LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation
Rainer Kraehenmann, Dan Pokorny, Helena Aicher, Katrin H. Preller, Thomas Pokorny, Oliver G. Bosch, Erich Seifritz and Franz X. Vollenweider
Frontiers in Pharmacology, 2017, Volume 8, Article 814, 1-9.
Doi : 10.3389/fphar.2017.00814
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.
Keywords : LSD, ketanserin, 5-HT2A receptor, mental imagery, primary and secondary process thinking, primary emotions, cognitive bizarreness, healthy subjects
There is now accumulating evidence (Sloman and Steinberg, 1996; Evans, 2008; Shanks, 2010) confirming and extending the early meta-psychological theory of Freud (Pribram and Gill, 1976) which posits that there exist two distinct modes of psychic functioning: primary process and secondary process. It is broadly believed that in normal adults, secondary process is a hierarchically higher-level cognitive mode which fulfills an adaptive, reflective, rule-bound function (“reality principle” in Freudian terms) and thus inhibits lower-level, automatic, motivation- and emotion-driven primary process (“pleasure principle” in Freudian terms) (Arminjon, 2011). Under altered psychophysiological conditions such as dreaming, hypnosis, meditation, sensory deprivation, respiratory maneuvers, trance, psychosis, and epilepsy, primary process may become the prevailing cognitive mode (Barr et al., 1972; Vaitl et al., 2005; Hermle and Kraehenmann, 2017). Primary process thinking can be operationalized and reliably assessed using formal linguistic measures such as image fusion; unlikely combinations or events; sudden shifts or transformations of images; and contradictory or illogical actions, feelings, or thoughts (Rapaport, 1950; Holt, 1956; Auld et al., 1968; Shevrin, 1996; Sloman and Steinberg, 1996; Brakel et al., 2000).
Previous studies (Landon and Fischer, 1970; Martindale and Fischer, 1977; Natale et al., 1978; Spitzer et al., 1996; Family et al., 2016; Kraehenmann et al., 2017) indicate that classical psychedelics such as lysergic acid diethylamide (LSD) and related compounds such as psilocybin activate mental processes which are closely related to primary process, such as vivid, dreamlike imagery, basic emotions, and bizarre thinking. For example, early linguistic studies (Landon and Fischer, 1970; Martindale and Fischer, 1977; Natale et al., 1978) investigated the effects of psychedelics on thought content using primary process dictionaries. They found that psychedelics acutely increase frequency of primary process words in subjective reports of healthy subjects. Moreover, recent studies (Spitzer et al., 1996; Family et al., 2016) showed that psychedelics enhance access to remote and non-obvious associations in tasks where subjects have to rely on automatic, intuitive and uncontrolled thinking. Finally, we (Kraehenmann et al., 2017) recently investigated the effects of LSD on imagery reports of healthy subjects. We found that LSD increased cognitive bizarreness, a formal measure of dreaming cognition, via activation of the serotonin 2A (5-HT2A) receptor. Taken together, previous research on the effects of psychedelics on thought processes indicate that psychedelics may shift cognition toward primary process thinking.
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. A better understanding of the cognitive mechanisms underlying psychedelic states of consciousness is important, especially given that there is accumulating qualitative evidence (Gasser et al., 2015; Belser et al., 2017; Watts et al., 2017) indicating that the therapeutic effects of psychedelics may be mediated by their acute effects on subjective experience. Therefore, in this study, we compared the post-peak effects of LSD, placebo and LSD after pre-treatment with the 5-HT2A receptor antagonist ketanserin on primary process thinking in mental imagery reports of healthy subjects. Primary index (PI), a formal measure of primary process thinking (Stigler, 2001; Frick et al., 2008), was used as primary endpoint in this study. We hypothesized that LSD would increase PI in verbal imagery reports. We further hypothesized that ketanserin would block the effects of LSD on PI and subjective experience. Finally, given the relative novelty of the primary endpoint variable (PI) in the field of cognitive neuroscience, we performed multiple correlation analyses to quantitatively assess the relationship between PI and other more common measures which had been frequently used to assess psychedelic-induced changes in state of consciousness, using a short version of the Altered State of Consciousness (5D-ASC) self-rating scale; ratings of mental imagery experience, using visual analog scales (VASs); and dreaming cognition, using cognitive bizarreness (BD) in the mental imagery reports.