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Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.
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SCIentIfIC RePoRTs | 7: 13187 | DOI:10.1038/s41598-017-13282-7
Psilocybin for treatment-resistant
depression: fMRI-measured brain
Robin L Carhart-Harris1, Leor Roseman1,2, Mark Bolstridge1, Lysia Demetriou5,6,
J Nienke Pannekoek1,7, Matthew B Wall1,4,5, Mark Tanner5, Mendel Kaelen1, John McGonigle5,
Kevin Murphy3, Robert Leech2, H Valerie Curran4 & David J Nutt1
Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its
therapeutic mechanisms are poorly understood. Here, cerebral blood ow (CBF) and blood oxygen-level
dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic
resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-
resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19
patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and
47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in
CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced
depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was
observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal
cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks,
as was decreased parahippocampal-prefrontal cortex RSFC. These data ll an important knowledge
gap regarding the post-treatment brain eects of psilocybin, and are the rst in depressed patients. The
post-treatment brain changes are dierent to previously observed acute eects of psilocybin and other
‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.
Psilocybin is the prodrug of psilocin (4-OH-dimethyltryptamine), a non-selective serotonin 2A receptor
(5-HT2AR) agonist and classic ‘psychedelic’ drug1. Both compounds occur naturally in the ‘psilocybe’ genus
of mushrooms, and are structurally related to the endogenous neurotransmitter serotonin (5-OH-tryptamine,
5-HT). Psilocybin has an ancient and more recent history of medicinal-use. Administered in a supportive envi-
ronment, with preparatory and integrative psychological care, it is used to facilitate emotional breakthrough
and renewed perspective2. Accumulating evidence suggests that psilocybin with accompanying psychological
support can be used safely to treat a range of psychiatric conditions1, including: end-of-life anxiety and depres-
sion35, alcohol and tobacco addiction6,7, obsessive compulsive disorder8, and most recently from our group,
treatment-resistant major depression9. Findings from healthy volunteer studies10 and trials with other psyche-
delics1113 supplement those from clinical studies showing that these drugs can have a rapid and lasting positive
impact on mental health, oen aer just one or two doses. Such outcomes raise a number of important questions,
including: what brain mechanisms mediate these eects?
Most human functional neuroimaging studies of psychedelics have focused on their acute eects with the aim
of elucidating the neural correlates of the ‘psychedelic state’14,15. Consistent with ndings from animal research16,
psychedelics appear to dysregulate cortical activity14,17, producing an ‘entropic’ brain state18, characterised by
compromised modular but enhanced global connectivity - referred to previously as network ‘disintegration’ and
1Psychedelic Research Group, Psychopharmacology Unit, Centre for Psychiatry, Department of Medicine, Imperial
College London, W12 0NN, London, UK. 2Computational, Cognitive and Clinical Neuroscience Laboratory (C3NL),
Department of Medicine, Imperial College London, W12 0NN, London, UK. 3Cardi University Brain Research Imaging
Centre (CUBRIC), School of Physics and Astronomy, CF24 4HQ, Cardiff, UK. 4Clinical Psychopharmacology Unit,
University College London, WC1E 6BT, London, United Kingdom. 5Imanova Centre for Imaging Sciences, Burlington
Danes Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. 6Investigative Medicine, Department
of Medicine, Imperial College London, London, United Kingdom. 7SU/UCT MRC Unit on Risk and Resilience in Mental
Disorders, Department of Psychiatry and Mental Health, University of Cape Town, South Africa. Correspondence and
requests for materials should be addressed to R.L.C.-H. (email:
Received: 1 June 2017
Accepted: 19 September 2017
Published: xx xx xxxx
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‘desegregation14. ese eects have been found to correlate with important aspects of the ‘psychedelic expe-
rience’, including ‘ego-dissolution14,17,19, and were predictive of post-acute changes in the personality domain
‘openness’20. To our knowledge, only one other very recent study has investigated >12 hour post-acute eects of
psychedelics on human brain function (although see12 and now21), and few have looked at anatomical changes
possibly related to psychedelic use22,23.
The present study focused on changes in brain function before versus after psilocybin in patients with
treatment-resistant depression who received two doses of the drug (10 mg followed by 25 mg, one-week apart)
as part of an open-label clinical trial. Arterial spin labelling (ASL) and blood oxygen level dependent (BOLD)
resting state functional connectivity (RSFC), were used to measure changes in cerebral blood ow (CBF) and
functional connectivity before (baseline) and one-day aer treatment with psilocybin (i.e. one day aer the 25 mg
dose). It has been suggested that the days subsequent to a psychedelic experience constitute a distinct phase,
referred to as the ‘aer-glow’, that is characterised by mood improvements and stress relief24. e rationale for
scanning one-day post-treatment was to capture brain changes related to this so-called aer-glow that might
correlate with current mood improvements and/or longer-term prognoses. We predicted that resting-state CBF
and FC would be altered post treatment and correlate with immediate and longer-term clinical improvements.
With regards to ‘longer-term’ clinical outcomes, we chose to focus on a 5-week post-treatment endpoint due
to a virtual 50:50 split between responders and non-responders at this time-point (QIDS-SR16) and that none of
the patients went on to additional (and thus, confounding) treatments within this time frame. A select number
of regions of interest were chosen a priori for CBF and RSFC analyses due to previous work implicating their
involvement in depression and its treatment, e.g2527.
Nineteen patients with diagnoses of treatment resistant major depression completed pre-treatment and one-day
post-treatment fMRI scanning. Excessive movement or other artefact meant that three patients were removed
from the ASL analyses and four from the RSFC (SI Appendix), leaving sample sizes of 16 (mean age = 42.8 ±
10.1 y, 4 females) and 15 (mean age = 42.8 ± 10.5 y, 4 females) for the ASL and BOLD analyses, respectively.
