Hard News by Russell Brown

9

Psychedelic science: Microdosing and more

At last year's Splore festival Listening Lounge sessions, one of the most popular discussions was the one on psychedelic therapy. So for this year's festival, I brought back two of the participants from that panel – Dr Will Evans and Amadeus Diamond – and was delighted to be able to bring in Dr Suresh Muthukumaraswamy of the University of Auckland School of Medicine.

Suresh carried out the neuroimaging for several key studies on the effects of LSD and other psychedelics on on the brain at Imperial College London – and he will soon launch a New Zealand-based study of a facet of the new science of psychedelics that is much more talked about than it is actually understood: microdosing.

The Auckland study, like most things in New Zealand, was disrupted by Covid-19, but Suresh and his team are hopeful of beginning it soon. So it seemed like a good time to publish this discussion. (Thanks, as ever, to Emma Hart for the transcribing.)

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Suresh, I'm going to start with you. What is microdosing and why is it interesting to you?

Suresh: I guess most people know what microdosing is, it's a kind of new movement that started about ten years ago, where people are taking very low doses of typically LSD or psilocybin, about a tenth of a trip. And it's kind of interesting because there's really no good scientific literature on it yet. 

The first time we talked about it, you basically said, "Who knows? Could be homeopathy."

S: It could be homeopathy, we don't know, right – from a scientific standpoint. Because there's just not the data out there. But it's kind of interesting because for a long time people have claimed that drugs like LSD and psilocybin create this long-term improvement in mood and all this wellbeing, etc, creativity, and that's kind of interesting. Microdosing is also kind of the same effect from these very low doses, but taken over a long period of time. 

You've done some of this research, the brain imaging for the key research, the studies at Imperial College and they were all full-blown psychedelic experiences – and they had therapeutic value, didn't they?

S: In those studies with LSD and psilocybin, we were giving people very large doses, trip doses of those drugs and then we were putting them into scanners, trying to work out how those drugs were changing their brain function, and then trying to relate that to the experiences that they were reporting.

To me, the scientifically interesting thing about microdosing is that it's long been claimed that those positive effects that people have when they take psychedelics are kind of related to that psychedelic experience that they experienced at the time of the trip. Now, the microdosing thing says, well actually, maybe they can get those same benefits without actually needing to have that psychedelic experience itself, and that to some extent turns the whole thing on its head. So it's just an interesting scientific question –what's going on there?

The really interesting part of your study is that people won't be sitting in a lab doing this. Initially they will, but they'll be out there, going to work, falling in love, driving cars.

S: Not driving cars.

Not driving cars. You couldn't get driving cars through. I've been telling people driving cars.

S: Not driving cars. Not doing surgery.

How is it going to work?

S: There have been previous studies where people were given single microdoses in a lab, and then people sit there for six hours, and that's it. To me, that's not a very good test of what a recreational microdoser might do, because what they do is they take a dose in the morning, and then they go out and they do their everyday activities, and it's about enhancing their current experience, with this microdose. So the  only way that you can satisfactorily test that is not by putting someone in a lab, cause our labs are so boring. These little white rooms full of clinical beeping equipment. So what we wanted to do here was basically have it so that people could take the drugs at home. So what we're going to do in the study is the first dose will be taken in the lab so we can monitor them, make sure everything's okay, and then for the next six weeks after that people will take the microdoses at home. 

So how do you verify that?

S: I could tell you that Russell, but it would kind of …

There are spoilers involved here.

S: When you're running any clinical drug trial, what you're asking is, how do we monitor adherence behaviour, that we want people to take this every third day, and what people are going to be doing? There'll be a kind of messaging system where we message them, and then they take the dose, and they film themselves taking the dose on their mobile phone, and they send that back in to the research team, and there's some codes on the drugs involved, so we know they're taking the dose, at the time – and noncompliant participants will be booted out of the study.

Now, the first question that people usually ask is, "How can I get on the study?" And the most interesting thing about eligibility is that for the time being at least, it's men only. Explain to me why.

S: Whenever we do a study we select a sub-population, right, and this caused a lot of grief about this. But you know, we limit 25-65, right, and people don't accuse me of being ageist. The reason we're only selecting men in this particular study is that we know some of the measurements that we're going to be taking, looking at brain plasticity, those vary over the menstrual cycle, and so that would, because our microdosing course is six weeks it would create a whole bunch of extra confounds that we can't control.

