Tryptophan
Nutrient Name: Tryptophan.
Synonyms: 1-Alpha-amino-3-indolepropionic acid, indole-alpha-aminopropionic acid,L-tryptophan, tryptophane, Trp.
| Drug/Class Interaction Type | Mechanism and Significance | Management | Allopurinol
| Allopurinol inhibits hepatic tryptophan pyrrolase activity, thereby (apparently) decreasing tryptophan breakdown and increasing levels of serotonin and melatonin. Coadministration of L-tryptophan and allopurinol may be effective in treating depression, especially refractory cases. Clinical significance probable, but evidence lacking consistency and rigor. | Caution. Concomitant use could be therapeutic with appropriate clinical management. | Clorazepate  | Potential competition between clorazepate and tryptophan may interfere with drug activity. Mechanism plausible but evidence minimal. | Monitor if concomitant use required. Separate intake. | Fluoxetine Selective serotonin reuptake inhibitor and selective norepinephrine reuptake inhibitor (SSRI and SNRI) antidepressants
/ /
| Combination of tryptophan's effect as serotonin precursor and activity of SSRI in inhibiting serotonin reuptake creates inherent risk of excessively elevated serotonin levels. This additive effect can result in rapid onset of severe symptoms but might also be applied purposefully within a tightly managed therapeutic protocol. | Generally avoid concomitant use. Transitional or continued concomitant use possible with close supervision and regular monitoring. | Lithium
/ 
| Lithium increases serotonin release and decreases metabolism. Genetic variation in tryptophan hydroxylase may play role in variable efficacy of lithium. Tryptophan administration may enhance the therapeutic efficacy of lithium and allow for reduced adverse drug effects by enabling lower lithium dosage. Evidence mixed. | Concomitant use could be therapeutic with appropriate clinical management. | Phenelzine Monoamine oxidase (MAO-A) inhibitors
| Serotonin is metabolized by MAO to 5-hydroxyindoleacetic acid, so combination of MAO inhibition and increased tryptophan intake carries high probability of resulting in clinically significant serotonin excess and major risk of serious adverse effects. | Avoid concurrent use. | Sibutramine
Serotonin agonists
| Serotonin agonists can increase serotonergic effect of tryptophan as a serotonin precursor, resulting in clinically significant serotonin excess and major risk of serious adverse effects. | Avoid concurrent use of tryptophan, as well as other serotonin agonists or precursors. | Tricyclic antidepressants (TCAs)
/ /
| Tryptophan can potentiate action of TCAs through its serotonergic effects, which could result in excessively elevated serotonin levels. This additive effect can result in rapid onset of severe symptoms but might also be applied purposefully within a tightly managed therapeutic protocol. | Caution. Concomitant use could be therapeutic with appropriate clinical management. |
Chemistry and Form
Levotryptophan,L-tryptophan.
Physiology and Function
Tryptophan is one of eight essential amino acids that must be obtained from the diet. Its primary functions include its role in niacin synthesis and as a precursor to both serotonin and melatonin. Approximately 98% of dietaryL-tryptophan is metabolized into nicotinic acid (niacin), and only a very small amount is metabolized into serotonin via the intermediary stage of 5-hydroxytryptophan (5-HTP). The unusual indole side chain of tryptophan serves as the nucleus of serotonin. Serotonin is synthesized through a two-step process involving a tetrahydrobiopterin-dependent hydroxylation reaction (catalyzed by tryptophan-5-monooxygenase) and then a decarboxylation catalyzed by aromaticL-amino acid decarboxylase. Tryptophan hydroxylase (TPH) is the rate-limiting biosynthetic enzyme in the serotonin pathway, regulates levels of serotonin, and is normally only about half-saturated. Serotonin is present at highest concentrations in platelets and in the gastrointestinal (GI) tract. Lesser amounts are found in the brain and the retina. Serotonin in the central nervous system (CNS) is metabolized by monoamine oxidase to 5-hydroxyindoleacetic acid (5-HIAA).
Melatonin ( N-acetyl-5-methoxytryptamine) is derived from serotonin within the pineal gland and the retina, where the necessary N-acetyltransferase enzyme is found.
Known or Potential Therapeutic Uses
Anodyne, antidepressant, antihyperglycemic, antihypertensive, galactagogue, melatonin precursor, niacin precursor, sedative, serotonin precursor.
