Can 5-HTP Lift Your Spirits
By Amping Up Your Serotonin Levels?

The human brain is a mystery that we (it, actually) will probably never completely understand. It has intrigued and challenged philosophers and scientists for centuries. This three-pound mass of tissue is composed of about 100 billion neurons (nerve cells), which communicate with each other via dozens (perhaps hundreds) of different kinds of neurotransmitter molecules that convey electrochemical messages from one neuron to the next. One way to imagine the brain's function is to envision every telephone, computer, satellite, TV, CD player, and video game in the world working together in perfect harmony to achieve a coordinated and desired response - but even that is far too simplified.

Despite the daunting complexity of the brain, researchers have begun to understand some important pieces of the puzzle. Take the neurotransmitter serotonin, for example. Serotonin is a small molecule released by one neuron to carry a signal to a neighboring neuron. The gap between them, called a synapse, is about one-billionth of an inch across. The receiving neuron has large protein molecules on its surface called serotonin receptors. The cumulative effect of zillions of tiny serotonin signals acting in a coordinated way is a bit of information. It could be a message to alter some aspect of mood, appetite, confidence, or sleep, for example.

In this article you will find the following sections. Click on a link to read a specific section, or use your scrollbar to review the entire article.

Depression May Mean Lower Serotonin
One of the best understood functions of serotonin is its role in regulating mood. In many individuals, low levels may be responsible for depression, as well as other symptoms, such as anxiety, loss of appetite, and sleep disturbances. Pharmaceutical drugs such as Prozac® regulate mood by increasing serotonin levels. They belong to a class of drugs called selective serotonin reuptake inhibitors (SSRIs), which are widely prescribed for depression.

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Metabolic pathway from tryptophan to serotonin

Here's how SSRIs work. Most serotonin molecules are recaptured by the transmitter neuron after their release by the receiver neuron so that they can be reused for another round of signaling; this saves the chemical energy that would be required to synthesize new serotonin molecules. Sometimes this "reuptake" process occurs too quickly, however, even before the serotonin has been able to activate the adjacent neuron. SSRIs prevent this premature reuptake, thus elevating serotonin levels in the synapse and facilitating better neural communication.

Natural Alternatives to SSRIs?
The trouble with prescription SSRIs is that they are synthetic compounds (unnatural products, you might say) to which human bodies are not adapted, and they can have undesirable side effects. There are, however, alternative, more natural means than prescription SSRIs which may increase serotonin levels in the brain and thus perhaps alleviate the symptoms of depression. These alternatives include the herb St. John's wort, the vitamin thiamine, and, especially, the amino acid derivative 5-hydroxytryptophan, or 5-HTP. We will get back to these shortly.

Depression is On The Rise
There has been a dramatic increase in recent years in the number of reported cases of depression. Indeed, one estimate is that major depression now occurs in the adult population at a rate between 5.0% and 10.3%. Sadly, not everyone gets treated for this condition, but the good news is that the percentage who do is on the rise. For example, a recent article in The Journal of the American Medical Association reported that the number of people receiving outpatient treatment* for depression increased from 0.7% of the U.S. population to 2.3% between 1987 and 1997.1

*Outpatient treatment can be either psychotherapy ("on the couch") or drug treatment. In patients diagnosed with depression, antidepressant drugs now account for most treatment, having increased from 37% in 1987 to 75% in 1997.

That's a significant increase, but, as the JAMA article points out, "Most individuals with depression receive no treatment for their symptoms. According to a recent report of the surgeon general, promoting treatment for people with depression is an even more significant problem than developing more effective treatments."

One reason why some people don't treat their depression is because of the side effects of the medications, such as nausea, headaches, anxiety, insomnia . . . the list goes on. This makes safe, natural alternatives to prescription drugs seem all the more desirable.

Serotonin is Produced from 5-HTP
Serotonin is synthesized in the neurons from tryptophan, an amino acid that must be obtained from food, because the body is incapable of synthesizing it. Neurons contain enzymes that convert tryptophan first into 5-HTP (5-hydroxytryptophan) and then into 5-HT (5-hydroxytryptamine, the chemical name for serotonin). Although we all have this ability, we may produce serotonin at different rates, and the efficiency of the process declines with age. In addition, our rates of serotonin reuptake may differ, which helps to explain why SSRIs are more effective in some people than others.

All in all, it's not surprising that people can have widely different levels of serotonin in their brains. Those with low levels may be especially susceptible to depression, anxiety, etc. Conventional wisdom says that if these individuals can increase the amount of serotonin in their brains, they may be able to alleviate their symptoms. So, how can we do that?

Need a Confidence Boost?
Have you been feeling a little unsure of yourself lately? Perhaps something has shaken your confidence in yourself. It may even have made you edgy with other people. We all have periods like that occasionally, because we all have flaws. And when we're feeling like that, we could sure use a boost.

Well, taking serotonin precursors may help, according to researchers at McGill University in Montreal. For a 26-day period, they monitored the mood states and behaviors of 98 male and female volunteers. Half were receiving tryptophan (1 mg three times per day), and the other half were receiving placebo. (Recall that in our brains, tryptophan leads to 5-HTP, which leads to serotonin. It's reasonable to assume, therefore, that if tryptophan showed a positive effect, 5-HTP would too.)

The individuals receiving tryptophan exhibited decreased "quarrelsome" behavior and increased "dominant" (self-confident) behavior. There were also improvements in mood, although not as consistently as in behavior. This is consistent with other studies showing that tryptophan enhances mood more readily in people who feel depressed than in those who don't (that's hardly surprising). The findings are also consistent with animal studies showing that increased serotonin function correlates with productive social interactions and dominance.

