Psilocybin, the psychoactive compound in “magic mushrooms,” is a promising intervention for patients with treatment-resistant depression (TRD) and appears to offer a rapid, sustained effect, new research shows.
Investigators led by David Nutt, MD, PhD, professor of neuropsychopharmacology, Imperial College, London, United Kingdom, collected pre- and posttreatment fMRI data on the use of psilocybin in 19 patients with severe major depression who had failed to respond to conventional treatments.
The patients experience dramatic improvements in depressive symptoms 1 day following treatment; close to half met criteria for full response at 5 weeks.
Whole-brain analyses showed post-treatment decreases in cerebral blood flow (CBF) in the temporal cortex, including the amygdala, which correlated with reduced depressive symptoms.
Moreover, increased connectivity was found in resting state functional connectivity (RSFC) and reintegration in the default mode network (DMN), suggested a larger “reset” mechanism.
“In depression, people get hooked into ruminative states in which they can’t stop thinking the thoughts underlying their depression, even if they want to,” Dr Nutt told Medscape Medical News.
“During exposure to psilocybin, the brain is in a different, more fluid state, where it is not possible to continue having their traditional negative thinking patterns, and in the majority, the brain resets into a nondepressive mode,” he said.
The study was published online October 13 in Scientific Reports.
A growing body of evidence has demonstrated that the use of psilocybin, in conjunction with appropriate psychological support, can facilitate emotional breakthrough, the authors write.
Prior research has found that psilocybin is helpful in treating a variety of psychiatric conditions, including end-of-life anxiety and depression, alcohol and tobacco addiction, and obsessive-compulsive disorder. A previous study conducted by Dr Nutt’s group found that it was also helpful in TRD.
These findings, coupled with research demonstrating that psilocybin and other psychedelics have “rapid and lasting positive impact on mental health” in healthy volunteers, raise an important question: What brain mechanisms mediate these effects?
fMRI has been used in previous studies to examine neural correlates in persons experiencing the acute effects of the “psychedelic state.” Findings suggest psychedelics “appear to dysregulate cortical activity, producing an ‘entropic’ brain state characterized by compromised modular but enhanced global connectivity ― referred to previously as network ‘disintegration’ and ‘desegregation.’ ”
These changes have been found to be “predictive of post-acute changes in the personality domain of ‘openness,’ ” the authors report.
However, only one other study investigated the effects of psychedelics on human brain function more than 12 hours after acute effects, and few studies have examined anatomic changes that might be related to psychedelic use.
To fill this gap, the researchers compared changes in brain function before and after administering psilocybin to patients with TRD. The patients received two doses of the drug (10 mg followed by 25 mg) 1 week apart as part of an open-label clinical trial.
The researchers used arterial spin labeling (ASL) and blood oxygen level– dependent (BOLD) RSFC to measure changes in cerebral blood flow (CBF) and functional connectivity before (baseline) and 1 day after treatment with the 25-mg dose of psilocybin.
The rationale for rescanning the brain 1 day later is based on research suggesting that the days following a psychedelic experience “constitute a distinct phase, referred to as the ‘afterglow,’ that is characterized by mood improvements and stress relief.”
The researchers sought to capture brain changes during that afterglow period that might be correlated with current mood improvements or with longer-term prognoses.
They chose to focus on a 5-week posttreatment endpoint as a result of a “virtual 50:50 split between responders and non-responders at that time point.” Within that time frame, none of the patients received additional treatments, which would have confounded the findings.
Of the 19 patients who completed pretreatment and day-1 posttreatment fMRI scanning, three experienced excessive movement or other artifact and were removed from the ASL analysis. Four were removed from the RSFC analysis, leaving samples sizes of 16 (mean age, 42.8 ± 10.1 years; four women) for the ASL and 15 (mean age, 42.8 ± 10.5 years; four women) for BOLD analyses.
Treatment with psilocybin produced “rapid and sustained antidepressant effects,” the authors report.
For the patients included in the ASL analysis (not including one patient whose first scan rating was not collected), the mean depression score, as determined on the basis of the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) for the week prior to the pretreatment scan, was 16.9 ± 5.1. For the day of the posttreatment scan, it was 8.8 ± 6.2 (change, −8.1 ± 6; t = −5.2; P < .001).
At 5 weeks posttreatment, the mean QIDS-SR16 score was 10.9 ± 4.8, down from 18.9 ± 3 at baseline screening (change, −8 ± 5.1; t = −6.3; P < .001).
For those included in the BOLD analyses, the mean change values were −7.3 ± 5.3 (change from scan 1 to scan 2) and −8.2 ± 5.2 (change from baseline to 5 weeks posttreatment).
The researchers described both contrasts as “highly significant" (t = −5.2 and t = −6.2; P < .001).
At 5 weeks, six of the BOLD and 16 of the ASL patients met criteria for treatment response, defined by ≤50% reductions in QIDS-SR16 score. All of the 19 study patients showed some decrease in depressive symptoms at 1 week, with 12 meeting criteria for response (change, −10.2 ± 5.3; t = −6.4; P < .001).
Of the 19 study patients, 18 showed some decrease in QIDS-SR16 score at week 5, and 47% met criteria for response (change, −9.2 ± 5.6; t = −6.7; P < .001).
Impact of the Psychedelic Experience
Pre- and posttreatment whole-brain CBF analyses showed posttreatment decreases that reached statistical significance in the left Heschl’s gyrus, the left precentral gyrus, the left planum temporale, the left superior temporal gyrus, the left amygdala, the right supramarginal gyrus, and the right parietal operculum.
