D-Phenylalanine

Clinical Studies


Phenylalanine is used for depression, attention deficit-hyperactivity disorder (ADHD), Parkinson's disease, chronic pain, alcohol withdrawal symptoms, osteoarthritis and rheumatoid arthritis. D-phenylalanine (DPA) increases the pain threshold, inducing a painkilling effect. DPA increases attention and activity in animals and has been shown to relieve depression in 60% of depressed patients. It produces sustained relief of depression in a significant number of patients, including some unresponsive to the standard treatments.


Published Clinical Studies
D-Phenylalanine



Therapy of depression by phenylalanine. Preliminary note.

Fischer E, Heller B, Nachon M, Spatz H.

To 23 subjects with endogenous depression after a previous unsuccessful treatment with common antidepressive drugs (imipramine-like or MAO inhibitors) dl- or d-phenylalanine was given in dialy oral doses of 50 or 100 mg during 15 days. A complete euthymia was obtained in 17 subjects between one and 13 days of treatment. No important adverse reaction was observed.

PMID: 1173765 [PubMed - indexed for MEDLINE]

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DL-phenylalanine markedly potentiates opiate analgesia - an example of nutrient/pharmaceutical up-regulation of the endogenous analgesia system.

Russell AL, McCarty MF.

Brampton Pain Clinic, Bramalea, Ontario, Canada.

In the author's clinical experience, concurrent treatment with DL-phenylalanine (DLPA) often appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain. An analysis of this phenomenon suggests that it may be mediated, at least in part, by up-regulation of the 'endogenous analgesia system' (EAS), a neural pathway that projects caudally from medullary nuclei to the dorsal horn of the spinal column; when stimulated by chronic pain or therapeutic measures such as opiates or acupuncture, the EAS suppresses activation of second-order pain-receptive neurons in the dorsal horn, and thereby alleviates pain. Since serotonin and enkephalins are key neurotransmitters in the EAS, it is reasonable to predict that measures which promote serotonin activity (such as 5-hydroxytryptophan and serotonin-reuptake inhibitors) as well as enkephalin activity (such as D-phenylalanine, an enkephalinase inhibitor) should potentiate EAS-mediated analgesia - a view consistent with much previous medical research. Comprehensive support of the EAS with well-tolerated nutrients and pharmaceuticals may amplify the analgesic efficacy of chronic opiate therapy, while enabling dosage reductions that minimize opiate side-effects. Analogously, this approach may complement the efficacy of acupuncture and other analgesic measures that activate the EAS. Copyright 2000 Harcourt Publishers Ltd. Publication Types:

  • Review
  • Review, Tutorial

PMID: 10998643 [PubMed - indexed for MEDLINE]

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[The participation of prostanoids in the realization of the cardioprotective, antistressor and anti-arrhythmic effects of enkephalins]

Lishmanov IuB, Maslov LN, Rebrova TIu, Fedotova TV.

It has been established that preliminary administration of D-Ala2-Leu5-Arg6-enkephalin, D-Met2-Pro5-enkephalinamide, and D-phenylalanine to experimental animals prevents a stress-induced increase of the content of thromboxane in the blood plasma and myocardium and induces a rise of the level of prostacyclin, PGF2 and PGE in the heart and blood plasma. The authors hold that the changes in the level of prostanoids may mediate cardioprotective and anti-stressor rather than antiarrhythmic effects of enkephalins.

PMID: 1284224 [PubMed - indexed for MEDLINE]

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Inhibition of the analgesia inhibitory system by D-phenylalanine and proglumide.

Takeshige C, Mera H, Hisamitsu T, Tanaka M, Hishida F.

Department of Physiology, Showa University School of Medicine, Tokyo, Japan.

