Imagine that you are an army doctor in World War II. A soldier is suffering from intense pain in a wounded leg. You quickly look for the pain-relieving morphine injection, but none are left. You grab the saline one, thinking, ‘What can you lose?’. You inject it, and soon the soldier’s pain starts to ease. But how?

Henry Beecher, an anesthesiologist, had this experience, inspiring him to lead placebo effect experiments.¹ Although researchers still do not fully understand the underlying mechanism, multiple studies focus on the factors influencing the placebo effect, from the macroenvironment to the patient’s attitude.

What is the placebo effect?

The placebo effect is one of the most widely known phenomena in medicine. The meaning of ‘placebo’ comes from Latin, translated as ‘I shall please’, and it usually refers to a pharmacologically inactive substance.² The placebo effect is benign, mainly due to treatment conditions, when the mind alone can influence the body's functions without any physical intervention.³ 

Medications are not the only things to have a placebo effect: ordinary products such as caffeine and alcohol (or more precisely, the lack of them) have similar effects. Studies show that the belief of alcohol or caffeine consumption can generate a similar stimulant effect as the actual products.^4,5 This is also true for fake surgeries J. Bruce Moseley performed fake knee operations, only making a small cut on the patient's leg. Out of the ten patients, eight reported significant improvement.⁶ Although the results did not seem to be long-term, these fake surgeries show the power of the placebo effect. 

Several studies demonstrate the vast variety and strength of the placebo effect, as it is a phenomenon that can be influenced by almost anything. In the following, we will take into consideration the possible factors that cause the placebo effect.

What can generate the placebo effect?

Macroenvironment

Let’s briefly consider what we think about these terms: disease, health, doctor, and treatment. Although they are seemingly defined the same by everyone, the cultural variations in their meanings are undeniable. For example, the holistic approach of medicine, which is an attitudinal approach to the overall wellness of the patients, is more popular in Eastern cultures (e.g., China, India), while mainstream medicine, which looks at the cause of illnesses and fixing the problems in the human body, is more popular in the West.⁷ 

These different starting points can affect the trust and expectations towards a treatment. A comprehensive study claimed that German participants experienced a much higher rate of placebo healing (>50%) in the case of ulcers, while in Brazil, it was around ~7%, despite identical protocols.⁸ Another study argues that these cultural differences also affect the strength of the placebo effect, but further research is needed.⁹

Microenvironment

Several studies concluded that the physical surroundings influence the placebo response. Regarding antidepressants, researchers have claimed that the academic environment (e.g., university, teaching hospital) creates a larger difference in the drug-placebo effect, compared to nonacademic sites (e.g., private research centres, research organisations).¹⁰ 

Another study found that aesthetic elements, such as modernised lighting, flooring, and lobby design, can increase the expectations of a more successful treatment, thereby enhancing the placebo effect.¹¹ Similarly, other results emphasise the importance of natural light and windows in hospitals that can shorten the recovery period.^12,13 Also, elements like décor, artwork, scent, and sounds can impact the placebo effect.¹⁴

Characteristics of the drug

Colour, size and shape

Multiple studies have confirmed that the medications’ colour can indicate different responses.^15,16 Warm shades, such as red, yellow and orange, are often considered stimulants, while cold colours, such as blue and green, are associated with a tranquilising effect. White capsules were expected to have the best result in headaches. This colour is also associated with analgesics and narcotics, while purple is associated with psychedelics and hallucinogens.¹⁷ Participants received identical placebos in size and form in a study, but in different colours. The results show that pink capsules indeed had a stimulating effect, while blue tablets worked as sedatives.¹⁸

The size of the drug can also alter the response to the treatment. In research, a bigger size was associated with a more substantial effect, while a smaller size was associated with a weaker one.¹⁹ It is worth noting that another one drew the opposite conclusion.²⁰ 

A study focused on multiple characteristics of a drug, including its form. Oval tablets and capsules, in which the powdered drug is in a fast-absorbing shell, are considered antibiotics, while hard, solid tablets are assumed to have analgesic, sedative, headache-relieving, antipyretic, and hypnotic effects.²¹

Dosing and route of drug administration

Studies assume that a more frequent dosage of medications induces a bigger (placebo) effect: twice a day compared to once a day, or four times a day versus twice a day.^18,22 However, it is worth mentioning that further research is needed to investigate this connection.

