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Background: Withdrawal from addictive drugs can be reduced by administering placebo deceptively, but in the clinic it is unethical to deceive the patient. Open-label placebo effects have been observed across a range of psychophysiological phenomena, and may also apply to drug withdrawal. Method: 24-hour abstinent heavy coffee drinkers ( N = 61) rated their caffeine withdrawal symptoms before being allocated to one of three groups. The Deceptive group was given decaffeinated coffee (decaf) and told it was caffeinated, the Open-Label group given decaf and told it was decaf and the Control group given water and told it was water. After 45 min, caffeine withdrawal was measured again. All participants rated their expectancies of withdrawal reduction from caffeinated coffee, decaf and water prior to being randomised and the end of the study. Results: There was a significant 9.5-point reduction in caffeine withdrawal in the Open-Label group (95% confidence interval (CI): 4.7, 14.3; p = 0.002), which was 8.6 points less than the Deceptive group (95%CI: 0.4, 16.8; p = 0.014) but 8.9 points greater than the Control group (95%CI: 0.6, 17.2; p = 0.012). Pre-randomisation, participants expected caffeinated coffee to reduce their withdrawal symptoms the most, followed by water and decaf, Pre-randomisation expectancy of withdrawal was only associated with amount of withdrawal reduction in the Deceptive group. Conclusion: It appears as if open-label placebo caffeine (i.e. decaf) can reduce caffeine withdrawal symptoms, even when people do not hold a conscious expectancy it will do so. There may be ways to integrate open-label placebo procedures into clinical interventions for drug dependence without violating informed consent.

Despite the theoretical prominence of expectancy and anxiety as potential mechanisms of the nocebo effect, not all studies measure expectancy and/or anxiety, and there are inconsistent findings among those that do. The present study sought to systematically review and meta-analyse available data to evaluate the relationship between expectancy, anxiety and the nocebo effect. The two key questions were: (1) whether nocebo manipulations influence expectancy and anxiety; and (2) whether expectancy and anxiety are associated with the subsequent nocebo effect. Fifty-nine independent studies (

Cognitive bias modification for interpretation (CBM-I) is an effective intervention for anxiety, but there is only a single trial in people with chronic pain. The aim of this randomized controlled trial was to test CBM-I with and without psychoeducation for people with chronic pain. We randomized 288 participants to 4 groups comprising treatment (CBM-I vs placebo) with or without psychoeducation. One hundred and eighty-three participants (64%) completed 4, 15-minute training sessions over 2 weeks. The coprimary outcomes were pain interference and pain intensity. We also measured interpretation bias, fear of movement, catastrophizing, depression, anxiety, and stress. Participants with more psychopathology at baseline were more likely to dropout, as were those allocated to psychoeducation. Intention-to-treat analyses using linear mixed models regression were conducted. Training effects of CBM-I were found on interpretation bias, but not a near-transfer task. Cognitive bias modification of interpretation improved both primary outcomes compared with placebo. For pain interference, there was also a main effect favoring psychoeducation. The CBM-I group improved significantly more than placebo for fear of movement, but not catastrophizing, depression, or anxiety. Cognitive bias modification of interpretation reduced stress but only for those who also received psychoeducation. This trial shows that CBM-I has promise in the management of pain, but there was limited evidence that psychoeducation improved the efficacy of CBM-I. Cognitive bias modification of interpretation was administered entirely remotely and is highly scalable, but future research should focus on paradigms that lead to better engagement of people with chronic pain with CBM-I.

Background Social learning can be highly adaptive—for example, avoiding a hotplate your friend just burnt themselves on—but it has also been implicated in symptom transmission. Social learning is particularly pertinent given the rapid increase in the use of online mediums for social interaction. Yet, little is known about the social transmission of symptoms online or social chains extending further than a single model–observer interaction. Purpose To explore whether socially induced symptoms could be propagated through a three-generation social transmission chain in an online setting. Methods We explored the social transmission of cybersickness following a virtual reality (VR) experience through online webcam interactions. One hundred and seventy-seven adults viewed a VR video in one of four links along a social transmission chain, after: viewing an actor model cybersickness to the VR video (First-Generation); viewing the First-Generation participant undergo VR (Second-Generation); viewing the Second-Generation participant undergo VR (Third-Generation); or naïve (Control). Results Cybersickness was strongest in First-Generation participants, indicating social transmission from the model. This was mediated by expectancy and anxiety. Whether or not subsequent generations experienced cybersickness depended on what the observed participant verbally reported, which is consistent with social transmission. Conclusions Results demonstrate that symptoms can be readily transmitted online, and that expectancy and anxiety are involved. Although it is inconclusive as to whether symptoms can propagate along a social transmission chain, there is some evidence of protection from symptoms when a model who does not report any symptoms is observed. As such, this research highlights the role of social transmission in the modulation of symptoms through virtual mediums.

