Chemistry and Forms

L-Phenylalanine andDL-phenylalanine (DLPA) are the commercially available forms of phenylalanine. However, phenylalanine appears in the following three chemical forms:

• L-Phenylalanine, the form of phenylalanine that occurs naturally in proteins within the human body.
• D-Phenylalanine, a synthetic mirror image ofL-phenylalanine.
• DL-Phenylalanine, a synthesized racemic mixture ofL-phenylalanine andD-phenylalanine.

Physiology and Function

L-Phenylalanine is an essential amino acid that serves as a precursor in the biosynthesis of other amino acids includingL-tyrosine. It plays a critical role in related biochemical processes involving the synthesis of several important neurotransmitters, principallyL-dopa, dopamine, epinephrine, and norepinephrine, as well as thyroxine and melanin. Through a different metabolic pathway,L-phenylalanine can also be converted to phenylethylamine (PEA). Phenylethylamine is a naturally occurring substance in the brain that appears to exert stimulant effects and elevate mood. It also influences the synthesis of many important brain neuropeptides, including vasopressin, adrenocorticotropic hormone (ACTH), somatostatin, enkephalin, and angiotensin II. Together with tryptophan, phenylalanine governs the release of the intestinal hormone cholecystokinin (CCK).

Hepatic conversion of phenylalanine to tyrosine can be impaired during infection, trauma, chronic illness, liver disease, or other forms of severe stress; thus making tyrosine a conditionally essential amino acid.

BecauseD-phenylalanine does not occur naturally, it cannot be converted toL-tyrosine,L-dopa, or norepinephrine and, when ingested, is primarily converted to phenylethylamine.D-Phenylalanine can increase levels of enkephalins by blocking enkephalinase, thereby inhibiting the breakdown of these opiate-like substances in the brain. This analgesic effect ofD-phenylalanine is inhibited by naloxone.

DL-Phenylalanine does not occur naturally in the human body.

Known or Potential Therapeutic Uses

Therapeutically, phenylalanine is primarily known for its proposed antidepressant and analgesic effects. Thus far clinical trials of various design, power and clinical relevance have resulted in mixed results. DLPA should be taken only under medical supervision because of its strong effects on neurotransmitters, mood, and central nervous system (CNS) function. It is generally recommended that phenylalanine be taken 15 to 30 minutes before meals to avoid competition from protein-derived amino acids.

Historical/Ethnomedicine Precedent

Phenylalanine has not been used historically as an isolated nutrient.

Possible Uses

Clinical application varies according to form.

• L-Phenylalanine: Appetite suppression, depression, vitiligo.
• D-Phenylalanine: Depression, osteoarthritis, Parkinson's disease, rheumatoid arthritis, and pain from a variety of causes, such as chronic back pain, dental pain, menstrual cramps, and migraines.
• DLPA: Alcohol withdrawal, depression, osteoarthritis, rheumatoid arthritis, and pain from a variety of causes (from action ofD-phenylalanine).

Deficiency Symptoms

Frank phenylalanine deficiency is considered a very uncommon occurrence, and the potential for deficiency is primarily associated with very low protein intake. Typical symptoms of phenylalanine deficiency include fatigue, confusion, behavioral changes, decreased alertness, impaired memory, poor vascular health, eye disorders (e.g., bloodshot eyes, cataracts), changes in appetite, and weight gain.

Dietary Sources

Cheese and meats are the richest dietary sources of phenylalanine, with most protein-containing foods providing someL-phenylalanine, for example, beef, poultry, pork, fish, milk, yogurt, cheese, eggs, soy products (including tofu, soy flour, and soy protein isolate), and certain nuts and seeds.

D-Phenylalanine does not naturally occur in foods.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) is a synthesized dipeptide, composed of aspartic acid and phenylalanine as the methyl ester. It is marketed as an ingredient in food products as NutraSweet and as an artificial sweetener (Equal).

Nutrient Preparations Available

Phenylalanine should generally be administered in theL-phenylalanine form, the naturally occurring isomer, as the preferred form in the treatment of all conditions other than pain and depression. In the treatment of these conditions, particularly chronic pain,D-phenylalanine exhibits unique activity in the CNS/brain and thus makes a critical contribution as part of DLPA. Thus, many health care professionals trained and experienced in nutritional therapeutics might suggest that DLPA is perhaps the only amino acid where the racemic mix is often clinically effective, or even preferable, in contrast to most amino acids, where the naturally occurringL-isomer is strongly if not exclusively recommended.

