As psychedelic treatments gain traction across Europe, Dr. Óscar Soto is helping shape their future from Barcelona. Dr. Soto is a psychiatrist, therapist, and researcher working at Parc Sanitari Sant Joan de Déu, where he has founded the ANIMA research group focused on the therapeutic value of altered states of consciousness, and completing his PhD at Universitat Autònoma de Barcelona, where he is researching the mechanisms of change underpinning psychedelic treatments. He co-founded and serves as Vice President of the Spanish Society of Psychedelic Medicine, and is trained in ketamine, psilocybin, MDMA, and 5-MeO-DMT therapy.
In this conversation with Psychedelic Alpha’s Josh Hardman, Soto reflects on how his early work in neuroscience and personal interest in philosophy converged to inform his current focus: understanding psychedelics across multiple mechanistic levels. We explore his doctoral research in more depth, alongside broader questions of trial design, therapeutic fidelity, and the evolving role of subjective experience in psychedelics and psychiatry. He also shares his views from the field, with a particular focus on clinical trials of 5-MeO-DMT.
I think a lot of psychiatrists have been approaching psychiatry or mental suffering from the wrong end—from biology and biological biomarkers, instead of the subjective experience.
Josh Hardman, Psychedelic Alpha: To get us started, could you tell us a bit about your background and how you became interested in psychedelics?
Dr. Óscar Soto: Well, I’m a psychiatrist, but I’m also very interested in philosophy, which I’m currently pursuing a master’s in. I started my research career in neuroimaging and, at that time, as with most psychiatrists, I was also very interested in the humanities, philosophy of the mind, and philosophy of science.
Professionally speaking, I became interested in psychedelics when I started reading the works of Robin Carhart-Harris on the neurobiological underpinnings of psychedelics, and how he would connect this with the free energy principle. He developed some very elegant theories on how the mind works based on psychedelics. I’m really interested in this because I think a lot of psychiatrists have been approaching psychiatry or mental suffering from the wrong end—from biology and biological biomarkers, instead of the subjective experience.
I think with psychedelics, we have the opportunity to really use the very intense subjective experience to learn their biological underpinnings and see what is happening there. It’s like going from a first-person perspective to a third-person perspective, instead of the other way around.
Hardman: I know you have worked on psychiatric trials with more conventional drugs. What would you say are the main differences working on those trials versus psychedelic studies?
Soto: Firstly, there are some biases. That’s what was being discussed with the MAPS/Lykos controversy. I think it’s important to be conscious of this bias, because most of the people that are involved in psychedelic research really like psychedelics and hence want this to be a success.
Equally, patients who come to participate in the trials really want to receive psychedelics, and often they come to the clinic really looking forward to their psychedelic experience. In other trials, people don’t care so much what the specific drug is, because they don’t know much about the subjective experience, the mechanisms of action, or the effects that it will have.
In terms of logistics, psychedelic trials are also much more complicated. That’s also why I think sponsors like our unit, or other units that are specialised in psychedelic trials, because lots of coordination is needed between different people for long periods of time, as well as specific facilities. Plus, a lot of training is needed, and this takes a lot of time and effort.
Hardman: With psychedelics, there’s lots of talk about ‘inner healing intelligence’ and the patient having to work through things themselves. Have you encountered patients being surprised by how much they’re expected to do on their own?
Soto: Definitely. This is another thing that I like about psychedelic research insofar as it has a broader impact on psychiatry as a whole. I think because of the dominating biological approach, some psychiatrists teach patients that they have an illness that is not part of who they are, and is something they must get rid of. Whereas with psychedelics, you have the opportunity to engage in a person-centred approach, in which the patient is engaged in an ongoing, collaborative process.
The media also plays a part here, because psychedelics are often talked about as a resetting of the brain that will eliminate the symptoms by itself. So when patients come in, a lot of psychoeducation is needed before the treatment. Some people are just not ready for this kind of work.
Hardman: When you say some people aren’t ready for the work, could it also be the case that some may not have the space or the time to do that work?
