What, Why and How Backfired? Nocebo Effect via a Analytical Method withTopic-Network of Qualitative Feedback on Mental Health Campaign from Audience with Depression

Section 1 | Nocebo Effect

Definition of Nocebo

Nocebo effect refers to negative outcomes that arise from psychological or contextual factors rather than any direct physiological action of a treatment. In essence, it is the “evil twin” of the placebo effect: whereas placebo effects produce beneficial outcomes due to positive expectations, nocebo effects produce adverse symptoms or worsened outcomes driven by negative expectations, conditioning, or other psychological processes (Colloc, 2024). Patients receiving inert placebos – or even active drugs – can experience side effects and symptom exacerbation purely because they anticipate them. These adverse nocebo responses can harm patients, undermining treatment adherence and therapeutic efficacy. The nocebo effect is therefore a critical phenomenon at the intersection of mind and body, illustrating how expectations and beliefs can manifest as real physiological and behavioral outcomes. In this report, we provide a comprehensive review of the nocebo effect, focusing on its psychological mechanisms (e.g. expectation, conditioning, attention, affect) and behavioral consequences (symptom reporting, adherence, treatment-seeking). We synthesize recent empirical findings from experimental studies and clinical contexts, discuss public health implications (such as vaccine hesitancy and health communications), and highlight practical strategies to minimize or manage nocebo effects.

Literature Review of Nocebo, Placebo and the Underlying Mechanism

History

Origin. The recognition that negative expectations can produce real symptoms has anecdotal roots in medicine and culture. An extreme example often cited is “voodoo death,” described by Walter Cannon in 1942, in which an individual’s intense belief in being cursed resulted in fatal physiological collapse Hale, 2021.

First Scientific Record. The formal study of nocebo phenomena, however, began in the mid-20th century. The term nocebo (Latin for “I shall harm,” as opposed to placebo – “I shall please”) was introduced by Walter P. Kennedy in 1961 to denote the harmful or unpleasant counterpart of the placebo response. Kennedy (1961) in that era observed that some research subjects experienced “toxic” reactions in placebo control groups, complicating clinical trials. As Kennedy mused in 1961, many a useful drug might have been prematurely discarded because a cluster of subjects – “nocebo reactors” – reported ill effects that were in fact psychologically induced (Kennedy, 1961). Earlier cases illustrated the power of expectation and conditioning, but systematic research remained limited.

Current Emphasize

A turning point came with the work of Barsky et al. (2002), who reviewed “nonspecific” medication side effects and explicitly framed them in terms of the nocebo phenomenon (Barsky, 2002). Barsky’s review highlighted key factors – patients’ expectations of adverse effects, learned associations from prior illnesses or treatments, negative affect (anxiety, depression) and somatization, and contextual cues – as drivers of nocebo-induced symptoms. This and other foundational work elevated the nocebo effect from a clinical curiosity to a subject of serious empirical inquiry. A very close documented report should be the operant/classical conditioning, such as food aversion, and adverse avoidance.

Over the last decade, research on nocebo effects has expanded engaging interdisciplinary fields. Neuroscientists have begun mapping the brain and neurochemical pathways of nocebo-induced pain and other symptoms. Psychologists have refined theories of expectation and learning to explain nocebo responses, and clinical trials researchers have quantified the real-world impact of nocebos on treatment outcomes.

