Irving Kirsch

• University of Plymouth

Trait responsiveness to verbal suggestions (suggestibility) is relevant to a diverse array of clinical and experimental psychological phenomena. An unresolved question is whether different forms of suggestibility, such as direct verbal suggestibility and indirect (interrogative and sensory) suggestibility, comprise a uniform, superordinate trait or...

Objective To investigate the efficacy and safety of open-label placebos (OLP) in premenstrual syndrome (PMS). Design Randomised controlled trial. Setting Switzerland, 2018–2020. Participants 150 women (18–45 years of age) with PMS or premenstrual dysphoric disorder. Intervention Random assignment (1:1:1) to treatment as usual (TAU), OLP without...

Trait responsiveness to verbal suggestions (suggestibility) is relevant to a diverse array of clinical and experimental psychological phenomena. An unresolved question is whether different forms of suggestibility, such as direct verbal suggestibility and indirect (interrogative and sensory) suggestibility, comprise a uniform, superordinate trait or...

Objective Expectations are highlighted as a key component in placebo effects. However, there are different approaches to whether and how placebo studies should account for expectations, and the direct contribution has yet to be estimated in meta-analyses. Using different methodological approaches, this meta-analysis and systematic review examines t...

This book sheds light on the translation of current mechanistic research on placebo effects to develop comprehensive and adequate strategies for better symptom management and treatment. This book identifies three core aspects to bridge state-of-the-art concepts with day-to-day clinical practice. First, lessons from mechanistic placebo research indi...

Background The efficacy of open-label placebos (OLPs) has been increasingly demonstrated and their use holds promise for applications compatible with basic ethical principles. Taking this concept one step further an imaginary pill (IP) intervention without the use of a physical pill was developed and tested in a randomized controlled trial (RCT). T...

Social interactions such as the patient-clinician encounter can influence pain, but the underlying dynamic interbrain processes are unclear. Here, we investigated the dynamic brain processes supporting social modulation of pain by assessing simultaneous brain activity (fMRI hyperscanning) from chronic pain patients and clinicians during video-based...

Objective: Placebo responses are significantly higher in children than in adults, suggesting a potential underused treatment option in pediatric care. To facilitate the clinical translation of these beneficial effects, we explored physicians' current practice, opinions, knowledge, and likelihood of recommending placebos in the future. Methods: A...

Transliminality may be considered as the tendency for an individual to experience a blurring of boundaries between unconscious and conscious states. The purpose of this study was to assess the relationship between transliminality, suggestibility (hypnotic and imaginative) and a range of other personality traits. Despite several hypotheses being pro...

Placebos have been shown to be beneficial for various conditions even if administered with full transparency. Hence, so-called open-label placebos (OLPs) offer a new way to harness placebo effects ethically. To take this concept one step further, this study aimed at evaluating placebo effects without the use of a physical placebo, i.e., by imaginin...

In placebo research, expectations are highlighted as one of the most influential subjective factors. While some studies have shown a relationship between expectations and pain relief, others have not. However, little is known about how methods of assessment of expectations may affect these conclusions. One of the fundamental considerations is that...

The patient-clinician therapeutic alliance is a powerful modulator shaping patients’ treatment experience and clinical outcomes. Before and after a 3-week electro-acupuncture intervention (6 sessions), fMRI hyper-scanning was applied to investigate the influence of either an Augmented (warm/attentive) or a Limited (neutral/business-like) clinician...

Objective: There is growing evidence that open-label placebo (OLP) may be an efficacious treatment for chronic and functional conditions. However, patient-level predictors of response to OLP have not been clearly identified. The aim of this study is to evaluate psychological predictors of response to OLP and to compare this to double-blind placebo...

Music interventions accommodate the profound need for non-pharmacological pain treatment. The analgesic effect of listening to music has been widely demonstrated across studies. Yet, the specific mechanisms of action have still to be elucidated. Although the endogenous opioid and dopamine systems have been suggested to play an important role, a dir...

Background & Aims Many of the reported adverse events in clinical trials of IBS are extra-intestinal symptoms, which are typically assessed by open-ended questions during the trial and not at baseline. This may lead to misattribution of some pre-existing symptoms as side effects to the treatment. Methods The current study analyzed data from a 6-we...

