Great Expectations: Recommendations for improving the methodological rigor of psychedelic clinical trials

Rationale: Psychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research.Objective: In this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research.Results: We found that although some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants’ expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies concern study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy.Conclusion: Incorporating these design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increase the ability to discern treatment-specific effects of psychedelic therapy

Human ventromedial prefrontal cortex lesions enhance expectation-related pain modulation

Pain is strongly modulated by expectations and beliefs. Research across species indicates that subregions of the ventromedial prefrontal cortex (VMPFC) play a fundamental role in learning and generating predictions about valued outcomes. Consistent with this overarching framework, neuroimaging studies of experimental pain indicate that VMPFC activation tracks expectations of pain relief and statistically mediates expectation-related reductions in responses to painful stimuli across a distributed pain processing network. However, lesion studies in preclinical models and in humans with refractory chronic pain suggest that VMPFC may play a more general role in representing the affective and motivational qualities of pain that contribute to its strong aversive drive. To test whether VMPFC is necessary for pain processing in general, or instead plays a more specific role in the modulation of pain by expectations, we studied responses to experimental heat pain in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage.All participants underwent quantitative sensory testing (QST) to characterize pain sensitivity, followed by a pain expectancy task. Participants were instructed that auditory cues would be followed by heat calibrated to elicit low or high pain. Following a conditioning phase, each cue was intermittently paired with a single temperature calibrated to elicit moderate pain. We compared ratings of moderate heat stimuli and subjective expectancy ratings as a function of cue to evaluate whether VMPFC lesions impact cue-based expectancy and expectancy effects on pain intensity and unpleasantness. We also analyzed QST measures to evaluate whether VMPFC lesions were associated with overall shifts in pain sensitivity.Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expectations as a function of pain-predictive cues, and stronger cue-based modulation of pain ratings, particularly for ratings of pain unpleasantness. There were no group differences in pain sensitivity, nor in the relationship between pain and autonomic arousal, indicating that the impact of VMPFC lesions is specific to expectancy-based modulation of pain unpleasantness.Our findings suggest that the VMPFC is not essential for basic subjective and physiological responses to painful stimuli. Rather, our findings of significantly enhanced cue- related expectancy effects may suggest that VMPFC plays an important role in updating expectations or integrating sensory information with expectations to guide subjective judgements about pain. Taken together, these results expand our understanding VMPFC’s contribution to pain and highlight the role of VMPFC in integrating cognitive representations with sensory information to yield affective responses.

Who benefits most from expectancy effects? A combined neuroimaging and antidepressant trial in depressed older adults

Depressed patients’ expectations of improvement drive placebo effects in antidepressant clinical trials, yet there is considerable heterogeneity in the magnitude of expectancy effects. The present study seeks to identify those individuals who benefit most from expectancy effects using baseline neuroimaging and cognitive measures. Older adult outpatients diagnosed with major depressive disorder (MDD) participated in a prospective, 8-week clinical trial in which expectancy was experimentally manipulated and its effects on depression outcome measured. Based on the literature, we selected a priori 12 cognitive and brain-based variables linked to depression and expectancy, together with demographic variables, and incorporated them into a combined moderator. The combined moderator was developed as a weighted combination of the individual moderators, and was used to identify individuals who benefited most from expectancy effects. The combined moderator was found to predict differential change in depression severity scores between the high- vs. low-expectancy groups with a medium-size effect (Spearman effect size: 0.28). While at the sample level no expectancy effect was found, the combined moderator divided older adults with MDD into those who did and those who did not improve as the result of expectancy manipulation, with those benefiting from the manipulation showing greater processing speed, executive function, and frontostriatal white matter tract integrity. The findings suggest that it is possible to identify a subgroup of older adult individuals with MDD for whom expectancy manipulation results in greater antidepressant treatment response, supporting a precision medicine approach. This subgroup is characterized by distinct cognitive dysfunction and neuroimaging impairments profiles.

