LSDLSD

LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation

This double-blind, within-subjects design, placebo-controlled study (n=25) found that LSD increased primary process thinking (implicit, associative, automatic, system 1) via serotonin (5HT) 2a receptor activation.

Authors

  • Erich Seifritz

Published

Frontiers in Pharmacology
individual Study

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.

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Research Summary of 'LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation'

Introduction

Sumiyoshi and colleagues frame the study within a long-standing distinction between two modes of mental functioning: secondary process thinking, a higher-level, reflective and rule-governed mode, and primary process thinking, an ontogenetically and evolutionarily older, associative, automatic mode that predominates in altered states such as dreaming. Earlier linguistic and behavioural studies suggested that classical psychedelics (LSD, psilocybin) promote cognitive features associated with primary process thinking — vivid, dreamlike imagery, bizarre associations and access to remote semantic links — but evidence from placebo-controlled, standardised human experiments with explicit measures of primary process thinking remained limited. It was also unclear whether such effects depend on activation of the serotonin 2A (5-HT2A) receptor and how they relate to subjective aspects of the psychedelic state.

Methods

Statistical analyses employed repeated-measures ANOVAs to compare drug conditions, with Bonferroni-corrected post hoc pairwise comparisons (two-tailed, significance p < 0.05). Multiple correlations between LSD–placebo difference scores for PI, 5D-ASC subscales, VAS measures and BD used Bonferroni-corrected Spearman correlations (corrected alpha reported as 0.0042). Analyses were performed in IBM SPSS Statistics 23.

Results

Correlations: The LSD-induced change in PI (LSD–Pla difference) correlated positively with changes in specific subjective domains. PI change correlated with disembodiment (r = 0.61, N = 25, p = 0.012, Bonferroni-corrected) and with blissful state (r = 0.63, N = 25, p = 0.012, Bonferroni-corrected). A very strong positive correlation was reported between PI change and cognitive bizarreness (BD) (r = 0.89, N = 25, p < 0.001, Bonferroni-corrected). These relations support an association between primary process thinking, dreamlike cognitive features and particular subjective qualities of the LSD state.

Discussion

Limitations acknowledged by the authors include measurement timing (the mental imagery task was conducted during the descending phase at 7 hours post-dose rather than at peak effects), and the absence of a dose–response assessment. The investigators state that peak effects were not measured here and that dose-dependency was not assessed, although they suggest, based on prior literature, that effects would likely scale with dose.

Conclusion

The study concludes that LSD, compared with placebo, enhances primary process thinking in healthy subjects and that this effect is closely tied to subjective experiences of disembodiment and blissful state. Blockade of the effect by ketanserin implicates 5-HT2A receptor activation as a necessary mechanism. The authors propose that these transient, dreamlike shifts in cognition illuminate cognitive mechanisms of psychedelic states and warrant further clinical research to test whether psychedelic-induced primary process thinking contributes to therapeutic outcomes.

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RESULTS

The statistical analyses were performed using IBM SPSS Statistics 23 software (IBM, Chicago, IL, United States). Repeatedmeasures analyses of variance (ANOVAs) were conducted to compare the drug effects in LSD, Ket+LSD, and Pla conditions. Significant main effects or interactions in the ANOVAs were followed by Bonferroni-corrected post hoc pairwise comparisons with a significance level of p < 0.05 (twotailed test). Bonferroni-corrected Spearman multiple correlations (Bonferroni-corrected alpha = 0.05/12 = 0.0042) were used to quantify the relations between the LSD-Pla difference scores for primary index ( PI), state of consciousness ( 5D-ASC), mental imagery experience ( VAS), and cognitive bizarreness ( BD).

