It's Not Just In Your Head—It's In Your Body's Power: The Placebo Effect

Placebos can work even when patients know they're taking an inactive substance. Studies show significant improvements in conditions, all while patients are fully informed they're taking sugar pills.

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We've been thinking about the placebo effect all wrong. For decades, we've dismissed it as "just the placebo effect"—a psychological trick, a nuisance variable in clinical trials, or worse, a form of deception. But what if that framing has prevented us from harnessing one of the most powerful healing mechanisms our bodies naturally possess?

Recent science reveals something far more profound: the placebo effect isn't just psychological—it's deeply biological, with measurable effects on brain chemistry and physical responses. And here's the kicker: it might work even when you know it's a placebo.

Beyond the Sugar Pill Myth

The conventional narrative goes something like this: a doctor gives a patient a sugar pill but tells them it's medicine. The patient believes it will help, and somehow, mysteriously, they feel better. It's been framed as "the lie that heals"—effective but fundamentally dishonest.

This framing created an ethical dilemma: beneficence versus autonomy. Is it okay to mislead someone, even if it helps them feel better? For over a century, medical professionals have wrestled with this question.

But emerging research reveals something revolutionary: placebos can work even when patients know they're taking an inactive substance. Studies on "open-label placebos" show significant improvements in conditions ranging from irritable bowel syndrome to chronic back pain, migraines, and even ADHD—all while patients are fully informed they're taking sugar pills.

What's happening here isn't trickery. It's biology.

Your Brain on Placebos

When you experience placebo pain relief, your brain releases endogenous opioids—your body's natural painkillers. PET scans show increased activity in regions like the rostral anterior cingulate cortex, mirroring what happens when you take actual opioid drugs.

In Parkinson's patients, placebo treatments trigger dopamine release in the striatum—just from the expectation of treatment. And in depression, placebos normalize activity patterns in frontal brain regions similarly to actual antidepressants.

These aren't subjective reports. They're measurable biochemical changes.

How Your Body Learns to Heal Itself

Multiple mechanisms drive these responses:

Classical conditioning: Remember Pavlov's dogs? Your body can be conditioned similarly. Pair a neutral stimulus (like a distinct taste) consistently with an active drug that causes a biological effect, and eventually, the body produces that same response just from the taste alone.

Expectations: What we believe will happen shapes our experience. Studies show pain relief treatments work better when people know they're receiving them versus when they're hidden. In depression trials, placebo responses are stronger when there are more active treatment arms—perhaps because people feel more hopeful.

The therapeutic relationship: Warmth, empathy, and trust from healthcare providers produce measurable effects. Studies link practitioner empathy to cold duration and physician characteristics to placebo response strength.

Ritual and context: More invasive procedures typically produce stronger effects than pills. Sham acupuncture often outperforms placebo pills for pain. For many orthopedic conditions, sham surgery can be as effective as the real procedure for pain and function long-term.

None of these mechanisms require deception. Each represents your body's remarkable capacity to activate its own healing processes.

The Dark Counterpart: The Nocebo Effect

The flip side of placebo is the nocebo effect—negative expectations creating negative outcomes. In drug trials, people in placebo groups routinely report side effects mimicking the actual drug's side effects—sometimes side effects only the placebo group experienced.

This highlights how profoundly our expectations shape our physical experience, for better or worse. It's why healthcare communication matters so deeply.

Beyond the Clinic: Everyday Applications

Understanding these mechanisms opens possibilities far beyond clinical settings:

Dose reduction through conditioning: By pairing medication with a distinctive stimulus, patients might eventually achieve similar effects with lower doses—reducing side effects and costs. This has shown promise for antihistamines, methadone for opioid dependence, melatonin, and even corticosteroids.

Managing our expectations: Seeking reliable information, positive stories, and support groups where people share successful experiences can foster beneficial expectations.

Cultivating healing relationships: Strong social support systems likely tap into these beneficial pathways—no medical intervention required.

Conscious engagement with healing rituals: The simple act of taking time for self-care, creating healing routines, or participating in wellness practices may activate these mechanisms.

The Ethical Reset: From Deception to Empowerment

This new understanding transforms the ethical conversation. Instead of "Is it okay to deceive patients to help them?" we can ask, "How can we help patients access their body's natural healing capacities?"

Open-label placebos represent the most direct route to patient agency—actively engaging with the idea that your mind and body can produce healing responses, even with an inert substance. It's empowering rather than deceptive.

Hard Boundaries: What Placebos Can and Cannot Do

Critical distinction: placebos work best for subjective symptoms like pain, mood, anxiety, and conditions like IBS. They don't cure cancer, fight infections, or mend broken bones.

This is where alternative medicine sometimes veers dangerously off course—suggesting approaches that help with anxiety will also cure serious diseases. When people forego effective conventional treatments based on these misunderstandings, the consequences can be tragic.

Not Blame, But Agency

Enhancing agency doesn't mean enhancing blame. We empower people by showing their potential influence, but must never make them feel responsible if they're still suffering.

This is especially important for nocebo effects or conditions sometimes labeled "psychosomatic." These conditions often respond well to placebos but carry a terrible stigma—the idea of it being "all in your head" just because we lack a clear biomarker or physiochemical explanation yet.

The Revolution Waiting to Happen

Medicine stands at a crossroads. We can continue treating the placebo effect as a nuisance variable to be controlled for in trials, or we can recognize it as a powerful healing mechanism to be understood and harnessed.

The latter path doesn't reject evidence-based medicine—it extends it. It doesn't abandon effective treatments—it complements them. It doesn't deceive patients—it empowers them.

What if standard medical care fully incorporated these insights? What if doctors were trained not just in pharmacology but in optimizing expectations, building therapeutic relationships, and teaching patients to access their body's healing capacities?

What if, instead of dismissing symptoms we can't explain with current technology as "psychosomatic," we recognized the profound interconnection between mind and body in all health conditions?

The science is clear: concepts we once thought of as purely subjective—expectation, value, meaning—have concrete physiological effects. They literally change brain activity and body chemistry, modulating perception, emotion, and physical health.

The placebo effect isn't a trick of the mind. It's the mind and body working together as they evolved to do. Understanding this doesn't diminish medicine—it elevates it, reminding us that healing has never been just about what we do to patients, but what happens within them.

The most powerful pharmacy in the world might be the one we all carry inside us. It's time we learned how to use it.

References:

Neurobiological Mechanisms of the Placebo Effect

Placebos as a Source of Agency: Evidence and Implications

The power of the placebo effect

Justice for Placebo: Placebo Effect in Clinical Trials and Everyday Practice

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STUDY MATERIALS

1. Briefing Document

Key Findings:

This briefing document synthesizes information from three sources to provide a comprehensive overview of the placebo effect. The sources highlight the transition from viewing placebos as inert substances or mere controls to recognizing them as complex phenomena with measurable neurobiological underpinnings. The ethical implications of using placebos, particularly in clinical practice, remain a significant point of discussion, while new approaches to harnessing placebo effects without deception are being explored.

Source 1: Excerpts from "Placebo as a Source of Agency: Evidence and Implications - PMC.pdf"

This source focuses on the ethical debate surrounding the use of placebos in clinical settings, particularly when it involves deception. It also raises important questions about the potential negative impacts of emphasizing placebo effects, especially in certain patient populations.

• Ethical Debate on Deceptive Placebo Use: There is a significant divide in ethical perspectives on the use of deceptive placebos.

• Arguments for Permissibility: Some argue that limited consent or "authorized deception" can be permissible if patients consent to the possibility of placebo use beforehand. Others suggest that deception is acceptable if patients would prioritize benefiting from the treatment over being told the truth.

• Kihlbom (10) and Shaw (11) argue for "a limited version of consent, which can maximize the benefits of placebos".

• Barnhill (12) suggests "informed consent and deceptive placebo use need not be seen as incompatible".

• Miller and colleagues, and later, Alfano (14), propose "authorized deception".

• Kolber (4) defends deception based on evidence that "patients would prefer to benefit than to be told the truth".

• Arguments Against Deceptive Placebo Use: Critics emphasize the potential harms of deception, including threats to trust and the risk of nocebo effects.

• Blease (17) suggests that asking for authorization might "paradoxically, lead to worse outcomes by way of nocebo effects".

• Asai and Kadooka (18) argue that "the clinical use of placebo and its acceptance would encourage undesirable labeling and contempt for the patient."

• Several authors point out that deceptive use "threatens trust and therefore care" (19, 20).

• Golomb (21) warns that "The willful breach of trust by doctors to patients on a policy basis may corrode not just that physician’s relationship with that patient, but may tarnish the reputation of all physicians as trustworthy purveyors of medical advice—abrogating all physicians’ effectiveness, always."

• Potential for Stigma and Harm: Highlighting placebo effects, particularly in conditions where psychological factors are sometimes emphasized, could inadvertently contribute to blame and stigma. This is a concern in utilizing conditioned, expectation-based, open-label, and relational placebo effects.

• The source questions: "Is it likely that thinking of these routes of intervention as placebo effects will reinforce stigma within these patient populations? How might we better characterize placebo phenomenon so that they can be harnessed while causing the least harm possible?"

• Alternative Approaches to Harnessing Placebo Effects: The source suggests focusing on the individual mechanisms driving placebo responses (e.g., conditioning, expectations) rather than the overarching term "placebo effect" to potentially mitigate stigma and harm.

• This approach is suggested by Alfano (14) and mirrors the idea of "throwing out the term entirely, as suggested by Nunn (106)".

• Funding and Conflict of Interest: The manuscript was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. The author declares no commercial or financial conflicts of interest.

Source 2: Excerpts from "Placebo Justice for Placebo: Placebo Effect in Clinical Trials and Everyday Practice.pdf"

This source advocates for a broader understanding and recognition of the placebo effect beyond its traditional role as a control in clinical trials. It emphasizes its neurobiological basis and therapeutic potential.

• Evolving Definition and Recognition of Placebo: The traditional definition of a placebo as a pharmacologically inactive substance is seen as insufficient. The placebo effect is a complex interplay of psychological and physiological factors.

• The source states that the "simplistic definition belies the intricate psychological and physiological phenomena associated with placebo, which stem from the interplay between patient expectations, clinician– patient dynamics, and the healthcare environment (Figure 1)."