Analyses show that invasive drug delivery methods lead to a strong placebo response to medications.²³ In one piece of research involving migraine patients, subcutaneous injection showed a bigger effect than oral tablets.²² A more recent study involved nasal treatment and an intravenous placebo in the analysis. In this case, the intravenous placebo was observed to have the most significant response in migraine patients. However, in the case of pain relief, this image has changed, and the subcutaneous placebo was the strongest one.²⁴ 

Branding and price

Branding can also generate a placebo effect. A study shows that the well-known ‘aspirin’-branded pills produced greater pain relief than the unbranded ones, regardless of whether they had an active drug or a placebo. This phenomenon was also observed amongst people without previous experience with aspirin, suggesting that the brand itself could create a more substantial placebo effect.²⁵

It is often considered that if something is more expensive, it also means better quality. When one study compared the effects of placebo analgesics at full price compared to discount price, participants reported that the cheaper version had a better effect.²⁶ Similarly, in the case of a painkiller cream, research concluded that the ‘low-priced’ had a smaller placebo effect than the ‘expensive’ medication.²⁷

Healthcare professional

Clinicians and experimenters can also amplify the placebo effect. A comprehensive study showed that the status and confidence of the healthcare professionals create differences in pain perception. Higher professional status resulted in minor pain and a better physical and emotional state. The placebo effect was larger if a medical staff member had higher confidence and more competence. Similarly, positive nonverbal behaviour, such as open body posture and friendliness, led to lower pain and a higher placebo effect.²⁸

Another factor is the suggestions from the medical staff. A positive attitude and approach from the healthcare professionals can decrease analgesic use and reduce pain.²⁹ Sentences such as ‘This treatment is effective’ or ‘I think this will work for you’ are huge indicators of pain relief and a larger placebo effect.²⁹

Patient

Besides the previously discussed factors, patients’ approaches to the treatment are also contributors to the placebo effect. Two psychological phenomena can increase the placebo effect: conditioning and positive expectation.

Classical conditioning is a learning process in which the behaviour of an organism is dependent on another stimulus. The most famous example of this phenomenon is the Pavlovian dogs. In this experiment, the dogs learnt to associate an initially neutral stimulus, a bell ringing, with food. After a while, dogs started salivating at the sound of the bell, even without any foo present. Regarding patients, taking a medication regularly for a symptom and later receiving only a placebo can also reduce the particular symptom effect.³⁰

Positive expectations can also fuel the placebo effect. Suggestions such as ‘I will feel better with this medicine!’ or ‘I’ve read on the internet that it is very efficient’ are powerful beliefs. In a study, researchers divided participants affected by depression into three groups. The first group believed they received antidepressants, which were actually placebos, whilst the second group were informed that they got placebos, and the third group received no treatment. Results show that despite being placebos, the first group’s mood improved the most.³¹

Summary

The placebo effect is a well-known and powerful effect in medicine. This phenomenon, when a patient receives only an inactive substance and their symptoms start to ease, depends on many different factors. Macroenvironmental and microenvironmental factors, such as cultural beliefs and the surroundings, can induce a larger placebo effect. The characteristics of a drug, like colour, dosage, route of administration, branding and price, can create a bigger effect. The status, competence and nonverbal behaviour of healthcare professionals can improve patients' experience. The medical staff's suggestions can generate a placebo effect similar to the patients' expectations. These factors can all influence the placebo effect, but further research is needed to understand the underlying mechanism.