A Trip in the Clinic: Are Psychedelics the Future of Depression Treatment?

1. A Shift in Mindset

“Psychedelics are to the study of the mind what the microscope is to biology or the telescope is to astronomy.” – Stanislav Grof [1]

Until recently, psychedelic drugs in psychiatry seemed implausible due to stigma and cultural taboos [2]. Psilocybin is now under serious investigation in academic psychiatry as a potential therapeutic tool [3,4,5].

Nearly one in three patients with depression are considered treatment-resistant [6]. For many, standard antidepressants can cause more harm than healing, with side effects such as weight gain, emotional blunting, insomnia, or sexual dysfunction [7]. Could psychedelics offer a new path when conventional therapies fall short?

2. What Are Psychedelics?

Psilocybin (the active ingredient in “magic mushrooms”) has been historically associated with counterculture and recreational use. Psychedelics (including psilocybin) comprise a class of compounds that are especially disassociative in nature and alter cognition and perceptions, primarily through 5-HT2A serotonin receptor agonism [8]. 

Long before these agents were included in the prohibitionist drug laws of the 20th century, psychedelics were used ceremonially, in Indigenous and spiritual practices around the world. While popular ceremonial uses included psychedelic mushrooms in Mesoamerica, or ayahuasca in the Amazon, such ceremonial practices were often not viewed as drugs, but tools for healing, insights and connections [9]. These earlier ways of using these compounds remind us that our modern clinical developments are in many ways musing in a kind of rediscovery of practices that have been part of human culture for many centuries.

3. How Do Psychedelics Work?

Psilocybin primarily acts as an agonist at the serotonin 5HT2A receptors. But its more profound effect may lie in disrupting the brain’s default mode network (DMN), a neural system tied to self-referential thought, overthinking, and rigid mental habits. The dominant model explaining this is REBUS (Relaxed Beliefs Under Psychedelics), which proposes that psychedelics relax the precision of top-down beliefs, reducing excessive rumination and making space for new insights [10]. By “relaxing” rigid cognitive patterns, psilocybin creates a temporary window where individuals can process information differently, update maladaptive mental frameworks, and become more psychologically flexible. This may help in depression, where rigid thought patterns dominate. Reduced DMN activity decreases reliance on old predictions, opening the brain to new perspectives [10].

Figure 1. Enhanced Brain Connectivity Following Psilocybin Administration. This network diagram visualises functional brain connectivity in individuals given a non-psychedelic compound (left) versus psilocybin (right). Each node represents a brain region, and lines reflect communication between them. Under psilocybin, cross-network connectivity dramatically increases, supporting the REBUS model and the entropic brain hypothesis, which propose that psychedelics facilitate a more flexible and integrated brain state. Petri G, Expert P, Turkheimer F, Carhart-Harris R, Nutt D, Hellyer PJ, et al. Homological scaffolds of brain functional networks. Journal of The Royal Society Interface. 2014 Dec 6;11(101):20140873. [11].

Psilocybin has the potential to produce real change psychologically in one or two doses, particularly when administered along with an intensive psychotherapy encounter [12,13]. In comparison, SSRIs can take weeks to establish an effect. Though there is conflicting evidence in the literature, there is concern of increased suicidality in the first weeks after starting therapy, particularly in younger patients [7]. Therefore, the structured nature of psychedelic therapy, with its emphasis on insight and integration, continues to appeal to many clinicians [5].

4. Current Clinical Trials

A Phase 2 trial published in 2021 found that psilocybin was at least as effective as escitalopram, the antidepressant control, in treating moderate to severe depression, with fewer side effects and a faster onset of action [3]. However, the trial involved a relatively small number of participants (59 in total) and administered psilocybin alongside psychological support, making it difficult to isolate the compound’s effect from the setting.

Figure 2. Change in Depression and Well-being Scores Following Psilocybin vs Escitalopram. Panel A shows changes in QIDS-SR-16 depression scores, and Panel B shows changes in WEMWBS well-being scores. Psilocybin produced faster and more substantial improvements in both domains compared to the SSRI, despite only two dosing sessions. Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, et al. Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine. 2021 Apr 15;384(15):1402-11.[3].

In 2022, COMPASS reported that COMP360 significantly reduced depression in patients who had failed two prior treatments [4].

In mid 2025, COMPASS reported its Phase 3 trial met its primary endpoint. Though full data is pending, this marks a historic milestone in psychedelic medicine [14].

Most psychedelic trials exclude patients with comorbidities, personality disorders, or complex social needs, exactly the kind of patients common in NHS mental health services. Implementing successful trials into everyday practice will require adjustments. Treatment must show not just that it is effective under best conditions, but that it is safe, scalable, and applied fairly across populations [6]. 