Table 1. Key Mechanisms of Nocebo and Illustrative Evidence

The table illustrates the broad range of settings in which nocebo effects appear – from laboratory pain induction to drug trials and public health scenarios – and reinforce the main mechanisms at work. With this knowledge, we can better appreciate why intervention strategies focusing on expectation, learning, attention, and emotional reassurance are effective. It conceptually related studies (2011–2025) examining expectancy, cognitive modulation, and pain, with their key outcomes and connection to Tracey’s 2010 review. Each supports the notion that expectations and cognitive context have measurable neurobiological effects on pain, engaging brain circuits that can either suppress or amplify pain, consistent with Tracey’s framework.
Mechanism Description Example Evidence
Negative Expectation (Cognitive) Anticipating adverse outcomes leads to actual symptoms via expectancy. The patient’s conscious or unconscious belief in harm triggers physiological changes and symptom perception. Headache suggestion: Two-thirds of volunteers developed headaches after being told a mild (placebo) electrical current would cause headache. Drug efficacy reduced: Telling patients an analgesic may not work abolishes its pain relief, whereas positive expectation doubles its effect.
Classical Conditioning Past pairing of a neutral stimulus with a negative experience causes the neutral cue to elicit the negative response on its own. In nocebo, contextual cues or prior experiences with side effects condition the patient to respond adversely even in a new situation. Chemotherapy cues: ~33% of chemo patients develop nausea upon entering the hospital or seeing equipment associated with prior treatments. Placebo asthma attack: Asthmatics had bronchospasm when exposed to a sham stimulus (e.g., inhaling saline presented as allergen) due to association with past attacks.
Social/Observational Learning Seeing or hearing about others’ negative experiences induces similar expectations and responses in oneself. The nocebo effect can spread via social contagion and media. Modeling pain: Participants who watched a video of someone appearing to be in pain during a sham procedure later reported higher pain in the same sham procedure. Mass psychogenic illness: Communities have experienced waves of symptoms (headaches, dizziness) after a rumored toxin exposure, despite no toxin present.
Attentional Focus Intense focus on bodily sensations and looking for symptoms increases detection and amplification of those symptoms. Expectation directs attention to any sign of trouble, which heightens symptom reporting. Breathlessness focus: Volunteers told to monitor for “nasal obstruction” felt more breathing difficulty than those focusing on “free flowing breath”. Somatic hypervigilance: People with high somatic awareness report more side effects on placebo – e.g. noticing benign heartbeat changes and labeling them a “reaction”.
Affective/Axiety Response Negative emotions (anxiety, fear, distress) trigger physiological stress responses and hyperarousal that manifest as symptoms; they also bias interpretation of sensations as harmful. Personality traits like neuroticism and depression increase this effect. Anxiety hormone link: Negative suggestions of pain caused higher cortisol and ACTH levels (stress hormones) along with more pain; a benzodiazepine eliminated both the anxiety response and the nocebo pain. Trait predisposition: Patients high in neuroticism or with depressive outlooks report more side effects and often discontinue treatments early due to perceived adverse symptoms.

Trace (2010) focuses on how expectations and cognitive factors modulate pain perception. The core question is how placebo analgesia (pain relief from positive expectancy), nocebo hyperalgesia (pain worsening from negative expectancy), andcognitive reappraisal of pain are mediated in the brain. Pain is not a direct readout of nociceptive input – instead, it is a subjective experience shaped by context, emotions, and cognitive appraisals. Tracey frames pain modulation via expectancy within the concept of top-down brain mechanisms: the brain actively interprets and modulates incoming pain signals based on expectations, rather than passively receiving them. This perspective aligns with emerging ideas (like predictive coding) that the brain uses prior beliefs to filter sensory information. Understanding these mechanisms is not only scientifically important but also clinically relevant for harnessing placebo effects, minimizing nocebo effects, and improving analgesic trials.

Neural Circuits of Pain by Expectancy (schematic SD)

Panel (a) shows key brain regions involved in cognitive modulation of pain. During placebo analgesia (red pathways), frontal regions (like dorsolateral PFC and rACC) that encode context and expectancy send signals via the PAG and RVM to inhibit incoming pain signals at the spinal level, resulting in reduced pain. During nocebo hyperalgesia (blue pathways), a different set of circuits involving the hippocampus (Hipp) and other limbic regions (not shown in this simplified schematic) can enhance pain. The nucleus accumbens (NAc) is a convergence point: increased opioid and dopamine release in NAc accompanies placebo analgesia, whereas the opposite (deactivation) occurs with nocebo. Abbreviations: S1/S2 – primary/secondary somatosensory cortex (pain intensity processing); Ins – insula; dACC – dorsal anterior cingulate cortex; vmPFC – ventromedial prefrontal cortex; dlPFC – dorsolateral PFC.

