Time-dependent effects of propranolol on motor-evoked potential amplitude in healthy subjects: a randomized crossover pilot study

Abstract

Introduction: Essential tremor is a common and potentially disabling movement disorder associated with dysfunction of the cerebello-thalamo-cortical network. Propranolol is a first-line treatment, but its therapeutic action has traditionally been attributed mainly to peripheral mechanisms. Because propranolol is highly lipophilic and crosses the blood–brain barrier, it may also exert direct central effects. However, its influence on human motor cortical excitability and its temporal profile remain insufficiently characterized. Using transcranial magnetic stimulation and motor-evoked potentials, this pilot study explored whether propranolol modulates corticospinal excitability and generated preliminary estimates to support a larger confirmatory study.

Objective: To evaluate, in a pilot study, the acute effect of a single 20 mg dose of propranolol on corticospinal excitability, measured through normalized motor-evoked potential amplitudes, compared with placebo in healthy participants.

Methodology: Nine healthy participants completed a randomized, placebo-controlled crossover study comprising two sessions separated by at least one week. Participants received a single 20 mg oral dose of propranolol in one session and placebo (sucralose) in the other, in randomized order. Resting motor threshold and input–output curves were obtained to determine the S₅₀ stimulation intensity. Motor-evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle every 10 s during four 30-min blocks: 0–30, 60–90, 120–150, and 180–210 min after administration. Normalized mean MEP amplitudes were analyzed using linear mixed-effects models (LMM) with Holm-adjusted contrasts. Change from block 1 was examined as a secondary analysis.

Results: The LMM showed a significant main effect of condition on normalized MEP amplitude (F₁,₅₆ = 12.91, p = 0.0007), with higher estimated marginal means under propranolol than placebo (1.353 vs. 0.987). The mean between-condition difference was 0.366 normalized units (95% CI: 0.162–0.570). Neither block nor the condition-by-block interaction was significant. In Holm-adjusted exploratory contrasts, propranolol produced a significantly greater MEP amplitude only at 120–150 min (Δ = 0.633, adjusted 95% CI: 0.107–1.158, pHolm = 0.0118).

In the secondary analysis, condition remained significant (F₁,₄₀ = 5.05, p = 0.030), with a greater mean increase under propranolol than placebo (difference = 0.249, 95% CI: 0.025–0.473). Block and interaction effects were not significant. The largest difference again occurred at 120–150 min (Δ = 0.454, unadjusted p = 0.023) but did not remain significant after Holm correction (p = 0.069).

Conclusions: A single 20 mg dose of propranolol increased normalized MEP amplitude compared with placebo in healthy participants, supporting a central modulatory effect on corticospinal excitability. Although no significant condition-by-time interaction was detected, the largest and most consistent difference occurred 120–150 min after administration. The change-from-baseline analysis supported the overall effect but provided only exploratory evidence for a specific temporal window. These preliminary findings support the feasibility of the protocol and justify confirmation in a larger, adequately powered study.