Placebo Effect

Analgesia is particularly susceptible to placebo responses. Recent studies in humans have provided important insights into the neurobiology underlying placebo-induced analgesia. However, human studies provide incomplete mechanistic explanations of placebo analgesia because of limited capacity to use cellular, molecular, and genetic manipulations. To address this shortcoming, this article describes the development of a rat model of conditioned analgesia in an operant pain assay. Specifically, rats were conditioned to associate a placebo manipulation with the analgesic effect of 1 mg/kg morphine (subcutaneously) on facial thermal pain. We found that conditioned (placebo) responding bore 3 of the hallmarks of placebo-induced analgesia: (1) strong interanimal variability in the response, (2) suppression by the opiate antagonist naloxone (5 mg/kg subcutaneously), and (3) a positive predictive relationship between the unconditioned analgesic effect and the conditioned (placebo) effect. Because of the operant nature of the assay and the use of only a mild noxious thermal stimulus, we suggest that these results provide evidence of placebo-induced analgesia in a preclinical model that utilizes an affective behavioral end point. This finding may provide opportunities for invasive preclinical studies allowing greater understanding of placebo-induced analgesia, thus paving the way for avenues to harness its benefits.

Experimental design of behavioral studies in animals generally includes placebo-treated controls. However, when placebo is administered by injection in experimental models of psychiatric diseases such as depression, where stress may affect the execution of the behavioral test, it is possible that injection per se may influence the behavioral response. Rats injected with clomipramine hydrochloride (1, 10 or 50 mg / kg), as compared to animals injected with physiological saline as placebo, showed a dose-dependent decrease of the immobility time in the despair test and of the number of floor units explored in the open field in the reserpine test. However, when animals injected with placebo or clomipramine 50 mg / kg were compared with untreated intact controls, it was found that the immobility time in the despair test was higher in the placebo-treated animals than in untreated intact controls. A difference was found between clomipramine-injected animals and untreated intact controls. In contrast, rats tested in the reserpine test, which is based on repeated drug injections, no difference was found between placebo-treated animals and untreated intact controls. These results indicate that stressful procedure of the experimental design may change the response of animals in behavioral tests. Studies with experimental models of depression, where stressful procedures are used, should include a control group of untreated intact animals.

In esteemed disciplines of science, such as physics, truth is not defined by a single publication. If a laboratory announces a new discovery, it is standard practice for other laboratories to promptly replicate the study, in order to confirm or refute its observations. The discovery does not become fact until at least one other laboratory confirms the observations, but preferably there should be multiple, independent confirmations. This principle should apply to the results reported by Peng et al. in this issue [8]. Peng et al. [8] announced astounding results, unprecedented and unrivalled in the history of research into the treatment of chronic discogenic low back pain. The treatment was simply an injection of 1 ml of 1% methylene blue and 1 ml of 2% lignocaine. In a randomized, placebo-controlled trial this treatment achieved reductions of mean scores from 72 to 20 for pain, and from 48 to 13 for disability. Some 19% of their patients achieved complete relief of pain, at 24 months, with a further 72% having only slight pain that required no medication. For these outcomes the number needed to treat was 2. Against these figures, the results of surgery, rehabilitation, behavioural therapy, and any other treatment for back pain pale into insignificance. Although seemingly simple, this treatment is not without foundation. Methylene blue is an inhibitor of nitric oxide-induced guanylate cyclase [1,3,4], and nitric oxide has been implicated in the inflammatory processes of disc degeneration and discogenic pain [2]. Nor should it be a concern that the response rate in the placebo group was low (12%). Not only is it within the expected range of placebo response rates, it is not unreasonable at a twoyear follow-up. If the results of Peng et al. [8] are true, this intervention will revolutionize the treatment of low back pain. Spinal surgery for back pain will be rendered essentially obsolete. Furthermore, and ironically, the treatment is not subject to any patent, and is readily available. Anyone who performs discography will be able to provide the treatment, at trivial extra cost. For ridding the world of back pain, this study would be worthy of nomination for a Nobel Prize; if the results are true. Credibility will be the principal issue that arises once this paper appears. Technically, there are no lethal flaws in the study. Standard techniques of diagnosis and treatment were used, which can be replicated. Validated instruments were used for group outcomes. Statistical significance was well and truly achieved. But those data are overshadowed by the categorical outcomes: 19% completely free of pain, and 72% requiring no medication. The 95% confidence intervals of these proportions are 6-32% and 57-87%, respectively, which is the range of outcomes that those who use this treatment should expect to achieve. The study comes from an esteemed group that has been active in major journals to date [5-7,9,10]. So, the source seems honourable and impeccable. What is not known is whether cultural

