Psilocybin for Treatment-Resistant Depression: An Interview with Dr. Robin Carhart-Harris


Dr. Robin Carhart-Harris, Head of the Psychedelic Research Group at Imperial College London, speaks about the use of psilocybin for treatment-resistant depression. This interview is part of a series covering the 2018 ASCP Annual Meeting.
Here are some key points from this interview:

  • Psilocybin, a psychedelic, is a 5-HT2A agonist
  • Stimulation of the 5-HT2A receptor promotes neural plasticity
  • A potential mechanism of action of psilocybin in treatment-resistant depression involves “brain resetting”
  • Psilocybin has a good safety profile
    • However, patients may experience challenging psychological experiences that may turn out to be frightening for some people
  • Administration of psychedelics needs to be done in a controlled environment with psychological support


Hello everyone, welcome to the Psychopharmacology Institute podcast. I’m your host, Dr. Wegdan Rashad. Today we are starting our series covering the 2018 American Society of Clinical Psychopharmacology Annual Meeting.

One of the presentations that got significant attention was by Dr. Robin Carhart-Harris, Head of the Psychedelic Research Group at Imperial College London.

He was speaking about the use of psilocybin for treatment-resistant depression.

In the last years, there has been a renewed interest in the therapeutic use of psychedelics in psychiatry.

For example, in 2017, the FDA granted Breakthrough Therapy Designation to MDMA for the treatment of PTSD. This means MDMA will now be studied for PTSD in Phase 3 trials

Now, going back to psilocybin for depression. Psilocybin is a non-selective agonist with psychoactive effects related to agonism of the 5-HT2A receptor subtype.

Recent work has supported the safety and efficacy of psilocybin for treating symptoms of anxiety and depression, including an open-label feasibility study from Dr. Carhart-Harris’ team.

At the ASCP annual meeting, Dr. Carhart-Harris summarized clinical and fMRI results from this trial.

He also presented preliminary observations from a subsequent double-blind randomized controlled trial, comparing changes in depression and imaging outcomes after a single dose of psilocybin versus 6 weeks of daily escitalopram for major depressive disorder.

In this interview you will learn about the potential mechanisms of action of psilocybin in depression, including its psychological effects and how it may be similar to ECT in some aspects. We also asked Dr. Carhart-Harris about the side effects profile of this psychedelic.

Dr. Rashad: What can you tell from a pharmacological standpoint on psychedelics in general and psilocybin in particular?

Dr. Carhart-Harris: So first of all, psychedelics, when I refer to psychedelics and other scientists who are prominent in this field would agree with this, we’re focusing on classic psychedelics. And those compounds have a specific pharmacology. They’re all agonists at the serotonin 2A receptor. And so we have quite a crisp definition there and knowledge of these compounds’ basic pharmacology. So for those who don’t know anything about these compounds but know a bit about psychopharmacology, here, the focus is serotonin but it’s that most interesting, at least in my view, aspect of serotonin. There is one of these 14 plus receptor subtypes that really has a dramatic effect on consciousness if stimulated at least in the way that psychedelics stimulate these receptors. So I think that makes serotonin even more intriguing as a major neuromodulator. And it tells us something about serotonin. It tells us something about what serotonin does. And through that, it tells us something about the brain.

Dr. Rashad: What substances are included in this classification of psychedelics?

Dr. Carhart-Harris: LSD is the most famous one. Then it’s psilocybin which is the prodrug of psilocin which is the direct serotonin 2A receptor agonist. These compounds have quite rich pharmacologies. They’ll hit other receptors and stimulate other receptors but the key finding is that if you specifically block the 2A receptor then you’ll abolish the effects, the characteristic effects of the psychedelics. So it’s a very reliable rule comparable, I suppose, in some way to an effective dose of antipsychotic correlating with its ability to block D2 receptors. So it’s one of those staples of pharmacology in a way.

Dr. Rashad: Can you tell us more on what the 5-HT2A receptor does?

