Tryptophan side effects, contrary to claims by many experts, are rather serious. Many nutritional supplement manufacturers and promoters advertise and market the substance as an exceedingly safe natural health product -with a preferential emphasis on numerous alleged benefits (e.g., fights depression, anxiety, attention deficit hyperactivity disorder (ADHD), premenstrual syndrome (PMS), and is a natural sleeping aid).
Yet, tryptophan side effects are seldom, if ever, mentioned or explained in a comprehensive manner, giving the impression that such data doesn't exist (or that there are only benefits of tryptophan).
The widespread unison agreement among experts and marketers in support of tryptophan's safety (and effectiveness) is reminiscent of an observation made by the entrepreneur and author Seth Godin:
“It's easy to pretend expertise when there's no data to contradict you.”
Fact is, there is plenty of solid data on tryptophan that contradicts the mainstream perspective. Tryptophan side effects are numerous, and several of them are quite problematic.
The plethora of scientific research suggests that it is best to avoid consuming L tryptophan as a stand-alone, individual nutritional supplement on a long-term basis in order to prevent the deterioration of your health due to some rather grave tryptophan side effects.
Generally, there are L tryptophan side effects of more minor importance and severity, such as most acute transient events, and there are the more problematic tryptophan side effects that often have a long “incubation period” until, eventually, worrisome health issues become evident.
In the body tryptophan is metabolized, via two basic pathways, the indole-kynurenine-niacin pathway and the serotonin-melatonin pathway (Chung & Gadupudi, 2011). Virtually all catabolites (besides niacin) are implicated with significant tryptophan side effects.
An experiment (Greenwood, et al., 1975) with a one-time dose of 5g of the amino acid evoked these immediate tryptophan side effects:
Similar studies confirmed these acute outcomes, including dizziness, fatigue, and lethargy, among the more customary actue tryptophan side effects (Yuwiler, et al., 1981; Cunliffe, et al., 1998).
Now, let's get on with tryptophan side effects of higher complexity and grimness...
A study (Trulson & Sampson, 1986) demonstrated that high doses of L-tryptophan caused liver damage in animals. Although the study authors reported that they used doses “within the range commonly taken by humans for sleep induction” it seems to contradict their methodological data.
According to the information in their study protocol, the amount they fed the animals would equate to around 6-8g/day of L-tryptophan for most people. A typical therapeutic tryptophan dosage (doses of L tryptophan for insomnia and depression) is in the 50mg-3g range (Braverman, 2003). The apparent discrepancy could be because higher doses of L-tryptophan, around 8-10g/day, were used not infrequently by a fair number of people during the 1980s and prior.
A similar animal study to the Trulson & Sampson (1986) experiment, using also comparably high doses of L tryptophan (roughly 4-6g/day for humans), didn't lead to tryptophan side effects such as morphological changes to the liver in healthy animals (Bucci, et al., 1982). Tryptophan side effects only appeared in those animals that had received a bypass treatment in their liver, which deranged their tryptophan metabolism. This allowed for the accumulation of high plasma tryptophan levels upon the administration of the amino acid (Bucci, et al., 1982).
Other studies on animals, however, raised more serious concerns about tryptophan and liver function...
Liver enzymes form highly mutagenic L-tryptophan degradation products (e.g., 3-amino-1-methyl-5H-pyrido[4,3-b]indole) that cause damage to the liver, including cancer (Nemoto, et al., 1979; Yamazoe, et al., 1980 & 1981; Ashida, et al., 1998; Suzuki, et al., 2008). In health people a low salt intake activates the serotonergic system and increases L-tryptophan decomposition substances (Sharma, et al., 1993), raising the risk for side effects of tryptophan.
An animal study indicated that the addition of miso, a fermented soybean product, prevented the liver injury that was caused by at least one of these mutagenic tryptophan breakdown components (Suzuki, et al., 2008). A study with humans found similar protective effects by drinking coffee (Bichler, et al., 2007). Sulforaphane, a constituent of broccoli, and curcumin, a constituent of the spice turmeric, are also antagonistic to the mutagenic impact of some decomposition products of tryptophan (Shishu, et al., 2002; Shishu & Kaur, 2003).
It had been demonstrated that white tea, much more so than green tea, reduced tryptophan side effects, such as mutagenic harm, from some of these poisonous metabolites (Santana-Rios, et al., 2001). Other investigations elucidated that some vitamins, such as beta-carotene, vitamin A, B6 & E, have ameliorating activities against these poisonous L tryptophan side effects from metabolites (Edenharder, et al., 1998; Chung & Gadupudi, 2011).
The biologist Raymond Peat, PhD, pointed out how an animal study on L tryptophan demonstrated that the amino acid may increase the risk for cataracts by disrupting the energy metabolism of the eye lens, and thus Peat cautioned against the practice of using tryptophan supplements (Peat, Spring 2006).
Research on human eye lenses revealed that at least some tryptophan metabolites bind with proteins in the lenses and may be responsible for the yellowing of the lens that often becomes evident with aging (Takikawa, et al., 2003). The catabolites' hampering of the metabolic energy processes in the lens, inducing a relative energy shortage, could partly account for the clouding effect of the lens because of a proportional impairment and inefficiency of removing cellular debris, such as cell components that got damaged by reactive oxygen species (free radicals).
As far as tryptophan side effects from its melatonin end product concern, the neurohormone especially shouldn't be consumed -even occasionally- during the daytime because melatonin has been found to react with sunlight (UVA rays), potentially leading to visual disturbances during daytime (Gagné, et al., 2009) like blurred vision (as experienced by some people), and eye damage (Wiechmann & O'Steen, 1992; Sugawara, et al., 1998; Kim, et al, 1999; Wiechmann, 2002; Wiechmann, et al., 2008).
Free radicals such as singlet molecular oxygen are among the principal light-induced harmful agents responsible for injury to the skin and eyes (Matuszak, et al., 2003). While melatonin is said to be a strong antioxidant it is capable of generating singlet molecular oxygen upon light stimulation, whether via UV or laser rays (Matuszak, et al., 2003; Maharaj, et al., 2005). Melatonin is elevated in animals with retinal damage (Hawlina, et al., 1992). Similarly, retinal dystrophy (=degeneration) upon the addition of melatonin were found in research projects involving humans (e.g., Mironova, et al., 1989). Ocular tryptophan side effects apparently encompass the use of melatonin.
