CME
Movement Disorders
Vol. 23, Suppl. 3, 2008, pp. S497–S508
Ó 2008 Movement Disorder Society
The History of Dopamine and Levodopa in the
Treatment of Parkinson’s Disease
Stanley Fahn, MD
Columbia University, New York, USA
Abstract: The discoveries of dopamine as a neurotransmitter
in the brain, its depletion in patients with Parkinson disease,
and its replacement with levodopa therapy were major revo-
lutionary events in the rise to effective therapy for patients
with this disorder. This review describes these events and the
persons who carried out these accomplishments. Their impact
The introduction of high dosage levodopa by George
Cotzias1,2 revolutionized the treatment of Parkinson’s
disease (PD), and L-dopa remains until this day the
most efficacious treatment for patients with PD. In
addition, L-dopa therapy had a major impact on
neurology, in general. (1) With the ability to improve
functional disability in a neurodegenerative disorder,
neurology became an attractive field for young medical
students. (2) Besides adding knowledge to the patho-
physiology of parkinsonism, L-dopa provided clues
about the nature of chorea and dystonia. (3) The
response and adverse effects associated with L-dopa
treatment contributed to a better understanding to the
organization of the basal ganglia.3–5 (4) The dramatic
benefit of L-dopa in PD attracted neurologists to study
this disorder, which in turned spawned the subspecialty
of movement disorders and the formation of The
Movement Disorder Society.
The impact of L-dopa in the treatment of PD and in
translational neuroscience cannot be overestimated, and
therefore, the history of how L-dopa came about is
revealing and instructive as we move forward looking
for even better treatments. Oleh Hornykiewicz has
Correspondence to: Stanley Fahn, MD, Neurological Institute, 710
West 168th Street, New York 10032.
E-mail: fahn@neuro.columbia.edu
Potential conflict of interest: Nothing to report.
Received 31 December 2007; Revised 28 January 2008; Accepted
18 February 2008
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/mds.22028
S497
went beyond a single clinical entity of parkinsonism, for it
opened up the beginning of a much better understanding of
the role of dopamine in other neurologic movement disorders
and also in many psychiatric diseases. Ó 2008 Movement
Disorder Society
Key words: levodopa; history
written extensively on the early history of dopamine
and L-dopa, and some of the material in this review
draws upon his excellent articles.6,7
THE BIOCHEMISTRY OF DOPAMINE
L-dopa is an abbreviation of L-3,4-dihydroxyphenylal-
anine. The decarboxylated amine 3,4-dihydroxyphenyle-
thylamine (also known as 3-hydroxytyramine) has been
abbreviated to dopamine (see Fig. 1). Today, we know
that the synthesis of dopamine proceeds from L-tyrosine
to L-dopa to dopamine (see Fig. 1).
According to Hornykiewicz,6 dopamine was first
synthesized by George Barger and James Ewens in
1910 at the Wellcome labs in London, England. Subse-
quently, also at the Wellcome labs, Henry Dale (who
later became Sir Henry) found it to be a weak sympa-
thomimetic, epinephrine-like compound,8 and years
later, in 1952, it was Dale who suggested its current
name of dopamine. D,L-dopa was synthesized chemi-
cally by Casimir Funk in 1911.9 Two years later, Mar-
cus Guggenheim at the Roche laboratories in Switzer-
land isolated L-dopa from fava beans (Vicia faba).10
He ingested 2.5 g of L-dopa and discovered its emetic
effect; otherwise he found it essentially without phar-
macologic activity (see Hornykiewicz7).
Little work was done on dopamine for the next 30
years, until Peter Holtz et al.11 in Germany discovered
the enzyme aromatic-L-amino-acid decarboxylase (also
called dopa decarboxylase), which, in mammalian tis-
S498
FIG. 1. Synthesis of levodopa (from its precursor L-tyrosine) and dopamine (from its precursor levodopa). In parentheses are the names of the
cofactors involved in the syntheses next to the enzymes each interacts with.
