Ketamine and Psilocybin Could Boost the “Integration of New Experiences” By Stimulating Nerves in the Brain
“Perhaps psychedelics, through the increase in the formation of dendritic spines, could improve the integration of new experiences,” Alex Kwan remarked.
Kwan, an associate professor of psychiatry at Yale University, was speaking during his recent Analytical Cannabis webinar, which detailed some of the latest breakthroughs his lab has made in relation to the neurobiology of psychedelic drugs.
Specifically, research from Kwan’s lab has suggested that dendritic plasticity may help support the idea that ketamine and psilocybin can help individuals adopt new perspectives and better process new experiences.
Studying psychedelics and the brain
Psychedelics such as ketamine have attracted significant attention in recent years following the discovery of their fast-acting antidepressant effects. What makes psychedelics particularly useful is that after this initial rapid antidepressant response the effects of a single dose appear to be sustained effectively over days and weeks to come.
Yet, despite the successful application of these drugs in psychedelic-assisted psychotherapy settings, the neurobiology behind these antidepressant effects remains largely unknown. Kwan and his team at Yale are doing their best to change that.
Speaking to Analytical Cannabis last December, Kwan described three different levels of investigation for studying the effects of psychedelics in the brain. The smallest of these is the molecular level, which relates to understanding exactly what is going on at different brain receptors. Then at the receptor level, or “systems” level, researchers can investigate how these compounds change individual neurons or groups of neurons in terms of their structure, function, and connectivity. Finally, researchers can consider the whole brain and use fMRI imagine or similar techniques to examine which areas of the brain are affected by a given psychedelic drug and to what extent.
“The systems level, this is the level that excites us the most,” Kwan said. “Because if you’re talking about neurons and you talk about action potential and how they fire and communicate with each other, ultimately I think this can lead to mechanistic understanding of how these compounds can influence behavior.”
Early work led by the late Professor Ronald Duman, a colleague of Kwan’s at Yale University, identified the dendritic spines as being a key site of action for ketamine’s effects in the brain. Dendritic spines are small membranous protrusions that extend off a neuron’s dendrite. These spines are normally the connection point between a neuron’s dendrite and an axon, and so dendritic spines play a very important role in facilitating neural communication.
Duman found that in a mouse model of depression, simulated by inducing chronic stress, mice tended to have fewer dendritic spines in their frontal cortex. But after a single dose of ketamine, many of these spines were restored.
“[With] the ketamine, even though only a single dose was administered, you see a reversal of these dendritic spines,” Kwan said. “So there’s a loss with stress and then a restoration with ketamine, which is very exciting because it seems like the single dose of ketamine, at least structurally, was able to reverse the atrophy that we’re seeing out of chronic stress.”
Explaining the long-lasting effects of fast-acting psychedelics
These structural changes in dendritic spine density offer a promising explanation for some of the long-lasting antidepressant effects of psychedelics. And so with these dendritic spikes in mind, research has continued to uncover more of the neurobiological mechanisms behind these psychedelic actions in the brain.
Monitoring the calcium ion influx involved in neural plasticity has been one focus taken on by Kwan’s colleagues; associate research scientist Farhan Ali, PhD, recently published optical imaging studies on live mice demonstrating a clear increase in the number of calcium events under the influence of ketamine.
“We have ketamine, leading to an increase in the amount of calcium in these dendritic spines, and we know that calcium can go into dendritic spines through voltage-gated calcium channels, but more so even, probably through a lot of the NMDA [N-methyl-d-aspartate] receptors there,” Kwan explained.
“However, if you know anything about ketamine, you would know that ketamine is an NMDA receptor antagonist. So that’s very counterintuitive, because how would blocking the NMDA receptor lead to an increase in calcium signals? So at this point Farhan and I thought that there must be something else in the cortex, some other neurons that might be responsible for this increase.”
The group began to think about a class of interneurons that specifically target the dendrites: somatostatin- (SST-) interneurons.
“We thought that if ketamine acts on the NMDA receptor on these SST interneurons, and indeed they also have NMDA receptors, then this will lead to a disinhibition two-step process that would relieve the inhibition at the dendrite spines, consistent with the increase in the calcium influx that we see in the spine component,” Kwan explained.
With more two-photon calcium imaging experiments, the Kwan Lab was able to identify patterns in keeping with this hypothesis of SST inter-neuronal involvement. Identifying this involvement was important, Kwan says, as the inhibitor innervations on a piece of dendrite are uneven. This means that changes in plasticity may be swayed toward certain types of dendritic spines and certain types of input onto a neuron.
“An important part of these drugs is not only to recognize that they induce plasticity, but also where and how they are inducing this plasticity,” said Kwan.
“You might not want plasticity all over your brain – you might not want to be able to make your whole brain malleable because you have memories you have certain skills that you want to retain. So you want only plasticity in certain regions and certain specific synapses,” he added.
Psychedelics may also improve the integration of new experiences
This observation of increasing dendritic spine density and increased plasticity in certain regions of the brain is interesting because this combination is also seen when the brain is trying to learn from new experiences.
In a previous Analytical Cannabis webinar, Gül Dölen, an associate professor of neuroscience at Johns Hopkins University, detailed how psychedelics can be used to reopen the “critical period” of learning that the brain goes through during childhood. In Dölen’s lab, this effect is being used to assess the effectiveness of MDMA-assisted psychotherapy in treating severe post-traumatic stress disorder.
The Kwan Lab is similarly interested in exploring how psychedelics can enter the brain and change its neural function to elicit some very profound alterations in behavior.
One of the more recent behavioral studies carried out in the Kwan Lab looked at learned helplessness in mice, which is an approximation for depressive-like behavior. In this test, the mice were placed in a chamber with two identical compartments. In the first part of the study, test mice were confined to one compartment where the floor would occasionally deliver a mild shock to the feet of the mouse. This continued for two days until the mouse learned that the shock was inevitable and learned hopelessness.
With helplessness established, the door to the second compartment – which did not have a shock floor – was opened on day three, and the researchers observed how many mice chose to enter this new compartment. On day four, the mice were given either psilocybin, ketamine, or a saline control, before being re-tested under escapable shock conditions.
They found a significant increase in successful escapes when the mice were given either ketamine or psilocybin, with psilocybin being slightly more effective. Using longitudinal two-photon imaging, the researchers also observed that the administration of psychedelics in this experiment resulted in the growth of new dendritic spines. Compared to those who had learned helplessness, spine density increased by roughly 10 percent for the mice given psychedelics. This change persisted for up to one month after administration of a single psychedelic dose.
“When do you usually see an increase in dendritic spines? You see it during adolescence when the neural circuit is developing, and you also see it when the animal is learning,” Kwan explained.
“Perhaps psychedelics, through the increase in the formation of dendritic spines, could improve the integration of new experiences.”
It seems clear then, that psychedelics such as psilocybin and ketamine can promote plasticity in certain parts of the brain, and that this affects neural circuitry in a way that can significantly influence behavior and learning. Used in conjunction with expert-led psychotherapy, this drug effect may have usefulness as a therapeutic to help combat depressive thinking or resolve traumatic memories.
“A lot of drugs can produce plasticity, so I think it matters a lot when and where are these [sic] plasticity being enhanced,” Kwan concluded. “We hope to understand how these drugs influence behavior, and moreover, we also think that these could be the fingerprint on how these compounds act. Understanding how they act on the brain could be a good biomarker for screening new compounds that might have similar actions, or maybe even improve actions for future medicine.”
