Open-label Placebo Research Articles

“I am open to self-belief”: A study examining the impact of open-label effects on postexercise affect and postintervention exercise behaviour

ABSTRACT The contribution of placebo effects can be measured by manipulating psychological factors, such as positive expectations for exercise outcomes, without the need for traditional placebos (such as inert substances). While placebo effects are well known, research has revealed intriguing findings suggesting that placebos can have beneficial effects even when studies are performed without deception. Open-label placebo (OLP) interventions (prescribed honestly), which harness the power of belief, may represent another effective method for enhancing the benefits of exercise effects. This study compared the efficacy of a conventional placebo intervention, an OLP intervention, and a control group among 89 individuals. Participants’ levels of affective response after exercise and exercise behaviour were assessed during the intervention period (4 weeks) and at follow-up (4 weeks). The results revealed similar levels of improvement in all outcomes across the three conditions. Both the conventional placebo and OLP intervention groups exhibited greater enhancements in postexercise enjoyment. OLP interventions demonstrated distinct advantages in terms of remembered affect and expectation fulfilment. Nonetheless, neither intervention directly stimulated postintervention exercise behaviour. Future studies should continue to explore the impact of OLP interventions on adherence to exercise behaviour.

Effects of Open-Label Placebos on Visual Food Cue Reactivity in Children and Adolescents

Background: A high level of food cue reactivity (FCR) is a risk factor for overeating and weight gain. This randomized trial investigated whether open-label placebos (OLPs: placebos honestly administered) can reduce FCR (reported appetite) in children and adolescents. Method: Children (n = 73; 8–12 years old) and adolescents (n = 187; 16–18 years old) were randomly assigned to either an OLP group or a control group (without OLP). Participants viewed images depicting food (sweets and fruits) and non-food items. Before viewing, the OLP group received a placebo for appetite reduction. Participants rated their desire to eat the depicted food items (0–100) and the perceived effectiveness of the OLP intervention. Results: The OLP exhibited a large effect in children, leading to a general reduction in appetite (group difference OLP vs. no OLP: M = −20.8; ηp2 = 0.20). This general effect was absent in adolescents, whose appetite reduction was restricted to fruits (OLP vs. no OLP: M = −8.1; ηp2 = 0.03). Additionally, children perceived the OLP as more effective than adolescents. Conclusion: The reduced response and skeptical attitudes of adolescents towards OLP treatment require further investigation.

Open-label placebos reduce weight in obesity: a randomized controlled trial

Obesity is a major public health problem worldwide. Different approaches are known to face this problem, for example, dieting, surgery, or drug interventions. It has also been shown that placebos may help to reduce weight and hunger feelings, but the use of placebos is linked to problems with respect to the patient-healthcare-provider relationship. However, recent studies demonstrated that even placebos without deception (open-label placebos) affect symptoms such as pain, anxiety, or emotional distress. Here we aimed to examine whether an open-label placebo may help to lose weight in obesity. Our study included fifty-seven overweight and obese patients who aimed to lose weight using a combination of diet and sports. Patients were randomly divided into two groups. Participants in the open-label placebo group received two placebos each day. A treatment-as-usual group received no pills. Primary outcome included changes of body weight. Secondary outcomes were change of eating behavior and self-management abilities. After 4 weeks we found that participants in the open-label placebo condition lost more weight than the treatment-as-usual group. Furthermore, OLP treatment affected eating behavior. No effects for self-management abilities were found. Although further research is necessary, open-label placebos might help individuals to lose weight.

