PERSPECTIVES

TR E N D S A N D
International Journal of Neuropsychopharmacology (1999), 2, 229–240. Copyright # 1999 CINP

Does phenylethylamine act as an endogenous

amphetamine in some patients ?

Paul A. J. Janssen1, Jose! e E. Leysen2, Anton A. H. P. Megens3 and Frans H. L. Awouters1

" Centre for Molecular Design, # Department of Biochemical Pharmacology and $ Department of General In Vivo Pharmacology,
Janssen Research Foundation, B-2340 Beerse, Belgium

Abstract
In brain capillary endothelium and catecholaminergic terminals a single decarboxylation step effected by

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aromatic amino-acid decarboxylase converts phenylalanine to phenylethylamine, at a rate comparable to that
of the central synthesis of dopamine. Phenylethylamine, however, is not stored in intra-neuronal vesicles and
is rapidly degraded by monoamine oxidase-B. Despite its short half-life, phenylethylamine attracts attention
as an endogenous amphetamine since it can potentiate catecholaminergic neurotransmission and induce striatal
hyperreactivity. Subnormal phenylethylamine levels have been linked to disorders such as attention deficit and
depression ; the use of selegiline (Deprenyl) in Parkinson’s disease may conceivably favour recovery from
deficient dopaminergic neurotransmission by a monoamine oxidase-B inhibitory action that increases central
phenylethylamine. Excess phenylethylamine has been invoked particularly in paranoid schizophrenia, in which
it is thought to act as an endogenous amphetamine and, therefore, would be antagonized by neuroleptics. The
importance of phenylethylamine in mental disorders is far from fully elucidated but the evolution of
phenylethylamine concentrations in relation to symptoms remains a worthwhile investigation for individual
psychotic patients.
Received 25 November 1998 ; Reviewed 18 January 1999 ; Revised 27 May 1999 ; Accepted 30 May 1999
Key words : Amphetamine, aromatic amino-acid decarboxylase, dopamine, phenylethylamine,
schizophrenia.