Mindfulness apps are becoming popular treatments for chronic pain and mental health, despite mixed evidence supporting their efficacy. Further, it is unclear whether improvements in pain are due to mindfulness-specific effects or placebo effects because no trials have compared mindfulness against a sham control. The objective of this study was to compare mindfulness against two sham conditions with differing proximity to mindfulness to characterize the relative contributions of mindfulness-specific and non-specific processes on chronic pain. We assessed changes in pain intensity and unpleasantness and mindfulness-specific and non-specific pain-related processes in 169 adults with chronic or recurrent pain randomized to receive a single 20-minute online session of mindfulness, specific sham mindfulness, general sham mindfulness or audiobook control. Mindfulness was not superior to shams for reducing pain intensity or un-pleasantness and no differential engagement of theorized mindfulness-specific processes was observed. However, mindfulness and both shams reduced pain unpleasantness relative to audi-obook control, with expectancy most strongly associated with this effect. Sham specificity had no influence on expectancy or credibility ratings, pain catastrophizing, nor pain effects. These findings suggest that improvements in chronic pain unpleasantness following a single session of online-delivered mindfulness meditation may be driven by placebo effects. Non-specific treat-ment effects including placebo expectancy and pain catastrophizing may drive immediate pain attenuation rather than theorized mindfulness-specific processes themselves. Further research is needed to understand whether mindfulness-specific effects emerge following longer durations of online training.

Background Choice has been proposed as a method of enhancing placebo effects. However, there have been no attempts to systematically evaluate the magnitude, reliability, and moderators of the influence of choice on the placebo effect. Purpose To estimate the effect size of choice on the placebo effect and identify any moderators of this effect. Methods Web of Science, PsycINFO, EMBASE, and PubMed were systematically searched from inception to May 2021 for studies comparing placebo treatment with any form of choice over its administration (e.g., type, timing) to placebo treatment without choice, on any health-related outcome. Random-effects meta-analysis was then used to estimate the effect size associated with the influence of choice on the placebo effect. Meta-regression was subsequently employed to determine the moderating effect of factors such as type of choice, frequency of choice, and size of the placebo effect without choice. Results Fifteen independent studies (N = 1,506) assessing a range of conditions, including pain, discomfort, sleep difficulty, and anxiety, met inclusion criteria. Meta-analysis revealed that choice did significantly enhance the placebo effect (Hedges’ g = 0.298). Size of the placebo effect without choice was the only reliable moderator of this effect, whereby a greater effect of choice was associated with smaller placebo effects without choice. Conclusions Treatment choice can effectively facilitate the placebo effect, but this effect appears more pronounced in contexts where the placebo effect without choice is weaker. Because most evidence to date is experimental, translational studies are needed to test whether providing choice in clinical scenarios where placebo effects are weaker may help boost the placebo effect and thereby improve patient outcomes.

Objective: Negative beliefs about medication and vaccine side-effects can spread rapidly through social communication. This has been recently documented with the potential side-effects from the COVID-19 vaccines. We tested if pre-vaccination social communications about side-effects from personal acquaintances, news reports, and social media predict post-vaccination side-effect experiences. Further, as previous research suggests that side-effects can be exacerbated by negative expectations, we assessed if personal expectations mediate the relationships between social communication and side-effect experience. Method: In a prospective longitudinal survey (N=551), COVID-19 vaccine side-effect information from three sources—social media posts, news reports, and first-hand accounts from personal acquaintances—as well as side-effect expectations, were self-reported pre-vaccination. Vaccination side-effect experience was assessed post-vaccination. Results: In multivariate regression analyses, the number of pre-vaccination social media post views (β = .17) and impressions of severity conveyed from personal acquaintances (β = .42) significantly predicted an increase in pre-vaccination side-effect expectations, and the same variables (βs = .11, .14, respectively) predicted post-vaccination side-effect experiences. Moreover, pre-vaccination side-effect expectations fully mediated the relationship between both sources of social communication and experienced side-effects from a COVID-19 vaccination. Conclusions: This study identifies links between personal acquaintance and social media communications and vaccine side-effect experiences and provides evidence that pre-vaccination expectations account for these relationships. The results suggest that modifying side-effect expectations through these channels may change the side-effects following a COVID-19 vaccination as well as other publicly discussed vaccinations and medications.

