We set out to assess the effects of otherwise inert placebo interventions provided with or without a psychological treatment rationale and with a neutral or trustworthy, friendly and empathetic behavior of the experimenter in three consecutive and independent experiments. In all three experiments, the employed placebos were inert when administered without a treatment rationale, but exerted significant effects on primary outcome when provided with a psychological treatment rationale and a trustworthy, friendly and empathetic behavior of the experimenter. Although only tested in the green morph -experiment, the provision of trustworthy, friendly and empathetic relationship alone had no effects on primary outcome per se, indicating that in the respective experiment, the observed placebo effects on primary outcome was not due to the interpersonal behavior of the experimenter. These observed placebo effects differed in size, with large immediate and short-term effects and small to medium mid-term effects. Interestingly, considering that participants in the respective experiments received the same placebo, the provision of a psychological treatment rationale alone, i.e. without a trustworthy, friendly and empathetic interpersonal behavior of the experimenter, as well as the provision of a trustworthy, friendly and empathetic interpersonal behavior of the experimenter alone, i.e. without a psychological rationale, rendered the placebo effectless. Importantly, the experimental manipulation of both, i.e. providing a psychological treatment rationale as well as the interpersonal behavior of the experimenter, led on the one hand to the expected effects and differences in perceived empathy of the experimenter, while on the other hand perceived response expectancy appeared unaffected.

From an empirical perspective, it needs to be noted that the observed placebo effects are of the same magnitude to those seen in comparable populations with similar outcomes, but obtained with placebos administered within a biomedical context, i.e. with a biomedical treatment rationale. For example, Darragh et al.27 reported that the administration of placebo “antistress’ intranasal serotonin or oxytocin spray” in healthy volunteers resulted in significant reductions in perceived stress, with effect sizes similar to those reported in the green flux - and green morph -experiment, i.e. between d = 0.40 and d = 1.0. Also, Koban et al.14 reported a reduction in social pain of d = 1.04 after the administration of an otherwise inert nasal spray with biomedical treatment rationale, i.e. that the nasal spray is a “powerful analgesic that is also effective in reducing emotional pain and negative affect” in subjects who experienced a recent unwanted breakup of their romantic relationship. Furthermore, it needs to be noted that the observed placebo effects also show resemblance to those seen in assumingly non-placebo psychological interventions. For example, psychological stress management trainings in healthy populations with comparable designs have been shown to yield reductions in perceives stress of the same magnitude than those obtained in the green flux - and the green morph -experiments28,29. Furthermore, although a direct comparison with effect sizes seen in psychotherapy trials is not warranted due to the fact that they are usually obtained in clinical populations, it needs to be noted that the reported effect sizes would also be not unexpected for psychotherapy trials30. Thus, our results show for the first time that placebos administered within a psychotherapeutic-like context and with a psychological treatment rationale have effects with approximately the same size as placebos provided within a biomedical context and with a biomedical treatment rationale as well as – assumingly non-placebo – psychological interventions.

From a theoretical perspective, the observation that the employed placebos only had effects when provided with a treatment rationale and in the context of a trustworthy, friendly and empathetic behavior of the experimenter both confirms and expands the current understanding of placebos and also sheds light on psychotherapy. First, studies examining the modulation of treatment effects by the patient-practitioner relationship have a long history. For example, Egbert et al.31 were able to demonstrate that “encouragement and education” led to a significant reduction in postoperative administration of narcotics, blindly rated objective and subjective report as well as shortened post-operative hospitalization. Likewise, a comparatively early study in primary care patients with minor illnesses showed that a positive consultation led to significantly better outcome in comparison to a negative consultation, irrespective of providing placebo or no treatment32. In their hallmark study, Kaptchuk et al.24 examined the effects of placebo acupuncture in irritable bowel syndrome, showing that this placebo procedure had moderate effects, which were almost doubled when provided with a friendly and empathetic patient-practitioner relationship. In psychotherapy, the relationship between patients/clients and therapists is an important determinant of outcome30, showing its effect irrespective of its perceived importance by the researcher33. Also, the effects of an empathetic and supportive relationship have been found to be clinically relevant, equaling the effects of bona fide psychotherapies after controlling for researchers’ allegiance6. On the basis of the results of the green morph -experiment, we reason that neither a therapeutic treatment rationale nor the provision of trustworthy, friendly and empathetic relationship alone is sufficient to obtain an effect nor that they are additive, but that these two intervention components interact synergistically. It is important to keep in mind that in interventions the therapeutic relationship is not aimless, but always embedded in a therapeutic setting, i.e. provided with a therapeutic rationale. Considering the importance of the therapeutic alliance for psychotherapy, it is interesting to note that – in contrast to placebos provided with a biomedical treatment rationale24 – placebos with a psychological treatment rationale do not show any effect when provided in a neutral and technical way. Thus, it seems that the alliance becomes more important when the rationale is provided within a psychotherapeutic-like context. This finding resembles the results of a recent placebo study demonstrating that the effects of expectations – on the basis of a biomedical treatment rationale – are moderated by warmth and competence of the care provider34. However, while the results of the green morph -experiment support the importance of a trustworthy, friendly and empathetic relationship, we did not observe any effects of a trustworthy, friendly and empathetic relationship on response expectancies, indicating that these factors are independent from each other. It is possible that these differences between studies employing placebos with either a biomedical or psychological treatment rationale are due to differences in their familiarity, i.e. that taking the proverbial (placebo) pill is different from participating in a (placebo) psychological treatment in terms of having previous experiences and also possible with regard to the extent to which the respective intervention is socially grounded.