Introduction particular to schizophrenic disorders. Treatment of nar-

The chemically related substances amphetamine (AMP),
dopamine (DA) and phenylethylamine (PEA) (Figure 1)
have frequently been linked to mental disease, and in
Figure 1. AMP, DA and PEA.
Address for correspondence : Dr F. H. L. Awouters, Centre for
Molecular Design, Janssen Research Foundation, Antwerpsesteenweg
37, B-2350 Vosselaar, Belgium.
Tel. : 32-14-61 20 60 Fax : 32-14-43 73 34
E-mail : frans.awouters!village.uunet.be
colepsy and other conditions with AMP, which started in
1935, has occasionally resulted in psychotic symptoms,
and a systematic description of such cases has led to the
view that AMP psychosis is clinically indistinguishable
from acute or chronic paranoid schizophrenia (Connell,
1958). Persons who are familiar with schizophrenic
patients and have the opportunity to see athletes doped
with excess AMP readily share this view.
Experimental administration of AMP to volunteers
resulted in psychotic behaviour within 1 wk, after
cumulative doses of 100–800 mg. The onset of frank
paranoid symptoms was usually abrupt and the larger
doses finally caused subjects to feel depressed rather than
elated (Griffith et al., 1972). Clinical follow-up for several
days is, therefore, often necessary to distinguish between
the short-lived paranoid episode due to stimulant abuse
and a true endogenous psychosis. Immediate adminis-
tration of antipsychotics (which reduce the symptoms of
either origin) would prevent this important differential
diagnosis.
The laboratory study of the effects of AMP in rats,
monkeys and other species expanded in conjunction with
the emergence of the early neuroleptics. Out of the many
effects of a series of 40 neuroleptics in rats, AMP
230 P. A. J. Janssen et al.
antagonism was the common effect that best represented
the clinical activity of these compounds, haloperidol
being one of the most potent and specific AMP
antagonists (Janssen et al., 1965). Therefore, haloperidol
was the neuroleptic of choice for investigating the
relationship of AMP antagonism with dopaminergic
neurotransmission and was used as a ligand in the
identification of D receptors in 1975.
#
PEA, the decarboxylation product of phenylalanine
(Phe), was found to mimic major effects of AMP, including
locomotor activation, the induction of stereotyped be-
haviour and the release of DA (Barroso and Rodriguez,
1996 ; Borison et al., 1977 ; Gianutsos and Chute, 1986 ;
Jackson, 1975 ; Ortmann et al., 1984). The hypothesis
that PEA is the endogenous AMP responsible for the
symptoms of paranoid schizophrenia was advanced
(Sandler and Reynolds, 1976). The purpose of the present
review is to re-examine this hypothesis and its impli-
cations in order to identify patients who present
symptoms accompanied by an excess or a deficiency of
PEA.
Metabolism of Phe
Phe is obtained exclusively from food, which provides an
adult with about 4 g\d. Major pathways of metabolic
transformation of Phe are shown in Figure 2. In this
scheme two pathways have been omitted. The essential
part of Phe that is required for new protein synthesis
declines from a maximum in early life (approx. 30 %) to a
very small part in advanced age. The second is β-
Figure 2. Metabolic pathways of Phe with pathological interest.
hydroxylation which leads to phenylethanolamine and is
activated in unusual experimental conditions (Saavedra,
1989).
The focus in this paper is on three pathways of known
pathological interest.
(1) Hepatic Phe hydroxylase converts a vital part of
dietary Phe to tyrosine (Tyr). The enzymatic activity
is dependent on the cofactor tetrahydropteridine,
which donates two hydrogens to form water with one
oxygen, whilst the other oxygen of molecular oxygen
is transferred to the 4-position of the phenyl ring of
Phe. Tetrahydropteridine is regenerated by nico-
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tinamide adenine dinucleotide phosphate (NADPH).
Some forms of increased Phe in the circulation
(hyperphenylalaninaemias) are attributed to abnormal
function or metabolism of tetrahydropteridine, but
accumulation of Phe in the organism is more serious in
genetic deficiency of the apoprotein. Numerous
mutations or other molecular errors of the Phe
hydroxylase gene have been reported in the
elucidation of the basis of phenylketonuria (PKU)
(Eisensmith et al., 1996 ; Guldberg and Guttler,
1994 ; Scriver, 1994 ; Tyfield, 1997).
(2) Phe can be decarboxylated to PEA which itself is
rapidly oxidized to phenylacetic acid (PAA) by
monoamine oxidase (MAO), particularly by MAO-B.
Obviously marked changes in brain PEA concen-
trations can be induced by altered activity of
aromatic amino-acid decarboxylase (AADC) or of
MAO-B. The neurochemical status of PEA is largely
based on an excellent review (Paterson et al., 1990), in
which some quantitative data on the synthesis and
metabolism of PEA can be found. The emphasis in the
present review is on the molecular biology of AADC
and MAO, which may account for some marked
species and individual differences.
Human AADC consists of two identical proteins of
480 amino acids. The sequence Asn-Phe-Asn-Pro-
His-Lys-Trp (corresponding to residues 298–304)
contains the binding site for the cofactor pyridoxal
phosphate (Figure 3) and is well-conserved across
species. The AADC gene consists of 15 exons and has
been mapped to chromosome locus 7 p12.3–p12.1
(Sumi-Ichinose et al., 1992).
In the haploid genome the AADC gene is present
as a single copy. However, a splice variant which lacks
exon 3 and leads to a 442 amino-acid protein has been
reported (O’Malley et al., 1995). The common AADC
substrates -dihydroxyphenylalanine (-DOPA) and
-5-hydroxytryptophan are not metabolized to DA
and serotonin [5-hydroxytryptamine (5-HT)] by this
splice variant.

