Neurobiological Mechanisms of the Placebo Effect

Correlation between subjective report (italics), arm rigidity (black circles), and subthalamic nucleus neuronal frequency discharge (bars) in two representative Parkinson's disease patients. The black arrow on the abscissa indicates placebo administration. Note the subjective sensation of well-being, along with arm rigidity decrease and neuronal firing rate reduction, in the placebo responder (a) but not in the nonresponder (b). Modified from Benedetti et al. (2004).

Effects of placebo on the activation of μ-opioid receptor-mediated neurotransmission. After correction for multiple comparisons, significant effects of placebo on the activation of the μ-opioid system (n = 14) were detected in the left DLPFC (x, y, z peak coordinates, -36, 13, 39; cluster size, 1403 mm³; z score, 4.27; p < 0.0001), rostral anterior cingulate (RACing; x, y, z, 14, 49, 13; cluster size, 3193 mm³, z score, 4.18; p < 0.0001), left nucleus accumbens (NAcc; x, y, z, -7, 11, -11; cluster size, 1332 mm³; z score, 4.83; p < 0.0001), and right anterior insula (Ins; x, y, z, 41, 10, -17; cluster size, 844 mm³; z score, 4.15; p < 0.05). The posterior right insula achieved subthreshold levels of significance (44, -15, 4; cluster size, 732 mm³; z score, 3.81; p < 0.0001 uncorrected for multiple comparisons). z scores of statistical significance are represented by the pseudocolor scale on the right side of the image and are superimposed over an anatomically standardized MRI image in coronal views. The left side of the axial and coronal images corresponds to the right side of the body (contralateral to pain) (radiological convention).

Individual data points for the magnitude of regional μ-opioid system activation in response to the placebo intervention. Individual data points for the change in the binding potential measure (μ-opioid receptor availability in vivo; B_max/K_d) from the pain condition to the pain plus placebo condition. A threshold of 10% increase in the activation of this neurotransmitter system, evidenced as a reduction in the binding potential measure during the placebo condition, was used to identify individuals that responded with a robust placebo effect on the activation of this system in each of the regions (dotted line). Colors depict the data for each individual subject to highlight regional differences in the individual placebo response. ACing_Rostral, Rostral (pregenual) region of the anterior cingulate; DLPFC_Left, left dorsolateral prefrontal cortex; Insula_Right, right insular cortex; N.Acc._Left, left nucleus accumbens.

Placebo-induced increases (placebo-controlled) in anticipation of pain (top left and slices at right) and during pain experience (bottom left) (from Wager et al., 2004). The threshold for display is set at p < 0.005, with the additional constraint of replication of effects within 10 mm across experiments 1 and 2. For space reasons, selected activations are shown.

Changes in regional glucose metabolism (FDG PET) in fluoxetine (top), placebo (middle), and cognitive (bottom) therapy responders measured before and after a standard course of each respective treatment. Axial (left), sagittal (middle), and coronal (right) views; increases are in red, and decreases are in blue. The fluoxetine and placebo group were studied as part of the same double-blind controlled experiment. A common pattern of cortical increases and limbic-paralimbic decreases is seen in both groups, with the active fluoxetine group showing additional changes in the brainstem, hippocampus, insula, and caudate. In contrast, CBT response is associated with a distinctly different pattern: dorsolateral and medial frontal decreases and hippocampal increases. These findings suggest that the placebo changes are unlikely attributable to passive psychotherapy effects but rather specific effects attributable to the effects of expectation and conditioning facilitated by the psychosocial context of the trial. Slice location is in millimeters relative to anterior commissure. Numbers are Brodmann designations. ACing, Subgenual cingulate BA 25; PCing, posterior cingulate; P, pons; Hc, hippocampus; PFC, prefrontal cortex BA 9; Ins, anterior insula; Cau, caudate; OFC, orbital frontal cortex BA 11; MFC, medial frontal cortex BA 9.

Time course of regional metabolic changes in drug nonresponders (left), drug responders (middle), and placebo responders (right). Ventral striatal and orbital frontal increases are seen uniquely at 1 week (Fig. 8, top panel; middle and right images) of both active and sham treatment in those patients that go on to show clinical response at 6 weeks. Such changes are not seen in patients who failed to respond (left image) and are no longer present in either group of responders once clinical remission has been achieved (6 week time point; bottom). In contrast, response-specific changes in prefrontal cortex and subgenual cingulate are seen only at 6 weeks (bottom) and not at the 1 week time point. VST, Ventral striatum; OFC, orbital frontal cortex BA 11; MFC, medial frontal cortex; ACing25, subgenual cingulate BA 25; PFC, prefrontal cortex BA 9; Ins, anterior insula; ACing24, anterior cingulate BA 24.