“[...] the pharmaceutical industry's myth has led people to believe that serotonin is the chemical of happiness, and that tryptophan is its benign nutritional precursor […].” (Raymond Peat, PhD, Biologist, in 2009)
Some studies (e.g., Metzner, et al., 2005; Frølund, et al., 2010; Edwards, et al., 2011) found that L tryptophan, and some of its derivatives like 5-hydroxytryptophan (5HTP), and serotonin (5-hydroxytryptamine or 5-HT) efficiently block a carrier protein for numerous protective substances, including GABA (gamma amino butyric acid), short chain fatty acids, glycine, proline (and for cancer drugs).
This indicates that L tryptophan supplements may excessively disrupt protein absorption in the intestine. And, it may hamper optimal brain function since the transporter protein is also present in the brain (and some other organs). Related research, for instance, indicated that certain tryptophan degradation substances may block the glycine receptor in the brain (Stone, 1993; Erhardt, et al., 2009).
These tryptophan side effects may partially explain the link between higher serotonin levels and migraines and mood disorders (Mohammad-Zadeh, et al., 2008) since among the many GABA benefits is its protective impact on brain cells (Vaishnav & Lutsep, 2002; Mirzoian, 2003) and GABA is reduced in people with mood and anxiety disorders (Shiah & Yatham, 1998; Brambilla, et al., 2003; Winkelman, et al. 2008; Streeter, et al., 2010) and also Alzheimer's Disease (Mohr, et al., 1986). Other tryptophan side effects, conferred by several degradation products, encompass the direct suppression of the functioning of GABA (Zarkovsky, 1986; Guilarte, et al., 1988; Kanai, et al., 1989).
Glycine and short chain fatty acids, like GABA, have an inhibitory calming action on the brain.
Animal studies (e.g., Pechenova, et al., 1983) have documented that tryptophan loading disturbs protein synthesis, leading to protein deficiency. Tryptophan side effects from “loading” the amino acid has also been reported in humans. The infusion of tryptophan in healthy young men, at commonly used doses (1g/day, 3g/day, 5g/day), depleted the levels of many other amino acids such as tyrosine which is vital for brain function -at all doses studied (Heuther, et al., 1992).
Some of tryptophan's breakdown products act as potent neurotoxins, via elevating excitatory glutamate levels and free radical production, while some metabolites (from tryptophan catabolism) appear to protect brain cells (Huether, et al., 1999; Stone, 2003; Sas, et al., 2007).
An in vitro study found that two tryptophan side effects were the depletion of brain antioxidants and increased lipid peroxidation (free radical production) in brain tissues (Feksa, et al., 2006). These particular tryptophan side effects, which are a result of an imbalance between neuroprotective and neurotoxic effects, are implicated in a number of degenerative brain diseases such as Alzheimer's, Parkinson's, and Huntington's Disease, but also in epilepsy and strokes (Németh, et al., 2005; Feksa, et al., 2006; Sas, et al., 2007; Reyes Ocampo, et al., 2014).
Closely related to these tryptophan side effects, in experiments it has been established that serotonin is capable of (temporarily) impairing the protective blood-brain barrier (Winkler, et al., 1995; Abbott, 2000; Sharma, 2004) which could lead to an increase in toxic events in the brain, such as edema (brain swelling) and brain degeneration (Sharma, 2004).
A researcher stated in his analysis that:
“Elevation of plasma and tissue serotonin occurs under a wide variety of neurological and psychiatric conditions.” (Sharma, 2004)
Concerning acute serotonin side effects and serotonin toxicity...
One of the worst case scenarios of an overload of serotonergic activity is the occurrence of the serotonin syndrome (symptoms usually appear within a day or a few days), which kills numerous people every year (Young, et al., 2008). Usually, this is an outcome of doctor prescribed polypharmacy whereas a person ingests numerous serotonin-boosting medications (such as selective serotonin reuptake inhibitors or SSRIs), or instances of great exposure to a single serotonin-augmenting agent (Ables & Nagubilli, 2010).
Some of the symptoms of serotonin syndrome are mental and neuromuscular agitation, confusion incoordination, seizures, fever, and organ failure (Ables & Nagubilli, 2010).
Many years ago researchers (e.g., Jacobs, 1991) have already warned that the external stimulation or manipulation of the serotonergic system by psychotropic drugs raises the levels of serotonin beyond the range from living under normal conditions, more reflective of a pathological (=diseased) state.
Yet, since around the 1980s, when the medical-pharmaceutical industry began to heavily promote the type of psychotropic drugs that specifically raise brain serotonin activity such as selective serotonin reuptake inhibitors, or SSRIs, it has become "common knowledge" that serotonin -"the chemical of happiness"- is the antidote to depression. The perpetual inundation of the public with the serotonin deficiency-depression paradigm (in support of the "chemical imbalance" model) has earned the drug companies a fortune ever since from the sale of serotonin-stimulating medications (i.e., SSRIs).
However, independent investigators, such as David Healy, MD, the author of several books on psychoactive drugs, stated that:
"[...] it is now widely assumed that our serotonin levels fall when we feel low [...]. But there is no evidence for any of this, nor has there ever been." (Healy, 2004) [emphasis added]
Another researcher and author of a number of books on SSRI's and other antidepressants, Peter R. Breggin, MD, pointed out that:
“Science does not possess the technology to measure biochemical imbalances in the living brain. The biochemical imbalances speculation is actually a drug company marketing campaign to sell drugs.” (Breggin, 2001) [emphasis added]
(But it isn't uncommon for the medical establishment to spread and sustain myths based on vested interests. Other examples are the myth of estrogen hormonal therapy, or the myth that mammograms do little harm and prevent women from succumbing to an early death from breast cancer -see The Mammogram Myth: The Independent Investigation Of Mammography The Medical Profession Doesn't Want You To Know About.)
