Increase Serotonin
With 5-HTP

erotonin (5-HT) is in the air! As we approach the 50th anniversary of its discovery next year, serotonin is finally coming into its own as a neurotransmitter.

In humans, the average adult body contains a total of only about 10 mg of 5-HT, yet over the last half century, it has become increasingly apparent that no other physiological substance possesses as many diverse actions. Like its catecholamine cousins, adrenaline, noradrenaline, and dopamine, serotonin (aka 5-hydroxytryptamine) acts throughout the body:

  • In the central nervous system (CNS), 5-HT has widespread and often profound implications, including a role in sleep, appetite, memory, learning, temperature regulation, mood, sexual behavior, cardiovascular function, muscle contraction, and endocrine regulation. Low levels of serotonin have been associated with impulsive behavior, aggression, overeating, depression, and suicide.
  • In the blood vessels, 5-HT constricts large arteries, thus playing a major role in the control of blood pressure.
  • In the intestines, 5-HT controls GI motility (movements of the stomach and intestinal musculature).
  • In the periphery, 5-HT is a major factor in platelet homeostasis.

In addition to these key functions, it appears that enhancing serotonergic activity may have implications for personality change. In his best-selling book, Listening to Prozac, psychiatrist Peter D. Kramer, MD, has argued that taking Prozac® and similar drugs may actually help some people reconfigure their personality. This assertion has opened a new population of Prozac users - those with no obvious psychiatric illness who just want to feel more confident, popular, mentally nimble, and emotionally resilient.1

The importance of 5-HT has not been lost on pharmaceutical companies or news media. In recent years, cover stories in national news magazines have repeatedly touted the virtues of Prozac and other members of the class of drugs known as selective serotonin reuptake inhibitors, or SSRIs, for their potential uses in alleviating everything from depression to heart disease. A recent article in The APA Monitor, the house organ of the American Psychological Association, asked, "Is Serotonin the Key to Treating Society's Most Heinous Ills?"2

And in an article in Drug Topics, University of Mississippi researcher Ronald F. Borne, PhD, called serotonin "The Neurotransmitter of the 90s."3 "Of the chemical neurotransmitter substances," writes Dr. Borne, "serotonin is perhaps the most implicated in the etiology or treatment of various disorders, particularly those of the central nervous system, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, stroke, obesity, pain, hypertension, vascular disorders, migraine, and nausea." Evidence suggests that every one of these disorders can be treated by either mimicking the actions of serotonin, enhancing its supply, or blocking its action.

Prozac and other SSRIs work by increasing the availability of serotonin in synapses (junctions between neurons) by blocking their reuptake (Fig. 1). You can also increase the availability of serotonin by taking supplements containing its metabolic precursors, the amino acids tryptophan and 5 hydroxy-tryptophan, (5-HTP), which increase the cell's output of serotonin. As you can see in Figure 1, nerve cells synthesize 5-HT by a two-step process that begins with tryptophan, which comes from dietary sources. Once taken up into a cell, tryptophan is converted into 5-HTP, which, in turn, is converted to serotonin.

Tryptophan supplements have a long history of use for treating depression and anxiety disorders and for enhancing sleep. Unfortunately, since 1988, the FDA has enforced regulations prohibiting the manufacture and sale of tryptophan. This has resulted in a dubious state of near total prohibition based on a single contaminated batch of the amino acid produced by a Japanese company during the late 1980s. Although serious side effects were associated with this batch, no adverse effects have ever been linked to any other batches of tryptophan. Nevertheless, the FDA has maintained its prohibition in the face of overwhelming evidence that it is not only unnecessary, but may be forcing people to take dangerous and expensive drugs to achieve the benefits they could achieve safely and inexpensively with tryptophan.

Fortunately, the FDA's prohibition does not apply to 5-HTP, the next step in serotonin metabolism. And while tryptophan prohibition may be needless and deplorable, it has had one unforeseen benefit: it has allowed us to focus on 5-HTP, which, it turns out, may be even better than tryptophan for treating suspected serotonin deficiency disorders in the brain.

5-HTP and Depression
Various behavioral and biochemical studies have shown that 5-HTP is closely involved in depressive disorders. In a French trial of 36 patients with severe depression who were treated with 5-HTP, the authors reported 28 positive results, four cases of intolerance to the treatment, and four treatment failures.4 A team of Japanese researchers gave 5-HTP to 24 patients hospitalized for depression. After 2 weeks of treatment, they observed a "marked amelioration of depressive symptoms" in seven patients with unipolar depression. The administration of 5-HTP was also found to be associated with a 30% increase in the levels of 5-HIAA, the primary metabolite of serotonin, in the patients' cerebrospinal fluid. This suggested that the exogenous 5-HTP was being converted to serotonin.5

Double-blind clinical trials that have compared the efficacy of tryptophan and 5-HTP in people with depression have found 5-HTP to be clearly superior.6 A few studies have also compared 5-HTP with standard tricyclic antidepressants (e.g., Elavil®), the most effective drugs for treating depression until the development of the SSRIs, and found 5-HTP to be at least as effective as these drugs in treating very severe depression and to have fewer side effects.7-9

5-HTP vs SSRIs
How does 5-HTP stand up against the current standard of treatment, the SSRIs? That was the important question asked in a double-blind, multicenter study by a team of Swiss and German psychiatric researchers headed by Dr. W. Pöldinger of the Psychiatrische Universitätsklinik in Basel, Switzerland.10 The subjects, all of whom were diagnosed with depression, received capsules containing either 5-HTP, 100 mg, three times a day, or fluvoxamine (an SSRI), 150 mg, three times a day. The subjects were evaluated at 0, 2, 4, and 6 weeks using standard depression rating scales. They also evaluated how they felt about themselves.

