Secrets of Serotonin

If you are the kind of person who likes to ask “Why?” “How does it work?” “Who says so?” and “Can you prove it?” this chapter will give you some answers. Question number one undoubtedly is, “What is serotonin?”

Serotonin is a neurotransmitter, a specialized molecule that allows nerve cells to communicate and interact with each other. Without neurotransmitters we would be unable to think, perceive, move, or even live. Serotonin also does double duty in the cardiovascular and gastrointestinal systems. It helps regulate the expansion and contraction of blood vessels and the function of platelets, the blood cells that cause blood to coagulate and close a wound. It also causes smooth muscles to contract, such as the abdominal muscles that aid digestion by pushing food through the GI tract.

About thirty neurotransmitters have been identified, some of them very specialized and others with a range of job duties in different parts of the brain and nervous system. Along with acetylcholine, dopamine and norepinephrine, serotonin is among the most significant in terms of the number and importance of the functions it helps carry out. In fact, the nerve cells that release and receive serotonin extend throughout the brain and down to the spinal chord. This serotonin system is the largest single system in the brain, influencing a broad range of basic functions from movement to mood.

All these different neurotransmitters work together in processing our thoughts, sensory perceptions, decisions, and actions. Although the cortex, the wrinkled “gray matter” of the brain, is in charge of making all “executive” decisions, the brain seems to function as a sort of democracy. Many different centers in the brain take part in processing basic information that helps to determine when we eat and sleep, whether we feel pain, whether our energy, mood, and motivation levels are up or down. The multiple neurotransmitters and the different processing centers provide a system of checks and balances. It's safe to assume that more than one neurotransmitter and one group of nerve cells are involved in carrying out each of the brain's many complex tasks. This way, one can pitch in and try to “cover” when another isn't doing its job. One of serotonin’s major roles is to modulate or control the effects of other neurotransmitters. Basically, this means it can influence the relative importance or priority of the messages sent by other neurotransmitters, giving them a green, red, or yellow light. This helps to explain why serotonin can have such pervasive effects on our mood and behavior, yet does not act alone. In the words of Thomas Carew, a Yale researcher, “Serotonin is only one of the molecules in the orchestra. But rather than being the trumpet or the cello player, it's the band leader who choreographs the output of the brain.”

The Lock and the Key to the Mystery

Like people, the body’s organs and cells have to communicate with each other in order to function and to survive. As their language, they use a great variety of specialized chemical messengers that include the neurotransmitters and the hormones. Serotonin and other messenger molecules pass signals from one cell to another by interacting with special gatekeeper molecules called receptors. It is a lock and key system, in which each messenger molecule can unlock and activate only a specific receptor type. When a messenger molecule attaches to the proper receptor, the receptor triggers a series of responses within the cell, which may then release its own messengers to pass the information on to yet other cells. Serotonin is known to unlock at least 14 different receptor “subtypes,” each thought to have a distinct role in influencing our moods, impulses, appetites and motivation.

Many common diseases are caused or aggravated by too much or too little activity by one or more of the body's many messenger molecules. This is true of conditions as varied as breast cancer, Parkinson's disease and hay fever. Drugs to treat these disorders often achieve their effects by mimicking the shape of a messenger molecule and “tricking” the receptor into responding. Others block the receptor and prevent it from interacting with its usual messenger molecule. Still others affect some part of the process by which the body produces the messenger molecule and then breaks it down after it is used. For example, Prozac, Zoloft and Paxil are “serotonin reuptake inhibitors,” also referred to as SRIs or SSRIs. Normally, serotonin is pumped back into the nerve cell that released it after it is used once. These drugs interrupt that process so that more serotonin is available to reach the target receptors. Most of the serotonin-active drugs act to increase the availability or activity of serotonin in the brain.

All of this is test tube-based theory. Does it really explains what happens when the drug reaches our bodies and brains? Probably, but there is some reason to doubt. Some “weak” serotonin reuptake inhibitors are just as good at relieving depression as more powerful SRIs. An antidepressant called tianeptine used in France actually has the opposite effect of Prozac—it increases reuptake or removal of serotonin—yet is quite effective in relieving depression. Perhaps all we can say with any certainty is that these drugs “tweak” an ailing serotonin system, stimulating it to normalize its functioning. Unfortunately, the power of that tweak can also cause changes in other neurochemical systems, producing imbalances and side effects.

