Depression

In the first half of 1997, three of the top 10 prescription drugs sold in the United States were Prozac and its chemical cousins, Zoloft and Paxil. In just 6-months, these three drugs combined brought in more than $1.6 billion to their respective pharmaceutical companies.

Prozac burst upon the scene in the late 1980’s as a major advance in the treatment of clinical depression. In the subsequent decades, researchers, physicians, and patients have discovered that many other common conditions – sometimes debilitating, but always difficult to treat – seem to respond to treatment with Prozac or one of its relatives. Scientific evidence suggests that these drugs may be effective for treating:

  • Depression
  • Anxiety Disorders
  • Obesity
  • Insomnia
  • Premenstrual syndrome (PMS)
  • Migraine
  • Obsessive-compulsive disorder (OCD)
  • Aggressive or violent tendencies
  • Fibromyalgia
  • Alcoholism

There is even reason to believe that these drugs may offer important benefits for some people who are not suffering from any recognized clinical condition, but who simply want to improve their personality

For all their benefits, though, these drugs have some important drawbacks, not the least of which is a disturbing loss of sexual desire and/or nausea and vomiting in as much as 30 to 40% of users. These and other unpleasant side effects, not to mention their high cost, have led many people to search for alternatives 

In this article, we are going to tell you about a remarkable natural alternative to Prozac and similar drugs. It is an amino acid named 5-hydroxy-tryptophan, or 5-HTP, for short. A growing base of scientific evidence, collected from studies conducted both in animals and people, suggests that 5-HTP does everything the drugs do, but with fewer adverse effects.

One reason 5-HTP and Prozac-like drugs have such similar effects is that they each act on the same chemical in the brain – a neurotransmitter called serotonin. A reduction in brain levels of serotonin is now widely believed to be an important factor in the development of all the conditions mentioned above.

The general effect of both 5-HTP and Prozac-like drugs is to increase the availability of serotonin at specific sites in the brain, known as “serotonin receptors.” Increasing the availability of serotonin at these receptors – by a variety of means – has generally been associated with alleviation of these disorders.

It wasn’t long before the mystery was solved. Beginning as early as 1990, numerous independent investigators began reporting the results of studies pointing strongly in the direction of a contaminant in the tryptophan produced by a single manufacturer, a Japanese company named Showa Denko. Showa Denko had altered the time-honored fermentation recipe for making tryptophan by introducing a new, untested strain of genetically altered bacteria. It turned out that virtually all the individuals who had become ill had been using the Showa Denko product.

Despite incontrovertible evidence that uncontaminated tryptophan produced by conventional fermentation methods does not cause EMS, the FDA’s tryptophan prohibition remains in force in the United States

The FDA’s tryptophan ban has had one unforeseen benefit, however. It has forced tryptophan users to look elsewhere for a means of enhancing their serotonergic function. Although many turned to SSRI’s, others have been giving 5-HTP a closer look. 5-HTP had been studied by scientists for many years, but it was not in widespread use by ordinary people, largely because tryptophan was more widely available, its effects were better-documented, and it was less costly to produce.

With tryptophan embargoed in the US, production of 5-HTP became viable. This has been a fortuitous development, because 5-HTP now actually appears to be even more effective than tryptophan in many important ways, especially for relief of depression. At the same time, according to the results of a rare head-to-head study, 5-HTP was found to be equally effective to an SSRI drug (fluoxamine) for relieving depression, while causing fewer unpleasant side effects.

Is 5-HTP the same as tryptophan?

No, although they are closely related amino acids. In fact, 5-HTP is a metabolite of tryptophan. This means that nerve cells use tryptophan to make 5-HTP. Brain researchers refer to tryptophan as a precursor of 5-HTP. 5-HTP, in turn, is a precursor of serotonin. In other words, in order to make serotonin, nerve cells take some tryptophan, which normally comes from the diet, turn it into 5-HTP and then turn the 5-HTP into serotonin.

Just as you can enhance your available serotonin by ingesting more tryptophan, you can also increase your serotonin supply by ingesting supplements containing the next amino acid in the metabolic chain – 5-HTP – and let the brain finish the job of making serotonin.

As a means of enhancing serotonergic activity, supplemental 5-HTP appears to have several advantages over tryptopha

  • 5-HTP is probably a more effective antidepressant than tryptophan.
  • Anxiety Disorders
  • A given molecule of 5-HTP is more likely to be converted to serotonin, compared with a given molecule of tryptophan; the body can convert tryptophan to any one of several other substances, in addition to 5-HTP. This suggests that a given dose of 5-HTP is more likely to be converted to serotonin than a given dose of tryptophan, and might also cause fewer unwanted side effects.
  • 5-HTP easily crosses the blood-brain barrier and therefore gets into the brain far more readily than does tryptophan. Tryptophan molecules that do not pass into the brain may increase serotonergic activity in other parts of the body, such as the gastrointestinal tract, which may result in unwanted side effects.

