Phenylalanine occurs in two chemical forms: L-phenylalanine, a natural amino acid found in proteins; and its mirror image, D-phenylalanine, a form synthesized in a laboratory. Some research has involved the L-form, others the D-form, and still others a combination of the two known as DL-phenylalanine.
In the body, phenylalanine is converted into another amino acid called tyrosine. Tyrosine in turn is converted into L-dopa, norepinephrine, and epinephrine, three key neurotransmitters (chemicals that transmit signals between nerve cells). Because some antidepressants work by raising levels of norepinephrine, various forms of phenylalanine have been tried as a possible treatment for depression.
D-phenylalanine (but not L-phenylalanine) has been proposed to treat chronic pain. It blocks enkephalinase, an enzyme that may act to increase pain levels in the body.
L-phenylalanine is an essential amino acid, meaning that we need it for life and our bodies can't manufacture it from other chemicals. It is found in protein-rich foods such as meat, fish, poultry, eggs, dairy products, and beans. Provided you eat enough protein, you are likely to get enough L-phenylalanine for your nutritional needs. There is no nutritional need for D-phenylalanine.
D- and DL-phenylalanine are typically taken at a dose of 100 to 200 mg daily for the treatment of depression.1 For the treatment of chronic pain, studies have used D-phenylalanine in doses as high as 2,500 mg daily.
It is best not to take your phenylalanine supplement at the same time as a high-protein meal, as it may not be absorbed well.
Weak and contradictory evidence has been used to advocate the use of D-phenylalanine as a general analgesic (pain relieving treatment).4-7
Highly preliminary evidence suggests that D-phenylalanine may be helpful for multiple sclerosis when combined with transcutaneous electrical nerve stimulation (TENS).11 D-phenylalanine has also been proposed as a treatment for Parkinson's disease (but see Safety Issues below).12
Although D- and DL- phenylalanine are marketed as treatments for attention deficit disorder, they do not appear to be helpful.13,14 Some proponents claim that phenylalanine works better when combined with tyrosine, glutamine, and gamma-aminobutyric acid (GABA), but this has not been proven.
What Is the Scientific Evidence for Phenylalanine?
A pair of double-blind comparative studies found that D- or DL-phenylalanine may be as effective as the antidepressant drug imipramine, and possibly work more quickly. The larger of the two studies compared the effectiveness of D-phenylalanine at 100 mg daily against the same daily dose of imipramine.15 Sixty people with depression were randomly assigned to take either imipramine or D-phenylalanine for 30 days. The results in both groups were statistically equivalent, meaning that phenylalanine was about as effective as imipramine. D-phenylalanine worked more rapidly, however, producing significant improvement in only 15 days. Like most antidepressant drugs, imipramine required several weeks to take effect.
The other double-blind study followed 27 people, half of whom received DL-phenylalanine (150 to 200 mg daily) and the other half imipramine (100 to 150 mg daily).16 When they were reevaluated after 30 days, both groups had improved by a statistically equal amount.
L-phenylalanine has also been tried as a treatment for depression, but not in studies that could provide a scientifically meaningful result.17,18
Unfortunately, there have not been any double-blind, placebo -controlled studies of phenylalanine for depression. This is too bad, since without such evidence we can't be sure that the supplement is actually effective. (For information on why such studies are so important, see Why Does This Database Rely on Double-blind Studies?)
The enzyme enkephalinase breaks down enkephalins, naturally occurring substances that reduce pain. D-phenylalanine (but not L-phenylalanine) is thought to block enkephalinase; this could lead to increased enkephalin levels, which in turn would tend to reduce pain.21 On this basis, D-phenylalanine has been proposed as a pain-killing drug.
However, as yet there is no meaningful evidence that it really works in this way. A small double-blind, placebo-controlled study reported evidence for the effectiveness of D-phenylalanine in chronic pain,21 but a careful re-examination of the math involved showed that it actually proved little.22 Another small double-blind, placebo-controlled study failed to find any benefits at all.23 Another study commonly described as showing D-phenylalanine effective suffered from many flaws (including the fact that it lacked a control group) and, therefore, can't be trusted.19,20
The long-term safety of phenylalanine in any of its forms is not known. Both L- and D-phenylalanine must be avoided by those with the rare metabolic disease phenylketonuria (PKU).
The maximum safe dosages of phenylalanine have not been established for young children, pregnant or nursing women, or those with severe liver or kidney disease.
There are some indications that the combined use of phenylalanine with antipsychotic drugs might increase the risk of developing the long-term side effect known as tardive dyskinesia, or worsen symptoms in those who already have it.24,25,26
1. Werbach MR. Nutritional Influences on Mental Illness: A Sourcebook of Clinical Research. Tarzana, CA: Third Line Press; 1991:141-142.
2. Heller B. Pharmacological and clinical effects of D-phenylalanine in depression and Parkinson’s disease. In: Mosnaim AD, Wolf ME, eds. Noncatecholic Phenylethylamines. Part 1. New York, NY: Marcel Dekker; 1978:397-417.
