Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users. — VialBase Research

Summary

Tesofensine is a triple reuptake inhibitor of noradrenaline, dopamine, and serotonin that was in development for the treatment of obesity, and because the abuse potential of triple reuptake inhibitors was not yet known, this study was undertaken specifically to evaluate its abuse-related effects in humans. The design was a single-dose, randomized, double-blind crossover study in 52 recreational stimulant users, comparing tesofensine against placebo, D-amphetamine as a positive control for dopaminergic and stimulant effects, and bupropion and atomoxetine as negative or unscheduled controls. Subjective and objective measures were assessed for 48 hours after drug administration. The internal validity check worked: D-amphetamine effects were significantly greater than placebo on all primary and secondary subjective measures, confirming that the study was capable of detecting a stimulant-type abuse signal if one existed. Against that benchmark, tesofensine’s effects were not significantly different from placebo and were lower than those of D-amphetamine 30 mg on all primary and most secondary measures. Compared with the negative controls, tesofensine’s effects were either lower than or not different from those of bupropion or atomoxetine — two agents that are not scheduled as controlled substances. The authors concluded that the abuse potential of tesofensine is no greater than that of bupropion or atomoxetine and that tesofensine is therefore unlikely to be recreationally abused.

Key Findings

• Single-dose, randomized, double-blind, crossover human abuse-potential study in 52 recreational stimulant users
• Comparators were placebo, D-amphetamine (positive stimulant control), and bupropion and atomoxetine (negative/unscheduled controls); subjective and objective measures were followed for 48 hours
• D-amphetamine produced significantly greater effects than placebo on all primary and secondary subjective measures, validating assay sensitivity
• Tesofensine was not significantly different from placebo, and was lower than D-amphetamine 30 mg on all primary and most secondary measures
• Tesofensine was either lower than or no different from bupropion and atomoxetine, supporting the conclusion that it is unlikely to be recreationally abused

Relevance to Tesofensine

This is the cleanest positive safety finding in the Tesofensine file and it deserves to be reported as such. A triple monoamine reuptake inhibitor that raises synaptic dopamine invites an obvious question about stimulant-like reinforcement and abuse liability, and this study answered that question with the right design: an established abuse-liability paradigm, a validated positive control that clearly separated from placebo, unscheduled active comparators, and a population of recreational stimulant users who are the most sensitive detectors of a euphoriant effect. Tesofensine did not separate from placebo. That is a meaningful reassurance and a fair point in the compound’s favour. Two limits keep it in proportion: it tested a single dose rather than chronic administration, and abuse potential is a distinct question from cardiovascular safety — the dose-dependent heart rate increase reported in the pooled weight-loss analysis (PMID 18356831) is untouched by this result. Low abuse liability is not the same as a benign safety profile, and it does nothing to resolve the integrity questions attached to the pivotal obesity trial.

Citation

Schoedel KA, Meier D, Chakraborty B, et al. Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users. Clinical pharmacology and therapeutics. 2010;88(1):69-78. doi:10.1038/clpt.2010.67.

See Also

• Parent compound: Tesofensine