Influencing the Insulin System by Placebo Effects in Patients With Diabetes Type 2 and Healthy Controls: A Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to investigate whether placebo effect induced by pharmacological conditioning with intranasal insulin can affect glucose, insulin, C-peptide, hunger, and memory in patients with diabetes type 2 and healthy controls. METHODS: Placebo effect was induced by pharmacological conditioning. Thirty-two older patients (mean age = 68.3 years) with diabetes type 2 and age- and sex-matched thirty-two healthy older adults (mean age = 67.8 years) were randomly assigned to a conditioned or a control group. On day 1, conditioned group received six administrations of intranasal insulin with a conditioned stimulus (CS; smell of rosewood oil), whereas the control group received a placebo with the CS. On day 2, both groups received a placebo spray with the CS. Glucose, insulin, and C-peptide were repeatedly measured in blood. Hunger and memory were assessed with validated measures. RESULTS: Intranasal insulin stabilized dropping glucose levels in patients ( B = 0.03, SE = 0.02, p = .027) and healthy men ( B = 0.046, SE = 0.02, p = .021), and decreased C-peptide levels in healthy controls ( B = 0.01, SE = 0.001, p = .008). Conditioning also prevented the drop of glucose levels but only in men (both healthy and patients; B = 0.001, SE = 0.0003, p = .024). Conditioning significantly decreased hunger in healthy participants ( B = 0.31, SE = 0.09, p < .001). No effects were found on other measures. CONCLUSIONS: Placebo effect induced by conditioning with intranasal insulin modifies blood glucose levels and decreases hunger in older adults, but its effects depend on health status and sex. Insulin conditioning might be beneficial for groups suffering from intensive hunger but seems not be particularly suitable for blood glucose reduction. TRIAL REGISTRATION: Netherlands Trial Register, NL7783 ( https://www.trialregister.nl/trial/7783 ).

Can contagious itch be affected by positive and negative suggestions?

Contagious itch can be evoked by observing people scratching. Verbal suggestions about to-be-received itch can influence itch intensity, as shown by placebo research, but it is unknown whether this extends to contagious itch. The current study aimed to replicate prior findings that listening to scratching and rubbing sounds elicits contagious itch, and to investigate whether suggestions can modulate this process. Healthy participants (n = 140) received positive or negative suggestions about itch in response to the sounds (aimed to decrease or increase expected itch, respectively), or no specific suggestions as a control. Participants listened to a number of audio fragments with scratching and rubbing sounds. The amount of expected itch as well as itch sensation after each audio fragment were measured by self-report. Suggestions had no effect on the expected itch. Both rubbing and scratching sounds significantly elicited itch in all groups. Scratching sounds induced more itch than rubbing sounds exclusively in the control group. These findings indicate that short suggestions might be not effective enough to modify the expectations of people regarding contagious itch. Furthermore, suggestions modulate contagious itch to some degree, but not in the hypothesized direction. Potential similarities and differences in the neurobiological mechanisms of contagious itch and nocebo effects are discussed.

Increasing the Effectiveness of a Physical Activity Smartphone Intervention With Positive Suggestions: Randomized Controlled Trial.

BACKGROUND: eHealth interventions have the potential to increase the physical activity of users. However, their effectiveness varies, and they often have only short-term effects. A possible way of enhancing their effectiveness is to increase the positive outcome expectations of users by giving them positive suggestions regarding the effectiveness of the intervention. It has been shown that when individuals have positive expectations regarding various types of interventions, they tend to benefit from these interventions more. OBJECTIVE: The main objective of this web-based study is to investigate whether positive suggestions can change the expectations of participants regarding the effectiveness of a smartphone physical activity intervention and subsequently enhance the number of steps the participants take during the intervention. In addition, we study whether suggestions affect perceived app effectiveness, engagement with the app, self-reported vitality, and fatigue of the participants. METHODS: This study involved a 21-day fully automated physical activity intervention aimed at helping participants to walk more steps. The intervention was delivered via a smartphone-based app that delivered specific tasks to participants (eg, setting activity goals or looking for social support) and recorded their daily step count. Participants were randomized to either a positive suggestions group (69/133, 51.9%) or a control group (64/133, 48.1%). Positive suggestions emphasizing the effectiveness of the intervention were implemented in a web-based flyer sent to the participants before the intervention. Suggestions were repeated on days 8 and 15 of the intervention via the app. RESULTS: Participants significantly increased their daily step count from baseline compared with 21 days of the intervention (t107=-8.62; P<.001) regardless of the suggestions. Participants in the positive suggestions group had more positive expectations regarding the app (B=-1.61, SE 0.47; P<.001) and higher expected engagement with the app (B=3.80, SE 0.63; P<.001) than the participants in the control group. No effects of suggestions on the step count (B=-22.05, SE 334.90; P=.95), perceived effectiveness of the app (B=0.78, SE 0.69; P=.26), engagement with the app (B=0.78, SE 0.75; P=.29), and vitality (B=0.01, SE 0.11; P=.95) were found. Positive suggestions decreased the fatigue of the participants during the 3 weeks of the intervention (B=0.11, SE 0.02; P<.001). CONCLUSIONS: Although the suggestions did not affect the number of daily steps, they increased the positive expectations of the participants and decreased their fatigue. These results indicate that adding positive suggestions to eHealth physical activity interventions might be a promising way of influencing subjective but not objective outcomes of interventions. Future research should focus on finding ways of strengthening the suggestions, as they have the potential to boost the effectiveness of eHealth interventions. TRIAL REGISTRATION: Open Science Framework 10.17605/OSF.IO/CWJES; https://osf.io/cwjes.

