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5-Hydroxytryptophan

Nutrient Name: 5-Hydroxytryptophan.
Synonyms: 5-HTP,L-5-hydroxytryptophan,L-5-HTP.
Related Substances:L-tryptophan; 5-hydroxytryptamine, 5-HT, serotonin.

Summary Table
nutrient description

Chemistry and Form

5-hydroxytryptophan (5-HTP) is similar in structure to tryptophan except that an OH group has been added to the fifth group of the carbon ring. Subsequently, the amino acid decarboxylase enzyme converts 5-HTP to 5-hydroxytryptamine (5-HT, serotonin).

Physiology and Function

Within the human body, the amino acidL-tryptophan is converted into 5-HTP. Tryptophan is one of eight essential amino acids that must be obtained from the diet. Its primary functions include its role in niacin (vitamin B3) 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-HTP. 5-Hydroxytryptamine (5-HT, serotonin) is a key neurotransmitter associated with sleep, mood, aggression, anxiety, locomotion, body temperature, feeding, and pain sensation. The central serotoninergic neuronal system is quite complex. Seven discrete major serotonin receptors, numbered 1 through 7, have been characterized; several of these have been further divided into A, B, and C subtypes. Each of these receptors binds serotonin, various drugs, and other ligands with varying avidity, and several of these serotonin receptor subtypes have functionally opposing roles, notably the effects of 5-HT1A and 5-HT2C receptor agonism on anxiety. The potent nausea-blocking agents used with many cancer chemotherapies specifically block the 5-HT3 receptor. The neuroendocrine effects of 5-HTP appear to be mediated through 5HT2A/5HT2C receptors.

5-Hydroxytryptophan crosses the blood-brain barrier (BBB, through a calcium-dependent mechanism) and affects hypothalamic-pituitary-adrenal activity by stimulating the central nervous system (CNS) synthesis and release of serotonin. Serotonin is synthesized in the CNS and gut using the unique indole moiety of tryptophan as its nucleus. Serotonergic neurons express the enzyme tryptophan hydroxylase (TPH), which catalyzes the conversion of tryptophan to 5-hydroxytryptophan. TPH is the rate-limiting biosynthetic enzyme in the serotonin pathway; it regulates levels of serotonin and is normally only about half-saturated. Serotonin is formed from tryptophan in a two-step process: after formation of 5-HTP by TPH, the final decarboxylation is catalyzed by aromaticL-amino acid decarboxylase (AADC), resulting in the conversion of 5-HTP to 5-HT (serotonin). The pineal gland is the major site for synthesis of melatonin, a methoxy derivative of tryptophan that modulates the sleep cycle, among other activities. The pineal gland also synthesizes serotonin, production of which is upregulated at night and controlled by beta-adrenergic signaling. 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 CNS is metabolized by the monoamine oxidase (MAO) enzyme to 5-hydroxyindoleacetic acid (5-HIAA). Levels of 5-HIAA in cerebrospinal fluid (CSF) are believed to reflect serotonergic activity in the CNS. Urinary levels are probably a less precise reflection but may be clinically useful.

nutrient in clinical practice

Known or Potential Therapeutic Uses

5-Hydroxytryptophan is primarily used in the treatment of anxiety, depression, insomnia, and other conditions typically associated with serotonin deficiency or dysregulatory states. Poldinger et al. 1 argue that, although 5-HTP appears to be treating depression, it may actually be treating a much broader condition, “serotonin deficiency syndrome.” This syndrome may manifest in any of a variety of forms, including depression, anxiety, sleeplessness, aggressiveness, agitation, obsessive-compulsive traits, migraines, and other common behavioral disorders.

5-Hydroxytryptophan is well absorbed, with approximately 70% of an oral dose reaching the bloodstream. Subsequently, some exogenous 5-HTP is rapidly decarboxylated in the peripheral vasculature to form serotonin, and the remainder crosses the BBB and increases synthesis of serotonin within serotonergic neurons. Therapeutic use of 5-HTP bypasses the conversion ofL-tryptophan into 5-HTP by TPH, the rate-limiting step in the synthesis of serotonin.

