This randomised feasibility study (n=37) evaluates psilocybin-assisted (microdoses x 6) frontal-midline theta neurofeedback (NF) to improve executive functions (EFs) in participants with psychiatric disorders. Despite no significant improvements in tasks-based EFs, the experimental group reported medium to high gains in daily EFs, indicating the potential benefits of this neuromodulation technique for enhancing daily functioning.
Executive function deficits, common in psychiatric disorders, hinder daily activities and may be linked to diminished neural plasticity, affecting treatment and training responsiveness. In this pioneering study, we evaluated the feasibility and preliminary efficacy of psilocybin-assisted frontal-midline theta neurofeedback (NF), a neuromodulation technique leveraging neuroplasticity, to improve executive functions (EFs). Thirty-seven eligible participants were randomized into an experimental group (n = 18) and a passive control group (n = 19). The experimental group underwent three microdose sessions and then three psilocybin-assisted NF sessions, without requiring psychological support, demonstrating the approach’s feasibility. NF learning showed a statistical trend for increases in frontal-midline theta from session to session with a large effect size and non-significant but medium effect size dynamical changes within sessions. Placebo effects were consistent across groups, with no tasks-based EF improvements, but significant self-reported gains in daily EFs-working memory, shifting, monitoring and inhibition-showing medium and high effect sizes. The experimental group’s significant gains in their key training goals underscored the approach’s external relevance. A thorough study with regular sessions and an active control group is crucial to evaluate EFs improvement and their specificity in future. Psilocybin-enhanced NF could offer significant, lasting benefits across diagnoses, improving daily functioning.
Executive function (EF) deficits are a transdiagnostic problem across psychiatric disorders, impairing everyday functioning and limiting recovery and treatment efficacy. The fronto-cingulo-parietal network underpins EFs, with frontal-midline (fm) theta oscillations (a 4–8 Hz EEG rhythm) implicated as a marker and mediator of top‑down control; higher fm-theta power typically relates to better EF performance. Neurofeedback (NF) trains participants to self‑regulate specific neural signals such as fm-theta and has shown medium-sized effects on components of EF, notably working memory updating, but substantial inter-individual variability and a notable proportion of 'non-responders' limit clinical translation. Impaired neuroplasticity in psychiatric populations may underlie reduced NF responsiveness, and recent preclinical and clinical evidence suggests that serotonergic psychedelics, including psilocybin, act as potent psychoplastogens via 5‑HT2A and TrkB/BDNF-related signalling.
Papers cited by this study that are also in Blossom
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Kopra, E., Cleare, A. J., Rucker, J. et al. · Journal of Affective Disorders (2022)
Enriquez-Geppert and colleagues conducted a randomised semi-naturalistic-lab feasibility study. Thirty-seven participants were recruited from an online microdosing workshop and randomised (Matlab rand()) to an experimental group or a passive control group; the passive control group was blind to the NF component to reduce motivational differences. Exclusion criteria included personal or family history of psychotic disorders, normal/corrected vision, and three weeks' drug abstinence prior to baseline. Pre- and post-assessments were conducted online in small Zoom groups, and NF took place in a sound-attenuated EEG lab at the University of Groningen. The experimental protocol comprised a one-week microdosing adjustment phase (participants self-selected an optimal dose within 0.5–2.0 g range of fresh Psilocybe mexicana truffles across three exploratory days), followed by a second week containing three microdose sessions paired with three psilocybin-assisted fm-theta NF sessions (Monday, Wednesday, Friday). Participants were advised to take the chosen microdose about two hours before each NF session. The passive control group had a two-week break during this period; both groups completed identical pre/post online testing schedules. Primary outcomes included two sets: objective experimental EF tasks delivered online (working memory updating via the reference-back task, set-shifting via a switching task, conflict monitoring via a picture-word interference task, and motor inhibition via a stop-signal task) and self-reported everyday EFs using four BRIEF-A subscales (Working Memory, Shift, Task Monitor, Inhibit). Participants also listed personal training priorities and rated pre/post functioning and satisfaction. Placebo and expectation proxies were assessed with standardised questionnaires (optimism, suggestibility, microdose expectancy, and NF/psilocybin‑NF attitudes). EEG NF used a 15-electrode cap; online processing drew fm-theta power from five electrodes (Fz, FC1, FC2, FCz, Cz), computed in 2 s segments shifted every 200 ms. Each laboratory NF session lasted ~70 minutes including six 5-minute NF blocks separated by breaks, with 5-minute resting baselines at start and end; feedback was a colour-saturation square updated every 200 ms indicating relative fm-theta power. Statistical analyses included repeated-measures ANOVAs for NF learning indices (session-to-session and block-wise changes), two-way RM ANOVAs for task RTs and accuracy, and one-sided t-tests for BRIEF-A subscales given directional hypotheses. Data preparation excluded participants with overall/subtask accuracy <60% and outlier SSRTs, resulting in analytic Ns of 31 (reference-back), 35 (switching), and 33 (stop-signal) for the respective tasks. A significance threshold of p ≤ .05 was used; where assumptions were marginally violated, nonparametric checks were performed and parametric results reported when consistent.
