Levodopa Chemical formula
Synonyms: Dihydroxyphenylalanine; dopa; Lévodopa; Levodopum. (−)-3-(3,4-Dihydroxyphenyl)alanine.
Cyrillic synonym: Леводопа.

💊 Chemical information

Chemical formula: C9H11NO4 = 197.2.
CAS — 59-92-7.
ATC — N04B A01.
ATC Vet — QN04BA01.


In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 6.2

(Levodopa). A white or slightly cream-coloured, crystalline powder. Slightly soluble in water; freely soluble in 1M hydrochloric acid but sparingly soluble in 0.1M hydrochloric acid; practically insoluble in alcohol. A 1% suspension in water has a pH of 4.5 to 7.0. Protect from light.

USP 31

(Levodopa). A white to off-white, odourless, crystalline powder. In the presence of moisture, it is rapidly oxidised by atmospheric oxygen and darkens. Slightly soluble in water; freely soluble in 3N hydrochloric acid; insoluble in alcohol. Store in a dry place in airtight containers at a temperature not exceeding 40°. Protect from light.


Extemporaneously prepared oral liquid dosage forms may be unstable and manufacturers’ formulations should be used where possible. 1 Water dispersible formulations of levodopa with benserazide are available in some countries but a method that can be used by patients to prepare daily solutions of levodopa with carbidopa has been suggested: 2 one litre of a solution in potable water may be prepared with ten crushed standard tablets of levodopa 100 mg with carbidopa 25 mg and 2 g of ascorbic acid added to stabilise the levodopa. 1. Walls TJ, et al. Problems with inactivation of drugs used in Parkinson’s disease. BMJ 1985; 290: 444–5. 2. Giron LT, Koller WC. Methods of managing levodopa-induced dyskinesias. Drug Safety 1996; 14: 365–74.

💊 Adverse Effects

Gastrointestinal effects, notably nausea, vomiting, and anorexia are common early in treatment with levodopa, particularly if the dosage is increased too rapidly. Gastrointestinal bleeding has been reported in patients with a history of peptic ulcer disease. The commonest cardiovascular effect is orthostatic hypotension, which is usually asymptomatic, but may be associated with faintness and dizziness. Cardiac arrhythmias have been reported and hypertension has occasionally occurred. Psychiatric symptoms occur in a high proportion of patients, especially the elderly, and include agitation, anxiety, euphoria, nightmares, insomnia or sometimes drowsiness, and depression. More serious effects, usually requiring a reduction in dosage or withdrawal of levodopa, include aggression, paranoid delusions, hallucinations, delirium, severe depression, with or without suicidal behaviour, and unmasking of psychoses. Psychotic reactions are more likely in patients with postencephalitic parkinsonism or a history of mental disorders. Excessive daytime sleepiness and sudden onset of sleep have been reported very rarely. Abnormal involuntary movements or dyskinesias are the most serious dose-limiting adverse effects of levodopa and are very common at the optimum dose required to control parkinsonism; their frequency increases with duration of treatment. Involuntary movements of the face, tongue, lips, and jaw often appear first and those of the trunk and extremities later. Severe generalised choreoathetoid and dystonic movements may occur after prolonged use. Muscle twitching and blepharospasm may be early signs of excessive dosage. Exaggerated respiratory movements and exacerbated oculogyric crises have been reported in patients with postencephalitic parkinsonism. Bradykinesia and akinesia, in the form of ‘end-of-dose’ deterioration and the ‘on-off’ phenomenon, may reemerge in patients with parkinsonism as a complication of long-term treatment, but may be due to progression of the disease rather than to levodopa. A positive response to the direct Coombs’ test may occur, usually without evidence of haemolysis although auto-immune haemolytic anaemia has occasionally been reported. Transient leucopenia and thrombocytopenia have occurred rarely. The effects of levodopa on liver and kidney function are generally slight; transient increases in liver enzymes, and in blood-urea nitrogen and serum-uric acid concentrations, have been reported. Levodopa may cause discoloration of the urine; reddish at first then darkening on standing. Other body fluids may also be discoloured. Some of the adverse effects reported may not be attributable directly to levodopa, but rather to the use of antimuscarinics, to increased mobility, or to the unmasking of underlying conditions as parkinsonism improves. Use with a peripheral dopa-decarboxylase inhibitor may reduce the severity of peripheral symptoms such as gastrointestinal and cardiovascular effects, but central effects such as dyskinesias and mental disturbances may occur earlier in treatment.

Incidence of adverse effects.

The major adverse effects of levodopa are dyskinesia in 75% of patients and psychiatric disturbances in 25%.1 Nausea and vomiting in 40 to 50% gradually regress and hypotension in 25 to 30% is generally asymptomatic. Less common adverse effects include cardiac arrhythmias, particularly atrial and ventricular ectopic beats and less commonly atrial flutter and fibrillation; palpitations and flushing often accompanied by excessive sweating; hypertension; polyuria, incontinence, and urinary retention, although antimuscarinic drugs often contribute to problems with micturition; and dark coloration of the urine and saliva. Rare adverse effects include abdominal pain, constipation, and diarrhoea; mydriasis, blurred vision, diplopia, and precipitation of glaucoma; headache; stridor; tachypnoea; and paraesthesias.
1. Calne DB, Reid JL. Antiparkinsonian drugs: pharmacological and therapeutic aspects. Drugs 1972; 4: 49–74.

Abnormal coloration.

Black pigmentation of rib cartilage has been noted at necropsy in patients treated with levodopa.1,2 Abnormal pigmentation is generally not seen at other sites2 but there have been isolated reports2,3 of patients who also had pigmentation of the intervertebral discs. Although the pigmentation appears to be irreversible it was considered to be probably harmless.2 It has been suggested that the pigmentation was due to deposition of dihydroxyphenylalanine (DOPA) in the cartilage.1It is known that DOPA will readily auto-oxidise in vitro in the presence of oxygen to a black pigment and this can also happen in vivo since black urine is a well known adverse effect of levodopa. Dark sweat and pigmentation of the skin and teeth are also known adverse effects. See also Effects on the Skin and Hair, below.
1. Connolly CE, et al. Black cartilage associated with levodopa. Lancet 1986; i: 690
2. Rausing A, Rosén U. Black cartilage after therapy with levodopa and methyldopa. Arch Pathol Lab Med 1994; 118: 531–5
3. Keen CE. BMJ 1998; 316: 240.


A change in taste sensation was reported1 in 23 of 514 patients treated with levodopa and a peripheral dopa-decarboxylase inhibitor; 2 of the 23 had total loss of taste initially. The altered taste, often described as insipid, metallic, or plastic, was first observed 3 to 32 weeks after beginning treatment, and lasted for 2 to 40 weeks. In an earlier report, 22 of 100 patients receiving levodopa alone had experienced changes in taste.2
1. Siegfried J, Zumstein H. Changes in taste under L-DOPA therapy. Z Neurol 1971; 200: 345–8
2. Barbeau A. L-DOPA therapy: past, present and future. Ariz Med 1970; 27: 1–4.

Effects on the blood.

