Psychedelic drugs have long been exiled to the fringes of medicine, dismissed as recreational drugs with limited therapeutic potential. That all changed with the breakthrough therapy status granted last year to psilocybin, the active compound found in psychedelic mushrooms, for its ability to rapidly reverse treatment-resistant depression. This has led to an explosion of interest in the field, with new institutes opening and new disorders identified as targets for psychedelic therapy. In our latest interview series, we discuss the potential of psychedelics to revolutionize clinical neuroscience with thought leaders in the field.
In this interview, we speak to Professor Johannes Ramaekers from Maastricht University. Prof Ramaekers has conducted research into controlled substances for years, touching on alcohol and cannabis’s effects on the nervous system. More recently, in a collaboration between Prof Ramaekers’s team and the UK-based Beckley Foundation, he investigated the effects of microdosing LSD. In this interview we discuss how LSD affects our mood, how mushrooms could boost creativity and why a Mexican toad has been an important part of psychedelic research.
Ruairi Mackenzie (RM): Could you introduce our readers to your research into psychedelic compounds?
Johannes Ramaekers (JR): So we are a group that has been involved in placebo-controlled drug trials for a very long time. In essence, we have a history of focusing or establishing the safety profiles of drug compounds. And that's also what we have been doing with a number of psychedelic drugs. But in addition, we're also very much interested in the potential therapeutic application of these compounds. We're looking to establish whether these compounds are safe to be used on a daily basis to find evidence for therapeutic applications, as well as the mechanisms that actually underlie these behavioral changes; changes in neuroplasticity in the brain, for example, that are underlying some of these psychedelic effects.
I think it's also good to say that we focus primarily on healthy volunteer models. So we are not a group of psychiatrists, we are all psychologists by training. We quite often set up studies with psychedelics, for example with psilocybin. We have just completed a study with microdoses of LSD. We've also done naturalistic studies have involved going to ceremonies where people are using psychedelics such as ayahuasca or 5-MeO-DMT to basically to get a better idea of the profile of these compounds. In terms of safety, do they affect vital signs, and if yes, is that of clinical relevance, how do they affect your cognitive function? Memory, attention, things like this and can we find indications for therapeutic application?
RM: Could you outline the findings from your research into LSD microdosing?
JR: We have just completed a study. I mean, it's interesting because there are so many people out there that are microdosing. And there are many people that attest to the positive outcomes of the microdosing treatment period. But these reports, of course, are anecdotal. And the solid scientific evidence to support these anecdotal reports has been missing for a long time. So there are several studies that have been initiated over the last year to actually find some scientific evidence. To actually test or falsify whether these claims are true or not.
And one of the problems that we always run into is that the people that microdose don't actually know the dose that they are taking; we call it a microdose but in essence it's not. A microdose would literally mean that you have 1,000th of your normal dose, but in this case is people are taking like 10% or 20% of the full dose, right? People are saying well, between five and maybe twenty micrograms could be a microdose.
So that's a very low dose. But if people buy LSD, and maybe it's on a blotter, users just take a small part of it with scissors. But it's not very carefully measured. Of course people estimate what their dose can be, but they don't have an actual sense of the real dose. So we also wanted to find out whether these effects are dose-related or whether they start at a certain dose. Finding out what is an effective microdose, basically.
So we set up this study in 24 healthy volunteers that all went through four treatment conditions. One of them was a placebo, and the other three conditions involved single microdoses of LSD. The dose was either 5, 10 or 20 micrograms; spanning the full range of what people considered to be a microdose.
Of course, the treatments were not always in the same order; they were balanced across the participants and double-blinded. People knew the treatments they were going through, but they didn't know in which order. So basically, they were blind at each treatment day. We were interested in a number of outcome measures. We were interested in mood, because there are claims that microdosing makes users feel better; it increases their positivity in terms of moods or outlook on life. Some people claim that it increases their creativity, or that they can focus better on the job that they are doing. So for this reason, we included tests of attention and tests of creativity. And we were also particularly interested in one therapeutic application, which is the treatment of chronic pain.
There is some interesting, but dated, work that goes back to the ‘60s and ‘70s showing that full doses of LSD can actually act as an analgesic, particularly in terminally ill patients.
It seemed to work very well. But at the same time, of course, if you receive a full dose, you have a full psychedelic experience. We were interested in finding out if you could actually use LSD as an analgesic at these low doses where you would not have this full-blown psychedelic effect.
What we found was that the highest dose that we administered – 20 micrograms – does actually increase positive mood consistently over time, but the magnitude of that change was very mild, I would say. Possibly this is because these are healthy volunteers who are otherwise very happy; there's not a lot of room for improvement. So maybe if you were to replicate a similar study in people who feel somewhat depressed, these positive changes could potentially be bigger, but the magnitude that we observed was relatively small.
