Once dismissed as dangerous countercultural drugs, psychedelics are now at the centre of a scientific revival that could reshape how we treat mental illness
Psychedelic drugs are substances that alter consciousness, sensory perception, and awareness of time and space. Some of the most well-known examples include LSD, psilocybin (found in magic mushrooms), and MDMA. Historically, these substances have been used for both recreational and religious purposes across various cultures. More recently, however, psychedelics have captured the interest of mental health professionals as a potential aid in psychotherapy.
With nearly 300 million people living with depression worldwide, according to the World Health Organisation, (and many not helped by current treatments) there’s growing pressure to find alternatives. Mental health professionals became interested in psychedelics due to their powerful effects on mood: people often report feelings of euphoria, emotional release, and heightened empathy during psychedelic experiences. Researchers believe psychedelics act on serotonin receptors and can temporarily disrupt brain activity, breaking rigid thought patterns. Therefore, it has been hypothesized that some of these drugs could assist the work of therapists in treating mental health conditions, such as post-traumatic stress disorder (PTSD) or depression.
As a result, research into the use of psychedelics as possible treatments for mental health conditions has grown exponentially over the past decade. A recent, small-scale trial, published by Johns Hopkins Medicine, reported that when therapeutic support was accompanied by two doses of psilocybin, depressive symptoms were reduced. Later follow-up research showed these benefits were sustained for up to a year in many participants. These results hint at the extraordinary potential of these substances for severe cases of depression, but without consistent standards, the path to approval remains uncertain.
Despite the promising results, this growing body of research is yet to translate into approved therapies that can reach patients. One explanation for this can come from the US Food and Drug Administration’s (FDA) recent rejection of MDMA-assisted therapy for PTSD. In their review, psychedelic research was described as a black box – a term that pointed, not to the drug itself, but to the lack of clarity around how the studies were conducted. This is due, in part, to the fact that many clinical studies for psychedelics don’t report certain aspects of the context in which studies take place.
While this might not sound like a big deal, it is critical when we remember that the effects of psychedelics aren’t determined by chemistry alone, but are also influenced by extra-pharmacological variables, such as the environment in which the drug is taken or the user’s mental state. These factors help explain why experiences with psychedelics can range from relaxing, to nightmarish or even to mystical. It is also why failing to report this information can lead to a lack of control over confounding variables and inability to replicate results – essential steps for gaining scientific confidence and regulatory approval. This further delays potential life-changing treatments to patients who need them.
These contextual influences are known as “set and setting”, a term that refers to two crucial factors that shape the user’s experience. “Set” encompasses the mental state of the person using the psychedelic drug: their thoughts, feelings, and expectations going into the experience. The effects of a substance will be different if the user is happy, scared, sad, or worried at the time of ingestion. Someone feeling calm and open may respond very differently than someone feeling anxious or fearful.
On the other hand, “setting” refers to the external environment that can have an influence on the psychedelic experience: the physical space, the time of day, and the people present, among many other factors. The psychedelic effect will vary if someone takes a drug recreationally with friends at a party, or if they take the same substance in a calm, clinical environment under the supervision of doctors, nurses and scientists.
These variables don’t just affect the subjective experience, they can also shape the therapeutic outcome. Despite this, many clinical studies often fail to describe set and setting in detail. This lack of consistency makes it difficult for scientists to compare results across different studies or and lead to contradicting findings, slowing progress towards approved, real-world treatments. To help address this gap, a recent study led by Pronovost-Morgan at Imperial College London, aimed to establish standardised guidelines for reporting the key setting variables in clinical, psychedelic research.
To this end, the team designed a multi-stage study using a structured survey methodology used to gather expert opinions and reach consensus. 89 experts, including psychedelic therapists, researchers, and even previous clinical trial volunteers, were recruited from 17 different countries, bringing a wide range of professional and personal perspectives. The outcome was the Reporting of Setting in Psychedelic Clinical Trials (ReSPCT) guidelines. This document outlines 30 important setting variables that should be reported when conducting psychedelic studies, to ensure greater transparency and reproducibility. They are grouped into four categories: Physical Environment, Dosing Session Procedure, Therapeutic Framework and Protocol, and Subjective Experiences.
Although the guidelines are yet to be applied in a clinical trial, tools like ReSPCT could improve the quality of psychedelic research and facilitate data comparison across different studies and institutions, thus improving the rigour and reliability of psychedelic research. In doing so, they bring us one step closer to understanding the potential of psychedelic-assisted therapies, and delivering them safely and effectively to improve the lives of those that need them.
Article written by Guido Lax an Integrative Neuroscience master’s student at The University of Edinburgh, currently working on visual processing.
Article edited by Eleanor Stamp, a Neuroscience PhD student at the Institute of Genetics and Cancer, University of Edinburgh, and an Online News Editor for EUSci.
Resources:
Pronovost-Morgan, C., Greenway, K. T., & Roseman, L. (2025). An international Delphi consensus for reporting of setting in psychedelic clinical trials. Nature Medicine, 1-10. https://doi.org/10.1038/s41591-025-03685-9
World Health Organisation: Depressive disorder (depression)
Gukasyan N, Davis AK, Barrett FS, et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Journal of Psychopharmacology. 2022;36(2):151-158. doi:10.1177/02698811211073759
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