Will ‘magic mushrooms’ be the future antidepressant?

By Natalie Christovic

Psychedelics, including psilocybin, are making a ‘come-back’ in psychiatry as potential tools to tackle depression.

On a bright spring’s day in March 2022, Sarah went on a trip to Lake Bled, Slovenia. She walked along a path seemingly engrained in diamonds, gazed upon perfectly symmetrical clouds, and listened to the trees hum a soothing twinkling melody. As you can see, this was no ordinary trip.

Along with her friends, Sarah, a student in her 20’s, decided to take psilocybin - a psychedelic compound found in ‘magic mushrooms’ motivated by an ever-growing curiosity to connect to her spiritual side. What she didn’t expect however, was to leave feeling like a new version of herself.

“I was scared it would change my inner world forever," she admitted, "which is ironic, because it did, but not in the way I imagined. I found serenity.”

Once seen as taboo, experiences like Sarah’s are now helping shape a new era in psychiatry.

Over 70% of psychedelic-related clinical trials have launched since 2017 [1], kick-starting what many call a “psychedelic renaissance” as researchers race to understand how these substances could improve mental wellbeing.

The urgency to tackle mental illness is clear. The World Health Organization (WHO) reported that more than a billion people are affected by mental health conditions globally [2], highlighting a need to expand and enhance available treatments.

Psilocybin is emerging as a promising suitor. When paired with psychotherapy, it has shown potential in supporting mental health conditions such as anxiety, eating disorders, PTSD, substance abuse [3], and most notably, depression [4], with some studies, improvements have been reported after just one dose.

In recent years, many countries have begun to shift their stance on psilocybin. For instance, in 2023, Australia took the leap and became the first to legalize psilocybin for medicinal use [5].

Despite this progress, there is still a substantial resistance to embrace psychedelic-assisted therapy in several parts of the world, including the UK.

So, will there come a day where psilocybin is deemed a safe and credible contender to traditional antidepressants? To explore this, we need to turn to the experts and the growing body of research. With these insights, we can start to slowly paint a picture of what its real-world use as a treatment for depression might look like.

A brief history of Psilocybin

‘Magic mushrooms’ aren’t a new character on the scene. Cave paintings dating back 10,000 BCE [6] include depictions of mushrooms with ‘psychedelic themes’ in Northern Australia. In many ancient and indigenous cultures, these mushrooms were viewed through a ritualistic and healing lens [7], with the South American Aztec Indians describing them as teonanácatl - ‘God’s Flesh’ [8].

Fast forward to 1958 when psilocybin was synthesised for the firsttime by a Swiss chemist called Albert Hofmann [4]. This sparked awealth of research into its potential therapeutic use for psychiatric disorders, such as anxiety and depression [7].

However, this era was short-lived. In 1971, psilocybin was classed as a ‘Schedule 1 substance’ - a category of drugs that have both high potential for abuse and no medicinal purpose [9]. This backlash was triggered by a rise in its recreational use and association with the ‘youth counterculture movement’.

Several decades later, psilocybin is beginning to shed its stigma. In 2018 the FDA (in the USA) granted it ‘break-through therapy’ status [10], marking their openness to considering it as a potential treatment if proven to be a safe and effective option. This turning point has allowed scientists to revisit long-standing questions and begin uncovering psilocybin’s true potential.

How does it work?

What might be behind psilocybin’s ‘magical’ effect on mental health illnesses? While there is still no single uniform answer to this question, researchers are starting to put the puzzle together, study by study.

“It helps when the mind gets stuck by promoting greater cognitive flexibility” says Tommaso Barba, a PhD candidate at Imperial College London “It seems to help disorders characterised by mental rigidity - like depression, anxiety and addiction.”

This flexibility, known as ‘neuroplasticity’, allows your brain to ‘reorganise’ itself and form new, healthier patterns of thought. fMRI scans on the brain under psilocybin back this notion, as they have found it changes the structure of our brain, making it more ‘flexible’ [11].

Going beyond this, psilocybin also supports ‘global integration’ - a ‘brain-wide’ connectivity that is linked to longer-lasting therapeutic effects in depressed patients [12]. Rebecca Harding, a PhD candidate at University College London explains how this might work. ‘‘It allows brain areas to communicate, helping to break out of thought patterns in an adaptive way, whereas SSRIs numb the feeling instead” she explained.

Beyond connectivity, researchers have explored another interesting concept: ego dissolution [13].

“A common experience is ego dissolution” Barba added, “creating a temporary expansion of consciousness allowing people to to see themselves from another point of view”.

This is a powerful shift in consciousness where the line between ‘the self’ and the ‘external world’ blurs, creating a feeling of being at one with your environment [13]. Scientists believe this occurs when psilocybin temporarily ‘quiets’ specific brain regions that are responsible for your sense of self.

Sarah’s psilocybin encounter echoes this, as she shared her newfound connection with nature.

“Trees and nature represent peace and goodness to me now. I feel like they’re above me.”

Can psilocybin ‘beat’ traditional antidepressants?

Research has put these treatments head-to-head to see which works best when fighting depression. Since 30-50% of users do not seem to respond to traditional antidepressants (such as SSRIs) [4] there is hope that psilocybin could be an additional effective long-term solution.

“Psilocybin could give you a more comprehensive relief for your depressive symptoms” said Barba “it gives you a fresh outlook of life that I don't think antidepressants do.”

