A Little Help From Serotonin

FOR RHESUS MONKEYS, LIFE IN THE WILD IS A little like high school. Some animals--call them losers--slouch around looking aggrieved. They're volatile and bellicose, slow to form alliances and loath to reconcile after a spat. One in five dies during the passage to adulthood. But while the losers scrap over bits of chow, other animals--call them winners--stay busy grooming each other. They maintain wide networks of allies. They deflect challenges without resorting to violence, and 49 out of 50 survive to produce offspring. Why do they fare so well? The answer is no doubt complicated, but the monkeys' spinal fluid provides an intriguing clue. In study after study, researchers at the National Institute on Alcohol Abuse and Alcoholism have found that the winners' nervous systems are loaded with serotonin.

As the 20th century winds down, we humans seem increasingly convinced that serotonin is the key to a good life--and it's easy to see why. This once obscure neurotransmitter is the secret behind Prozac, the drug that revolutionized the pursuit of happiness 10 years ago this winter. Prozac and its mood-altering cousins all work by boosting serotonin's activity in the brain. So do Redux and fenfluramine, the blockbuster diet drugs that were pulled off the market this fall due to safety concerns. Even Imitrex, the hot new migraine treatment, works its magic via serotonin. Somehow serotonin is implicated in just about everything that matters to us--from winning friends and wielding power to managing anxiety and controlling appetites and impulses. So what is serotonin? How does it work? And why is it in such short supply? Those issues are still murky, but science is yielding some clues.

Serotonin is so basic to life that even worms and sea slugs make it. The substance abounds in our bloodstreams, but our brains produce separate supplies via cells known as raphe nuclei. Rooted near the base of the skull, these specialized neurons extend like branching vines through the brain and spinal cord, each one maintaining links with a half-million target cells. When a nerve impulse reaches a branch ending, the neuron releases serotonin into a tiny space, or synapse. Serotonin molecules then lock into receptors on the target cell, transmitting a message that travels through the nervous system. Microseconds later, the neuron that released the chemical takes it back in--a process known as reuptake.

What does serotonin say during its moment in the synapse? It depends on the target. Our nervous systems harbor at least 14 classes of serotonin receptors, each tailored to a distinct piece of the molecule. Since different types of brain cells sport different receptors, their responses to serotonin vary widely. Serotonin excites the motor neurons, which govern muscle activity, but it quiets the sensory neurons that mediate hunger and pain. It also pacifies neurons in the limbic system, the brain's Department of Animal Instincts. ""Serotonin puts the brakes on primitive behaviors like sex, aggression and excessive feeding,'' says Dr. Larry Siever of New York's Mount Sinai School of Medicine.

Small wonder, then, that high serotonin can foster social success. In a classic series of experiments with vervet monkeys, UCLA scientists Michael McGuire and Michael Raleigh found that males who had achieved high rank within a group's social hierarchy had nearly twice as much serotonin in their blood as low-ranking males. But that's not to say they were born leaders; further analysis showed that social standing had as much effect on the animals' serotonin as serotonin had on their status. If an alpha male was displaced by a challenger, his blood count would quickly plummet--and when an upstart came into power, his serotonin level would surge. Raleigh and McGuire found they could deplete a leader's serotonin simply by keeping him behind a one-way mirror, where his peers couldn't acknowledge his dominance displays.

People's social lives are more complicated than monkeys', but not entirely different. When Raleigh and McGuire analyzed blood samples from 48 UCLA fraternity boys, the average serotonin level was nearly 25 percent higher among officers than among members. And when Raleigh compared his own serotonin count with that of his lab director (McGuire), the boss's was 50 percent higher.

Rising to the top may involve some scrapping, but serotonin doesn't foster aggression. ""Serotonin provides a restraint mechanism, a kind of behavioral seat belt,'' says Dr. John Mann of Columbia University. Whether you look at monkeys, dogs, horses or humans, the most aggressive individuals are typically those with the lowest serotonin levels. Drugs that boost serotonin's activity tend to dampen a wide range of impulses (including sexual ones that need no dampening), and they can help violent people get a grip. Yasmin Hamani has seen it happen. When her autistic daughter was 8 years old, her annoying repetitive behaviors turned violent. If Hamani turned her back, the child would sneak up and sink her nails into an exposed piece of flesh with swift pinches that drew blood. She would kick people in church and grab at women's hair in the supermarket. One of her schools confined her to a four-foot pen to protect the other kids. When the child was 11 and increasingly uncontrollable, Dr. Edwin Cook at the University of Chicago tried treating her with Prozac. The drug didn't cure her autism, but violent outbursts stopped. ""Everyone loves her now,'' says Hamani.

Violence is one possible consequence of low serotonin, but there are many others. Without the chemical's leveling effects, we grow more vulnerable to all kinds of impulses--whether to gamble, buy things, steal things or eat things. And low serotonin can have devastating effects on mood. It plays major roles not only in depression and suicide but in premenstrual syndrome (PMS), seasonal affective disorder (SAD) and routine morning grumpiness (RMG).

You might conclude from all this that more serotonin is always better. But just as a serotonin deficiency can unleash destructive impulses, an overly active serotonin system can leave a person paralyzed by obsessions and compulsions. People with compulsive disorders become hyperaware of potential threats--possibly because serotonin is overstimulating the receptors involved in planning and vigilance--and they develop bizarre rituals for managing their anxiety. Incessant cleaning and checking are the classic manifestations, but there are many others. Hypochondria, once dismissed as an annoying bid for sympathy, is now viewed as a type of obsessive-compulsive illness. So is body dysmorphic disorder (BDD), a grim fixation on some flaw in one's appearance. Dr. Eric Hollander of New York's Mount Sinai has seen people undergo two dozen surgeries to correct perceived defects. ""This isn't a trivial illness,'' he says. ""There is a high rate of suicide among these patients.''