Research using infusions of radiolabeled 5-HTP and positron-emission tomography (PET) scanning found that significantly less 5-HTP crossed the BBB into the brains of depressed subjects than into the brains of normal controls. Such findings have been interpreted to suggest that the transport of 5-HTP across the BBB may be compromised in major depression.

5-Hydroxytryptophan was introduced into the U.S. market in 1994.L-Tryptophan had been tarnished in the late 1980s and early 1990s by toxic effects of contaminated material produced by one Japanese supplier. In contrast, the related compound 5-HTP could be used for a therapeutically similar effect, but without the attendant susceptibility to contamination; 5-HTP is not produced by microbial biosynthesis requiring subsequent purification steps.

Historical/Ethnomedicine Precedent

5-Hydroxytryptophan has not been used historically as an isolated nutrient.

Possible Uses

Aggressive behavior, alcohol addiction, anxiety, attention deficit–hyperactivity disorder, bipolar disorder, bulimia, childhood headaches, depression, Down syndrome, fibromyalgia, hepatitis, insomnia, migraine, narcolepsy, obesity, obsessive-compulsive disorder, pain syndromes, Parkinson's disease, premenstrual syndrome, rheumatoid arthritis, schizophrenia, seasonal affective disorder, sleep apnea, sleep disorder–related headaches (children), sleep paralysis, systemic lupus erythematosus, tension headaches, Tourette's syndrome, weight management.

Deficiency Symptoms

Standard definitions of deficiency states have not been established, given endogenous synthesis, and because the relationship between 5-HTP status and serotonin-shortage syndrome is controversial. However, many clinicians and researchers have considered anxiety, depression, insomnia, and other conditions as deriving from diminished serotonin status and therefore implicitly some measure of 5-HTP deficiency.

Dietary Sources

Diets low in tryptophan may result in reduced synthesis of serotonin and melatonin, butL-tryptophan from dietary sources does not directly influence or contribute to 5-HTP levels.

Dosage Forms Available

Capsule, tablet; typically containing 25, 50, or 100 mg.

Source Materials for Nutrient Preparations

An alcoholic extraction process is used to extract 5-HTP from the seeds of the Griffonia simplicifolia, an African plant. The resulting oily solid is then purified into a dry solid at 99% or higher purity levels.

Dosage Range

Adult

Dietary: Not applicable per se.

Supplemental/Maintenance: 5-HTP is usually not taken except for therapeutic purposes.

Pharmacological/Therapeutic: Oral: 50 to 100 mg one to three times daily; occasionally, doses up to 200 mg three times daily may be appropriate. Doses of 100 to 200 mg daily may be effective for many individuals, and dosages used in clinical trials have ranged from 150 to 900 mg daily over 2 weeks to 6 months. Dosages are usually divided throughout the day, with possible increased dosage before bedtime; 5-HTP is often taken only before bedtime to enhance sleep. Orally administered 5-HTP is considered to provide the most rapid absorption when taken on an empty stomach.

Toxic: Excessive oral intake of 5-HTP could theoretically induce a state of serotonin excess, but levels necessary to exceed such a threshold have not been established and would most likely vary significantly among individuals based on health status, comorbid conditions, and pharmacogenomics.

Pediatric (<18 Years)

Dietary: Not applicable per se.

Supplemental/Maintenance: 5-HTP is usually not taken except for therapeutic purposes.

Pharmacological/Therapeutic: Data are lacking on dosage for 5-HTP administration in children. Such usage is not recommended in sources reviewed.

Toxic: Data are lacking on toxicity of 5-HTP in children.

Laboratory Values

Serotonin may be relevant and could be assessed via urinary levels of 5-hydroxyindoleacetic acid (5-HIAA), the chief breakdown metabolite of serotonin.

safety profile

Overview

Individuals taking higher doses of 5-HTP have reported anxiety, digestive upset, headache, lethargy, and muscle pain, with GI symptoms being the most common. Theoretically, serotonin syndrome could result from use of excessive levels of 5-HTP, especially in combination with medications, herbs, or other supplements that alter serotonin levels or impair regulation. Some individuals with compromised liver function might not be able to regulate 5-HTP properly and require close medical supervision. Further, contaminants reported in some commercially available sources of 5-HTP may be associated with symptoms similar to eosinophilia-myalgia syndrome (EMS), which was linked to contaminated tryptophan in the late 1980s and early 1990s; however, recent reports of such incidents are lacking.

