Impact of psilocybin on cognitive A systematic review

Authors: Shakila Meshkat, Triana Juliana Tello‐Gerez, Fatemeh Gholaminezhad, Benjamin T. Dunkley, Amy C. Reichelt, David Erritzoe, Eric Vermetten, Yanbo Zhang, Andrew Greenshaw, Lisa Burback, Olga Winkler, Rakesh Jetly, Leah M. Mayo, Venkat Bhat

Abstract

Psilocybin is a classic psychedelic with demonstrated preliminary clinical efficacy in a range of psychiatric disorders. Evaluating the impact of psilocybin on cognitive function is essential to unravel its potential benefits and risks. In this systematic review, we assessed psilocybin's effect on cognitive function through a comprehensive search of electronic databases from inception to January 2024, identifying 20 articles involving 2,959 participants. While 85% of studies were conducted in healthy volunteers, most of these studies (85%) used macrodoses, ranging from 45 μg/kg to 30 mg/70 kg. Various cognitive aspects were evaluated and yielded mixed results. Global cognitive function, and processing speed remained mostly unchanged in healthy individuals; However, a limited number of studies reported improvements in certain areas such as sustained attention, working memory, and executive function especially in patients with treatment‐resistant depression (TRD). Emotional processing was positively modified, particularly in TRD patients. Psilocybin was observed to enhance emotional empathy without significantly altering cognitive empathy and social cognition. Cognitive flexibility and creative cognition were noted to initially decline but could potentially improve over time. Additionally, with respect to learning and memory skills, psilocybin showed promise in improving specific memory types such as semantic associations and associative learning, while its effects on episodic and verbal memory have been less pronounced compared to other cognitive enhancers. The observed mixed findings underscore the complexity of psilocybin's cognitive influence. Further research is essential to provide a clearer understanding of psilocybin's impact on cognitive domains and to guide the development of safe and effective interventions.

Classic psychedelics include psilocybin {3‐(2‐[dimethylamino] ethyl)‐1H‐indol‐4‐yl dihydrogen phosphate}, N,N‐dimethyltryptamine and ergolines such as lysergic acid diethylamide. ^1^ Psilocybin was first discovered in mushrooms of the Psilocybe genus, and is dephosphorylated in the small intestines to its active metabolite, psilocin, which has a range of receptor interactions, including serotonin (5‐HT) receptors 1A, 2A, 2B and 2C agonist effects. ^1^ , ^2^ Of note, the activation of the 5‐HT2A receptor by psilocin is proposed to confer hallucinogenic effects. ^1^ , ^2^ Preliminary evidence supports the efficacy of psilocybin in several psychiatric conditions including major depressive disorder (MDD), treatment‐resistant depression (TRD), obsessive–compulsive disorder, alcohol and nicotine dependence, and cancer‐related anxiety. ^2^ , ^3^ , ^4^ , ^5^ , ^6^ Starting from the early to mid‐1960s, psilocybin found its application in psychiatric medicine and psychodynamic‐oriented psychotherapy. ^7^ Its initial isolation by Albert Hofmann in 1957, followed by synthesis in 1958 by Sandoz Pharmaceuticals: Basel, Switzerland, under the trade name Indocybin, played a crucial role in its development. ^7^ , ^8^ However, the progress of psilocybin research faced a significant setback when it was legally sanctioned and classified as a schedule 1 substance due to international legal restrictions. ^9^ Nonetheless, there has been renewed interest and resurgence in studying psilocybin's effects since the mid‐1990s. ^10^

Dosing with psilocybin results in an altered state of consciousness, characterized by shifts in emotional state and perception. ^11^ The psychological impacts of psilocybin encompass feelings of euphoria, hallucinations, dissociation, and altered cognitive states as well as impacting empathy, creativity, and subjective well‐being. ^12^ , ^13^ The therapeutic advancement of psilocybin for mental health disorders relies on targeting the neural mechanisms of cognitive and emotional processing. ^14^ Studies have revealed that serotonergic psychedelics can acutely alter activity within the neural circuits. ^14^ Importantly, psychedelic‐induced changes align with the concept of neuroplasticity, emphasizing the brain's capacity to undergo adaptive and transformative structural and functional alterations, thereby impacting cognition. ^15^

Cognitive deficits play a significant role in the development, progression, and treatment of mental disorders. ^16^ Many psychiatric disorders are characterized by impairments in cognitive function, which can significantly hinder a person's ability to function in real‐world situations. ^17^ The serotonin system, which is targeted by psychedelic compounds, may represent a promising target for pharmacological modulation of cognitive functioning and has been implicated in the pathophysiology of various mental health disorders. ^17^ , ^18^ Therefore, it is necessary to better understand the short‐ and long‐term effects of psilocybin on cognition.

In the realm of research with psilocybin, there exists a notable gap of knowledge regarding its effects on cognitive processes such as attention, memory, and executive functions in humans. Existing research, although limited, suggests the potential for psilocybin to influence cognition through its interaction with 5‐HT receptors and functionally downregulating default mode network (DMN) activity. ^19^ , ^20^ However, a comprehensive understanding of the specific cognitive mechanisms involved, the short‐ and long‐term effects, and potential therapeutic implications of psilocybin on cognitive function, is still lacking. Understanding psilocybin's impact on cognitive functions is crucial for elucidating its therapeutic potential and associated risks, essential for its safe and effective clinical use. Addressing this knowledge gap will inform evidence‐based decisions, optimizing psilocybin's application in treating psychological and cognitive conditions. This systematic review aims to comprehensively evaluate psilocybin's cognitive effects, guiding future research and clinical practice in psychedelic medicine.