Open-Label Placebo Injection for Chronic Back Pain With Functional Neuroimaging

Chronic back pain (CBP) is a leading cause of disability. Placebo treatments often provide as much pain relief as bona fide treatments, such as steroid injections. Open-label (honestly prescribed) placebos (OLPs) may relieve CBP without deception, but OLP mechanisms remain poorly understood. To investigate the long-term efficacy and neurobiological mechanisms of OLP for CBP. A randomized clinical trial of CBP with longitudinal functional magnetic resonance imaging (MRI) comparing OLP with usual care, with 1-year follow-up, was conducted in a university research setting and a community orthopedic clinic. Participants were individuals aged 21 to 70 years with CBP. The trial was conducted from November 2017 to August 2018, with 1-year follow-up completed by November 2019. Data analysis was performed from April 2020 to May 2024. The primary analysis was conducted on an intention-to-treat sample. Participants randomized to OLP received a 1-time subcutaneous lumbar saline injection presented as placebo accompanied by information about the power of placebo to relieve pain, alongside their ongoing care. Usual care participants continued their ongoing care. The primary outcome was pain intensity (0-10, with 0 indicating no pain and 10 the most intense) at 1 month posttreatment. Secondary outcomes included pain interference, depression, anxiety, anger, and sleep quality. Functional MRI was performed before and after treatment during evoked and spontaneous back pain. A total of 101 adults (52 [51.4%] females; mean [SD] age, 40.4 [15.4] years) with moderate severity CBP (mean [SD], 4.10 [1.25] intensity; duration, 9.7 [8.5] years) were enrolled. Compared with usual care, OLP reduced CBP intensity posttreatment (relative reduction, 0.61; Hedges g = 0.45; 95% CI, -0.89 to 0.04; P = .02). Through 1-year follow-up, pain relief did not persist, although significant benefits were observed for depression, anger, anxiety, and sleep disruption (Hedges g = 0.3-0.5; all P < .03). Brain responses to evoked back pain for OLP vs usual care increased in rostral anterior cingulate and ventromedial prefrontal cortex and decreased in somatomotor cortices and thalamus. During spontaneous pain, functional connectivity analyses identified OLP vs usual care increases in ventromedial prefrontal cortex connectivity to the rostral ventral medulla, a pain-modulatory brainstem nucleus. No adverse effects of treatment were reported by participants. In this randomized clinical trial of OLP vs usual care, a single nondeceptive placebo injection reduced CBP intensity for 1 month posttreatment and provided benefits lasting for at least 1 year posttreatment. Brain mechanisms of OLP in a clinical population overlap with those of deceptive placebos in healthy volunteers, including engagement of prefrontal-brainstem pain modulatory pathways. ClinicalTrials.gov Identifier: NCT03294148.

The effect of open-label placebo on allergic rhinitis symptoms: A systematic review and meta-analysis of randomized controlled trials.

The evidence regarding the open-label placebo effect on allergic rhinitis symptoms remains uncertain. Open-label placebo significantly reduced the frequency of symptoms in allergic rhinitis patients with similar safety profiles; however, there was no effect on the severity of symptoms and impairment due to symptoms. The statistically significant impact on symptom frequency can be considered not clinically significant.

Preoperative Anxiolysis and Treatment Expectation (PATE Trial): open-label placebo treatment to reduce preoperative anxiety in female patients undergoing gynecological laparoscopic surgery - study protocol for a bicentric, prospective, randomized-controlled trial.

One of the most common concerns of patients undergoing surgery is preoperative anxiety, with a prevalence of up to 48%. The effects of preoperative anxiety continue beyond the preoperative period and are associated with more severe postoperative pain and poorer treatment outcomes. Treatment options for preoperative anxiety are often limited as sedatives cause side effects and their efficacy remains controversial. Placebo research has shown that optimization of positive treatment expectations, as can be achieved through placebo administration and education, has clinically relevant effects on preoperative anxiety, pain and treatment outcomes. As the administration of masked placebos raises ethical questions, clinical studies have increasingly focused on the use of open, non-deceptive placebo administration (open-label placebo, OLP). The use of OLPs to reduce preoperative anxiety and modify clinically relevant postoperative outcomes has not yet been investigated. This bicentric, prospective, randomized-controlled clinical trial (PATE Trial; German Registry for Clinical Studies DRKS00033221), an associated project of the Collaborative Research Center (CRC) 289 "Treatment Expectation", aims to alleviate preoperative anxiety by optimizing positive treatment expectations facilitated by OLP. Furthermore, this study examines a potential enhancement of these effects through aspects of observational learning, operationalized by a positive expectation-enhancing video. In addition, patient's perspective on the self-efficacy and appropriateness of OLPs prior to surgery will be assessed. To achieve these objectives, female patients will be randomized into three groups before undergoing gynecological laparoscopic surgery. One group receives the OLP with a positive rationale conveyed by a study physician. A second group receives the same intervention, OLP administration and rationale provided by a physician, and additionally watches a video on OLP presenting a satisfied patient. A third group receives standard treatment as usual (TAU). Outcome measures will be effects on preoperative anxiety and postoperative experience, particularly visceral and somatic postoperative pain. As the non-deceptive administration of placebos; when indicated; may yield positive outcomes without side effects, and as current treatment of preoperative anxiety is limited, evidence from clinical placebo research has the potential to improve outcomes and patient experience in the surgical setting.