Conditioned hormonal responses: A systematic review in animals and humans.

In contrast to classical conditioning of physiological responses such as immune responses and drug effects, only a limited number of studies investigated classical conditioning of endocrine responses. The present paper is the first systematic review that integrates evidence from animal and human trials regarding the possibility to condition the endocrine responses. Twenty-six animal and eight human studies were included in the review. We demonstrated that there is accumulating evidence that classical conditioning processes are able to influence specific endocrine responses, such as cortocosterone/cortisol and insulin, while more limited evidence exists for other hormones. Animal and human studies were generally consistent in their findings; however, the limited number of human studies makes it difficult to generalize and translate the results of animal research to humans. Next to methodological recommendations for future studies, we suggest several ways how classically conditioned endocrine responses can be used in clinical practice.

Placebo Effects in the Neuroendocrine System: Conditioning of the Oxytocin Responses.

OBJECTIVE: There is evidence that placebo effects may influence hormone secretion. However, few studies have examined placebo effects in the endocrine system, including oxytocin placebo effects. We studied whether it is possible to trigger oxytocin placebo effects using a classical conditioning paradigm. METHODS: Ninety-nine women were assigned to a conditioned, control, or drug control group. In the two-phase conditioning paradigm, participants in the conditioned and drug control groups received an oxytocin nasal spray combined with a distinctive smell (conditioned stimulus [CS]) for three acquisition days, whereas the control group received placebo spray. Subsequently, the conditioned and control groups received placebo spray with the CS and the drug control group received oxytocin spray for three evocation days. Salivary oxytocin was measured several times during each day. Pain sensitivity and facial evaluation tests previously used in oxytocin research were also administered. RESULTS: On evocation day 1, in the conditioned group, oxytocin significantly increased from baseline to 5 minutes after CS (B[slope] = 19.55, SE = 5.88, p < .001) and remained increased from 5 to 20 (B = -10.42, SE = 5.81, p = .071) and 50 minutes (B = -0.70, SE = 3.37, p = .84). On evocation day 2, a trend for increase in oxytocin was found at 5 minutes (B = 15.22, SE = 8.14, p = .062). No placebo effect was found on evocation day 3 (B = 3.57, SE = 3.26, p = .28). Neither exogenous nor conditioned oxytocin affected pain or facial tasks. CONCLUSIONS: Results indicate that oxytocin release can be conditioned and that this response extinguishes over time. Triggering hormonal release by placebo manipulation offers various clinical possibilities, such as enhancing effects of pharmacological treatments or reducing dosages of medications. TRIAL REGISTRATION: The study was registered as a clinical trial on www.trialregister.nl (number NTR5596).

Enhancing Placebo Effects in Somatic Symptoms Through Oxytocin.

OBJECTIVE: Placebo effects relieve various somatic symptoms, but it is unclear how they can be enhanced to maximize positive treatment outcomes. Oxytocin administration may potentially enhance placebo effects, but few studies have been performed, and they have had conflicting findings. The study aim was to investigate the influence of positive verbal suggestions and oxytocin on treatment expectations and placebo effects for pain and itch. METHODS: One hundred eight female participants were allocated to one of the following four groups: (1) oxytocin with positive verbal suggestions, (2) placebo with positive verbal suggestions, (3) oxytocin without suggestions, and (4) placebo without suggestions. The administration of 24 IU oxytocin or a placebo spray was preceded by positive verbal suggestions regarding the pain- and itch-relieving properties of the spray or no suggestions, depending on group allocation. Pain was assessed with a cold pressor test, and itch was assessed with histamine iontophoresis. RESULTS: Positive verbal suggestions induced expectations of lower pain (F = 4.77, p = .031) and itch (F = 5.38, p = .022). Moreover, positive verbal suggestions elicited placebo analgesia (F = 5.48, p = .021) but did not decrease itch. No effect of oxytocin on the placebo effect or on expectations was found. CONCLUSIONS: Positive suggestions induced placebo analgesia but oxytocin did not enhance the placebo effect. Study limitations are that we only included a female sample and a failure to induce placebo effect for itch. Future studies should focus on how oxytocin might influence placebo effects, taken into account the role of sex, dose-dependent effects, and various expectation manipulations. TRIAL REGISTRATION: The study was registered as a clinical trial on www.trialregister.nl (number 6376).