Soto: Definitely. For example, with the 5-MeO-DMT trials, it’s expected that there could be flashbacks and reactivations that can impact your daily life in the days or weeks after. One of the good things with sponsored trials is that we have people from lower socioeconomic backgrounds who wouldn’t normally be able to access these treatments. However, this can be complicated because when we ask them to take a couple of days off for integration, some people just can’t.
Hardman: The topline data from companies developing 5-MeO-DMT hasn’t included much about flashbacks or reactivations. Why do you think that is?
Soto: We have to wait until the official peer-reviewed publications, but I do think there are some very important questions.
First of all, these events are expected biologically and this is something that is explained to patients in the informed consent. So this is something that can happen and, in my experience, it does happen. Importantly, though, I do only have access to the subset of participants with whom I’ve been working.
I think it’s also important to consider the way these things are asked and reported. This is one of the big issues in psychedelic research: we are using models of adverse events designed for conventional drugs, but a lot of the adverse events or unexpected events that happen with psychedelics are specific to psychedelics. So we really need to use tailored instruments, including longer follow-ups. Sometimes these things happen weeks or months afterwards, so I think there might be a bias there.
But again, I’m only speaking from my experience, and that isn’t representative of the entire research.
This is one of the big issues in psychedelic research: we are using models of adverse events designed for conventional drugs, but a lot of the adverse events or unexpected events that happen with psychedelics are specific to psychedelics.
Hardman: People working with 5-MeO in the underground say that it’s quite common for everything to look fine for the first few days or even weeks, and then one month, or even six months later, people can experience real issues with ontological shock and destabilisation. Have you seen that these things can come up quite a bit later?
Soto: I think so. It’s very difficult to predict, but if we are speaking specifically about 5-MeO: on the one hand, there are flashbacks, which are mostly related to biological or neurobiological causes. And then there is ontological shock, which is more related to what happened during the experience and how this relates to your values.
With the latter, I think you should be able to ensure that, with proper integration, there is a support system in place so you can address this. What happens normally with ontological shock is that people have a reductionist view of the world that gets challenged. So it is often possible to foresee this and accompany that person. However, this resulting change in values can happen with any psychedelic, which is why this should be included in informed consent.
Hardman: I have spoken with people who are worried about the balance between including a lot of stuff in the informed consent, whilst also being careful not to prime participants into thinking they’re going to have negative experiences.
Soto: Firstly, I want to address the adverse events issue. Current evidence suggests that if you give people a very long list of adverse events, they are more likely to happen.
Interestingly, in the United States, randomised controlled clinical trials (RCTs) offer more freedom in how you address these kinds of issues with participants, whereas it’s much more rigid in the European Union. Over here, it’s mandated that you have a very long list in which you explain everything (i.e. possible short and long-term side effects). I think this might be one of the reasons why we see differences in trial reports from different sponsored clinical trials, even if they are using the same substance, because of the way the different countries are addressing the informed consent, or the expectations.
Hardman: Are there any other things in these clinical or sponsored trials that are difficult to navigate?
Soto: I think if the trials allowed for a more flexible schedule, that would be amazing. Some patients ask for more integration sessions, for example, and more support. You can provide this to an extent, of course, because we always prioritise their well-being, even if some instances result in a protocol deviation. But, primarily, we still need to comply with the model. As a therapist who is trained in other models, this can be difficult.
I think if the trials allowed for a more flexible schedule, that would be amazing. Some patients ask for more integration sessions, for example, and more support.
Hardman: So you have to be quite strict with yourself in terms of how you interact with the patient?
Soto: Exactly. However, some of the models we are using are quite smart. For example, in the Compass Pathways model, they allow for some openness and flexibility whilst retaining all the fidelity items that are needed for approval and marketing. But yes, sometimes you are constantly monitoring yourself to see if you are doing the right thing.
Hardman: And in some cases, you are actually being monitored, right? I know some sponsors are using AI software called mpathic, which monitors what the therapist is saying and gives them a fidelity score and feedback.
