Table 2.

Summary of Studies Included for the Systematic Review

Psychedelic	Author/s	Study Design	Sample Characteristics	Outcome Measures	Neuroimaging Technology	Outcome Measures (Results)	Brain Modulation	Limitations/risk of bias
Psilocybin (2 mg in 10-mL saline, applied IV)	(Carhart-Harris et al., 2012)	Open-label, within-subjects, Placebo-controlled.	N=15 healthy participants (2 females) were experienced psychedelic drug users Mean age = 32	Intensity of subjective effects which was measured in a visual analogue scale (VAS) format.	3T fMRI (BOLD, ASL, rsfMRI)	All 10 VAS items were scored significantly higher than placebo, suggesting psilocybin had a clear hallucinogenic effect.	DMN modulation Decreased CBF and BOLD response in the ACC, PCC, precuneus, bilateral angular cortex and mPFC. Additional Modulation Decreased BOLD and blood flow in the putamen, subthalamic nuclei and visual cortex. Supporting Model REBUS	Participants had a history of hallucinogenic drug use, which may confound expectations for the placebo condition and the amount (and type of hallucinogen) used previously may vary considerably between individuals affecting reliability and reproducibility. Additionally, there was also a relatively small sample size.
Psilocybin (2 mg in 10-mL saline, applied IV)	(Carhart-Harris et al., 2014)	Open-label, within-subjects, Placebo-controlled.	N=15 healthy participants (2 females) were experienced psychedelic drug users Mean age = 32	NA	3T fMRI (BOLD, ASL, rsfMRI)	NA	DMN modulation There was significantly greater mean variance of synchrony (a measure of ‘chaos’ or uncertainty) in the DMN in the psilocybin group compared to controls. Using a single patient administered with psilocybin, probability distributions showed that the predictability of the network synchrony was more difficult compared to a placebo control. Additional modulation Similarly, to the DMN, increased variance in synchrony was found in the salience and frontoparietal networks. Supporting Model REBUS	As the probability distribution was only assessed in one control and treated individual, these findings must be interpreted as exploratory and would need subsequent replication.
Psilocybin (10 mg followed by 25 mg, one-week apart)	(Carhart-Harris et al., 2017)	Open-label, within-subjects clinical trial	N = 16 particpants (4 females) diagnosed with treatment resistant depression. Mean age = 43	The Primary Clinical outcome was the 6-item QIDS-SR16	3T fMRI (BOLD, rsfMRI & ASL)	All but one patient showed some decrease in QIDS-SR16 score at week 5 (with one showing no change) and 47% met criteria for a response.	DMN modulation Increased DMN integrity one-day post-treatment via both seed and network methodology. However, patients who scored highest on ‘peak’ or ‘mystical’ experiences had the greatest decreases in RSFC in DMN regions such as the PCC. Additional modulation Increased vmPFC RSFC with the inferior-lateral parietal cortex (iLPC) post treatment and decreased PH RSFC. Decreased CBF in the left amygdala, Heschl’s gyrus, left planum temporal, and left superior temporal gyrus. Supporting Model REBUS	Absence of a placebo-control condition. Correction for multiple testing was not applied to the specific ROI analyses, which can produce a false-positive (type 1 error) result. Additionally, there was also a relatively small sample size.
Psilocybin (0.2-0.3 mg/kg, p.o)	(Madsen et al., 2021)	Single blinded repeated measures design.	N = 15 healthy individuals with no psychedelic use within a year of the study. Mean age = 34	11D-ASC, MEQ and EDI	3T fMRI (rsfMRI)	There was a moderate to strong positive correlation (R = 0.57 – 0.6) between subjective drug effects and ASC, MEQ and EDI scores. There was a strong correlation between plasma psilocin levels and subjective drug effects (R2 = 0.73)	DMN modulation Increased blood psilocin levels were significantly associated with reduced RSFC within the DMN (specifically mPFC, PCC and precuneus) and there was a significant association between increased blood psilocin concentrations and increased between-network average RSFC. Additional modulation Local correlation analysis found that blood psilocin levels was significantly negatively correlated with brain regions involved in the executive control network such as the visual cortex, bilateral temporal regions, and the bilateral anterior PFC. Supporting Model REBUS	Participants were prepared for a potential strong psychoactive experience by medical professionals which may have produced an expectancy effect and increased the subjective drug effects. Furthermore, a placebo control was not used and the sample size is relatively low, which was partially remedied through a repeated measures design (which increases power).
