Psilocybin and new alternatives to antidepressants

Dr David Cox

Dr David Cox

Freelance health journalist and former neuroscientist interested in a wide variety of life science topics. David also writes for The Guardian, BBC, National Geographic, NBC News, Wired, TIME and others.

Mental Health - what are the new alternatives to antidepressants?

Over the past decade, there has been a startling rise in the number of people taking antidepressant medications. Numbers have spiked even more over the past couple of years as the impact of the Covid-19 pandemic and repeated lockdowns have exerted a toll on mental health, with an estimated $26.25 billion worth of antidepressant medications being dispensed around the globe in 2020.

However psychiatrists are growing increasingly concerned about the potential long term side effects of taking prescription pills to deal with symptoms of depression and anxiety.

The most popular antidepressants medications – selective serotonin reuptake inhibitors or SSRIs – affect the action of the neurotransmitter serotonin not only in the brain but throughout the body. As a result, scientists fear that disrupting serotonin over the course of many years or decades could have an impact on a whole range of bodily functions such as digestion, immune function, and many other processes.

Some scientists have already reported concerning findings that people who use SSRIs have a 14% higher risk of heart attacks and strokes, while an association has even been made between these medications and risk of dementia.

“All patients who have been taking antidepressants for the first or second time in their life and have successfully improved in their mood should stop the antidepressants around six to nine months after they have returned to a stable, healthy mental state,” says Carmine Pariante, professor of biological psychiatry at King’s College London, who has 2,267 topic citations for antidepressants on

But antidepressants are not a permanent cure, and relapses are common. Last year, scientists at the University of York reported that 56% of patients experience a recurrence of symptoms after stopping treatment. 

As a result there is a growing drive to find alternative mental health treatments which are both more effective and safe to use over a prolonged period of time.

The rise of app-based therapies

One hope is that technology can offer some new alternatives. The World Economic Forum have reported that there are now more than 10,000 mental health apps on the market, with the pandemic seeing people flocking to digital platforms ranging from chatbox psychologists to mood tracking apps. 

Psychiatrists feel that the increasing popularity of these technologies could capture a treasure trove of data relating to different mental health conditions.

“By allowing patients to record things like their level of optimism on a daily basis, they give clinicians a lot more information than a weekly or monthly visit,” says Jimmy Potash, professor of psychiatry at John Hopkins Medicine. “They have the power to add even richer amounts of useful information as they can track things like activity levels, changes in the volume and speed of voice on phone calls, and the amount and quality of sleep. All of this can reveal a lot about depression.”

However, there are also a number of concerns about the growing role of technology in mental health. The industry is almost entirely unregulated, and while many digital platforms claim to be useful at diagnosing depression, there is little evidence of their efficacy. Potash is also concerned that patients may start opting for apps over seeing a psychiatrist in person.

“The danger to my mind is that people will eschew reaching out to mental health professionals when they are in the kind of depression that is serious and potentially life threatening because of the belief that their app will get them out of their bad state and give them what they need,” says Potash. “Depressed people often retreat inward, and the promise of digital solutions could inadvertently exacerbate that.”

Psilocybin and new alternatives to antidepressants

While antidepressants can help many patients, there remain a substantial proportion who do not respond at all to medications. Somewhere between 12 and 20% of depression sufferers are ‘treatment-resistant’, meaning that all other approaches have failed.

As a result, newer therapies such as ketamine-based treatments and the psychedelic drug psilocybin, have been receiving growing attention from psychiatrists.

While psilocybin works by making patients more receptive to the benefits of psychotherapy, ketamine acts directly on the brain’s biology. Researchers believe that it has the ability to repair damaged connections between cells involved in mood.

In 2019, the US Food and Drug Administration made a landmark decision to license a ketamine-based drug called Spravato, the first novel treatment for depression in decades. “What’s particularly interesting about ketamine is that it has multiple effects throughout different brain biologies,” says Carlos Zarate, head of experimental therapeutics and pathophysiology at the US National Institute of Mental Health, who has 6,309 citations for antidepressants on

“We’ve been finding that it seems to have more broad spectrum effects than conventional antidepressants, it seems to make a significant improvement in anehdonia symptoms, anxiety symptoms, post-traumatic stress disorder (PTSD) symptoms, so there’s something that makes ketamine much more unique than other treatments.”

Future therapies

Neither ketamine nor psilocybin are a complete panacea. These drugs do not work for all patients, while concerns persist about their side-effect profiles, which can include hallucinations, out-of-body experiences, as well as fluctuations in blood pressure.

As a result, psychiatrists are also investigating more invasive approaches. Over the past twenty years, different forms of neuromodulation from transcranial magnetic stimulation – which involves using magnetic fields to stimulate nerve cells in the brain – to deep brain stimulation (DBS) have been intensely studied, with mixed results. This is thought to be because most devices only stimulate one area of the brain, while depression is likely to involve different brain regions in different people.

However a new approach, which was pioneered by scientists at the University of California San Francisco last autumn on a patient with treatment-resistant depression, has yielded promising results. After identifying a specific pattern of neural activity which indicated the onset of the patient’s symptoms, they embedded a DBS device into her brain which was designed to recognise the pattern and neutralise it.

It proved extremely successful, and some psychiatrists believe it could represent the future of treatment for patients with the most severe forms of depression.

“This would only be reserved for people with a lifelong history of depression, that has never improved with treatment,” says Pariante. “But we need treatment options for patients at every stage of the disease, including the most severe ones.”

Because depression is such a heterogeneous disease, Pariante feels that the way forward is to find new ways to personalise treatment based on the patient’s genetic or hormonal profile.

“At the moment one of the biggest problems is that we don’t know early on who are the patients that are going to respond to a particular drug or not,” he says. “So you have people continuously switching from one medication to another over the course of months. I feel the future is being able to categorise patients based on neuroimaging scans or other biomarkers which point to the underlying cause of their disease.”