Reports of effects of levodopa on the blood are mostly confined to individual case reports. A study in 365 patients, receiving levodopa in a mean daily dosage of 4.04 g, found that 32 developed a positive direct Coombs’ test, the majority after between 3 and 12 months of therapy, but none developed haemolytic anaemia.1 However, occasional cases of auto-immune haemolytic anaemia have been reported;2-4 in one case, dosage reduction and addition of a peripheral dopa-decarboxylase inhibitor largely abolished haemolysis,3 but in another, haemolysis recurred on re-institution of levodopa with carbidopa and required corticosteroid treatment.4 A case of severe acute non-haemolytic anaemia related to levodopa therapy has also been reported.5 Although levodopa is widely stated to produce leucopenia in some patients, there are few published reports. However transient minor decreases in total leucocyte counts were reported in 3 of a group of 80 patients receiving levodopa.6 Severe thrombocytopenia has been reported in 2 patients who had received levodopa for 3 and 2 years respectively;7,8 the condition was apparently an auto-immune response and responded to prednisone therapy and withdrawal of levodopa.
1. Joseph C. Occurrence of positive Coombs test in patients treated with levodopa. N Engl J Med 1972; 286: 1401–2
2. Territo MC, et al. Autoimmune hemolytic anemia due to levodopa therapy. JAMA 1973; 226: 1347–8
3. Lindström FD, et al. Dose-related levodopa-induced haemolytic anaemia. Ann Intern Med 1977; 86: 298–300
4. Bernstein RM. Reversible haemolytic anaemia after levodopacarbidopa. BMJ 1979; 1: 1461–2
5. Alkalay I, Zipoli T. Levodopa-induced acute non-hemolytic anemia. Ann Allergy 1977; 39: 191
6. Barbeau A. L-Dopa therapy in Parkinson’s disease: a critical review of nine years’ experience. Can Med Assoc J 1969; 101: 791–800
7. Wanamaker WM, et al. Thrombocytopenia associated with longterm levodopa therapy. JAMA 1976; 235: 2217–19
8. Giner V, et al. Thrombocytopenia associated with levodopa treatment. Arch Intern Med 2003; 163: 735–6.

Effects on the cardiovascular system.

There have been conflicting reports on the effects of peripheral dopa-decarboxylase inhibitors on orthostatic hypotension attributed to levodopa therapy. In a study,1 supine and erect systolic blood pressure was found to be significantly higher in parkinsonian patients given levodopa with carbidopa than in those receiving levodopa alone, suggesting that the peripheral actions of dopamine contribute to levodopa-induced hypotension. However, another study2 found no change in the incidence and degree of orthostatic hypotension after giving levodopa with carbidopa and, similarly, no difference in the frequency of ventricular arrhythmias. See also Effects on Kidney Function, below and Cardiovascular Disorders, under Precautions, below.
1. Calne DB, et al. Action of -α-methyldopahydrazine on the blood pressure of patients receiving levodopa. Br J Pharmacol 1972; 44: 162–4
2. Leibowitz M, Lieberman A. Comparison of dopa decarboxylase inhibitor (carbidopa) combined with levodopa and levodopa alone on the cardiovascular system of patients with Parkinson’s disease. Neurology 1975; 25: 917–21.

Effects on electrolytes.

See Effects on Kidney Function, below.

Effects on the endocrine system.

Single doses of levodopa given to healthy subjects cause an increase in plasma concentrations of glucose, insulin, and glucagon, as well as of growth hormone1 and there has been concern over the potential endocrine effects of levodopa therapy in patients with Parkinson’s disease.2 A study of carbohydrate metabolism in 24 patients with Parkinson’s disease indicated that these patients had abnormally low rates of glucose utilisation when untreated, apparently due to impaired insulin release, and this was not altered when levodopa therapy was given.3 However, a similar study completed by 19 patients2 noted increased impairment of glucose utilisation after levodopa therapy for 1 year with a delayed hypersecretion of insulin in response to a glucose load similar to the metabolic changes of acromegaly. It was considered that patients given levodopa for parkinsonism should be monitored for evidence of diabetes mellitus or frank acromegaly.2 Postmenopausal bleeding occurred in varying degrees in 12 of 47 women treated with levodopa.4 In one case bleeding was severe enough to warrant interrupting treatment and subsequent dosage reduction.
1. Rayfield EJ, et al. -Dopa stimulation of glucagon secretion in man. N Engl J Med 1975; 293: 589–91
2. Sirtori CR, et al. Metabolic responses to acute and chronic dopa administration in patients with parkinsonism. N Engl J Med 1972; 287: 729–33
3. Van Woert MH, Mueller PS. Glucose, insulin, and free fatty acid metabolism in Parkinson’s disease treated with levodopa. Clin Pharmacol Ther 1971; 12: 360–7
4. Wajsbort J. Post-menopausal bleeding after -dopa. N Engl J Med 1972; 286: 784.

Effects on the eyes.

Both miosis1 and mydriasis2 have been reported with levodopa. For a report of the exacerbation of oculogyric crises by levodopa, see Extrapyramidal Effects, below.
1. Spiers ASD, et al. Miosis during -dopa therapy. BMJ 1970; 2: 639–40
2. Weintraub MI, et al. Pupillary effects of levodopa therapy: development of anisocoria in latent Horner’s syndrome. N Engl J Med 1970; 283: 120–3.

Effects on the gastrointestinal tract.

Although gastrointestinal bleeding has more commonly been reported in patients with a history of peptic ulceration, there is a rare report1 of acute melaena and non-specific gastritis associated with levodopa therapy in a 56-year-old man without any previous evidence of a gastric disorder. See also Dysgeusia, above.
1. Riddoch D. Gastritis and -dopa. BMJ 1972; 1: 53–4.

Effects on kidney function.

Levodopa 1 to 2 g given to 7 patients with idiopathic or postencephalitic Parkinson’s disease produced significant increases in renal plasma flow, glomerular filtration rate, and sodium and potassium excretion.1 It was considered that the natriuretic effects could contribute to the orthostatic hypotension commonly seen in patients receiving levodopa. There is a report of a patient who developed hyponatraemia when given levodopa with carbidopa.2 The patient had previously had a similar reaction with amantadine. On each occasion symptoms disappeared when dopaminergic medication was withdrawn and recurred on rechallenge. Inappropriate secretion of antidiuretic hormone was suggested as a possible mechanism. Levodopa has also been reported to have a kaliuretic effect, resulting in hypokalaemia, in some parkinsonian patients;3 the effect could be prevented by also giving a peripheral dopa-decarboxylase inhibitor.
1. Finlay GD, et al. Augmentation of sodium and potassium excretion, glomerular filtration rate and renal plasma flow by levodopa. N Engl J Med 1971; 284: 865–70
2. Lammers GJ, Roos RAC. Hyponatraemia due to amantadine hydrochloride and L-dopa/carbidopa. Lancet 1993; 342: 439
3. Granérus A-K, et al. Kaliuretic effect of -dopa treatment in parkinsonian patients. Acta Med Scand 1977; 201: 291–7.

Effects on mental function.

