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EMA adds psychedelics to major depression guidelines



EMA adds psychedelics to major depression guidelines

The European Medicines Agency (EMA) has updated its general guidelines on the development of medicinal products for Major Depressive Disorder (MDD) to include a section on psychedelic therapy.

With up to two-thirds of MDD patients not responding to current therapies, there is an urgent need for new and innovative treatments. 

The area of psychedelic research has in recent years produced increasing clinical evidence that points towards these therapies as being potentially efficacious treatments for the condition.

The guidelines – previously updated in 2002 and 2013 – now include a section on these therapies in light of this research.

The update specifically addresses topics such as trial designs in difficult-to-treat patients, clinical development requirements for new rapid-acting therapies, clinical development requirements to target sub-domains of depression, requirements for clinical trials in children and adolescents as well as extrapolation from adult data, and gender and drug metabolism differences in patient populations.

The section on psychedelics addresses, in particular, issues concerning the development of psychedelic medicines and the “new paradigm of psychedelic-associated psychotherapy in the field of MDD”.

The guidelines read: “Psychedelics are currently being recognised in psychiatry as potential treatment options to treat various medical conditions including depression. 

“Psychedelic-assisted psychotherapy faces several challenges mainly related to standardisation, training, monitoring and safety that need to be addressed in specific study designs.”

Psychedelic clinical trials 

The document highlights that the effects of psychedelic agents present a number of challenges for the design, conduct and interpretation of clinical trials.

Such challenges include:

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Placebos and comparators

The psychoactive of psychedelics are very noticeable, making the choice of comparator and blinding difficult during clinical trials.

Expectancy and unblinding 

With increasing headlines and discussion around the potentially beneficial effects of psychedelic therapies, positive expectations can sometimes lead to “overestimation bias” as well as disappointment for patients if expectations are not met – which the guidelines highlight can lead to the worsening of symptoms for patients.

The guidelines read: “Different strategies such as low dose or active placebo, i.e. alternative substances with a distinct mechanism of action but with a similar psychoactive effect have been considered to make it more difficult to guess the treatment arm. The use of independent and blinded external raters could help to mitigate the effects of unblinding and expectancy.”


The document highlights the vital need for the dose-effect relationship of psychedelics to be characterised, emphasising the need for individualised dosing due to “individual variability in drug metabolism, age, sex, or personality…”.

Effect maintenance

The guidelines highlight the current lack of knowledge on the sustainability of the action and the long-term effects of psychedelics – emphasising that “the ability to change the perception of reality can have unknown implications for depressed patients (anxiety with derealisation, negative trips).”


With the majority of clinical trials investigating psychedelics administering the treatments alongside psychotherapy, the guidelines note that clinical trials will have to demonstrate that the effect of the psychedelic-assisted therapy is not due to psychotherapy alone.

The guidelines read: “The framework of operation (protocol) as well as preparatory and post-dose integration sessions and whether this needs to be adapted to the type of psychedelic need to be clearly defined. 

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“Type, length and frequency of psychotherapy and training need to be standardised to the maximum possible effect, despite ethnic and cultural differences.”

Read the full guidelines here:

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SRI and non-SRI patients experience similar antidepressant effects of psychedelics



SRI non-SRI patients similar antidepressant effects psychedelics

A new study has shed light on the impact of psychedelics in patients taking SRIs, finding similar antidepressant effects as those not taking SRIs.

Increasing research is showing that psychedelics hold promise as potential new treatments for mental health conditions. However, how psychedelics interact with commonly prescribed antidepressants – serotonin reuptake inhibitors (SRIs) – is largely unknown.

This is a barrier to the advancement of psychedelics as mental health treatments, as those who may need these treatments the most are likely to be taking, or have taken at some point, SRIs.

Typically, due to this lack of knowledge on the safety of taking psychedelics when on antidepressants, many participants of clinical trials are required to stop using them for two weeks before taking part in a trial.

Additionally, some research has suggested that those taking SRIs may experience less therapeutic effects from psychedelics, such as psilocybin, than those who have never taken them. For example, one study found that patients who had been taking the antidepressant Escitalopram experienced fewer therapeutic effects than those who had not.

Now, a new survey study of people using psychedelics in real-world settings has investigated the interaction between these two medicines, comparing the acute psychedelic effects and subsequent changes in wellbeing and depressive symptoms in those on psychiatric medication and those who are not. 

SRI vs non-SRI

For this study, the team analysed the subjective differences and changes in wellbeing and depressive symptoms in participants both before and after the psychedelic experiences.

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They found that patients who were not taking SRIs experienced significantly more intense subjective effects than those who were not. This group also experienced stronger mystical experiences and more challenging emotional breakthrough experiences.