Treatment with psilocybin produced rapid and sustained antidepressant eects. For the patients included
in the ASL analysis (minus one patient whose scan 1 rating was not collected), the mean depression score
(QIDS-SR16) for the week prior to the pre-treatment scan was 16.9 ± 5.1, and for the day of the post-treatment
scan, it was 8.8 ± 6.2 (change = 8.1 ± 6, t = 5.2, p < 0.001). e mean QIDS-SR16 score at baseline (screen-
ing) was 18.9 ± 3, and for 5-weeks post-treatment, it was 10.9 ± 4.8 (change = 8 ± 5.1, t = 6.3, p < 0.001).
Mean change values for those included in the BOLD analyses were 7.3 ± 5.3 (change from scan 1 to scan 2) and
8.2 ± 5.2 (change from baseline to 5 weeks post-treatment). Both contrasts were highly signicant (t = 5.2 and
6.2, p < 0.001). Six of the 15 (BOLD) and 16 (ASL) patients met criteria for treatment response (50% reduc-
tions in QIDS-SR16 score) at 5 weeks. Of the full 19 patients, all showed some decrease in depressive symptoms
at 1 week, with 12 meeting criteria for response (change = 10.2 ± 5.3, t = 6.4, p < 0.001). All but one patient
showed some decrease in QIDS-SR16 score at week 5 (with one showing no change) and 47% met criteria for
response (change = 9.2 ± 5.6, t = 6.7, p < 0.001).
Whole-brain CBF was calculated pre and post treatment and contrasted (Fig.1). Only decreases in CBF were
observed post treatment (vs pre), and these reached statistical signicance in the le Heschl’s gyrus, le precentral
gyrus, le planum temporale, le superior temporal gyrus, le amygdala, right supramarginal gyrus and right
parietal operculum (TableS1). Based on previous ndings of increased amygdala blood ow and metabolism in
depression25, reductions in amygdala CBF were compared with the reductions in depressive symptoms between
scan 1 and 2 (i.e. decreased depressed mood at the time of scanning), and a signicant relationship was found
(r = 0.59; p = 0.01). Aer splitting the sample into responders and non-responders at 5-weeks post-treatment, and
then comparing CBF changes in a t-test, no signicant dierence was found (t = 0.11; p = 0.46).
Next, seed-based RSFC analyses were performed using the BOLD data. Based on previous data implicating
their involvement in the pathophysiology of depression and response to treatments2527, four regions of interest
(ROIs) were chosen: 1) the subgenual anterior cingulate cortex (sgACC), 2) the ventromedial prefrontal cortex
(vmPFC), 3) the bilateral amygdala, and 4) the bilateral parahippocampus (PH) (Figs24 and SI Appendix,
Increased sgACC RSFC was observed with the posterior cingulate cortex/precuneous (PCC) post-treatment
(Fig.2) but this eect did not correlate with reductions in depressive symptoms between scan 1 and 2 (r = 0.2;
p = 0.24) and nor did it predict treatment response at 5 weeks (t = 1.3; p = 0.11).
Increased vmPFC RSFC was observed with the bilateral inferior-lateral parietal cortex (ilPC) post-treatment.
is eect did not correlate with reductions in depressive symptoms between scan 1 and 2 (r = 0.26; p = 0.17)
but did predict treatment response at 5 weeks, with responders showing signicantly greater vmPFC-ilPC RSFC
increases than non-responders (t = 2.1; p = 0.03).
Decreased PH RSFC was observed with a PFC cluster incorporating the lateral and medial prefrontal cortex.
is eect did not correlate with reductions in depressive symptoms between scan 1 and 2 (r = 0.08; p = 0.38)
but did relate to treatment response at 5 weeks, with responders showing signicantly greater PH-PFC RSFC
decreases than non-responders (t = 1.9, p = 0.04). Amygdala RSFC was not signicantly altered post treatment.
Analyses of within network RSFC using 12 previously identified canonical RSNs14 revealed increased
default-mode network (DMN) (t = 2.7, p = 0.018), dorsal attention network (DAN) (t = 2.2, p = 0.042), and
posterior opercular network (POP) (t = 2.7, p = 0.016) RSFC post-treatment; however, these changes failed to
survive Bonferonni correction for multiple comparisons (revised α = 0.05/11 = 0.0042) and did not correlate
with depression outcomes, e.g. the relationship between change in DMN RSFC and reduced QIDS-SR16 scores
between scan 1 and 2 were non-signicant (r = 0.25; p = 0.18) and neither were changes in DMN RSFC predictive
of outcomes at 5 weeks (t = 0.58; p = 0.28). Analyses of between network RSFC using the same 12 RSNs, revealed
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SCIentIfIC RePoRTs | 7: 13187 | DOI:10.1038/s41598-017-13282-7
decreased RSFC between the DMN and right frontoparietal network (rFP) (t = 3.6, p = 0.0031) and increased
RSFC between the sensorimotor network (SM) and rFP (t = 2.2, p = 0.045) (Fig.5); however, these eects did not
survive FDR correction for multiple comparisons and did not relate to reduced QID-16 scores between scan 1
and 2, nor response at 5 weeks.
Lastly, based on indications from previous work4,5,10 we explored the possibility that the quality of the acute
‘psychedelic’ experience may have mediated the post-acute brain changes. We focused on a rating scale factor
related to ‘peak’ or ‘mystical’ experience and used scores for the high-dose psilocybin session as a covariate in a
Figure 1. Whole-brain cerebral blood ow maps for baseline versus one-day post-treatment, plus the dierence
map (cluster-corrected, p < 0.05, n = 16). Correlation chart shows post-Treatment changes in bilateral amygdala
CBF versus changes in depressive symptoms (r = 0.59, p = 0.01). One patient failed to completed the scan 2
QIDS-SR16 rating, reducing the sample size to n = 15 for the correlation analysis. In all of the images, the le of
the brain is shown on the le.
