Cross-cultural study of a biochemical abnormality in paranoid schizophrenia

We studied 24-hour urinary excretion of phenylethylamine (PEA) and creatinine in 50 schizophrenic (39 paranoid and 11 nonparanoid) and 19 nonpsychiatric patients from Bombay, India. Methods for diagnosis, clinical assessment, and 24-hour urine collection were identical to those used in an earlier study done in a Washington, D.C. hospital. Clinical evaluations were done in Bombay, while urinary PEA and creatinine estimations were performed at NIMH, Washington, without knowledge of the subjects' identity. Paranoid schizophrenic patients had significantly greater 24-hour urinary excretion of PEA than both nonparanoid schizophrenic patients and nonpsychiatric controls. The mean amount of PEA per g creatinine in urine was also highest for paranoid schizophrenic patients. Our findings provide cross-cultural support to the possibility of abnormal PEA metabolism in at least some patients with paranoid schizophrenia.     

Urinary phenethylamine response to d-amphetamine in 12 boys with attention deficit disorder

Urinary phenethylamine (PEA), an endogenous amine similar to amphetamine in both molecular structure and pharmacological properties, was studied in 12 boys with attention deficit disorder with hyperactivity. d-Amphetamine and placebo were given for 14 days each in a counterbalanced crossover design; double-blind teacher behavior ratings and motor activity measurements were also obtained. Excretion of PEA, phenylacetic acid, creatinine, and d-amphetamine were measured. PEA was significantly increased and phenylacetic acid was unchanged after d-amphetamine administration, and change in PEA excretion correlated significantly with d-amphetamine excretion. There was no significant relationship between either clinical response to drug and change in PEA or phenylacetic acid excretion.     

Phenylethylaminergic mechanisms in attention-deficit disorder

Urinary excretion (24-hr) of beta-phenylethylamine (PEA), phenylacetic acid (PAA), phenylalanine (Phe), and p-tyrosine (Tyr), and plasma levels of PAA, Phe, and Tyr were examined in 18 normal children and 26 children diagnosed as having attention-deficit hyperactivity disorder (ADHD). The results indicated that urinary excretion (expressed per g of creatinine) of free and total PEA was significantly lower in the ADHD patients, and plasma levels of Phe and Tyr were also decreased in the ADHD subjects compared with the normal controls.     

Urinary trace amine excretion and platelet monoamine oxidase activity in schizophrenia

The relationship between subtypes of schizophrenia classified by ICD-9 and 24-hour urinary beta-phenylethylamine (PEA) and phenylacetic acid (PAA) excretion has been studied. Schizophrenia was divided into two types: paranoid and nonparanoid. Increased urinary PEA excretion was found in paranoid schizophrenics, but urinary PAA excretion did not show any significant difference between schizophrenics and normal subjects. A relationship between platelet monoamine oxidase (MAO) activity and urinary PEA excretion was found. These findings offer some indication that PEA may play a role in the pathogenesis of schizophrenia.     

Increase in urinary beta-phenylethylamine preceding the switch from mania to depression: a "rapid cycler"

beta-Phenylethylamine (PEA), an endogenous amphetamine-like substance, is known to increase central catecholamine metabolism and has been hypothesized to have an etiological importance in affective disorders. A case of a "rapid cycler" who showed increased PEA excretion before the switch from mania into depression was reported. In order to evaluate whether the patient's cycle of moods could be prevented by modulating PEA metabolism, carbidopa (peripheral dopa decarboxylase inhibitor) and safrazine (monoamine oxidase inhibitor) were administered during the manic and depressive periods of the patient, respectively. Carbidopa exacerbated the manic symptoms, although it decreased PEA excretion. Safrazine induced the increase of PEA without any beneficial effect on the depressive symptoms. These findings may suggest that PEA plays the role of a biochemical trigger in the switch mechanism of a rapid cycler, especially in the switch from mania to depression.     

Stimulants, urinary catecholamines, and indoleamines in hyperactivity. A comparison of methylphenidate and dextroamphetamine

Children with attention deficit disorder with hyperactivity were given either methylphenidate hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's effects were distinctly different from those of dextroamphetamine. After methylphenidate administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites was unchanged by either drug. Urinary PEA excretion was not significantly changed after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine. Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic acid excretion. Effects of dextroamphetamine were not tested.     

