Placebo and Nocebo – Illuminating Medicine’s Mysteries Through the Power of Expectations

What Are Placebo and Nocebo?

Placebois the effect of patients' positive expectations about their health, whereas nocebo is the effect of negative expectations. Placebo produces beneficial outcomes, while nocebo produces harmful outcomes. These effects occur in many clinical contexts, including treatment with an active agent or placebo, clinical research, provision of information about treatments, and public health campaigns.

The placebo effectis a positive effect produced by a pharmacologically inactive drug formulation or positive suggestion. The word is Latin in origin and means to please.

The nocebo effectmeans that a person's negative expectations about a situation adversely affect them. For example, believing a drug will cause adverse effects may produce more effects than expected even with a pharmacologically inactive drug, or a negative suggestion may adversely affect the person. To illustrate quickly, many people with gas, bloating, and irregular bowel movements now eliminate food groups to control their symptoms. Two well-known examples are lactose and gluten. Even with lactose intolerance, for example, a person is considered able to tolerate up to 12 grams daily. In a study of lactose-related nocebo effects, almost half of participants without actual lactose intolerance reacted to dairy as though they had it. This was thought to result from nocebo, negative expectations adversely affecting the person.

Placebo and Nocebo in Different Responses to the Same Treatments

Variation in treatment responses and patients' experiences of symptoms is partly related to placebo and nocebo effects. Determining the frequency and intensity of placebo effects in clinical practice is difficult, and effects vary widely in experimental settings. Pain or psychiatric disorder treatments have shown placebo responses similar to active treatment responses in many double-blind studies (see placebo as a treatment relieves cancer-related fatigue).

In clinical trials , a quarter of placebo recipients discontinue treatment because of adverse effects. This suggests nocebo may contribute to discontinuation or nonadherence to active treatment.

What Are the Neurobiological Mechanisms of Placebo and Nocebo?

Placebo effects have been associated with release of substances involved in pain relief and well-being, such as endogenous opioids, endocannabinoids, dopamine, oxytocin, and vasopressin. Each substance's effects are specific to the target system, such as pain, movement, or immunity, and diseases such as arthritis or Parkinson's. Dopamine release, for example, contributes to placebo effects in Parkinson's treatment but not in chronic or acute pain.

Exacerbation of experimentally induced pain through verbal suggestion—a nocebo effect involving verbal or written information about clinical worsening or potential adverse effects—has been shown to be mediated by cholecystokinin, a neuropeptide. Cholecystokinin is a hormone involved in fat and protein digestion, and neuropeptides are molecules neurons use for communication. The effect is blocked by proglumide, a mixed cholecystokinin type A and type B receptor antagonist. Such verbally induced hyperalgesia, increased pain sensitivity, is associated with increased hypothalamic–pituitary–adrenal activity in healthy people. Diazepam, a benzodiazepine derivative, antagonizes both hyperalgesia and this hyperactivity, suggesting a role in nocebo effects for anxiety .

Genetic influences on placebo and nocebo effects have been linked to dopamine, opioid, and endocannabinoid gene mutations (haplotypes of single-nucleotide polymorphisms).

Expectations, Verbal Suggestions, and Framing Effects

The molecular events and neural network changes underlying placebo and nocebo effects are mediated by expectations or anticipated future outcomes . When consciously accessible, these are called expectancies, which can be measured and are influenced by changes in perception and cognition. They can be acquired through previous drug effects and adverse effects, such as analgesia after medication, verbal instructions that a drug will reduce pain, or social observation of relief in another person taking it. However, some expectations and placebo/nocebo effects are not consciously accessible. An immunosuppressive response can, for example, be conditioned in kidney transplant patients by administering a neutral stimulus previously paired with an immunosuppressive agent. The neutral stimulus alone reduces T-cell proliferation.

In clinical settings, expectations are influenced by how a drug is described or “framed,” a cognitive bias in which choices depend on positive or negative presentation. After surgery, for example, morphine administered with the instruction “the treatment you are about to receive is powerful in relieving your pain” provided significantly greater benefit than hidden administration, when patients did not know its timing. Directly suggesting adverse effects may also become self-fulfilling. For example, cardiac disease and hypertension patients taking atenolol were studied for sexual adverse effects and erectile dysfunction incidence—the number of new cases of a disease in a population over a given period—and these potential adverse effects occurred in %31 of specifically informed patients versus %16 of patients not told about them. In addition, prostate hypertrophy and asthma studies found adverse effects more frequently in informed than uninformed patients.

Learning Mechanisms in Placebo and Nocebo Effects

Learning and classical conditioning contribute to both effects. Many clinical situations show that neutral stimuli previously associated through classical conditioning with beneficial or adverse drug effects later evoke benefit or adverse effects when encountered without the active drug.

