Sometimes life seems to be a ceaseless struggle. If you’re mentally healthy, you can accept the things you cannot change and alter those you can.
People with depression tend to see life’s challenges as outside their control. They are poor at solving life’s problems, which undermines their ability to alter their life for the better. Their failed attempts fuel their depression. Conventional antidepressants may make little if any difference.
That’s why psychedelics attract so much attention as a new option for people with treatment-resistant depression – they can fundamentally change the way mentally ill patients view and respond to life’s challenges. “Psychedelic drugs may alter the experience of reality and the way inferences of the world are made, realigning what is expected with what is perceived,” researchers commented in JAMA Psychiatry recently.1
“So far, trials demonstrate considerable potential for using psychedelic drugs to treat complex mental health conditions, particularly among those more resistant to traditional therapies,” says Tom McDonald, chief executive officer at Clerkenwell Health, Europe’s first specialist contract research organisation dedicated to running clinical trials using psychedelic-assisted therapies and other cutting-edge mental health treatments.
“We are working in an emerging field, where there are many as yet unanswered questions, including how psychedelics will be administered and managed in the real world, frequency of treatment, as well as the long-term safety and efficacy profile of these compounds,” says Dr Guy Goodwin, chief medical officer at Compass Pathways, where a synthetic psilocybin called COMP360 has been developed.
Psilocybin is structurally similar to serotonin2 and seems to affect serotonin and, indirectly, glutaminergic and dopaminergic pathways.3
“Psilocybin is believed to work by acting as a partial agonist at serotonin 2A receptors,” says Goodwin. “This may create new connections in the brain, which could positively alter how people feel and perceive their surroundings.”
Nevertheless, GPs won’t be writing prescriptions for psychedelics any time soon as the psychedelic is only one part of the management pathway for people with serious mental health issues.
“Psychological support is a key part of the structured preparation before patients take a psychedelic,” says Goodwin. “This support ensures they are ready emotionally and mentally for what they may face during their psychedelic experience and are able to gain as much as possible from it. It also ensures they feel safe and secure during the process.”
Neither are psychedelics a quick fix. After receiving the psychedelic, behavioural changes need to consolidate the initial improvements.2 While this optimises outcomes for patients, the management pathway complicates clinical studies. “The therapeutic environment, the impact of patients’ wider experiences and the complementary skill sets needed to administer psychotherapeutic and pharmacological treatments create added operational challenges for clinical studies,”
Tom McDonald says.
Seeing the world differently
Psychedelics can fundamentally change the way people with mental health issues see the world – that’s the whole point.
“Data from our phase 2b study of COMP360 psilocybin in treatment-resistant depression,4 where patients have tried at least two antidepressants without success, suggest that positive psychedelic experiences facilitate emotional breakthroughs that may change thought patterns in people with depression,” Guy Goodwin says. “This experience is driven by dose and correlates with the effect on depressive symptoms.”
During the phase 2b study, about 30 per cent of 79 people with treatment-resistant depression were in remission three weeks after a single 25mg dose of COMP360.4 “These results are promising,” he says. “Our phase 3 programme seeks to confirm the findings and investigate if a second dose of COMP360 psilocybin increases rates of treatment response and remission seen in the phase 2b study.”
Unlike traditional antidepressants, psychedelics rapidly improve mood. In one study, 27 patients with moderate to severe unipolar depression received two sessions of psilocybin with supportive psychotherapy. A week after treatment, 71 per cent of patients had responded (at least a 50 per cent reduction in scores on a depression rating scale), while 58 per cent were in remission.
The benefits persist: 12 months after the second dose, 75 per cent showed a treatment response and 58 per cent were in remission.5,6 Enhanced synaptic activity and also connectivity probably underlie the sustained improvements often seen after psychedelic administration.3
Psychedelics may be effective in other cases of difficult-to-treat depression. Understandably, for instance, many people with advanced cancer experience mental health issues, including end-of-life depression and anxiety.7,8 Researchers at the University of Texas MD Anderson Cancer Center plan to assess psilocybin in people with controlled advanced cancer experiencing mental health issues in a study that will start next year.8
“It is important to have the correct infrastructure that can deliver these potential treatments to ensure people in need can access them”
Psychedelics show considerable promise in psychiatric diseases other than treatment-resistant depression, including personality disorders, eating disorders, PTSD [post-traumatic stress disorder] and more complex presentations of comorbidities, says Tom McDonald. Studies are also assessing psychedelics for addictions, LSD as an anxiolytic and psilocybin for anorexia nervosa.3,7,9
People with anorexia, for instance, desperately need new treatments. Mortality among those with the disease is 18 times higher than among the general population, partly because of the increased suicide risk. About half of people with anorexia relapse and a fifth follow a chronic course.3
A phase 1 open-label study assessed COMP360 in 10 adult women with anorexia nervosa. Five patients were in partial remission. Following a single dose of the synthetic psilocybin, nine women felt more positive about life endeavours, eight said the experience was among the five most meaningful of their lives and seven reported a change in personal identity and overall quality of life. Nine patients, however, felt that one session was insufficient.3
Study design challenging
Designing studies assessing psychedelics is particularly difficult. “With regards to psychedelics and psychedelic-assisted therapy, there are unique conceptual and practical challenges for trial delivery, such as issues with blinding and expectancy,” McDonald comments.