Barba and his colleagues conducted a study where they compared the long-term effect of a six-week intensive treatment program using either psilocybin or escitalopram (a common antidepressant) in depressed patients [14]. They then assessed their symptoms again at a 6 months follow up [14]. “Psilocybin didn’t outperform SSRIs on core depressive symptoms - but it did on wellbeing, positive emotions, social functioning, and sense of meaning” Barba explained.

Psilocybin’s ability to match - and in some aspects exceed - the effectiveness of SSRIs was further supported by a study conducted by Harding and her colleagues. They played music to participants with depression and observed how they responded to the ‘surprises’ in the tunes while being treated with either psilocybin or escitalopram [15].

While both treatments were equally effective in treating depressive symptoms, psilocybin went the extra mile, showing a significantly larger effect in reducing anhedonia (a loss of pleasure)[15].

Additionally, escitalopram seemed to diminish feelings of music-induced ‘vitality’, supporting the idea that traditional antidepressants can cause "emotional blunting" - the numbing of both positive and negative emotions [16]. “We saw that escitalopram flattened positive responses tounexpected moments, while psilocybin did not” says Harding.

However, despite these promising outcomes, Barba shed some light on why going down the psilocybin-assisted therapy route as opposed to SSRIs might not be for everyone. “It could be more emotionally challenging to navigate, because it's not about taking a pill at home and continuing with your day-to-day life.”

There is a general understanding among scientists that this comparison needs more research to be conclusive. However, these results offer a promising start for the use of psilocybin as another treatment for depression. As Harding expressed “Psychiatry has such low response rates - so adding another tool to the toolbox would be really valuable.”

What does Psilocybin-assisted therapy look like?

It is important to note that psilocybin-assisted therapy is conducted in a clinic under supervision and guidance - with its label reading ‘please do not try this at home’.

“It's almost like a surgical intervention on the psyche” explained Barba “it's always done under the supervision of a mental health professional - with therapy before and after.”

However, it might not be as ‘clinical’ as you first imagine. Psychedelic-assisted therapy is usually conducted in specially designed ‘non-traditional’ medical rooms [17]. These rooms are designed with comfort in mind - soft furniture, muted colours, and warm lighting. Patients can be given noise cancelling earphones to listen to calming music and eye masks to wear to shut out the external world and focus internally.

Are there risks?

Like all medication, psilocybin comes with some potential risks. The ‘who, what, where, when, and why’ of these risks are important to assess when considering its use on a wider scale. Let's talk about the first hurdle: side effects. Patients have reported having ‘muddled thinking’ and ‘paranoid ideas’ when having a ‘bad trip’ [13]. Psilocybin has also been found to cause somatic symptoms such as dizziness, weakness, and tremors in some patients, as well as nausea and vomiting in some cases [18]. What’s important to mention is that the noted side effectsof psilocybin (when used in therapeutic contexts) are usually temporary, lasting usually between 6-8 hours of the ‘trip’ [4], but should still be taken into consideration.

Another risk to address is psilocybin’s potential risk in causing prolonged psychosis. A few studies reported that some patients experienced prolonged psychosis, lasting longer than 48 hours. This is incredibly rare in otherwise healthy subjects however - with a prevalence of 0.08 - 0.09% [18]. It does appear to be more predominant in psychiatric participants with a prevalence of 0.18%, highlighting the need to take this into consideration with vulnerable patients.

Next, the elephant in the room: are they actually dangerous? Well, despite popular speculation, clinical trials have found little to no signs of toxicity when taking psilocybin [18]. As Barba emphasised ‘Psychedelics aren’t harmless, but the danger isn’t toxicity - it’s taking them in unsafe settings without support.”’

Another myth to bust is that psilocybin is an addictive drug. According to research, this is not true - psilocybin appears to have no addictive potential [18], despite being classed as a ‘Schedule 1 substance’.

Will psilocybin become a widely accepted treatment for depression in the future?

“In the future, I imagine there will be dedicated psychedelic clinics where patients will have comprehensive support,” says Barba.

Significant legal and societal barriers remain before this future can become a reality. To work towards legalisation for medical purposes, more extensive research conducted on a longer and larger scale is needed.

Harding explained her stance from a researcher’s perspective: “We need more standardised frameworks and protocols to improve the quality of our data, while also widening the demographic of research participants so findings are more representative.”

Of course, there’s another common barrier - money. The cost of psilocybin-assisted therapy doesn’t come cheap, as a trained professional is required to stay with the patient for long periods of time - often between 6-8 hours [19]. “I think it could potentially be quite an expensive option, and so might not be accessible for everyone” says Barba.

Perhaps one of the most complex barriers is the deeply ingrained societal stigma. While this is a tricky element to tackle, some recent surveys offer some hope. For instance, when asking a sample of healthcare professionals (in the US) about their opinion on psilocybin within a medical context, 96% showed support for medicinal use [20].

For Sarah, the impact was deeply personal. “It's sad that something which made me calmer has been stigmatised - my experience brought me to a state of well-being as my baseline.”

So, will psilocybin ever be considered a safe, effective, and accessible alternative to traditional antidepressants? While the answer to that question remains uncertain, the ‘psychedelic renaissance’ is challenging a long-standing stigma with a clear goal in mind: fighting mental illness. Psilocybin may never replace traditional antidepressants but instead could stand alongside them - offering light at the end of the tunnel for those who have found no relief elsewhere.

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