ObjectivesTo compare attitudes of mental health (MH) professionals towards trials of methylenedioxymethamphetamine-assisted psychotherapy (MDMA-AP), with a neutrally labelled pharmacotherapy trial.DesignA randomised controlled vignette study design, with experimenters blinded to group condition.SettingParticipants were recruited online via professional societies.ParticipantsPsychiatrists, psychologists and MH researchers from across Australia.InterventionsParticipants were randomly allocated to read a vignette about a trial of either MDMA-AP or a neutrally labelled pharmacotherapy.OutcomesComparison of the difference in four attitudes towards MDMA-AP and control: How likely they were to (1) recommend participating, or (2) object to participating in the trial; (3) their predicted efficacy; and (4) concerns about the safety of the trial.ResultsThere were no overall differences between professional’s attitudes towards MDMA-AP (n=51) and the control pharmacotherapy (n=43) trial vignettes. Psychiatrists were less likely to recommend participation in the MDMA-AP than the control trial (d=0.72, p=0.02), but did not differ in other attitudes. Psychologists and researchers did not differ in any attitudes. The correlation between professional experience and both: (1) concern about, and (2) strength of objection to, the trial, was higher for MDMA-AP, than control (d=0.60, p=0.01 andd=0.40, p=0.03, respectively).ConclusionsPsychiatrists, but not psychologists or researchers showed more hesitancy in recommending trials of MDMA-AP versus an unknown pharmacotherapy. Experienced MH professionals were more likely to have negative views about MDMA-AP trials than less experienced MH professionals. This may reflect the experience of prior unfulfilled pharmacotherapy innovation or exuberance associated with fewer years of practice. Research into, and implementation of, MDMA-AP may face barriers with certain MH professionals, which will need be addressed if MDMA-AP continues to show promise as an efficacious treatment.Trial registration numberThe study design was registered with the ANZCTR (ACTRN12620001068954).

A growing body of cross-cultural survey research shows high percentages of clinicians report using placebos in clinical settings. One motivation for clinicians using placebos is to help patients by capitalising on the placebo effect’s reported health benefits. This is not surprising, given that placebo studies are burgeoning, with increasing calls by researchers to ethically harness placebo effects among patients. These calls propose placebos/placebo effects offer clinically significant benefits to patients. In this paper, we argue many findings in this highly cited and ‘hot’ field have not been independently replicated. Evaluating the ethicality of placebo use in clinical practice involves first understanding whether placebos are efficacious clinically. Therefore, it is crucial to consider placebo research in the context of the replication crisis and what can be learnt to advance evidence-based knowledge of placebos/placebo effects and their clinical relevance (or lack thereof). In doing so, our goal in this paper is to motivate both increased awareness of replication issues and to help pave the way for advances in scientific research in the field of placebo studies to better inform ethical evidence-based practice. We argue that, only by developing a rigorous evidence base can we better understand how, if at all, placebos/placebo effects can be harnessed ethically in clinical settings.

Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies – overshadowing (Experiment 1) and pre-exposure (Experiment 2) – could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode ‘activated’, which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings. Perspective Nocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.

Beliefs about cause and effect, including health beliefs, are thought to be related to the frequency of the target outcome (e.g., health recovery) occurring when the putative cause is present and when it is absent (treatment administered vs. no treatment), this is known as contingency learning. However, it is unclear whether unvalidated health beliefs, where there is no evidence of cause–effect contingency, are also influenced by the subjective perception of a meaningful contingency between events. In a survey, respondents were asked to judge a range of health beliefs and estimate the probability of the target outcome occurring with and without the putative cause present. Overall, we found evidence that causal beliefs are related to perceived cause–effect contingency. Interestingly, beliefs that were not predicted by perceived contingency were meaningfully related to scores on the paranormal belief scale. These findings suggest heterogeneity in pseudoscientific health beliefs and the need to tailor intervention strategies according to underlying causes.