Dr. Carhart-Harris: Yes. So there’s increasing evidence that 2A stimulation promotes neural plasticity but plasticity more broadly so behaviors that you could link in with plasticity like cognitive flexibility, learning, at least low-level learning, extinction learning, sensitivity to context, vulnerability to environment. And this is a component of what serotonin does if you want that is receiving increasing attention in recent years. You got the likes of Belsky and Branchi writing on this, the double-edged sword of plasticity that you promote serotonergic functioning and you promote sensitivity to context. And this is especially true with the 2A receptor. In fact, that rule about serotonin probably has most to do with 2A than any other receptor subtype. I would submit to that idea.

Dr. Rashad: In your presentation, you mentioned psilocybin has a good safety profile. What type of side effects did you see?

Dr. Carhart-Harris: Although it has a good safety profile, it will be wrong to suggest it’s entirely safe. And so where’s the catch here? And there always will be one. There’s no free lunch. It’s always the case. So where should we be looking? So at least in terms of what we know at the moment because there may be things that we don’t know of course but we know that the experience can be challenging. I guess this has been popularized by the idea of a bad trip. We don’t refer to difficult experiences in that way because there’s some suggestion that challenging psychological experiences can still be therapeutic if there’s some kind of breakthrough or cathartic release and emotional release. But that might not be for everyone. That might be frightening for people. In fact, you know, it is frightening for lots of people. And they might prefer if they’re suffering from a depression, for example, to have a less abrasive treatment, maybe go on an SSRI and have a more protracted sort of subtle effect that enables them to cope better. That’s the beauty of choice, isn’t it? People can always choose.

I suppose the major limitation with psychedelics is that they can be psychologically agitative. They can be difficult. Because of that, you need to control the context in which they’re given. It seems to be so important. I mean, we could do with better science to directly demonstrate that it’s important and there are challenges as to why that hasn’t been done yet. But it seems a pretty solid assumption that controlling the context in a positive way, having psychological support around the experience as well as during it is a major component in this treatment model. So yeah, I talked about the difficult experience.

Also, people report headaches the next day and that’s quite prevalent. It also seems to be dose dependent at least with psilocybin that they report having a headache a day after a high dose psilocybin session. But these headaches are transient. To my knowledge, it’s fine to take a headache medication to alleviate those symptoms. And of course, someone who’s had depression for decades which is often the case in treatment-resistant depression would say, “Well, I’ll take a day of a headache over everything that I’ve lived through over all these years.”

Dr. Rashad: Can you give an overview of how psilocybin might work and then elaborate for someone who’s not very familiar with the concept of network reintegration?

Dr. Carhart-Harris: Take a system, the brain, the mind. It exists in a place. It’s dynamic. It’s changing all the time. But it sits in a place between extreme disorder and extreme order. It’s neither frozen nor so diffuse that it has no organization and it can’t hold any information within it. So it sits in a sweet spot, this Goldilocks zone between extreme order and disorder. And what psychedelics seem to do is that they’ll shift the system a bit closer towards disorder. And we can measure that and we can use a classic measure of disorder.

That translates very neatly to our uncertainty about the behavior of a system. If the system is more disordered, we’re less certain about how it’s going to behave. And that measure is entropy. It’s a measure that’s been applied successfully throughout physics in the context of thermodynamics and statistical physics and information theory as well, so in computing, for example.

Anyway, it’s this measure of broadly speaking how a system may become disordered and so we become less certain about its behavior. It becomes more unpredictable. So that’s what psychedelics seem to do.

Can use metaphors here -as long as people realize that they’re metaphors- but they do come from observations whether of the phenomenology or the brain effects because both are valid.

I’ve used one of shaking a snow globe. You take a globe that’s got those little snow bits. And you all have seen them in airports and such like in souvenir shops. And it’s settled. The snow is all at the bottom. Say you pick it up, you shake it and there’s disorder there. But then the snow will settle again.

And this is this principle of a resetting or reconfigurating the brain and it’s an analogy that’s being used traditionally in the context of electroconvulsive therapy but it’s also being used now in the context of some of the novel treatments that are being explored for, say, treatment-resistant depression, the likes of ketamine.

