By Lane Lenard, Ph.D.
obert Louis Stevenson's The Strange Case of Dr. Jekyll and Mr. Hyde has long been viewed as a dissection of the Good and Evil that can exist within a single human being. As the well-known story goes, Jekyll ingests his formula and is temporarily transformed from a conservative, well-respected English physician into a vain, uninhibited, terrifyingly violent criminal. Not only has Jekyll and Hyde stood the test of time as a morality tale, studies in brain chemistry and behavior more than a century later have shown Stevenson to have had remarkable prescience regarding the role of the neurotransmitter serotonin.
Of course, Jekyll's formula was simply a fictional plot device. Other than somehow releasing some of man's baser instincts, Stevenson could have had no idea what was actually going on neurochemically.
But the 100+ years of research on brain chemistry since Stevenson wrote his Victorian classic have revealed that anything that interferes with the actions of serotonin in the brain can bring about a syndrome that resembles Jekyll's transformation to Hyde. While certainly less dramatic than the transformation described by Stevenson, serotonin deficiency bears a striking resemblance in various manifestations as an increased tendency toward anxiety, depression, out-of-control disinhibition, and violence. Conversely, enhancing the activity of the serotonin system may have exactly the opposite effects in many people. Given our current knowledge of neurochemistry, there can be little doubt that if Stevenson were writing today, Jekyll's transforming formula would have been a potent anti-serotonergic agent.
Dr. Jekyll was initially trying to prove a philosophical point when he took this potion. It's hard to imagine anyone today knowingly taking such a potion, and yet, millions of people do things every day - many of them loudly and frequently endorsed by the general medical community, the Food and Drug Administration (FDA), and many other "experts" - that significantly reduce the brain's serotonergic function. The consequences of their behavior, including increased risk of depression, anxiety, alcoholism, suicide, and violent death, are only now coming to be recognized.
Among the best studied of these Jekyll-and-Hyde-like "potions" are the cholesterol-lowering drugs (e.g., Lopid, Questran, Lescol, Mevacor, Zocor, Pravachol) and the appetite-suppressors fenfluramine (the "fen" of fen-phen fame) and dexfenfluramine (the best-selling Redux). Fenfluramine (trade names, Pondimin and Ionamin) and Redux both act by depleting serotonin and may permanently destroy serotonergic neurons in the brain. Even weight-loss diets that are extremely low in fat have also been noted to cause Hyde-like behavior patterns in some people. Mortality associated with violence (suicides and injuries) has been observed to increase following the use of cholesterol-lowering drugs.1 In another study, patients with low cholesterol showed hypersensitivity to detecting anger and sadness in themselves.2 Apparently, these too result in reduced serotonin, although usually without the permanent damage caused by fenfluramine and Redux. Both of these drugs have recently been removed from the market, in part, because of their potent anti-serotonergic effects.
Serotonin, or 5-hydroxytryptamine (5-HT), was first isolated from blood exactly 50 years ago and was later identified as a neurotransmitter in the central nervous system (CNS). As a neurotransmitter, serotonin possesses a range of effects unmatched by any similar substance. Like its catecholamine cousins, adrenaline, noradrenaline, and dopamine, serotonin acts all over the body:3
Nerve cells synthesize 5-HT by a two-step process that begins with the essential amino acid tryptophan, which must come from dietary sources. Once taken up into a nerve cell, tryptophan is converted into 5-hydroxytryptophan (5-HTP) with the help of the enzyme tryptophan hydroxylase (TPH). 5-HTP is converted in turn to 5-HT (serotonin). Studies show that taking supplements of tryptophan or 5-HTP will increase the amount of serotonin available for use by neurons.5 (Note: Chronic stress, with its concomitant increases in cortisol, can inhibit the conversion of dietary tryptophan to 5-HTP, but not 5-HTP to 5-HT. This suggests an advantage of using 5-HTP instead of tryptophan for relieving problems associated with stress.)
