Effects of Daily L-Dopa Administration on Learning and Brain Structure in Older Adults Undergoing Four Weeks of Cognitive Training: A Randomised, Parallel-Group, Double-Blind, Placebo-Controlled Trial

Background: Cognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signaling in plasticity. We investigated whether transient enhancement of dopaminergic neurotransmission via administration of L-dopa improves effects of cognitive training on performance. Methods: Participants for this randomised, parallel-group, double-blind, placebo-controlled trial were recruited via newspaper advertisements. Inclusion criteria were: age of 65-75 years, Mini-Mental State Examination score >25, absence of serious medical conditions. Eligible subjects were randomly allocated to either receive 100/25mg L-dopa/benserazide or placebo prior to each of twenty cognitive training sessions administered during a four-week period. Participants and staff were masked to group assignment. Primary outcomes were latent variables of spatial and verbal fluid intelligence. This trial was preregistered at the European Clinical Trial Registry, EudraCT#2016-000891-54. Findings: Between January 1st and October 10th 2017, we screened 235 people from the population in Stockholm, Sweden and randomly assigned 63 eligible subjects to receive L-dopa (n=32) or placebo (n=31) during cognitive training. Compared to the placebo group, subjects receiving L-dopa improved less in spatial intelligence (-0·267 SDs; 95% CI [-0·498, -0·036]; p=0·024). Change in verbal intelligence did not significantly differ between the groups (-0·081 SDs, 95% CI [-0·242, 0·080]; p=0·323). Adverse events occurred for 10 subjects (31%) in the active and for 7 participants (23%) in the control groups. Interpretation: The results speak against early pharmacological interventions in older healthy adults to improve cognitive functions by targeting the dopaminergic system and provide no support for learning-enhancing properties of L-dopa supplements. The findings warrant closer investigation about the cognitive effects of early dopamine-replacement therapy in neurological disorders. Trial Registration Number: This trial was preregistered at the European Clinical Trial Registry, EudraCT#2016-000891-54. Funding: European Research Council (ERC Grant agreement #617280-REBOOT), Wallenberg Clinical Scholars, and Stiftelse Stockholms Sjukhem. Declaration of Interest: We declare no competing interests. Ethical Approval: The study protocol was approved by the regional ethics review board in Stockholm (2016-1897-31/1) and the Swedish medical product agency (20016000891-54). Participants provided written informed consent before enrolment.