How Do We Know?

As you may have guessed, there is no good way to know what a chemical is doing, in real time, within the brain of a living person. Sophisticated techniques to study the brain's chemistry in action are now being used in animals, but these are too invasive to be used in human volunteers. Our current understanding of serotonin is based on animal studies, on autopsies of disease and suicide victims, and on more limited studies of human volunteers with serotonin-related conditions.

Many people are uncomfortable with animal experimentation, yet neurotransmitter research is one of the areas in which it provides invaluable help in understanding the brain and treating its disorders. Typically, rats are given a serotonin-active drug or diet, their behavior is observed, then they are killed and their brains are studied.

Autopsies of people provide important information, especially in understanding the role of serotonin in suicide and Alzheimer's disease. Clinical studies involving patients can obtain good data by analyzing the level of serotonin metabolite (its chemical breakdown product) in the spinal fluid or other “markers” of serotonin activity in the blood. Some studies give a serotonin-active treatment to volunteers, and then use verbal or written questionnaires to find out the impact on their mood or appetite. All these studies have limitations, but taken together, they provide an impressive body of evidence to show serotonin's importance to our daily functioning.

Serotonin Does Not Act Alone

We mentioned the fact that the brain puts more than one neurochemical system in charge of each aspect of mood, behavior, movement, and mental activity. Norepinephrine, also called noradrenaline, is believed to have a secondary role in setting our moods. In the brain's “wiring circuits,” the norepinephrine system seems to run fairly parallel to the serotonin system, suggesting some different and some overlapping functions. A few drugs that act mainly on the norepinephrine system are quite effective in treating depression. In the realm of mood, norepinephrine is an “activating” chemical. It is released in response to stimulants such as coffee and amphetamines, in response to stress, and in anxiety attacks. In contrast, serotonin activity is believed to promote a feeling of calm and well-being.

Serotonin's Source

Where does serotonin come from? It is synthesized in different parts of the brain and body, where it can be stored or released. The most important raw ingredient is an amino acid called tryptophan. Amino acids are the building blocks of protein, and tryptophan is found in abundance in all high-protein foods, such as dairy products, eggs, meat and fish. Vegetarians also have many good sources for tryptophan, including seeds, nuts, and a number of vegetables. When these foods are digested, their amino acids, including tryptophan, enter the bloodstream and are carried to tissues that will use them to synthesize the body's own proteins and other essential molecules, including serotonin.

Some dramatic experiments with animals and human volunteers have demonstrated how dependent we are on dietary tryptophan for our moods. Animals who are deprived of tryptophan will show noticeable behavior changes, becoming much more aggressive. In one study, healthy men were given one of two amino acid “cocktails” to drink as their meal. One mixture contained no tryptophan; the other contained tryptophan as well as other dietary amino acids. It was a double-blind “is-it-Coke-or-Pepsi” type of experiment. Neither the volunteers nor the researchers knew which cocktail was which until the study was over. The results? The men who drank the mixture without tryptophan had remarkable deteriorations in mood on that day. On the day they were given the “normal” amino acid mixture, their moods did not change in any significant way.

So will a cheeseburger make you cheerful? Should you load up on protein in order to feel better? Although it is true that tryptophan comes from protein, not from fats or carbohydrates, you actually need a well-timed carbohydrate meal or snack in order to increase the amount of tryptophan reaching your brain. How this works—and how you can use it for your benefit—will be explained later in chapter 8.

You may be wondering why people take an antidepressant drug to increase serotonin availability to the brain. Why not just take serotonin itself? The answer is that serotonin cannot pass from the bloodstream into the brain. The brain controls and limits the number of substances passing into it, somewhat like a nation that guards its borders, allowing only a certain number of “foreigners” to enter. This “border check” is called the blood-brain barrier. The blood vessels which carry oxygen and nutrients to the brain have less permeable walls than the vessels that “service” the rest of the body. This is a safety feature. If we drink, eat or inhale something toxic, our brains have a better chance of continuing to function. The brain, of course, welcomes the amino acids it needs to function, but they can pass out of the blood into the brain only very slowly and in relatively small numbers.