Figure 1. Neural circuits of pain by expectancy

Nocebo Effect as the Opposite of Expectancy

The flip side of expectancy: the nocebo effect, where expecting more pain or negative outcomes actually increases pain. Just as positive beliefs engage analgesic systems, negative beliefs engage pain-facilitatory systems. During nocebo suggestions (e.g. warning a patient a stimulus will hurt more), subjects often experience greater pain and anxiety. Imaging studies show that anticipation of high pain (a nocebo-like state) activates regions associated with anxiety and threat: the hippocampus and parahippocampal cortex, the amygdala, and brainstem areas. Heightened activity in these regions correlates with increased pain perception under negative expectancy. In one fMRI experiment Tracey cites, subjects were given two levels of painful heat and two levels of expected pain; the results demonstrated that believing a stimulus will be extremely painful led to amplified pain responses in the “pain matrix” and in frontal/limbic circuits, compared to when they believed the same stimulus would be mild. This provides a clear neuroanatomical framework for nocebo: expectations of pain drive greater activation of pain-processing regions and anxiety circuits, thereby worsening pain.

A distinguishing neurochemical feature of nocebo hyperalgesia is the involvement of cholecystokinin (CCK), a neuropeptide that opposes opioids. Tracey notes that anticipatory anxiety triggers the release of CCK, which can blunt analgesia and even induce hyperalgesia. Indeed, studies have found that blocking CCK receptors (with antagonists) can potentiate placebo analgesia – essentially removing a “brake” on opioid analgesia, which underscores CCK’s role in nocebo responses. Behaviorally, heightened anxiety is central to nocebo. The review cites evidence that simply inducing anxiety can worsen pain via the hippocampal–brainstem network. A recent neuroimaging study showed that nocebo-induced pain increases were specifically associated with activation of the hippocampus (a region for contextual fear memory) and other regions tied to anticipatory anxiety, distinct from the opioid-driven circuit of placebo analgesia. In other words, negative expectations don’t just mirror placebo in reverse; they partially rely on different brain chemistry and circuitry – e.g. anxiety-related pathways and CCK, rather than endorphins. This is consistent with the idea that stress and anxiety can open the “pain gates” at both brain and spinal levels, undoing the pain inhibition . Tracey concludes that, much as placebo research teaches us how to relieve pain, nocebo research warns us of the powerful capacity of negative beliefs to exacerbate pain. Clinically, this means physicians must be careful with their words and the context they set, as to not inadvertently induce nocebo effects (for example, by emphasizing potential pain or side effects in a way that heightens patient anxiety).

Similar Mechanism Mental Phenomenon: Any Cognitive Involved Reappraisal.

In addition to placebo/nocebo expectancies that are externally induced (e.g. by instructions or context), Tracey’s review discusses the related concept of cognitive reappraisal – an internally driven strategy where one consciously alters the meaning of pain. Examples of reappraisal include encouraging oneself that “the pain is not harmful” or viewing pain in a detached, unemotional way. Such strategies can significantly reduce pain and its emotional distress. Tracey connects this to the placebo mechanism: both involve changing one’s interpretation of pain. In fact, a placebo suggestion might work by implicitly prompting a reappraisal of the situation – the person thinks of the stimulus as less threatening or believes they have relief on board. This “reinterpretation of the meaning of adverse events” is essentially cognitive reappraisal, and it engages overlapping neural circuitry with placebo analgesia.