So why not just ingest serotonin?>

This seemingly logical solution turns out not to work, because serotonin has an even harder time getting into the brain than does tryptophan. Most of the serotonin found in the brain is produced here

The 5-HTP and tryptophan used in supplements are also produced in very different ways. As noted earlier, tryptophan is synthesized in a laboratory by a fermentation process, not unlike that used to make beer or wine. 5-HTP occurs naturally in the seeds of a West African medicinal plant called Griffonia simplicifolia. Production basically involves extracting the 5-HTP from these seeds.

Why is Serotonin so important?

Serotonin was first identified 50-years ago, and ever since scientists have been finding more functions for this ubiquitous substance. Even though the body contains only a tiny amount of serotonin (about 10 mg) at any one time, it is clear that serotonin plays an important role in many different bodily functions

iven these widespread functions, it is not hard to understand why, if the serotonin system goes awry, there could be profound changes in the way we feel, think, and act.

For the most part, reduced serotonin activity in the brain results in conditions such as insomnia, depression, anxiety, increased appetite, loss of impulse control, increased aggressiveness, and others. To the extent that they help bring serotonin activity back into normal balance, 5-HTP, as well as Prozac and other drugs, can be extremely effective in restoring normal behavior, feelings, and thought processes.

5-HTP and Prozac et al each enhance serotonergic activity in different ways. How they differ may help explain why 5-HTP is superior. To understand the differences, we need to take a look at the unimaginably tiny space where two neurons meet, ground zero for neurotransmitter activity. This space is known as the synapse.

Prozac and 5-HTP differ markedly in the way they enhance secotonergic function. Whereas 5-HTP provides the raw materials for the body to make new serotonin, Prozac and other SSRI drugs interfere with the normal metabolism of serotonin in the synapse, preventing excess serotonin molecules from being naturally deactivated. Either way, the amount of serotonin available to stimulate serotonin receptor sites increases.

Who we are, how we feel, what we do, how our bodies function: these arise out of the sum total of billions of neuroelectrical micro-events involving the actions and interactions of relatively few molecules of serotonin and other neurotransmitters within the cramped confines of a few billion synapses.

Under normal conditions, the brain is well equipped to handle the infinite complexity of neurochemical events that accompanies the events of daily living. Alter their natural flow and balance, though, and things can start to change very quickly. Reductions from normal serotonin levels in the brain or an imbalance between serotonin and other neurotransmitters can cause symptoms ranging from mild anxiety and depression to overeating, alcoholism, aggressive behavior, hallucinations, delusions, paranoia, and suicide

Researchers at the University of Texas Houston Health Science Center found that reducing serotonin levels can have a rapid and profound effect on human behavior. They gave a serotonin-lowering dietary formulation (doses of 25 gm or 100 gm) to 10 healthy men in a controlled laboratory setting following 24 hours on a low-tryptophan diet. This regimen had previously been shown to significantly reduce serotonin levels in the brain. The men taking the 100-gm formula (resulting in lower serotonin) showed a significant increase in aggressive behavior (compared with their baselines). This behavior change occurred within only 5-hours of ingesting the serotonin-lowering formula. The 25-gm dose took 6 hours to produce the same effect.

As we shall discuss in the sections that follow, replenishing serotonin y supplying additional 5-HTP has been shown to have a wide variety of beneficial effects, the best-documented of which is relief of depression.

Do you have “Serotonin Deficiency Syndrome?”

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 SSRI’s, which increase serotonin levels in the synapse, can alleviate all these disorders.

These two facts have caused some researchers, led by Dr. Walter Poldinger, of the Psychiatrische Universitatsklinik, 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. Poldinger 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 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 serotoninwas a crucial neurotransmitter in depression was first proposed in the mid-1970’s. 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 signifies that the brain is not producing 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.

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 previously, there are two basic ways to normalize serotonergic functioning in the brain in someone with 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 most other antidepressant pharmaceutical agents work. Even St. John’s wort is thought to relieve depression, at least partly, by blocking serotonin reuptake.

The evidence that 5-HTP can reduce depression has been accumulating for three decades. In preliminary studies dating back to the late 1960’s and early 1970’s, 5-HTP given to seriously depressed people was reported to produce dramatic and sudden improvements. In a 1975 study from Japan, 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.

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 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/or treatment for longer periods of time. It is typical for people taking SSRI’s 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 (e.g. 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 SSRI’s were not yet available) and was associated with fewer adverse effects.

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

This important study – a head-to-head comparison of 5-HTP and the SSRI drug Luvox (fluvoxamine) – was conducted by a team of researchers led by Dr. Walter Poldinger, and the results were published in 1991. 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.