(- - - Asn-Phe-Asn-Pro-His) (Trp - - -)
Figure 3. Schiff’s base of pyridoxal phosphate with the
ε-NH2 group of Lys303 in human AADC.
Figure 4. Peripheral AADC inhibitors.
AADC activity is high in neurons that produce and
store the classical neurotransmitters DA, norepine-
phrine (NE) and 5-HT. In brain tissues with low
innervation by such neurons (e.g. the cerebellum),
most of the AADC activity is from a second important
source, the capillary endothelium. Chronic adminis-
tration in rats of the psychostimulants N,N-diethyl--
lysergamide and phencyclidine markedly up-regulates
(about doubles) the messenger RNA levels corre-
sponding to the AADC gene (Buckland et al., 1997).
The opposite has been reported for AMP. It is clear
that tissue-specific control of AADC activity is still a
relatively unexplored and poorly understood field
(Berry et al., 1996).
For the -DOPA treatment of Parkinson’s disease
peripheral AADC inhibitors have been developed (Figure
4). Carbidopa is commonly co-administered with -DOPA
to prevent a considerable fraction of the administered
dose from being peripherally metabolized to DA, in-
cluding the -DOPA that reaches brain capillary AADC.
The metabolism of an exogenous -DOPA tracer (6-
[18F]fluoro--DOPA) has been found to be increased in
PEA, an endogenous psychostimulant ? 231
(- - - Ser-Gly-Gly) (Tyr - - -)
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Figure 5. The flavin coenzyme of MAO, bound to a cysteine
of the apoprotein, to ribose and Deprenyl.
the striatum of patients with schizophrenia. In one study
in five patients the average estimates of the DOPA–
decarboxylation rate constants in caudate and putamen
were somewhat higher than in healthy volunteers (Reith
et al., 1994).
MAO catalyses the oxidative deamination of amines to
the corresponding aldehydes, which in a further rapid step
are oxidized to the acids. PEA has higher affinity for the
B than for the A form of MAO. The very short half-life of
PEA in mouse brain has been estimated at about half a
minute and is attributed to the highly efficient degradation
by MAO-B.
MAO is a sulphydryl flavoprotein. The covalent link
is made between the 8-methyl group of flavin and the
cysteine of the sequence Tyr-Cys-Gly-Gly-Ser (Youdim,
1978). MAO inhibitors of the propargyl and hydrazine
classes bind irreversibly to the nitrogen in position 5 of
the flavin. Some inhibitors inactivate rather selectively
MAO-A (e.g. chlorgyline) or MAO-B (e.g. Deprenyl)
(Figure 5). A Deprenyl dose of 10 mg\d for 1 wk reduces
human MAO-B activity to about 10 % of its initial level
(Riederer and Youdim, 1986).
Genetic deficiency of MAO-B has been reported to
greatly increase the urinary excretion of PEA in the
absence of overt psychotic symptoms. When both forms
of MAO are absent the excretion of PEA is further
markedly increased, as well as that of several other
amines, and in addition, psychotic symptoms are present
(Lenders et al., 1996).
Whereas the AADC which produces PEA from Phe is
abundant in catecholaminergic neurons, immunocyto-
chemical investigation did not disclose the major enzyme
for PEA breakdown to PAA, i.e. MAO-B (Levitt et al.,
232 P. A. J. Janssen et al.
1982). It is therefore likely that a high rate of PEA
formation in catecholaminergic terminals leads to higher
local concentrations than are generally assumed on the
basis of the average levels in the brain area.
Briefly, in brain capillary endothelium and catechol-
aminergic terminals a single decarboxylation step effected
by AADC converts Phe to PEA, at a rate comparable to
the central synthesis of DA. PEA, however, is not stored
in intraneuronal vesicles and is rapidly degraded by
MAO. Despite its short half-life, PEA attracts attention as
an endogenous AMP since it can potentiate catechol-
