Why Do Some People Experience More Side Effects? The Answer May Lie in Personality
Have you ever taken a medication and experienced side effects before even knowing if it would actually work? A new study suggests the answer may lie less in the drug itself and more in how the brain forms expectations. The findings reveal how personality influences health and why some people suffer significantly more during treatment than others.
When a doctor prescribes a medication, the expectation is that it will provide benefits; however, some people report various side effects, even when taking a pill containing no active ingredients. This phenomenon, known as the nocebo effect, occurs when the expectation that something will cause harm contributes to the actual onset of symptoms.
Although this mechanism has been known for years, one question remained unanswered: why are some people far more susceptible to this effect than others? A new study indicates that part of the explanation may lie in a personality trait known as neuroticism, characterized by a heightened tendency toward anxiety, worry, insecurity, and emotional sensitivity.
People with high levels of neuroticism often interpret everyday situations more negatively. They tend to anticipate problems, worry more about the future, and pay closer attention to signals from their own bodies. This does not mean they are imagining symptoms or "making up illnesses." On the contrary, the physical sensations are real. What differs is how the brain perceives, interprets, and assigns meaning to the information coming from the body.
Researchers believe that this heightened vigilance can cause minor discomforts, which would normally go unnoticed, to be perceived as significant symptoms.
To investigate this hypothesis, scientists recruited 275 healthy volunteers. Before the experiment, all participants completed questionnaires assessing personality traits, specifically their level of neuroticism, and indicated which side effects they expected to experience during the study. They were then divided into groups.
Some received a pill containing a drug called sulpiride, while others received a placebo, a pill with no pharmacological effect.
Additionally, some volunteers were given information emphasizing the possibility of side effects, whereas others received more neutral instructions. Throughout the experiment, researchers carefully recorded any symptoms reported by participants both before and after the intervention.
The most interesting aspect of the study was that the scientists were able to distinguish the effects caused by the drug from those produced by the participants' expectations. Since the dose of sulpiride used typically does not cause noticeable symptoms after a single administration, any significant increase in complaints could be attributed primarily to how each individual interpreted the experience.
The results showed that individuals with higher levels of neuroticism began the study expecting to experience more side effects; subsequently, they were the ones who reported the most physical symptoms, regardless of whether they had received the actual drug or the placebo.
To better understand this relationship, researchers used statistical models capable of identifying how one variable influences another. The analyses showed that personality did not directly increase side effects. Instead, neuroticism led people to form more negative expectations about the treatment, and these expectations increased the likelihood of perceiving and reporting physical symptoms.
In other words, the brain appears to prime the body to expect an unpleasant experience. This state of anticipation heightens attention to bodily sensations, making minor discomforts far more noticeable and intense.
From a neuroscience perspective, this finding makes perfect sense. Studies show that brain regions involved in anticipation, such as the prefrontal cortex, the insula, the anterior cingulate cortex, and the amygdala, play a role in shaping expectations and interpreting bodily sensations.
When a person believes a treatment might cause problems, these areas can heighten the brain's vigilance regarding the body, altering the perception of pain, discomfort, nausea, or other physical sensations. This process is neither conscious nor voluntary; it is a biological response in which expectations directly influence the functioning of the brain circuits responsible for symptom perception.
The authors emphasize that the results do not imply that individuals with higher levels of neuroticism should be viewed as "more fragile" or that their symptoms are imaginary. On the contrary, the study demonstrates how psychological and biological factors interact to shape each individual's experience during medical treatment. The research also highlights the importance of communication between doctors and patients.
Clear, realistic, and balanced explanations regarding benefits and risks can reduce overly negative expectations and, consequently, mitigate the nocebo effect. In the future, understanding each patient's psychological profile could help healthcare professionals provide more personalized guidance, thereby improving both treatment adherence and quality of life.
READ MORE:
Trait Neuroticism and the Nocebo Effect: The Mediating Role of Side-Effect Expectations
Anton Fischer, Li-Ching Chuang, Nick Augustat, Pia von Blanckenburg, and Erik M. Mueller
Journal of Personality, 1-11, 14 February 2026
Abstract:
Neuroticism has not only been linked to heightened negative expectations and general somatic complaints but also to increased nocebo responses following medical treatments. Since side-effect expectations are considered a main driver of nocebo responses, we tested whether side-effect expectations mediate the neuroticism–nocebo relationship in a pharmacological study of healthy individuals. Participants (N = 275) provided self-reported neuroticism and pretreatment side-effect expectations before completing a 2 × 2 factorial design, receiving a placebo or the dopamine antagonist sulpiride (400 mg), which typically does not cause noticeable side effects after a single dose. Regardless of substance, participants received a substance vs. placebo expectation manipulation. We assessed self-reported somatic symptoms at baseline and during the intervention. Neuroticism correlated with baseline somatic symptoms and with preintervention side-effect expectations. Both neuroticism and side-effect expectations, but not the pharmacological treatment or the explicit expectation manipulation, were associated with nocebo responses, defined as the relative increase in somatic symptoms from before to after the intervention. Crucially, path analyses indicated preintervention expectations partially mediated the neuroticism-nocebo link. These results suggest that negative expectations associated with neuroticism contribute to nocebo responses, potentially creating a feedback loop whereby negative expectations heighten side effects, reinforcing negative expectations in future treatments.
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