Kim Kuypers is an associate professor in the Faculty of Psychology and Neuroscience at Maastricht University. Her research focuses on the neurobiology underlying flexible cognition, empathy and well-being. At the ECNP Congress in Vienna she will present on the biological and cognitive effects of small doses of a psychedelic in a session she co-chairs with ECNP president Gitte Moos Knudsen (S03 – Towards personalised psychedelic applications: understanding its treatment success, Saturday, 15 October, 16.50-18.10). Here she speaks to ECNP press officer Tom Parkhill.
TP: I interviewed Guy Goodwin about psilocybin, around 18 months ago. I knew nothing about it, but it was tremendously interesting. Microdosing is obviously very different. Why now?
KK: It’s a new field, and there are lots of unknowns. Let me give you some background. We have a longstanding history of doing studies with MDMA, and also with psilocybin, but at full doses. Around five years ago there was a lot of media hype about microdosing, and we were discussing it over lunch (“is it homeopathic..?”), we were also doing a study for the Beckley Foundation, which has an interest in microdosing, and this led to our first placebo-controlled study.
Microdosing is taking small amounts of a drug repeatedly. People work to different schedules. Some take it every day, some microdose every other day. It’s very variable. We were thinking about initiating a study, but we realised that we didn’t know what a microdose was. We understood that it was one tenth or one twentieth of a full dose, but what is a regular dose, out there in the real world? So we decided first to do a dose-finding study. We picked LSD as our substance, and we gave 5, 10, or 20 micrograms to our volunteers.
What would a normal LSD dose be?
In placebo-controlled studies with healthy volunteers the normal dose is between 100 and 200 micrograms. So we started with 5 micrograms, then we doubled that microdose, and then doubled the microdose again. We ran this in healthy volunteers and we had some positive findings. Some had an increase in positive moods, but this was very individual, not everyone responded. We had some effects with the lowest dose, but most effects with the highest dose. With some it was variable. We also showed a decrease in pain sensitivity, which might indicate that it is suited for pain treatment.
We also showed that BDNF, which is a marker of neuroplasticity, increased at four and six hours after intake. This showed at 20 micrograms after four and six hours, but not for 10 micrograms. For me, that’s an indication that it does something at the biological level, the fact that we find these biological measures and other studies find something on EEG or imaging. There’s an interesting study with psilocybin where the researchers recorded speech, and the computer could distinguish between the LSD group and the placebo group based on the sentiments and verbosity of speech, and other parameters (see https://pubmed.ncbi.nlm.nih.gov/35676541/). We see a scattered pattern of findings though.
I’ve been reading an recent article by Harriet Witt. She says that overall repeated dosing of LSD does nothing, but reading the article closely you can see that there is an effect in questionnaires and a computer task. I’d disagree that LSD microdosing does nothing, but we should understand what it does and doesn’t do. We recently completed a survey where we followed (for four weeks) a group of people with ADHD who were intending to start microdosing. They took LSD or psilocybin, according to their own schedule, and we saw a decrease in symptoms at two and four weeks. We also had a group which took conventional medication next to their microdosing and their symptoms were only decreased after four weeks, so the process of symptom reduction seemed to go slower compared to people who only microdosed.
We are going to start a placebo-controlled study in ADHD people to find out whether microdosing really works. If you look into motives, people take psychedelics for all sorts of different reasons. If you compare those who microdose with those who don’t, then those who microdose have lower anxiety levels, lower depression levels, better well-being. There are lots of anecdotal reports from people, so I think we need to follow that thread. We know for example that people claim that microdosing will give relief from their depression. We did a survey comparing microdosing with full dosing and conventional medication for – amongst other things – depression. While microdosing was reported to decrease their symptoms more than the conventional treatment they had previously received, the full dose was seen as better than microdosing.
I also see trends – there are companies selling microdoses – it’s very professionally done. They look like packets of paracetamol, which alarms me a bit, because people may think it’s an approved medicine. What these companies also do is that they offer coaching. This is something we want to look at: what does it do to you if microdosing is combined with coaching? It’s a more holistic approach. If you think about it in terms of neuroplasticity, you could say that you have a window of opportunity in which you can do some therapy. But these are all still question marks. It’s still a field in its infancy, but I think we shouldn’t only remain focused on full psychedelic doses. For example I don’t think that ADHD would be helped by taking a full dose of LSD, but perhaps microdosing might.