The results were startling. Both treatment groups showed a significant and nearly equal reduction in depression beginning at week 2 and continuing through week 6. After 4 weeks, the 15/36 patients treated with 5-HTP and 18/33 patients treated with fluvoxamine had improved by at least 50%, according to scores on the depression rating scales. By week 6, the two groups had about equal numbers showing 50% improvement (Fig. 2). When the numbers were totaled at the end of the study, the researchers found that the mean percentage improvement from baseline to the final assessment was actually greater for the patients treated with 5-HTP. The number of treatment failures was also higher in the fluvoxamine group (17%) than in the 5-HTP group (6%), although this difference was not statistically significant. The patients' self-assessments of how they were feeling closely paralleled the scores on the depression rating scales.

Adverse side effects from both treatments were rare and generally mild, usually occurring during the first few days of treatment and then disappearing. Overall, 5-HTP appeared to be better tolerated than the SSRI.

Relieving Anxiety
In an earlier study, ten patients diagnosed with anxiety syndromes were treated with 5-HTP. A significant reduction in anxiety was observed on three different scales designed to measure anxiety.11 In a study of 20 people with panic disorders, several experienced a feeling of "relief" after receiving 5-HTP.12

Enhancing Sleep
One of the main reasons people used to take tryptophan during the pre-prohibition days was to enhance their sleep. Serotonin seems to affect sleep, because one of its major metabolic pathways leads directly to melatonin, widely acknowledged today as the hormone that helps determine our sleep-wake cycle. By taking tryptophan or 5-HTP to increase your production of serotonin, you're also increasing your production of melatonin. While the role of tryptophan in sleep has been well-documented,13-16 only a few studies have looked at the connection between 5-HTP and sleep. French researchers found that 100 mg of 5-HTP resulted in significant improvement in people described as "mildly insomniac."17 Looking at sleep patterns in cats, a Norwegian scientist found that 5-HTP had effects on sleep that were similar to those produced by tryptophan.18

Suppressing Appetite
SSRIs are being increasingly prescribed to suppress appetite in people who want to lose weight. It appears that 5-HTP may have a similar effect. According to British researcher, J. Blundell, of the University of Leeds, of the many appetite suppressants found to be "active" in laboratory animals, very few have clinical potential. Among the most promising candidates, he argues, are those, like 5-HTP, that increase brain levels of serotonin.19

A group of Italian researchers reported that 20 obese patients taking 5 HTP (900 mg/day) lost a significant amount of weight, had lower carbohydrate intake, and consistently became sated earlier than a similar group taking a placebo. They concluded that since 5-HTP was well tolerated, it could be safely used to treat obesity.20

Preventing Migraine Headaches
Migraine headaches are closely associated with serotonergic activity. Drugs deemed most effective for halting migraine attacks (e.g., sumatriptan and dihydroergotamine) block specific serotonin receptors in the brain. SSRIs have also been effective in some people in preventing migraines. A few studies have found that 5-HTP may also be able to prevent migraines. Spanish researchers gave 5-HTP or methysergide, a long-time migraine treatment, to 124 migraineurs. They noted significant improvement in 71% of the 5-HTP-treated people and 75% of the methysergide-treated people. Among those treated with 5-HTP, improvement took the form of reduced intensity and duration of the headache with frequency remaining unchanged; in addition, 5-HTP caused far fewer side effects than methysergide. The authors suggested that 5 HTP could be a treatment of choice in migraine prophylaxis.21

A group of Italian researchers confirmed the prophylactic effect of 5-HTP in 40 patients with migraine in a double-blind study. The patients were randomized to receive either 5-HTP (400 mg/day) or placebo for 2 months. By the end of 2 months, more than 90% of the 5-HTP-treated patients responded with a reduction in headache severity, frequency and duration compared with only 16% of the placebo-treated patients.22 In another Italian study, researchers found that administering 5-HTP (5 mg/kg/day) for 3 months to children with either migraine or tension-type headaches resulted in an increase in ß-endorphin and a significant reduction in the frequency and intensity of their headaches.23

Depression & Heart Disease: The Serotonin Connection
It is becoming increasingly apparent that psychological depression is a major contributor to heart disease morbidity and mortality, on a par with more familiar risk factors, such as poor diet, lack of exercise, high blood pressure, high stress, and cigarette smoking. This finding suggests the possibility that anything you can do to minimize or eliminate serious depressive episodes, whether using antidepressants or 5-HTP, may also help reduce your risk of suffering a heart attack.