Psilocybin (0.2-0.3mg/kg, p.o)	(McCulloch et al., 2022)	Open-label, within-subjects longitudinal design (mean = 98 days between psilocybin sessions and follow up questionnaires).	N = 10 healthy participants (6 male)	NEO PI-R, MAAS, 11D-ASC, EDI and PEQ.	3T fMRI (rsfMRI) measurments at baseline, 1 week and 3-month time points. PET ([11C]Cimbi-36) was used at baseline and 1 week time points.	Participants reported increases in trait openness, mindfulness and increased positive attributes in the PEQ.	DMN modulation Psilocybin did not significantly modulate within DMN FC or the FC between the DMN and other networks and a small effect size was observed (d ≈0.20). Additional modulation Psilocybin statistically decreased the ECN FC at 1 week but not 3 months post administration. Additionally, a moderate-strong negative correlation was found between ECN FC at 1 week and MAAS scores at 3 months. Supporting model None	The primary limitation of this study was a small sample size, although authors did report effect sizes. Furthermore, the trial was unblinded (open label) and without a control group.
Psilocybin (315 μg/kg, p.o.)	(Smigielski et al., 2019)	Randomized, double-blind, placebo-controlled	N = 38 (23 males) healthy long-term meditators. Mean age = 52	5D-ASC scale was administered to assess acute psychedelic effects. Furthermore, PEQ was administered 4 months after the intervention.	3T fMRI (BOLD & rsfMRI)	Psilocybin significantly increased specific dimensions of the 5D-ASC such as Oceanic Self-Boundlessness, Visionary Restructuralization and Vigilance Reduction. After 4 months the psilocybin group scored significantly higher on the PEQ than the placebo control group.	DMN Modulation Significantly increased positive states of ego dissolution (i.e Oceanic self-boundlessness), was associated with the decoupling of FC between the anterior (mPFC) and posterior DMN (PCC) during open awareness meditation for the psilocybin group compared to the placebo condition. Supporting Model REBUS	Participants were experienced meditators meaning they may respond uniquely to psychotropic medication, limiting generalisability. Furthermore, the study was conducted in a mindfulness retreat, which may have further bolstered the positive psychological effects which may differ from a traditional lab-based setting.
Psilocybin (25 mg/70kg, p.o.)	(Barrett et al., 2020a)	Open-label, within-subjects longitudinal pilot study.	N = 12 (5 male) healthy volunteers who had limited previous use of psychedelics (median = 1). Mean age = 32	Various questionaries were administered one day before, one week after and one month after the psilocybin intervention. These questioners include: PANAS-X, POMS, The Dispositional Positive Emotions Scale (DPES) and the Depression Anxiety Stress Scale (DASS) Finally, participants’ personality traits were measured via The Big Five inventory (BFI)	3T fMRI (rsfMRI & BOLD)	There were significant subacute changes (1 week post treatment) on DASS stress scores, PANAS negative affect, depression, total mood disturbance and trait anxiety. All of these changes except trait anxiety returned to baseline at the one-month post-psilocybin time point.	DMN Modulation RSFC was increased across brain networks (including the DMN) and out of a possible 35,778 connections, 695 were significantly found to be different from baseline. Additional modulation Negative affect was decreased 1-week post-psilocybin administration and there was decreased amygdala activity in response to emotional stimuli. Additionally, 1-week after the psilocybin ingestion increased responses in reward-learning, attention and decision-based networks were observed. One-month after the initial psilocybin experience increased responses in the somatosensory and fusiform gyrus were measured. Supporting Model None	Key limitations which make the findings of this study liable to biases and confounding factors are lack of a placebo or positive control small sample size.
Psilocybin (25mg/70kg, p.o.)	(Barrett et al., 2020b)	Single-blinded placebo-controlled	N= 15 healthy long-term meditators (5 female), who had been administered 25mg/70 kg dose in a previous study two months before this initial trial. Mean age =51	Subsequent to each resting state scan participants subjective effects of the intervention were measured via an verbal 11 point scale (0-‘none’, 10 ‘extreme’). Participants were then required to rate three subjective experiences related to mindfulness: presence, letting go and equanimity (emotional poise). Participants also rated their subjective effects against the MEQ and whether they experience has a positive or negative valance.	3T fMRI (BOLD)	Psilocybin increased subjective experiences compared to baseline across various domains. These included 'now-ness’/presence, letting go, awareness, pure-being and pure awareness, timelessness, joy, sacredness and total MEQ scores.	DMN modulation Psilocybin significantly decreased FC between the claustrum and the DMN. DMN integrity was correlated with right claustrum connectivity with the DMN. Significantly less FC was observed between the DMN and the right insula Additional modulation There was increased connectivity between the claustrum and the FPN. Subjective effects of psilocybin were associated with the amplitude of low-frequency fluctuations and variance within the claustrum. Despite the correlation between subjective effects and neural effects yielding moderate correlation coefficients these associations did not survive multiple comparisons. Supporting model CCC	A single dose of psilocybin was assessed and multiple active doses would allow the appropriate dose-dependent analysis to occur. Furthermore, the sample was highly specific as it was comprised of individuals who had a long-term meditation practice and had already received psilocybin in an experimental setting. Finally, the average age of participants was relatively high compared to other studies in the field.
