Posted on 18 Sep 2010 02:31
By Eric Troy, Ground Up Strength
Many people, with or without any scientific evidence, are firmly convinced that the particular foods they eat have a direct influence on their mood, anxiety level and alertness. Perhaps the most well known manifestation of this belief is that certain foods make us sleepy, particularly those with high levels of the amino acid tryptophan. Turkey, at least in the US, is thought to cause sleepiness due to it's high level of tryptophan and this is said to explain why we are so desperate for a nap after Thanksgiving dinner.
The hormone melatonin, or N-acetyl 5-methoxytryptamine, is derived from the amino acid tryptophan in the brain and tryptophan is also used to synthesize the excitatory neurotransmitter serotonin, or 5-OH tryptamine. The level of these substances in the brain certainly have an influence on our state of restfulness or restlessness.
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Nevertheless, the turkey tryptophan connection has been largely debunked. The reason for this, however, is generally misunderstood or misreported. The levels of tryptophan in turkey are comparable to other meats. So, for example, a pork chop contains as much, or more tryptophan as an equivalent amount of turkey, meaning turkey and it's tryptophan content alone cannot be taken to be the culprit for the drowsiness so many of us experience after the holiday meal.
Holiday Meals, Tryptophan, and Sleepiness: It's the Carbs, Man
The actual culprit seems to be the huge carbohydrate blast, including alcohol, that we usually get during these feasts. These meals contain a much larger ratio of carbohydrate to protein when the starches, vegetables, deserts, and alcohol is factored in. A carbohydrate rich meal can increase levels of brain tryptophan and serotonin. As a matter of fact, this can happen even if the meal completely lacks tryptophan.
What happens is that the release of insulin from the carbohydrate ingestion causes the uptake of most of the large neutral amino acids such as valine, leucine, tyrosine, and phenylalanine into muscle cells, leaving tryptophan behind in the blood plasma. Just why tryptophan levels do not decline like the LNAA's is not exactly clear but it may be due to it's binding to albumin molecules on sites that were freed when the free fatty acids occupying them were also released by insulin action. As a result, after this large carbohydrate infusion, plasma tryptophan levels are relatively high.
The LNAA's and tryptophan usually compete for a common carrier molecule for transport across the blood-brain barrier into the neurons. So, when the plasma levels of the LNAA's decrease significantly from a high carbohydrate meal, tryptophan gets a free ride, causing neuronal levels of serotonin to increase.
Warm Milk and Tryptophan
The same thing may happen when you drink a glass of warm milk before bedtime but how the milk being warm affects this is unknown, if it affects it at all. It is true that lactose, the carbohydrate in milk reacts to very high temperature treatment by browning and isomerization. The browning is called the "Maillard reaction" and this occurs between the lactose and the milk's proteins. The flavor and color of milk is affected by the Maillard reaction and a bitter taste occurs. The isomerization causes the lactose (bonded galactose and glucose) to be rearranged to lactulose which is one galactose molecule linked to one fructose molecule. However this isomerization occurs at very high temperatures, upwards of 275 degrees farenheith (135 degress celcius) and would probably not affect the availability of carbohydrate or influence the carbohydrate- serotonin reaction. Still, it is at least feasible that milk or any moderately high carbohydrate intake before bedtime could influence sleepiness. This would presumably occur regardless of the protein level in the food and the tryptophan content of milk has no bearing, warm or not.
There Isn't Enough Tryptophan in There?
So, if these meals really do make us sleepy it is the carbohydrate that is thought to be responsible, regardless of protein levels in the meal. Still, it has often been reported that turkey doesn't make us sleepy "because there isn't enough tryptophan in it". This, further, has led to statements concerning the amount of turkey it would take to actually make one sleep due to direct action. I have read statements such as "it would take 40 pounds of turkey to get enough tryptophan to make you sleepy".