sues, converts L-dopa to dopamine (see Fig. 1). This
discovery provided a mechanism for the formation of
dopamine in the brain from an exogenous source, since
L-dopa, unlike dopamine itself, can cross the blood
brain barrier. Shortly after the discovery of dopa decar-
boxylase, both Holtz12 and, independently, Hermann
Blaschko13 at the physiological laboratories in Cam-
bridge proposed that L-dopa and dopamine were inter-
mediate metabolites in the biosynthetic pathway of the
catecholamines, epinephrine, and norepinephrine (see
Fig. 2). This hypothesis was later shown to be correct,
although it still failed to explain completely the physi-
ologic significance of dopamine. Over the next decade
or two, Peter Holtz and others continued to study do-
pamine and found that it could lower blood pressure in
animals and that it could be detected in many periph-
eral tissues, including the adrenal medulla, heart, and
kidney.14
In 1956, Oleh Hornykiewicz began working in
Blaschko’s laboratory, now located in Oxford, and was
assigned the task of determining whether blood pres-
sure was directly affected by dopamine, or if some
other product of dopamine was responsible. Hornykie-
wicz showed that, indeed, dopamine did lower blood
pressure and that L-dopa had a similar effect.15
It was not known until later how L-dopa was
formed; the enzyme tyrosinase which can convert tyro-
Movement Disorders, Vol. 23, Suppl. 3, 2008
S. FAHN
sine to L-dopa is present in skin and other pigmented
tissues, but not in sympathetic tissue or in brain. In the
early 1960s, Toshiharu Nagatsu from Japan was a
postdoctoral fellow in Sidney Udenfriend’s laboratory
at the National Heart Institute, a component of the
National Institutes of Health (NIH). Udenfriend’s lab
was engaged in catecholamine biochemistry, especially
as it relates to sympathetic tissue. Nagatsu et al.16 dis-
covered the enzyme tyrosine hydroxylase that converts
L-tyrosine to L-dopa. This turned out to be a very
important discovery, since tyrosine hydroxylase is the
rate-limiting enzyme in forming L-dopa, dopamine, and
indeed, all of the catecholamines. Nagatsu subse-
quently returned to Japan and continued his studies of
this pathway. In 1994, his lab identified the gene defect
responsible for dopa-responsive dystonia (DRD), also
known as Segawa’s disease or hereditary progressive
dystonia with diurnal fluctuations, a rare type of dysto-
nia that is responsive to L-dopa therapy. The gene re-
sponsible for this disease encodes for GTP cyclohydro-
lase 1 (GCH1), which is the rate-limiting enzyme for
the biosynthesis of tetrahydrobiopterin, a cofactor for
the formation of tyrosine hydroxylase and other aro-
matic amino-acid hydroxylases.17 Molecular genetics
research by Nygaard et al.18 had mapped the DRD
gene to an area on chromosome 14q a few years ear-
lier, but the Nagatsu lab which had been studying
 DOPAMINE AND LEVODOPA IN THE TREATMENT OF PD S499

FIG. 2. Biochemical pharmacology of dopamine. The diagram shows the synthesis and catabolism of dopamine, along with the enzymes
involved. L-dopa and dopamine are precursors to norepinephrine, which in turn could be further metabolized to epinephrine (not shown). COMT
catalyzes the 3-O-methylation of levodopa (not shown) as well as dopamine (and other catechols). MAO deaminates and oxidizes the mono-
amines, dopamine, norepinephrine, epinephrine, and serotonin (only the dopamine pathway is shown). MAO, monoamine oxidase; COMT, cate-
chol-O-methyltransferase.

GCH1, was able to make the gene identification for
this autosomal dominant disorder.
DOPAMINE IN THE BRAIN
As progress was being made throughout the 1950s
and 1960s on defining the mechanisms involved in do-
pamine biosynthesis, physiologists and pharmacologists
were making headway in understanding the physiologi-
cal actions of various intermediates of the catechol-
amine pathway. Arvid Carlsson, then a postdoctoral
fellow in Bernard Brodie’s cardiac pharmacology lab
at NIH, was investigating the mechanism whereby re-
serpine lowers blood pressure and slows heart rate.
Brodie’s lab had shown that reserpine lowered sero-
tonin levels19 and had proposed that loss of serotonin
was responsible for reserpine’s cardiovascular effect
and also for its neurologic effect of ‘‘tranquilisation’’
(now recognized as akinesia). Carlsson, however, won-
dered if perhaps it was not serotonin, but rather a cate-
cholamine, that was responsible for lowering blood
pressure and for the akinetic effect of reserpine. In 1957
he observed that norepinephrine and epinephrine dis-
appeared more or less completely from tissues, includ-
ing brain, after reserpine treatment,20 the same effect
that Brodie and coworkers had shown for serotonin.