What you're trying to do in a study is, you've got this little signal you're trying to dig out, right, in the noise, and if you just add extra noise into your study you make it that much harder to actually find the signal you're looking for. So what we decided in this particular study is that it would be better and more optimal to just stick with men at this stage, so we can basically decrease that noise level to make us more sensitive to what we're trying to see. If we do a subsequent study, then we could move into the female population.

You're saying "at this stage". You're hoping, I gather that this is just the first stage of an ongoing study.

S: It could be. It depends on the results, right. If we don't see anything, it's just like, well, it might be time to shut up shop, it's all homeopathy, we can stop microdosing. Or you can stop microdosing.

You're imagining it ...

S: And go home and go back to the old way of doing things. But if we do find effects, then there would definitely be an avenue for future studies.

That would also require funding. Now you've had a couple of benefactors to get this far. Who have they been? You don't have to tell me their names.

S: We have one local person gave us a chunk of cash. We had someone from Silicon Valley reached out and has given us some funding as well, and I've got another person who's a very famous person who is looking at potentially giving us some more funding, so you might have noticed we did this kind of media blitz, right, and that was really done to draw in donors.

Will: We've got that Everyday Hero page as well. So if anyone wants to contribute five dollars, Everyday Hero, psychedelics. I think we've raised about four thousand.

Part of that media blitz is also something that we announced on stage here a year ago, which is a foundation devoted to psychedelic therapy, the Entheos Foundation. Does one of you want to talk about that?

S: I'll let you talk about that, Amadeus.

Amadeus: Sure, so the Entheos Foundation is essentially New Zealand's first psychedelic funding venue. We're just in the very final stages of getting all the approval from the charities services, so we've been working with a lawyer, getting a lot of the wording right, cause we've made the submission and obviously we expected a lot of push-back and clarifications and making sure that everything was legal and above-board and everything, so we've been working with that, and we've been just making sure we're dotting the ts and crossing the is getting that all across the board. So we basically have two prongs. One of them is funding research, things like Suresh's trial, and then also education. So coming to events like this, putting on our own events to promote good accurate information, as unbiased as we can, around psychedelics and therapy, but also a few other things.

W: Our mission is to fund and promote research and education in the use of psychedelics as medicine, and to provide the public with evidence-based socially-responsible information about the use of psychedelics in medicine, psychotherapy, and indigenous practice.

A: That's a point that we should probably be quite firm on as well, is indigenous practice is such an important part of at least the base of knowledge for all of this. Not necessarily something like a clinical trial, but in general, the use of psychedelics and the socially responsible way to look at them is you really need to have a look at that ancient wisdom and take that into account and have a look at what people have been doing for thousands of years before trying to reinvent the wheel. So that's something that we really need to keep in mind as we go forward as well.

See, this is an interesting thing for someone like you, Suresh, because you are scientist, you're a researcher. Will's a doctor. And yet I'm often quite fascinated at the cordial relationship between you guys and the psychedelic community. I went to a gathering at Will's place and on one hand there were researchers like you and Paul Glue from Otago University – and on the other there were people who run ayahuasca ceremonies. How do you navigate that, Suresh?

S: It's tricky.

Because you're not an evangelist, you're emphatically not an evangelist, are you?

S: No, I'm definitely not a psychedelic evangelist.

W: We do that part.

S: I'm just a boring laboratory scientist that is interested by these questions. But as a scientist, you're still a member of society. So yeah, you try as much as possible to be objective and study these things objectively so that there's accurate data out there that other people can interpret in a particular way. And so as much as possible you try to be objective. But at the same time, you are still a member of society and we do stuff for society. It is a tricky space to navigate.

Will, there is an active therapeutic community out there, isn't there? I met some very interesting people at your party who are doing different kinds of holistic therapy.

W: Yeah. And we're trying to bridge that and bring it above board. So we've just started as, I guess in affiliation with Entheos, but also as a precursor to a study that we've just submitted to ethics review, looking at the use of MDMA-assisted therapy in end of life anxiety and depression. We need a group of professional psychotherapists that can actually do this work above ground, that their boards are happy with. So we have a group of about 30 psychotherapists meeting on a monthly basis, working towards a policy change, working towards preparing the groundwork for when this does come on board, because we're a couple of years away from legalisation of MDMA in America. And similarly psilocybin.

