The chemistry behind the placebo effect

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One phenomenon within medicine which has always fascinated me is the placebo effect. The placebo effect can be defined as either a psychological or physiological improvement due to treatment of a patient with either an intent substance, such as a sugar pill, or a simulated procedure. Although numerous studies have been conducted on possible explanations for the placebo effect, so far no decisive conclusion has been reached. It’s more indicative that the effect is caused by the patient's expectation of the treatment, rather than as a direct effect of the drug or procedure.

In modern medicine, a placebo drug is often used as a control in clinical trials. For example, when trialling the COVID AstraZeneca vaccine recently, some volunteers were unknowingly given placebo vaccines. Most notably, certain antidepressants have failed to provide more benefits than the placebo effect, suggesting how the placebo effect could be more psychological than physical. Interestingly, the colour, size and price of a pill can also affect patient expectations for effectiveness of the drug. A study in 2008 found that participants who took a painkiller sold at a relatively higher price experienced greater pain tolerance when subjected to a mild electric shock.

Ethical issues can surround the use of placebo medications within clinical trials. The researchers know that the medication is fake, but they imply that the treatment is real. This could be considered dishonest, and against the bioethical code of medical practitioners. The declaration of Helsinki has updated their guidelines surrounding placebo use in clinical trials, and states that they can only be used when there isn’t another effective option for a control.

Possible explanations for the placebo effect have a physiological and psychological basis, and are influenced by factors such as expectations and cultural beliefs. Studies have shown that the release of the neurotransmitter dopamine in the ventral striatum in the brain could influence the placebo effect. Also, patients with chronic illnesses who frequently experience a positive outcome from their treatment, and therefore strongly anticipate

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therapeutic benefit, could be experiencing a form of the placebo effect. This positive expectation from treatment is especially common in patients with Parkinson’s disease, who experienced dopamine release in the basal ganglia in the brain, and this draws the associations between increased dopamine activity and the placebo effect. Parkinson’s disease is unusual in how it is affected by the placebo effect, since the placebo effect usually only impacts levels of pain and nausea, or patient reported outcomes, rather than actual diseases which aren’t dependent on patient perception.

However, it should also be considered whether the placebo effect is actually an unintentional impact of confounding variables. The placebo effect could be due to a response bias from subjects, for example from answers of politeness, or experimental subordination. Moreover, the placebo effect could possibly be due to non inert ingredients inside placebo medications having an unintended effect. However, this is unlikely since placebo medications are usually just sugar pills. Also, since so many studies have been conducted using the placebo effect, it’s unlikely to be completely due to confounding variables only.

As well as positively impacting the treatment of a patient, the placebo effect also has an effect on a number of other physiological systems. These organ systems include the nervous system and digestive system. For example, placebos can decrease the levels of appetite stimulating hormones by convincing the participant they have eaten calorie rich food. Appetite levels are then decreased based on expectation alone. Furthermore, researchers have also found that placebos can affect the immune system. For example, in one study it was found that watching advertisements for the anti allergy drug Claritin led to the drug being more effective than in participants who didn’t receive propaganda promoting the drug.

A more negative aspect to the placebo effect is called the nocebo effect. This is when a patient who receives an inert substance experiences a negative effect or a worsening of symptoms. This is due to negative expectations from the treatment, rather than an outcome from the substance itself. Ethically, this issue has to be considered in clinical trials, due to the number of side effects which can be associated with placebo treatment. Furthermore, withdrawal symptoms can also occur after a placebo treatment. For example, a study by the Women’s Health Initiative study of hormone replacement therapy for menopause found that moderate or

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severe withdrawal symptoms were reported by 4.8% of those on placebo.

I think the placebo effect can have both positive and negative therapeutic effects. This is demonstrated by both the negativity of the nocebo effect and potential for withdrawal symptoms, and the positive association between placebo medication and the relieval of sickness. The placebo effect must be further investigated in order to gain a more conclusive understanding of the neurochemistry behind the effect.

By Lara Weeks

References and further reading: https://s4be.cochrane.org/blog/ 2014/08/06/the-placebo-effect/

https://www.britannica.com/science/ placebo-effect

https:// www.neuroscientificallychallenged.co m/blog/influence-placebos-brain

https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC6013051/ https://www.health.harvard.edu/ mental-health/the-power-of-theplacebo-effect

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