Clinical neuroscience and neurobiology of placebo and nocebo effects

Abstract

Placebo effects refer to changes in outcomes driven by learning and expectations, and they can shape responses to both pharmacologic and non-pharmacologic interventions. This chapter examines the neurobiology of placebo and nocebo effects, with an emphasis on findings from human research. Drawing primarily from controlled laboratory studies, we highlight neuroimaging and transcriptomic mechanisms that shed light on the formation of placebo and nocebo responses. In particular, this chapter highlights how expectations and contextual cues can enhance or diminish the efficacy of both pharmacologic and non-pharmacologic interventions. A focus is placed on the role of open-label, cost perception, branding, and treatment modality in modulating placebo effects. The neurochemical basis of placebo analgesia is also examined, with a central role identified for endogenous opioids, and additional contributions from the endocannabinoid and dopaminergic systems. Neuroimaging studies reveal brain networks and structural markers that predict placebo responsiveness. Genetic and transcriptomic insights add a molecular layer to this understanding as well as RNA expression profiles, helping to identify placebo responders. Finally, the chapter emphasizes the clinical relevance of nocebo effects, detailing how negative expectations and communication can worsen outcomes. We also discuss the clinical relevance of these mechanisms, particularly in rheumatology, where both functional and structural brain changes have been observed. It advocates for improved communication strategies, personalized consent, and ethical integration of placebo science to optimize pain care and clinical trial designs. Future research should focus on translating individual variability in placebo and nocebo effects into strategies for advancing personalized and precision medicine.

1. Introduction

Placebo hypoalgesia is widely recognized as a product of patients’ expectations, prior learning, suggestibility, verbal suggestions and interpersonal interactions between patients and clinicians (Colloca & Benedetti, 2005). This phenomenon represents one of the most robust psychological mechanisms capable of altering clinical outcomes. In recent years, placebo responses have gained increasing attention due to their profound impact on randomized clinical trials, sometimes complicating the assessment of drug efficacy (Neogi & Colloca, 2023; Tuttle et al., 2015).

Placebo effects can modulate outcomes across various medical conditions and interventions (Colloca & Barsky, 2020). Their influence has been extensively documented in both experimental and clinical pain contexts, including populations with chronic pain disorders such as idiopathic pain, neuropathic pain (Petersen et al., 2012; Petersen et al., 2014; Vase et al., 2014), low back pain (Carvalho et al., 2016; Hashmi et al., 2012), knee osteoarthritis (Tetreault et al., 2016), irritable bowel syndrome (Kaptchuk et al., 2008; Vase et al., 2003; Vase et al., 2005), and migraine (Kam-Hansen et al., 2014). Neuroimaging and pharmacological investigations have demonstrated that placebo hypoalgesia engages several endogenous systems, including opioids, endocannabinoids, oxytocin, vasopressin, and dopamine. These systems contribute to placebo effects based on the specific illness and neurobiological targets involved. This chapter focuses on the neurobiological, psychological, and contextual mechanisms shaping placebo and nocebo responses in pain treatment and nociception. Thus, for the sake of clarity we define expectancy, expectations, learning/conditioning and suggestibility.

Expectancy is a dynamic, predictive belief about the likelihood of a future outcome, such as symptom relief or pain worsening, often formed through prior experiences, social cues, or verbal suggestion (Colloca & Benedetti, 2006; Colloca & Miller, 2011a). Expectancies operate implicitly and are closely linked to placebo and nocebo responses.

Expectation is a specific belief or anticipation about what will happen in a given context. In the context of pain and placebo, expectation refers to a person’s belief that a treatment (real or inert) will produce pain relief or exacerbation. Our research shows that expectations are shaped by prior conditioning, observation, and suggestion, and they modulate endogenous pain regulatory mechanisms (Raghuraman et al., 2025; Schenk et al., 2017). It acts as a mediating cognitive process that links treatment context to symptom modulation.

Learning refers to the acquisition or modification of knowledge, behaviors, or physiological responses based on experience. In placebo research, learning mechanisms are foundational to how expectations are formed and reinforced. We emphasize that learning can occur through verbal suggestion, direct experience, or observational learning, each shaping the strength and persistence of placebo and nocebo effects (Colloca & Miller, 2011c).