Neuroimaging of cognitive reappraisal (from studies of emotional pain and physical pain) shows activation of the lateral prefrontal cortex (PFC), particularly the dorsolateral and ventrolateral PFC, and concomitant reduction of limbic activity (such as in the amygdala). Tracey cites studies where successful reappraisal of pain (for example, imagining the pain is under one’s control or is unimportant) activated the vlPFC and vmPFC and decreased the perceived “suffering” component of pain. One study mentioned showed that when subjects believed pain could be controlled or when they used detachment strategies, the ventrolateral PFC was engaged, which in turn was associated with reduced pain unpleasantness. The vlPFC likely helps generate an alternative interpretation that down-regulates the emotional impact of pain. Additionally, Tracey notes the orbitofrontal cortex (OFC) appears to be involved in evaluative and motivational aspects of pain modulation – e.g. tracking the “desire for relief”. A person’s desire to be rid of pain can amplify placebo effects (by enhancing expectation) but also complicate nocebo effects (conflict between wanting relief and expecting pain). The OFC’s role in reward/value might underlie how relief is valued and pursued in these contexts.

Placebo effect and Cognitive Reappraisal. Importantly, Tracey (2010) synthesizes that placebo analgesia and cognitive reappraisal share a overlap in neural substrates. Both rely on the PFC and ACC to exert top-down influence and both can dampen activity in the insula, thalamus, and other pain-responsive regions. This overlap suggests that placebo effects may essentially be tapping into our brain’s general cognitive regulation capacities. In support, she points out that individuals who are skilled at emotion regulation (reappraisal) tend to also show larger placebo analgesic responses. Moreover, experimental data (Petrovic et al. 2005; Zhang & Luo 2009) showed that a placebo treatment can not only reduce pain but also reduce negative emotional reactions to unpleasant images, implying a domain-general modulation of aversive experience. All this leads to Tracey’s proposal that cognitive reappraisal is likely one mechanism by which placebos exert their effects. When a doctor gives a patient a placebo (or even an active treatment with positive suggestion), the patient’s brain might reappraise the painful condition – “I’m being cared for, I will get better” – which then engages frontal control systems to actually blunt pain signals. This is a powerful convergence of psychology and biology: the mere reinterpretation of pain can cause the brain to release analgesic chemicals and alter neural transmission.

Building on this, a very recent meta-analysis by Monachesi et al. (2025) compared brain activation patterns from many fMRI studies of placebo analgesia and of instructed reappraisal of aversive stimuli. They found that both placebo and reappraisal reliably engage the DLPFC and lateral orbitofrontal cortex, underscoring a shared core network for top-down control. Interestingly, they noted a distinct lateralization: placebo analgesia activation were more right DLPFC-weighted, whereas reappraisal of emotion was more left DLPFC-weighted. This suggests that while there is overlap, the two processes are not identical – each may recruit a slightly different configuration of frontal-subcortical circuits (perhaps due to the more deliberate nature of reappraisal vs. the more belief/expectancy nature of placebo). Nonetheless, the convergence is far more notable than the divergence. These converging lines of evidence firmly establish cognitive reappraisal as one pathway by which expectancy shapes pain, fulfilling Tracey’s prediction that engaging the PFC’s regulatory abilities is central to placebo analgesia

In the realm of integrated mechanisms, Wager (2015) synthesizing a huge body of evidence on the neuroscience of placebo effects. They affirm that placebo effects (especially analgesia) are mediated by multiple brain systems – including the pain modulatory network (ACC, PFC, PAG), the reward circuitry (ventral striatum/NAc and dopaminergic pathways), and the emotion/anxiety circuitry (amygdala, insula). These authors provide a conceptual framework that placebo effects are essentially “brain–mind responses to context information” – exactly in line with Tracey’s description of context (social cues, verbal suggestions, treatment setting) influencing internal states (expectations, trust, anxiety). They present placebo analgesia as a multi-step process: interpretation of treatment context → activation of expectations and associated neurotransmitters → modulation of physiological systems (like endogenous opioids, cortisol, etc.) → changes in symptom experience.