Thirty-seven participants (mean age 24 years, SD = 4.3; 20 female, 16 male, 1 other) completed the study. Most were students; 33 were not on regular medication. Twenty participants reported previous psychedelic use. The experimental group took an average fresh-truffle microdose of 1.14 g (SD = 0.52), consuming it on average 2.2 hours (SD = 0.35) before NF sessions. Participants reported high motivation and commitment and rated NF strategy effectiveness and session difficulty at moderate levels. Neurofeedback outcomes used two learning indices. The session-to-session learning index (mean relative theta amplitude across the six blocks per session, analysed across SESSION 1–3) approached significance: RM ANOVA F(2,34) = 3.185, p = .054, partial eta squared η2p = .158, indicating a moderate effect size after only three sessions. Within-session block-wise changes (start baseline, NF blocks 1–6, end baseline) were not significant after Greenhouse–Geisser correction: F(2.457, 41.765) = 1.303, p = .285, η2p = .071. Placebo and expectancy measures (optimism, suggestibility, microdose expectancy, and NF/psilocybin‑NF attitudes) showed no significant differences between experimental and passive control groups, with medium expectations for microdosing and moderately high expectations for NF. Objective online EF tasks produced no notable group-by-condition effects. For example, the reference-back RT and accuracy, task-switching RT and accuracy, and stop-signal RT analyses all returned non-significant GROUP, CONDITION, and interaction effects (selected statistics: reference-back RT GROUP F(1,29) = 1.473, p = .235; reference-back ACC CONDITION F(1,29) = 5.551, p = .025 driven by non-switch > switch improvement but not interacting with GROUP). The picture-word conflict monitoring task was excluded due to low performance (12/37 below the 60% accuracy threshold). In contrast, self-reported everyday EFs on BRIEF-A showed significant, sizeable improvements in the experimental group versus the passive control group across all four targeted subscales: Working Memory t(35) = 2.69, p = 0.0054, Cohen's d = 0.885; Shifting t(35) = 2.08, p = 0.0226, d = 0.683; Monitoring t(35) = 2.63, p = 0.0063, d = 0.865; Inhibition t(35) = 2.63, p = 0.0067, d = 0.857. The experimental group shifted Working Memory scores from a pre-intervention deficit range into a range interpreted as normal functioning. Analyses of participant-defined priority areas found significant pre–post improvements in Cognition (t(16) = 3.895, p = .001, d = .876), Presence (t(17) = 3.566, p = .002, d = 1.052), and Mood (t(12) = 2.520, p = .027, d = .966). Connection did not show significant changes. Participants reported medium-to-good satisfaction with achieved outcomes in these areas.
Enriquez-Geppert and colleagues interpret their findings as a feasibility demonstration for combining repeated psilocybin microdosing with fm-theta neurofeedback to potentially enhance neuroplasticity and NF learning. They highlight a modest, near-significant session-to-session increase in fm-theta self-regulation after three psilocybin-assisted NF sessions, but no reliable within-session changes across NF blocks. The investigators suggest that psilocybin's acute effects—even at low doses—could influence within-session self-regulation and that future work should determine optimal timing to preserve neuroplasticity benefits while minimising disruptive acute effects. While no improvements were detected on objective laboratory EF tasks after this shortened three-session protocol, the experimental group reported large, significant improvements in everyday EF functioning across Working Memory, Shifting, Monitoring and Inhibition domains. The authors propose that subjective, ecologically valid gains may emerge earlier or be more sensitive to this combined intervention than standard computerised measures, and that a greater number of NF sessions (the typical protocols extend to seven or eight sessions) might be needed to transfer objective task performance. The discussion notes distinctive features of the microdosing procedure used here: participants self-titrated an individual ‘‘optimal’’ microdose during an adjustment week rather than applying a fixed dose. The authors argue this approach mirrors real-world practice and may reduce inter-subject variability arising from metabolic and receptor differences. They also emphasise the semi-naturalistic design as a strength for ecological validity. Key limitations acknowledged by the investigators are the reduced number of NF sessions and the absence of an active control group, which constrain causal attribution. Although explicit expectancy and placebo proxy measures did not differ between groups, the authors concede that implicit placebo effects cannot be fully excluded. They recommend future studies include an active control condition, larger samples, and systematic exploration of dosing, timing of drug administration relative to NF, and longer NF schedules. Overall, the authors conclude that psilocybin-assisted NF is practicable and shows promise as a transdisciplinary, potentially transdiagnostic approach to augment NF by leveraging transient increases in neuroplasticity. They call for replication and optimisation studies to establish efficacy, dosing/timing parameters, and the durability of effects.
