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Correct guess rate (CGR) curves for self-blinding microdose trial outcomes. Each panel shows the estimated treatment p-value (blue; scale shown on left y-axis) and effect size (red; scale shown on right y-axis), with their corresponding confidence interval, as a function of CGR. Horizontal purple dashed line represents the p = .05 threshold, vertical green dashed line corresponds to the trial’s original CGR (= 0.72), while the black dashed line corresponds to a perfectly blinded trial (CGR = 0.5). Outcomes in the top row (Positive and Negative Affection Scale (PANAS) and Mood visual analogue scale) are significant according to unadjusted analysis (green dashed line intersects p-value estimate below 0.05), but become insignificant after CGR adjustment (black dashed line intersects p-value estimate above 0.05), arguing that these findings could be false positives driven by AEB. Energy VAS remains significant even after CGR adjustment, although the effect size is reduced by ~ 40%. This finding suggests that microdosing increases self-perceived energy beyond what is explainable by expectancy effects, although the remaining effect is small (Hedges’ g = .34). Finally, CGR adjustment has little impact on the cognitive performance score as both the p-value and the effect estimate remain close to a constant. This finding suggests that this measure is not affected by AEB, possibly because cognitive performance was not self-rated, rather measured by objective computerized tests, see Table 2 for numerical results.
Source publication
In medical trials, ‘blinding’ ensures the equal distribution of expectancy effects between treatment arms in theory; however, blinding often fails in practice. We use computational modelling to show how weak blinding, combined with positive treatment expectancy, can lead to an uneven distribution of expectancy effects. We call this ‘activated expec...
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... Such extra-pharmacological and -therapeutic effects on acute experience would pose a major validity threat to the present study as it would be possible that disappointment effects in the ET arm counteracted experiential elements during dosing day 2, e.g., producing more negatively valenced experience and moving participants further away from mystical experience. As there is no evidence to support or refute this possibility, in line with calls to better measure components of the blinding process (Szigeti et al., 2023), we encourage scientists to measure disappointment effects closely in future trials. ...
The mechanisms by which Psilocybin Therapy (PT) improves depression remain an important object of study, with scientists actively exploring acute psychological experiences and neurobiological processes as candidates. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we investigated whether acute psychological experiences could meaningfully account for the unique efficacy of PT versus Escitalopram Treatment over a core 6-week trial period. An exploratory-factor-analysis-derived single-factor of depression was used as the outcome. Among a comprehensive set of acute experiences related to psilocybin, so-called “mystical experience” and “ego dissolution” were unique in mediating the effect of treatment condition on depressive response with high specificity. Higher reported levels of mystical experience, emotional breakthrough, and intense responses to music-listening were furthermore associated with greater antidepressant response. These results provide qualified support for the causal mechanistic role of acute psychological experiences in the treatment of depression via PT.
... We therefore suggest that, after conducting a controlled study, researchers continue to engage participants in online surveys, which are inexpensive, so that they may measure whether there are any longitudinal effects attributable to microdoses after participants no longer consume the substances. Finally, participants should be asked whether they think that they are in the experimental or placebo group and what evidence they have for this observation; these rates and responses should be reported (39). ...
... This is particularly noteworthy as a doseresponse curve for microdosing has yet to be identified. Indeed, the placebo effect may play an outsized role in the case of psychedelics (10,37), making the importance of controlling for expectancy particularly important (39). If journals and reviewers were to require sampling strategies and power analyses, the quality of the data obtained would be substantially higher. ...
Introduction
The practice of taking small, sub-hallucinogenic doses of psychedelics, known as microdosing, has exploded in popularity over the last decade. Users claim benefits ranging from improved mood and enhanced creativity to an increased sense of meaning and connectedness in life. While research on microdosing is still lagging behind the shift in public opinion, several papers have been published in the last five years which attempted to assess the effects of microdosing.
Methods
This review paper aimed to critically analyze the research practices used in the recent wave of microdosing research: We reviewed 15 papers published before the closing date of this review in March 2022.
Results
Our review concludes that it is premature to draw any conclusions about the efficacy or safety of microdosing since the research quality cannot be considered confirmatory.
Discussion
We propose some potential causes for the current state of the literature and some suggestions for how these causes may be ameliorated.