Methods

Search strategy

We conducted a comprehensive search on three databases (MEDLINE, PsycINFO, Embase) through OVID from inception to January 2024. We adhered to Preferred Reporting Items for Systematic Review and Meta‐Analysis Statement for this systematic review. ^21^ Relevant articles were identified using the following (psilocybin or magic mushrooms or psilocybine or psilocibin or psiloc*) AND (cognition or cognitive or cognitive function or CI or cognitive impairment or cognitive disorder or memory or executive function or global impairment or neuropsychological test or speed or attention or processing or memory disorder or processing speed or executive control or cognitive processes or cognitive decline or cognition test). Further articles were identified by conducting searches on Google Scholar and manually examining the reference lists of relevant papers. No limitations were placed on publication date or language during this screening process.

The search for past and ongoing clinical trials was performed on ClinicalTrials.gov (https://clinicaltrials.gov/). The search terms ‘psilocybin’ and ‘cognition’ were utilized, without any limitations on the study status. The search was conducted on May 10, 2023.

Eligibility criteria

To streamline the screening process and eliminate duplicate articles, all search results were imported into the Covidence platform (covidence.org) for systematic review management. Two independent reviewers (S. M., T. J. T. G.) performed a comprehensive screening of all articles in two distinct stages. For the first level screening, the reviewers assessed the titles and abstracts of the articles. Subsequently, for the second‐level screening, full texts were thoroughly reviewed. Conflicts between two reviewers were resolved through discussion and consultation with V. B. Studies were included if they (i) original studies; (ii) evaluated the effect of psilocybin in humans with focus on cognitive function in both clinical or non‐clinical populations using at least one neurocognitive assessment as a primary or secondary outcome; (iii) included participants were not diagnosed with comorbid structural or biologically based brain disease or traumatic brain injury, mild cognitive impairment, or dementia; and (iv) in English. Any study designs (clinical trials, observational studies, and case reports/series) that captured the data on the effect of psilocybin on cognition were allowed. Systematic reviews, narrative reviews, meta analyses, animal studies, studies using the same dataset and letters to the editor were excluded.

Data extraction

Two reviewers independently (S. M., T. J. T. G.) reviewed the full text of eligible articles and extracted the following year of publication, author, study design, country, patient demographics (mean age, percentage female, sample size), outcome measure, intervention, study design, results, adverse events, therapy principles and conclusion. Furthermore, relevant information such as sample size, clinical diagnosis, study design, treatment administration method and dosage, as well as start, registration, and completion dates, were extracted from the registered clinical trials.

Quality assessment

For randomized trials, the Cochrane Collaboration's tool is used to assess the risk of bias. This tool examines five bias from the randomization method, bias due to deviations from intended interventions, bias arising from missing outcome data, bias in outcome assessment, and bias in the selection of reported results. ^22^ , ^23^

Results

Search results

The systematic search resulted in 348 records. We removed duplicates (n = 4) and screened the title and abstract of the remaining records (n = 344). Three hundred and fourteen records were excluded based on our inclusion criteria. Subsequently, we reviewed the full‐text of 30 records. Out of 30 records, 10 records were excluded; six had no neurocognitive assessment and four did not report results pertaining to cognitive outcomes. Finally, 20 articles involving 2,959 participants met the inclusion criteria and were included in this systematic review. ^12^ , ^24^ , ^25^ , ^26^ , ^27^ , ^28^ , ^29^ , ^30^ , ^31^ , ^32^ , ^33^ , ^34^ , ^35^ , ^36^ , ^37^ , ^38^ , ^39^ , ^40^ , ^41^ , ^42^ , ^43^ Study selection details are indicated in Figure 1 and the quality assessment results are outlined in Fig. S1. We also included eight registered clinical trials; detailed characteristics can be found in Table S1 and Figs. S2 and S3.

Characteristics of included published studies

The majority of studies enrolled healthy participants (85%) (Fig. 2), with most focusing on acute (short‐term) (12 studies [60%]) cognitive effects of psilocybin, rather than long‐term effects (Fig. 3a,b). While the majority of studies focused on healthy subjects (85%), three studies (15%) specifically assessed the impact of psilocybin on cognition in individuals with MDD ^24^ and TRD. ^25^ , ^26^ Several key distinctions among studies revolved around the doses administered, the targeted population (healthy individuals vs psychiatric disorders), and the timing of cognitive assessments relative to psilocybin administration. Most studies utilized doses ranging from 115 to 315 μg/kg, with only two studies opting for higher doses of 30 mg/70 kg (Fig. 4). ^24^ , ^27^ Among the six studies ^12^ , ^25^ , ^26^ , ^27^ , ^28^ , ^30^ employing graded psilocybin doses, four revealed a dose‐dependent gradient. Additionally, two studies investigated the cognitive effects of microdosing (0.5–0.7 g of dried psilocybin mushrooms). ^32^ , ^33^ In two of these studies, treatment involved two dosing sessions of psilocybin alongside psychotherapy. Variety of cognitive domains such as global cognitive function, attention, processing speed, working memory, emotional processing, social cognition, empathy, cognitive flexibility, creative cognition, memory, learning and executive function were evaluated in included studies. Detailed characteristics of included studies are summarized in Tables 1, 2, Figs. S4 and S5. Figure 5 indicates the overall psilocybin effect on different cognitive function domains.