After returning to Sweden and establishing his own
laboratory at the University of Lund, Carlsson showed
that D,L-dopa, not 5-hydroxytryptophan (the precursor
of serotonin), reversed the akinetic effect of reserpine
in rabbits.21 In dramatic fashion, reserpinized rabbits,
after receiving D,L-dopa, went from being totally un-
responsive to alert, with their drooping ears popping
up almost immediately (see Fig. 3). The action of
DOPA was markedly potentiated by monoamine oxi-
dase (MAO) inhibitors, emphasizing that the observed
effect was not caused by DOPA itself but rather by
amines formed from it. This discovery really put dopa
and catecholamines on the map, at least in regard to
reserpine’s akinetic effect, but which catecholamine

Movement Disorders, Vol. 23, Suppl. 3, 2008

S500
FIG. 3. Response of reserpinized akinetic rabbits to D,L-dopa. Top: Reserpine-treated rabbits become akinetic and immobile (note the floppy
ears). After treatment with D,L-dopa, the rabbits perked up and became mobile, recovering from akinesia (note the erect ears). From Carlsson A,
Lindqvist M, Magnusson T. The 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 1957;180:1200.
was responsible for the effect was not known at that
time. Carlsson et al. were unable to detect any increase
of norepinephrine or epinephrine in brain when DOPA
was given to reserpinized animals, and wondered about
dopamine, which had been assumed to be only an in-
termediate in the formation of norepinephrine and epi-
nephrine. The reversal of the akinetic effect of reser-
pine in humans by L-dopa was reported in 1960 by
Degkwitz and coworkers.22
At about this time, Kathleen Montagu23 in Hans
Weil-Malherbe’s laboratory near London, along with
Weil-Malherbe and Bone,24 showed, for the first time,
that dopamine was present in the brain. Actually, 6
years earlier, Raab and Gigee25 had discovered a cate-
cholamine-like compound in the brain with a regional
distribution in the striatum and that increased after
dopa administration; today their unknown brain sub-
stance is considered to have been dopamine.6,7
Carlsson et al., meanwhile, developed a new chemi-
cal fluorescent assay technique to measure dopamine in
tissue, for there was previously no method to measure
the microgram quantities suspected. He then showed
that not only was it present in the brain, but that it was
depleted with reserpine and restored with L-dopa.26
Working in Carlsson’s lab, two medical students, Åke
Bertler and Evald Rosengren, mapped the distribution
Movement Disorders, Vol. 23, Suppl. 3, 2008
S. FAHN
of dopamine in dog brain, demonstrating that it was
concentrated in the basal ganglia,27 quite distinct from
the regional distribution of norepinephrine and epi-
nephrine; and this was simultaneously shown in human
brain by another one of Carlsson’s collaborators, Isamu
Sano.28 All of these findings led Carlsson to speculate,
at the 1959 international pharmacology meeting, that
dopamine was somehow responsible for PD.29 Carls-
son, of course, went on to win the 2000 Nobel Prize in
Physiology or Medicine for his work on dopamine,
along with Paul Greengard and Eric Kandel, for their
work on signal transduction in the nervous system and
the molecular basis of memory, respectively.
DOPAMINE AND PARKINSON’S DISEASE
Hornykiewicz, back in Vienna from being a post-
doc in Blaschco’s lab in Oxford, began to measure
postmortem brain dopamine in people with PD, posten-
cephalitic parkinsonism, Huntington’s disease and in
other extrapyramidal disorders, as well as in control
brains, and in 1960, published a landmark paper show-
ing for the first time a marked depletion of dopamine
in the caudate and putamen of patients only in the PD
and postencephalitic parkinsonian brains.30 Six years
later, following several other of his seminal papers on
 DOPAMINE AND LEVODOPA IN THE TREATMENT OF PD
postmortem biochemistry of PD, Hornykiewicz pub-
lished a major review article in Pharmacological
Reviews positing that striatal dopamine deficiency is
correlated with most of the motor symptoms of PD.31
Over the next 5 years or so, using Nils-Ake Hillarp’s
technique of histofluorescence, Nils-Eric Andén, Ann-
ica Dahlström, and Kjell Fuxe in Sweden mapped
dopamine pathways in the brain of rodents and dis-
covered the nigrostriatal pathway that goes from cell
bodies of the A9 neurons in the midbrain to their nerve
terminals in the striatum.32 At about the same time,
Louis Poirier and Ted Sourkes in Montreal were meas-
uring dopamine in the nigra of animals and showed
that striatal dopamine levels fall when the nigra is
injured, thus tying together the nigrostriatal pathway
anatomically and pathologically.33 Thus, there was ex-
perimental evidence of dopamine in the nigrostriatal
neurons and their depletion in the striatal target follow-
ing a lesion in the cell bodies in the substantia nigra,
the known pathologic feature of human PD.
