Large-scale brain analysis reveals multiple pathways to placebo effects on pain.

[23.07.2026] International consortium combines brain imaging data from 16 studies and 409 participants to show that different placebo induction methods engage distinct neural mechanisms

Essen, Germany, and Hanover, NH, USA – Scientists have long known that expectations can reduce pain. What remained unclear was whether different ways of generating placebo effects rely on the same biological mechanisms. A new study published in Nature Communications now provides compelling evidence that they do not.

Researchers from the Collaborative Research Center/Transregio 289 Treatment Expectation (www.treatment-expectation.de/en) at University Medicine Essen, together with the international Placebo Imaging Consortium, analyzed brain imaging data from 409 participants in 16 studies on placebo-related pain relief. Their findings reveal that placebo pain relief induced by verbal suggestion alone and placebo analgesia strengthened by learning from experience rely on overlapping but partly distinct neural pathways, demonstrating that there is no single neurobiological mechanism underlying placebo pain relief.

The study is one of the largest neuroimaging investigations of placebo analgesia to date and represents a unique international effort to combine participant-level data from laboratories across Europe and North America. By pooling individual brain imaging datasets rather than relying on published summary results, the researchers were able to uncover patterns that individual studies cannot.


Different routes to the placebo effect

Placebo effects rely on an individual’s expectation of pain relief, which can be shaped in two different ways. In one approach, participants receive verbal information suggesting that a treatment will reduce pain. In the other, verbal suggestions are combined with conditioning, allowing participants to directly experience pain relief during a learning phase.

Previous studies had shown that prior treatment experiences can strengthen placebo analgesia. However, it remained unclear whether this stronger effect emerged through the same biological mechanisms or through distinct neural pathways.

To answer this question, the research team compared brain responses across studies using either verbal instructions alone or verbal instructions combined with hands-on experience (conditioning). While both approaches activated common placebo-related networks, the analysis revealed important differences.

Both methods increased activity in brain regions associated with cognitive control and attention while reducing activity in areas involved in pain processing. However, conditioning additionally engaged brain systems linked to context representation and pain modulation and produced stronger reductions in activity within sensory and insular regions involved in processing painful input. Conditioning was also associated with stronger modulation of established brain markers of nociceptive pain processing.

Together, the findings suggest that placebo analgesia can emerge through multiple biological routes rather than a single unified mechanism.

Learning from heterogeneity

For many years, variability across placebo studies has posed a challenge for researchers seeking to identify consistent brain mechanisms. The new study suggests that part of this variability reflects meaningful biological differences rather than experimental noise.

"Because placebo studies can differ widely in their experimental details, it has been difficult to identify the brain processes they have in common.," says Prof. Tamas Spisak, first author of the study and researcher at University Medicine Essen. "By combining participant-level data from many laboratories around the world, we were able to show that some of this heterogeneity is actually informative. Different placebo induction methods leave distinct signatures in the brain, and large collaborative datasets allow us to uncover these patterns."

The findings were made possible through the Placebo Imaging Consortium, an international collaboration established to share neuroimaging data and expertise across laboratories studying placebo effects.

"This study highlights the power of team science," says Prof. Tor D. Wager, co-leader of the Placebo Imaging Consortium and professor at Dartmouth College, USA. "Questions about the mechanisms of placebo effects are often too complex to be answered by individual laboratories working alone. By bringing together researchers and datasets from across the world, we were able to address a longstanding question in the field and see how experience that reinforces prior suggestions plays a critical role in making placebo effects powerful."

Implications for medicine

Placebo effects contribute substantially to treatment outcomes across many areas of medicine, particularly in pain management. Understanding how different placebo

mechanisms operate could help researchers and clinicians develop more targeted approaches to harness beneficial treatment expectations and learning processes.

"For decades, placebo research has shown that expectations can influence pain. What has remained unclear is whether different ways of creating those expectations rely on the same underlying biology," says Prof. Ulrike Bingel, neurologist, spokesperson of CRC/TRR 289 Treatment Expectation, and senior author of the study. "Our findings suggest that they do not. By identifying distinct neural pathways, we move closer to understanding which mechanisms are engaged in different clinical situations. In the future, this knowledge may help us develop more targeted strategies to support patients' own pain-relieving systems and optimize treatment outcomes."

The researchers emphasize that placebo effects are not simply imagined improvements. Rather, they are accompanied by measurable changes in brain activity that alter how pain is processed and experienced.

The findings not only advance understanding of one of medicine's most fascinating phenomena but also demonstrate how large-scale international collaborations can reveal fundamental biological mechanisms that remain hidden in smaller studies.


About the study

Title: Meta-analytic evidence for distinct neural correlates of conditioned vs. verbally induced placebo analgesia

Link: https://www.nature.com/articles/s41467-026-74743-0.epdf

The study analyzed individual participant data from 16 functional neuroimaging studies involving 409 participants. Researchers compared placebo analgesia induced by verbal suggestion alone with placebo analgesia induced by verbal suggestion combined with conditioning. The analysis revealed both shared and distinct neural mechanisms underlying the two approaches and showed that conditioning engages additional brain systems associated with pain modulation and nociceptive processing.


About CRC/TRR 289 “Treatment Expectation”

The Collaborative Research Center/Transregio 289 Treatment Expectation investigates how expectations influence treatment outcomes across a broad range of medical conditions. Bringing together researchers from multiple disciplines and institutions, the consortium seeks to understand the psychological, neurobiological, and clinical mechanisms through which expectations shape health and recovery. For more details see