Psilocybin (2mg in 10-mL saline, applied IV)	(Varley et al., 2020)	Open-label, within-subjects, Placebo-controlled.	N=15 healthy participants (2 females) were experienced psychedelic drug users Mean age = 32	NA	3T fMRI (BOLD & rsfMRI)	NA	DMN modulation Higuchi fractal dimension of BOLD time series was not significant for the DMN. Supporting Model REBUS Increased Higuchi fractal dimension was found in the Dorsal-Attentional network.	Limitations are small sample size and the Higuchi fractal dimension is not often used for BOLD signals as the number of samples in each time series is lower than EEG or MEG, decreasing the strength of these findings. Additionally, it is also likely that with psilocybin the time-series may be too short for the Higuchi fractal dimensions values to be reliable enough for replication. Furthermore, the parcellation values (1000 ROIs) may not be enough for a truly valid analysis of the fractal dimensionality of FC networks.
Psilocybin (0.17mg/kg, p.o.)	(Mason et al., 2020)	Double-blind, placebo-controlled, parallel-group design	N = 60 (25 female) healthy participants who had a history of psychedelic and substance use. Participants were excluded if they had used a psychedelic within 3 months of the study. Mean age = 23	5D-ASC scale and EDI were administered 360 minutes after drug administration.	7T fMRI (rsfMRI & MRS)	Administration of psilocybin was correlated with increased ratings of all sub-dimensions of 5D-ASC and the EDI.	DMN modulation Significantly less coactivation of the anterior and posterior DMN. Increased FC between the DMN and the FPN and SLN. Higher levels of glutamate in the mPFC, were associated with negatively experienced ego dissolution, and lower levels of glutamate in the mPFC was associated with positively experienced ego dissolution. Additional Modulation Widespread increases in between-network FC. Supporting Model REBUS	The increased BOLD sensitivity due to the high magnetic field may mean that geometric distortions become more prominent, thereby affecting the BOLD signal in inferior brain regions. Additionally, the scanning time was short from a test-retest perspective. The dose administered in this study was low-moderate compared to other trials, and this dose is also not capable of inducing a total ego dissolution.
Psilocybin (2 mg in 10-mL saline, applied IV)	(Carhart-Harris et al., 2013)	Within-subjects placebo-controlled study	N=15 healthy participants (2 females) were experienced psychedelic drug users. Mean age = 32	NA	3T fMRI (BOLD & rsfMRI)	NA	DMN modulation Significant increases in the FC between the anterior DMN and TPN’s such as the SLN, as well as the FPN, the AUD and dAN. Additional modulation Thalamic-DMN FC was nonsignificant Supporting Model REBUS	This was a new analysis of a previously published data set (Carhart-Harris et al., 2012), thus similar potential limitations and biases apply for the data collection process.
Psilocybin (2mg in 10mg of saline, administered IV)	(Muthukumaraswamy et al., 2013)	Within-subjects single-blind study	N = 15 healthy male participants. Mean age = 34.5	Upon 5 minutes of administration subjective experiences were deciphered using a 100-point VAS scale of 24 questions whilst in the MEG scanner. The 24 items consisted of questions like ‘I saw geometric patterns’, ‘the experience had a supernatural quality’ and ‘I felt a profound inner peace’.	MEG	17 out of 24 items were significantly higher in the psilocybin group compared to placebo, suggesting that psilocybin clearly altered participants subjective experience and was almost exclusively positive.	DMN modulation Decreased spectral power in key areas of the DMN such as the PCC. Specifically, decreases in the delta, theta, alpha, beta and low gamma frequency bands corresponded to the posterior regions. Decreased power and neuronal desynchronisation occurred in bilateral prefrontal cortices ranging from the alpha to gamma frequencies. Supporting Model REBUS	All participants had previous experience with psychedelic drugs and were all male, and were excluded if they have had an adverse side-effect to psychedelics resulting in decreased generalisability. The study was only single-blinded, rather than double-blinded. Finally, MEG artifacts were removed (caused by large muscle/head movements) at the pre-processing stage which may have been associated with specific aspects of the psychedelic experience.
