From psychedelic trips to treating Treatment-Resistant Depression. The possible gamechanger COMP360
- Anish Marella
- 10 hours ago
- 5 min read
Written by Anish Marella
Psychiatric medicine is undergoing a seismic shift as Compass pathways announce successful results from its Phase 3 trial (COMP006).
Treatment-Resistant Depression (TRD), affects the lives of 4 million adults TRD in the USA alone. Defined as a condition where a patient has tried at least two different antidepressant medications without seeing a significant improvement. Currently, TRD has only 1 approved drug in the USA (Spravato) and in the UK, MHRA requires strict supervision for the administration of Spravato as it is classified as a Schedule 2 controlled substance. However, results portrayed by COMP360 seem hopeful, with a drug that has been portrayed to be rapid and durable.
Understanding TRD
TRD is a chronic condition far more debilitating than Major Depressive Disorder (MDD) alone. According to the STAR D trial (Sequenced Treatment Alternatives to Relieve Depression), the chances of achieving remission are essentially cut in half once a patient is forced to move to a third line of antidepressants. TRD is associated with significantly longer episode duration, individuals are more likely to have chronic depression greater than 2 years as well as time till remission is longer and relapse rates are higher. Finally, those with TRD face a significantly higher risk of suicide.
What is COMP360?
COMP360 is a pharmaceutical-grade synthetic version of psilocybin, a naturally occurring psychedelic compound found in over 200 species of fungi. Unlike "magic mushrooms," COMP360 is a standardised chemical entity designed for use within a strictly controlled medical framework. The drug is only one side of the coin; the therapy is delivered through a unique three-step treatment model:
Preparation: Patients meet with a therapist to establish a foundation of trust and set clear expectations for the experience.
Administration: The session occurs in a clinical setting. The patient wears eye shades and listens to a curated playlist while a therapist remains present for the entire duration of the drug’s effects.
Integration: In the days following the dose, the therapist helps the patient process the insights gained during the session and apply them to their daily life.
This is because COMP360 it is intended to induce an intense, time-limited altered state that may enable psychological change. The therapeutic container is built to manage safety, optimise outcomes, and satisfy regulators.
The Phase 3 Data: COMP005 and COMP006
The results of the two Phase 3 trials (COMP005 and COMP006) together with Phase 2b data represent a robust dataset of over 1,000 participants. Though 005 only included USA participants, 006 included individuals from Europe and Canada as well as the USA.
In clinical trials for depression, the primary tool used is the Montgomery-Åsberg Depression Rating Scale (MADRS), a 10-item tool that assesses symptoms like sadness, tension, and appetite on a 0-60 scale. A reduction of 25% in the MADRS score is considered clinically meaningful. One of the keys takeaways from both trials is the rapid onset of action. Significant differences in symptoms were demonstrated the day after administration. This stands in stark contrast to traditional SSRIs, which often require a "test drive" of several weeks before a clinician can determine if they are effective.
COMP005 (Single Dose Focus): In this trial, 25% of participants achieved a clinically meaningful reduction in MADRS at Week 6, with that response maintained through 26 weeks after just one or two 25mg doses.
COMP006 (Dose Exploration): This trial confirmed that the 25mg dose remains the "preferred dose," showing a statistically significant difference of -3.8 MADRS against the 1mg control at Week 6.
Furthermore, the data suggests that retreatment can be a powerful tool. In Part B of the COMP005 trial, over 40% of patients who showed progress but had not yet remitted by Week 6 went into full remission after receiving a second dose.
“The Phase 3 data from Compass Pathways marks a genuinely important moment for the field. A 4-point separation on MADRS may appear modest at face value, but in the context of treatment-resistant depression this sits firmly in line with, if not competitive against existing treatments - of which currently non are uniquely licensed in isolation for TRD. The real signal, however, lies elsewhere. A 40% response rate following just two 25mg doses is unprecedented in TRD populations, particularly given the historical difficulty of shifting outcomes in this group. Crucially, the study did not simply outperform placebo, but also demonstrated meaningful separation from an active 1mg control , an essential methodological bar in psychedelic trials. Perhaps most compelling is the durability of effect, which appears to extend well beyond what we typically observe with ketamine-based approaches or augmenting antidepressants. In short, Compass have met their primary endpoints while beginning to demonstrate something the field has long sought: not just rapid antidepressant effects, but sustained ones. Further data will be key in understanding the full clinical and mechanistic implications and I look forward to seeing those data and the FDA responses which will come this year.”
Safety within both trials
In any trial involving high-risk TRD patients, safety is the primary concern. The safety data from these trials indicated that COMP360 is generally well-tolerated. Common Side Effects included headache, nausea, visual hallucinations, and transient anxiety. In COMP005, 66% of Treatment-Emergent Adverse Events (TEAEs) occurred on the day of administration with 88% being resolved within a day. Similar effects occured in COMP006 with 73% of TEAs occurring on the day with 83% of those being resolved within a day. Between both trials there was 17 treatment emergent serious adverse events (SAEs) from a total of 14 participants all together. This equated to 5% of the trial in COMP005 and 2% in 006. The Independent Data Safety Monitoring Board (DSMB) found no evidence of a clinically meaningful imbalance in suicidality between the treatment arms. Serious suicidal ideation was reported in less than 1% of participants, and the only instance of suicidal behaviour occurred in the 1mg control arm, not the high-dose group.
Comparing COMP360 to the current drug on the market
The current market leader in the USA for TRD treatment is Spravato. However, the COMP360 data suggests a significant advantage in terms of treatment burden. A patient on Spravato may need up to 10 treatments to achieve the effect that COMP360 achieves at Week 6 with just one or two doses. While Spravato requires frequent maintenance every one to two weeks, COMP360 has demonstrated durability lasting at least six months from a single administration cycle. Furthermore, the economic impact of mental illnesses is staggering. Major depression represents a $93 billion economic cost in the US. While TRD patients represent only one-third of all MDD patients treated with drugs, they disproportionately account for 47% of the overall cost. Currently the National Institute for Health and Care Excellence (NICE) does not recommend Spravato (esketamine nasal spray) for TRD in England, Wales or Northern Ireland due to cost-effectiveness concerns. This underscores a desperate need for a treatment that works efficiently, reducing the long-term societal and economic burden. Therefore, the results from the phase 3 trial hint towards COMP360 to be a cost-effective alternative to Spravato.
Conclusion
The FDA has already granted COMP360 "Breakthrough Therapy" designation, a status reserved for drugs that show significant potential over existing options. The company is currently moving through a rolling submission process and expects to complete their full New Drug Application (NDA) by the 4th quarter of this year.
With the Phase 3 program showing that successful results are reproducible, COMP360 is well-positioned to possibly be a leading treatment. The dual clinical benefits of rapid onset and long-term durability demonstrated by COMP360 signal a new, promising blueprint for treating TRD.