CONCLUSION

The main finding of this study was that LSD increased primary process thinking, a lower-level, automatic, motivationand emotion-driven mode of mental organization which is characterized by image fusion; unlikely combinations or events; sudden shifts or transformations of images; and contradictory or illogical actions, feelings, or thoughts. Specifically, we show that LSD, in comparison with placebo, increased primary index, a formal linguistic measure of primary process thinking in the imagery reports(Table). Furthermore, we found that the effect of LSD on primary index was completely blocked by ketanserin, a 5-HT2A receptor antagonist (Table). Finally, we show that the LSD-induced increase in primary index was related to LSD-induced disembodiment and blissful state (Figures). Our finding that LSD acutely increased primary process thinking is supported by both direct and indirect evidence:, for example, assessed the effects of low-dose (0.08 mg/kg orally) psilocybin on several linguistic parameters. It was found that psilocybin decreased sentence length and syntactic and rhetorical complexity, but increased linguistic concreteness and stereotypy, consistent with primary process thinking. Furthermore,used content-analytic measures to directly test the hypothesis that psilocybin (0.08-0.2 mg/kg) induces primary process thinking. They showed that psilocybin increased primary process words, particularly content related to regressive imagery. Moreover,investigated the effects of low to medium dose LSD (15-100 mcg) on speech patterns of depressed patients during psychoanalytic sessions. They found that LSD increased the patients' use of novel figurative language and of primary process-related words, respectively, consistent with an increase in primary process thinking. Furthermore,andinvestigated the effects of LSD on primary process responses to the Rorschach projective test. They found highly significant LSD effects on formal measures of primary process thinking, including features such as image fusion, fluid transformations of percepts, autistic logic, logical contradictions, verbal condensations, loosening of memory, and unlikely combinations. Finally, recent double-blind, placebo-controlled studies lend further support to the notion that psychedelics enhance primary process thinking:for example, used word-pairs of different semantic distance and showed that psilocybin increased indirect semantic priming, i.e., priming for remotely related word-pairs. Interestingly, the authors interpreted their results as evidence that psilocybin "in fact leads to an increased availability of remote associations and thereby may bring cognitive contents to mind that under normal circumstances remain non-activated." Similar effects were found for LSD in a recent double-blind, placebo-controlled study by. Taken together, both our results and previous evidence indicate that psychedelics induce an altered state of consciousness which is characterized by primary process cognition. Our findings are also in line with recent neuroimaging data: the entropic brain theory, for example, holds that secondary process (the cognitive mode of the Freudian "ego") is coded by default mode network (DMN) regions and provides top-down predictions to reduce free-energy associated with the primary process (the Freudian "id") within (para)limbic and anti-correlated neural networks, converting free energy into bound energy. According to the entropic brain theory, psychedelics induce an "unconstrained, " "high-entropy" cognitive state whereby DMN activity breaks down, leading to broadband alterations in resting-state functional connectivity between regions that show little connectivity in a baseline state. However, contrary to such cognitive shift models, which posit that psychedelics decrease secondary process thinking, leading to disinhibition of primary process thinking ("ego regression, " in psychoanalytical terms), our data did not show a statistically significant effect of LSD on SP, while there was a significant increase in PP during LSD compared to placebo (Table). These findings seem to suggest that there is no simple "shift" or "transition" from secondary toward primary process thinking during psychedelic states: secondary process thinking during psychedelic states appears preserved, while there is an increase in primary process thinking. This may be an important feature distinguishing night dreams from psychedelic experiences. In fact, a recent neuroimaging studyshowed that psychedelics increase rather than decrease neural activity in cortical areas that are thought to mediate the features of secondary process thinking, including dorsolateral prefrontal cortex (DLPFC) and temporal cortex. Therefore, psychedelic states may be best conceptualized as hybrid states of consciousness which share features of both dreaming and waking consciousness. This is supported by a recent neuroimaging studywhich showed that dreaming (and hence unaware) subjects regained self-awareness in their dreams (they became "lucid") following frontal low current stimulation of gamma activity over DLPFC regions. In fact, the close neurophenomenological similarity between psychedelic states and lucid