Background Vaccines are being administered worldwide to combat the COVID-19 pandemic. Vaccine boosters are essential for maintaining immunity and protecting against virus variants. The side effects of the primary COVID-19 vaccine (e.g., headache, nausea), however, could reduce intentions to repeat the vaccination experience, thereby hindering global inoculation efforts. Purpose The aim of this research was to test whether side effects of a primary COVID-19 vaccine relate to reduced intentions to receive a COVID-19 booster. The secondary aim was to test whether psychological and demographic factors predict booster intentions. Methods Secondary data analyses were conducted on a U.S. national sample of 551 individuals recruited through the online platform Prolific. Key measures in the dataset were side effects reported from a primary COVID-19 vaccination and subsequent intentions to receive a booster vaccine. Psychological and demographic variables that predicted primary vaccination intentions in prior studies were also measured. Results Booster intentions were high. COVID-19 booster vaccine intentions were uncorrelated with the number of side effects, intensity of side effects, or occurrence of an intense side effect from the primary COVID-19 vaccine. Correlational and regression analyses indicated intentions for a booster vaccination increased with positive vaccination attitudes, trust in vaccine development, worry about the COVID-19 pandemic, low concern over vaccine side effects, and democratic political party affiliation. Conclusions Side effects of a primary COVID-19 vaccine were not directly associated with lower intentions to receive a booster of the COVID-19 vaccine early in the pandemic. However, many variables that predict primary vaccination intentions also predict booster intentions.

Objective Meta-analyses indicate that mindfulness meditation is efficacious for chronic and acute pain, but most available studies lack active control comparisons. This raises the possibility that placebo-related processes may account, at least in part, for mindfulness effects. The objective of this study was to develop a closely matched sham mindfulness condition to establish whether placebo effects contribute to mindfulness-based interventions for pain. Methods We developed and validated a closely matched sham mindfulness intervention then compared it with 6 × 20-minute sessions of focused-attention mindfulness and a no-treatment condition in 93 healthy volunteers undergoing acute experimental heat pain. Results The sham mindfulness intervention produced equivalent credibility ratings and expectations of improvement as the mindfulness intervention but did not influence mindfulness-related processes. In contrast, mindfulness increased "observing"relative to no treatment but not sham. Mindfulness (F(1,88) = 7.06, p =.009, ηp2 = 0.07) and sham (F(1,88) = 6.47, p =.012, ηp2 = 0.07) moderately increased pain tolerance relative to no treatment, with no difference between mindfulness and sham (F(1,88) = 0.01, p =.92, ηp2 < 0.001). No differences were found for pain threshold. Similarly, neither mindfulness nor sham reduced pain intensity or unpleasantness relative to no treatment, although mindfulness reduced pain unpleasantness relative to sham (F(1,88) = 5.03, p =.027, ηp2 = 0.05). Conclusions These results suggest that placebo effects contribute to changes in pain tolerance after mindfulness training, with limited evidence of specific effects of mindfulness training on pain unpleasantness relative to sham, but not no treatment. To disentangle the specific analgesic effects of mindfulness from placebo-related processes, future research should prioritize developing and incorporating closely matched sham conditions. Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN12618001175268).

Successful blinding in double-blind RCTs is crucial for minimizing bias, however studies rarely report information about blinding. Among RCTs for depression, the rates of testing and success of blinding is unknown. We conducted a systematic review and meta-analysis of the rates of testing, predictors, and success of blinding in RCTs of antidepressants for depression. Following systematic search, further information about blinding assessment was requested from corresponding authors of the included studies. We reported the frequency of blinding assessment across all RCTs, and conducted logistic regression analyses to assess predictors of blinding reporting. Participant and/or investigator guesses about treatment allocation were used to calculate Bang's Blinding Index (BI). The BI between RCT arms was compared using meta-analysis. Across the 295 included trials, only 4.7% of studies assessed blinding. Pharmaceutical company sponsorship predicted blinding assessment; unsponsored trials were more likely to assess blinding. Meta-analysis suggested that blinding was unsuccessful among participants and investigators. Results suggest that blinding is rarely assessed, and often fails, among RCTs of antidepressants. This is concerning considering controversy around the efficacy of antidepressant medication. Blinding should be routinely assessed and reported in RCTs of antidepressants, and trial outcomes should be considered in light of blinding success or failure.

The nocebo effect is a concerning phenomenon in which adverse outcomes are triggered by the treatment context. Faasse (2019) summarises recent evidence on mechanisms of the nocebo effect, proposes ...

