The second phase to be exact. This year the newly minted Centre for Psychedelic Research at Imperial College London began conducting a first-of-its-kind phase II clinical trial designed to test how effective the hallucinogenic compound psilocybin is at treating patients with major depressive disorder versus a current prescription antidepressant, escitalopram. While several clinical trials using psilocybin have been catching headlines recently, the research at Imperial College is taking the next step by comparing psilocybin, the active ingredient in magic mushrooms, with the current standard of care, to see just how much better, if at all, psychedelics can make the lives of patients.

Why the sudden interest in psychedelic compounds?

It may surprise you to know that the idea of using psychedelics during psychotherapy has been around for some time, and can be traced back to the modern rediscovery of psychedelics in the 1940s and 50s. Less than 10 years after its rediscovery by renowned chemist Albert Hoffman, psilocybin was already being synthesised in commercial labs and sold as a novel psycho-therapeutic drug under the brand name indocybin, sharing a place on the shelf with over-the-counter LSD, branded as Delysid. Despite showing promise as psychotherapeutics in many clinical studies throughout the 50s, the spread of psilocybin and LSD out of the clinic and into the general public worried the American government. Afraid that the values of middle-class Americans were being eroded, the government banned psychedelics, labelling them as being “without any currently accepted medical use in treatment.” Research into the medicinal benefit of psychedelic compounds was almost completely abandoned by the end of the 1970s and yet the idea that the intense experiences induced through the psychedelic state might help patients reconcile grief or engrained addictive behaviour persisted in the minds of a few pioneers.

Interest was reignited in 2001 following FDA approval for a clinical trial showing that psilocybin could reduce obsessive behaviour in patients with OCD, and again in 2006 with a study showing that psilocybin-induced spiritual experiences could have long-lasting positive effects on wellbeing and behaviour, even in healthy patients. In effect, these two studies opened the floodgates on FDA approval for clinical trials using psychedelics and granted long sought after credibility to the emotional significance of “the trip” and what is now called the psychedelic therapy model, in which patients without a history of schizophrenia are given high-dose psychedelics and are guided through the trip by trained therapists under controlled conditions.

How does psilocybin-assisted psychotherapy work?

The experiences that follow taking a psychedelic are highly contextual and deeply personal, the word psychedelic is itself derived from the Greek words psyche (mind) and dēlos (manifest), alluding to the highly individual effects of taking these molecules. The types of experiences that participants encounter during guided sessions can vary hugely, but cases of reconciliation with past grief, deep personal introspection or feelings of bliss are consistently reported. This is an important factor in the treatment mechanism of the psychedelic therapy model. Rather than blunting the emotions of patients with depression, which is a commonly reported side effect of antidepressants, psilocybin-assisted psychotherapy has granted them insights into the emotional root of their issues, with some patients revealing that they had achieved one of the most significant emotional breakthroughs of their lives during psilocybin-assisted psychotherapy. It is easy then to misinterpret psilocybin as a wonder drug which can fast-track the benefits of visiting a psychologist or taking antidepressants, which often require months of sessions or repeat prescriptions to achieve results. But this is not the case, psilocybin is thought to push the brain into a more flexible state wherein negative thought patterns can be loosened and through heightened association new personal insights can be uncovered. Combined with the support of trained therapists, the psychedelic state can lead patients to find new perspective on events in their past. Indeed, it may be through reconnection with the past that the benefits of psilocybin are achieved, in line with a newly proposed feature of depression called derailment, which suggests that an inability to identify with past versions of yourself can cause a loss of identity and purpose which may lead to depression.

Pharmacology versus psychedelics

Rather than aiming to treat a single chemical imbalance in the brain, as do traditional antidepressants, called selective serotonin re-uptake inhibitors (SSRIs), psilocybin assisted psychotherapy uses the brain states created through altering that chemistry to bring about lasting emotional improvement. But how good is it? Does the psychological benefit persist or do patients relapse shortly afterwards? The lack of head-to-head comparison has so far prevented researchers from objectively quantifying the benefit of psychedelics versus antidepressants. This is where the clinical trial at ICL comes into play. In this trial, patients with major depressive disorder will be randomised to receive psilocybin at varying dosages and six weeks of daily escitalopram or placebo, with all patients participating in guided psychotherapy. The effectiveness of both treatments will be determined through self-assessed questionnaires on depressive symptoms as well as fMRI scans of the brain, paying special attention to areas of the brain sensitive to emotional stimuli.

As previous research has shown, depressed patients show greater activation of the amygdala, an area of the brain sensitive to emotional stimuli, when they are confronted with visual stimuli that evoke negative reactions, such as angry or fearful faces, a response that is dampened by antidepressants. Conversely, psilocybin has been found to cause increased amygdala activation in response to both negative and positive visual stimuli and the strength of this activation predicted reductions in the severity of symptoms in patients with treatment-resistant depression. The attenuation of visually stimulated amygdala activation in patients receiving antidepressants and enhancement in patients receiving psilocybin gives credence to the hypothesis that psilocybin can put patients with depression back in touch with their emotions.

Using fMRI to study how psilocybin and SSRIs can alleviate the symptoms of depression despite their different mechanism in the brain can offer researchers insights into the complex neurobiology of these conditions. fMRI also offers researchers a chance to more objectively assess the magnitude of relief from depressive symptoms and, by combining this analysis with questionnaires, conclusively demonstrate the therapeutic potential of psilocybin-assisted psychotherapy. When the results of this study are published it will be interesting to see, not only which treatment offered the most benefit to patients, but also what aspects of the psychedelic-trip can predict the best outcomes for patients and if these meaningful experiences can be sought out and encouraged in our daily lives.

If you would like to volunteer for this study, please contact the study coordinator Bruna Giribaldi on b.cunha@imperial.ac.uk.