October 25, 2021

I, Science

The science magazine of Imperial College

The placebo effect is like a slightly embarrassing trick you play on someone who’s never heard it before. There’s no deception that makes a person look so gullible or so much of a hypochondriac as to bring them back to health with a treatment that does nothing at all.

However, although it’s still debated, the placebo effect is a real health issue and affects every clinical trial. For that reason, to see the placebo effect as a blemish upon the power of medicine is not useful anymore – but it begs the question: why, if a person has it in them to get better, do they need an imaginary helping hand to do so?

A new paper looks at the placebo effect in the light of evolution and may bring us closer to an answer. As with many studies of evolution, it offers counter-intuitive explanations based on common-sense principles. Its crux is the idea of a trade-off.

Today, health tends to be a major priority for everyone, all the time. But you can probably remember a time when a friend who should have been resting up instead worked through a sickness, and perhaps regretted it. Now imagine yourself as a somewhat dim-witted animal beset on all sides by predators, uncertain of the source of its next meal, and in constant competition for mates. Imagine that you fall ill. If recovering means going down with a fever, hiding, or fasting for a few days, would you put that ahead of fleeing enemies, finding shelter or stocking up on energy? Unlike your friend, your choice will decide how many offspring you ultimately raise.

Peter Trimmer of the University of Bristol and his colleagues suggest you would not. They describe the response of an organism to an illness as a decision about what resources to invest in which problems. With mathematical models they show that the optimal amount one puts into fighting illness could be lower in bad times than in good ones. This is a bit counterintuitive, right – that you should try less hard when the going gets tough?

How do they know what is optimal? The authors calculate this using the common currency of all evolutionary “decisions”, reproductive value (RV). RV is a count of the number of children you will have in your lifetime. Natural selection favours organisms with greater total RV across their lives, because these pass on more of their genes to the next generation, and they to the next, and so on.

Evolution “decides” to do whatever will maximise RV. So, when you’re ill but have other problems too, evolution has an RV dilemma: being ill reduces your RV, because you can’t make as many babies, but being dead makes it zero. If getting better right now increases your chance of dying at all, it might be worth waiting for a better shot.

But this again seems counterintuitive. Why would getting better increase your chance of dying? When people recover from serious health problems – not cuts and colds but breaks and sprains, gut or blood infections, and so on – it’s a big investment. Injured joints sometimes work better before they become inflamed, but inflammation has to happen as part of the healing process. Major infections provoke fever, but a proper fever is incapacitating, preventing the victim eating or moving, which puts you at risk of starving or being attacked. Trimmer & co argue that evolution has designed us to pick our battles against disease, recuperating fastest when the time is right.

But none of this explains why “sham” acupuncture is twice as effective as normal treatment for lower back pain. Does it?

Trimmer and his co-authors’ implicit suggestion is that when you use a placebo – be it an empty pill or fake acupuncture – and you’re convinced that it will help you, your body starts making itself better to take advantage of the favour. As an analogy, why do you go shopping just because there is a sale on? And why then do you buy twice as much as you need? It’s not that the sale makes it easier to earn money, to spend it, or to carry your haul home. It’s that you’re gambling on saving money in the long run, even though you end up spending extra money that day. The equivalent of the placebo effect would be that you’re given a 20%-off voucher for a shop you like, go there and load yourself up with things you want, only to find that the voucher expired yesterday. You’re already at the till, so you just buy it all anyway. In Trimmer & co’s theory, a placebo is a fake bonus just like that voucher, and it makes your body think that getting better right now will be cheaper than doing so later.

This theory was originally put forward by Nicholas Humphreys ten years ago, and the new study builds on his work. It depends on the idea that beliefs can influence how much effort your body puts into getting well. According to Humphreys’ definition of a working placebo, the patient must be aware they are receiving it and expect that it will improve their health. You could be giving someone a sugar pill to “cure their stomach ulcers”, or injecting them with salt water to control their arthritis. Such treatments can actually work, which implies that belief is what is important.

We don’t normally think of things like immunity and metabolism as being under the direct control of our minds. However, science is offering up plenty of evidence that this is the case. Some hormones, such as growth hormone, come from nerve cells, and the pituitary “gland” is actually a part of the brain. We’ve all heard of stress hormones, and more to the point, the nervous system can affect the production of antibodies or regulate signalling to immune cells. In fact, rats can be trained to turn down their immune system in response to a specific taste. We don’t know how belief might drive better health, but this is an active and continuing research area.

So, Trimmer et al’s paper in a nutshell is that a placebo offers your body a bit of encouragement, which gets recovery into gear. But this study has further implications. It’s another step towards a slightly, but unsettlingly, different view of what medicine actually is.

The Trimmer et al paper proposes that the body responds not to sugar in a pill, but to your belief in its effects. If you believe good things, this is translated into decreased stress, a boosted immune response, or other changes. But why should those changes be triggered only by fake drugs? The truth is that they are not.

The quality of doctor-patient relationships is now recognised as a major influence on patient recovery rate and speed. Warmth, politeness, attentiveness, and other reassuring features can make a surprisingly big difference. Reviews have found that the most important contributor to the outcome of psychotherapy is the quality of the therapist-client relationship. More difficult to believe is one study of patients recovering from surgery, which showed that staying in a room with a nice view noticeably improved recovery when compared to staying in one with a view of a brick wall.

It seems that patients’ emotional and social relationships with the treatments they receive and whom they get them from is very important. How healthcare systems should respond to this is an ethically and scientifically difficult question. Perhaps, if dependence on belief is built into our bodily functions, healthcare should try to make use of it. Hospitals may be more efficient if they do all they can to cultivate a comfortable, reassuring environment. Of course, years of tradition behind the doctor’s “bedside manner” and a nursing culture devoted to responsible and sensitive care mean that medicine already embraces this principle. Science might just be playing catch-up by explaining it.

There is one particularly intractable issue, though. For the placebo effect to work, we need to believe that a treatment could make us better. But according to Humphreys’ theory, if we believe that a treatment works, it will make us better, regardless of whether it does or not. So the more we believe in the medicines we get from doctors, the more they help us. This raises the possibility that modern medicine works partly just because we believe in it.

For instance, recent research has suggested that many antidepressants are no more effective than placebos. Antidepressants are widely prescribed by psychiatrists, make a great deal of money for pharmaceutical companies, and certainly appear to help some people. But now I know the evidence behind them is weak, antidepressants may never help me, because I’ve lost my faith that they work. We have a situation where better evidence about the effectiveness of medicines might actually prevent them from helping patients.

To take the analogy from earlier even further, just as the economy might benefit from allowing false advertising and dodgy offers if they help get people into shops, public health might benefit from increasing patients’ confidence in medicine because optimism and emotional well-being improves their recovery.

The medical profession has always been socially and intellectually exclusive. We trust medics because they are highly trained and regulated, and we trust drugs because developing them requires so much time, money and proof. But if trust is part of what makes medicine work, then the ongoing drive to make medicine more open and evidence-based may actually hurt it (and us).

Trimmer & co’s evolutionary perspective on medicine suggests that it suits us to tolerate illness until we’re best-equipped to fight it. It may also imply that our health benefits from a limited, slightly rose-tinted understanding of medicine. Maybe, when it comes to medicine, we’re better off finding out only what makes us feel better.