From a methodological point of view, the call to abandon randomized placebo-controlled trials in psychotherapy research is well founded10, but that does not imply that the pursuit for specificity is futile. Rather, the examination of placebos provided with psychological treatment rationales would not only offer insights into the potential and the limits of expectancy and plausibility in the context of a therapeutic alliance, but also help to examine effects and mechanisms of these treatment components, regardless of their definition as being characteristic or incidental to a given treatment theory35. Considering that the existence and size of specific effects of psychological interventions when compared to placebo conditions is functional to the operationalization of the latter5,36, still too little is known about the effects and mechanisms of placebos provided with a psychological treatment rationale.

Several aspects need critical examination. First, it can be argued that neither the intervention nor the way the relationship between experimenter and participant, resembles psychotherapy or the relationship between patients/clients and therapists in psychotherapy. However, with regard to the former, psychotherapy can take many forms, and as such, it is not defined by methods, but rather by its main goal to change feelings and behaviors. In this line of reasoning, our placebo interventions could well qualify as possible psychotherapeutic interventions. With regard to the latter, again, there is no universal definition of the relationship between patients/clients and therapist in that psychotherapists and psychotherapies vary in the degree they rely on, position or use the relationship. Also, although our attempts to experimentally manipulate the relationship quality can be seen as pragmatic and superficial, it led to designated effects in the subjective perception of participants and also, it has been shown that “even (…) “superficial psychotherapy” (…) has very powerful effect(s) on patients (with postoperative pain)” (quote from31, quotation mark in original, parenthesis by authors). Second, our attempts to standardize the interpersonal behavior of the experimenters were guided by the caution not to over-regulate the interpersonal encounter. Thus, and for example, we did not standardize the frequency or intensity of eye contact or number of questions answered by the experimenters and it is possible that the interpersonal encounter differed in these aspects between participants and also between experimenters. Therefore, although we were able to validate our approach by its effects on the secondary outcome, it is possible that this outcome was caused by different interpersonal behavior and processes. Third, we did not include a ‘control plus’ condition in the green dot - and the green flux -experiment and thus we can only speculate whether the observed effects of the ‘placebo plus’ conditions are due to the interaction of response expectancy and trustworthy, friendly and empathetic interaction of experimenter with participants or solely driven by the later. Fourth, our primary outcome was restricted to subjective parameters, i.e. momentary mood and perceived stress by self-report. Although this kind of assessment and outcome is customary in the evaluation of psychological interventions, the inclusion of physiological parameters would have corroborated our effects on subjective outcome. Fifth, we did not assess the secondary outcome in control conditions as the used items explicitly referred to an interventional context, e.g. I feel that the therapist is trustworthy. As both the use of this wording would have changed the provided rational for the control conditions as much as a rephrased wording would have rendered these items incomparable between conditions, we did not assess secondary outcome in the control conditions. However, the verbal and interpersonal behavior of experimenters in the control conditions were manualized as in all other conditions (see Appendix). Finally, we tested only healthy participants to increase internal validity. Although this might preclude direct implications for clinical research, we are confident that our results are informative for both placebo and psychotherapy research and that in future, this should be expanded also to clinical populations. Also, it needs to be noted that we employed three different variations of the same theme, i.e. ‘green’ and ‘moving’. The majority of participants were psychology students at the Universities of Basel and although participants were asked not disclose study details to fellow students, we changed the appearance of the placebos between experiments to minimize possible unblinding effects.

In conclusion, our results show that placebos with a psychological treatment rationale are possible and effective, when provided in a trustworthy, friendly and empathetic relationship, at least in healthy subjects. This opens the door for genuine placebo research in the realm of psychotherapy and the results of this research would not only be of interest for placebo research, but also inform the conceptualization and testing of psychological interventions.