Introduction to placebo effects in medicine: mechanisms and clinical implications

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.     

New insights into the placebo and nocebo responses

In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.     

Semiotic Mechanisms Underlying Niche Construction

The explanatory value of niche construction can be strengthened by firm footing in semiotic theory. Anthropologists have a unique perspective on the integration of such diverse approaches to human action and evolutionary processes. Here, we seek to open a dialogue between anthropology and biosemiotics. The overarching aim of this paper is to demonstrate that niche construction, including the underlying mechanism of reciprocal causation, is a semiotic process relating to biological development (sensu stricto) as well as cognitive development and cultural change. In making this argument we emphasize the semiotic mechanisms underlying the niche concept. We argue that the “niche” in ecology and evolutionary biology can be consistent with the Umwelt of Jakob von Uexkull. Following John Deely we therefore suggest that investigations into the organism—environment interface constituting niche construction should emphasize the semiotic basis of experience. Peircean signs are pervasive and allow for flexible interpretations of phenomena in relation to the perceptual and cognitive capacities of the behaving organism, which is particularly pertinent for understanding the relation of proximate/ultimate selective forces as co-productive (i.e., reciprocal). Additionally, theoretical work by Kinji Imanishi on the evolution of daily life and Gregory Bateson’s relational view of evolution both support the linkage between proximate and ultimate evolutionary processes of causation necessitated by the niche construction perspective. We will then apply this theoretical framework to two specific examples: 1) hominin evolution, including uniquely human cultural behaviors with niche constructive implications; and 2) the multispecies and anthropocentric niche of human-dog coevolution from which complex cognitive capacities and semiotic relationships emerged. The intended outcome of this paper is the establishment of concrete semiotic mechanisms and theory underlying niche constructive behavior which can then be applied to a broad spectrum of organisms to contextualize the reciprocal relation between proximate and ultimate drivers of behavior.     

How placebo responses are formed: a learning perspective

Despite growing scientific interest in the placebo effect and increasing understanding of neurobiological mechanisms, theoretical conceptualization of the placebo effect remains poorly developed. Substantial mechanistic research on this phenomenon has proceeded with little guidance by any systematic theoretical paradigm. This review seeks to present a theoretical perspective on the formation of placebo responses. We focus on information processing, and argue that different kinds of learning along with individuals' genetic make-up evolved as the proximate cause for triggering behavioural and neural mechanisms that enable the formation of individual expectations and placebo responses. Conceptualizing the placebo effect in terms of learning offers the opportunity for facilitating scientific investigation with a significant impact on medical care.     

Cultural variations in the placebo effect: ulcers, anxiety, and blood pressure

An analysis of the control groups in double-blind trials of medicines demonstrates broad variation--from 0 to 100 percent--in placebo effectiveness rates for the same treatment for the same condition. In two cases considered here, drug healing rates covary with placebo healing rates; placebo healing is the ultimate and inescapable "complementary medicine." Several factors can account for the dramatic variation in placebo healing rates, including cultural ones. But because variation differs by illness, large placebo effects for one condition do not necessarily anticipate large placebo effects for other conditions as well. Deeper understanding of the intimate relationship between cultural and biological processes will require close ethnographic scrutiny of the meaningfulness of medical treatment in different societies.     

Towards an ecosystem semiotics: Some basic aspects for a new research programme

The paper argues that ecosystem should be recognized as semiotic systems and that it is necessary to carry out studies of the ongoing semiotic processes in addition to traditional ecosystem research. It is suggested that interpretation of ecosystems within such a semiotic framework is of utmost importance and essential if we want to fully understand the complexity issue and how complex behaviour comes about at this level of biological hierarchy. This area—called ecosystem semiotics—is suggested to become a new direction of study dedicated to this understanding.As a consequence of the ontic character of ecosystem complexity, studies on the importance of semiotic processes can only be synthesized through modelling efforts. Hitherto, this type of process with a few exceptions has been neglected or at best only implicitly integrated and accounted for in ecosystem models. In the future, ecosystem models will need to integrate this type of behaviour in order to get full insight into the causal mechanisms behind the emergence of their complex behaviour. In addition, the concept of exergy in its classical form derived by Evans is suggested as a platform to integrate thermodynamic information of the systems as a complexity measure. The thermodynamic information may be split into parts that causally originate in the ontic existence of various ecosystem elements. Ecosystem semiotics is thought to considerably increase the thermodynamic efficiency of the ecosystem, leading to an increase in thermodynamic information and for instance ascendancy that would not have existed if it was not emerging from the semiotic processes.In other words, by incorporating semiotics, we add a “metaphysical” layer to our models, which may be referred to as the semiotype of the system. The semiotype acts as downward causation on the lower layers of interactions and allows for modification and adaptations of existing genotype or phenotype possibilities that would not be possible without the existence of semiosis and cognitive processes.     