Possible Uses
Agalactia, anorexia, bulimia, appetite suppression, bipolar disorder, carcinoid syndrome, dementia, depression, fibromyalgia, Hartnup's disease, hypertension, insomnia, mania, menopausal symptoms, migraine headaches, obesity, pain syndromes, parkinsonism, phenylketonuria, psychosis, premenstrual syndrome, schizophrenia, serotonin deficiency syndrome.
Deficiency Symptoms
A deficiency of tryptophan may lead to depression, edema, hair depigmentation, insomnia, lethargy, liver damage, muscle loss, pellagra, slowed growth in children, and suicidal thoughts. Metabolic disturbances associated with tryptophan deficiencies are carcinoid syndrome and Hartnup's disease. Symptoms of serotonin deficiency syndrome (SDS) include nervousness, anxiety, sleep disorders, mood disorders, and excessive appetite.
Dietary Sources
Tryptophan is the least abundant amino acid in foods. It tends to be deficient in most dietary proteins and has an uneven distribution. The richest dietary sources include fish, meat, dairy, eggs, nuts, and wheat germ. The seeds of evening primrose are a particularly rich plant source of tryptophan. There is lingering controversy as to the degree to which dietary levels of tryptophan intake affect serotonin and melatonin levels.
Dosage Forms Available
Capsule.
Source Materials for Nutrient Preparations
SyntheticL-tryptophan is manufactured by a fermentation process using pure glucose as a substrate. The products of fermentation are then separated and purified by filtration and purification procedures.
Dosage Range
Adult
- Dietary: Minimum daily requirements are estimated as 0.25 g for males and 0.15 g for females.
- Average U.S. daily intake: 1.0 to 1.5 g.
- Recommended dietary allowance (RDA): 200 mg per day.
- Supplemental/Maintenance: Supplementation usually not necessary.
- Pharmacologic/Therapeutic: 0.5 to 4.0 g per day, short-term use. Occasionally, doses of 8 to 12 g daily, given in three or four equally divided doses, are used in the treatment of depression.
WhenL-tryptophan is prescribed within the context of integrative clinical management, the dosage will typically start low and increase gradually as needed. Clinical response will often require 60 days to demonstrate full benefits. Daily dosage usually does not exceed 1 gram per 100 pounds of body weight (1 g/100 lb).
Toxic: 7 g per 150 lb body weight.
Overview
L-Tryptophan is an essential amino acid generally considered to have a low risk of toxicity, when used at typical dietary or supplemental intake levels, barring contraindications.
Nutrient Adverse Effects
General Adverse Effects
Anorexia, dizziness, drowsiness, dry mouth, headache, nausea, sexual disinhibition.
Long-term supplementation or treatment with tryptophan may increase plasma levels of other amino acids, potentially resulting in various adverse effects.
Adults
Studies in humans have shown that 100 mg/kg/day of tryptophan, corresponding to 7 g/150 lb, can cause gastric irritation, vomiting, and head twitching. A dosage of 800 mg/kg given to rhesus monkeys did not produce detectable clinical adverse effects.
Although tryptophan is a naturally occurring substance in the body, controversies surround serious adverse reactions to reported contaminants in bothL-tryptophan and 5-HTP.
Special Issues
During 1989, 35 deaths and many cases of severe allergic reaction, in the form of the eosinophilia-myalgia syndrome characterized by high eosinophil counts, scleroderma-like muscle pain, and thickening of the skin, were associated with consumption of tryptophan supplements. The Food and Drug Administration (FDA) removedL-tryptophan from the U.S. market by pursuant to these events. Subsequent investigation determined that a single manufacturer in Japan had employed a new bacterial strain to synthesizeL-tryptophan, and that this bacterium had introduced toxic byproducts that contaminated particular batches of the product.
As a serotonin precursor,L-tryptophan intake could theoretically contribute to “serotonin syndrome,” an excess accumulation of serotonin in the synapses, characterized by altered mental states, autonomic dysfunction, and neuromuscular abnormalities (see later discussion).
Mutagenicity
Animal tests involving oral or subcutaneous administration ofL-tryptophan or its metabolites have not yielded evidence of statistically significant increases in incidence of neoplasms. However, evidence indicates that foods containing tryptophan may carry an increased risk of carcinogenicity, especially to breast and bladder tissues, when they have been charbroiled or heated to high temperatures.
Life Stage
Inadequate research-based evidence exists to demonstrate any particular age-related effects on pediatric or geriatric populations as a result of increased tryptophan intake.