Cognitive impairments is a transdiagnostic feature, common to all forms of psychopathology, which in particular affects executive functions (EFs). EFs orchestrate other cognitive abilities to facilitate goal-driven actions and adapt behaviour in novel demanding situations, thus EFs are pivotal for success in daily life. Executive dysfunctions, on the other hand, are associated with reduced autonomy, impeded functional recovery (e.g., and comprise the efficacy of both behavioural and pharmacological therapies across a spectrum of disorders. At the same time, global mental health problems are on the rise, causing premature death and significant costs for individuals, families, and society. This highlights the need for better, accessible, and scalable intervention and prevention programs, with an additional focus on enhancing executive functioning. Unfortunately, the treatments of these disorders target cognition with insufficient effects, leaving executive dysfunctions insufficiently addressed. EFs rely on the intact neural functioning of the frontocingulo-parietal networkwith frontal-midline (fm) theta described as the brain communication mechanism of this network. The midcingulate cortex (MCC) and the dorsolateral prefrontal cortex are suggested to be the main generators of fm-theta. An increase in fm-theta power is usually associated with improved cognitive processing and predicts successful performance in EFs. The absence of fm-theta upregulation is associated with reduced task performance in EFs. A neuroscientific method directly targeting cognitive processes by enabling participants to self-regulate the neural underpinnings is neurofeedback (NF). During NF, real-time measurements of target neural activity are collected, analysed, and provided as feedback to participants, allowing them to gradually acquire selfmodulation over specific brain functions (e.g.. Two critical aspects of NF hold potential for advancing treatment development. Firstly, NF builds on learning mechanisms, such as procedural conditions and skill acquisition are involved. Secondly, it promotes neuroplasticity through mechanisms like Hebbian mechanisms, homeostatic plasticity, and structural plasticity. This reflects the brain's capacity to adapt and reorganize itself in response to a changing environment, here also in the context of NF. Critically, fm-theta NF using EEG has shown effectiveness in enhancing EFs in healthy individuals, as demonstrated with lab-independent research by. Viviani and Velessi'ssystematic review underscored that NF protocols targeting fm-theta are the most successful EEG protocols thus far regarding the improvement of EFs. Additionally, metaanalytic work on the specific EFs component working memory updating confirms a medium-sized effect through fm-theta NF. However, NF encounters inherent challenges in training and treatment approaches. Notably, inter-individual variability in learning to self-regulate brain activity, along with the presence of 'non-responders', demands focused attention and solutions. Recent advancements in NF methodology encompass real-time brain activity decoding, personalized NF tailored to individual anatomical and functional networks, and innovative NF techniques involving semantically guidance through mental states (51). Regarding the application of fm-theta NF in (sub) clinical training, NF-specific improvements have been shown at sixmonths follow up. However, a greater percentage of nonresponders reported psychiatric disorders or suspicions. A recent mega-analysis on fm-theta NF also suggests that psychiatric disorders and EFs complaints may impede the ability to self-regulate fm-theta. Additionally, recent advances indicate that impaired neuroplasticity plays a pivotal role in neuropsychiatric disorders (e.g. 54; 55; 56) which might also negatively influence training and treatment outcomes. Interestingly, psychedelics like psilocybin and LSD have shown rapid and long-lasting clinical benefits even after only a few doses, notably in conditions such as treatment resistant depression. The crucial effect of psychedelics on neuroplasticity involves both inter-and intracellular (62) activation of the 5HT2a receptor, initiating a signalling cascade that drive neuroplastic changes. Moreover, psychedelics exhibit a strong affinity for binding directly to the brain-derived neurotrophic factor (BDNF) receptor TrkB, making them potent psychoplastogens that create a critical period for activity-dependent effects. One challenge in the widespread clinical use of psychedelics is their potent hallucinogenic properties, which requires close monitoring during extended sessions in controlled environments. However, recent reports suggest that repeated microdosing of psychedelics (i.e. taking a sub-threshold amount, typically 1/10th to 1/20th of a therapeutic dose around 3-4 times per week), yields similar biomarkers of neuronal plasticity. Consequently, microdosing holds potential for complementing NF training by enhancing activitydependent alterations of neural networks of a neuromodulator. To fully optimise the capacity of cognitive improvement and sustainability of its effects in daily life through fm-theta NF, we propose a synergistic approach by integrating this NF protocol with a potent neuroplasticity enhancer. In this feasibility study, we employed a brief three-session combining psilocybin with fm-theta NF following an adaptation microdosing week. This approach aims to assess the practicality and initial efficacy of this psychedelic-assisted NF training. Our study design adopts a semi-naturalistic lab setting, incorporating experimental assessments of EFs, self-reported EFs evaluations in participant's daily lives, and considerations of their training priorities, all contributing to enhancing ecological validity of NF training.
Participants were recruited from an online microdosing workshop of the Dutch Microdosing Institute, where the study was introduced as a general assessment of microdosing's impact on cognition. Informed consent was obtained and participants were screened prior to participation to ensure that they met the following exclusion criteria: (1) no history of psychotic disorders (including family), (2) normal or corrected vision, (3) three weeks of drug abstinence prior to the first measurement. Participants were randomly allocated (using the rand. Matlab function) to either the experimental or passive control group. To minimise motivational differences, the passive control group was blind to the inclusion of NF from the experimental group. Participation in this study was voluntary, and no rewards were given. The study was approved by the Ethical Committee Psychology of the University of Groningen and was conducted in accordance with the Declaration of Helsinki.
