Could microdosing with psychedelics help treat depression?

Psychedelics are back in vogue, but some doctors, researchers and indeed patients are more cautious about results

There has been a resurgence of interest in the use of psychedelics or consciousness altering substances such as psilocybin – the active ingredient in “magic mushrooms” to treat depression.

The American author, journalist and psychedelics advocate Michael Pollan says there has never been a more exciting – or bewildering – time in the world of psychedelics. Take for example, the Psychedelics Science 2023 conference in Denver, Colorado, hosted by the Multidisciplinary Association for Psychedelic Studies (MAPS), which attracted 12,000 people.

Everyone from medical doctors and psychotherapists to pharmaceutical companies, self-improvement gurus and individuals seeking spiritual transformation is jumping on the bandwagon. Alongside this is a vibrant subculture of microdosing, or low dose use of psychedelics, which is attracting individuals who want to improve their mood, reduce anxiety and/or boost focus and creativity.

But some doctors, researchers and indeed patients are more cautious about results from small studies which report statistically significant benefits for patients with “treatment resistant” depression or so-called secondary depression, which is linked to a physical disease process such as cancer.


So, who should we trust? Are there real possibilities for a more considered reappraisal of the 20th century experimental use of psychoactive drugs (including LSD, ketamine and psilocybin) by advocates including the late controversial American psychologist Timothy Leary; the Scottish psychiatrist RD Laing; and the late Irish psychiatrist Ivor Browne?

A recent systematic review of randomised controlled trials by researchers Athina-Marina Metaxa and Mike Clarke looked at seven trials involving 436 participants with depression. These studies compared psilocybin as a treatment for symptoms of depression with controls such as placebo, niacin (vitamin B) and microdoses of psychedelics – with and without psychotherapy.

The researchers concluded that while changes in depression scores were significantly greater after treatment with psilocybin than with another treatment, further analysis is required to account for types of depression (primary or secondary depression), variations between self-reported or clinician-assessed depression scales and whether participants had previously used psychedelics or not.

Commenting on the systematic review, Prof David Nutt head of neuropsychopharmacology in the department of medicine at Imperial College London (ICL), said it confirmed smaller studies by suggesting that “psilocybin looks rather good as an antidepressant”.

“It is pleasing to see the field advancing as well as it is, especially given the mental health crisis facing most western countries,” Prof Nutt said.

Prof Nutt is part of ICL’s psychedelic research group which has been supported by Compass, a biotechnology company focused on new mental health therapies including psilocybin therapy, and the Usona Institute which tests consciousness expanding medicines and psychedelic therapies.

Dr Paul Keedwell, consultant psychiatrist at Cardiff University Hospital in Wales, described the study as a welcome review of the “efficacy of a single dose of psilocybin in the treatment of depression”.

“There are some concerns about the expectation effects because the majority of patients knew when they were getting the active condition, or the higher dose of the same drug. However, these concerns are tempered by the fact that improvements were maintained for up to 12 weeks in one study,” Dr Keedwell said.

He added that the main disadvantage is that some patients find the psychedelic effects unpleasant and care must be taken to ensure a calm environment for the treatment. “Psychologist preparation before and debriefing after dosing are crucial,” he said.

In an editorial on the use of psilocybin for depression in the British Medical Journal, Riccardo De Giorgi lecturer in psychiatry at the University of Oxford, and Roger Ede, a patient, said that whether psychedelics should be widely used for the treatment of depression remains contentious. “Polarised views between hardline supporters and critics are unlikely to be helpful for clinical decision-making,” they said.

De Giorgi and Ede are concerned that some advocates for psilocybin note only negligible side effects while other researchers report “confusional states, substance misuse, intentional self-harm, suicidal behaviour and psychotic symptoms, especially in people with pre-existing vulnerabilities”.

They conclude that the review by Metaxa and Clarke “did not quantitatively assess the safety of psilocybin use in people with depression”. [Since the systematic review was published on May 1st, concerns have been raised about an error in the calculation of standardised mean differences which is likely to have overestimated the benefits of psilocybin].

In his recent reader’s guide to microdosing in the Aeon newsletter, Tunde Aideyan a counselling psychology doctoral student at Northeastern University in Boston, acknowledged that potential cardiovascular side effects of psilocybin are a growing concern among medics.

“Given the neurochemical mechanism whereby psychedelics mimic serotonin and trigger various receptors in the brain, the effect of repeated dosing is an important question,” he wrote, adding that because serotonin can constrict blood vessels and increase blood pressure, the effects of repeated dosing on the cardiovascular system requires more research.

Other research has found that, compared to other recreational substances, psilocybin is among the least harmful with minor physiological side effects. Brain imaging studies have also shown that psychedelics alter neural connections in the brain, leading to suggestions that they could reduce so-called depressive ruminations.

Dr Brendan Kelly, professor of psychiatry at Trinity College Dublin (TCD) and consultant psychiatrist at Tallaght University Hospital, says there is huge interest in psilocybin currently because it has been a long time since there was a new treatment for depression.

“There is also considerable therapeutic enthusiasm which is good but the history of psychiatry is full of therapeutic enthusiasms that were not supported by evidence and sometimes proven to be misguided so caution is needed,” he says.

Dr Kelly says that the evidence from studies so far is that a significant dose (25mg) combined with psychological therapy is required to see results. But he adds that “mindset and setting matter enormously for psychedelics research”.

“Studies to date have shown that the physical side effects are very minor and are easy to manage in the correct clinical setting. Most studies include one to three sessions with a therapist beforehand to ensure a positive mindset. This reduces the chances of a negative experience. During the treatment, there is usually music playing and gentle lighting and the therapist remains present throughout the experience, which can be up to eight hours,” Dr Kelly says.

Acknowledging that this resource-intensive model of care for a new treatment would be very demanding on publicly-funded healthcare, Dr Kelly says: “We need to prove the concept first and then figure out the settings.” Pharmaceutical and venture capital companies keeping a close eye on developments are keenly aware of the huge market for new treatments for depression.

In Ireland, psilocybin is currently classified as a dangerous substance with no medical or scientific value and its cultivation, possession, consumption, manufacture, sale, supply or marketing is prohibited. In February 2023, Australia became the first country in the world to legalise psilocybin for medical use, prescribed by a licensed psychiatrist. In the United States, some cities have decriminalised use of psilocybin.

Meanwhile, researchers at TCD led by psychiatrist John Kelly are part of a multi-centre double-blind (ie, neither researchers nor patients know whether a placebo or active drug is administered) clinical trial across Europe and North America into the use of psilocybin with psychological support to treat depression.

In a 2019 Cambridge University Press article entitled The Psychedelic Renaissance: The Next Trip for Psychiatry? Researchers discussed the key differences between recreational and therapeutic uses of psilocybin. “In contrast to recreational use, therapeutic use is conducted in a controlled, supportive environment with trained therapists. The building of a trusting relationship with the team/therapists is pivotal to maximise the therapeutic effect, while minimising the risk of adverse events,” the researchers wrote.

Dr Brendan Kelly remains cautiously optimistic: “Giving people powerful psilocybin substances involves risk but poorly treated depression has huge risks of suffering, self-harm and suicide.”