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Psilocybin 'Rewires' the Brain to Alleviate Depression

New research points to a general mechanism that may explain how psychedelics act on the brain to alleviate depression and potentially other psychiatric conditions marked by fixed patterns of thinking, including ruminationand excessive self-focus.

Led by investigators from the University of California San Francisco and Imperial College London's Centre for Psychedelic Research, the findings come from a new analysis of brain scans of almost 60 patients with resistant depression treated with psilocybin.

"Not much is known about the changes in brain function after psychedelic experience. There has been much more research done on the acute brain action of psychedelics, but there is very little on the post-acute or subacute changes in brain function," study investigator Robin Carhart-Harris, PhD, former head of the Imperial Centre for Psychedelic Research and now director of the Neuroscape Psychedelics Division at UCSF, and senior author of the study, told Medscape Medical News.

"This research is a major advance because it is showing replication across two datasets with different designs. One in which the scanning is done 1 day after intervention and the other one when the posttreatment scanning is done 3 weeks after the second of two psilocybin therapy sessions," Carhart-Harris added.

The study was published online today in Nature Medicine.

A Disruptor?

Psilocybin is one of a number of psychedelics under investigation as a potential therapy for psychiatric disorders. In the last 15 years, at least six separate clinical trials have reported impressive improvements in depressive symptoms with psilocybin therapy. Several studies have tested a synthesized a form of the drug to treat patients with depression and anxiety — with promising results.

However, the therapeutic action of psilocybin and other serotonergic psychedelics is still not completely understood, although it is known that they affect 5-HT2A receptors and are hypothesized to briefly disrupt these connections, allowing them to reform in new ways in the days and weeks following treatment.

This research assessed the subacute impact of psilocybin on brain function in two clinical trials of depression:

The first trial was an open-label trial of oral psilocybin in patients with treatment-resistant depression.

Patients had baseline clinical assessment and resting-state functional MRI, followed by fixed-order "low" (10 mg) and "high" (2 5mg) psilocybin therapy dosing days separated by 1 week. Of the 19 patients recruited, three were excluded as a result of excessive fMRI head-motion. The team confirmed an antidepressant effect of psilocybin in 16 patients via reduced questionnaire scores from baseline.

Brain network modularity was significantly reduced 1 day after psilocybin therapy in 10 of 16 participants (mean difference, −0.29; t15 = 2.87, 95% CI 0.07 - 0.50, P = .012, d = .72). This result implies an increase in functional connectivity between the brain's main intrinsic networks. Pre- vs post-treatment change in modularity significantly correlated with change in Beck Depression Inventory (BDI) score at 6 months, relative to baseline (r14 = 0.54, 95% CI, 0.14 - 0.78, P = .033). Results imply that decreased brain modularity 1 day after psilocybin therapy relates to long-term improvements in symptom severity. Effective Antidepressant Alternative? The second trial was a double-blind phase 2 randomized controlled trial comparing psilocybin with escitalopram (Lexapro). Twenty-one patients were included in the escitalopram imaging sample and 22 patients were included in the psilocybin imaging sample.

Patients received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). Functional MRI was recorded at baseline and 3 weeks after the second psilocybin dose.

On average, BDI-measured reductions in depressive symptom severity were significantly greater under psilocybin than escitalopram, indicating superior efficacy of psilocybin therapy vs escitalopram.

Evidence indicated that the reduction in network modularity and its relationship to depression severity was specific to the psilocybin group. In the escitalopram group, network modularity did not change from baseline and there was no significant correlation between changes in modularity and changes in BDI scores.

Post-psilocybin therapy changes in network flexibility were correlated with changes in BDI score. After FDR-correction, increased executive network (EN) dynamic flexibility strongly correlated with greater symptom improvement at the 6-week primary endpoint for the psilocybin arm (r20 = −0.76, 95% CI, −0.90 to −0.50, P = .001). There were no significant correlations between changes in BDI scores and changes in dynamic flexibility in the escitalopram arm. "These findings are important because for the first time we find that psilocybin works differently from conventional antidepressants, making the brain more flexible and fluid and less entrenched in the negative thinking patterns associated with depression. This supports our initial predictions and confirms psilocybin could be a real alternative approach to depression treatments," study investigator David Nutt, DM, head of the Imperial Centre for Psychedelic Research in London, said in a release. "In previous studies we had seen a similar effect in the brain when people were scanned whilst on a psychedelic, but here we're seeing it weeks after treatment for depression, which suggests a carry-over of the acute drug action," said Carhart-Harris. Durable Effect? "We don't yet know how long the changes in brain activity seen with psilocybin therapy last, and we need to do more research to understand this," said Carhart-Harris, who is a member of the UCSF Weill Institute for Neurosciences. "If the changes don't last, then is it related to relapse into a depressive episode?" adds Carhart-Harris. "We need to do follow up scans to see where people's brains are at 3 months or even 6 months after treatment. "We do know that some people relapse, and it may be that after a while their brains revert to the rigid patterns of activity we see in depression. "One exciting implication of our findings is that we have discovered a fundamental mechanism via which psychedelic therapy works not just for depression but other mental illnesses, such as anorexia or addiction. We now need to test if this is the case, and if it is, then we have found something important," added Carhart-Harris. Successful phase 3 double-blind RCTs will be required to achieve licensing for psilocybin therapy, but pragmatic trials may better address questions regarding treatment practicability, specificity, and optimization. Given the emerging research into psychedelic therapy, it is important for large-scale trials to establish the generalizability, reliability, and specificity of the drug's antidepressant response. So how close are we to full federal approval for psilocybin in the treatment of depression? Carhart-Harris estimates that within 4-5 years is realistic at the federal level. At the state level, in Oregon psilocybin therapy is on track for approval next year, including for patients currently undergoing treatment for depressive disorders. In addition, things are opening up in Canada, with some special-access opportunities, he said. The researchers caution that while these findings are encouraging, trials assessing psilocybin for depression have taken place under controlled, clinical conditions, using a regulated dose formulated in a laboratory, and involved extensive psychological support by a mental health professional — before, during, and after dosing. Taking psychedelics in the absence of these combined safeguards may not have a positive outcome. The research was supported by funding from the Alex Mosley Charitable Trust and founding donors of the Imperial Centre for Psychedelic Research. First author Richard Daws, PhD, who is now based at King's College London, was supported by the Imperial College London EPSRC Centre London for Doctoral Training (CDT) in Neurotechnology. Nature Medicine. Published online April 11, 2022. Full text

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