Regression to the mean (RTM) is a widespread statistical phenomenon. It is a group phenomenon that occurs whenever an extreme group is selected from a population based on the measurement of a particular variable. If a second measurement is then taken for the same group, the second mean will be closer to the population mean than the first measurement. This decrease (or increase) can be mistakenly attributed to a treatment effect; the conclusion can be drawn that an effect results from treatment when it in fact results from chance. Any intervention that is aimed at a group or characteristic that is very different from the average will appear to be successful because of RTM. It is therefore important that any genuine reductions because of the treatment are separated out from the effect of RTM. If the problem is ignored then this will lead to errors in the interpretation of results and, potentially, decisions made on the evidence of those results. This paper highlights the importance of the issue and its effects on many common clinical, public health and managerial decisions.

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.

Objective: Conventional models of placebo effects assume that all mind-body responses associated with expectation can be explained by ordinary causal processes. This experiment tested whether some placebo effects may also involve retrocausal, or time-reversed, influences.

The logic of the randomized double-blind placebo control group design is presented, and problems with using the design in psychotherapy are discussed. Placebo effects are estimated by examining clinical trials in medicine and psychotherapy. In medicine, a recent meta-analysis of clinical trials with treatment, placebo, and no treatment arms was conducted (Hróbjartsson & Gøtzsche, 2001), and it was concluded that placebos have small or no effects. A re-analysis of those studies, presented here, shows that when disorders are amenable to placebos and the design is adequate to detect the effects, the placebo effect is robust and approaches the treatment effect. For psychological disorders, particularly depression, it has been shown that pill placebos are nearly as effective as active medications whereas psychotherapies are more effective than psychological placebos. However, it is shown that when properly designed, psychological placebos are as effective as accepted psychotherapies. © 2005 Wiley Periodicals, Inc. J Clin Psychol 61: 835–854, 2005.

The use of placebo may have accompanied healing and medical practices since their origins (Plato; Charmides, 155-156). Recent experimental data indicate that we would be well advised to further consider placebo eVects in future therapeutic strategies, with a better knowledge of their potency, psychological basis and underlying neurobiological mechanisms. Current research in the areas of pain, depression and Parkinson's disease has uncovered some of the potential neurobiological mechanisms of placebo eVects. These data indicate that conscious expectation and unconscious behavioral conditioning processes appear to be the major neurobiological mechanisms capable of releasing endogenous neurotransmitters and/or neurohormones that mimic the expected or conditioned pharmacological eVects. To date, research on placebo responses aVecting immune-related diseases is scarce, but there are consistent indications that skin and mucosal inXammatory diseases, in particular, are strongly modulated by placebo treatments. However, the brain's capability to modulate peripheral immune reactivity has been impressively demonstrated by paradigms of behavioral conditioning in animal experiments and human studies. Thus, placebo eVects can beneWt end organ functioning and the overall health of the individual through positive expectations and behavioral conditioning processes.