Psilocybin (0.17mg/kg, p.o.)	(Mason et al., 2021)	Randomized, placebo-controlled, double-blind, parallel-group design	N=60 healthy participants (25 female) with previous experience with a psychedelic drug (but not within 3 months of the trial) Mean age = 23 Male to Female ratios were NA.	The 5D-ASC scale was administered 360 min after the drug and placebo intervention.	7T fMRI (MRS & rsfMRI)	Psilocybin increased ratings on all (sub)dimensions of the 5D-ASC, specifically ‘insight’ which was particularly pertinent to this study.	DMN modulation Significantly less coactivation was found within both the anterior and posterior DMN. Significant increases in between-network FC was observed for the DMN and the FPN and SLN. Additional modulation The FC within the FPN and SN was not significantly altered. Supporting Model REBUS	A limitation of the study is that behaviour measures taken outside of the scanner were correlated with resting-state connectivity.
Psilocybin (2mg in 10mg of saline, applied IV)	(Tagliazucchi et al., 2014)	Within-subjects placebo-controlled study.	N=15 healthy participants (2 females) were experienced, psychedelic drug users. Mean age = 32	NA	3T fMRI (BOLD & rsfMRI)	NA	DMN modulation Decreased low-frequency power and frequency scaling exponent (suggesting a poorly correlated signal) were observed in higher-order cognitive networks such as the DMN and this was juxtaposed with increased point processing rate. Additional modulation Increased amplitude of the BOLD signal was found within the hippocampus and ACC. Supporting Model REBUS	This was a new analysis of a previously published data set (Carhart-Harris et al. 2012), thus similar limitations and biases apply for the data collection process. Additionally, in this analysis, a limited number of regions were included in the definition of dynamical states. Consequently, it is possible that the change in brain dynamics is influenced/modulated by brain regions outside the scope of the analysis which involves known FC parameters to a pair of nodes.
Psilocybin (170 and 215 μg/kg p.o.)	(Kometer et al., 2015)	Double-blind, placebo-controlled study (within-subjects design)	N = 50 healthy subjects (22 females) Mean age = 25	The 5D-ASC was administered retrospectively (after all subjective effects of the treatment had dissipated) .	HD-EEG	Psilocybin significantly increased all sub-scaled of the 5D-ASC. Interesting there was a drug*dose*subscale interaction which led to a post-hoc analysis which showed that higher self-rated scores for hallucination and blissful states was dose-dependent.	DMN modulation Significant psilocybin-induced reduction in low-frequency bands (<20Hz) in the PCC and the retrosplenial cortex. Furthermore, there was a reduction in the source density in most frequency bands in regions such as the precuneus, ACC, cuneus and parahippocampal gyrus. Alpha 1 (8-10Hz) and partially alpha 2 (10.5-13Hz) reductions were found across areas in the posterior-parietal cortex and mainly isolated to the right hemisphere. Supporting Model REBUS	This paper relies on source localization and connectivity of deep structures (parahippocampal gyrus), which is highly contested as being possible with EEG.
Psilocybin (2mg in 10mL of saline)	(Roseman et al., 2014)	Within-subjects placebo-controlled study.	N=15 healthy participants (2 females) were experienced psychedelic drug users Mean age = 32	NA	3T fMRI (BOLD, rsfMRI & ASL)	NA	DMN modulation A significant increase in coupling between specific RSN such as: DMN-lFP, DMN-dAN, DMN2-ECN, DMN2-lFP, DMN2-dAN, DMN2-DAN2 and VisL-DMN. Supporting Model REBUS	This was a new analysis of a previously published data set (Carhart-Harris et al. 2012), thus similar limitations and biases apply for the data collection process. There was a significant correlation between head movement in the scanner and certain between network connectivity (i.e VisL-DMN).
