Study shows psychedelic drug psilocybin gives comparable long-term antidepressant effects to standard antidepressants, but may offer additional benefits

A direct comparison between the experimental psychedelic drug psilocybin and a standard SSRI antidepressant shows similar improvement of depressive symptoms, but that psilocybin offers additional longer-term benefits.

The comparison, between psilocybin (the active ingredient in “magic mushrooms”) and the SSRI escitalopram gave similar long-term improvements in depressive symptoms over a 6-month period, however patients taking psilocybin also reported better psychosocial functioning including experiencing a greater sense of meaning in life and psychological connectedness.

The work is presented for the first time at the ECNP Congress in Milan. A related paper will appear in the peer-reviewed journal Lancet eClinicalMedicine¹ to coincide with the conference presentation (see details below). Lead researcher Mr Tommaso Barba (PhD candidate from Imperial College, London) said:

“This is the first work to compare the long-term effects of these two drugs in the context of overall well-being, not just freedom from depression.  In previous work we had found that both treatments led to comparable improvements in alleviating symptoms of depression at the 6-week mark, such as sadness and negative emotions.  However, this work shows that psilocybin outperformed escitalopram in several measures of well-being, meaning in life, work and social functioning. These results appeared to be maintained over a 6-month follow-up period. In addition, in previous work* we had found that psilocybin also improves sexual drive, in contrast to SSRIs which tend to lower libido in many patients. So overall it seems psilocybin might give additional positive mental health benefits.”  

SSRI drugs (selective serotonin reuptake inhibitors), such as Prozac, Paxil and Zoloft, are one of the main types of drugs used to treat depression. However, around a third of patients don’t respond to SSRI treatment, so for them psilocybin may offer an alternative, although this was not studied in this trial.

Tommaso Barba continued:

“SSRIs work well, but not for everyone. They are also associated with some side effects. However this work implies that psilocybin generally seems to offer a real alternative, and perhaps additional benefits, to people who are worried about taking conventional antidepressants”.

The researchers, from Imperial College in London, undertook a 6-month study (phase 2, double-blind, randomised controlled trial) with 59 patients with moderate to severe depression. 30 were treated with a single dose of psilocybin, 29 patients were given a six-week course of escitalopram. Each group received similar psychological support of around 20 hours in total. Both groups showed significant improvement in depressive symptoms, even up to 6 months after treatment (the researchers stopped monitoring at 6 months). However those given psilocybin reported greater improvements in social functioning and psychological connectedness, with large effect sizes.

Co-first author Dr David Erritzoe, Clinical Director and Deputy Head of the Centre for Psychedelic Research, Imperial College, London, commented:

“This is important because improving connectedness and having greater meaning in life can significantly enhance a person's quality of life and long-term mental health. The study suggests that psilocybin therapy might be a more holistic treatment option for depression, addressing both the symptoms of depression and overall well-being. This could make a substantial difference in the overall happiness and daily activities of those suffering from depression, providing a more joined-up approach to mental health treatment”.

The researchers note that the patients were only treated for 6 weeks, and that many of the patients received additional treatments over the 6-month follow up.

Dr Erritzoe cautioned:

“Psilocybin is still an experimental drug; it has not yet been approved for general use. It is administered in highly controlled and protected environments: these precautions are not found in recreational psychedelic use, which is known for having unpredictable and potentially harmful effects, especially for vulnerable people struggling with mental health issues”. 

Commenting, Johan Lundberg (Adjunct Professor of Psychiatry at the

Department of Clinical Neuroscience, Karolinska Institute, Stockholm) said:

“This report is an important attempt to compare the clinical value of psilocybin compared to a state-of-the-art treatment of major depressive disorder. The results come with several caveats, including the lack of a non-inferiority analysis and failure to report other interventions given during the follow-up period. That said, as a hypothesis generating piece it may benefit the field substantially.  For now, we don’t know if psilocybin will be approved for the treatment of major depression, but if so, it won’t be for everyone. Some future patients might prefer psychedelic treatment over SSRI, but some patients may be intimidated by the dramatic alterations in perception and confrontations with challenging emotions that psychedelic drugs promote”.

This is an independent comment, Professor Lundberg was not involved in this work.

Notes:

1. Publication details: Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial. In press at Lancet eClinicalMedicine. Authors: David Erritzoe, Tommaso Barba, Kyle T. Greenway, Roberta Murphy, Jonny Martell, Bruna Giribaldi, Christopher Timmermann, Ashleigh Murphy-Beiner, Michelle Baker Jones, David Nutt, Brandon Weiss, and Robin Carhart-Harris. Paper reference 10.1016/j.eclinm.2024.102799
2. See Psychedelic experiences linked with improved sexual function | Imperial News | Imperial College London