The impact of an illness perception conversation on open-label placebo response in knee osteoarthritis: A randomised controlled trial

ObjectiveTo compare the effect of an illness perception conversation (IPC), relative to a research participation conversation (RPC), on 2-week changes in knee pain in patients with knee osteoarthritis. MethodThis was a randomised single-blind trial. Patients were randomised to two matched conversations. An Illness Perception (IP) conversation concerning the participant’s knee pain-related IP or a research participation conversation, concerning the participant’s motivation for participating in research. Both conversations were followed by an open-label intraarticular saline injection in the most symptomatic knee. The primary outcome was change in knee pain from baseline to 2 weeks follow-up on a 100 mm Visual Analogue Scale (VAS). Key secondary outcomes included the Knee injury and Osteoarthritis Outcome Score (KOOS) subscales: Activities of daily living (ADL) and Quality of life (QoL). Main analyses were based on the intention-to-treat population using repeated measures mixed effects linear models. Results103 patients were randomised to the IPC group (n = 52) and the RPC group (n = 51). VAS knee pain scores changed statistically significantly from baseline to end of treatment in both groups, -13.7 (SE: 3.2) in the IPC group and -13.0 (SE: 3.1) in the RPC group with an adjusted between-group difference of -0.7 (95% CI: -8.3 to 6.9; P= 0.85). Likewise, no group differences were seen in KOOS ADL and KOOS QoL. ConclusionA conversation concerning knee pain-related IP did not augment the pain-relieving effect of an open-label placebo injection, when compared to a similar control conversation concerning motivations for participating in research. TRIAL REGISTRATIONNCT05225480

Placebo and Nocebo Effects on Sports and Exercise Performance: A Systematic Literature Review Update.

Sports performance could be affected by placebo and nocebo effects. The last literature review on placebo and nocebo effects on sports and exercise performance was published in 2019. In the past five years, several new studies have been published. This review aimed to update the previous synthesis and evaluate the results of new studies focusing on placebo or nocebo interventions in sports and exercise by determining the form and magnitude of their effect. Hence, we searched for empirical studies published from 2019 until the end of May 2024 indexed in PubMed, Medline, Web of Science, EBSCO, and Google Scholar databases. The search yielded 20 eligible studies with control or baseline-control conditions, focusing on nutritional, mechanical, and other mixed ergogenic aids. They yielded small to large placebo effects (Cohen's d) for nutritional (d = 0.86), mechanical (d = 0.38), cream and gel (d = 0.05), and open-label placebo (d = 0.16) interventions. The pooled effect size for placebo effects was moderate to large (d = 0.67), larger than in the earlier review, suggesting that placebo effects can improve motor performance even more than previously reported. However, based on five measures from three studies, the nocebo effects were almost twice as large (d = 1.20). Accordingly, the current findings support and expand the last review in the field by yielding additional support for placebo and nocebo effects in sports and exercise.

Reducing Emotional Distress with Open-Label Placebos: Assessing the Role of Motor Engagement in Pill Consumption.