Background: Systematic reviews of randomized trials show that empathic care (a core component of person-centered care) and placebos can reduce chronic back pain. However, this evidence has rarely been implemented and public knowledge of empathy and placebos is limited. Objectives: We conducted a trial ('OPTICARE') in a real-life setting. The trial and its aftermath were filmed for a British Broadcasting Corporation (BBC) Horizon documentary. Methods: Eligible participants aged 18-75 years with self-reported persistent back pain (>3 months) were randomised to: (1) Control group (SC): had a standard consultation and a leaflet describing NHS recommendations for back pain. (2) Standard placebo group (SP): received a three-week course of placebo pills (2 capsules, twice a day) and a standard (5-10 minute) general practice (GP) consultation. (3) Empathy and placebo group (EP): received the same as SP treatment as the standard placebo group and a longer (15-30 minute) consultation with a doctor prompted to be highly empathetic. Self-reported changes in pain after 3 weeks were measured using the Visual Analogue Scale and the Roland Morris Disability Questionnaire. The process was filmed by Windfall Films. Results: The documentary, entitled 'The Placebo Experiment: Can My Brain Cure My Body?' was first broadcast on BBC Two in the UK on 4 October 2018. It was watched by 1.9 million people. Almost all of the 117 participants in the trial reported a reduction in pain and magnitude of placebo effects is similar in real world settings as it is in clinical trials. Conclusions: This was the largest placebo study we are aware of that was conducted with a main purpose of educating the public about placebo effects and the first known published report of a study designed for a documentary. Although the trial suffered from a number of limitations, including contamination and lack of power, it is contended that randomised trials of placebo treatments can be conducted so that they benefit and educate the public.

A Randomized, Double-Blind, Placebo-Controlled Crossover Study Article Type: Original Study Section/Category: Abstract: Background: The beneficial effect of sulpiride augmentation of clozapine therapy for treatment resistant schizophrenia patients is enhanced by its antisalivatory effect on clozapine-induced hypersalivation (CIH). Amisulpride, like sulpiride, is a substitute benzamide derivative with higher selective binding to the D2/D3 dopamine receptor. We hypothesized that add-on amisulpride would also be beneficial in controlling CIH.

Rationale : A neutral stimulus repeatedly paired with administration of a drug may elicit a conditioned response. This process, termed pharmacological classical conditioning, may be important in the understanding of placebo effects. Objective : The unconditioned response to caffeine is increased physiological and psychological arousal. The present study investigated whether stimuli associated with the use of caffeine, i.e. the smell and taste of coffee, elicited a conditioned increase in arousal. It was also investigated whether conditioned arousal modulated the unconditioned arousal induced by caffeine. Methods: Twenty subjects who drank at least two cups of coffee per day were exposed to four conditions in a within-subjects design, where the subjects received coffee or orange juice crossed with placebo or 2 mg /kg caffeine. Dependent variables were skin conductance responses and startle reflexes to 85 dB noise bursts, skin conductance levels, blood pressure, heart rate, and subjective measures of arousal. Results: Both caffeine (caffeinated juice) and caffeine-associated stimuli (decaffeinated coffee) increased subjective and physiological arousal. When caffeine and caffeine-associated stimuli were presented together (caffeinated coffee), a non-significant tendency towards an additive effect of the conditioned arousal on the unconditioned arousal to caffeine was seen in some dependent variables. Conclusions: Presentation of caffeine-associated stimuli to caffeine-users elicited conditioned responses similar to the unconditioned drug response. Thus, pre-sentation of caffeine-associated stimuli could be used as an experimental model of placebo effects.

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.

The voice of conscience, in Heideggerian existentialism, stands for humanity's inherent potency to call himself into an authentic way of living. Heidegger, through this concept, calls us to acknowledge the range of our possibilities in life before death than regret what we have already done. Since authentic living is a process than an end-no salvation being possible in this world-being sensitive to the call is trying to be authentic throughout life. As such, the call acts like taking placebos which keep us hopeful while we are in bad health, although there might be no cure. Paul Auster's Mr Vertigo, being a novel filled with existential themes, can be read to concretise the existential intonation of Heideggerian conscience, following Auster's own existential outlook into the human condition. This paper, by applying an interdisciplinary approach, thus reads Mr Vertigo in the light of Heidegger's certain existential concepts and the implications they have concerning how our existential conscience has a placebo effect. As such, this paper is to argue that Auster's Yehudi in Mr Vertigo plays the role of Walt's voice of conscience to help him with an authentic life style, the novel meanwhile highlighting how the call of conscience can help Heidegger's "Dasein" with the infinity of possibilities it has before death in a world determined by contingency.

