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Levodopa, also known as L-DOPA, is a which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like or . Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat (as ).

of levodopa include , the wearing-off phenomenon, dopamine dysregulation syndrome, and levodopa-induced dyskinesia, among others. The drug is a centrally permeable monoamine precursor and of dopamine and hence acts as a dopamine receptor agonist. Chemically, levodopa is an , a phenethylamine, and a . The major reason for enhanced risks for levodopa induced dyskinesia (LID) and OFF phases during late PD is the progressive dying of nigrostriatal dopaminergic neurons. This results in the conversion of levodopa into dopamine in serotonergic neurons (which cannot re-uptake dopamine and have no proper regulatory capacity for dopamine synthesis) becoming the major dopamine source in the dorsal striatum, leading to the striatal dopamine concentration following the pulsatile oral administration of levodopa with large fluctuations (see the schematic graph figure). On the other hand, in a disease like , in which dopamine synthesis is low but without progressive degeneration of dopaminergic neurons, lifelong administration of low doses of levodopa is believed to be without serious side effects.

Levodopa was first synthesized and isolated in the early 1910s. The antiparkinsonian effects of levodopa were discovered in the 1950s and 1960s. Following this, it was introduced for the treatment of Parkinson's disease in 1970.


Medical uses
Levodopa crosses the protective blood–brain barrier, whereas dopamine itself cannot. Thus, levodopa is used to increase dopamine concentrations in the treatment of Parkinson's disease, , dopamine-responsive dystonia and Parkinson-plus syndrome. The therapeutic efficacy is different for different kinds of symptoms. and rigidity are the most responsive symptoms while are less responsive to levodopa therapy. Speech, , postural instability, and freezing gait are the least responsive symptoms.

Once levodopa has entered the central nervous system, it is converted into dopamine by the aromatic -amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Pyridoxal phosphate (vitamin B6) is a required cofactor in this reaction, and may occasionally be administered along with levodopa, usually in the of . Because levodopa bypasses the enzyme tyrosine hydroxylase, the rate-limiting step in dopamine synthesis, it is much more readily converted to dopamine than tyrosine, which is normally the natural precursor for dopamine production.

In humans, conversion of levodopa to dopamine does not only occur within the central nervous system. Cells in the peripheral nervous system perform the same task. Thus administering levodopa alone will lead to increased dopamine signaling in the periphery as well. Excessive peripheral dopamine signaling is undesirable as it causes many of the adverse seen with sole levodopa administration. To bypass these effects, it is standard clinical practice to coadminister (with levodopa) a peripheral DOPA decarboxylase inhibitor (DDCI) such as (medicines containing carbidopa, either alone or in combination with levodopa, are branded as (Aton Pharma) Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), Syndopa and Stalevo (Orion Corporation) or with a (combination medicines are branded Madopar or Prolopa), to prevent the peripheral synthesis of dopamine from levodopa). However, when consumed as a botanical extract, for example from M pruriens supplements, a peripheral DOPA decarboxylase inhibitor is not present.

Inbrija (previously known as CVT-301) is an inhaled powder formulation of levodopa indicated for the intermittent treatment of "off episodes" in patients with Parkinson's disease currently taking carbidopa/levodopa. It was approved by the US Food and Drug Administration (FDA) on 21 December 2018, and is marketed by Acorda Therapeutics.

Coadministration of without a DDCI accelerates the peripheral of levodopa to such an extent that it negates the effects of levodopa administration, a phenomenon that historically caused great confusion.

In addition, levodopa, co-administered with a peripheral DDCI, is efficacious for the short-term treatment of restless leg syndrome.

The two types of response seen with administration of levodopa are:

  • The short-duration response is related to the half-life of the drug.
  • The longer-duration response depends on the accumulation of effects over at least two weeks, during which ΔFosB accumulates in nigrostriatal neurons. In the treatment of Parkinson's disease, this response is evident only in early therapy, as the inability of the brain to store dopamine is not yet a concern.


Available forms
Levodopa is available, alone or in with , in the form of immediate-release oral tablets and capsules, oral tablets and capsules, orally disintegrating tablets, as a powder for inhalation, and as an suspension or (via ). In terms of combination formulations, it is available with (as levodopa/carbidopa), with (as levodopa/benserazide), and with both carbidopa and (as levodopa/carbidopa/entacapone). In addition to levodopa itself, certain of levodopa are available, including (melevodopa/carbidopa) (used orally) and (foslevodopa/foscarbidopa) (used subcutaneously).


Side effects
The of levodopa may include:

  • , especially if the dosage is too high
  • , although these are uncommon
  • , which is often reduced by taking the drug with food, although reduces drug absorption. Levodopa is an amino acid, so protein competitively inhibits levodopa absorption.
  • Gastrointestinal bleeding
  • Disturbed respiration, which is not always harmful, and can actually benefit patients with upper airway obstruction
  • and
  • Extreme states, particularly , but also excessive
  • Vivid or
  • Auditory or visual hallucinations
  • Effects on learning; some evidence indicates it improves , while impairing other complex functions
  • and
  • A condition similar to stimulant psychosis

Although many adverse effects are associated with levodopa, in particular psychiatric ones, it has fewer than other antiparkinsonian agents, such as and dopamine receptor agonists.