Clinical studies on the phenylethylamine hypothesis of affective disorder: urine and blood phenylacetic acid and phenylalanine dietary supplements

To test the hypothesis that 2-phenylethylamine (PEA) modulates affect, plasma levels and urinary excretion of its main metabolite, phenylacetic acid (PAA), were studied in depressed and manic subjects, and the mood-elevating effects of its precursor, L-phenylalanine, were studied in depressed subjects. Mean total plasma PAA concentrations were 491.83 +/- 232.84 ng/ml in 12 healthy volunteers and 300.33 +/- 197.44 ng/ml in 23 drug-free patients with major depression. The 24-hour urinary PAA excretion was also measured in 48 healthy volunteers (141.1 +/- 10.2 mg PAA/24 hr) and in 144 patients with major depression (78.2 +/- 41.0 mg PAA/24 hr). The results suggest that low plasma and urinary PAA may be state markers for depression and are compatible with the PEA hypothesis. In further support, phenylalanine elevated mood in 31 of 40 depressives.     

Pemoline and urinary excretion of catecholamines and indoleamines in children with attention deficit disorder

To test the hypothesis that any change in urinary noradrenergic excretion accompanies drug-induced improvement in attention deficit disorder with hyperactivity, the authors gave pemoline (mean dose, 2.9 mg/kg of body weight) to 11 boys with this disorder in a 4-week open trial. Pemoline administration improved behavior but did not significantly change urinary catecholamine excretion. Serotonin excretion was unchanged, but phenylethylamine (PEA) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased. Clinical responders and nonresponders did not differ with respect to baseline urinary monoamine excretion or change in PEA and 5-HIAA excretion.     

Plasma phenylethylamine and phenylalanine in chronic schizophrenic patients

The hypothesis that phenylethylamine (PEA) is an endogenous psychotogen in schizophrenics, particularly those with the paranoid subtype, has been previously studied by measuring PEA levels in urine and cerebrospinal fluid (CSF) of schizophrenic patients. However, plasma PEA may more accurately reflect simultaneous alterations of PEA in many organ systems, as might occur in a genetic disorder of PEA metabolism. No study to date has examined phenylalanine (Phe), which is thought to be a precursor of PEA, in the same patients who had PEA measured. In this study, we measure both plasma PEA and Phe in 17 drug-free schizophrenic patients and 17 matched controls. Plasma PEA in normal controls was found to be lower by three orders of magnitude compared to normal controls from previous studies--a finding that has not previously been reported. PEA was significantly lower in those schizophrenic patients who had a Research Diagnostic Criteria diagnosis of paranoid schizophrenia. PEA did not differ between patients and controls, and the correlation between plasma Phe and PEA was not significant.     

Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis

Objective. To assess the efficacy and safety of palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the N-acylethanolamines family, in reducing pain severity in patients with pain associated to different pathological conditions. Methods. This was an observational study conducted on 610 patients who were unable to effectively control chronic pain with standard therapies. PEA (600?mg) was administered twice daily for 3 weeks followed by single daily dosing for 4 weeks, in addition to standard analgesic therapies or as single therapy. The primary outcome measure was the mean score pain severity evaluated by the numeric rating scale. Safety was also evaluated. Results. PEA treatment significantly decreased the mean score pain intensity evaluated in all patients who completed the study. The PEA effect was independent of the pain associated pathological condition. PEA-induced decrease of pain intensity was present also in patients without concomitant analgesic therapy. Importantly, PEA showed no adverse effects. Conclusions. In this study, PEA was effective and safe in the management of chronic pain in different pathological conditions.     

Urinary phenylethylamine correlates positively with hypomania,and negatively with depression,paranoia, and social introversion on the MMPI

Summary It has been suggested that phenylethylamine (PEA) may play a role in the modulation of affective behavior. The aim of the present study was to test this hypothesis. Urinary PEA excretion was determined in 32 drug-free healthy volunteers, and the MMPI was used for personality assessment. In support of this hypothesis, a significant positive correlation between PEA and hypomania (r = 0.50; P < 0.05) and a significant negative correlation between PEA and depression (r = –0.58; P < 0.01) was observed in the female subgroup. Furthermore, PEA correlated significantly negatively with hypochondriasis (r = –0.65; P < 0.01), paranoia (r = 0.49; P < 0.05), and social introversion (r = –0.60; P < 0.05). These results are the first evidence in normal individuals either that PEA itself might play a role in the modulation of affective behaviour, or alternatively that PEA could be related to mechanisms responsible for the modulation of affective behavior.     