Psilocybin Open-label trial. (10mg and 25 mg of oral psilocybin separated by a week.) DB-RCT Psilocybin arm 25 mg of oral psilocybin duplicated three weeks later. Between each dose, 3 weeks of daily placebo capsules were taken. Escitalopram arm Participants ingested 2 x 1 mg of psilocybin 3 weeks apart. Between psilocybin doses 10mg of daily escitalopram was orally ingested.	(Daws et al., 2022)		Open-label trial N = 19 patients (4 females) diagnosed with treatment-resistant depression. Mean age = 43 DB-RCT N = 59 patients (8 females) with major depressive disorder. Mean age = 44.5	In both experiments the Quick Inventory of Depressive Symptoms (QIDS) and the BDI-1A scores were used to assess depression severity in both studies. These measurements were taken at baseline, 1 week, 3 months and 6 months in the open trial and at 2,4 and 6 weeks in the DB-RCT.	3T fMRI (BOLD, rsfMRI)	Baseline scores of BDI were higher for the patients with treatment resistant depression then major depressive disorder. In the open-label trial psilocybin decreased median BDI scores at 1 week, 3 months and 6 months compared to baseline. In the DB-RCT both psilocybin and escitalopram decreased median BDI scores compared to baseline with the most pronounced decrease in the psilocybin condition.	DMN modulation Open-label trial DMN recruitment decreased and its between network integration with the ECN and SLN increased 1-day after psilocybin administration. Decreased brain modularity predicted improved clinical outcomes at 6 months post treatment. DB-RCT Brain network modularity was significantly reduced at the primary end point, 3 weeks after psilocybin therapy (no differences were found for escitalopram). This decrease in modularity was associated with positive treatment outcomes. Additional modulation Post-psilocybin changes in the dynamic flexibility of various brain networks were correlated with changes in depressive symptomatology. Supporting Model REBUS	Limitations There was a much larger proportion of males to females in the study and fMRI scans were conducted while eyes were closed so it is possible that participants may have fallen asleep for periods of time. Repeated scanning sessions would have also been superior to single scanning recordings. Psilocybin did not outperform citalopram in QIDS scores in the latter trial, and QIDS was the primary outcome of the original trials. However, in the re-analysis the Beck’s Depression Inventory was used as the primary analysis. Furthermore, testing significance with a one-tailed t-test (rather than two tailed) despite an a-priori prediction has been challenged as has the conducting of a post-hoc analysis (between the two treatments) without there being a significant interaction.
Ayahuasca (1mL/kg, 0.36 mg/mL of N,N-DMT, 1.86 mg/mL of harmine, 0.24 mg/mL of harmaline, and 1.20 mg/mL of tetrahydroharmine)	(Pasquini et al., 2020)	Randomized placebo-controlled trial	N = 43 physically and mentally healthy, who were ayahuasca naïve (20 males). Mean age = 31	Acute psychedelic experience was quantified via the Hallucinogenic Rating Scale (HRS). This was administered approximately 4 hours after ayahuasca and placebo ingestion.	1.5T fMRI (BOLD & rsfMRI)	Ayahuasca increased all subscales of the HRS which all survived multiple correction testing with the exception of the volitional subscale.	DMN modulation Significant decreases in FC within the PCC and increased FC within the ACC. There is an increase in the FC between the DMN and the SLN, VN and the SMN. Supporting Model REBUS	A significant limitation is the application of liberal voxel-wise statistical thresholds which can increase the likelihood of false-positive (type 1 error) results. The study garnered a low statistical power due to the sample size and strength of the MRI scanner (1.5T).
Ayahuasca (2.2 mL/kg, 0.8mg/ml of DMT and 0.21 mg/ml of harmine)	(Palhano-Fontes et al., 2015)	Open-label, Cohort study.	N = 10 participants (5 male) who were mentally healthy and had at least 5 years of regular (twice a month) ayahuasca use. Mean age = 29	Subjective effects caused by Ayahuasca were measured via the BPRS and the YMRS at baseline, 40 minutes, 80 minutes and 200 minutes.	1.5T fMRI (BOLD & rsfMRI)	5 out of the 11 items in the YMRS were statistically significant (at 80 min). These were elevated mood, speech, increase motor activity-energy, speech, language-thought disorder and content compared to baseline. The results from the BPRS were not presented.	A reduction in the BOLD signal of the DMN regions such as mPFC, ACC, PCC, IPL which is primarily driven by a reduction in the PCC/Precuneus seed. No significant difference in DMN-TPN orthogonality was found after ayahuasca consumption. Supporting Model REBUS	The study was limited to experienced users, limiting generalisability. The fixed effects analysis used, further limits the generalisability of the findings. No placebo group was present. The acquisition of fMRI data was not controlled for order effects. The sample of 10 participants is comparatively low to similar studies. The 1.5T fMRI is known to have decreased spatial resolution when compared to an MRI scanner with a higher magnetic field.