Nutrient Adverse Effects

Nausea and mild GI distress are the most common adverse effects generally associated with 5-HTP intake. Such GI symptoms affect only a minority of users, and then only occasionally. They usually lessen or disappear in the first few days or weeks of use. Headache, drowsiness, anxiety, and generalized muscle pain have also been reported. Research indicates that the incidence of such adverse reactions is minimal and usually only associated with higher dosage levels than typically used. Careful dose titration for each individual will usually prevent or minimize the occurrence of nausea and other adverse effects. Anecdotal clinical experience has suggested that, in patients very sensitive to GI effects of 5-HTP, a time-release preparation of 5-HTP from a compounding pharmacy will overcome this problem.

Adverse Effects Among Specific Populations

Individuals diagnosed with liver disease or compromised liver function may have limited capacity to metabolize 5-HTP and should avoid concomitant use with substances known to impair hepatic function or cause liver damage. Likewise, individuals with scleroderma or other autoimmune diseases may be more susceptible to an adverse reaction to 5-HTP intake; such cases also require consultation with a health care professional trained and experienced in prescribing physiologic agents such as 5-HTP.

Genotoxicity and Teratogenicity

Pregnancy and Nursing

The safety of exogenous 5-HTP intake during pregnancy and breastfeeding has not been established at this time.

Infants and Children

Data are lacking regarding toxicity and safety parameters for 5-HTP administration in infants and children. A high level of caution is suggested, especially given concerns of adverse effects among children receiving selective serotonin reuptake inhibitor (SSRI) therapy. Such pharmacological manipulation of serotonin levels and regulatory processes is generally not recommended, and significant caution is warranted, especially given the continued reports of adverse effects (and limited efficacy) in children being treated with conventional antidepressants, particularly SSRIs. 2

Sparse anecdotal clinical evidence suggests that 5-HTP is well tolerated and can be effective as an alternative in children for whom experienced clinicians have recommended SSRI therapy for anxiety and depression, or in pervasive developmental disorders. In the absence of clinical trials, such therapy should be undertaken only by clinicians experienced in child psychiatry/psychology, in concert with clinicians experienced with 5-HTP and other nutraceutical therapies. SSRIs and 5-HTP may be hazardous to combine in both children and adults.

Contraindications

Because of the generally accepted risk of excessive serotonin levels and resultant effects, it is usually recommended that 5-HTP not be taken concomitantly with antidepressant medications (SSRIs, tricyclics, MAO-A inhibitors) or other serotonin-modifying agents. Given the rapid action of orally administered 5-HTP and the potentially high risk of complications, such concomitant administration should be avoided, except possibly under close supervision of and regular monitoring by health care professionals trained and experienced in both conventional pharmacology and nutritional precursor therapeutics, preferably within the context of an inpatient research setting. Direct evidence of such adverse interactions is minimal, but caution is advisable.

Precautions and Warnings

It has occasionally been recommended that individuals with asthma avoid oral 5-HTP intake, based on the theory that the condition could be aggravated by elevating levels of any serotonin precursor, and that higher dosage levels in particular might increase the risk of exercise-induced asthma and fatigue. There is no substantial clinical evidence of this, but it should be kept in mind as a possibility, if a patient with underlying asthma were to experience exacerbation while taking 5-HTP. Given the pharmacokinetics involved, discontinuation of the 5-HTP should result in rapid resolution of the exacerbation, were this to occur.

