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Pre-treatment with the 5HT2A antagonist ketanserin blocks psilocybin's effect on cognitive flexibility. a Average trials-to-criterion for baseline (PRE, gray open circles) and ketanserin-psilocybin condition (KET + PSI, orange circles, n = 14). b Number of completed sets in baseline and ketanserin-psilocybin conditions. c Fraction of correct responses averaged across all sets in baseline and ketanserin-psilocybin conditions. d Average trials-to-criterion for baseline (PRE, gray open circles) and ketanserin-saline conditions (KET + SAL, pink circles, n = 11). *p = 0.026, paired t-test. e Number of completed sets in baseline and ketanserin-saline conditions. f Fraction of correct responses averaged across all sets in baseline and ketanserin-saline conditions. *p = 0.05, paired t-test. g Average trials-to-criterion for baseline (PRE, gray open circles) and SB242084-psilocybin conditions (SB + PSI, green circles, n = 11). *p = 0.032, Wilcoxon sign-rank test. h Number of completed sets in baseline and SB242084-psilocybin conditions. i Fraction of correct responses averaged across all sets in baseline and SB242084-psilocybin conditions. j Average trials-to-criterion for baseline (PRE, gray open circles) and SB242084-saline conditions (SB + SAL, teal circles, n = 11). k Number of completed sets in baseline and SB242084-saline conditions. l Fraction of correct responses averaged across all sets in baseline and SB242084-saline conditions. *p = 0.031, paired t-test.
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Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A p...
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... of psilocybin and other psychedelics, so we investigated whether agonism of 5HT2A receptors played a role in the cognitive effects we observed. We pre-treated rats with the 5HT2A antagonist ketanserin (1 mg/kg, i.p.) 10 min before injection of either psilocybin or saline. Ketanserin blocked the effect of psilocybin on cognitive flexibility (Fig. 5a−c, n = 14; trials to criterion, p = 0.231; completed sets, p = 0.688; fraction correct, p = 0.469; see also Supplementary Fig. S4). This was also evident when comparing the ketanserin + psilocybin group to the saline control group (Fig. S2h, p = 0.431). We therefore conclude that the effects of psilocybin are at least partly mediated by ...
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... injected with ketanserin followed by saline also showed a performance improvement comparable to psilocybin-treated animals. They required fewer trials to reach criterion (Fig. 5d, p = 0.026, n = 11), while completing a similar number of sets as during baseline (Fig. 5e, p = 0.680), and showed a subtle but significant increase in the percent of correct trials (Fig. 5f, p = 0.050). We also found a significant effect when comparing to the saline control group (Fig. S2h, p = 0.0004). This effect of ketanserin is ...
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... injected with ketanserin followed by saline also showed a performance improvement comparable to psilocybin-treated animals. They required fewer trials to reach criterion (Fig. 5d, p = 0.026, n = 11), while completing a similar number of sets as during baseline (Fig. 5e, p = 0.680), and showed a subtle but significant increase in the percent of correct trials (Fig. 5f, p = 0.050). We also found a significant effect when comparing to the saline control group (Fig. S2h, p = 0.0004). This effect of ketanserin is consistent with a previous report [35] and suggests a complex relationship between 5HT2A ...
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... ketanserin followed by saline also showed a performance improvement comparable to psilocybin-treated animals. They required fewer trials to reach criterion (Fig. 5d, p = 0.026, n = 11), while completing a similar number of sets as during baseline (Fig. 5e, p = 0.680), and showed a subtle but significant increase in the percent of correct trials (Fig. 5f, p = 0.050). We also found a significant effect when comparing to the saline control group (Fig. S2h, p = 0.0004). This effect of ketanserin is consistent with a previous report [35] and suggests a complex relationship between 5HT2A receptor function and cognitive ...
