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Do You Have "Serotonin 

Deficiency Syndrome?"


by John Morgenthaler & Lane Lenard, PhD


Depression, anxiety, insomnia, overeating,

PMS, migraine, OCD, aggressive or violent tendencies, fibromyalgia, alcoholism, and bulimia are all associated with relatively low levels of serotonin. At the same time, treatments like tryptophan, 5-HTP, and the

SSRIs, which increase serotonin levels in the synapse, can alleviate all these disorders.


These two facts have caused some researchers,

led by Dr. Walter Pöldinger, of the Psychiatrische Universitätsklinik, in Basel, Switzerland, to conclude that these disorders may each represent a different manifestation of the same underlying disorder, which they call "serotonin deficiency syndrome." In other words, when you feel depressed, anxious, etc, you may not be suffering from "depression" or "anxiety" per se, but rather from a generalized reduction in serotonin activity. Depending on your individual physiology, you may experience this as depression, anxiety, or other symptoms. Pöldinger suggests that this syndrome can best be treated by restoring normal serotonin levels, preferably using 5-HTP.

5-HTP: The Natural Antidepressant

The scientific realization that depression is often the psychological/emotional manifestation of a biochemical imbalance has revolutionized the way we view and treat this disorder. Not only does it remove much of the stigma traditionally attached to depression -- "It's not me, it's my serotonin!" -- it has also spurred the development of treatments, from natural amino acids to high-tech pharmaceuticals to bright lights, that now allow many people with serious depression to lead normal lives.

The idea that serotonin was a crucial neurotransmitter in depression was first proposed in the mid-1970s.15 This conclusion was based partly on the observation that many people with depression had low levels of a metabolite of serotonin -- 5-hydroxyindoleacetic acid (5-HIAA) -- in the fluid that surrounds their brain and spinal cord. Low 5-HIAA suggests that the brain is not producing -- and therefore not metabolizing -- a normal amount of serotonin.

Researchers also discovered that people who had attempted suicide had abnormally low levels of 5-HIAA in their brains. This finding suggested that a serotonin deficiency may actually predispose some people to kill themselves.16-18

If low serotonin causes all these negative effects, does restoring this deficit bring you back to "normal?" The overwhelming weight of the evidence suggests that it does.

As we discussed in the previous chapter, there are two basic ways to normalize serotonergic functioning in the brain in someone with a serotonin deficiency:

   Increase the amount of serotonin nerve cells produce. This is how 

      tryptophan and 5-HTP work.


   Slow down the degradation of serotonin already produced. This is 

      how Prozac and virtually all other antidepressant pharmaceutical 

      agents work. Even St. John's wort is thought to relieve depression,

      at least partly, by blocking serotonin reuptake.

Accumulating Evidence

The evidence that 5-HTP can reduce depression has been accumulating for three decades.* In preliminary studies dating back to the late 1960s and early 1970s, 5-HTP given to seriously depressed people was reported to produce dramatic and sudden improvements.19-21 In a 1975 study from Japan,22 24 adults hospitalized with severe depression took 300 mg of 5-HTP daily for up to 2 weeks. At the conclusion of the study, seven individuals were showing "marked" improvement, and two were showing "mild" improvement. Moreover, those who responded did so quite rapidly -- in 3 to 7 days -- and continued to experience antidepressive effects for several weeks after they stopped taking the 5-HTP.

* (This clinical literature is largely unknown among US physicians, because most of it has been carried out in Europe or Japan, and much of it, especially the early studies, was not published in English language journals.)

Although improvement by about one-third of the patients may not seem all that impressive on its face, we need to consider three important qualifications of these results: first, the patients were all severely depressed, thus stacking the deck against any potential treatment. Second, even the best antidepressants generally have only about a 60 to 80% response rate. Third, this was a test of a single dose for a fixed -- and relatively short -- period of time. It is possible that some people may require higher doses and treatment for longer periods of time. It is typical for people taking SSRIs and other antidepressant drugs to require at least 2 to 3 weeks before feeling their full effect. The fact that nine patients taking 5-HTP showed noticeable improvement within only 3 to 7 days is actually quite remarkable.

Various other small studies compared 5-HTP with placebo or other active substances thought to have antidepressant activity (eg, tryptophan, imipramine, l-deprenyl). In a review of all the early clinical studies, one author concluded that 5-HTP has definite antidepressant properties that are comparable to other available drugs (the SSRIs were not yet available) and was associated with fewer adverse effects.23

Since many of these early studies included relatively few subjects or lacked some important controls, it is impossible to draw firm conclusions from them. Thus, these results should be considered suggestive, but far from conclusive. A more recent, well-controlled, comparative study puts 5-HTP treatment for depression on far firmer footing, showing it to be equal to or better than a state-of-the-art SSRI.

The Key Comparative Study

This important study -- a head-to-head comparison of 5-HTP and the SSRI drug Luvox7 (fluvoxamine) -- was conducted by a team of researchers headed by Dr. Walter Pöldinger of the Psychiatrische Universitätsklinik, Bern, Switzerland, and the results were published in 1991.10 The investigators gave 69 depressed patients either 5-HTP or fluvoxamine; treatment lasted 6 weeks. The researchers employed a double-blind design, so that neither the patients nor the researchers knew which treatment a given patient was getting until the study was over. The patients' degree of depression was assessed objectively using standard depression rating scales (Hamilton Rating Scale for Depression, HRSD), as well as the more subjective global impressions of investigators and the patients themselves.