In his book "Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare" (2013) author and research scientist Peter Gøtzsche, MD explained that "the chemical imbalance hoax" is inescapably showcased by the fact that the number of mentally disabled has skyrocketed since the introduction of psychotropic medications (antidepressants and antipsychotics) whereas you would expect to find the exact opposite if these drugs were to actually correct an alleged chemical imbalance in the brain. In fact, Gøtzsche argued that these drugs create psychological disorders, especially the way they are being prescribed (Gøtzsche, 2013).
These were also among the findings and conclusions brought forward a few years earlier in some other books. In their exhaustive efforts, the authors, Joanna Moncrieff, MD, Grace Jackson, MD, and Robert Whitaker, solidly documented, with many brain images, illustrations, graphs, and references, that psychopharmaceuticals, particularly on an ongoing long-term protocol of usage (the mode these drugs are commonly used), cause brain shrinkage, neurodegeneration, dementia, premature death, and are the culprit for the epidemic of mental illness and disability in America (Moncrieff, 2008; Jackson, 2009; Whitaker, 2010 & 2011).
Truth be told, there is disturbing, sound evidence on how the intake of SSRIs (e.g., Prozac, Paxil, Zoloft) can lead to violence, suicide, and sexual dysfunction (Breggin, 1995 & 2001; Glenmullen, 2000; Healy, 2004; Burwell & Stith, 2008; Gøtzsche, 2013). The drug company that created Prozac, for example, already knew before they began to market the drug worldwide to the unsuspecting public that it significantly increases the risk of suicide (Healy, 2004). In 2006 a drug maker of one of these SSRIs admitted that the medication raises the risk of suicide eight times (Jay, 2010).
In an interview Breggin stated that:
"One of the things that in the past had been known about depression is that it very, very rarely leads to violence. It's only been since the advent of these new SSRI drugs that we have murderers, sometimes even mass murderers, taking antidepressant drugs."
Other tryptophan side effects, or more accurately, serotonin side effects from the use of SSRIs, have been uncovered.
Several research reports found that the long-term use of SSRIs leads to osteoporosis and hip fractures in both genders and at all age ranges, from adolescents to elderly people (Diem, et al., 2007; Haney, et al., 2007 & 2010; Williams, et al., 2008; Calarge, et al., 2007 & 2011), probably by increasing prolactin concentrations (Calarge, et al., 2007; Allport, 2008; Peat, Sept. 2011) and the stress hormone cortisol (Peat, Nov. 2008). Melatonin, for example, was denoted to stimulate prolactin release in healthy young women and men (Webley, et al., 1988; Okatani, et al., 1994; Kostoglou-Athanassiou, et al., 1998). Experiments on animals (e.g., Weinstock, et al., 1985) corroborated that melatonin amplifies the stress hormone prolactin.
Serotonin raises both prolactin (Jørgensen, 2007; Oberweis & Gragnoli, 2012) and cortisol (Peat, Nov. 2008). And, both of these substances contribute to osteoporosis (Peat, Sept. 2011).
In addition, it was also discovered that serotonin in the intestine, rather than merely in the brain from the influence of SSRIs, causes bone loss (Peat, Sept. 2011). Thus, “plain” serotonin, rather than some idiosyncratic effect of SSRIs, is causatively involved in osteoporosis. And arguably, the bone loss disease can be included on the list of tryptophan side effects since the amino acid is the basic precursor to serotonin.
The lucrative trend surrounding the "artificial" up-regulation of serotonin by drugs to, supposedly, improve brain function hadn't gone unnoticed by promoters of nutritional supplements. To get their share of the profitable marketing of serotonin as the vehicle to "emotional bliss", and to distinguish themselves from the drug companies, many supplement promoters have been claiming that tryptophan, the precursor for serotonin, is an effective, cheaper alternative to the serotonin-enhancing medications, and that this alternative is allegedly devoid of tryptophan side effects because it is a "natural" substance.
Besides the already mentioned reports on the destruction of brain antioxidants and the generation of free radicals in neuronal tissue by the amino acid, other brain dysfunction has been linked to tryptophan side effects from metabolites. One of the principal L-tryptophan catabolites, 3-hydroxy-kynurenine (3-HK), augments oxidative stress in the brain and is able to induce depression, epileptic seizures, and other brain damage (Guilarte & Wagner, 1987; Stone, 2003; Wichers & Maes, 2004).
Elevated levels of 3-HK and another product of the kynurenine pathway, kynurenic acid (KA or KYNA), have also been found in people with schizophrenia, and the research indicates these substances are also involved in allied psychiatric disorders such as bipolar disorder, previously more often referred to as manic depression (Linderholm, et al., 2007; Erhardt, et al., 2009; Johansson, et al., 2013).
Among other brain-related tryptophan side effects are impaired learning capabilities from higher levels of serotonin (Peat, Spring & Summer 2009). This may relate to the findings of clinical investigations which reported that serotonin strongly decreased blood flow in the brain (Grome & Harper, 1983; Hajdu, et al., 1993; Aleksandrin, et al., 2005). Poor cerebral circulation means that brain cells receive less nutrients, oxygen, and energy, leading to poor cognitive performance.
Focused attention is not compromised, but rather improved, by a tryptophan deficiency in the brain (Mendelsohn, et al., 2009). Alongside the positive cognitive ramifications of improved blood circulation in the brain from a tryptophan deficiency, this is probably also the result of a corresponding lack of activation of excitatory dopamine neurons by certain tryptophan catabolites (Linderholm, et al., 2007; Erhardt, et al., 2009). As might be expected, the excessive stimulation of brain cells by dopamine hampers cognitive function which is evident in attention deficit disorder (ADD) and Attention-deficit/hyperactivity disorder (ADHD). This speaks against the routine use of tryptophan for ADHD and ADD, as to prevent cognitive-neurological tryptophan side effects.