Patient–clinician concordance in behavior and brain activity has been proposed as a potential key mediator of mutual empathy and clinical rapport in the therapeutic encounter. However, the specific elements of patient–clinician communication that may support brain-to-brain concordance and therapeutic alliance are unknown. Here, we investigated how...

While patient/clinician relationships significantly impact pain outcomes, the behavioral and neural mechanisms supporting this phenomenon are unknown. Specifically, the precise role of facial expressions in contributing to analgesia and brain-to-brain communication has not been investigated. In this Hyperscan fMRI study, we explored how pain-relate...

Research suggests that a good patient-clinician therapeutic alliance can improve clinical outcomes. In this ongoing, longitudinal study, we applied fMRI hyper-scanning to determine whether behavioral, neural, and clinical variables associated with the therapeutic relationship between chronic pain patients and their clinicians influences clinical ou...

The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional neuroimaging studies of evoked pain under stimulus-intensity-matched placebo and control conditions, encompassing 603 healthy participants from 20 (out of 28 eligible) studies. We f...

It is commonly believed that blinding to treatment assignment is necessary for placebos to have an effect. However, placebos administered without concealment (i.e., open-label placebos [OLP]) have recently been shown to be effective in some conditions. This study had two objectives: first, to determine whether OLP treatment is superior to no-pill c...

Expectancies can shape pain and other experiences. Generally, experiences change in the direction of what is expected (i.e., assimilation effects), as seen with placebo effects. However, in case of large expectation-experience discrepancies, experiences might change away from what is expected (i.e., contrast effects). Previous research has demonstr...

Long-term follow-up of patients treated with open-label placebo (OLP) are non-existent. Herein, we report a 5-year follow-up of a three-weeks OLP randomized controlled trial (RCT) in chronic low back pain patients. We re-contacted the original participants of original RCT and reassessed their pain, disability, and use of pain medication. We obtaine...

Introduction: Clinical and laboratory studies demonstrate that placebo and nocebo effects influence various symptoms and conditions after the administration of both inert and active treatments. Objective: There is an increasing need for up-to-date recommendations on how to inform patients about placebo and nocebo effects in clinical practice and...

The patient-clinician interaction can powerfully shape treatment outcomes such as pain but is often considered an intangible “art of medicine” and has largely eluded scientific inquiry. Although brain correlates of social processes such as empathy and theory of mind have been studied using single-subject designs, specific behavioral and neural mech...

Background and aim: Despite recent publications, practitioners remain unfamiliar with the current terminology related to the placebo and nocebo phenomena observed in clinical trials and practice, nor with the factors that modulate them. To cover the gap, the European Headache Federation appointed a panel of experts to clarify the terms associated...

This paper connects findings from the field of placebo studies with research into patients’ interactions with their clinician’s visit notes, housed in their electronic health records. We propose specific hypotheses about how features of clinicians’ written notes might trigger mechanisms of placebo and nocebo effects to elicit positive or adverse he...

The patient-clinician interaction can powerfully shape treatment out-comes such as pain, but is often considered an intangible 'art-of-medicine', and has largely eluded scientific inquiry. Although brain correlates of social processes such as empathy and theory-of-mind have been studied using single-subject designs, the specific behavioral and neur...

We present 21 prominent myths and misconceptions about hypnosis in order to promulgate accurate information and to highlight questions for future research. We argue that these myths and misconceptions have (a) fostered a skewed and stereotyped view of hypnosis among the lay public, (b) discouraged participant involvement in potentially helpful hypn...

Importance Placebo responses in the treatment of erectile dysfunction (ED) are poorly described in the literature to date. Objective To quantify the association of placebo with ED outcomes among men enrolled in placebo-controlled, phosphodiesterase 5 inhibitor (PDE5I) trials. Data Sources For this systematic review and meta-analysis, a database s...

Introduction Recent evidence suggests that for certain clinical conditions, placebos can improve clinical outcomes even without deception. These so-called open-label placebos (OLPs) bear the advantage of a significant lower risk of adverse events and comply with ethical principles. Although premenstrual syndrome (PMS) seems to be considerably susce...