How to Study Placebo Responses in Motion Sickness with a Rotation Chair Paradigm in Healthy Participants

Placebo responses occur in every medical intervention when patients or participants expect to receive an effective treatment to relieve symptoms. However, underlying mechanisms of placebo responses are not fully understood. It has repeatedly been shown that placebo responses are associated with changes in neural activity but for many conditions it is unclear whether they also affect the target organ, such as the stomach in motion sickness. Therefore, we present a methodology for the multivariate assessment of placebo responses by subjective, behavioral and objective measures in motion sickness with a rotation chair paradigm. The physiological correlate of motion sickness is a shift in gastric myoelectrical activity towards tachygastria that can be recorded with electrogastrography. The presented study applied the so-called balanced placebo design (BPD) to investigate the effects of ginger compared to placebo and the effects of expectations by verbal information. However, the study revealed no significant main or interactional effects of ginger (as a drug) or information on outcome measures but showed interactions when sex of participants and experimenters are taken into considerations. We discuss limitations of the presented study and report modifications that were used in subsequent studies demonstrating placebo responses when rotation speed was lowered. In general, future placebo studies have to identify the appropriate target organ for the studied placebo responses and to apply the specific methods to assess the physiological correlates.     

Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing

Using a comparative analysis of Navajo healing ceremonials, acupuncture and biomedical treatment, this essay examines placebo studies and ritual theory as mutually interpenetrating disciplines. Healing rituals create a receptive person susceptible to the influences of authoritative culturally sanctioned 'powers'. The healer provides the sufferer with imaginative, emotional, sensory, moral and aesthetic input derived from the palpable symbols and procedures of the ritual process-in the process fusing the sufferer's idiosyncratic narrative unto a universal cultural mythos. Healing rituals involve a drama of evocation, enactment, embodiment and evaluation in a charged atmosphere of hope and uncertainty. Experimental research into placebo effects demonstrates that routine biomedical pharmacological and procedural interventions contain significant ritual dimensions. This research also suggests that ritual healing not only represents changes in affect, self-awareness and self-appraisal of behavioural capacities, but involves modulations of symptoms through neurobiological mechanisms. Recent scientific investigations into placebo acupuncture suggest several ways that observations from ritual studies can be verified experimentally. Placebo effects are often described as 'non-specific'; the analysis presented here suggests that placebo effects are the 'specific' effects of healing rituals.     

Signs of the Self: An Exploration in Semiotic Anthropology

Peirce's general theory of signs, or semiotic, as he called it, yields a theory of the self that sees it both as the object and the subject of semiotic systems. From this viewpoint, the locus, unity, and continuity of the self will be found in the systems of signs that constitute the dialogues between utterers and interpreters of the signs. Personal identity, in this theory, is also a social and cultural identity and is not confined to the individual organism. Peirce's anti-Cartesianism, which denies intuitive and introspective knowledge of the self, derived that knowledge from the fallible inferences we all make from the observations of external facts, including the signs of the self. This laid the foundation for a semiotic psychology as well as for a semiotic anthropology. [self, semiotic anthropology, personal identity, C. S. Peirce]     

Spirituality: an overlooked predictor of placebo effects?

Empirical findings have identified spirituality as a potential health resource. Whereas older research has associated such effects with the social component of religion, newer conceptualizations propose that spiritual experiences and the intrapersonal effects that are facilitated by regular spiritual practice might be pivotal to understanding potential salutogenesis. Ongoing studies suggest that spiritual experiences and practices involve a variety of neural systems that may facilitate neural 'top-down' effects that are comparable if not identical to those engaged in placebo responses. As meaningfulness seems to be both a hallmark of spirituality and placebo reactions, it may be regarded as an overarching psychological concept that is important to engaging and facilitating psychophysiological mechanisms that are involved in health-related effects. Empirical evidence suggests that spirituality may under certain conditions be a predictor of placebo response and effects. Assessment of patients' spirituality and making use of various resources to accommodate patients' spiritual needs reflect our most current understanding of the physiological, psychological and socio-cultural aspects of spirituality, and may also increase the likelihood of eliciting self-healing processes. We advocate the position that a research agenda addressing responses and effects of both placebo and spirituality could therefore be (i) synergistic, (ii) valuable to each phenomenon on its own, and (iii) contributory to an extended placebo paradigm that is centred around the concept of meaningfulness.     