dreamingmay shed some light on the therapeutic potential of psychedelic-induced experiences: they are not just "epiphenomena" of underlying neuronal oscillations, but rather induce conscious learning experiences that promote selfknowledge and psychological insight. The human brain is a hierarchically organized and evolutionally layered organ, and this basic structure is reflected in the cognitive organization of the mind. Primary process thinking has been related to neuronal activation of ontologically early, subcortical and limbic regions of the brain which code for instinctual drives and primal affective experiences. In addition, previous neuroimaging studiesindicate that psychedelics such as psilocybin modulate information processing in both cortical and subcortical memory and emotion circuits of the brain (e.g., cingulate cortex, temporal cortex, insula, amygdala, hippocampus). This is supported by recent receptor binding studies showing a dense and widespread expression of 5-HT2A/5-HT1A receptors in both cortical and subcortical areas of the human brain. This may explain why, in psychedelic states, basic drives and primary emotions are strongly activated and substantially influence cognition and behavior. In fact, there is consistent evidence that psychedelics, especially during drug peak effects, induce high emotional arousal: ". . .intense, labile, personally meaningful emotionality is uniformly produced, with periodic episodes of overwhelming feeling". Even under high-dose drug conditions, most subjects describe their imagery as highly pleasurable and rewarding ("cosmic joy"), coming along with feelings of "boundlessness" and "unity" ("oceanic boundlessness"). Moreover, previous factor analytical studiessupport the view that psychedelics induce altered states of consciousness based on two main factors: visual imagery on the one hand, and emotionally experienced alterations in self-awareness and loss of self-/body-boundaries on the other hand. Taken together, our results are entirely consistent with this view because LSD significantly induced vivid imagery on the VAS subscale, blissful state (positively valenced mood state) and disembodiment on the 5D-ASC subscale (Supplementary Figure). Recent behavioraland neurobiological studiesmay help explain why psychedelics are such potent modulators of visual imagery, emotions, and self-/ body-awareness. For example, it has been shown that 5-HT2A receptor activation in the brain is a central mechanism underlying psychedelic-induced imagery, positive mood states, and alterations in the sense of self and body. Therefore, our results are consistent with this view because ketanserin-pretreatment of LSD completely blocked the observed subjective and behavioral effects of LSD (Tableand Supplementary Figure). Given that 5-HT receptors are widely expressed in the human brain, they have important functions in the regulation of mood states, instinctual drives, sleep, and dreaming. In fact, wehave recently shown that 5-HT2A receptor activation by LSD induces dreamlike imagery, correlating with LSD-induced loss of self-boundaries and cognitive control. Given that there is a broad phenomenological and neurophysiological overlap between psychedelic states and dreaming, and given that primary process thinking is the prevalent cognitive mode in dreams, it is plausible to assume that 5-HT2A receptor activation by psychedelics induces dreamlike imagery which is related to primary process thinking, emotion activation, and alterations in the sense of self and body. This is strongly supported by our results because LSD-induced primary process thinking was positively correlated with LSD-induced cognitive bizarreness, a formal measure of dreaming cognition (Figure), and was related to both LSD-induced blissful state (Figure) and disembodiment (Figure) on the 5D-ASC. Finally, this is also supported by previous neuroimaging studieswhich found that both psychedelics and rapid-eye movement dreams activate temporal lobe regions, leading to visual imagery and changes in the sense of self and body. The close relationship between primary process thinking, dream-like cognitive bizarreness, imagery intensity and emotionality during LSD in conjunction with guided mental imagery relative to guided imagery during placebo implicates that LSD in combination with mental imagery induces inner experiences which are different from those produced by either LSD alone or guided mental imagery alone. Given that mental imagery and dreams establish privileged access to latent relational and emotional schemes, LSD and other classical psychedelics might be beneficially used as add-on pharmacotherapeutics to deepen psychotherapeutic processes. In fact, early clinical studies between 1950 and 1970 used LSD in a similar way., for example, showed that the combination of hypnosis and LSD produced more profound alterations in consciousness than either hypnosis or LSD alone. Future clinical studies could test this hypothesis by using a study design with several treatment arms comparing either psychedelics without psychotherapy versus psychedelics in conjunction with psychotherapy versus psychotherapy alone.

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