Who is blind in psychedelic research? Letter to the editor regarding: blinding and expectancy confounds in psychedelic randomized controlled trials

Abstract

Dear Editors, Unblinding is an important confounding in pharmacological research potentially affecting rigor and objectivity of the scientific data underlying evidence-based medicine. Therefore, I want to commend the work by Muthukumaraswamy et al. [1] reporting on this problem in clinical trials with psychedelics (Ketamine, LSD, psilocybin and ayahuasca), which are rapidly becoming a focus of increased attention and hope, but also concern. The authors presented an in-depth and carefully argued overview of unblinding (also called de-blinding, unmasking or de-masking) including promising alternatives and careful procedures to improve research practices. The two blinding indexes, the distinction between malicious and benign unmasking and the nine different study designs, four of which they do not recommend, are welcome. These were complemented by straightforward statistical estimates of average treatment effect avoiding inflation of effect-sizes because of unblinding, considering four inducers of healing: active treatment, placebo effect, therapeutic alliance and spontaneous or ‘natural’ healing. Furthermore, the two psychometric measures to evaluate expectancy can add important information at low cost. All of these expert suggestions should be noted by researchers not only when designing studies with psychedelics, because unblinding and underreporting became pervasive in pharmacology [2,3]. This can bias large scale pharmaceutical practices with consequences for regulatory approvals, potentially affecting millions of patients. However, we must critically examine if the proposed research program is pragmatic, if it can improve standards of care and if it can solve conceptual challenges in psychedelic research and psychopharmacology in general. First, two of the suggested designs involve more than two conditions, thus potentially increasing the number of patients necessary for adequate statistical power. Unfortunately, sample size estimates were not presented. Yet, a larger number of patients may increase costs and given these are not currently demanded by regulatory authorities, it is unlikely that the pharmaceutical industry would invest in such designs, while the academic sector may face financial obstacles for implementation. To complicate matters further, ethical considerations may hinder these proposals, not limited to the issue of patient deception, rightly pointed out by the authors. There are more serious concerns, as recently happened in the first Phase 3 trial with MDMA-assisted therapy for the treatment of PTSD: the only three serious adverse events occurred in the placebo group, with one patient having two episodes of suicidal behavior and another having one episode of suicidal ideation leading to self hospitalization [4]. Regarding active comparators, evidence from MDMA research, unfortunately missing in the paper, is useful: low dose MDMA can be stressful and trying for patients, propitiating drop-outs [5], thus these designs may violate clinical equipoise. Therefore, the proposed research program may not be pragmatically and ethically implemented. Second, it is dubious if the suggested practices will benefit patients. While research aims to isolate pharmacological effects from other variables in order to regulate and authorize drug marketing, in clinical practice patients always expect something out of the treatments they search for, and therapeutic alliance and placebo effects are always part of the process. Finally, we need to examine if it actually makes sense to try to disentangle the contributions of these inductors of healing as relatively independent variables, or if they are so intertwined as to make the goal of such research unachievable in principle. The question as to whether psychopharmacology can be reduced to objective and quantitative measures alone bears on epistemic considerations regarding what is psychiatry, what are mental disorders and mental health. The etymology of psychopharmaceuticals comes from psȳkhē, from the Greek ‘breath, life, or soul,’ similarly included in the 1956 ‘psychedelic’ (‘mind manifesting’) neologism by psychiatrist Humphry Osmond. Then is it logical to consider that people should not become consciously aware of changes in their feelings, emotions, sensations and thoughts when the treatment is exactly aiming at people’s feelings, emotions and thoughts? Is it coherent to strive for pure objectivity if the symptoms of the disorders and the effects of the drugs are mostly subjectively felt? If we expect to find drugs which minimize or eliminate chronic symptoms including intense fear, anxiety or sadness, how could patients’ feelings change without them becoming consciously aware of it? And if they do not perceive it, thus preserving masking, wouldn’t it actually mean that the drug did also not exert any useful effect? In other words, if a drug has therapeutic effect in psychiatry, would not this most often strongly correlate with unmasking, and if masking is maintained, could it be indicative of minor