Data collection for both the pre and post assessment occurred online, enabling participants to be tested within their home environments. Fm-theta NF was performed with three sessions in a sound-attenuated EEG lab at the Heymans Institute at the University of Groningen, Netherlands. Both groups followed an identical three-week schedule for pre-and post measurements. In the initial week, pre measurements were taken, and the experimental group began the adjustment week. During the second week, the experimental group engaged in three NF sessions alongside their microdosing regime. These psilocybin-assisted NF sessions took place on Mondays, Wednesdays, and Fridays,adhering to a schedule of alternating dosing days. While the experimental group underwent the microdose adjustment and the psilocybin-assisted NF week, the passive control group had a two-week break. In the third week, both groups participated in the post assessments. Following this, the experimental group completed their study participation, whereas the passive control group commenced microdose. They began with the adjustment week and preceded by a week on a stable dose. This phase concluded with a final assessment, no longer falling within the study's scope (see Figure). (ii) Online pre -post assessments Measurements (pre-, post) were performed online via Zoom in small groups with a maximum of three participants. After a common introduction, the measures were conducted in individual break-out rooms and monitored by one or two experimenters. The measurements had a uniform structure and lasted about 180 min, consisting of demographic questionnaires and cognitive assessment. Three domains were assessed: (1) general placebo and expectancy (by general susceptibility and optimism, as well NF and psilocybin-assisted NF specific experiences, attitudes and expectations), (2) EFs (by self-rated EFs in daily life and four computerised experimental EFs tasks), (3) functional abilities (by participant's priorities). The questionnaires were implemented through Qualtrics software (). The EFs tasks were programmed with OpenSesame software (v. 3.3.10), performed using the cross-platform graphical experiment builderand hosted on MindProbe JATOS 3.7.2 server.
The Revised Life Orientation Task was used to assess dispositional optimism. This questionnaire consists of ten questions that relate to the general outlook on life. Participants rated them on a fivepoint Likert scale ranging from "strongly disagree" to "strongly agree". The Short Suggestibility Survey, a shortened version of the Multidimensional Iowa Suggestibility Scale, was used to assess trait susceptibility. Questions assess susceptibility to suggestion in daily life, by determining the inclination to follow trends or others' opinions and arguments. This scale consists of 21 questions, and was collected on a 100 point scale. Psilocybin microdose expectancy was assessed using the adapted scale. Participants rate their confidence in microdosing and its alignment in their daily routine. This questionnaire consists of four items, each scored on a 100 point scale. The Experiences, Attitudes, and Expectations regarding Neurofeedback Questionnaire (75) consists of six questions regarding their confidence and trust in NF in general, and with psilocybin-assisted NF specifically, each scored on a 100 point scale.
Four EFs tasks gauged core functions: working memory updating, set shifting, conflict monitoring and motor inhibition. Tasks shared stimuli (animal pictures, animal words or letters) and trial structure, and involved fast and accurate categorisation of animal pictures or words/letter stringsinto two categories (land or sea animals, or letter case). Word/letter strings were centrally presented above animal pictures, and enclosed by a colour frame. We used blue and orange coloured frames for conflict monitoring, task switching and memory updating tasks, and green and purple coloured frames for inhibition tasks (each colour was prepared in 10 different shades from which was randomly selected in each trial). The coloured frames indicated whether pictures or words/strings should be categorised, the colour was counterbalanced across participants. Each trial began with a 300-600 ms fixation-cross, followed by a stimulus presentation up to 2000-2300 ms during which participants could respond. This followed by the presentation of the fixationcross presentation up to 2600 ms. Responses involved pressing the keyboard letters with index fingers ('X' for the left hand and 'M' for the right hand). Each task began with the instructions and practice trials, giving the participant the opportunity to practise the task again. Tasks included four blocks, separated by short breaks, except the stop-signal task which comprised eight blocks (see 77). The reference-back task (76) was used to measure working memory updating. The task consisted of sequences of a reference and comparison trials. On the comparison trials, it had to be decided whether the animal category corresponds to the category of the last reference. Reference trials could change or remain the same (update vs no-update) and were followed by a max of five comparison trials. Reference trials, comprising a 1:3 ratio to comparison trials, were marked by a distinct colour frame from comparison trials. The reference category of land and sea animals was presented randomly and equally often. There were 240 trials. Set-shifting was measured with a switching task. Animal pictures were categorized as usual, however instead of the words, this task presented letter strings on the animal pictures that had to be categorised into upper and lower case. Participants' current categorization task was indicated by the colour frame and could change or stay (switch vs stay). There were 172 trials, the first 32 trials served as baseline trials without changing the categorization. In the remaining 140 trials, switching between task categorization occurred with a 4:6 ratio. A picture-word interference task was used to measure conflict monitoring. Here animal pictures and words were either the same, e.g. a picture of a whale on which the word "whale" was presented or could be different, e.g. a picture of a whale on which the word 'rabbit' was shown (conflict vs no conflict). An equal number of congruent and incongruent trials was presented, with a total of 140 trials. Coloured frames indicated the categorization task. A stop signal task (78) was used to assess motor inhibition. While mostly categorising animal pictures, participants had to stop when the stop-signal was presented. A stop-signal was indicated by a colour frame change and presented with a stopsignal delay (SSD) after the stimuli onset in stop trials (e.g. 78; 79). The SSD, set at 250 ms, was dynamically adjusted based on participants' performance success of stopping in 50% of the stop trials. After each correct stop trial, 50 ms were added; after an incorrect stop 50ms were subtracted. If a threshold of 90 ms or 910 ms was exceeded, SSD was reset to 250ms. This task consisted of 400 trials in which 25% were stop trials. In the trial sequence no two stop trials could be presented after each other.