Objective: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. Methods: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). Results: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P ‫؍‬ .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P interaction ‫؍‬ .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). Conclusion: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk. ( J Vasc Surg 2010;52:825-33.)

Mean effect sizes for changes in depression were calculated for 2,318 patients who had been randomly assigned to either antidepressant medication or placebo in 19 double-blind clinical trials. As a proportion of the drug response, the placebo response was constant across different types of medication (75%), and the correlation between placebo effect and drug effect was .90. These data indicate that virtually all of the variation in drug effect size was due to the placebo characteristics of the studies. The effect size for active medications that are not regarded to be antidepressants was as large as that for those classified as antidepressants, and in both cases, the inactive placebos produced improvement that was 75% of the effect of the active drug. These data raise the possibility that the apparent drug effect (25% of the drug response) is actually an active placebo effect. Examination of pre-post effect sizes among depressed individuals assigned to no-treatment or wait-list control groups suggest that approximately one quarter of the drug response is due to the administration of an active medication, one half is a placebo effect, and the remaining quarter is due to other nonspecific factors.

Constipation is a major source of distress for patients with cancer, significantly affecting quality of life. It can be secondary to disease sequelae, side effects of treatment, or preexisting conditions. It often is unrecognized, underassessed, and ineffectively managed. Nurses play a key role in the prevention and management of constipation and need evidence-based interventions. This article summarizes the existing research evidence for constipation interventions and identifies gaps. Many of the strategies have been evaluated in nononcology populations; researchers should evaluate their effectiveness in oncology populations. F Many expert opinions are available on the prevention and management of constipation in patients with cancer, but no high-level evidence supports the recommendations.

Substances and interventions with no specific therapeutic effect have been in use since the dawn of history. The term placebo has first been mentioned in the Scriptures, but it was not until the 19th century that it appeared in a medical context. Although lay people like Voltaire, and physicians such as Sir William Osler, have raised the possibility that much of what physicians did had no specific therapeutic effect, this notion was not shared by the public at large or by the medical profession. It was only by the end of the 18th century that a placebo-controlled trial has been conducted, repudiating the therapeutic effect of mesmerism. The advent, in the late 1940s, of effective treatments, which also had serious adverse effects, made the distinction between placebo and putative, active drug effects more relevant and urgent, and cleared the way for double-blind, randomized, placebo-controlled trials. This in turn triggered an ethical debate on the use of placebo, both in research and in clinical practice. Anthropologists, sociologists, physiologists, and medical researchers are all focusing their efforts on understanding the mechanism, role and modulating factors of placebo.

A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson's disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the ventral striatum of patients with Parkinson's disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson's disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson's disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively.

The placebo effect, with its central role in clinical trials, is acknowledged as a factor in sports medicine, although until recently little has been known about the likely magnitude and extent of the effect in any specific research setting. Even less is known about the prevalence of the effect in competitive sport. The present paper reviews 12 intervention studies in sports performance. All examine placebo effects associated with the administration of an inert substance believed by subjects to be an ergogenic aid. Placebo effects of varying magnitudes are reported in studies addressing sports from weightlifting to endurance cycling. Findings suggest that psychological variables such as motivation, expectancy and conditioning, and the interaction of these variables with physiological variables, might be significant factors in driving both positive and negative outcomes. Programmatic research involving the triangulation of data, and investigation of contextual and personality factors in the mediation of placebo responses may help to advance knowledge in this area.