Recent sham-controlled studies suggest placebo effects contribute to acute pain relief after mindfulness interventions. However, the specific effects of mindfulness processes and their interaction with placebo effects remain unclear. This study aimed to characterize the role of mindfulness and placebo processes underlying mindfulness-based pain attenuation. Both treatment (focused attention mindfulness vs sham) and instruction (told mindfulness vs told sham) were manipulated in a balanced placebo design. Changes in acute heat pain were evaluated in 153 healthy adults randomized to receive 6 × 20 minutes of 1 of 4 treatment by instruction interventions or no treatment. Participants receiving any intervention demonstrated improved pain outcomes (unpleasantness, intensity, and tolerance) relative to those receiving no treatment. The instruction manipulation increased expectation for pain relief in those told mindfulness relative to those told sham, but there were no main effects or interactions of treatment or instruction on pain outcomes. However, irrespective of actual intervention received, the belief of receiving mindfulness predicted increased pain threshold and tolerance, with expectancy fully mediating the effect on pain tolerance. These findings suggest a lack of specific effects of mindfulness and instruction on acute pain. Nonetheless, participants' expectancies and beliefs about the treatment they received did predict pain relief. Together with the overall improvement after any intervention, these findings suggest that expectancy and belief may play a stronger role in attenuating acute pain in novices following brief mindfulness interventions than the actual mindfulness-specific processes or instructions delivered.

Attribute framing presents an ethically sound approach for reducing adverse nocebo effects. In past studies, however, attribute framing has not always decreased nocebo effects. The present study used a sham tDCS procedure to induce nocebo headaches to explore factors that may contribute to the efficacy of attribute framing. Participants (N = 174) were randomized to one of three between-subject conditions: a no-headache instruction (control) condition and two conditions in which headaches were described as either 70% likely (negative framing) to occur or 30% unlikely (positive framing) to occur. Results revealed nocebo headaches in both framing conditions, as compared to the control condition. Attribute framing did not influence headache measures recorded during the sham tDCS task, but framing did have a modest influence on one of two headache items completed after the task. Results suggest that attribute framing could have a stronger influence on delayed nocebo effect measures or retrospective symptom reports; a finding that may explain inconsistencies in the existing framing-nocebo effect literature. Exploratory analyses also revealed that low negative affect was associated with stronger nocebo and attribute framing effects, although these effects were found on only a few headache measures. It is concluded that researchers should further investigate the influence of attribute framing on nocebo headaches as a function of both timing and emotional factors.

Background Side effect warnings can contribute directly to their occurrence via the nocebo effect. This creates a challenge for clinicians and researchers, because warnings are necessary for informed consent, but can cause harm. Positive framing has been proposed as a method for reducing nocebo side effects whilst maintaining the principles of informed consent, but the limited available empirical data are mixed. Purpose To test whether positive attribute framing reduces nocebo side effects relative to negative framing, general warning, and no warning. Methods Ninety-nine healthy volunteers were recruited under the guise of a study on virtual reality (VR) and spatial awareness. Participants were randomized to receive positively framed (“7 out of 10 people will not experience nausea”), negatively framed (“3 out of 10 people will experience nausea”), general (“a proportion of people will experience nausea”), or no side effect warnings prior to VR exposure. Results Receiving a side effect warning increased VR cybersickness relative to no warning overall, confirming that warnings can induce nocebo side effects. Importantly, however, positive framing reduced cybersickness relative to both negative framing and the general warning, with no difference between the latter two. Further, there was no difference in side effects between positive framing and no warning. Conclusions These findings suggest that positive framing not only reduces nocebo side effects relative to negative framing and general warnings, but actually prevents nocebo side effects from occurring at all. As such, positive attribute framing may be a cheap and ethical way to reduce nocebo side effects.

IntroductionInsomnia is a prevalent sleep disorder that causes substantial personal and societal harm. There is evidence that placebo interventions can reduce insomnia symptoms, but this research has involved deceptively administering the placebo under the guise of a real medication (conventional placebo, CP), which has obvious ethical constraints. Open-label placebo (OLP) treatment, in which a placebo is administered with full disclosure that there are no active ingredients, has been proposed as a method of using the placebo effect ethically, but the efficacy and acceptability of OLP for insomnia is currently unknown.Methods and analysisThis study uses a cohort multiple randomised controlled trial design to compare OLP, CP and no treatment for insomnia. Two-hundred and sixty-seven participants with self-reported insomnia symptoms (Insomnia Severity Index, ISI ≥10) will be recruited into an observational study and have their sleep monitored over a 2-week period. Participants will then be randomised to one of three groups: invite to OLP, invite to CP described deceptively as a new pharmacological agent, or no invite/observational control. Those in OLP and CP accepting the invite receive identical placebos for a 2-week treatment period while sleep is monitored in all participants. The primary outcome is ISI at the end of the treatment period. Secondary outcomes include treatment uptake and clinically significant response rates, objective and subjective sleep parameters, fatigue, mood, expectancy, treatment satisfaction and side effects. Predictors of uptake and responses to OLP and CP will be explored.Ethics and disseminationThe trial has been approved by The University of Sydney Human Research Ethics Committee. Written informed consent is obtained from every participant. OLP and CP participants accepting the invite undergo an additional consent process. Results will be disseminated via peer-reviewed conference proceedings and publications.Trial registration numberACTRN12620001080910.