In particular, conditioning is a form of learning where a neutral stimulus becomes capable of eliciting a response after being paired with an active one. In the placebo context, classical conditioning involves pairing an inert treatment (e.g., a saline injection) with an active analgesic (e.g., morphine), such that the inert treatment alone eventually produces analgesia. Information is used along with conditioning cues to inform study participants. Only in some instances, verbal information was omitted (Babel et al., 2017). We have shown that conditioning can induce robust and durable placebo responses, sometimes independent of conscious expectations (Colloca & Miller, 2011c).

Suggestibility refers to an individual’s propensity to accept and internalize verbal, visual, or contextual cues that influence their perceptions, behaviors, or physiological responses. In placebo research, suggestibility plays a central role in shaping the degree to which a person responds to therapeutic rituals, instructions, or social cues, often serving as a moderator of placebo or nocebo effects (Colloca & Miller, 2011b; Corsi & Colloca, 2017). It reflects a dispositional trait but can also be state-dependent.

2. Factors shaping placebo and drug response in pain treatment

Placebo mechanisms can influence outcomes across pharmacologic and non-pharmacologic interventions (Colloca, 2019). In some therapeutic contexts, particularly those involving integrative or complementary treatments like homeopathy, the clinical benefits may largely or entirely stem from placebo-related mechanisms driven by patient expectations (Colloca et al., 2013; Mathie et al., 2017; Vickers et al., 2018). Expectancy and placebo effects are known to significantly enhance the efficacy of pain treatments, including opioids such as morphine. In fact, open administration of treatment, where the patient is aware of receiving the intervention, has been shown to elicit substantially greater pain relief compared to hidden administration, regardless of whether the drug is opioid or non-opioid based (e.g., buprenorphine, tramadol, ketorolac, metamizole) (Colloca et al., 2004). Additionally, external factors such as the cost of treatment, with higher-priced medications producing larger placebo effects (Kam-Hansen et al., 2014; Waber et al., 2008), branding, generic versus name-brand labels (Faasse et al., 2016), and mode of administration, such as sham acupuncture vs oral placebo (Meissner et al., 2013), also significantly modulate placebo responsiveness. To effectively distinguish between drug and placebo responses and minimize confounding effects, the inclusion of a no-treatment control group (Vase et al., 2015) and tools to measure patient expectations (Colloca, 2017) are now considered essential in randomized clinical trials. Similarly, when designing laboratory-based experimental studies involving suggestions, expectations, and learning procedures (e.g., observational, operant, classical, or partial reinforcement conditioning), several factors must be considered. For instance, placebo conditions should be compared with appropriately matched control conditions. Including a natural history group is also crucial, as it helps differentiate true placebo effects from regression to the mean, bias, and other confounding influences (Colloca et al., 2008). In experimental pain research, parameters such as pain stimulus duration (phasic vs tonic) and modality (e.g., thermal, chemical) influence the occurrence and magnitude of placebo hypoalgesia (Vase et al., 2009). Moreover, personality traits have been investigated as factors influencing placebo effects. We have shown that those who are highly susceptible tend to report stronger placebo analgesia, even when controlling for expectation (Corsi & Colloca, 2017). Also, children with high magical thoughts have larger placebo effects (Krummenacher et al., 2014). Additionally, in a study by Whalley and Brooks investigating the effects of nitrous oxide on imaginative suggestibility and imagery vividness, findings indicated that nitrous oxide inhalation significantly increased both imaginative suggestibility and the vividness of mental imagery, independent of participants’ expectations about the drug’s effects.(Whalley & Brooks, 2009) Thus, suggestion-based components of placebo effects plausibly include susceptibility as an independent predictor.

While a single scale for personality traits has been deemed uninfluential (Kang et al., 2023), Wang et al. have shown that the Research Domain Criteria framework (Cuthbert & Insel, 2010) can help identify domains that are associated with placebo and nocebo effects. For instance, emotional distress is predictive of a smaller magnitude of placebo effects in both chronic pain and pain-free healthy controls. Participants suffering from chronic pain have higher reward seeking which is associated with higher expectations of benefit (Wang et al., 2022). Negative valence domains such as catastrophizing and fear of pain and emotional distress are associated with smaller placebo effects and larger nocebo effects suggestive of a mechanism of maladaptive cognitive appraisal affecting the ability to activate neurochemical bases of placebo analgesia.