Meaning Matters: The Biosemiotic Basis of Bioethics

If the central problem in philosophical ethics is determining and defining the scope of moral value, our normative ethical theories must be able to explain on what basis and to what extent entities have value. The scientific foundation of contemporary biosemiotic theory grounds a theory of moral value capable of addressing this problem. Namely, it suggests that what is morally relevant is semiosis. Within this framework, semiosis is a morally relevant and natural property of all living things thereby offering us an ecological, as opposed to merely environmental, ethic. A consequence of this semiotic theory is that living things are accorded inherent moral value based on their natural relational properties—their ability to signify. This consequence establishes a hierarchy of inherent moral value based on the scope of signification: the larger the Umwelten, the greater the value. This paper argues that a robust semiotic moral theory can take into account a much wider scope of inherent value.. These consequences have positive ramifications for environmental ethics in their recognition of the natural ecological networks in which each organism is bound. This presentation of a biosemiotic model of value offers a justificatory strategy for our contemporary moral intuitions concerning our semiotic/moral relationships with living things while also productively pushing our normative ethical boundaries.     

Placebos and painkillers: is mind as real as matter?

Considerable progress has been made in our understanding of the neurobiological mechanisms of the placebo effect, and most of our knowledge originates from the field of pain and analgesia. Today, the placebo effect represents a promising model that could allow us to shed new light on mind-body interactions. The mental events induced by placebo administration can activate mechanisms that are similar to those activated by drugs, which indicates a similarity between psychosocial and pharmacodynamic effects. These new neurobiological advances are already changing our conception of how clinical trials and medical practice must be viewed and conducted.     

Multi-Level Semiosis: a Paradigm of Emergent Innovation

In this introductory article to the special issue on Multi-level semiosis we attempt to stage the background for qualifying the notion of “multi-levelness” when considering communication processes and semiosis in all life forms, i.e. from the cellular to the organismic level. While structures are organized hierarchically, communication processes require a kind of processual organization that may be better described as being heterarchical. Theoretically, the challenge arises in the temporal domain, that is, in the developmental and evolutionary dimension of dynamic semiotic processes. We discuss the importance of this fundamental difference in order to explain how levels, domains and orders of magnitude, on the one hand, and synchronic and diachronic processes, on the other, contribute to the overall organization of every living being. To account for such multi-level organization, semiotic freedom is assumed to be a scalar property that endows living systems at different levels and domains with the capacity to ponder selectively the overall structural coherence and functional compatibility of their heterarchical processing, which is increasingly less conditioned by the underlying molecular determinism.     

Pharmacological and Expectancy Effects of a Low Amount of Alcohol Drinking on Outcome Valuation and Risk Perception in Males and Females

The high-dose, alcohol-induced influences on risk perception and loss aversion depend on sex. On the other hand, low-dose alcohol has less effect on risky behavior. However, the effect of low-dose alcohol on subjective valuation of gain or loss and also the effect of placebo (expectancy of alcohol) on risk perception have not been fully investigated. We investigated the effects of low-dose alcohol (0.02 g/100 ml blood alcohol concentration) and placebo effects on subjective risk perception and subjective valuation of uncertain gain and loss in females and males. Participants in the control group and the placebo group were served alcohol-free, wine-flavored beverage and participants of alcohol group were served wine (14% alcohol). The placebo group was not informed that the drink was not alcohol but the control group was informed. Then paper–pencil tasks for subjective risk perception and valuation of gain or loss were performed 45 min after drinking the beverage. The participants were asked to draw the line on a 180 mm scale for each question. The placebo effects as well as the low-dose alcohol effects were observed in subjective valuations of gain or loss. Except for effect of beverages, a gender difference was also observed for subjective likelihood. The females estimated a low-probability loss as more likely and estimated a high-probability gain as less likely than did the males. From the Stevens’ law fitting analysis, the placebo, not alcohol, significantly induced the psychophysical effect of the subjective valuation of gain or loss. These results indicate that the psychological effects of expectancy of alcohol (placebo) could be a major factor in changing the subjective valuation of gain or loss over the pharmacological effects of a small amount of alcohol (like a glass of wine). Furthermore, these results also indicate that gender differences should be taken into account when investigating pharmacological or psychological effect on decision-making.     

