How the Placebo Effect Works

A placebo is a fake treatment, a medical intervention that does not contain any physically or pharmacologically active substances with a direct ability to induce therapeutic effects. Yet, its effect is real. When you’re told that something is going to produce a specific effect on you, even though it does not really have the ability to do so, it is highly likely that you will feel it. And that is the reason why clinical trials use placebos as a control to accurately determine the efficacy of a drug.

Although the placebo effect has been acknowledged since the 18^th century, only recently has there been an interest in understanding how it works. The placebo effect is currently regarded as a set of complex psychological and neurobiological mechanisms built up from verbally induced expectations, from learning and conditioning processes, from social context, from previous experiences, and modulated by emotions, motivation and attitude.

Expectations affect our perception – pain, a relatable example

Pain is a subjective experience that heavily relies on psychological and emotional mechanisms. This makes it highly prone to placebo responses, and this is the field in which the placebo effect has been most extensively studied. It is also a very relatable context: it is highly likely that you have experienced the subjectivity and the volatility of painful experiences.

Expectation is a key determinant in pain. If you’re told that piercing your ear will hurt, it most likely will. Likewise, if you’re told that it is totally painless, it’s more likely that it will not hurt. If you go into a dentist’s office assuming it will hurt, it most likely will. But maybe if you witnessed someone having a tooth removed without flinching you would feel less pain – your expectations would change and you would be conditioned to feel less pain. And indeed, studies have demonstrated that social conditioning is a key factor in the perception of pain - the observation of pain relief in another person can induce analgesia as effectively as a placebo. All of these aspects influence the experience of pain and are a gateway for the placebo effect.

The placebo effect goes beyond analgesia

Placebo analgesia is the most widely studied placebo response. But the placebo effect is not only observed in the context of pain. It is observed whenever an effect can be suggested by verbal, social or physical cues, and whenever expectations, memories and emotions capable of modulating disease outcomes can be elicited.

Depression is another clinical context in which the placebo effect has been studied with interesting results. In this case, it is somewhat easy to speculate how expectations, memories and emotions may influence the outcome of antidepressant therapy. But in depression, placebo administration has been shown to reduce glucose metabolism in specific brain regions - this is a rather intriguing effect.

But even more intriguing are the placebo effects on motor performance that have been reported in Parkinson’s disease patients - it has been found that placebo administration can increase the production and action of the neurotransmitter dopamine in areas of the brain where it is lacking and increase the activity of neurons in these areas associated with the symptoms of Parkinson’s disease, leading to better motor performance. This can be regarded as an expectation-induced dopamine release, which is a powerful effect.

The neurobiological mechanisms of the placebo response

The placebo response entails highly complex mechanisms, most of which are poorly understood. It is likely that the placebo effect arises as a combination of multiple factors: neuropharmacological, neurophysiological, cognitive, affective and behavioral. Research on the placebo effect therefore requires an integration of different fields of neuroscience.

Research has showed that, besides expectation, memory and learning mechanisms are also important contributors to placebo responses. Verbal suggestions of an effect and conditioning cues are believed be associated with memory mechanisms that are capable of triggering autonomic and neuroendocrine responses, emotions and behaviors. And an example of the impact of learning mechanisms is what is known as pharmacological conditioning: if, while undergoing an analgesic pharmacological treatment, the drug is replaced by a placebo, the effect is likely to carry on; your brain learns that the pills you’ve been taking induce a certain effect and it keeps reproducing it by itself, releasing neuromodulatorsthat trigger the activation of analgesic molecules.

Opioids, one of our most important endogenous pain-relieving systems, seem to play a central role in placebo analgesia. Brain regions in which opioids are released during administration of placebo analgesics are also associated with learning, thereby explaining the maintenance of placebo effects. But numerous other molecules have also been linked to the placebo effect, such as the neurotransmitter dopamine, important in reward mechanisms, or the hormone oxytocin, commonly known as the love hormone.

There also seems to be no single specific brain region responsible for the placebo effect. Placebo analgesia, for example, has been found to be able to reduce the activation of the amygdala and insula, two brain structures with key roles in emotional processing. But an anxiolytic placebo effect associated with altered activity in different brain regions has also been demonstrated.

Different neuronal pathways associated with cognitive, affective and motivational processing have been implicated in the generation of placebo responses, including pathways involved in valuation, emotion and expectation that can affect both sensory and functional aspects of pain.

Can the placebo effect be used as therapy?

There are still more questions than answers when it comes to the placebo effect. But it is clear that understanding it would be extremely relevant to therapeutic approaches. Besides determining its neurological mechanisms, research may eventually uncover how the placebo effect can be actively used in clinical contexts. There have already been attempts to apply placebos as drug effect enhancers or even partial substitutes of pharmacological therapies with interesting results. But this is still far from being a standardised option.

The complexity of the placebo effect is evident. And there’s a long road ahead until it is fully understood. But given its power, it’s a goal worth pursuing.

As can be read in the Dhammapada:

“What we are today comes from our thoughts of yesterday, and our present thoughts build our life of tomorrow: Our life is the creation of our mind.”

References

Benedetti F (2014). Placebo effects: from the neurobiological paradigm to translational implications. Neuron, 84(3):623-37. doi: 10.1016/j.neuron.2014.10.023

Colloca L, et al (2013). Placebo analgesia: psychological and neurobiological mechanisms. Pain, 154(4):511-4. doi: 10.1016/j.pain.2013.02.002

Kaptchuk TJ, Miller FG (2015). Placebo Effects in Medicine. N Engl J Med, 373(1):8-9. doi: 10.1056/NEJMp1504023

Klinger R, et al (2013). Placebo analgesia: Clinical applications. Pain, 155(6):1055-8. doi: 10.1016/j.pain.2013.12.007

Lidstone SC, et al (2010). Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry, 67(8):857-65. doi: 10.1001/archgenpsychiatry.2010.88

Peciña M, et al (2014). Neurobiology of placebo effects: expectations or learning? Soc Cogn Affect Neurosci., 9(7):1013-21. doi: 10.1093/scan/nst079

Wager TD, Atlas LY (2015). The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci, 16(7):403-18. doi: 10.1038/nrn3976

Zubieta JK, Stohler CS (2009). Neurobiological mechanisms of placebo responses. Ann N Y Acad Sci, 1156:198-210. doi: 10.1111/j.1749-6632.2009.04424.x