• Neuroimaging studies "reveal that placebo treatments activate brain regions involved in pain modulation...while engaging endogenous pathways that underpin therapeutic outcomes [1]."

• Historical Context and Growing Prominence: The use of placebos as controls in clinical trials began in the 1930s. Dr. Henry Beecher's work during World War II and his subsequent 1955 paper, "The Powerful Placebo," were pivotal in establishing the placebo effect as a "measurable and clinically relevant phenomenon."

• Beecher estimated that "up to 35% of therapeutic effects in clinical practice could be attributed to placebo responses [10]."

• Studies involving sham procedures, such as the 1959 RCT on internal mammary artery ligation for angina, further highlighted the therapeutic potential of placebos.

• Neurobiological Underpinnings: The source emphasizes the neurobiological basis of placebo effects, citing neuroimaging studies that demonstrate activation of specific brain regions and engagement of endogenous pathways.

• The aim is to establish that "placebos should no longer be viewed merely as controls or fake treatments in clinical trials but recognized as valid therapeutic modalities that leverage human interactions and the expectation of benefit to produce real, measurable changes in health."

• The source suggests reframing the placebo effect as an "activator of innate healing mechanisms rather than merely an inert comparator."

• Evidence in Specific Conditions: The source provides examples of studies demonstrating the efficacy of placebos and sham treatments in various conditions.

• Tambiah et al. found that both placebo (0.9% sodium chloride solution) and sham (dry needle) injections in knee osteoarthritis showed "significant improvements in pain and function" [23].

• Vollert et al. observed "significant reductions in pain and inflammation" with placebo injections in rheumatoid arthritis [18].

• An RCT in Parkinson's disease patients with DBS electrodes showed that "open interruptions of DBS stimulation led to a significant reduction in movement velocity, while open increases in stimulation intensity resulted in a more pronounced improvement in movement velocity [31]." This highlights the influence of patient awareness.

• Challenges with 0.9% Sodium Chloride Solution as a Control: The use of 0.9% sodium chloride solution as a control in injection-based trials is questioned, particularly in inflammatory conditions.

• Manchikanti et al.'s review found "no significant difference between the two treatments when analyzed directly" when comparing corticosteroids to 0.9% sodium chloride solution in epidural injection studies [39].

• The source argues that sodium chloride solution is not a true control in inflammatory areas due to its ability to "wash out inflammatory mediators, providing a transient benefit."

• The lack of significant difference observed in the Paget et al. study of platelet-rich plasma (PRP) versus sodium chloride solution for ankle osteoarthritis may be attributed to the sodium chloride solution's potential to mask the effects of PRP [40].

• Authors and Funding: The authors are N.N. Knezevic, A. Sic, S. Worobey, and E. Knezevic. The research received no external funding.

Source 3: Excerpts from "Placebo Neurobiological Mechanisms of the Placebo Effect - PMC.pdf"

This source delves into the neurobiological underpinnings of the placebo effect, exploring the specific brain regions and neurotransmitter systems involved. It also discusses the interplay of expectation and conditioning.

• Neurobiological Basis of Placebo Effect: The placebo effect is not merely a psychological phenomenon but has identifiable physiological bases that modulate perception, emotion, and physical processes.

• The study of the placebo effect is the study of how "the context of beliefs and values shape brain processes related to perception and emotion and, ultimately, mental and physical health."

• "subjective' constructs such as expectation and value have identifiable physiological bases, and that these bases are powerful modulators of basic perceptual, motor, and internal homeostatic processes."

• Involvement of Endogenous Opioid Systems: A key finding is the involvement of endogenous opioid systems in mediating placebo analgesia.

• It was shown in 1978 that "placebo analgesia could be blocked by the opioid antagonist naloxone, which indicates an involvement of endogenous opioids (Levine et al., 1978)."

• Placebo analgesia can be mediated by both opioid and non-opioid mechanisms, depending on the procedure used to induce the response (Colloca and Benedetti, 2005; Amanzio and Benedetti, 1999).

• Placebo-activated endogenous opioid systems have a "somatotopic organization" (Benedetti et al., 1999b).

• Placebo-activated opioid systems can also affect respiratory centers and the cardiovascular system (Benedetti et al., 1999a; Pollo et al., 2003).

• Expectation vs. Conditioning: The source explores the roles of conscious expectation and unconscious conditioning in mediating placebo responses.

• Expectations of analgesia/hyper-algesia and motor improvement/worsening can antagonize conditioning procedures (Benedetti et al., 2003).

• However, expectations did not affect hormonal secretion, suggesting that placebo responses are mediated by conditioning for unconscious physiological functions (like hormone secretion) and by expectation for conscious processes (like pain and motor performance), even when conditioning is involved (Benedetti et al., 2003).

• The placebo effect "seems to be a phenomenon that can be learned either consciously or unconsciously, depending on the system that is involved".

• Neuroimaging Evidence: Neuroimaging studies have identified specific brain regions involved in placebo effects.

• PET studies using a μ-opioid receptor-selective radiotracer demonstrated activation of endogenous opioid neurotransmission with placebo administration [Zubieta et al., 2005a]. This activation was observed in regions such as the left dorsolateral prefrontal cortex (DLPFC), pregenual rostral right anterior cingulate, right anterior insular cortex, and left nucleus accumbens.

• "Significantly higher levels of activation were obtained for the condition in which placebo was administered."

• Activation in the pregenual anterior cingulate correlated with pain intensity, unpleasantness, and tolerance.

• fMRI studies also point to the involvement of the prefrontal cortex in expectation of placebo analgesia and changes in pain processing (Wager et al., 2004b).

• Studies on depression show overlapping patterns of metabolic changes in responders to both active antidepressants (fluoxetine) and placebo, particularly in prefrontal, parietal, and cingulate regions (Mayberg et al., 2000, 2002). This suggests common pathways mediating response, potentially involving expectation and conditioning.

• Role of Brain Regions: Specific brain regions are implicated in mediating placebo effects, including:

• Prefrontal Cortex (DLPFC, VLPFC, OFC): Involved in expectation, self-regulation, and cognitive modulation of pain and emotion.

• Anterior Cingulate Cortex (rostral, pregenual): Involved in pain modulation and affective responses.

• Insular Cortex (anterior): Involved in interoception and affective processing.

• Nucleus Accumbens: Involved in reward processing and motivation.

• Individual Variability: The neurochemical response to placebo varies among individuals and is influenced by factors such as pain experience and internal affective state (Zubieta et al., 2005b).

• Funding and Contributions: The work was supported by grants from the National Institutes of Health, the Italian Ministry of University and Research, and Eli Lilly & Company. All authors contributed equally.

Overall Themes and Connections:

These sources collectively demonstrate a shift in understanding the placebo effect from a confounding factor to a biologically active phenomenon. The neurobiological evidence supports the idea that expectations and conditioning can trigger real physiological changes. This understanding fuels the ethical debate around deceptive placebo use, as the potential for benefit is acknowledged alongside the risks to trust and potential for stigma. The exploration of open-label placebos and focusing on the mechanisms of placebo response represent attempts to harness these effects ethically in clinical practice. The historical perspective highlights the growing recognition of the placebo effect's significance in both research and clinical care. The challenges in using substances like 0.9% sodium chloride solution as inert controls further underscore the complexity of placebo effects and the need for careful consideration in study design.

Further Considerations:

• The interplay between the patient-clinician relationship and placebo effects (mentioned in Source 2 and supported by Source 1's focus on trust and relational effects) warrants further exploration.

• Developing ethical frameworks for utilizing non-deceptive placebo effects in clinical practice remains a critical area of research.

• Further understanding of the individual variability in placebo response, as highlighted in Source 3, could lead to more personalized and effective treatment strategies.

This briefing document provides a concise overview of the key ideas and facts presented in the provided sources. It underscores the complexity and growing importance of the placebo effect in medicine and research.

2. Quiz & Answer Key

Quiz

1. According to the "Placebo as a Source of Agency" excerpt, what are some of the arguments made in favor of using deceptive placebos in clinical practice?

2. What are some of the key arguments against the deceptive use of placebos in clinical practice, as outlined in the "Placebo as a Source of Agency" excerpt?

3. The "Placebo as a Source of Agency" excerpt discusses the potential for placebo effects to reinforce notions of blame and moral failing in certain patient populations. What specific types of placebo effects are mentioned in this context?

4. According to the "Justice for Placebo" excerpt, how has the traditional definition of a placebo evolved in modern medicine?

5. Who was Dr. Henry Beecher, and what was the significance of his work regarding the placebo effect during World War II?

6. The "Justice for Placebo" excerpt discusses the appropriateness of using 0.9% sodium chloride solution as a control in injection-based clinical trials. What is the main concern raised about its use, particularly in inflammatory conditions?

7. According to the "Neurobiological Mechanisms of the Placebo Effect" excerpt, what was the initial key finding in 1978 that indicated a biological basis for placebo analgesia?

8. The "Neurobiological Mechanisms of the Placebo Effect" excerpt describes how the placebo response can be mediated by different mechanisms depending on the circumstances. What are the two primary mechanisms discussed, and when are they thought to be more dominant?

9. In the Parkinson's disease study mentioned in the "Neurobiological Mechanisms of the Placebo Effect" excerpt, what physiological changes were observed in "placebo responders" at the single neuron level?

10. The "Neurobiological Mechanisms of the Placebo Effect" excerpt discusses neuroimaging studies of placebo analgesia. What specific brain regions were shown to have statistically significant effects of placebo on μ-opioid system activation?

Quiz Answer Key

1. Arguments in favor of deceptive placebo use include the idea that a limited version of consent is sufficient to maximize benefits, that informed consent and deceptive use can be compatible, that deception is permissible if consented to beforehand ("authorized deception"), and that patients might prefer benefit over being told the truth.

2. Arguments against deceptive placebo use include the potential for nocebo effects even with authorized deception, the risk of encouraging undesirable labeling and contempt for the patient, and the threat to trust between physicians and patients, potentially tarnishing the reputation of the medical profession as a whole.

3. The excerpt mentions conditioned, expectation-based, open-label, and relational placebo effects in the context of potentially reinforcing notions of blame and moral failing in certain patient populations.

4. The traditional definition of a placebo was a pharmacologically inactive substance or "sugar pill" used as a control. This has evolved to recognize placebos as valid therapeutic modalities that leverage psychological and physiological factors, rather than just inert comparators.