The Behavior Rating Inventory of Executive Function -Adult Version (BRIEF-A; (80)), was used to assess EFs in everyday life. Participants self-assess their EF capabilities across a range of behaviours (e.g., "I have difficulty moving from one task to another") via a three-point scale ("never", "sometimes", "often"). BRIEF-A consists of nine subscales, for this study we focused on four: Working Memory, Shift, Task Monitor, and Inhibit. These subscales correspond directly to the four objective EFs tasks. Measures of functional ability in everyday life using participants' priorities Participants were first asked to express their individual training goals, by using open-endedquestions, with the option to specify up to four priorities. They then rated their current functioning on a scale from 1-100 (pre-functioning), and the expected level of functioning they aimed to achieve post psilocybin-assisted NF (expected functioning). Following the intervention, participants were then asked to reevaluate their functioning (post-functioning) and indicate their satisfaction with the extent to which they had attained their expected outcomes (satisfaction). Participant goals were grouped qualitatively based on broad descriptives. Cognition (n = 17) describes goals that were focused on regulating mental processes. Presence (n = 18) refers to goals centred around mindfulness and bodily awareness. Mood (n = 13) refers to goals that target up regulation of well being or removal of anxiety. Connection (n = 5) refers to goals revolving around increased sociability. Other (n = 9) categories goals that do not fit the aforementioned descriptives. (iii) EEG recordings and pre-processing EEG measurements were conducted by trained research assistants. The EEG was recorded using a 15 Ag/AgCl electrodes Waveguard connect cap, an average reference Twente Medical Systems International B.V. (TMSI) REFA amplifier, and Openvibe recording software. Electrode placement followed the international 10-20 system. Electrode impedances were regularly checked to ensure they were below 10 k. The amplifier provided 24-bit resolution EEG data at a sampling rate of 256 Hz.
Substance description: Psilocybin Participants used 12 g of fresh Psilocybe mexicana truffles, portioned in 1 g vacuum packs. These were obtained via microdose.nl, the partner-shop of the Dutch Microdosing Institute. Participants received a study participation discount code from the Dutch Microdosing Institute that covered the truffles costs if redeemed.
In the adjustment phase of the first week, participants sought their optimal psilocybin dose, exploring on Tuesday, Thursday and Saturday with one varied dose until satisfied with their chosen amount. The Microdosing Institute advised a dosage range of 0.5 g to 2 g.
Three 30 min NF sessions were performed for upregulation of fm-theta. The experimental group was advised to take their psilocybin dose two hours before the NF appointment, which was scheduled in the morning. This time corresponds with the time of the so-called peak, where both psilocybin blood concentration as well as intensity of acute effects reach their peak (e.g.. A NF session began with EOG calibration, which involves calculating the subject-specific artifact-associated frequency band. Each of NF sessions comprised six five-minute blocks of NF, separated by self-paced breaks. Before and after the NF blocks, a fivemin resting-state measure was taken (start/end baseline). Participants rested with open eyes, avoiding cognitive activity. During NF blocks, they aimed to upregulate their fm-theta power via feedback (see. Participants were provided a NF logbook, which included a list of strategies and short questionnaires for each block and session. The five steps of the real-time processing pipeline are described below. First, data acquisition was based on five electrodes covering the fm-brain region (Fz, FC1, FC2, FCz, Cz), the nose served as reference, and Fp1 and Fp2 to monitor ocular activity. Second, online data processing was based on the computation of frequency spectra through fast Fourier transformation and a Hamming window for data segments of 2 sec, shifting every 200ms. Data underwent online detrending and rectification. The subject-specific artefactassociated frequency band was monitored for eye blink detection and rejection (see 86). Third, for feature generation and selection, the raw power value of each 2 sec segment in the fm-theta frequency range (4-8Hz) was compared to the corresponding start baseline power. Fourth, real-time feedback was conveyed through a coloured square on the computer screen that exhibited a colour gradient from highly saturated red to grey to highly saturated blue (with 21 colour gradations). The colour saturation was updated every 200 ms. Red indicated an fm-theta power increase, blue a decrease, and grey either an eye blink or no power change relative to the start-baseline of the specific NF session. The feedback saturation scale covered 95% of the amplitude range, with values above 97.5% or below 2.5% indicated by maximum red or blue saturation. Fifth, participants were instructed to colour the square as red and as often as possible. They were provided a list of strategies from NF literature and motivated to find their own strategies and use their most effective one. For NF, the software NF Suite 2.0 (87) was used. In all, the NF session took roughly 70 minutes. Neurofeedback training -Self-reports effectiveness of used neurofeedback strategies To assess the subjective efficacy of applied NF strategies, participants briefly explained the strategy employed and rated its effectiveness on a seven-point Likert scale in their NF logbook after each NF block. Low scores indicate more efficient EFs in everyday life, while higher scores indicate difficulties.
Participants self-reported their motivation for participating in the study, their level of commitment to the study, and their perception of difficulty, using a seven-point Likert scale in their NF logbook.