Place-Based Drivers of Mortality: Evidence from Migration

We estimate the effect of current location on elderly mortality by analyzing outcomes of movers in the Medicare population. We control for movers’ origin locations as well as a rich vector of pre-move health measures. We also develop a novel strategy to adjust for remaining unobservables, using the correlation of residual mortality with movers’ origins to gauge the importance of omitted variables. We estimate substantial effects of current location. Moving from a tenth to a ninetieth percentile location would increase life expectancy at age 65 by 1.1 years, and equalizing location effects would reduce cross-sectional variation in life expectancy by 15 percent. Places with favorable life expectancy effects tend to have higher quality and quantity of health care, less extreme climates, lower crime rates, and higher socioeconomic status. (JEL H51, I1, I11)

The relationship of health-related expectancies, fruit and vegetable intake, and positive mood: expectancies are important, but not in the way you expect

PurposeGreater fruit and vegetable (F&V) intake has been linked to more positive mood. Here, the purpose of this paper is to examine if this relationship is mediated by expectancies about their benefit to health/mental health.Design/methodology/approachParticipants completed a new questionnaire to assess expectancies related to F&V intake. This was administered alongside a validated food-frequency measure of F&V intake, an assessment of positive and negative mood state and other measures.FindingsParticipants held strongly positive expectations about the physical and mental health benefits of consuming F&V. The authors observed a significant relationship between self-reported F&V intake and positive mood (d = 0.52). Importantly, this effect was largely (but not completely) independent of expectancies. The authors also observed that expectancies about F&V intake were independently predictive of positive mood (d = 0.47).Originality/valueThis is the first study to explore expectancy effects in the mental health benefits of F&V intake. These data suggest that positive expectancies about F&V intake, and F&V intake itself, are both predictive of positive mood. The former finding is probably a placebo effect, whereby people believe they are consuming sufficient F&V (even if they are not) and so experience mood-related benefits due to their positive expectations. The latter finding is consistent with F&V exerting a biologically beneficial effect on the brain.

Reward and expectancy effects on neural signals of motor preparation and execution

The prospect of rewards can have strong modulatory effects on response preparation. Importantly, selection and execution of movements in real life happens under an environment characterized by uncertainty and dynamic changes. The current study investigated how the brain's motor system adapts to the dynamic changes in the environment in pursuit of rewards. In addition, we studied how the prefrontal cognitive control system contributes in this adaptive control of motor behavior. To this end, we tested the effect of rewards and expectancy on the hallmark neural signals that reflect activity in motor and prefrontal systems, the lateralized readiness potential (LRP) and the mediofrontal (mPFC) theta oscillations, while participants performed an expected and unexpected action to retrieve rewards. To better capture the dynamic changes in neural processes represented in the LRP waveform, we decomposed the LRP into the preparation (LRPprep) and execution (LRPexec) components. The overall pattern of LRPprep and LRPexec confirmed that they each reflect motor preparation based on the expectancy and motor execution when making a response that is either or not in line with the expectations. In the comparison of LRP magnitude across task conditions, we found a greater LRPprep when large rewards were more likely, reflecting a greater motor preparation to obtain larger rewards. We also found a greater LRPexec when large rewards were presented unexpectedly, suggesting a greater motor effort placed for executing a correct movement when presented with large rewards. In the analysis of mPFC theta, we found a greater theta power prior to performing an unexpected than expected response, indicating its contribution in response conflict resolution. Collectively, these results demonstrate an optimized motor control to maximize rewards under the dynamic changes of real-life environment.