5. Dr. Henry Beecher was a physician who observed the significant analgesic effects of saline injections during World War II when morphine was scarce. His subsequent work and 1955 paper "The Powerful Placebo" were pivotal in establishing the placebo effect as a measurable and clinically relevant phenomenon.

6. The main concern about using 0.9% sodium chloride solution as a control in injection-based trials, especially in inflammatory conditions, is that it is not truly inert. When injected into inflamed areas, it can wash out inflammatory mediators, providing a transient benefit that can confound the results and mask the effects of the active treatment.

7. The initial key finding in 1978 that indicated a biological basis for placebo analgesia was the demonstration that placebo analgesia could be blocked by the opioid antagonist naloxone, suggesting the involvement of endogenous opioids.

8. The two primary mechanisms discussed are expectation and conditioning. Expectation is thought to be more dominant when conscious physiological processes like pain and motor performance are involved, while conditioning is suggested to play a larger role when unconscious physiological functions, such as hormonal secretion, are affected.

9. In placebo responders with Parkinson's disease, researchers observed a significant decrease in neuronal discharge and a reduction of bursting activity of subthalamic neurons after placebo administration.

10. Neuroimaging studies showed statistically significant effects of placebo on μ-opioid system activation in the left dorsolateral prefrontal cortex (DLPFC), pregenual rostral right anterior cingulate, right anterior insular cortex, and left nucleus accumbens.

3. Essay Questions

1. Analyze the ethical debate surrounding the deceptive use of placebos in clinical settings, drawing on the arguments presented in the "Placebo as a Source of Agency" excerpt for and against this practice. Discuss the implications for patient autonomy, trust, and potential harms.

2. Discuss the historical evolution of the placebo's role in medicine, from an "inert substance" to a recognized "valid therapeutic modality," as outlined in the "Justice for Placebo" excerpt. What key studies and observations contributed to this shift in understanding?

3. Explain the neurobiological mechanisms underlying the placebo effect as described in the "Neurobiological Mechanisms of the Placebo Effect" excerpt, focusing on the role of endogenous opioids and the activation of specific brain regions.

4. Compare and contrast the concept of expectation-activated opioid systems and conditioning-activated specific subsystems as mediators of the placebo response, using examples provided in the "Neurobiological Mechanisms of the Placebo Effect" excerpt.

5. Drawing on insights from all three excerpts, discuss the potential challenges and opportunities associated with harnessing placebo effects in clinical practice, considering ethical concerns, the need for a better understanding of mechanisms, and the potential for stigma.

4. Glossary of Key Terms

• Placebo: Traditionally, a pharmacologically inactive substance (e.g., sugar pill) used as a control in clinical trials. More broadly, it refers to the psychological and physiological phenomena associated with patient expectations, clinician-patient dynamics, and the healthcare environment that can lead to therapeutic outcomes.

• Nocebo Effect: The experience of negative effects or worsening of symptoms due to negative expectations or beliefs about a treatment or intervention.

• Clinical Trials: Research studies conducted with human participants to evaluate the safety and efficacy of medical interventions, often employing placebo controls.

• Informed Consent: The ethical principle requiring that patients are fully informed about the risks, benefits, and alternatives of a medical intervention before agreeing to it.

• Authorized Deception: A concept where patients consent beforehand to the possibility of receiving a deceptive intervention, such as a placebo, in a clinical setting.

• Conditioning: A learning process where an association is formed between a neutral stimulus and a previously meaningful stimulus, leading to a learned response (in the context of placebos, associating the placebo with a real treatment's effects).

• Expectation: A patient's belief about the likely outcome of a medical intervention, which can significantly influence their response to the treatment, including placebo effects.

• Open-Label Placebo: Administering a placebo to a patient while openly disclosing that it is a placebo, often accompanied by an explanation of the placebo effect.

• Relational Placebo Effects: Therapeutic benefits arising from the quality of the relationship between the patient and the healthcare provider.

• Stigma: Negative attitudes, beliefs, and discrimination directed towards individuals or groups, particularly in the context of health conditions.

• Neurobiological Underpinnings: The underlying biological and neural mechanisms that explain a psychological or behavioral phenomenon, such as the placebo effect.

• Endogenous Opioids: Opioid-like substances naturally produced by the body, which play a role in pain modulation, mood, and other physiological processes.

• Naloxone: An opioid antagonist that blocks the effects of opioids, used in studies to determine if endogenous opioid systems are involved in a response.

• Neuroimaging: Techniques such as fMRI (functional magnetic resonance imaging) and PET (positron emission tomography) used to visualize and measure brain activity.

• μ-opioid receptors: A type of opioid receptor in the brain and body that is primarily involved in mediating the effects of opioid drugs and endogenous opioids, including pain relief and reward.

• Anterior Cingulate Cortex (ACC): A brain region involved in a variety of functions, including pain processing, emotion regulation, and cognitive control, implicated in placebo effects.

• Dorsolateral Prefrontal Cortex (DLPFC): A brain region associated with executive functions, working memory, and cognitive control, shown to be activated during placebo responses.

• Nucleus Accumbens (NAcc): A brain region involved in reward, motivation, and reinforcement learning, also implicated in the neurobiology of the placebo effect.

• Insular Cortex (Insula): A brain region involved in processing bodily sensations, emotions, and interoception, which shows activity changes during placebo analgesia.

• Sham Procedure: A control procedure in clinical trials that mimics a medical intervention but lacks the active therapeutic component, used to account for the effects of the procedure itself and patient expectations.

• 0.9% Sodium Chloride Solution: A saline solution often used as a placebo control in injection-based clinical trials.

5. Timeline of Main Events

• 1930s: Placebos begin to be used as control groups in clinical trials, exemplified by Drs. Diehl, Baker, and Cowan's study "Cold Vaccines: An Evaluation Based on A Controlled Study".

• Mid-20th Century (during World War II): Dr. Henry Beecher observes the analgesic effects of saline solution injections in injured soldiers during a morphine shortage, marking a key moment in recognizing the placebo effect as a clinical phenomenon.

• 1955: Henry Beecher formalizes his observations and research on the placebo effect in his groundbreaking paper, "The Powerful Placebo," which establishes the placebo effect as a measurable and clinically relevant phenomenon and estimates that up to 35% of therapeutic effects in clinical practice could be attributed to placebo responses.

• 1959: An RCT on internal mammary artery ligation for angina shows that patients undergoing the sham procedure report similar symptom improvements as those receiving the actual surgery, further highlighting the therapeutic potential of placebos and solidifying the use of placebo controls in clinical trials.

• 1965: Melzack and Wall publish their "Pain mechanisms: a new theory." (Cited in Zubieta et al. 2005b)

• 1966: Lasky et al. publish a study on placebo effects in schizophrenic patients. (Cited in Placebo_ as a Source of Agency)

• 1968: Luparello et al. publish a study on the influences of suggestion on airway reactivity in asthmatic subjects. (Cited in Placebo_ as a Source of Agency)

• 1978: It is demonstrated that placebo analgesia can be blocked by the opioid antagonist naloxone, indicating the involvement of endogenous opioids in the neurobiology of the placebo effect. This finding is presented in a paper by Levine, Gordon, and Fields.

• 1980: Posner publishes on the orienting of attention. (Cited in Zubieta et al. 2005b)

• 1980: Crawford publishes "Healthism and the medicalization of everyday life." (Cited in Placebo_ as a Source of Agency)

• 1981: Sox et al. publish on psychologically mediated effects of diagnostic tests. (Cited in Placebo_ as a Source of Agency)

• 1982: Watkins and Mayer publish on the organization of endogenous opiate and nonopiate pain control systems. (Cited in Zubieta et al. 2005b)

• 1983: Gracely et al., Grevert et al., and Levine and Gordon publish studies demonstrating naloxone reversal of placebo analgesia under conditions of expectation. (Cited in Zubieta et al. 2005b)

• 1984: O'Neill publishes "Paternalism and partial autonomy." (Cited in Placebo_ as a Source of Agency)

• 1984: Akil et al. publish on endogenous opioids. (Cited in Zubieta et al. 2005b)

• 1986: Hashish et al. publish on anti-inflammatory effects of ultrasound therapy and a major placebo effect. (Cited in Placebo_ as a Source of Agency)

• 1988: Coryell and Noyes publish on placebo response in panic disorder. (Cited in Placebo_ as a Source of Agency)

• 1988: Kalin et al. publish on opiate modulation of separation-induced distress. (Cited in Zubieta et al. 2005b)

• 1989: Allport publishes on visual attention. (Cited in Zubieta et al. 2005b)

• 1990: Horwitz et al. publish on treatment adherence and risk of death after a myocardial infarction. (Cited in Placebo_ as a Source of Agency)

• 1990: Lipman et al. publish on peak B endorphin concentration in cerebrospinal fluid in chronic pain patients and during placebo response. (Cited in Zubieta et al. 2005b)

• 1991: Hayden publishes "A practical approach to chronic fatigue syndrome." (Cited in Placebo_ as a Source of Agency)

• 1991: Lazarus publishes "Cognition and motivation in emotion." (Cited in Zubieta et al. 2005b)

• 1991: Ma and Han publish neurochemical studies on the mesolimbic circuitry of antinociception. (Cited in Zubieta et al. 2005b)

• 1992: Rizvi et al. publish on reciprocal connections between the medial preoptic area and the midbrain periaqueductal gray. (Cited in Zubieta et al. 2005b)

• 1993: Greco publishes "Psychosomatic subjects and the ‘duty to be well’." (Cited in Placebo_ as a Source of Agency)

• 1995: Benedetti, Amanzio, and Maggi publish on the potentiation of placebo analgesia by proglumide. (Cited in Zubieta et al. 2005b)

• 1995: Desimone and Duncan publish on neural mechanisms of selective visual attention. (Cited in Zubieta et al. 2005b)

• 1995: Ernst and Resch publish on the concept of true and perceived placebo effects. (Cited in Placebo_ as a Source of Agency)

• 1996: Benedetti publishes on the opposite effects of opioid and cholecystokinin antagonists on placebo analgesia. (Cited in Zubieta et al. 2005b)

• 1996: Firestone et al. publish on regional cerebral blood flow increases with opiate analgesics. (Cited in Zubieta et al. 2005b)

• 1996: Hyman and Nestler publish "Initiation and adaptation: a paradigm for understanding psychotropic drug action." (Cited in Zubieta et al. 2005b)