Ayahuasca (0.3 mg/mL DMT, 0.86 mg/mL harmine, 0.17 mg/mL tetrahydroharmine, and 0.04 mg/mL harmaline. Average consumption was 148 mL.)	(Sampedro et al., 2017)	Open-label, uncontrolled study	N = 16 healthy volunteers (6 females) with prior experience with ayahuasca. Mean age = 39	Participants filled out two questioners in the post-acute stage of the intervention. For enduring effects these questioners were then administered at a two month follow up. These questionaries were the HRS and a mindfulness questionnaire. The mindfulness questionnaire was a Spanish adaptation of the FFMQ, the Experiences Questionnaire and the short version of the Self-Compassion questionnaire. The mindfulness questionnaire was also administered at baseline.	3T fMRI (BOLD & rsfMRI)	At the post-acute stage significant differences from baseline were observed for the FFMQ non-judging and nonreacting subscale.	DMN modulation Glutamate levels in the PCC were lower compared to baseline (post-acute phase). Increased coupling from the PCC to the ACC, and visual areas were found. Additional modulation The superior rostral ACC seed was found to have increased coupling with subcortical regions such as the parahippocampal, hippocampal and amygdala. Supporting Model REBUS	There was no control/placebo group and all participants were experienced ayahuasca users (who showed high levels of baseline mindfulness). The study only looked at sub-acute effects and cannot be interpreted to infer the same persistent changes.
Ayahuasca	(Bouso et al., 2015)	Cross-sectional study.	N = 44 psychologically healthy participants (12 male) who had taken ayahuasca an average of 123 times, with minimal exposure to other drugs. Mean age = 41	Personality was assessed at using a Spanish version of the TCI-R questionnaire.	3T fMRI (BOLD)	Ayahuasca had a significant difference in harm avoidance (specifically the sub-item of anticipatory worry) and self-transcendence compared to controls.	DMN Modulation Cortical thinning was observed in the precuneus, the MFG, SFG and the PCC. Conversely, there was cortical thickening found in the ACC and precentral gyrus. Supporting Model REBUS	Due to the cross-sectional nature of the study, causality could not be inferred/established. The participants were also limited to long term users and what level of ayahuasca use (i.e., a certain threshold) to illicit the corresponding change in brain structure was not determined.
LSD (100 μg, p.o.)	(Müller et al., 2018)	Double-blind, randomised, cross-over study	N = 20 healthy (10 male) participants. Only 2 participants had previous psychedelic use and both were only on a single occasion. Mean age = 32	Subjective effects were measured three hours after the ingestion of psilocybin or placebo, using the 5D-ASC scale.	3T fMRI (BOLD)	Ratings in all major dimensions of the 5D-ASC were significantly increased for the LSD group compared to the placebo-control	DMN modulation Significantly decreased coactivation within the medial-posterior DMN was observed. No significant correlation was found between DMN integrity and ego dissolution measures. Widespread increases in between network FC were observed (i.e increased FC between the DMN and the SLN, VN and SMN). Additional modulation Decreased coactivation also occurred parts of the VN and sensorimotor network. Additionally, there was Increased FC between key hubs such as the precuneus, ACC, striatum and RSN’s for the LSD condition compared to placebo. Supporting Model None	Measurements of known FC confounders like increased heart rate and blood pressure (which LSD is known to alter), were only recorded at one-time point before the fMRI scan and a nuisance regression that continuously monitored these parameters may have been optimal.
LSD (75µg, IV injected)	(Lebedev et al., 2016)	Placebo controlled counter-balanced design.	N = 20 healthy volunteers (four females). All participants were required to have had previously used a classical psychedelic (Mean LSD use = 14). Mean age = 31	The standard 240-item revised NEO-PI-R, was administered twice to assess (possible) personality changes invoked by LSD. The NEO-PI-R was administered at baseline and 2-weeks after the LSD or placebo intervention. A VAS was completed inside the scanner and immediately after the scanning by the participants. A key facet of experience that the VAS questions assessed was ego-dissolution.	3T fMRI (BOLD, & rsfMRI)	In-scanner reports of ‘ego dissolution’ were significantly positively correlated with the ‘mystical’ quality of the experience.	DMN modulation Increased cortical entropy and significant increases were observed in the DMN and precuneus. Additional modulation Cortical entropy was a predictor of changes in the personality trait openness. Supporting Model REBUS	One of the MRI scanning conditions listened to music and the order of this group was not counter-balanced which obscures its specific influence from pharmacodynamics. Furthermore, music may also have facilitated the entropic effects of LSD by inducing a meditative like states in participants, leading to greater effect sizes and significance.