Psychiatric complications were the single commonest reason for stopping levodopa treatment in a follow-up study of 178 patients with idiopathic Parkinson’s disease, 81 of whom were still taking levodopa after 6 years.1 Within 2 years, levodopa was withdrawn because of toxic confusional states (21 patients), paranoid psychosis (6), unipolar depression (2), and mania (1). The incidence of visual hallucinations increased as treatment continued but, as with toxic confusional states, patients generally improved when levodopa was withdrawn. Before treatment, 40 patients had suffered severe depression and levodopa produced sustained improvement in only 2. After 6 years, 20 of the 81 patients remaining were moderately or severely depressed and were rarely improved by withdrawal or reduction in dosage of levodopa. Increasing dementia affected 26 of the 81 patients after 6 years; withdrawal of levodopa in 5 failed to improve cognitive disabilities, but increased parkinsonism. Another study2 reported that 141 of 400 patients being treated for Parkinson’s disease developed mental disorders. In this study certain acute states, particularly anxiety, on-off hallucinations, and fits of delirium were linked to treatment with levodopa, whereas dementia and depression were not. Long-term use of levodopa and dopamine agonists has been associated with a number of behavioural disturbances, including hypersexuality (see Effects on Sexual Function, below), punding (purposeless repetitive acts), excessive gambling or shopping (see below), and other obsessive behaviour such as compulsive eating.3 Reduction in dopaminergic therapy can lead to cessation or improvement in symptoms. Some patients may develop dopamine dysregulation syndrome (see Abuse, under Precautions, below). A 12-month study of 1281 patients in the USA treated with dopamine agonists for Parkinson’s disease found that 9 were suffering from excessive gambling.4 All patients had received levodopa, 8 pramipexole, and the remaining patient pergolide. The rate of pathological gambling was 1.5% in the 529 patients taking pramipexole. The authors considered that this was not unexpected given the general availability of casinos in the local area and an incidence in the general US population of 0.3 to 1.3%. An analysis5 of 11 patients who began pathological gambling after starting therapy with pramipexole (9 cases) or ropinirole (2 cases) found that in 8 patients such behaviour resolved when the drug was tapered or stopped; follow-up was not available in the other 3. In 7 patients the symptoms had developed within 1 to 3 months of achieving maintenance dose or after dose increases of dopamine agonist therapy. Of the 11 patients, 3 had not received levodopa. Cabergoline therapy has also been associated with pathological gambling.6 Similar behaviour described as being markedly increased in "on" periods has been reported in other patients treated with levodopa.7 Pathological gambling has also been associated with misuse of dopaminergics.8 Sleep-related complaints have occurred and were reported by 74 of 100 patients with Parkinson’s disease.9 All 74 were on levodopa and the prevalence of symptoms increased with the duration of treatment. Symptoms included insomnia, excessive daytime somnolence, altered dream phenomena, nocturnal vocalisation, involuntary myoclonic movements, and rarely, sleepwalking. Sleep fragmentation, which includes insomnia and somnolence, was the most common symptom overall. It has been suggested10 that in patients with mild to moderate disease levodopa and dopamine agonists could cause sleep disruption. However, these drugs produce beneficial effects on nocturnal disabilities in patients with more severe disease. Reports11-17 of daytime somnolence or sudden onset of sleep with various other dopamine agonists, including apomorphine, bromocriptine, cabergoline, lisuride, pergolide, piribedil, pramipexole, quinagolide, and ropinirole, suggest that this is a class effect of dopaminergic antiparkinsonian therapy, and patients should be warned of the possible risks (see Precautions, below). The risk of somnolence may be increased in those patients taking combinations of dopaminergics.15,18
1. Shaw KM, et al. The impact of treatment with levodopa on Parkinson’s disease. Q J Med 1980; 49: 283–93
2. Rondot P, et al. Mental disorders in Parkinson’s disease after treatment with -Dopa. Adv Neurol 1984; 40: 259–69
3. Burn DJ, Tröster AI. Neuropsychiatric complications of medical and surgical therapies for Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17: 172–80
4. Driver-Dunckley E, et al. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003; 61: 422–3
5. Dodd ML, et al. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005; 62: 1377–81
6. Adverse Drug Reactions Advisory Committee (ADRAC). Pathological gambling with cabergoline. Aust Adverse Drug React Bull 2005; 24: 15. Also available at: http://www.tga.health.gov.au/ adr/aadrb/aadr0508.pdf (accessed 16/02/06
7. Molina JA, et al. Pathologic gambling in Parkinson’s disease: a behavioral manifestation of pharmacologic treatment? Mov Disord 2000; 15: 869–72
8. Gschwandtner U, et al. Pathologic gambling in patients with Parkinson’s disease. Clin Neuropharmacol 2001; 24: 170–2
9. Nausieda PA, et al. Psychiatric complications of levodopa therapy of Parkinson’s disease. Adv Neurol 1984; 40: 271–7
10. van Hilten B, et al. Sleep disruption in Parkinson’s disease: assessment by continuous activity monitoring. Arch Neurol 1994; 51: 922–8
11. Frucht S, et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999; 52: 1908–10
12. Schapira AHV. Sleep attacks (sleep episodes) with pergolide. Lancet 2000; 355: 1332–3
13. Ferreira JJ, et al. Sleep attacks and Parkinson’s disease treatment. Lancet 2000; 355: 1333–4
14. Pirker W, Happe S. Sleep attacks in Parkinson’s disease. Lancet 2000; 356: 597–8
15. Committee on Safety of Medicines/Medicines and Healthcare Products Regulatory Agency. Dopaminergic drugs and sudden sleep onset. Current Problems 2003; 29: 9. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON007450&RevisionSelectionMethod= LatestReleased (accessed 16/02/06
16. Houmann CN. et al. Sleep attacks in patients taking dopamine agonists: review. BMJ 2002; 324: 1483–7
17. Plowman BK, et al. Sleep attacks in patients receiving dopamine-receptor agonists. Am J Health-Syst Pharm 2005; 62: 537–40
18. Etminan M, et al. Increased risk of somnolence with the new dopamine agonists in patients with Parkinson’s disease: a metaanalysis of randomised controlled trials. Drug Safety 2001; 24: 863–8.

Effects on respiration.

Respiratory crises, including attacks of gasping, panting, sniffing, puffing, and breath-holding, occurred in 12 of 25 patients with postencephalitic parkinsonism during treatment with levodopa.1 A further 8 developed respiratory and phonatory tics, including sudden deep breaths, yawns, coughs, giggles, sighing, grunting, and moaning. All 20 patients also suffered tachypnoea, bradypnoea, and asymmetrical movement of both sides of the chest, paradoxical diaphragmatic movements, and reversal of inspiratory and expiratory phases. The induction of respiratory crises may be prompt or greatly delayed; 3 patients only developed crises after more than 9 months of treatment with levodopa. Crises were readily precipitated by psychophysiological arousals such as rage and exertion. Most of the patients who developed marked respiratory disorders had shown slight irregularities of respiratory rhythm, rate, and force before receiving levodopa. In another report a distressing dose-related irregularity in the rate and depth of breathing occurred when a patient with Parkinson’s disease was given levodopa with benserazide.2 The respiratory abnormality was completely suppressed by use of tiapride, with no reduction in the efficacy of levodopa.
1. Sacks OW, et al. Side-effects of L-dopa in postencephalitic parkinsonism. Lancet 1970; i: 1006
2. De Keyser J, Vincken W. -Dopa-induced respiratory disturbance in Parkinson’s disease suppressed by tiapride. Neurology 1985; 35: 235–7.

