Background The clinical benefit of drugs for patients is not only through pharmacological mechanisms, but also through non-pharmacological action (placebo effect). There are several reports that the placebo effect was involved in brain activity and gene polymorphisms of a chemical mediator.

Purpose To study the hypothesis, we conducted a clinical trial using caffeine in order to examine whether responder or non-responder to placebo is associated with blood-flow changes in the prefrontal area of the brain and particular polymorphisms of the serotonin transporter-linked polymorphic region (5-HTTLPR).

Material and methods We performed a randomised double-blind clinical trial using caffeine and lactose (placebo) for 3 days with a wash-out period of the middle day. Forty-two healthy adults were randomly assigned to two groups. Twenty-one participants took caffeine on the first day and placebo on the third day, and 21 participants took placebo on the first day and placebo on the third day. Activity in the prefrontal area of the brain was measured in terms of blood flow using near-infrared spectroscopy (NIRS) as an objective indicator. Self-reported feelings of drowsiness on established scales (Stanford Sleepiness Scale) were used as subjective indicators. Polymorphisms of 5-HTTLPR were evaluated by PCR methods. This study was approved by the Ethics Committee of our university.

Results After placebo administration, improvement of sleepiness was significantly enhanced, a similar extent to that after caffeine medication. Among the 42 participants, 22 showed S/S type polymorphism in the serotonin transporter (52.4%), 17 showed S/L type (40.5%) and three showed L/L type (71%). Statistical analysis of the results indicate that participants with L/L genotype showed a significantly greater placebo response in terms of both self-reported feelings of drowsiness and blood flow in the prefrontal area of the brain associated with working memory.

Conclusion Our results support the hypothesis that participants with L/L type homozygosity of the serotonin transporter-linked polymorphic region are most responsive to the placebo effects.

References and/or Acknowledgements The authors thank the participants who took part in this trial

Conflict of interest: Corporate-sponsored research or other substantive relationships: This study was supported by Grants-in-Aid for Scientific Research and Japan Society For The Promotion of Science.