What this type of calculation is based on is not clear but it is likely an effort to correlate the amount of tryptophan in turkey with the typical dosage that people take in supplement form. This is a mistake. The amount of turkey or any other protein source you eat should have no influence on sleep as the intake of LNAA's from this protein source will result in an increase of plasma levels of these amino acids. This will cause competition for brain-uptake of these aminos to increase since, again, the LNAA's and tryptophan compete for a common carrier. So a large protein intake causes brain levels of tryptophan (and serotonin) to decrease, not increase.
The failure of the tryptophan content of protein foods to increase brain levels of tryptophan and serotonin leads many people to conclude that supplemental tryptophan doesn't work. However, it is competition with the other amino acids which causes protein rich foods to fail in tryptophan elevation. This should not be taken to mean that large doses of tryptophan taken alone would also fail. And indeed supplemental tryptophan as a sleep aid has been very popular in the past and many users swear by its effectiveness. But the tryptophan content of protein containing foods is irrelevant except for it's impact on nutrition needs.
Will a Tryptophan Supplement Help Me Sleep?
Although reports from studies into the effect of tryptophan vary widely as to its effects on mood, memory, and sleep, it does seem to act as a mild sedative and to improve sleep in those with sleep problems. Those with mild insomnia or who need extra time to fall asleep seem to get the best results from tryptophan supplementation, whereas the results for people with normal sleep have been mixed or completely absent. Mixed also, are the results of tryptophan loading on those with severe insomnia or with psychiatric illness. Tryptophan has also been reported to have beneficial affects on mood, depression, irritability and mood swings in women with premenstrual dysphoric disorder (PMDD), and sleep apnea. There is even investigation into tryptophan's ability to reduce cigarette cravings. Evidence for all of these behavioral and mood effects is limited, however, and they would probably coincide with an increase in serotonin production, making its affect, if beneficial at all, similar to antidepressant drugs.
By this time it should be clear to the reader that for L-tryptophan alone to be an effective sleep aid it would need to be taken alone and preferably on an empty stomach. Various articles are still portraying L-tryptophan supplementation and drinking a glass of milk as two equal alternatives. While some people may indeed feel more relaxed after drinking milk or after warm milk, this relaxation cannot to be said to have anything to do with the presence of the tryptophan amino acid in milk. So if you want to know whether tryptophan helps you fall asleep, you will need to take it in tablet form as a stand-alone supplement.1
So How Much Tryptophan Do I Take?
Dosage recommendations range from 500 to 1000 mg (1 gram). Although higher dosages may be used if needed. The lowest effective dose may be best due to some remaining concerns about possible harmful side effects (see below for more info).
I've Heard Tryptophan May Be Dangerous. What About That?
On November 17, 1989 the FDA and the United States Center for Disease Control issued a nationwide recall of all L-tryptophan dietary supplement products contain 100 mg or more of the substance and later expanded the recall to include a request for all products containing L-tryptophan except for some food products. Tryptophan remained off the market until 1994 and the passage of the Dietary Supplement Health and Education Act when it was allowed to be sold again as a supplement if manufactured domestically. However, since almost all tryptophan was imported into the US the recall effectively removed the products from the market. Imported products remained banned until 2005.
Eosinophilia-Myalgia Syndrome (EMS)
The withdrawal of tryptophan supplements from the US market and other countries came about because of a number of cases of Eosinophilia-Myalgia Syndrome (EMS) thought to be connected to the use of tryptophan supplements. EMS is a severe neurological condition resulting from high numbers of eosinophil granulocytes (a type of white blood cell) in the blood. The esinophils cause inflammation in nerve, muscle, and connective tissues. Symptoms include severe, often debilitating muscle pain (myalgia) and joint pain, weakness, swelling in the limbs, coughing, rash, fatigue, shortness of breath, difficulty talking and concentrating, memory impairment, oral ulcers and severe fever.