The exposure to stressors or living under (progressively) stressful conditions, including during aging, increases the production of oxidative tryptophan degradation chemicals such as the kynurenines, particularly in the brain which may contribute to the cognitive decline with advancing age (Kepplinger, et al., 2005; Reyes Ocampo, et al., 2014), suggesting that such predicaments or contexts:
In animal experiments, for example, pyridoxine supplements (vitamin B6) prevented or ameliorated some of the deleterious kynurenine-mediated tryptophan side effects in the brain (such as memory/cognitive impairment) seen with pneumonia-incited bacterial meningitis (Barichello, et al., 2014).
Brain-related tryptophan side effects have also been reported in the scientific literature from one of the amino acid's end products, melatonin. Studies (e.g., Carman, et al., 1976; Dubocovich, et al., 1990) found that the addition of melatonin worsened depression, or, respectively, the suppression of melatonin improved symptoms of despair.
EMS is a group of debilitating inflammatory connective tissue disorders that tend to affect many organs and tissues.
The 1989 tryptophan eosinophilic myalgia incident killed a number of people and seriously disabled many victims permanently (Braverman, 2003).
However, it was mainly a transient, epidemic catastrophe. The reason for this is that the tryptophan-EMS disaster was virtually exclusively the result of product contamination by one particular nutritional supplement manufacturer (Showa Denko).
Nevertheless, it appears likely that the development of tryptophan-associated EMS is assisted and augmented by inflammatory, natural tryptophan metabolites (Gross, et al., 1999; Rieber & Belohradsky, 2010) because untainted L tryptophan has been shown to lead to an increase of free radical production (lipid peroxidation) in muscles (Ronen, et al., 1999). Myalgia (muscle pain) is a distinctive feature of EMS and fibromyalgia.
Another study, conducted by US government researchers, that compared EBT-tainted L-tryptophan (an analogue toxin implicated in the tryptophan-EMS epidemic of 1989-1990) to pure tryptophan supplements on rats (at a human equivalent dose of 5-6g/day over a prolonged time period) noted that:
"This study also strongly suggests that control L-TRP [=pure tryptophan] alone plays an important role in this [=EMS] and possibly other fibrosing illnesses, because it is associated with mild but significant myofascial thickening and alterations in peripheral mononuclear cell phenotypes, as well as with significant pancreatic pathology." (Love, et al., 1993) [explanation & emphasis added]
That is, the ingestion of an unadulterated version of the amino acid led to tryptophan side effects, such as the impairment of immunity, alterations in muscle tissue, and the growth of excessive connective tissues (fibrosis) and other structural modifications in the pancreas, supporting the existing evidence that L-tryptophan itself is problematic -at least at proportionally high, but not hugely excessive, doses since up to 3g/day is not considered a "high dose" (the average intake dose of contaminated tryptophan-associated EMS victims was at around 2g/day, with a range from 10mg to 35g/day, and people who consumed 4g/day, and more, had a greater likelihood to develop EMS [Crist, 2005]).
In a study report the authors stated in reference to the adulterated tryptophan eosinophilic myalgia disaster of 1989:
“Since only a fraction of persons who ingested implicated batches of LT [=L-tryptophan] developed disease, additional factors likely played pathogenetic roles.” (Okada, et al., 2009) [explanation & emphasis added]
Since there are indications that the unique, most probable source of the 1989 L tryptophan-EMS catastrophe still hasn't been really resolved in the United States, it is conceivable that more tryptophan EMS cases will surface. At least one new tryptophan EMS case has appeared in 2010 after the ingestion of a L-tryptophan nutritional supplement from the United States, other tryptophan EMS cases have also turned up in recent times (for detailed information on the tryptophan-EMS epidemic of 1989 read my article L Tryptophan: The Truth About The FDA Tryptophan Recall Of 1989).
The amino acid's significant inflammatory potential is prominent among many tryptophan side effects. For example, rats fed a higher tryptophan diet for a prolonged time experienced greater inflammation in their lungs, leg muscles, and other organs, and tissue damage was intensified by a tryptophan metabolite (Gross, et al., 1999). Other investigations indicated that some inflammatory degradation products of L tryptophan have diabetogenic activities (Ellis & Presley, 1973; Gerras, et al., 1977).
While serotonin, a product of tryptophan metabolism, can induce muscle degeneration (Beitner, et al., 1983; Peat, Fall 2006), another frequent, and possibly more likely, culprit for this type of damage are L-tryptophan decomposition substances.
Because the L tryptophan intake dose corresponds positively with inflammatory metabolites of the amino acid (Okuno, et al., 2008) and because most supplemental tryptophan doesn't convert into serotonin in humans (only about 1-5% [Glenmullen, 2000; Peat, March 2011]) but rather into inflammatory breakdown elements (Green, et al., 1980; Heuther, et al., 1992). These injurious tryptophan decomposition products remain elevated with longer term consumption of supplemental tryptophan (Green, et al., 1980), particularly with higher doses (around 2-8gm/day).
Inflammatory L tryptophan metabolites dramatically increase the production of reactive oxygen species (free radicals or oxidative stress) after the ingestion of a large dose (6gr) of the amino acid (Forrest, et al., 2004).
Other inflammatory conditions are linked to tryptophan side effects.
Studies (e.g., Smith & Garrett, 2005) indicate that the consumption of moderate-high dose tryptophan supplements leads to an elevation of histamine, an inflammatory substance involved in many degenerative diseases (including multiple sclerosis [Peat, Nov. 2008]), by blocking its degradation.
Tryptophan side effects also extend to inflammation involving melatonin. In people with nighttime asthma and rheumatoid arthritis, for example, it is melatonin side effects, such as increased inflammation, that contribute to the longevity of the diseases (Sutherland, et al., 2003; Cutolo, et al., 2005).
Serotonin, which is increased by L tryptophan loading (Mateos, et al., 2009), is clearly implicated in cardiovascular disease and other tryptophan side effects (Gaddum & Hameed, 1954; Koren-Schwartzer, et al., 1994; Mohammad-Zadeh, et al., 2008; Peat, Summer 2009; Maclean & Dempsie, 2009 & 2010).
In an investigative paper the researchers commented on...