In the brain, the enzymes involved in catecholamine
synthesis are transported from the cell body in the
nigra into nerve terminals, where dopamine is formed.
Dopamine is synthesized in the cytosol and transported
into synaptic vesicles via the vesicular monoamine
transporter 2 (VMAT2). From the synaptic vesicles,
dopamine is released in a quantal manner when a
nerve impulse traveling down the axon reaches the
nerve terminal. Once in the synaptic cleft, dopamine
can act on both postsynaptic and presynaptic dopamine
receptors. If there is excessive dopamine accumulation
in nerve terminal cytoplasm or if dopamine transport
into the synaptic vesicles is blocked by inhibition of
VMAT2 (a target of both reserpine and tetrabenazine),
elevated cytosolic dopamine levels results. This cyto-
solic dopamine can be auto-oxidized into toxic pro-
ducts that could lead to neurodegeneration; the neuron
defends itself by condensing cytosolic dopamine into
neuromelanin34 or metabolizing the dopamine by
MAO and catechol-O-methyltransferase (COMT) to
form homovanillic acid. The latter mechanism accounts
for the depletion of brain catecholamines following re-
serpine or tetrabenazine treatment.
THE ERA OF L-DOPA THERAPY IS BORN
Even before the nigrostriatal dopamine pathway had
been mapped by histofluorescence, Oleh Hornykiewicz
in 1960, after discovering striatal dopamine deficiency
in the brains of patients with PD, began to consider L-
dopa as a possible treatment for PD. He approached
Walther Birkmayer, a clinical neurologist in Vienna,
S501
offering him about 2 g of L-dopa he had kept from
Blaschko’s lab to test in PD patients. Intravenous
injections of the L-dopa produced dramatic, but tran-
sient, benefit in these patients, heralding the beginning
of the era of L-dopa therapy.35 Over the next several
years, some investigators throughout the world showed
similar benefits using higher doses of L-dopa,36–41
while other investigators reported no benefits with sim-
ilar doses.42–45 The first person to use really high doses
of DOPA was Patrick McGeer in Vancouver, British
Columbia. Even with 5 g of D,L-dopa per day, McGeer
failed to show a benefit.46
Then in 1967, the major breakthrough occurred. The
dose-limiting side effect of anorexia, nausea, and vom-
iting had previously impeded using higher dosages of
D,L-dopa. George Cotzias developed a new approach,
which in principle is still used today. He started
patients on a very low dose of D,L-dopa to avoid the
gastrointestinal adverse effects, and then raised the
dose very gradually, eventually giving up to 16 g per
day.1 Patients with PD tolerated this very slow, gradual
build-up of dosage and then began to achieve dramatic,
revolutionary benefit as therapeutic doses were
reached. They reported marked improvement in 8
patients and less improvement in two others. Of the 8
who received 12 g or more per day, 7 showed marked
benefit. Granulocytopenia was seen in 4 patients, and
bone marrow examination revealed vacuoles in the my-
eloid cells in 4 of the 12 patients with bone marrow
examinations. Because of the hematologic problems
and because D-dopa is not metabolized to form
dopamine, Cotzias et al. subsequently used L-dopa,2
and these hematologic problems were no longer
encountered.
Interestingly, Cotzias initially was not trying to use
D,L-dopa to restore brain dopamine levels, but was try-
ing to repigment the brain, i.e. restore loss of neurome-
lanin.1 He apparently was not impressed with the con-
cept that parkinsonism could be due to low striatal do-
pamine. Before trying D,L-dopa, he tried phenylalanine,
the precursor of tyrosine, in an attempt to increase neu-
romelanin, but parkinsonism worsened on phenylala-
nine,1 probably reflecting competition of tyrosine’s
entry into brain due to oversaturation of the aromatic
amino-acid transport mechanism. With the success of
high dosage D,L-dopa, Cotzias accepted the concept
that the drug was restoring brain dopamine. It turns out
with subsequent investigations that the brain’s neuro-
melanin is not restored with L-dopa therapy.47 While
Cotzias was testing high dosage L-dopa following his
breakthrough results with D,L-dopa, Yahr et al. was
conducting a double-blind trial with L-dopa and
Movement Disorders, Vol. 23, Suppl. 3, 2008
S502
showed similar dramatic benefit,48 as that observed by
Cotzias et al.2
Many subsequent reports showed significant im-
provements in 75% of patients with parkinsonism.
