IngredientsPhenylalanine is an essential α-amino acid with the chemical formula C₉H₁₁NO₂, essential for the biosynthesis of proteins and a variety of important biomolecules. This amino acid exists in three forms: L-phenylalanine, the natural form found in food and used in protein synthesis; D-phenylalanine, a synthetic form not commonly used by the human body; and DL-phenylalanine, a combination of both forms.
The stereoisomer D-phenylalanine (DPA) can be produced by conventional organic synthesis, either as a single enantiomer or as a component of the racemic mixture. It does not participate in protein biosynthesis, although it is found in proteins in small amounts — particularly in aged proteins and food proteins that have been processed. The biological functions of D-amino acids remain unclear, although D-phenylalanine has pharmacological activity at niacin receptor 2.
By convention, amino acids are referred to as D or L based upon whether the configuration about the α-carbon corresponds to the D or L stereoisomer of glyceraldehyde, the arbitrary standard. Most naturally-occurring amino acids are L-amino acids, despite the fact that certain of them are dextrorotatory when placed in aqueous solution at neutral pH. Most enzymes which act upon amino acids have asymmetric binding domains which recognize only the L-form of the amino acid. Accordingly, most naturally-occurring proteins comprise L-amino acids.
D-Phenylalanine is registered in the PubChem database under Compound ID (CID) 71567 and carries the CAS registry number 673-06-3. DL-Phenylalanine (DLPA), the racemic mixture, has the molecular formula C₉H₁₁NO₂ and a molar mass of 165.19 g/mol.
Although phenylalanine racemase, which converts L-Phe to D-Phe, has been identified in Bacillus brevis, to our knowledge humans do not synthesize D-Phe. Despite identical physical and chemical properties to L-phenylalanine, only L-enantiomers were selected during evolution as protein constituents. The biological relevance of D-amino acids in mammals started to emerge in the 1990s, when novel sensitive analytical techniques made it possible to separate and quantify amino acid enantiomers. Certain bacteria, such as members of the genus Bacillus, possess D-aminotransferases for making D-amino acids, enzymes that reversibly catalyze the transamination of various D-amino acids and corresponding α-keto acids.
D-phenylalanine is found in proteins in small amounts — particularly in aged proteins and food proteins that have been processed. Phenylalanine (as the L-form) was first isolated in 1881 from lupine seedlings.
D-phenylalanine is commercially available as a dietary supplement in three principal forms:
D-phenylalanine itself has no documented history of traditional or ethnobotanical use as a standalone preparation. Unlike many botanical supplements, it is not derived from a plant traditionally used in folk medicine, but rather emerged from mid-twentieth-century biochemical research. Its story is one of scientific discovery rather than traditional application.
Studying phenylalanine for the treatment of depression attracted enthusiasm in the 1970s and 1980s, interest having since waned because of the few positive efficacy studies. The foundational pharmacological work on D-phenylalanine as an enkephalinase inhibitor was conducted principally by Seymour Ehrenpreis and colleagues starting in the late 1970s. D-phenylalanine has been known to inhibit carboxypeptidase A (Hartruck and Lipscomb, 1971) and was subsequently shown to possess analgesic properties (Ehrenpreis et al., 1978; Della Bella et al., 1979) as well as antidepressant action (Beckmann et al., 1977).
Research published between 1978 and 1982 demonstrated that D-phenylalanine inhibits carboxypeptidase A-like enkephalinase activity and produced significant analgesia in rodent models and early human chronic pain reports, establishing the mechanistic foundation for DLPA analgesic claims.
Supplementation with phenylalanine has been recommended for decades (Growdon et al., 1977), although few controlled studies exist to investigate claims of effectiveness. The clinical use of D-phenylalanine and DLPA for pain and mood disorders was particularly active in orthomolecular medicine circles during the 1980s, when it was studied as a natural adjunct to acupuncture analgesia, as a stand-alone analgesic, and as an antidepressant amino acid precursor.
The primary proposed mechanism that distinguishes D-phenylalanine pharmacologically from its L-counterpart is its capacity to inhibit enkephalin-degrading enzymes. The L-form serves as an essential dietary amino acid, a direct precursor to tyrosine, and ultimately to the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine. The D-form, absent from natural proteins, is proposed to inhibit enkephalin-degrading enzymes (enkephalinases/neprilysin), potentially prolonging the action of endogenous opioid peptides and contributing to analgesic effects.