Global cognitive function

Two studies investigated the effects of psilocybin on global cognitive function in healthy participants. Rucker et al. ^30^ studied the lasting effects of psilocybin on global cognitive function in 89 healthy subjects. Participants received either placebo or psilocybin (10 or 25 mg), along with psychotherapy sessions. Global cognitive function was measured using Cambridge Neuropsychological Test Automated Battery (CANTAB) global composite score at baseline (day −1), 8 and 29 days after treatment. The primary endpoint of this study was day 8. Overall, the CANTAB battery, when comparing psilocybin‐naïve and psilocybin‐experienced participants, yielded similar results.

Barrett et al. ^27^ studied the acute cognitive effects of psilocybin and the NMDA receptor antagonist dextromethorphan (DXM) among 22 healthy participants. The study measured global cognitive functioning using the mini‐mental status examination (MMSE). ^27^ Participants who received either 10, 20, or 30 mg/70 kg psilocybin, 400 mg/70 kg of DXM, or placebo completed the MMSE 2 h after each drug administration. None of the participants who ingested psilocybin, and all but one DXM participant, exhibited any discernible alterations in global cognitive function as assessed by the MMSE. ^27^

Overall, none of the two studies that investigated the effects of psilocybin on global cognitive function in healthy participants reported significant changes following the psilocybin administration.

Attention and processing speed

Seven studies evaluated psilocybin effects on processing speed and either overall attentional performance or specific aspects of attention, such as sustained attention and visuospatial attention through different tests in different settings. Hasler et al. evaluated sustained attention, the ability to maintain focus on a task, with the Frankfurt Attention Inventory (FAIR). In the study, the test was administered approximately 140 min after drug intake. Eight healthy participants received either placebo or different doses of psilocybin at least 2 weeks apart (very low 45/kg, low 115 μg/kg, medium 215 μg/kg, high 315 μg/kg). ^28^ Results of this study indicated that although the acute effects of psilocybin (i.e. within 2 h after drug administration) did not affect task clarity and decision making, cognitive processing and sustained attention were reduced. ^28^ Consistently, Vollenweider et al. ^12^ , in a randomized clinical trial (RCT) on psilocybin (three 115, 215, 315 μg/kg) in healthy individuals, revealed a dose‐dependent reduction in sustained attention as indicated by reduction in FAIR attentional performance capacity, performance quality, and attentional continuity performance.

Carter et al. ^34^ conducted an RCT that measured effects of either 215 μg/kg psilocybin, placebo, the 5‐HT2A receptor antagonist ketanserin (50 mg), or psilocybin plus ketanserin on attention in eight healthy volunteers. Attention was measured using a multiple‐object tracking task which was administered 120 min after the drug intake. While there were no significant differences between the four drug conditions during the pretest phase, a significant reduction of attentional performance was reported following both psilocybin and psilocybin with ketanserin pretreatment.

Cavanna et al. ^32^ evaluated the effect of microdoses of psilocybin on attention in 34 healthy participants. Subjects received two doses of 0.5 g of dried Psilocybe cubensis separated by 2 days, and on the second day participants completed the tests. Consistent with the above‐mentioned studies, impaired attentional performance was observed as measured by trail making test (TMT) and attentional blink task. However, there was a notable increase in the time needed to complete part A of the TMT test. ^32^ Duke et al. ^35^ evaluated the effect of psilocybin (0.2 mg/kg) or dextro‐amphetamine (DA) (30 mg) on attention and working memory of healthy participants using TMT, part A and part B. Both DA and psilocybin significantly increased the time needed to complete the test, implying reduced working memory with both. However, DA had a significantly greater effect on part A and part B than placebo, and psilocybin had a significantly greater effect on part A and part B than DA. ^35^ Additionally, Gouzoulis‐Mayfrank et al. ^36^ , randomized 32 healthy individuals to four drug groups (psilocybin 0.2 mg/kg, 3,4‐methylenedioxyethamphetamine [MDE], dmethamphetamine, placebo, n = 8 each) and assessed visuo‐spatial attention 1 h before and between 75 and 95 min after the ingestion of the drug, using the covert orienting of attention task (COVAT). Whereas MDE did not affect reaction time (RT), low response inhibition and prolonged RT were reported in those receiving psilocybin. ^36^

Lastly, Rucker et al. ^30^ evaluated sustained attention using Rapid Visual Information Processing. A trend towards an increased sustained attention was observed for the 10 and 25 mg psilocybin doses by day 29 compared with baseline, which was not detected either against the placebo or between the two doses of psilocybin. ^30^

Overall, in the acute setting following psilocybin intake, both studies that administered the FAIR test showed decreased performance and continuity values, but not efficiency scores. ^12^ , ^28^ Two studies reported decreased performance in visual attention, measured through the COVAT and multiple object tracking tests. ^34^ , ^36^ Attentional performance measured by the trail‐making test also decreased, and a significant increase in the time needed to complete the task following a microdosing regimen was observed. ^32^ , ^35^ In the post‐acute setting, there was a non‐significant trend towards improved sustained attention. ^30^

Working memory

Five studies evaluated the effects of psilocybin on working memory on healthy participants. Nikolič et al. ^37^ conducted a study with 20 healthy volunteers to examine the impact of psilocybin on the consolidation of working and verbal memory. Although they found no evidence of cognitive decline in memory consolidation, they were also unable to demonstrate any improvement in memory consolidation from psilocybin using memory tests, including the Groton Maze Learning Task and Rey Auditory Verbal Learning Test. ^37^

