LSD and language: Decreased structural connectivity, increased semantic similarity, changed vocabulary in healthy individuals.

Language has been explored as a window into the mind. Psychedelics, known to affect perception and cognition, seem to change language, but a systematic, time-dependent exploration is lacking. Therefore, we aimed at mapping the psychedelic effects on language over the time course of the acute and sub-acute effects in an explorative manner. For this, 24 healthy volunteers (age [mean±SD, range]: 35±11, 25-61 years; 33% women) received 50 µg lysergic acid diethylamide (LSD) or inactive placebo in a randomized, double-blind, placebo-controlled, crossover study. We assessed different language productions (experience reporting, storytelling), components (structure, semantics, vocabulary) and time points (+0 h to +24 h). Language productions included 5-min experience reporting (+1.5 h, +6.5 h) and 1-min storytelling (+0 h, +2 h, +4 h, +6 h, +24 h). Language structure was assessed by computing speech topology (SpeechGraphs), semantics by semantic distances (FastText), vocabulary by word categories (LIWC). LSD, compared to placebo, changed language structure, including decreased verbosity, lexicon, global and local connectivity (+1.5 h to +4 h); decreased semantic distances between neighbouring words and overall words (+2 h to +24 h); and changed vocabulary related to grammar, persons, time, space and biological processes (+1.5 h to +24 h). In conclusion, low to moderate LSD doses changed language over diverse production types, components and time points. While simpler and disconnected structure and semantic similarity might reflect cognitive impairments, changed vocabulary might reflect subjective perceptions. Therefore, language under LSD might provide a window into the psychedelic mind and automated language quantifications should be better explored as valuable tools to yield more unconstrained insights into psychedelic perception and cognition.

Nootropic effects of LSD: Behavioral, molecular and computational evidence.

The therapeutic use of classical psychedelic substances such as d-lysergic acid diethylamide (LSD) surged in recent years. Studies in rodents suggest that these effects are produced by increased neural plasticity, including stimulation of the mTOR pathway, a key regulator of metabolism, plasticity, and aging. Could psychedelic-induced neural plasticity be harnessed to enhance cognition? Here we show that LSD treatment enhanced performance in a novel object recognition task in rats, and in a visuo-spatial memory task in humans. A proteomic analysis of human brain organoids showed that LSD affected metabolic pathways associated with neural plasticity, including mTOR. To gain insight into the relation of neural plasticity, aging and LSD-induced cognitive gains, we emulated the experiments in rats and humans with a neural network model of a cortico-hippocampal circuit. Using the baseline strength of plasticity as a proxy for age and assuming an increase in plasticity strength related to LSD dose, the simulations provided a good fit for the experimental data. Altogether, the results suggest that LSD has nootropic effects.

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

Psychedelics acutely impair cognitive functions, but these impairments decline with growing experiences with psychedelics and microdoses may even exert opposing effects. Given the recent evidence that psychedelics induce neuroplasticity, this explorative study aimed at investigating the potential of psychedelics to sub-acutely change cognition. For this, we applied a randomized, double-blind, placebo-controlled, crossover study with 24 healthy volunteers receiving 50 µg lysergic acid diethylamide (LSD) or an inactive placebo. Sub-acute changes in cognition were measured 24 h after dosing, including memory (Rey-Osterrieth Complex Figure, ROCF; 2D Object-Location Memory Task, OLMT; Rey Auditory-Verbal Learning Test, RAVLT), verbal fluency (phonological; semantic; switch), design fluency (basic; filter; switch), cognitive flexibility (Wisconsin Card Sorting Test, WCST), sustained and switching attention (Trail Making Test, TMT), inhibitory control (Stroop Task) and perceptual reasoning (Block Design Test, BDT). The results show that when compared to placebo and corrected for Body Mass Index (BMI) and abstinence period from psychedelics, LSD sub-acutely improved visuospatial memory (ROCF immediate recall points and percentage, OLMT consolidation percentage) and phonological verbal fluency and impaired cognitive flexibility (WCST: fewer categories achieved; more perseveration, errors and conceptual level responses). In conclusion, the low dose of LSD moderately induced both "afterglow" and "hangover". The improvements in visuospatial memory and phonological fluency suggest that LSD-assisted therapy should be explored as a novel treatment perspective in conditions involving memory and language declines such as brain injury, stroke or dementia.