LSD, afterglow and hangover: Increased episodic memory and verbal fluency, decreased cognitive flexibility

Increasing evidence suggests that psychedelics such as LSD, psilocybin and ayahuasca might constitute promising treatments in psychiatric conditions including mood, anxiety and substance use disorders (dos Santos et al., 2016; Krebs and Johansen, 2012). Beyond that, there is increasing interest in their therapeutic potential for other conditions including obsessive-compulsive disorders (OCD), post-traumatic stress disorders (PTSD), eating disorders, cluster headache and other pain conditions (Castellanos et al., 2020; Krediet et al., 2020; Lafrance et al., 2017; Moreno et al., 2006). Interestingly enough, psychedelic research has hitherto largely neglected clinical conditions involving sudden or gradual cognitive decline including brain injury, stroke or dementia. Merely one study on healthy older adults reported no effects of LSD microdoses on several cognitive domains, including reaction time, visual memory and learning, visual attention and spatial working memory (Family et al., 2020). However, psychedelics might exert benefits in conditions involving memory and language impairments given the recent findings of psychedelic-induced neuroplasticity, neurogenesis, neuroprotective and anti-inflammatory effects (Inserra et al., 2021; Shao et al., 2021). Moreover, the main target of psychedelics, serotonin 2A (5-HT_2A) receptors, play an important role in cognitive processes such as executive functions, learning and memory (Lane et al., 2008; Zhang and Stackman, 2015).

During their acute effects, psychedelics seem to disturb perception, cognition and behaviour. Subjective and neurophysiological evidence indicates that psychedelics impair subjective cognitive functioning (Schmid et al., 2015; Studerus et al., 2011) and affect the brain's executive control and dorsal attention network (Tagliazucchi et al., 2014). Behavioural evidence suggests that psychedelics impair concentration skills including visual sustained attention, attentional tracking, disengaging and reorienting attention and simple and complex arithmetic performance (Carter et al., 2005; Krus et al., 1963; Vollenweider et al., 2007); executive functions including working memory, cognitive flexibility and inhibitory control (Barrett et al., 2018; Bouso et al., 2013; Pokorny et al., 2019; Quednow et al., 2012); and learning and episodic memory including recall (drawing geometric figures, recalling objects, syllables, paired associate words and sentences) and recognition (letters) (Barr et al., 1972; Barrett et al., 2018; Jarvik, Abramson and Hirsch, 1955; Silverstein and Klee, 1958).

However, the notion that psychedelics merely impair cognition has been challenged. Regular ayahuasca use has been associated with better executive functions and increased cortical thickness in the anterior cingulate cortex (ACC), a brain area important for attention and inhibitory control (Bouso et al., 2015, 2012). Acute impairments in executive functions (as measured by the Tower of London) were only observed in occasional but not experienced ayahuasca users, although the observed groups were small (Bouso et al., 2013). Microdoses were associated with increased attention (Hutten et al., 2020), convergent thinking (Prochazkova et al., 2018) and subjective cognition (Cameron, Nazarian and Olson, 2020; Lea et al., 2019), although other findings comprised unchanged overall cognitive performance (Szigeti et al., 2021), fluid intelligence (Prochazkova et al., 2018), working memory (Bershad et al., 2019) and cognitive control, and even impaired information processing and subjective control and cognition (Hutten et al., 2020). Studies in naturalistic settings found increased convergent thinking up to four weeks and increased subjective and behavioural cognitive flexibility at 24 h after ceremonies with ayahuasca and 5-Methoxy-N,N-dimethyltryptamin (5-MeO-DMT) (Murphy-Beiner and Soar, 2020; Uthaug et al., 2019, 2018). Increased cognitive and neural flexibility was also observed in patients with depression up to four weeks after psilocybin therapy (Doss et al., 2021).