Two studies assessed working memory with the spatial span test. ^31^ , ^34^ Carter et al. ^34^ investigated the impact of 215 μg/kg psilocybin on spatial working memory (SWM) in eight healthy volunteers. They discovered no significant influence on the correct recall of boxes in sequence (‘span length’) for both drug and time. This absence of effect persisted when comparing placebo and psilocybin conditions before and 120 min after drug intake in a 2 × 2 anova. Furthermore, the total number of errors in sequence order or location (‘total errors’) remained unaffected by drug administration or time of testing, further affirming the lack of psilocybin's impact on SWM performance. ^34^ Wittmann et al. ^31^ examined the impact of high (250 μg/kg) and medium (115 μg/kg) doses of psilocybin on the SWM of 12 healthy individuals using the same test. The test was accomplished at 0, 100 and 360 min after drug/placebo intake. The analysis showed no overall treatment effect, a significant effect over measurement time, and a significant interaction effect. Also, the analysis showed a significant interaction effect between measurement time and treatment group. A priori contrasts revealed a significant difference only in the contrast between placebo and high‐dose (HD) psilocybin between t1 and t0 (P < 0.011). Therefore, at the peak of effects, only HD psilocybin (not medium dose) impaired spatial span task performance, as indicated by span length. ^31^

Umbricht et al. ^38^ investigated the impact of psilocybin (0.28 mg/kg) on working memory using the AX continuous performance test in healthy individuals 70 min after psilocybin administration. The study revealed a substantial reduction in response accuracy and working memory during psilocybin administration which was independent of inter stimulus intervals. This effect was not attributed to a more liberal response bias induced by psilocybin. Finally, Rucker et al. ^30^ reported an increase in working memory using SWM.

In summary, five studies evaluated the impact of psilocybin on working memory, all of them worked with healthy subjects and only one evaluated the effects in the post‐acute setting. In the acute setting, two studies demonstrated impaired performance with doses over 0.25 mg/kg, ^31^ , ^38^ and two others showed no effect of psilocybin on working memory. ^34^ , ^37^ In the post‐acute setting, Rucker et al. ^30^ demonstrated a trend towards better performance for 25 mg dose compared to baseline, but no difference from placebo.

Emotional processing

Four studies evaluated the effect of psilocybin on emotional processing; three of these on healthy subjects ^30^ , ^33^ , ^39^ and one on subjects with TRD. ^26^ Kometer et al. ^39^ evaluated the acute effects of psilocybin, with or without ketanserin pretreatment, on emotional processing through the emotional go/no‐go task in 17 healthy participants 130 min after treatment. In this within subject design study, participants underwent four different experimental days, separated at least 2 weeks apart. Each session involved pretreatment with either placebo or ketanserin (50 mg) followed by placebo or psilocybin (215 g/kg) after 1 h. ^39^ The administration of psilocybin resulted in an increase in RT, with longer RTs observed for negative and neutral words compared to positive words, indicating a heightened response bias towards positive words. Moreover, psilocybin led to increased error rates based on word valence, specifically elevating error rates for neutral words while not affecting those for positive or negative words. These changes were observed irrespective of pretreatment with ketanserin. Using the same task, Marschall et al. ^33^ evaluated the effects of seven doses of approximately 1.5 mg psilocybin over 3 weeks on emotional processing in 52 healthy subjects. Contrary to the results by Kometer et al. the results showed that at 1.5 h after self‐administration of psilocybin, emotional processing had a significant effect on RTs, but the specific experimental conditions (placebo vs psilocybin) did not. ^33^

Interestingly, Stroud et al. ^26^ explored the lasting effect of psilocybin on emotional processing in 17 participants with TRD, and reported that psilocybin, along with psychotherapeutic support, appears to improve emotional processing in this indication. Patients participated in two dosing sessions, the first with 10 mg of psilocybin and 25 mg in the second, and received psychotherapy sessions including a preparation session, inner directed therapy during psilocybin treatment and an integration session after treatment. ^26^ One month after administration of psilocybin, participants completed the Dynamic Emotional Expression Recognition Task. Results showed that at pretreatment baseline, patients were slower at recognizing facial emotions compared with controls. After psilocybin, this difference was remediated. Emotion recognition was faster at follow‐up compared with baseline in patients but not controls. Lastly, Rucker et al. ^30^ reported no difference between either psilocybin group and placebo in the reading the mind in the eyes test scores relative to baseline.

The four studies assessing emotional processing had different experimental designs and studied various populations, yielding mixed results. Of the two studies employing the emotional go/no‐go task, the one using a microdosing regimen found no difference between the placebo and control groups. ^33^ In contrast, Kometer et al. ^39^ reported a significant difference with a 0.215 mg/kg dose, noting increased RTs and error rates depending on word valence. In the post‐acute setting with healthy participants, no significant effect of psilocybin was observed. ^30^ However, in the study involving participants with TRD, the authors found faster emotion recognition 1 month after psilocybin administration. ^26^

Social cognition and empathy

Regarding the effects of psilocybin on empathy levels, Pokorny et al. ^40^ compared the acute effects of psilocybin (0.215 mg/kg) with placebo in 32 healthy subjects using the multidimensional empathy test administered 160 min post treatment. Compared to placebo, psilocybin increased both explicit and implicit emotional empathy. However, no change in cognitive empathy and no significant main effect for psilocybin were indicated. Consistently, in the study by Cavanna et al. ^32^ , no significant changes were reported in cognitive empathy levels as measured by the cognitive‐affective empathy test. Lastly, Rucker et al. ^30^ reported similar empathy and social cognition scores across psilocybin and placebo groups and time points of the study assessed by the pictorial empathy test, scale of social responsibility, social value orientation and Toronto Empathy Questionnaire.