Olfactory exposure to late-pregnant and lactating mice causes stress-induced analgesia in male mice.

In an attempt to improve reproducibility, more attention is being paid to potential sources of stress in the laboratory environment. Here, we report that the mere proximity of pregnant or lactating female mice causes olfactory-mediated stress-induced analgesia, to a variety of noxious stimuli, in gonadally intact male mice. We show that exposure to volatile compounds released in the urine of pregnant and lactating female mice can themselves produce stress and associated pain inhibition. This phenomenon, a novel form of female-to-male chemosignaling, is mediated by female scent marking of urinary volatiles, such as n-pentyl-acetate, and likely signals potential maternal aggression aimed at defending against infanticide by stranger males.

Food anticipatory hormonal responses: A systematic review of animal and human studies.

Food anticipatory hormonal responses (cephalic responses) are proactive physiological processes, that allow animals to prepare for food ingestion by modulating their hormonal levels in response to food cues. This process is important for digesting food, metabolizing nutrients and maintaining glucose levels within homeostasis. In this systematic review, we summarize the evidence from animal and human research on cephalic responses. Thirty-six animal and fifty-three human studies were included. The majority (88 %) of studies demonstrated that hormonal levels are changed in response to cues previously associated with food intake, such as feeding time, smell, and sight of food. Most evidence comes from studies on insulin, ghrelin, pancreatic polypeptide, glucagon, and c-peptide. Moreover, impaired cephalic responses were found in disorders related to metabolism and food intake such as diabetes, pancreatic insufficiency, obesity, and eating disorders, which opens discussions about the etiological mechanisms of these disorders as well as on potential therapeutic opportunities.

Effects of Oxytocin on Placebo and Nocebo Effects in a Pain Conditioning Paradigm: A Randomized Controlled Trial.

Oxytocin has been shown to increase trust, decrease anxiety, and affect learning as has been observed in conditioning paradigms. Trust, anxiety, and learning are important factors that influence placebo effects. In this study, we investigated whether oxytocin can increase placebo analgesia, decrease nocebo hyperalgesia, and influence extinction processes of both. Eighty male volunteers were assigned to a 40 IU of oxytocin nasal spray group, or to a placebo control group. Placebo analgesia and nocebo hyperalgesia were induced by a conditioning procedure in combination with verbal suggestions. The results demonstrate that the conditioning procedure successfully elicited significant placebo analgesia and nocebo hyperalgesia responses (P < .001). Furthermore, extinction was observed (P < .001), although placebo and nocebo responses did not return to baseline and remained significant. Oxytocin did not influence placebo analgesia or nocebo hyperalgesia and had no effect on extinction. This study provides support against the placebo-boosting effects of oxytocin and was the first one to demonstrate that it also did not influence nocebo effects or extinction processes, however, these results pertain to only a male sample. As managing placebo and nocebo effects has widespread clinical implications, further research should investigate other neurobiological or behavioral pathways to boost placebo and decrease nocebo effects. PERSPECTIVE: The present study demonstrated that placebo analgesia and nocebo hyperalgesia can be successfully induced by conditioning and verbal suggestions. We could not confirm the hypothesis that oxytocin affects either of these phenomena. Other pharmacological agents and behavioral manipulations for increasing placebo and decreasing nocebo effects should be investigated.

Effects of oxytocin administration and conditioned oxytocin on brain activity: An fMRI study.

It has been demonstrated that secretion of several hormones can be classically conditioned, however, the underlying brain responses of such conditioning have never been investigated before. In this study we aimed to investigate how oxytocin administration and classically conditioned oxytocin influence brain responses. In total, 88 females were allocated to one of three groups: oxytocin administration, conditioned oxytocin, or placebo, and underwent an experiment consisting of three acquisition and three evocation days. Participants in the conditioned group received 24 IU of oxytocin together with a conditioned stimulus (CS) during three acquisition days and placebo with the CS on three evocation days. The oxytocin administration group received 24 IU of oxytocin and the placebo group received placebo during all days. On the last evocation day, fMRI scanning was performed for all participants during three tasks previously shown to be affected by oxytocin: presentation of emotional faces, crying baby sounds and heat pain. Region of interest analysis revealed that there was significantly lower activation in the right amygdala and in two clusters in the left superior temporal gyrus in the oxytocin administration group compared to the placebo group in response to observing fearful faces. The activation in the conditioned oxytocin group was in between the other two groups for these clusters but did not significantly differ from either group. No group differences were found in the other tasks. Preliminary evidence was found for brain activation of a conditioned oxytocin response; however, despite this trend in the expected direction, the conditioned group did not significantly differ from other groups. Future research should, therefore, investigate the optimal timing of conditioned endocrine responses and study whether the findings generalize to other hormones as well.