ÌÇÐÄvlog

Under the psychedelic therapy paradigm,¹ instead of looking at drug efficacy, researchers look at experience efficacy, defined as how certain experiences can be therapeutic. To test experience efficacy, researchers need to develop new research tools to manipulate the experience without changing the pharmacology.

We suggest that intentional cognitive interruptions can help inquire into experience efficacy by experimentally interfering with the experience. To strengthen this suggestion, we present a secondary analysis from our 2023 N,N-dimethyltryptamine (DMT) study,² investigating whether it is possible to interrupt the psychedelic experience by increasing cognitive load and whether an interrupted experience is associated with reduced long-term mental health changes. We hypothesized that subjective ratings of the psychedelic experience would be lower when task demands were higher and reductions in long-term depressive symptoms would be larger with fewer task demands during the experience.

This quality improvement study was approved by the National Research Ethics Committee London–Brent and Health Research Authority and is reported following the reporting guideline. Participants provided informed consent (eMethods in Supplement 1). Healthy volunteers participated in 2 testing days separated by 2 weeks. On each testing day, participants underwent 2 separate intravenous DMT or placebo administrations while being scanned with combined functional magnetic resonance imaging and electroencephalography in a randomized fashion.² In the rating scan, participants were asked to verbally rate the subjective intensity of drug effects every minute in real time, while the no rating scan had no ratings and participants merely rested. Therefore, we were able to assess the association of interruptions from the rating procedure with the DMT experience.

Subjective ratings of the experience were measured retrospectively using the 11 Dimensions Altered States of Consciousness (11D-ASC) questionnaire³ after drug effects subsided. The Quick Inventory of Depressive Symptomatology (QIDS) was measured 1 day before and 2 weeks after DMT.

The analysis included 20 volunteers (mean [SD] age, 33.5 [7.9] years; 7 female [35.0%]) based on previous publications.^2,4 Using the total ASC score, we confirmed that the total mean (SD) ASC score was higher for the no rating (0.36 [0.08]) than rating (0.29 [0.10]) condition (P < .001; within-participant paired t test). In further exploratory analysis of 11D-ASC factors, not all factors had equal differences by rating group. Factors previously identified as moderators of clinical efficacy^5,6 had higher scores in the no rating condition (Figure).

We further tested if decreases in depressive symptom ratings after DMT were larger for the no rating condition. To avoid carryover effects, we looked only at changes after the first scan and compared the 12 participants who received DMT first in the rating condition with 8 participants who received DMT first in the no rating condition. Repeated-measure analysis of variance was used to test for an interaction between time (before vs after DMT) and group (rating vs no rating). An interaction was observed for group × time [F_1,18 = 5.9; P = .03; ηp²â€‰= 0.247], with a greater mean (SD) reduction in QIDS after the no rating (−1.25 [1.04]) than rating (−0.17 [0.94]) scan (P = .01). No significant differences were observed for baseline mean (SD) QIDS measures of the no rating (3.12 [1.46]) compared with the rating (1.92 [1.78]) group (P = .12; unpaired t test).

This quality improvement study’s results suggest that contextual manipulation, such as cognitive interruption (via giving subjective ratings in this study), may be used to study experience efficacy. Conclusions are limited by a small sample size, relatively mild interruption, and status as a secondary analysis of data not intended to test this hypothesis.

For future studies, we suggest that an intentional interruption should be more cognitively demanding than merely asking for ratings. We hope that future psychedelic studies will include contextual manipulation as a procedure to examine safety and efficacy.

Accepted for Publication: May 15, 2024.

Published: July 15, 2024. doi:10.1001/jamanetworkopen.2024.22181

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2024 Roseman L et al. ÌÇÐÄvlog Open.

Corresponding Author: Leor Roseman, PhD, Department of Psychology, University of Exeter, Perry Road, Exeter EX4 4QG, United Kingdom (l.roseman@exeter.ac.uk).

Author Contributions: Dr Roseman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Roseman, Nutt, Carhart-Harris, Timmermann.

Acquisition, analysis, or interpretation of data: Roseman, Erritzoe.

Drafting of the manuscript: Roseman, Carhart-Harris.

Critical review of the manuscript for important intellectual content: Erritzoe, Nutt, Timmermann.

Statistical analysis: Roseman, Timmermann.

Obtained funding: Nutt.

Administrative, technical, or material support: Roseman, Erritzoe, Nutt.

Supervision: Erritzoe, Nutt, Carhart-Harris.

Conflict of Interest Disclosures: Dr Erritzoe reported being a paid scientific advisor for Aya Biosciences, Clerkenwell Health, and Mindstate Design Labs. Dr Nutt reported serving as a scientific advisor for Awakn, Psyched Wellness, and Compass Pathways. Dr Carhart-Harris reported serving as a scientific advisor for Mydecine, Maya Health, Osmind, Synthesis Institute, Tryp Therapeutics, Journey Colab, Journey Space, Beckley Psytech, and Usona Institute. No other disclosures were reported.

Funding/Support: This study was funded via a donation by Patrick Vernon. Dr Timmermann was funded by the Chilean government through Comisión Nacional de Investigación Científica y Tecnológica, Anton Bilton, and founding funders of the Centre for Psychedelic Research. The Beckley Foundation mediated Patrick Vernon’s support.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: The authors would like to thank Lisa Luan, MSc; Hannes Kettner, MSc; and Luke Williams, MSc (Imperial College London), for assistance in data collection and Sam Turton, PhD; Luigi Espasiano, MD; Jonny Martell, MD; Sharad Haridas, MD; Camilla Day, MD; and Roberta Murphy, MD (Imperial College London); Matthew Nour, MD, PhD (University College London); and James Rucker, MD, PhD (Kings College London), for providing medical cover during study visits. None of these contributors were compensated for their support.