Pregnancy and Nursing
Well-designed controlled clinical trials with human subjects have not been undertaken, nor have case reports been qualified and systematically analyzed, regarding effects ofL-tryptophan during pregnancy or breastfeeding. In some animals the equivalent of 8 g per day was found to be teratogenic. However,L-tryptophan intake by pregnant women and lactating mothers has not been shown to cause birth defects or other pregnancy or lactation problems. It is not known whetherL-tryptophan passes into breast milk. However,L-tryptophan has not been reported to cause problems in nursing babies. Nevertheless, caution should be used with supplementation or administration during pregnancy or breastfeeding, and any such usage during pregnancy should be supervised and closely monitored.
Laboratory Values
Tryptophan levels in the blood vary greatly when measured by different laboratories. Tryptophan can be measured by fluorometric and high-performance liquid chromatography (HPLC) techniques. Some experts believe chromatography may be the most accurate. Other, indirect methods can also be employed, such as the tryptophan load test. This test involves measuring a metabolite of tryptophan, xanthurenic acid, in the urine after a standard 2-g dose is given. The more xanthurenic acid found in the urine, the greater is the need for either vitamin B6or tryptophan.
Contraindications
Achlorhydria, bladder cancer, cataracts, diabetes mellitus, female infertility, pregnancy, psoriasis; sensitivity toL-tryptophan. May exacerbate rheumatoid arthritis.
Precautions and Warnings
L-Tryptophan is best taken with a low-protein, carbohydrate-rich meal or snack to minimize risk of digestive distress. Also, an insulin response to carbohydrate facilitates transfer of serum tryptophan into the CNS (thought to be the reason serotonin-deficient people crave carbohydrates). Minimizing concomitant protein intake decreases competition between tryptophan and other dietary protein–derived amino acids for transport through the blood-brain barrier.
Strategic Considerations
The therapeutic effects ofL-tryptophan, especially as an antidepressant, are related to its ability to increase serotonin synthesis in the CNS. Emerging research indicates that baseline availability ofL-tryptophan, prolactin, and large, neutral amino acids (LNAAs) are key factors that predict response to antidepressant treatment in major depression. The major concern with tryptophan supplementation or administration with regard to drug interactions is the risk of inducing serotonin syndrome. This potentially dangerous situation results from an excess serotonin availability in the CNS at the 5-HT1A receptor; some interaction with dopamine and 5-HT2 receptors is also likely to be involved. Clinical trials have demonstrated thatL-tryptophan causes a significant increase in the level of the serotonin metabolite, 5-HIAA, in the lumbar cerebrospinal fluid, corresponding to an increased turnover of serotonin in the CNS.
Serotonin syndrome carries potentially serious clinical consequences and is characterized by the triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities. The serotonin syndrome is similar to the neuroleptic malignant syndrome and is usually differentiated by the setting of recent addition of a serotonergic agent. Specific symptoms can include agitation, anxiety, ataxia, confusion, delirium, diaphoresis, diarrhea, fever, hyperreflexia, myoclonus, incoordination, shivering, nausea, vomiting, or tremor. This phenomenon most often occurs in the presence of selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, opioids, and other serotonergic agents, when the serotonin system has been modulated by another serotonergic agent or compromised by illness. SSRIs, particularly fluoxetine, are most frequently involved in reported instances of drug interactions inducing serotonin syndrome; as a consequence of their long elimination half-life (1 week for fluoxetine), the risk of interactions persists for several days or even weeks after SSRI withdrawal.
Many clinicians and some researchers have investigated potential synergistic benefits from coadministration of tryptophan and various psychoactive pharmaceutical agents. Although the consequences of adverse effects can be clinically significant, the available evidence suggests that such risk is less probable, and adverse effects less severe, with tryptophan than with 5-HTP. Caution is requisite to use of tryptophan, in any dose, during antidepressant or other medication therapy, and this warrants close supervision and regular monitoring within an integrative context. 5-HTP should never be combined with SSRIs or MAO inhibitors in any dose, except possibly in a carefully monitored inpatient clinical research setting.