Soto: Yeah, all the sessions are recorded, so somebody will check them. There’s also a fidelity rating, so they will see if we are compliant with the model. If we’re not, a flag appears and it might be listed as a protocol deviation.
Also, in the trials we’ve worked on that involve psychological support (or any kind of psychological intervention), we have clinical supervision with therapists where we can bring our cases and receive feedback.
Hardman: Earlier on you were saying that psychiatry is very focused on the biomedical model, whereas in psychedelics there are these competing theories. Some people are discussing a brain reset and focusing on things like neuroplasticity or even inflammation, whereas others are focusing more on the subjective and the psychological side. Do you think that the psychedelic experience, or the ‘trip’, is going to be proven to be necessary for the benefits we’re seeing?
What I'm trying to show in my research is that it's not about one mechanism or the other, but rather you have different levels of explanation, and they interact with each other.
Soto: I really like this question because it’s the subject of my PhD. What I’m trying to show in my research is that it’s not about one mechanism or the other, but rather you have different levels of explanation, and they interact with each other.
If you decide, for example, that neuroplasticity is needed to improve depression, this neuroplasticity still happens in a context. Neuroplasticity just means that your synapses and connections in your neurons can change and create new behaviours and patterns. But if you are not feeding the system with new behaviours and new patterns, how can this translate into improvements or symptoms? So I think the subjective experience is necessary because it helps you shape these behaviours and patterns.
I think maybe in the future there will be psychedelics without a psychedelic experience (e.g., neuroplastogens) which might be helpful for the kind of patients we were talking about earlier who are, for whatever reason, not able to embark on a full-blown psychedelic experience.
However, regardless of this, these compounds will still open a critical period of neuroplasticity, and so you will need to have some kind of tailored intervention to change their behaviours. Otherwise, they will just slide back to the previous state whenever given the opportunity, like when a stressor happens.
What I’m researching is the psychological mechanisms of change—those which connect the subjective experience with the neurobiological mechanisms. Namely, I think these are: psychological flexibility, meaning attribution, and social identity. These are the kind of mechanisms of change that we see in psychotherapy, and that probably explain why psychedelics create changes in your psychology or your mind.
Neuroplasticity just means that your synapses and connections in your neurons can change and create new behaviours and patterns. But if you are not feeding the system with new behaviours and new patterns, how can this translate into improvements or symptoms?
Hardman: Are there any other non-drug factors that you think are really important?
Soto: Yes, many of the elements of set and setting. For example, I think another limitation in trials is that we have to use the same music. Music needs to be researched much more—it has a huge impact, positive or negative.
Also, neuroplastogens could have a negative impact if they increase neuroplasticity in a negative context. It has also been proven that SSRIs also increase neuroplasticity and work better with psychotherapy. So we’re not really doing anything new with psychedelics, and it is fundamental that we understand the context-dependence of our interventions.
In terms of psychedelics and neuroplasticity, I like the theory of two receptors. One paper contends that serotonin plays a dual role via 5HT1 and 5HT2a receptors: agonism of 5HT1 receptors helps you tolerate difficult situations—much like SSRIs do—but when tolerance is no longer adaptive, 5HT2a receptor also comes into play so you can create a drastic change in your behaviour and environment, and this is the receptor that most psychedelics act on. This gives a nice evolutionary reason for why our minds have the ability to enter into these states.
Regarding other factors, apart from set and setting, I think because of how our society works, we’re focusing a lot on the individual, but the inter-individual environment is also very important. I think group settings are super powerful and interesting, and we should research this more. Not only in terms of cost efficiency, but I think treatment can be much more powerful in a group setting. There is this sense of belonging, this sense of being part of the same thing.
Hardman: Earlier on you mentioned critical periods. I know Gül Dölen’s research suggests that there’s a relationship between the duration of the acute subjective effects and the duration of the subsequent opening of the critical period. Have you seen any major differences between short-acting psychedelics, for example with 5-MeO, and with longer-acting psychedelics, like psilocybin?