More serious are the effects of chronic levodopa administration in the treatment of Parkinson's disease, which include:

  • End-of-dose deterioration of function
  • "On/off" oscillations
  • Freezing during movement
  • Dose failure ()
  • at peak dose (levodopa-induced dyskinesia)
  • Possible dopamine dysregulation: The long-term use of levodopa in Parkinson's disease has been linked to the so-called dopamine dysregulation syndrome.

Rapidly decreasing the dose of levodopa can result in neuroleptic malignant syndrome.

Clinicians try to avoid these side effects and adverse reactions by limiting levodopa doses as much as possible until absolutely necessary.

Metabolites of dopamine, such as , are known to be dopaminergic neurotoxins. The long term use of levodopa increases oxidative stress through monoamine oxidase led enzymatic degradation of synthesized dopamine causing neuronal damage and cytotoxicity. The oxidative stress is caused by the formation of reactive oxygen species (H2O2) during the monoamine oxidase led metabolism of dopamine. It is further perpetuated by the richness of Fe2+ ions in striatum via the Fenton reaction and intracellular . The increased oxidation can potentially cause mutations in DNA due to the formation of 8-oxoguanine, which is capable of pairing with adenosine during . See also the catecholaldehyde hypothesis.


Pharmacology

Pharmacodynamics
Levodopa is a dopamine precursor and of and hence acts as a non-selective dopamine receptor agonist, including of the D1-like receptors (D1, D5) and the D2-like receptors (D2, D3, D4).


Pharmacokinetics
The of levodopa is 30%. It is into by aromatic--amino-acid decarboxylase (AAAD) in the central nervous system and periphery. The elimination half-life of levodopa is 0.75 to 1.5hours. It is 70–80% in .


Chemistry
Levodopa is an and a substituted phenethylamine and .

Analogues and prodrugs of levodopa include , , , and XP-21279. Some of these, like melevodopa and foslevodopa, are approved for the treatment of Parkinson's disease similarly to levodopa.

Other analogues include , an antihypertensive agent, and (L-DOPS), a norepinephrine precursor and prodrug.

6-Hydroxydopa, a prodrug of 6-hydroxydopamine (6-OHDA), is a potent dopaminergic neurotoxin used in scientific research.


History
Levodopa was first synthesized in 1911 by Torquato Torquati from the bean. It was first isolated in 1913 by Marcus Guggenheim from the V.faba bean. Guggenheim tried levodopa at a dose of 2.5mg and thought that it was inactive aside from and .

In work that earned him a Nobel Prize in 2000, scientist first showed in the 1950s that administering levodopa to animals with drug-induced () Parkinsonian caused a reduction in the intensity of the animals' symptoms. In 1960 or 1961 Oleh Hornykiewicz, after discovering greatly reduced levels of dopamine in autopsied brains of patients with Parkinson's disease, published together with the neurologist Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered levodopa in patients. This treatment was later extended to manganese poisoning and later parkinsonism by and his coworkers, who used greatly increased oral doses, for which they won the 1969 ., retrieved 1 April 2013

(2025). 9781934559871, Demos Medical Publishing. .
The first study reporting improvements in patients with Parkinson's disease resulting from treatment with levodopa was published in 1968.

Levodopa was first marketed in 1970 by Roche under the brand name Larodopa.

The describes this treatment in human patients with encephalitis lethargica in his 1973 book Awakenings, upon which is based.

was added to levodopa in 1974 and this improved its .


Society and culture

Names
Levodopa is the of the drug and its , , , , , , and .
(2025). 9781475720853, Springer US. .
(2025). 9789401144391, Springer Netherlands. .
(2025). 9783887631017, Medpharm Scientific Publishers. .


Research

Novel formulations and prodrugs
New levodopa formulations for use by other routes of administration, such as subcutaneous administration, are being developed.

Levodopa , with the potential for better , reduced fluctuations in levodopa levels, and reduced "on–off" phenomenon, are being researched and developed.


Depression
Levodopa has been reported to be inconsistently effective as an in the treatment of depressive disorders. However, it was found to enhance psychomotor activation in people with depression.


Motivational disorders
Levodopa has been found to increase the willingness to exert for in humans and hence appears to show pro-motivational effects. Other dopaminergic agents have also shown pro-motivational effects and may be useful in the treatment of motivational disorders.


Age-related macular degeneration
In 2015, a retrospective analysis comparing the incidence of age-related macular degeneration (AMD) between patients taking versus not taking levodopa found that the drug delayed onset of AMD by around 8years. The authors state that significant effects were obtained for both dry and wet AMD.


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