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PH RSFC analysis. e PH was specically chosen due to previous work implicating its involvement in related
states14. Results revealed that patients scoring highest on ‘peak’ or ‘mystical’ experience had the greatest decreases
in PH RSFC in limbic (e.g. bilateral amygdala) and DMN-related cortical regions (e.g. the PCC). See the supple-
mentary le for the relevant maps and discussion.
e present study goes some way to addressing an important knowledge gap concerning the post-acute brain
eects of serotonergic psychedelics. Its ndings suggest that changes in brain activity observed just one-day aer a
high dose psychedelic experience are very dierent to those found during the acute psychedelic state. Specically,
whereas the acute psychedelic state in healthy volunteers is characterised by modular disintegration14,15,28 and
global integration14,19,29, there are trends towards modular (re)integration and minimal eects on global integra-
tion/segregation post psilocybin for depression. Relating the blood ow ndings to what has been seen previously
in the acute psychedelic state is somewhat more complicated due to inconsistencies in this literature – likely due
to analysis approaches and interpretation14,15,30: Here we saw decreased CBF bilaterally in the temporal lobes,
including the le amygdala one-day post treatment. Decreased absolute CBF in subcortical and high-level asso-
ciation cortices have been previously reported with intravenous (I.V.)15 and now oral psilocybin30 but increased
CBF and metabolism have also been reported with I.V. LSD14, oral psilocybin31, and oral ayahuasca32.
Much recent research has focused on the involvement of the default-mode network in psychiatric disor-
ders33, and particularly depression34,35. We previously observed decreased DMN functional integrity under psil-
ocybin15 and LSD14, and others have with ayahuasca28. Here however, increased DMN integrity was observed
one-day post treatment with psilocybin, both via seed (i.e. vmPFC and sgACC) and network-based approaches.
Previous work has suggested that increased DMN integrity may be a marker of depressed mood and speci-
cally, depressive rumination34,36. On this basis, increased DMN integrity post psilocybin may be surprising. e
post-treatment increases in within-DMN RSFC and sgACC-PCC RSFC did not relate to symptom improvements
but vmPFC-ilPC RSFC did (see Fig.3). is apparent divergence from previous ndings36,37 is intriguing, and
deserves further discussion (below).
It should be noted that ndings of elevated within-DMN RSFC in depression are not entirely consistent in
the literature3841. For example, using a DMN-focused analysis, precuneus-DMN RSFC39 was found to be lower
in patients than in healthy controls, and normalised aer treatment with electroconvulsive therapy (ECT) - and
only in responders39 – consistent with the present ndings. Lower precuneus-DMN RSFC in depression was also
seen in a separate study and the degree of this abnormality correlated with autobiographical memory decits40.
In another study, lower PCC-dmPFC and PCC-ilPC RSFC were seen in rst-episode depressed patients relative
Figure 2. Top two rows = sgACC (purple) RSFC before and aer psilocybin treatment (hot colours = regions
of signicantly positive coupling). Bottom row reveals regions where there was a signicant increase in sgACC
RSFC post-treatment (hot colours). All maps are cluster-corrected, p < 0.05, Z > 2.3.
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SCIentIfIC RePoRTs | 7: 13187 | DOI:10.1038/s41598-017-13282-7
to healthy controls41. In the present study, we saw increased within-DMN RSFC post treatment with psilocybin,
and increased vmPFC-bilateral ilPC RSFC was predictive of treatment response at 5 weeks (Fig.3). ese ndings
suggest a commonality in the antidepressant action of ECT and psilocybin39 in which DMN integrity is decreased
acutely (at least by the latter14,15,28) and increased (or normalised) post-acutely, accompanied by improvements
in mood. is process might be likened to a ‘reset’ mechanism in which acute modular disintegration (e.g. in the
DMN) enables a subsequent re-integration and resumption of normal functioning.
Recent meta-analyses of studies of resting-state CBF in depression have yielded relatively mixed results34,42,
although ndings of increased thalamic34,42 and sgACC metabolism are relatively consistent34. Here, we did not
nd any post-treatment changes in thalamic or sgACC CBF with psilocybin, either in whole-brain or ROI-based
Figure 3. Top two rows = vmPFC (purple) RSFC before and aer psilocybin treatment (hot colours = regions
of signicantly positive coupling). Bottom row reveals regions where there was a signicant increase in vmPFC
RSFC post-treatment (hot colours). All maps are cluster-corrected, p < 0.05, Z > 2.3. Increased coupling
between the vmPFC and the displayed regions (bottom row) was predictive of clinical response at 5-weeks post-
treatment. Chart shows mean values and positive standard errors.
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analyses. We did observe decreased CBF bilaterally in the temporal cortex however, including the le medial tem-
poral lobe and specically, the le amygdala. Given previous ndings of elevated resting-state amygdala CBF and
metabolism in mood disorders25,43,44, the reduction in amygdala CBF observed here, and its relation to symptom
severity, could be viewed as a possible remediation eect. Moreover, generalised decreases in CBF are (again) con-
sistent with what has been previously reported with ECT45, i.e. most studies have documented an increase in CBF
in the acute ‘ictal’ state, including in the amygdala45; however, the post-ictal period is characterised by decreased
CBF, and oen in those regions that were most perfused during seizure45. Acutely increased CBF has previously
been reported with ayahuasca32 and LSD15 and increased glucose metabolism has been observed in the acute
Figure 4. Top two rows = Bilateral PH (purple) RSFC before and aer psilocybin treatment (hot
colours = regions of signicantly positive coupling). Bottom row reveals regions where there was a signicant
decrease in PH RSFC post-treatment (cold colours). All maps are cluster-corrected, p < 0.05, Z > 2.3. Decreased
coupling between the PH and the displayed regions (bottom row) was predictive of clinical response at 5-weeks
post-treatment (t = 1.9, p = 0.04). Chart shows mean values and negative standard errors.
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state with oral31 but not I.V. psilocybin15. us, a post-acute reversal of acute increases in CBF could be seen as
consistent with the post-treatment ‘reset’ mechanism proposed above – although recent work has laid into ques-
tion whether oral psilocybin does indeed cause increases in brain absolute CBF30. It would be challenging (but
not impossible) to carry out acute and post-acute imaging in future trials of psilocybin for depression, and this
may be necessary if the ‘reset’ model is to be properly tested. In such a study, we would advise focusing on BOLD
RSFC (and perhaps simultaneous EEG-related measures) rather than CBF, due to RSFC and EEG oering more
direct and reliable indices of brain activity and function than more dicult to interpret measures such as CBF.
e inclusion of a healthy control group, exposed to a consistent treatment procedure, would further strengthen
the design of such a study, as would the inclusion of a placebo and/or active comparator arm.
e present study’s other major positive nding was a decrease in RSFC between the bilateral parahippocam-
pus and the PFC, an eect that (like increased vmPFC-ilPC RSFC) was predictive of treatment response at 5
weeks. Curiously, a post-hoc exploratory analysis suggested that acute ‘peak’ or ‘mystical-type’ experiences under
psilocybin may mediate the post-acute changes in parahippocampal RSFC (including decreased PH-PCC RSFC).