However, they also found that both groups had similar drug-induced visual experiences.

Importantly, they found that the group who were taking antidepressants reported similar improvements in wellbeing and depressive symptoms following the psychedelic experience to those who were not taking them. 

Speaking to Psychedelic Health, study co-lead Tommaso Barba, at the Centre for Psychedelic Research, Imperial College London, commented: “I think we don’t have a definitive answer yet, the combination seems to work and it seems to induce a therapeutic response, if this response is lower than on people who are not on these drugs is still a sort of open question. 

“Our study suggests it’s not lower, but it’s a naturalistic survey study, with overall small sample and lack of laboratory controls.”

Barba points to a study that suggests people on SRIs have reduced intensity of the acute psychedelic experience, but notes this only occurred in half of the participants, and highlights another study that showed that psilocybin therapy seems efficacious in patients that were also using SRIs, as the reductions in depression were comparable to another study that involved patients who were not on medications.

“What is lacking now is a randomised trial in which two groups, one on SRI and one not, are directly compared in laboratory settings,” said Barba.

“I think that the current evidence, with other results, show that taking people off SRIs before psilocybin therapy was associated with reduced therapeutic efficacy compared to people who were unmedicated at the entrance of the trial, suggesting that discontinuing medications is not warranted, and maybe people are not required to do so and could be kept on them.”

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In their paper, the research team concludes that: “Individuals presumed to be on serotonergic antidepressants during psychedelic use display reduced subjective effects but similar antidepressant effects compared to those not undergoing SRI treatment.

“Further controlled research is needed to comprehend the interplay between serotonergic antidepressants and psychedelics, illuminating potential therapeutic benefits and limitations in clinical contexts.”

For example, serotonin has been implicated in several major psychiatric disorders, with low levels contributing to conditions such as depression. SRIs work by making more serotonin available in the brain.

As highlighted by Thomas and Malcolm in a 2022 paper, mental health conditions that are targeted by psychedelic medicines are most often managed with SRIs, “so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents.”

Serotonin toxicity is a condition that is often induced when two or more serotonin-elevating drugs are used in combination. The condition leads to too much serotonin within brain synapses and can sometimes be life-threatening, causing symptoms such as seizures, irregular heartbeat and unconsciousness.

Thomas and Malcolm emphasise that due to the ability of psychedelics and SRIs to increase serotonin, some combinations may present a significant risk of serotonin toxicity.

In this survey study, the researchers highlight that only two modern studies have investigated the interaction between SRIs and psychedelics which have presented partially contradictory results.

The team has also emphasised that their findings could have implications for modifying research design and inclusion criteria for certain clinical studies, as well as for informing future medical use of psychedelics in order to maximise positive outcomes and the efficacy of the treatments.

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The study team included leading psychedelic researchers Tommaso Barba, Jessica Barbut Siva and Hannes Kettner at the Centre for Psychedelic Research, Imperial College London; Joanna Kuc, Experimental Psychology, University College London; Professor Robin Carhart-Harris, Ralph Metzner Distinguished Professor in the Department of Neurology at the University of California, San Francisco; Dr David Erritzoe, Clinical Director in Centre for Psychedelic Research & Clinical Senior Lecturer in Psychiatry at Imperial College London; Professor David Nutt, Professor of Neuropsychopharmacology at Imperial College London.

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Psychedelic research secures first-ever European Union grant of €6.5 million



Psychedelic research secures first-ever European Union grant of €6.5 million

Marking a historic first for Europe, the European Union has funded research into psychedelic therapy as part of its Horizon Europe programme. 

The EU has awarded €6.5 million to a consortium of 19 partners from nine different European countries for a clinical trial – the PsyPal trial.

The trial will study psilocybin-assisted psychotherapy for psychological and existential distress in people who are diagnosed with either chronic obstructive pulmonary disorder (COPD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) or atypical Parkinson’s disease (APD). 

The consortium includes psychiatrists, palliative care physicians, psychologists, experts in psilocybin therapy, researchers focusing on spiritual care and representatives from religious institutions. 

Throughout the trial, the PsyPal consortium will be engaging with the Psychedelic Access and Research Europe Alliance (PAREA), a non-profit reform group that has been campaigning for access to psychedelic therapy in Europe.

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Tadeusz Hawrot, Executive Director of PAREA, told Psychedelic Health: “I couldn’t be happier with this development. Advocating for EU-funded research on psychedelics is part of PAREA’s DNA. 

“It is particularly crucial to explore their potential in areas with significant unmet mental health needs, where commercial interest is lacking, such as in palliative care. With a growing body of promising results in the medical use of psychedelics, what we urgently need now are more European multisite studies. 

