Placebo Effect

Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a 'self-blinding' citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.

BackgroundContextual effects (i.e., placebo response) refer to all health changes resulting from administering an apparently inactive treatment. In a randomized clinical trial (RCT), the overall treatment effect (i.e., the post-treatment effect in the intervention group) can be regarded as the true effect of the intervention plus the impact of contextual effects. This meta-research was conducted to examine the average proportion of the overall treatment effect attributable to contextual effects in RCTs across clinical conditions and treatments and explore whether it varies with trial contextual factors.MethodsData was extracted from trials included in the main meta-analysis from the latest update of the Cochrane review on "Placebo interventions for all clinical conditions" (searched from 1966 to March 2008). Only RCTs reported in English having an experimental intervention group, a placebo comparator group, and a no-treatment control group were eligible.ResultsIn total, 186 trials (16,655 patients) were included. On average, 54% (0.54, 95%CI 0.46 to 0.64) of the overall treatment effect was attributable to contextual effects. The contextual effects were higher for trials with blinded outcome assessor and concealed allocation. The contextual effects appeared to increase proportional to the placebo effect, lower mean age, and proportion of females.ConclusionApproximately half of the overall treatment effect in RCTs seems attributable to contextual effects rather than to the specific effect of treatments. As the study did not include all important contextual factors (e.g., patient-provider interaction), the true proportion of contextual effects could differ from the study's results. However, contextual effects should be considered when assessing treatment effects in clinical practice.Trial registrationPROSPERO CRD42019130257 . Registered on April 19, 2019.

BackgroundSeveral studies demonstrated that placebo treatment may have a significant impact on many different symptoms. While in the traditional view concealment of the placebo is essential, recent studies report intriguing evidence that placebos may work even without deception. For example, it has been demonstrated that open-label placebos can improve symptoms in allergic rhinitis. However, the mechanisms of how placebos without concealment work remain unknown.Trial designIn order to examine expectancy effects we conducted a randomized controlled trial (N = 46), in which patients with allergic symptoms received either placebos without deception or no pills at all. In half of those patients we induced positive expectations about the placebo effect. After two weeks we tested whether symptoms and quality of life had changed.ResultsResults revealed that open-label placebos improved allergic symptoms more than the control group. Inducing positive expectations had no effects on the improvement of allergic symptoms (the primary and more objective outcome), but on mental sum scores of the quality of life questionnaire.ConclusionsPlacebos without deception can improve symptoms in allergic rhinitis. Positive expectations do not contribute to the efficacy of open-label placebos, but seem to have an effect on more global and subjective well-being (mental or emotional quality of life).Clinical trial registration numberGerman Clinical Trials Register, DRKS00012303.

AbstractPrior experiences, conditioning cues, and expectations of improvement are essential for nocebo hyperalgesia expression. The neural circuits that communicate with brainstem pain modulatory nuclei during nocebo hyperalgesia responsivity are underexplored. In this study, we employed a classical conditioning and expectation model in 25 healthy human participants and measured brain activity using ultra-high field functional magnetic resonance imaging. We assessed forebrain activity changes as well as noxious stimulus-independent and -dependent connectivity changes with the lateral midbrain periaqueductal gray matter (lPAG). We found hyperalgesia-related signal increases in the orbitofrontal cortex, insula, and amygdala. In addition, we found stimulus-dependent lPAG connectivity changes with the orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices and stimulus-independent lPAG connectivity with the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens during hyperalgesia. Whilst these connectivity changes are all associated with hyperalgesia, dynamic causal modelling analysis revealed that the dorsolateral prefrontal cortex was principally responsible for driving the lPAG. Overall, our results show that there is a complex relationship between forebrain activation and connectivity with brainstem pain modulation circuitry that results in the behavioural expression of nocebo hyperalgesia.