Serotonin in Sickness and in Health

Health is more subtle and complex than disease, and much less well understood. The list of disorders in which serotonin abnormalities are believed to be a major factor keeps expanding. It includes mania, depression, anxiety, personality disorders, suicide, impulsive acts of violence and aggression, obsessive-compulsive behavior, some types of sexual problems, alcoholism, eating disorders, sleep disturbances, and perhaps schizophrenia and Alzheimer's disease. In addition, serotonin abnormalities underlie migraine, cluster headache and other forms of chronic headache. It is also thought to contribute to some cardiovascular conditions, including Raynaud's disease and hypertension.

Because the list is so long and includes such extremes of behavior, from mild anxiety to murderous aggression, some researchers have suggested that a better way of understanding serotonin in health and disease is to focus on its normal roles in regulating mood, impulse and appetite. When serotonin functioning is thrown out of balance, the impact can be felt in any number of ways. Depending on genetics and environment, that imbalance might make itself known as migraines, bingeing, anxiety, obsessive-compulsive behavior, depression or out-of-control impulsiveness.

Mood

Low moods and low serotonin go together—a finding that has been confirmed in study after study for several decades. Most of these studies are based on patients—people who are significantly ill and have sought medical treatment. Yet all the evidence suggests that the normal role for serotonin is to balance and adjust our normal mood shifts—somewhat like the bass/treble knob on your stereo. It has a role in “habituation,” the process in which the brain learns that a particular recurring sensation is not all that important and should be ignored. When the serotonin system is functioning normally, it helps us keep a steady frame of mind in the face of all the things happening to us and around us. It helps us “tune out” the unimportant stuff and respond in a balanced way to the things that do matter.

We would like to be happy and carefree all the time, but there are times when it's appropriate to be sad, cautious or worried. Serotonin helps establish that response and our corresponding activity and impulse level. Twenty thousand years ago, it may have been appropriate to be subdued and listless all winter long, or when the weather didn't permit us to hunt or gather food. It isn't now, yet many of us still respond powerfully to season, weather and time of day. Or react too sensitively to stress and to other triggers in our over-civilized lives. Our serotonin system becomes less active in response to environmental influences, and we then get the mood-food-migraine symptoms. However, you can take counterbalance the impact of environmental factors and daily stresses on the serotonin system. Some food and lifestyle choices will depress serotonin functioning, while others will enhance it.

Motivation

Motivation is difficult to define, but we all know when we have it, or when we don't. Being “down” for any reason seems to rob us of our motivation. We know we should go out, call a friend, get busy, do something. We know that activity and exercise makes us feel better, but we can't shake the low mood and the lack of motivation. We stay in front of the tv or in bed, maybe with a carton of ice cream to comfort us.

In animals, serotonin has been shown to have an important role in initiating movement. Serotonin seems to be the “switch” regulating movement versus sensory perception. Have you ever noticed that a cat or dog will “freeze” to listen to a sound or to watch a bird or squirrel? At that moment when the animal holds still and uses its senses, serotonin activity drops. When the animal moves again, serotonin activity returns. We often think of ourselves as doing “ten things at once” but we humans also tend to freeze when we want to pay attention to something important.

An anxious person or animal often becomes hyperalert to sights and sounds, perhaps forcing their low serotonin even lower! Reduced serotonin activity could be the common link between depressed mood and the apathy, the lack of interest in moving and doing, that so often comes over us when we are low. Some people, when they are seriously depressed, will have a physical slowing of speech, movement, and responsiveness that can be quite noticeable to others around them.

Impulse Control and Aggression

On a results level, serotonin seems to have a very important role in inhibiting impulsive behavior and action. We generally think of inhibition as an undesirable trait. However, without inhibitions, we would quickly ruin relationships, lose jobs, and quite possibly land in jail! We would certainly eat and drink and act on sexual or aggressive impulses with no thought for the consequences.

Of course, none of us are born knowing how to behave ourselves. We learn to control our impulses in response to rewards and punishments handed out by parents, siblings, teachers, and playmates. Although normal impulse control is a complex, learned behavior, abnormal impulse control is now believed to be related to poor serotonin system functioning. Children and adolescents who have a history of poor impulse control—excessive aggressiveness, setting fires and antisocial behavior—have been found to have abnormally low serotonin levels. Extreme forms of impulsive or aggressive behavior—violence against others or self (suicide, self-mutilation) also show a strong link with low serotonin availability in the brain.