Dosage Forms Available

Capsule, powder, tablet; topical cream.

Source Materials for Nutrient Preparations

L-Phenylalanine is commercially produced by a bacterial fermentation process. DLPA andD-phenylalanine are synthesized.

Dosage Range

Adult

• Dietary:   Recommended dietary allowance (RDA): 14 mg per kg body weight per day, or about 1 g for a 70-kg adult.
• Supplemental/Maintenance:   Usually not necessary. Optimal levels of intake have not been established.
• Pharmacological/Therapeutic:    L-Phenylalanine is usually provided in doses of 500 mg, typically taken one to three times daily, preferably between meals. Doses of 100 to 200 mg daily are often used in the treatment of depression. The dosage range in most cases is 750 to 3000 mg daily for adults. Doses as high as 50 to 100 mg/kg have been used in studies of those with vitiligo, an autoimmune process in which melanocytes are destroyed, resulting in patches of depigmented skin.

DL-Phenylalanine (DLPA) is the most common form of phenylalanine used as a nutraceutical, typically in dosages ranging from 75 mg to 1500 mg daily. DLPA is 50%D-phenylalanine and 50%L-phenylalanine and generally comes in capsules containing 375 to 750 mg. One to two capsules are usually taken in the morning on waking, preferably on an empty stomach. Doses used in research on pain relief were 4 g before an acute painful episode, such as surgery, or 500 mg three times daily for chronic pain.

• Toxic:   The maximum safe dosage level of phenylalanine, in any form, has not been established. Doses in excess of 1500 mg/day may produce adverse effects.

Experienced practitioners of nutritional medicine generally caution that dosages of various forms of phenylalanine should never exceed 2400 mg/day. Concern has also been raised that prolonged use of anyD-isomer amino acid may eventually exert a toxic effect.

Pediatric (<18 Years)

• Dietary:   RDA (recommended dietary allowances):
  • Birth to 4 months: 125 mg/kg/day
  • 5 months to 2 years: 69 mg/kg/day
  • 3 to 12 years: 22 mg/kg/day
  • Adolescents, 14 to 18 years: 14 mg/kg/day
• Supplemental/Maintenance:   Not currently recommended for children.
• Pharmacological/Therapeutic:   Specific treatment recommendations have not established.
• Toxic:   No toxic dosage level established specifically for infants and children.

Laboratory Values

Serum or Plasma Phenylalanine

That use of phenylalanine684 PhenylalanineNutrient-

• Children: 26 to 86 µmol/L
• Adults: 41 to 68 µmol/L

Overview

L-Phenylalanine and DLPA are generally considered safe in most individuals at usual dosage levels. Some sources caution that DLPA should be taken only under medical supervision because of its potentially strong effects on neurotransmitters, mood, and CNS function. Although no serious adverse effects have been reported in humans taking phenylalanine, dosage levels greater than 1500 mg/day should be supervised by a health care professional trained and experienced in nutritional therapeutics.

Nutrient Adverse Effects

General Adverse Effects (Adults)

L-Phenylalanine

Animal studies have reported toxicity symptoms at dosage levels of 100 mg/kg or more. Burkhart and Burkhart, ¹ two leading phenylalanine researchers, have expressed concerns about potential toxicity with high-dosage administration in humans.

DL-Phenylalanine

The maximum safe dosage level of DLPA is unknown. Within clinical trials 1500 mg/day or less of DLPA has not induced consistent toxicity in healthy subjects. Some researchers and clinicians have reported occasional anxiety, nausea, dyspepsia, and transient headaches. Cautions regarding LPA are most likely equally applicable to DLPA.

Adverse Effects Among Specific Populations

Phenylketonuria

Phenylketonuria (PKU) is an inherited error of metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH; phenylalanine 4-monoxygenase). PAH utilizes tetrahydrobiopterin to convert phenylalanine into tyrosine, a critical step in dopamine biosynthesis. Loss of this enzyme results in mental retardation, organ damage, and unusual posture and in cases of maternal PKU, can severely compromise pregnancy as a result of the accumulation of phenylalanine and its neurotoxic metabolites. Classic PKU is an autosomal recessive disorder, caused by mutations in both alleles of the gene for PAH, found on chromosome 12. Mild hyperphenylalaninemia (phenylketonuria II) is a phenotypically mild form of PKU that will predominate when the individual is heterozygous for the two mutations of PAH.