Nocebo Effects and Anxiety Mechanisms. While placebo analgesia initially received more research attention, recent years have seen a surge in nocebo-focused studies. Blasini et al. (2017) conducted a comprehensive overview of nocebo effects on pain. They reiterated that nocebo pain responses are not merely the absence of placebo, but have an active mechanism: primarily, the induction of anticipatory anxiety and activation of stress pathways. On the hormonal side, nocebo suggestions (e.g. “this will hurt a lot”) can trigger cortisol release and HPA-axis upregulation – essentially a mild stress response that can make pain worse. This was actually demonstrated by Benedetti et al., who showed that pairing an inert treatment with negative suggestions elevated cortisol (a stress hormone) in humans. In the brain, as Tracey described, regions like the hippocampus and amygdala are instrumental. A 2018 brain imaging study by Schmid et al. showed that nocebo hyperalgesia uniquely activated the hippocampus, and connectivity analyses suggested the hippocampus influenced pain-processing regions under nocebo conditions, whereas placebo activated more prefrontal-to-PAG connectivity. This aligns well with the idea of an “anxiety/fear network” driving nocebo. Furthermore, nocebo effects have been linked to the neurotransmitter CCK: Colloca and colleagues found that administering a CCK antagonist (proglumide) can block or reduce nocebo hyperalgesia, essentially by preventing CCK from exerting its anxiety-enhancing, anti-opioid effects. This pharmacological approach mirrors Tracey’s note that CCK mediates anticipatory anxiety’s effect on pain. Personality research such as Morton (2009) also expanded: individuals high in trait anxiety or with a pessimistic outlook tend to show stronger nocebo responses (and weaker placebo responses), as shown in studies by Geers et al. and others. This underscores that the mechanisms Tracey described can vary between people – some are more prone to the dark side of expectancy.

Figure 2 Density Distribution on Self/Object Relate Topic’s

From a clinical perspective, these findings emphasize minimizing nocebo effects: for instance, in obtaining informed consent or discussing side effects, phrasing can be important (“some patients experience relief” vs. “it might not work and can have these side effects”). There is growing interest in interventions to reduce nocebo-related anxiety, such as relaxation techniques or partial information disclosure, though ethical aspects are complex. Nevertheless, the consensus from recent literature is clear: nocebo effects are real and biologically mediated by anxiety and pro-nociceptive signaling, and thus should be mitigated in clinical practice whenever possible. This is precisely the caution Tracey raised – that failing to address patients’ negative expectations can inadvertently magnify pain and undermine therapies.