These three studies evaluated social cognition and empathy in both acute and post‐acute settings, as well as following a microdosing regimen. A significant difference between the placebo and psilocybin groups was observed only in the acute setting, with the psilocybin group showing increased explicit and implicit emotional empathy. ^40^ The other two studies found no difference between the placebo and psilocybin groups in social cognition and empathy tests in the post‐acute setting or after a microdosing regimen. ^30^ , ^32^

Cognitive flexibility and creative cognition

Inconsistent results were reported on the effects of psilocybin on cognitive flexibility and creative cognition, considering different psychiatric indications and various drug regimens used in these studies. Cavanna et al. ^32^ reported no significant effects of psilocybin microdosing (0.5 g of dried mushrooms) on cognitive flexibility and creative cognition in healthy subjects, assessed by the cognitive flexibility scale (CFS), the Remotes Associates Test (RAT; convergent thinking), the alternative uses task (AUT; divergent thinking), and the Wallach–Kogan Test (WK; divergent thinking). ^32^ However, in another study Mason et al. ^41^ reported a time‐related differentiation of effects on creative thinking by psilocybin. This study evaluated the acute and lasting effects of psilocybin (0.17 mg/kg psilocybin) on creativity in 60 healthy subjects utilizing the picture concept task and the AUT at three baseline, treatment day and 7 days after the treatment. Psilocybin acutely decreased both convergent and divergent thinking compared to placebo, with convergent thinking still reduced at the 7‐day follow‐up. Additionally, psilocybin acutely decreased fluency and significantly increased novelty at the 7‐day follow‐up. Although aspects of divergent thinking were impaired during the acute psychedelic state, they were increased after 7 days, represented by the generation of a higher quantity of novel ideas for uses of an everyday object on the AUT compared to placebo. ^41^

Doss et al. ^24^ evaluated the lasting effects of psilocybin on cognitive flexibility in 22 participants with MDD. Participants received 20 mg/70 kg and 30 mg/70 kg of psilocybin across two sessions, 1–3 weeks apart. The cognitive flexibility was evaluated using the Penn conditional exclusion test 4 weeks before the first psilocybin administration, then 1 and 4 weeks after the second session. Sustained positive changes were shown in cognitive flexibility in patients with MDD, independent of changes in depressive symptoms as assessed by GRID‐Hamilton Depression Rating Scale. ^24^

Nayak et al. ^42^ investigated the effects of psilocybin on cognitive flexibility in healthy participants. The study comprised six sequential web‐based surveys, including the CFS. Results revealed a significant increase in self‐reported cognitive flexibility at 2–4 weeks and 2–3 months post‐psilocybin. The increase in cognitive flexibility was positively correlated with higher scores on the Mystical Experience Questionnaire at both time points, suggesting that individuals with more profound mystical experiences exhibited a greater rate of improvement in cognitive flexibility over time. ^42^

Overall, these studies demonstrated that psilocybin affects cognitive flexibility and creative cognition only in the post‐acute setting, not following a microdosing regimen. ^24^ , ^32^ , ^41^ , ^42^ In the post‐acute setting, a decrease in convergent thinking and increased novelty scores was observed 7 days after psilocybin administration. ^41^ Additionally, there was an increase in both objective and self‐reported cognitive flexibility in healthy participants as well as in subjects with depression. ^24^ , ^42^

Memory and learning

The main three investigated aspects of memory and learning in psilocybin studies were associative learning, semantic associations, and episodic memory. Rucker et al. ^30^ measured the effect of psilocybin on episodic memory using Paired Associates Learning‐Total Errors Adjusted (PAL‐TEA). The results of this study indicated no changes in PAL‐TEA following psilocybin administration. ^30^

Spitzer et al. ^43^ conducted an RCT in eight healthy subjects to evaluate the acute effects of psilocybin on semantic associations. Participants underwent two sessions a week apart, including one with 0.2 mg/kg psilocybin capsules and one placebo session. ^43^ Participants performed the lexical decision paradigm test before and at minutes 50, 150 and 220 after treatment. The results showed no effect of psilocybin with the indirect priming effect, but a significant increase of indirect semantic priming under psilocybin was indicated, which implies an increased availability of remote associations. ^43^

In a study by Barrett et al. ^27^ associative learning and short‐term memory in 22 healthy participants was assessed using a word encoding/recognition task and the substitution recall segment of the DSST. Psilocybin was administered in three doses 10, 20, and 30 mg/70 kg. Significant positive effects of the drug condition were noted on word recall accuracy and word recognition. ^27^ Planned comparisons revealed a notable difference between the DXM and 10 mg/70 kg psilocybin conditions for the familiarity index and the recollection index in the word recall task. Both psilocybin and DXM led to a decrease in the free recall of words, but DXM exhibited a more pronounced impact on free recall compared to psilocybin. Additionally, DXM selectively reduced recognition sensitivity and diminished the involvement of both familiarity and recognition processes compared to the 10 mg/70 kg dose of psilocybin. Regarding substitution recall in the DSST, both psilocybin and DXM induced impairments in associative learning. In summary, both drugs influenced incidental associative learning, and while DXM affected episodic memory selectively, psilocybin did not produce the same effect. ^27^

In summary, in the post‐acute setting, the study by Rucker et al. ^30^ showed no effect of psilocybin on episodic memory. On the other hand, in the acute setting, both studies showed an effect of psilocybin; Spitzer et al. ^43^ showed an increase in indirect semantic priming and Barrett et al. ^27^ showed a dose‐dependent decrease in word‐recall accuracy.