Laboratory findings of this disorder include leukocytosis, elevated eosinophilia, elevated aldolase, (with a normal creatine kinase (CK)) and abnormal liver function
The first reports of this disorder came from New Mexico in 1989 when three women reported incapacitating myalgia and diplayed peripheral eosinophilia. They all were found to have been taking a tryptophan supplement. One of these women, a healthy 44 year-old woman from Santa Fe with a history of allergic rhinitis started had started taking an L-tryptophan supplement in July of 1989 to help with here insomnia. Two months later she had developed a cough, shortness of breath and weakness. She presented with a puffy face, abdominal pain, mucosal ulcers, myalgia and weakness. Her white blood cell (WBC) count was 11,900 cells/mm3, with an eosinophil count of 42%. Her condition worsened through October, with her WBC risingto 18,200 and eosinophil count to 45%.
Her doctor, upon consulting with a rheumatologist, was informed of another patient who had been hospitalized in Santa Fe with similar symptoms and eosinophil count. Eventually over 1500 cases were reported to the CDC and 38 of them resulted in death all with a clear link to tryptophan supplmentation, according to the CDC (click this footnote)2 The actual number of US cases is probably higher since the possible symptoms are similar to fibromyalgia, chronic fatigue syndrome, lupus erythematosus, or arthritis and are likely to be misdiagnosed. Worldwide over 5000 cases have been reported since the initial outbreak. Most patients eventually improved or recovered, with most improving or resolving after 18 to 24 months, although some peripheral neuropathy remained. Other than prednisone which was useful during the acute stages of the illness, no other medication was reported to help with most of the chronic problems resolving on their own.
The EMS outbreak was eventually traced to products sold by a Japanese company, Showa Denko K.K. which had used various cost-cutting manufacturing shortcuts which resulted in a host of contaminants and impurities. Although reports vary as to the number and nature of contaminants found in actual tryptophan samples from the company, high performance liquid chromatographic analysis of some samples showed up to 60 minor contaminants, six of which the report associated with EMS. Reports are ambiguous at best, however, and it cannot rightly be said that a specific causative agent (or agents) has been found since epidemiological studies lack the power of "proof" without the addition of controlled trials.
However, one important substance known as EBT (1,1'-ethylidenebis[L-tryptophan]), otherwise known as "peak E" has been implicated. MTCA (1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid has also been noted. Both chemicals are closely related to L-tryptophan.
Although the company used several questionable methods of manufacture, including using vats associated with fertilizer and reducing the amount of carbon used to filter and purify the product, most of the speculation regarding the origin of the contaminants has centered on the companies use of genetically engineered bacteria to produce the enzyme. This bacteria was meant to produce tryptophan at much higher levels than normal, thus increasing efficiency. The production of food supplements, such as amino acids by bacterial fermentation is very common and tryptophan has been produced this way for many years. Bacteria produce many enzymes, however, so it is desirable to find ways to increase the production of certain target enzymes. Showa Denka inserted several genes into the bacteria to this end. The fact that the company was allowed to immediately place the resulting tryptophan on the market as dietary supplements without any further safety testing other than a history of "safe consumption" of their earlier, non-genetically engineered, products has been a subject of bitter criticism.
What seems to be clear is that products originating from Showa Denka contained contaminants and were associated with toxic affects leading to illness in many users and death in some. However, although there seems to be a fair consensus that the outbreak was a result of contaminants it is far from a foregone conclusion.
Could Tryptophan Itself Be a Culprit in EMS? What about Health Conditions?
Research has continued and it is possible that pure L-tryptophan itself plays a role in development of EMS and that some people may be predisposed to this development, even when using a supplement which is free of contaminants.
According to Smith and Garret, since elevated blood eosinophilia and myalgia can be induced by excessive histamine activity and since an overload of tryptophan can cause increased formation of formate and indolyl metabolites, several of which inhibit the degradation of histamine, tryptophan loading itself can lead to EMS type syndromes. Histamine action must be controlled by factors that terminate their actions. Anything that interferes with these factors can cause rapid and excessive histamine action and this, in turn, leads to the eosinophilia activity. Furthermore some people may be more sensitive to increases in histamine and tryptohphan.