On an everyday, law-abiding level (no guns, knives or fists), aggression is difficult to define and quantify. We often think of it as a wholly negative quality, but in fact appropriate expression of aggression is an essential survival and success skill. Because of the difficulty of defining and studying complex character traits, it is not known whether healthy levels of aggressiveness and assertiveness are also regulated by serotonin, yet many researchers believe this is a reasonable assumption.

Appetite

On an everyday level, serotonin controls appetite. The sight, smell or expectation of food stimulates serotonin release in the hypothalamus, a part of the brain known to regulate feeding and sleep. As eating begins, serotonin continues to rise, until it registers in the hypothalamus as the experience of satisfaction or satiety. That “full” feeling in your stomach actually comes from your brain!

Even though a half-dozen other brain chemicals are known to be involved in regulating appetite and food intake, the influence of serotonin is impressive. In experiments, if you increase serotonin availability or activity you will tend to reduce food consumption. If you decrease serotonin system activity you will tend to increase food consumption.

Alcohol and nicotine cravings

Alcohol may be our oldest medicinal and recreational drug. Millions of people “self-medicate” anxiety or depression with a drink. How many old movies have you watched in which Humphry Bogart or some other poker-faced tough guy poured a few belts or got downright drunk in order to deal with fear, loss or confusion? You don't have to be “alcoholic” to have problems with alcohol. You may be drinking more than you would like, more than you consider healthy, yet find that you crave alcohol to smooth or lift your mood in the same way that other people crave chocolate or potato chips. In both cases, low serotonin availability may excite the craving. Drinking alcohol temporarily raises serotonin levels, then lowers them. As a treatment for feeling low, booze brings us even lower.

The evidence linking smoking to serotonin is more limited. The brain has specific receptors which interact with nicotine and which are responsible for the symptoms of craving and withdrawal that make quitting so difficult for smokers. It has been speculated that serotonin may make a contribution as well through its role in controlling craving and impulse. In experiments with animals, nicotine will increase serotonin activity in some parts of the brain. Also, serotonin-active treatments will decrease the frequency with which rats “give themselves” nicotine. No one has yet trained a rat to hold a cigarette and puff, but once they are given nicotine, they are hooked. They will run through a maze, work a treadmill or push a lever over and over—in effect, “walk a mile for a Camel”—to get another dose! A particular type of serotonin receptor is thought to have a role in reinforcing the stimulating and gratifying effects of stimulants such as caffeine and nicotine.

As most smokers, ex-smokers and their significant others know all too well, the toughest part of quitting is dealing with the mood and appetite changes they experience. People trying to quit cold-turkey will become very irritable, and either sudden or slow nicotine withdrawal will increase appetite and food cravings. Virtually every ex-smoker will gain a few pounds, and for many people this is the biggest deterrent to stopping. The fact that the mood-and-food symptoms of smokers attempting to quit match those of serotonin-deficient conditions suggests that nicotine does interact with the serotonin system in complex, not-fully-understood ways. If you are a smoker who would like to quit but have not been able to do so, following the dietary guidelines in Part 3 may help make your mood and food symptoms more tolerable. You should expect a short-term weight gain, however, and postpone any dieting until after you have your moods and eating habits back to normal.

Drug Abuse

If “low” serotonin makes you feel “low,” will “high” serotonin make you feel “high”? Well, in a way, yes, but it's temporary, dangerous and illegal! Several abused drugs are known to act on the serotonin system. MMDA (Ecstasy) is a very powerful serotonin-active drug. Although it may have effects on other neurochemical systems, it produces its feelings of euphoria and tranquility primarily through its action on serotonin receptors. Several hallucinogenic drugs, including LSD and psilocybin, resemble the serotonin molecule so closely that they are also believed to produce their psychedelic effects by acting on serotonin receptors.

