Table 2.

Investigational Drugs for LID

Drug		Mechanism of Action		Clinical Trial Results
Glutamate receptor antagonists and modulators
Gocovri (extended-release amantadine)		Non-competitive antagonist at glutamate NMDA receptor		Significant reduction in UDysRS scores, increase in ON time without troublesome dyskinesia and decrease in OFF time, from EASE LID (NCT02136914) and EASE LID 3 (NCT02274766) trials.
Dipraglurant		Negative allosteric modulator of mGlu5 receptor		Phase II randomized, double-blind, placebo-controlled study (NCT01336088) showed safety and tolerability and antidyskinetic efficacy.
Foliglurax		Positive allosteric modulator of mGlu4 receptor		Phase IIa randomized, double-blind, placebo-controlled study (NCT03162874) failed in showing efficacy on LID.
L-4-chlorokynurenine		Inhibition of glutamate NMDA receptor activation (selective antagonism of glycine’s modulatory binding site)		Phase II randomized, double-blind, placebo-controlled, crossover proof-of-concept study (NCT04147949) will test efficacy on LID.
Naftazone		Glutamate release inhibitor		Phase II randomized, double-blind, placebo-controlled crossover study (NCT02641054) did not show efficacy on LID.
Serotonin receptor agonists
Eltoprazine		Serotonin 5-HT1A/B receptor agonist		Phase I/IIa study proved safety, tolerability and antidyskinetic properties of 5 mg eltoprazine. Multicenter phase II, randomized, double-blind, placebo-controlled crossover dose-finding study (NCT02439125) has no posted results yet.
Buspirone		Serotonin 5-HT1A receptor agonist, D2 receptor antagonist, alpha-1 receptor agonist		Phase I randomized, placebo-controlled, double-blind study (NCT02589340) is testing efficacy of combination therapy with buspirone and amantadine on LID.
JM-010		Serotonin 5-HT1A and 5-HT1B/D receptor agonist		Phase II randomized, double-blind, double dummy, placebo-controlled study (NCT03956979) is testing efficacy of two doses of JM-010 on LID.
5-hydroxytryptophan		Serotonin precursor		Phase IIa randomized, double-blind, placebo-controlled crossover study showed a significant improvement in LID as assessed by UDysRS and UPDRS part IV scores.
Drugs acting on other targets
Mesdopetam		Dopamine D3 receptor antagonist	Phase IIa study (NCT03368170) showed tolerability and reduction in LID severity. A phase IIb/III randomized, double-blind, placebo-controlled study (NCT04435431) is investigating Mesdopetam efficacy in 140 patients.
Pridopidine		σ1 receptor agonist	Phase II randomized, double-blind, placebo-controlled study to assess efficacy, safety, and pharmacokinetics of pridopidine for LID (NCT03922711) with no results posted yet.
Zonisamide		Inhibition of voltage-gated sodium channels, T-type calcium channels, MAO-B and carbonic anhydrase. GABA receptor agonist	Randomized, phase IV, open-label pilot study investigating tolerability and efficacy in treating LID has currently passed its completion date and has not been recently updated (NCT03034538).
Continuous intracerebroventricular (ICV) dopamine administration			Proof-of-concept phase I/IIb study of continuous ICV A-dopamine administration, to assess safety and feasibility and a subsequent 2-month, phase IIb, single-blind, randomized crossover study to assess efficacy on LID (NCT04332276) is ongoing.