (4).

Perhaps trying to understand how a chemical can cause a state of euphoria would help us figure out how to achieve it naturally. Then, we can make some sense of, or at least hypothesize about, the neurobiology which underlies the depth of human experience.

From even some accounts I outlined above, one can see how complex the feelings brought about by this drug really are. Finding the muse and everything that encompasses it, is a quite complicated behavior, not to mention the vision of world peace and love! It seems unlikely that a simple chemical should cause such a wide range of effects.

Previously, I have done research on how antidepressants work and I was surprised, and even shocked, to discover that the prevailing explanation of the effects of ecstasy on the brain is quite similar, if not identical to that given for antidepressants. Although I did not find this to be a satisfactory explanation, as I outline it this time, I will attempt to find some explanations on why it has become so fashionable, sort of speak, and what credit we can give to the theory as well as what contradictions and inconsistencies still remain. If we are to get a step closer to understanding the truth behind the neurobiological theory that explains the effects of ecstasy, we should explore not only how many things we can account for in terms of the theory, but also how many things we can account for without it.

Ecstasy, also clinically known as Methhylenedioxymethanphetamine or MDMA, can be swallowed, smoked or injected. Once the drug enters the body it goes through extraction by the liver and then reaches the circulatory system and is transmitted through the blood vessel wall to the place where it does its job - the brain. The drug is dispersed into other parts of the body but there it has no pharmacological activity (5).

From research of rats, scientists hypothesize that MDMA promotes significant release of serotonin from presynaptic vesicles (6). In normal circumstances, the brain has strict control over the amount of serotonin circulating among the neurons. Only a special subset of neurons have the ability to release or respond to serotonin. And even they exercise restraint by having special serotonin transporter proteins which pump it out of the synapse and back into the neuron shortly after it is released. The main effect of ecstasy in rats is to prevent the return of serotonin to neurons by occupying their binding sites on the transporter proteins, effectively preventing serotonin re-uptake. As a result, serotonin levels rise sharply when MDMA is occupying the binding sites, and the signaling between the neurons is amplified. However, the produced “high,” which is thought to be caused by an increase in serotonin levels, eventually fades when the neurons are drained of all their serotonin stores. A number of researchers speculate that this depletion of serotonin may cause the psychological “crash” that is experienced by some users (7).

It is important to note that serotonin is linked to at least a dozen other drugs and disorders, particularly those of the central nervous system. They include depression, obsessive-compulsive disorder, stroke, schizophrenia, obesity, pain, hypertension, vascular disorders, and even nausea and migraines! (6). Before I turn to the problems of the serotonin hypothesis, it is important to see why it has become so popular and the types of hypothesis it has produced.

Researchers generalized the task of serotonin to that of modification of responses of neurons to a range of other neurotransmitters. This could point to a theory why serotonin could potentially influence the most subtle and most encompassing of human attributes - mood. If we assume that behavior is controlled by various chemical reactions in the brain and the communication pathways involve and are influenced by various chemicals that are produced, then if serotonin fine tunes responses of neurons to other neurotransmiters it can potentially influence behavior. Also, serotonin is made up of groups of neurons which emit axons that enervate other neurons throughout the entire nervous system. Neurons communicate through electrical signals which travel between their axons. The fact that anatomically serotonin can send signals to various neurons can account for its role in mood regulation. For example, serotonin’s axons reach neurons in the cortex, area of the brain which is thought to account for thinking and “creative” functions, the midbrain which controls appetite, and the hypothalamus, which is involved with hormonal functioning of the entire body (8). Animal studies also show that serotonin interacts with certain sex hormones to orchestrate sexual behavior. Of course, this can be correlated with the various sexual effects of ecstasy (9).

Theoretically a single chemical such as serotonin is capable in participating in various chemical reactions that produce different products that can, depending on their reactive specificity, go on to react further and cause different products to form. Also various other factors such as relative size of ionization constants of these reactions could influence which reactions predominate and thus which products are present in greater amounts. Therefore, different behavioral patterns may arise depending on the chain of reactions caused by ecstasy and by the concentrations of various chemicals produced. It is conceivable that the chemical reactions behind these behavioral patterns can potentially start from the influence of a single chemical. However, as Yale neuropsychologist Thomas J. Carew points out: “Serotonin is only one of the molecules in the orchestra” (9). So what are the other molecules and instruments that we are missing in this account?

