Orthostatic stability with intravenous levodopa

Shan H. Siddiqi, M.D. (1), Mary L. Creech, R.N., M.S.W., L.C.S.W. (2), Kevin J. Black, M.D. (1-4)* ORCID 0000-0002-6921-9567

Departments of (1) Psychiatry, (2) Neurology, (3) Radiology, and (4) Anatomy & Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA

* Address correspondence to Dr. Black at Campus Box 8134, 660 S. Euclid Ave., St. Louis, Missouri, USA or kevin@WUSTL.edu

Publication notice

This is a preprint of an article whose final published version is now freely available at https://peerj.com/articles/1198/. Preferred citation:

Siddiqi SH, Creech ML, Black KJ. Orthostatic stability with intravenous levodopa. PeerJ 3:e1198, 2015. doi: 10.7717/peerj.1198. PubMed PMID: 26336641.


Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson’s disease (PD). Levodopa is the precursor for dopamine, and intravenous dopamine would strongly affect vascular tone, but peripheral decarboxylase inhibitors are intended to block such effects. Pulse and blood pressure, with orthostatic changes, were recorded before and after intravenous levodopa or placebo—after oral carbidopa—in 13 adults with a chronic tic disorder and 16 tic-free adult control subjects. Levodopa caused no statistically or clinically significant changes in blood pressure or pulse. These data add to previous data that support the safety of i.v. levodopa when given with adequate peripheral inhibition of DOPA decarboxylase.


levodopa, intravenous, carbidopa, randomized controlled trial, blood pressure, heart rate, Tourette syndrome


The first therapeutic use of levodopa for Parkinson disease (PD) was by the intravenous route (Birkmayer et al., 1961; Birkmayer et al., 1998; Hornykiewicz, 2010). Oral administration is preferred clinically due to ease of use, although intravenous (i.v.) levodopa infusion has been favored in certain clinical circumstances (Chase et al., 1994; Abramsky et al., 1974; Horai et al., 2002; Mizuno et al., 2009).

The i.v. route has advantages for some research purposes as well (Black et al., 2004; Black et al., 2010; Black et al., 2015). However, levodopa is approved by the U.S. Food and Drug Administration for treatment of PD and other parkinsonian conditions only in a tablet formulation. In the U.S., giving an approved drug by another route for research purposes may require an investigational new drug (IND) application if changing the route of administration “significantly increases the risks (or decreases the acceptability of the risks)” (§21 CFR 312.2(b)(iii)). Some have assumed that this might hold for i.v. compared to oral levodopa.

In fact, however, numerous studies have reported on brief (\(<\)24 hr) infusions or large single-dose i.v. boluses, and i.v. levodopa has been tolerated approximately as well as oral levodopa (Abraham et al., 2015; Siddiqi et al., 2015). One study even deliberately attempted to induce hallucinations by giving high-dose i.v. levodopa to patients at high risk, but produced no hallucinations (Goetz et al., 1998). However, data on hemodynamic effects of i.v. levodopa have been limited over the past 20 years, and such results have not yet been quantitatively reported in the presence of a peripheral decarboxylase inhibitor (Abraham et al., 2015; Siddiqi et al., 2015).

Here we provide quantitative data, from a double-blind, random-allocation crossover study, on orthostatic blood pressure and pulse responses to i.v. levodopa in the presence of adequate carbidopa pretreatment.



44 generally healthy adults (23 with Tourette syndrome or chronic motor tic disorder [TS] and 21 tic-free healthy control [HC] subjects) enrolled in a study investigating dopaminergic effects on cortical function during a working memory task as measured by functional magnetic resonance imaging (ClinicalTrials.gov identifier NCT00634556). The study was approved by the Human Research Protection Office (IRB) of Washington University in St. Louis (project #05–0832, #201105100), and all subjects provided written documentation of informed consent prior to participation. This study was performed under FDA IND #69,745, Kevin J. Black, Sponsor-Investigator. After the first 10 subjects had been enrolled, the FDA asked us to record orthostatic blood pressure and pulse before and during the infusions. No subjects took any dopaminergic or antidopaminergic medications at baseline, including levodopa, dopamine agonists, or antipsychotics. Six subjects dropped out or were withdrawn from the imaging study (claustrophobia 1, abnormal structural MRI 1, scheduling problems 2, vomiting 2). Complete vital signs were still available for one of the two subjects who w