Choice and the Placebo Effect: A Meta-analysis

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

Infrequent intranasal oxytocin followed by positive social interaction improves symptoms in autistic children: a randomized clinical trial

There are currently no approved drug interventions for social behavior dysfunction in autism spectrum disorder (ASD). Previous trials investigating effects of daily intranasal oxytocin treatment have reported inconsistent results and have not combined it with positive social interaction. However, In two preclinical studies we established that treatment every-other-day rather than daily is more efficacious in maintaining neural and behavioral effects by reducing receptor desensitization. We aimed to establish whether 6-weeks of intranasal oxytocin compared with placebo treatment, followed by a period of positive social interaction, would produce greater symptom improvements in children with ASD. A double-blind, randomized, cross over design trial was completed including 41 children with ASD aged 3-8 years. Primary outcomes were the Autism Diagnostic Observation Schedule-2 (ADOS-2) and social responsivity scale-2 (SRS-2). Secondary measures included other autism-related questionnaires and social attention assessed using two eye-tracking paradigms. A clinical reliable change index analysis revealed improvements in ADOS-2 total scores in 44% of children. Improvements in SRS-2 and behavioral adaptability scores were also found and correlated with increased basal saliva oxytocin concentrations. Additionally, oxytocin improved restrictive and repetitive behavior scores and increased time spent viewing dynamic social compared to geometric stimuli and the eye region of angry, happy and neutral expression faces. There were no adverse side-effects of oxytocin treatment. Overall, our results demonstrate that 6 weeks of intranasal oxytocin treatment administered every other day and followed by positive social interactions can improve clinical, eye-tracking and questionnaire-based assessments of symptoms in young autistic children.

Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome

Background and Aims: Irritable bowel syndrome (IBS), a functional pain disorder of gut-brain interactions, is characterized by a high placebo response in randomized clinical trials (RCTs). Catechol-O-methyltransferase (COMT) rs4680, which encodes high-activity (val) or low-activity (met) enzyme variants, was previously associated with placebo response to sham-acupuncture in an IBS RCT. Examining COMT effects and identifying novel genomic factors that influence response to placebo pills is critical to identifying underlying mechanisms and predicting and managing placebos in RCTs.Methods: Participants with IBS (N = 188) were randomized to three placebo-related interventions, namely, double-blind placebo (DBP), open-label placebo (OLP), or simply trial enrollment without placebo treatment [no placebo (i.e., no pill) treatment control (NPC)], for 6 weeks. COMT rs4680, gene-set, and genome-wide suggestive (p < 10−5) loci effects on irritable bowel symptom severity score (IBS-SSS) across all participants were examined.Results: Participants with IBS homozygous for rs4680 met (met/met) had the greatest improvement across all arms, with significantly greater improvement compared to val/val in DBP (beta (SE), −89.4 (42.3); p = 0.04). Twelve genome-wide suggestive loci formed a gene regulatory network highly connected to EGR1, a transcription factor involved in placebo-related processes of learning, memory, and response to stress and reward. EGR1 gene expression in peripheral blood mononuclear cells (PBMC) was significantly reduced at the endpoint across all treatment arms (log fold-change, −0.15; p = 0.02). Gene-set enrichment analysis returned three genome-wide significant ontology terms (GO:0032968, GO:0070934, and GO:0070937) linked to transcription regulation and GO:0003918 associated with DNA topoisomerase regulation.Conclusion: These results suggest common molecular mechanisms in response to varying forms of placebo that may inform personalized IBS treatment and placebo response prediction.Clinical Trial Registration:ClinicalTrials.gov, Identifier: NCT0280224.

Optimising treatment expectations in chronic lower back pain through observing others: a study protocol for a randomised clinical trial

