Smart Life Update:

Tryptophan, 5-HTP and Serotonin

L-Tryptophan metabolism plays a vital role in our health. Not only is tryptophan an essential amino acid for building proteins and enzymes, but it serves as the precursor for 1) the brain neurotransmitter serotonin, and 2) the hydrogen (energy) carriers NADH and NADPH. Each of these three roles is essential for the maintenance of life, health and consciousness.

In the last 30 years, L-tryptophan’s importance has expanded into the political realm as its utility for enhancing serotonin levels has become appreciated by consumers and researchers alike. Tryptophan was popularized in the early 70s by a series of articles promoting its sleep-enhancing properties. Due to the therapeutic nature of these health claims, the FDA tried to censor tryptophan-related publications involving health claims and restrict tryptophan’s over-the-counter availability. They failed to accomplish either goal. For two decades, tryptophan’s popularity grew. By the late 80s, an estimated 14 million people were using tryptophan to improve mood, reduce irritability, reduce premenstrual symptoms, lessen chronic pain, lose weight, treat alcoholism, and get a better night’s sleep.

In 1989, the then-largest manufacturer of L-tryptophan changed their manufacturing process and introduced two large batches of contaminated tryptophan into the world marketplace. Within months, an epidemic of eosinophilia myalgia syndrome (EMS) began to develop. Eventually, thousands of people got sick and more than a hundred died.

In the early stages of the investigation, tryptophan consumption was implicated in EMS. This prompted the FDA to temporarily block sales of tryptophan while the investigation proceeded. Eventually, researchers traced the problem to lots of tryptophan manufactured by one company, Showa Denko. The FDA, however, argued against that finding and used the EMS epidemic as an excuse to ban all tryptophan from the US over-the-counter market. Although twenty years late, the FDA finally accomplished what it set out to do in the early 70s — to get rid of tryptohan.

The Serotonin Connection

Within the limited view of the tryptophan fiasco, the FDA’s ban seemed merely an overreaction prompted by resentment that had festered for twenty years. However, much more important issues were at play behind the scenes. Tryptophan’s efficacy is primarily based on its ability to raise serotonin levels, and a whole new class of serotonin drugs were waiting in the FDA’s wings for approval.

Just days after the FDA banned tryptophan, the cover of Newsweek announced the arrival of Prozac, a “selective serotonin reuptake inhibitor” which became the blockbuster drug of the 90s. Unlike tryptophan, which raised serotonin levels by making more serotonin, Prozac raised serotonin levels by inhibiting the reuptake (recycling) of serotonin. Fortunately for Eli Lilly & Co, tryptophan’s unavailability had created a serotonin vacuum that Prozac could fill. And fill it it did. Prozac’s popularity and profitability were wildly spectacular.

Although Prozac was successful at raising serotonin levels and relieving many of the symptoms of serotonin deficiency, it had a dark side. Reports of suicides, bizarre personality changes and anti-sexual side effects began to emerge. So did reports of Prozac resistance, whereby regular dosage increases were required to maintain effect.

Some of these problems were caused by the unnatural way that Prozac modulated serotonin levels. By interfering with the reuptake, reuse and/or recycling) of serotonin, Prozac actually caused decreases in the cellular stores of serotonin that are needed to maintain increased serotonin levels at the target neurons. In simpler words, Prozac 1)undermined its own action, and thereby 2) created a greater clinical need for its use. This is exactly opposite to the way tryptophan increases serotonin by increasing serotonin stores.

During the following years, other serotonin reuptake inhibitors entered the market. Many did quite well economically. Whether these drugs would have done well faced with open competition from tryptophan will never be known. However, it does seem an improbable and fortuitous coincidence that the FDA eliminated Prozac’s only competition at exactly the right time to facilitate Prozac’s market success.

Enter 5-Hydroxy-L-Tryptophan

In the dietary supplement market, the serotonin vacuum created by the FDA’s ban of L-tryptophan remained unfilled for years. Nutrition-conscious consumers shunned the SRIs. In 1994, Congress finally passed the Dietary Supplement Health & Education Act which protected dietary supplements as foods, and made them independent from FDA drug regulations. This allowed the tryptophan metabolite 5-hydroxy-L-tryptophan (5-HTP) to thrive in the the over-the-counter market.