Table 2. Related Studies and Their Relevance

Table 2 provides a structured summary of selected post-2010 studies/reviews that parallel Tracey (2010) in examining expectancy, reappraisal, and pain modulation, integrating neuroimaging and mechanistic insights. Each of these works builds upon and extends the key themes from Tracey’s review – namely, the critical role of brain mechanisms (opioid, dopamine, descending modulatory circuits) in placebo/nocebo, and the integration of cognitive processes (expectation, emotion regulation) with pain physiology.
Study Design & Participants Methodology Key Findings Relevance to Tracey (2010)
Bingel et al. (2011) Within-subject experiment in healthy adults; 3 conditions of drug expectancy (positive, none, negative) during opioid analgesia. fMRI during heat pain with open vs. hidden vs. nocebo instruction; measured brain activity, pain reports. Positive expectation doubled analgesic effect of remifentanil, while negative expectation (nocebo) abolished it. fMRI: positive expectancy activated descending pain-inhibitory network (rACC–PAG), negative expectancy activated hippocampus (anxiety circuit). Demonstrates causal impact of expectancy on pain and drug efficacy. Confirms Tracey’s claim that beliefs modulate pain via descending opioids (placebo) or via anxiety pathways (nocebo). Illustrates nocebo’s engagement of hippocampal fear mechanisms.
van der Meulen et al. (2017) Placebo analgesia fMRI study in 30 healthy volunteers; additionally assessed each person’s cognitive reappraisal ability. Behavioral reappraisal task (emotion regulation) + placebo analgesia paradigm with sham cream; fMRI of brain activity and connectivity (PPI). Individuals with higher reappraisal skill had larger placebo analgesia. DLPFC activity during placebo correlated with pain relief magnitude and with reappraisal scores. Placebo condition increased DLPFC–PAG connectivity. Direct evidence that cognitive reappraisal mechanisms contribute to placebo analgesia, as Tracey theorized. Identifies DLPFC as a key initiator of top-down analgesia (consistent with Tracey’s PFC emphasis) and shows expectancy-driven analgesia engages the PAG (endogenous opioids).
Büchel et al. (2014) Theoretical review (Perspective article). Synthesis of recent placebo research; proposes predictive coding model. Pain modulation by placebo is explained as Bayesian brain predictions damping nociceptive input. The strength (precision) of expectation determines placebo response magnitude. Opioid and dopamine systems are posited to encode expectation value/precision. Provides a computational framework supporting Tracey’s view that the brain actively shapes pain based on expectations. Extends her ideas by formalizing how expectations (priors) and prediction errors could drive the placebo/nocebo effects. Emphasizes same neurochemicals (opioids, dopamine) highlighted by Tracey, but in predictive coding terms.
Wager & Atlas (2015) Comprehensive narrative review of placebo neuroscience and clinical data. Meta-analysis of neuroimaging findings; conceptual framework linking context, brain, and health outcomes. Placebo effects are brain–mind responses to context, not just “fake” effects. Multiple brain systems involved: PFC/ACC–PAG opioidergic network, NAc dopamine/reward pathways, and reduced limbic/insular responses. Placebo and drug effects share common pathways (e.g. placebo engages same opioid receptors as analgesic drugs). Social context (suggestion, doctor-patient cues) drives internal expectancies and emotions (see Fig. 1) which modulate symptom outcomes. Reinforces Tracey’s main points with extensive evidence: confirms involvement of descending opioids, dopamine, and cognitive-evaluative regions in placebo analgesia. Strengthens the argument that clinician context and patient expectations are integral to treatment outcomes (Tracey’s therapeutic implications). Also echoes her note that without frontal functioning (as in Alzheimer’s) placebo responses wane. Provides a unifying mind-brain model very consistent with Tracey’s perspective.
Monachesi et al. (2025) Coordinate-based meta-analysis of fMRI studies (Placebo analgesia studies vs. Cognitive reappraisal studies); included data from dozens of experiments, healthy participants. Activation Likelihood Estimation (ALE) meta-analysis to find brain regions consistently activated by placebo analgesia and by reappraisal; direct comparison of the two. Both placebo analgesia and reappraisal reliably activate dorsolateral PFC and midline frontal regions (overlap in top-down control network). However, placebo expectations showed greater right DLPFC lateralization, whereas reappraising emotions/pain showed more left DLPFC activation. Suggests a common core mechanism with subtle lateralized differences. Validates Tracey’s assertion of overlapping neural substrates between placebo and reappraisal (PFC, ACC involvement in both). The shared recruitment of DLPFC underscores cognitive control as a fundamental mechanism in expectation-driven pain relief. The lateralization difference provides nuance to Tracey’s idea, indicating that while similar, the precise neural implementation of an instructed cognitive strategy versus an induced belief may differ slightly.

Conclusion

We now have compelling evidence that the placebo effect is not an oddity or trick of the mind, but rather a manifestation of the brain’s capacity to regulate physiology based on expectations – a capacity rooted in identifiable neural systems. Placebo analgesia emerges from the concerted action of the prefrontal cortex, cingulate, and brainstem opioid systems, often hand-in-hand with dopamine-driven reward/value signals (Watson, 2012). Nocebo effects, conversely, tap into the brain’s harm-alarm systems – the hippocampus, amygdala, CCK, and stress hormones – producing very real increases in pain and other symptoms. Cognitive reappraisal, whether invoked deliberately or as a byproduct of placebo suggestion, appears to be a common language through which the mind speaks to the body’s pain pathways (Vandermeulen, 2017). These findings collectively validate Tracey’s portrayal of pain as a multidimensional experience that the brain actively constructs from both sensory and psychological inputs.