• 1996: Montgomery publishes on efficacy in long term treatment of depression. (Cited in Zubieta et al. 2005b)

• 1996: Rubinstein et al. publish on the absence of opioid stress-induced analgesia in mice lacking β-endorphin. (Cited in Zubieta et al. 2005b)

• 1997: Benedetti publishes on cholecystokinin receptors and their modulation of opioid analgesia. (Cited in Zubieta et al. 2005b)

• 1997: Adler et al. publish on regional brain activity changes associated with fentanyl analgesia. (Cited in Zubieta et al. 2005b)

• 1997: Kienle and Kiene publish "The powerful placebo effect: fact or fiction?" (Cited in Zubieta et al. 2005b)

• 1997: Rainville et al. publish on pain affect encoded in human anterior cingulate but not somatosensory cortex, noting modulation by hypnosis in this region. (Cited in Zubieta et al. 2005b)

• 1997: Sora et al. publish on opiate receptor knockout mice. (Cited in Zubieta et al. 2005b)

• 1997: Zhang et al. publish on inhibitory effects of electrically evoked activation of ventrolateral orbital cortex on the tail-flick reflex. (Cited in Zubieta et al. 2005b)

• 1998: Ader publishes on conditioned immunomodulation. (Cited in Zubieta et al. 2005b)

• 1998: Kirsch and Sapirstein publish a meta-analysis on antidepressant medication titled "Listening to Prozac but hearing placebo." (Cited in Zubieta et al. 2005b)

• 1998: Nelson and Panksepp publish on brain substrates of infant-mother attachment. (Cited in Zubieta et al. 2005b)

• 1998: Schlaepfer et al. publish on the site of opioid action in the human brain. (Cited in Zubieta et al. 2005b)

• 1998: Stewart et al. publish on using pattern analysis to predict differential relapse on fluoxetine and placebo. (Cited in Zubieta et al. 2005b)

• 1998: Zhang et al. publish on inhibitory effects of electrical stimulation of ventrolateral orbital cortex on the rat jaw-opening reflex. (Cited in Zubieta et al. 2005b)

• 1999: Amanzio and Benedetti publish "Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems." (Cited in Zubieta et al. 2005b)

• 1999: Benedetti, Baldi, Casadio, and Maggi publish on inducing placebo respiratory depressant responses in humans via opioid receptors. (Cited in Zubieta et al. 2005b)

• 1999: Benedetti, Arduino, and Amanzio publish on somatotopic activation of opioid systems by target-directed expectations of analgesia. (Cited in Zubieta et al. 2005b)

• 1999: DeRubeis et al. publish a mega-analysis of four randomized comparisons of medications versus cognitive behavior therapy for severely depressed outpatients. (Cited in Zubieta et al. 2005b)

• 1999: De Craen et al. publish on the placebo effect in the treatment of duodenal ulcer. (Cited in Placebo_ as a Source of Agency)

• 1999: Duman, Malberg, and Thome publish on neural plasticity to stress and anti-depressant treatment. (Cited in Zubieta et al. 2005b)

• 1999: Enserink publishes "Can the placebo be the cure?" (Cited in Zubieta et al. 2005b)

• 1999: Ikemoto and Panksepp publish on the role of nucleus accumbens dopamine in motivated behavior. (Cited in Zubieta et al. 2005b)

• 1999: Price et al. publish an analysis of factors that contribute to the magnitude of placebo analgesia. (Cited in Zubieta et al. 2005b)

• 2000: Ader publishes on classical conditioning in the treatment of psoriasis. (Cited in Placebo_ as a Source of Agency)

• 2000: De Craen et al. publish on the placebo effect in the acute treatment of migraine, noting that subcutaneous placebos are better than oral placebos. (Cited in Placebo_ as a Source of Agency)

• 2000: Freo et al. publish on the time course and location of changes in animal studies of selective serotonin reuptake inhibitors antidepressants. (Cited in Zubieta et al. 2005b)

• 2000: Khan, Warner, and Brown publish an analysis of the FDA database on symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials. (Cited in Zubieta et al. 2005b)

• 2000: Casey et al. publish on selective opiate modulation of nociceptive processing in the human brain. (Cited in Zubieta et al. 2005b)

• 2000: Mayberg et al. publish on regional metabolic effects of fluoxetine in major depression. (Cited in Zubieta et al. 2005b)

• 2000: McGrath et al. publish on predictors of relapse during fluoxetine continuation or maintenance treatment of major depression. (Cited in Zubieta et al. 2005b)

• 2000: Quitkin and Klein publish on necessary conditions to assess anti-depressant efficacy. (Cited in Zubieta et al. 2005b)

• 2000: Quitkin et al. publish on the validity of clinical trails of antidepressants. (Cited in Zubieta et al. 2005b)

• 2000: Schultz, Tremblay, and Hollerman publish on reward processing in primate orbitofrontal cortex and basal ganglia. (Cited in Zubieta et al. 2005b)

• 2001: Ader publishes on conditioned immunomodulation. (Cited in Zubieta et al. 2005b)

• 2001: Andrews publishes "Placebo response in depression: bane of research, boon to therapy." (Cited in Zubieta et al. 2005b)

• 2001: Bao, Chan, and Merzenich publish on cortical remodeling induced by activity of ventral tegmental dopamine neurons. (Cited in Zubieta et al. 2005b)

• 2001: Brody et al. publish on regional brain metabolic changes in patients with major depression treated with paroxetine or interpersonal therapy. (Cited in Zubieta et al. 2005b)

• 2001: De la Fuente-Fernandez et al. publish on investigations of the biological substrates of the placebo effect. (Cited in Zubieta et al. 2005b)

• 2001: Drolet et al. publish on the role of the endogenous opioid system in the regulation of the stress response. (Cited in Zubieta et al. 2005b)

• 2001: Handy et al. publish on combined expectancies using event-related potentials. (Cited in Zubieta et al. 2005b)

• 2001: Hrobjartsson and Gotzsche publish "Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment." (Cited in Zubieta et al. 2005b)

• 2001: Miller and Cohen publish "An integrative theory of prefrontal cortex function." (Cited in Zubieta et al. 2005b)

• 2001: Phelps et al. publish on activation of the left amygdala to a cognitive representation of fear. (Cited in Zubieta et al. 2005b)

• 2001: Martin et al. publish on brain blood flow changes in depressed patients treated with interpersonal psychotherapy or venlafaxine hydrochloride. (Cited in Zubieta et al. 2005b)

• 2001: Vaidya and Duman publish "Depresssion—emerging insights from neurobiology." (Cited in Zubieta et al. 2005b)

• 2001: Wagner et al. publish on dose-dependent regional cerebral blood flow changes during remifentanil infusion. (Cited in Zubieta et al. 2005b)

• 2001: Zubieta et al. publish on regional mu opioid receptor regulation of sensory and affective dimensions of pain. (Cited in Zubieta et al. 2005b)

• 2002: Barsky et al. publish on nonspecific medication side effects and the nocebo phenomenon. (Cited in Zubieta et al. 2005b)

• 2002: Bencherif et al. publish on pain activation of human supraspinal opioid pathways. (Cited in Zubieta et al. 2005b)

• 2002: Lieberman et al. publish "The neural correlates of placebo effects: a disruption account." (Cited in Zubieta et al. 2005b)

• 2002: Mayberg et al. publish "The functional neuroanatomy of the placebo effect." (Cited in Zubieta et al. 2005b)

• 2002: Ochsner et al. publish "Rethinking feelings: an FMRI study of the cognitive regulation of emotion." (Cited in Zubieta et al. 2005b)

• 2002: Petrovic and Ingvar publish "Imaging cognitive modulation of pain processing." (Cited in Zubieta et al. 2005b)

• 2002: Petrovic et al. publish "Placebo and opioid analgesia—imaging a shared neuronal network." (Cited in Zubieta et al. 2005b)

• 2002: Pollo et al. publish on expectation modulating the response to subthalamic nucleus stimulation in Parkinsonian patients. (Cited in Zubieta et al. 2005b)

• 2002: Schultz publishes "Getting formal with dopamine and reward." (Cited in Zubieta et al. 2005b)

• 2002: Zubieta et al. publish on mu-opioid receptor mediated antinociception differences in men and women. (Cited in Zubieta et al. 2005b)

• 2002: Walsh et al. publish on placebo response in studies of major depression. (Cited in Zubieta et al. 2005b)

• 2003: Ader publishes on conditioned immunomodulation. (Cited in Zubieta et al. 2005b)

• 2003: Benedetti et al. publish on conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses, suggesting expectation affects conscious processes (pain, motor performance) while conditioning affects unconscious processes (hormone secretion). (Cited in Placebo_ as a Source of Agency and Zubieta et al. 2005b)

• 2003: Mayberg publishes on modulating dysfunctional limbic-cortical circuits in depression. (Cited in Zubieta et al. 2005b)

• 2003: Pollo et al. publish "Placebo analgesia and the heart," finding that opioid-mediated placebo analgesia also affects the cardiovascular system. (Cited in Zubieta et al. 2005b)

• 2003: Vase et al. publish on the contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. (Cited in Placebo_ as a Source of Agency and Zubieta et al. 2005b)

• 2003: Volkow et al. publish on expectation enhancing the regional brain metabolic and reinforcing effects of stimulants in cocaine abusers. (Cited in Zubieta et al. 2005b)

• 2003: Wager and Smith publish a meta-analysis of neuroimaging studies of working memory. (Cited in Zubieta et al. 2005b)

• 2003: Wager et al. publish a meta-analysis of functional brain anatomy in emotion. (Cited in Zubieta et al. 2005b)

• 2003: Zubieta et al. publish on the regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission. (Cited in Zubieta et al. 2005b)

• 2003: Zubieta et al. publish on COMT val158met genotype affecting mu-opioid neurotransmitter responses to a pain stressor. (Cited in Zubieta et al. 2005b)

• 2004: Apkarian et al. publish on chronic back pain being associated with decreased prefrontal and thalamic gray matter density. (Cited in Zubieta et al. 2005b)

• 2004: Benedetti et al. publish on recording from single neurons after placebo administration in Parkinson's disease patients with implanted electrodes, observing neuronal changes linked to clinical placebo response. (Cited in Zubieta et al. 2005b)