aminergic neurotransmission and induce striatal hyper-
reactivity (see below).
(3) Finally, the third metabolic pathway of Phe (Figure 2)
starts with deamination to phenylpyruvic acid. Further
metabolites, including PAA, are greatly increased in
the urine of patients with PKU and are responsible for
its characteristic odour. It is, therefore, not possible to
make a useful estimate of the total PEA formation in
the organism, on the basis of the excretion of PAA,
which is an end product of two different pathways.
The deamination of Phe, and transaminations of
amino acids in general, are effected through pyridox-
alphosphate-based catalytic centres, sufficiently sim-
ilar to that shown in Figure 3 for AADC, to question
in which conditions the formation of either PEA or
phenylpyruvic acid is favoured. It is possible that
deamination dominates in the presence of an excess
substrate, as in PKU.
In the metabolism of Phe there is no pathway analogous
to the homogentisic acid pathway of Tyr, in which the
phenyl ring is split into the 4-carbon acids, acetoacetic and
fumaric acid. The excess of Phe in PKU cannot be
funnelled off through this pathway.
The action of AMP
Common observations and measurements in laboratory
animals injected with AMP reveal a number of changes
from normal. The following summary is based on a
number of studies (Deller and Sarter, 1998 ; Ellinwood et
al., 1973 ; Randrup and Munkvad, 1967 ; Rebec and
Bashore, 1984 ; Segal and Kuczenski, 1987 ; Seiden et al.,
1993) and, of course the own experience gained with an
AMP antagonism since the early neuroleptics (Janssen et
al., 1965) up to the risperidone-like neuroleptics (Janssen
and Awouters, 1994).
AMP activates cardiovascular and metabolic processes
which are linked mainly to the systemic actions of
endogenous catecholamines on adrenergic receptors.
Marked increases in heart rate, cerebral circulation and
L-Phe
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Figure 6. DA release by AMP-like stimulants.
oxygen consumption are well-known effects, that sustain
behavioural activation. First, ‘ normal ’ behaviour such as
running and rearing is intensified (at generally effective
doses of 0.5–2.5 mg\kg). The hyperactivity patterns vary
with the physical constraints of the observation field and
usually show an abrupt transition to ‘ stereotyped
movements ’ at increasing AMP doses (  5 mg\kg).
Relentless oral (licking and biting) and head movements
occur in the absence of locomotor activity. Indifference to
environmental stimuli that alert a normal rat is a further
characteristic of this phase. With appropriate dose
regimens, rats or monkeys do not become gradually
tolerant to the effects of AMP ; on the contrary, they may
develop more intense responses to the same dose. After
induction, such a state of increased sensitivity may last for
weeks.
Neuroleptics have been reported to antagonize the
effects described above, including the process of
sensitization. This broad AMP antagonism generally
restores a normal state, as long as the neuroleptic dose
matches the AMP dose (Niemegeers and Leysen, 1982).
The corresponding neurochemical events have been
elucidated in great detail.
In the striatum (caudate-putamen) and nucleus
accumbens, AMP reaches DA terminals from neurons of
the A9 (substantia nigra, pars compacta) and A10 (ventral
tegmental) areas. By way of the DA transporter AMP
enters and accumulates in the axonal vesicles, which
causes the DA transporter to operate in a way which is
opposite to DA reuptake (Figure 6). AMP administration
in rats elevates the extracellular DA concentration in all
terminal fields possessing DA transporters (Sharp et al.,
1987). The affinity of d-AMP for DA and NE transporters
is of the same order as that of the authentic neuro-