As shown in Figure 3, both the 5-HTP- and the fluvoxamine-treated patients showed a highly statistically significant reduction in depression scores that gradually increased at 2, 4, and 6 weeks. By week 6, 22/34 (65%) 5-HTP-treated patients had improved by more than 50%, compared with 21/29 (72%) of the patients in the fluvoxamine group, but this difference was not statistically significant.

Overall, there was virtually no difference between the two groups in terms of antidepressive effect, although a closer examination of the data suggested a slight advantage for 5-HTP. The patients= and investigators= evaluations of the degree of depression generally paralleled those of the objective tests. There were more treatment failures in the fluvoxamine group than in the 5-HTP group (17.2% vs 5.9%), but again, this difference was not statistically significant.

For both groups, the most common adverse effects encountered were gastrointestinal in nature, including nausea, heartburn, stomach discomfort, constipation, and reduced appetite. Most of these occurred within the first few days of treatment.

Although the two treatments differed little in terms of relative tolerance or safety, 5-HTP again appeared to come out looking slightly better. Fourteen patients in the 5-HTP group (39%) reported a total of 43 adverse events, compared with 18 patients (54%) in the fluvoxamine group, who reported a total of 50 adverse events (Fig. 4). For four of these fluvoxamine patients, the adverse effects were so bad they had to drop out of the study. Only one 5-HTP patient dropped out.

While none of these differences was statistically significant, one difference was highly significant. The adverse effects associated with 5-HTP were significantly milder (Fig. 5).

To sum up the two major results of this important clinical trial:

   5-HTP and fluvoxamine were equally effective in relieving 



   5-HTP was superior to fluvoxamine in terms of tolerance and

      safety, because 5-HTP was associated with fewer adverse side

      effects that were also significantly less severe, compared with

      those caused by the SSRI.

Patentability and Promotion

If 5-HTP is such a good antidepressant, why have most physicians never heard of it, while the use of SSRIs continues to explode? Dr. Pöldinger and his colleagues wondered why as well. "With all due deference to scientific scepticism," they wrote, "the reluctance by some authors of recent textbooks on the subject and by others to concede 5-HTP its place among acknowledged pharmacotherapeutics routinely applied against depression does not seem warranted, neither on empirical nor theoretical grounds."10

The reason 5-HTP has been largely ignored by most conventional physicians can be summed up in one word -- patentability. Like all commercial drugs, SSRIs are patented compounds that can be marketed exclusively by the companies that own the patent. This gives them an sole right to market the drug until the patent expires, usually after 17 years. Exclusivity offers pharmaceutical companies a huge financial incentive to develop patentable products, and it justifies the enormous expenditures required to gain FDA approval for the product. Once the patent expires, though, anyone can market the product generically. The added competition inevitably forces prices, and consequently profit margins, straight down.

As a naturally occurring substance -- like water, table salt, or vitamin E -- 5-HTP cannot be patented. Anyone can market 5-HTP, just as anyone can market vitamins or generic drugs, provided the product meets accepted standards of quality and purity.

With no guarantee of exclusivity, it is rare for a pharmaceutical company to absorb the hundreds of millions of dollars in development costs involved in years of laboratory and clinical trials, not to mention millions more for promotion once the product is "launched.' When faced with a natural product such as 5-HTP, a pharmaceutical company's typical response is to study how it works and then try to create/synthesize a brand new -- and patentable -- molecule that does approximately the same thing. It matters little whether the synthetic product is as good as or as safe as the natural one. The only relevant conditions, as far as FDA is concerned, are that the new product is significantly better than an inactive placebo and that it does not present an unacceptable risk to the patient. This is an unfortunate fact of life in the pharmaceutical industry, and we cannot blame pharmaceutical companies for acting this way. Given the way patent laws and FDA drug regulations are written, this is the only way they can maximize profits.

One unfortunate consequence of this system is that safe, effective, natural products such as 5-HTP are rarely evaluated in the large, well-controlled clinical trials required to gain acceptance by the medical/government regulatory establishment. The fact that drugs are always evaluated this way makes it easy to dismiss 5-HTP or other such products as having "insufficient" support to recommend their use, compared with the Prozacs of the world.

In light of these facts, the only conclusion we can usually draw about whether the drugs are actually better than the natural products is, "We don't know," because the relevant comparative studies are almost never done. Pöldinger's comparison of 5-HTP and fluvoxamine was indeed a rare event in pharmaceutical research.

With the deck stacked against 5-HTP, it should come as no surprise that few physicians have ever heard of it, and fewer still are willing to recommend it. Nevertheless, Pöldinger's results demonstrate that 5-HTP may be every bit as good as the SSRIs and probably safer and more tolerable. Although it would certainly be useful to confirm these results in a large-scale US clinical trial, given 5-HTP's "generic" nature, the enormous costs of such a trial make it highly unlikely that anyone will ever run one.  


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