Pain is a ubiquitous experience encompassing perceptual, autonomic, and motor responses. Expectancy is known to amplify the perceived and autonomic components of pain, but its effects on motor responses are poorly understood. Understanding expectancy modulation of corticospinal excitability has important implications regarding deployment of adaptive and maladaptive protective behaviours in anticipation of pain. We developed a protocol to compare corticospinal excitability to expected high pain, expected low pain, and critically low pain when high pain was expected. Expecting high pain suppressed corticospinal excitability and heightened perceptual and autonomic responses to the low-pain stimulus, as with increased noxious stimulation (ie, expected high pain). Multilevel modelling revealed that perceived pain mediated the effect of both noxious stimulation and this expectancy-modulated pain on autonomic responses, but corticospinal excitability did not. These results demonstrate that merely expecting pain influenced all pain components. Findings shed new light on the aetiology of expectancy-modulated pain, whereby expecting pain mobilises the motor system to protect the body from harm by a protective withdrawal reflex, associated with reduced corticospinal excitability, and activates similar processes as increased nociceptive stimulation. This has significant practical implications for the treatment of pain, particularly in scenarios where avoidance of pain-related movement contributes to its maintenance.

Previous meta-analyses investigating attentional biases towards pain have used reaction time measures. Eye-tracking methods have been adopted to more directly and reliably assess biases, but this literature has not been synthesized in relation to pain. This meta-analysis aimed to investigate the nature and time course of attentional biases to pain-related stimuli in participants of all ages with and without chronic pain using eye-tracking studies and determine the role of task parameters and theoretically relevant moderators. After screening, 24 studies were included with a total sample of 1425 participants. Between-group analyses revealed no significant overall group differences for people with and without chronic pain on biases to pain-related stimuli. Results indicated significant attentional biases towards pain-related words or pictures across both groups on probability of first fixation (k = 21, g = 0.43, 95% confidence interval [CI] 0.15-0.71, P = 0.002), how long participants looked at each picture in the first 500 ms (500-ms epoch dwell: k = 5, g = 0.69, 95% CI 0.034-1.35, P = 0.039), and how long participants looked at each picture overall (total dwell time: k = 25, g = 0.44, 95% CI 0.15-0.72, P = 0.003). Follow-up analyses revealed significant attentional biases on probability of first fixation, latency to first fixation and dwell time for facial stimuli, and number of fixations for sensory word stimuli. Moderator analyses revealed substantial influence of task parameters and some influence of threat status and study quality. Findings support biases in both vigilance and attentional maintenance for pain-related stimuli but suggest attentional biases towards pain are ubiquitous and not related to pain status.

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 train clinicians how to disclose this information. Methods: Based on previous clinical recommendations concerning placebo and nocebo effects, a 3-step, invitation-only Delphi study was conducted among an interdisciplinary group of internationally recognized experts. The study consisted of open- and closed-ended survey questions followed by a final expert meeting. The surveys were subdivided into 3 parts: (1) informing patients about placebo effects, (2) informing patients about nocebo effects, and (3) training clinicians how to communicate this information to the patients. Results: There was consensus that communicating general information about placebo and nocebo effects to patients (e.g., explaining their role in treatment) could be beneficial, but that such information needs to be adjusted to match the specific clinical context (e.g., condition and treatment). Experts also agreed that training clinicians to communicate about placebo and nocebo effects should be a regular and integrated part of medical education that makes use of multiple formats, including face-to-face and online modalities. Conclusions: The current 3-step Delphi study provides consensus-based recommendations and practical considerations for disclosures about placebo and nocebo effects in clinical practice. Future research is needed on how to optimally tailor information to specific clinical conditions and patients’ needs, and on developing standardized disclosure training modules for clinicians.

