DL-Phenylalanine

Phenylalanine is an essential amino acid: the L-form is part of every dietary protein and supplies 4–6 g a day in a meat-based Western diet [7]. DL-phenylalanine is the racemic chemical, an equal mix of that L-form and its mirror image, D-phenylalanine, which is not built into human protein. The combination was promoted in the late 1970s and 1980s because each half seemed to offer something different—L-phenylalanine as a precursor of catecholamines and phenylethylamine, D-phenylalanine as a putative "enkephalinase" inhibitor that might extend the body's own opioid signalling [1][9].

Depression. A 1975 note reported that 17 of 23 people with treatment-resistant endogenous depression became euthymic within two weeks on 50–100 mg/day of DL- or D-phenylalanine [10]. Beckmann's open study gave 75–200 mg/day to 20 depressed inpatients; 12 were discharged without other treatment and 4 did not respond [3][11]. His double-blind follow-up compared 150–200 mg/day with the same dose of imipramine in 40 inpatients for 30 days. Only 27 finished, and the groups did not differ on the Hamilton scale, although imipramine helped anxiety and sleep sooner; the authors themselves urged careful interpretation [4]. "No difference from imipramine" in 27 completers is not proof of equivalence, and none of these studies had a placebo arm.

Pain. Animal work found that D-phenylalanine produced naloxone-reversible analgesia in mice and potentiated acupuncture analgesia, and it was then tried in people with chronic pain [2][9]. The one randomized, double-blind, placebo-controlled trial—30 people with long-standing mixed chronic pain, 250 mg four times a day for four weeks per arm—found no analgesic effect: 25% reported more relief on D-phenylalanine and 22% on placebo [5]. The positive human reports are small or uncontrolled: attenuated tourniquet pain in eight volunteers, enhanced acupuncture analgesia in Japanese experiments, and relief of incident pain in nine terminally ill cancer patients [12][13][14][15]. In monkeys, 500 mg/kg gave no significant or naloxone-reversible analgesia [16].

Attention. In adults with ADHD, a two-week double-blind crossover of DL-phenylalanine against placebo improved mood and mood lability, and global improvement approached significance in the 13 of 19 who finished. The benefit was gone within three months of continued open use, and a later open trial of L-phenylalanine did nothing [17]. D-phenylalanine 20 mg/kg/day had no effect in 11 hyperactive boys [18].

Other uses. L-phenylalanine combined with UVA light is the application reviewers consider most promising: small trials, including a 32-patient double-blind trial, reported repigmentation of vitiligo, but they were of poor methodological quality and could not be pooled [19][20][21]. A 20-patient randomized trial of a supplement combining D-phenylalanine with L-glutamine and 5-HTP reduced psychiatric symptom scores during alcohol withdrawal, but the mixture makes it impossible to credit D-phenylalanine [22]. Ten grams of L-phenylalanine before a meal cut intake by 184 kcal in lean men but had no overall effect in overweight women, and the D-form did not reproduce L-phenylalanine's hormone effects [7][8][23].

The L-half is converted by phenylalanine hydroxylase to L-tyrosine, the precursor of dopamine and noradrenaline [6][24]. It is also the precursor of phenylethylamine (PEA), a trace amine that modulates aminergic synapses and is broken down by MAO-B. Sabelli's review noted lower levels of PEA's main metabolite in depressed patients and argued that L-phenylalanine lifts mood mainly when MAO-B is inhibited [1]; an uncontrolled series of 155 patients given selegiline plus L-phenylalanine is the main clinical support [25]. Extra precursor does not act uniformly: in people with tardive dyskinesia, the effect of a phenylalanine challenge depended on fasting amino-acid levels [26].

The D-half is the source of the "DLPA for pain" idea. D-phenylalanine was proposed to block the carboxypeptidase that degrades enkephalins, and in mice it gave long-lasting, naloxone-reversible analgesia whose potency tracked inhibition of enkephalin breakdown [2][5]. The translation is weak. In rats it blunted cold-swim stress analgesia rather than adding to it [27]; in monkeys it gave no opioid-mediated analgesia [16]; in people it lowered plasma enkephalinase activity but, unlike captopril and thiorphan, was not reported to lower it in cerebrospinal fluid [28]. The mood hypothesis for the D-form is also shaky: in rats, D-phenylalanine raised brain phenylalanine but did not change catecholamines, serotonin or PEA, and was not converted to PEA [29].