It has been posited that ingesting a pill constitutes a pivotal action that facilitates the effects of open-label placebos (OLPs: placebos honestly prescribed). In the present OLP experiment, the motor components of a placebo treatment were systematically varied. The participants (n = 183) were randomly allocated to one of four groups that all viewed aversive pictures. The 'active OLP' group took a placebo pill with specific instructions concerning the sequence of motor actions for the intake. The 'usual OLP' group swallowed the pill (without specific motor instructions), while the third group received an 'imaginary OLP' (no pill intake). The fourth group applied cognitive reappraisal (CR; active control group) to reduce emotional distress. The participants rated their affective state as well as the efficacy and plausibility of the treatment approach. Moreover, blood pressure and pulse were recorded as indicators of bodily arousal. The four groups did not differ in their valence ratings and physiological measures. The 'imaginary OLP' received higher ratings for both effectiveness and plausibility than the 'usual OLP'. CR was rated as superior relative to all OLP conditions. In conclusion, reducing emotional distress with OLPs does not necessitate the consumption of a placebo pill. In terms of acceptability and ease of implementation, CR stands as a well-established alternative.

Development and Psychometric Evaluation of the Hope in Medicine Scale.

Hope is an integral, multi-dimensional part of seeking medical treatment. The aim of this study was to develop a self-report scale, the Hope in Medicine (HIM) scale, to measure different modes of hoping in relation to the course of symptoms, the effects of treatment, and supporting medical research. We examined the psychometric properties of the scale in a sample of 74 allergic rhinitis patients participating in a 2-week randomized-controlled trial comparing open-label placebos (OLP) with treatment as usual (TAU). The HIM scale had a Cronbach's α of .78. An exploratory factor analysis revealed four factors: realistic hope (i.e., hoping for specific positive outcomes such as improvement in symptoms), transcendent hope (i.e., non-directed hoping that things will turn out positively), utopian hope (i.e., hoping to contribute to greater knowledge), and technoscience hope (i.e., hoping for scientific breakthroughs). Speaking to the convergent validity of the scale, realistic hope was moderately related to treatment expectancies (r = .54); transcendent hope was related to optimism (r = .50), treatment expectancies (r = .37), self-efficacy (r = .36), and inversely correlated with pessimism (r = -.43). Hope subscales predicted neither course of symptoms nor impairment. The HIM scale is a questionnaire with adequate internal consistency allowing to assess four modes of hoping. Preliminary results for its convergent validity are promising. Yet, further validation is needed.

A Fictionalist Account of Open-Label Placebo.

The placebo effect is now generally defined widely as an individual's response to the psychosocial context of a clinical treatment, as distinct from the treatment's characteristic physiological effects. Some researchers, however, argue that such a wide definition leads to confusion and misleading implications. In response, they propose a narrow definition restricted to the therapeutic effects of deliberate placebo treatments. Within the framework of modern medicine, such a scope currently leaves one viable placebo treatment paradigm: the non-deceptive and non-concealed administration of "placebo pills" or open-label placebo (OLP) treatment. In this paper, I consider how the placebo effect occurs in OLP. I argue that a traditional, belief-based account of OLP is paradoxical. Instead, I propose an account based on the non-doxastic attitude of pretence, understood within a fictionalist framework.

Open-label placebos enhance test performance and reduce anxiety in learner drivers: a randomized controlled trial

Passing the driving school test can be very challenging, especially in big cities, where up to 52% of all students fail this test. Consequently, many learner drivers experience stress and anxiety. For some learner drivers these feelings can be extreme and negatively affect the performance in the driving test. Different strategies to face anxiety and stress are known, including, for example, psychological or pharmacological approaches and even placebo pills. Recent intriguing findings have also demonstrated that placebos without deception, so-called open-label placebos, successfully reduce anxiety. Here we aimed to test effects of this novel treatment for learner drivers. We investigated whether open-label placebos affect test performance and feelings of anxiety in learner drivers. Sixty-eight healthy participants (mean age 21.94 years, 26 females) were randomized into two groups. The open-label placebo group received placebo pills two weeks before the driving test (two pills each day). The control group received no treatment. Results revealed that the open-label placebo group experienced significantly less anxiety than the control group before the test (measured with the State-Trait-Anxiety-Inventory, STAI-S, and the German Test Anxiety Inventory, PAF). Moreover, in the open-label placebo group less learner drivers failed the driving test (29.41% vs. 52.95%). The results suggest that open-label placebos may provide an ethical unproblematic way to experience less anxiety and might also enhance the probability to pass the driving test. We discuss possible mechanisms of open-label placebos and limitations of our findings.