We’ve spoken in the past about the use of drugs in sport, and I can see some parallels there. We have pharmaceutical products being developed by people “on the ground’, rather than it being a top-down development by pharmaceutical companies. As you say, they are obviously using microdosing for a variety of conditions – so where does a rigorous researcher start? Another point is that when I interviewed Guy Goodwin on how psilocybin works, he said that psilocybin’s effects last just a brief period of time, a couple of hours, and this means that you can fit administration in a working day, whereas LSD last much longer, it’s more difficult to incorporate in a day. The full psilocybin dosage was supervised, so the psychedelic experience, the trip, was part of the treatment. Microdosing is obviously very different.
Yes, and that’s a whole discussion in the field. David Olson has compounds which are analogues of psychedelics, but without the psychedelic effects, and he describes them as ‘psychoplastogens’, meaning that they produce neuroplasticity. So that brings up the question: is it the neuroplasticity which has the therapeutic effect, or is it the psychedelic experience? We can’t really say, but of course with microdosing you don’t have the psychedelic experience, so the effect needs to come from somewhere else. When I see BDNF changes, I think that perhaps it might come from that. But this also worries me because if you are going to microdose repeatedly, will you have a BDNF response repeatedly, or will the effect be flattened? When you take a psychedelic repeatedly, you induce tolerance to the effect, so how is it if you microdose, will you still have the effect? These are questions we need to answer.
What are the barriers to investigating microdosing psychedelics? They are banned, and of course people who use them are using them illegally. Have drug companies shown an interest?
We’re about to begin an ADHD microdosing study with MindMed. They have an interest, but they also have full psychedelic dose studies in their portfolio. We know that if we give a psychedelic once or twice then it will have an effect on depression. With microdosing it’s something different. You need the right dose, you need the right schedule, it may be more tricky for a company to develop these drugs, but the need to take repeated doses may be commercially interesting.
Do the psychedelics have different qualitative effects?
In the past there were studies that showed that LSD can have a stimulant effect, perhaps similar to amphetamines. There is some evidence that the effect of psilocybin is different.
Findings from one study have suggested that LSD (25 mcg) induces stimulant effects, as the effects were similar to those of amphetamine (20 mg). For psilocybin this has not been found. In light of therapy with low doses of LSD or psilocybin it is necessary to know whether they have a different, and perhaps a complementary, effect pattern that could be employed successively to treat different symptoms (‘cognitive’ or ‘affective’) observed in one psychiatric disorder. The main thrust of our work is to discover if it works – will it help ADHD? But of course we will look into the underlying mode of action.
You’re working on ADHD, is this the main target for the field?
We’re looking at ADHD, yes. I have heard of other studies looking at microdosing treatment of depression. I think it’s important that we look at the full potential of treatment, which if course depends on the mechanisms. It might be that you take a full psychedelic dose if you are depressed, that you also have therapy, but alongside that you microdose. But again, we need to know more about the therapeutic mechanism.
I’ve seen reports that response to treatment is in some ways dependent on personality, on the individual.
Yes, this is true with full psychedelic doses, but it has also been found that full preparation is vital. For example people who are not able to surrender to the experience don’t seem to respond as well as those who do. I’d say that the more preparation, more support, the better. The preparation is largely to explain to people what they should expect. I like the fact that people are given time. Often if you go to a doctor or therapist you know the clock is ticking. With this type of therapy there’s more space, you get to know your therapist, to an extent, you bond. It’s partly about giving people some time, letting them know that you are there for them.
I think we need to listen to people, to understand what they are doing. There are microdosing companies which offer coaching. They start with titration sessions with their participants. I really like the idea that they want to tailor the treatment to the person. The whole psychedelic field is bringing the person to the front, making the person central to the treatment, and trying to understand their needs.
Symposium
S03 – Towards personalised psychedelic applications: understanding its treatment success
Saturday 15 October 2022
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