3. Neurochemical basis of placebo analgesia

Over the past four decades, pain researchers have consistently demonstrated that the placebo effect is intimately linked with the brain’s endogenous opioid system. Using the opioid antagonist naloxone (Amanzio & Benedetti, 1999; Benedetti, 1996; Eippert, Bingel et al., 2009; Eippert, Finsterbusch et al., 2009; Levine et al., 1978) and receptor binding assays targeting μ-opioid receptors (Wager et al., 2007; Zubieta et al., 2005) pharmacological studies have confirmed the opioid system’s central role in placebo analgesia. Initial research by Levine and colleagues showed that the pain-relieving effects of placebo could be blocked by naloxone, implicating endogenous opioids as mediators of the response (Levine et al., 1978). Later studies extended this finding by showing that morphine-like analgesia could be reproduced via placebo when administered after a sequence of morphine treatments, and that this effect could again be blocked with naloxone (Amanzio & Benedetti, 1999; Benedetti et al., 2007). μ-opioid receptors (MOPRs), which are heavily expressed in brain regions such as the thalamus and periaqueductal gray (PAG), are known to regulate pain perception during opioid treatment (Oroszi & Goldman, 2004). While endogenous opioids play a foundational role, other neuromodulatory systems have also been implicated in placebo analgesia. The endocannabinoid system, for instance, has been shown to mediate non-opioid placebo effects. The administration of a CB1 receptor antagonist such as rimonabant reversed conditioned analgesic responses initially produced by ketorolac, indicating the capacity of placebo mechanisms to recruit cannabinoid pathways (Benedetti et al., 2011; Benedetti et al., 2013). The dopaminergic system has also been studied, although findings are more nuanced. PET imaging studies using radioligands like raclopride have linked dopamine release in the ventral basal ganglia, especially the nucleus accumbens, with placebo analgesia (Scott et al., 2008). However, dopamine antagonists and agonists have failed to consistently modulate placebo effects in both healthy individuals and patients with chronic neuropathic pain (Skyt et al., 2018; Wrobel et al., 2014). While these results suggest dopamine may not directly induce analgesia, its involvement in expectation formation and reward processing remains evident (Jarcho et al., 2016; Skyt et al., 2018). Interestingly, research in Parkinson’s disease has shown that pharmacological conditioning with dopamine agonists like apomorphine can elicit dopamine-like placebo effects. In vivo studies using single-neuron recordings and PET imaging have further confirmed dopamine contribution to placebo responsiveness in this context (Benedetti et al., 2004; Benedetti et al., 2009; de la Fuente-Fernandez et al., 2001; Lidstone et al., 2010; Mercado et al., 2006).

4. Enhancing placebo analgesia with neuropeptides vasopressin and oxytocin

Studies have demonstrated the potential to enhance placebo hypoalgesia through the administration of vasopressin and oxytocin agonists. Intranasal delivery of these agents has been shown to boost expectancy-induced analgesia, underscoring their modulatory role in social behavior and stress regulation (Colloca et al., 2016; Kessner et al., 2013). These neuropeptides exhibit sex-specific effects in both animal and human models. For instance, vasopressin has been associated with aggression in male animals and affiliative behaviors in females, mediated through actions in regions such as the septum, hypothalamus, and ventral pallidum (Bielsky et al., 2005; Donaldson & Young, 2008). In humans, vasopressin has been implicated in social bonding, emotional regulation, and sex-differentiated responses to social stimuli (Feng et al., 2015; Thompson et al., 2004, 2006). Pharmacokinetic studies confirm that vasopressin administered intranasally can reach the central nervous system and maintain stable cerebrospinal fluid concentrations for a sustained period (Born et al., 2002). A randomized, double-blind, parallel design study showed that vasopressin significantly enhanced verbally induced placebo effects in women, particularly those with lower cortisol levels and lower trait anxiety (Colloca et al., 2016). Notably, this effect was not observed in men, aligning with previous evidence of sex differences in vasopressin-mediated social behaviors. The implications of these findings suggest a potential pharmacological pathway to augment placebo analgesia, particularly through mechanisms related to social cognition and stress modulation. The receptor distribution patterns of vasopressin spanning cortical, limbic, and subcortical areas such as the cingulate cortex, amygdala, and nucleus accumbens support its role in shaping expectancy and reward-based learning (Freeman et al., 2014). These data reinforce the conceptual model that placebo effects are partly shaped by the individual’s interpretation of and response to meaningful social cues (Moerman & Jonas, 2002). Interestingly, it has been shown that oxytocin can increase responses to verbal suggestions such as in the context of hypnosis (Bryant & Hung, 2013; Bryant et al., 2012). It was postulated that oxytocin may increase modulation of analgesia operating through interpersonal trust and prestige, key conditions for inducing placebo responses in suggestible individuals, yet Skvortsova et al. provided support against the placebo-boosting effects of oxytocin on placebo and nocebo effects or their extinction processes at in a cohort of men (Skvortsova et al., 2020).

