mission, or biased reporting. However, recent research reveals that the placebo effect is a real biological response, and illuminates the underlying mechanisms driving this phenomenon.
Placebos elicit biological responses
Contrary to popular belief, patients don’t just imagine placebo responses. Rather, numerous brain-imaging studies have confirmed that placebos cause measurable changes in neurobiological signaling pathways . How can a sugar pill lead to a tangible physical response? The key to understanding the placebo is that it is not just the inert therapy itself, but also the expectation surrounding that therapy.
Say you are experiencing pain and spontaneously decide to eat a sugar pill – chances are you won’t feel better. However, if you describe your symptoms to a physician, who then prescribes you the same pill (unbeknownst to you, it’s just sugar), you expect that pill to have a therapeutic benefit. This expectation activates reward pathways in the brain, in turn stimulating the release of substances called endorphins, which are chemically similar to opiates like morphine. Like morphine, these endorphins bind to opioid receptors and cause pain relief. Therefore, in response to positive expectations of treatment, your brain becomes flooded with its own supply of natural painkillers. This effect can be partially negated by a chemical called naloxone, which was developed for patients who overdose on opiates, such as morphine or heroine. Naloxone acts by blocking key opioid receptors in the central nervous system, and partially prevents placebo responses. This means that the placebo effect can be biochemically modulated!
The opioid system is not the only pathway at play when it comes to placebos. For example, placebos also increase the release and uptake of dopamine, a neurotransmitter involved in reward-motivated behavior and decreased pain sensitivity. Specifically, in anticipation of benefit when a placebo is administered, dopamine receptors are activated in regions of the brain associated with reward.
As further evidence that the placebo effect is a genuine biological phenomenon, genetics can influence the strength of the effect. Specifically, genetic signatures that alter the opioid and dopamine signaling pathways are predictive of whether a patient is more or less likely to experience a strong placebo effect. For example, patients with opioid receptors that are less active are less likely to be placebo responders. On the other hand, patients with reduced dopamine metabolism, and therefore higher dopamine levels in the brain, are more likely to experience a strong placebo effect.
The placebo as a (not so) negative control
While placebos are grounded in a patient’s psychological reaction to receiving treatment, they can act via the same biological pathways as painkillers. In fact, placebos are so good at causing pain relief that the placebo effect is stealing the spotlight in recent clinical trials for new pain medications.
In order to be approved by the Federal Drug Administration (FDA), new drugs must prove more efficacious than placebos in clinical trials. However, in the pain field this is becoming an increasingly tall order. An analysis of 84 clinical trial results for neuropathic pain conducted since 1996 found that, while the responses to the drugs have remained about the same, the responses to the placebo have increased over the past two decades. Why might the placebo effect be growing stronger? It’s hypothesized that the increasingly showy and large-scale setting of clinical trials, combined with direct-to-consumer advertising by pharmaceutical companies, may raise patients’ expectations of drug efficacy. The result: placebo effects in pain are now so large that pharmaceutical companies have an increasingly hard time proving drug efficacy.
That being said, for most drugs the placebo effect and drug effects should be additive. In other words, a patient’s response to a drug should be equivalent to the drug’s biochemical effects plus the placebo effect. Therefore, if a drug can’t outperform a placebo in a 