IntroductionChronic lower back pain (CLBP) is a frequent cause of medical consultations worldwide, and it results in decreased quality of life and disability. Current treatments for CLBP are often not effective, and alternatives are urgently needed. Three promising possibilities have emerged: (1) open-label placebo treatment reduces chronic pain, (2) placebo treatment is as efficacious as opioid treatment with a high correlation between patient expectation and treatment outcome, and (3) observing positive effects in another patient can improve functional capacity. We hypothesise that treatment expectations can be positively influenced through social observation and improve treatment outcome.Methods and analysisIn our clinical trial, we will randomise patients with CLBP into five groups. Two groups receive either a 3 week course of treatment with an analgesic (ANA) (metamizole/dipyrone) or with open-label placebos (OLP). For one of each group, we will build treatment expectations through observational learning and assess its impact on the treatment. For this purpose, one group each will watch either a positive or a neutral video. The intervention groups will be compared with a control group that will not be given any medication or observational learning. Participants will be recruited via all institutions in the Hamburg metropolitan area that treat patients with CLBP. Patients are eligible for inclusion if they are at least 18 years or older, have CLBP (of at least 3 months duration), and agree to potentially receive an active ANA or an OLP. Patients with pain-related “red flags” will be excluded. The study requires 150 participants (30 participants per group) to assess the differences in the primary outcome, pain intensity. Secondary outcomes include changes in treatment expectations, anxiety, comorbid depression, stress-related neuroendocrine measures, functional and structural connectivity, functional capacity, and ANA consumption. All outcomes and treatment expectations will be measured before and after the intervention and 3 months post-intervention.Ethics and disseminationEthical approval was obtained in January 2020 from the Hamburg Medical Ethics Council (ref number PV7067). Outcomes will be disseminated through publications in peer-reviewed journals and presentations at national and international conference meetings.Trial registration numberThe approved trial protocol was registered at the German Clinical Trials Register (DRKS) and can be found at drks.de (Identifier: DRKS00024418).

Effect of homeopathic treatment used in commercial boar semen diluent on sperm viability

Background: It has been speculated that the homeopathic treatment of sperm cells in order to improve semen quality could be promising. However, few data is available and its use in spermatozoa requires investigation. It is well established that mitochondrial membrane potential is an important viability parameter of spermatozoa and it is intimately related to reproductive efficiency. In this manner, new technologies in order to improve the activity of sperm cells and, finally, the fecundity of swine herds are of extremely importance. Due to the lack of knowledge of homeopathic treatment effect on spermatozoa, the aim of the present study was to verify the effect of three different homeopathic treatments on viability of boar sperm cells. Methods: semen samples were obtained from two sexually mature boars (18 mo of age). The boars were cross bred, with similar genetics of Pietrain versus Duroc, BP 450 progeny from a supplier company of similar reproductive performance animals. The animals were maintained in individual stalls, study conducted in Sao Paulo - Brazil. Three homeopathic treatments: Pulsatilla 6CH, Avena 6 CH or both, compared to placebo treatment (sucrose), the homeopathic medicaments or the control were administrated as globules manipulated according Brazilian Homeopathic Pharmacology. Each globule weighted 30 mg and contained sucrose as vehicle. One dose of two globules was added per 100 mL of diluted boar semen, which were chilled for 24 or 48 hours. All samples were labeled in codes in order to allow all laboratory analysis and evaluations being performed as a blind test. Data were tested for normality of residues and homogeneity of variances using the Guided Data Analysis software. Variables and interactions were analyzed by the PROC MIXED of the SAS package (SAS Institute Ins. Cary, NC). Adjusted least squares means (LSMEANS) of treatments were compared using the Tukey Test. Results: The different treatments contributed to maintain acrossome integrity for prolonged periods of cooling over 48 hours. The use of Pulsatilla was effective in maintaining high sperm mitochondria activity up to 24 hours from harvesting. Conclusion: Homeopathic medications can be used in artificial insemination in order to improve the quality of cooled and stored pig semen [1]. Keywords: homeopathy, swine semen, sperm viability. Reference [1] Soto, F. R. M.; Vuaden, E. R.; Coelho, C. P.; Bonamin, L. V.; Azevedo, S. S. A.; Benites, N. R.; Barros, F. R. O.; Goissis, M. D.; Assumpção, M. E. O. D.; Visintin, J. A.; Marques, M. G. Effects of the utilization of homeopathic elements in commercial diluent on swine sperm viability. In Vitro Cell.Dev.Biol.—Animal. 47:205–209, 2011.