5. Neuroimaging predictors of placebo hypoalgesia

Efforts to identify neurobiological markers of placebo hypoalgesia have gained momentum as a strategy to advance personalized approaches to pain management. Brain imaging research has pointed to distinct structural and functional features that help distinguish individuals who respond to placebo from those who do not. Functional neuroimaging studies, in particular, have shown that placebo-induced pain relief is linked to alterations in activity and connectivity within several key regions, including the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), hypothalamus, amygdala, and periaqueductal gray (PAG) (Bingel et al., 2006; Craggs et al., 2008; Eippert, Bingel, et al., 2009; Wager et al., 2004). The DLPFC appears to initiate placebo analgesic responses, while the rACC, which connects to the PAG, is associated with downstream pain inhibition (Krummenacher et al., 2010; Lui et al., 2010). Placebo-induced reductions in pain-related brain activity have been documented in the thalamus, insula, and somatosensory cortices (Bingel et al., 2006; Eippert, Bingel et al., 2009; Lui et al., 2010; Wager et al., 2004). Notably, placebo hypoalgesia also modulates spinal cord activity, where fMRI studies show decreased dorsal horn activation on the side of pain stimulation, supporting the notion of top-down suppression of nociceptive signaling (Eippert, Finsterbusch et al., 2009). Resting-state connectivity studies have identified specific networks that predict placebo responsiveness. Connectivity between the DLPFC and midcingulate cortex, as well as between dorsomedial prefrontal and insular cortices, correlates with individuals’ likelihood to experience pain relief from placebo (Hashmi et al., 2012). Gray matter density in the DLPFC, insula, and nucleus accumbens has also been associated with higher levels of placebo analgesia and novelty seeking traits linked to reward sensitivity (Schweinhardt et al., 2009). Further, voxel-based morphometry and white matter anisotropy studies have shown that placebo responders exhibit greater structural integrity in pathways connecting pain modulation centers, including stronger fiber connections between the rACC, DLPFC, and PAG (Stein et al., 2012). Other findings suggest these brain-based predictors remain stable over time and across treatment conditions. One study found that limbic volume asymmetry, sensorimotor cortical thickness, and prefrontal-limbic connectivity patterns accurately distinguished placebo responders in chronic pain trials, even after washout periods. Psychological traits such as interoceptive awareness and openness were also linked to increased placebo sensitivity (Vachon-Presseau et al., 2018). Suggestibility has also been associated with distinctive neural profiles, including altered functional connectivity in frontal-parietal and salience networks, and heightened responsiveness in the insula and anterior cingulate cortex (Landry et al., 2017). Additionally, suggestibility is associated with structural and functional brain markers, such as increased connectivity in frontal executive networks, that could increase suggestibility after hypnotic induction (Hoeft et al., 2012). These findings suggest that brain imaging markers may help identify individuals who are more likely to benefit from placebo treatments in pain management (Fig. 1).

Fig. 1. Neural mechanisms involved in expectancy-driven modulation of pain signaling.

Prior therapeutic experiences, contextual treatment cues, interpersonal interactions, verbal suggestions, and observational learning shape expectations that engage brain regions responsible for regulating pain. Key areas include the dorsolateral prefrontal cortex (dlPFC), ventromedial prefrontal cortex (vmPFC), anterior insula (aINS), dorsal anterior cingulate cortex (dACC), primary somatosensory cortex (SI), secondary somatosensory cortex and dorsal posterior insula (SII/dpINS), medial thalamus (mThal), nucleus accumbens/ventral striatum (Nc/VS), periaqueductal gray (PAG), and rostral ventromedial medulla/spinal cord (RVM/Spinal Cord). Pain signaling is influenced by both ascending and descending pathways, with specific regions showing either increased (red) or decreased (blue) activation. Genetic and transcriptomic factors, including single nucleotide polymorphisms (SNPs) and RNA expression changes, may further contribute to individual differences in placebo responsiveness.