The researchers compared the reductions in amygdala CBF with the reductions in depressive symptoms between scan 1 and 2 and found a significant relationship (r = 0.59; P = 0.01), consistent with previous research suggesting increased amygdala blood flow and metabolism in depression. However, these changes lost significance when, at posttreatment week 5, the sample was split into those who demonstrated a response and those who did not and a comparison was made with CBF changes in a t-test, (t = 0.11; P = .46).
The researchers then utilized seed-based RSFC analyses of BOLD data. They focused on four regions of interest in the brain: the subgenual anterior cingulate cortex (sgACC), the ventromedial prefrontal cortex (vmPFC), the bilateral amygdala, and the bilateral parahippocampus (PH). These regions were chosen on the basis of previous data that implicated their involvement in the pathophysiology of depression and response to antidepressive treatments.
Of these comparisons, increased vmPFC RSFC within the bilateral inferior-lateral parietal cortex (ilPC) posttreatment predicted treatment response at 5 weeks, with responders showing significantly greater vmPFC-ilPC RSFC increases than nonresponders (t = 2.1; P = 0.03).
Decreased PH RSFC was observed with a PFC cluster that incorporated the lateral and medial prefrontal cortex, which related to treatment response at 5 weeks, when responders showed significantly greater PH-PFC RSFC decreases than nonresponders (t = −1.9, P = 0.04).
During analyses of within-network RSFC, using 12 previously identified canonical resting state networks (RSNs), the researchers found increased 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 posttreatment. However, after further statistical analyses, these changes did not significantly correlate with depression outcomes.
Similarly, although study of between-network RSFC using the same 12 RSNs revealed decreased RSFC between the DMN and right frontoparietal network (rFP) (t = −3.6; P = .0031) and increased RSFC between the sensorimotor network (SM) and rFP (t = 2.2; P = .045), the effects did not reach statistical significance after further statistical analysis.
The researchers wanted to ascertain whether the psychedelic experience may have mediated the postacute brain changes. They found that the greatest decreases in PH RSFC in limbic (eg, bilateral amygdala) and DMN-related cortical regions occurred in the patients who scored highest on “peak” or “mystical” experience.
The findings of this study “suggest that changes in brain activity observed just one-day after a high dose psychedelic experience are very different to those found during the acute psychedelic state,” the researchers note.
“Specifically, whereas the acute psychedelic state in healthy volunteers is characterized by modular disintegration and global integration, there are trends towards modular (re)integration and minimal effects on global integration/segregation post psilocybin for depression.”
“There were several noteworthy changes that we observed,” said Dr Nutt. “The first is that the amygdala, which is related to negative emotion, calmed down, which is what happens if a person takes antidepressants for a few weeks and is one of the most reliable impacts of antidepressants.”
The reason, he explained, is that psilocybin “works on 5HT 2A receptors, which fast-forwards what an antidepressant might do over a longer period.”
A second important finding of the study is the change in the DNN, which is related to internal thinking about the self, the past, and other aspects and that get “locked into a particular pattern during depression.”
He described the DNN as having a whole series of different modes, “like a complicated metro map within the brain.” Some connections were enhanced during the study, and others were reduced following treatment, “consistent with the idea that the drug remodels brain connectivity.”
Patients described their posttreatment experience as a “reset” or a “reboot,” possibly indicating the experiential impact of this DNN remodeling.
Dr Nutt acknowledged that he was not surprised by the outcome of improvements in depression, but he was surprised by some of the imaging data. Although the brains of healthy volunteers do reset following administration of psilocybin, they “reset differently” from those of patients with depression.
“What we wanted to do was to break up the default modes, which are abnormal in depression. It turns out that different parts of the default mode are involved with different aspects of depression, maybe some with depression itself and others with getting over depression.”
He noted that there was a “strong relationship” between enhanced peak experiences, referred to by some as mystical states, and improvement in depression but cautioned that “this does not necessarily mean that these experiences will predict antidepressant effects.”
"Groundbreaking" Psychedelic Science
Commenting on the study for Medscape Medical News, Frederick Barrett, PhD, assistant professor of psychiatry and behavioral sciences, Behavioral Pharmacology Research Unit, Johns Hopkins School of Medicine, Baltimore, Maryland, called the study “groundbreaking” and described Dr Nutt’s team as “a very productive and influential group doing psychedelic science.”
The study “begins to put some dimensions to the potential neurobiological basis of the therapeutic effects of psychedelics, since preliminary evidence has suggested that they might be useful in treating mood disorders and addiction,” he said.
He noted that the study is limited because it had an open-label design without a control group, “in the order of a phase 1 study, when you are asking whether a drug has any effect and is worth continuing to study.”
In answering this question, “the original preliminary 2016 study by the same researchers exceeded expectations in its outcome, and now the follow-up with neuroimaging adds weight.”
The small sample size is also a limitation, but, again, the design of the study is similar designs often used in phase 1 studies, he said.
He cautioned that individuals should not try to self-medicate with psilocybin. “In the absence of FDA [US Food and Drug Administration] approval, there is no immediate clinical path. But this research can lead to other clinical trials, which, if successful, would lead to clinical application.”
Dr Nutt agreed that it is premature to treat TRD with psilocybin, but that further research could pave the way to its future use in clinical practice.
“These drugs can revolutionize our understanding of the brain. Depression is one of the most dangerous mental illnesses, and the use of psilocybin as a potential treatment is not something to be ignored.”
This research was supported by the Medical Research Council UK, the Alex Mosley Charitable Trust, and the Safra Foundation. The study presents independent research, part of which was carried out at the Imperial Clinical Research Facility. The authors have disclosed no relevant financial relationships.
Sci Reports. Published online October 13, 2017. Full text
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