Sex, Drugs, and the Neurobiology of the Placebo Effect

  • David R. Rubinow
    Address correspondence to David R. Rubinow, M.D., Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, 333 South Columbia Street, Suite 304 MacNider Hall, Chapel Hill, NC 27514.
    Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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      If you have ever been engaged in clinical research, you may have had this experience: the first six patients on the open trial of a new compound respond brilliantly, but then the next six patients completely fail to respond, shattering your fantasies of discovering a therapeutic cure. Or perhaps you have observed that initial published findings demonstrating the efficacy of the next novel treatment are not subsequently replicated—another victim of the dreaded placebo response! In this issue of Biological Psychiatry, Colloca et al. (
      • Colloca L.
      • Pine D.S.
      • Ernst M.
      • Miller F.G.
      • Grillon C.
      Vasopressin boosts placebo analgesic effects in women: A randomized trial.
      ), far from attempting to avoid the placebo response, attempt to induce it in the service of better understanding its neurobiological substrate. The authors compare the effects of intranasal oxytocin, vasopressin, and saline as well as a no-treatment condition on the analgesic efficacy of a cue (a green light) that the subjects are told will signal the presence of an electrical stimulus that will reduce the painful effects of an administered electric shock. The authors observe that the analgesic efficacy of the cue (which is inactive) is seen only in the women who received a vasopressin 1A/1B receptor agonist. The authors conclude that these sex-specific effects of vasopressin may help “shape placebo responsiveness,” possibly in the service of individualized therapeutic outcomes.
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        • Colloca L.
        • Pine D.S.
        • Ernst M.
        • Miller F.G.
        • Grillon C.
        Vasopressin boosts placebo analgesic effects in women: A randomized trial.
        Biol Psychiatry. 2016; 79: 794-802
        • Walum H.
        • Waldman I.D.
        • Young L.J.
        Statistical and methodological considerations for the interpretation of intranasal oxytocin studies.
        Biol Psychiatry. 2016; 79: 251-257
        • Button K.S.
        • Ioannidis J.P.
        • Mokrysz C.
        • Nosek B.A.
        • Flint J.
        • Robinson E.S.
        • et al.
        Power failure: Why small sample size undermines the reliability of neuroscience.
        Nat Rev Neurosci. 2013; 14: 365-376
        • Leng G.
        • Ludwig M.
        Intranasal oxytocin: Myths and delusions.
        Biol Psychiatry. 2016; 79: 243-250
        • Levine J.D.
        • Gordon N.C.
        • Fields H.L.
        The mechanism of placebo analgesia.
        Lancet. 1978; 2: 654-657
        • de la Fuente-Fernández R.
        • Schulzer M.
        • Stoessl A.J.
        Placebo mechanisms and reward circuitry: Clues from Parkinson’s disease.
        Biol Psychiatry. 2006; 56: 67-71
        • Schultz W.
        Neuronal reward and decision signals: From theories to data.
        Physiol Rev. 2015; 95: 853-951
        • Feng C.
        • Hackett P.D.
        • DeMarco A.C.
        • Chen X.
        • Stair S.
        • Haroon E.
        • et al.
        Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans.
        Brain Imaging Behav. 2015; 9: 754-764
        • Meyer-Lindenberg A.
        • Domes G.
        • Kirsch P.
        • Heinrichs M.
        Oxytocin and vasopressin in the human brain: Social neuropeptides for translational medicine.
        Nat Rev Neurosci. 2011; 12: 524-538
        • Albers H.E.
        Species, sex and individual differences in the vasotocin/vasopressin system: Relationship to neurochemical signaling in the social behavior neural network.
        Front Neuroendocrinol. 2015; 36: 49-71
        • Czerniak E.
        • Davidson M.
        Placebo, a historical perspective.
        Eur Neuropsychopharmacol. 2012; 22: 770-774

      Linked Article

      • Vasopressin Boosts Placebo Analgesic Effects in Women: A Randomized Trial
        Biological PsychiatryVol. 79Issue 10
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          Social cues and interpersonal interactions strongly contribute to evoke placebo effects that are pervasive in medicine and depend upon the activation of endogenous modulatory systems. Here, we explore the possibility to boost placebo effects by targeting pharmacologically the vasopressin system, characterized by a sexually dimorphic response and involved in the regulation of human and nonhuman social behaviors.
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