Prozac would seem an unlikely remedy. Its job, after all, is to amplify serotonin's effect, by slowing its removal from the synapse. Yet Prozac and the other ""selective serotonin reuptake inhibitors'' (SSRIs) are proving as useful against compulsive disorders as they are against impulsive ones. How could the same drugs alleviate such disparate problems? Most experts credit the body's drive to maintain equilibrium. If a neuron is responding poorly to serotonin, blocking reuptake may simply compensate for the shortfall. But if a neuron is already overstimulated, it may compensate for the extra exposure by responding less vigorously. ""It's a leap to think "I hate my nose so I'll take Prozac','' says Dr. Katharine Phillips of Butler Hospital in Providence, R.I. ""But it can make a difference.''

SSRI therapy won't give you a new nose, but it can change your waistline. Fenfluramine (brand name Pondimin) and dexfenfluramine (Redux), the wildly popular weight-loss drugs that were pulled off the market in September, had chemical actions very similar to Prozac's. By boosting serotonin activity in particular brain regions, they helped dieters feel sated before downing that third bowl of Chunky Monkey. But the fenfluramines packed a double whammy: besides slowing serotonin's removal from the synapse, they forced neurons to release more of it. And unlike Prozac, they seemed to cause a dangerous buildup of waxy material on people's heart valves. The cause of that problem is still unknown; it was seen mainly in people who took ""fen-phen,'' a combination of fenfluramine and the stimulant phentermine. But it was serious enough to send Redux and Pondimin into oblivion.

Obesity specialists despaired at the time, but they're now finding safer ways to protect people from their cravings. The FDA recently approved a new diet pill called Meridia, which (like Prozac) enhances serotonin's activity without stimulating its release. Researchers are finding that Prozac itself can safely promote weight loss when combined with phentermine. And enthusiasts are now touting various strategies for boosting serotonin without resorting to drugs at all.

If the brain weren't so well insulated, we could simply pop some pure serotonin when our spirits or our bellies started to sag. But serotonin can't enter the nervous system from outside. The brain makes its own supply from tryptophan, an amino acid found in protein-rich foods such as meat, fish and milk. The tryptophan in a hamburger can enter the brain, but as you've probably noticed, hamburgers don't cure depression. That's because tryptophan-rich foods are packed with a variety of amino acids that compete for passage across the blood-brain barrier. Picture a crowd in front of a department store with a single revolving door, says University of Pittsburgh pharmacologist John Fernstrom. ""Tryptophan wants to get in, but it has to stand in line.''

Back in the 1970s Fernstrom and Dr. Richard Wurtman of MIT discovered that the best way to shorten that line is simply to eat a carbohydrate. Carbs enter the bloodstream as glucose--and any rise in blood glucose causes the pancreas to secrete insulin. Insulin pushes glucose and various amino acids out of the blood and into fat and muscle cells. But it doesn't mop up tryptophan. So when insulin sweeps through the bloodstream, the crowd at the revolving door disperses and tryptophan glides freely into the brain, where it can be used to make serotonin.

After showing that carb-munching could increase brain serotonin in rats, Wurtman and his wife, Judith, a nutritional scientist at MIT, started thinking about people. Is it possible, they wondered, that people who binge on cookies, chips and candy are unconsciously seeking serotonin? Encouraged by clinical studies showing that obese people draw most of their excess calories from such carb-rich snacks, Judith Wurtman developed a theory of weight management. In books like ""The Carbohydrate Craver's Diet'' and ""The Serotonin Solution,'' she claims that a regimen of low-fat, high-carb snacks (toast, pretzels, rice cakes) can quash your cravings without making you fat. It's an interesting idea, but she has yet to document its advantages. In an unpublished study, she compared her diet with a conventional weight-loss plan in 27 obese women. The results didn't differ much--volunteers lost 10 to 12 pounds on her regimen, versus 8 to 9 on the other one--but she says her program left people feeling happier and more vigorous. Fernstrom, the Wurtmans' former collaborator, is skeptical. ""There's a lot of hype with this stuff,'' he says, ""and people are making money based on it.''

Supplement makers are hoping to get their share. They used to do a brisk business in L-tryptophan, an amino acid that people took orally to keep the brain adequately supplied. That product was banned in the 1980s, after a contaminated batch caused widespread illness and several deaths. But tryptophan is now returning to health-food stores in a new form called 5-HTP (5-hydroxytryptophan). It crosses the blood-brain barrier as readily as L-tryptophan, and once inside the brain it's more readily converted into serotonin. Small studies in Europe have found 5-HTP helpful in treating depression. It performed as well as the SSRI Luvox in one Swiss experiment and caused fewer side effects. If that finding holds, 5-HTP could be a godsend for depressed people who find that drugs spoil their sleep, sex and appetite. St. John's wort, the popular herb, shows similar promise.

But don't assume that supplements or drugs will make you lean, charming and powerful. Our serotonin systems are affected not only by what we ingest but by our genes, experiences and attitudes--and by the countless other chemicals racing through our brains. Scientists may someday learn how all these forces interact, but a good life will still take work. ""Your serotonin system doesn't rule you,'' says Siever. ""If you have vulnerabilities associated with low serotonin functioning--guilt, submissiveness, low self-esteem--you can learn to compensate for them.'' And if you're lucky, you'll be rewarded with a rise in serotonin.