Much evidence links serotonin abnormalities to alcoholism and other substance abuse. Substance abusers do have lower levels of serotonin activity, and serotonin-active drugs decrease alcohol and drug abuse both in humans and in rats—who are not so different from us after all! However, the degree of improvement varies greatly from individual to individual. It is thought that low serotonin may contribute to substance abuse through serotonin's effects on impulse control, food and fluid intake, and on mood. Anxiety, depression, and poor impulse control are often part of the profile and the problems underlying alcohol and drug abuse.

Heart and Blood Flow

Serotonin is found in platelets, the blood cells that clump together to close wounds, and it helps them do this important job. It also has complex roles in regulating blood flow to the brain, heart, and gastrointestinal tract. It regulates blood vessel elasticity and can act as either a vasodilator (causing vessels to expand) or a vasoconstrictor (causing vessels to narrow), depending on where and when it is released.

Because of its complex action in controlling blood flow and blood pressure, serotonin abnormalities are also thought to have a role in a number of other cardiovascular conditions, including some forms of hypertension (high blood pressure). These include peripheral vascular diseases, which are circulatory problems involving the blood vessels in the extremities, the hands and feet, and sometimes the lower legs as well. One of these, Raynaud's disease, is characterized by numbness, discoloration, and pain in the fingers or toes on exposure to cold. Although it is called a disease, it usually does not require treatment, though it can sometimes interfere with activities. Serotonin appears to be involved in some forms of hypertension (high blood pressure). Ketanserin, a serotonin-active drug that acts to lower serotonin availability, has been used to lower blood pressure.

Migraine and Other Chronic Headache

Serotonin is believed to have a major role in causing migraine headache, cluster headache, and possibly tension headache. In persons who are prone to migraine, there is a defect in a specific type of serotonin receptor that normally causes blood vessels to constrict. Because of this defect, different irritating triggers can cause vessels supplying blood to the brain to expand (dilate), putting pressure on surrounding tissues and causing pain and tenderness. Antidepressants are often, but not always effective in preventing these headaches. Some people will find that their migraines will miraculously go away if they take Prozac, while others will get the worst migraines they've ever had.

In general, low brain serotonin levels are associated with increased sensitivity to pain, and chronic pain sufferers appear to have reduced serotonin functioning. Serotonin is known to have an effect on pain awareness, in part by controlling the release of a pain-signalling brain chemical called substance P.

Gastrointestinal Effects

Serotonin causes the smooth muscle of the gut to contract when it is released by the nerves supplying the muscle. Contractions of the abdominal smooth muscles are involved in normal digestion and in nausea and vomiting. There is an important practical application for this fact. Serotonin-active drugs are being developed that will help cancer patients avoid or minimize the nausea and vomiting that are often the most unpleasant side effects of chemotherapy.

Sleep-Wake Cycle

Serotonin activity in the brainstem is highest while we are wide awake and absent during REM sleep, the period of sleep in which we are actively dreaming. During REM sleep, when serotonin function is close to nil, we are temporarily paralyzed, since serotonin is necessary for initiating voluntary muscle movement. This is an important “safety feature” provided by serotonin, since without it we would attempt to act out our dreams, hurting ourselves and possibly others. As we wake up in the morning, serotonin activity increases, providing us with “get-up-and-go,” literally and figuratively. Since sleep and mood are both regulated by serotonin, mood problems tend to bring sleep problems with them, either insomnia or hypersomnia (oversleeping). People with low serotonin have been found to spend less time in non-REM sleep, the longest part of the normal sleep cycle. Restless leg syndrome, the annoying muscle twitches and restlessness that interfere with sleep, has also been related to low serotonin functioning.

During the night, serotonin is metabolized by the brain to create melatonin, a very important neurohormone you may have read about it. Between them they regulate the sleep-wake cycle, keeping us alert during the daylight hours and allowing us to sleep at night.

Mental Functioning

During periods of depression and anxiety, people do poorly on tests of mental functioning, such as memory and concentration. These results are paralleled in experiments with animals who are given a serotonin-depleting drug or diet. It is not clear whether serotonin has a direct role in mental functioning. It may be that a decline in motivation and attention, rather than in actual mental ability, is the explanation for why low mood states and poor mental functioning seem to go together. On a practical level, it hardly matters. When our mood is depressed, so is our mental performance.