Allopurinol (Oxypurinol; Aloprim, Apo-Allopurinol, Lopurin, Purinol, Zyloprim). | | Beneficial or Supportive Interaction, with Professional Management |
Probability:
2. ProbableEvidence Base:
EmergingEffect and Mechanism of Action
Human and animal studies consistently indicate that allopurinol causes elevated brain levels of tryptophan. Allopurinol is a xanthine oxidase inhibitor and is typically used to lower blood levels of uric acid to prevent gout and adjunctively with certain forms of chemotherapy. However, allopurinol also inhibits hepatic tryptophan pyrrolase activity and prevents the reduction in the indole levels induced by heme precursor 5-aminolevulinate (5-ALA). Daytime administration of 5-ALA can reduce brain tryptophan and serotonin levels because of saturation of liver tryptophan pyrrolase. Saturation of this enzyme with heme results in enhanced activity, leading to increased catabolism of tryptophan and thus making less tryptophan available to the brain. Thus, Daya et al. demonstrated that 5-ALA alters brain tryptophan and serotonin levels without changing pineal serotonin and melatonin concentrations. It is hypothesized that increased levels of serotonin and melatonin, as a result of decreased tryptophan breakdown, can result in an antidepressant and analgesic effect.
Research
Over the decades, research on the effects of inhibition of tryptophan pyrrolase by allopurinol has elicited several distinct patterns but evolved to no certain conclusion. Many (but not all) studies have observed measurable effects of allopurinol on tryptophan metabolism. Green et al. investigated the effect of oral administration of allopurinol (300 mg daily) or nicotinamide (500 mg twice daily) on the metabolism of an oral L-tryptophan load (50 mg/kg). Their findings were interpreted to suggest that allopurinol and nicotinamide were unlikely to be of value as tryptophan pyrrolase inhibitors in vivo and therefore would not increase the therapeutic effect of L-tryptophan when given to treat depressive illness. However, Stern and Mendels reviewed a preliminary study involving eight individuals diagnosed with refractory depression using a combination of L-tryptophan and allopurinol. The investigators reported that five of the trial participants demonstrated full remission. Throughout the course of study on this topic, the various authors have continued to stress the need for further, double-blind, controlled studies to evaluate the safety and efficacy of this combination therapy.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
Controlled clinical trials will be necessary to determine whether the adjunctive use of allopurinol during tryptophan therapy can provide clinical efficacy in the treatment of depression or other conditions responsive to tryptophan supplementation. In the meantime, health care practitioners experienced in therapeutic nutrition and qualified in conventional pharmacology who might be interested in experimenting with this potential synergistic therapy at low dosage levels, and possible gradual escalation, are advised to supervise and regularly monitor any such patients. No investigators have expressed concern with adverse effects from this interaction, but such clinical practice is recommended as judicious.
Clorazepate (Gen-Xene, Tranxene). | | Potential or Theoretical Adverse Interaction of Uncertain Severity |
Probability:
4. PlausibleEvidence Base:
InadequateEffect and Mechanism of Action
L-Tryptophan and dipotassium clorazepate potentially compete, such that high intake of tryptophan might interfere with the intended therapeutic action of the medication.
Research
In vitro research by Coassolo et al. demonstrated the competitive binding of L-tryptophan and dipotassium clorazepate, a benzodiazepine, for human serum albumin.
Clinical Implications and Adaptations
Further research, preferably human clinical trials, is needed to determine the probability, risk settings, and clinical significance of this plausibly significant interaction. Separate intake if concomitant use necessary.
- Evidence: Fluoxetine (Prozac, Sarafem).
- Extrapolated, based on similar properties: Citalopram (Celexa), duloxetine (Cymbalta), escitalopram (S-citalopram; Lexapro), fluvoxamine (Faurin, Luvox), paroxetine (Aropax, Deroxat, Paxil, Seroxat), sertraline (Zoloft), venlafaxine (Effexor).
| | Minimal to Mild Adverse Interaction—Vigilance Necessary | | Bimodal or Variable Interaction, with Professional Management | | Beneficial or Supportive Interaction, with Professional Management |
Probability:
1. CertainEvidence Base:
EmergingEffect and Mechanism of Action
L-Tryptophan acts as a serotonin precursor, and the selective serotonin reuptake inhibitors (SSRIs) are designed to increase the functional level of serotonin in the brain by inhibiting its reuptake into the presynaptic neurons. Fluoxetine is a potent and selective inhibitor of presynaptic serotonin reuptake, therefore increasing the amount of serotonin in the synaptic cleft. Increased intake of L-tryptophan can potentially elevate levels of serotonin in the CNS. Such concomitant elevation of serotonin and inhibition of its reuptake presents both the opportunity for possible therapeutic synergy and the risk of potentially dangerous serotonin excess.