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

  • 5-HTP and fluvoxamine were equally effective in relieving depression
  • 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 SSRI’s continues to explode? Dr. Poldinger and his colleagues wondered why as well.

The reason 5-HTP has been largely ignored by most conventional physicians can be summed up in one word – patentability. Like all commercial drugs, SSRI’s are patented compounds that can be marketed exclusively by the companies that own the patent. This gives them the 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, 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 Prozac’s 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. Poldinger’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 are willing to recommend it. Nevertheless, Poldinger’s results demonstrate that 5-HTP may be every bit as good as the SSRI’s 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.

How Safe is 5-HTP?

When taking any substance that alters the body’s neurochemistry, it is always important to proceed with caution, and 5-HTP is no exception. It is almost inevitable that too high a dose will cause adverse effects, and it is possible that some of these could be serious. Having said this, we should point out that 5-HTP is an exceptionally safe nutritional supplement that has rarely, if ever, been associated with serious problems.

The most common side effects associated with oral 5-HTP are generally related to gastrointestinal upset, including nausea, vomiting, heartburn, and stomach pain. For most people, these tend to be mild and transient. Oral 5-HTP at doses of 100 to 300 mg/day has never been reported to cause significant changes in blood, liver, lung, metabolic, or kidney function.

As we noted earlier, for example, the Poldinger et al study, which compared 5-HTP with the SSRI fluvoxamine in people with depression, found that the SSRI-treated subjects experienced significantly more, and more severe, adverse effects that did those treated with 5-HTP. Overall, the authors stated, “5-HTP-induced adverse events worthy of note are rare within the therapeutic dose range.

CENTROPHENOXINE 

5-HTP may sometimes cause GI upset, because serotonin (produced from 5-HTP) is a major neurotransmitter in the gut. It has therefore been suggested that people taking oral 5-HTP should also take a drug like carbidopa (called a peripheral decarboxylase inhibitor, or PDI) that prevents the metabolism of 5-HTP to serotonin in the periphery but not in the brain and spinal cord. As a result, less serotonin is produced in the periphery to upset the GI system, and more 5-HTP is made available in the brain to make more serotonin where it is needed most. In essence, the use of a PDI means that a lower dose of 5-HTP can go a much longer way.

Is a PDI really necessary, though? Probably not. 5-HTP has been combined with a PDI in some studies and has been given alone in others. Either way it still raises serotonin levels in the brain, although you may need less 5-HTP when combined with a PDI. A Swiss study of 25 depressed patients found no difference in antidepressant efficacy between those who took 5-HTP alone and those who took it in combination with a PDI. Although the 5-HTP group experienced somewhat more GI side effects, the 5-HTP + PDI group had more psychopathological side effects, such as acute anxiety.

Thus, one would have to ask, why add another drug (which requires a prescription) to your regimen if you can get the same therapeutic benefit without it? Of course, if you find 5-HTP’s GI side effects to be intolerable, you may want to consult with your physician about trying one of these drugs.

It has also been suggested that 5-HTP may cause GI upset directly by irritating the stomach lining. If so, then another possible means of reducing GI side effects may be to take 5-HTP in the form of enteric coated tablets, which dissolve only in the intestine. This is the form that Poldinger’s group used and which resulted in very few side effects, but is not readily available in the US.

Is Serotonin Syndrome a Concern?

Serotonin syndrome is a potentially serious disorder caused by the availability of too much serotonin in the body. Symptoms include confusion, fever, shivering, sweating, diarrhoea, muscular in coordination, exaggerated reflexes, and violent muscular contractions. Although serotonin syndrome has occasionally caused death, most people make a full recovery, once the causative agents are removed.

The drugs most commonly associated with serotonin syndrome are those that block the normal metabolism of serotonin — the MAO inhibitors, the SSRIs, and the tricyclic antidepressants — and thus increase its availability at certain serotonin receptors. Serotonin syndrome rarely if ever occurs when these drugs are taken by themselves. Rather, it is combinations, such as an SSRI plus an MAO inhibitor, or one of these drugs plus tryptophan, that most increases the risk of serotonin syndrome

There have been no published reports of serotonin syndrome occurring in someone taking 5-HTP. Nevertheless, there is no reason to think that, given the right combination of drugs and doses, it could not occur. Common sense would dictate, therefore, that 5-HTP be combined with drugs known to affect serotonin metabolism only with the greatest of care and under the supervision of a knowledgeable physician

Other Safety Concerns 

Concern has been raised by some people that 5-HTP might increase the risk of a heart attack by enhancing the tendency of blood platelets to clot or by causing coronary arteries to go into spasm. Although it is unclear what the origin for this theoretical concern is, the facts speak for themselves. There has never been a single published report of 5-HTP causing a heart attack. The risk, if it exists at all, would seem to be extremely small and could probably be counteracted by a sensible nutritional program that includes supplements known to reduce platelet aggregation and coronary vasospasm, including vitamins C and E, calcium, magnesium, fish oil, and low-dose aspirin. Other concerns related to the concomitant use of vitamin B6 and the promotion of heart muscle and valve fibrosis by 5-HTP also seem to have no basis in fact.