Resveratrol treatment does not reduce arterial inflammation in males at risk of type 2 diabetes: a randomized crossover trial

Purpose Resveratrol has shown promising anti-inflammatory effects in in vitro and animal studies. We aimed to investigate this effect on arterial inflammation in vivo. Methods This was an additional analysis of a double-blind randomized crossover trial which included eight male subjects with decreased insulin sensitivity who underwent an 18F-fluoroxyglucose (18F-FDG) PET/CT after 34 days of placebo and resveratrol treatment (150 mg/day). 18F-FDG uptake was analyzed in the carotid arteries and the aorta, adipose tissue regions, spleen, and bone marrow as measures for arterial and systemic inflammation. Maximum target-to-background ratios (TBRmax) were compared between resveratrol and placebo treatment with the non-parametric Wilcoxon signed-rank test. Median values are shown with their interquartile range. Results Arterial 18F-FDG uptake was non-significantly higher after resveratrol treatment (TBRmax all vessels 1.7 (1.6–1.7)) in comparison to placebo treatment (1.5 (1.4–1.6); p=0.050). Only in visceral adipose tissue, the increase in 18F-FDG uptake after resveratrol reached statistical significance (p=0.024). Furthermore, CRP-levels were not significantly affected by resveratrol treatment (p=0.091). Conclusions Resveratrol failed to attenuate arterial or systemic inflammation as measured with 18F-FDG PET in subjects at risk of developing type 2 diabetes. However, validation of these findings in larger human studies is needed.

The Effect of Ant Plant on the Increase of CD4 Count in PLHIV in the Papua Province

The ant plant (Myrmecodia pendans), an epiphyte of Hydnophytinae (Rubiceae), has long been used for traditional medication. This research aimed to examine the effect of ant plant on the increase of CD4 count in PLHIV in Papua Province and to identify the effect of ant plan supplementation on the increase of CD4 in PLHIV. The research used true experimental design with modified randomized control group pretest-posttest design. The pretest was performed by conducting a preliminary count of CD4 in both the intervention and control groups, to which ART has been administered. The intervention group was supplemented with the ant plant on a daily basis, while the control group was given a placebo treatment with tea. Based on the results, it can be concluded that PLHIV given ant plant supplementation may have a higher increase in their CD4 count after receiving an intervention for one month than those who only received ART. Further research is needed to investigate the effect of the ant plant on the viral load in PLHIV.

Testosterone promotes Coxsackievirus B3 pathogenesis in an oral inoculation mouse model

Enteroviruses initiate infection in the gastrointestinal tract, and sex is often a biological variable that impacts infection. The role of sex hormones on enterovirus pathogenesis, however, is unclear. Previous data indicate that sex hormones can influence intestinal replication of Coxsackievirus B3 (CVB3), an enterovirus in the Picornavirus family. To determine if testosterone promotes CVB3 infection, male mice were castrated and provided placebo or testosterone-filled capsules. We found that testosterone-treated mice shed significantly more CVB3 in the feces and succumbed to CVB3-induced disease at a higher rate than castrated mice given a placebo. Treatment of male mice with an androgen receptor antagonist, flutamide, protected male mice from CVB3-induced lethality, further confirming the role of testosterone in viral pathogenesis. We also observed higher viral loads in peripheral tissues of testosterone-treated mice and an increase in the cytokine and chemokine response. Finally, we found that testosterone treatment in female mice increased fecal CVB3 shedding but had no impact on viral lethality. Overall, these data indicate that testosterone and androgen receptor signaling can promote CVB3 replication in the intestine and enhance CVB3 lethality in a sex-dependent manner.

A review of Cochrane reviews on pharmacological treatment for attention deficit hyperactivity disorder

ABSTRACT. Attention deficit hyperactivity disorder (ADHD) is one of the most frequent childhood psychiatric problems. Objective: The objective of this study was to identify, synthesize the results, and critically evaluate all Cochrane systematic reviews (SRs) on the pharmacological interventions for children and adolescents (up to age 18) diagnosed with ADHD. Methods: The search was performed in the Cochrane Database of Systematic Reviews (via Wiley) in July 2020. Results: The search strategy resulted in four SRs of high methodological quality, analyzing 51 randomized clinical trials (9,013 participants). Compared to placebo, treatment with tricyclic antidepressants (TCAs) (desipramine), amphetamine, and methylphenidate showed improvement in symptoms such as difficulty concentrating, impulsivity, and hyperactivity in the short term (up to 6 months). There was an increase in the occurrence of adverse events, such as reduced appetite, difficulty sleeping, and abdominal pain. Insufficient evidence was found to support the effects of supplementation with polyunsaturated fatty acids. Conclusions: The use of TCAs, amphetamine, and methylphenidate in children and adolescents with ADHD seems to present positive effects and higher rates of minor adverse events when compared to placebo.