Research
In an early trial involving zimelidine for the treatment of depression, Walinder et al. found that the administration of the relatively high dose of 45 mg per pound body weight of DL-tryptophan, a synthetic variation of L-tryptophan, did not result in adverse effects. Zimelidine is an SSRI medication, similar in action to paroxetine, that was withdrawn worldwide in September 1983 because of the risk of Guillain-Barré syndrome associated with its use.
Research into the relationship between tryptophan depletion and the therapeutic mechanisms and efficacy of SSRI medications provides useful data in understanding the tryptophan-SSRI interaction pattern. Short-term reduction in plasma tryptophan (tryptophan depletion) produces a relapse of depressive symptoms in 60% of previously depressed patients recently recovered with SSRI treatment. Barr et al. investigated the hypothesis that SSRI treatment itself may confer vulnerability to the development of depressive symptoms during tryptophan depletion. They conducted a double-blind placebo-controlled involving six healthy individuals who underwent tryptophan depletion before and after 6 weeks of treatment with fluoxetine, 20 mg/day. Their findings showed no increased vulnerability to the mood-lowering effects of tryptophan depletion as a result of fluoxetine treatment. From these data the researchers determined that treatment with SSRIs alone does not produce the depressive effects of tryptophan depletion observed in SSRI-treated depressed and obsessive-compulsive disorder patients.
In a subsequent trial looking at the differential pathways of antidepressant action in desipramine and fluoxetine, Delgado et al. studied 55 individuals diagnosed with, but not currently medicated for, depression who were randomly assigned to antidepressant treatment with either desipramine or fluoxetine, then administered amino acid drinks capable of inducing tryptophan depletion. Whereas eight (of 15) fluoxetine responders reported relapse of significant depressive symptoms, only one (of 15) of the desipramine responders and none of the control subjects relapsed. The researchers concluded that rapid depletion of plasma tryptophan transiently reverses the antidepressant response in many patients taking fluoxetine, but not desipramine, and that antidepressant response to fluoxetine appears to be significantly dependent on serotonin (5-HT) availability. An important finding of this study is that various SSRI antidepressants mediate their therapeutic effects through different mechanisms. Recent investigation by Porter et al. into the connection between tryptophan availability and variable response to different antidepressant medications further demonstrates that patients with a tryptophan level below the mean improved significantly more than those with a higher level but with comparable serum steady-state drug levels.
Meltzer et al. have found that fluoxetine potentiates the 5-HTP-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive-compulsive disorder.
More directly, Levitan et al. conducted a randomized, double-blind, placebo-controlled trial that examined the antidepressant and hypnotic effects of combining tryptophan and fluoxetine. In this small, preliminary clinical study, 30 individuals diagnosed with major depressive disorder were treated with fluoxetine and either tryptophan or placebo for 8 weeks. The investigators concluded that “combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep.” The cumulative message of the assembled research strongly suggests that large-scale, well-designed clinical trials are warranted to confirm and clarify the emerging pattern indicated by the various findings.
No available report or trial evidence suggests an adverse interaction response when fluoxetine has been combined with a protein-rich diet containing significant levels of L-tryptophan.
Reports
Unsupervised coadministration of an SSRI agent with tryptophan carries a moderate risk for higher incidence of serotonin-associated unintended effects and adverse events. Specifically, reports have suggested that when taken in the form of a nutraceutical, L-tryptophan can interact adversely with fluoxetine, resulting in the following adverse effects, which are not associated with either drug alone: agitation, restlessness, poor concentration, nausea, diarrhea, and worsening of obsessive-compulsive disorder. These apparently interaction-induced symptoms disappeared as soon as the tryptophan was discontinued. In a review of five case reports, Steiner and Fontaine noted that signs and symptoms of CNS toxicity, both central and peripheral, developed within a few days of adding tryptophan (1-4 g/day) to ongoing fluoxetine therapy. Typical symptoms included nausea and vomiting, agitation, anxiety and restlessness, headache, dizziness, and increased perspiration.
