Impact of Psilocybin on Motor Function in Healthy Participants: A Phase 1, Randomised, Triple-Blind, Dose-Finding Study

Background: Psychedelics exert widespread effects on brain activity, but their impact on motor function is unclear. This is clinically relevant given the emerging interest in psychedelic-assisted physical therapy for disorders of motor function. This study examined the feasibility and safety of administering movement tasks following low-to-moderate doses of psilocybin in healthy volunteers.

Methods: Healthy adult participants were randomly assigned three psilocybin doses consisting of either (1) 5 mg, 10 mg and 15 mg or (2) 10 mg, 15 mg and 20 mg, with at least 1 week between doses. Movement tasks were administered at 1.5 h, 3 h and 4.5 h post-dose. Participants, physiotherapists and statisticians were blinded to the dosing order. Feasibility was assessed by evaluating completion of the de Morton Mobility Index and Functional Movement Exploration (assessing gross motor function). Safety outcomes included vital signs and adverse events. Additional exploratory motor outcomes included the Action Research Arm Test (assessing upper limb functional performance), Box and Block Test (Original and Modified versions) (combining dexterity with motor speed), Digit Symbol Substitution Test (combining motor speed with intellectual functions) and Reaction Time Ruler Drop Test (assessing reaction time). Alterations in conscious states and blinding efficacy were also assessed. Outcomes were summarised descriptively and with post hoc linear mixed-effects modelling performed to explore dose- and time-related effects.

Results: A total of 13 participants (62% male) were enrolled, with a median age of 33 years (range 22-39 years), median height of 177 cm (155-188 cm) and median weight of 74 kg (51-94 kg). One participant was unable to complete several movement tasks at 20 mg. Nausea (n = 8, 62%) and headache (n = 7, 54%) were the most common adverse events. No serious adverse events or adverse events related to movement task administration occurred. Median values [interquartile ranges] remained near-perfect for the de Morton Mobility Index (92.5-100.0 [85.0-100.0]), Functional Movement Exploration (100.0 [96.0-100.0]) and Action Research Arm Test (56.0-57.0 [52.0-57.0]). Baseline Box and Block Test (Original) median scores (65.0 [60.0-67.0]) improved to 79.0 [70.0-83.0] at 5 mg and 4.5 h post-dose (5 mg-4.5 h), and worsened to 57.5 [51.0-64.0] at 20 mg-1.5 h. Baseline Box and Block Test (Modified) median scores (48.0 [47.0-53.0]) worsened to 43.0 [35.0-45.0] at 20 mg-1.5 h. Baseline Digit Symbol Substitution Test median scores (73.0 [66.0-77.0]) improved to 87.0 [81.0-90.0] at 10 mg-4.5 h, and worsened to 62.0 [54.0-86.0] at 20 mg-1.5 h. Reaction Time Ruler Drop Test scores lacked consistent dose-related changes. Alterations in conscious states were greatest at 20 mg. Participants and physiotherapists correctly guessed the administered dose 53% and 50% of the time, respectively.

Conclusions: Movement tasks were feasible during psilocybin dosing up to 15 mg. No significant safety concerns related to movement task participation during the acute drug effects were observed. At 20 mg, impairments were observed in movement tasks that combined motor and additional cognitive functions. These findings inform future studies utilising psilocybin-assisted physical rehabilitation in clinical populations.

Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12621000560897. Date registered: 12 May 2021.