Soto: I think the difference between short-acting and long-acting also has to do with intensity and the nature of the experience. These short-acting psychedelics are really different phenomenologically, so to really understand the difference between short and long experiences we should, for example, try a formulation of psilocybin that is two hours long, or utilise IV DMT.
I think the thing with longer psychedelic experiences is that you can compose a narrative to your experience; different things happen and you can elaborate meaning during the experience. Whereas with 5-MeO-DMT, you have this very intense experience that can be mind-blowing and can totally change the way you see the world, but you don’t have the capacity to navigate the experience and to really understand what’s going on until afterwards.
In my experience, this is also a very different kind of work in terms of preparation and integration, because it has more to do with surrendering and really opening and allowing the experience to happen. With psilocybin, you have the capacity to kind of steer a little bit of what’s going on. With ketamine, they say it’s like a bicycle—you need to pedal a little bit to move forward in the experience. So I think all of these different drugs will be tools that we will be able to use in a tailored way, depending on the characteristics of the participant and the specific disorder.
Hardman: When you were discussing that it’s not just the length but also the subjective qualities and intensity, I was thinking that a cool study would be to use IV drug delivery to make every drug last two hours. You could then compare them. Then again, I’m not sure if anyone would consent to being on 5-MeO for two hours!
If you had unlimited resources and funding capabilities, what would be your dream trial to design and run?
Soto: Well, because of my interest in understanding how these different levels of explanation interact, I think for me it would be very interesting to have information on what’s going on phenomenologically, neurobiologically, psychometrically and psychologically. This could look like connecting neuroimaging biomarkers with language analysis powered by artificial intelligence. I think this is a very powerful tool right now to gather phenomenological information, first-person perspectives, and really uncover hidden patterns. And I think it will be very interesting to compare, as you said, different psychedelics to see what’s going on.
In terms of implementation and understanding how to use psychedelics in practice, it would be good to compare different kinds of psychotherapies with the same psychedelic. For example, comparing a structured psychotherapy with a more non-directive psychotherapy, and then we can start to understand how psychedelics work from a psychotherapy perspective.
Hardman: Okay, so this would be a large factorial design, with different drugs and psychotherapy conditions, with the aim of determining what contributed to what, alongside collecting a range of other measures and data?
Soto: Exactly. You would need infinite resources, though, as this would require a lot of patients for your power analysis.
Hardman: Are there any other burning things you would like to mention?
Soto: I would say that, right now, a lot is happening in terms of regulations in countries like Germany and the Czech Republic, and Europe is starting to fund very ambitious projects involving psychedelics through competitive grants, such as the PsyPal project.
On the other hand, some pharmaceutical companies based in the United States are becoming reluctant to do their trials in Europe because it is very difficult to market any new drug, as you have to negotiate with 27 countries. This is creating a different landscape, where public and political initiatives are paving the way to integrate psychedelic-assisted therapies within public health systems, and we might see huge advances in this regard in the coming months.
I’d also like to reinforce my point about the importance of the first-person perspective—or the subjective experience. This is a huge opportunity to understand what happens when you have a mental disorder or when you suffer, and how to deal with it. If we don’t investigate this further, we risk losing it and reverting to treating patients as a black box.
Some patients might tell you, and this happens a lot with treatment-resistant depression, that they feel they’re not improving, even though the psychometric scales say they are. So you tell them: ‘No, no, you’re better. It doesn’t matter what you’re saying—I think you’re better, because the psychometric scale says you’re better.’ This points to a dislocation between how we measure symptoms, and the subjective experience of those who suffer.
All of this points to the urgent need to take into account the patient’s perspective and first-person experience. And I think one of the important things with psychedelics is the opportunity to bring this back into psychiatry.
All of this points to the urgent need to take into account the patient's perspective and first-person experience. And I think one of the important things with psychedelics is the opportunity to bring this back into psychiatry.
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