• 2004: Fields publishes "State-dependent opioid control of pain." (Cited in Zubieta et al. 2005b)

• 2004: Hrobjartsson and Gotzsche publish an update to their systematic review on the powerlessness of placebo. (Cited in Zubieta et al. 2005b)

• 2004: Koerselman et al. publish a randomized, placebo-controlled study of repetitive transcranial magnetic stimulation in depression. (Cited in Zubieta et al. 2005b)

• 2004: Lieberman et al. publish on the neural correlates of placebo effects. (Cited in Zubieta et al. 2005b)

• 2004: Moles et al. publish on deficit in attachment behavior in mice lacking the mu-opioid receptor gene. (Cited in Zubieta et al. 2005b)

• 2004: Ochsner et al. publish on neural systems supporting the cognitive down- and up-regulation of negative emotion. (Cited in Zubieta et al. 2005b)

• 2004: Pagnin et al. publish a meta-analytic review of the efficacy of ECT in depression. (Cited in Zubieta et al. 2005b)

• 2004: Singer et al. publish on empathy for pain involving affective but not sensory components of pain. (Cited in Zubieta et al. 2005b)

• 2004: Wager and Feldman Barrett publish on functional specialization of the insula in motivation and regulation. (Cited in Zubieta et al. 2005b)

• 2004: Wager, Reading, and Jonides publish a meta-analysis of neuroimaging studies of shifting attention. (Cited in Zubieta et al. 2005b)

• 2004: Wager et al. publish on placebo-induced changes in fMRI in the anticipation and experience of pain, providing convergent evidence for the reliability of findings across different pain modalities and suggesting that placebo expectancies involve active neurobiological processes in the frontal lobes. (Cited in Zubieta et al. 2005b)

• 2005: Colloca and Benedetti publish "Placebos and painkillers: is mind as real as matter?", exploring opioid and non-opioid mechanisms in placebo analgesia. (Cited in Zubieta et al. 2005b)

• 2005: Corrigan publishes "On the stigma of mental illness: practical strategies for research and social change." (Cited in Placebo_ as a Source of Agency)

• 2005: DeRubeis et al. publish on cognitive therapy vs medications in the treatment of moderate to severe depression. (Cited in Zubieta et al. 2005b)

• 2005: Finniss and Benedetti publish a review suggesting expectation and conditioning are principle mediators of placebo effects. (Cited in Zubieta et al. 2005b)

• 2005: Khan et al. publish on the magnitude of placebo response and drug–placebo differences across psychiatric disorders. (Cited in Placebo_ as a Source of Agency)

• 2005: Lieberman et al. publish an fMRI investigation of race-related amygdala activity. (Cited in Zubieta et al. 2005b)

• 2005: Pacheco-Lopez et al. publish on expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. (Cited in Placebo_ as a Source of Agency)

• 2005: Patel et al. publish a meta-analysis on the placebo effect in irritable bowel syndrome trials. (Cited in Placebo_ as a Source of Agency)

• 2005: Petrovic et al. publish on placebo in emotional processing and a generalized modulatory network. (Cited in Zubieta et al. 2005b)

• 2005: Phan et al. publish on neural substrates for voluntary suppression of negative affect. (Cited in Zubieta et al. 2005b)

• 2005: Pitz et al. publish on defining the predictors of the placebo response in irritable bowel syndrome. (Cited in Placebo_ as a Source of Agency)

• 2005: Shapiro and Meslin publish "Belmont revisited: ethical principles for research with human subjects." (Cited in Placebo_ as a Source of Agency)

• 2005: Zubieta et al. directly examine whether placebo with expectation of analgesia activates endogenous opioid neurotransmission using PET, finding significant activation in specific brain regions and correlations with pain ratings and tolerance. (Cited in Zubieta et al. 2005b)

• 2005: Zubieta et al. publish on individual variations in the neurochemistry of the placebo effect, suggesting internal affective state and affective quality of pain are significant predictors. (Cited in Zubieta et al. 2005b)

• 2006: Colloca and Benedetti publish "How prior experience shapes placebo analgesia." (Cited in Placebo_ as a Source of Agency)

• 2006: Kaptchuk et al. publish a randomized controlled trial comparing sham device versus inert pill placebo treatments. (Cited in Placebo_ as a Source of Agency)

• 2006: Pacheco-Lopez et al. publish on expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. (Cited in Placebo_ as a Source of Agency)

• 2007: Benedetti et al. publish "When words are painful: unraveling the mechanisms of the nocebo effect." (Cited in Placebo_ as a Source of Agency)

• 2007: Dickson et al. publish on stigma and the delegitimation experience in people living with chronic fatigue syndrome. (Cited in Placebo_ as a Source of Agency)

• 2007: Mondaini et al. publish on finasteride 5 mg and sexual side effects, questioning how many are related to a nocebo phenomenon. (Cited in Placebo_ as a Source of Agency)

• 2008: Goebel et al. publish on behavioral conditioning of antihistamine effects in patients with allergic rhinitis. (Cited in Placebo_ as a Source of Agency)

• 2008: Cheek publishes "Healthism: a new conservatism?" (Cited in Placebo_ as a Source of Agency)

• 2008: Sandler and Bodfish publish a pilot study on open-label use of placebos in the treatment of ADHD. (Cited in Placebo_ as a Source of Agency)

• 2008: Waber et al. publish on commercial features of placebo and therapeutic efficacy. (Cited in Placebo_ as a Source of Agency)

• 2008: Zhang et al. publish a meta-analysis on the placebo effect and its determinants in osteoarthritis. (Cited in Placebo_ as a Source of Agency)

• 2009: Barnhill publishes "What it takes to defend deceptive placebo use." (Cited in Placebo_ as a Source of Agency)

• 2009: Golomb publishes "Doctoring the evidence: the case against lying to patients about placebos," arguing that deceptive placebo use threatens trust in physicians. (Cited in Placebo_ as a Source of Agency)

• 2009: Nunn publishes "It’s time to put the placebo out of our misery," suggesting throwing out the term "placebo effect". (Cited in Placebo_ as a Source of Agency)

• 2009: Schwab publishes "When subtle deception turns into an outright lie." (Cited in Placebo_ as a Source of Agency)

• 2009: Shaw publishes "Prescribing placebos ethically: the appeal of negatively informed consent," arguing for a limited version of consent for placebo use. (Cited in Placebo_ as a Source of Agency)

• 2009: Whalley and Hyland publish on motivational predictors of contextual benefits of therapy. (Cited in Placebo_ as a Source of Agency)

• 2010: Ader et al. publish on conditioned pharmacotherapeutic effects. (Cited in Placebo_ as a Source of Agency)

• 2010: Kaptchuk et al. publish a randomized controlled trial in irritable bowel syndrome demonstrating effects of placebos without deception. (Cited in Placebo_ as a Source of Agency)

• 2011: Barnhill defends a view in which informed consent and deceptive placebo use need not be incompatible. (Cited in Placebo_ as a Source of Agency)

• 2011: Taft et al. publish on perceptions of illness stigma in patients with inflammatory bowel disease and irritable bowel syndrome. (Cited in Placebo_ as a Source of Agency)

• 2012: Colloca and Finniss publish "Nocebo effects, patient–clinician communication, and therapeutic outcomes." (Cited in Placebo_ as a Source of Agency)

• 2012: Wells and Kaptchuk publish "To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent." (Cited in Placebo_ as a Source of Agency)

• 2012: Rose et al. publish on choice and placebo expectation effects in the context of pain analgesia. (Cited in Placebo_ as a Source of Agency)

• 2013: Justman publishes "The finasteride riddle." (Cited in Placebo_ as a Source of Agency)

• 2013: Rommelfanger publishes an opinion piece on a role for placebo therapy in psychogenic movement disorders. (Cited in Placebo_ as a Source of Agency)

• 2013: Benedetti publishes "Placebo and the new physiology of the doctor–patient relationship." (Cited in Placebo_ as a Source of Agency)

• 2013: Hossenbaccus and White publish a content analysis of views on the nature of chronic fatigue syndrome. (Cited in Placebo_ as a Source of Agency)

• 2014: Wartolowska et al. publish a systematic review on the use of placebo controls in the evaluation of surgery. (Cited in Placebo_ Justice for Placebo)

• 2015: Petkovic et al. publish a protocol for a systematic review and meta-analysis on the effects of placebos without deception. (Cited in Placebo_ as a Source of Agency)

• 2016: Blasini et al. publish on open-label placebo for opioid use disorder. (Cited in Placebo_ as a Source of Agency)

• 2016: Blease, Carel, and Geraghty publish on epistemic injustice in healthcare encounters, with evidence from chronic fatigue syndrome. (Cited in Placebo_ as a Source of Agency)

• 2016: Krummenacher et al. publish on effects of open-label placebos. (Cited in Placebo_ as a Source of Agency)

• 2016: Valtorta et al. publish a systematic review and meta-analysis on loneliness and social isolation as risk factors for coronary heart disease and stroke. (Cited in Placebo_ as a Source of Agency)

• 2017: Birkhauer et al. publish a meta-analysis on trust in healthcare professionals and health outcomes. (Cited in Placebo_ as a Source of Agency)

• 2017: Charlesworth et al. publish a systematic review and meta-analysis on the effects of placebos without deception compared with no treatment. (Cited in Placebo_ as a Source of Agency)

• 2017: Louw et al. publish a systematic review of sham surgery in orthopedics. (Cited in Placebo_ Justice for Placebo)

• 2017: van Maanen et al. publish a pilot study on classical conditioning for preserving the effects of short melatonin treatment in children with delayed sleep. (Cited in Placebo_ as a Source of Agency)

• 2018: Blease publishes "Consensus in placebo studies: lessons from the philosophy of science." (Cited in Placebo_ as a Source of Agency)

• 2018: Blease and Friesen publish on placebo effects and racial and ethnic health disparities. (Cited in Placebo_ as a Source of Agency)

• 2018: Colloca publishes "Preface: The Fascinating Mechanisms and Implications of the Placebo Effect." (Cited in Placebo_ Justice for Placebo)

• 2018: Kaptchuk publishes "Open-label placebo: reflections on a research agenda." (Cited in Placebo_ as a Source of Agency)

• 2018: Miller publishes "Reining in the placebo effect." (Cited in Placebo_ as a Source of Agency)