Boosting open-label placebo effects in acute induced pain in healthy adults (BOLPAP-study): study protocol of a randomized controlled trial.

Pain is a highly prevalent symptom in the hospital setting, but treatment options remain limited. Harnessing the placebo effect in an ethical manner could provide a new possibility to reduce pain in clinical practice. So called open-label placebos (OLP) have been shown to elicit significant effects in reducing acute pain. But, before implementation, more knowledge concerning the properties of OLPs is needed. This study aims to assess the duration of analgesic effects from OLP and to determine the possibility of boosting such effects. This is the protocol of an ongoing (first patient enrolled in March 2023) single-site randomized trial investigating OLPs in two parts (i.e., substudies). In both parts, pain will be induced in healthy adults using an intradermal electrical stimulation model. Participants in Part 1 will have two study visits: An interventional visit with one OLP injection accompanied by an evidence-based treatment rationale and a control visit with no treatment. For Part 2, participants will be randomized into three groups: (1) A fixed-time "Booster" group including one single repetition of the OLP injection at a fixed time point, (2) an on-demand "Booster" group including one single repetition of the OLP injection on-demand, and (3) a control group who will receive just one OLP injection. Differences in pain ratings over time (using the Numeric Rating Scale) will be analyzed with several two-sample t-tests. The time point for a fixed-time "Booster" in Part 2 will be derived from Part 1 with additional statistical tools such as a broken-stick mixed-effect model. This study aims to further characterize the analgesic effects of OLPs. In doing so, it will provide valuable information needed for later implementation of OLPs in clinical practice, where they could play a role in multimodal analgesic concepts. The "Ethikkommission Nordwest- und Zentralschweiz" (BASEC 2023-00296) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal. This study is registered at ClinicalTrials.gov (NCT05819476) and is listed in the Swiss National Registry at kofam.ch (SNCTP000005470).

Open-label placebo is an evidence-based treatment option for many chronic conditions.

Open-label placebo is an evidence-based treatment option for many chronic conditions.

Would You Take an Open-Label Placebo Pill or Give One to Your Child? Findings from a Cross-Sectional Survey

Would You Take an Open-Label Placebo Pill or Give One to Your Child? Findings from a Cross-Sectional Survey

Can observational learning reinforce open-label placebo hypoalgesia?

Previous research has indicated that an open-label placebo can reduce pain in both healthy participants and patients with chronic pain. Because nondeceptive placebos seem to be an effective and more ethical alternative to deceptive placebos, optimizing this kind of treatment is essential. Observational learning was previously shown to induce the deceptive placebo effect; therefore, this study aimed to verify its effectiveness in fortifying the open-label placebo effect. Healthy volunteers (N = 117) were randomly assigned to 4 groups: open-label placebo with observational learning (OLP + OBL), open-label placebo (OLP), deceptive placebo with observational learning (OBL), or control group. Participants underwent baseline and testing measurements, during which they self-reported pain induced by heat stimulation. Between assessments, placebo cream was openly administered in the OLP and OLP + OBL groups. The OLP + OBL group next watched a model experiencing hypoalgesia after cream application. In the OBL group, participants received placebo cream with no information about its effect, and then they watched the model. The placebo effect was successfully evoked in all experimental groups (OLP + OBL, OLP, and OBL), which confirms the effectiveness of both open-label and deceptive placebo interventions for pain reduction. However, the hypoalgesic effect was of similar magnitude in the OLP and OLP + OBL groups, which indicates that observation did not contribute to the effect. The results showed that reinforcing the open-label placebo by observational learning may be redundant, but more research is needed to confirm these findings.

Choice over placebo administration enhances open-label placebo hypoalgesia.