Clinical Implications and Adaptations
A review of the evidence suggests an emerging, but not yet coherent and articulate, consensus supporting the proposition that L-tryptophan, in graduated dosages in the range of 2 to 4 g daily, can be used adjunctively with SSRI medications to enhance the clinical effectiveness of treatment for depression and other appropriate conditions. The ability of tryptophan to enhance, but not necessarily forcefully elevate, serotonin levels appears to exert a beneficial synergistic effect in conjunction with fluoxetine and some other SSRIs. However, the variable mechanisms of action among different SSRIs, along with individual pharmacogenomic variability, life stage and gender factors, and other metabolic influences, may account for differing therapeutic responses and occurrences of adverse effects.
Such an integrative therapeutic strategy warrants close supervision and regular monitoring within the context of coordinated care by health providers trained and experienced in both clinical nutrition and conventional pharmacology. However, the concomitant use of supplemental L-tryptophan and an SSRI such as fluoxetine outside such a context of active clinical management is contraindicated and potentially dangerous. A rapid onset of symptoms indicating an adverse response, particularly CNS toxicity, is highly probable in the event that a serotonin syndrome reaction or other adverse event does develop.
All available evidence strongly indicates that tryptophan-related data cannot be extrapolated to a clinical opportunity for safely combining 5-HTP and SSRI medications, and that all warnings and contraindications are amplified.
Lithium carbonate (Camcolit, Carbolith, Duralith, Eskalith, Li-Liquid, Liskonum, Litarex, Lithane, Lithobid, Lithonate, Lithotabs, PMS-Lithium, Priadel). | | Beneficial or Supportive Interaction, with Professional Management | | Prevention or Reduction of Drug Adverse Effect |
Probability:
2. ProbableEvidence Base:
EmergingEffect and Mechanism of Action
Lithium intake raises cortisol levels, and both lithium and supplemental tryptophan can elevate serotonin and cortisol levels as part of their therapeutic action. Concomitant use of these agents may induce excessively elevated serotonin levels and disrupt regulation of cortisol and other neuroendocrine substances.
Research
Lithium increases serotonin release and decreases metabolism. Despite lithium's proven efficacy as a long-term treatment for recurrent mood disorders (bipolar syndromes), individuals show a variable response, ranging from complete efficacy to no influence at all. Serotonergic pathways appear to be of importance in the mechanisms of the action of lithium. Much recent research has focused on identifying possible predictors of response through molecular genetic studies. Recent research has observed an association between genetic variation in tryptophan hydroxylase (TPH) and aggressive and anger-related traits. It is becoming apparent that clinical predictors account for about half the variance in lithium response, and genetic factors probably play a substantial role in both risk factors and response factors in affective disorders.
In 1999, Serretti et al. published one of several papers examining the possible association between the TPH gene variants and prophylactic efficacy of lithium in mood disorders. In a review from 2002, Serretti reported that the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has been associated with long-term efficacy of lithium in two independent studies; marginal associations have been reported for TPH and inositol polyphosphate 1-phosphatase (INPP1). Even though no unequivocal susceptibility gene for lithium efficacy has been identified, individual pharmacogenomic variability significantly influences response patterns. Within that context, manipulation of tryptophan metabolism and serotonin synthesis appears to play an important role.
In 1983, Brewerton and Reus published the results of a small, double-blind clinical trial in which lithium therapy for bipolar disorder or schizoaffective disorders generated significantly enhanced outcomes with adjunctive administration of L-tryptophan, 2 to 4 g three times daily.
Reports
Clinical observations suggest that L-tryptophan can serve as a clinically effective adjunct to lithium therapy, particularly in the treatment of some individuals diagnosed as bipolar with mania or depression for whom lithium, alone or in combination with neuroleptics or tricyclics, has demonstrated limited or no effect.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
L-Tryptophan offers a valuable adjunct to lithium therapy in the management of some individuals with bipolar affective disorders. In addition to enhanced therapeutic efficacy, such coordinated administration of lithium and L-tryptophan provides an opportunity to reduce lithium doses and decrease attendant adverse effects, particularly in controlling acute mania and other severe conditions for which higher, more toxic doses of lithium are often required. Concomitant therapy may also achieve therapeutic efficacy with some individuals previously unresponsive to lithium alone or in combination with other psychoactive agents.
Some bipolar patients have demonstrated an increased sensitivity to L-tryptophan administration, with adverse reactions occurring at levels as low as 1 to 2 g daily. Low initial dose levels, slow and graduated increases in dosage, and regular monitoring are important to safe and effective concomitant medication.