• 2018: Petrosky et al. publish findings on chronic pain among suicide decedents from the National Violent Death Reporting System. (Cited in Placebo_ Justice for Placebo)

• 2018: Blasini et al. publish on the role of patient-practitioner relationships in placebo and nocebo phenomena. (Cited in Placebo_ Justice for Placebo)

• 2019: Dorius et al. publish on national and geographic trends in Medicare reimbursement for pain management. (Cited in Placebo_ Justice for Placebo)

• 2020: Perfitt, Plunkett, and Jones publish on the placebo effect in the management of chronic pain. (Cited in Placebo_ Justice for Placebo)

• 2022: Gedin et al. publish a systematic review and meta-analysis on placebo response and media attention in randomized clinical trials assessing cannabis-based therapies for pain. (Cited in Placebo_ Justice for Placebo)

• 2022: Vollert et al. assess placebo injections in rheumatoid arthritis. (Cited in Placebo_ Justice for Placebo)

• 2022: Tambiah et al. investigate the use of placebo and sham injections in knee osteoarthritis. (Cited in Placebo_ Justice for Placebo)

• 2022: Colloca publishes "Neurobiological Mechanisms of the Placebo and Nocebo Effect: Applications Beyond Pain Therapy." (Cited in Placebo_ Justice for Placebo)

• 2024: Wiest et al. publish on national and geographic trends in Medicare Reimbursement for Pain Management 2014–2023. (Cited in Placebo_ Justice for Placebo)

• 2025: Knezevic, Sic, Worobey, and Knezevic publish "Justice for Placebo: Placebo Effect in Clinical Trials and Everyday Practice."

Cast of Characters:

• Henry Beecher: A key figure in the history of placebo research. During World War II, he observed the analgesic effects of saline in soldiers, which led to his formal work on the placebo effect. His 1955 paper "The Powerful Placebo" is considered groundbreaking and helped establish the placebo effect as a clinically relevant phenomenon.

• Fabrizio Benedetti: A prominent researcher in the neurobiology of the placebo effect. His work has investigated the mechanisms of placebo analgesia, including the involvement of endogenous opioids, and the distinction between expectation-activated and conditioning-activated placebo responses. He has also researched the effects of placebo on motor performance in Parkinson's disease and hormonal secretion. (Cited in Placebo_ as a Source of Agency, Placebo_ Justice for Placebo, and Placebo_ Neurobiological Mechanisms)

• Ted J. Kaptchuk: A researcher known for his work on open-label placebos (placebos administered with full disclosure). His research has demonstrated that placebos can have effects even when patients know they are receiving an inert substance. (Cited in Placebo_ as a Source of Agency and Placebo_ Justice for Placebo)

• Jon-Kar Zubieta: A researcher who has investigated the neurobiological substrates of the placebo effect using neuroimaging techniques like PET. His work has provided evidence for the activation of endogenous opioid neurotransmission in response to placebo with expectation of analgesia. (Cited in Placebo_ Neurobiological Mechanisms)

• Howard S. Mayberg: A researcher who has studied the functional neuroanatomy of the placebo effect in depression using neuroimaging. Her work has identified brain regions showing similar metabolic changes in both active drug and placebo responders. (Cited in Placebo_ Neurobiological Mechanisms)

• Tor D. Wager: A researcher who has used fMRI to investigate the neural mechanisms underlying placebo analgesia, particularly in the context of expectation. His work suggests that placebo expectancies involve active neurobiological processes in the frontal lobes. (Cited in Placebo_ Neurobiological Mechanisms)

• Luana Colloca: A researcher who has investigated the mechanisms and implications of both placebo and nocebo effects, including the role of patient-practitioner relationships. (Cited in Placebo_ as a Source of Agency, Placebo_ Justice for Placebo, and Placebo_ Neurobiological Mechanisms)

• Christine Blease: A researcher who has raised concerns about the ethical implications of deceptive placebo use, suggesting it could lead to nocebo effects and epistemic injustice. (Cited in Placebo_ as a Source of Agency)

• A. Barnhill: Has defended the view that informed consent and deceptive placebo use need not be incompatible. (Cited in Placebo_ as a Source of Agency)

• F.G. Miller: Has argued that deception is permissible as long as patients consent to it first (authorized deception). (Cited in Placebo_ as a Source of Agency)

• A. Alfano: Has argued for authorized deception in the context of placebo use and suggested focusing on individual routes by which outcomes are improved rather than thinking of placebo effects as a whole. (Cited in Placebo_ as a Source of Agency)

• A. Kolber: Has defended deception in placebo use based on evidence that patients would prefer to benefit than be told the truth. (Cited in Placebo_ as a Source of Agency)

• M. Asai: Has argued that the clinical use of placebo could encourage undesirable labeling and contempt for the patient. (Cited in Placebo_ as a Source of Agency)

• K. Kadooka: Has argued that the clinical use of placebo could encourage undesirable labeling and contempt for the patient. (Cited in Placebo_ as a Source of Agency)

• B.A. Golomb: Has noted that the willful breach of trust by doctors regarding placebos could corrode the reputation of all physicians. (Cited in Placebo_ as a Source of Agency)

• R. Nunn: Has suggested throwing out the term "placebo effect" entirely. (Cited in Placebo_ as a Source of Agency)

• O. O'Neill: Mentioned in reference to paternalism and partial autonomy. (Cited in Placebo_ as a Source of Agency)

• A.P. Schwab: Mentioned in reference to subtle deception turning into an outright lie. (Cited in Placebo_ as a Source of Agency)

• N. Mondaini, P. Gontero, G. Giubilei, G. Lombardi, T. Cai, A. Gavazzi, et al.: Authors of a study questioning the nocebo phenomenon related to finasteride side effects. (Cited in Placebo_ as a Source of Agency)

• S. Justman: Author of "The finasteride riddle." (Cited in Placebo_ as a Source of Agency)

• D. Finniss: Co-author with Colloca on "Nocebo effects, patient–clinician communication, and therapeutic outcomes" and co-author with Benedetti of a review on expectation and conditioning. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• R.E. Wells: Co-author with Kaptchuk on the nocebo effect and informed consent. (Cited in Placebo_ as a Source of Agency)

• H.T. Shapiro: Editor of "Belmont revisited: ethical principles for research with human subjects." (Cited in Placebo_ as a Source of Agency)

• W. Coryell, R. Noyes: Authors of a study on placebo response in panic disorder. (Cited in Placebo_ as a Source of Agency)

• S.P. Hayden: Author of "A practical approach to chronic fatigue syndrome." (Cited in Placebo_ as a Source of Agency)

• L. Vase, M.E. Robinson, G.N. Verne, D.D. Price: Authors of studies on placebo effects in irritable bowel syndrome patients. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• A. Khan, R.L. Kolts, M.H. Rapaport, K.R. Krishnan, A.E. Brodhead, B.A. Browns: Authors of a study on placebo response across psychiatric disorders. (Cited in Placebo_ as a Source of Agency)

• S.M. Patel, W.B. Stason, A. Legedza, S.M. Ock, L. Conboy, et al.: Authors of a meta-analysis on the placebo effect in irritable bowel syndrome trials. (Cited in Placebo_ as a Source of Agency)

• G. Pacheco-Lopez, H. Engler, M.B. Niemi, M. Schedlowski: Authors of studies on immunomodulatory placebo effects. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• W. Zhang, J. Robertson, A. Jones, P. Dieppe, M. Doherty: Authors of a meta-analysis on the placebo effect in osteoarthritis. (Cited in Placebo_ as a Source of Agency)

• K.S. Rommelfanger: Author of an opinion piece on the role of placebo therapy in psychogenic movement disorders. (Cited in Placebo_ as a Source of Agency)

• T. Luparello, H.A. Lyons, E.R. Bleecker, E.R. McFadden Jr.: Authors of a study on suggestion and airway reactivity in asthmatic subjects. (Cited in Placebo_ as a Source of Agency)

• B.I. Hashish, W. Harvey, M. Harris: Authors of a study on anti-inflammatory effects of ultrasound therapy. (Cited in Placebo_ as a Source of Agency)

• A. Pollo, E. Torre, L. Lopiano, M. Rizzone, M. Lanotte, A. Cavanna, B. Bergamasco: Authors of studies on expectation and response to subthalamic nucleus stimulation in Parkinsonian patients and placebo analgesia and the heart. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• L. Colloca, F. Benedetti: Co-authors on multiple studies related to placebo and nocebo effects, including neurobiological mechanisms and the role of prior experience. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• M. Lanotte: Co-author on studies with Benedetti and others on placebo/nocebo responses in Parkinsonian patients and the nocebo effect. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• L. Lopiano: Co-author on studies with Benedetti and others on placebo/nocebo responses in Parkinsonian patients. (Cited in Placeado_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• S. Vighetti: Co-author on studies with Benedetti and others on placebo/nocebo responses and placebo analgesia and the heart. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• I. Rainero: Co-author on studies with Benedetti and others on placebo/nocebo responses and placebo analgesia and the heart. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• J. Birkhauer, J. Gaab, J. Kossowsky, S. Hasler, P. Krummenacher, C. Werner, et al.: Authors of a meta-analysis on trust in healthcare professionals. (Cited in Placebo_ as a Source of Agency)

• A.D. Sandler, J.W. Bodfish: Authors of a pilot study on open-label placebo for ADHD. (Cited in Placebo_ as a Source of Agency)

• E. Friedlander, J.M. Kelley, M.N. Sanchez, E. Kokkotou, J.P. Singer, et al.: Co-authors on Kaptchuk's open-label placebo study in IBS. (Cited in Placebo_ as a Source of Agency)

• S. Kam-Hansen, M. Jakubowski, I. Kirsch, D.C. Hoaglin: Co-authors on a study about altered placebo and drug labeling. (Cited in Placebo_ as a Source of Agency)

• P. Krummenacher, C. Werner, P. Neukirch, J. Gaab: Authors of a study on effects of open-label placebos. (Cited in Placebo_ as a Source of Agency)

• G. Petkovic, J.E. Charlesworth, J. Kelley, F. Miller, N. Roberts, J. Howick: Authors of a protocol and systematic review on effects of placebos without deception. (Cited in Placebo_ as a Source of Agency)

• J.E. Charlesworth, M. Hunter, I. Onakpoya: Co-authors on a systematic review on effects of placebos without deception. (Cited in Placebo_ as a Source of Agency)