The first hints that serotonin played an important role in regulating aggressive behaviors came in the mid-1970s when researchers doing postmortem examinations on suicide victims noticed that these people had reduced levels of a major metabolite of serotonin called 5-hydroxyindoleacetic acid (5-HIAA) in their cerebrospinal fluid.6 Subsequent studies found lower levels of 5-HIAA in people who had attempted suicide, had severe depression, or had shown tendencies to harm themselves or others.7
CROSS-SPECIES AGGRESSION CONTROL
Serotonin's influence over aggressive tendencies goes way back in the evolution of life. Studies over a wide range of species, from crustaceans to fish to lizards to hamsters to mice to dogs to nonhuman primates to human beings, have all demonstrated essentially the same results: reducing serotonergic activity leads to increases in aggressive behavior, and enhancing serotonergic function decreases aggressive behavior.7-13
This relationship can have some interesting ramifications. For example, animals that have been selected for domesticity (i.e., reduced aggression) may have higher brain levels of serotonin than their wild counterparts. Russian researchers studying silver foxes, for example, found that those selected for more than 30 years for tame behavior and no defensive reactions to humans had higher levels of both serotonin and 5-HIAA in various regions of the brain, compared with wild silver foxes bred in captivity. They also found higher levels of tryptophan hydroxylase (TPH, the primary enzyme involved in the production of serotonin) and lower levels of monoamine oxidase (MAO, the enzyme that removes serotonin from the synapse) in the domesticated animals.14
So sensitive is this serotonergic system that natural variations in serotonin levels among animals on a normal diet can affect their behavior in profound ways, possibly even spelling the difference between life and death. A team of researchers from the National Institute of Alcohol Abuse and Alcoholism (NIAAA) has been studying a colony of free-ranging rhesus monkeys living on a 475-acre sea island. Among their most important findings: those monkeys with the lowest CSF levels of 5-HIAA (indicating low serotonin) stand the greatest chance of getting injured and/or dying young.15
The NIAAA researchers first took blood and CSF samples from 49 2-year-old male rhesus monkeys and then set them free on the island. Over the next 4 years, they closely and systematically observed the animals' behavior, paying particular attention to aggressive interactions. At the end of 4 years, six of the monkeys were dead, and five others were missing and presumed dead.
In retrospect, the animals' fate could have been predicted by their CSF 5-HIAA at age 2. Not a single monkey from the highest CSF 5-HIAA concentration quartile died or went missing. By contrast, 46% of the dead or missing came from the low end of the 5-HIAA concentration spectrum, with all but one coming from the two bottom quartiles.
The authors also observed that the monkeys that turned up dead or missing were the ones most likely to initiate or escalate aggressive encounters. Not surprisingly, these aggressive animals stood the greatest risk of suffering trauma or injury. Of the six animals whose death could be ascertained, four had died as a result of injuries sustained in a fight, and all four had had among the lowest levels of 5-HIAA at age 2.
More subtle variations in social behavior have also been related to serotonin levels.16Among 26 adolescent male rhesus monkeys from the same island colony, for example, those with the highest levels of CSF 5-HIAA concentration were seen spending more time grooming other group members and staying in close proximity to others. Those with the lowest levels of CSF 5-HIAA were more likely to leave their social groups at a younger age, an indication of lower social competence. Low CSF 5-HIAA animals were also observed to take greater physical risks, including longer leaps in the trees at greater heights. The authors suggested that this behavior indicated impaired impulse control.15
The drug parachlorophenylalanine (pCPA) inhibits serotonin synthesis, reducing the availability of serotonin in the brain. When pCPA is given to vervet monkeys, it makes them irritable and aggressive. When these same animals are then treated with the selective serotonin reuptake inhibitor (SSRI) Prozac or the serotonin precursor 5-hydroxytryptophan (5-HTP), both of which increase the availability of serotonin in brain synapses, there is no increase in aggressiveness.16
Since the body normally synthesizes serotonin from dietary tryptophan, altering the diet can also change behavior. For example, animals placed on a tryptophan-free diet, leading to reduced serotonin levels, have greater aggressive tendencies, especially during competitive social interactions like feeding.16
When it comes to the need for serotonin, human beings appear to be no different than their cousins in the swamp. Feed us too little tryptophan and we can become impulsive, depressive, aggressive, and violent. Feed us enough tryptophan or 5-HTP and these traits diminish or disappear.
In one study, human subjects ingested an amino acid beverage that was devoid of tryptophan. This "unbalanced" mixture not only deprives the body of new tryptophan for making serotonin, it also interferes with the body's utilization of the tryptophan already in the brain. Within 5 or 6 hours after taking this formulation, subjects were found to have an 80% or more drop in plasma tryptophan levels and a concomitant "lowering" of mood.19
Researchers at the University of Texas, Houston Health Science Center gave this low-tryptophan formula (25 gm or 100 gm) to 10 healthy men in a controlled laboratory setting following a 24-hr low-tryptophan diet. They then observed the men's behavior and noted any aggressive tendencies. The men taking the 100-gm formula (lower tryptophan) showed a significant increase in aggressive responding (compared with baseline) within only 5 hours. The 25-gm formula took 6 hours to produce the same effect.20
VIOLENCE: INNER- AND OUTER-DIRECTED
Researchers have found that violence related to low serotonin can be either inner- or outer-directed. A group of Danish scientists measured 5-HIAA and other serotonin metabolites in the CSF of 16 men convicted of criminal homicide, 22 men who attempted suicide and 39 healthy male controls. The lowest levels of 5-HIAA were found in those men who had killed a sexual partner or had attempted suicide.21
Investigators at Columbia University evaluated personality variables and CSF 5-HIAA levels in 26 patients considered to be "self-mutilators."22 In addition to serotonergic dysfunction indicated by lower 5-HIAA levels, compared with controls, self-mutilators were found to have significantly more severe character pathology and greater lifetime aggression; they were more antisocial, and had greater impulsivity, chronic anger, and somatic anxiety.