The most recent piece of evidence for this correlation was a study from the Johns Hopkins University School of Hygiene and Public Health. The findings showed that those who experienced even a single major depressive episode (e.g., at least 2 weeks of profound sadness), had a risk factor for heart attack that was more than four times higher than in those with no history of serious depression. This risk was independent of other typical risk factors for heart disease.24

Although terms like "a heavy heart," "heartbreak," "heartache," and others have long been used to describe the feelings associated with psychological depression, the link between depression and heart disease goes beyond mere metaphor. The Hopkins study was only the latest in a long line of clinical trials dating back to the mid-1970s:

  • In one 1976 study of depressed patients undergoing electroconvulsive ("shock") therapy, both suicide and MI rates were significantly higher in those who were deemed to have been inadequately treated (ie, more depressed).25
  • In a 1987 study of 50 patients undergoing coronary angiography at the Washington University School of Medicine, 18% were diagnosed with major depression.26
  • People with heart disease and depression tend to stay depressed longer, which may just worsen their cardiac condition. This connection was revealed by another Washington University study in which 200 patients undergoing diagnostic cardiac catheterization and coronary angiography also underwent a psychiatric diagnostic interview. The researchers found that 17% of the patients were in the midst of a major depressive episode, and another 17% were having a minor depressive episode. In the following 12 months, half the patients with a major depression either remained depressed or relapsed. Nearly half those with minor depression got better, but 42% subsequently became even more depressed. It was concluded that if major depression is left untreated in people with coronary heart disease, it tends to persist. Moreover, people with minor depression are nearly as likely to become seriously depressed as to get better.27
  • The same Washington University researchers reported that major depression was the best predictor of "major cardiac events" (MI, coronary artery bypass surgery, angioplasty, and death) among 52 patients followed for 12 months after cardiac catheterization.28
  • People with established coronary artery disease have a significantly poorer prognosis if they are also depressed, compared with those who are not depressed, according to a study from Duke University. The researchers studied more than 700 men and women in Denmark, all of whom were born in 1914. They received physical and psychological examinations at age 50 and again at age 60 to establish a baseline. In the ensuing years (up to 1991), 122 (17%) of the participants suffered a heart attack and a total of 290 (40%) died. Those who were seriously depressed at baseline were three times more likely to have a heart attack and to die. The researchers concluded that it was chronic depression, rather than one or more discrete depressive episodes, that was responsible for the increased incidence of heart attacks and death.29
  • People with clinical depression have a decreased ability to vary their heart rate in response to external and internal stimuli. This relative inflexibility of cardiac function may reduce their chances of surviving coronary artery disease.30
  • Anxiety and depression may increase the chances of developing high blood pressure (hypertension), according to the results of a large longitudinal study based on data from the National Health and Nutrition Examination I (NHANES-I) Epidemiologic Follow-up Study. The researchers followed 2992 people, who initially had no signs of hypertension, for 7 to 16 years. Baseline levels of anxiety and depression were assessed using standard psychological tests. At the conclusion of the study, it was clear that people who were anxious or depressed stood a greater chance of developing high blood pressure, and that this was even more of a risk for blacks than for whites.31
  • High job stress may increase your risk of an MI or stroke by making it easier for your blood to clot. Using a group of 22 Israeli accountants as subjects, researchers tested the ability of the men's blood to coagulate on numerous occasions, both during a high-stress tax season and during a more relaxing, low-stress period. Several coagulation factors were found to be significantly elevated during the high-stress season but not during the low-stress season.32

Raising Serotonin Levels
If depression is a disease of the psychological "heart," given the link between depression and cardiovascular disease, one can't help wondering whether antidepressant therapy, ranging from SSRIs to 5-HTP, might be capable of alleviating the morbidity and mortality associated with the diseases of the physical heart as well.

Such a conclusion would not be surprising, given the proposal that all the disorders that are treatable by enhancing serotonin function, ranging from depression and anxiety to migraine, obesity, insomnia, and heart disease, may all be different aspects of a broad-based serotonin deficiency syndrome (SDS).10

It is very common for some or all of the symptoms of the above disorders to cluster in a single person. How SDS manifests in a given individual may depend on other neurochemical conditions, or it may depend on their personality or other environmental factors. The most likely scenario is that some or all of these conditions and factors contribute.

References

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  14. Ouichou A, Pevet P. Implication of tryptophan in the stimulatory effect of delta-sleep-inducing peptide on indole secretion from perfused rat pineal glands. Biol Signals. 1992;1:78-87.
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  21. Titus F, Davalos A, Alom J, Codina A. 5-Hydroxytryptophan versus methysergide in the prophylaxis of migraine. Randomized clinical trial. Eur Neurol. 1986;25:327-329.
  22. De Benedittis G, Massei R. 5-HT precursors in migraine prophylaxis: A double-blind cross-over study with L-5-hydroxytryptophan versus placebo. Clin J Pain. 1986;3:123-129.
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