Up to 30% of people with depression don’t respond to treatment with anti-depressants – possibly due to differences in biology between patients and that it often takes a long time to respond to the drugs – with some people quitting then after a while.
But various clinical trials are increasingly proving that psychedelics like psilocybin, the active compound in “magic mushrooms, can rapidly treat depression, including for cancer-related anxiety and depression.
Yet, writes Clare Tweedy, Teaching Fellow in Neuroscience, University of Leeds, in The Conversation, little is known about how psilocybin actually works to relieve depression in the brain.
Two studies, published in The New England Journal of Medicine and Nature Medicine, have shed some light on this mysterious process.
Psilocybin is a hallucinogen that changes the brain’s response to a chemical called serotonin. When broken down by the liver (into “psilocin”), it causes an altered state of consciousness and perception in users.
Previous studies, using functional MRI (fMRI) brain scanning, have shown that psilocybin seems to reduce activity in the medial pre-frontal cortex, an area of the brain that helps regulate numerous cognitive functions, including attention, inhibitory control, habits and memory. The compound also decreases connections between this area and the posterior cingulate cortex, an area that may play a role in regulating memory and emotions.
An active connection between these two brain areas is normally a feature of the brain’s “default mode network”. This network is active when we rest and focus internally. By reducing the activity of the network, psilocybin could be removing the constraints of the internal “self” – with users reporting an “opened mind” with increased perception of the world around them.
Interestingly, rumination, a state of being “stuck” in negative thoughts, particularly about oneself, is a hallmark of depression. And we know that patients with higher levels of negative rumination tend to show increased activity of the default mode network compared with other networks at rest – literally becoming less responsive to the world around them. It remains to be seen, however, if the symptoms of depression cause this altered activity, or if those with a more active default mode network are more prone to depression.
The most compelling evidence of how psilocybin works comes from a double-blind randomised controlled trial (the gold-standard of clinical studies) that compared a group of depressed people taking psilocybin with those taking the existing anti-depressant drug escitalopram – something that’s never been done before. The trial was further analysed using fMRI brain scans, and the results were compared with other fMRI findings from another recent clinical trial.
Just one day after the first dose of psilocybin, fMRI measures revealed an overall increase in connectivity between the brain’s various networks, which are typically reduced in those with severe depression. The default mode network was simultaneously reduced, while connectivity between it and other networks was increased – backing up previous, smaller studies.
The dose increased connectivity more in some people than others. But the studies showed those who had the biggest boost in connection between networks also had the greatest improvement in their symptoms six months later.
The brains of people taking escitalopram, on the other hand, showed no change in connectivity between the default mode and other brain networks six weeks after treatment started. It is possible that escitalopram may bring about changes at a later point. But the rapid onset of psilocybin’s anti-depressant effect means it may be ideal for people who don’t respond to existing anti-depressants.
The study proposes that the observed effect may be due to psilocybin having more concentrated action on receptors in the brain called “serotonergic 5-HT2A receptors” than escitalopram. These receptors are activated by serotonin and are active throughout network brain areas, including the default mode network. We already know that the level of binding by psilocybin to these receptors leads to psychedelic effects. Exactly how their activation leads to changes in network connectivity is still to be explored though.
The end of traditional antidepressants?
This raises the question of whether altered activity of the brain’s networks is required for treating depression. Many people taking traditional anti-depressants still report an improvement in their symptoms without it. In fact, the study showed that, six weeks after starting treatment, both groups reported improvement in their symptoms.
According to some depression rating scales, however, psilocybin had the greatest effect on overall mental well-being. And a greater proportion of patients treated with psilocybin showed a clinical response compared with those treated with escitalopram (70% versus 48%). More patients in the psilocybin group were also still in remission at six weeks (57% versus 28%). The fact that some patients still do not respond to psilocybin, or relapse after treatment, shows just how difficult it can be to treat depression.
What’s more, mental health professionals supported both treatment groups during and after the trial. The success of psilocybin is heavily dependent on the environment in which it is taken. This means it is a bad idea to use it for self-medicating. Also, patients were carefully selected for psilocybin-assisted therapy based on their history to avoid the risk of psychosis and other adverse effects.
Regardless of the caveats, these studies are incredibly promising and move us closer to expanding the available treatment options for patients with depression. What’s more, internalised negative thought processes are not specific to depression. In due course, other disorders, such as addiction or anxiety, may also benefit from psilocybin-assisted therapy.
Study 1 details
Increased global integration in the brain after psilocybin therapy for depression
Richard E. Daws, Christopher Timmermann, Bruna Giribaldi, James D. Sexton, Matthew B. Wall, David Erritzoe, Leor Roseman, David Nutt & Robin Carhart-Harris
Published in Nature Medicine on 11 April 2022
Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck’s depression inventory was the primary outcome measure (MR/J00460X/1). The second trial was a double-blind phase II randomised controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder 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’). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose (NCT03429075).
In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin’s antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organisation were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.
Study 2 details
Trial of Psilocybin versus Escitalopram for Depression
Robin Carhart-Harris, Bruna Giribaldi, Rosalind Watts, Michelle Baker-Jones, Ashleigh Murphy-Beiner, Roberta Murphy, Jonny Martell, Allan Blemings, David Erritzoe, and David J. Nutt.
Published in NEJM on 15 April 2021
Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.
In a phase 2, double-blind, randomised, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support.
The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.
A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favoured psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.
On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favoured psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants.
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