Focusing on parahippocampal-PFC RSFC, this has generally been found to be elevated in depression46, and con-
sistently so across the duration of a resting-state scan47. Prefrontal-limbic circuitry has been linked with top-down
suppression of aective responsiveness48 and lower resting-state amygdala-vmPFC RSFC in combination with
amygdala hyperfusion was found to relate to state-anxiety in healthy individuals43, corroborating separate nd-
ings49. Seven days of citalopram has been found to reduce amygdala-vmPFC50 and dorso-medial PFC-le hip-
pocampal RSFC51 in healthy volunteers, somewhat consistent with the present ndings.
In conclusion, here we document for the rst time, changes in resting-state brain blood ow and functional
connectivity post-treatment with psilocybin for treatment-resistant depression. Decreased blood ow was found
to correlate (in the amygdala) with reductions in depressive mood. Increased within-DMN RSFC was observed
post-treatment, using both seed and network-based analyses, and specic increases in RSFC between the vmPFC
and bilateral ilPC nodes of the DMN were greatest in individuals who maintained treatment-response at 5 weeks.
Finally, decreased PH-PFC RSFC was observed post-treatment and this was also predictive of treatment-response
at 5 weeks. An exploratory post-hoc analysis revealed that acute ‘peak’ or ‘mystical’ experience during the
high-dose psilocybin session was predictive of these changes in PH RSFC.
is study is limited by its small sample size and absence of a control condition. Moreover, correction for
multiple testing was applied to the full RSN but not the specic (hypothesis-based) ROI analyses. Future research
with more rigorous controls should serve to challenge and develop the present study’s ndings and inferences.
Assessing the relative contributions of, and potential interactions between, the dierent treatment factors (e.g. the
drug and the accompanying psychological support) may be a particularly informative next step.
is study was approved by the National Research Ethics Service (NRES) committee London – West London
and was conducted in accordance with the revised declaration of Helsinki (2000), the International Committee
on Harmonisation Good Clinical Practice (GCP) guidelines and National Health Service (NHS) Research
Governance Framework. Imperial College London sponsored the research which was conducted under a Home
Oce license for research with schedule 1 drugs. e Medicines and Healthcare products Regulatory Agency
(MHRA) approved the study. All patients gave written informed consent, consistent with GCP.
Figure 5. Dierences in between-RSN RSFC or RSN ‘segregation’ before and aer therapy. Each square
in the matrix represents the strength of functional connectivity (positive = red, negative = blue) between a
pair of dierent RSNs (beta values). e matrix on the far right displays the between-condition dierences
in covariance (t values). e RSNs are: 1) medial visual network, 2) lateral visual network, 3) occipital pole
network, 4) auditory network, 5) sensorimotor network, 6) DMN, 7) parietal cortex network, 8) the dorsal
attention network, 9) the salience network, 10) posterior opercular network, 11) le frontoparietal network, 12)
right frontoparietal network. White asterisks represent signicant dierences (P < 0.05, non-corrected). Both of
the signicant dierences did not survive FDR correction for multiple comparisons.
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Imaging vs clinical outcomes. To explore relationships between signicant imaging outcomes and the
main clinical outcomes, we chose to focus on changes in depressive symptoms from: 1) pre-Treatment to scan
2 (i.e. one-day post-treatment), and 2) pre-Treatment to 5 weeks post-Treatment. e primary clinical outcome
measure, the 16-item Quick Inventory of Depressive Symptoms (QIDS-SR16) was chosen for this purpose.
Relationships between imaging outcomes and contemporaneous decreases in depressive symptoms were calcu-
lated using a standard Pearsons r, and relationships with the longer-term (i.e. at 5 weeks post-treatment) changes
in depressive symptoms were calculated by splitting the sample into responders (>50% reduction in QIDS-SR16
scores) and non-responders at this time-point, and then performing a one-tailed t-test on the relevant imaging
outcomes (one-tailed as directionality was unequivocally implied by the direction of the signicant imaging out-
come). We used a revised version of the QIDS-SR16 for 24-hour measurement for the post-treatment scan in
order to get a contemporaneous, state-related index of depressive symptoms at this time-point.
Anatomical Scans. Imaging was performed on a 3 T Siemens Tim Trio using a 12-channel head coil
at Imanova, London, UK. Anatomical images were acquired using the ADNI-GO (Alzheimer’s Disease
Neuroimaging Initiative, Grand Opportunity52) recommended MPRAGE parameters (1 mm isotropic vox-
els, TR = 2300 ms, TE = 2.98 ms, 160 sagittal slices, 256 × 256 in-plane FOV, flip angle = 9 degrees, band-
width = 240 Hz/pixel, GRAPPA acceleration = 2).
BOLD fMRI Resting State Acquisition. T2*-weighted echo-planar images (EPI) were acquired for the
functional scan using 3 mm isotropic voxels, TR = 2000 ms, TE = 31 ms, 36 axial slices, 192 mm in-plane FOV,
ip angle = 80 degree, bandwidth = 2298 Hz/pixel, GRAPPA acceleration = 2, number of volumes = 240, 8 min.