6. Genetic and transcriptomic insights into placebo hypoalgesia

In addition to insights from neuroimaging, research has increasingly focused on the genetic underpinnings of placebo hypoalgesia, aiming to identify biomarkers that predict individual variability in response to placebo treatments. Several candidate genes have been linked to the modulation of pain and emotional regulation systems, with particular emphasis on genes involved in the opioid and dopaminergic pathways. One of the most studied genetic markers is the A118G single-nucleotide polymorphism (SNP) in the opioid receptor mu subunit OPRM1 gene, which encodes the μ-opioid receptor. Individuals carrying the G allele have shown altered receptor binding and a diminished response to opioid analgesics (Oroszi & Goldman, 2004). In placebo studies, the G allele has been associated with reduced placebo analgesia, suggesting a biologically mediated mechanism involving endogenous opioids (Pecina & Zubieta, 2015; Zubieta et al., 2005). Other genes of interest include fatty acid amide hydrolase (FAAH) and (catechol-O-methyltransferase) COMT, which are involved in the endocannabinoid and catecholaminergic systems, respectively. Variants in the FAAH gene, such as C385A, affect anandamide degradation and may influence non-opioid placebo responses (Benedetti et al., 2011). The COMT Val158Met polymorphism impacts dopamine metabolism in the prefrontal cortex and has been linked to pain perception and placebo response variability, with Met/Met carriers often displaying greater placebo analgesia (Hall et al., 2012). These genetic factors contribute to the mechanistic understanding of placebo effects and provide insight into the role of gene-environment interactions. For instance, the impact of OPRM1 variants on placebo responsiveness has been shown to vary based on psychosocial context and prior learning (Colloca et al., 2019). Epigenetic modifications, such as DNA methylation patterns in stress- and reward-related genes, are also emerging as potential modulators of placebo-related phenotypes. Recent transcriptomic research has added an important layer of insight by exploring genome-wide gene expression profiles associated with placebo responsiveness. In a study of individuals with chronic temporomandibular disorder (TMD) and overlapping pain conditions, RNA sequencing identified 667 differentially expressed genes (DEGs) that were associated with placebo hypoalgesia (Colloca et al., 2024). Of these, 97 % were upregulated in individuals exhibiting greater placebo effects, and six genes, namely, CCDC85B, FBXL15, HAGHL, PI3, SELENOM, and TNFRSF4, showed significant and validated associations. Enrichment analyses of these DEGs highlighted biological processes such as RNA metabolism, SLIT/ROBO signaling, and ribonucleoprotein biogenesis, suggesting that transcriptomic regulation may play a critical role in modulating placebo responsiveness. These findings suggest a potential association between neuronal integrity, RNA-processing pathways, and an individual’s sensitivity to placebo-induced pain relief. As research in transcriptomics continues to expand, there is growing promise for uncovering stable molecular signatures that may guide the development of stratified clinical trials and more targeted therapeutic strategies. Future research should determine how genetic and transcriptomic predictors may be moderated by suggestibility, which could interact with genetic predispositions or epigenetic changes.

7. Placebo effects in osteoarthritis: Recent advances and clinical trial implications

Osteoarthritis (OA), a prevalent chronic pain condition, has emerged as a robust clinical model for studying placebo mechanisms. Evidence shows that individuals with OA often display high placebo responsiveness, particularly in trials assessing pain and functional outcomes (Neogi & Colloca, 2023). Patient expectations, prior treatment experiences, and the psychosocial context of care delivery influence this high responsiveness. Neuroimaging studies in OA populations have identified brain activity changes during placebo analgesia that mirror those observed in experimental pain settings. Functional connectivity between the DLPFC and other regions involved in emotion and pain regulation, such as the ACC, nucleus accumbens, and PAG, has been associated with stronger placebo responses (Neogi & Colloca, 2023). These neural correlates support the idea that expectation-driven modulation of pain processing occurs through top-down mechanisms that are conserved across both clinical and laboratory environments. In OA, contextual cues such as therapeutic rituals, provider behavior, and verbal suggestions are pivotal in enhancing placebo effects. This insight has led to the development of novel trial designs aimed at leveraging and accounting for placebo responses, including the use of open-label placebo, dose-extending placebo paradigms, and expectation-matched controls (Neogi & Colloca, 2023). Incorporating these insights into clinical practice and drug development could lead to more accurate assessments of treatment efficacy and improved patient outcomes. Rather than treating placebo as a nuisance variable, OA research demonstrates the value of understanding and ethically integrating placebo mechanisms into both therapeutic and methodological frameworks.