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... also binds to 5HT2C receptors. While ketanserin binds more strongly to 5HT2A receptors, it has moderate affinity at 5HT2C receptors. We, however, found that the 5HT2C antagonist SB242084 (1 mg/kg, i.p.) did not impact psilocybin's enhancement of cognitive flexibility in the set-shifting task (Fig. 5g-I, n = 11; trials to criterion, p = 0.0322; completed sets, p = 0.484; fraction of correct responses, p = 0.249; see also Supplementary Fig. S5). Injection of SB242084 followed by saline produced a trend towards impaired performance (Fig. 5j-l, n = 11; trials to criterion, p = 0.062; completed sets, p = 0.762; fraction of correct ...
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... ketanserin binds more strongly to 5HT2A receptors, it has moderate affinity at 5HT2C receptors. We, however, found that the 5HT2C antagonist SB242084 (1 mg/kg, i.p.) did not impact psilocybin's enhancement of cognitive flexibility in the set-shifting task (Fig. 5g-I, n = 11; trials to criterion, p = 0.0322; completed sets, p = 0.484; fraction of correct responses, p = 0.249; see also Supplementary Fig. S5). Injection of SB242084 followed by saline produced a trend towards impaired performance (Fig. 5j-l, n = 11; trials to criterion, p = 0.062; completed sets, p = 0.762; fraction of correct responses, p = 0.031). ...
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... (1 mg/kg, i.p.) did not impact psilocybin's enhancement of cognitive flexibility in the set-shifting task (Fig. 5g-I, n = 11; trials to criterion, p = 0.0322; completed sets, p = 0.484; fraction of correct responses, p = 0.249; see also Supplementary Fig. S5). Injection of SB242084 followed by saline produced a trend towards impaired performance (Fig. 5j-l, n = 11; trials to criterion, p = 0.062; completed sets, p = 0.762; fraction of correct responses, p = 0.031). The same results were seen when comparing the SB242084 groups to the saline animals ( psilocybin treatment is likely independent of its action at 5HT2C receptors. Lastly, we analyzed the impact of each treatment on the average ...
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... This study contrasts with previous preclinical psychedelic reversal learning studies in terms of drug administration timepoints (46)(47)(48)(49)(50). We administered the psychedelic or saline control 15 days before the start of the reversal protocol. ...
... In a two-choice visual discrimination task, 25CN-NBOH (1-2 mg/kg) was found to have no significant effects on reversal learning in mice when administered acutely, immediately before testing (49). Other previous rodent studies using attentional set-shifting and T-maze paradigms found impairment of flexible learning with acute administration of the psychedelics DOI (1 mg/kg) or 25CN-NBOH (1 mg/kg) on cognitive flexibility (48,50). However, one study found the enhanced cognitive flexibility with acute psilocybin (1 mg/kg) in the same attentional set shifting paradigm that found impairment following administration of DOI (50). ...
... Other previous rodent studies using attentional set-shifting and T-maze paradigms found impairment of flexible learning with acute administration of the psychedelics DOI (1 mg/kg) or 25CN-NBOH (1 mg/kg) on cognitive flexibility (48,50). However, one study found the enhanced cognitive flexibility with acute psilocybin (1 mg/kg) in the same attentional set shifting paradigm that found impairment following administration of DOI (50). The differences in the acute effects of psychedelics on reversal learning may be due to the study design, discussed below, as well as a combination of drug and dose. ...
Psychedelic drugs have shown therapeutic potential for the treatment of multiple neuropsychiatric disorders chiefly by promoting long-lasting plasticity in the prefrontal cortex (PFC). A critical function of the PFC is the ability to apply previously learned rules to novel scenarios, a skill known as cognitive flexibility. Here, we show that a single dose of 25CN-NBOH, a serotonin 2A receptor-preferring psychedelic, improves performance on a relatively complex flexible reversal learning task in mice, measured 2-3 weeks after the dose. This effect was seen in both male and female mice. This behavioral finding complements previous cellular results showing that a single psychedelic dose induces long-term structural changes in the PFC and uniquely demonstrates sustained improvements in cognitive flexibility in a novel behavioral paradigm weeks after the initial psychedelic dose in mice. This high throughput task also provides a rapid, automated way to assess other candidate psychedelics for their impact on cognitive flexibility in mice.