A recent systematic review confirmed that many clinicians remain uncertain about psychedelic-assisted therapy, which was seen as an issue of concerns of patient expectations, conservatism regarding reputation, and a lack of long-term evidence [15].

Study	Participants	Intervention	Control	Outcomes	Side Effects
Imperial College (2021) [3]	60	2 high-dose psilocybin sessions + therapy	Daily escitalopram	Similar antidepressant effect; faster onset	Mild, transient (nausea, headache)
COMPASS Pathways Phase 2b (2021) [4]	233	25 mg COMP360 + therapy	1 mg psilocybin	37% response, 29% remission at week 3	Transient anxiety, headache
COMPASS Phase 3 (2025) [14]	>800	25 mg COMP360 + therapy	Placebo	Primary endpoint met, superior symptom reduction	No new safety concerns
Haikazian et al. (2023) [12]	9–12 RCTs (600 total)	Psilocybin-assisted therapy	Placebo or escitalopram	Large effect sizes (Hedges’ g ≈ 0.62–0.69)	Generally mild and transient (e.g., nausea, headache)

Table 1. Summary of Key Clinical Trials and Meta-Analytic Findings on Psilocybin-Assisted Therapy for Depression. It includes sample sizes, interventions, controls, outcomes, and side effects from the Imperial College (2021) head-to-head trial with escitalopram, the COMPASS Pathways Phase 2b and Phase 3 trials, and a recent meta-analysis by Haikazian et al. (2023) synthesising results from 9–12 randomised controlled trials.

5. Why Psychedelics Matter in Psychiatry

Conventional antidepressants, particularly SSRIs, are often default interventions for low mood and depression. But for many patients, these medications offer little relief. The STAR*D trial, one of the largest and most comprehensive studies of depression treatment, revealed a sobering reality: after two failed antidepressant trials, the likelihood of full remission declines sharply, with diminishing returns from each subsequent option tried [7].

Psychedelics take a different path. Instead of daily pills, psilocybin is given in one or two high-dose sessions, guided by structured therapy before and after. The compound matters, but the process of preparation, experience, and integration shapes the outcome [3,4].

Professor David Nutt sees this as a shift from symptom suppression to emotional processing. He describes psychedelics not as conventional drugs, but as “tools for listening to the brain, not just overriding it” [2].  SSRIs may address emotions in a flattening manner and take weeks to work, while psychedelic therapy offers emotional depth in fewer, intense sessions. For many people, these are not just different approaches to symptom management; these are two fundamentally different pathways that can result in a psychological reset [10,16].

Safety concerns are being considered through clinical evidence. A systematic safety review published in 2025 assessed psilocybin therapy and concluded it was well tolerated in controlled settings and reported no harmful outcomes and only transient adverse events of anxiety, nausea, and headache [17]. It is important to consider that these clinical trials involved screened participants without medical exclusions and psychiatric comorbidity (e.g., bipolar disorder, psychotic disorders). Even in these screened populations, there were rare reports of suicidal ideation [12].

If psychedelic therapy is widely accessible to larger and more diverse populations who are likely to have different complex or undiagnosed psychiatric histories, this raises the question of safety in terms of serious adverse events. There is an imminent need for longitudinal safety data on psychedelics in diverse populations and the establishment of safeguards related to thorough psychological and medical screening, professional supervision in-session, and structured integration support after-session [12,17].

Traditional psychopharmacologic treatments provide stability. Psychedelics aim to instigate transformation. Disconnection is not just about relief of symptoms; it is about recovering meaning [2].

One compound that bridges this divide is ketamine. Though not a classic psychedelic, ketamine has psychedelic-like effects and acts on glutamate pathways through NMDA receptor antagonism. It provides rapid antidepressant effects within hours and is already used in acute psychiatric crises, including suicidal ideation. Ketamine may complement the psychedelic model, acting as a stabiliser in emergency settings, while psilocybin and related therapies are reserved for long-term psychological transformation [18].

6. The Challenges: Implementing Psychedelic Therapy

Science is advancing faster than implementation. While the data continues to grow in favour of its use, psilocybin remains far from routine clinical practice. The barriers are no longer primarily scientific. They are legal, cultural, and structural (and they may prove just as challenging).

Legal Barriers: Science vs the Law

In the UK, psilocybin remains in the same legal class as heroin as a Schedule I substance under the Misuse of Drugs Regulations 2001, meaning that the government recognises no medical use and considers it to have a high risk of harm (even with an increasing amount of clinical evidence to the contrary). Because of this classification, researchers have a long and expensive process to obtain licenses, which complicates progress and deters funding [19]. For many years, David Nutt and his associates have railed against this sort of restriction as an outdated model of science, drowning out advances in psychiatry, and insisted that science is way behind the law [2,19]. A 2025 Parliamentary report noted a growing chorus of voices from researchers and clinicians, requesting that psilocybin be rescheduled to Schedule II, which would relax research restrictions and allow for NHS trials of psilocybin [20].