Effects on sexual function.

An increase in libido, over and above the effects of improved mobility and well-being, has been reported in parkinsonian patients receiving levodopa or dopamine agonists. One report noted increased libido but no improvement in sexual performance in 4 of 80 patients receiving levodopa1 while another reported a moderate increase in sexual interest in 4 of 7 male patients.2 There have also been reports of hypersexuality and deviant sexual behaviour in patients with Parkinson’s disease receiving levodopa or dopamine agonists.3-6In some cases this was associated with increased dosage and possibly abuse of the drugs. Symptoms often improved on dosage reduction or withdrawal. Hypersexual behaviour and hypergenitalism have also been reported in a pre-pubertal boy given levodopa for behavioural disturbances.7 Some workers8 have commented that dopaminergics such as cabergoline are being promoted illegally on the Internet for male sexual enhancement and warn of the potential for abuse and serious adverse effects. Clitoral tumescence and increased libido has been noted in a woman receiving bromocriptine to suppress lactation9 but there has been a report of sexual dissatisfaction and decreased libido in 3 women receiving bromocriptine for hyperprolactinaemia.10
1. Barbeau A. -Dopa therapy in Parkinson’s disease: a critical review of nine years’ experience. Can Med Assoc J 1969; 101: 791–9
2. Brown E, et al. Sexual function and affect in parkinsonian men treated with -dopa. Am J Psychiatry 1978; 135: 1552–5
3. Vogel HP, Schiffter R. Hypersexuality—a complication of dopaminergic therapy in Parkinson’s disease. Pharmacopsychiatry 1983; 16: 107–10
4. Jiménez-Jiménez FJ, et al. Possible zoophilia associated with dopaminergic therapy in Parkinson disease. Ann Pharmacother 2002; 36: 1178–9
5. Kaňovský P, et al. Penile erections and hypersexuality induced by pergolide treatment in advanced, fluctuating Parkinson’s disease. J Neurol 2002; 249: 112–14
6. Berger C, et al. Sexuelle Delinquenz und Morbus Parkinson. Nervenarzt 2003; 74: 370–5
7. Korten JJ, et al. Undesirable prepubertal effects of levodopa. JAMA 1973; 226: 355
8. Pinero A, et al. Cabergoline-related severe restrictive mitral regurgitation. N Engl J Med 2005; 353: 1976–7
9. Blin O, et al. Painful clitoral tumescence during bromocriptine therapy. Lancet 1991; 337: 1231–2
10. Saleh AK, Moussa MAA. Sexual dysfunction in women due to bromocriptine. BMJ 1984; 289: 228.

Effects on the skin and hair.

Two women who were given levodopa, up to 3 g daily, developed diffuse alopecia in addition to other adverse effects.1 Repigmentation of hair has occurred in a white-bearded man after being treated with levodopa 1.5 g daily for 8 months.2 Vitiligo has been reported3 in a patient with Parkinson’s disease following addition of tolcapone to his levodopa/carbidopa regimen. The development of vitiligo was attributed to the increase in plasma-levodopa concentrations brought about by concomitant use of tolcapone. See also Melanoma, under Precautions, below.
1. Marshall A, Williams MJ. Alopecia and levodopa. BMJ 1971; 2: 47
2. Grainger KM. Pigmentation in Parkinson’s disease treated with levodopa. Lancet 1973; i: 97–8
3. Sabaté M, et al. Vitiligo associated with tolcapone and levodopa in a patient with Parkinson’s disease. Ann Pharmacother 1999; 33: 1228–9.

Extrapyramidal effects.

Choreiform movements were the major dose-limiting complication of long-term treatment with levodopa in a follow-up study of 178 patients with idiopathic Parkinson’s disease, 81 of whom were still taking levodopa after 6 years.1 Dyskinesias usually appeared in the first year and became more severe and generalised with time. Certain distinctive patterns of involuntary movements occurred as follows:
peak-dose movements affected 65 of the 81 patients and were dose-related. Movements were usually choreic, affecting the face and limbs, but dystonic and ballistic movements were also seen; characteristically they began 20 to 90 minutes after an oral dose and lasted from 10 minutes to 4 hours with a tendency to be more severe mid-way through the interdose period
biphasic movements presenting as 2 distinct episodes of chorea or dystonia within each interdose period occurred in only 3 patients
early morning and ‘end-of-dose’ dystonia was present in 15 patients after 6 years of treatment with levodopa, but rarely developed during the first 3 years
nocturnal myoclonus occurred in 12 patients The frequency, intensity, and complexity of spontaneous fluctuations in performance were greatly enhanced by long-term levodopa therapy. Two clinically distinct types of fluctuation, ‘endof-dose’ deterioration and the ‘on-off’ phenomenon, were related to treatment. ‘End-of-dose’ deterioration or the ‘wearing-off’ effect affected 52 patients after 6 years of treatment and was characterised by progressive reduction in the duration of benefit from each dose with a gradual return of nocturnal and early morning disability in some patients. The ‘on-off’ phenomenon affected 14 patients who experienced completely unpredictable swings from relative mobility, usually accompanied by involuntary movements, to periods of profound bradykinesia and hypotonia. In addition, ‘freezing episodes’ and abrupt falls became increasingly common and affected 50 patients after 6 years compared with 33 before therapy.
1. Shaw KM, et al. The impact of treatment with levodopa on Parkinson’s disease. Q J Med 1980; 49: 283–93.
OCULOGYRIC CRISIS. After initial remission, oculogyric crises in 5 of 25 patients with postencephalitic parkinsonism recurred and were subsequently severely exacerbated during treatment with levodopa.1 One patient, who previously had not had oculogyric crises, developed severe crises in the fourth month of therapy with levodopa. During these crises forced gaze deviation was always accompanied by severe neurological and mental symptoms, some of which were scarcely tolerable.
1. Sacks OW, Kohl M. -Dopa and oculogyric crises. Lancet 1970; ii: 215–16.


There have been reports of elevated serum uric acid concentrations in patients receiving levodopa, but some of these are of doubtful significance since levodopa has been shown to give falsely-elevated uric acid concentrations by colorimetric methods.1 However, hyperuricaemia as measured by more specific methods,2,3 with a few cases of overt gout,2,3 has also been reported.
1. Cawein MJ, Hewins J. False rise in serum uric acid after -dopa. N Engl J Med 1969; 281: 1489–90
2. Honda H, Gindin RA. Gout while receiving levodopa for parkinsonism. JAMA 1972; 219: 55–7
3. Calne DB, Fermaglich J. Gout induced by -dopa and decarboxylase inhibitors. Postgrad Med J 1976; 52: 232–3.


Reports of hypersensitivity reactions to levodopa have included a vasculitis characterised by neuromyopathy, periarteriolitis with eosinophilia,1 and a lupus-like auto-immune syndrome.2
1. Wolf S, et al. Neuromyopathy and periarteriolitis in a patient receiving levodopa. Arch Intern Med 1976; 136: 1055–7
2. Massarotti G, et al. Lupus-like autoimmune syndrome after levodopa and benserazide. BMJ 1979; 2: 553.