It is conceivable that these problems could arise if there were excess peripheral serotonin. But, since very little serotonin is produced from 5-HTP outside of the central nervous system, the danger seems remote at best.

5-HTP Dosing Guidelines 

The dose of 5-HTP that has most often been reported in the scientific literature and prescribed by physicians is 300 mg per day. When taking 5-HTP for depression, anxiety, or fibromyalgia, the general practice in scientific studies has been to take 100 mg three times a day. This dosing regimen may leave some people too sleepy during the day, however.

Some physicians have found it best to start their patients on 5-HTP at a dose of 150 to 200 mg at bedtime. If this is insufficient to provide antidepressant/anti-anxiety relief, they can take additional doses of 33 to 50 mg during the day. The number of these doses should be adjusted to a level that provides adequate relief without causing daytime sedation.

If you are taking 5-HTP to enhance sleep, it is probably best to take the entire 300-mg dose at bedtime. The dose used in the best migraine study was 400 mg (100 mg four times per day).34 The dose found to effectively suppress appetite was 900 mg per daily (300 mg three times per day).51 Incidentally, the fact that this very high dose of 5-HTP was used without significant side effects can be taken as an indication of the general safety of this substance

Different individuals may require higher or lower doses than these, but these are good starting points. As with any drug, it is usually better to start with a low dose and increase it gradually. If you find that a lower dose delivers the therapeutic effect you are looking for, then you can stop there. If the 300-mg dose seems inadequate, you can slowly increase it (preferably under your physician’s supervision). In any case, always be alert for adverse side effects. If a given dose makes you feel uncomfortable, either physically or mentally, back off the dose and do not go any higher until you consult with a knowledgeable physician. In most cases, lowering the dose will quickly cause the adverse effects to disappear.

What About Taking 5-HTP with Prozac or Other Drugs? 

Although basic dosing of 5-HTP is fairly straightforward, it becomes significantly more complicated if you are currently taking other drugs that affect serotonin levels, such as an SSRI (eg, Prozac, Luvox, Paxil, Effexor, Zoloft), a tricyclic antidepressant (eg, Elavil, Tofranil, Pamelor), or St. John’s wort. If you are taking one of these drugs and want to switch to 5-HTP, it is recommended that you first consult with your physician, because taking them together can cause a potentially dangerous elevation of serotonin levels. Never attempt to combine 5-HTP with any of these drugs without the help of a physician.

It is usually necessary to gradually lower the dose of your SSRI (or other drug) as you gradually increase the dose of 5-HTP. Since each individual is likely to react differently to a given combination of doses, your physician will probably want to monitor your responses to these drug combinations very closely. If you experience any symptoms of serotonin overload, such as confusion, fever, shivering, sweating, diarrhoea, muscular in coordination, exaggerated reflexes, or violent muscular contractions, the dose of one or both agents can be easily and safely adjusted until the symptoms disappear. Eventually, the SSRI can probably be completely eliminated.

Can You Benefit from Taking 5-HTP? 

The growing awareness among medical researchers of the importance of the neurotransmitter serotonin to our mental and physical well-being has been a boon to the companies that manufacture and market SSRIs, because these drugs enhance serotonergic activity in the brain. For many people these drugs have been extremely beneficial. But like most synthetic drugs, they all have important drawbacks.

As the body of research on 5-HTP continues to accumulate, it is becoming increasingly evident that this natural amino acid and precursor to serotonin has all the clinical benefits of the SSRIs while producing far fewer adverse effects. At the present time, there is scientific evidence that 5-HTP can have therapeutic or prophylactic benefits in depression, anxiety, insomnia, migraine, fibromyalgia, and weight loss, conditions for which SSRIs are being widely prescribed today. Preliminary evidence suggests that SSRIs may also be useful for treating the discomforts of premenstrual syndrome (PMS) and for reducing aggressive or violent tendencies. Although there have been no studies specifically showing that 5-HTP cab be beneficial in these latter conditions, it may only be a matter of time before such studies are done.

From all published evidence so far, 5-HTP appears to be quite safe when used according to standard dosing guidelines. However, 5-HTP does affect a major neurotransmitter system in the body. If you think you might benefit from taking it, we therefore recommend that you consult with a physician who has had experience treating patients with 5-HTP. This is especially important if you are currently taking drugs for depression, anxiety, insomnia, appetite suppression, migraine, or fibromyalgia, including the SSRI’s, tricyclic antidepressants, St. John’s Wort and others. Your physician will probably want to adjust the dosing of your current drug and 5-HTP.