Oxathridine use linked to pseudohallucinations

Administration of oxathridine, a first-in-class histamine-3 receptor partial agonist, results in some serious adverse events (AEs), including orthostatic hypotension and pseudohallucinations in healthy male volunteers, results of a study have shown.

This randomized, double-blind, placebo-controlled study included the NeuroCart, which consisted of a battery of drug-sensitive neurophysiological tests. Forty male volunteers participated in the study and received oxathridine orally as an aqueous solution.

After dosing, the authors performed safety and NeuroCart tests (ie, adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], and Sustained Attention to Response Task [SART]) at set times.

Oxathridine was administered at the following doses: 0.5, 2.5, 5.0, 0.25, and 1.5 mg. At 5.0 mg, “unacceptable and unanticipated” AEs (ie, hypotension and pseudohallucinations) occurred. This dose also increased all three VAS Bowdle subscale scores: VAS external (confidence interval [CI], 0.183‒0.476; p<0.0001), VAS internal (CI, 0.127‒0.370; p=0.0001), and VAS feeling high (CI, 0.263‒0.887; p=0.0006).

Additionally, 2.5 mg and 5.0 mg oxathridine had statistically significant effects on AT (2.5 mg: CI, -8.28 to -1.60; p=0.0048; 5.0 mg: CI, -8.10 to -1.51; p=0.00530), BS (2.5 mg: CI, 0.6‒80.2; p=0.0455; 5.0 mg: CI, 5.9‒93.1; p=0.0205), and SPV (2.5 mg: CI, -59.0 to -15.9; p=0.0011; 5.0 mg: -43.9 to -1.09; p=0.0399).

“Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics,” the authors said.