“We require clinical trials involving larger and more diverse patient populations to further establish their efficacy and safety. Generating more clinical data on the safety and efficacy of psychedelic compounds will pave the way for the marketing authorization process in Europe, accelerating the delivery of these medicines to patients who are often in desperate need of more treatment options.

“Jeremy Farrar – a former Director of Wellcome Trust and current WHO Chief Scientist – once said about Horizon Europe that it is globally regarded as the best internationally co-operative endeavor anywhere in the world. 

“Importantly, this new EU project will not only advance our understanding of psychedelic therapies but also help establish psychedelics as legitimate, emerging mental health treatments.”

The PsyPal Trial

Following in the footsteps of previous research which has demonstrated the potential benefits of psychedelic-assisted therapy for people living with terminal cancer, the study is the first clinical trial to investigate the safety and effects of psilocybin in non-oncology palliative care patients.

The trial will be led by the University Medical Centre Groningen (UMCG) in the Netherlands in collaboration with HumanKindLabs and will begin early this year. Locations for the trial include the UMCG, the Champalimaud Foundation in Portugal, the National Institute of Mental Health in the Czech Republic, and the University of Copenhagen and the Bispebjerg Hospital in Denmark. 

During the trial, participants will take part in two psychedelic therapy sessions – receiving either psilocybin or a placebo. 

In a statement, Robert Schoevers, head of psychiatry at the UMCG and principal investigator of PsyPal, stated: “We are eager to see if we can ease the suffering of these patients whilst also examining longer-term patient and family outcomes of this treatment, something that often gets overlooked but that is of enormous importance.” 

As well as immediate clinical outcomes, the trial will be studying whether or not the therapy can help sustain the well-being of patients and their families post-treatment. 

The trial will utilise peer support and online tools to “enhance coping mechanisms and alleviate distress as people approach the end of their lives.”

Horizon Europe

Established in 2021 the Horizon Europe programme was launched to accelerate research and innovation in Europe and is running with a budget of €95.5 billion.

Schoevers added: “We are absolutely thrilled that the EU is supporting this ambitious collaborative study. There is growing recognition that psychedelic treatments may help patients for whom alternatives are not effective, and I am very glad we are receiving support from this highly prestigious funding program. 

“It really helps to strengthen the collaboration between researchers from different countries and disciplines, focusing on potentially transformative interventions for severe, currently treatment-resistant mental disorders.” 

Principal investigator Robert Schoevers (UMCG) attends a patient receiving psychedelic-assisted therapy.’ 

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First psilocybin trial for bipolar depression shows promising results



First psilocybin trial for bipolar depression shows promising results

The first-ever psilocybin trial for treatment-resistant bipolar type II disorder has shown 80% of participants meeting remission criteria 12 weeks after treatment.  

JAMA Psychiatry recently published results from the first-of-its-kind clinical trial conducted at Sheppard Pratt. The study explored the efficacy and safety of a single dose of synthetic psilocybin accompanied by psychotherapy in treating individuals with treatment-resistant bipolar type II disorder (bipolar II). 

The 12-week, open-label trial, initiated and led by Scott T. Aaronson, chief science officer of the Institute for Advanced Diagnostics and Therapeutics at Sheppard Pratt, and funded by Compass Pathways, included 15 participants aged 18 to 65 with treatment-resistant bipolar II. 

Each participant had experienced an episode of bipolar II for a period greater than three months and documented at least two failed pharmacological treatments within the current episode. 

After discontinuing psychotropic medications at least two weeks prior to the trial, participants were administered a single dose (25mg) of synthetic COMP360 psilocybin in a controlled setting. 

Therapists held sessions with patients during the eight-hour dosing day as well as for three sessions prior to the trial’s start and for three integration sessions post-treatment. Funding for the study will also allow for patient results to be monitored up to two years following treatment.

Aaronson stated: “The results we saw from this trial are encouraging and further support the clinical study of psychedelics in patients with treatment-resistant bipolar II.

”One participant compared the transformation she experienced to taking a deep breath after breathing through a straw for years. These are the types of stories we are hearing from people who struggled with this disorder for years, many whom had lost hope that their bipolar II could ever be treated.”

In this small pilot study, there were no findings that patients had developed symptoms of psychosis during treatment and 73% of participants met remission criteria on the Montgomery Asberg Depression Rating Scale three weeks post-treatment. 

A total of 80% also experienced remission with no increase in bipolar II symptoms such as mania, hypomania, or suicidality twelve weeks after treatment. The results of this study suggest the efficacy and safety of psilocybin in treatment of bipolar II depression, but cannot be extrapolated to the study of psilocybin to treat bipolar I disorder.

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