Imprinting: expanding the extra-pharmacological model of psychedelic drug action to incorporate delayed influences of sets and settings

Abstract

BackgroundPsychedelic drug experiences are shaped by current-moment contextual factors, commonly categorized as internal (set) and external (setting). Potential influences of past environments, however, have received little attention.AimsTo investigate how previous environmental stimuli shaped the experiences of patients receiving ketamine for treatment-resistant depression (TRD), and develop the concept of “imprinting” to account for such time-lagged effects across diverse hallucinogenic drugs.MethodsRecordings of treatment sessions and phenomenological interviews from 26 participants of a clinical trial investigating serial intravenous ketamine infusions for TRD, conducted from January 2021 to August 2022, were retrospectively reviewed. A broad literature search was undertaken to identify potentially underrecognized examples of imprinting with both serotonergic and atypical psychedelics, as well as analogous cognitive processes and neural mechanisms.ResultsIn naturalistic single-subject experiments of a 28-year-old female and a 34-year-old male, subjective ketamine experiences were significantly altered by varying exposures to particular forms of digital media in the days preceding treatments. Higher levels of media exposure reduced the mystical/emotional qualities of subsequent psychedelic ketamine experiences, overpowering standard intention-setting practices and altering therapeutic outcomes. Qualitative data from 24 additional patients yielded eight further spontaneous reports of past environmental exposures manifesting as visual hallucinations during ketamine experiences. We identified similar examples of imprinting with diverse psychoactive drugs in past publications, including in the first-ever report of ketamine in human subjects, as well as analogous processes known to underly dreaming.Conclusions/interpretationPast environmental exposures can significantly influence the phenomenology and therapeutic outcomes of psychedelic experiences, yet are underrecognized and understudied. To facilitate future research, we propose expanding the contextual model of psychedelic drug actions to incorporate imprinting, a novel concept that may aid clinicians, patients, and researchers to better understand psychedelic drug effects.Clinical trial registrationClinicalTrials.gov, identifier NCT04701866.

The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression

“…By reducing the external stimuli that ground patients in their physical environments, patients describe blindfolds as greatly increasing the degree and intensity of perceptual changes induced by ketamine. Likely as a result of blindfolds and other contextual factors, and in contrast to others ( 166 ), we have consistently found that subanesthetic dosages of ketamine, e.g., 0.5 mg/kg, can produce powerfully psychedelic experiences including high scores on the Mystical Experience Questionnaire ( 164 , 167 ).…”

“…In this article, we present the Montreal model of ketamine for TRD, a biopsychosocial approach developed gradually over years of real-world clinical experiences and research endeavors. Our aim has been to help bridge the current divide between biomedical and psychedelic models of ketamine while aiding in the interpretation of our recent and upcoming research results ( 12 , 13 , 145 , 164 , 169 ). We have thus endeavored to provide sufficient information for researchers and clinicians from diverse backgrounds to understand our approach, from its theoretical underpinnings up to its session activities and clinical implementation.…”

“…Although further study is needed, we have found that presenting ketamine experiences as being reflective of one’s inner landscape is consistent with their phenomenology and is beneficial overall. Experiences characterized by autobiographical memories, bizarre symbolism, and even recent media exposure can all be sources of catharsis and/or insight ( 164 )—but only with supportive contexts and adequate psychological support.…”