L-DOPA crosses the protective blood–brain barrier, whereas dopamine itself cannot. Thus, L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. This treatment was originally developed by George Cotzias and his coworkers. Once L-DOPA has entered the central nervous system, it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC). Pyridoxal phosphate (vitamin B6) is a required cofactor in this reaction, and may occasionally be administered along with L-DOPA, usually in the form of pyridoxine.
Besides the central nervous system, L-DOPA is also converted into dopamine from within the peripheral nervous system. The resulting hyperdopaminergia causes many of the adverse side effects seen with sole L-DOPA administration. To bypass these effects, it is standard clinical practice to co-administer (with L-DOPA) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines combining L-DOPA and carbidopa are branded as Lodosyn, Sinemet, Parcopa, Atamet, Stalevo) or with a benserazide (combination medicines are branded Madopar, Prolopa), to prevent the peripheral synthesis of dopamine from L-DOPA. Co-administration of pyridoxine without a DDCI accelerates the peripheral decarboxylation of L-DOPA to such an extent that it negates the effects of L-DOPA administration, a phenomenon that historically caused great confusion.