For instance, some people who agree to take part in a psychedelic trial may be particularly open to alternative medicine and new age beliefs.5 Others are particularly desperate. “Many people put themselves forward for trials because they’ve had poor or limited success with conventional and currently available treatments,” he says. “Many of these people refer to their participation in trials as a ‘last resort’.”
“Expectation management is important. Trial participants need to be aware of what is possible, but also what is not,” he continues. “Well designed patient-facing materials can reduce the impact of expectancy on outcomes,” he adds.
Expectations drive placebo effects but, given the nature of the psychedelic experience, blinded study designs are difficult, if not impossible. “Blinding is, unfortunately, an unavoidable challenge in psychedelic studies and can affect how results are interpreted,” McDonald says.
“One approach is to use active placebos, although this is far from being a perfect solution. It is essential that blinding as a potential confounder is built into the trial design and the communications around the trial. Recording expectancy effects is also useful.”
Nevertheless, current methods struggle to capture all the outcomes in psychedelic studies. “For most psychiatric conditions, questionnaires are still the gold standard, although immediacy biases [preferring the most readily available option] and self-reporting can call their accuracy into question,” McDonald says.
“Questionnaires do not capture the psychologically complex and unique nature of psychedelic experiences, and by extension the fact that different individuals have very different experiences. While the industry is working on new methods that will capture this variety more effectively, they are far from perfect. A greater focus on gathering more longitudinal and qualitative data alongside quantitative [outcomes] would hugely improve our understanding.”
Safety and efficacy
Psychedelics seem well tolerated in the short term. Headaches (reported by eight of the 10 patients), fatigue (seven patients) and nausea (three patients) were the most common adverse events in the study of COMP360 for anorexia.3
In other studies, rates of nausea and headache with psilocybin are between 4-22 and 15-50 per cent respectively.2 Psychedelics’ long-term safety and efficacy is less clear.
Psilocybin seems to have little if any potential for dependence and is physiologically safe in overdose.2 While regular use can cause tolerance, it does not seem to cause a withdrawal syndrome or psychosis but may exacerbate or uncover existing psychosis.2 Further studies need to fully characterise any risk of psychosis, mania, suicidal behaviour and self-harm.2 “There is still a lot we don’t know,” McDonald says. “We don’t know which drugs are best suited to treating certain conditions and how we tailor treatment plans to ensure they are used as effectively as possible.”
Integrated into pathways?
Implementing treatment in pressurised NHS psychiatric services will prove an acid test. “We designed our clinical studies to ensure that they address the right questions for regulators and payors, so that COMP360 can be integrated into health systems and commercial health plans, if proven to be safe and effective,” says Guy Goodwin.
“It is important to have the correct infrastructure that can deliver these potential treatments to ensure people in need can access them. If approved, we expect that specialised interventional psychiatry treatment centres would initially deliver COMP360 psilocybin. These have the infrastructure, capabilities, workforce and experience treating people with treatment-resistant depression.”
“We need to ask how access to these new treatments will sit alongside existing mental health treatments and how they could be introduced and integrated at scale to relieve pressure elsewhere in the system,” agrees Tom McDonald. “There is a need for further trials and more robust data to produce a stronger evidence base demonstrating psychedelics’ efficacy, especially when paired with psychotherapy, in treating issues such as severe depression, alcohol-use disorder or PTSD.
“Until we see head-to-head studies, the debate about the best way to deliver talking therapy alongside psychedelics will continue,” he concludes.
1. JAMA Psychiatry 2023; DOI: 10.1001/jamapsychiatry.2023.1412
2. BJPsych Bulletin 2023; DOI: 10.1192/bjb.2023.25
3. Nature Medicine 2023; DOI: 10.1038/s41591-023-02455-9
4. New England Journal of Medicine 2022; 387:1637-1648
5. JAMA Psychiatry 2021; 78:481-489
6. Journal of Psychopharmacology 2022; 36:151-158
7. Psychopharmacology 2022; 239:1809-1821
8. International Journal of Gynecological Cancer 2023; DOI: 10.1136/ijgc-2023-004659
9. Trends in Pharmacological Sciences 2021;42:929-942