• J.P. Rose, A.L. Geers, H.M. Rasinski, S.L. Fowler: Authors of a study on choice and placebo expectation effects in pain analgesia. (Cited in Placebo_ as a Source of Agency)

• R.L. Waber, B. Shiv, Z. Carmon, D. Ariely: Authors of a study on commercial features of placebo and therapeutic efficacy. (Cited in Placebo_ as a Source of Agency)

• E. Ernst, K.L. Resch: Authors of a study on the concept of true and perceived placebo effects. (Cited in Placebo_ as a Source of Agency)

• A.J. de Craen, J.G. Tijssen, J. de Gans, J. Kleijnen: Authors of studies on the placebo effect in migraine and duodenal ulcer. (Cited in Placebo_ as a Source of Agency)

• D.E. Moerman, S.H. Heisterkamp, G.N. Tytgat: Co-authors on a study on the placebo effect in duodenal ulcer. (Cited in Placebo_ as a Source of Agency)

• W.B. Stason, R.B. Davis, A.R. Legedza, R.N. Schnyer, C.E. Kerr, D.A. Stone, B.H. Nam, I. Kirsch, R.H. Goldman: Co-authors on Kaptchuk's sham device vs inert pill study. (Cited in Placebo_ as a Source of Agency)

• M. Pitz, M. Cheang, C.N. Bernstein: Authors of a study on predictors of the placebo response in IBS. (Cited in Placebo_ as a Source of Agency)

• R.I. Horwitz, C.M. Viscoli, L. Berkman, R.M. Donaldson, S.M. Horwitz, C.J. Murray, et al.: Authors of a study on treatment adherence and risk of death after myocardial infarction. (Cited in Placebo_ as a Source of Agency)

• H.C. Sox Jr., I. Margulies, C.H. Sox: Authors of a study on psychologically mediated effects of diagnostic tests. (Cited in Placebo_ as a Source of Agency)

• M. Greenblatt, et al.: Co-author on a protocol for open-label dose-extending placebos for opioid use disorder. (Cited in Placebo_ as a Source of Agency)

• B. Whalley, M.E. Hyland: Authors of a study on motivational predictors of contextual benefits of therapy. (Cited in Placebo_ as a Source of Agency)

• N.K. Valtorta, M. Kanaan, S. Gilbody, S. Ronzi, B. Hanratty: Authors of a systematic review on loneliness and social isolation. (Cited in Placebo_ as a Source of Agency)

• P.W. Corrigan: Author of "On the stigma of mental illness." (Cited in Placebo_ as a Source of Agency)

• A. Dickson, C. Knussen, P. Flowers: Authors of a study on stigma and the delegitimation experience in chronic fatigue syndrome. (Cited in Placebo_ as a Source of Agency)

• T.H. Taft, L. Keefer, C. Artz, J. Bratten, M.P. Jones: Authors of a study on perceptions of illness stigma in IBD and IBS patients. (Cited in Placebo_ as a Source of Agency)

• H. Carel, K. Geraghty: Co-authors with Blease on epistemic injustice in healthcare encounters. (Cited in Placebo_ as a Source of Agency)

• M. Greco: Author of "Psychosomatic subjects and the ‘duty to be well’." (Cited in Placebo_ as a Source of Agency)

• Z. Hossenbaccus, P.D. White: Authors of a content analysis on views on chronic fatigue syndrome. (Cited in Placebo_ as a Source of Agency)

• R. Crawford: Author of "Healthism and the medicalization of everyday life." (Cited in Placebo_ as a Source of Agency)

• J. Cheek: Author of "Healthism: a new conservatism?" (Cited in Placebo_ as a Source of Agency)

• P. Friesen: Co-author with Blease on placebo effects and racial and ethnic health disparities, and the author of the manuscript "Placebo as a Source of Agency". (Cited in Placebo_ as a Source of Agency)

• Drs. Diehl, Baker, and Cowan: Authors of an early study ("Cold Vaccines") that used placebos as control groups in clinical trials. (Cited in Placebo_ Justice for Placebo)

• Tambiah et al.: Investigated the use of placebo and sham injections in knee osteoarthritis. (Cited in Placebo_ Justice for Placebo)

• Vollert et al.: Assessed placebo injections in rheumatoid arthritis. (Cited in Placebo_ Justice for Placebo)

• Manchikanti et al.: Conducted a systematic review and meta-analysis to evaluate the efficacy of 0.9% sodium chloride solution as a placebo in epidural injection studies. (Cited in Placebo_ Justice for Placebo)

• Paget et al.: Conducted an RCT comparing platelet-rich plasma to sodium chloride solution placebo in ankle osteoarthritis. (Cited in Placebo_ Justice for Placebo)

• N.N. Knezevic: Conceptualization, writing, and supervision for "Justice for Placebo". (Cited in Placebo_ Justice for Placebo)

• A. Sic: Writing, visualization, investigation, and methodology for "Justice for Placebo". (Cited in Placebo_ Justice for Placebo)

• S. Worobey: Writing and investigation for "Justice for Placebo". (Cited in Placebo_ Justice for Placebo)

• E. Knezevic: Writing, visualization, investigation, and methodology for "Justice for Placebo". (Cited in Placebo_ Justice for Placebo)

• J.S. Perfitt, N. Plunkett, S. Jones: Authors on the placebo effect in the management of chronic pain. (Cited in Placebo_ Justice for Placebo)

• A. Louw, I. Diener, C. Fernández-de-Las-Peñas, E.J. Puentedura: Authors of a systematic review of sham surgery in orthopedics. (Cited in Placebo_ Justice for Placebo)

• E. Petrosky, R. Harpaz, K.A. Fowler, M.K. Bohm, C.G. Helmick, K. Yuan, C.J. Betz: Authors of a study on chronic pain among suicide decedents. (Cited in Placebo_ Justice for Placebo)

• K. Wartolowska, A. Judge, S. Hopewell, G.S. Collins, B.J. Dean, I. Rombach, D. Brindley, J. Savulescu, D.J. Beard, A.J. Carr: Authors of a systematic review on the use of placebo controls in the evaluation of surgery. (Cited in Placebo_ Justice for Placebo)

• M. Blasini, N. Peiris, T. Wright: Co-authors with Colloca on open-label placebo and patient-practitioner relationships. (Cited in Placebo_ as a Source of Agency and Placebo_ Justice for Placebo)

• G. Wiest, A. Dorius, C. Bateman, M. Day: Authors on national and geographic trends in Medicare Reimbursement for Pain Management. (Cited in Placebo_ Justice for Placebo)

• F. Gedin, S. Blomé, M. Pontén, M. Lalouni, J. Fust, A. Raquette, V. Vadenmark Lundquist, W.H. Thompson, K. Jensen: Authors of a systematic review and meta-analysis on placebo response and media attention in trials for cannabis-based therapies for pain. (Cited in Placebo_ Justice for Placebo)

• R. Ader: Researcher known for work on classical conditioning in the context of placebo effects. (Cited in Placebo_ as a Source of Agency and Placebo_ Neurobiological Mechanisms)

• M. Amanzio: Co-author with Benedetti on studies distinguishing expectation-activated and conditioning-activated placebo analgesia. (Cited in Placebo_ Neurobiological Mechanisms)

• L. Adinolfi: Co-author on a protocol for open-label dose-extending placebos for opioid use disorder. (Cited in Placebo_ as a Source of Agency)

• A.M. Belcher, T.O. Cole: Authors on a protocol for open-label dose-extending placebos for opioid use disorder. (Cited in Placebo_ as a Source of Agency)

6. FAQ

What is the placebo effect?

The placebo effect refers to the measurable health improvements that occur following the administration of a pharmacologically inactive substance or intervention, such as a sugar pill or a sham procedure. These improvements are not due to the inherent properties of the treatment itself but rather stem from a complex interplay of psychological and physiological factors. These factors include a patient's expectations of benefit, the nature of the clinician-patient relationship, and the overall healthcare environment surrounding the treatment. Essentially, it demonstrates how the belief in a treatment, even an inert one, can trigger the body's own healing mechanisms and lead to real, observable changes in health outcomes. Historically, placebos were primarily used as controls in clinical trials to determine the true efficacy of active treatments, but there is a growing recognition of their potential therapeutic role when utilized ethically and appropriately.

What are the neurobiological mechanisms underlying the placebo effect?

The placebo effect is not merely a psychological phenomenon but has identifiable physiological bases involving the brain and body's endogenous systems. Research, particularly neuroimaging studies, has revealed that placebo treatments can activate specific brain regions and engage various neurotransmitter pathways. A key mechanism identified is the involvement of the endogenous opioid system. Studies using opioid antagonists like naloxone have shown that placebo analgesia (pain relief) can be blocked, indicating the release of the body's natural pain-relieving opioids. Neuroimaging studies, such as PET scans, have demonstrated that placebo administration with the expectation of analgesia activates μ-opioid receptors in brain areas like the dorsolateral prefrontal cortex, anterior cingulate, anterior insular cortex, and nucleus accumbens. These brain regions are involved in pain modulation, reward processing, and emotional regulation. Beyond opioids, non-opioid mechanisms can also contribute, particularly when the placebo response is induced through conditioning procedures following exposure to non-opioid drugs. The placebo effect highlights how subjective constructs like expectation and value can powerfully modulate sensory, affective, and even homeostatic processes in the body.

How does expectation influence the placebo effect?

Expectation is a crucial component of the placebo effect. A patient's conscious expectation of receiving a beneficial treatment can directly influence their physiological and psychological responses. For example, studies have shown that verbally induced expectations of analgesia or motor improvement can significantly impact pain levels and motor performance, respectively. Neuroimaging research suggests that expectations of pain relief activate areas in the brain, including the prefrontal cortex, involved in anticipating and processing pain. This anticipation of benefit can trigger the release of endogenous substances, such as opioids, leading to measurable symptom relief. The strength and clarity of these expectations, often shaped by the clinician-patient interaction and the characteristics of the treatment (e.g., the perceived potency of an injection versus a pill), can significantly influence the magnitude of the placebo response.

How does conditioning contribute to the placebo effect?

