MIND Foundation’s INSIGHT Conference took place from August 31 to September 3 in Berlin, exploring the latest frontiers in psychedelic medicines – from clinical developments to neuroplasticity, VR, breathwork and beyond.
Bringing together a host of psychedelic researchers, clinicians, entrepreneurs and patients, INSIGHT 2023 put the spotlight on psychedelic neuroscience.
Exploring topics such as non-clinical forms of psychedelic drug use, mindfulness, the philosophy of psychedelic experience, psychedelics in art, as well as patient and therapist spiritualities and more, the conference also facilitated learning from indigenous communities.
Bridging the gap between psychedelics and neuroscience
David Olson, Director of the Institute for Psychedelics and Neurotherapeutics at UC Davis, as well as Co-Founder and Chief Innovation Officer at Delix Therapeutics, presented the talk ‘Bridging the Gap Between Basic Science and Clinical Research in Psychedelic Neuroscience’.
Olson discussed his group’s work in his academic laboratory which is interested in finding new treatments for stress-related neuropsychiatric diseases, such as depression and PTSD.
“A hallmark of all of these illnesses is the atrophy of key brain regions, in particular, the prefrontal cortex,” said Olson.
“The prefrontal cortex is really critical because it controls motivation, fear and reward. A hypothesis in the field has been that if you could identify chemical stimuli that can induce the growth of cortical neurons, such as the growth of new dendrites, or if you zoom in on one of these dendrites to see the growth of these dendritic spines, if you can promote that type of growth, you might be able to achieve a few different really interesting results.”
Such results would either be a rapid-acting response, a response that might be sustained over a long period of time, or the treatment might work across indications “because the PFC is such a critical hub”.
Olson highlighted one such molecule as ketamine, which is capable of promoting both neurogenesis and synaptogenesis.
“I think ketamine is super exciting for the field because it’s pushing us in a completely new direction, a direction that is more in line with a healing-based approach trying to repair these damaged neural circuits,” commented Olson.
“One of the issues [with ketamine] is really its lack of circuit level of selectivity. The primary target of ketamine is the NMDA receptor, which is found broadly across the entire brain. When we got into this area, we were thinking very deeply about what receptors might be selectively expressed in the specific neurons and brain regions that we really care about for treating these stress-related neuropsychiatric diseases – that really led us to study the serotonin or 5-HT2A receptor.”
One of the first experiments carried out by Olson and his team was to treat cultured cortical neurons with psychedelics and look at neuronal morphology. The team found that neurons treated with DMT and LSD had substantially more complex dendritic arbors.
Olson noted that super-resolution microscopy also revealed an increase in the number of dendritic spines and that the team also found that even in short stimulation periods of one hour or 15 minutes, there were profound increases in cortical neuron growth.
“The trick is you have to give the neurons time to grow,” said Olson. “If you just stimulate for an hour, fix and stain, you see absolutely no change in morphology, but if you stimulate for an hour, give the neurons a couple of days to grow then you can see pretty large differences.
“We find that even after the drug has been cleared from the body, we get this long-lasting increase in dendritic spine density, and that’s accompanied by functional effects including increases in both the amplitude and the frequency of these spontaneous excitatory postsynaptic currents.”
This work was carried out in 2018, and since, a group of researchers at Yale University carried out a study to see how long the effects lasted. The team gave a single dose of psilocybin to male and female mice and found that psilocybin induced an increased density of cortical spines in the prefrontal cortex for over a month.
Olson and his team then wanted to further understand the mechanism behind this process. To do this, the team blocked the 5-HT2A receptor – which is known for mediating the hallucinogenic effects of psychedelics – with an antagonist.
“If you give a 5-HT2A antagonist to people, you completely block the subjective effects of those drugs. And what we find is that the two antagonists can completely block the effects of psychedelics from the three different structural classes,” Olson said.
The team then looked at two downstream kinases – TrkB and mTOR – finding that when both of these were blocked, psychedelics were no longer able to promote cortical neuron growth.
Further tests revealed that serotonin could not promote cortical neuron growth despite the 5-HT2A receptor being responsible for psychedelic-induced structural neuroplasticity.
Olson commented: “It didn’t really make sense until we got a particular structure-activity relationship study finished. We started making some small modifications to serotonin-like molecules and we noticed that, as you started to add methyl groups, going from one methyl group to two methyl groups, you saw a much bigger effect on cortical neuron growth.
“We tried to correlate the activity of the 5-HT2A receptor when it was heterologously expressed in a non-neuronal cell like a HEC cell with cortical neuron growth, and we saw absolutely no correlation at all. If anything, we saw a slight negative correlation.”
This led the team to the hypothesis that the reason that serotonin cannot do the same thing as something like DMT is because it can’t access the target.
“We thought maybe the 5-HT2A receptor was on the inside of the cell,” said Olson.
The team began looking for where the neuron was located and found that for the 5-HT2A receptor, everything is localised intracellularly.
Olson concluded: “….psychedelics can promote structural neural plasticity to the activation of a particular intracellular population of the 5-HT2A receptor, really highlighting the role of location bias in their signaling.”