“[...] the damaging effects of serotonin, whose concentration in plasma increases in many diseases and is implicated as playing an important role in circulation disturbances.” (Assouline-Cohen, et al., 1998) [emphasis added]
To briefly refer to the history of tryptophan, since the late 19th century it was noted that a compound, which was identified in 1948 as serotonin, can induce platelet aggregation which leads to blood clumping or blood clots (Woolley & Shaw, 1954; Donaldson & Gray, 1959). The observation led to the adoption of one of the early names for the substance, thrombotonin, a derivative of thrombus (=blood clot).
Since the late 1930s it had been recognized that a substance, which turned out to be serotonin, is involved in the development of high blood pressure by constricting blood vessels (Donaldson & Gray, 1959). This physiological event is analogous to serotonin's “contracting” effect in gut muscles causing intestinal peristalsis which is the physiological process of rhythmically pushing food along in the gut (Gaddum & Hameed, 1954; Woolley & Shaw, 1954).
There has been scientific evidence (e.g., Weinstock, et al., 1985) demonstrating that tryptophan side effects from serotonin, such as blood vessel constriction (vasoconstriction), leading to high blood pressure (hypertension) , also occurs with melatonin.
“It could be concluded that tryptophan metabolites play a complementary role in promoting carcinogenesis […].” (Chung & Gadupudi, 2011)
Serotonin's established involvment in the promotion of blood clotting (coagulation) has further ramifications.
Research in the 1960s by Domenico Agostino, VMD and Eugene Cliffton, MD showed that a greater propensity of blood clotting correlates with a higher probability for cancer metastasis which is the spreading around of cancer in the body (Martin, 1977). By the way, this idea had first been proposed at around the mid 19th century (Trousseau, 1865; Marinho & Takagaki, 2008).
Blood clots develop because blood platelets become too numerous or very “sticky” (platelet aggregation). Agostino and Cliffton reasoned that cancer cells find a protective cover in blood clots by getting trapped among the sticky cells, making it difficult or impossible for the immune system to detect them (Agostino & Cliffton, 1962 & 1963). This process assists cancer cells in their growth, progression, and dispersion inside the body (Agostino & Cliffton, 1962 & 1963).
The link between clotting and metastasis is soundly corroborated (Boccaccio & Medico, 2006; Mousa, 2006; ten Cate & Falanga, 2008).
In a more recent research paper the author stated that:
“Hypercoagulation is documented in virtually all cancer types, [...], and is the second leading cause of death in cancer patients.” (Mousa, 2006)
In spite of the findings by Agostino and Cliffton decades ago, it is still better known that cancer cells can activate excessive coagulation (blood clotting by platelet aggregation), rather than that hypercoagulation assists and facilitates the progression of cancer into advanced metastasis (Mousa, 2006).
Notwithstanding, it establishes that one of the indirect tryptophan side effects, via serotonin, is the promotion of metastatic cancer.
Equally disturbing, a research investigation (Friedman, et al., 2009) that studied many types of pharmaceutical medications found, for instance, that Prozac and Paxil, two serotonin-activating drugs (SSRI antidepressants), are quite possibly carcinogenic (=cancer-causing).
The inflammatory nature of several of the breakdown substances of L tryptophan, leads to one of the worst direct tryptophan side effects: the causation and promotion of cancer.
In the 1950s researchers demonstrated that specific tryptophan metabolites and the addition of “unnatural” DL-tryptophan to the diet of test subjects cause bladder cancer in animals (Dunning, et al., 1950; Pipkin, et al., 1969). In other experiments the same cancer-causing tryptophan breakdown compounds were recovered after adding the “natural” L-tryptophan (Brown & Price, 1956).
At least some of these catabolic substances are highly mutagenic and, as mentioned, can induce liver cancer (Nemoto, et al., 1979; Yamazoe, et al., 1980 & 1981; Ashida, et al., 1998; Suzuki, et al., 2008). Certain tryptophan degradation substances can also form carcinogenic nitrosamines which have been shown to cause bladder cancer, including in humans (Cohen, et al., 1979; Watanabe, et al., 1979; Ohta, et al., 1983; Abdel-Tawab, et al., 1986; Watanabe, 1997; Chung & Gadupudi, 2011). Tryptophan metabolites are also involved in other types of cancers such as cervical cancer (Fotopoulou, et al., 2011).
Two of the mutagenic tryptophan catabolites, 3-amino-1, 4-dimethyl-5H-pyrido [4, 3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, are widely present in the envirionment and have been found in cigarette smoke, airborne particles, rain water, and cooked food (Manabe & Wada, 1991). In a study on rats, 3-amino-1-methyl-5H-pyrido[4,3-b]indole significantly increased the incidence of liver and bladder cancer (Takahashi, et al., 1993). Smokers have an increased risk of bladder cancer (Brennan, et al., 2001) and probably of liver cancer too (HHS, 2004).
In addition, there are tryptophan side effects associated with existing cancer. Specifically, immune dysfunction has been connected to tryptophan side effects, enabling the malignancy's survival and promoting its progression.
Investigators observed that in malignant tumors several tryptophan metabolites (kynurenine, etc.), nurtured by the catabolizing enzymes indoleamine-2,3-dioxygenase and tryptophan-2,3-dioxygenase, notably inhibit “antitumor immune responses” by inducing apoptosis (=cell suicide) in healthy cells of the immune system (Frumento, et al., 2002; Zamanakou, et al., 2007; Opitz, et al., 2011; Platten, et al., 2012). Tryptophan-derived kynurenine is actively involved in human brain cancers (Opitz, et al., 2011).
Thus, L-tryptophan is the only amino acid that is capable of causing cancer in humans (Peat, Fall 2006). The most likely way, besides through the nitrosamine-metabolite route, is by tryptophan's role as an estrogen-imitating agent (Peat, Spring 2009).
A moderate dose of 900mg/day of supplemental tryptophan, added to an experimental diet of six healthy women, increased these carcinogenic metabolites very significantly, compared to receiving only the experimental diet (Watanabe, et al., 1979). The excretion of the L tryptophan metabolites correspond proportionally to the dietary/supplemental intake (Brown & Price, 1956). One of the toxic tryptophan catabolites, 3-hydroxykynurenine, apart from its implication in human bladder cancer, also “has affinity for the pancreas” (Watanabe, 1997). Another harmful metabolite or tryptophan poison, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, caused an increase in invasive pancreatic cancer in a study on hamsters (Yoshimoto, et al., 1999).