For therapeutic use.

W: For therapeutic use, absolutely.

A: Well that depends, there have been all these decriminalisation campaigns have been pretty successful getting unanimous decisions on city councils in the US, Santa Cruz a few weeks ago, Oakland, Denver.

W: Yeah, legalising nature.

A: Yeah, decriminalise nature, exactly. So who knows what's going to happen with that, that might keep rolling on.

On the other hand, we've got Phase 2 trials at Douglas Pharmaceuticals in West Auckland of a slow-release ketamine product that they hope will treat treatment-resistant depression. Because I've talked to you about this, Suresh, you can give a rat ketamine and the rat gets un-depressed, same with people, but it doesn't last. I wonder whether we're actually at the stage of discovering some of the best therapeutic strategies.

W: Well, ketamine is one of those easy ways in to this kind of work. And we've started actually a subgroup that's looking at ketamine-assisted psychotherapy. I could write a script for ketamine now, and someone could have that legally in a clinic setting and have some psychotherapy around it, and probably get similar benefits to most of the other major psychedelics. It's paradoxical because these substances are illegal, so any conscientious professional is not going to do psychotherapy in a legal setting. But how do you get the training, how do you know how to do that safely? And so it's Catch 22. So ketamine might be a way in.

So what is the effect here? What is, in biomedical terms, what is the beneficial effect here, and is it better than SSRIs, with which we are currently flooded?

S: In terms of effect size, they're probably roughly equivalent. And that's nice for when we talk about populations and stuff like that, right. But that doesn't help individuals. Because what you see when you get patients coming in to your clinical trials like we do, we've done multiple depression trials, every patient's kind of a bit different

And SSRIs, they get a bad rap, often. But actually there's a huge silent majority out there that they go in to their GP, they get their first SSRI, they don't have much side effects and actually after a couple of weeks, it actually really helps them. And they have a really good clinical outcome from that, and they don't go on crusades against SSRIs. So for some people it's really effective, for others it's not.

So the way I think about it is, what the general population needs is a lot of options, of different therapeutic strategies that are evidence-based, that they could potentially use to help them, and of course that doesn't necessarily just mean drugs, that could also mean psychotherapeutic approaches and also electrical or magnetic stimulation approaches. 

Right, which is interesting.

W: I'd go a step further, though. I mean, there's no substance out there for mental healthy where it's a one hit for six months plus benefit. And in fact, the landmark study on the psychedelic effect, which we can generalise to most of the psychedelics, which is that essentially they reset the brain. They have this effect of decreasing the default mode network, which is this brain network responsible for a lot of our everyday thoughts but also our rumination and self-talk.

The default mode network is basically how we get up and go to work in the morning and not walk into traffic, isn't it?

W: Right, and that gets locked into kind of negative patterns and negative states. We don't know exactly the relevance of it, but the point is that psychedelics suppress that. And the landmark study out of Johns Hopkins and NYU back in 2016, they  published the effect of one dose of psilocybin, the active compound in magic mushrooms, having a six-month benefit. After one dose, and psychotherapy on either side, for depression and anxiety in end of life.

They've followed up that study now, four years down the line, and 70% of the participants, initially 80% of the participants had a significant decrease in their depression and anxiety scores, carried out to six months which is when they stopped following up. They followed up four years later, and 70% of them still have effect. So SSRIs are a daily thing, this is a one-hit kind of out-of-the-ballpark kind of deal. Which can't actually be commercialised. I think they will give SSRIs a run for their money. But to reiterate what Suresh is saying, SSRIs have a role, definitely.

Amadeus, if we were to go and bring out Netflix on our televisions or our phones at the moment, we would see there's a new series on called GOOP Lab, which is Gwyneth Paltrow's evidentially-dubious self-help program. And the first episode is a psychedelic therapy one. They go to Mexico. The episode itself is okay, but then subsequently there's an episode about energy healing. Is there a problem with psychedelic therapy being seen in the context of less well-evidenced approaches?