Although a complete remission was rarely obtained,
akinesia and rigidity were generally most benefited,
and many who had been unable to turn in bed or arise
from a chair became able to do so. Tremor had a
more variable response; sometimes it was eliminated
by L-dopa, and in other patients, the tremor was resist-
ant. A number of other symptoms, including postural
instability and speech disturbance, were typically unaf-
fected by L-dopa therapy, suggesting these resistant
symptoms are not due solely to dopamine deficiency.
As seen in the early days of L-dopa therapy, this drug
does not have an immediate antiparkinsonian effect,
and it may take several days to weeks of high dosage
therapy to achieve the desired degree of benefit. Once
a patient has been primed, though, then restarting L-
dopa after a withdrawal period brings on the benefit
almost immediately.
We can interpret the introduction of high dosage
L-dopa therapy by Cotzias as a revolutionary treatment
for PD, not just an evolutionary one, for it brought a
new way to treat the disease, which still dominates the
current therapy of the disorder. Subsequent to the early
investigator-initiated clinical trials, Hoffman-La Roche,
where L-dopa was first isolated, was able to synthesize
the compound and initiated company-sponsored clinical
trials, leading to regulatory approval of L-dopa for
treatment of PD.
COMPLICATIONS SEEN IN THE EARLY
DAYS OF L-DOPA THERAPY
The initial paper by Cotzias et al.1 describing the
successful use of high dosage D,L-dopa in patients with
PD did not mention motor complications. Adverse
effects that were mentioned were predominantly ano-
rexia, nausea, vomiting, faintness, and hematologic
changes. Cotzias et al.2 then substituted L-dopa for D,L-
dopa, which eliminated the hematologic adverse
effects. That article also presented the first report of
L-dopa-induced dyskinesias, as well as mental symp-
toms of irritability, anger, hostility, paranoia, insomnia,
and an awakening effect. The dyskinesias described
were chorea, myoclonus, hemiballism (ipsilateral to the
side of a prior thalamotomy), and dystonia. These
investigators noted that the adverse effects would sub-
side with a lowering of the dosage of L-dopa. They
also reported that the appearance of dyskinesias is not
an early occurrence after initiating L-dopa therapy.
Movement Disorders, Vol. 23, Suppl. 3, 2008
S. FAHN
Dyskinesias were not seen during the first 3 weeks of
treatment, but occurred later on.
The next paper reporting on the use of L-dopa was
by Yahr et al.48 In their 60 patients, gastrointestinal
adverse effects were encountered in 51, dyskinesias in
37, hypotension in 14, cardiac abnormalities in 13, and
psychiatric symptoms in 10. By 1970 McDowell
et al.49 and Schwarz and Fahn50 were reporting that
dyskinesias were as common as gastrointestinal side
effects. They noted that the gastrointestinal effects could
often be avoided by building up the dose of L-dopa
very slowly, and that often patients build up tolerance,
with the result that few patients would have persistent
gastrointestinal difficulties. On the other hand, dyskine-
sias, although occurring later, would persist, and would
increase and become more prominent with continuing
treatment. By 1971, dyskinesias were noted to be the
most common dose-limiting adverse effect.51 The
abnormal movements were seen in all parts of the
body, and most often were choreic in nature.
The first review article on L-dopa-induced dyskine-
sias was presented by Duvoisin,52 based on an analysis
of L-dopa therapy in 116 patients with PD. He found
that by 6 months of treatment, 53% of patients had
developed dyskinesias; by 12 months, 81% had.
Although described earlier by Cotzias et al.2 myoclonic
jerks in patients with PD, especially as a toxic reaction
to L-dopa was further elaborated by Klawans et al.53
Besides dyskinesias, treating physicians began to
become more aware of motor fluctuations, especially
as the return of parkinsonian symptoms during these
episodes were more prominent due to the underlying
worsening of the disease. Various terms were coined to
label these fluctuations. ‘‘On–off’’ was coined in 1974
to describe a sudden loss of L-dopa’s benefit and
replacing it with the parkinsonian state (the ‘‘off’’
state).52,54–56 The speed of this change was likened to
that of a light switch turning on and off. The ‘‘on’’
state was equated with the time when the patient was
having a good response from L-dopa; the ‘‘off’’ state,
when L-dopa was not working. The reemergence of the
‘‘on’’ state was sometimes sudden, without even the
benefit of another dose of L-dopa. But often the ‘‘on’’
state would not appear until another dose of
L-dopa was ingested. The more common gradual
development of the ‘‘off’’ state, taking many minutes to
develop and appearing as the plasma levels of L-dopa
had fallen, was labeled in 1976 as the ‘‘wearing-off’’
phenomenon by Fahn57 and also the ‘‘end-of-dose’’
deterioration by Marsden and Parkes.58 Both of these
terms refer to the identical clinical situation and have
been used interchangeably since.