  • Note:   During the early 1990s a substance designated as “Peak X” was reportedly found in low concentrations in some 5-HTP preparations. Speculation arose that it might be linked to the EMS previously associated with contaminated batches ofL-tryptophan, which contained larger amounts of “Peak X,” although the exact structure of this component and a causative role in EMS were never definitively established. No substantive evidence ever confirmed a connection between this substance and alleged incidents of 5-HTP toxicity, nor was it ever conclusively proven to have caused or contributed to any adverse events or toxicity reactions.

interactions review

Strategic Considerations

An evolving body of evidence indicates that 5-HTP may be as effective as many conventional medications in the treatment of depression, anxiety, insomnia and other neuroendocrine conditions, generally with fewer adverse effects. “In functional dimensional parlance, treating a serotonin deficiency is tantamount to treating all symptoms figuring as behavioral expressions of the serotonin-dependent psychological dysfunctions,” write Poldinger, Calanchini, and Schwarz. 1

For many years, a broad assumption in the medical literature is that drug-nutriceutical interactions involving 5-HTP represent significant risks of frequent occurrence, severe character, and seemingly self-evident pharmacological characteristics. Such interactions between 5-HTP and pharmacological agents could theoretically be relatively common because 5-HTP and many medications with which it may interact are used to treat the same conditions and patient populations. Oral ingestion of 5-HTP in animals and humans seems to be able to cause symptoms (primarily diarrhea) associated with elevated serotonin. In an experimental model, 5-HTP plus a MAO inhibitor has been shown to produce a syndrome similar to serotonin syndrome. 3 However, there is a surprising dearth of scientific evidence from controlled clinical trials or documented case reports supporting or detailing this interaction of presumably high probability. A significant number of the “interactions” attributed to 5-HTP are actually extrapolations derived from case reports and trials involving drugs, particularly those that interfere with serotonin metabolism or regulation, and as such function through a fundamentally different mechanism of action than the nutritive supply enhancement model of therapeutics employing 5-HTP. The lack of documented interactions involving 5-HTP, in contrast to SSRIs or other pharmacological agents directly manipulating serotonin levels by impairing the regulatory processes of serotonin breakdown, might be interpreted to suggest that enhancement of 5-HTP levels through oral intake, in contrast to SSRIs or other pharmacological agents directly manipulating serotonin levels, may enable serotonin production when needed, without forcing up serotonin levels when feedback systems signal saturation. No evidence has emerged to indicate that serotonin syndrome or other adverse interaction phenomena can result from combining an SSRI agent with a protein-rich diet containing significant levels ofL-tryptophan. Although a naturally occurring intermediate, 5-HTP is normally self-regulated in the body, with elevated levels rarely reported. Most likely, if 5-HTP production is upregulated for some reason (e.g., SNPs, diet, lifestyle), causing increased serotonin production, the body compensates by upregulating serotonin reuptake, keeping everything in balance.

Nevertheless, the combined use of 5-HTP and antidepressant drugs (including tricyclics, MAO inhibitors, and SSRIs, as well as other serotonin agonists) all present a significant probability of increased risk of adverse effects. In particular, widespread warnings have cautioned against the risk of serotonin syndrome, a dangerous but relatively rare condition caused by excess serotonin levels that could theoretically result from simultaneous 5-HTP intake in individuals whose serotonin regulation has been impeded by such medications. This potentially dangerous situation results from 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. 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, and tremor. This phenomenon most often occurs with SSRIs, 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 often involved in reported drug interactions inducing serotonin syndrome; because of their long elimination half-life (1 week for fluoxetine), the risk of interactions persists for several days or even weeks after SSRI withdrawal. Simultaneously elevating serotonin levels through introduction of precursors while inhibiting serotonin uptake and breakdown risks interaction scenarios. 5-HTP should never be combined with SSRIs or MAO inhibitors at any dose, except possibly in a carefully monitored inpatient clinical research setting.

Conversely, the concomitant use of 5-HTP and serotonin antagonists is likely to reduce the effectiveness of these agents. Nevertheless, the likelihood and frequency of such adverse events, as well as the respective levels of drug and nutrient intake at which this toxic effect might occur, remain unknown.

More broadly, clinicians treating individuals with depression, insomnia, and related conditions face the more profound and demanding task of helping these patients restore their lives to a healthy level of functionality, stability, and resilience. Comprehensive positive clinical outcomes cannot be achieved simply by medicating patients in adverse or stressful life circumstances. The fundamental therapeutic interventions in such circumstances require that health care providers work together to reempower these individuals by encouraging and supporting lifestyle changes involving exercise and healthy diet, changes in dysfunctional work or relationship behaviors and patterns, psychological counseling, and the challenges of personal growth. Despite repeated promises of pharmacologically induced emotional well-being based on “correction” of “brain chemistry,” clinicians face the daily challenge of viewing antidepressants or other psychopharmacological interventions as “bridge therapies” within a broader therapeutic strategy, as “crutches” that give way to free walking and renewed vigor and equilibrium.