In the United States, standards of practice mandate that newborns be tested for PKU during the initial 48 to 72 hours after delivery. If not diagnosed and treated before 3 weeks of age, PKU can cause severe, irreversible mental retardation.

Prudence suggests that high blood levels of phenylalanine (and tyrosine) be avoided in individuals with severe liver disease; such elevation may contribute to encephalopathy, mental impairment, and coma.

Pregnancy and Nursing

Phenylalanine is generally contraindicated because of potential adverse effects on the fetus.

Evidence is lacking in the scientific literature to suggest or confirm any adverse effects related to fetal development during pregnancy or to infants who are breast-fed associated with phenylalanine administration.

Infants and Children

Testing for PKU is critical before any administration. Otherwise, no adverse effects have been reported. However, sufficient research-based evidence is lacking to guarantee the safety of phenylalanine in infants and children.

Contraindications

Phenylalanine should not be taken by phenylketonuric individuals because they lack the enzyme necessary to metabolize phenylalanine.

Exogenous phenylalanine is generally considered contraindicated during pregnancy or while nursing.

Phenylalanine should be used with caution by people with hypertension; it may raise blood pressure in some individuals.

Phenylalanine (and tyrosine) should be avoided by individuals with cancer, especially pigmented melanoma.

Use of phenylalanine may be contraindicated for individuals with hyperthyroidism or schizophrenia, particularly when high dopamine levels are present in the brain. Exogenous phenylalanine (or tyrosine) administration could theoretically result in elevated brain dopamine levels and symptom aggravation.

Precautions and Warnings

L-Phenylalanine should not be taken with foods high in protein because it competes with other amino acids for a position on the same amino acid carrier.

Avoid concomitant administration of phenylalanine and tyrosine because of potential additive effects.

Some derivative sources suggest that phenylalanine should be avoided by individuals taking monoamine oxidase (MAO) inhibitors, presumably because ofL-phenylalanine's role in synthesis of dopamine, norepinephrine, and epinephrine. However, this potential for an adverse interaction has not been substantiated by clinical studies; in fact, some research points to synergistic value of such a combination at appropriate dosage levels.

The use of phenylalanine-containing aspartame by individuals with Parkinson's disease is the subject of ongoing controversy. Ingestion of aspartame, the artificial sweetener, may induce a rapid increase in brain levels of phenylalanine. Aspartame is generally contraindicated in individuals with phenylketonuria (PKU). Statements implying that aspartame is “safe” in Parkinson's disease patients derive solely from a single-day, poorly designed study by Karstaedt and Pincus ² involving 16 levodopa-treated patients with Parkinson's disease. Some clinicians and researchers have suggested that aspartame may be contraindicated in such individuals because of potential for rapid elevation of phenylalanine and effect on levodopa levels. Long-term, independent clinical trials are lacking.

Strategic Considerations

Management of chronic pain may constitute the most common use of phenylalanine in conventional medicine and the professional practice of natural therapeutics. Several trials of varying design quality, size, and power have been conducted with mixed findings. ^3,4Two preliminary studies suggest possible analgesic action ofD-phenylalanine. ^5,6In contrast, Walsh and other researchers at the University of Texas published two critical articles. They noted potentially flawed design in a letter challenging the hypothesis ofD-phenylalanine analgesic action via mediation of opiate receptors. ⁷ In a double-blind trial, they reported that usingD-phenylalanine (250 mg four times daily) for 4 weeks was no more effective than placebo for 30 people with various types of chronic pain, including 13 individuals with low back pain. ⁸ That use of phenylalanine as pharmacological monotherapy is not representative of its application by health care professionals trained and experienced in nutritional therapeutics.

In a small, two-part, placebo-controlled clinical trial more relevant to typical integrative approaches, Kitade et al. ⁹ hypothesized thatD-phenylalanine (DPA) might prolong analgesia induced by acupuncture through its known activity of blocking carboxypeptidase, an enzyme that degrades enkephalins (endogenous neuropeptides that bind to opiate receptors in the CNS). This team of Japanese researchers administered DPA (4 g/day) to individuals with chronic low back pain half an hour before they received acupuncture. The results were good or excellent for 18 of the 30, but not statistically significant because of small sample size. These researchers arrived at a similar conclusion when tooth extraction was performed on 56 patients under acupuncture anesthesia, with 18 subjects receiving 4.0 g DPA orally 30 minutes before treatment and 38 given placebo. These researchers also found that the combined DPA-acupuncture effect was slightly better when DPA was given on the previous day in three 0.5-g doses than a single 4-g dose administered 30 minutes before treatment.