Biochemical effects of L-deprenyl in atypical depressives

To examine the biochemical effects of 10-30 mg/day L-deprenyl, measurement of 24-hr urinary output of phenylethylamine (PEA), 3-methoxy 4-hydroxy phenylethyleneglycol (MHPG), and L-deprenyl's amphetamine metabolites were carried out before and during the treatment of atypical depressives. Platelet monoamine oxidase (MAO) activity was also assessed. With L-deprenyl 10-30 mg/day, the expected MAO B inhibition occurred, as indicated by significant increase in urinary PEA excretion and virtual disappearance of platelet MAO activity. Twenty-five to 33% of the daily dose of L-deprenyl was recovered as urinary methamphetamine or amphetamine. Excretion of MHPG was significantly decreased with L-deprenyl 10-20 mg/day. Overall, the results suggest that L-deprenyl's antidepressant effects are mediated by some mechanism other than, or in addition to, MAO B inhibition.     

Beta-phenylethylamine and noradrenergic function in depression.

1. The relationship between plasma levels of beta-phenylethylamine (PEA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) was investigated in depressive patients. 2. The mean PEA level in plasma in healthy subjects was 1.19 ng/ml (N = 32). No clearly age-related difference was found. The plasma levels of PEA were measured in major depression, but no significant difference was found between healthy and depressive subjects. 3. Plasma levels of MHPG correlated positively with age in healthy subjects (N = 22, R = 0.71, p less than 0.01). There was no significant difference in MHPG levels between healthy subjects and depressive patients. 4. There was no significant correlation between PEA and MHPG levels in healthy subjects; however, in depressive patients, there was a significant negative correlation between plasma PEA levels and plasma MHPG levels (N = 14, R = -0.73, p less than 0.05). These results suggested that PEA may regulate noradrenergic function in depression.     

Platelet monoamine oxidase B and plasma beta-phenylethylamine in Parkinson's disease

OBJECTIVE: To evaluate the correlation between changes in platelet monoamine oxidase type B (MAO-B) activity and plasma beta-phenylethylamine (PEA) concentrations in patients with Parkinson's disease and controls. METHODS: Platelet MAO-B activity and plasma PEA were measured with gas chromatography-mass spectrometry (GC-MS) in patients with Parkinson's disease treated with levodopa (12 men and 12 women) or selegiline (three men and three women), and physically healthy subjects as a control group (10 men and 10 women). RESULTS: Platelet MAO-B activity was significantly higher in the Parkinson's disease group (mean 542 (SD 318) pmol/10(7) platelets/30 min) than in the control group (mean 349 (SD 307) pmol/10(7) platelets/30 min) (p<0.05). By contrast, the plasma PEA concentrations in patients with Parkinson's disease were significantly lower than in the control group (mean 532 (SD 243) pg/ml; 931 (SD 560) pg/ml) (p<0.01). The plasma PEA concentrations in patients with Parkinson's disease treated with selegiline were prominently higher than in patients with no selegiline treatment (p<0.001). There was a significantly negative correlation between platelet MAO-B activity and plasma PEA concentrations in patients (n=24, r=-0.466, p<0.001). CONCLUSIONS: The increase in platelet MAO-B activity and decrease in plasma PEA concentrations in patients with Parkinson's disease may be involved in the pathophysiological processes of the disease, and these changes are reversed by treatment with selegiline.     

Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy

We assessed the effect of palmitoylethanolamide (PEA) on pain and nerve function in patients with chemotherapy-induced painful neuropathy, in 20 patients undergoing thalidomide and bortezomib treatment for multiple myeloma. All patients were evaluated before and after a two-month treatment with PEA 300 mg BID using pain and warmth thresholds; blinded examiners measured motor and sensory nerve fibre function and laser-evoked potentials. Although no variables returned to normal values, pain and all neurophysiological measures ? assessing Aα, Aβ, and Aδ fibres ? significantly improved (P < 0.05). In contrast, warmth thresholds, assessing unmyelinated afferents, remained unchanged (P > 0.50). Although a placebo effect might play a role in the reported pain relief, the changes in neurophysiological measures indicate that PEA exerted a positive action on myelinated fibre groups. PEA, possibly by moderating mast cell hyperactivity, relieved conduction blocks secondary to endoneural edema. In a severe condition such as painful neuropathy associated with multiple myeloma and chemotherapy, a safe substance such as PEA provides significant restoration of nerve function.     

