In this study, we demonstrated that IBS patients homozygous for the COMT val158met methionine allele (met/met) were the most responsive to placebo treatment. Heterozygous (val/met) patients showed an intermediate response, and homozygous valine (val/val) patients showed essentially no placebo mediated symptom improvement. To our knowledge, this is the first study to demonstrate genetic modulation of true placebo effects disassociated from changes related to disease natural history and regression to the mean. It is also the first study to demonstrate a relationship between different levels of placebo treatment and COMT genotype.
Our regression analysis showed that as the number of COMT val158met met alleles increased progressively from 0 to 1 to 2, and COMT activity decreased, theoretically making more dopamine available in the prefrontal cortex, placebo responses increased in a linear fashion. Further, there was a significant interaction between number of methionine alleles and placebo treatment arm. Examination of the interactions illustrated in and , showed that the relationship between number of COMT met alleles and placebo response occurred primarily in the augmented placebo arm, with a smaller effect in the limited placebo arm, and no effect (IBS-SSS) or a reverse effect (Adequate Relief) in the waitlist control arm. Taken together, these results strongly suggest that COMT val158met, specifically the met/met genotype, is a potential marker for placebo responders in IBS. Furthermore the finding that this genotype is associated with a positive outcome only in groups given a placebo (and not in the waitlist control group) is of particular importance, as it indicates that it is a predictor of the placebo effect, not just improvement in general.
To date, the search for placebo biomarkers has been elusive. The three previous studies we are aware of which looked for a genetic link to the placebo response lacked the critical no-treatment control 
. Neither of the two studies that examined the relationship between COMT and placebo response found a statistically significant relationship 
. The third study on severe anxiety disorder (SAD) found that polymorphisms in two serotonin-related genes, the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G703T polymorphism of tryptophan hydroxylase-2, had a significant effect on placebo 
. However the involvement of the amygdala and these two serotonin-related enzymes suggests that these associations may be unique to SAD and not necessarily generalizable to the placebo response mechanism. Furthermore in the absence of a no-treatment control that would have allowed a clear separation between placebo effects and such phenomenon as regression to the mean, spontaneous remission or the natural waxing and waning of illness, these studies could not rule out whether their findings were a result of a genuine psychobiological process or merely improvement that would have happened without placebo treatment.
Four other placebo-controlled studies designed to examine the effects of tolcapone, a COMT inhibitor, looked at the association between COMT val158met genotype, cognition and information processing 
. Mentioned en passant
in their reports was the observation that the met/met subjects had a statistically significant placebo effect, whereas the val/val subjects were unresponsive to placebo treatment. Although this research paradigm is distinctly different from IBS, these findings support our hypothesis and suggest that the COMT mediated placebo response pathway might be generalizable across multiple conditions. Nonetheless, other replications of our study that prospectively hypothesize a COMT involvement with placebo effects and include a no treatment control will be critical to confirm our findings.
Positioned at the intersection of catecholamine metabolism, memory 
, reward processing 
, confirmation bias 
and pain regulation 
, COMT presents an interesting candidate for a placebo response marker. The inverted U-shaped dopamine response curve, reported in many COMT functional studies suggests a narrow range for optimum dopamine cortical function 
. One might therefore hypothesize that drugs that interfere with the dopaminergic pathway might affect the observed response to treatment by shifting the component of the treatment response resultant from placebo. Indeed several studies that examine the effect of amphetamine 
or tolcapone 
relative to a placebo treatment have observed that met/met subjects tend be unresponsive or worsen relative to placebo response when treated with these drugs, suggesting there is an optimum level of dopamine associated with placebo effect. Identifying biological characteristics of placebo responders and non-responders could be key to managing underlying placebogenic factors to benefit patients by delivering personalized medicine, for example by adjusting the dose of medication in accordance to the subject's placebo susceptibility or selecting a different class of drugs for the individualized patient.
Our study illuminates the persistent failure to identify reliable characteristics of placebo responders 
. Beyond using a no-treatment control another unique feature of our study was the inclusion of an augmented therapeutic relationship. The therapeutic relationship is considered an active component of non-specific placebo treatment 
; its presence may be needed to identify reliable predictors of the placebo effect 
. Prior studies did not include an arm in which the placebo was administered within the context of an augmented therapeutic relationship. Indeed, many of these studies were done with volunteer subjects in experimental rather than clinical contexts in which there was no therapeutic relationship at all. Although this unique design of our study is an asset, it also poses a limitation on using other studies to retrospectively validate our findings, as most clinical trials do not include a no-treatment control. Another limitation of this study is its small sample size and the absence of a power calculation. Given that our study was a secondary data analysis of an existing dataset, the sample size was already fixed. Although a small sample size increases the risk of a type II error (failing to find a significant difference that exists in the population), it does not challenge the validity of results showing significant effects. Hence, our results deriving from a clear hypothesis are still reliable.
It is unlikely that a single locus like COMT, fully accounts for a complex behavioral phenotype like placebo response. However, given that COMT val158met is a functional polymorphism, which results in a three to four-fold reduction in prefrontal dopamine, it has a greater potential to contribute to behavioral variability than other non-functional or noncoding polymorphisms. That COMT has been implicated in multiple disorders i.e. major depressive disorder, Parkinson's and pain, might be deemed as a weakness in its candidacy for a placebo response marker. However we argue that this wide association with disease and drug treatments might be why it is such a powerful potential target for modulating placebo effects.
IBS is a functional condition characterized by a diversity of symptoms measured by subjective instruments, which also poses another limitation to our study. It should be noted though, that placebo treatment is especially thought to influence the experience and perception of subjective symptoms such as depressed mood and pain, rather than directly modifying disease pathophysiology 
Finally, the power of the patient-doctor interaction to enhance healing is one of the hallmarks of clinical medicine, and increasingly resources are devoted to teaching clinicians how to communicate warmth and caring to their patients 
. Our findings reinforce this healing benefit for met/met patients and raise an interesting question. Despite their best efforts, many a warm and caring physician has had patients that seemed to derive minimum benefit from their empathic attentions. Our findings that val/val patients are less influenced by the placebo treatment, regardless of whether it is delivered in an augmented or limited context, potentially shed some light on this clinical challenge.