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Toxic L-tryptophan: Shedding Light on a Mysterious Epidemic
by William E. Crist
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L-tryptophan Section from "Dietary Supplements and Their Discontents: FDA Regulation and the Dietary Supplement Health and Education Act of 1994," Rutgers Law Journal, Winter 2000
By Joshua H. Beisler
A. L-tryptophan
L-tryptophan, a synthetically-produced amino acid, was used in the United States by more than thirty million people over the course of three decades as a treatment for depression, insomnia, overeating, and various other disorders. Much research has been done on its clinical efficacy, particularly as a treatment for depression. Its low incidence of side effects makes it an attractive alternative to therapy with traditional antidepressants. In October 1989, a contaminated batch of L-tryptophan was implicated in an outbreak of a rare disease known as eosinophilia-myalgia syndrome ("EMS"), whose symptoms include "severe muscle and joint pain (myalgia), high fever, weakness, swelling in the arms and legs, and shortness of breath." This tragedy ultimately claimed approximately fifteen hundred victims, with fifty fatalities.
Responding to the tragedy, the FDA recalled L-tryptophan in the fall of 1989, and on March 22, 1990, the FDA completely banned the public sale of L-tryptophan. This ban is still in effect today, and the FDA continues to allege that L-tryptophan might be a cause of EMS. However, this point of view constitutes the minority opinion. All of the victims of EMS exclusively ingested L-tryptophan manufactured by the Japanese company Showa Denko, and the two main epidemiological studies on the outbreak concluded that EMS can be traced to a contaminant of L-tryptophan generated during an untested production process.
The Centers for Disease Control reported, "EMS must be caused by a product contaminant." Another study found, "The outbreak of [EMS] in 1989 resulted from the ingestion of a chemical constituent that was associated with specific tryptophan-manufacturing conditions at one company." Admitting that "[o]ther investigators have suggested that tryptophan itself or its metabolites may contribute to the induction of [EMS] in susceptible persons," the authors nevertheless conclude, "Our data demonstrate that the syndrome is not induced by tryptophan itself ... [a]t this time the pathogenesis of the inflammatory changes of [EMS] remains speculative." Despite the seriousness of the disease, only one in 250 people who ingested the contaminated L-tryptophan ultimately contracted EMS.
L-tryptophan continues to be safely used in Canada, as well as European countries such as Italy, Spain, France, and Germany. In addition, no cases of EMS have ever been attributed to uncontaminated L-tryptophan. Furthermore, the FDA continues to allow the use of L-tryptophan in infant formulas, medical foods, and weight-loss products. EMS has never been associated with the use of these products. As a final crowning irony, the United States government issued patent number 5185157 on February 9, 1993, to use L-tryptophan to treat and cure EMS, and in fact, L-tryptophan may be the only effective treatment for EMS.
Faced with evidence of the questionable safety and efficacy of L-tryptophan, the FDA continues to forbid over-the-counter sale of L-tryptophan. The FDA claims that only "95 percent of the cases of EMS were traces [sic] to L-tryptophan supplied by Showa Denko K.K. of Japan." This statement implies that the other five percent came from other source(s), which would in turn make it more likely that L-tryptophan is a possible cause of EMS, but this is not the case. Rather, this simply means, "Three to five percent of the EMS cases have not been definitively linked to Showa Denko's product." However, because any epidemiological study involves a retroactive reconstruction of the events that led to the outbreak, this failure to definitively determine all the facts is hardly unusual. This three to five percent ambiguity is rendered even more insignificant by the FDA's own admission: "[N]o other company's product has been definitively linked to EMS."
Considering that L-tryptophan (1) has never been associated with EMS in any of the many other countries that allow its over-the-counter sale; (2) has never been associated with EMS absent a product contaminant; (3) is safely used in the United States in infant formulas, medical foods, weightloss products, and animal feed; and (4) may be the only effective treatment for EMS, the three to five percent ambiguity amounts to an extremely weak justification for the continued ban of L-tryptophan. A far better remedy would be to allow L-tryptophan back onto the market while creating some form of quality control to prevent a recurrence of a manufacturing defect like the one suffered by Showa Denko. The FDA's persistent use of the L-tryptophan controversy as a justification for increasing its regulatory power is disingenuous because of the paucity of evidence that links uncontaminated L-tryptophan to EMS or health problems of any kind.
Political pressures have played a role in the FDA's decision to ban L-tryptophan as well as its desire to increase its regulatory power over dietary supplements. In an FDA Dietary Supplement Task Force report dated June 15, 1993, the task force admits, "The Task Force considered various issues in its deliberations, including ... what steps are necessary to ensure that the existence of dietary supplements on the market does not act as a disincentive to drug development." This is a particularly disturbing issue for the FDA to consider when developing regulatory guidelines for dietary supplements because it has far more to do with eliminating competition in the pharmaceutical industry than preserving the public health. Furthermore, this admission illustrates the conflict of interest that has plagued FDA regulation of dietary supplements from the beginning.