Stigma: Cultural Legacy

Cultural memory still exerts influence. Psilocybin, LSD, and other psychedelics are still influenced by connotations of the illegality of the countercultural 1960s, as well as fears of psychosis and unpredictability that permeate their use. These narratives continue to shape attitudes among clinicians. Much of this stigma can be traced back to the prohibition era led by U.S. narcotics commissioner, Harry Anslinger. His drug policy, through mid-20th century moral panic, reinforced political and cultural resistance to psychedelics that has proven tenacious [21]. A recent systematic review confirmed that many clinicians remain ambivalent about psychedelic-assisted therapy; this was perceived as a problem of patients’ expectations, conservatism towards reputation, and a general lack of long-term evidence [15]. Shifting public policy will require shifting professional mindsets as well.

The NHS Challenge: Time, Space, and Staffing

Even with reduced stigma and legal change, feasibility remains an issue. Psychedelic therapy involves extensive preparation, day-long monitoring sessions, and follow-up integration therapy, which are far more resource-intensive than a routine medication review. A 2024 BMJ editorial warned that unless mental health infrastructure is redesigned to accommodate this model, the NHS may find itself unable to deliver the care, no matter how effective the treatment proves to be [22].

Trial Limitations vs Clinical Reality

Another issue is who gets tested in trials. Most psychedelic trials exclude patients with comorbidities, personality disorders, or complex social needs, exactly the kind of patients common in NHS mental health services. Implementing successful trials into everyday practice will require adjustments. Treatment must show not just that it is effective under best conditions, but that it is safe, scalable, and applied fairly across populations [12,17]. 

Media Framing: Between Hope and Hype

Public discourse about psychedelics has contributed to the research agenda, but with this comes a level of concern. Headlines announcing “magic mushrooms” as miracle cures can raise hopes much higher than the evidence suggests. This hype not only shapes public opinion but may also bias clinical trials. Participants often enter studies with strong expectations, and researchers may be influenced by subtle confirmation bias. Grounded communication is essential to make psychedelic therapy sustainable. This might require messaging that balances hope with realism and sets clear expectations about who psychedelics can help and how [2].

7. Where Do We Go From Here?

Psychedelic therapy is no longer an outlying area of psychiatry. Research and regulation are making it more mainstream. Most recently, a Phase 2 trial published in the Journal of Affective Disorders examined the effects of a single 25 mg dose of COMP360 psilocybin psychotherapy in individuals suffering from treatment-resistant depression. The authors reported major improvements in mood, anxiety, and functioning, and no unexpected adverse events were reported related to safety after one single acute dose of psilocybin [14]. Although not a Phase 3 trial, it adds evidence and increases confidence toward advancing to larger trials, including the ongoing Phase 3 program led by COMPASS Pathways, which recently announced that they had achieved success on their primary endpoint [14].

Within the profession, momentum is building. A recent commentary in the British Journal of Psychiatry by Carhart-Harris and Nutt urged psychiatrists to begin preparing, not just by understanding the evidence, but by rethinking models of care [5]. Psychedelic-assisted therapy is not just a new drug protocol. It blends pharmacology with guided experience and requires space and trust [23].

Yet the path from trial to treatment is complex. Even if psilocybin or ketamine or MDMA-assisted therapies are licensed, questions will remain. Who will deliver these therapies? How will they be funded? Where will they fit into a system already stretched thin? The NHS is not equipped for multi-hour sessions or structured integration. Adopting this model in the NHS needs more than new drugs, it demands new care frameworks [22].

This requires new training, updated NICE guidance, and equitable access. These therapies should not become solely associated with private clinics.

Listening to patients is vital. While trials measure symptom scores, they cannot always capture the emotional and existential depth of a psychedelic experience. In a qualitative study of psilocybin-assisted psychotherapy for individuals with cancer, one participant reflected, “I was the cloud, I was everything… this was me. And it was so wonderful… to believe that. And I still do – that is me” [24].

This shows how the treatment helps process distress at a fundamental level. Moving the field forward responsibly means listening closely to these stories, not only for safety, but for insight into the deeper nature of healing itself.

That being said, there is reason to be cautiously optimistic. What was once dismissed as fringe and even preposterous is now being discussed in leading journals, on policy and news sites, and in clinical board rooms. In another 10 years, it is certainly plausible to imagine psychedelic-assisted therapy being a part of mainstream psychiatry. Perhaps not as a silver bullet, but as another option for those with no options left.

The big question isn’t whether psychedelics have potential, but whether systems and societies have the capacity to embrace that potential responsibly. Can the NHS, academia, and the public address stigma, build infrastructure, and provide fair access for those who need it most? The science is arriving. What happens next is up to us.

References

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