... Previous studies on psilocybin and decision-making indicate that psilocybin may improve cognitive flexibility [72][73][74]; a further study found that psilocybin may reduce punishment by changing one's concerns for the outcome of their game partner in a social decision-making task [73]. The current findings add to a growing literature in this area highlighting a range of effects that emerge in different task contexts, and which perhaps have similar underlying mechanisms. ...
Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit active inference and reinforcement learning computational models to a novel two-armed bandit reversal learning task capable of capturing engagement behaviour in rats. The model revealed that after receiving psilocybin, rats achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.
... Psilocybin will be kept at -20ºC for storage throughout the experiment [16]. The compound will be dissolved in a saline solution and diluted to a concentration of 1mg/ml. . ...
Introduction: Huntington’s Disease (HD) is a progressive, neurodegenerative disease that causes significant amounts of neuron death in the brain. It is a genetic disorder, resulting from the over-repetition of the CAG sequence in the gene that codes for the huntingtin protein. Currently, there are no viable cures or treatments to slow or stop the progression of this disorder, making it a target candidate for treatment research. However, given the difficulty and complexity of in treating the genetic cause of HD in adults, a more viable approach may involve treating the resulting neurodegeneration with neuroprotective compounds, such as psilocybin. As such, our study proposes the usage of psilocybin to treat HD due to its neuroprotective, neurotrophic, and neuroplastic effects, resulting in a decreased rate of neuron loss and increased synaptic density. Methods: We propose an in-vivo experiment using several groups of zQ175 knock-in (KI) mice, which will mimic HD in the mice. Following 8 weeks, the mice’s brains will be extracted at different time intervals to analyze the progression of neuronal death using histology and immunohistochemistry, which should inform us about the progression of HD in the different groups of mice. Moreover, throughout this experiment, the motor control of the mice will be observed using the rotarod test, the raised beam test, and the footprint test. Data from these tests will act as behavioral markers for HD, providing an alternate source of information on the progression of HD in the mice. Expected Results: KI mice are expected to have lower rates of neuronal death, higher amounts of synaptic density, and higher scores on average across the three motor behavior tests, compared to the non-treated KI mice. Discussion: These results could provide insight into potential treatments for slowing the progression of HD. If successful, possible next steps could be to determine the efficacy of psilocybin in clinical trials for HD. Conclusion: This study is expected to provide information on the usage of psilocybin as a treatment for HD. If the expected results are obtained, psilocybin may help improve the quality of life for those afflicted with HD.
... In rodents, acute administration of psilocybin has been observed to enhance cognitive flexibility, with specificity noted in the augmentation of switching between previously learned behavioral strategies rather than influencing Pavlovian reversal learning. The 5HT 2AR antagonist ketanserin was found to attenuate psilocybininduced effects on set-shifting, while a 5HT2C-selective antagonist exhibited no such influence (Torrado Pacheco et al., 2023). For healthy adults and individuals with Major Depressive Disorder (MDD), psilocybin treatment has shown promise in augmenting cognitive and neural flexibility (Doss et al., 2021;Nayak et al., 2023). ...
Alzheimer’s disease (AD) stands as a formidable neurodegenerative ailment and a prominent contributor to dementia. The scarcity of available therapies for AD accentuates the exigency for innovative treatment modalities. Psilocybin, a psychoactive alkaloid intrinsic to hallucinogenic mushrooms, has garnered attention within the neuropsychiatric realm due to its established safety and efficacy in treating depression. Nonetheless, its potential as a therapeutic avenue for AD remains largely uncharted. This comprehensive review endeavors to encapsulate the pharmacological effects of psilocybin while elucidating the existing evidence concerning its potential mechanisms contributing to a positive impact on AD. Specifically, the active metabolite of psilocybin, psilocin, elicits its effects through the modulation of the 5-hydroxytryptamine 2A receptor (5-HT2A receptor). This modulation causes heightened neural plasticity, diminished inflammation, and improvements in cognitive functions such as creativity, cognitive flexibility, and emotional facial recognition. Noteworthy is psilocybin’s promising role in mitigating anxiety and depression symptoms in AD patients. Acknowledging the attendant adverse reactions, we proffer strategies aimed at tempering or mitigating its hallucinogenic effects. Moreover, we broach the ethical and legal dimensions inherent in psilocybin’s exploration for AD treatment. By traversing these avenues, We propose therapeutic potential of psilocybin in the nuanced management of Alzheimer’s disease.