The reputed analgesic activity of DL-phenylalanine may be explained by the possible blockage by D-phenylalanine of enkephalin degradation by the enzyme carboxypeptidase A. To evaluate the potency of D-phenylalanine as an inhibitor of enkephalinases it was shown that the compound significantly reduced degradation of the oligopeptides (D-Ala²-D-Leu⁵) enkephalin (DAPLE) and Tyr-D-Ala-Gly-Phe (TAAGP) in rat intestinal mucosa. However, D-phenylalanine was much less effective when studied in vitro for inhibitory activity against both enkephalinase A and enkephalinase B activity obtained from calf brain. Interestingly, the addition of just one amino acid to form the dipeptide D-Phe-Tyr markedly enhances the inhibitory potency. D-phenylalanine has been shown to inhibit the degradation of both enkephalins and β-endorphin.
When administered to humans, D-Phe potentiates analgesia (pain relief) and eases depression by inhibiting enkephalinase, which degrades enkephalin peptides, leading to the activation of the opioid delta receptors. These findings, together with kinetic data, suggest that exogenously administered D-amino acids are able to act as effective neuromodulators and highlight the importance of D-amino acid oxidase (DAO) for metabolism of many of these molecules.
D-phenylalanine is metabolized to phenylethylamine (PEA), an amphetamine-like compound that occurs normally in the human brain and has been shown to have mood-elevating effects. Although PEA can be synthesized from L-phenylalanine, a large proportion of that amino acid is preferentially converted to L-tyrosine. D-phenylalanine is therefore the preferred substrate for increasing the synthesis of PEA — although L-phenylalanine would also have a mild antidepressant effect because of its conversion to L-tyrosine and its partial conversion to PEA.
Phenylethylamine (PEA), an endogenous neuroamine, increases attention and activity in animals and has been shown to relieve depression in 60% of depressed patients. It has been proposed that PEA deficit may be the cause of a common form of depressive illness. Depressed patients excrete lower levels of PEA in their urine, and these results have been replicated in urine as well as blood plasma.
Phenylalanine is closely related structurally to dopamine, epinephrine (adrenaline), and tyrosine. Phenylalanine is converted into tyrosine, which then becomes converted into catecholamine neurotransmitters. Consequently, supplementation with phenylalanine has been presumed to have antidepressant effects. This pathway is mediated predominantly by the L-enantiomer component of DLPA or supplemental L-phenylalanine.
D-amino acid oxidase (DAO) degrades the gliotransmitter D-serine, a potent endogenous ligand of N-methyl-D-aspartate type glutamate receptors. DAO is also the primary enzyme responsible for the oxidative deamination and thus the clearance of exogenously administered D-phenylalanine in mammalian tissues. D-amino acid oxidase catalyzes the oxidative deamination of D-amino acids. The definition of human DAAO substrate specificity demonstrated that D-cysteine is the best substrate; however, the flavoenzyme shows a preference for hydrophobic amino acids, some of which are molecules relevant in neurotransmission, including D-kynurenine, D-DOPA, and D-tryptophan.
The biological functions of D-amino acids remain unclear, although D-phenylalanine has pharmacological activity at niacin receptor 2. The functional significance of this interaction in the context of supplementation has not been established in human clinical research.
Research and clinical interest in D-phenylalanine has centered on the following body systems and health areas:
The D-amino acids D-phenylalanine and D-leucine produce naloxone-reversible analgesia; electroacupuncture also produces analgesia which is blocked by naloxone. Combining the two treatments produces an additive effect with a larger analgesia than that produced by either treatment given alone; this combined effect is also blocked by naloxone. Methionine- and leucine-enkephalin produce mild and transient analgesic effects, presumably because of enzymatic degradation. Administration of high (250 mg/kg) doses of D-phenylalanine retards the degradation process and elicits analgesia which is reversed by naloxone and which summates with electroacupuncture analgesia.
D-phenylalanine is also anti-inflammatory and has proven to be beneficial in many human patients with chronic, intractable pain. In an open study, 78 chronic pain patients were given 750–1,000 mg D-phenylalanine daily. Preliminary studies of chronic pain patients showed a response rate to DPA from 32% to 75%.
A double-blind crossover evaluation of a randomized parallel design was conducted to determine the efficacy of DPA in 30 subjects with chronic pain from varied etiology which was unrelieved by multiple therapeutic interventions. Each patient received a stabilized therapeutic regimen consisting of four weeks of either DPA 250 mg or lactose (placebo) orally four times a day. After four weeks, the DPA and placebo groups were crossed over for an additional four weeks of treatment. Pain was quantified using a visual analog pain scale and a cold pressor test. Data from the pain questionnaires revealed more pain relief on DPA reported by 25% of the patients, more pain relief on placebo reported by 22% of the patients, and no difference in pain relief reported by 53% of the patients. Lowest pain level of the visual analog scale was reported by 47% of the patients on DPA and 53% on placebo. The investigators concluded: "There appears to be no significant analgesic effect from D-phenylalanine in chronic pain patients when compared to placebo."