Purpose. The purpose of this article is to compare vision therapy/orthoptics, pencil pushups, and placebo vision therapy/orthoptics as treatments for symptomatic convergence insufficiency in adults 19 to 30 years of age. Methods. In a randomized, multicenter clinical trial, 46 adults 19 to 30 years of age with symptomatic convergence insufficiency were randomly assigned to receive 12 weeks of office-based vision therapy/orthoptics, office-based placebo vision therapy/orthoptics, or home-based pencil pushups. The primary outcome measure was the symptom score on the Convergence Insufficiency Symptom Survey. Secondary outcome measures were the near point of convergence and positive fusional vergence at near. Results. Only patients in the vision therapy/orthoptics group demonstrated statistically and clinically significant changes in the near point of convergence (12.8 cm to 5.3 cm, p ‫؍‬ 0.002) and positive fusional vergence at near (11.3⌬ to 29.7⌬, p ‫؍‬ 0.001). Patients in all three treatment arms demonstrated statistically significant improvement in symptoms with 42% in office-based vision therapy/orthoptics, 31% in office-based placebo vision therapy/orthoptics, and 20% in home-based pencil pushups achieving a score <21 (our predetermined criteria for elimination of symptoms) at the 12-week visit. Discussion. In this study, vision therapy/orthoptics was the only treatment that produced clinically significant improvements in the near point of convergence and positive fusional vergence. However, over half of the patients in this group (58%) were still symptomatic at the end of treatment, although their symptoms were significantly reduced. All three groups demonstrated statistically significant changes in symptoms with 42% in office-based vision therapy/orthoptics, 31% in office-based placebo vision therapy/orthoptics, and 20% in home-based pencil push-ups meeting our criteria for elimination of symptoms. (Optom Vis Sci 2005;82:E583-E595)

Polycystic ovary syndrome (PCOS), the most common female endocrinopathy, is associated with hyperandrogenism, ovulatory dysfunction and obesity (1). PCOS increases the risk of hyperinsulinaemia, insulin resistance and type 2 diabetes. Type 2 diabetes results primarily from insulin resistance and is correlated with both hyperandrogenaemia and obesity (1). Women with PCOS often develop hypertension and have an increased likelihood of developing cardiovascular risk factors (2). They also appear to have impaired mental health (3, 4). Common features of PCOS can be highly distressing to patients and body image appears to be strongly associated with depression (5), and there are also indications that anorexia nervosa coexists with PCOS (6). Taken together, PCOS-related symptoms lead to higher levels of depression, psychological and psychosexual morbidity, and increased exposure to stressful stimuli.

The field of placebo research has made considerable progress in the last years and it has become a major focus of interest. We know now that the placebo effect is a real neurobiological phenomenon and that the brain's 'inner pharmacy' is a critical determinant for the occurrence of psychobiological and behavioural changes relevant to healing processes and well-being. However, harnessing the advantages of placebo effects in healthcare is still a challenge. The first part of the theme issue summarizes and discusses the various kinds of placebo mechanisms across medical fields, thereby not only focusing on two main explanatory models-expectation and conditioning theory-but also taking into account empathy and social learning, emotion and motivation, spirituality and the healing ritual. The second part of the issue focuses on questions related to transferring knowledge from placebo research into clinical practice and discusses implications for the design and interpretation of clinical trials, for the therapeutic settings in daily patient care, and for future translational placebo research.

The placebo effect has been a source of fascination, irritation, and confusion within biomedicine over the past 60 years. Although scientific investigation has accelerated in the past decade, with particular attention to neurobiological mechanisms, there has been a dearth of attention to developing a general theory of the placebo effect. In this article, we attempt to address this gap. To set the stage, we review evidence relating to the reality and clinical significance of the placebo effect. Next we investigate the scope and limits of the placebo effect by examining the hypothesis that the placebo effect operates predominantly by modifying the experience and perceptions of illness symptoms, such as pain, anxiety, and fatigue, rather than by modifying the pathophysiology of disease. Based on this background, we characterize the placebo effect as a form of interpersonal healing, as distinct from spontaneous natural healing and from technological healing dependent on physiologically active pharmaceuticals or procedures. Finally, we argue that research on the placebo effect has the potential to revitalize the art of medicine.