The placebo response: its putative role as a functional salutogenic mechanism of the central nervous system

The concept of placebo has evolved over time. Generally believed to be the basis of the premodern pharmacopoeia, the placebo has been adopted in practice as a harmless but unscientific approach towards alleviating symptoms. Currently, many medical scientists view placebos pejoratively as confounding elements in the analysis of randomized control trials.This article examines the changing attitudes towards placebos and the persistent controversies that surround their administration. The possible role of the placebo response as a functional salutogenic brain mechanism is considered, and elements of Edelman's neurobiological model of self and attractor theory are combined to explain how a unitary response by the central nervous system might yield diverse placebo effects. It is concluded that placebo responses are rooted in the complexity of mind/body interactions and that their underlying physiological mechanisms may be elucidated via methods that directly examine brain activity as the basis of subjective experience.     

Towards an Evolutionary Biosemiotics: Semiotic Selection and Semiotic Co-option

In biosemiotics, living beings are not conceived of as the passive result of anonymous selection pressures acted upon through the course of evolution. Rather, organisms are considered active participants that influence, shape and re-shape other organisms, the surrounding environment, and eventually also their own constitutional and functional integrity. The traditional Darwinian division between natural and sexual selection seems insufficient to encompass the richness of these processes, particularly in light of recent knowledge on communicational processes in the realm of life. Here, we introduce the concepts of semiotic selection and semiotic co-option which in part represent a reinterpretation of classical biological terms and, at the same time, keep explanations sensitive to semiosic processes taking place in living nature. We introduce the term ‘semiotic selection’ to emphasize the fact that actions of different semiotic subjects (selectors) will produce qualitatively different selection pressures. Thereafter, ‘semiotic co-option’ explains how semiotic selection may shape appearance in animals through remodelling existing forms and relations. Considering the event of co-option followed by the process of semiotic selection enables us to describe the evolution of semantic organs.     

Motivation and placebos: do different mechanisms occur in different contexts?

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic-pituitary-adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.     

Dicent Symbols in Non-Human Semiotic Processes

Against the view that symbol-based semiosis is a human cognitive uniqueness, we have argued that non-human primates such as African vervet monkeys possess symbolic competence, as formally defined by Charles S. Peirce. Here I develop this argument by showing that the equivocal role ascribed to symbols by ??folk semiotics?? stems from an incomplete application of the Peircean logical framework for the classification of signs, which describes three kinds of symbols: rheme, dicent and argument. In an attempt to advance in the classifying semiotic processes, Peirce proposed several typologies, with different degrees of refinement. Around 1903, he developed a division into ten classes. According to this typology, symbols can be further analysed in three subclasses (rheme, dicent, argument). I proceed to demonstrate that vervet monkeys employ dicent symbols. There are remarkable implications of this argument since ??symbolic species theory?? fails to explore the vast Peircean semiotic philosophy to frame questions regarding the emergence and evolution of symbolic processes.     

Placebo, meaning, and health

Placebos are boon and bane to medical theory and clinical practice. On the one hand, randomized controlled trials employ concealed allocations of placebo to control for effects not due to specific pharmacological mechanisms. As a result, nearly all of evidence-based medicine derives from principles and practices based on placebo. On the other hand, medical researchers and physicians have tended to ignore, minimize, or deride placebos and placebo effects, perhaps due to values emphasizing scientific understanding of mechanistic pathways. We argue that intention, expectation, culture, and meaning are central to placebo-effect phenomena and are substantive determinants of health. We introduce three dualities that are integral to placebo/meaning phenomena: body-mind, subconscious-conscious, and passive-active. These placebo-related dualities should be acknowledged, explored with research, and incorporated in theory. While we view consideration of placebo and meaning effects as essential to any adequate understanding of human health, we feel that lessons from this area of inquiry may already provide practical tools for astute clinicians. Toward this end, we list eight specific clinical actions: speak positively about treatments, provide encouragement, develop trust, provide reassurance, support relationships, respect uniqueness, explore values, and create ceremony. These clinical actions can empower patients to seek greater health and may provide a healthful sense of being cared for.     

Behavioural conditioning as the mediator of placebo responses in the immune system

Current placebo research postulates that conditioning processes are one of the major mechanisms of the placebo response. Behaviourally conditioned changes in peripheral immune functions have been demonstrated in experimental animals, healthy subjects and patients. The physiological mechanisms responsible for this 'learned immune response' are not yet fully understood, but some relevant afferent and efferent pathways in the communication between the brain and the peripheral immune system have been identified. In addition, possible benefits and applicability in clinical settings have been demonstrated where behaviourally conditioned immunosuppression attenuated the exacerbation of autoimmune diseases, prolonged allograft survival and affected allergic responses. Here, we summarize data describing the mechanisms and the potential clinical benefit of behaviourally conditioned immune functions, with particular focus on learned placebo effects on allergic reactions.