Does all this mean that increased serotonin will turn you into a "nice bully" (dominant but not quarrelsome)? No - but it just might make you feel more confident of yourself in everyday situations. So, if you're feeling a bit stepped on, maybe you need to step up your serotonin production.

A rather obvious, straightforward way is to increase the amount of the serotonin precursor 5-HTP. Indeed, the authors of a recent review article identified 108 clinical trials in the medical literature that explored the benefits of 5-HTP and its precursor, tryptophan, in reducing the symptoms of depression.2 They adopted very stringent criteria for including studies in their analysis (nearly half of the studies were excluded from review to begin with because they had not focused on either 5-HTP alone or tryptophan alone), and very few made the grade. Regardless, the final analysis concluded that 5-HTP is better than placebo at alleviating the symptoms of depression. Further, the authors stated that 5-HTP may be a good alternative approach for patients with mild depression who wish to avoid traditional (i.e.,pharmacological) antidepressants.

Natural Antidepressants - An Alternative to Drugs?
For centuries before we knew about 5-HTP, the herbal remedy St. John's wort (Hypericum perforatum) had been used to improve mood and alleviate the symptoms of depression. Several recent clinical studies have indeed shown that St. John's wort (wort means plant, by the way) is an effective antidepressant. A review article published in 1996 concluded that extracts of this plant are more effective than placebo for treating mild to moderate cases of depression,3 and a number of more recent studies support this conclusion.

St. John's wort is a natural serotonin reuptake inhibitor, but not a selective one - hence it is an SRI but not an SSRI. Unlike drugs in the SSRI category, it is not specific for serotonin: it has a broad spectrum of action, inhibiting the reuptake of other neurotransmitters, such as dopamine, norepinephrine, GABA, and L-glutamate. This unusual property is attributed to hyperforin, which is now believed to be the principal active compound in St. John's wort.4 Research is ongoing to determine what other compounds are active and how they work.

The Symptoms of Depression
Depression can be difficult to recognize, in yourself or in others. According to the National Institute of Mental Health, symptoms of depression include the following:
  • Persistent sad, anxious, or "empty" mood
  • Feelings of hopelessness, pessimism
  • Feelings of guilt, worthlessness, helplessness
  • Loss of interest or pleasure in hobbies and activities that were once enjoyed, including sex
  • Decreased energy, fatigue, being "slowed down"
  • Difficulty concentrating, remembering, making decisions
  • Insomnia, early-morning awakening, or oversleeping
  • Loss of appetite or weight loss, or overeating and weight gain
  • Thoughts of death or suicide; suicide attempts
  • Restlessness, irritability
  • Persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders, and chronic pain
    Of course, some of these symptoms are regularly experienced by healthy people. Conversely, not everyone who is depressed will experience every symptom.

    So how do you know if someone is truly depressed? Three additional factors must be considered: intensity, duration, and number of symptoms. A large number of intense symptoms that persist for a long time almost certainly indicates serious depression. As a general rule, a thorough clinical diagnosis is required if four or more of the symptoms of depression persist for more than two weeks, or if the symptoms significantly interfere with work or home life.

    From recent research, we know that hyperforin can induce changes in the sodium concentration inside the neurons. Many proteins are sensitive to sodium, and changes in its concentration can alter the conformation of the protein molecules, which in turn regulates their activity. Thus hyperforin appears to improve mood by regulating sodium levels in our neurons.

    Thiamine Helps Maintain Serotonin Levels
    Thiamine is a B-vitamin (B1) that plays many important roles in the body. One of these is to help regulate serotonin levels in the brain. Indeed, thiamine deficiency may significantly impair serotonergic (serotonin-mediated) signaling processes. For example, animal studies suggest that replenishing thiamine in deficient animals reinstates normal serotonin function.

    It is not surprising, therefore, that thiamine supplementation has a positive impact on mood in both young and elderly human patients. In one study, healthy elderly women with a marginal thiamine deficiency were monitored for a ten-week period. Following supplementation with thiamine (10 mg/day), the women exhibited improvement in general well-being and decreased fatigue, compared with control subjects.5

    Another study involved 120 younger women who did not exhibit any thiamine deficiency.6 Half of them received thiamine (50 mg/day), and half received a placebo. After two months of supplementation, the women in the thiamine group significantly improved their performance on both cognitive and psychological tests that measured mood. These results suggest that thiamine has a beneficial effect on mood even when women are not thiamine-deficient.

    As we have seen, several natural agents may help with depression. Two such are thiamine and hyperforin from St. John's wort. Needless to say, 5-HTP and also judicious amounts of vitamin B6, calcium, magnesium, and niacin are believed to nourish neurons properly and support normal serotonergic function.

    If life's puzzle has you flummoxed and it seems that some of the pieces are missing, perhaps one of them is your serotonin. Boosting your serotonin levels might go a long way toward helping you battle your blues.


    1. Olfson M, Marcus SC, Druss B, et al. National trends in the outpatient treatment of depression. J Am Med Assoc 2002:287:203-9.
    2. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression (Cochrane Review). In: The Cochrane Library, Issue 4, 2001. Oxford: Update Software.
    3. Linde K, Ramirez G, Mulrow CD, et al. St. John's wort for depression - an overview and meta-analysis of randomised clinical trials. Brit Med J 1996;313:253-8.
    4. Muller WE, Singer A, Wonnermann M. Hyperforin - antidepressant activity by a novel mechanism of action. Pharmacopsychiatry 2001;34:S98-102.
    5. Smidt LJ, Cremin FM, Grivetti LE, Clifford AJ. Influence of thiamin supplementation on the health and general well-being of an elderly Irish population with marginal thiamin deficiency. J Gerontol 1991;M16-22.
    6. Benton D, Griffiths R, Haller J. Thiamin supplementation mood and cognitive functioning. Psychopharmacology 1997;129:66-71.

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