Barth, et al. surmise a link between patients with so-called "Functional Somatic Sydrome" which is an umbrella term encompassing such things as fibromyalgia, chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS) and multiple chemical sensitivity. Barth and colleagues hypothesized that since tryptophan is particularly taken by individuals with functional somatic sydrome that EMS may develop as an allergic reaction to the contaminant "peak E" (mentioned above). Their studies found a heightened immunological reactivity towards l-tryptophan and peak E in these individuals may implicated EMS as an allergic disease.
Maybe It Wasn't the Tryptophan Supplements At All
Horwitz and Daniels, however, criticized the methodology of the epidemiologic studies of the relationship between intake of L-tryptophan and the occurrence of eosinophilia-myalgia syndrome. They studied information provided in the published reports and underlying data and documentation of the studies obtained from the US Centers for Disease Control and state health department and complained of diagnostic bias, publicity, recall and reporting bias, bias in the inclusion and exclusion of cases and controls, inequalities between cases and controls in the indications for the use of LT, and failure to ensure that the exposure to LT preceded the onset of symptoms of EMS. They assert that the assumption that the underlying cause of the EMS outbreak was tryptophan supplements or some contaminant is unfounded and that research into the true cause of the outbreak should continue without this assumption.
The reader should bear in mind that virtually all disease outbreaks and subsequent reaction by state and federal agencies are met with criticism much of which has the tone of "arm-chair quaterbacking". It would be surprising not to find flaws in the edemiological response to such outbreaks since all outbreaks are unique and the response is an emergency response in the midst of a public health crisis. As said above, it is not a foregone conclusion that a contaminant(s) was responsible for the EMS outbreak or, indeed, that tryptophan was the underlying culprit at all, despite a widespread consensus. But post-facto criticism of these findings do not come close to establishing the safety of tryptophan, which is prone to contamination even at the best of times and may be implicated even in the absence of contamination. Although it is a distinct possibility that tryptophan supplements, and particulary those from Showa Denko, were not to blame for the EMS outbreak, any flaws in the epidemiological methods, whether real or imagined, do not establish that tryptophan supplements were NOT the culprit, as some authors have asserted. As Horwitz and Daniels themselves concluded, more research should be done to assertain for certain the cause of the disease, whether it turns out to be tryptophan supplements or not. For now the jury is still out but there is room for some reasonable doubt as to the safety of tryptophan supplements into the future. It is up to the user to decide whether or not to take tryptophan supplements.
Tryptophan Sources: Where Can I get the Good Stuff?
There are many suppliers of tryptophan including from China, Canaday, Japan and the U.S. Accoring to ConsumerLab many of these suppliers produce the amino-acid as a feed additive for livestock. One apparently high quality source of tryptophan comes from a Japanese company Ajinomoto. This company's branded product is called "TryptoPure" and during the ban on tryptophan imports between 1989 and 2995 this was teh only product allowed to be imported for pharmaceutical use. It is still reportedly use in pharmaceutical products and in infant formulas.
Some products that claim to be made with the TryptoPure L-tryptophan are Swanson, Doctor's Best, Life Extension, Doctor's A-Z, Jarrow Formulas, Blue Bonnet, Life Enhancement, Pure Encapsulations and Progressive Labs.
Possible L-Tryptophan Drug Interactions
There are many possible interations between dietary L-tryptophan supplements and pharmaceutical drugs. Of special concern are any drugs with erotonergic activity such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists, ergot alkaloids, lithium, phenylpiperidine opioids, dextromethorphan, and even St. John's wort. Use of any of these drugs along with tryptophan could increase the risk of "serotonin syndrome" (SS) which is a rare but extremely serious and potentially fatal condition. SS is thought to result from the hyperstimulation 5-HT1A and 2A receptors in the brainstem. Please consult your pharmacist and doctor about the medication you are taking and how it may interact with an L-tryptophan supplement before you consider using one.