Suicide, the ultimate expression of "auto-aggression," has long been linked to low serotonin levels. In one meta-analysis, five out of seven studies reported reduced levels of serotonin and/or 5-HIAA in the brain stems of suicide victims. Reduced brain levels were also seen in those who had attempted suicide but failed.23
As one might expect, drugs that interfere with serotonergic function can increase aggressive behavior. British scientists gave 35 healthy subjects dexfenfluramine (better known as the recently departed diet drug Redux), which is known to deplete serotonin (sometimes permanently). Using a questionnaire to assess the subjects' hostility and aggression, they found that dexfenfluramine treatment in male subjects (but not females) was associated with an increase in hostility and aggression scores.23
CHOLESTEROL AND VIOLENT DEATH
One of the more puzzling findings of recent years has been an increase in depression, suicide and violent death among people taking cholesterol-lowering drugs or on severely cholesterol-restricted diets.24-29 In other words, taking these widely recommended steps to reduce your risk of death from coronary heart disease and stroke may place you at greater risk of serious depression, suicide, or death due to violence.
How can this be? Although the exact relationships have yet to be worked out, it appears that the missing link between low cholesterol and violent death may be serotonin. This association was demonstrated most clearly in a study of juvenile cynomolgus monkeys fed a diet high in fat and either high or low in cholesterol. The animals were then observed for 8 months.
The researchers found that animals on the low-cholesterol diet were more aggressive, less affiliative, and had significantly lower CSF 5-HIAA levels compared with those on the high-cholesterol diet. "These monkeys went at it hammer and tong," says Jay Kaplan, Ph.D., who led the study. "They engaged in more contact aggression - highly charged impulsive fighting - than the other monkeys.30 Kaplan believes that people on low-cholesterol diets may be experiencing the same kind of impulsive aggression.
Kaplan raises the heretical question, "Can low-fat, low-cholesterol diets actually do some people more harm than good?" "For people who already have low serotonergic activity, a low-cholesterol diet might shove them across some threshold that makes them more likely to do things they might not otherwise do," he said.31
The precise mechanism linking cholesterol, serotonin, and aggressive behavior has yet to be elaborated, although a few hypotheses have been put forward. One hypothesis emphasizes cholesterol's role as a major component of brain cell membranes. Reducing cholesterol to too low a level may affect the fluidity and viscosity of these membranes, which contain the receptors for serotonin.29
According to another hypothesis, low cholesterol may be accompanied by a decrease in serum-free tryptophan, which results in a decrease in serotonin synthesis.To test this hypothesis, a group of Dutch researchers compared serotonin metabolism in subjects whose serum cholesterol was chronically low with another group whose cholesterol levels were normal. They found that plasma serotonin levels were 21.3% lower in the low-cholesterol group, suggesting a disruption of serotonin metabolism.32
SEROTONIN, ALCOHOL & AGGRESSION
The relationship between alcohol, depression, and violence is well-known. A high proportion of suicide victims are found to have been drinking heavily at the time of their death. Similarly, perpetrators (and victims!) of violent crimes are often intoxicated at the time of the crime.33
In animal studies, some drugs that decrease serotonin activity increase alcohol consumption. But when animals are given serotonin, tryptophan, 5-HTP, or an SSRI, their alcohol consumption drops. Rats that have been bred to prefer drinking alcohol to water have been found to have reduced serotonin activity compared with normal rats.34
Human studies have consistently demonstrated reduced alcohol intake among various groups, including social drinkers and alcohol-dependent males, taking SSRIs.34Alcoholics have also been shown to have reduced serotonin function activity as indicated by low levels of 5-HIAA.35,36
Chronic alcohol use actually appears to increase serotonin concentration in the CSF and to facilitate serotonin activity. However, as soon as drinking stops, serotonin levels drop concurrently with the appearance of alcohol withdrawal symptoms. It is thought that the decrease in serotonin associated with withdrawal may contribute to the craving for alcohol that occurs during this period. If abstinence is maintained, serotonin levels gradually return to normal.34
(This seems to suggest that, if you're going to have a drink, take a 5-HTP capsule with it, or in advance, or on a regular basis. Although informal studies have been done to test this hypothesis, you may find yourself less likely to want a second (or third) drink. And you might have fewer withdrawal symptoms and hangovers.)