The mechanisms underlying acute psychedelic-induced changes in episodic memory are just beginning to be understood. For example, it has been unclear whether the episodic memory impairments were attributable to impaired encoding or retrieval. Psilocybin-induced decreased recall (of previously categorized words) was attributed to impaired encoding, since encoding was conducted during drug peak and recall three hours afterwards, however, some persisting drug effects might still have impacted the recall (Barrett et al., 2018). The non-classic psychedelic 3,4-methylenedioxymethamphetamine (MDMA), exhibiting both psychedelic and stimulant effects, impaired encoding (emotional pictures) but not retrieval 48 h afterwards, as compared to placebo (Doss et al., 2018). In mice, the 5-HT_2A psychedelic TCB-2 improved memory extinction (trace and delay fear) and recognition (novel objects) if applied between encoding and retrieval, pointing to psychedelic-induced improved memory consolidation (Zhang et al., 2013).

On receptor level, psychedelic-induced impairments in working and episodic memory, cognitive flexibility and inhibitory control are blocked by the 5-HT_2A antagonist ketanserin (Pokorny et al., 2019; Quednow et al., 2012; Van Wel et al., 2011), emphasizing the crucial role of serotonergic activity in psychedelic-induced cognitive processes. However, the relationship between cognitive flexibility and the 5-HT_2A receptors is mixed. While the 5-HT_2A blockade is associated with impairments (Amodeo et al., 2017; Furr et al., 2012), no changes (Boulougouris and Robbins, 2010) and enhancements in rodents (Amodeo et al., 2017, 2014; Baker et al., 2011), the 5-HT_2A activation by psychedelics is principally associated with impairments in humans and rodents (Amodeo et al., 2020; Pokorny et al., 2019), although a recent rodent study reported no changes (Odland et al., 2021).

Overall, these findings suggest that psychedelics might enhance cognition under certain conditions, depending on previous experience, dose and time point after intake. In light of this, we aimed at examining the sub-acute effects of low-dose LSD on diverse aspects of cognition in an explorative, placebo-controlled, double-blind study.

Methods

This work is part of a larger study, details of which - including further information on participants, drug and procedures - is published elsewhere (Wießner et al., 2021a).

Results

Data from one to two subjects were lost in OLMT, RAVLT, VFT and Stroop due to application errors. The GLM results without covariates are shown in table S2 and figure S1. The GLM results with covariates are described below (for detailed values, see table 1, for estimated marginal means and standard errors of measurement, see table S3).

Discussion

To our knowledge, this is the first study to assess the sub-acute effects of psychedelics on cognition in a randomized, double-blind, placebo-controlled design. Overall, the effects of the low 50 μg dose were not strong in the morning after drug administration and mixed with period and order effects but provide insights into prolonged LSD-induced effects on cognitive processes. The results indicate that LSD, compared to placebo, sub-acutely improved visual memory (immediate retrieval (ROCF) and

Role of funding source

IW received funding from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; Finance Code 001), SR received funding from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grants 308775/2015–5 and 408145/2016–1) and the Sao Paulo Research Foundation (grants 2013/07699–0 (Neuromathematics) and 2014/10068–4). These funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report;

Contributors

IW, RO, LOM, SR and LFT contributed to the study design. IW, MF and LFT recruited and selected the participants. IW, RO and MF collected the data. IW, RO, FPF and DBA contributed to data analysis and interpretation. IW wrote the manuscript. IW and FPF created the figures. RO, MF, FPF, LOM, AF, DBA, SR and LFT reviewed the manuscript.

Declaration of competing interest

SR declares the following patent application as a competing interest: a) Patent applicants (The Beckley Foundation, Universidade Federal do Rio Grande do Norte); b) Name of inventors: Not yet listed; c) Application number: 1 911 024.6; d) Status of application: pending.

Acknowledgements

We thank Eliana Falchi Parra Carvalho da Silva, Flavia Ribeiro, Hervé Yviquel, Jens G. Klinzing and Raphael Egel for their support with the test material, Alexandre A. D. Pontual for his support in the study conceptualization, Jon Sharp for the English language revision and Valerie Bonnelle for miscellaneous help. Funding for this study was provided by the Beckley Foundation, the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001, the Conselho Nacional de