 DOPAMINE AND LEVODOPA IN THE TREATMENT OF PD
A new dyskinetic state related to the timing of
L-dopa dosing was described in 1977. Up to this point,
all dyskinesias were considered to occur at the peak
effect of the L-dopa dose. Muenter et al.59 described
dyskinesias appearing at the beginning and at the end
of the dose, which they called ‘‘D-I-D’’ for dystonia
(dyskinesia)-improvement-dystonia (dyskinesia). These
workers contrasted this to the much more common
peak-dose dyskinesia, labeled by Muenter as ‘‘I-D-I.’’
Subsequently, the D-I-D phenomena have been labeled
diphasic dyskinesias.60,61 Such dyskinesias most typi-
cally appear in the legs.60
Not all dyskinesias appear at the peak, the begin-
ning, or the ending of the dose. Lees et al.62 described
that painful ‘‘off’’ period dystonic cramps can appear,
especially in the foot in the early morning on awaken-
ing. Melamed63 elaborated on this phenomenon and
labeled it early-morning dystonia, pointing out that this
occurs when the effect of the previous night’s dose of
L-dopa had completely worn off. This is a dyskinesia,
appearing as a dystonia, rather than as chorea, that
occurs during the ‘‘off’’ state, a time when bradykine-
sia and other signs of the parkinsonian state would
have been manifested. Instead, the ‘‘off’’ state dystonia
is seen in place of parkinsonism. Early morning dysto-
nia is the most common type of ‘‘off’’ dystonia, but
these tight, cramped muscles can appear at other times
of the day when the medication wears off. In addition
to ‘‘off’’ dystonia, dystonic postures can be seen as a
peak-dose dyskinesia, but is less common than peak-
dose chorea. Melamed later described the mechanism
of delayed ‘‘ons’’ and dose-failures following a dose of
64
L-dopa as due to poor gastric absorption.
STEPS TAKEN TO ENHANCE THE
EFFECTIVENESS AND REDUCE THE
ADVERSE EFFECTS OF L-DOPA THERAPY
L-aromatic amino acid decarboxylase inhibitors, such
as a-methyldopa, had been developed and were used
for the treatment of hypertension. By attaching an
azide moiety to these compounds, they are no longer
able to penetrate the blood-brain barrier, and thus
could inhibit the conversion of L-dopa to dopamine in
the peripheral system, and still allow this enzymatic
step to occur centrally. The development of such pe-
ripheral dopa decarboxylase inhibitors was the next
major step making L-dopa more potent while reducing
gastrointestinal adverse effects. Carbidopa and bensera-
zide are such peripheral decarboxylase inhibitors and
are used commercially. When given with L-dopa, they
allow for up to a 4-fold increase in the availability of a
S503
given dose because peripheral metabolism to dopamine
is blocked. More importantly, these agents block the
gastrointestinal side effects due to peripheral dopamine
acting upon the vomiting center of the area postrema,
which is not protected by the blood-brain barrier. The
combination of L-dopa with carbidopa into a single tab-
let was commercially marketed under the trade name
of Sinemet, to indicate without (sine) emesis. Sinemet
(carbidopa/L-dopa) was initially sold in 1:10 ratios as
10/100 and 25/250 mg strength tablets. But because
many patients require at least 50–75 mg of carbidopa a
day to have adequate inhibition of peripheral dopa de-
carboxylase, a 25/100 mg tablet was later marketed, and
is probably the most common strength utilized today. In
some patients even 75 mg per day of carbidopa is inad-
equate, and nausea, anorexia, or vomiting still occurs.
Because such patients could benefit from higher doses
of carbidopa without needing additional L-dopa, carbi-
dopa became available as a separate tablet, which is
available under the trade name of Lodosyn. The combi-
nation of benserazide and L-dopa is marketed under the
brand name of Madopar. A number of studies showed
the advantage of L-dopa combined with a peripheral de-
carboxylase inhibitor compared to L-dopa alone.65–72
The next enzyme inhibitor to be studied as an
adjunct to L-dopa in the treatment for PD was selegi-
line (formerly called deprenyl), an irreversible inhibitor
of MAO type B. The action of MAO is to oxidatively
deaminate monoamines, including dopamine (see Fig.