This chapter presents ethnographic and social neuroscientific insights on the emerging subculture of juicing: an extreme eating practice grounded in food beliefs about purity and pollution enacted through a set of highly prescriptive rituals to ‘flush’ out undesirable substances and achieve ‘cleansing’. Drawing on our ethnographic evidence and recent work in cognitive anthropology, the philosophy of psychiatry, and social neuroscience, we argue that the positive results achieved by juicers are largely attributable to the prosocial rewards of constructing a juicer identity reinforced in ritual, and to implicit sociocognitive substrates of the placebo effects. The cult-like dimensions of juicing culture, in turn, presents us with a fascinating window for the study of emergent sociality and its physiological effects, and, by extension, for the theoretical and empirical study of embodiment in cultural epidemiology

The concept of placebo response has evolved in the past few years from the clinical trial setting and medical practice to a psychobiological model that gives us important information on how the patient's brain is modified by the psychosocial context around the therapy. In this review, some examples will be given where physiological or pathological conditions are altered following the administration of an inert substance along with verbal instructions tailored to induce expectation of a change, and explanations will be presented with details on neurotransmitter changes and neural pathways activated. Although nothing is known about the biological underpinnings of the placebo response in the respiratory system, this review may help extending the neurobiological investigation of placebos from conditions such as pain and Parkinson's disease to respiratory disorders and symptoms such as cough.

In this article we explore the ethics of manipulating verbal information for the sake of influencing health-outcomes through placebo and nocebo responses. Recent scientific research on placebo and nocebo effects has drawn attention to the ways in which communication by health professionals may modulate the symptoms of patients across an array of highly prevalent conditions such as pain, depression, anxiety, insomnia, irritable bowel syndrome, migraine and Parkinson’s disease. The positive and negative effects of clinicians’ communication on patient outcomes pose important ethical issues, which we describe in this article under the label of “the ethics of therapeutic communication” (TC). We begin by reviewing available evidence supporting the claim that doctor-patient communication has therapeutic effects. We then identify in truthfulness, helpfulness and pragmatism three morally relevant considerations that can guide clinicians in therapeutic communication with their patients. Finally, we examine the ethics of using TC to enhance the effectiveness of proven medical interventions and open-label placebos.

As old as healing itself, the placebo effect is an important yet seemingly misunderstood phenomenon in conventional medical science. In a broad sense it occurs when patients experience positive results more from psychological rather than chemical origins. Much of antidepressants hidden efficacy has been found to be attributed to this effect, conversely, alternative medicine has embraced the notion and calls it self-healing. There is a major correlation between the placebo effect and the doctor-patient relationship. The placebo is more than just a control tool, it has the ability to be a positive force in the conventional medical understanding of the power of mind over body.

The aim of this review was to determine the magnitude of the placebo and nocebo effect on sport performance. Articles published before March 2019 were located using Medline, Web of Science, PubMed, EBSCO, Science Direct, and Scopus. Studies that examined placebo and nocebo effects of an objective dependent variable on sports Performance, which included a control or baseline condition, were included in the analysis. Studies were classified into two categories of ergogenic aids: 1) nutritional and 2) mechanical. Cohen’s d effect sizes were calculated from 32 studies involving 1,513 participants. Small to moderate placebo effects were found for both placebo (d = 0.36) and nocebo (d = 0.37) effects and when separated by nutritional (d = 0.35) and mechanical (d = 0.47) ergogenic aids. The pooled effect size revealed a small to moderate effect size across all studies (d = 0.38). Results suggest that placebo and nocebo effects can exert a small to moderate effect on sports performance.

The past decades have seen an explosion of studies on empathy in various academic domains including affective neuroscience, psychology, medicine, and economics. However, the volumes of research have almost exclusively focused on its evolutionary origins, development, and neurobiological bases, as well as how the experience of empathy is modulated by social context and interpersonal relationships. In the present paper, we examine a much less attended side of empathy: why it has a positive impact on others? After specifying what the construct of empathy encompasses, we briefly review the various effects of empathy on health outcomes in the domain of medicine. We then propose two non-mutually exclusive mechanistic explanations that contribute to explain the positive effects of physician empathy on patients. (1) The social baseline theory (SBT), building on social support research, proposes that the presence of other people helps individuals to conserve metabolically costly somatic and neural resources through the social regulation of emotion. (2) The free energy principle (FEP) postulates that the brain optimizes a (free energy) bound on surprise or its complement value to respond to environmental changes adaptively. These conceptualizations can be combined to provide a unifying integrative account of the benefits of physicians’ empathetic attitude  on their patients and how it plays a role in healing beyond the mere effect of the therapeutic alliance.