Adverse effects after ingestion of 80 to 100 g of levodopa over a 12-hour period by a parkinsonian patient included hypertension initially, followed by hypotension of a few hours’ duration, sinus tachycardia, and symptomatic orthostatic hypotension for more than a week.1 Marked confusion, agitation, insomnia, and restlessness were the most prominent clinical symptoms and did not disappear completely for over a week; severe anorexia and insomnia persisted for 2 to 3 weeks. After the overdose the patient had virtually no signs of parkinsonism and received no levodopa or antimuscarinic medication for 6 days; rigidity and akinesia began to recur on the fourth day.
1. Hoehn MM, Rutledge CO. Acute overdose with levodopa: clinical and biochemical consequences. Neurology 1975; 25: 792–4.

Withdrawal syndromes.

Withdrawal of antiparkinsonian drugs, particularly levodopa, has been implicated in the development of a syndrome resembling the neuroleptic malignant syndrome,1-6 characterised by fever, muscle rigidity, profuse sweating, tachycardia, tachypnoea, and elevated muscle enzyme values.1 Several fatalities have occurred.1,2 It has been suggested that the neuroleptic malignant syndrome is associated with blockade of dopamine receptors in the striatum, leading to increased rigidity and heat production, and in the hypothalamus, resulting in impaired thermoregulation7 and it seems reasonable that withdrawal of levodopa might have a similar effect in patients with depleted central dopamine concentrations. Thus, the use of a ‘drug holiday’ to manage fluctuations in response to levodopa is no longer recommended. Fever, extrapyramidal symptoms and raised creatine kinase concentrations, resembling a very mild form of the neuroleptic malignant syndrome, have also been reported in parkinsonian patients exposed to stress such as dehydration or infection but without any change in medication.8
1. Friedman JH, et al. A neuroleptic malignantlike syndrome due to levodopa therapy withdrawal. JAMA 1985; 254: 2792–5
2. Sechi GP, et al. Fatal hyperpyrexia after withdrawal of levodopa. Neurology 1984; 34: 249–51
3. Figà-Talamanca L, et al. Hyperthermia after discontinuance of levodopa and bromocriptine therapy: impaired dopamine receptors a possible cause. Neurology 1985; 35: 258–61
4. Gibb WRG, Griffith DNW. Levodopa withdrawal syndrome identical to neuroleptic malignant syndrome. Postgrad Med J 1986; 62: 59–60
5. Serrano-Dueñas M. Neuroleptic malignant syndrome-like, or— dopaminergic malignant syndrome—due to levodopa therapy withdrawal: clinical features in 11 patients. Parkinsonism Relat Disord 2003; 9: 175–8
6. Mizuno Y, et al. Malignant syndrome in Parkinson’s disease: concept and review of the literature. Parkinsonism Relat Disord 2003; 9 (suppl 1): S3–S9
7. Henderson VW, Wooten GF. Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade? Neurology 1981; 31: 132–7
8. Mezaki T, et al. Benign type of malignant syndrome. Lancet 1989; i: 49–50.

💊 Treatment of Adverse Effects

Reduction in dosage reverses most of the adverse effects of levodopa. Nausea and vomiting may be diminished by increasing the dose of levodopa gradually, and/or by taking with or after meals, although taking levodopa on a full stomach may lead to lower plasma concentrations. Gastrointestinal effects may also be reduced by giving an antiemetic such as cyclizine or domperidone but not a phenothiazine (see Antipsychotics, under Interactions, below). Use with a peripheral dopa-decarboxylase inhibitor reduces peripheral but not central adverse effects. Orthostatic hypotension may respond to the use of elastic stockings. The benefits of gastric decontamination are uncertain. However, activated charcoal should be considered in adults who have ingested more than 2 g (or more than the total daily dose, whichever is greater), and in children who have taken more than 200 mg, if they present within 1 hour of ingestion. Supportive measures should also be instituted. Pyridoxine may increase the metabolism of levodopa (see Nutritional Agents, under Interactions, below) but its value in overdosage has not been established; it does not reduce the effects of levodopa given with a peripheral dopa-decarboxylase inhibitor.

Nausea and vomiting.

For reference to the use of domperidone in the management of nausea and vomiting associated with levodopa in patients with Parkinson’s disease, see under Uses and Administration of Domperidone.


Atypical antipsychotics such as clozapine have been tried in the management of psychosis occurring as a complication of parkinsonism and of drugs such as levodopa used in its treatment.

💊 Precautions

Levodopa is contra-indicated in patients with angleclosure glaucoma and should be used with caution in open-angle glaucoma. Caution is also required in patients with cardiovascular disease, pulmonary disease, endocrine disorders, psychiatric disturbances, osteomalacia, hepatic or renal disease, or a history of peptic ulceration. Periodic evaluations of hepatic, psychiatric, haematological, renal, and cardiovascular functions have been advised. Since an association between levodopa and activation of malignant melanoma has been suspected (although not confirmed), it is generally recommended that levodopa should not be given to patients with (or with a history of) the disease or with skin disorders suggestive of it. Parkinsonian patients who benefit from levodopa therapy should be warned to resume normal activities gradually to avoid the risk of injury. Treatment with levodopa should not be stopped abruptly. Excessive daytime sleepiness and sudden onset of sleep may occur with levodopa and caution is advised when driving or operating machinery; patients who suffer such effects should not drive or operate machinery until the effects have stopped recurring. Levodopa inhibits prolactin secretion and may therefore interfere with lactation. Food interferes with the absorption of levodopa, though levodopa is usually given with or immediately after meals to reduce nausea and vomiting. However, patients experiencing the ‘on-off’ phenomenon may benefit from dosage on an empty stomach.


Abuse of levodopa and dopamine agonists in patients with Parkinson’s disease has been reported.1-6 The term dopamine dysregulation syndrome, has been used to describe a condition where there is a compulsive and dysregulated use of dopaminergic drugs beyond that needed to achieve relief of motor symptoms and which is harmful to the patient.7 Patients have progressively increased the dosage of levodopa to obtain psychotropic effects such as euphoria despite accompanying dystonia and other extrapyramidal adverse effects. Withdrawal often led to craving, drug-seeking behaviour, and mood disturbances such as depression, features resembling a psychological dependence syndrome. Abuse in patients without parkinsonism has also occurred.8 See also Effects on Sexual Function under Adverse Effects, above.
1. Nausieda PA. Sinemet "abusers". Clin Neuropharmacol 1985; 8: 318–27
2. Soyka M, Huppert D. L-dopa abuse in a patient with former alcoholism. Br J Addict 1992; 87: 117–18
3. Spigset O, von Schéele C. Levodopa dependence and abuse in Parkinson’s disease. Pharmacotherapy 1997; 17: 1027–30
4. Merims D, et al. Is there addiction to levodopa in patients with Parkinson’s disease? Mov Disord 2000; 15: 1014–16
5. Müller U, et al. Levodopa-Abhängigkeit bei Parkinsonkrankheit: Fallbericht und Literaturübersicht. Nervenarzt 2002; 73: 887–91
6. Borek LL, Friedman JH. Levodopa addiction in idiopathic Parkinson disease. Neurology 2005; 65: 1508
7. Burn DJ, Tröster AI. Neuropsychiatric complications of medical and surgical therapies for Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17: 172–80
8. Steiner I, Wirguin I. Levodopa addiction in non-parkinsonian patients. Neurology 2003; 61: 1451.

