The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we performed two experiments in which the responses to thermal pain stimuli were assessed. The first experiment assessed whether a conditioning paradigm, using clearly visible cues for high and low pain, could induce placebo and nocebo responses. The second experiment, in a separate group of subjects, assessed whether conditioned placebo and nocebo responses could be triggered in response to nonconscious (masked) exposures to the same cues. A total of 40 healthy volunteers (24 female, mean age 23 y) were investigated in a laboratory setting. Participants rated each pain stimulus on a numeric response scale, ranging from 0 = no pain to 100 = worst imaginable pain. Significant placebo and nocebo effects were found in both experiment 1 (using clearly visible stimuli) and experiment 2 (using nonconscious stimuli), indicating that the mechanisms responsible for placebo and nocebo effects can operate without conscious awareness of the triggering cues. This is a unique experimental verification of the influence of nonconscious conditioned stimuli on placebo/nocebo effects and the results challenge the exclusive role of awareness and conscious cognitions in placebo responses.analgesia | hyperalgesia | consciousness P lacebo and nocebo effects are critical components of medical practice and clinical research. Placebo analgesia and nocebo hyperalgesia are the most robust and well studied of these effects. Learning is known to play an important role in placebo and nocebo effects and the dominant theories invoke classical conditioning and expectancies as explanatory tools (1). Both rely on a notion that the conscious perception of sensory or social stimuli, such as the cue that triggers expectancy or the conditioned stimulus in classical conditioning, are needed to obtain placebo responses. In some circumstances, conditioning may be an automatic nonconscious process, but in most cases, it seems to involve the formation of expectations (2-4). However, it is not known whether conscious perception of a conditioned stimulus is needed to elicit a conditioned response.There is a large literature suggesting that behavior can be motivated by stimuli that are not consciously perceived, because they are presented at low intensities or masked from conscious awareness (5, 6), sometimes referred to as subliminal stimuli. Nonconscious operations are considered a fundamental feature of human cognition, for example in reward processing (7,8), fear learning (9, 10), and social behavior (11,12). Furthermore, evidence suggests that conditioned responses may be acquired outside of conscious awareness (13-15). Neuroimaging studies of the human brain suggest that certain structures, such as the striatum and ...

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