A contrasting perspective from clinical practice: 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.
Evidence assessment: The single well-controlled, double-blind crossover study failed to demonstrate statistically significant analgesic benefit for D-phenylalanine in chronic pain. Uncontrolled studies from the 1970s–1980s reported benefits but were subject to significant methodological limitations. Evidence for analgesia in humans is currently inconclusive.
A distinct and better-supported area of research is the combination of DPA with acupuncture. It has been claimed that the mechanism of acupuncture analgesia can be explained in part by endogenous opioids. If an inhibitor of the endorphin degrading enzyme is administered, the analgesic effect of acupuncture should be prolonged due to increased endorphin levels. A study investigated whether pre-administration of DPA could enhance the analgesic effect of acupuncture in humans. In all five subjects whose pain threshold was raised after acupuncture anesthesia (respondents), the rise in pain threshold was significantly prolonged by DPA. Of 10 subjects whose pain threshold remained almost unchanged after acupuncture anesthesia (non-respondents), the pain threshold was increased by DPA in 5 cases. The rise in pain threshold was most prominent when DPA was administered 30 minutes before the start of acupuncture. In all 4 respondents in whom the raised pain threshold persisted after DPA and acupuncture, the raised pain threshold dropped after intravenous injection of naloxone (10 mg). These findings show that DPA enhances the analgesic effect of acupuncture by the endorphin mechanism.
A second clinical study examined DPA's effects on acupuncture analgesia in chronic low back pain and dental procedures: Thirty patients suffering from chronic low back pain were treated with acupuncture 30 minutes after the oral administration of 4.0 grams of DPA. The results were: excellent in 7 cases, good in 11, fair in 6, and poor in 6. Cases graded excellent and good were then compared with a placebo group. The effect was increased 26% in the DPA-acupuncture group, which showed no statistically significant difference (P<0.1). In a second arm of the same study, in 56 patients undergoing tooth extraction under acupuncture anesthesia, 18 had received 4.0 grams of DPA orally 30 minutes earlier. The results were excellent in 8, good in 6, fair in 3, and poor in 1. These findings show that DPA has an enhancing effect on acupuncture analgesia and anesthesia in clinical practice.
Acupuncture analgesia was potentiated by protection of endogenous opioid peptides using peptidase inhibitors such as D-amino acids, D-phenylalanine, and bacitracin.
Evidence assessment: Small uncontrolled and marginally controlled trials suggest DPA may enhance acupuncture analgesia via opioidergic mechanisms, with naloxone-reversibility providing mechanistic support. The low back pain study did not reach statistical significance. Evidence is preliminary and limited to small samples.
In a large trial, 455 patients with depression were given up to 400 mg per day of D-phenylalanine for 2–6 months. Individuals with a diagnosis of endogenous depression showed the most improvement; after 15 days, 73% were asymptomatic and 23% had significant improvement. In a group of patients with reactive depression, 53% recovered and 23% had significant improvement of their symptoms. There was no significant effect on patients who had been diagnosed with depression after age 50.
In two double-blind studies comparing equal doses of imipramine to either 100 mg D-phenylalanine or 150–200 mg DL-phenylalanine, improvement in psychometric testing and clinical improvement after 30 days were similar, with the majority of patients improving. However, one double-blind trial demonstrated that DPA (150–200 mg/day) was equally as effective compared to imipramine (150–200 mg/day) among patients treated for endogenous depression. A single-blinded study failed to show benefit from DPA (median dose, 350 mg/day) for endogenous depression.
A critical assessment of the literature reaches a measured conclusion: a search of MEDLINE, EMBASE, and Cochrane databases identified only three English-language clinical trials that contain unique patient data. All three were open-label studies without randomization and without placebo controls. After reviewing a number of studies, Sabelli (2002) concluded that the antidepressant effect of phenylalanine was weak but potentially useful, especially as an adjunct to prescription antidepressants.
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. Phenylalanine cannot be recommended for the treatment of depression based on the available controlled evidence base as of the early 2000s reviews.
The PEA connection: fourteen patients with major depressive episodes who responded to PEA treatment (10–60 mg orally per day, with 10 mg/day selegiline to prevent rapid PEA destruction) were reexamined 20 to 50 weeks later. The antidepressant response had been maintained in 12 patients. Effective dosage did not change with time. There were no apparent side effects. PEA produces sustained relief of depression in a significant number of patients, including some unresponsive to standard treatments. This study used PEA directly, not D-phenylalanine itself, but is relevant as D-phenylalanine is a metabolic precursor to PEA.