... findings support the notion that psychedelics specifically reduce sustained attention or vigilance but not cognitive control (as is needed for accuracy-based tasks). Additional confirmatory evidence is provided by research regarding creative performance under the influence of psychedelics 99,111,186 and animal research 187,188 showing an increased ability to switch action patterns under psilocybin. Furthermore, this model of increased cognitive flexibility aligns with results regarding neuropsychological consequences of long-term psychedelic use. ...
Classic psychedelics and MDMA have a colorful history of recreational use, and both have recently been re-evaluated as tools for the treatment of psychiatric disorders. Several studies have been carried out to assess potential long-term effects of a regular use on cognition, delivering distinct results for psychedelics and MDMA. However, to date knowledge is scarce on cognitive performance during acute effects of those substances. In this systematic review and meta-analysis, we investigate how cognitive functioning is affected by psychedelics and MDMA during the acute drug effects and the sub-acute (“afterglow”) window. Our quantitative analyses suggest that acute cognitive performance is differentially affected by psychedelics when compared to MDMA: psychedelics impair attention and executive function, whereas MDMA primarily affects memory, leaving executive functions and attention unaffected. Our qualitative analyses reveal that executive functioning and creativity may be increased during a window of at least 24 h after the acute effects of psychedelics have subsided, whereas no such results have been observed for MDMA. Our findings may contribute to inform recommendations on harm reduction for recreational settings and to help fostering differential approaches for the use of psychedelics and MDMA within a therapeutic framework.
... Nevertheless, it is intriguing to hypothesize that rapid neuroplasticity induced by ketamine or psilocybin produces therapeutic effects by virtue of modifying how affective or cognitive events are processed. One possibility is that increased plasticity is related to enhancements in cognitive flexibility that have been observed in humans and rodents upon psilocybin administration (76,77). Alternatively, it could be a question of reopening a critical period of plasticity relevant to traumatic memories, emotional processing, or development of the self (78). ...
... Previous studies on psilocybin and decision-making indicate that psilocybin may improve cognitive flexibility (69)(70)(71); a further study found that psilocybin may reduce punishment by changing one's concerns for the outcome of their game partner in a social decision-making task (70). The current findings add to a growing literature in this area highlighting a range of effects that emerge in different task contexts, and which perhaps have similar underlying mechanisms. ...
Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit computational models of underlying decision-making mechanisms to behaviour in rats. The model revealed that rats treated with psilocybin achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.
... The chosen dosage of DOI has been shown to elicit a robust head twitch response, a behavioral marker for hallucinogenic effects, 65,66 and consistent behavioral effects. 67,68 For ketamine, 10 mg/kg is commonly used in preclinical models of psychiatric disorders and has demonstrated robust and long-lasting neural and behavioral changes at this dose. ...
Introduction: Serotonergic psychedelics and ketamine produce rapid and long-lasting symptomatic relief in multiple psychiatric disorders. Evidence suggests that despite having distinct molecular targets, both drugs may exert therapeutic benefit via their pro-neuroplastic effects. Following treatment with ketamine or serotonergic psychedelics, patients are reported to be more open to behavioral change, which is leveraged for psychotherapy-assisted reframing of narratives of the self. This period of enhanced behavioral change is postulated to be supported by a post-treatment window of enhanced neural plasticity, but evidence for such “metaplastic” effects is limited. In this study, we tested for neural plasticity and metaplasticity in murine hippocampus.
Methods: Brain slices were obtained from C57BL/6J mice 24 h after treatment (intraperitoneal injection) with saline, ketamine, or the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Extracellular fiber volleys (FVs) and field excitatory postsynaptic potentials (fEPSPs) were recorded in stratum radiatum of CA1 in response to stimulation of Schaffer collateral fibers before and after induction of short-term potentiation (STP) and long-term potentiation (LTP).