For example, environmental or taste cues repeatedly paired with morphine can later produce analgesia when paired with placebo instead. Psoriasis patients receiving reduced glucocorticoid doses interspersed with placebo, called dose-extending placebo, had relapse rates similar to full-dose recipients. A control group with the same gradual glucocorticoid taper but no interspersed placebo had a relapse rate three times higher than the dose-extending placebo group. Similar conditioned effects have been reported in chronic insomnia treatment and amphetamine treatment in children with attention deficit hyperactivity disorder.

Previous therapeutic experience and learning also guide nocebo effects. Of women receiving breast cancer chemotherapy, % 30 experience anticipated nausea when exposed to neutral environmental cues previously associated with traveling to hospital, meeting medical staff, or entering an infusion-like room. This is called anticipatory nausea . Newborns cry after repeated blood draws and later show pain behaviors as soon as alcohol cleansing precedes a draw. Showing an asthma patient an allergen in a sealed container can trigger an attack. A liquid without beneficial biological effects, given with an active drug having a distinctive taste and noticeable adverse effects, such as a tricyclic antidepressant, may evoke those effects when given with placebo. Visual cues, such as lights and images paired with experimentally induced pain, can later trigger pain on their own.

Noninfectious Contagious Conditions…

Learning About Others' Experiences can produce placebo and nocebo effects. Observing pain relief in someone else produces placebo effects similar in magnitude to analgesia induced by previous firsthand therapy. Experimental evidence shows social connection and modeling can cause adverse effects. Witnessing someone report placebo adverse effects, pain from an inert, chemically inactive ointment, or effects of breathing air described as “potentially toxic/harmful” causes adverse effects in participants exposed to the same placebo, ointment, or room air.

In mass communication and media reports, information obtained online, and direct exposure to other people with symptomspromote nocebo responses. Reported adverse effect rates for cholesterol-lowering statins, for example, correlate with the intensity of negative statin coverage. In a recent example, after negative press and television stories about harmful changes to a thyroid drug formulation, reported adverse effects increased 2000-fold , limited to the specific symptoms mentioned in the publicity.

Effects of Placebo and Nocebo on Research and Clinical Practice

Identifying people more likely to experience placebo and nocebo effects may be useful at treatment initiation.

Some associated characteristics are known, but future studies may provide better evidence. Optimism and suggestibility donotappear closely related to placebo susceptibility. Among active drug recipients, some evidence suggests nocebo effects are more likely in anxious people, those with medically unexplained symptom histories, or greater psychological distress. Evidence concerning sex differences is inconclusive. Imaging, polygenic risk, genome -wide association and twin studies may clarify how brain mechanisms and inheritance contribute to biological changes underlying placebo and nocebo effects.

Trust and Communication Relieve Symptoms

Communication Between Patient and Clinicianaffects the likelihood of placebo effects and reporting adverse effects of active drugs and placebos. Trust in the doctor and a positive relationship with open communication have been shown to relieve symptoms. Patients with colds who perceive their doctor as empathetic report less severe and shorter symptoms than those who do not. Patients perceiving empathy also have lower objective measures, such as interleukin-8 and neutrophil counts, of inflammation . Doctors' positive expectations also contribute to placebo effects. A small study comparing narcotic analgesics, strong painkillers, with placebo after tooth extraction found greater pain reduction in patients whose doctor knew they received the analgesic.

Describe Treatments Realistically but Positively…

One way to use placebo effects to improve therapeutic outcomes is to describe treatments realistically but positively. Increasing expectations of benefit has been shown to improve responses to morphine, diazepam, deep brain stimulation, intravenous remifentanil, topical lidocaine, complementary and integrative approaches, such as acupuncture, and even surgery.

Laboratory, genetic, and other research assesses placebo and nocebo effects with appropriate control groups, discovers underlying molecular and genetic mechanisms, and investigates drivers of individual susceptibility to better understand them.

In clinical practice, placebo and nocebo mechanisms are learned and explained to patients as a basis for encouraging recovery. Positive associations are preferred, and negative links between interventions and contextual factors minimized. Interventions are delivered in a positive context, and coping strategies suggested. Patients are encouraged to describe prior positive or negative intervention experiences. Realistic possible effects are presented to avoid discrepancies between expectations and reality. Expectations about treatment and outcomes are recorded as part of the medical history. Patients are encouraged to discuss aligning expectations with anticipated therapeutic outcomes. Adverse effect information is framed to minimize nocebo effects. Communication strategies reduce nonadherence or discontinuation. Educational strategies, such as video clips of positive treatment experiences, improve outcomes.

In clinical trials, patients are initially asked how much improvement they expect from active treatment and whether they believe they received it. Language presenting the intervention's benefit–risk profile is standardized, as are therapeutic visit duration and number across study sites. Framing strategies for adverse effect information are standardized, along with questions and structured checklists used to collect adverse effect data.

Conclusion

Placebo and nocebo effects are powerful, pervasive, and common in clinical practice. Neurobiological mechanisms, treatment information, expectations, previous drug or procedure experiences, and the therapeutic setting can all produce these effects. Strategies promoting placebo and preventing nocebo may improve therapeutic outcomes and minimize unwanted symptom exacerbation in clinical practice and trials.