Acute psilocybin enhances cognitive flexibility in rats

Pacheco, Alejandro Torrado; Olson, Randall J.; Garza, Gabriela; Moghaddam, Bita

doi:10.1101/2023.01.09.523291

Cited by 9 publications

(6 citation statements)

References 99 publications

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“…Going forwards, homing in on clinically relevant domains of cognition will specify our findings further. With alterations in cognitive flexibility being cited as an integral marker of the therapeutic effects of classical psychedelics 91 , more expansive assessments of executive function such as set-shifting paradigms -may highlight novel differences [92][93][94] .…”

Section: Discussionmentioning

confidence: 99%

Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition

Mallaroni

Mason

Reckweg

et al. 2023

Preprint

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2,5-dimethoxy-4-bromophenethylamine (2C-B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it′s acute effects and distinctions from classical progenitors have yet to be characterised in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C-B (20 mg) in comparison to psilocybin (15mg) and placebo in a within-subjects, double-blind, placebo-controlled study of 22 healthy psychedelic-experienced participants. 2C-B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared to placebo, as indexed by the Digit Symbol Substitution Test (DSST), Tower of London (TOL) and Spatial Memory Task (SMT). Neither compound produced empathogenic effects on the Multifaceted Empathy Test (MET). 2C-B induced transient pressor effects to a similar degree as psilocybin. The duration of self-reported effects of 2C-B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorisation of 2C-B as a subjectively ″lighter″ psychedelic. Tailored dose-effect studies are needed to discern the pharmacokinetic dependency of 2C-B′s experiential overlaps.

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Section: Discussionmentioning

confidence: 99%

Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition

Mallaroni

Mason

Reckweg

et al. 2023

Preprint

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“…Clinical researchers found that therapeutic effects of serotonergic psychedelics in humans are mediated by increased cognitive flexibility following drug experience, a finding recapitulated in rodent models [25][26][27][28] . Evidence from human, rodent, and molecular research converges on the hypothesis that psilocybin generates highly plastic brain states conducive to modifying circuits that underlie inflexible, maladaptive behaviors via 5HT2R and TrkB activation 2,17,[29][30][31][32][33][34][35][36] .…”

Section: Introductionmentioning

confidence: 91%

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

Rogers,

Heller,

Corder

2024

Preprint

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The serotonin 2 receptor (5HT2R) agonist psilocybin has demonstrated rapid and long-lasting efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. Psilocybin may accomplish this by inducing rapid and stable dendritic plasticity. However, the impact of psilocybin on patterns of neural activity underlying sustained changes in cognitive and behavioral flexibility has not been characterized. To test the hypothesis that psilocybin enhances behavioral flexibility by rapidly and persistently altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the retrosplenial cortex across a five-day trace fear learning and extinction assay. Leveraging tensor component analysis to identify neurons that modulate activity on multiple temporal scales, we found that a single-dose of psilocybin induced cortical ensemble turnover between fear learning and extinction days while oppositely modulating activity in fear- and extinction- active neurons. The extent of suppression of fear-active neurons and recruitment of extinction-active neurons were both predictive of psilocybin-enhanced fear extinction. These results both align with hypotheses that psilocybin enhances behavioral flexibility by recruiting new populations of neurons and introduce a new mechanism involving the suppression of fear-active populations in the retrosplenial cortex.

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“…Within this framework, 5-HT neuromodulation then serves a role in responding to stress by improving the computational efficiency of the processes required to learn and maintain such successful representations. The ability to efficiently learn and maintain adaptive predictive representations is precisely the construct of cognitive flexibility (Ionescu, 2012)-the characteristic that enables animals or humans to adaptively generate appropriate behavioral responses based on changing sensory stimuli-which psychedelics have been demonstrated to improve (Doss et al, 2021;Torrado Pacheco, Olson, Garza, & Moghaddam, 2023), and is believed to be generally associated with serotonin signalling (Matias et al, 2017).…”

Section: Serotonergic Neuromodulation As a Stress Response Systemmentioning

confidence: 99%

A dual-receptor model of serotonergic psychedelics

Juliani,

Chelu,

Graesser

et al. 2024

Preprint

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Serotonergic psychedelics have been identified as promising next-generation therapeutic agents in the treatment of mood and anxiety disorders. While their efficacy has been increasingly validated, the mechanism by which they exert a therapeutic effect is still debated. A popular theoretical account is that excessive 5-HT2a agonism disrupts cortical dynamics, relaxing the precision of maladaptive high-level beliefs, thus making them more malleable and open to revision. We extend this perspective by developing a theoretical framework and simulations based on predictive processing and an energy-based model of cortical dynamics. We consider the role of both 5-HT2a and 5-HT1a agonism, characterizing 5-HT2a agonism as inducing stochastic perturbations of the energy function underlying cortical dynamics and 5-HT1a agonism as inducing a global smoothing of that function. Within our simulations, we find that while both agonists are able to provide a significant therapeutic effect individually, mixed agonists provide both a more psychologically tolerable acute experience and better therapeutic efficacy than either pure 5-HT2a or 5-HT1a agonists alone. This finding provides a potential theoretical basis for the clinical success of LSD, psilocybin, and DMT, all of which are mixed serotonin agonists. Our results furthermore indicate that exploring the design space of biased 5-HT1a agonist psychedelics such as 5-MeO-DMT may prove fruitful in the development of even more effective and tolerable psychotherapeutic agents in the future.

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Acute psilocybin enhances cognitive flexibility in rats

Cited by 9 publications

References 99 publications

Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition

Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

A dual-receptor model of serotonergic psychedelics

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