At the same time, we also found that there were some cognitive tasks in which the participants actually performed worse [compared to control] and particularly in one test where we measured working memory and information processing. But again, the magnitude of the changes was very mild and there was one attention test where they actually performed better. It was noticeable, but not a very strong effect. And the other effect was that people actually were able to better manage their pain. So the pain endurance actually increased under LSD.
It was quite an interesting outcome, I would say, because if it all had been a placebo effect, then we wouldn't have found anything, I guess, compared to control, but there were some changes that were very consistent and that were statistically strong, but in terms of magnitude, they were really mild. Mild but consistent, that's the summary, I think.
RM: Were there any effects from the microdosing on creativity; was that something you measured?
JR: I didn't mention that. We have this test that we call a story writing test, and indeed at the lowest microdose, we did see some positive improvement there. But that was only one of the creativity tasks that we used. One picked up the effect and the others did not, so it's a kind of a mixed bag result.
RM: Was the effect seen at the higher doses?
JR: No, we only observed it at the lower dose.
RM: So how do the doses that people took in the study compare to recreational doses – what would the effects be?
JR: It would be in the same range that people are taking recreationally. But I think the general idea [behind microdosing] is that you take a dose that is sub-perceptual, in the sense that you hardly notice that you have taken it. From the data that we've seen, that would be the case for five micrograms and probably also for 10. But not so much for 20 micrograms. There, people did actually notice that they had taken the dose. They didn't have a full-blown psychedelic experience at all. They could act normally and do their normal day-to-day operation – buy some groceries and go to work – all that was completely possible, but there were some changes in the sensory input, so colors may be a bit brighter and things like that. So these effects are somewhat noticeable. At low doses, they were not.
RM: So what would your next stage for this research? Would you look at patient populations who have a therapeutic need?
JR: That could be one follow up. What we've done is defined the range where we can expect some positive changes, but this was a single dose administration, and people are not taking single doses. They treat themselves for weeks, twice or three times a week. So now we are recruiting volunteers to participate in the follow-up study, which will be similar, but people will go through repeated doses over a period of four weeks; two doses for four weeks. So eight doses in total. Then of course, we will want to see whether the effects we found here will be replicable or even become stronger because people have repeated administration.
RM: I know you've published a paper on the creative aspect of psilocybin. Could you outline for the readers what you know about the impact on the creativity of psilocybin?
JR: With psilocybin, there are some brain imaging studies that are quite interesting and that showed changes to some brain networks, which are brain areas that are known to collaborate to support behavioral functions like visual or auditory function, such as attentional networks or executive cognitive functional networks. Within these networks, you see, the internal communication decreases when people are under the influence of psilocybin or any other psychedelic. But the crosstalk between these brain networks actually increases. So that seems to indicate that there's a lessening of the boundaries that are put around these networks. That enables more crosstalk and more communication between these networks, which suggests that there's increased flexibility within the brain processing of stimuli and information that comes in. This increased crosstalk may be underlying some of the changes that people subjectively report in their creativity.
RM: Is the evidence here more anecdotal or have there been replicable studies?
JR: As far as I know, they are still anecdotal. Also we did one study that was a naturalistic study where we actually did find that people under psilocybin have increased levels of creativity. So that's definitely encouraging, but at the same time that it was a naturalistic study, where people's performances are measured from before the psilocybin treatment relative to after the treatment, but there's no control group. And ideally, you should have a placebo control group to control for expectations that people have.
So, I think so that's nice, interesting evidence, but that's not solid evidence, and we need to replicate the findings in the laboratory where experiments are actually very well controlled. That still needs to happen.
RM: You have published some work on synthetic psychedelics – why would we use these?
JR: We did some work on 5-MeO-DMT, which is a compound that you can find in the glands of a toad in Mexico and the United States; [this is Bufo alvarius, the Sonoran Desert Toad] people milk the toad. 5-MeO-DMT is basically a poison that the toad needs to protect him from predators, but 5-MeO-DMT is also the strongest psychedelic that we know of today. It's quite popular in in the underground culture. Ceremonies of people organize to smoke the dried poison, basically the dried venom of this Bufo alvarius and we did a naturalistic study where we followed people before and after they smoked 5-MeO-DMT but also 4 weeks later.
We tried to assess aspects of their mental health and found that there were reductions in anxiety and symptoms of depression, and reductions in levels of stress that we could see already within 24 hours of smoking but also still four weeks later.
Again, this is a very interesting study, but we were lacking the control group here. So this is also a study that needs to be replicated in a laboratory. Then again, you don't want to go to the desert and kill a number of toads to get the poison. So rather than chasing the toad, and maybe having it go extinct or something like that, it's better to turn to the synthetic alternative. This is where we should be going. It’s a clear example of what advantage a synthetic component can be over the natural component that you can find with this toad. With the synthetic compound, it's much easier to produce and much easier to control [the dose]. And so we would say, “Leave the toad alone. Just go for the synthetic compound.”
Interviews have been edited for length and clarity