How people choose between options with differing outcomes (explore-exploit) is a central question to understanding human behaviour. However, the standard explore-exploit paradigm relies on gamified tasks with low-stake outcomes. Consequently, little is known about decision making for biologically-relevant stimuli. Here, we combined placebo and explore-exploit paradigms to examine detection and selection of the most effective treatment in a pain model. During conditioning, where 'optimal' and 'suboptimal' sham-treatments were paired with a reduction in electrical pain stimulation, participants learnt which treatment most successfully reduced pain. Modelling participant responses revealed three important findings. First, participants' choices reflected both directed and random exploration. Second, expectancy modulated pain - indicative of recursive placebo effects. Third, individual differences in terms of expectancy during conditioning predicted placebo effects during a subsequent test phase. These findings reveal directed and random exploration when the outcome is biologically-relevant. Moreover, this research shows how placebo and explore-exploit literatures can be unified.

Psychological models of chronic pain (CP) highlight cognitive-processing biases (ie, attentional biases, interpretation biases, and attentional control) as pivotal processes that uniquely and synergistically impact the development and maintenance of CP. Very few studies explore multiple cognitive biases, and no studies have examined these 3 processes together in a CP sample. Furthermore, there is a lack of research investigating the relationship between these cognitive processes and pain-relevant variables (eg, pain intensity and pain catastrophising). The current study aimed to (1) compare attentional biases, interpretation biases, and attentional control in people with and without CP, (2) explore their interrelationships, and (3) explore their association with pain-related variables. Seventy-four participants with CP and 66 without pain volunteered. Participants completed a visual scanning task with eye tracking, a recognition task, and a flanker task. Traditional and Bayesian analysis indicated no effect of pain status on cognitive-processing biases. All participants, regardless of pain status, demonstrated attentional biases towards pain on some indices of early and late attention, but not interpretation bias or attentional control. There was weak evidence of associations between attentional biases, interpretation biases, and attentional control. Pain intensity was significantly correlated with interpretation biases, and follow-up analyses revealed people with high pain intensity demonstrated an interpretation bias towards pain significantly more than those with low pain intensity. Findings suggest that attentional biases towards pain are ubiquitous, but for people with moderate-to-severe pain, interpretation biases may have a role worthy of further research.

Background: Negative expectancies can exacerbate withdrawal symptoms via the nocebo effect. As such, information provided about dose reductions during attempts to taper a drug could contribute to withdrawal symptoms and increase the likelihood of relapse. The current study tested whether blinding participants to dose reductions during a supervised caffeine dose taper reduced these nocebo-induced withdrawal symptoms. Methods: Three groups of moderate to heavy coffee drinkers had their dose of caffeine reduced (tapered) from 300 mg per day to 0 mg over the course of five days and reported withdrawal symptoms twice daily. Groups were given differing information about how much caffeine they were receiving. An Open Reduction group was given accurate information about dose reductions. A Blind Reduction group was given no dose information whatsoever. A Deceptive Reduction group was misinformed about dose, with instructions suggesting that the dose remained on 300 mg for three days then dropped to 0 mg. Results: The Open Reduction group reported more pronounced caffeine withdrawal symptoms than the Deceptive Reduction group on the days with the greatest discrepancy between actual dose and informed dose, indicating a nocebo effect of open versus deceptive reductions. In addition, the rate of increase in reported withdrawal symptoms in the Blind Reduction and Deceptive Reduction groups was less than that of the Open Reduction group. Conclusion: These results suggest that awareness of dose reductions during a dose taper can result in a nocebo withdrawal effect, and that removing this awareness can reduce withdrawal. This has important implications for standard supervised dose-tapering practice, where patients are aware of the timing and magnitude of dose reductions.

This systematic review and meta-analysis aimed to determine the size of the placebo effect for insomnia symptoms when comparing placebo treatment with no treatment. PsycINFO, MEDLINE, and CINAHL databases were systematically searched for studies allocating participants with insomnia symptoms (diagnosed or self-reported) to receive a placebo that they were led to believe was an active treatment or to a no treatment control group. Thirteen independent studies (n = 566) met inclusion criteria. Meta-analysis indicated a reliable placebo effect whereby placebo treatment led to improved perceived sleep onset latency (SOL; Hedges g = 0.272), total sleep time (TST; Hedges g = 0.322), and global sleep quality (GSQ; Hedges' g = 0.581), when compared with no treatment. There was no effect on objective assessment of SOL, however only a few studies reported this outcome and there were insufficient sample sizes to meta-analyse other objective outcomes. Moderator analysis indicated that the placebo effect for perceived insomnia symptoms was quite consistent across different variables. The present findings provide strong evidence for placebo effects for perceived insomnia symptoms, but not on the only objective measurement with sufficient sample size to meta-analyse, namely objective SOL. This has important implications for the treatment of insomnia symptoms and the design and interpretation of clinical trials for insomnia symptoms.

