Methodological issues undermine evidence about adverse effects of psilocybin-
assisted psychotherapy
We read with interest the recent meta-analysis of acute adverse effects of psilocybin in the treatment of depression and anxiety, in which the authors report that findings “ suggest a tolerable acute adverse effect profile for therapeutic doses of psilocybin”
1. Unfortunately, upon closer examination we noted issues in the approach taken that may affect the validity of this conclusion.
The main methodological concern identified relates to the risk of bias assessment, which found low risk of bias across studies. We are unclear how this rating could have been arrived at given the widespread functional unblinding that has hampered interpretation of evidence in this field.
2 The authors purported to include only double-blind studies in the review, excluding one single-blind trial. However, most included studies – although described as double blind – did not assess the integrity of blinding. One that did, found that therapists were able to correctly identify the treatment allocation for 97% of participants
3. Even in studies where no assessment of blinding was conducted, the acute and side effects of psilocybin reported support the likely occurrence of functional unblinding. These factors are not reflected in the risk of bias ratings reported.
A second key issue relates to the narrow framing of the review to focus only on the acute effects of psilocybin – as if these could be separated out from the overall effects of psilocybin-assisted psychotherapy – by definition a combined treatment modality. This resulted in the review reporting that no serious adverse events (SAEs) occurred in the studies reviewed within the limited time-frame covered (i.e., within 24 hours after dosing). Yet, one included study documented
nineteen SAEs, including suicidal ideation and self-injurious behaviour, occurring after the initial dosing day
4. Moreover, these events were dose-dependent. Thus, the evidence generated using such a limited timeframe is clearly insufficient to describe the actual risk of harms associated with this treatment modality.
Despite these limitations, we note that this report has already received extensive media and social media coverage, resulting in a current Altmetric rating in the 99% percentile for same age articles.
There is widespread public interest in psychedelic-assisted psychotherapies and increasing moves towards implementing these methods in clinical practice in various jurisdictions. Given this, it is imperative to more comprehensively assess potential harms of psilocybin-assisted psychotherapy to protect patients, facilitate informed
consent, and mitigate risks associated with psychedelic-assisted treatment.
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