Table 1. Average affinity (pIC value, klog M, 2–4 assays)
&!
of monoamines for neurotransmitter transporters (T) on
neuronal plasma membranes
DA-T NE-T 5-HT-T
DA 7.2 7.4 5.1
NE 6.7 7.3 4.0
5-HT 5.3 6.0 7.5
d-AMP 7.0 7.2 5.3
PEA 6.4 6.8 4.8
(Table reproduced by courtesy of J. E. Leysen and L. Heylen,
Department of Biochemical Pharmacology, Janssen Research
Foundation.)
transmitters (Table 1). Furthermore, the AMP condition
has been mimicked by selective elimination of the DA
transporter gene in mice. These animals, which are smaller
than wild-type mice, run relentlessly in their cages (Giros
et al., 1996). The normal phasic process of intermittent,
depolarization-induced DA release into the synapses (with
brief activation of postsynaptic D receptors, followed by
#
reuptake) gives way to augmented burst-firing patterns of
the target neurons in association with persistent high DA
concentrations in synapses.
After modest AMP doses (0.2 and 0.4 mg\kg) in
anaesthesized rhesus monkeys extracellular DA concen-
trations of the striatum, as measured by microdialysis,
increase substantially. From basal levels of approx. 5 n
they rose on average to approx. 30 and 80 n at the two
AMP doses (Breier et al., 1997), thereby slightly reducing
[""C]raclopride binding to D receptors (by a maximum of
#
10 and 21 %). In rats, after relatively high AMP doses
(5–8 mg\kg) extracellular DA reached peak values of
approx. 30-fold baseline 0.5 h after administration
(Clausing et al., 1995 ; Kuczenski et al., 1997).
The in vivo microdialysis studies document the wide
variability in individual DA responses to the same dose of
AMP. The lowest and highest extracellular concentrations
were separated by a factor of approx. 10 (Breier et al.,
1997 ; Kuczenski et al., 1997). In patients with schizo-
phrenia DA release by AMP was reported to be higher
than in normal subjects ; wide variability, however, also
resulted in considerable overlap between the two groups
(Breier et al., 1997 ; Laruelle et al., 1996).
Accustomed as we are to classical synaptic trans-
mission, it may be asked whether the large extracellular
DA concentrations induced by AMP are only the
expression of a forced overflow from synapses. It has been
proposed that this extracellular DA causes an ‘ atypical ’
mode of dopaminergic neurotransmission (Kawagoe et al.,
1992) or stimulation of various types of autoreceptors
(Grace, 1995). It is further possible that extrasynaptic DA
PEA, an endogenous psychostimulant ? 233
concentrations which are sufficient to stimulate D
#
receptors (  50 n) may be important in the process of
sensitization and in the induction of aberrant behaviour,
such as stereotypies.
Finally, in electrophysiological studies on the firing of
single striatal neurons, it was found that some neurons
were inhibited by DA while other neurons were activated.
Most relevant, however, is that in freely moving animals
elevated striatal firing rates predominate within the active
neuronal circuits. AMP further increases these movement-
related firing rates (West et al., 1997).
AMP effects and their relation to neurochemical events
have been discussed in this review largely on the basis of
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studies in laboratory animals. Such discussion may be
relevant to function and dysfunction in human basal
ganglia and to the paradoxical use of AMP-like stimulants
in the so-called ‘ attention-deficit hyperactivity disorder ’.
AMP itself has been reported to act in part by stimulating
the synthesis of endogenous PEA (Borison et al., 1975 ;
Chuang et al., 1981). As indicated in Figure 6, PEA, in
turn, can be considered to act as an AMP-like stimulant,
although shorter-acting than AMP. It must be recognized,
however, that the affinity of PEA for the catechol-
aminergic transporters appears to be 3- to 4-fold lower
than that of d-AMP (Table 1). Both amines, however,
have only low affinity for the 5-HT transporter, which is
reflected for PEA in approx. 100-fold lower activity to
release 5-HT from the nucleus accumbens in comparison
with the release of DA (Nakamura et al., 1998).
In addition to competitive inhibition of the uptake of
DA and NE in brain tissue by PEA (and also p-tyramine)
(Horn, 1973) it is possible that trace amines cause changes
in postsynaptic membrane excitability (Jones and Boulton,
1980).
Catecholaminergic neurotransmission
Potentiation of neurotransmission by PEA has been
reported to apply equally to neurons innervated by NE
and by DA (Paterson et al., 1990). The relations between
their most prominent projections should, therefore, be
briefly examined. Medium-sized, ovoid cell bodies in the
pars compacta of the substantia nigra, of primates were
proposed as corresponding to dopaminergic neurons
(Marchand et al., 1979). Corresponding cells in the rat are
generated, migrate and settle in days 12–15 of gestation
(Marchand and Poirier, 1983). These cells make up the
nigrostriatal tract (Figure 7, striatal microanatomy). The
cell bodies of a second tract are located in the ventral
tegmental area, with major projections to the nucleus
accumbens and the prefrontal cortex. The noradrenergic
neurons of the central nervous system are located within
several brainstem nuclei, in particular the locus coeruleus,
234 P. A. J. Janssen et al.