The two halves are handled differently. D-phenylalanine reaches higher plasma peaks, about a third is converted to the L-form, and 27–38% is excreted unchanged [30]. D-amino acid oxidase, the enzyme that acts on D-amino acids such as D-serine and D-DOPA, is the likely first step of that conversion [31]. In growing mice fed amino-acid diets, D-phenylalanine replaced 28–81% of the nutritional value of the L-form, depending on how much of each the diet contained [32]. Part of any DLPA dose therefore simply becomes extra L-phenylalanine.

In the gut, L-phenylalanine stimulates CCK, PYY, insulin and glucagon, which accounts for its short-term appetite and glucose effects; at the same dose D-phenylalanine did not stimulate insulin, glucagon or GIP [7][8].

DLPA is the racemate; L-phenylalanine and D-phenylalanine are sold separately too. The clinical literature is split by form: the depression trials used DL-phenylalanine [3][4], the pain and pediatric trials D-phenylalanine [5][18], and the vitiligo and appetite studies L-phenylalanine [7][19]. Results from one form cannot be transferred to another: in the same 11 volunteers, 10 g of the L-form raised insulin, glucagon and GIP while 10 g of the D-form did not [8]. In a two-person isotope study, oral D-phenylalanine reached about three times the plasma peak of L-phenylalanine, and a quarter to a third of it was lost in urine [30].

Phenylketonuria is the hard stop. People with PKU lack working phenylalanine hydroxylase; phenylalanine builds up and damages the brain, causing intellectual disability, epilepsy and, in adults, executive-function and mood problems [24][36]. In pregnancy, high maternal phenylalanine is a teratogen: untreated classic maternal PKU causes microcephaly and intellectual disability in most offspring, with lower but real risks at lower levels [37]. Phenylalanine supplements have no place in PKU or in pregnancy with raised phenylalanine.

In healthy adults, the best dedicated study gave 3, 6, 9 and 12 g/day of phenylalanine to healthy Japanese men for four weeks at each dose. There were 25 mild or moderate adverse events in seven men (gastrointestinal symptoms, headache, cold-like symptoms, tiredness), mostly at the lower doses and none judged treatment-related; blood chemistry changed only trivially, and plasma tyrosine rose at 12 g/day. The authors set a no-observed-adverse-effect level of 12 g/day [6][38]. The study was open-label, all-male, four weeks per dose and did not state the enantiomer. Single 10 g doses of L- or D-phenylalanine caused no reported side effects in healthy adults [7][8], though 10 g L-phenylalanine raised nausea ratings in overweight women [23].

The older trials used far smaller doses and reported little: no important adverse reactions at 50–100 mg/day in depression, none in boys on 20 mg/kg/day D-phenylalanine, and none in the vitiligo trials [10][18][35][39]. D-phenylalanine has no long-term human safety data.

Tardive dyskinesia. A 100 mg/kg phenylalanine drink increased involuntary movements to a clinically meaningful degree in 18 men with schizophrenia and tardive dyskinesia, compared with placebo [40].

MAO inhibitors. L-phenylalanine is the precursor of phenylethylamine, which MAO-B normally clears. Combining L-phenylalanine with selegiline was used deliberately to raise brain phenylethylamine in depression [1][25]. That is a pharmacological combination, not a neutral pairing, and the published series was uncontrolled.

Levodopa. Phenylalanine is one of the large neutral amino acids that compete with levodopa for entry into the brain. In Parkinson's patients on ordinary diets, everyday fluctuations in these amino acids mattered little next to swings in levodopa itself [41]; gram doses of supplemental phenylalanine were not studied.

Antipsychotics. A phenylalanine load worsened tardive dyskinesia in men on long-term antipsychotic treatment [40].