Clinical Research: Phase 1 - Phase 4

The Placebo Problem, Part 5: The Placebome

This is the fifth installment of our look at placebo response issues in analgesia and psychiatry clinical trials. Read other posts in the series here.

Studies examining genetic variants associated with high or low placebo responses – the “placebome” – are relatively recent, but represent an important line of research that can yield insights into both the placebo’s underlying mechanisms and also potentially identify populations that display especially high or low responses. While we’re not there yet, the idea of increasing randomized controlled trial (RCT) efficiency by screening for and excluding high placebo responders is certainly an attractive one.

To date, placebome studies have been plagued by small sample sizes, and no comprehensive genome-wide association studies (GWAS) have yet been performed; nevertheless, the existing literature has yielded some exciting clues. If you read last week’s post on the neurobiological mechanisms underlying the placebo response, the key players in today’s story will be familiar. Existing placebo-associated variants are located primarily in genes that regulate the levels of dopamine, endogenous opioids, and endocannabinoids in the brain.


The rs4680 single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene, which encodes an enzyme that breaks down dopamine and other catecholamines, has some of the best evidence for involvement in the placebo response. It’s also one of the most widely-studied dopamine polymorphisms. The substitution of amino acids, a valine (val) for a methionine (met), in rs4680 reduces the activity of the enzyme by as much as fourfold in homozygous (met/met) individuals, and is associated with increased dopamine in the prefrontal cortex. The minor met/met allele is quite common, found in about one-quarter of Caucasian populations.

In a trial of irritable bowel syndrome (IBS) patients, met/met carriers displayed the highest placebo response, val/met carriers had intermediate levels, and val/val carriers had the lowest. An examination of placebo response to acute pain in healthy individuals found similar results: met/met individuals experienced the greatest placebo analgesia.

In addition to rs4680, other COMT SNPs, as well as SNPs in other dopamine-related genes, have been linked to the magnitude of placebo response. For example, an allele associated with low activity of another dopamine catabolizing enzyme, monoamine oxidase A (MAO-A), was linked with improved placebo response in several trials of depression.

Opioids and endocannabinoids

It seems a common theme is emerging: individuals with higher dopamine levels have larger placebo responses across a variety of patient populations, including healthy controls. The evidence for genetic variation in endogenous opioid and endocannabinoid systems playing a role in placebo response, on the other hand, is thus far considerably sparser.

In one study, homozygous carriers of a mu opioid receptor gene (OPMR1) variant associated with reduced receptor function had less placebo-induced activation of dopamine signaling in the nucleus accumbens than carriers with normal receptor function. In terms of endocannabinoids, the gene encoding the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) has been linked to placebo response magnitudes. Homozygous carriers of the allele previously associated with higher endocannabinoid levels in response to pain displayed higher levels of placebo analgesia than homozygous carriers of the other allele.

Join us next week for the next installment of the Placebo Problem series, where we’ll dive into the details of how the placebo effect is measured. We’ll take a look at the paradigms used in clinical trials as well as in research studies designed specifically to assess placebo effects.

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