Phenylalanine for the Treatment of Depression

By Barak Gaster, MD

Although quite a bit is known about the molecular function of common antidepressants, surprisingly little is known about the pathophysiology of depression itself. Many theories have been proposed, mainly based on inferences from the actions of antidepressants on various neurotransmitters, but no conclusive evidence offers a more detailed understanding of causation beyond this.

One of the many causation hypotheses holds that depression may be related to total body deficiencies of one or more catecholamines. This has led some researchers to wonder whether supplementing the diet with catecholamine precursors may alleviate the symptoms of depression.

One such precursor is the amino acid phenylalanine. Although studying phenylalanine for the treatment of depression attracted enthusiasm in the 1970s and 1980s, interest has since waned because of the few positive efficacy studies and the fortunate emergence of other effective and relatively well-tolerated antidepressants.

Pharmacology

There are two isomer forms of phenylalanine: l-phenylalanine and d-phenylalanine. L-phenylalanine occurs in nature as one of the 20 amino acids forming the building blocks of human proteins. Because it cannot be synthesized in the body and must be present in the diet, it is termed an essential amino acid. L-phenylalanine is found in significant quantities in all protein-rich foods such as meat, fish, eggs, milk, and beans.

The molecule d-phenylalanine is the synthetic mirror image of l-phenylalanine and is not found in nature. Both the l-form and the d-form have been tested in clinical trials. A synthesized racemic mixture of the two forms, referred to as dl-phenylalanine, also is available commercially.

Mechanism of Action

L-phenylalanine is the first precursor in the four-step biosynthesis of norepinephrine. At least one study has suggested that oral consumption of phenylalanine may increase plasma levels of norepinephrine.1 Pyridoxine is known to be a cofactor in the first step of this four-step synthetic process, raising the possibility that co-administration of pyridoxine along with phenylalanine may be beneficial.

Another possible mechanism of action for phenylalanine involves phenylethylamine (PEA), another neuroamine whose deficiency also has been postulated to play a role in depression. In at least one study, ingestion of phenylalanine seemed to be associated with an increase in PEA production.2

Clinical Trials

A search of MEDLINE, EMBASE, and Cochrane databases using the keyword phenylalanine identified only three English-language clinical trials that contain unique patient data. All three were open-label studies without randomization and without placebo controls.

The largest of the three trials included 40 patients diagnosed with recurrent or continuous bipolar or unipolar depression.3 The patients were treated with one 500 mg tablet of l-phenylalanine per day, with dose increases thereafter of one additional tablet per day until one of the following endpoints was reached: Patients had a "therapeutic response," they experienced an adverse event, or they reached a 14 g total daily dose. Patients also received 100 mg bid of pyridoxine. The duration of treatment for each patient was "at least three weeks," although no further information on treatment length was given. Of the 40 patients, 31 were said to have improved. The method of determining improvement was not defined.

The two other trials suffered from similarly poor methodology. One studied 200-600 mg d-phenylalanine per day (mean 350 mg) in 11 patients.4 Only two patients showed improvement; two were dropped from the study because of dramatic worsening of their depression. The other study included 29 patients with bipolar or unipolar depression who were treated with 2-6 g/d of l-phenylalanine.5 None of the patients who had unipolar depression showed improvement.

Adverse Effects

In the largest of the studies described above, adverse events included headache, nausea, constipation, and anxiety. Pregnant patients should use extreme caution using phenylalanine as birth defects have been related to elevated serum phenylalanine levels in women with unrecognized phenylketonuria.6

Drug Interactions

In patients with Parkinson’s disease, phenylalanine may interfere with the action of levodopa.7 It also should not be used in combination with antipsychotics as there have been at least two reports of worsening tardive dyskinesia associated with the use of phenylalanine.8,9

Formulation

Commercially available formulations include l-phenylalanine and the synthetic racemic mixture dl-phenylalanine. Both come in 500 mg and 600 mg tablets.

Dosage

Given the paucity of data, no definite dosage recommendations can be made. If it is to be used, there appears to be slightly more data for l-phenylalanine than the d- or dl- forms. One reasonable approach seems to be to start with a dose of 500 mg once per day and gradually increase the dose up to 6 g daily. There is some suggestion that combining phenylalanine with pyridoxine 100 mg bid may be beneficial.

Conclusion

No well-designed studies of phenylalanine have been performed, and those that have been reported have not shown evidence of efficacy. Assessment of these data is made even more difficult by the variety of doses and isomer types of phenylalanine that have been tested.

Recommendation

Phenylalanine cannot be recommended for the treatment of depression. Potential drug interactions and adverse effects warrant special vigilance against its use in patients with psychotic disorders, those with Parkinson’s disease, and in pregnancy.

References

1. Sabelli HC, Javaid JI. Phenylethylamine modulation of affect: Therapeutic and diagnostic implications. J Neuropsychiatry Clin Neurosci 1995;7:6-14.

2. Sandler M, et al. Trace amine deficit in depressive illness: The phenylalanine connexion. Acta Psychiatr Scand Suppl 1980;280:29-39.

3. Kravitz HM, et al. Dietary supplements of phenylalanine and other amino acid precursors of brain neuroamines in the treatment of depressive disorders. J Am Osteopath Assoc 1984;84(1 Suppl):119-123.

4. Mann J, et al. D-phenylalanine in endogenous depression. Am J Psychiatry 1980;137:1611-1612.

5. Sabelli HC, 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.

6. Levy HL, Waisbren SE. Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. N Engl J Med 1983;309:1269-1274.

7. Eriksson T, et al. On-off’ phenomenon in Parkinson’s disease: Relationship between dopa and other large neutral amino acids in plasma. Neurology 1988;38: 1245-1248.

8. Mosnik DM, et al. Tardive dyskinesia exacerbated after ingestion of phenylalanine by schizophrenic patients. Neuropsychopharmacology 1997;16:136-146.

9. Gardos G, 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.