Over 11 million people in the United States report opioid misuse, almost exclusively (>90%) from prescription opioids [1]. Doctors are facing increasing pressure to reduce opioid prescriptions, particularly for acute pain. In the United States, nearly 50% of the states passed legislation between 2016 and 2017 that regulated initial opioid prescript...

Side effects are frequent in pharmacological pain management, potentially preceding analgesia and limiting drug tolerability. Discussing side effects is part of informed consent, yet can favor nocebo effects. This study aimed to test whether a positive suggestion regarding side effects, which could act as reminders of the medication having been abs...

The single-arm first phase of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was designed to assess the efficacy of a selective serotonin reuptake inhibitor in “real-world” patients. STAR*D improvement scores and response rates based on the Hamilton Rating Scale for Depression (HRSD), which had been designated as the prim...

Background: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching int...

Objectives Expectation can significantly modulate pain and treatment effects. This study aims to investigate if boosting patients' expectancy can enhance the treatment of knee osteoarthritis (KOA), and its underlying brain mechanism. Methods Seventy-four KOA patients were recruited and randomized to three groups: boosted acupuncture (with a manipu...

Placebo treatments and healing rituals share much in common, such as the effects of expectancy, and have been used since the beginning of human history to treat pain. Previous mechanistic neuroimaging studies investigating the effects of expectancy on placebo analgesia have used young, healthy volunteers. Using functional magnetic resonance imaging...

Importance Depressive disorders (DDs), anxiety disorders (ADs), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) are common mental disorders in children and adolescents. Objective To examine the relative efficacy and safety of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors...

Research on open-label placebos questions whether deception is a necessary characteristic of placebo effects. Yet, comparisons between open-label and deceptive placebos are lacking. We therefore assessed effects of open-label and deceptive placebos in comparison to no treatment with a standardized experimental heat pain paradigm in a RCT in healthy...

Background Placebo medications, by definition, are composed of inactive ingredients that have no physiological effect on symptoms. Nonetheless, administration of placebo in randomized controlled trials (RCTs) and in clinical settings has been demonstrated to have significant impact on many physical and psychological complaints. Until recently, conv...

Objective: To determine the placebo component of treatment responses in patients with intellectual disability (ID). Methods: A statistical meta-analysis comparing bias-corrected effect sizes (Hedges g) of drug responses in open-label vs placebo-controlled clinical trials was performed, as these trial types represent different certainty of receiv...

In randomized controlled trials (RCTs), medication side effects may lead to beliefs that one is receiving the active intervention and enhance active treatment responses, thereby majoring drug-placebo differences. We tested these hypotheses with an experimental double-blind RCT of a nonsteroidal anti-inflammatory medication (NSAID) with and without...

Objectifs Le but de cette étude est de déterminer s’il existe une réponse au placebo chez les patients déficients intellectuels (DI) d’origine génétique. Ces patients présentent en effet une atteinte des capacités qui semblent cruciales pour susciter une réponse au placebo. Matériel et méthodes Nous avons réalisé une méta-analyse (logiciel CMA) co...

Objective: To assess parental attitudes regarding placebo use in pediatric randomized controlled trials and clinical care. Study design: Parents with children under age 18 years living in the US completed and submitted an online survey between September and November 2014. Results: Among all 1300 participants, 1000 (76.9%; 538 mothers and 462 f...

This randomized controlled trial was performed to investigate whether placebo effects in chronic low back pain could be harnessed ethically by adding open-label placebo (OLP) treatment to treatment as usual (TAU) for 3 weeks. Pain severity was assessed on three 0- to 10-point Numeric Rating Scales, scoring maximum pain, minimum pain, and usual pain...

Background: Expectancy is widely accepted as a key contributor to placebo effects. However, it is not known whether non-conscious expectancies achieved through semantic priming may contribute to placebo analgesia. In this study, we investigated if an implicit priming procedure, where participants were unaware of the intended priming influence, aff...

Our experience with the world is shaped not only directly through personal exposure but also indirectly through observing others and learning from their experiences. Using a conditioning paradigm, we investigated how directly and observationally learned information can affect pain perception, both consciously and non-consciously. Differences betwee...

This study explores the conceptual relationship between the placebo effect and psychotherapy. There is considerable evidence that the placebo effect can be exceptionally powerful under some circumstances. This begs the question: How much of the effectiveness of psychotherapy is attributable to the placebo effect? In an effort to answer this questio...