Cardiovascular disorders.

A high incidence of cardiovascular adverse effects was reported in early studies of levodopa, but both Parkinson’s disease and heart disease are common in the elderly and adverse cardiac effects of levodopa may be less prevalent than was first thought. A study in 40 patients1 concluded that, apart from those with severe orthostatic hypotension or unstable coronary disease, levodopa may be used safely in parkinsonian patients with heart disease. Others2 noted that levodopa and bromocriptine cause cardiac arrhythmias in less than 1% of all patients, the incidence for levodopa with a peripheral dopa-decarboxylase inhibitor being lower still. Nevertheless, caution is advised in patients with cardiovascular disease.
1. Jenkins RB, et al. Levodopa therapy of patients with parkinsonism and heart disease. BMJ 1972; 3: 512–14
2. Parkes JD, et al. Amantadine-induced heart failure. Lancet 1977; i: 904.

Diabetes mellitus.

For reference to concern over the potential of levodopa to impair glucose utilisation, see Effects on the Endocrine System under Adverse Effects, above.


There has been concern over the effects of levodopa on melanoma in view of the ability of malignant melanoma cells to convert levodopa to melanin and isolated reports of melanoma developing or being exacerbated during levodopa therapy continue to appear. However, in a survey of 1099 patients with primary cutaneous malignant melanoma only one had taken levodopa.1 It was concluded that levodopa therapy is not an important factor in the induction of malignant melanoma. Furthermore, use of levodopa in daily doses of up to 4 g with carbidopa in 17 patients with metastatic melanoma failed to provide any evidence that levodopa accelerated the progression of the disease.2 Reviews3,4 of these and later reports concluded that the purported link between levodopa and malignant melanoma was tenuous. For a report of antineoplastic chemotherapy used for the treatment of melanoma reducing the efficacy of levodopa, see under Interactions, below.
1. Sober AJ, Wick MM. Levodopa therapy and malignant melanoma. JAMA 1978; 240: 554–5
2. Gurney H, et al. The use of L-dopa and carbidopa in metastatic malignant melanoma. J Invest Dermatol 1991; 96: 85–7
3. Siple JF, et al. Levodopa therapy and the risk of malignant melanoma. Ann Pharmacother 2000; 34: 382–5
4. Fiala KH, et al. Malignant melanoma and levodopa in Parkinson’s disease: causality or coincidence? Parkinsonism Relat Disord 2003; 9: 321–7.


Levodopa alone and with carbidopa has been associated with fetal abnormalities in animals given high doses; no teratogenic effect has been noted with carbidopa alone. However, 2 women with parkinsonism who received levodopa with carbidopa or levodopa alone throughout their pregnancies gave birth to normal infants.1
1. Cook DG, Klawans HL. Levodopa during pregnancy. Clin Neuropharmacol 1985; 8: 93–5.


For adverse effects associated with withdrawal of levodopa, see under Adverse Effects, above.

💊 Interactions

The therapeutic or adverse effects of levodopa may be affected by interactions with a variety of drugs. Mechanisms may include effects on catecholamine metabolising enzymes, neurotransmitters, or receptor sites, effects on the endocrine system, and effects on gastrointestinal absorption. Drugs that modify gastric emptying may affect the absorption of levodopa.


A study1 in 7 healthy subjects showed that use of spiramycin with levodopa and carbidopa resulted in reduced plasma-levodopa concentrations and an increase in its peripheral metabolism. A hypertensive reaction and severe tremor occurred when isoniazid was given to a patient receiving levodopa;2 it was not certain whether isoniazid was acting as an MAOI.
1. Brion N, et al. Effect of a macrolide (spiramycin) on the pharmacokinetics of -dopa and carbidopa in healthy volunteers. Clin Neuropharmacol 1992; 15: 229–35
2. Morgan JP. Isoniazid and levodopa. Ann Intern Med 1980; 92: 434.

Antidementia drugs.

Increasing the dose of tacrine worsened parkinsonian symptoms in an elderly woman with Alzheimer’s disease and mild parkinsonism; symptoms responded to levodopa with carbidopa, but recurred when the dose of tacrine was again increased.1
1. Ott BR, Lannon MC. Exacerbation of parkinsonism by tacrine. Clin Neuropharmacol 1992; 15: 322–5.


BUPROPION. Caution has been advised with bupropion because of reports of a higher incidence of adverse effects during use with levodopa. MAOIS. Giving levodopa with non-specific MAOIs such as phenelzine, pargyline, nialamide, or tranylcypromine may cause dangerous hypertension;1-4 it is recommended that levodopa should not be given with, or within at least 14 days of stopping, an MAOI. Hypertensive reactions to levodopa with tranylcypromine were inhibited by carbidopa,5 but licensed product information for preparations containing levodopa with carbidopa or benserazide still contra-indicates their use with MAOIs. The incidence of adverse effects may be increased if levodopa is used with moclobemide, a monoamine oxidase type A inhibitor. Selegiline, a monoamine oxidase type B inhibitor, is used to enhance the antiparkinsonian effect of levodopa.
1. Hunter KR, et al. Monoamine oxidase inhibitors and -dopa. BMJ 1970; 3: 388
2. Hodge JV. Use of monoamine oxidase inhibitors. Lancet 1965; i: 764–5
3. Friend DG, et al. The action of L-dihydroxyphenylalanine in patients receiving nialamide. Clin Pharmacol Ther 1965; 6: 362–6
4. Sharpe J, et al. Idiopathic orthostatic hypotension treated with levodopa and MAO inhibitor: a preliminary report. Can Med Assoc J 1972; 107: 296–300
5. Teychenne PF, et al. Interactions of levodopa with inhibitors of monoamine oxidase and -aromatic amino acid decarboxylase. Clin Pharmacol Ther 1975; 18: 273–7.
SSRIS. There was some evidence from a prescribing study that SSRIs might exacerbate parkinsonism resulting in increased doses of levodopa or addition of adjunctive drugs.1
1. van de Vijver DAMC, et al. Start of a selective serotonin reuptake inhibitor (SSRI) and increase of antiparkinsonian drug treatment in patients on levodopa. Br J Clin Pharmacol 2002; 54: 168–70.
TRICYCLIC ANTIDEPRESSANTS. Although tricyclic antidepressants have generally been used safely with levodopa,1 hypertensive crises have occurred in some rare cases. Such events have been reported in patients receiving amitriptyline or imipramine and levodopa with carbidopa.2,3 Imipramine has been reported to impair the rate of levodopa absorption,4 presumably due to its antimuscarinic properties (for the effect of antimuscarinics on the absorption of levodopa, see below).
1. Hunter KR, et al. Use of levodopa with other drugs. Lancet 1970; ii: 1283–5
2. Rampton DS. Hypertensive crisis in a patient given Sinemet, metoclopramide, and amitriptyline. BMJ 1977; 2: 607–8
3. Edwards M. Adverse interaction of levodopa with tricyclic antidepressants. Practitioner 1982; 226: 1447–8
4. Morgan JP, et al. Imipramine-mediated interference with levodopa absorption from the gastrointestinal tract in man. Neurology 1975; 25: 1029–34.
TRYPTOPHAN. See Amino Acids under Nutritional Agents, below.