BOLD Pre-processing. Four dierent but complementary imaging soware packages were used to analyse
the fMRI data. Specically, FMRIB Soware Library (FSL)53, AFNI54, Freesurfer55 and Advanced Normalization
Tools (ANTS)56 were used. Fieen subjects were used for this analysis: one subject was discarded from the
analysis due to an injury in parietal cortex and three subjects were discarded due to high levels of head move-
ment. Principally, motion was measured using frame-wise displacement (FD)57. e criterion for exclusion was
subjects with >20% scrubbed volumes with a scrubbing threshold of FD = 0.5. For the 15 subjects that were
used in the analysis, there was no signicant dierence in the mean FD (meanFDbefore = 0.179 ± 0.088, mean-
FDaer = 0.158 ± 0.084, p = 0.23). e mean percentage of scrubbed volumes for before and aer treatment was
4.6 ± 5% and 3.5 ± 5.2%, respectively (p = 0.56). e maximum of scrubbed volumes for before and aer treat-
ment was 17.3% and 17.7%, respectively. e following pre-processing stages were performed: 1) removal of the
rst three volumes; 2) de-spiking (3dDespike, AFNI); 3) slice time correction (3dTshi, AFNI); 4) motion cor-
rection (3dvolreg, AFNI) by registering each volume to the volume most similar, in the least squares sense, to all
others (in-house code); 5) brain extraction (BET, FSL); 6) rigid body registration to anatomical scans (BBR, FSL);
7) non-linear registration to 2 mm MNI brain (Symmetric Normalization (SyN), ANTS); 8) scrubbing58 - using
an FD threshold of 0.5, scrubbed volumes were replaced with the mean of the surrounding volumes. 9) spatial
smoothing (FWHM) of 6 mm (3dBlurInMask, AFNI); 10) band-pass ltering between 0.01 to 0.08 Hz (3dFou-
rier, AFNI); 11) linear and quadratic de-trending (3dDetrend, AFNI); 12) regressing out 9 nuisance regressors
(all nuisance regressors were band-pass ltered with the same band-pass lter as above): out of these, 6 were
motion-related (3 translations, 3 rotations) and 3 were anatomically-related (not smoothed). Specically, the ana-
tomical nuisance regressors were: 1) ventricles (Freesurfer, eroded in 2 mm space), 2) draining veins (DV) (FSL’s
CSF minus Freesurfer’s Ventricles, eroded in 1 mm space) and 3) local white matter (WM) (FSL’s WM minus
Freesurfer’s subcortical grey matter (GM) structures, eroded in 2 mm space). Regarding local WM regression,
AFNI’s 3dLocalstat was used to calculate the mean local WM time-series for each voxel, using a 25 mm radius
sphere centred on each voxel59.
Seed-based RSFC. Based on prior hypotheses, 4 seeds were chosen for these analyses: 1) the bilateral PH,
vmPFC, sgACC and bilateral amygdala. e PH seed was constructed by combining the anterior and poste-
rior parahippocampal gyrus from the Harvard-Oxford probabilistic atlas, which was then thresholded at 50%.
e vmPFC seed was the same as one previously used by our team in analyses of the acute eects of LSD60,
psilocybin61 and MDMA62. e sgACC seed was a 5 mm sphere centred at ±2 28 -5 (MNI_152 coordinates)
based on63. Bilateral amygdala seed was based on Harvard-Oxford probabilistic atlas, threshold at 50%. Mean
time-series were derived for these seeds for each RS scan. RSFC analyses were performed using FSL’s FEAT for
each subject. Pre-whitening (FILM) was applied. A higher level analysis was performed to compare pre-treatment
and post-treatment conditions using a mixed-eects GLM (FLAME 1 + 2), cluster corrected (z > 2.3, p < 0.05).
MRIcron was used to display the results.
Resting State Networks (RSN). RSNs were derived using Independent Component Analysis (ICA) per-
formed on data acquired separately as part of the Human Connectome Project (HCP)64. is procedure is identi-
cal to one used previously with LSD60. Briey, 20 independent components (ICs) were derived, of which the same
12 functionally meaningful RSNs were identied, namely: medial visual network (VisM), lateral visual network
(VisL), occipital pole network (VisO), auditory network (AUD), sensorimotor network (SM), default-mode net-
work (DMN), parietal cortex network (PAR), dorsal attention network (DAN), salience network (SAL), posterior
opercular network (POP), le fronto-parietal network (lFP) and right fronto-parietal network (rFP).
Integrity (within-RSN RSFC). Network integrity was calculated for each RSN for both pre-treatment and
post-treatment. All 20 HCP ICA components were entered into FSL’s dual regression analysis65. e rst step of
the dual regression used the components as regressors applied to the 4D BOLD datasets for each subject, resulting
in a matrix of time-series for each ICA. e second step involved regressing these time-series into the same 4D
Content courtesy of Springer Nature, terms of use apply. Rights reserved
SCIentIfIC RePoRTs | 7: 13187 | DOI:10.1038/s41598-017-13282-7
scan data to get a subject-specic set of spatial maps (parameter estimate (PE) images). For each subject and for
each condition, within each of the 12 RSNs of interest (threshold = 3), the mean PE across voxels was calculated.
is mean PE represents the integrity value. Subsequently, paired t-tests were used to calculate the dierence in
integrity between conditions for each RSN (Bonferroni corrected for 11 RSNs, with no correction for DMN as we
had a prior hypothesis).
Segregation (between-RSN RSFC). Between-RSN RSFC was calculated in a similar manner to previ-
ous analyses involving acute LSD60 and psilocybin66. Specically, a 12 × 12 matrix was constructed representing
RSFC between dierent RSN pairs. For each subject and for each condition, the time-series for the relevant pair
of RSNs, was entered into a GLM, resulting in a PE value representing the strength of functional connectivity
between them. GLM was used rather than correlation coecients because dierences between Pearsons corre-
lations could be a result of either signal or noise dierences; therefore, it is preferable to perform regression and
look for pre-treatment and post-treatment dierences on the PE67. e GLM was estimated twice: 1) each RSN as
a dependant variable in one model, and 2) each RSN as an independent variable in the second model. ese two
PE values were then averaged together, to generate a symmetric 12 × 12 matrix (Fig.4b). ree 12 × 12 matrices
were created as follows: 1) the group mean PE values for pre-Treatment treatment, 2) the group mean PE values
for post-Treatment treatment, and 3) paired t-test to compare the PE values for the two conditions, pre-Treatment
and post-Treatment treatment (two-tailed, 5000 permutations).
