# Brain and Genetic Predictors of Individual Differences in Pain and Placebo Analgesia

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2021 · $623,968

## Abstract

Project Summary
Throughout history, placebo effects have been variously considered as tricks played upon the gullible by medical
practitioners and powerful but mysterious healing forces. With the advent of direct measurements of human
brain function, modern science has shown that placebo effects are neither of these. Rather, they reflect the
principled impact of psychological and brain processes on diseases of the brain and body. Placebo effects
represent an opportunity because they provide a window into internal brain processes that influence health, and
a challenge because many clinical trials have now failed due to large and durable placebo responses, at great
cost to health care providers and consumers.
Definitive studies of the brain pathways involved in placebo responses—and the genetic, environmental, and
neural factors that lead some individuals to respond more strongly than others—are critical to harnessing placebo
effects, eliminating or controlling placebo responses in clinical trials, and understanding the psychological and
brain factors that predispose one to successful treatment and “spontaneous” improvement. Placebo analgesia
is the best-studied type of placebo effect, with well-developed paradigms and preliminary data on its brain
mechanisms. This background provides a foundation for larger-scale, definitive studies.
In this project, we propose the first such large-scale study of brain mechanisms of placebo analgesia, combining
neuroimaging, behavioral, and genetic approaches. It builds on 15 years’ experience in PI Wager’s laboratory
on fMRI and placebo analgesia and 40 years of genetics research at the Institute for Behavior Genetics (IBG) at
the University of Colorado, Boulder. We will use fMRI to characterize the neural bases of placebo effects in 600
twins recruited from the Colorado Twin Sample and predict individual differences in placebo effects across two
forms of pain. In Aim 1, we will develop models that predict the magnitude of individuals’ placebo effects in pain
and pain neurophysiology based on a) fMRI activity, b) brain structure, and a combination of personality,
behavioral, and cognitive measures that can be deployed clinically. In Aim 2, we conduct the first analyses of
heritability of placebo effects and their neural predictors, and genetic correlations that can identify brain features
whose relationships with placebo effects are genetic in origin. In Aim 3, we leverage the >50,000 person
Enhancing Neuro-Imaging Genetics through Meta-analysis (ENIGMA) consortium to identify genome-wide
associations with placebo-linked brain features and develop polygenic risk scores for placebo effects. The
research products from this endeavor will include data and models useful for characterizing and screening
participants in clinical trials, assessing interactions between placebo responses and other treatments, and
assessing placebo effects across disorders.

## Key facts

- **NIH application ID:** 10103804
- **Project number:** 5R01DA046064-04
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Naomi P. Friedman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $623,968
- **Award type:** 5
- **Project period:** 2018-04-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10103804

## Citation

> US National Institutes of Health, RePORTER application 10103804, Brain and Genetic Predictors of Individual Differences in Pain and Placebo Analgesia (5R01DA046064-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10103804. Licensed CC0.

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