Abstract

Background: Prior work has shown that the acute psychoactive effects of classic psychedelics seem to have an essential impact on the therapeutic efficacy (Yaden & Griffiths, 2021). However, there have been cases of subjects who did not experience any acute, subjective drug effects, for example in dosing studies (Garcia-Romeu et al., 2021). Unfortunately, these cases are rarely discussed although anecdotal evidence has already been described over decades in different studies with different substances, even with high dosages (Grof et al., 1973; Strassman et al., 1994).

Even if these cases seem to be scarce (Müller et al., 2020) they could have significant implications for the therapeutic use of psychedelics and their informed consent. Insights would not only allow the psychedelic therapy to be more inclusive by embracing a wider population, but also help to gain better insight on the mechanisms underlying its promising effects.

Aims & Objectives: Our aim is to find similar cases in a systematic literature review. To our knowledge, this would be the first description of this special cohort.
Methods: An electronic databases search for relevant articles (Medline via PubMed) was systematically performed in April 2023 without restrictions in language. For methodological reasons, only studies from 1994 to 2023 and only studies in humans were included. Keywords included different classic psychedelics, dosing, clinical and experimental studies. Mini- or microdosing studies were not included.

Results: 288 relevant studies were extracted. So far, only five subjects could be identified that showed no subjective effects. However, most cases were not presented individually and in most of the studies, only mean effects of psychometric scales of subjective effects (e.g. 5D-ASC) were given. Nevertheless, estimates of experienced researchers go up to 1 in 50 patients (Matthias Liechti, personal communication). Aiming to find potential commonalities, research groups will be contacted to ask for these rare but existent cases.

Discussion & Conclusion: This previously undescribed subgroup of subjects may provide a new perspective and challenge to existing concepts in psychedelic therapy and research. Could there be another way to treat patients with psychedelic therapy that are resistant to its acute effects? Molecular polymorphisms (Schmitz et al., 2022) and phenomenological therapeutic effects (Roseman et al., 2017) should be further investigated under this aspect.