... For example in another recent trial of psilocybin-assisted therapy, 94% of participants correctly guessed their treatment allocation, indicating that blinding was broken (Bogenschutz et al., 2022). Based on this consideration, a number of authors have expressed concerns over the methodological soundness of psychedelic trials, arguing that expectancy effects may be biasing the observed results despite the formal blinding procedures (Burke & Blumberger, 2021;Muthukumaraswamy et al., 2021;Szigeti, Nutt, Carhart-Harris, & Erritzoe, 2023). In the case of 'psychedelic microdosing', where users regularly take small doses of a psychedelic drug without clinical supervision (Polito & Liknaitzky, 2022), a number of studies, including some that were placebo-controlled (Cavanna et al., 2022;de Wit, Molla, Bershad, Bremmer, & Lee, 2022;Szigeti et al., 2021) suggest that positive expectancy may play an important role in driving positive responses highlighting a need to investigate expectancy and related effects in all psychedelic trials. ...
... escitalopram expectancy when allocated to the escitalopram arm and psilocybin expectancy when allocated to the psilocybin arm). We choose to analyze the data this way because the 25 mg psilocybin used in the current trial induces strong psychological and physical effects that can be reliably recognized and attributed to psilocybin by most patients (Muthukumaraswamy et al., 2021), thus, blinding integrity is unlikely to have been maintained (Szigeti et al., 2023). Similarly, blinding integrity is also often violated in SSRI trials (Scott, Sharpe, & Colagiuri, 2022). ...
... However, the lack of association for the psilocybin arm is surprising given that expectancy effects are associated with improved outcomes across a wide range of medical diagnoses and therapeutic approaches (Tambling, 2012), including one naturalistic study of psychedelic use that assessed expectancy with a self-constructed binary (yes/ no) questionnaire (Weiss, Miller, Carter, & Keith Campbell, 2021), rather than using a continuous scale. Suspicion has been expressed that in psychedelic trials the combination of the lack of effective blinding, strong demand characteristics, and related confirmation biases may positively bias trial outcomes (Burke & Blumberger, 2021;Muthukumaraswamy et al., 2021;Szigeti et al., 2023). Our results partially alleviate these suspicions, as we did not find a significant association between psilocybin-specific efficacy-related expectations and efficacy-related outcomes. ...
Background
To investigate the association between pre-trial expectancy, suggestibility, and response to treatment in a trial of escitalopram and investigational drug, COMP360, psilocybin, in the treatment of major depressive disorder (ClinicalTrials.gov registration: NCT03429075).
Methods
We used data ( n = 55) from our recent double-blind, parallel-group, randomized head-to-head comparison trial of escitalopram and investigational drug, COMP360, psilocybin. Mixed linear models were used to investigate the association between pre-treatment efficacy-related expectations, as well as baseline trait suggestibility and absorption, and therapeutic response to both escitalopram and COMP360 psilocybin.
Results
Patients had significantly higher expectancy for psilocybin relative to escitalopram; however, expectancy for escitalopram was associated with improved therapeutic outcomes to escitalopram, expectancy for psilocybin was not predictive of response to psilocybin. Separately, we found that pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, but not in the escitalopram arm.
Conclusions
Overall, our results suggest that psychedelic therapy may be less vulnerable to expectancy biases than previously suspected. The relationship between baseline trait suggestibility and response to psilocybin therapy implies that highly suggestible individuals may be primed for response to this treatment.
... For example, Muthukumaraswamy et al. 5 recommend to assess the cause of unblinding, whether it is benign (i.e., due to positive treatment effects) or malicious (i.e., due to side-effects of the treatment). This recommendation was followed up upon by Szigeti et al., 6 who also developed the Correct Guess Rate Curve, which statistically adjusts for unblinding. Lastly, Muthukumaraswamy et al. 5 and Aday et al. 2 suggest to measure not only blinding quality but also the magnitude of expectancies, which has been successfully implemented in both micro-and macrodosing studies. ...
... 138 Blinding integrity tools in the context of psychedelic micro-dosing studies have also been recently developed, as well as recommendations to improve blinding issues in psychedelic trials. 139 The impact of preparatory sessions on expectancy, as well as the set and setting and other controllable factors in psychedelics sessions, should be also thoughtfully considered as possible factors influencing outcomes. 140 Specific safety considerations in psychedelic trials for those with pain and/or OUD ...
The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the emerging role of psychedelics in the management of chronic pain and opioid use disorder (OUD), two critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy (LTOT) who develop marked tolerance to opioid-induced analgesia. Despite the magnitude of this problem, there is a scarcity of controlled studies investigating pain management alternatives for these populations. Drawing from preclinical and human evidence, we highlight the potential of psychedelics to act on shared neurobiological substrates of chronic pain and opioid use disorder, potentially reversing pain-and opioid-induced neuroadaptations, such as central sensitization. We elaborate on the multifaceted dimensions of the pain experience (sensory, affective, and cognitive) and their intersections that overlap with opioid-related phenomena (opioid craving and withdrawal), hypothesizing how these processes can be modulated by psychedelics. After summarizing the available clinical research, we propose mechanistic insights and methodological considerations for the design of future translational studies and clinical trials, building on a shared clinical and neurobiological understanding of chronic pain and OUD. Our intention is to provide timely perspectives that accelerate the development and exploration of novel therapeutics for chronic pain and OUD amidst the escalating opioid crisis.