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is research was supported by a Medical Research Council UK Clinical Development Pathway Funding Scheme
(DPFS). RCH is supported by the Alex Mosley Charitable Trust. DJN is supported by the Safra Foundation (DJN
is the Edmond J. Safra Professor of Neuropsychopharmacology). is report presents independent research, part
of which was carried out at the Imperial Clinical Research Facility.
Author Contributions
R.L.C.-H. designed the study, acquired the data and wrote the paper, R.L.C.-H. and L.R. conceived of the reported
analyses and L.R. performed these, M.B. was the principal study psychiatrist, L.D. helped acquire the data, J.N.P.
supervised patients and helped acquire the data, M.B.W. oversaw the scanning protocol and constructed the
scanner ratings, M.T. was the main radiographer for the study, M.K. supervised patients, J.Mc.G. advised on the
scanning protocol and analysis, K.M. advised on the A.S.L. parameters and carried out the A.S.L. analyses, R.L.
oversaw the R.S.F.C. analyses, H.V.C. was a senior collaborator on the project, D.J.N. sanctioned the study and
edited the paper. All authors viewed and approved the nal manuscript and had the opportunity to comment on
earlier dras.
Additional Information
Supplementary information accompanies this paper at
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Supplementary resource (1)

... Traditional antidepressants are poorly efficacious, require chronic dosing for symptomatic relief, and frequently fail to result in complete remission of major depression. 1,2 Psychedelics have been shown to have rapid persistent antidepressant and anxiolytic effects in humans from only one or two doses, [3][4][5][6][7][8] and antidepressant-like effects in rats [9][10][11] and fruit flies. 12 The mechanism underlying these effects is not fully understood, but it is believed to involve increased neuroplasticity. ...
... As psilocybin did reverse aCRS-induced behavioral deficits (Figs. [3][4][5], it is unlikely that Grm2 expression in the dorsal DG or ventral HIP is relevant to OPS or active coping in the FST. These data suggest that the characteristic persistent cognitive deficiencies may be a consequence of functional, not major structural differences. ...
... A single dose of psilocybin produced long-lasting normalization of pattern separation and FST activities in aCRS rats (Figs. [3][4][5], but without persistent increases in mRNA of a panel of genes relevant to synaptic density across several brain regions (Fig. 6). Although there is considerable evidence that psychedelics initiate an acute period of synaptic plasticity, 13,41 our results may indicate that functional plasticity, not structural plasticity, underlies the persistent antidepressant-like effects of psilocybin in our model. ...
... Downstream activation of glutamate receptors, NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid promote rapid neurotrophic and neuroplastic effects 128,129 . During the hyperplastic period, increased global connectivity with specific connectivity of sensory cortices has been reported [130][131][132] , followed by context-dependent reorganization after exposure 132 . Evidence suggests that therapeutic efficacy requires psychotherapy before and after exposure and is correlated with the positive quality of the psychedelic experience 133,134 . ...
... Downstream activation of glutamate receptors, NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid promote rapid neurotrophic and neuroplastic effects 128,129 . During the hyperplastic period, increased global connectivity with specific connectivity of sensory cortices has been reported [130][131][132] , followed by context-dependent reorganization after exposure 132 . Evidence suggests that therapeutic efficacy requires psychotherapy before and after exposure and is correlated with the positive quality of the psychedelic experience 133,134 . ...
... Emerging therapies and their putative circuit effectsSelective dopamine 3 receptor modulation of reward circuit processes178,179 Negative-allosteric modulator of the α-7 nicotinic acetylcholine receptor modulating negative affect circuit processes 183Glycine transporter 1 inhibitor modulating glutamatergic pathways through NMDA receptors and cognitive circuits and processes 184Neuroactive steroid and GABA A receptor agonist modulating excitatory-inhibitory GABAergic pathways and default mode connectivity 187Serotonergic hallucinogens modulating global internetwork connectivity and social reward and negative affect processes[130][131][132]135 ...
Psychiatric disorders are highly prevalent, often devastating diseases that negatively impact the lives of millions of people worldwide. Although their etiological and diagnostic heterogeneity has long challenged drug discovery, an emerging circuit-based understanding of psychiatric illness is offering an important alternative to the current reliance on trial and error, both in the development and in the clinical application of treatments. Here we review new and emerging treatment approaches, with a particular emphasis on the revolutionary potential of brain-circuit-based interventions for precision psychiatry. Limitations of circuit models, challenges of bringing precision therapeutics to market and the crucial advances needed to overcome these obstacles are presented. This Review provides a timely overview of new technological advances and treatment approaches, with a particular emphasis on brain-circuit-based interventions for precision psychiatry.
... Positron emission tomography (PET) scans show psilocybin increases in glucose metabolism in the PFC, anterior cingulate, and temporomedial cortex (66). In depressed patients, reductions in within-DMN FC has been observed after treatment with psilocybin (67)(68)(69), specifically between the vmPFC and right angular gyrus (69), and between the parahippocampus (PH) and PFC (67). Reduced PH-PFC FC has been associated with improvements in depression scores post-treatment (67), supporting the hypothesis that hyper-connectivity of the DMN underpins depressive symptoms. ...
... Positron emission tomography (PET) scans show psilocybin increases in glucose metabolism in the PFC, anterior cingulate, and temporomedial cortex (66). In depressed patients, reductions in within-DMN FC has been observed after treatment with psilocybin (67)(68)(69), specifically between the vmPFC and right angular gyrus (69), and between the parahippocampus (PH) and PFC (67). Reduced PH-PFC FC has been associated with improvements in depression scores post-treatment (67), supporting the hypothesis that hyper-connectivity of the DMN underpins depressive symptoms. ...
... However, increases in FC have been observed postpsilocybin in depressed patients between the vmPFC and the bilateral inferior lateral parietal cortex (iIPC) (67) and between the ACC and PCC (67,70). Increased vmPFC-iIPC FC (but not increased ACC-PCC FC) was associated with treatment response at 5-weeks (67). ...