Background: Genetically determined Intellectual Disability (ID) is an intractable condition that involves severe impairment of mental abilities such as learning, reasoning and predicting the future. As of today, little is known about the placebo response in patients with ID. Objective: To determine if placebo response exists in patients with gen...

Significance It is unclear to what extent new learning can take place outside of conscious awareness. In the present study, we used psychophysical measures and classical conditioning to establish whether psychologically mediated analgesic and hyperalgesic responses could be acquired by unseen (subliminally presented) stimuli. Our study demonstrates...

The Division 30 (American Psychological Association)'s revised definition of hypnosis (2014) is analyzed, and it is considered to be really an old definition, written by Spiegel & Spiegel in 1987. In addition, the biases of the new definition are analyzed, concluding that, as a whole, it alters the consensus of other definitions, which hinders rese...

Hypnosis has long generated controversy as a recall-enhancement method. Concerns about hypnosis are warranted by findings of a tradeoff between the number of memories recalled and memory accuracy. Moreover, witnesses often express confidence in hypnotically augmented remembrances, regardless of their accuracy, increasing the risk of juror bias stem...

This article elucidates an integrative model of hypnosis that integrates social, cultural, cognitive, and neurophysiological variables at play both in and out of hypnosis and considers their dynamic interaction as determinants of the multifaceted experience of hypnosis. The roles of these variables are examined in the induction and suggestion stage...

Fundamental aspects of human behavior operate outside of conscious awareness. Yet, theories of conditioned responses in humans, such as placebo and nocebo effects on pain, have a strong emphasis on conscious recognition of contextual cues that trigger the response. Here, we investigated the neural pathways involved in nonconscious activation of con...

Background Attention to and perception of physical sensations and somatic states can significantly influence reporting of complaints and symptoms in the context of clinical care and randomized trials. Although anxiety and high neuroticism are known to increase the frequency and severity of complaints, it is not known if other personality dimensions...

Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly...

Objective: Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD p...

Hypnosis comprises two components: an induction procedure centering on the suggestion to enter a hypnotic state, and imaginative suggestions for various changes in experience and behavior. Hypnotherapy is the addition of hypnosis to a psychological or medical treatment. Research indicates that hypnosis can augment the effects of psychological treat...

The effects of posthypnotic suggestion on health-related behavior, using a behavioral measure of adherence, were investigated. Three hundred twenty-three students covering the full range of hypnotic suggestibility were prescribed an easy (mood rating) or a difficult (physical activity) task. Participants were randomly assigned to receive either a)...

Expectancy and conditioning are often tested as opposing explanations of placebo analgesia, most commonly by pitting the effects of a conditioning procedure against those of a verbally induced expectation for pain reduction. However, conditioning procedures can also alter expectations, such that the effect of conditioning on pain might be mediated...

Information provided to patients is thought to influence placebo and drug effects. In a prospective, within-subjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a control. In six subsequent migra...

In this study participants were provided with either the standard rationale that accompanies the Harvard Group Scale of Hypnotic Susceptibility: A (Shor & Orne, 196224. Shor , R. E. and Orne , E. C. 1962. Harvard Group Scale of Hypnotic Susceptibility, Form A, Palo Alto, CA: Consulting Psychologists Press. View all references) or a rationale that...

Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditionin...

To investigate the effectiveness of non-benzodiazepine hypnotics (Z drugs) and associated placebo responses in adults and to evaluate potential moderators of effectiveness in a dataset used to approve these drugs. Systematic review and meta-analysis. US Food and Drug Administration (FDA). Randomised double blind parallel placebo controlled trials o...

Appendix 3: Full details of studies included

Appendix 2: Modified Jadad score

Appendix 1: Details of how to obtain drug trial data from FDA

Neuroimaging studies have suggested the presence of alterations in the anatomo-functional properties of the brain of patients with chronic pain. However, investigation of the brain circuitry supporting the perception of clinical pain presents significant challenges, particularly when using traditional neuroimaging approaches. While potential neuroi...

Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional...

The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we per...

A controversy in the field of hypnosis has centered on the question of whether there is a uniquely hypnotic state of consciousness and, if so, whether it is causally related to responsiveness to suggestion. Evidence from brain imaging studies has been used to support claims for various altered state hypotheses, without resolving the debate. The des...

