The placebo effect occurs when an inert treatment such as a dummy pill, fake injection or sham surgery leads to a real clinical improvement in symptoms. So strong is the effect it can be the bane of clinical trials, which must prove a drug’s efficacy beyond a placebo control. An assistant professor of medicine at Harvard medical school, Kathryn T Hall is a leader in placebo research. Her new book, Placebos, unpicks their power.
You argue that placebo effects are underappreciated. How?
They are often seen as more of a novelty than a bona fide neuropsychological response. Physicians can feel uncomfortable because this unknown phenomenon can have a big impact. And many clinical triallists seem to be in denial about the threat of placebos to drug development. I want to bring placebos to common conversations – not just as an anomaly or something to “beat” in clinical trials, but as something that we can think seriously about and maybe even harness.
How powerful can placebos be?
Often as powerful as many medications. Take pain – for which there can be a high placebo response. The placebo effect can rival painkillers like ibuprofen or even morphine in some cases. The response is strongest in more neurological and psychological conditions; placebo effects appear to have little impact on the outcome of clinical trials to treat cancer, viruses or bacterial infections. Other conditions with high placebo responses in clinical trials include depression, irritable bowel syndrome [IBS], epilepsy, hypertension and asthma. And not everyone responds equally.
How do placebos work?
Since the early 2000s researchers have been using neuroimaging to watch the brain in the process of responding to placebos. And there is a lot going on: it is a real neurological response involving multiple parts of the brain working together. In pain, for example, incoming signals get sent to the pain processing regions of our brain but there is a modulating influence of those signals by other regions of the brain that can create meaning and context around the pain we’re experiencing. Response to a placebo treatment can induce opioid signalling, which helps our body control pain, and dopamine signalling, which can help us feel good.
Surprisingly some surgery has been found to be no better than placebos.
The cost of doing sham surgery is quite high. You need to have the surgeon in the room, the smells and the paraphernalia, and perform a large number [in order to gather reliable data]. But there are a few cases where sham and real surgeries have been compared. Popular surgeries that have demonstrated in recent times to be no better than the sham include arthroscopy [keyhole] surgery for knee osteoarthritis and for shoulder impingement.
You note that few new drugs to treat neurological and psychological conditions are being approved: they are failing in clinical trials because they can’t beat the placebo response. Should drugs fail if they don’t beat a placebo?
Several pharmaceutical companies have now stopped looking for drugs for chronic pain and depression because beating the placebo is so difficult and expensive; meanwhile the number of people suffering from these conditions grows. We have set a very high bar for modern drugs. There are some strategies being investigated to minimise the effect of placebo responders in clinical trials but these novel designs, which deviate from the gold standard, will take time to unfold. You can toe the line and argue we do need to make drugs better than placebos. But perhaps we could also be looking for what works for some people and is safe.
Can you predict a placebo responder?
Personality traits have been looked at. Openness to experience and extroversion are the two more frequently observed, but these are not reliable predictors. Brain signatures via neuroimaging show it is possibly based on brain anatomy. We have also started to look at genetics, which has been my research focus. The genes that influence your placebo response can be called your “placebome”.
Placebo therapy faces a bind: telling people they are being given fake medicine may prevent the placebo effect from working. Nonetheless, should we be trying to use placebos in medicine today to treat patients?
In Germany the use of placebos in clinical practice is accepted for minor conditions and if certain requirements are met – though bioethicists worry patients’ rights are being violated. Trademarked placebo pills such as Zeebo are also available, although they have not been tested in clinical trials. To me, what suggests a path forward are the small clinical trials of so-called open-label placebos (OLPs) – in which the patient knows they are receiving a placebo and the rationale for how they can work is explained. The trials, for conditions such as back pain, cancer-related fatigue and IBS, report significant benefit of OLPs compared with no treatment.
What is the nocebo effect?
It is the negative impact that negative information or expectations can have on clinical outcomes. Say you’re told an injection is going to hurt, you’re probably going to feel sore, and it might make you tired. And, sure enough, it can increase your experience of those symptoms.
Black patients and other patients of colour can experience nocebo effects that their white counterparts don’t. What is going on?
People who have been historically marginalised haven’t always, for good reason, come to expect good help or attention from their physicians. Not only may they miss out on the beneficial placebo effect of a physician who takes the time to listen, understand and care, but their previous negative experiences and those shared by friends and family can drive negative expectations, which may result in nocebo effects that worsen their symptoms and reduce adherence [to what is prescribed].
Alternative medicines, such as homeopathy, haven’t shown consistent efficacy over that of a placebo. Are they worth it simply for the placebo response, or is it unfair to offer patients expensive treatments that don’t work in and of themselves?
Both western and complementary medicines offer treatments that don’t work for every patient every day. With the guidance of trained practitioners, individuals need to find the thing that works for them, so long as it is safe. Homeopathy has beaten placebos in many trials, but that might in part be because of the prolonged clinical consultations which we know can have a profound positive effect.
Can we create a placebo response just by the power of our mind? Can we think ourselves well?
If somebody can, good for them. I haven’t been able to. There’s a power in the interaction with a licensed or trusted healer. It is of telling your story, having it heard and “taking something” prescribed based on that interaction.
Could we develop drugs to activate or boost a placebo effect?
The science tells us that, indeed, the placebo pathway is a druggable target. And this is a profound observation. It could be that that is how we’ve developed drugs all along – that unbeknown to us we have been drugging the placebo pathway! What remains to be seen is whether we can intentionally use drugs to boost placebo effects.
• Placebos by Kathryn T Hall is published by MIT Press (£13.99). To support the Guardian and Observer order your copy at guardianbookshop.com. Delivery charges may apply
