Decreased brain modularity after psilocybin therapy for depression.

Abstract

Importance Psilocybin therapy shows antidepressant potential; our data link its antidepressant effects to decreased brain network modularity post-treatment. Objective To assess the sub-acute impact of psilocybin on brain activity in patients with depression. Design Pre vs post-treatment resting-state functional MRI (fMRI) was recorded in two trials: 1) Open-label treatment-resistant depression (TRD) trial with baseline vs 1 day post-treatment fMRI (April-2015 to April-2016); 2) Two-arm double-blind RCT in major depressive disorder (MDD), fMRI baseline vs 3 week after psilocybin-therapy or 6 weeks of daily escitalopram (January-2019 to March-2020). Setting Study visits occurred at the NIHR Imperial Clinical Research Facility.Participants Adult male and female patients with TRD or MDD. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies)Study 1: Two oral doses of psilocybin (10mg and 25mg, fixed order, 7 days apart). fMRI was recorded at baseline and one day after the 25mg dose. Study 2: either: 2 x 25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin-arm’), or 2 x 1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram [10-20mg] (‘escitalopram-arm’). fMRI was recorded at baseline and 3 weeks after the 2nd psilocybin dose, which was the final day of the 6-week daily capsule ingestion. Main Outcome(s) and Measure(s) Beck Depression Inventory and fMRI network modularity. Results Study 1: In 16 adults (mean age [SD], 42.8 [10.1] years, 4 [25%] female), psilocybin therapy was associated with markedly decreased BDI scores at 1 week (mean difference, -21; 95% CI=[-27.3, -14.7], P<.001) and 6 months (mean difference, -14.19; 95% CI=[-21.3, -7.1], P<.001). Decreased network modularity at one day post-treatment correlated with treatment response at 6 months (Pearson, 0.64; P=.01). Study 2: In 43 adults (42.7 [10.5] years, 14 [33%] female), antidepressant effects favoured the psilocybin-arm at 2 (mean difference, -8.76; 95% CI=[-13.6, -3.9], P=.002) and 6 weeks (mean difference, -8.78; 95% CI=[-15.6, -2.0], P=.01). Specific to the psilocybin-arm, improvements at the 6-week primary endpoint correlated with decreased network modularity (Pearson, -0.42, P=.025). Conclusions and Relevance Consistent efficacy-related functional brain changes correlating with robust and reliable antidepressant effects across two studies suggest a candidate antidepressant mechanism for psilocybin therapy: decreased brain network modularity. Trial registration ClinicalTrials.gov identifier: NCT03429075

Psilocin, LSD, mescaline, and DOB all induce broadband desynchronization of EEG and disconnection in rats with robust translational validity

“…At the same time, LSD has been shown to have a time-biphasic behavioral effect: the first phase lasting approximately an hour is mediated by 5-HT2A receptors, and the second phase that follows is mediated by D2 and D4 receptors [65][66][67]. Indeed, D2 and D4 receptor agonist promotes a EEG power increase within the frequency range of the alpha band (8)(9)(10)(11)(12) [68,69]. In our previous study, we also showed that mescaline had potent stimulatory locomotor effects in a novel environment [19].…”

“…One of the hypothesized mechanisms underlying their unique and rapid effects is explained by dramatically switching the brain functional connectivity states (for more see refs. [10][11][12]) which may be evaluated by functional neuroimaging methods such as PET, fMRI, or EEG.…”

Rediscovering Psilocybin as an Antidepressive Treatment Strategy

“…A further analysis also considered the fMRI data of a phase 2 trial on psilocybin vs. escitalopram, focusing on neural network modularity. Although this preprinted study is currently still under review and results have to be considered as preliminary, the authors observed a significantly reduced brain network modularity [56]. According to these neuroimaging findings with differential acute and short-term post-treatment effects, one hypothesis regarding the mechanism of psilocybin is that the 5-HT 2A -agonism may provoke an "entropic brain state" suggestive for "resetting" brain networks, particularly within DMN [14].…”

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

“…This might explain the relative increases in connectivity with the non-DMN associated areas in previous work, and the non-ECN associated areas in the current results. This is an emerging concept in work on classic psychedelics, has been shown with acute challenge studies (Petri et al, 2014), and may also be related to clinical anti-depressive effects of psychedelic therapy (Daws et al, 2021). Further work will be needed with specialised analysis techniques to investigate this possibility.…”