L-Tryptophan, when administered to individuals undergoing lithium therapy, might increase some adverse effects associated with lithium therapy by potentiating the lithium effect; these include nausea, vomiting, dermatological eruptions, psoriasis, and alopecia. Gradual reduction of lithium in chronic cases, such as treatment of bipolar disorder, not only may be valuable for reduction of typical adverse effects associated with lithium, but also may be necessary because of an increase in lithium concentrations resulting from potentiation by L-tryptophan. Monitoring lithium concentrations for at least 2 weeks after introduction of L-tryptophan or making changes in lithium dosage is appropriate with such individuals. Individuals being treated for acute mania may be particularly sensitive to exacerbations because of alterations in effective concentrations of lithium. In such cases it may be appropriate to decrease the lithium dosage, especially with doses above 900 to 1200 mg per day. Implementation of such integrative strategies warrants active supervision and close monitoring by health care professionals trained and experienced in clinical nutrition and conventional pharmacology. Pharmacogenomic variability, particularly involving TPH polymorphisms, appears to influence both individual susceptibility to bipolar disorder and related conditions and therapeutic response to lithium and L-tryptophan.
- Evidence: Phenelzine (Nardil).
- Extrapolated, based on similar properties: MAO-A inhibitors: Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), procarbazine (Matulane), tranylcypromine (Parnate).
- Related but evidence lacking for extrapolation: MAO-B inhibitors: Pargyline (Eutonyl), rasagiline (Azilect), selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak).
| | Potentially Harmful or Serious Adverse Interaction—Avoid |
Probability:
1. CertainEvidence Base:
ConsensusEffect and Mechanism of Action
The MAO-A inhibitor medications elevate serotonin concentrations because CNS serotonin is metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid (5-HIAA). Concomitant intake of L-tryptophan can then result in amplified serotonergic effects.
Research
Combined use of tryptophan and MAO inhibitors increases the risk of adverse drug effects. MAO inhibitors can induce potentiation of sympathomimetic substances and related compounds and result in a hypertensive crisis.
Reports
The most common adverse effects caused by the combination of L-tryptophan and MAO inhibitors are nausea, dizziness, and headache, usually immediately or shortly after coadministration. L-Tryptophan, 20 to 50 mg/kg, and MAO inhibitors, at standard therapeutic dosages, when taken together, have been reported to cause drowsiness, ethanol-like intoxication, hyperreflexia, and clonus. Levy et al. documented three cases of multiple adverse effects from phenelzine-tryptophan combination treatment, including myoclonus, hyperreflexia, and diaphoresis. Single case reports of adverse reactions to the drug combination include confusional states, hypomanic behavior, ocular oscillation, ataxia, and myoclonus. On occasion, reactions have approached the severity of classic serotonin syndrome with tremor, hypertonus, myoclonus, and hyperreactivity. Reports concur that such symptoms resolve shortly after cessation of L-tryptophan intake; no detrimental long-term effects have been documented.
Clinical Implications and Adaptations
The concomitant use of tryptophan and MAO inhibitors represents a particularly high probability of clinically significant adverse effects and is strongly contraindicated. Individuals taking phenelzine or other MAO inhibitors should avoid unsupervised supplemental intake of L-tryptophan. Similar adverse reactions are known to occur with concomitant use of MAO inhibitors and sympathomimetic drugs (including amphetamines, cocaine, methylphenidate, dopamine, epinephrine, and norepinephrine) or related compounds (e.g., methyldopa, L-dopa, L-tyrosine, ephedra, ephedrine, pseudoephedrine, phenylalanine), as well as food sources of tyramine, such as red wine and aged cheese.
- Evidence: Sibutramine (Meridia, Reductil).
- Extrapolated, based on similar properties: Almotriptan (Axert), buspirone (Buspar), dihydroergotamine (DHE-45), ergotamine, eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), zolmitriptan (Zomig).
| | Potentially Harmful or Serious Adverse Interaction—Avoid |
Probability:
1. CertainEvidence Base:
ConsensusEffect and Mechanism of Action
Serotonin agonists can enhance the serotonergic effect of other serotonin agonists, as well as serotonin precursors, thereby increasing the risk of augmenting serotonin activity to toxic levels. In particular, the additive effect on serotonin activity resulting from concomitant use of L-tryptophan and pharmaceutical serotonin agonists presents a significant risk of inducing serotonin syndrome.