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Introduction: Current treatment options for major depressive disorder (MDD) have limited efficacy and are associated with adverse effects. Recent studies investigating the antidepressant effect of serotonergic psychedelics-also known as classic psychedelics-have promising preliminary results with large effect sizes. In this context, we conducted a review of the putative neurobiological underpinnings of the mechanism of antidepressant action of these drugs. Methods: A narrative review was conducted using PubMed to identify published articles evaluating the antidepressant mechanism of action of serotonergic psychedelics. Results: Serotonergic psychedelics have serotonin (5HT)2A agonist or partial agonist effects. Their rapid antidepressant effects may be mediated-in part-by their potent 5HT2A agonism, leading to rapid receptor downregulation. In addition, these psychedelics impact brain derived neurotrophic factor and immunomodulatory responses, both of which may play a role in their antidepressant effect. Several neuroimaging and neurophysiology studies evaluating mechanistic change from a network perspective can help us to further understand their mechanism of action. Some, but not all, data suggest that psychedelics may exert their effects, in part, by disrupting the activity of the default mode network, which is involved in both introspection and self-referential thinking and is over-active in MDD. Conclusion: The mechanisms of action underlying the antidepressant effect of serotonergic psychedelics remains an active area of research. Several competing theories are being evaluated and more research is needed to determine which ones are supported by the most robust evidence.
... 5-HT2AR signaling has also been shown to enhance neural plasticity, the capacity of the brain to adapt and change by making new synaptic connections and neural pathways (Carhart-Harris et al., 2017, p. 1091. Catlow et al. (2013) stated that chemicals that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis, the production of new neurons (Catlow et al., 2013, p. 481). ...
Psychedelic compounds have shown extraordinary potential in treating a wide range of neuropsychiatric disorders. Psilocybin, for example, has now been shown in several clinical trials to induce a rapid (within days) and persistent (3-12 months) improvement in human major depressive disorder, treatment-resistant depression, and other neuropsychiatric conditions. Here we review the preclinical models and experimental approaches that have been used to study the neurobiological actions of psychedelic drugs. We further summarize the insights these studies have provided into the possible mechanisms underlying the induction of these therapeutic actions, including the receptors to which psychedelics bind and the second messenger signaling cascades that they activate. We also discuss potential biological processes that psychedelics may alter to produce the lasting amelioration of symptoms, including improvements in synaptic structure and function and suppression of inflammation. Improved mechanistic understanding of psychedelic drug actions will aid in the advancement of these promising new medicines.
Psychiatry has a promising future at this point of time as we are getting close to starting the second quarter of the twenty-first century. Expansions in different dimensions of the field are exponential. This chapter is an attempt at capturing some of the most significant future directions in the field including biological, psychological, social, technological, financial, educational, and legal aspects of the field spanning across etiological, diagnostic, therapeutic, and preventative future directions.
Recent studies have demonstrated the promise of psilocybin therapies in creating positive changes for those with poor mental health across multiple diagnostic categories, including major depressive disorder (MDD), end-of-life anxiety, and obsessive-compulsive disorder (OCD). While there may be a large population that is eligible to participate in psilocybin therapy based on psychiatric diagnosis and medical clearance, little attention has been given to intrapersonal and interpersonal factors that might influence patient's readiness (i.e., eligibility and capacity) for psychedelic interventions. This paper proposes that readiness assessment includes both intrapersonal and interpersonal factors in order to improve safety, patient care, and treatment outcomes. While at the present time a reliable and valid instrument has not been developed, we propose that three specific areas of focus - patient presentation, therapeutic alliance, and patient safety - may be used to establish a patient's readiness for psilocybin therapy, thus increasing therapy optimization and personalization.
In this thesis, the author investigates the therapeutic potential of psychedelics through literature analysis. First, he places psychedelics in a historical context and presents the current legal regime. Through the presentation of the psychedelic experience through aspects of safety, physiological effects, neurobiological effects and psychological effects, the author answers the question of how, if at all, psychedelics work in combination with psychotherapy. In the discussion, the author notes that psychedelics: (a) create new connections between different centers in the brain; (b) release high-level beliefs of the default brain network, (c) reduce normal ego functions, (d) enhance feelings of connection with others, nature and self and lead from avoidance of emotions to acceptance; (e) affect the personality structure.
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Background: Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine (DMT) and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network (DMN), purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers, and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here we investigated in an open-label uncontrolled study in sixteen healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications, and their association with mindfulness measures. Methods: Using 1H-magnetic resonance spectroscopy (MRS) and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior (PCC) and anterior (ACC) cingulate cortex after a single ayahuasca dose. Results: MRS showed post-acute reductions in Glx (glutamate+glutamine), creatine and NAA-NAAG (N-acetylaspartate+N-acetylaspartylglutamate) in the PCC. Connectivity was increased between the PCC and the ACC, and between the ACC and limbic structures in the right medial temporal lobe (MTL). Glx reductions correlated with increases in the "Non-Judging" subscale of the Five Facets Mindfulness Questionnaire. Increased ACC-MTL connectivity correlated with increased scores on the Self-Compassion questionnaire. Post-acute neural changes predicted sustained elevations in "Non-Judging" two months later. Conclusions: These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the PCC, a key region within the DMN, and increased connectivity between the ACC and MTL structures involved in emotion and memory, potentially underlie the post-acute psychological effects of ayahuasca.
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Plant-based psychedelics such as psilocybin have an ancient history of medicinal use. After the first English-language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aides to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programmes. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and 3 separate clinical trials of psilocybin for depressive symptoms. In this Circumspective piece, Robin Carhart-Harris and Guy Goodwin share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.Neuropsychopharmacology accepted article preview online, 26 April 2017. doi:10.1038/npp.2017.84.
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Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. Trial Registration identifier: NCT00465595
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Background: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. Trial registration: Identifier: NCT00957359.
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Background: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. Methods: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. Findings: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. Interpretation: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. Funding: Medical Research Council.