Effects of psilocybin microdosing on awe and aesthetic experiences: a preregistered field and lab-based study

There is an increased societal trend to engage in microdosing, in which small sub-hallucinogenic amounts of psychedelics are consumed on a regular basis. Following subjective reports that microdosing enhances the experience of nature and art, in the present study we set out to study the effects of psilocybin microdosing on feelings of awe and art perception. In this preregistered combined field- and lab-based study, participants took part in a microdosing workshop after which they volunteered to self-administer a psilocybin microdose or a placebo for three consecutive weeks, while the condition was kept blind to the participants and researchers. Following a 2-week break, the condition assignment was reversed. During each block, participants visited the lab twice to measure the effects of psilocybin microdosing vs. placebo. We used standardized measures of awe, in which participants reported their experiences in response to short videos or when viewing abstract artworks from different painters. Our confirmatory analyses showed that participants felt more awe in response to videos representing funny animals and moving objects in the microdosing compared to the placebo condition. However, about two-third of our participants were breaking blind to their experimental condition. Our exploratory findings suggest that expectancy-effects may be a driving factor underlying the subjective benefits of microdosing.

Efficacy and Underlying Mechanism of Acupuncture in the Treatment of Posttraumatic Stress Disorder: A Systematic Review of Animal Studies

Acupuncture is a nonpharmacological intervention that can be useful in the clinical management of posttraumatic stress disorder (PTSD), especially in situations with a lack of medical resources, including large-scale PTSD events such as disasters. Some clinical studies have reported the clinical effect of acupuncture in improving PTSD symptoms, but the underlying therapeutic mechanism has yet to be explored. Therefore, this review summarized the underlying therapeutic mechanisms of acupuncture in animal PTSD models. A comprehensive search was conducted in 14 electronic databases, and two independent researchers performed study selection, data extraction, and the methodological quality assessment. Twenty-four relevant studies were included in this review and summarized according to the proposed main mechanisms. In behavioral evaluation, acupuncture, including manual acupuncture and electro-acupuncture, reduced anxiety and fear responses and weakened fear conditioning, improved sleep architecture, reduced depressive symptoms, and alleviated disturbance of spatial learning and memory of PTSD animal models. The therapeutic mechanisms of acupuncture proposed in the included studies could be classified into two categories: (1) regulation of stress responses in the neuroendocrine system and (2) promotion of neuroprotection, neurogenesis, and synaptic plasticity in several brain areas. However, the methodological quality of the included animal studies was not high enough to produce robust evidence. In addition, mechanistic studies on specific aspects of acupuncture that may affect PTSD, including expectancy effects, in human PTSD subjects are also needed.

Evaluating cannabidiol (CBD) expectancy effects on acute stress and anxiety in healthy adults: a randomized crossover study

Rationale Cannabidiol (CBD) has been reported to attenuate stress and anxiety, but little is known about the extent to which such effects result from pharmacological versus expectancy factors. Objectives We evaluated whether CBD expectancy alone could influence stress, anxiety, and mood, and the extent to which beliefs regarding CBD effects predicted these responses. Methods In this randomized crossover study, 43 health adults (23 women) attended two experimental laboratory sessions, where they self-administered CBD-free hempseed oil sublingually. During one session, they were (incorrectly) informed that the oil contained CBD and in the other session, that the oil was CBD-free. Following administration, participants engaged in the Maastricht Acute Stress Test (MAST). Heart rate variability (HRV) was assessed continuously, and subjective state was assessed at baseline, 90-min following oil administration, immediately following the MAST, and after a 10-min recovery period. Results The CBD expectancy condition was associated with increased sedation as well as with changes in HRV that were consistent with heightened anticipatory stress regulation. Overall, there were no systematic changes in subjective stress, or anxiety, according to expectancy condition. However, participants who endorsed strong a priori beliefs that CBD has anxiolytic properties reported significantly diminished anxiety in the CBD expectancy condition. Conclusions CBD expectancy alone impacted several subjective and physiological responses. Additionally, expectancy-related factors were implicated in anxiolytic effects of CBD for those who believed it was helpful for such purposes, emphasizing the need to measure and control for CBD-related expectancies in clinical research that involves the administration of CBD.