2). MAO comes in two genetically distinct isoforms,
known as MAO-A and MAO-B. Each has relatively
selective substrates. Dopamine is metabolized by both
types, whereas serotonin and tyramine (present in some
foods) are preferential substrates of MAO-A. MAO-A
is more enriched in nerve terminal mitochondria,
thereby metabolizing cytosolic dopamine that isn’t
taken up and sequestered into the synaptic vesicles.
MAO-B is located predominantly in glial mitochondria
and is available to metabolize dopamine released into
the synaptic cleft and not taken back up into the nerve
terminal by the action of the dopamine transporter.
MAO-A inhibition makes patients susceptible to risks
associated with high dietary levels of tyramine. If tyra-
mine is not degraded by MAO-A present in the gut, ty-
ramine enters the body and acts as a false transmitter,
entering noradrenergic nerve terminals and synaptic
vesicles displacing norepinephrine, which then can trig-
ger sudden hypertension, leading to cerebral hemorrhage
or other complications. This is commonly known as the
‘‘cheese-effect’’ because of the presence of high levels
of tyramine in some fermenting cheeses (as well as in
other fermented foods such as aged meat and some red
Movement Disorders, Vol. 23, Suppl. 3, 2008
S504 S. FAHN
wines). Selective MAO-B inhibitors are not associated
with this risk. Drugs that inhibit both MAO-A and
MAO-B (nonselective inhibitors) have been commer-
cially available since the 1950s for the treatment of
depression. Although excellent antidepressants, the risk
of the cheese-effect (unless patients strictly adhere to a
low tyramine diet) has made such nonselective inhibi-
tors extremely unpopular, especially since many other
types of antidepressants have now been developed.
Use of nonselective MAO inhibitors with L-dopa
(especially in the absence of a peripheral dopa decar-
boxylase inhibitor) can result in hyper- and hypoten-
sive episodes. However, inhibitors of MAO-B can be
taken safely with L-dopa; these potentiate the sympto-
matic benefit of L-dopa by about one-third lower dos-
age of L-dopa,73,74 probably by inhibiting brain metab-
olism of dopamine formed from L-dopa therapy. The
first MAO-B inhibitor studied was deprenyl, now
called selegiline.75–77 Two such MAO-B inhibitors are
now commercially available, selegiline and rasagiline.
Both drugs have been demonstrated to have anti-par-
kinsonian effects particularly in treating the wearing-
off effect78–80 and both have been studied for their
potential to slow the clinical progression of PD,74,81–84
but these topics are beyond the scope of this review.
Another catabolic route for both dopamine and L-
dopa is 3-O-methylation, catalyzed by the enzyme
COMT (see Fig. 2). Two inhibitors of this enzyme, tol-
capone and entacapone, are commercially available
and have been demonstrated to reduce the wearing-off
effect when used as adjuncts to L-dopa.85–92 These
COMT inhibitors slow the peripheral metabolism of L-
dopa, thereby delaying the elimination of plasma L-
dopa. Recent interest has focused on the potential use
of L-dopa plus a COMT inhibitor in early disease to
prevent the development of motor complications.93
Another approach to provide a longer plasma half-
life of L-dopa is the development of delayed release
formulations of L-dopa, and some clinical studies
showed effectiveness with such compounds.94–109 One
product is called carbidopa/L-dopa extended release,
with the brand name of Sinemet CR (for continuous
release); another is Madopar hydrodynamically bal-
anced system. Dopamine agonists that act directly on
the dopamine receptor have also been developed, but
are not covered in this review.
THE DEBATE OVER WHEN TO
START TREATMENT
When Birkmayer and Hornykiewicz35 first gave in-
travenous L-dopa to patients with PD, the results they
Movement Disorders, Vol. 23, Suppl. 3, 2008
reported were spectacular, although transient, with
patients getting out of their wheelchairs and walking.
