key milestones
in psychedelic research

How it all started

Just over nine years ago, in 2012, two studies from the Imperial College of London changed the way we look at psychedelics in therapeutic contexts. In the first study, published in Proceedings of the National Academy of Sciences (PNAS), 30 healthy volunteers had psilocybin infused into their blood while inside magnetic resonance imaging (MRI) scanners, which measure changes in brain activity.

The scans showed that activity decreased in “hub” regions of the brain — areas that are especially well-connected with other areas.

In the second study, published online by the British Journal of Psychiatry, it was discovered that psilocybin enhanced volunteers’ recollections of personal memories, which the researchers suggest could make it useful as an adjunct to psychotherapy. These two studies laid the groundwork for future studies in psychedelic assisted psychotherapy for treatment-resistant depression.

Four years later, in 2016, it was confirmed that two doses of psilocybin, the active substance in the mushrooms, was sufficient to lift resistant depression in all 12 volunteers for three weeks, and to keep it away in five of them for three months. The size of the trial and the absence of any placebo meant that the research, funded by the Medical Research Council was a proof of principle only.

On November 2020, a John Hopkins study concluded that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. This suggests that psilocybin may be effective in the much wider population of patients who suffer from major depression than previously appreciated.

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The latests results

In the spring of 2021, in a six-week trial, 30 out of 59 adults with moderate to severe major depressive disorder were randomly allocated to receive two 25mg doses of psilocybin three weeks apart, a dose that head of research Dr Carhart-Harris, said was high enough to produce the kind of experiences often described as existential or even “mystical”.

The other 29 participants were given two very low, or “inactive”, doses of psilocybin three weeks apart. This was to ensure any differences in outcomes between the groups would not simply be down to the expectation of being given psilocybin. The day after the first dose of psilocybin, this group began a daily dose of escitalopram, the strength of which increased over time. 

“We started to see a decrease in the severity of depressive symptoms”

The results, published in the New England Journal of Medicine, reveal that after six weeks both groups showed, on average, a decrease in the severity of depressive symptoms, according to scores from a questionnaire completed by the participants. However, this reduction did not differ significantly between the two groups.

Nonetheless, the team noted that 57% of patients in the high-dose psilocybin group were judged to be in remission for their depression by the end of the six weeks, compared with 28% in the escitalopram group, while neither group had serious side-effects.

2021 outbreak

In the summer of 2021, the first evidence of depression treatment at the neuronal level was published by Yale University researchers. In this paper, researchers show that a single dose of psilocybin given to mice prompted an immediate and long-lasting increase in connections between neurons.

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“We not only saw a 10% increase in the number of neuronal connections, but also they were on average about 10% larger, so the connections were stronger as well,” said Yale’s Alex Kwan, associate professor of psychiatry and of neuroscience and senior author of the paper.

Previous laboratory experiments had shown promise that psilocybin, as well as the anesthetic ketamine, can decrease depression.

The new Yale research found that these compounds increase the density of dendritic spines, small protrusions found on nerve cells which aid in the transmission of information between neurons. Chronic stress and depression are known to reduce the number of these neuronal connections.

Behavioral Improvements and increased neurotransmitter activity

Using a laser-scanning microscope, Kwan and first author Ling-Xiao Shao, a postdoctoral associate in the Yale School of Medicine, imaged dendritic spines in high resolution and tracked them for multiple days in living mice.

They found increases in the number of dendritic spines and in their size within 24 hours of administration of psilocybin. These changes were still present a month later. Also, mice subjected to stress showed behavioral improvements and increased neurotransmitter activity after being given psilocybin.

For some people, psilocybin, an active compound in “magic mushrooms,” can produce a profound mystical experience. The psychedelic was a staple of religious ceremonies among indigenous populations of the New World and is also a popular recreational drug.

It may be the novel psychological effects of psilocybin itself that spurs the growth of neuronal connections, Kwan said.

“It was a real surprise to see such enduring changes from just one dose of psilocybin,” he said.  “These new connections may be the structural changes the brain uses to store new experiences.”

We’re only starting to see the tip of the iceberg.

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