Reports
The product information provided by the manufacturer of sibutramine states that “because [sibutramine] inhibits serotonin reuptake, it should not be administered with other serotonin agonists.”
Clinical Implications and Adaptations
The concomitant use of L-tryptophan and agents that enhance serotonin activity is contraindicated and should be undertaken only in the context of close clinical supervision and regular monitoring. Adverse effects of a dangerous additive interaction are likely to be characterized by rapid onset of toxicity symptoms.
- Evidence: Clomipramine (Anafranil), imipramine (Janimine, Tofranil).
- Extrapolated, based on similar properties: Amitriptyline (Elavil); combination drug: amitriptyline and perphenazine (Etrafon, Triavil, Triptazine); amoxapine (Asendin), desipramine (Norpramin, Pertofrane), doxepin (Adapin, Sinequan), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), trimipramine (Surmontil).
- Related, no longer on market: Zimelidine.
| | Minimal to Mild Adverse Interaction—Vigilance Necessary | | Bimodal or Variable Interaction, with Professional Management | | Beneficial or Supportive Interaction, with Professional Management |
Probability:
2. ProbableEvidence Base:
MixedEffect and Mechanism of Action
L-Tryptophan can potentiate the action of tricyclic antidepressants (TCAs) through its serotonergic effects.
Research
A review of the research literature and clinical practice observations suggest clinically significant variability in the character and significance of interactions between L-tryptophan and various TCAs. Human clinical trials indicate that the dosage levels of L-tryptophan administration and the mechanism of action of the particular TCA affected the character and strength of potential interactions with TCAs. In a human trial, Chouinard et al. enhanced imipramine therapy for bipolar disorder by expanding the therapeutic strategy to incorporate L-tryptophan (6 g/day) and niacinamide (1500 mg/day), compared with imipramine alone. Lower adjunctive doses of L-tryptophan (4 g/day) and niacinamide (1000 mg/day) suggested a significant but less efficacious effect in potentiating imipramine compared with the higher levels of administration. However, when the higher levels of L-tryptophan and niacinamide were administered to individuals diagnosed with depression, evidence of synergistic benefit was lacking.
Related research on antidepressant therapy using other TCAs demonstrated that larger dosages of L-tryptophan did not contribute to increased therapeutic benefit, with 6 g daily failing to provide therapeutic effect, whereas 4 g daily demonstrated therapeutic efficacy. In a placebo-controlled trial with 24 individuals, Walinder et al. found “significantly more rapid improvement” in those administered L-tryptophan with clomipramine than in those given clomipramine with placebo for endogenous depression, “especially with regard to the depression-anxiety cluster of symptoms.” In contrast, further research by Walinder et al. found that tryptophan in combination with zimelidine was not superior to zimelidine with placebo with respect to antidepressant activity. Recent investigation by Porter et al. and others into the connection between tryptophan availability and variable response to different antidepressant medications shows that patients with tryptophan level below the mean improved significantly more than those with a higher level but with comparable serum steady-state drug levels.
Thus, human clinical trials indicate that the dosage levels of L-tryptophan and preexisting endogenous blood levels of the amino acid, as well as the mechanism of action of the particular TCA, affected the character and strength of potential synergistic interactions between tryptophan supplementation and TCAs.
Nutritional Therapeutics, Clinical Concerns, and Adaptations
The coordinated administration of TCAs and L-tryptophan can achieve clinically significant synergistic effect within the context of an integrative therapeutic strategy. Pretreatment tryptophan depletion status and carefully calibrated dosages of L-tryptophan, typically 4 g daily, appear to be primary factors in determining probability of optimal effect. Once stabilization occurs, reduction of antidepressant levels can be considered if consistent with the expressed patient treatment goals, particularly with a history of adverse effects attributable to the TCA. Evolving personalized treatment protocols with close supervision and regular monitoring by health care professionals trained and experienced both in nutritional therapeutics and conventional psychopharmacology offer opportunities for deriving clinical benefits greater than what might be achieved by conventional antidepressant medications alone.
Tryptophan competes with the other large, neutral amino acids (LNAAs)—tyrosine, phenylala, valine, leucine, and isoleucine—for transport across the blood-brain barrier. When tryptophan is therapeutically administered, it is usually given with vitamin B 6 , apart from meals, with a small amount of carbohydrate to facilitate uptake by the brain. Tryptophan's action can also be supported by coadministration of vitamins B 3 and C, the other cofactors necessary for its metabolism.
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