Doctors are learning to harness placebo power while being honest with patients

The Opinion ar cle by Poulter et al. (1) provides an important conceptual anchor for this Topic by addressing misunderstandings surrounding contextual effects in musculoskeletal pain. The authors highlight four key sources of tension between clinicians and researchers: terminology, clinical relevance, beliefs and expecta ons, and sta s cal es ma on methods. They argue that contextual factors are components of all therapeu c encounters, and call for clearer defini ons, improved repor ng prac ces, and construc ve interdisciplinary dialogue. Their reflec ons suggest that these phenomena should not be viewed as unusual problems to eliminate, but as integral elements of clinical care that require though ul integra on and rigorous inves ga on. This conceptual groundwork sets the stage for the empirical contribu ons that follow.A central transla onal focus of this research topic concerns open-label placebos (OLPs), which aim to harness placebo effects while maintaining transparency. Paschke-Dahl and Klinger (2) inves gated OLPs in fibromyalgia pa ents undergoing gluten challenge in a 2×2 design (gluten vs. sham gluten; neutral vs. posi ve OLP instruc ons). Posi ve OPL instruc ons were associated with decreases in pain over me, while neutral OPL instruc ons were associated with increases. Gluten itself showed no significant effect on pain or indiges on, and a strong correla on was observed between expected and actual pain relief. These findings highlight the relevance of expecta on-related processes in symptom modula on within this context. Two secondary analyses further suggest that responsiveness to OLPs may depend on the psychological profile of par cipants individual characteris cs. Frisaldi et al. (3) report that in medical students, OLP intake (compared to no interven on) was associated with improved test performance among those with higher test anxiety and among students adop ng beneficial learning strategies. Similarly, Caliskan et al. (4) found that in chronic low back pain pa ents, lower baseline pain catastrophizing predicted objec ve improvement in spinal mo on velocity in the OLP plus treatment-as-usual group, whereas those with higher catastrophizing did not show this benefit. Together, these studies underscore the importance of examining psychological moderators when considering OLP implementa on. Complemen ng these findings, Nascimento et al. (5) explored pa ents' a tudes toward OLP implementa on through qualita ve focus groups involving individuals with chronic back pain, chronic migraine, or chemotherapy-induced nausea/emesis. Iden fied themes reflected both interest and ambivalence of using OLPs. To the extent pa ents were willing to consider OLPs trust and clinician credibility were prerequisites. These findings suggest that successful clinical transla on depends not only on demonstra ng efficacy, but also on how OLPs are communicated and embedded within therapeu c rela onships, consist with prior work on the importance of perceived warmth and competence from a healthcare provider (6).Just as posi ve expecta ons can enhance outcomes, nega ve expecta ons can amplify adverse experiences. Addressing this challenge, Asan et al. (7) present a preregistered, double-blind randomized controlled clinical trial protocol designed to test whether op mized communica on during informed consent for lumbar puncture can reduce headache-related impairment compared to standard communica on. The protocol is mo vated by evidence that risk disclosure can increase reports of side effects by enhancing nega ve expecta ons. Importantly, the study aims to mi gate poten al nocebo-associated effects without withholding informa on cri cal to pa ents, thereby aligning ethical transparency with symptom preven on. This contribu on exemplifies the prac cal and ethical complexi es at the heart of placebo and nocebo transla on: improving outcomes while preserving pa ent autonomy and trust.Clinical applica on of placebos also unfolds within legal and regulatory frameworks. Richard et al. in "A Dose of Doubt" report qualita ve findings from Swiss primary care physicians, who described using impure placebos in prac ce and emphasized risk-benefit evalua on as a primary jus fica on (8). Knowledge of regula ons varied, and par cipants generally did not perceive a strong need for addi onal formal regula on. In a complementary legal analysis in "Noble Humbug?", Richard et al. examined binding and non-binding laws across France, Germany, Switzerland, the UK, and the USA (9). They report that placebo use is o en indirectly regulated through informed consent statutes rather than placebo-specific legisla on, and that professional guidelines, such as those from the American Medical Associa on, outline condi ons under which placebo use may be permissible. The authors emphasize that unauthorized placebo use may carry legal implica ons, highligh ng the importance of clear standards and transparent communica on. The emergence of OLP is discussed as a development with poten al to address ethical tensions while preserving clinical flexibility.The importance of therapeu c context is further reflected in the retrospec ve study by Vora et al (10), examining outcomes of an interdisciplinary func onal restora on program for adults with highimpact chronic pain and clinically elevated catastrophizing. Par cipants demonstrated sta s cally significant improvements in func onal performance, sa sfac on with func on, pain ra ngs, mood, and catastrophizing following program comple on. The authors describe the program's emphasis on collabora on, valida on, trust, self-efficacy, and posi ve expecta ons. These findings align with broader themes in this Topic regarding the clinical relevance of enriched therapeu c encounters.The Perspec ve by Furmark et al. (11) revisits debates surrounding SSRI and placebo effects in social anxiety disorder. The authors report findings from neuroimaging studies in which SSRI and placebo responders showed equal reduc ons in amygdala ac vity alongside comparable symptom improvements. They also discuss evidence from expecta on manipula on and open-hidden administra on designs sugges ng that overt SSRI administra on yielded greater symptom reduc on than covert administra on. Furthermore, serotonin transporter occupancy did not correlate with symptom improvement, underscoring the complexity of pharmacological and expectancy-related mechanisms. These findings challenge the idea that SSRIs are effec ve solely due to their serotonergic ac vity and underscore the importance of the interplay between neurobiology and psychological expecta on in treatment response. Extending expectancy research into affect regula on, Schäfer and Rief experimentally inves gated differently framed decep ve placebo instruc ons (antecedent-focused vs. response-modula ng) in healthy volunteers following shame induc on (12). Both placebo framings influenced changes in state shame, rumina on, and cogni ve flexibility rela ve to control. Personality traits, including experien al avoidance and emo onal control, modulated responses in the antecedent-focused condi on. This work expands the scope of placebo research beyond symptom relief to cogni ve and affec ve processes.Finally, Faria et al. explored physicians' perspec ves on the integra on of genera ve ar ficial intelligence into healthcare (13). A majority of surveyed physicians had used genAI tools, primarily for administra ve tasks, and many believed such tools could improve pa ent care or increase me for direct interac on. However, responses were more divided regarding empathy and placebo-related processes, and over half agreed that genAI-human interac ons could increase pa ent anxiety. As digital tools increasingly shape clinical workflows, these findings highlight the importance of examining how technological media on may interact with rela onal and expecta on-related dimensions of care.Across diverse methodologies and clinical contexts, the contribu ons in this Research topic converge on a shared message: placebo and nocebo effects are not topics of mere academic curiosity, but clinically relevant processes embedded within communica on, expecta ons, interpersonal dynamics, and healthcare systems. They have both direct and indirect roles in pa ent outcomes. The studies presented here advance understanding of when and for whom OLP approaches may be beneficial, how communica on strategies might reduce nocebo-associated harms, how legal frameworks shape prac ce, the poten al benefits and consequences of AI integra on with pa ent care in these domains, and how neurobiological and psychological mechanisms interact. Bridging experimental insight and clinical implementa on remains a complex task. Yet, by integra ng conceptual clarifica on, empirical analyses, qualita ve perspec ves, communica on protocols, and legal scholarship, this collec on takes meaningful steps toward op mizing the therapeu c poten al of placebo and nocebo effects in clinical se ngs, leveraging beneficial expectancy effects while mi ga ng unintended harms.