Psilocybin, the active ingredient in magic mushrooms, is often seen as a controversial compound due to its psychedelic properties and potential for abuse and misuse as a recreational drug. However, there is growing evidence, through rigorous scientific studies, that psilocybin could be an effective therapeutic for a wide range of neurology indications from depression to migraine and various forms of addiction.

On November 8, Compass Pathways announced positive topline results from the largest clinical trial to date of psilocybin. The randomised, controlled, double-blind Phase IIb trial (NCT03775200) enrolled 233 patients and evaluated a single dose of COMP360 (psilocybin), in conjunction with psychological support from specially trained therapists for treatment-resistant depression (TRD). The trial compared two active doses of COMP360 (25mg and 10mg) against a comparator 1mg dose. At least twice the number of patients in the 25mg group showed response and remission at Week 3 and Week 12, compared with the 1mg group. However, there was no statistical significance between the 10mg and 1mg groups at Week 3. The response was defined as a ≥50% improvement in Montgomery Asberg Depression Rating Scale (MADRS) total score from baseline and remission was defined as a MADRS total score ≤10.

A large portion of patients with major depressive disorder (MDD), approximately a third, do not respond to two or more adequately dosed antidepressant therapies and are referred to as having TRD. There is a significant unmet need for therapies that can treat this patient population, thus these positive efficacy results for psilocybin are encouraging and support the Breakthrough Therapy Designation that the Food and Drug Administration (FDA) granted to COMP360 in 2018. Additionally, currently available antidepressants show effects only after several weeks of treatment, highlighting a key need for treatments with a rapid onset of action, particularly for patients who have severe depression or TRD and require hospitalisation. In Compass’ Phase IIb trial, the high dose (25mg) COMP360 group demonstrated statistical significance on the MADRS efficacy endpoint on the day after the COMP360 psilocybin was administered.

Even before the results of this trial, key opinion leaders interviewed by GlobalData were excited by the potential impact psychedelics such as psilocybin could have on the treatment of depression. In particular, they felt this novel way of treating the disorder could lead to shorter-term treatment with lasting benefits, which would be hugely beneficial for patients who currently rely on maintenance treatments with a high pill burden.

Despite the positive results, the trial results for COMP360 raised important concerns surrounding the safety of psilocybin. Three participants in the high dose (25mg) group displayed suicidal behaviour, with two reports of suicidal ideation in each of the higher-dose (25mg and 10mg) arms. Suicide is the most serious consequence of MDD and it is particularly prevalent in patients with more severe depression such as those with TRD. Therefore, any therapy that has the potential to increase suicidal ideation/behaviour, especially in vulnerable populations, carries significant concern. However, it should be noted that suicidal behaviour is common in patients with TRD and further investigation will be required to determine whether the adverse effects seen were due to the psilocybin or the disease itself. The outcome of a larger Phase III trial will be vital in determining the safety of psilocybin and whether the benefits will outweigh the risks in such a hard-to-treat patient population.