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Figure 7. Electron micrograph from rat striatum showing part of a neuron (N) and a capillary (C). The adjacent neuropil is
characterized by profiles of various cell processes including presynaptic axon terminals filled with synaptic vesicles (s) and
postsynaptic dendritic spines (d). The brain parenchyma is separated from the capillary lumen by a blood–brain barrier composed
of endothelial cells with tight junctions (arrow), the basement membrane (arrowhead) and the astrocytic endfeet (a).
(Reproduced by courtesy of J. Van Reempts, Life Sciences, Janssen Research Foundation.)

and project widely along a more dorsally and a more
ventrally located fibre bundle.
Levels of NE and DA in the extracellular fluid are
frequently correlated. Stimulation of the NE neurons of
the locus coeruleus increases the electrophysiological
activity of DA neurons in the ventral tegmental area
(Grenhoff et al., 1993). The increase in extracellular NE in
the medial prefrontal cortex induced by various means is
accompanied by an equally important increase in extra-
cellular DA (Gresch et al., 1995). AMP and cocaine have
been reported to increase extracellular DA in the
prefrontal cortex largely through blockade of the NE
carrier (Tanda et al., 1997).
Both monoamines are involved in self-stimulation
reward responding (Crow, 1976). The maintenance of
such electrical self-stimulation is, however, thought to
require integrity of the dopaminergic, but not necessarily
of the noradrenergic transmission. Selective genetic
elimination in mice of DA β-hydroxylase which is
essential for the synthesis of NE and epinephrine, is
mostly lethal in utero owing to cardiac abnormalities,
except when the mothers are treated with the direct NE
precursor dihydroxyphenylserine. The surviving mutant
females have very low resistance to cold, are fertile, but
lack some critical components of ‘ maternal behaviour ’,
which again can be corrected by the NE precursor
(Thomas and Palmiter, 1997).
It can be concluded provisionally that noradrenergic
neurotransmission is important in the development of
‘ go-behaviour ’ in response to appropriate external stim-
uli, whereas the subcortical DA neurotransmission is
activated by stimuli that have been sorted and integrated
by previous learning (Tassin, 1994).
Mental disorders potentially linked to PEA
‘ Deviant behaviour ’ in PKU
The most striking increase in the supply of the substrate
for the formation of PEA occurs in PKU. Usually this
severest form of excessive circulating Phe is defined by
plasma concentrations at least 20 times higher than the
normal average and genetic inheritance of virtually
inactive mutants of Phe hydroxylase. Strict diet based on
low Phe content for many years reduces but does not
normalize plasma Phe. This measure, however, is effective
against poor brain development and deficient
myelinization in the newborn. The metabolic brain
toxicity of Phe is commonly ascribed to the amino acid
itself (Scriver et al., 1995), since competition for transport
to the brain by the large neutral amino-acid transport
system reduces the availability of Tyr and tryptophan
(Trp) (the precursors for the synthesis of DA, NE and 5-
HT). In addition, higher Phe levels compete in the
hydroxylation of Tyr and Trp (Krause et al., 1985). Some
psychotic symptoms in grown-up PKU patients may
respond to the addition of the precursor amino acids Tyr