Dogs excrete relatively large amounts of tryptophan metabolites and bladder cancer is rather common (Brown & Price, 1956). Cats excrete practically none of these catabolic substances and are almost free of bladder cancer (Brown & Price, 1956). Bladder cancer is relatively common in humans and people with bladder cancer excrete large doses of tryptophan degradation products after ingestion of the amino acid compared to control subjects without disease (Brown & Price, 1956; Searle, 1976). Yet, the excretion of large amounts of some tryptophan catabolites is mainly linked to a vitamin B6 deficiency, rather than to the incidence of bladder cancer (Birt, et al., 1987).
A deficiency of vitamin B6 seems to aggravate the synthesis of some of these injurious metabolites if an excess of L tryptophan is ingested (Gerras, et al., 1977; Green, et al., 1980; Guilarte & Wagner, 1987; Chung & Gadupudi, 2011). Conversely, proper vitamin B6 status prevents the accumulation of tryptophan degradation products (Barichello, et al., 2014).
Because vitamin B6 and niacin (vitamin B3) serve “complementary” functions in at least one of the tryptophan metabolic pathways (Ellis & Presley, 1973), and one of the health benefits of niacin, an end product of the kynurenine pathway (Le Floc'h, et al., 2011), is that an increase of the vitamin also reduces tryptophan catabolites (Alifano, et al., 1964; Yaryura-Tobias, et al., 1977). Insufficiencies of vitamin B2, B6, iron, or an amino acid imbalance reduce the conversion of tryptophan to niacin (Nagalski & Bryla, 2007) and instead help transfer the amino acid into serotonin via the intermediate substance 5-hydroxytryptophan (5-HTP), elevating the risk of tryptophan side effects from destructive metabolites and serotonin.
There are other tryptophan side effects from unfavorable interactions with certain substances or products.
Estrogen, as from Hormonal Replacement Therapy (HRT) or the birth control pill, can increase certain tryptophan degradation chemicals, even without consuming additional L tryptophan, by interfering with the metabolic pathways that convert tryptophan to vitamin B3 (Ellis & Presley, 1973). This positive relationship between estrogen and tryptophan catabolites was verified in both women and men (Ellis & Presley, 1973). Estrogen can also increase serotonin (Murray & Pizzorno, 1998; Peat, Sept. 2012).
It is reasonable to conclude that these biological events are contributing aspects in the promotion of breast cancer seen with the use of HRT (Rothenberg, 2005; Ravdin, et al., 2007). With the use of HRT, and the birth control pill, and during pregnancy and menopause, and while under stress, there is an increased need for vitamin B6 and vitamin B3 (Ellis & Presley, 1973; Hoffer, 1994). During pregnancy, for instance, the turn-over of tryptophan to niacin (niacin synthesis) is increased three times (Jacob & Swendseid, 1996).
The degree of effectiveness of vitamin B6 to prevent the creation of (some) poisonous tryptophan decomposition products depends on its dose. At least 30mg/day of vitamin B6 is required for more comprehensive protection in high-risk individuals (Ellis & Presley, 1973), and probably in people who supplement with tryptophan.
However... vitamin B6 doesn't prevent all tryptophan side effects.
A randomized double-blind study (e.g., Newling, et al., 1995) revealed that a comparison between trial subjects who received a vitamin B6 supplement and those who got a placebo didn't notably change the rate of recurrent bladder cancer, despite that there were certain differences in the parameters of tryptophan metabolites between the two study groups.
There are other scientific observations that suggest to not rely solely and faithfully on vitamin B6 for the prevention of (all) tryptophan side effects.
Because beyond the scope of vitamin B6 and its modulating action on L tryptophan...
...serotonin and melatonin -alongside with tryptophan metabolites (Kaminsky, et al., 1991)- interfere and inhibit the energy-creating metabolic processes such as mitochondrial cell respiration and thyroid function (Mueller, et al., 1976; Rom-Bugolavskaia, et al., 1997; Wright, et al., 1997 & 2000; Peat, Fall 2006, Spring & Summer 2009). Animal experiments demonstrated that one of the side effects of melatonin is its dampening action on cellular energy output (Reyes-Toso, et al., 2003 & 2006; López, et al., 2009), and human studies (e.g., Carman, et al., 1976; Murphy, et al., 1996; Satoh & Mishima, 2001) showed that melatonin, even at a low dose of 0.5mg, decreases body temperature -indicative of metabolic interference.
Another denotation of melatonin's “down-regulating” activities upon the human metabolism is that sleeping for extended periods in total or near complete darkness, which naturally stimulates melatonin synthesis, decreased melatonin output (Danilenko, et al., 2009), suggesting a systemic defensive biological reaction of the organism to prolonged exposure of the substance.
This basic anti-metabolic effect of serotonin, melatonin and tryptophan promotes fatigue and lowers endurance (Peat, Spring 2009), and may be involved in the link between fibromyalgia and tryptophan, and probably in many, if not most, negative tryptophan side effects. Melatonin, for example, is elevated in people with fibromyalgia (Korszun, et al., 1999), and chronic fatigue syndrome (Knook, et al., 2000). Numerous people reported feeling tired and groggy in the morning, or throughout the day, after taking a melatonin supplement prior to going to sleep the night before -symptoms of what some people call a “melatonin hangover”.
Many people have noticed significant weight gain after taking melatonin supplements for some time. The large use of tryptophan, melatonin, and serotonin-activating agents (e.g., SSRIs) may be a contributing factor in the obesity epidemic, which is most prominent in the US with its great consumption of these substances.
