The Placebo Effect

Primer

The Placebo Effect is the tendency of any medication or treatment, even an inert or ineffective one, to exhibit results simply because the recipient believes that it will work.

Placebo Response Rates

Children

  • Children and adolescents can have even higher rates of placebo response (up to 46% response on placebo for depression, compared to a mean medication response of 59%). This rate has also been increasing over time.[4]

Mechanism

  • The placebo effect is thought to be mediated by the interplay between unconscious conditioning and conscious expectations.

Dopamine

  • The neurotransmitter dopamine is also the salience and “excitement” neurotransmitter in the brain, while catechol-O-methyltransferase (COMT) is an enzyme that breaks down monoamine and dopamine.
    • Individuals with the Val/Val polymorphism of COMT are particularly effective at breaking down dopamine, and thus lower dopamine levels and the lowest placebo response.
    • Individuals with the Met/Met polymorphism are not as good at breaking down dopamine, and thus have the high levels of dopamine, and in general have a greater placebo response.
    • Individual with the Val/Met heterozygotes polymorphism have an intermediate placebo response.[5]
  • Interestingly, COMT has also been found to be linked to schizophrenia as well.

Nocebo

  • The nocebo effect is the opposite of the placebo effect, where patient is experiences with harmful side effects or worsening of symptoms due to negative psychological expectations of a treatment. The amygdala is thought to mediate the nocebo effect.

Healthcare

Clinicians' Expectations and Beliefs May Also Drive Placebo Responses

  • The placebo effect in healthcare is pervasive, and occur in all aspects of medicine. For example, placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma.[6]

Subtle Suggestions

Maybe Placebo Effect is Powerless?

Empathy

  • Clinicians that exhibit more empathy, as perceived by patients with the common cold, have significantly shorter duration and severity of illness, and have marked immune system changes.[7]. The effects of a practitioner on a patient's response can have dramatic impacts.[8]

Prescribing Placebos

  • Psychiatrists in particular are aware of the placebo effect, and may prescribe sub-therapeutic doses of medications.[9]

ADHD

Side Effects

Placebo and NNT

  • The Number Needed to Treat (NNT) can be a misleading figure when one factors in the placebo response. The NNT can be very misleading in a randomized placebo-controlled trial, because the placebo response also contributes to the NNT in the active medication arm, and not just the placebo arm![10][11]

Daily Life

  • When wines are marketed as more “expensive,” individuals are inclined to report increased pleasantness as well.[12]

Resources

For Patients

For Providers

Articles
Research

References

1) Bschor, T., Nagel, L., Unger, J., Schwarzer, G., & Baethge, C. (2024). Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis. JAMA psychiatry.
2) Bschor, T., Nagel, L., Unger, J., Schwarzer, G., & Baethge, C. (2024). Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis. JAMA psychiatry.
3) Sonawalla, S. B., & Rosenbaum, J. F. (2002). Placebo response in depression. Dialogues in Clinical neuroscience, 4(1), 105.
4) Rutherford, B. R., & Roose, S. P. (2013). A model of placebo response in antidepressant clinical trials. American Journal of Psychiatry, 170(7), 723-733.
5) Hall, K. T., Loscalzo, J., & Kaptchuk, T. J. (2015). Genetics and the placebo effect: the placebome. Trends in molecular medicine, 21(5), 285-294.
6) Wechsler, M. E., Kelley, J. M., Boyd, I. O., Dutile, S., Marigowda, G., Kirsch, I., ... & Kaptchuk, T. J. (2011). Active albuterol or placebo, sham acupuncture, or no intervention in asthma. New England Journal of Medicine, 365(2), 119-126.
7) Rakel, D. P., Hoeft, T. J., Barrett, B. P., Chewning, B. A., Craig, B. M., & Niu, M. (2009). Practitioner empathy and the duration of the common cold. Family medicine, 41(7), 494.
8) Kaptchuk, T. J., Kelley, J. M., Conboy, L. A., Davis, R. B., Kerr, C. E., Jacobson, E. E., ... & Park, M. (2008). Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. Bmj, 336(7651), 999-1003.
9) Raz, A., Campbell, N., Guindi, D., Holcroft, C., Déry, C., & Cukier, O. (2011). Placebos in clinical practice: comparing attitudes, beliefs, and patterns of use between academic psychiatrists and nonpsychiatrists. The Canadian Journal of Psychiatry, 56(4), 198-208.
10) Roose, S. P., Rutherford, B. R., Wall, M. M., & Thase, M. E. (2016). Practising evidence-based medicine in an era of high placebo response: number needed to treat reconsidered. The British Journal of Psychiatry, 208(5), 416-420.
11) de Craen, A. J., Vickers, A. J., Tijssen, J. G., & Kleijnen, J. (1998). Number-needed-to-treat and placebo-controlled trials. The Lancet, 351(9099), 310.
12) Plassmann, H., O'doherty, J., Shiv, B., & Rangel, A. (2008). Marketing actions can modulate neural representations of experienced pleasantness. Proceedings of the National Academy of Sciences, 105(3), 1050-1054.