Unfortunately, we can only hypothesize at this point, partly because most of the research is done on rats, not humans, and the experiments which are done on humans have quite “shaky data.” It is difficult to reach conclusions from data produced from retrospective research on humans, rather than prospective research. As pointed out at the Novartis Foundation Press Conference: “There is the difference between studying the brains of humans who say they have taken MDMA in the past (whether recently or not) and studying the brains of humans before and after actually giving them MDMA” (10). In the first case there are obvious methodological difficulties. For example, differences in the brains of MDMA users, compared to non users who are the control group could be preexisting. Another boundary in understanding effects of ecstasy has to do with ethical questions. As Professor Ricaurte mentioned at the conference, it is certainly unethical to ask human subjects to be involved in a study whose purpose is to “see whether or not we can destroy serotonin nerve terminals in you brain” and thus get a step closer to other routes of MDMA (10).

So there are uncertainties in the method by which the serotonin theory is constructed and thus its reexamination is necessary. You can not trust a hypothesis based on an experiment that has shaky data to begin with.

From my research, I noticed that most studies make a lot of generalization about the substances in question. Human beings always strive to sort everything out on shelves, and that is apparent in case of the serotonin hypothesis, although here I do not believe it is desirable. As I mentioned earlier, researchers generalized the task of serotonin to that of “modification of responses of neurons to a range of neurotransmitters.” From this generalization a theory that serotonin influenced mood came about. Although there is a substantial amount of evidence that serotonin does play a role in mood, its role is more subtle and complex. For example, various experiences of users are very specific. That is, while one user gets in touch with his “inner spirit” and expands his mind in a creative manner, another user gets a depressive effect. In between these two ends of the spectrum of experience, there are countless other experiences, the type and degree of which is so fined tuned that it becomes impossible to think that each was brought about merely by the decrease or increase of a serotonin levels in the brain.

Theoretically, it is conceivable that a single chemical starts an array of chemical reactions that might lead to various behaviors. However, to think of human experience as simply a level of a particular chemical is quite limiting in terms of understanding the nervous system. First of all, there are many other molecules in “the orchestra” that can precipitate in neural communication. Also, chemicals circulating in the fluids of our body can bind and influence neurons, not necessarily at their synapses.

Another important question to consider is that if the “high” is produced by high levels of serotonin, why is it not produced in all people taking ecstasy? This suggests that there is something more involved with the experience of the “high.” Even those researchers who support the serotonin hypothesis agree that the brains of individuals are different. Such things as memory and the complex phenomenon we refer to as personality come into play. If they did not, human experience would loose its depth because everyone would respond to stimulation in the same way. Two people would have an identical “high.” Obviously this is not the case. The brains of people must be different in some intricate ways, otherwise the same movie would trigger same emotions in two people, this rarely occurs. Basically, this amounts to the fact that the effects of a chemical, such as MDMA, depend on other players (the chemicals and neural aggregations present at the time) as well as what these players are doing at that time.

If one uses the metaphor of the operation of the orchestra being like the nervous system, it becomes apparent that two peoples’ brains have the same instruments (neurons, chemicals, etc.) which make up an orchestra. However, the time at which each instrument plays by itself or in concord with another, the pitch (levels of a particular chemical), and amount and types of instruments present (chemicals and specific neural connections presents especially in the viciniity of influence) determine the kind of a symphony that is heard. The brain in this analogy, is also different in the persons considered due to their genome, previous experiences, personality, environment, and other factors which come into play when shaping a person’s perception of the external world. When one considers the endless possibilities of elements (chemicals, neural connections) that are involved in the playing out of the symphony, it soon becomes apparent that the symphony, or the depth of human experience, can not be entirely based on “the one molecule in the orchestra.”

WWW Sources

2)Various accounts of trips listed in an index

3)Too many pills - a personal account of ecstasy user

4)Disillusionment- a personal account of ecstasy user

5)Team Project on the WWW for the Biological Bases of Behavior-1998

6)Serotonin: the neurotransmitter for the 90’s

7)Atrip into the unknown, illicit drug ecstasy

8)The Harvard Mahoney Neuroscience Institute Letter

9)Neurotransmitter of the ‘90s: serotonin production

10)Novartis Foundation Meeting

| Course Home Page | Back to Brain and Behavior | Back to Serendip |