Impressive new research, led by scientists from Maastricht University in the Netherlands, has uncovered a new neurochemical mechanism by which psilocybin generates its hallucinogenic effects. The research also revealed a direct relationship between a psychedelically-induced subjective sense of ego dissolution and this particular neurochemical process. New Atlas spoke to Natasha Mason, lead author on the new study, to learn more.
The death of the ego
A rapidly growing body of evidence is being generated by researchers all over the world supporting the therapeutic benefits of psychedelic compounds. Psilocybin, the primary psychoactive compound found in magic mushrooms, has been demonstrating such profound efficacy in early trials for treating major depression the FDA has twice granted it a Breakthrough Status designation over the past year.
Exactly how psilocybin generates its beneficial therapeutic effects is still unclear, both physiologically and psychologically. Anecdotally, perhaps the most commonly reported subjective effect of a psychedelic drug is a disruption to one’s sense of ego. It has been so frequently reported over decades that suggesting psychedelics generate a feeling of "oneness with the universe" is virtually a trite cliche at this point.
Nevertheless, this blurring, or even complete disintegration, of the distinction between our subjective sense of self and the external environment under the influence of psychedelics has long fascinated researchers. Timothy Leary called it “ego-loss” back in the 1960s, while more modern scientists variously use terms including ego-death, ego-disintegration and ego-dissolution.
Considering ego-dissolution is a seemingly fundamental part of many psychedelic experiences, researchers are beginning to explore how this deeply subjective phenomenological sensation could be mediating the therapeutic benefits of these drugs. And, even more intriguing, how our brain chemistry is influencing the way we experience our sense of self.
Ego-dissolution, in and of itself, is not necessarily positive. Schizophrenia, for example, is significantly associated with disturbances to one’s subjective sense of self. So research into exactly how psychedelics could be chemically modulating a person’s sense of self not only offers extraordinarily fascinating insights into the neuroscience of the self, but is fundamentally important if these drugs are going to be deployed as medicines in therapeutic contexts.
It's not just serotonin
“As you may know, there is a growing interest in the therapeutic utility of serotonergic 5-HT2A agonists (i.e., psychedelics) like psilocybin, for disorders like treatment-resistant depression, anxiety, addiction, and PTSD,” explains Natasha Mason, from the Department of Neuropsychology and Psychopharmacology at Maastricht University. “Distortions of self-experience are a critical symptom of these disorders, and accumulating evidence is showing that the therapeutic efficacy of psychedelics is strongly associated with the level of self-consciousness during treatment.”
A great deal of recent research has focused on how compounds such as LSD and psilocybin generate their psychedelic effects by stimulating 5-HT2A serotonin receptors in the brain. However, less research has explored the broad downstream effects on other neurotransmitters following 5-HT2A stimulation.
Mason and her team set out to specifically focus on what effect psilocybin had on glutamate levels in two key regions of the brain previously associated with ego. Glutamate is an important excitatory neurotransmitter, fundamentally responsible for cognitive functions such as learning and memory. Its role in mental illness, from schizophrenia to anxiety, has been hypothesized for years.
Using a double-blind study design with placebo control, the researchers recruited 60 volunteers, administering each either psilocybin or an inactive placebo. Alongside evaluating subjective states using well-established surveys measuring ego dissolution, resting state functional magnetic resonance imaging (MRI) focused expressly on glutamate levels in the medial prefrontal cortex and the hippocampus.
“Our first main finding was that psilocybin changed levels of glutamate, a powerful and abundant excitatory neurotransmitter, in key areas of the brain,” Mason explains. “This is important from a neuropsychopharmacological perspective, as it has been hypothesized (but never shown in humans) that this neurotransmitter plays a role in drug effects (historically effects have been linked to only serotonin).”
Just this finding would have made the study relevant enough. As Mason notes, this is the first research to demonstrate psilocybin directly mediating alterations to glutamate levels in a human brain. Previous animal studies have demonstrated this mechanism, but until now it has only been hypothesized as occurring in humans.
The second part of the team’s study involved investigating the correlations between these psilocybin-induced glutamate changes in the brain and the subjects’ self-reported sense of ego.
How does psilocybin dissolve our sensation of ego?
“The second main finding, and the more surprising one,” Mason explains, “was that psilocybin-induced changes in this chemical, glutamate, predicted changes in the subjective experience of individuals' sense of self. We saw that different brain regions corresponded with the different types of ego dissolution, giving us more insight into how these drugs are affecting certain brain regions, and how this can modulate a person’s experience of their sense of self.”
The general pattern observed in the study, compared to placebo imaging, was an increase in glutamate concentration levels in the medial prefrontal cortex and a decrease in glutamate concentration levels in the hippocampus. These changes were relative to the placebo group, and the researchers were able to predict whether subjects were experiencing positive or negative types of ego dissolution based on these specific glutamate concentrations.
"Here 'negatively experienced' ego dissolution is the loss of autonomy and self-control of thought processes, intentionality, decision making, and spontaneous movements," Mason tells New Atlas, explaining the spectrum of ego dissolution experiences. "'Positively' experienced ego dissolution is the depersonalization associated with positive emotional states, like heightened mood and euphoria. Examples of questions addressing these two ‘types' of ego dissolution are, 'I felt like a puppet or marionette' (negative); 'I felt one with my surroundings' (positive)."
Importantly, Mason suggests the psilocybin experience does not generate a singular type of ego dissolution. So, degrees of both positive and negative ego dissolution can be reported during the same psychedelic experience.
The most exciting finding in the study is that negative ego dissolution experiences correlated with glutamate changes in the medial prefrontal cortex and positive ego dissolution experiences seemed to be linked to changes in hippocampal glutamate. These brain-region-specific changes in glutamate concentrations were significant enough to be predictive of the positive and negative ego dissolution ratings subjectively reported by the participants.
We know they work, but we don't know how they work
So, have scientists quite literally stumbled on the neurochemical origins of our ego? Not exactly. Mason is keen to stress this study only focused on glutamate concentrations in two specific brain regions.
"Indeed," she adds, "other brain areas are definitely playing a role in the experience of the sense of self."
Hypothetically, far into the future, while it may one day be possible for scientists to create custom-designed molecules that directly influence a person’s sense of self, that isn’t really the goal of this kind of research. Instead, Mason and her team are much more interested in the biological mechanisms that generate the positive therapeutic outcomes being seen in modern clinical trials.
Psychedelic research undeniably sits on the fringes of modern science. Old lines between mind and body are being blurred as scientists use psychedelic compounds to illuminate the strange relationship between our subjective experience and our neurochemistry. We may be just a few years away from psychedelic clinics legally administering these compounds in therapeutic contexts.
We are increasingly discovering these compounds do work … but we still don’t really know how they work.
And by answering the question, how do psychedelics work, we also inadvertently shine a light on other questions science has shied away from for decades. How do our brains generate our sense of self? What is the neurochemistry of consciousness?
The new study was published in the journal Neuropsychopharmacology.