None other than a Two-time Nobel Prize Winner, Otto H. Warburg, PhD, MD, (1883-1970) proved a long time ago (in the 1920s/30s) that the development of cancer begins with “a respiratory defect” in normal cells:
“Cancer cells originate from normal body cells […]. [...] first [there] is the [...] injuring of respiration […].” (Warburg, 1956) [explanation added]
“Because no cancer cell exists, the respiration of which is intact, it cannot be disputed that cancer could be prevented if the respiration of the body cells would be kept intact.” (Otto H. Warburg, PhD, MD, in 1966)
Many people, for example the biologist Raymond Peat, PhD and the cancer researcher Thomas N. Seyfried, PhD, have subsequently written about, or extended on, Warburg's concepts, in some cases spanning over several decades already.
Seyfried, for example, provided overwhelming evidence that cancer is a metabolic disease due to respiratory/mitochondrial dysfunction (Seyfried, 2012).
Analogous and overlapping findings come from Peat's research...
Serotonin, for which tryptophan is the precursor of, increases the stress hormone cortisol (Peat, Nov. 2008). Cortisol and cortisone interfere with cellular energy metabolism (Simon, et al., 1998; Peat, Nov. 2008).
Melatonin, too, increases cortisol in older women (Cagnacci, et al., 1995) and cortisol is increased in aged, healthy people of both genders (Ferrari, et al., 1995). Since tryptophan is the most fundamental precursor for both serotonin and melatonin, this line of evidence suggests that the amino acid shouldn't be raised (with advancing age) to minimize the fostering of tryptophan side effects from serotonin-melatonin-cortisol ramifications.
When the mitochondrial respiration of cells is impaired (as from cortisol, for instance) lactic acid will form which in itself suppresses cellular energy production (Peat, Sept. 2008). Serotonin can raise lactate levels, by activation of aerobic glycolysis, and lowers the principal energy substrate, ATP, in the brain and skin (Koren-Schwartzer, et al., 1994; Ashkenazy-Shahar & Beitner, 1997; Assouline-Cohen, et al., 1998). Stress too, whether physical or psychological in origin, elevates lactate levels (Uehara, et al., 2005).
Lactic acid promotes mitogenesis (cell division) and increased levels of lactate is a core feature of cancer (Peat, Sept. 2008). Even a small increase of serotonin has been shown to stimulate mitogenesis (Zolkowska, et al., 2006).
Besides serotonin's amplification of lactate, it also directly inhibits mitochondrial enzymes of respiration (Medvedev, 1990; Medvedev & Gorkin, 1991). Analogous to serotonin side effects on cell energy production are the specific tryptophan side effects from nitrosamines. That is, nitrosamines restrict the blood circulation's ability to transport oxygen (Martin, 1977). Oxygen, of course, is essential for the efficient generation of energy (oxidative respiration).
One of the health benefits of vitamin C is that it can effectively inhibit the formation of cancer-causing nitrosamines from tryptophan decomposition products (Schlegel, et al., 1970; Schlegel, 1975; Tannenbaum, 1989; Tannenbaum, et al., 1991), thereby greatly reducing DNA damage to cells (Arranz, et al., 2007). Vitamin E, too, appears to have this restrictive impact on nitrosamines (Wagner, et al., 1985).
Although these vital nutrients can restrict the dangers from a tryptophan poison (metabolite), they appear to have no noticable influence on the energy-restrictive activities of serotonin.
Bottom line on tryptophan side effects from tampering with cellular energy metabolism?
Because of the synthesis of serotonin and melatonin from tryptophan all of these substances are factors in harmful energy-disruptive events. And because the chronic tampering of metabolic energy processes (as could be expected from prolonged intake of tryptophan supplements) will decrease cellular metabolism (Mela, et al., 1976), the use of a supplement of tryptophan seems ill adviced.
Especially since the addition of supplemental vitamin B6, vitamin C, and other nutrients do not provide full spectrum protection against all tryptophan side effects from the damaging tryptophan degradation elements, and other tryptophan-derived culprits of carcinogenesis.
What is tryptophan used for?
L-tryptophan is essential for growth (Segall & Timiras, 1976; De Marte & Enesco, 1986; Sidransky, 2001). Thus, the amino acid has a most vital role predominantly during marked times of development and maturation which, for humans, occurs in the early period of life.
Similar findings have been reported with animals. Older animals, particularly females, seem less prone to experiencing tryptophan side effects incurred from a deficiency of the amino acid, such as reduced growth or diminished skeletal development, than young animals (Moehn, et al., 2012).
Apparently, the essential human requirement for L-tryptophan seems to diminish with age (Peat, Fall 2009). Elderly people have less tryptophan in their blood than young people (Caballero, et al., 1991; Sarwar, et al., 1991). This makes the addition of tryptophan supplements in (advancing) adulthood proportionally redundant, and quite possibly even detrimental.
Studies on animals (e.g., Segall & Timiras, 1976; De Marte & Enesco, 1986; Ooka, et al., 1988) demonstrated that depriving young animals of tryptophan increased mortality, while the deficit of L tryptophan decreased mortality in older animals.
In terms of lifespan-restraining tryptophan side effects, study data has affirmed that impaired cellular tryptophan uptake, decreasing its intracellular content (leading to a relative lack of tryptophan), is a pro-longevity mechanism (He, et al., 2014).
Besides extending longevity, a tryptophan-deficient diet also increased the animals resistance to stressors, reduced their risk of developing tumors, and extended their reproductive ability, and preserved their youthful outward appearance longer, all of which is analogous to the beneficial effects observed from experiments with calorie restriction (Segall & Timiras, 1976; Segall, 1977).
Age-associated chronic degenerative diseases, such as cancer, brain disorders, or heart disease, are linked to tryptophan side effects.
As aforecited, one of the insidious tryptophan side effects is that toxic degradation metabolites, such as kynurenic acid (KYNA) produced from kynurenine, increase with aging (Kepplinger, et al., 2005; Reyes Ocampo, et al., 2014).
A reasonable assumption is that this is the result, in part, of the stimulating action of:
And, exacerbating these two age-related erosive events, some catabolites
of tryptophan can lead to the formation of mutagenic nitrosamines or
the activation of an immunosuppressive receptor (which is usually
triggered by toxicants such as xenobiotics), promoting carcinogenesis
(Mezrich, et al., 2010; Chung & Gadupudi, 2011).