Phenytoin has been shown to diminish the therapeutic effect of levodopa in patients with parkinsonism or chronic manganese poisoning.1 The mechanism of the interaction was considered uncertain.
1. Mendez JS. Diphenylhydantoin: blocking of levodopa effects. Arch Neurol 1975; 32: 44–6.


Use of levodopa with guanethidine may cause increased hypotension.1 Clonidine has been reported to inhibit the therapeutic effect of levodopa, possibly by stimulating central alpha-adrenoceptors.2 Methyldopa and levodopa may enhance each other’s therapeutic or adverse effects, although there has been mention of the inhibitory effect of methyldopa on the therapeutic response to levodopa.3,4 Reserpine and other rauwolfia alkaloids may oppose the antiparkinsonian effects of levodopa by central depletion of dopamine; UK licensed product information advises that use together should be avoided.
1. Hunter KR, et al. Use of levodopa with other drugs. Lancet 1970; ii: 1283–5
2. Shoulson I, Chase TN. Clonidine and the anti-parkinsonian response to -dopa or piribedil. Neuropharmacology 1976; 15: 25–7
3. Cotzias GC, et al. -Dopa in Parkinson’s syndrome. N Engl J Med 1969; 281: 272
4. Kofman O. Treatment of Parkinson’s disease with -dopa: a current appraisal. Can Med Assoc J 1971; 104: 483–7.


Antimuscarinic antiparkinsonian drugs may enhance the therapeutic effects of levodopa but by delaying gastric emptying they may also reduce its absorption.1
1. Algeri S, et al. Effect of anticholinergic drugs on gastro-intestinal absorption of L-dopa in rats and in man. Eur J Pharmacol 1976; 35: 293–9.


A patient with Parkinson’s disease noted1that the efficacy of levodopa was reduced each time he received dacarbazine for the treatment of melanoma. As serum-dopamine concentrations were unchanged it was suggested1 that dacarbazine might compete with levodopa at the blood-brain barrier.
1. Merello M, et al. Impaired levodopa response in Parkinson’s disease during melanoma therapy. Clin Neuropharmacol 1992; 15: 69–74.


The therapeutic effects of levodopa may be diminished by CNS dopamine inhibitors including phenothiazine derivatives1 such as prochlorperazine.2 Butyrophenones such as haloperidol and thioxanthenes such as flupentixol might be expected to have a similar effect due to their antidopaminergic properties.
1. Yahr MD, Duvoisin RC. Drug therapy of parkinsonism. N Engl J Med 1972; 287: 20–4
2. Duvoisin RC. Diphenidol for levodopa induced nausea and vomiting. JAMA 1972; 221: 1408.


Reversible deterioration of parkinsonism has been reported in patients receiving levodopa who were also given benzodiazepines such as diazepam,1,2 nitrazepam1 (although the evidence was equivocal), or chlordiazepoxide.3 In one case parkinsonian symptoms resolved without alteration in the medication.1
1. Hunter KR, et al. Use of levodopa with other drugs. Lancet 1970; ii: 1283–5
2. Wodak J, et al. Review of 12 months’ treatment with L-dopa in Parkinson’s disease, with remarks on unusual side effects. Med J Aust 1972; 2: 1277–82
3. Yosselson-Superstine S, Lipman AG. Chlordiazepoxide interaction with levodopa. Ann Intern Med 1982; 96: 259–60.


Adverse effects including hallucinations, confusion, headache, and nausea and worsening of symptoms have been reported1,2 in patients with Parkinson’s disease taking levodopa when also given baclofen.
1. Skausig OB, Korsgaard S. Hallucinations and baclofen. Lancet 1977; i: 1258
2. Lees AJ, et al. Baclofen in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1978; 41: 707–8.

Gastrointestinal drugs.

ANTACIDS. Some studies have suggested that taking an antacid before a dose of levodopa enhances the absorption of levodopa, apparently by enhancing gastric emptying and reducing metabolism of levodopa in the stomach.1,2 This was particularly marked in a case report in a patient with prolonged gastric emptying time.1 However, another study in 8 patients with presumably normal gastric motility, only 3 of whom had Parkinson’s disease, found no significant increase in overall absorption of levodopa when given with an antacid although there was some evidence of increased absorption in some of the patients.3 UK licensed product information (Madopar CR; Roche) states that antacids reduce the absorption of levodopa from the modifiedrelease preparation by 32%.
1. Rivera-Calimlim L, et al. -Dopa treatment failure: explanation and correction. BMJ 1970; 4: 93–4
2. Pocelinko R, et al. The effect of an antacid on the absorption and metabolism of levodopa. Clin Pharmacol Ther 1972; 13: 149
3. Leon AS, Spiegel HE. The effect of antacid administration on the absorption and metabolism of levodopa. J Clin Pharmacol 1972; 12: 263–7.
ANTIEMETICS. Metoclopramide is a dopamine antagonist and may cause extrapyramidal symptoms including parkinsonism; however, it accelerates gastric emptying and has been reported1 to increase the rate of levodopa absorption. The importance of timing has been noted2 since levodopa delays gastric emptying and metoclopramide antagonises this effect. Licensed product information advises caution when using metoclopramide with levodopa. Domperidone has been reported to increase the bioavailability of levodopa slightly.3
1. Morris JGL, et al. Plasma dopa concentrations after different preparations of levodopa in normal subjects. Br J Clin Pharmacol 1976; 3: 983–90
2. Berkowitz DM, McCallum RW. Interaction of levodopa and metoclopramide on gastric emptying. Clin Pharmacol Ther 1980; 27: 414–20
3. Shindler JS, et al. Domperidone and levodopa in Parkinson’s disease. Br J Clin Pharmacol 1984; 18: 959–62.
PROKINETICS. Maximum plasma concentrations of levodopa are increased by cisapride.1 See also Metoclopramide and Domperidone, under Antiemetics, above.
1. Neira WD, et al. The effects of cisapride on plasma -dopa levels and the clinical response in Parkinson’s disease. Mov Disord 1995; 10: 66–70.

General anaesthetics.

The general anaesthetics cyclopropane and halothane lower the threshold for ventricular arrhythmias to sympathomimetic amines, including dopamine, and should probably not be used within 6 to 8 hours of levodopa.1,2 Although other general anaesthetics are now usually preferred, it was suggested that, in any case, levodopa could safely be taken before surgery when given with a peripheral dopa-decarboxylase inhibitor.3
1. Goldberg LI, Whitsett TL. Cardiovascular effects of levodopa. Clin Pharmacol Ther 1971; 12: 376–82
2. Bianchine JR, Sunyapridakul L. Interactions between levodopa and other drugs: significance in the treatment of Parkinson’s disease. Drugs 1973; 6: 364–88
3. Anonymous. Surgery and long-term medication. Drug Ther Bull 1984; 22: 73–6.