Executive function

Executive function was evaluated by two studies, both using the digit symbol substitution test (DSST). Barrett et al. ^27^ studied the acute cognitive effects of psilocybin in healthy volunteers. Executive function as measured by the DSST, showed a main effect of drug condition, as well as an interaction between drug condition and time point on the number of attempted trials. ^27^ Similarly, a main effect for drug condition on accuracy and interaction between drug condition and time point. Regarding the accuracy of attempted responses, psilocybin did induce a dose‐dependent decrease in attempted responses, indicating a successful speed‐accuracy trade‐off during the effects of psilocybin. In summary, both study drugs (psilocybin and DXM) caused impairment in DSST while acutely under the influence of drug. ^27^ However, in a study by Goodwin et al. ^25^ in patients with TRD, it was indicated that higher doses of psilocybin (25 and 10 mg) are associated with greater improvements in DSST scores compared to a lower dose (1 mg). This trial with 233 TRD participants administered DSST 3 weeks after treatment with a single dose of psilocybin (25, 10 or 1 mg). The difference in least‐squares mean change (standard error) in the DSST from baseline to week 3 for 25, 10 and 1 mg was 6.4 (0.84), 5.4 (0.87) and 4.8 (0.84), respectively. The difference between the 25 mg psilocybin group and the 1 mg control group was 1.5 (95% CI: −0.8, 3.8), and for the 10 mg group was 0.5 (95% CI: −1.8, 2.8). This study suggests a potential dose‐dependent improvement trend in cognitive performance 3 weeks post‐dosing. ^25^

In conclusion, in the acute setting, a dose‐dependent decrease in executive function performance was observed in the psilocybin group. Conversely, in the post‐acute setting, subjects with TRD exhibited a dose‐dependent, non‐significant trend towards increased scores at week 3 compared to baseline in the psilocybin group. ^25^

Discussion

In this review, we systematically identified, reviewed, and evaluated 20 published studies, which investigated the effect of psilocybin on cognitive function. Our systematic review on psilocybin's effect on cognitive function revealed nuanced findings. While global cognitive function in healthy individuals showed negligible effects, certain domains such as executive function exhibited potential improvements. Attention was consistently impaired by psilocybin in the acute phase, except in one study where sustained attention showed a non‐significant trend towards improvement 29 days after psilocybin administration. Working memory was not consistently impaired by psilocybin but showed deficits under specific conditions or doses. Psilocybin showed promise in modifying emotional processing, enhancing positive emotional bias and recognition of emotional expressions, especially in TRD patients, emphasizing the importance of therapeutic support. Furthermore, it can enhance emotional empathy without significantly altering cognitive empathy. Cognitive flexibility and creative cognition were initially impaired but transformed into improvements, particularly in settings involving significant psychological or mystical experiences.

Psilocybin's acute effects on cognition appear to follow a dose‐dependent gradient, with different doses showing distinct cognitive responses. Higher doses have been associated with both enhancements and impairments in cognitive performance, underscoring the importance of dosage optimization for desired outcomes. ^12^ , ^25^ , ^27^ , ^28^ , ^30^ , ^31^ The precise mechanisms underlying these dose dependent effects warrant further investigation. Understanding the temporal dynamics of psilocybin's cognitive effects is crucial for interpreting study findings accurately. Acute assessments conducted up to 24 h after psilocybin ingestion provide insights into immediate cognitive changes, whereas longer‐term assessments reveal the persistence and trajectory of these effects over time. The diverse range of study populations, including both healthy individuals and those with mood disorders such as MDD and TRD, offers valuable insights into the differential effects of psilocybin across distinct clinical contexts. While healthy participants may exhibit alterations in attention, working memory, and emotional processing, individuals with depression may experience cognitive improvements alongside mood enhancements following psilocybin‐assisted therapy. ^25^ , ^26^ Exploring the underlying neurobiological mechanisms mediating psilocybin's effects on cognition remains a frontier in psychedelic research. Neuroimaging studies have implicated alterations in brain connectivity, neurotransmitter systems, and neural plasticity as potential drivers of psilocybin‐induced cognitive changes. ^34^ , ^39^ Integrating psilocybin‐assisted therapy into existing treatment paradigms for depression, anxiety, and substance use disorders may offer a novel approach to addressing cognitive deficits and promoting overall psychological well‐being. Longitudinal studies examining the enduring cognitive effects of repeated psilocybin dosing and exploring potential biomarkers of treatment response are warranted.