There is controversy about a causal role of serotonin (5-HT) in depression, some arguing that there is no proof for impaired brain 5-HT function in depressed patients. Major depressive disorder comes with multiple endophenotypes; not surprisingly classical antidepressants (tricyclics, MAO inhibitors, SSRIs, SNRIs) are not universally effective. Most antidepressants target the 5-HT system, partially if not exclusively, but treatment-resistant depression (TRD) remains a major issue. The most recent and heavily investigated class of potential rapid acting antidepressant, anxiolytic, and/or anti PTSD drugs, namely psychedelics (psilocybin, LSD, DMT, ayahuasca, etc..) or entactogens (MDMA, ibogaine), all target the 5-HT system, at least in part. Phase II / III clinical trials support psychedelics- and/or MDMA-assisted psychotherapy as a new class of rapid acting treatments for GAD, MDD, TRD, PTSD, and other disorders. Psilocybin and MDMA have FDA breakthrough status for TRD/MDD and PTSD, respectively, whereas LSD just received FDA breakthrough status for GAD. All psychedelics act as 5-HT2A receptor agonists, although LSD, DMT, psilocybin may also target other 5-HT and/or dopamine receptors. Psychedelics produce rapid onset and long-lasting antidepressant effects after one or two administrations. They all promote synaptogenesis and synaptic plasticity. Neuroinflammation plays a major role in anxiety, depression, PTSD. Interestingly, psychedelic-induced 5-HT2A receptor agonism has profound anti-(neuro)inflammatory effects. Altogether, the 5-HT system plays an essential, but not unique role in MDD and related disorders. MDD, TRD and PTSD may be considered as biochemical, neurological and immune conditions, given the emerging role of neuroplasticity and neuroinflammation, which until recently, have been overlooked.
Psychedelic drugs such as psilocybin and ketamine are returning to clinical research and intervention across several disorders including the treatment of depression. This chapter focusses on psychedelics that specifically target the 5-HT2A receptor such as psilocybin and DMT. These produce plasma-concentration related psychological effects such as hallucinations and out of body experiences, insightful and emotional breakthroughs as well as mystical-type experiences. When coupled with psychological support, effects can produce a rapid improvement in mood among people with depression that can last for months. In this chapter, we summarise the scientific studies to date that explore the use of psychedelics in depressed individuals, highlighting key clinical, psychological and neuroimaging features of psychedelics that may account for their therapeutic effects. These include alterations in brain entropy that disrupt fixed negative ruminations, a period of post-treatment increased cognitive flexibility, and changes in self-referential psychological processes. Finally, we propose that the brain mechanisms underlying the therapeutic effect of serotonergic psychedelics might be distinct from those underlying classical serotonin reuptake-blocking antidepressants.
Background
In a recent clinical trial examining the comparative efficacy of psilocybin therapy (PT) versus escitalopram treatment (ET) for major depressive disorder, 14 of 16 major efficacy outcome measures yielded results that favored PT, but the Quick Inventory of Depressive Symptomatology, Self-Report, 16 items (QIDS-SR 16 ) did not.
Aims
The present study aims to (1) rationally and psychometrically account for discrepant results between outcome measures and (2) to overcome psychometric problems particular to individual measures by re-examining between-condition differences in depressive response using all outcome measures at item-, facet-, and factor-levels of analysis.
Method
Four depression measures were compared on the basis of their validity for examining differences in depressive response between PT and ET conditions.
Results/Outcomes
Possible reasons for discrepant findings on the QIDS-SR 16 include its higher variance, imprecision due to compound items and whole-scale and unidimensional sum-scoring, vagueness in the phrasing of scoring options for items, and its lack of focus on a core depression factor. Reanalyzing the trial data at item-, facet-, and factor-levels yielded results suggestive of PT’s superior efficacy in reducing depressed mood, anhedonia, and a core depression factor, along with specific symptoms such as sexual dysfunction.
Conclusion/Interpretation
Our results raise concerns about the adequacy of the QIDS-SR 16 for measuring depression, as well as the practice of relying on individual scales that tend not to capture the multidimensional structure or core of depression. Using an alternative approach that captures depression more granularly and comprehensively yielded specific insight into areas where PT therapy may be particularly useful to patients and clinicians.