Stimulation of a nonacupuncture point (NAPS) does not normally produce analgesia in the same way that stimulation of an acupuncture point does. However, NAPS did produce dexamethasone reversible analgesia after intraperitoneal treatment with D-phenylalanine (DPA) or proglumide, or after microinjection of these compounds into such parts of the analgesia inhibitory system (AIS) as the lateral centromedian nucleus of the thalamus and part of the posterior hypothalamus. Inhibition of acupuncture analgesia (AA), or of morphine analgesia (MA) by 0.5 mg/kg, IP, which is equivalent to AA after AIS lesion, and of potentials in the lateral periaqueductal central gray evoked by repetitive NAPS or stimulation of the AIS, were antagonized by DPA. Disappearance of AA and MA in morphine tolerant acupuncture responder and nonresponder rats was reversed to reproduce the same magnitude of analgesia after proglumide application. The reproduced AA and MA were antagonized by dexamethasone. These results indicate that DPA and proglumide antagonized the AIS and unmasked the dexamethasone reversible AA and MA.

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Amino acid--induced insulin release from the perfused rat pancreas. The influence of phenylalanine and tyrosine.

Mackowiak P.

Department of Animal Physiology and Biochemistry, Academy of Agriculture, Poznan.

The effects of L or D phenylalanine and L tyrosine on insulin release from the perfused rat pancreas were investigated. It was found that in the presence of D-glucose, all three amino-acids stimulate insulin secretion. After L-Phe had been removed from perfusate in the presence or absence of L-Tyr, the secondary rise of insulin release (an "off response") was noticed. This phenomenon did not follow to either D-Phe or L-Tyr.

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[Comparative characteristics of the functioning of brain structures exposed to morphine and D-phenylalanine]

Iarosh AK, Goruk PS, Luk'ianov EA.

In experiments on rats it was shown that morphine and D-phenylalanine in doses of 5 and 100 mg/kg, respectively, produce a similar by the degree increase of pain reaction thresholds at stimulation of paws through the electrified floor of the chamber. Experiments on rabbits demonstrated that the main factor in morphine action is a decrease of excitability and blood filling of the reticular formation of the midbrain and the central gray matter and an increase of excitability of the dorsal hippocamp without significant changes in the frontal cortex excitability. D-phenylalanine also caused a decrease of excitability of the reticular formation but in contrast to morphine failed to change excitability of the dorsal hippocamp and enhanced excitability of the central gray matter.

PMID: 3582628 [PubMed - indexed for MEDLINE]

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Attenuation of tourniquet-induced pain in man by D-phenylalanine, a putative inhibitor of enkephalin degradation.

Nurmikko T, Pertovaara A, Pontinen PJ.

Department of Neurology, University Central Hospital, University of Tampere, Finland.

The effect D-phenylalanine (DPA), a putative inhibitor of enkephalin degradation, on the two separate pain components produced by the submaximal effort tourniquet test was evaluated in healthy human volunteers (N = 8). DPA attenuated the increase of the intensity of the ischemic and pressure pain components with increasing ischemia duration, but only the effect on the pressure pain component was significant. The results support some earlier reports suggesting that DPA has analgesic properties.

PMID: 2895566 [PubMed - indexed for MEDLINE]

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[Analgesic effect, tolerance development and dependence potential of D-phenylalanine]

Dove B, Morgenstern E, Gores E.

In comparison to well-established non-narcotic analgesics, the amino acid D-phenylalanine produces similar, dose-dependent analgesic effects in animal experiments, but acts significantly longer. Neither a tolerance of mice to D-Phe after administration for 10 d nor a development of drug dependence in rats following treatment for 6 weeks could be regarded.

PMID: 4070349 [PubMed - indexed for MEDLINE]

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D-phenylalanine and other enkephalinase inhibitors as pharmacological agents: implications for some important therapeutic application.

Ehrenpreis S.