The coadministration of DPA and conventional analgesics represents an integrative approach to care that warrants further research.DL-Phenylalanine (DLPA) is the most common form of phenylalanine administered for pain relief by health care professionals, at a typical dose of 1500 to 2500 mg per day. Further research employing placebo-controlled double-blind pain studies, as well as outcomes-based research for assessing multidisciplinary interventions, is warranted to evaluate the efficacy of phenylalanine in the treatment of pain syndromes and to determine dosage levels, synergies, and other aspects of therapeutic protocols for its effective integration into clinical care models.

Although not conclusively established by large, well-designed human trials, a solid theoretical foundation, broad anecdotal reports, and numerous preliminary studies suggest therapeutic benefit in using phenylalanine as part of a comprehensive therapy for depression. Administration ofL- orDL-phenylalanine alone, with other nutrients, or with conventional medications and psychotherapy, can support healthy neurotransmitter levels by enhancing production of dopamine and norepinephrine. Health care professionals treating individuals diagnosed with depression are advised to query patients about self-medication; present evidence-based options for integrative therapies employing exercise, dietary changes, nutrient coadministration, botanical medicine, acupuncture, stress resilience training, and other appropriate therapies; and offer support in the form of supervision, monitoring, and collaboration with other health care providers.

Tardive dyskinesia (TD), a condition characterized by unusual, uncontrollable body movements, was first brought to the attention of the medical community in 1973 by Crane. ¹⁰ Since then, clinicians and researchers have studied this largely irreversible and untreatable neurological disorder in patients receiving long-term neuroleptic agents. In 1992 the American Psychiatric Association estimated that TD occurs in at least 5% of patients taking certain antipsychotic medications annually. Within 3 years, 15% of these patients develop TD, and its prevalence often exceeds 50% of all patients in long-term antipsychotic medication studies. The disease affects children and adults of all ages, with higher rates among older populations. In a controlled study, Yassa et al. ¹¹ found that 41% of patients age 65 and older developed TD within 24 months. It is estimated that TD could affect as many as 1 million Americans. Concomitant use of conventional antipsychotic medications and phenylalanine, a dopamine precursor, could theoretically increase the risk of developing neuroleptic-induced TD by elevating levels of dopamine, norepinephrine, and epinephrine. Phenylalanine supplementation, particularly when self-prescribed and unmonitored, should generally be avoided by individuals under treatment with antipsychotic agents, including phenothiazine and butyrophenone types and newer, atypical antipsychotic agents. In clinical trials, vitamin E has reduced the severity of TD, especially involuntary movements. ^12,13In a double-blind, placebo-controlled, crossover study, Lerner et al. ¹⁴ observed that coadministration of vitamin B6can control TD. Concomitant choline and lecithin may also reduce TD symptoms. Nutritional support can be therapeutically efficacious when appropriate to the individual being treated, strategically planned, and applied with monitoring within an integrative therapeutic framework.

The role of amino acid intake and therapeutics within integrative approaches to oncology is not well researched. Increased expression of various tyrosine kinase enzymes is key to growth and cell signaling in a wide variety of tumor types. A low-phenylalanine and low-tyrosine diet has shown some potential in limiting tumor growth in animal models. However, Harvie et al. ¹⁵ found that patients with advanced cancer do not appear to tolerate or accept such a diet. In a small pilot study involving 22 patients with advanced metastatic melanoma and 15 patients with metastatic breast cancer, the diet was restricted to 10 mg/kg/day each of phenylalanine and tyrosine in foods or supplements. Only three patients with metastatic melanoma and three with metastatic breast cancer agreed to start the diet. After 1 month, these researchers attempted to establish the effect of the diet on nutritional status; immune cell function; plasma levels of phenylalanine, tyrosine, and tryptophan; and quality of life, as measured by Hospital Anxiety and Depression scores. All the patients who followed the restricted diet reported adverse effects, particularly increases in anxiety and depression. Although slight increases in white cell counts and neutrophils were observed, patients on the diet also experienced declines in weight, with loss of fat and fat-free mass.

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