Evidence assessment: Available human data on D-phenylalanine or DLPA for depression are predominantly from open-label, uncontrolled studies with small samples. The existing double-blind trials are few, small, and methodologically limited. Evidence is currently insufficient to support a clinical recommendation.
Research on phenylalanine and vitiligo has primarily investigated the L-form, with relevance to DL-phenylalanine supplementation. In vitro L-phenylalanine uptake/turnover studies on primary epidermal melanocytes originating from vitiligo patients demonstrated a significantly decreased calcium-dependent L-phenylalanine uptake and turnover compared to healthy control cells.
To evaluate the efficacy of L-phenylalanine (L-Phe) in combination with UVA therapy for vitiligo, an open trial (149 patients, 18 months) and a small double-blind trial (32 patients, 6 months) were conducted. Oral L-Phe loading resulted in peak plasma levels after 30–60 minutes and a slight increase in plasma tyrosine. Response to L-Phe plus UVA irradiation was positive, and various grades of repigmentation not exceeding 77% in the open and 60% in the double-blind trial were observed. An increased L-Phe dose resulted in increased plasma levels but not in improved clinical results. The optimal L-Phe dose appears to be lower than 50 mg/kg/day. Although it is difficult to draw firm conclusions from the investigation, L-Phe may have a place in the treatment of vitiligo and its role merits further investigation.
A larger study examined 200 patients: overall, 90.9% of participants showed improvement, with 68.5% of patients achieving an improvement of 75% or more. L-phenylalanine in combination with 0.025% clobetasol propionate and sunlight during sunny months or UVA lamps in winter appears to improve evolutive vitiligo without side effects, and is therefore especially recommended on the face or for children. This 75% improvement rate was reached 87.9% of the time on the face, 60.4% on the trunk, and 54.6% on the limbs. There was a moderate response to the treatment in patients with focal and segmental vitiligo. There was a slight additional improvement in patients receiving UVA lamp light.
A systematic review of natural health products for vitiligo found: L-phenylalanine monotherapy was assessed in one trial, and as an adjuvant to phototherapy in three trials. All reported beneficial effects. However, the review also noted: it was not possible to pool data from any studies for meta-analytic purposes due to the wide difference in outcome measures and poor quality of reporting. Reports investigating the efficacy of natural health products for vitiligo exist, but are of poor methodological quality and contain significant reporting flaws. L-phenylalanine used with phototherapy shows promise and warrants further investigation.
L-Phenylalanine may be administered both orally (50–100 mg/kg of body weight) or topically, and provides better results if combined with UV exposure. The oral administration of phenylalanine (50–100 mg/kg of body weight) combined with UVA exposure (also known as PAUVA) has been a known therapy for vitiligo for some time.
Evidence assessment: The vitiligo evidence base involves L-phenylalanine specifically. The combined PAUVA (phenylalanine + UVA) approach shows consistent positive findings in multiple studies, but methodological quality is generally low (open-label, no randomized placebo-controlled trials of adequate size). The evidence is preliminary to moderate in strength for L-phenylalanine with phototherapy.
A 2021 randomized crossover study from Imperial College London investigated differential hormonal effects of L- and D-phenylalanine in humans. The aim was to investigate the effects of L-phenylalanine on gastroenteropancreatic hormone release, glucose levels, subjective appetite and energy intake in humans, and to determine whether these effects were stereoisomer-specific by comparing them with D-phenylalanine. The study concluded that ingestion of L-phenylalanine, but not D-phenylalanine, increases insulin, glucagon and GIP concentrations without appearing to have a marked effect on appetite.
While preprandial insulin release may explain effects of L-phenylalanine on postprandial glucose, it is improbable that D-phenylalanine improves glycaemic control in this fashion, as it did not stimulate insulin or GIP preprandially. There was a trend for postprandial GLP-1 concentrations to be higher following ingestion of L- or D-phenylalanine relative to placebo, although these effects did not reach statistical significance. Considering that GLP-1 and PYY are co-localized and secreted, and the trend towards a main effect of treatment for PYY, it is possible that both GLP-1 and PYY are involved in the reduction in postprandial glucose concentrations, and that the absence of a significant effect is attributable to sample size.