Many studies indicate that deceptively administered placebos can improve pain outcomes. However, the deception involved presents an ethical barrier to translation because it violates informed consent and patient autonomy. Open-label placebos (OLPs), inert treatments that are openly administered as placebos, have been proposed as an ethically acceptable alternative. Early studies have suggested that OLP can improve pain outcomes, but important questions remain as to how to maximise OLP hypoalgesia to improve treatment outcomes in pain patients. This study investigated whether providing choice over when to administer an OLP treatment has the capacity to enhance OLP hypoalgesia using an electrocutaneous pain paradigm. One hundred thirty-two healthy volunteers were randomised to 3 types of treatment: OLP with choice, OLP without choice, and no treatment (natural history). The OLP groups were further randomised such that half were tested with a consistent pain intensity and the other half were tested with variable pain intensity to mimic day-to-day variability in pain intensity in health settings. The results indicated that treatment provided with choice exhibited greater OLP hypoalgesia than that provided without choice and that greater expectancy mediated this effect. Of interest, there was no evidence for OLP hypoalgesia without choice relative to natural history. Furthermore, variability in pain intensity did not affect OLP hypoalgesia. The current findings present novel evidence that choice over treatment administration may be a cheap and effective strategy for boosting the efficacy of OLPs in the clinical care of pain.

Open-label placebo hypoalgesia: what works for whom under which circumstances.

Open-label placebo hypoalgesia: what works for whom under which circumstances.

Open-label placebo treatment does not enhance cognitive abilities in healthy volunteers

The use of so-called ‘smart drugs’ such as modafinil to improve cognitive performance has recently attracted considerable attention. However, their side effects have limited user enthusiasm. Open-label placebo (OLP) treatment, i.e., inert treatments that are openly disclosed to individuals as having no active pharmacological ingredient, has been shown to improve various medical symptoms and conditions, including those related to cognitive performance. OLP treatment could therefore be an exciting alternative to pharmacological cognitive enhancers. Here, we used a randomized-controlled design to investigate the effect of a 21-day OLP treatment on several sub-domains of cognitive performance in N = 78 healthy volunteers. Subjective and objective measures of cognitive performance as well as different measures of well-being were obtained before and after the treatment period. Using a combination of classic Frequentist and Bayesian analysis approaches showed no additional benefit from OLP treatment in any of the subjective or objective measures of cognitive performance. Our study thus highlights possible limitations of OLP treatment in boosting cognitive performance in healthy volunteers. These findings are discussed in the light of expectancy-value considerations that may determine OLP efficacy.

Study protocol: combined N-of-1 trials to assess open-label placebo treatment for antidepressant discontinuation symptoms [FAB-study

BackgroundAntidepressant discontinuation is associated with a broad range of adverse effects. Debilitating discontinuation symptoms can impede the discontinuation process and contribute to unnecessary long-term use of antidepressants. Antidepressant trials reveal large placebo effects, indicating a potential use of open-label placebo (OLP) treatment to facilitate the discontinuation process. We aim to determine the effect of OLP treatment in reducing antidepressant discontinuation symptoms using a series of N-of-1 trials.MethodsA series of randomized, single-blinded N-of-1 trials will be conducted in 20 patients with fully remitted DSM-V major depressive disorder, experiencing moderate to severe discontinuation symptoms following antidepressant discontinuation. Each N-of-1 trial consists of two cycles, each comprising two-week alternating periods of OLP treatment and of no treatment in a random order, for a total of eight weeks. Our primary outcome will be self-reported discontinuation symptoms rated twice daily via the smartphone application ‘StudyU’. Secondary outcomes include expectations about discontinuation symptoms and (depressed) mood. Statistical analyses will be based on a Bayesian multi-level random effects model, reporting posterior estimates of the overall and individual treatment effects.DiscussionResults of this trial will provide insight into the clinical application of OLP in treating antidepressant discontinuation symptoms, potentially offering a new cost-effective therapeutic tool. This trial will also determine the feasibility and applicability of a series of N-of-1 trials in a clinical discontinuation trial.Trial registrationClinicalTrials.gov: NCT05051995, first registered September 20, 2021.