There's little doubt, though, that low serotonin activity combined with high alcohol intake is a dangerous combination. Finnish researchers have found that brain serotonin turnover is low among alcoholic, impulsive, habitually violent offenders. Not only does low serotonin seem to predispose people to alcoholism, it may also make them more aggressive, violent, and suicidal. The risk of violence or other antisocial behavior may be compounded in men whose testosterone levels are high.37,38
How does serotonin modulate these responses? Researchers Robert O. Pihl and colleagues at McGill University speculate that serotonin modifies the response to threat. In people with normal serotonin function, anxiety (the emotional response to threat) inhibits socially inappropriate responses, such as aggression. In people with depleted serotonin, however, anxiety loses its inhibitory effect while retaining its emotional intensity. As a result of this imbalance, a person might become aggressive despite the intense anxiety induced by the threat of punishment.34
Pihl et al state that people with low serotonin are likely "to appear depressed and aggressive, more driven by appetites (more motivated by food, water, sex, and drugs of abuse), and more impulsive (less able to control behavior) in the face of threat." They may also be more likely to use aggression to achieve rewards or deter punishment, and they may be less sensitive to social control of such behavior. Specifically with regard to alcohol, decreased serotonin may lead to an inability to terminate drinking once started. And if a person with low serotonin starts drinking, the result is likely to be an increase in aggressive behavior. "The combination of impulsivity [due to low serotonin] with alcohol-induced fearlessness and hyperactivity appears prone to produce aggressive acts or to culminate in victimization," the authors write.34
REVERSING SEROTONIN DEFICIENCY
If low serotonergic function can lead to aggressive and violent behavior, can reversing a serotonin deficiency restore more normal behavior? Although this area has not been studied systematically, some evidence suggests that it may. Serotonergic function can be enhanced in two basic ways: by providing the metabolic precursors for serotonin or by preventing the inactivation of serotonin that is released into the synapse.
Increasing serotonin synthesis. When taken up into neurons, the amino acids tryptophan and 5-HTP are converted into serotonin. Most studies with these amino acid precursors have involved people with depression, but the results are encouraging, particularly for 5-HTP. In one double-blind study, 5-HTP was found to be equal to an SSRI antidepressant drug in alleviating depression with fewer and less severe adverse effects. In addition to alleviating depression, 5-HTP seems to be capable of alleviating a wide range of symptoms of what Pöldinger has called the "serotonin deficiency syndrome," which includes depression, anxiety, aggression, sleep disturbances, obsessive-compulsive traits, and other behavioral manifestations.5
In another double-blind study, researchers gave tryptophan or placebo to a group of aggressive psychiatric inpatients. Injections of antipsychotics and other medications were also given, as needed, to control violent behavior. Although tryptophan treatment had no effect on the number of violent incidents, it significantly reduced the need for injections of antipsychotic and sedative drugs.39
Inhibiting serotonin inactivation. Serotonin released into the synaptic cleft is normally inactivated by either being taken back up into the neuron that released it (reuptake) or metabolized by the enzyme monoamine oxidase (MAO). Drugs that inhibit this inactivation, including the selective serotonin reuptake inhibitors (SSRIs) like Prozac (fluoxetine) and others and, to a lesser degree, MAO inhibitors, have been shown to be effective antidepressants.
A few studies suggest that SSRIs may also be able to control aggressive or violent behavior. In one study in dogs, for example, fluoxetine was found to be effective in managing dominance aggression.40 In humans, preliminary data suggest that fluoxetine may also decrease aggressive behavior and feelings of anger or hostility.41 In adult male lizards (Anolis carolinensis), fluoxetine injections significantly reduced aggressive responding in males.12
TOWARD A BETTER WORLD
Dr. Jekyll's formula dramatically exposed mankind's darker side. With the benefit of a century of neurobiological research, we can only marvel at Stevenson's insights, not only into the human character, but also into its biochemical basis. While he in all likelihood had no concept of serotonergic mechanisms, he described with astonishing accuracy the behavioral effects of serotonin depletion.
It's probably safe to say that the world would be a better, safer, happier place if everyone's serotonergic functioning could be maintained at optimal levels. Scientific evidence confirms that preventing or restoring serotonin depletion results in decreased depression, alcoholism, aggression, violence, appetite disorders, sleeping disorders, migraine headaches, and many other benefits.
While this is not to say that tryptophan or 5-HTP should be added to the drinking water, the growing body of literature on the adverse effects of reduced serotonin function, including those caused by medically sanctioned practices such as following a low-cholesterol diet, taking cholesterol-reducing drugs or serotonin-depleting drugs (e.g., fenfluramine and Redux) should turn our thoughts to serious consideration of the benefits of precursor dietary supplementation. The proven and potential benefits of enhancing serotonergic function, especially by taking serotonin precursors such as 5-HTP or tryptophan [should the latter ever become available again] are enough to allow us to visualize the day when the Hydes are permanently disabled and the good Dr. Jekylls are empowered.