LSD (75 µcg (IV) in 10 mL saline)	(Speth et al., 2016)	Placebo-controlled crossover study.	N = 20 healthy volunteers (four females). All participants were required to have had previously used a classical psychedelic (Mean LSD use = 14). Mean age = 31	The size of the subjective effects of LSD were quantified and assessed by a VAS with 20 increments.	3T fMRI (BOLD & rsfMRI)	The subjective effect of LSD was first detected around 10 minutes after LSD infusion, and peaked around 120 minutes after LSD administration. After 7-8 hours after IV LSD, subjective effects subsided.	DMN modulationDMN disintegration predicted fewer cognitive agencies related to mental space for the past (i.e less mind-wandering to past events). Supporting Model REBUS	A small sample size (n = 15, 5 were excluded) were used for the fMRI scan which can lead to false positives and unreliable results. It is also possible that reduced mentation to the past was not a unique feature of LSD but rather a motif shared by many other intoxicants. Finally, one of the key findings, that DMN disintegration predicts less mentation of the past was not statically significant (p = 0.54), yet the authors seem to think that the mild correlation strength (r = 0.51), is sufficient to still conclude that DMN disintegration is correlated with memories of the past.
LSD (75 µg of LSD, administered IV via a 10ml solution)	(Jobst et al., 2021)	Placebo-controlled crossover study	N = 20 healthy volunteers (four females). All participants were required to have had previously used a classical psychedelic (Mean LSD use = 14). Mean age = 31	Not Applicable	3T fMRI (BOLD & rsfMRI)	Not Applicable	DMN modulation A significant difference in the PILI of the DMN for the LSD condition compared to placebo. Additional modulation A significant difference in the PILI of the limbic RSN for the LSD condition compared to placebo. Increased variability in brain states across all brain regions was also observed. Supporting Model REBUS	The model of analysis used contained some limitations such as homogeneity. For instance, there was a presupposition that all brain regions have the same intrinsic neural dynamics (alpha = 0), thus the differences in the dynamics of this model were a result of varying effective connectivity. However, it is not obvious that intrinsic neural dynamics are constant in the brain and most likely vary between networks, brain structures, and cell types. Furthermore, since the model was constructed upon BOLD signals the frequency range was limited to slow frequencies.
LSD (13 μg and 26 μg p.o.)	(Murray et al., 2022)	Double-blind, placebo-controlled study	N = 22 (8 female)Mean age = 25 Participants were healthy young adults with prior use of psychedelics (unless they experienced an adverse reaction).	Subjective mood states were recorded before drug intake and in 60-min intervals after drug administration. These measures were the DEQ, the ARCI, and the POMS. Furthermore, at the end of each session participants were required to complete a drug-identification and 5D-ASC questionnaire.	EEG	LSD significantly increased ratings of ‘Feel High’, ‘Like Drug’ and ‘Want More’ on the DEQ. Likewise, LSD (compared to placebo) significantly increased Elation, Anxiety and Positive Mood on the POMS. Finally, on the ACRI LSD had amphetamine-like effects, euphoric effects and increased energy and intellectual efficiency. The peak subjective experiences occurred 2-3 hours upon LSD ingestion. The end of session questionnaire revealed that most participants correctly identified whether they received a ‘placebo’ or ‘hallucinogen’ at the 26 μg session. For the 13 μg LSD session guesses were less accurate. The 26 μg group was the only group to significantly alter scores on the 5D-ASC.	DMN modulation LSD reduced oscillatory amplitude across three major hubs of the DMN (mPFC, PCC, bTPC) for five frequency bands (delta [1-4 Hz], theta [4-8 Hz), alpha [8-13 Hz], beta [13-30 Hz] and gamma [30-80Hz]). The effects were most pronounced for electrodes placed on the PCC. Supporting model REBUS	An important limitation of the data extraction and analysis is the fact that a dipole or distributed source detection of intracranial spectral density was not included. Therefore, this study is prone to the inverse problem of inferring the source of scalp recorded signals from deeper brain regions.
LSD (75 µg of LSD, administered IV via a 10ml solution)	(Varley et al., 2020)	Single-blind, placebo-controlled balanced-order design	N = 20 healthy volunteers (four females). All participants were required to have had previously used a classical psychedelic (Mean LSD use = 14). Mean age = 31	Not Applicable	3T fMRI (BOLD & rsfMRI)	Not Applicable	DMN modulation Higuchi fractal dimension was found to be insignificant for the DMN. Additional modulation Additional modulation Significant increase in fractal dimensions in the visual network, dorsal-attention network, and fronto-parietal network. Supporting model REBUS	The same limitations and biases as Varley et al. (2020) (psilocybin), apply, which have been outlined above.
