Factory reset for the brain- Is this how psilocybin works?

Today’s study analyzed the effects of psilocybin on the human brain.

We know that psilocybin causes disruptions to our perceptions of space and time. That’s kind of key to the whole “being a psychedelic” thing it’s got going on, right?

We also have evidence from clinical trials that a single psilocybin dose can have rapid, sustained relief of depression, addiction, and anxiety symptoms – often lasting for weeks.

But what accounts for psilocybin’s ability to produce both rapid and long-lasting effects? And, are there detectable changes in the brain that relate to psilocybin’s effects? Finally – does the “psychedelic experience” one has play any role in psilocybin’s long-lasting antidepressant effect?

Study Methods

In this study, individual brain changes were tracked using precision functional mapping, which uses repeated functional magnetic resonance imaging (fMRI) to reveal brain changes over time. fMRI allowed researchers to map blood-flow changes across different regions of the brain, which can reveal how neurons communicate with each other.

One limitation to this study we’ll address here: it only involved seven (7) participants. All healthy adults between the ages of 18 and 45 years. Participants underwent fMRI sessions before taking any drug (this gives the baseline reading). They also underwent an fMRI session beginning 1 hour after taking a drug. Seven participants is enough to get excited about the possibilities revealed by this study, but it’s not nearly large enough to make sweeping conclusions. This is a key way scientific research works: we build off findings from previous studies.

“What drugs were used?”, you ask. Participants received either 25 mg psilocybin or 40 mg methylphenidate, a stimulant used to treat ADHD. Methylphenidate served as the comparator, as it is a central nervous system (CNS) stimulant – providing a good comparator versus psilocybin when scanning the brain and looking for changes. If you received psilocybin in the first session, you received methylphenidate at the next session, and vice versa. Sessions were conducted 1 to 2 weeks apart.

Study Results

The trial found that psilocybin “massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate.” This was noted across most of the cerebral cortex, particularly within the basal ganglia, cerebellum, hippocampus, and thalamus.

“Massively disrupted functional connectivity” means that groups of neurons which normally fire together ceased to fire together after the participant took psilocybin. It’s thought that psilocybin’s agonist actions at 5-HT2A receptors cause desynchronization across neurons that typically activate together.

It’s important to note that many of these changes lasted for only a few hours (although one key link showed signs of disruption for weeks). And, the entire brain was not affected. Most changes were noted in an area of the brain called the default mode network (DMN), which I wrote about in a previous article detailing thoughts on how psychedelics may work.

Essentially, the DMN typically activates when we’re not engaged in a cognitive task – like when we’re daydreaming. It’s believed to be responsible for our mind wandering and projecting anxieties about the future (“What if I lose my job? What if I can’t pay my bills? What if I’m not good enough to achieve my goals?”). Past studies have shown an increase in activity in the DMN in people with depression, with decreased functional connectivity to other parts of the brain.

So no, taking a single dose of psilocybin won’t change “you” or make you forget who you are. But it may hit the reset button on portions of the brain responsible for sending intrusive, negative thoughts that you can’t seem to stop.

Another key finding I want to highlight involves the subjective psychedelic experience. The researchers found that changes in brain functional connectivity (FC) correlated with how intense participants rated their individual psychedelic experience. This was done by comparing a participant’s responses on the 30-item Mystical Experience Questionnaire(MEQ30) to brain imaging and function data in each session.

Again, this study is too small to draw definitive conclusions. But it hints at the possibility that the intensity of your psychedelic experience may correlate to the intensity of beneficial effects you feel in the weeks following ingesting psilocybin.

Why is This Important?

There’s a saying I (and many other students) learn in pharmacy school – “neurons that fire together, wire together.” When a group of neurons fire together once, no big deal. As they continue firing together over and over again, they start to “wire” together – forming connections that makes them more likely to fire together again.

“Cool, but what does this have to do with anything?” Psilocybin’s ability to cause long-lasting relief of depressive and anxiety symptoms may be related to its ability to desynchronize neurons.

A key symptom of depression is rumination – a tendency to focus on negative thoughts related to the self. Self-rumination has been linked to more severe depression. Thoughts related to the self have been linked to brain regions near the cortical midline, including the posterior cingulate cortex and medial prefrontal cortex (both of which are housed within the cerebral cortex, where psilocybin disrupts functional connectivity). Research has also revealed differences in activity within these cortices between people with depression and those without during periods of self-referential thinking.

So, how do we disrupt this pattern of self-rumination? Psilocybin seems like one way. By causing desynchronization across neurons in these brain areas, psilocybin can end the self-rumination spiral. These neurons are no longer wired to fire together. Thus, a person with depression may find it easier to not get caught in a self-rumination spiral, and instead stay in the present moment.