The functional neuroanatomy of unipolar major depression was investigated using positron emission tomography to measure differences in regional cerebral blood flow (BF). A relatively homogeneous subject group was obtained using criteria for familial pure depressive disease (FPDD), which are based upon family history as well as upon symptoms and course. Because of the absence of certain knowledge about the pathophysiology of mood disorders and their underlying functional neuroanatomy, we used data obtained from the subtraction of composite images from one-half of depressed and control subjects to identify candidate regions of interest. The major cortical region defined in this manner was statistically tested on a second set of subjects. Using this strategy, we found increased BF in an area that extended from the left ventrolateral prefrontal cortex onto the medial prefrontal cortical surface. Based upon the connectivity between these portions of the prefrontal cortex and the amygdala and evidence that the amygdala is involved in emotional modulation, activity was measured in the left amygdala and found to be significantly increased in the depressed group. A separate group of subjects with FPDD who were currently asymptomatic were also imaged to determine whether these findings represented abnormalities associated with the depressed state, or with a trait difference that might underlie the tendency to become depressed. Only the depressed group had increased activity in the left prefrontal cortex, suggesting that this abnormality represents a state marker of FPDD. Both the depressed and the remitted groups demonstrated increased activity in the left amygdala, though this difference achieved significance only in the depressed group. This suggests that the abnormality involving the left amygdala may represent a trait marker of FPDD, though further assessment in a larger sample size is necessary to establish this. These data along with other evidence suggest that a circuit involving the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and medial thalamus is involved in the functional neuroanatomy of depression.
Psilocybin, the active compound in psychedelic mushrooms, is an agonist of various serotonin receptors. Seminal psilocybin positron emission tomography (PET) research suggested regional increases in glucose metabolism in frontal cortex (hyperfrontality). However, a recent arterial spin labeling (ASL) study suggests psilocybin may lead to hypo-perfusion in various brain regions. In this placebo-controlled, double-blind study we used pseudo-continuous ASL (pCASL) to measure perfusion changes, with and without adjustment for global brain perfusion, after two doses of oral psilocybin (low dose: 0.160 mg/kg; high dose: 0.215 mg/kg) in two groups of healthy controls (n = 29 in both groups, total N = 58) during rest. For all neuroimaging analyses we controlled for sex and age and used family-wise error corrected p values. Both dose groups reported profound subjective drug effects as measured by the Altered States of Consciousness Rating Scale (5D-ASC) with the high dose inducing significantly larger effects in four out of the 11 scales. After adjusting for global brain perfusion, psilocybin increased relative perfusion in distinct right hemispheric frontal and temporal regions and bilaterally in the anterior insula and decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions. Whereas, psilocybin significantly reduced absolute perfusion in frontal, temporal, parietal, and occipital lobes, and bilateral amygdalae, anterior cingulate, insula, striatal regions, and hippocampus. Our analyses demonstrate consistency with both the hyperfrontal hypothesis of psilocybin and the more recent study demonstrating decreased perfusion, depending on analysis method. Importantly, our data illustrate that relative changes in perfusion should be understood and interpreted in relation to absolute signal variations.
Objective: To identify patients’ perceptions of the value of psilocybin as a treatment for depression. Method: Twenty patients enrolled in an open-label trial of psilocybin for treatment-resistant depression participated in a semistructured interview at 6-month follow-up. Thematic analysis was used to identify patients’ experiences of the treatment and how it compared with previous treatments. Results: Two main change processes were identified in relation to the treatment. The first concerned change from disconnection (from self, others, and world) to connection, and the second concerned change from avoidance (of emotion) to acceptance. A third theme concerned comparison between psilocybin and conventional treatments. Patients reported that medications and some short-term talking therapies tended to reinforce their sense of disconnection and avoidance, whereas treatment with psilocybin encouraged connection and acceptance. Conclusions: These results suggest that psilocybin treatment for depression may work via paradigmatically novel means, antithetical to antidepressant medications, and some short-term talking therapies.
Background: Functional connectivity in the "default mode network" (DMN) is changed in depression, and evidence suggests depression also affects the DMN's spatial topography and might cause a dissociation between its anterior and posterior regions. As antidepressive treatment affects anterior and posterior regions of the network differently, how depression and treatment change DMN-organization is crucial for understanding their mechanisms. We present a novel way of assessing the coherence of a network's regions to the network as a whole, and apply this to investigate treatment-resistant depression and the effects of electroconvulsive therapy (ECT). Methods: Resting-state functional MRI was collected from 16 patients with treatment-resistant depression before and after ECT and 16 healthy controls matched for age and sex. For each subject, the mean time series of the DMN was used as a regressor for each voxel within the DMN, creating a map of "network coherence" (NC). The obtained maps were compared across groups using permutation testing. Results: NC was significantly decreased in depressed subjects in the precuneus and the angular gyrus. With ECT the NC normalized in responders (n=8), but not in non-responders (n=8). Conclusions: We present a novel method of investigating within-network coherence and apply this to show that in depression, a large area of the DMN shows a decrease in coherence to the network as a whole. Although tentative due to the small sample size, we find that this effect is not present after ECT in those improving clinically, but persists in patients not responding to ECT.
Personality is known to be relatively stable throughout adulthood. Nevertheless, it has been shown that major life events with high personal significance, including experiences engendered by psychedelic drugs, can have an enduring impact on some core facets of personality. In the present, balanced-order, placebo-controlled study, we investigated biological predictors of post-lysergic acid diethylamide (LSD) changes in personality. Nineteen healthy adults underwent resting state functional MRI scans under LSD (75µg, I.V.) and placebo (saline I.V.). The Revised NEO Personality Inventory (NEO-PI-R) was completed at screening and 2 weeks after LSD/placebo. Scanning sessions consisted of three 7.5-min eyes-closed resting-state scans, one of which involved music listening. A standardized preprocessing pipeline was used to extract measures of sample entropy, which characterizes the predictability of an fMRI time-series. Mixed-effects models were used to evaluate drug-induced shifts in brain entropy and their relationship with the observed increases in the personality trait openness at the 2-week follow-up. Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness. Moreover, the predictive power of the entropy increases was greatest for the music-listening scans and when "ego-dissolution" was reported during the acute experience. These results shed new light on how LSD-induced shifts in brain dynamics and concomitant subjective experience can be predictive of lasting changes in personality. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.