Isolde de Jong started her internship with APRA in November 2018, ever since she is reporting activities within the organization. As a student of applied psychology with a main interest in psychedelic research, she developed a strong curiosity in the biological mechanisms of certain entheogenic plants and other substances. With this internship she hopes to achieve a better understanding of psychedelic research and to help destigmatize the subject.
by Isolde de Jong
Edited by Jennifer Them
“How long will this last, this delicious feeling of being alive, of having penetrated the veil which hides beauty and the wonders of celestial vistas? It doesn’t matter, as there can be nothing but gratitude for even a glimpse of what exists for those who can become open to it.”
― Alexander Shulgin, Pihkal: A Chemical Love Story
Above you can read a quote from one of my favourite psychedelic elders, Alexander Shulgin. A quote written down while on the substance LSD-25, perfectly demonstrating the feeling of a greatly expanded range of possible subjective experience, both in negative and positive directions. In fact, the word psychedelic coined by Aldous Huxley and Humphrey Osmond, signifies “mind-manifesting” or “mind-revealing”. But what does that mean? Could that “mind-expanding” quality be linked to more connectivity between certain areas in the brain, as fMRI studies seem to suggest? Or perhaps, could it be related to increased neural plasticity?
Last summer, the psychedelic world got stirred up by the paper “Psychedelics promote structural and functional neural plasticity” from Ly et al. (2018) which stated that psychedelics such as DMT, LSD and DOI are capable of making neurons more likely to branch out in rodents. Rodents are often used in biomedical research for their similarities with humans in behavioural and genetic characteristics. Ly et al. (2018) showed that serotonergic psychedelics are able to induce structural and functional changes that are accompanied by an increased number of synapses and functional properties. They also identified the molecular pathways that appear to promote these neural changes.This induced neuroplasticity could play an important role in explaining the efficacy of psychedelics in treating depression and addiction.
To get a better understanding of the paper and its implications, APRA organized a Journal Club for its members led by Rudolf Faust, a neurobiologist at the Dutch Institute for Neuroscience and Psychiatry. His research is focused on the dopamine system and as a postdoc Rudolf is working on understanding how dopamine release is regulated in brain regions involved in the formation of habits. Rudolf is working in the laboratory of Ingo Willuhn, who studies neuroplasticity of the dopamine system and how that may contribute to disorders like addiction, obsessive compulsive disorder and the symptoms of Parkinson’s disease. Therefore, he was the perfect candidate to present the paper.
After the talk given by Rudolf I went home with a head full of questions concerning the potential future implications of this paper. When I was given the opportunity to interview Rudolf, I saw this as a perfect chance to dig deeper into the matter by covering his thoughts concerning the presented study and to talk about his personal dreams and future plans. A week later we sat around the table.
Something I really like in people is the ability to be utterly curious about life, a character trait a lot of scientist seem to share. In my interview with Rudolf, he mentioned that curiosity, discovering things that nobody has seen before is the main motivation behind his work.The research Rudolf does is still in it’s infant stages because a lot is still unknown about the formation of habits, however, better therapies could be formed for neuropsychiatric diseases and neurological disorders when we understand how the dopamine system works. The last part seems to be important for Rudolf, who had a few friends suffering from neuropsychiatric disorders and even had close friends dying from drug abuse. “I hope that someday I could contribute to a better treatment then that is currently practised” Rudolph added.
After some chit chat about his life and interests, I presented Rudolph questions I had gathered from APRA members. The questions go more in depth regarding the paper and his own thoughts about it.
Isolde: In popular science imagery, neuroplasticity is often associated with creativity and flexible thinking, and therefore seen as something mostly or entirely positive and beneficial. Do you think this is truly the case? If not, when do you think it can become even harmful?
Rudolf: I think PTSD is a great example of a disorder in which harmful neuroplasticity might occur, but not much is known about neuroplasticity in this context. What I do know is the dominant theory in science about neuroplasticity in addiction as it is my field of work. Let me explain, the general idea behind addiction is that it is a disorder of neuroplasticity. Drugs hijack the brain and cause maladaptive plasticity that directs more behaviour towards the drug. Sadly this theory hasn’t led to any major clinical breakthroughs yet. I do believe that neuroplasticity is involved in addiction in someway or another and certainly when we talk about the recovery part of addiction. In the past decades research hasn’t been paying attention so much to the role of environment in regulating vulnerability to addiction and now people are realizing that the stories are more complicated than just the drug hijacking the brain.