The consumption of a supplement of tryptophan will likely nurture or augment these disastrous age-associated disease states, by raising injurious tryptophan derivatives (particularly in the presence of a vitamin B6 deficiency and a vitamin B3 deficiency).
Furthermore, tryptophan side effects in regards to greater mortality were shown in animal experiments (e.g., Catrina, et al., 2001) using melatonin, whereas the study authors cautioned:
“[...] melatonin had a deleterious effect on the survival rate raising the question whether it is correct to assume that the hormone shows lack of adverse reactions.” [emphasis added]
In regard to serotonin's involvement in the promotion of higher mortality, one of its anti-longevity effects is conceivably the reabsorption of phosphate (a pro-inflammatory chemical) by the kidneys since klotho, an anti-aging protein, facilitates the excretion of phosphate from the kidneys (Peat, Nov. 2012).
Since tryptophan, serotonin, and melatonin meddle with basic energy production in cells, and since metabolic efficiency and functionality decreases proportionally with aging (Fannin, et al., 1999; O'Toole, et al., 2010) due to various factors, it seems coherent in biological terms that these substances are less prevalent, thus less “essential” or needed, in older people, as a further decrease of an already suboptimal general metabolic working order will aggravate physiological function systematically, increase the risk for disease (as exemplified and foreshadowed with tryptophan side effects), promote the aging process, and explains the increased mortality related to the administration of these substances.
Several tryptophan side effects, such as tryptophan's carcinogenic activities, the deterioration of metabolic energy function, and the promotion of hypertension, can rather readily account for a greater death rate.
“[...] tryptophan is one of the most toxic amino acids.” (Okuno, et al., 2008)
It is evident that distressing tryptophan side effects are not exactly non-existent.
While insufficient knowledge exists about the upper tolerable intake of L-tryptophan for humans, enough scientific data has been generated to make valid generalizations about its degree of toxicity. It warrants caution.
Interestingly, glycine, another amino acid, may be the ideal antagonist to many unwelcoming L tryptophan side effects (Peat, Fall 2006), alongside vitamin B6.
Speaking of vitamin benefits...
The use of multivitamin supplements has also a general protective action. For example, during the tryptophan EMS disaster in 1989 those people who took multivitamin supplements prior to consuming the tainted Showa Denko amino acid supplement, had a substantially lower risk of experiencing severe EMS-tryptophan side effects (Hatch & Goldman, 1993).
In people with EMS, harmful degradation substances of tryptophan are elevated due to a disturbance in tryptophan metabolism (Varga, et al., 1993). It is fair to presume that the use of multivitamin supplements will (partly) correct this biological imbalance or defect, and consequently ameliorate (in part) certain tryptophan side effects, even from EMS. After all, a deficiency of vitamin B6, for instance, leads to the accumulation of noxious L-tryptophan decomposition products, exacerbating the disturbances in tryptophan metabolism.
Critical individual differences in the mode and utilization of nutritional supplements, therefore, may provide part of the explanation that only a relative minor pool of people (1 in 250 -[Beisler, 2000]) fell ill with EMS among the very many consumers who ingested the L tryptophan tainted by Showa Denko (Murray & Pizzorno, 1998).
Of course, these beneficial findings to avert tryptophan side effects from injurious impact should not be misconstrued as some fundamental approval to ingest individual moderate-high doses of L tryptophan (click on “10 Tips To Avoid Risks” off the home page, and see Tip #10 for a logical explanation for this).
In the end, the research finding that L tryptophan, 5-hydroxy tryptophan, and serotonin can all block a carrier substance of many compounds, including L-glycine (Metzner, et al., 2005; Frølund, et al., 2010; Edwards, et al., 2011), and that degradation elements of tryptophan can impair glycine receptors in the brain (Stone, 1993), plus tryptophan's inflammatory-degenerative activities via serotonin, suggests to minimize the intake of moderate-high doses of this amino acid by single-element supplementation to avoid adverse long term effects of tryptophan.
“The use of supplements of tryptophan, hydroxytryptophan, or of the serotonin promoting antidepressant drugs, seems to be biologically inappropriate.” (Raymond Peat, PhD, Biologist, in 2009)
Serotonin “has a basic growth regulating and defensive function” (Ray Peat, PhD, Biologist, Personal Communication, 17-April-2011). This explains why normally about 95% of it is found in the (large) intestine (Donaldson & Gray, 1959; Peat, March 2011) where a huge number of potentially harmful bacteria dwell.
But from a biological point of view, it appears that serotonin's defensive combative feature isn't generally required in the rest of the body because only around 1-5% of serotonin is found in the brain and equally little serotonin is made from L-tryptophan (Glenmullen, 2000; Peat, March 2011).
In all probability, serotonin's presence at increased amounts outside the intestine exerts suppressive destabilizing activities, especially over time. For instance, its increased levels found in disturbances of cardiovascular circulation appears to be testimony of that. In situation of chronic injury serotonin exerts detrimental effects as in abnormal wound healing, the development of tissue fibrosis, and impaired organ regeneration (Mann & Oakley, 2012). A plausible implication thereof is that the continuous, sustained upregulation or activation of the substance (by artificial means) may lead to various consequential serotonin/tryptophan side effects as aforementioned.
Therefore, the truth about tryptophan appears to be that, generally, this amino acid shouldn't be consumed as an individual product on a prolonged basis because of its plentiful presence in the environment and due to its inherent higher risk profile. (In Side Effects Of Dietary Supplements -Top 10 Tips To Avoid Them I elaborated on why the intake of individual single nutrient supplements tends to increase the health risks from dietary supplements.)
By consuming L tryptophan as a single-element supplement (or by taking a selective serotonin reuptake inhibitor/SSRI), especially in conjunction with poor protein nutrition (inadequate intake of high protein foods) and sub-optimal micronutrient intake, you will probably assist in directing, over time, your body's physiology into an inflammatory-degenerative state, thereby increasing the risk for morbidity and mortality.
As a result...
... the omission of adding this serotonin/melatonin-producing single amino acid will likely forestall a host of potentially harmful tryptophan side effects.
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