A placebo can make you feel a little better – and now we know how to boost the effect. Drugs based on hormones that make us more cooperative seem to enhance the placebo effect. The finding could lead to changes in the way some trials are performed.

Sometimes a sugar pill can be all you need, even when you know it doesn’t contain any medicine. We’re still not entirely sure why. The brain’s natural painkillers, such as dopamine and opioids, seem to be involved, but other factors may be at work too. Evidence that a compassionate, trustworthy carer can speed recovery suggests that there is also a social dimension to the placebo effect.

“This interaction between the patient and care provider seems to be based on a more complex system,” says Luana Colloca at the University of Maryland in Baltimore.


Hormones that modulate our social behaviour might play a role. Last year, a team led by Ulrike Bingel of the University Duisburg-Essen in Germany, found that oxytocin – the so-called “cuddle chemical” that is thought to help us trust, bond and form relationships – seems to boost the placebo effect, at least in men.

In the study, Bingel’s team applied an inert ointment to the arms of male volunteers. Half of them were told that the cream would reduce the degree of pain caused by the painfully hot stimulus subsequently applied. Men who were told that they were receiving pain relief said that the heat was less painful than those who knew that the cream was inert. When oxytocin was squirted up volunteers’ noses, the men reported being in even less pain. The team didn’t test oxytocin in women.

Trust issues

Colloca wondered if another hormone – vasopressin – might have a similar effect. Vasopressin has also been linked to trust and commitment to relationships. “We know that receptors for oxytocin and vasopressin are in very similar areas of the brain,” says Colloca.

To find out, her team administered moderately painful electric shocks to the fingers of 109 men and women. The intensity of the shock was tailored to each individual so that they all reported the same, moderate level of pain. The participants were also told that each time they saw a green light, the electric shock would be reduced, but that it would be kept at the same level when a red light was displayed. In reality, the level of intensity never changed.

In addition, each participant was given a sniff of either vasopressin, a placebo of salt water, a very low dose of oxytocin or nothing at all.

Colloca’s team compared the pain ratings of the volunteers when they were shown a red light to the scores given when they saw a green light. Any difference represents a placebo effect, says Colloca. All of the volunteers experienced the placebo effect, but it was more significant in women given vasopressin.

This makes sense, says Colloca. Previous research suggests that while vasopressin seems to promote aggression and rivalry between men, it encourages “tend-and-befriend” tendencies among women. Colloca administered the treatments herself, and although the women didn’t outwardly behave any differently, , she thinks that the women given vasopressin probably felt more at ease, and were cooperative and trusting of her as a care provider.

“It is remarkable,” says Rene Hurlemann at the University of Bonn in Germany. He thinks that hormones like vasopressin may be responsible for the placebo effects seen in some clinical trials.

Trial and improvement

“Many clinical trials for drugs for depression have struggled to produce results that are better than placebo,” he says. “Some say that antidepressants don’t work, but I think that’s nonsense.” Instead, hormone systems may be altered in some diseases like depression. “This has been completely overlooked in medical trials,” says Hurlemann.

In future, researchers might be able to find ways to block the effects of hormones like oxytocin and vasopressin in clinical trials, or at least factor them in, and put a stop to the potential skewing of trial results.

As drugs, the hormones could also be used to enhance the effects of other medicines – but it might be easier to work on improving the environment a person is in when they are receiving medical treatment, says Tor Wager at the University of Colorado at Boulder. “We like to think that a drug does one thing, but the context in which it is given can modify its effects,” he says.

The social aspects of medical treatment appear to be especially important, says Wager. In his own research, Wager says he has found that providing people with positive or negative information about others changes their perception of pain – to a greater degree than the typical measures of placebo effect. “There seems to be something special about social feedback,” he says.

Colloca hopes the hormones can be applied in treatments for chronic pain. “We know the best care providers interact well with their patients,” she says. “It might be possible to help a person control their pain by enhancing this cooperation response.”

Journal reference: Biological Psychiatry, doi.org/6zq