This chapter provides a synthetic overview of the contemporary debate over the ethics of placebos and placebo effects in both clinical and research contexts. Section 1 briefly reconstructs how ethical attitudes toward the use of placebos have changed during the last century following the emergence of autonomy in medical ethics. Next, Sections 2–4
chart the main ethical issues concerning the use of placebos in clinical settings, examining: the ethics of deceptive placebos; the ethics of placebos without deception; and the ethics of modulating placebo and nocebo effects without placebos. Finally, Section 5 outlines the role of placebos in research, discussing the ethics of placebos as controls in clinical experiments.

In 2001, a study made the startling discovery that in tests 46% of subjects were unable to separate the placebo effect from established antidepressants from the US Food and Drug Administration (FDA) database (Laughren 2001). This is a qualitative study of the role of the placebo effect on 11 couples after a consultation with a predictive medical astrologer led to conception and the birth of a healthy baby. The astrologer advised them on the optimum times for in-vitro fertilisation (IVF) treatment. How did astrology work from the participants’ point of view? Does a positive or negative predisposition to astrology affect the success of the outcome? Can the effectiveness of astrology give new insight into the placebo effect? How could this be tested and measured in a statistical study?

Data from 33 randomized treatment studies were subjected to a meta-analysis to address questions surrounding the efficacy of psychological approaches in the treatment of specific phobia. As expected, exposure-based treatment produced large effects sizes relative to no treatment. They also outperformed placebo conditions and alternative active psychotherapeutic approaches. Treatments involving in vivo contact with the phobic target also outperformed alternative modes of exposure (e.g., imaginal exposure, virtual reality, etc.) at post-treatment but not at follow-up. Placebo treatments were significantly more effective than no treatment suggesting that specific phobia sufferers are moderately responsive to placebo interventions. Multi-session treatments marginally outperformed single-session treatments on domain-specific questionnaire measures of phobic dysfunction, and moderator analyses revealed that more sessions predicted more favorable outcomes. Contrary to expectation, effect sizes for the major comparisons of interest were not moderated by type of specific phobia. These findings provide the first quantitative summary evidence supporting the superiority of exposure-based treatments over alternative treatment approaches for those presenting with specific phobia. Recommendations for future research are also discussed.

Nocebo hyperalgesia is a phenomenon that is opposite to placebo analgesia and whereby expectation of pain increase plays a crucial role. In recent times, both the neuroanatomical and the neurochemical bases of the nocebo effect and of nocebo-related effects have begun to be explored. Here, we highlight recent advances in our understanding of the neurobiology of the nocebo hyperalgesic effect.

Neuroscience was an integral part of psychosomatic medicine at its inception in the early 20th century. Since the mid-20th century, however, psychosomatic research has largely ignored the brain. The field of neuroscience has burgeoned in recent years largely because a variety of powerful new methods have become available. Many of these methods allow for the noninvasive study of the living human brain and thus are potentially available for integration into psychosomatic medicine research at this time. In this first paper we examine various methods available for human neuroscientific investigation and discuss their relative strengths and weaknesses. We next review some basic functional neuroanatomy involving structures that are increasingly being identified as relevant for psychosomatic processes. We then discuss, and provide examples of, how the brain influences end organs through "information transfer systems," including the autonomic, neuroendocrine, and immune systems. The evidence currently available suggests that neuroscience holds great promise for advancing the goal of understanding the mechanisms by which psychosocial variables influence physical disease outcomes. An increased focus on such mechanistic research in psychosomatic medicine is needed to further its acceptance into the field of medicine. Key words: neuroscience, brain imaging, information transfer systems, autonomic nervous system, neuroendocrinology, psychoneuroimmunology.