8. The neurobiology and clinical relevance of nocebo effects

While placebo effects highlight the potential for positive expectancy to improve outcomes, nocebo effects reveal how negative expectations can harmfully influence health. Nocebo responses are adverse outcomes to inert treatments that often occur in both experimental and clinical settings and may be triggered by verbal suggestions, prior negative experiences, social observation, and clinician-patient communication (Colloca, 2024). Neurobiologically, nocebo effects are linked to the activation of stress pathways involving the hypothalamic–pituitary–adrenal axis, increased cortisol release, and activity in brain regions such as the ACC, hippocampus, and PAG. Functional imaging studies have identified a neural circuitry, particularly involving the rACC–PAG–spina cord axis, associated with nocebo-induced hyperalgesia (Tinnermann et al., 2017). These effects are potentiated when patients perceive treatments as expensive, unsafe, or likely to produce side effects (Colloca, 2024). Behavioral mechanisms include classical and observational conditioning, where nocebo responses can generalize across pain modalities. Negative expectations can amplify sensory experiences and lead to clinical symptoms, such as increased pain, itch, and shortness of breath. Experimental findings suggest that even a single exposure or suggestion can induce robust nocebo hyperalgesia, and these responses can be resistant to extinction (Colloca et al. 2008, 2024). In clinical trials, nocebo effects significantly impact drug adherence, perceived efficacy, and dropout rates. Disclosures in informed consent documents, particularly about side effects, can inadvertently increase side effect reporting in placebo arms. Meta-analyses have documented high rates of adverse events in placebo groups across trials for depression, migraine, fibromyalgia, and statin therapy, emphasizing the clinical burden of nocebo responses (Amanzio et al., 2009; Rief et al., 2006). Emerging work on biosimilars illustrates how public perception and framing can contribute to reduced efficacy and treatment discontinuation. Patient-clinician communication, educational strategies, and framing of medication information play a crucial role in shaping outcomes and adherence (Colloca, 2024). Ethically, managing nocebo effects presents challenges. While clinicians must disclose side effect risks, such communication can inadvertently trigger nocebo responses. Innovative frameworks like “authorized concealment” and positive framing have been proposed to navigate this ethical dilemma. Personalizing informed consent processes based on patient preferences and susceptibility may offer a path forward for reducing unintended harm (Miller & Colloca, 2011). For example, it is critical to consider susceptibility levels when we frame informed consents as it has been shown that suggestibility correlates with nocebo effects (Stein et al., 2025) increasing vulnerability. Understanding and addressing nocebo effects is essential for enhancing therapeutic outcomes, maintaining trust, and improving adherence in clinical trials and practice.

9. Conclusions

Recent advances in the neuroscience of placebo and nocebo effects have highlighted how thoughts, emotions, and expectations can influence biology. Placebo hypoalgesia involves multiple systems, including endogenous opioids, cannabinoids, dopamine, oxytocin, and vasopressin. These systems work through specific brain circuits that regulate how we perceive and respond to pain. Over the past decade, imaging and pharmacology studies have outlined how these networks operate, while genetic and transcriptomic studies have started to explain why some people respond more strongly to placebo than others. Understanding these factors is not just of academic interest, it has real value for clinical trials and patient care. If we can identify who is more likely to respond to placebo based on brain activity or gene expression, we can improve trial designs, avoid unnecessary treatments, and better tailor therapies. Osteoarthritis research provides a good example of how this can work in practice. Patients with OA often respond well to placebo, and recent studies have shown how brain connectivity and contextual cues play a role in shaping this effect (Neogi & Colloca, 2023). Rather than dismissing this as noise, clinicians and researchers are starting to treat the placebo response as a meaningful part of treatment. New findings from transcriptomic studies add another layer to our understanding. In particular, gene expressions related to RNA metabolism and ribonucleoprotein pathways may help explain who is more likely to experience placebo pain relief (Colloca et al., 2024). As science continues to move toward multi-omics approaches, combining genetics, transcriptomics, and neuroimaging, we’ll get closer to using this information in routine care. Just as important is a growing awareness of nocebo effects. Negative expectations, especially around side effects, can lead to real harm. Learning how to communicate more effectively, structure consent forms thoughtfully, and reduce unnecessary anxiety could make treatments more effective and safer (Colloca, 2024). The future of placebo and nocebo research brings together neuroscience, psychology, and molecular biology. By doing so, we can better understand how meaning and context shape health and learn how to use those forces to help rather than harm.