It is perhaps a bit of regulatory irony that sales of 5-HTP, which can raise serotonin levels far beyond those of tryptophan, are unrestricted, while the much milder tryptophan, whose metabolism to serotonin is safely feedback regulated, is prohibited. This backwards, topsy-turvy regulatory state is a direct consequence of the FDA’s misregulation of dietary supplements and the politicization of what should have been a simple public health decision.

New 5-HTP Books

This year has seen the publication of two new books on 5-HTP. Michael Murray’s book, 5-HTP: The Natural Way to Overcome Depression, Obesity and Insomnia (Bantam Books, New York, 1998, ISBN 0-553-10784-4, $23.95 hardback), offers the public a rave review for 5-HTP. Dr. Murray is a prolific author in the field of natural medicine, a naturopathic doctor, and a faculty member at Bastyr University in Seattle. Although I found his book thorough, easy to read, rich in clinical anecdotes and well referenced, it was too one sided for my tastes. There were also a few unfortunate examples of technical misinformation presented about 5-HTP and tryptophan.

One of the book’s biggest weaknesses was its superficial coverage of possible risks and problems that might be associated with 5-HTP. For example, the possibility of over-production of serotonin in the bloodstreams of people who take 5-HTP without a peripheral decarboxylase inhibitor drug (e.g., carbidopa, benserazide) is dismissed with reference to a single study comparing 5-HTP alone to 5-HTP with benserazide. Most of the 5-HTP in Europe is combined with carbidopa, not benserazide, an issue which is never mentioned by Murray.

Also superficial is his comparison of 5-HTP to tryptophan. Murray writes “The crisis that resulted from the contaminated supplies of L-tryptophan proved to be a blessing in disguise because it shifted the spotlight to 5-HTP” which is “by all measures [...] far superior to tryptophan.” He justifies that judgment by asserting that, unlike fermented tryptophan, 5-HTP extracted from Griffonia simplicifolia “is not vulnerable to contamination.” This statement is patently absurd. Contaminants can just as easily be produced by the natural metabolism of plants as from fermentation (which is itself a natural biological process). The purification of 5-HTP from seeds uses the same basic extraction technology that is used to extract tryptophan from fermented cultures. The only difference lies in the specific chemicals which are being extracted, and the specific chemicals which are being left behind. I suspect that many of the non-tryptophan chemicals produced by bacterial fermentation are identical to chemicals found in Griffonia seeds. Both are living biological systems, and both have robust tryptophan biosynthetic pathways.

Murray also compares a 70% absorption of 5-HTP into the bloodstream to a 3% conversion of tryptophan into serotonin. While these figures are interesting and should be mentioned, they shed no light on the relative merits of tryptophan and 5-HTP. It’s an apples-to-oranges comparison.

In another comparison, Murray points out that 5-HTP cannot be converted into kynurenine, as tryptophan can. Yet never does he discuss what 5-HTP can be converted into, from which one can judge the significance of the comparison. Using similar logic, I could argue that because knives can’t cause explosions, they must be safer than firecrackers.

It is difficult to compare risks of 5-HTP with those of tryptophan because tryptophan metabolism of is far more thoroughly investigated than is 5-HTP and serotonin metabolism [Huether and Schuff-Werner, 1996]. I think it is inappropriate for Murray to ignore speculations that oxidation of 5-hydroxyindoles (i.e., 5-HTP and serotonin) may produce free radical intermediates, and possibly a quinone imine [Napolitano, 1988]. Both 5-HTP and serotonin, but not tryptophan, inhibit in vitro copper-catalyzed oxidation of LDL lipids [Huether and Schuff-Werner, 1996], suggesting the possibility that 5-HTP and serotonin may play significant roles as antioxidants. Murray seems fixed on the idea that the activation of the kynurenine pathway is bad, yet this activation happens under many conditions which are not associated with pathology, such as the third trimester of pregnancy [Fuchs et al., 1996]. Although some kynurenine metabolites (especially quinolinic acid) are known to be excitotoxic, others are known to block excitotoxicity. The role that these metabolites play in health and disease is not sufficiently understood to make gross generalizations.