IMPORTANCE: Single-blind placebo run-in (PRI) periods are common in randomized clinical trials (RCTs) of treatment for depression. They aim to increase sensitivity to detect drug effects; however, the association of PRI periods with study outcomes remains unclear. This is concerning given the costs of PRI periods to patients and investigators. OBJECTIVE: To examine the association of the use of PRI periods with the placebo response, drug response, and drug-placebo difference among RCTs of antidepressants. DATA SOURCES: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO, as well as repositories of unpublished studies, were systematically searched up to July 2021. STUDY SELECTION: Included studies were double-blind, placebo-controlled RCTs of antidepressant medication among adults with depressive disorders. DATA EXTRACTION AND SYNTHESIS: Data were extracted into a coding sheet, including the characteristics of studies, the characteristics of PRI periods, and the outcomes of studies. MAIN OUTCOMES AND MEASURES: Study outcomes were the primary depression symptom measure reported by the RCT. These outcomes were used to calculate effect sizes (Hedges g) of the within-group drug response and placebo response as well as the drug-placebo difference. Random-effects meta-analysis was used to calculate effect sizes, and subgroup analyses were used to compare outcomes depending on use of PRI periods. RESULTS: A total of 347 trials (representing 89 183 participants) were included; 174 studies (50%) reported using a single-blind PRI period. Response outcome data were available for 189 studies. Studies using PRI periods reported a smaller placebo response (g = 1.05 [95% CI, 0.98-1.11]; I(2) = 82%) than studies that did not use a PRI period (g = 1.15 [95% CI, 1.09-1.21]; I(2) = 81%; P = .02). Subgroup analysis showed a larger drug response size among studies that did not use a PRI period (g = 1.55 [95% CI, 1.49-1.61]; I(2) = 85%) than those that did use a PRI period (g = 1.42 [95% CI, 1.36-1.48]; I(2) = 81%; P = .001). The drug-placebo difference did not differ by use of PRI periods (g = 0.33 [95% CI, 0.29-0.38]; I(2) = 47% for use of a PRI period vs g = 0.34 [95% CI, 0.30-0.38]; I(2) = 54% for no use of PRI periods; P = .92). The likelihood of response to drug vs placebo also did not differ between studies that used a PRI period (odds ratio, 1.89 [95% CI, 1.76-2.03]) and those that did not use a PRI period (odds ratio, 1.77 [95% CI, 1.65-1.89]; P = .18). CONCLUSIONS AND RELEVANCE: This study suggests that RCTs using PRI periods yield smaller within-group changes across both placebo and drug groups compared with RCTs without PRI periods. The reduction in effect size across groups was equivalent in magnitude. Consequently, PRI studies do not observe larger drug-placebo differences, suggesting that they do not increase trial sensitivity. As such, given the resources and probable deception required and risk to external validity, the practice of using PRI periods in RCTs of antidepressants should be ended.

Past experimental laboratory and correlational data from observational research has shown that knowledge of the price of wine influences the consumer’s subjective experience. However, there is limited prior research that has explicitly manipulated price information in a realistic wine tasting setting. A total of 140 participants tasted three different low-, mid- and high-priced wines with open, deceptive, or no price information and rated them for taste intensity and pleasantness. In our community sample, intensity of taste ratings for open, deceptive and blind price information reflected retail prices, thus more expensive wines were rated as more intense in taste. However, while pleasantness ratings did not differ for open and no price information, deceptive up-pricing of low-price wine significantly influenced ratings for pleasantness, whereas deceptive down-pricing of high-price wine had no effect on pleasantness ratings. Thus, pricing information differentially influences the consumer’s subjective experience of wine, with no effects on intensity of taste ratings and no effects on pleasantness ratings with correct or no price information, but increased pleasantness of low-price wine when provided with a deceptive higher price. Thus, in wine may lay the truth, but its subjective experience may also lie in the price.