Placebo Effect versus Nocebo Effect

In placebo-controlled clinical trials, a placebo refers to an inactive or inert substance or treatment that has no specific therapeutic effect on a person's health condition but is given or administered with the intention of maintaining the blinding of the study (i.e., the participants and/or investigators do not know if the active treatment or placebo is given). Placebo can be in the form of a pill (sugar pill), injection, or any other treatment method that resembles a real medical intervention. However, during the clinical trial, the placebo may have a therapeutic effect and have an impact on the outcome measures. 

The placebo effect is defined as a beneficial effect experienced by a clinical trial participant due to receiving a placebo (inactive substance) believing it to be an active treatment. The placebo effect has been discussed quite extensively in the literature. The Placebo Effect can come from psychological factors (the act of physically taking a pill may elicit a positive response) and neurobiological factors. (increased levels of “feel-good” neurotransmitters, like endorphins and dopamine). 

I posted several articles to discuss the placebo effect in placebo-controlled clinical trials. 

• Placebo Effect, Honest Placebo, Open-label Placebo
• Placebo effect and its impact on the overall treatment effect
• Placebo Effect and The Choice of Placebo

Now there is a term 'nocebo effect' (it is not a typo). In a newly released draft guidance by FDA "Psychedelic Drugs: Considerations for Clinical Investigations", the 'nocebo effect' is specifically mentioned: 

An AWC study uses a design that permits a valid comparison with a control to provide a quantitative assessment of a drug’s effect. In the context of psychedelic drug development, the use of a traditional placebo as a control can be problematic for assessing efficacy. Subjects receiving an active drug experience functional unblinding because of the intense perceptual disturbances that can develop; those who receive a placebo in the context of high expectancy may experience a nocebo effect (i.e., worsening symptoms as a result of knowing they did not get active treatment). However, an inactive control allows for better contextualization of any safety findings. Alternatives to an inert placebo (e.g., subperceptual doses of a psychedelic drug, other psychoactive drugs that mimic some aspects of the psychedelic experience) may be considered as well. 

The nocebo effect is defined as a negative effect experienced by a clinical trial participant due to receiving a placebo (inactive substance) believing it to be a harmful treatment. With the help of the ChatGPT, the following table compared the differences between the placebo effect and the nocebo effect. 

Aspect	Placebo Effect	Nocebo Effect
Definition	A positive response to an inactive treatment, often due to the person's belief in the treatment's effectiveness.	A negative response to a treatment, often due to the person's belief that the treatment will cause harm or have adverse effects.
Psychological Mechanisms	Expectation of improvement, conditioning, and the power of suggestion.	Expectation of harm, conditioning, and the power of suggestion.
Potential Chemical Mechanisms	Belief and expectation trigger the release of endorphins, dopamine, and other neurochemicals, leading to perceived improvement in symptoms.	Belief and expectation trigger the release of stress hormones (e.g., cortisol) and activate the brain’s pain pathways, leading to perceived worsening of symptoms.
Common Occurrences	In clinical trials, as a control group receiving an inactive treatment (e.g., sugar pill).	In clinical trials, when participants experience side effects despite receiving an inactive treatment, or when they're informed about potential side effects
Impact on Treatment	Can lead to an actual improvement in symptoms or a perceived improvement in well-being	Can cause or exacerbate symptoms, leading to a perceived worsening of health
Importance in Research	Helps determine the true efficacy of a treatment by comparing it to the placebo group	Highlights the importance of considering participants' expectations and beliefs when designing and interpreting clinical trials.
Clinical Use	Utilized in clinical trials as a control to assess the effectiveness of new treatments.	Considered a challenge in clinical trials as it can lead to false negative outcomes or increased reports of adverse effects.
Impact on Clinical Trial Outcome	Making the outcome measures in placebo group artificially better than what they should be. Underestimating the treatment difference. Lowering the statistical power.	Making the outcome measures in placebo group artificially worse than what they should be. On the efficacy side, overestimate the treatment difference. Increasing the statistical power.
Ethical Considerations	May be considered deceptive if participants are not informed about the possibility of receiving a placebo	Raises questions about the balance between informing participants of potential side effects and avoiding the creation of negative expectations
Examples	- Feeling relief from pain after taking a sugar pill, believing it to be a painkiller. - Experiencing reduced anxiety after receiving a fake treatment, thinking it is an anti-anxiety medication.	- Developing side effects (e.g., nausea, dizziness) after taking a harmless sugar pill, convinced it is a potent medication. - Perceiving worsening of symptoms despite receiving an inert substance, assuming it is a harmful treatment.