Initially, the NF output was normalized to the overall power (1 -40 Hz) into the following frequency bands: theta (ITP ± 1), delta (ITP 3.5-1.5 Hz), alpha (ITP + 3-5 Hz), and beta (ITP + 7-24 Hz). Two learning indices were employed to assess the impact of fm-theta NF training on theta upregulation. Upregulation of fm-theta was assessed by determining the increase in fm-theta amplitude of a particular block to the session's start baseline.The first learning index reflects fm-theta across the training (i.e. changes between sessions). Mean relative theta amplitude across all six NF blocks was calculated for each session, and subsequently the training effects were analysed using repeated measures (RM) ANOVA with SESSION (1-3) as the within-subject factor. The second learning index, represents the dynamical changes across the blocks (i.e. within sessions). The average relative theta amplitude was computed for the blocks in each session. Effects were analyzed using RM ANOVA with within-subject factor BLOCK (start baseline, NF blocks 1 -6, and end baseline). (ii) Experimental and self-rated executive functions Online experimental executive function tasks For each task, difference values were calculated for RTs (RTs pre -RTs post) and accuracy (accuracy post -accuracy pre), respectively, reflecting positive changes for positive values. For each task a twoway repeated measures ANOVA was calculated for RTs and accuracy as dependent variables with GROUP (experimental, passive control) as between subject factor and CONDITION (reference back task: updating, no-updating; task switching: switch, no-switch, picture-word interference task: conflict, no conflict) as within subject factor. For the stop-signal task, only RTs were considered, since accuracy is dynamically adjusted to 50% during task performance. Assumptions of normality and homogeneity of variance were tested. In case of violation, nonparametric/robust tests were performed using Wilcox's paired and non-paired tests, robust ANOVA based on (89)).
A difference score (prepost) was calculated for the four subscales: Working Memory, Shift, Task Monitor, and Inhibit. To assess the difference between GROUPS (experimental, passive control). Based on the hypothesis of improved self-reports for the experimental group, one-sided t-tests for independent samples was calculated for each subscale, and assumptions of homogeneity, and normality tested. Participant training priorities Functionality differences in the different priority areas that participants reported as their individual training goals were assessed using a series of pairedsamples t-tests.Assumptions of normality were assessed using a Shapiro-Wilk test.
Participants whose overall and subtasks' accuracies were below 60% were excluded. The conflict monitoring task exhibited significantly poorer performance, with 12 out of 37 participants scoring below the threshold. Consequently, we opted to exclude the task from the analysis. The poor performance in this task could be attributed to its placement as an initial task in the online assessment, with participants being less familiar with the environment and the novel tasks. In the Inhibition task we excluded participants whose overall SSRT was outside the range ± 2.5 standard deviations from the mean and whose overall accuracy was below 60%. After accuracy checking, 31, 35 and 33 out of 37 participants were included in the analysis of the reference back, switching, and stop-signal task, respectively. For statistical tests, a p-value of ≤ .05 was used to determine significant differences. In some analysis, assumptions were slightly violated. Since the effects remained significant in the nonparametric test, we report the results of the parametric tests. Effect size for RM ANOVA was indicated by partial eta squared (η 2 p) and interpreted as small (< .06), medium (≥ .06), or large (≥ .14). Statistical analyses were performed using software R (version 4.1.0).
(a) Participant characteristics 37 participants took part in this study (20 female, 16 male, 1 other) with a mean age of 24 yrs (SD = 4.3). Of these, 31 were right-handed (5 left-handed, 1 ambidexter). Most were students (28 students, 5 employed, 3 unemployed, 1 other), with 21 completing a secondary school and 16 a university degree. Most spoke German (n = 12), followed by Dutch (n = 6), and the remainder spoke other languages as their mother tongue. Most participants were not taking regular medication (n = 33). Two participants reported taking either antihistamine and vitamin B12 & D. The majority (n = 28) had no psychiatric disorders beyond those in the exclusion criteria, nine indicated comorbidities, and two reported medication for related conditions (citalopram or methylphenidate and escitalopram). Half of the participants (18 out of 37) reported regular drug use, and half of this subgroup used multiple drugs (10 of 18). Among those using regular drugs, most exclusively consumed cannabis (n = 8). Additionally, the majority of the participants mentioned previous psychedelic use (n =20), ranging from five to 20 times. In this subgroup, the last time of use was more than half a year ago (n = 11), followed by more than three weeks within the last month (n = 10).
Participants took on average a microdose of 1.14 g (SD = 0.52) of Psilocybin Mexicana truffles which they consumed an average 2.2 hours (SD = 0.35) before visiting the lab. The night before the NF sessions, they slept an average of seven hours (SD = 0.68), drank before coming to the labs an average of 0.64 cups of coffee or tea (SD = 0.43), and felt relatively fit (mean = 5, SD = 1.1) on a scale from 0-7. In general, they reported being highly motivated (mean = 6, SD = .03), feeling very connected (mean = 5.7, SD = 0.66) and very committed (mean = 6,SD = 0.88) to the study, on a scale from 0-7. The NF sessions were perceived as moderately difficult (mean = 4.2, SD = 1.24). Participants rated their strategies for increasing fm-theta as moderately good (mean = 4.2, SD = 1) on a scale from 0-7.
The RM ANOVA of the first learning index (averaged change per session relative to the start baseline) approached significance, F(2, 34) = 3.185, p = .054, with η 2 p = .158, already after only three NF sessions, and suggesting a moderate effect size. The RM ANOVA of the second learning index (relative to baseline, averaged change per block) indicated (after applying Greenhouse-Geisser correction) no significant differences within the sessions, F(2.457, 41.765) = 1.303, p = .285, η 2 p = .071. (see Figure).