Our meta-analysis examining the efficacy of antidepressant medication (Kirsch et al. 2008), based on trials submitted to the Food and Drug Administration (FDA) for antidepressant drug approval, concluded that clinically significant improvement in depression attributable to antidepressants as opposed to placebo appeared only for samples with excepti...

Prémio de Melhor Poster

This functional Magnetic Resonance Imaging (fMRI) study investigated high and low suggestible people responding to two visual hallucination suggestions with and without a hypnotic induction. Participants in the study were asked to see color while looking at a grey image, and to see shades of grey while looking at a color image. High suggestible par...

In prospective experimental studies in patients with asthma, it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention. We compared the effects of a bronchodilator, two placebo interventions, and no intervention on outcomes in patients with asthma. In a doub...

Theoretical positions on the altered-state issue are viewed on a continuum rather than a dichotomy. While differences between some pairs of positions have little or no substantive interest, others are important to understanding the nature of hypnotic phenomena. Recent brain imaging data from the University of Hull are reviewed with respect to their...

Although the induction of a hypnotic state does not seem necessary for suggestive modulation of the Stroop effect, this important phenomenon has seemed to be dependent on the subject's level of hypnotic suggestibility. Raz and Campbell's (2011) study indicates that suggestion can modulate the Stroop effect substantially in very low suggestible subj...

This article reports a consensus that was reached at an Advanced Workshop in Experimen-tal Hypnosis held as part of the joint annual conference of the British Society of Medical and Dental Hypnosis (BSMDH) and the British Society of Experimental and Clinical Hyp-nosis (BSECH). The unanimous consensus was that conventional definitions of hypnosis an...

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Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irrit...

To assess the effects of modeling and its interaction with gender in the production of psychogenic symptoms. Healthy volunteers were asked to inhale an inert substance described as a suspected environmental toxin that had been reported to provoke 4 physical symptoms. Subsequently, half of the participants observed a confederate inhale and display t...

Topics include: defining hypnosis; historical background of hypnosis and hypnotherapy; indications and contraindications for the use of hypnosis in therapy; and basic hypnotic procedures (introducing hypnosis, a standard hypnotic induction, other induction techniques, deeping techniques, posthypnotic suggestions, preparing for subsequent sessions,...

The Handbook of Clinical Hypnosis is divided into sections that cover general clinical considerations, hypnosis theoretical models, hypnotic techniques, specific clinical applications, and contemporary issues. The book is intended for anyone who wishes to learn about clinical hypnosis. It introduces the novice hypnotherapist to the basics of hypno...

We examined two potential correlates of hypnotic suggestibility: dissociation and cognitive inhibition. Dissociation is the foundation of two of the major theories of hypnosis and other theories commonly postulate that hypnotic responding is a result of attentional abilities (including inhibition). Participants were administered the Waterloo-Stanfo...

To evaluate new generation antidepressants in relation to the placebo response. I review meta-analyses in which response to antidepressant medication and response to placebo were calculated. All but one of these meta-analyses included unpublished as well as published trials. Most trials failed to show a significant advantage of SSRIs over inert pla...

To determine whether placebo responses can be explained by characteristics of the patient, the practitioner, or their interpersonal interaction. We performed an analysis of videotape and psychometric data from a clinical trial of patients with irritable bowel syndrome who were treated with placebo acupuncture in either a warm empathic interaction (...

The 'default mode' network refers to cortical areas that are active in the absence of goal-directed activity. In previous studies, decreased activity in the 'default mode' has always been associated with increased activation in task-relevant areas. We show that the induction of hypnosis can reduce anterior default mode activity during rest without...

It is well established that expectation can significantly modulate pain perception. In this study, we combined an expectancy manipulation model and fMRI to investigate how expectation can modulate acupuncture treatment. Forty-eight subjects completed the study. The analysis on two verum acupuncture groups with different expectancy levels indicates...

Recent advances in placebo research have demonstrated the mind's power to alter physiology. In this study, we combined an expectancy manipulation model with both verum and sham acupuncture treatments to address: 1) how and to what extent treatment and expectancy effects - including both subjective pain intensity levels (pain sensory ratings) and ob...