Are Adverse Events Induced by the Acute Administration of Calcineurin Inhibitor Cyclosporine A Behaviorally Conditioned in Healthy Male Volunteers?

Abstract

Purpose: The learned immunosuppressive placebo response has been demonstrated in experimental animals, healthy humans, and patients, and is suggested as a therapy for improving immunopharmacologic treatment. It remains unclear, however, whether potential adverse events induced by the drug are also behaviorally conditioned. Employing an established taste-immune learning paradigm in healthy humans using the calcineurin inhibitor and immunosuppressive drug cyclosporine A (CsA) as an unconditioned stimulus, we investigated whether and to what extent perceived adverse events induced by acute CsA administration are behaviorally conditioned.

Methods: A total of 68 healthy male subjects were exposed to the established taste-immune learning paradigm, receiving either placebo or CsA (10 mg/kg) as an unconditioned stimulus, and a novel-tasting drink as a conditioned stimulus.

Findings: Subjects repeatedly receiving CsA during acquisition reported significantly more adverse events than did placebo-receiving subjects. However, during reexposure to the conditioned stimulus, the reported adverse events did not differ from those in the placebo control condition.

Implications: These data indicate that acute adverse events are not behaviorally conditioned during the learned immunosuppressive response. Our results further strengthen the great potential clinical relevance of employing the learned immunosuppressive placebo response as a therapy to support immunopharmacologic regimens, ultimately aiming to reduce the medical dosages required, thereby minimizing adverse drug events while maximizing the therapeutic benefit in patients. German Clinical Trial Register (www.drks.de) identifier: DRKS00007693.

Keywords: adverse events; behavioral conditioning; calcineurin inhibitor; cyclosporine A.