Possible symptoms of Serotonin Syndrome
- Agitation or restlessness
- Rapid heart rate
- Dilated pupils
- Loss of muscle coordination or twitching muscles
- Heavy sweating
- Abdominal Cramping
- Goose bumps
- High fever
- Heart Arrhythmia (Irregular heartbeat)
- Tachycardia (Rapid heartbeat)
- Blood Pressure Lability (Blood pressure fluctuation from normal to high)
- Neuromuscular problems (hyperreflexia, myoclonus, tremor, rigidity, and ataxia)
- Unconsiousness (Coma)
Depression Medications that could interact negatively with tryptophan
- citalopram (Celexa)
- escitalopram (Lexapro)
- fluoxetine (Prozac)
- paroxetine (Paxil)
- sertraline (Zoloft)
- amitriptyline (Elavil)
- mipramine (Tofranil)
- venlafaxine (Effexor)
Benzodiazepines that could interact negatively with tryptophan
- Alprazolam (Xanax®)
- Chlordiazepoxide (Librium®, Limbitrol®, Librax®)
- Clonazepam (Klonopin®)
- Clorazepate (Tranxene®)
- Diazepam (Valium®)
- Estazolam (ProSom®)
- Flurazepam (Dalmane®)
- Lorazepam (Ativan®)
- Midazolam (Versed®)
- Oxazepam (Serax®)
- Quazepam (Doral®)
- Temazepam (Restoril®)
- Triazolam (Halcion®)
Monoamine oxidase inhibitors (MAOIs), that could interact negatively with tryptophan
- Isocarboxazid (Marplan®)
- Phenelzine (Nardil®)
- Rasagiline (Azilect®)
- Selegiline (Eldepryl®, Emsam®, Zelapar®)
- Tranylcypromine (Parnate®)
Phenothiazines that could interact negatively with tryptophan
- Chlorpromazine (Thorazine®)
- Perphenazine (Trilafon®)
- Prochlorperazine (Compazine®, Compro®)
- Thioridazine (Mellaril®)
- Trifluoperazine (Stelazine®)
- Tramadol (Rybix™ ODT, Ryzolt®, Ultram®, Ultram® ER) or tramadol/acetaminophen (Ultracet®)
- St. John's wort
Migraine Medications that could interact negatively with tryptophan
- Triptans (migraine medications)
- Almotriptan (Axert®)
- Eletriptan (Relpax®)
- Frovatriptan (Frova®)
- Naratriptan (Amerge®)
- Rizatriptan (Maxalt®)
- Sumatriptan (Imitrex®)
- Zolmitriptan (Zomig®)
- Sumatriptan injection (Sumavel™ DosePro™))
Pain Medications that could interact negatively with tryptophan
- Tramadols (pain medications)
- Rybix ODT
- Ultram ER
- Ultracet (also contains acetaminaphen)
Sedatives or Tranquilizers that could interact negatively with tryptophan
- diazepam (Valium)
- lorazepam (Ativan)
- clonazepam (Klonopin)
Health Conditions that May Preclude the use of L-Tryptophan
- liver disease;
- kidney disease;
- eosinophilia (high levels of a certain type of white blood cells)
2011 Update on Possible Tryptophan Related EMS Cases
Since this article was published there has been one reported and published case of EMS associated with L-Tryptophan. In addition there have been two other reports made to the FDA of EMS and two reports of muscle pain related to tryptophan, between 2003 and 2010. Note that the tryptophan ban was lifted in 2005. The potential danger of tryptophan to consumers, if any, is far from definitive. Consumers should be aware that there may be a danger of EMS related illness to some users who are biologically susceptible and this danger may not be related to impurities in the product. However, the extent to which this danger exists has not been shown. 20,21
Melatonin, which has no similar adverse incidents related to it's use, does seem to work for some people. Even in studies, however, the effects are far from universal. It should be noted that the American Academy of Sleep Medicine does not recommend the use of melatonin for sleep promotion without the supervision of a doctor. Also, in Europe, melatonin is only available with prescription. Typical dosage is about 3mg of an extended release formula taken one hour before bedtime.
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