Nutritional agents.

AMINO ACIDS. The transport of levodopa into the brain is subject to competition from chemically related L-amino acids, especially the other aromatic amino acids phenylalanine, tyrosine, tryptophan, and histidine.1 A highprotein diet or the large neutral amino acids phenylalanine, leucine, or isoleucine have been shown to reduce the therapeutic effect of levodopa given by intravenous infusion to parkinsonian patients; such alterations in the absorption and transport of levodopa may contribute to the fluctuating responses seen in Parkinson’s disease, the so-called ‘on-off’ phenomenon2. In contrast, a study in healthy subjects3 found that while a low-protein meal appeared to cause a small reduction in levodopa absorption, a high-protein meal had no such effect. Other reported interactions with amino acids include methionine-antagonism of the therapeutic effect of levodopa in parkinsonism4 and tryptophan-reduced blood concentrations of levodopa.5
1. Daniel PM, et al. Do changes in blood levels of other aromatic aminoacids influence levodopa therapy? Lancet 1976; i: 95
2. Nutt JG, et al. The “on-off” phenomenon in Parkinson’s disease: relation to levodopa absorption and transport. N Engl J Med 1984; 310: 483–8
3. Robertson DRC, et al. The influence of protein containing meals on the pharmacokinetics of levodopa in healthy volunteers. Br J Clin Pharmacol 1991; 31: 413–17
4. Pearce LA, Waterbury LD. L-methionine: a possible levodopa antagonist. Neurology 1974; 24: 640–1
5. Weitbrecht W-U, Weigel K. Der Einfluß von -Tryptophan auf die -Dopa-Resorption. Dtsch Med Wochenschr 1976; 101: 20–2.
IRON SALTS. Levodopa forms complexes with iron salts and ferrous sulfate has reduced bioavailability of levodopa by about 50% in healthy subjects.1 Giving ferrous sulfate to 9 patients with Parkinson’s disease receiving levodopa with carbidopa reduced the area under the curve for levodopa by 30%; the reduction was greater than 75% for carbidopa. Although this was associated with deterioration in some patients’ disability, the average reduction in efficacy of therapy did not achieve statistical significance.2
1. Campbell NRC, Hasinoff BB. Iron supplements: a common cause of drug interactions. Br J Clin Pharmacol 1991; 31: 251–5
2. Campbell NRC, et al. Sinemet-ferrous sulphate interaction in patients with Parkinson’s disease. Br J Clin Pharmacol 1990; 30: 599–605.
PYRIDOXINE. The enzyme responsible for the decarboxylation of levodopa, L-amino acid decarboxylase, is dependent on pyridoxine and pyridoxine supplements have been reported to enhance the peripheral metabolism of levodopa to dopamine leaving less available to cross the blood-brain barrier for central conversion to dopamine;1-4 pyridoxine therefore inhibits the action of levodopa but this can be stopped by use of a peripheral dopa-decarboxylase inhibitor.3,4
1. Carter AB. Pyridoxine and parkinsonism. BMJ 1973; 4: 236
2. Leon AS, et al. Pyridoxine antagonism of levodopa in parkinsonism. JAMA 1971; 218: 1924–7
3. Cotzias GC, Papavasiliou PS. Blocking the negative effects of pyridoxine on patients receiving levodopa. JAMA 1971; 215: 1504–5
4. Yahr MD, Duvoisin RC. Pyridoxine, levodopa, and -α-methyldopa hydrazine regimen in parkinsonism. JAMA 1971; 216: 2141.


Antagonism of the beneficial effects of levodopa in parkinsonism has been reported when patients were also given papaverine,1,2 and it was recommended that the combination should be avoided. However, a later study3 in 9 patients receiving levodopa with a peripheral dopa-decarboxylase inhibitor found no changes in the control of Parkinson’s disease when they were also given papaverine for 3 weeks.
1. Duvoisin RC. Antagonism of levodopa by papaverine. JAMA 1975; 231: 845
2. Posner DM. Antagonism of levodopa by papaverine. JAMA 1975; 233: 768
3. Montastruc JL, et al. Does papaverine interact with levodopa in Parkinson’s disease? Ann Neurol 1987; 22: 558–9.


Isolated case reports suggest that penicillamine increases plasma-levodopa concentrations.1
1. Mizuta E, et al. Effect of -penicillamine on pharmacokinetics of levodopa in Parkinson’s disease. Clin Neuropharmacol 1993; 16: 448–50.


It has been suggested that sympathomimetics such as adrenaline or isoprenaline may enhance the cardiac adverse effects of levodopa.1
1. Goldberg LI, Whitsett TL. Cardiovascular effects of levodopa. Clin Pharmacol Ther 1971; 12: 376–82.

💊 Pharmacokinetics

Levodopa is rapidly absorbed from the gastrointestinal tract by an active transport system. Most absorption takes place in the small intestine; absorption is very limited from the stomach, and since decarboxylation may take place in the stomach wall, delays in gastric emptying may reduce the amount of levodopa available for absorption. Peak plasma concentrations are achieved within 2 hours of oral doses. Levodopa is about 10 to 30% bound to plasma proteins. Levodopa is rapidly decarboxylated by the enzyme aromatic L-amino acid decarboxylase, mostly in the gut, liver, and kidney, to dopamine, which is metabolised in turn, principally to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Other routes of metabolism include O-methylation, transamination, and oxidation, producing a variety of minor metabolites including noradrenaline and 3-O-methyldopa; the latter may accumulate in the CNS due to its relatively long half-life. The elimination half-life of levodopa itself is reported to be about 30 to 60 minutes. Unlike dopamine, levodopa is actively transported across the blood-brain barrier, but because of the extent of peripheral decarboxylation very little is available to enter the CNS unless it is given with a peripheral dopadecarboxylase inhibitor. In the presence of a peripheral dopa-decarboxylase inhibitor the major route of metabolism of levodopa becomes the formation of 3-Omethyldopa by the enzyme catechol-O-methyltransferase. About 80% of an oral dose of levodopa is excreted in the urine within 24 hours, mainly as dihydroxyphenylacetic and homovanillic acids. Only small amounts of levodopa are excreted unchanged in the faeces. Levodopa crosses the placenta and is distributed into breast milk.
1. Nutt JG, Fellman JH. Pharmacokinetics of levodopa. Clin Neuropharmacol 1984; 7: 35–49
2. Cedarbaum JM. Clinical pharmacokinetics of anti-parkinsonian drugs. Clin Pharmacokinet 1987; 13: 141–78
3. Robertson DRC, et al. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol 1989; 28: 61–9
4. Robertson DRC, et al. The influence of levodopa on gastric emptying in man. Br J Clin Pharmacol 1990; 29: 47–53.

💊 Uses and Administration

Levodopa, a naturally occurring amino acid, is the immediate precursor of the neurotransmitter dopamine. The actions of levodopa are mainly those of dopamine. Unlike dopamine, levodopa readily enters the CNS and is used in the treatment of conditions, such as Parkinson’s disease, that are associated with depletion of dopamine in the brain. Levodopa is rapidly decarboxylated by peripheral enzymes so that very little unchanged drug is available to cross the blood-brain barrier for central con
Published November 11, 2018.