Objective: An open-label, dose-finding Phase I/II clinical trial was conducted to test safety and tolerability of low-dose ketamine infusion to treat levodopa-induced dyskinesia (LID), and to find an effective dose-range for outpatient use. Update on a prior Late Breaking Abstract reporting pilot analyses.

Background: Low-dose ketamine infusions are effective therapy for depression and chronic pain. Our prior preclinical and case report data [1-3] suggest that low-dose ketamine treatment has short-term antiparkinsonian activity and importantly can reduce existing LID long-term (≥3 mo) after an initial 10-hour total treatment.

Method: Two 5-hour low-dose ketamine infusions within a one-week period. Measured outcomes: UDysRS (Unified Dyskinesia Rating Scale); UPDRS (Unified Parkinson’s Disease Rating Scale); depression, HAM-D scale; pain, numeric pain scale. Subject diaries of ON/OFF symptoms and plasma samples for pharmacokinetic analysis of ketamine were collected. Statistics: linear mixed effects models; paired t tests (patient diaries).

Results: Analyses of the dose-finding study, show safety and tolerability in a population of subjects with moderate to advanced PD, indicating possible efficacy with a large effect size. We screened 13 subjects: 3 screen failures, 10 enrolled, 1 did not complete the infusion due to nausea, 9 had complete infusions. The maximum tolerated infusion rate ranged from 0.20-0.30 mg/kg/hr. The side effects that prompted reduction of infusion rate were mostly discomfort due to dissociation or hypertension. No adverse events occurred post-infusion. UDysRS: 45% reduction from baseline on Infusion day 2 (p=0.011), 50% at 3-week (p=0.007) and 41% at 3-month (p=0.013) post-ketamine. UPDRS: 11% reduction during Infusion 2 (p=0.504), 31% at 3-weeks (p=0.021) and 6% at 3-months (p=0.213). HAM-D: >70% reduction on Infusion day 2 (p<0.001), >50% at 3-weeks (p=0.004). Worst pain: 25% reduction at 3-weeks (p=0.026). Patient diaries at 3-weeks (n=6): twofold increased ON time without LID vs baseline (p=0.024), reduced ON time with non-disruptive LID (p=0.035); reduced ON time with disruptive LID (p=0.02).

Conclusion: Our results provide further support for the repurposing of subanesthetic ketamine for individuals with LID. A multi-center, double-blind, placebo-controlled Phase II/III trial, with midazolam as active-placebo, is planned to start in 2023.

References: [1] Bartlett MJ et al. (2016) Neurosci Lett;
[2] Sherman SJ et al. (2016) Case Rep Neurol;
[3] Bartlett MJ et al. (2020) Exp Neurol;

Declaration of Competing Interest:
TF and SJS have a patent for the use of ketamine as a novel treatment for levodopa-induced dyskinesia associated with Parkinson’s disease, that was licensed to PharmaTher Inc. in October 2020, and have consulted for PharmaTher Inc..

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MDS Abstracts - https://www.mdsabstracts.org/abstract/subanesthetic-infusion-of-ketamine-produces-long-term-reduction-in-levodopa-induced-dyskinesia-and-depression-in-individuals-with-parkinsons-disease/