Similar dramatic results, but longer lasting, were seen
by Cotzias with high dosage oral L-dopa.2 In the early
1970s, Fahn speculated that patients diagnosed with
PD should be treated with L-dopa as soon as the diag-
nosis was made to allow the exogenous supply of do-
pamine to maintain activation of dopamine receptors,
thereby easing the overactive remaining dopamine
neurons not to work so hard. Such overactivity of re-
sidual dopamine neurons is one of the compensatory
mechanisms for insufficient dopamine release in the
striatum due to the marked loss of dopamine nerve
terminals there. This compensatory mechanism was
proposed by Hornykiewicz,110 who showed that the
ratio of homovanillic acid to dopamine was increased
in the striatum of PD subjects compared to healthy
subjects, indicating an increased activity of remaining
presynaptic dopamine neurons to keep dopamine
receptors activated. By providing an exogenous route
to activate dopamine receptors, treatment with L-dopa
(or dopamine agonists) early in PD might permit
remaining dopamine neurons to be less active and
hopefully not die so quickly. Although Fahn did not
use the word then, this concept is in keeping with the
idea that L-dopa would be neuroprotective or at least
provide a disease modifying effect. Early treatment
with L-dopa, however, brought with it unintended con-
sequences: patients developed dyskinesias, wearing
off, and sudden on and off periods. These observa-
tions prompted Fahn and others to think that late
treatment would be more beneficial, and in 1978 he
wrote, with Donald Calne, a proposal suggesting that
L-dopa treatment should be delayed until symptoms
had become severe to avoid these motor complica-
tions.111
Debates have continued ever since, with some, such
as Markham and Diamond112 advocating earlier rather
than later treatment based on retrospective analysis
that early treatment delays severity. When Cohen113
suggested that the neuron’s own dopamine can cause
oxidative stress by being oxidized to oxyradicals, and
that this could lead to degeneration of dopamine neu-
rons if insufficient antioxidative mechanisms are avail-
able; this concept raised the suspicion that perhaps
L-dopa by increasing cytosolic dopamine could be
toxic and hasten further loss of dopamine neurons. The
potential for L-dopa to promote dopaminergic neuronal
loss in patients with PD was debated without
resolution. To hopefully resolve the uncertainty, the
Parkinson Study Group developed the clinical trial,
Earlier versus Later L-dopa in PD (ELLDOPA trial),
 DOPAMINE AND LEVODOPA IN THE TREATMENT OF PD
FIG. 4. Photographs of the 3 giants who pioneered the development of levodopa therapy for Parkinson’s disease. Pictured are Arvid Carlsson,
Oleh Hornykiewicz, and George Cotzias, obtained from the World Wide Web. [Color figure can be viewed in the online issue, which is available
at www.interscience.wiley.com.]
which was designed to assess the effect of low, me-
dium, and high doses of carbidopa/L-dopa on disease
progression, measured by first treating patients with
early PD for 40 weeks and then withdrawing the symp-
tomatic drug for 2 weeks and assessing severity of the
disease. Although the hypothesis was that L-dopa
would be toxic at higher doses and thereby hasten dis-
ease progression, surprisingly the clinical results sug-
gested that higher doses may be protective and should
be started early.114 However, neuroimaging data col-
lected in the same study contradicted the clinical
results, suggesting instead that L-dopa may accelerate
the loss of nigrostriatal dopamine nerve terminals or
modify the dopamine transporter. Thus, the debate
remains unresolved.
At the Movement Disorder Congress in Kyoto,
Japan, in October 2006, Fahn raised the question to
the audience of over 1,000 attendees as to what dose
of L-dopa was the plateau dose they usually attempt to
reach before proceeding to higher dosages if clinical
benefit is insufficient; almost unanimously, the plateau
dose was 25/100 mg of carbidopa/L-dopa three times
daily (Fahn, personal observations). Only one attendee
went higher, to 37.5/150 mg three times daily. The
result of this ‘‘survey’’ suggests that without proven
benefit of a neuroprotective effect of L-dopa at higher
dosages, clinicians cannot warrant using a higher dose
because of the potential for motor complications.
CONCLUSION
In looking back at the history of developing L-dopa
as an effective therapy for PD, three early pioneers
S505
(see Fig. 4) stand out among all others as giants in
their contributions. Carlsson’s work led to the realiza-
tion that dopamine is a neurotransmitter in brain, that
there is high dopamine concentration in the striatum,
that dopamine depletion from reserpine is responsible
for the akinetic effect, and that PD is related to dopa-
mine in brain. Hornykiewicz showed that striatal dopa-
mine is deficient in PD and that the greater the deple-
tion, the more severe the disease; he also was the first
to suggest using L-dopa to treat the disease. Cotzias
showed how one could safely use high enough doses
of L-dopa to be effective, and this led to the successful
introduction of L-dopa into the treatment of PD.
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