Drug development is an extremely expensive process, but it does not follow that consumers should be denied dietary supplements merely to aid production of pharmaceuticals. This admission from the FDA greatly angered the dietary supplement community and probably fueled consumer efforts to pass DSHEA.
Nonetheless, the introduction of 5-hydroxytryptophan ("5-HTP") into the market may help rectify the damage caused by the FDA's ban of L-tryptophan. 5- HTP is a metabolite of L-tryptophan that increases the amount of serotonin in the brain in a very similar way. However, because it is a metabolite, 5-HTP is one step closer to serotonin than L-tryptophan. Other factors suggest that 5-HTP is a superior product to L-tryptophan. Studies also indicate that 5-HTP is as effective as conventional antidepressants, and is perhaps an even more potent psychiatric tool. Clinical trials indicate that 5-HTP and L-tryptophan have significantly fewer side effects than antidepressants like Prozac.
In a recent press release, the FDA warned, "FDA scientists have confirmed the presence of impurities in some 5-hydroxy-L-tryptophan (5-HTP) products currently marketed and widely promoted as dietary *533 supplements." In its report, the FDA states that one of these impurities found is "Peak X," which "was identified in one case of the illness eosinophilia-myalgia syndrome (EMS) associated with 5HTP [sic] in 1991. Impurities similar to 'Peak X' were also found in L-tryptophan that was associated with a 1989 epidemic of EMS." Again, this is very slippery language. Peak X, although it was indeed associated with the L-tryptophan tragedy, was never proven to be the cause of EMS. Its presence has absolutely no proven impact on the safety of 5-HTP or L-tryptophan. Consequently, the presence of Peak X may be completely insignificant. A recent paper released by the Mayo Clinic also claims to have found traces of Peak X in samples of 5-HTP. The amount found in the samples examined by the Mayo Clinic amounted to "a tiny fraction of 1%," although the authors chose to obscure this fact by not "present[ing] their findings in absolute terms (i.e., the actual percentage of impurity)." Reporting the actual percentage of impurity would have resulted in "too many zeroes after the decimal point to be impressive." The amount of Peak X found in the samples was as small as 0.71 parts per million. This is hardly a significant finding and should not be a cause of concern for people using 5-HTP. Also, the FDA report does not disclose the levels of Peak X found in their samples, mentioning only that their "analytical results are consistent with those obtained and published by researchers from the Mayo Clinic." This implies that the amount of Peak X found in the FDA samples was equally insignificant.
Dietary supplement manufacturers responded to the allegations by examining their product and found nothing. The FDA is careful to note, "The exact cause of the 1989 epidemic and of the case of EMS associated with 5HTP [[sic] remain[s] unclear," but the context nonetheless implies a causal link between EMS and 5-HTP, all on the basis of a single, unreferenced, anonymous case where EMS was "associated" with 5-HTP. Buried at the end of this latter article is an admission that the "FDA is unaware of any recent illnesses associated with the 5HTP [sic] products being sold as dietary supplements." The use of the word "unaware" suggests that recent cases of 5-HTP-associated EMS probably exist, but that the FDA is simply not aware of them, an insinuation that has no factual basis. No cases of EMS have ever been proven to be caused by 5-HTP (or, for that matter, uncontaminated L-tryptophan). One wonders why it so imperative to report the presence of inconsequential amounts of Peak X when there is not even a proven causal link between Peak X and EMS, especially considering the thousands, if not millions, of consumers who have ingested 5-HTP without suffering any adverse effects. Does this finding really merit such rapt attention when over one hundred thousand fatalities result from the use of FDA-approved prescription drugs every year?
One of the most interesting aspects of the recent allegations surrounding 5-HTP is that 5-HTP is not synthetically produced, which is significant because the batch of L-tryptophan implicated in the 1989 outbreak of EMS became tainted due to an error in the manufacturing process. Manufacturers extract 5-HTP from the seed of the African plant Griffonia simplicifolia, and hence 5-HTP "is not vulnerable to contamination." Consequently, the chance of 5-HTP ever being associated with an outbreak of EMS is extremely small, if not non-existent.
The L-tryptophan tragedy involved much pain and suffering and hence readily facilitates inflammatory portrayals. The FDA must be praised for its prompt attention to this tragedy. However, through efforts to increase its regulatory control of dietary supplements, the FDA has exploited this unfortunate tragedy and often cites to the incident when recommending greater regulatory control over dietary supplements. The FDA asserts that it simply wants to make the public aware of the potential harms and benefits of dietary supplements and repeatedly emphasizes that more information is needed to corroborate health claims made by dietary supplement manufacturers. The FDA's ban of L-tryptophan, however, illustrates that the FDA's motivations for increasing its regulatory power include an unacknowledged political element
Reprinted with permission of Rutgers Law Journal.
Note: Full-referenced version of article will appear shortly.
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