A: It's a double-edged sword. On one side of it, it's a completely new demographic, that's a target audience that we probably have not really reached before, although Suresh and I did do an interview with Next magazine late last year that will be published shortly. So there is some interest in that area, but you also don't want to mislead people too much, which is I assume what you're getting at. And there's also some sort of ethical problems around how they made that episode and how they sourced their teachers and the substance and all this sort of thing. But as with most things, you do need a hook. And I think if people see something like that, that's pretty superficial and pretty unhelpful overall, they're going to dig a little bit deeper and find good information, because most of the information out there is good. Most people in the psychedelic space are pretty conscientious and ethical people.

You know the people in that space internationally. You go to the conferences. What's happening research-wise at the moment?

A: Quite a bit. One of the things I was going to mention that was going to dovetail off what Will was saying in terms of psychedelics versus SSRIs is that they're so widely applicable. So you have basically two, to put it very simply, you have two groups, the tryptamines and phenethylamines and that covers most of the drugs that are used in psychedelic science. And you can have them used for depression and anxiety in palliative care. You can have them used for depression and anxiety in non-palliative patients. You can have them used as addiction therapy.

A study out of NYU and Johns Hopkins has used psilocybin to treat tobacco addiction, and they had about an 83% success rate at six-month followup there. LSD's also being used for alcohol dependence. Johns Hopkins is now running a trial using psilocybin for eating disorders. Alzheimer's research.

Obviously, the data aren't in for most of these things, but there's at least good reason to think that you can get benefit on so many different neurological issues through this one very specific group of drugs. So there is a lot of research being done out of Johns Hopkins and NYU and that's not even to mention the MDMA. Will, I'll let you go over the MDMA work that's being done.

W: Yeah, as mentioned, the FDA have deemed MDMA and psilocybin as breakthrough drugs, meaning that they have potential therapeutic use that is quite profound, so they've cut the red tape. So they're in Phase 3 trials of MDMA for treatment-resistant PTSD, and that I think is affiliated with the Pentagon, because they're veterans.  mean, the suicide rate of the veterans coming back ... We just got a message through Entheos today from a veteran asking for psychedelic therapy here. So they're anticipating MDMA will get through there and become prescribable.

And let's be clear, this is therapy, this isn't giving someone an E and letting them get on with it, is it? This is as an adjunct to therapy. 

W: It's arguable that just taking it without the support may have an effect, but we don't have a study that shows that, because it's unethical. And it does expose you to a certain degree of risk. I think you need to be in the right set and setting, set meaning your own state of mind, hence four hours of psychotherapy beforehand, and the mantra there with the psychotherapists is, if there's anything you don't want to talk about, let's talk about that. And get things out. And then you have the experience, and then you have another four hours of integration. So that's where the effect really is.

A: Integration is so important.

W: And it speaks to this initial question of, is it the substance, is it the mystical experience? It seems to point to the mystical experience having a profound association. But ultimately I think it's a false distinction, it's a false dichotomy. We have daily experiences, our lives are psychedelic whether we take the substance or not. And I think thinking about it in that as a whole will make more sense. But you won't be able to reduce it down to a meaningful outcome in a study.

And the microdosing thing also, just to link it back to that, it's a way for us to get it into the mainstream, and to get people thinking about it in a more acceptable way. When I speak to my medical colleagues and I talk about microdosing, they're much more open to the concept than if I talk about a macrodose. And just having that initial lead-in I think is really important. So I think Gwyneth Paltrow, good on her for bringing it to the mainstream. People can come to the Entheos website to get more information.

Suresh? Last word.

S: Does it have to be the last word? Because it's going to be a negative word. I was just going to say that there is an alternative view to those views as well, that actually from a scientific perspective the evidence for psychedelics as therapy at this point is actually pretty weak. And the studies are small, they're isolated.

One of the problems with clinical trials when you have outcome measures that aren't objective and they're subjective, is that there's deblinding effects, cause the patients know which trial arm they're in. That is, they know that they haven't taken the placebo, cause they've been tripping for 12 hours.

And the more media there is around these things, then the more likely they are from expectancy effects to have these kind of positive results. And I have done clinical trials before where we've seen really big placebo effects. So at this point, if you were someone who's sitting at NICE in the UK doing an evidence evaluation, at the moment your evaluation would have to be that it's pretty weak at this point, but that doesn't mean that we shouldn't be doing more research on it, and coming up with better designs to try to come up and to try to solve some of those issues. So I think it's still at a research stage.

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