Two studies have suggested that individuals may experience enhanced cognitive flexibility and creativity in the days and weeks following a psilocybin experience. ^24^ , ^42^ This post‐acute period, often referred to as the ‘afterglow’, is characterized by a heightened sense of novelty, openness to new ideas, and divergent thinking. Research has shown that psilocybin can facilitate the dissolution of rigid thought patterns and promote unconventional problem‐solving strategies, which may persist beyond the acute effects of the drug. ^39^ These findings have significant implications for harnessing psilocybin's potential as a catalyst for creativity enhancement and cognitive enrichment in both clinical and non‐clinical settings. The post‐acute phase following a psilocybin experience is also marked by shifts in mood and emotional resilience. ^24^ , ^26^ Many individuals report feelings of increased emotional openness, empathy, and connectedness with others, which may endure for days or even weeks after the acute effects have subsided. These changes in affective processing are thought to arise from alterations in 5‐HT receptor signaling and neuroplasticity induced by psilocybin, leading to a recalibration of emotional reactivity and regulation. ^34^ , ^39^ Moreover, the profound insights and spiritual experiences often reported during psilocybin sessions can foster a sense of existential meaning and psychological well‐being that persists beyond the immediate drug effects. ^44^ The post‐acute period serves as a critical window for the integration and consolidation of insights gained during the psychedelic experience. ^45^ Through reflective practices such as journaling, meditation, and psychotherapy, individuals can deepen their understanding of the transformative experiences catalyzed by psilocybin and integrate them into their sense of self and worldview. ^46^ This process of meaning‐making facilitates psychological integration, facilitates the resolution of existential concerns, and fosters a sense of coherence and authenticity in one's life narrative. ^46^ Moreover, integration practices play a vital role in mitigating potential adverse effects and maximizing the therapeutic benefits of psilocybin therapy. ^47^ Research into the mechanisms underlying these post‐acute effects can inform the development of novel therapeutic approaches targeting mood disorders, addiction, and existential distress.

Comparing the acute and post‐acute effects of psilocybin unveils a nuanced journey of cognitive and emotional transformation. In the acute phase, individuals undergo profound alterations in perception and consciousness, experiencing vivid hallucinations, ego dissolution, and heightened emotional intensity. ^2^ This period, lasting 4–6 h, often leads to enhanced introspection, insight, and altered sense of self. ^2^ In contrast, the post‐acute phase extends beyond the immediate experience, manifesting in improved cognitive flexibility, emotional resilience, and enduring changes in personality traits. ^24^ While acute effects are intense and transient, postacute effects are subtler but more enduring, influencing mood, cognition, and behavior over days, weeks, or even months. ^48^ Understanding the dynamic interplay between these phases is crucial for optimizing therapeutic outcomes, as integration practices during the post‐acute period can help individuals consolidate insights, and maximize the long‐term benefits of psilocybin‐assisted therapy.

The variability in results within the domain of cognitive function, even when studies focus on similar cognitive tasks such as attention, memory, or executive function, can be attributed to several factors. Firstly, differences in study design, including variations in sample size, participant demographics, dosing regimens of psilocybin, and the specific measures used to assess cognitive performance, contribute significantly. Studies may also vary in the timing of assessments post‐psilocybin administration, influencing the observed effects on cognitive domains. Moreover, the inclusion criteria and health status of participants (e.g. healthy volunteers vs individuals with psychiatric disorders) can introduce variability in baseline cognitive abilities and responsiveness to psilocybin. Additionally, the contextual factors during testing, such as the environment and psychological state of participants, could influence cognitive outcomes. These multifaceted factors highlight the complexity of studying psilocybin's effects on cognition and underscore the importance of comprehensive study design and analysis to better understand and interpret these varying results.

The exact mechanisms underlying how psilocybin may impact cognition are still subjects of ongoing investigation. One prominent theory proposes that psilocybin interacts with 5‐HT receptors in the brain, particularly the 5‐HT2A receptor. ^49^ This interaction leads to changes in neurotransmitter activity, with 5‐HT2A receptor activation modulating the release of key neurotransmitters such as dopamine and glutamate, which are integral to cognitive processes. ^50^ , ^51^ Other, recent preclinical studies have demonstrated that psilocin acts as an allosteric modulator of Tropomyosin receptor kinase B, the receptor for brain derived neurotrophic factor, a critical signaling molecule for the induction of synaptic protein synthesis. ^52^ As synaptic plasticity is known to be essential for cognition, and has been shown to be altered in mood disorders, this neurobiological mechanism provides insights into how psychedelics may exert their therapeutic efficacy. Furthermore, other studies have shown that treatment of cultured neurons with psychedelics is capable of increasing neuritogenesis and can induce spinogenesis when administered systemically. ^53^ Moreover, two‐photon imaging in live mice has shown increases in dendritic spines in the prefrontal cortex for up to 30 days following psilocybin administration. ^54^