Another neurotransmitter called acetylcholine is generally believed to have the leading role in memory. However, serotonin may take the “best supporting” role nomination, with a strong secondary influence on our ability to learn and remember. Animals can still learn and use memory when given treatments that deplete either acetylcholine or serotonin levels. However, a treatment that deprives them of both neurotransmitters will result in profound loss of memory and learning skills.

Serotonin functioning decreases in old age and with Alzheimer's Disease. Autopsies have shown a drop in the number of serotonin receptors. At this point, it is believed that low serotonin functioning may be responsible for the mood and behavior problems of Alzheimer's victims, who are often anxious and depressed and may become very aggressive and impulsive in the later stages of the disease. Antidepressants have been reported effective in improving mood and behavior for these patients, potentially a very great benefit for them and for their caregivers.

Can You Have Too Much of Such a Good Thing?

If too little serotonin is linked with depression, anxiety, bulimia, bingeing, insomnia, out-of-control aggression, migraine, and alcoholism, then do you want to have as much as serotonin in your system as possible? If we are talking about natural approaches to increasing your body's serotonin's supply, then the answer is yes, if you are currently troubled, however slightly, by negative moods or bingeing. However, an overdose or combined action of serotonin-active drugs can be quite serious.

Serotonin Syndrome

Serotonin syndrome is an emergency condition caused by an overdose or accumulation of serotonin-active drugs. The symptoms include confusion, agitation, profuse sweating, high fever, and muscle rigidity. It is not easily diagnosed, particularly when the sufferer's confusion and agitation make it difficult to identify the underlying cause. Treatment involves administering fluids plus medication to control blood pressure, which is usually high. Usually the syndrome resolves within a few days, but it has been fatal in a very few cases.

Serotonin syndrome has occurred when an individual has been taken off a particular type of antidepressant known as monoamine oxidase inhibitors (MAOIs) and then started on a different antidepressant within two weeks, before the MAOI has ceased to act. Although very effective for depression and migraine, MAOIs are now rarely prescribed because they require special dietary restrictions to avoid toxic food-drug interactions. Occasionally, serotonin syndrome will occur someone who is taking multiple serotonin-active drugs for different medical conditions. The abused drug MMDA (Ecstasy) can cause serotonin syndrome at doses normally taken by abusers.

Healthy individuals taking an antidepressant at prescribed doses are not at risk, but serotonin syndrome has occurred in frail elderly persons who have been prescribed too high a dosage for their age, weight, and general health. If the dietary supplement L-tryptophan becomes available again in the future, you should not take it along with a serotonin-active drug unless your doctor advises you to do so.

Too Thin—Too Much Serotonin?

Some researchers believe that self-starvation or anorexia may be related to elevated serotonin in certain parts of the brain. Several studies have reported that anorexics have higher levels of serotonin metabolite in their spinal fluid, implying a higher level of serotonin activity, both during their fasting and purging episodes and after long-term weight restoration. Since serotonin produces a feeling of fullness or satiety after eating, individuals with higher serotonin activity might have too little appetite or feel full after eating very little. A role for some type of serotonin abnormality is likely, since sufferers are often depressed, anxious, and obsessive, which are all serotonin-associated problems.

Chemistry + Events = Mood + Behavior

It's currently fashionable to see our personalities, our diseases and our problems as more or less determined by genes and hormones. To a large extent, this is because researchers are discovering so much so fast about the chemistry of life and disease. But we should never forget that the other half of the equation—our environment, our lifestyles and our experiences—has just as great an influence. There certainly are some inherited tendencies that are absolute. Blue-eyed parents will produced blue-eyed children. If a mother or father has Huntingdon's disease, the children who inherit the gene will inevitably develop the disease. For the most part, though, our genes and our hormones only program our tendencies. Serotonin abnormalities do seem to be inherited. How they play out depends upon our daily experiences and our environment. We certainly can't control everything that happens to us. But we can choose a lifestyle that acts to stabilize and enhance serotonin functioning, so that our mood, food or migraine symptoms become much more manageable and less frequent.

Secrets of Serotonin by Carol Hart. You can now order the updated 2008 edition via Amazon or Barnes & Noble.

Excerpted from the original 1996 edition. Copyright ©1996 Lynn Sonberg Book Associates. Reprinted with permission. For private use only, not to be reprinted.

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