In addition to conscious expectation, classical conditioning plays a significant role in eliciting placebo responses, particularly for unconscious physiological functions like hormonal secretion. This involves associating a neutral stimulus (the placebo) with an active treatment that produces a specific physiological response. After repeated pairings, the neutral stimulus alone can evoke a similar response. For instance, if a patient receives a drug that affects hormone levels and then a placebo, the placebo may trigger the same hormonal changes due to the learned association. While conscious expectation appears to be more dominant for modulating conscious processes like pain and motor performance, conditioning can be a powerful driver of placebo effects, especially when the physiological response is not under conscious control.

What is the nocebo effect and how does it relate to placebos?

The nocebo effect is the opposite of the placebo effect. It refers to the experience of adverse effects or symptom worsening following the administration of an inert substance or intervention, driven by negative expectations or beliefs. Just as positive expectations can lead to healing, negative expectations can lead to harm or the manifestation of side effects. For example, if a patient is warned about potential side effects of a medication, they may experience those side effects even if they receive a placebo. The nocebo effect is also mediated by neurobiological mechanisms and can involve the activation of brain regions associated with fear and anxiety, potentially influencing pain pathways and other physiological systems in a detrimental way. Understanding and mitigating the nocebo effect is crucial in clinical practice, particularly when discussing potential risks and side effects with patients.

What are the ethical considerations surrounding the use of placebos in clinical practice?

The ethical use of placebos in clinical practice is a subject of considerable debate, primarily due to the issue of deception. Traditionally, administering a placebo while claiming it is an active treatment involves misleading the patient, which conflicts with the principle of informed consent and can erode trust in the clinician-patient relationship and the medical profession as a whole. While some argue that limited deception is permissible if it maximizes patient benefit, others emphasize the potential harms of deceptive practices, including the risk of nocebo effects and the reinforcement of undesirable labeling and contempt for patients. The concept of "authorized deception," where patients consent beforehand to the possibility of receiving a placebo, has been proposed as a way to potentially mitigate some ethical concerns, but its effectiveness and ethical implications are still debated. Alternative approaches, such as open-label placebos where patients are informed they are receiving a placebo but are told about its potential benefits, are also being explored to harness placebo effects without deception.

How are placebos used in clinical trials?

In clinical trials, placebos traditionally serve as a control to determine the true efficacy of an investigational treatment. Participants are often randomized to receive either the active treatment or a placebo, and the outcomes are compared. This helps researchers differentiate the effects of the active drug or intervention from the non-specific effects associated with receiving any form of treatment (the placebo effect). Ideally, the placebo used should be as inert as possible and indistinguishable from the active treatment to minimize bias. However, there are ongoing discussions about the appropriateness of certain placebos, such as saline injections, which may have some physiological effects and might not be a true inert control, particularly in conditions involving inflammation. The use of sham procedures in surgical trials also falls under the realm of placebo controls, raising similar ethical considerations.

What are the broader implications of understanding the placebo effect beyond clinical trials?

Recognizing the powerful influence of the placebo effect has significant implications beyond its role in clinical trials. It highlights the crucial impact of the clinician-patient relationship, the healthcare environment, and individual beliefs and expectations on health outcomes. Understanding the neurobiological underpinnings of the placebo effect can inform strategies to enhance the therapeutic benefits of active treatments by leveraging these non-pharmacological factors. This could involve improving communication, fostering positive expectations, and creating supportive healthcare environments. Furthermore, studying the placebo effect provides insights into the mind-body connection and the potential for harnessing the body's innate healing capabilities. It suggests a need to broaden our conception of therapeutic interventions to include psychological and relational aspects, not just the pharmacological properties of drugs. However, it also raises concerns about potential stigma and the reinforcement of blame, particularly for conditions with psychological components, if not characterized carefully. The goal is to utilize the understanding of placebo phenomena to maximize therapeutic outcomes while minimizing harm and upholding ethical principles.

7. Table of Contents

Introduction (00:00)

Introduction to Heliox podcast and the concept of placebo effect beyond just "sugar pills"

Historical Perspective (01:00)

Discussion of how placebo was historically framed as "the lie that heals" and the ethical tensions between beneficence and autonomy

Mechanisms of Placebo Response (03:10)

Exploration of the key pathways that produce placebo effects, including classical conditioning, expectations, and the therapeutic relationship

Open Label Placebos (09:15)

Examination of research showing placebos can work even when patients know they're taking a placebo, with examples from IBS, migraines, and chronic pain studies

Factors Affecting Placebo Response (13:00)

Discussion of elements that influence placebo effect strength, including treatment choice, perceived cost, invasiveness, frequency, and social learning

Practical Applications (15:30)

Exploration of how placebo mechanisms can be used to enhance agency, including conditioning paired with medication, managing expectations, and building therapeutic relationships

Beyond Clinical Settings (19:00)

Discussion of how placebo principles operate in everyday contexts like online health communities, workplace wellness programs, and supportive relationships

The Nocebo Effect (22:15)

Examination of the "dark side" of placebo - how negative expectations can create negative outcomes

Research Challenges (23:40)

Overview of the difficulties in studying placebo effects, including high placebo response rates in trials and differences between trial settings and routine care

Neurobiological Basis (25:00)

Detailed exploration of the brain chemistry behind placebo responses, including endorphin release, dopamine activation in Parkinson's patients, and brain changes in depression

Invasive Procedures and Ritual (29:30)

Discussion of how context and ritual impact placebo effects, with examples of sham surgery and acupuncture having powerful effects

Ethical Implications (31:45)

Consideration of the ethical shift from questions about deception to questions about enhancing patient agency

Limitations and Responsible Use (33:20)

Important discussion of what placebos can and cannot do, distinguishing between placebo-responsive conditions and those requiring specific biomedical intervention

Conclusion (35:00)

Final reflections on the mind-body connection in healing and invitation for listeners to reconsider their views on the power of belief and relationships in wellbeing

8. Index

Agency, 16:10, 19:30, 31:45, 33:40 Alternative medicine, 20:00, 34:00 Anterior cingulate cortex, 26:10, 27:20 Antidepressants, 28:00 Autonomy versus beneficence, 02:20 Bayesian predictive processing, 11:00 Brain activity, 25:00, 26:10, 27:40, 28:00 CBT (Cognitive Behavioral Therapy), 28:15 CCK (Cholecystokinin), 26:00 Classical conditioning, 05:10, 06:30, 16:00 Clinical trials, challenges in, 23:40, 24:20 Cost, perceived, 14:30 Depression, 08:10, 13:40, 28:00 Dopamine, 27:30, 28:30 Embodied cognition, 11:00 Empathy, 07:40, 08:00, 17:30 Endogenous opioids, 25:40, 26:00, 27:20 Expectations, 06:30, 07:00, 12:00, 14:00, 16:30, 22:30, 27:40, 28:30 Homeopathy, 20:20 IBS (Irritable Bowel Syndrome), 09:40, 10:10, 31:00, 34:20 Invasive procedures, 14:20, 29:30 Low back pain, 07:20, 09:30, 30:30 Migraines, 09:30 Naloxone, 25:50 Nocebo effect, 02:30, 22:15, 33:40 Open-label placebos, 09:15, 10:30, 15:30, 19:30, 31:00 Opioid system, 25:40, 26:40, 27:00 Opioid use disorder, 30:40 Pain relief, 07:00, 25:20, 26:00, 27:00, 30:00 Parkinson's disease, 27:30 Patient expectations, 07:20, 17:00 PET scans, 26:20, 27:40 Polypharmacy, 17:10 Psychosomatic conditions, 21:15, 33:45 Relationship, therapeutic, 07:30, 17:30, 20:20 Ritual, therapeutic, 11:00, 18:00, 29:40, 31:00 Side effects, 16:10, 17:10, 22:30 Social learning, 14:40 Social support, 08:20, 17:40 Spine procedures, 30:20 Stigma, 21:20, 33:50 Striatum, 27:40, 28:10 Surgery, sham, 29:45, 30:00 Uncertainty, 28:40 Vaccine hesitancy, 21:00

9. Post-Episode Fact Check

The podcast content on the placebo effect appears to be scientifically accurate and represents current understanding in this field. Here's my assessment of the key claims:

1. Open-label placebos working: ✓ ACCURATE - Multiple studies have demonstrated that placebos can work even when patients know they're receiving them. Ted Kaptchuk's work at Harvard with IBS patients is well-documented, and other studies have shown similar effects for conditions like migraines and low back pain.

2. Neurobiological mechanisms: ✓ ACCURATE - The podcast correctly describes how placebo responses involve measurable changes in brain chemistry, including endogenous opioid release for pain and dopamine release in Parkinson's patients. PET scan studies have indeed shown activity in the anterior cingulate cortex during placebo analgesia.

3. Classical conditioning: ✓ ACCURATE - The description of conditioned physiological responses is consistent with research on conditioned immunosuppression and other examples where neutral cues can trigger physiological responses after repeated pairing with active treatments.

4. Therapeutic relationship: ✓ ACCURATE - Research does support the claim that practitioner empathy, trust, and warmth contribute significantly to treatment outcomes.

5. Limitations of placebo effects: ✓ ACCURATE - The podcast correctly acknowledges that placebo effects primarily affect subjective symptoms like pain and mood rather than directly affecting pathophysiological processes like tumor growth or infections.

6. Nocebo effects: ✓ ACCURATE - The description of negative expectations creating adverse outcomes is well-established in research.

7. Invasive procedures having stronger effects: ✓ ACCURATE - Studies have indeed shown that more invasive procedures (like sham surgery) often produce stronger placebo effects than pills, as described.

8. Brain regions involved: ✓ ACCURATE - The podcast correctly identifies key brain regions involved in placebo responses, including the prefrontal cortex, anterior cingulate, and insula.

The content appears to synthesize information from reputable research and presents a balanced view of both the possibilities and limitations of placebo effects. It avoids exaggerated claims while accurately representing the current state of scientific understanding on this topic.

Why This Matters

This podcast provides an important reframing of the placebo effect from something dismissive ("just the placebo effect") to something empowering - our body's innate capacity for self-healing that has measurable biological effects. The discussion of open-label placebos is particularly significant as it shifts the ethical conversation away from deception toward patient empowerment.

Understanding how expectations, conditioning, and therapeutic relationships affect health outcomes has implications not just for clinical medicine but for how we think about healing more broadly in society. The careful distinction between conditions that respond well to placebo (like pain and mood) versus those requiring specific medical intervention is an important clarification that prevents potential misuse of this information.

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