LSD (75 µg of LSD, administered IV via a 10ml solution)	(Carhart-Harris et al., 2016)	Single-blind, placebo-controlled balanced-order design	N = 15Mean age = 31 Participants all had previous psychedelics use (except within 6 weeks of the first scanning day) and were healthy individuals.	An 11-factor ASC questionnaire was completed at the end of each scanning day. An additional questionnaire was administered directly after MRI and MEG scanning and consisted of VAS-style ratings for 21 items.	3T fMRI (BOLD & ASL) and MEG	All of the items on the ASC questionnaire were significantly increased for LSD compared to placebo with the exception of anxiety. Upon MRI scanning, participants rated 18/21 items significantly higher than placebo. The three items which showed no significant difference where ‘I felt afraid’, ‘I feared losing control of my mind; and ‘I felt suspicious and paranoid’ The results were similar for the MEG group where 15/21 Items were significantly different as a results of LSD administration compared to placebo. A control item for both scans ‘I felt entirely normal’ was rated higher for the placebo group.	DMN modulation There was decreased DMN integrity and CBF and this correlated with measures of ego dissolution. Decreased segregation between the DMN and salience network was observed, however, this was not significantly correlated with ego dissolution. Supporting model REBUS	The indirect measure of neural activity via CBF, should be approached with caution as this measure has poor temporal resolution and is prone to the confounder of neurovascular coupling as a result of the drug. Additionally, the experimental protocol may have been strenuous for participants with the different scan types of ASL, BOLD and MEG, where fatigue may occur and confound findings. This could be overcome by a simultaneous EEG-fMRI analysis.
LSD (100 µg p.o)	(Preller et al., 2018)	Double-blind, randomized, cross-over study	24 healthy participants (19 males) Mean age = 25	5D-ASC	3T fMRI (rsfMRI)	LSD significantly increased mean scores across scales on the 5D-ASC with a peak effect at 180 minutes after administration	DMN modulation GBC was found within higher order associative brain regions. For instance, reduced GBC was found within the mPFC, a key DMN brain region. Additional modulation Increased GBC across sensory and somatomotor functional networks was observed. Interestingly the hyper-and hypo- connectivity motifs across the brain were significantly correlated and driven primarily by 5-HT2A and possibly 5-HT7 antagonism. Changes in connectivity patterns within the somatosensory network and not the DMN were associated with subjective experiences. Supporting Model REBUS and CSTC	Although a strength of this study is the removal of global signal artifacts, it is possible that such an analysis can also remove pharmacologically induced brain signal alterations. Furthermore, there was more than three times as many males than females in the cohort.

Abbreviations: SLN (salience network), CBF (cerebral blood flow), VN (visual network), AUD (auditory network), RSN (resting-state network), TPN (task-positive network), FPN (frontoparietal network), PILI (Perturbational Integration Latency Index), bTPC (bilateral temporoparietal cortex), IPL (inferior parietal lobule), dAN (dorsal attention network), VisL (visual-Lateral), DMN2 (Hybrid of anterior DMN and Executive Control Network), ECN (executive control network), lFP (left frontoparietal network), ASL (arterial spin labelling), DTI (Diffusion Tensor Imaging), IV (intravenously), BOLD (Blood Oxygen Level Dependent) HD (High Density) rs (resting state), NA (not available), MRS (Magnetic Resonance Spectroscopy), QIDS-SR16 (Quick Inventory of Depressive Symptoms), 11D-ASC (11- Dimension Altered States of Consciousness), MEQ (Mystical Experiences Questionnaire) and EDI (Ego-Dissolution Inventory), Persisting Effects Questionnaire (PEQ), NEO PI-R (NEO Personality Inventory-Revised), MAAS (Mindfulness Attention Awareness Scale), PANAS-X (the Positive and Negative Affect Scale), POMS (The Profile of Mood States), DPES (The Dispositional Positive Emotions Scale), DASS (Depression Anxiety Stress Scale), GBC (Global Brain Connectivity), MEG (magnetoencephalography), (DEQ) Drug Effects Questionnaire, ACRI (Addiction Research Centre Inventory), bTPC (bilateral temporoparietal cortex), Temperament and Character Inventory-Revised (TCI-R), MFG (medial frontal gyrus), SFG (superior frontal gyrus), Five Facet Mindfulness Questionnaire (FFMQ), Young Mania rating Scale (YMRS), IPL (Inferior parietal lobule), BPRS (Brief Psychiatric Rating Scale), DB-RCT (Double-blind randomised control trial).