A number of compounds have been shown to inhibit the degradation of enkephalins. As expected, these compounds produce naloxone reversible analgesia and potentiate the analgesia produced by enkephalins and by acupuncture. One of these, D-phenylalanine, is also anti-inflammatory. D-phenylalanine has proven to be beneficial in many human patients with chronic, intractable pain. It is proposed the enkephalinase inhibitors may be effective in a number of human "endorphin deficiency diseases" such as depression, schizophrenia, convulsive disorders and arthritis. Such compounds may alleviate other conditions associated with decreased endorphin levels such as opiate withdrawal symptoms.

PMID: 6128872 [PubMed - indexed for MEDLINE]

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Metabolism of an amino acid with antidepressant properties.

Borison RL, Maple PJ, Havdala HS, Diamond BI.

The amino acid D-phenylalanine exerts antidepressant properties which are believed to be due to its metabolism to brain phenylethylamine. We now show that in mice, the increase in brain phenylethylamine levels induced by L-phenylalanine, but not D-phenylalanine, is antagonized by drugs which block the stereospecific decarboxylase enzyme. Our results show that D-phenylalanine metabolism to phenylethylamine is independent of pathways involving L-phenylalanine.

PMID: 694233 [PubMed - indexed for MEDLINE]

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Amphetamine increases glutamate efflux in the rat ventral tegmental area by a mechanism involving glutamate transporters and reactive oxygen species.

Wolf ME, Xue CJ, Li Y, Wavak D.

Department of Neuroscience, FUHS/The Chicago Medical School, North Chicago, Illinois 60064-3095, USA. marina.wolf@finchcms.edu

We have shown that amphetamine produces a delayed and sustained increase in glutamate levels in the ventral tegmental area, a region containing dopamine cell bodies important in acute and chronic effects of amphetamine administration. The present study characterized the mechanism underlying amphetamine-induced glutamate efflux. It was abolished by the glutamate uptake inhibitor dihydrokainate, but unaffected by perfusion with a low Ca(2+)/high Mg(2+) solution, implicating glutamate transporters. Because reactive oxygen species inhibit glutamate uptake, we examined the effect of amphetamine on hydroxyl radical formation by perfusing with D-phenylalanine (5 mM) and monitoring p-tyrosine production. Although no increase in hydroxyl radical formation was detected, D-phenylalanine completely prevented the amphetamine-induced increase in glutamate efflux, as did systemic injection of another trapping agent, alpha-phenyl-N-tert-butyl nitrone (60 mg/kg). Thus, amphetamine-induced glutamate efflux may involve reactive oxygen species. In other studies, we found that repeated coadministration of alpha-phenyl-N-tert-butyl nitrone with amphetamine attenuated the development of behavioral sensitization. This supports prior results indicating that the increase in glutamate efflux produced by each amphetamine injection in a chronic regimen is important in triggering drug-induced adaptations in ventral tegmental area dopamine neurons, and that such adaptations may in part represent a response to metabolic and oxidative stress.

PMID: 10987845 [PubMed - indexed for MEDLINE]

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[Enhanced resistance to emotional stress through the use of D-phenylalanine]

Iumatov EA, Sarychev EI, Kozlovskii II, Mineeva MF, Demidov VM, Morozov IS, Kozlovskaia MM.

Stress-protective action was studied of D-phenylalanine, having an ability to decrease destruction of endogenic enkefalins. In the experiments stability of the experimental (receiving D-phenylalanine) and control groups of male rats of August line to emotional stress was compared in conditions of immobilization stress by parameters of animals survival rate, adrenal glands hypertrophy development, involution of thymus, pathologic changes in lungs (abscesses development), ulcero-dystrophic disturbances in stomach, and also the activity and kinetic properties of enzyme tyrosin-hydroxylase in the hypothalamus were determined. It was shown that by several of the mentioned physiological parameters the D-phenylalanine significantly increased the animals stability to the emotional stress and decreased tyrosinhydroxylase activity which participates in activation of catecholaminergic processes.

PMID: 1676203 [PubMed - indexed for MEDLINE]