The results of the two placebo effect assessment questionnaires revealed no significant differences between the experimental and passive control groups. Additionally, expectation related to microdosing, NF, and psilocybin-assisted NF did not exhibit any significant differences between both groups. Notably, participant expectations for microdosing, were medium, slightly higher for psilocybin-assisted NF, and moderately high for NF alone (see Table
Main effects GROUP, CONDITION and their interaction of the RM ANOVAs assessing pre-post difference of RTs and ACC of the objective EFs tasks were not significant, except for two however these were not specific for a group and for the EFs condition A summary of the statistical results per task is given in the following. (Reference-back task RT: GROUP F(1,29) = 1.473, p = 0.235, η 2 p = 0.05), CONDITION (F(1,29) = 1.060, p = 0.312, η 2 p = 0.04), GROUP x CONDITION (F(1,29) = 1.707, p = 0.202, η 2 p = 0.06)). (Reference-back task ACC: GROUP (F(1,29) = 1.204, p = 0.282, η 2 p = 0.04) was not significant. The main effect of CONDITION was significant (F(1,29) = 5.551, p = 0.025, η 2 p = 0.16)), having no switch CONDITION bigger improvement than switch CONDITION (M = 0.021, SE = 0.0089, t(29) = 2.356, p(adj. holm) = 0.025). The interaction was not significant (F(1,29) = 0.718, p = 0.404, η 2 p = 0.02). (Task-switching RT: GROUP (F(1,33) = 1.098, p = 0.302, η 2 p = 0.03), CONDITION (F(1,33) = 0.045, p = 0.833, η 2 p = 0.001)), GROUP x CONDITION (F(1,33) = 1.791, p = 0.190, η 2 p = 0.05)). (Task-switching ACC: GROUP(F(1,33) = 1.676, p = 0.205, η 2 p = 0.05), CONDITION (F(1,33) = 1.595, p = 0.215, η 2 p = 0.05), GROUP x CONDITION (F(1,33) = 0.430, p = 0.517, η 2 p = 0.01). (Stop-Signal task: GROUP (F(1,31) = 0.159, p = 0.693, η 2 p = 0.005), CONDITION (F(1,31)
Raw scores of the scales Shifting, Monitoring and Inhibit were in the normal functioning rate. Before psilocybin-assisted NF, both groups exhibited an excess of the threshold for self-rated Working Memory in daily life, indicating cognitive deficits in this domain. Self-reports of EFs in daily life showed significantly greater improvements in the experimental group after participating in psilocybin-assisted NF compared to the passive control group in all four subscales (Working Memory: t(35) = 2.69, p = 0.0054, d = 0.885; Shifting: t(35) = 2.08, p = 0.0226, d = 0.683, Monitoring: t(35) = 2.63, p = 0.0063, d = 0.865, Inhibition: t(35) = 2.63, p = 0.0067, d = 0.857). These changes reflected more efficient EFs experienced in daily activities with high effect sizes. In terms of Working Memory, the experimental group receiving psilocybin-assisted NF showed an improvement in their scores and reached a range indicating normalized functioning after training, while the passive control group continued to show deficits (see Figure). (iii) Measures of functional ability in everyday life using participants' priorities Before engaging in psilocybin-assisted NF, the experimental group rated their functioning within a moderate range, with mean scores around 50 on a 0 -100 scale. They expected slightly improved functioning, with expected scores ranging between 62 and 73 after training. The following findings were yielded, which include also the achieved scores (see Figurebelow). Significant differences were observed for Cognition, Presence and Mood when comparing functioning ratings before and after undergoing psilocybin-assisted NF. These differences mean notable improvements in these three areas (pre vs post functioning Cognition t(16)= 3.895, p=.001, d =.876; pre vs post functioning Presence t(17)=3.566, p=.002, d = 1.052; pre vs post functioning Mood t(12)=2.520, p=.027, d =.966). Their satisfaction with these results can be regarded as a medium for Cognition and Mood, regarding Presence as good. However, considering Connection there was no significant difference between functioning before and after psilocybinassisted NF pre vs post functioning t(4)=0.634, p=.560, d =.479). Still connection illustrated a nonsignificant difference between expected and post functioning (t(4)=0.562, p=.604, d=.417).