Concentrations of β-Phenylethylamine in Plasma and Plateletes of Schizophrenics

Abstract: The plasma and platebet PEA levels of 20 normal subjects and 17 schizophrenic patients were investigated using a high-performance liquid chromatography. In the normals the mean plasma and platelet levels of PEA were 4.9 ± 1.9 ng/ml and 1.78 ± 1.01 ng/mg protein, respctively, while in the schizophrenics, those were 12.1 ± 7.9 ng/ml and 0.77 ± 0.5 ng/mg protein, respectively. The plasma PEA levels of the schizophrenics were significantly higher than those of the normals, and the platelet PEA levels of the schizophrenics were lower than those of the normals.     

Phenylethylamine and phenylacetic acid in CSF of schizophrenics and healthy controls

Summary Phenylethylamine (PEA) is an endogenous substance with amphetamine-like stimulant properties. On the basis of this ability an abnormal brain PEA metabolism has been proposed as an etiological factor in some forms of schizophrenia.In the present study 28 schizophrenic patients and 15 healthy controls were investigated. No significant difference from control values was found in PEA concentration in cerebrospinal fluid (CSF) of either untreated or neuroleptic-treated schizophrenics. However, 2 schizophrenics with highest BPRS scores had extremely high PEA concentrations. Free phenylacetic acid (PAA), the major metabolite of PEA, was significantly decreased in ummedicated but not in drug-treated schizophrenics.Because of the assumed neuromodulatory properties of PEA, it is suggested that lowered PAA concentrations and the tendency for PEA to be elevated may imply that altered central neurotransmission occurs in certain forms of schizophrenia.     

Concentrations of beta-phenylethylamine in plasma and plateletes of schizophrenics

The plasma and platelet PEA levels of 20 normal subjects and 17 schizophrenic patients were investigated using a high-performance liquid chromatography. In the normals the mean plasma and platelet levels of PEA were 4.9 +/- 1.9 ng/ml and 1.78 +/- 1.01 ng/mg protein, respectively, while in the schizophrenics, those were 12.1 +/- 7.9 ng/ml and 0.77 +/- 0.5 ng/mg protein, respectively. The plasma PEA levels of the schizophrenics were significantly higher than those of the normals, and the platelet PEA levels of the schizophrenics were lower than those of the normals.     

Decreased cerebrospinal fluid levels of beta-phenylethylamine in patients with Rett syndrome

To clarify the mechanism of brain impairment in Rett syndrome, we measured the cerebrospinal fluid levels of beta-phenylethylamine (PEA) in 17 patients with Rett syndrome. Findings were compared with those obtained in age-matched controls and diseased controls. The cerebrospinal fluid level of PEA was significantly lower in patients with Rett syndrome than in the controls (31% of control values). The alteration in the cerebrospinal fluid level of PEA may reflect dopamine system impairment in Rett syndrome.     

Phosphoethanolamine and ethanolamine are decreased in Alzheimer's disease and Huntington's disease

Measurements of both phosphoethanolamine (PEA) and ethanolamine (EA) were made in postmortem brain samples from patients with Alzheimer's disease (AD) and Huntington's disease (HD) using high-performance liquid chromatography with electrochemical detection. In AD levels of PEA were significantly reduced by 64% in temporal cortex, 48% in frontal cortex and 40% in hippocampus. In HD concentrations of PEA were significantly reduced by 76% in the caudate, 53% in putamen and 48% in the nucleus accumbens. EA concentrations showed similar but smaller reductions in both diseases. Both PEA and EA are involved in phospholipid metabolism and can be released with depolarizing stimuli in some circumstances. Since two diverse neuropathologic processes can result in depleted levels of both amines in their respective regions of pathologic predilection, it is likely that the depletions accompany neuronal death.