3. Beckmann H, Athen D, Olteanu M, et al. DL-phenylalanine versus imipramine: a double-blind controlled study. Arch Psychiat Nervenkr. 1979;227:49-58.
4. Balagot RC, Ehrenpreis S, Kubota K, et al. Analgesia in mice and humans by D-phenylalanine: Relation to inhibition of enkephalin degradation and enkephalin levels. Adv Pain Res Ther. 1983;5:289-293.
5. Walsh NE, Ramamurthy S, Schoenfeld LS, et al. D-phenylalnine was not found to exhibit opiate receptor mediated analgesia in monkeys [letter]. Pain.1986;26:409-410.
6. Budd K. Use of D-phenylalanine, an enkephalinase inhibitor, in the treatment of intractable pain. Adv Pain Res Ther. 1983;5:305-308.
7. Walsh NE, Ramamurthy S, Schoenfeld LS, et al. Analgesic effectiveness of D-phenylalanine in chronic pain patients. Arch Phys Med Rehabil. 1986;67:436-439.
8. Siddiqui AH, Stolk LM, Bhaggoe R, et al. L-phenylalanine and UVA irradiation in the treatment of vitiligo. Dermatology. 1994;188:215-218.
9. Camacho F, Mazuecos J. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Arch Dermatol. 1999;135:216-217.
10. Schulpis CH, Antoniou C, Michas T, et al. Phenylalanine plus ultraviolet light: preliminary report of a promising treatment for childhood vitiligo. Pediatr Dermatol. 1989;6:332-335.
11. Winter A. New treatment for multiple sclerosis. Neurol Orthop J Med Surg. 1984;5:39-43.
12. Heller B, Fischer E, Martin R. Therapeutic action of D-phenylalanine in Parkinson's disease. Arzneimittelforschung. 1976;26:577-579.
13. Zametkin AJ, Koroum F, Rapoport JL. Treatment of hyperactive children with D-phenylalanine. Am J Psychiatry. 1987;144:792-794.
14. Wood DR, Reimherr FW, Wender PH. Treatment of attention deficit disorder with DL-phenylalanine. Psychiatry Res. 1985;16:21-26.
15. Heller B. Pharmacological and clinical effects of D-phenylalanine in depression and Parkinson’s disease. In: Mosnaim AD, Wolf ME, eds. Noncatecholic Phenylethylamines. Part 1. New York, NY: Marcel Dekker; 1978:397-417.
16. Beckmann H, Athen D, Olteanu M, et al. DL-phenylalanine versus imipramine: a double-blind controlled study. Arch Psychiat Nervenkr. 1979;227:49-58.
17. Sabelli HC, Fawcett J, Gusovsky F, et al. Clinical studies on the phenylethylamine hypothesis of affective disorder: urine and blood phenylacetic acid and phenylalanine dietary supplements. J Clin Psychiatry. 1986;47:66-70.
18. Kravitz HM, Sabelli HC, Fawcett J. Dietary supplements of phenylalanine and other amino acid precursors of brain neuroamines in the treatment of depressive disorders. J Am Osteopathic Assoc. 1984;84(suppl):119-123.
19. Balagot RC, Ehrenpreis S, Kubota K, et al. Analgesia in mice and humans by D-phenylalanine: Relation to inhibition of enkephalin degradation and enkephalin levels. Adv Pain Res Ther. 1983;5:289-293.
20. Walsh NE, Ramamurthy S, Schoenfeld LS, et al. D-phenylalnine was not found to exhibit opiate receptor mediated analgesia in monkeys [letter]. Pain.1986;26:409-410.
21. Budd K. Use of D-phenylalanine, an enkephalinase inhibitor, in the treatment of intractable pain. Adv Pain Res Ther. 1983;5:305-308.
22. Walsh NE, Ramamurthy S, Schoenfeld LS, et al. D-phenylalnine was not found to exhibit opiate receptor mediated analgesia in monkeys [letter]. Pain.1986;26:409-410.
23. Walsh NE, Ramamurthy S, Schoenfeld LS, et al. Analgesic effectiveness of D-phenylalanine in chronic pain patients. Arch Phys Med Rehabil. 1986;67:436-439.
24. Richardson MA. Amino Acids in Psychiatric Disease. Washington, DC: Psychiatric Press; 1990.
25. Mosnik DM, Spring B, Rogers K, et al. Tardive dyskinesia exacerbated after ingestion of phenylalanine by schizophrenic patients. Neuropsychopharmacology. 1997;16:136-146.
26. Gardos G, Cole JO, Matthews JD, et al. The acute effects of a loading dose of phenylalanine in unipolar depressed patients with and without tardive dyskinesia. Neuropsychopharmacology. 1992;6:241-247.
27. Nutt JG, Woodward WR, Hammerstad JP, et al. The "on-off" phenomenon in Parkinson's disease. Relation to levodopa absorption and transport. N Engl J Med. 1984;310:483-488.
Last reviewed December 2015 by EBSCO CAM Review Board
Last Updated: 12/15/2015
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