EFs deficits are pervasive across psychiatric disorders and significantly worsen daily functioning. Particularly in this group, responsiveness to fm-theta NF seems reducedand a potential reason might be impaired neural plasticity (54). Together, this hinders the effectiveness of NF-based interventions and limits their applicability as transdiagnostic treatment. This study provides a groundbreaking pharmacological approach in the field of NF by integrating the potential neuroplastic agent psilocybin into NF paradigms, and demonstrates the feasibility and practicality. After three sessions of psilocybin-assisted NF, participants showed a promising trend in improving self-regulation of fmtheta. When comparing the experimental and passive control groups, no notable improvements were observed in objective EFs tasks following the shorter version of psilocybin-assisted NF. Nonetheless, significant differences between the two groups emerged when evaluating self-rated EFs in daily life. The experimental group that underwent psilocybin-assisted NF exhibited significant improvements in all four EFs domains, accompanied by substantial effect sizes when compared to the passive control group. Additionally, participants in the experimental group indicated treatment priorities across five domains: Cognition, Presence, Mood, Connection, and Other. Importantly, the majority of these training goals showed significant functionality improvements w following psilocybinassisted NF. In the subsequent discussion, we will elaborate five key aspects: the rationale behind our approach for optimization of NF outcomes, the primary study results of the intervention, special features of the microdosing protocol, study limitations, and the implications and conclusions drawn from the psilocybin-assisted NF study. (a) Optimising neurofeedback by improving the overall brain state and readiness for learning NF shows potential for clinical applications, with ongoing advancements in methodology for precise brain activity identification and extraction. Additionally, human-computer/human-factor approaches consider taskspecific factors, cognitive/motivational traits, and technology acceptance for NF optimisation. Complementary to these efforts, our study focuses moreover on enhancing overall brain state and its readiness for learning, aiming to boost neuroplasticity to amplify NF's impact: the current approach therefore combines fm-theta NF with psilocybin. While previous research on psychedelics has largely focused on high-dose studies, including those that highlight acute neuroplasticity (as reviewed by 64), as well as sustained neuroplastic effects specifically of psilocybin (91; 92), recent preclinical evidence is also revealing neuroplasticity changes resulting from repeated microdoses of psilocybinand LSD in humans. As we delve deeper into understanding the complex mechanisms of neuroplasticity and the varied effects of psychedelics, the next logical step emerges: skillfully utilizing these insights to improve therapeutic interventions. Our study is the first to integrate repeated microdosing with NF, a dosage regime that enhances clinical feasibility by minimising psychoactive effects, functional impairment, and the demand for extensive healthcare support, which is optimal for NF.
The fm-theta self-regulation results revealed variations in the two learning indicators, providing insights on this specific psilocybin-assisted NF protocol. The learning curve across sessions mirrors existing literature, with an initial increase from the first NF session to the second, a plateau, and subsequent fm-theta amplitude growth in subsequent sessions. However, our findings differ slightly regarding the second learning index indicating within session learning, which here suggests potential substance effects within a session. This raises the question of the optimal time for integration. Combining interventions that include pharmacological aspects, can introduce disruptive effects that may interfere with the treatment. In the context of psilocybin-assisted NF, this implies that psilocybin's effects could impact the self-regulation of brain activity, also at very low dosages. Future research should pinpoint the optimal timing for minimising potential adverse substance effects on brain activity while preserving the essential neuroplasticity window. The current study took a comprehensive approach, encompassing both experimental EF tasks and participants' self-assessment of their daily life EFs. This dual approach enhances our understanding of cognitive performance in more ideal conditions and its practical application in everyday life. Regarding the transfer of psilocybin-assisted NF to EFs, we found notable effects on self-reported daily life EFs with a high effect size. However, there were no discernible effects observed in experimental objective tasks. This might suggest that just three sessions may enhance existing daily life EF capacities without immediate improvements in objective task performance. These may manifest later with the typical duration of fm-theta NF. However, this interpretation should be treated with caution, as an active control group and a larger number of sessions would be required. The reduced number of fm-theta NF sessions to three sessions in this feasibility study makes it challenging to specify the improvement compared to the standard training duration of sevenor eight sessions. Furthermore, the incorporation of participant priorities is deemed essential in the development of effective treatments. Participant priorities identified in our study encompassed various goals, including cognition, and the results indicate significant effects in this regard. This means that participants perceive favourable effects in their priority areas when undergoing psilocybin-assisted NF, underscoring the importance of considering these outcomes for the future acceptance and feasibility of the training in real-world applications. Additionally, this approach supports ecological validity and facilitates the assessment of benefits into real-life scenarios.
In this study, we aimed to create a practical environment that combines elements of both controlled laboratory conditions and the complex realities of everyday life. To ensure a subjective effect based approach we use a unique dosing strategy where participants are encouraged to find their own optimal dose during an adjustment week based on their experiences, following standardized instructions. We observed a stable dose-range between 0.3g and 2.0g of fresh truffles after the adjustment week. This deviates from the "one size fits all" approach seen in other studies on psilocybin microdosing. Given the high variability of subjective effects given a fixed dose (e.g. 100), which appears to stem from variable genetic factors influencing the metabolism of psychedelics (e.g. functionality of liver enzymes, (101; 102)) and 5HT2a receptor functionality (103), this subjective dose finding method provides an advantage. It helps create a consistent experience for participants by circumventing these differences in drug sensitivity and metabolism rates, potentially reducing variability of the drug effect. Additionally this methodology closely reflects real world practices outside of trials where individuals often adjust their doses to maximize benefits while minimizing potential negative effects (104; 105).
This feasibility study has two main limitations: the aforementioned reduced number of sessions, and the absence of an active control group raises questions about the specific nature of proposed improvements. Despite implying a passive control group, we evaluated both placebo and expectation effects. The results did not differ between the experimental and control groups, indicating that the improvement in self-reports of experienced EFs in daily life might probably be less due to explicit effects. Nevertheless, implicit placebo effects may play a role (106).
Our study pioneers the feasibility and practicality of psilocybin-assisted NF. This approach offers a unique perspective to psychiatric disorders by targeting crucial transdiagnostic cognitive factors, such as EFs, and employing a transdisciplinary approach that integrates neuropharmacology, cognitive neurosciences and psychology. The potential of psilocybin-assisted NF lies in the potential to achieve an increased state of neuroplasticity for a critical period of time, during which NF can be introduced. If confirmed by future replications, this will ultimately lead to improved and sustained outcomes.
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