References: 

• Wartolowska, Colloca, and Amandzio (2023) Editorial: The nocebo effect and its consequences for clinical trials and clinical practice
• Colloca and Barsky (2020) Placebo and Nocebo Effects
• Colloca and Miller (2011) The nocebo effect and its relevance for clinical practice
• Ferreres, Banos, and Farre (2004)Nocebo effect: the other side of placebo.
• Mitsikostas (2009) Nocebo is the enemy, not placebo. A meta-analysis for the nocebo effect in headaches
• Amanzio, Corazzini, Vase, & Benedetti (2016). A systematic review of adverse events in placebo groups of anti-migraine clinical trials. 
• Wolters, Peerdeman, and Evers (2019) Placebo and Nocebo Effects Across Symptoms: From Pain to Fatigue, Dyspnea, Nausea, and Itch
• Hoffman, et al (2022) Vaccine hesitancy prospectively predicts nocebo side-effects following COVID-19 vaccination

Placebo effect and its impact on the overall treatment effect

RCTs (randomized, controlled clinical trials) are still the golden standard in clinical research. In RCTs, the most common control group is the Placebo. According to Wikipedia, a placebo is a sham substance or treatment which is designed to have no known therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In order to maintain the blinding (masking), the placebo group may include additional excipients similar to the experimental drug so that the placebo group will have the same characteristics as the experimental drug in shape, size, color, texture, weight, taste, smell,......

Placebo is assumed to have no therapeutic effect or detrimental effect. However, the assumption may not be true especially when the composition of the placebo is in consideration. 

In previous article "Placebo Effect, Honest Placebo, Open-label Placebo", we discussed the placebo effect in diseases in the CNS and psychological area or in diseases with subjective symptom measures. In the post "Placebo effect and the choice of placebo", we discussed the composition of the placebo and some 'placebo' may actually have therapeutic effect. For example, in clinical trials to test the therapeutic effects of IGIV, the  low concentration of albumin may be selected as the placebo control - the low concentration of albumin may actually have the therapeutic effect. In both of these cases, the placebo effect or potential therapeutic effect from the 'placebo' can cause the unexpected higher response rate in Placebo arm, therefore decrease the difference between the experimental drug and the placebo groups, result in the failed trials. 

On the flip side, the placebo can have detrimental effect. There are quite some recent discussions about the placebo having the detrimental effect - consequently, the overall treatment effect observed in the clinical trials may not be due to the therapeutic effect of the experimental drug, but due to the detrimental effect of the placebo group. In other words, the overall treatment effect can be  overestimated due to the detrimental effect of the placebo.

Here are some articles discussing the potential detrimental effects of the placebo in clinical trials to study the effects of fish oil in the prevention of the cardiovascular events. The REDUCT-IT trial was published in NEJM and was the pivotal trial resulting in the FDA and EMA's approval. According to the study protocol, "the matching placebo capsule is filled with light liquid paraffin and contains 0 mg of AMR101 (icosapent ethyl [ethyl-EPA])." The detrimental effect of the placebo may come from the paraffin. 

• Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy
• Amarin stands behind Vascepa after new analysis raises questions about its efficacy
• New analysis of Amarin’s Vascepa resurrects big questions about effectiveness
• New Biomarker Data Add to Concerns Over REDUCE-IT Trial
• Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies

When we conduct the placebo-controlled clinical trials, the composition of the placebo needs to be carefully considered and the potential therapeutic effect from the placebo needs to be minimized.