LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation

Abstract

Rationale: Stimulation of serotonin 2A (5-HT2A) receptors by lysergic acid diethylamide (LSD) and related compounds such as psilocybin has previously been shown to increase primary process thinking – an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects.Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). The main outcome variable in this study was primary index (PI), a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) rating scale.Results: LSD, compared with placebo, significantly increased primary index (p < 0.001, Bonferroni-corrected). The LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p < 0.05, Bonferroni-corrected), and blissful state (p < 0.05, Bonferroni-corrected) on the 5D-ASC. Both LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin.Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and psychedelic states of consciousness.

Psychedelics, Meditation, and Self-Consciousness

“…As previously mentioned, early studies with mescaline and LSD reported depersonalization-like effects which occasionally involved a loss of bodily awareness (Guttmann and Maclay, 1937 ; Savage, 1955 ; Von Mering et al, 1955 ; Sedman and Kenna, 1964 ). In the psychometrically validated 5D-OAV questionnaire commonly used to assess the subjective experience of altered states of consciousness (Studerus et al, 2010 ), healthy participants score rather high on the “disembodiment” factor, which includes the item “it seemed to me as if I did not have a body anymore,” after administration of psilocybin (Kometer et al, 2012 ; Bernasconi et al, 2014 ; Preller et al, 2016 ; Pokorny et al, 2017 ) and LSD (Schmid et al, 2015 ; Carhart-Harris et al, 2016a , b ; Kraehenmann et al, 2017 ; Liechti et al, 2017 ; Preller et al, 2017b ). The strength of the subjective effects of LSD (as measured by the mean score on the 5D-ASC questionnaire) was found to correlate with the magnitude of increase in functional connectivity in a somatomotor network including the primary motor and sensorimotor cortices, the caudal premotor cortex and the superior parietal lobule (Preller et al, 2017a ).…”

“…Likewise, there is converging evidence from subjective reports that psychedelic drugs can induce a loss of spatial self-location, associated to loss of boundary between self and world and a feeling of unity with everything (Millière, 2017 ): “I felt myself mold into the world around me…,” “My mind started to blend with everything” (R.M., unpublished data from online survey). On the psychometrically-validated 5D-ASC questionnaire, subjects score high on the factor related to “experience of unity” after administration of LSD (Schmid et al, 2015 ; Carhart-Harris et al, 2016a , b ; Kraehenmann et al, 2017 ; Liechti et al, 2017 ; Preller et al, 2017b ) and to a slightly lesser extent psilocybin (Kometer et al, 2012 ; Bernasconi et al, 2014 ; Preller et al, 2016 ; Pokorny et al, 2017 ). This factor includes the items “it seemed to me that my environment and I were one” and “everything seemed to unify into oneness”.…”

LSD acutely impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision-making

“…The study was approved by the Ethics Committee of the Department of Public Health of the Canton of Zurich, Switzerland, and the use of LSD was authorized by the Swiss Federal Office for Public Health, Department of Pharmacology and Narcotics, Berne, Switzerland. The current data were collected as part of a larger study (Kraehenmann et al, 2017;Preller et al, 2017Preller et al, , 2018b and the study was registered at clinicaltrials.gov (NCT02451072).…”

Large-scale brain networks and Freudian ego

“…i) There are also reports that 5-HT 2A receptor partial agonism leads to a decreased inner functional connectivity among large-scale brain networks along with an increased inter functional connectivity among the same large-scale brain networks (Kraehenmann et al, 2017a;Kraehenmann et al, 2017b;Müller, Dolder, Schmidt, Liechti, & Borgwardt, 2018;Nichols, 2016, p. 273;Northoff et al, 2006, p. 450;Palhano-Fontes et al, 2015). All psychedelic drugs act as 5-HT 2A receptor partial agonists (Aghajanian & Marek, 1999).…”