Evidence assessment: The stereospecificity of phenylalanine's effects on gastrointestinal hormones is an emerging area. The 2021 human study demonstrates that D-phenylalanine does not significantly stimulate insulin, GIP, or GLP-1 in the same way as the L-form. This is early-stage clinical research in small samples.
In reviewing the effects of D-phenylalanine in the treatment of pain, endogenous depression, and Parkinson's disease, preliminary studies indicate a diminution of urinary phenethylamine elimination in Parkinson's disease patients and also diminished in endogenous depression. Phenethylamine is also present in the brain and is believed to antagonize pharmacologically induced Parkinson-like states in animals. A proposed hypothesis about neurohumoral mechanisms involved in extrapyramidal motility regulation supposes that phenethylamine and dopamine control the activity of extrapyramidal structures whose balance can be disrupted by diminishing phenethylamine/dopamine activity.
Evidence assessment: Interest in D-phenylalanine for Parkinson's disease is based on preliminary mechanistic hypotheses and observations of reduced PEA levels. There are no adequate controlled clinical trials. Evidence is very preliminary.
It has been proposed that 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. These claims are based on mechanistic reasoning and have not been substantiated by adequate controlled clinical trials in humans.
The following dosages are reported strictly as observed in sourced clinical and research literature:
Phenylalanine is an essential nutrient, but some individuals are born with a genetic disorder, phenylketonuria (PKU), that prevents them from metabolizing phenylalanine, and if untreated, phenylalanine accumulates in the body, becomes converted into phenylpyruvate, and the individual usually develops seizures, brain damage, and mental retardation. PKU is a rare autosomal recessive genetic disorder characterized by an inability of the body to break down phenylalanine, caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). The estimated prevalence of PKU is 1 in 15,000 births in the United States. All forms of supplemental phenylalanine, including D-phenylalanine, are contraindicated in individuals with PKU.
Doses higher than 5,000 mg a day may be toxic and can cause nerve damage. High quantities of DL-phenylalanine may cause mild side effects such as nausea, heartburn, and headaches.
DL-phenylalanine should not be used in people taking antipsychotic drugs, as it may cause or worsen symptoms of tardive dyskinesia (TD). TDs are involuntary movements of the tongue, lips, face, trunk, and limbs that can occur in people taking antipsychotic drugs long term. Phenylalanine should be used with caution in individuals with schizophrenia, as it can make a movement disorder (tardive dyskinesia) worse.
Monoamine oxidase inhibitors (MAOIs) are an older class of antidepressant drugs. L-phenylalanine and the selective MAO inhibitor selegiline (Eldepryl, Deprenyl) may strengthen the antidepressant effects of phenylalanine. They should not be taken together. The rationale is that phenylalanine is metabolized to PEA and related trace amines, which are themselves substrates for MAO; inhibiting MAO while increasing substrate supply risks dangerous accumulation of these vasoactive amines.
Levodopa interaction is rated as major. Levodopa is used for Parkinson's disease. Taking phenylalanine along with levodopa can make Parkinson's disease worse. Phenylalanine should not be taken if a patient is taking levodopa.
Phenylalanine may have a moderate interaction with baclofen. Phenylalanine might decrease how much baclofen the body absorbs.
Potential drug interactions and adverse effects warrant special vigilance against phenylalanine use in patients with psychotic disorders, those with Parkinson's disease, and in pregnancy.
DL-phenylalanine may cause symptoms of anxiety, jitteriness, and hyperactivity in children.
Study subjects tolerated 4-week-long oral supplementation of phenylalanine or serine without treatment-related adverse events. A clinical no-observed-adverse-effect level (NOAEL) of phenylalanine supplementation in healthy adult males was determined to be 12 g/day.
D-phenylalanine occupies an unusual position in the supplement landscape: it has a well-articulated biological rationale (enkephalinase inhibition, PEA production) and substantial preclinical support, but human clinical evidence is sparse, dated, and methodologically weak across all indications. The most rigorous controlled trial available for analgesia found no statistically significant effect. Depression evidence rests on open-label, non-randomized studies. The vitiligo research primarily concerns L-phenylalanine combined with phototherapy and, while showing consistent positive signals, lacks high-quality randomized controlled trials. Newer metabolic and endocrine research demonstrates meaningful stereospecificity between L- and D-forms, clarifying that some hormonal effects attributed to phenylalanine are L-form-specific. No large-scale, well-controlled clinical trials on D-phenylalanine alone have been published in the modern era. Its clinical evidence base is of low to very low quality overall, and the supplement is used primarily on the basis of mechanistic plausibility and decades-old preliminary human data.
Health conditions that D-phenylalanine may help support.
Body systems that D-phenylalanine may help support.
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