and Trp to the diet, without simultaneous reduction of the
availability of Phe (Gu$ ttler and Lou, 1986).
When dietary restrictions are relaxed after blood–brain
barrier maturation, moderately high plasma Phe concen-
trations may still affect brain function. One study
mentions the occurrence of the difficulty of retaining
information or of inhibitory control in resisting first
inclinations (Diamond, 1994). Executive performance has
also been reported to be deficient (Smith, 1994).
It remains to be examined whether increased Phe
turnover in PKU contributes to some of the symptoms of
this disorder (Wolf and Mosnaim, 1983). Upon early
discontinuation of low Phe diet, antisocial and aggressive
behaviour was reduced by reinstitution of the diet,
whereas the more common hyperactive behaviour per-
sisted regardless of the prevailing Phe level (Potocnik
and Widhalm, 1994).
The group of schizophrenias
Despite the diversity within the group of schizophrenias
and the variability of symptoms in patients since an early
date, attempts have been made to define a fundamental
abnormality. When introducing the new word ‘ schizo-
phrenia ’ in 1911, Bleuler wished to counteract miscon-
ceptions linked to the older term of ‘ Dementia praecox ’ ;
he added immediately, ‘ For the sake of convenience, I use
the word in the singular, although it is apparent that the
group includes several diseases ’ (Bleuler, 1950, p. 8). His
extensive description of the fundamental and accessory
symptoms illustrates the diversity of the schizophrenic
disorders.
At the end of the book Bleuler (1950) writes :
It is probable that in the normal psyche there are inhibitions
which prevent the use of disparate associational material and
hinder the transition to another theme, except under the
influence of special forces (affects, distractions from outside). If
these inhibitions can be overcome in the normal psyche, it is
obvious that they can fail completely in schizophrenia. In any
event, schizophrenics not only exclude normal associations, but
also make completely incorrect links. This in itself may be one of
the reasons why the schizophrenic’s thoughts are so easily lost
in irrelevancies and why such strange associations crop up in the
train of thoughts. This lack of inhibition explains the various
combinations of different ideas. (p. 360)
Addressing the present state of knowledge, Lidsky (1997)
comments on the ‘ neuro-psychiatric implications of basal
ganglia dysfunction ’. For decades the involvement of the
basal ganglia in motor functioning has been stressed in
neuroscience, but this tendency is changing, so that now
non-motor processes are encompassed. The unconscious
processing of sensory stimuli (Mettler, 1955), the gating
of sensory information into other parts of the brain
PEA, an endogenous psychostimulant ? 235
(Schneider, 1984) and the development of context-
dependent processes (Calabresi et al., 1997 ; Houk, 1995)
all involve activity of the basal ganglia and contribute to
the formation of learned responses, for which normal
dopaminergic neurotransmission is crucial (Aosaki et al.,
1994).
Lidsky concludes : ‘ Viewed in this manner, consider-
ation of schizophrenic symptoms as, in part, reflections of
basal ganglia dysfunction appears plausible and findings
of both structural and also functional abnormalities in the
basal ganglia of schizophrenics ’ brains do not appear
anomalous. Whether basal ganglia dysfunction might
have any etiological role in schizophrenia is, however,
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quite a different issue.’
In a remarkable review on regional neuropathology in
schizophrenia (Shapiro, 1993) the long list of structural
brain abnormalities does not include significant changes
of the basal ganglia, except for motor control, which may
possibly lead to tardive dyskinesia. Meanwhile, it has
been reported that compared with normal subjects, some
schizophrenic patients show enlarged volumes of basal
ganglia structures (Hokama et al., 1995) ; the number of
striatal neurons is increased (Beckmann and Lauer, 1997) ;
the variability of 18F-DOPA uptake in the caudate and
putamen of schizophrenic patients is much higher than in
control subjects (Dao-Castellana et al., 1997).
Some dysfunctions of the basal ganglia can be linked to
abnormal dopaminergic neurotransmission and possibly
to PEA involvement. In paranoid schizophrenia urinary
PEA excretion is generally increased. In five studies in
which gas chromatographic–mass spectrometric analysis
was used the overall median excretion in paranoid
schizophrenia patients was 17 g in 24 h, vs. 5.6 g for
controls and 8 g in non-paranoid patients (O’Reilly and
Davis, 1994). The possible aetiological role of PEA in
paranoid schizophrenia is further sustained by findings
that high BPRS (Brief Psychiatric Rating Scale) ratings in
patients were accompanied with high PEA cerebrospinal
fluid levels (see Yoshimoto et al., 1987). In Bleuler’s book
paranoid schizophrenia was considered already as a
distinct group of schizophrenia. Now, in view of its
striking resemblance to AMP psychosis in comparison
with other groups, it is likely that in paranoid patients the
expression of PEA excess will be more frequent and
pronounced than in non-paranoid patients.
Parkinson’s disease
In Parkinson’s disease a rather selective loss of A9 neurons
in the substantia nigra and a concomitant reduction of
their projections to the striatum constitute the anatomical
basis of dopaminergic deficiency and hence of the
prominent motor and psychic symptoms. Changes in gait,
236 P. A. J. Janssen et al.
rigid body posture, slow initiation of movements and
tremor occur concurrently with delayed verbal response
and depression, i.e. a complex outcome of basal ganglia
dysfunction. The histological findings also lie at the origin
of the now classical substitution therapy : the remaining
functional neurons are offered a supplement of the
proximal DA precursor -DOPA, of which the dose can