While psilocybin preferentially activates the 5‐HT2A receptor, it also exerts an activating effect on the 5‐HT1A receptor. Studies that used ketanserin pretreatment, a preferential 5‐HT2A antagonist, did not show significant differences in emotional processing or attentional processing, suggesting the involvement of the 5‐HT1A receptor in modulating the cognitive changes observed. ^34^ , ^39^ Recent preclinical findings highlight the dual role of 5‐HT receptors in the actions of psychedelics. ^55^ These studies emphasize that while 5‐HT2A receptors predominantly mediate the perceptual and psychedelic effects, ^56^ 5‐HT1A receptors may play a significant role in modulating cognitive and emotional processing, ^57^ potentially contributing to the therapeutic effects observed in clinical studies. Further research is warranted to elucidate the specific mechanisms and interactions between these receptor subtypes, which could inform the development of more targeted therapeutic approaches using psilocybin and related compounds. Furthermore, psilocybin‐induced alterations in neural connectivity and network dynamics, as observed using functional magnetic resonance imaging studies, may contribute to cognitive effects by temporarily disrupting the DMN. ^58^ , ^59^ This network is linked to self‐referential thoughts, and its transient suppression might foster a more flexible cognitive state. ^58^ , ^59^ Additionally, ongoing exploration of psilocybin's impact on neuroplasticity, dendritic remodeling, and synaptic pruning suggests a potential mechanism for cognitive benefits, promoting the growth of new neural connections and eliminating less efficient ones. ^60^ , ^61^ The psychedelic experience induced by psilocybin, marked by altered perceptions and increased introspection, is also considered a factor that might contribute to cognitive flexibility, empathy and creativity. ^40^ , ^62^ , ^63^ However, it is crucial to emphasize that these mechanistic hypotheses remain plausible and require further research for a comprehensive understanding of the intricate pathways through which psilocybin influences cognition. The evolving field of research, characterized by ongoing studies, aims to elucidate the complexities of psilocybin's effects on the brain and cognitive functions.

Stroud et al. ^26^ reported that a larger decrease in RT in the Dynamic Emotional Expression Recognition Task correlated with a greater reduction in anhedonia among depressed individuals receiving psilocybin. This correlation implies that as individuals become more proficient at recognizing and processing emotional expressions, they also experience a greater relief from anhedonia. Anhedonia, a hallmark symptom of depression characterized by a diminished ability to experience pleasure, often accompanies deficits in emotional processing. ^64^ Therefore, the observed association between improvements in emotional processing and reductions in anhedonia indicates that psilocybin may target underlying mechanisms involved in both emotional processing and anhedonic symptoms. One interpretation of this correlation is that psilocybin treatment enhances emotional processing capabilities, leading to a normalization of affective responses and ultimately reducing anhedonia. By facilitating more adaptive emotional responses to stimuli, psilocybin may alleviate anhedonic symptoms and restore the ability to experience pleasure. However, it is important to recognize that correlation does not imply causation. While the observed relationship between improved emotional processing and reduced anhedonia is intriguing, it does not establish a direct causal link between the two. Other factors, such as changes in mood, cognition, or neural circuitry, could mediate the observed correlation. Furthermore, the interpretation of this correlation should consider potential confounding variables and alternative explanations. Further research is needed to elucidate the causal relationships and underlying mechanisms involved, as well as to explore the clinical implications of these findings for the treatment of depression and related mood disorders.

While our review provides a comprehensive synthesis of studies on the changes in cognitive function following psilocybin, it is crucial to acknowledge several limitations. The marked heterogeneity across selected studies, encompassing variations in participant characteristics, study designs, and cognitive assessment methodologies, presents a substantial challenge for direct comparisons and generalizability. Furthermore, limited sample sizes in certain studies may compromise statistical power and the reliability of findings. The diverse range of psilocybin doses, administration protocols, and concurrent psychotherapy further complicates result interpretation. Additionally, the predominant focus on acute effects in existing research leaves a gap, with relatively few longitudinal studies examining sustained cognitive function changes. The use of varied assessment tools across studies presents a challenge in establishing a standardized framework for comprehensive understanding of psilocybin's impact. Moreover, the review is constrained by the relatively small number of available studies. This, in conjunction with the diverse methodologies employed, underscores the need for caution in drawing definitive conclusions. The observed heterogeneity in participant demographics, study designs, and cognitive assessment tools precludes the feasibility of conducting a meta‐analysis to quantitatively synthesize findings, emphasizing the current limitations and the imperative for further research in this growing field.

In conclusion, our comprehensive review synthesizes existing studies on the cognitive effects of psilocybin, providing insights into its multifaceted impact across various domains. The gathered evidence indicates potential alterations in cognition. Psilocybin's interaction with 5‐HT receptors, neural connectivity changes, and the psychedelic experience are hypothesized mechanisms influencing cognition. However, limitations present challenges. The absence of a standardized framework underscores the nascent stage of research in this field. Future studies should focus on further investigating specific cognitive domains, such as sustained attention, working memory, and executive functions, to address the inconsistencies observed. Methodological improvements are larger sample sizes will enhance the reliability of findings, standardized cognitive assessments will ensure consistency, and longitudinal study designs will help track both acute and post‐acute effects. Additionally, exploring the effects of varying dosages, different contexts, and diverse population types, particularly in clinical settings, will provide a more comprehensive understanding of psilocybin's cognitive impacts.

Disclosure statement

V. B. is supported by an Academic Scholar Award from the University of Toronto Department of Psychiatry and has received research support from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ontario Ministry of Health Innovation Funds, Royal College of Physicians and Surgeons of Canada, Department of National Defense (Government of Canada), New Frontiers in Research Fund, Associated Medical Services Inc. Healthcare, American Foundation for Suicide Prevention, Roche Canada, Novartis, and Eisai. A. C. R. is Chief Innovation Officer at PurMinds NeuroPharma. R. J. is the CMO of Mydecine Innovation Group. D. E. is a paid advisor for Aya Biosciences, Lophora Aps, Clerkenwell Health, and Mindstate Design Lab.

Author contributions

V. B. conceptualized the article and contributed to the overall design. S. M. contributed to the concept, overall design, article selection, review, study quality appraisal, manuscript preparation and submission. T. J. T. G. contributed to article selection, study quality appraisal, and manuscript preparation. All authors contributed to review and editing. All authors have approved the final manuscript and note that this is our original work.

Supporting information