The human brain is way more complex than what we have seen in the study in rodents which are used to study neuroplasticity usually due to their simple nervous system. How do you think the results of the study from Ly et al. can be translated to the human brain and what possibilities do we have to research that in humans.
Even though the human brain is way more complex than the brain of rodents, there are some commonalities. For example, some brain areas that are important for decision making seem to have the same function in rodents, monkeys and humans. Also the part of the brain I am working on, the striatum, is conserved between rodents and humans. So therefore I think you can translate a lot especially concerning the striatum which is well characterized in both humans and rats and is actually pretty similar. So in terms of understanding the dopamine system and reward function, I think a good amount will translate from rodents to humans. Also the pathway of addiction seems to be commonly shared between humans and rodents. Even though the modern paradigm that addiction is a disorder in neuroplasticity in the brain hasn’t yet produced any breakthroughs, there are some promising transcranial magnetic stimulations studies going on which are based on rats that had their neuroplasticity manipulated using optogenetics.
What questions do you think the paper Ly et al. raises as potential future directions of development for psychedelic research?
I would think the researchers of the paper are trying to screen for drugs that have a potential of treating psychiatric disorders. There has been a new interest in psychedelic research mainly due to the lack of new discoveries since the breakthrough with SSRI’s. The existing drugs just don’t really work that well. The problem with psychedelic research is that the government barely wants to fund it. Sadly we still have to deal with this slight stigma around the subject that makes it harder to do research. But as the legal barriers fall, more openness will follow. Still, there are promising studies being done; look at the outstanding results with the MDMA PTSD study. In a matter of fact it’s so promising that even under Trump, MDMA is FDA rewarded as a breakthrough therapy.
What do you think about the relevance of psychedelics for your field of research? What neuroscientific questions, if any, do you think psychedelics might help answer?
When you look at the documented experiences with psychedelics, from both underground research and psychedelic work done back in the days in the United States, I think there is good evidence that psychedelics can help break bad habits and ways of living that may not be the best for people. So yes, there is a big intersection with my field of research. My hypothesis for now would be that psychedelics induce neuroplasticity that can help people break free of their addictions. And the challenges we face today is the lack of understanding of how psychedelics insert their effects on the brain. For example, we know that the 5-HT2A receptor is extremely important but we don’t know which receptors in which part of the brain are responsible of mediating different effects of the drugs.Therefore it’s difficult to design experiments and to make testable hypothesis.
If money wasn’t a factor, what kind of research would you do?
I would definitely work on psychedelics, probably on how psychedelics influence neuroplasticity. I think neuroplasticity is important for the effects on psychedelics and perception, although even that field is in its infancy. Therefore, I would like to go back to some of the old hypothesis that people made about how psychedelics might work in the brain. On the other hand I would also take inspiration of all the imaging work that has been done in people under the influence of psychedelics. An interesting topic for me would also be to test what circuits in the brain are important for mediating specific perceptual and cognitive effects of psychedelics. The idea behind is that you present your subject to different stimuli and have it respond in a certain way depending on the nature of the stimulus. Then, you can generate curves of how well a subject can perceive things like luminants, speed or pitch. It’s a general technique to look at how well people can report whether they perceived specific stimulus validity. Ultimately I would like to also look at mechanisms of how psychedelics can disrupt habits.
What would you advice/message to aspiring scientist be (interested in psychedelics or more generally).
My advice would be that it is very important to get good training. If you want to research psychedelics, the most legitimate way to do it is through academia. Of course there are ways to skip the academic world, it might be more easy to do your own research if you are a botanist. The best advice I can give to young scientist is to get into the labs and seek out the opportunities to research psychedelics. Even today there isn’t that much research happening on psychedelics yet. So, plan what you want to work on in your training and get into the lab! Also the whole controversy around psychedelics seems to change a bit so the time is now.
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Photo by Zeiss Microscopy