Results: Before LTP induction, responses differed across treatment groups (F2,67 = 5.407, p = 0.00665), with fEPSPs enhanced in slices from DOI-treated animals (p = 0.0182), but not in ketamine-treated animals (p = 0.9786), compared with saline. There were no treatment effects on LTP (F2,56 = 0.6, p = 0.516), but there were on STP (F2,56 = 4.409, p = 0.0167), with enhanced STP in DOI-treated animals (p = 0.0352), but not in ketamine-treated (p = 0.9999) animals, compared with saline. A presynaptic component to the mechanism for the DOI effects was suggested by (1) significantly enhanced FV amplitudes (F2,61 = 3.17, p = 0.049) in DOI-treated animals (p = 0.0457), but not in ketamine-treated animals, compared with saline (p = 0.8677); and (2) enhanced paired pulse ratios (F2,61 = 3.581, p = 0.0339) in slices from DOI-treated animals (p = 0.0257), but not in ketamine-treated animals (p = 0.4845), compared with saline.
Conclusions: DOI, but not ketamine, induced significant neuroplastic and metaplastic effects at hippocampal CA1 synapses 24 h after treatment, likely in part via a presynaptic mechanism.
... Given the growing appreciation in behavioural neuroscience that these types of behavioural tests (i.e. the forced swim test) do not reliably translate to human depressive syndromes [35] and that reinforcement learning tasks offer key advantages including more relevant clinical links and repeatability [36], these early approaches clearly need to be redressed. Other key methodological details in prior studies need to be considered, particularly the role of multiple dosing (cross-over) designs, antagonising 5-HT2AR with ketanserin (a compound with many known non-serotonergic binding sites [37]), and the measurable motoric side effects of acute psilocybin administration [38]. ...
... Not only does ketanserin bind multiple serotoninergic and non-serotonergic receptors but it also only blocks~30% of 5-HT2AR in the rat cortex [76]. It is plausible, therefore, that partial blockade with ketanserin shifts the binding of psilocybin to other 5-HTR subtypes, including 5-HT1A, which may explain the acute improvement in reversal learning after ketanserin alone previously reported in rats [38]. ...
... If adaptive cognition requires an appropriate balance between 5-HT1A and 5-HT2A receptor function [49], our molecular findings suggest that individuals exhibiting elevated 5-HT1AR function (or for that matter reduced 5-HT2AR function) may not respond positively (since further elevation or reduction elicited by psilocybin would push them into the tail ends of the inverted "U"). It is also important to note, in light of the recent observation that psilocybin, administered acutely, did not facilitate flexibility [38], that there are important methodological differences that may explain this discordance. Specifically, we examined effects of psilocybin post-acutely, using a single administration paradigm, and the reversal learning task used in the present study relied on action-outcome learning rather than Pavlovian cue-outcome learning. ...
Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1 A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2a and Htr1a, respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.
... Psychedelic treatments may enhance the brain mechanisms underlying psychotherapeutic change, perhaps by opening a window of enhanced neural plasticity (Lepow et al., 2023). Psychedelic treatment may augment nonspecific but potent mechanisms of change associated with psychotherapy more generally (Gukasyan & Nayak, 2021) or may enhance more specific psychotherapeutic processes, such as the development of value-based living (Sloshower et al., 2020), extinction learning (Feduccia & Mithoefer, 2018), or cognitive flexibility (Torrado et al., 2023). ...
Novel treatments are required for the 30-50% of individuals with obsessive-compulsive disorder (OCD) who remain resistant to first-line pharmacological and psychotherapeutic treatments. Recent pilot data suggest benefit from psilocybin-assisted psychotherapy (PAP) and from imagery rescripting (ImRs). We explore psychological mechanisms of change underpinning both interventions that appear to allow for reprocessing of negative emotions and core beliefs associated with past aversive events. A next critical step in PAP is the development of psychotherapeutic frameworks grounded in theory. We propose that basing PAP on an ImRs framework may provide synergistic benefits in symptom reduction, modification of core beliefs, and value-based living.