be limited by the use of a peripheral decarboxylase
inhibitor such as carbidopa. In this way it is possible to
mask completely the symptoms of the disease. As further
loss of dopaminergic terminals progresses ‘ on-and-off ’
perceptions of patients increase, which are poorly con-
trolled by changes in oral (pulse) therapy, but can be
avoided with continuous -DOPA infusion.
Symptoms of Parkinson’s disease are mimicked in a
number of conditions, of which the best known is the
parkinsonism associated with excessive doses of neuro-
leptics. Blockade of striatal D receptors is the obvious
#
cause of the deficit in dopaminergic neurotransmission
and its relief by ‘ dose reduction ’ is equally straight-
forward.
PEA as a potential neuromodulator of catechol-
aminergic neurotransmission, can be invoked to assist the
low levels of DA in Parkinson’s disease. The use of
selegiline (Deprenyl) at a dose of 10 mg\d indirectly
increases PEA concentrations by inhibition of MAO-B,
whereas DA metabolism is not affected, at least not in the
rat (Paterson et al., 1991). In this view, higher PEA
concentrations would support dopaminergic neurotrans-
mission without the need of higher or more persistent DA
concentrations.
Other mental disorders
Several studies have explored the potential involvement
of PEA in various disorders, frequently by measuring the
free concentration of PAA, the proximal metabolite of
PEA. In an early, preliminary communication PAA in
cerebrospinal fluid was reported to be significantly
elevated in schizophrenia (Sandler et al., 1978). No such
support for the PEA hypothesis of schizophrenia was
found by other investigators (Gattaz et al., 1985 ; Sharma
et al., 1995) and significantly lower PAA concentrations in
the cerebrospinal fluid were found in hospitalized Indian
schizophrenic patients (Davis et al., 1991). Part of the
inconsistencies may be due to the fact that PAA is formed
by both pathways 2 and 3 of Phe metabolism (Sharma
et al., 1995). The direct conclusions of these studies,
however, remain valid : PAA in the cerebrospinal fluid is in
all normal control groups 2–4 times lower than its con-
centration in the most productive brain part, the caudate
nucleus (Durden and Boulton, 1982) ; neuroleptic treat-
ment of schizophrenic patients does not affect PAA
concentrations (Sharma et al., 1995). Perhaps the mental
disorder with the most consistent absolute increase in
PAA is manic disorder, in which a 74 % increase was
found (Sharma et al., 1995) ; in schizophrenia certain
symptoms, such as hostility and suspiciousness may best
correlate with PAA in cerebrospinal fluid (Faull et al.,
1989 ; Sharma et al., 1995).
In a study on the urinary PEA response to d-AMP
(15–20 mg\d) in boys with attention deficit disorder,
PEA excretion correlated significantly with d-AMP
excretion (Zametkin et al., 1984). The average PEA
excretion increased approx. 16-fold, whereas PAA excre-
tion was unchanged. Behavioural responders had sig-
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nificantly lower PEA excretion in the placebo period than
did the non-responders. More recently PEA urinary
excretion was reported to be 3-fold lower in children with
attention deficit\hyperactivity disorder (Baker et al.,
1991).
High psychosis ratings and bizarre behaviour in a few
‘ bipolar ’ women during episodes of mania and depression
had at times high urinary PEA excretion rates in placebo
conditions (Karoum et al., 1982). The largest differences in
monoamine excretion, in comparison with control sub-
jects with equally severe affective disorder but without
psychotic episodes, were in the excretion of PEA (approx.
12-fold higher) and DA (approx. 2-fold higher). The
significance of these findings is unclear, especially as the
patients with high PEA excretion had histories of frequent
stimulant use.
It has further been reported that urinary PEA excretion
in healthy volunteers correlates negatively with certain
personality traits (depression, hypochondriasis, paranoia
and social introversion) and positively with hypomania
(Moises et al., 1986).
Finally, although there is no consistent evidence of a
PEA deficit in depression (Davis and Boulton, 1994), a
sustained antidepressant effect of PEA replacement (oral
PEA 10–60 mg\d, with 10 mg selegiline) has been
reported in patients with major depressive episodes
(Sabelli et al., 1996).
Final comments
Certain drugs that are standard medication for disorders
of behaviour and mental performance can be linked to
PEA. Large increases in PEA excretion occur at therapeutic
doses of AMP in attention deficit\hyperactivity disorder,
particularly in the responders to such treatment. The
therapeutic response to neuroleptics is most striking in the
subgroup of patients with paranoid schizophrenia, in
which urinary PEA is generally elevated.
The significance of PEA in mental patients, despite all
the technical difficulties and the controversial results, is

likely to be further explored. It appears necessary,
however, to avoid expectations that a particular clinical
disorder or a symptom can be unequivocally linked to
PEA concentrations below or above a fixed limit in a body
fluid or a tissue. Whether the concept of an endogenous
AMP really applies to PEA – and this is still a sound
hypothesis – there may be special occasions on which, for
some patients an excess of PEA can be shown. Such
occasions would pertain to the acute development of
psychosis rather than to chronic states.
The rapid transition to a manic episode might often be
related to stimulated PEA synthesis in the brain. When
considering the sensitizing power of PEA in the basal
ganglia, the high production rate may be transient and
already have abated by the time of a correct diagnosis.
In general, it also appears worthwhile to look for drugs
which intervene more selectively in the production, action
and inhibition of central PEA.
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