One of Murray’s most dubious assertions is that 5-HTP “passes into the brain immediately” while tryptophan “must compete with other proteins to be transported across the blood-brain barrier.” Notwithstanding the erroneous substitution of the word protein for amino acid, this claim is unsubstantiated and unreferenced. It is also contradicted by a published study of active 5-HTP transport in kidney cells which establishes that: 1) 5-HTP absorption is inhibited by competition from L-dopa (which indicates that 5-HTP uses the same large neutral amino acid transport protein that L-dopa uses), 2) 5-HTP transport is stereoselective (in other words, L-5-HTP is transported but D-5-HTP is not, indicating no passive absorption), and 3) 5-HTP absorption is saturable at 50 millimolar concentration (saturation indicates that passive absorption of 5-HTP is minimal) [Vieira-Coelho and Soares-da-Silva, 1997]. Each of these observations suggest that 5-HTP absorption requires the same active transport protein needed to absorb tryptophan, which is fully consistent with the fact that 5-HTP is, in fact, a large neutral amino acid. This means that 5-HTP absorption is limited by the same competitive transport dynamics as tryptophan. In other words, absorption of 5-HTP, like tryptophan, is optimized when taken 1) without protein (which minimizes amino acid competition), and/or 2) with carbohydrates (which induces insulin that further reduces amino acid competition). This has, indeed, been noted by clinicians.

Although I remain open to the possibility that there may be some kind of passive transport mechanism for 5-HTP in addition to active transport, I have been unable to find a reference that documents such a possibility.

5-HTP: Nature’s Serotonin Solution

The second 5-HTP book this year is Dr. Ray Sahelian’s 5-HTP: Nature’s Serotonin Solution (Avery Publishing Group, New York, 1998, ISBN 0-89529-871-6, $10.95 paperback). Although weaker in anecdotes and less technical in its scope, it has two huge advantages over Murray’s book: 1) it is written from a foundation of extensive personal experiences with 5-HTP (described in detail in Chapter 2), and 2) it includes a broad range of expert opinions about 5-HTP by doctors using 5-HTP in clinical practice (Chapter 10). Although these opinions are sometimes more cursory than Michael Murray’s descriptions of 5-HTP use in his clients, it provides a much broader-based picture of how 5-HTP (and tryptophan) can (and are) being used. Unlike Murray, Sahelian and the other clinicians have positive things to say about tryptophan when they discuss 5-HTP.

Like Murray, Sahelian’s book covers all the myriad of well established uses for 5-HTP including: 1) losing weight (and suppressing carbohydrate food cravings), 2) mood elevation (alleviating depression), 3) promoting calmness (diminishing anxiety), 4) reducing obsessiveness and compulsiveness (OCD), 5) diminishing a broad range of fibromyalgia symptoms, and 6) enhancing sleep (treating insomnia). It also mentions less established but no less important applications of 5-HTP to 1) treating alcoholism, 2) alleviating migraine headaches, 3) reducing premenstrual syndrome (PMS), 4) reducing attention deficits and hyperactivity, 5) treating autism, and much more. Sahelian’s inclusion of information about nutrients and herbs other than 5-HTP which may help with these conditions and possibly enhance the activity of 5-HTP is a very nice touch.

One of Sahelian’s exceptional chapters is his discussion of the many practical variables that can influence 5-HTP’s effectiveness: when to take it, what to take it with, how much to take, whether to take it with meals or on an empty stomach, whether to take it with caffeine, how to minimize daytime sleepiness, how to avoid tolerance, how to incorporate other supplements with 5-HTP, and whether to take vitamin B-6 with 5-HTP.

On the whole, Dr. Sahelian’s book on 5-HTP is an excellent effort, with a well balanced appraisal of the pros and cons of 5-HTP, unmarred by the technical errors found in Dr. Murray’s book. Anybody interested in using 5-HTP would be well served to read it and add it to their personal library.

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