The notion is that you take a system that’s become entrenched in pathology. It’s fallen into a pattern or patterns that aren’t healthy and those patterns have become reinforced for whatever reasons. And so you can introduce psychedelics and you can shake things up and you can work on revising or updating some of those patterns and likely the beliefs which they relate to and so essentially revise your belief structure.

Dr. Rashad: What is the future of psilocybin?

Dr. Carhart-Harris: It’s fun because it’s quite uncertain. But it might shock people to hear that there are visions that are being manifested. At least, plans are in place to do a major multi-site trial which could if it’s successful lead to psilocybin being licensed within five years. And so not just in university settings but hospitals around the world, psilocybin could become a licensed treatment for depression. Now, the implications of that are of course massive and there are all sorts of different interesting questions that come in. What would that do to the unlicensed use of psilocybin and other psychedelics? What are the effects of psychedelics in people who aren’t necessarily unwell? All sorts of things, you know, not just negative, positive as well. But this is a real possibility now that psilocybin could become a medicine in mental health care and that’s really exciting.

Dr. Rashad: What’s the status of that multi-site trial?

Dr. Carhart-Harris: It’s ongoing. The drug is being made. The sites are in place both in Europe and the US, in Canada, 15 different countries. So plans are in place for 400 plus patient trial. The trial has been organized in communication with the regulators, with the European Medicines Agency and the FDA. And so now, it’s just up to science and testing to see whether it’s really what we think it could be.

Dr. Rashad: So do you have any final comments? Thinking of this audience, clinical psychiatrists, what would you say are the two like takeaway messages here if any?

Dr. Carhart-Harris: I think psychedelics offer a way of looking at the serotonin system that’s quite novel. I mean, of course, people have been talking about plasticity for a while. For me, the draw with psychedelics, it’s fair to say, has always been what they tell us about nature. It’s not what they tell us about the psychedelic state. That’s too restrictive. It’s what they tell us about the mind and the brain and the relationship between the two and then the implications on mental health. So I would really hope that people appreciate more these powerful tools, these powerful scientific potentially therapeutic tools.


So, to summarize, psychedelics like LSD, MDMA, and psilocybin are chemicals that are agonists are the serotonin 2A receptor.

Stimulation of this receptor promotes neural plasticity. It contributes to cognitive flexibility, extinction learning, sensitivity to context and vulnerability to environment. It has a good safety profile. However, patients may experience challenging psychological experiences, that may turn out to be frightening for some people. That is why administering psychedelics needs to be done in a controlled environment with psychological support. Commonly as well, people may report dose-dependent, transient headaches which are easily treated with headache medications.

The way they produce their therapeutic effects, like Dr. Carhart-Harris beautifully illustrated, is analogous to shaking a snow globe. When shaken it creates disorder, and then the fragments tend to settle again. What psychedelics seem to do is that they shift the system a bit closer towards disorder. It is based on the principle of a resetting the brain which was borrowed from how electroconvulsive therapy is traditionally explained.

A brain that has fallen into unhealthy, pathological patterns, may benefit from psychedelics that can allow revising or updating some of those patterns, allowing belief restructuring.

The future of psilocybin is an exciting one. There is a multi-site trial happening as we speak, that if successful could result in psilocybin being licensed for treatment-resistant depression within 5 years.

The use of psychedelics in mental health care is a novel and still controversial issue. However, the therapeutic potentials for these agents are being discovered further every day. Be sure that you will hear more about psychedelics in psychiatry in the upcoming times!

The following people participated in this episode: Dr. Flavio Guzman as the general editor, Andy Rhode as the audio engineer, Pamela Gonzalez as the project manager and myself Dr. Wegdan Rashad as the host. We would like to thank Dr. Robin Carhart Harris for joining us in today’s podcast.

Thank you for joining us in today’s podcast until the next episode, good bye!

References and further reading

Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. E., … & Rickard, J. A. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-upPsychopharmacology235(2), 399-408.

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