Nutraceuticals and herbal therapeutics that enhance neurotransmitter status can play important primary or adjunctive roles in such a broader strategic approach. Such a multimodality approach can often provide safe and effective intervention during certain phases of the therapeutic process to “round out” pharmacology or as alternatives to medications that primarily preempt or interfere with self-regulatory feedback systems.

nutrient-drug interactions
Dextroamphetamine and Related Stimulant Medications
Carbidopa and Related Antiparkinsonian Medications
Chlorimipramine and Related Tricyclic Antidepressants
Lithium Carbonate
Selective Serotonin Reuptake Inhibitor and Serotonin-Norepinephrine Reuptake Inhibitor (SSRI and SNRI) Antidepressants
Selegiline and Related Monoamine Oxidase (MAO) Inhibitors
Sibutramine and Related Serotonin Agonists
Sumatriptan, Zolmitriptan, and Related 5-Hydroxytryptamine Receptor Agonists (Triptans)
Almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), zolmitriptan (Zomig). See also Sibutramine and Related Serotonin Agonists.
Potentially Harmful or Serious Adverse Interaction—Avoid

Probability: 2. Probable
Evidence Base: Preliminary

Effect and Mechanism of Action

Triptans are 5-hydroxytryptamine (5-HT1B/1D) agonists; they also activate the 5-HT1B receptors on coronary arteries, which is the basis for the potentially dangerous adverse effect of coronary spasm with use of triptans. Their antimigraine activity is attributed to stimulation of serotonin receptors in the brain. 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. The introduction of exogenous 5-HTP into the context of pharmaceutical serotonin agonists carries a significant risk of an additive effect, resulting in excessive elevation of functional serotonin levels and potentially inducing serotonin syndrome.

Research

As a class, triptans are well known for a high degree of variability in their therapeutic action, numerous adverse effects, and frequent interactions with other agents. In a paper reviewing the safety and clinical use of triptans, Tepper 40a wrote: “Some triptans have the potential for significant drug-drug interactions (sumatriptan, rizatriptan, and zomitriptan and monoamine oxidase inhibitors; rizatriptan and propranolol; zolmitriptan and cimetidine; and eletriptan and CYP3A4 metabolized medications and p-glycoprotein pump inhibitors).” In an important review paper, Saper 40b simply declared: “What matters is not the differences between triptans, but the differences between patients.”

Nevertheless, despite the apparently formulaic potential for clinically significant interactions, there remains a lack of scientific evidence from human studies directly supporting or detailing this pharmacologically probable interaction. No clinical trials have investigated the potential interaction between triptan agents and 5-HTP.

Reports

A search of the literature reveals no documented case reports confirming interactions between triptan selective serotonin receptor agonists and 5-HTP. Thus, scientific evidence is lacking as to the frequency, character, or severity of this potential interaction.

Clinical Implications and Adaptations

Triptans are a primary therapy for migraines within conventional practice, and several studies have demonstrated efficacy of 5-HTP in the treatment of migraines. 41-43 Consequently, there is a need for explicit communication and coordination to prevent the combined use of these agents, particularly with unsupervised patient self-care. Even though a potentially valuable synergy could develop from the careful combining of 5-HTP (or L-tryptophan) with triptans, such experimentation would be premature and should be considered potentially dangerous until well-designed, controlled clinical trials have been conducted.

The concomitant use of 5-HTP and agents such as triptan selective serotonin receptor agonists that enhance serotonin activity is contraindicated and, if determined to be therapeutically necessary in a particular case, should only be undertaken within 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.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims
“Atypical Antipsychotics”
Monoamine Oxidase (MAO-A) Inhibitors
Tramadol
Trazodon e
Venlafaxine
Zolpidem
nutrient-nutrient interactions
Melatonin
S -Adenosylmethionine (SAMe)
Tryptophan
Vitamin B 6 (Pyridoxine)
herb-nutrient interaction
St. John's Wort
Citations and Reference Literature
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