Recent research is Proceedings of the National Academy of Sciences It suggests that psychedelic substances change the way brain activity travels across the surface of the brain. This study provides evidence that drugs such as LSD, psilocybin, and MDMA reliably reduce the flow of information into the brain’s core networks associated with introspection. These findings provide a new biological explanation for both the therapeutic potential and psychological risks of using psychedelics to treat mental health conditions.
The default mode network is a collection of interconnected brain regions that are highly active when a person is resting and thinking about themselves. Scientists link this network to introspection, daydreaming, and maintaining a rigid sense of self. In many mental illnesses, such as depression and schizophrenia, the default mode network tends to function abnormally. Because of this relationship, researchers want to know exactly how potential psychiatric treatments affect this particular network.
“The use of psychedelic drugs is increasing faster than our understanding of how these drugs affect the brain, especially at the level of large-scale brain networks,” said Adam Pines, a postdoctoral researcher at Stanford University who led the study with study lead author Leanne M. Williams. “Clinically, these unresolved questions limit our ability to know which patients are likely to benefit from psychedelic treatment and which are at risk of harm.”
Previous studies typically measured brain activity as if it were fixed in place. Rather than tracking how the signals physically moved through brain tissue, they looked at the average activity of resting regions over time.
Brain activity always moves in a specific direction, from low-level sensory areas to high-level thinking areas and vice versa. The upward movement is called bottom-up processing and involves responses to basic sensory input. This downward movement is known as top-down processing, where the brain applies past experiences and expectations to interpret incoming information.
“Existing theories of psychedelic action tend to disagree on the core point of whether psychedelics increase or decrease ‘bottom-up’ brain activity (activity that moves from lower brain areas to higher brain areas),” Pines said. “From our perspective, this core assumption was not systematically tested.”
To test this assumption, the researchers employed an analytical technique called optical flow. This technique is typically used in computer vision to track the movement of physical objects across video frames. By applying this technique to brain scans, the researchers were able to assess the directional flow of brain activity frame by frame, capturing the precise movement of signals across the cortical surface.
Researchers combined data from four independent studies to test how different psychedelics affect the flow of brain activity. “Deriving conclusive evidence from psychedelic research is notoriously difficult,” Pines says. “We sought to establish our results beyond a reasonable doubt by replicating our findings across nine different case-control comparisons using four datasets and two completely different neuroimaging techniques.”
The first three studies involved human participants who received specific drugs and underwent functional magnetic resonance imaging. This type of brain scan, sometimes called fMRI, measures changes in blood flow to detect active areas of the brain. Before performing the optical flow analysis, the authors masked segments of the data interrupted by head movements to ensure high accuracy of the measurements.
In the first study, 14 healthy adult participants were given either a placebo, 80 milligrams of MDMA, or 120 milligrams of MDMA. MDMA is a synthetic substance that alters mood and perception. Participants completed multiple scanning sessions over different days, allowing researchers to compare brain activity with and without the active drug.
The second study evaluated the effects of psilocybin, an active hallucinogenic compound found in magic mushrooms. Six healthy participants underwent multiple fMRI scans. During some sessions, they were given 25 milligrams of psilocybin. On other days, they received either no drug or an active placebo called methylphenidate, a stimulant that mimics the physical arousal caused by psilocybin.
The third study focused on LSD, a powerful chemical that alters perception and thinking. Eighteen healthy participants received an intravenous infusion of either LSD or a saline placebo. After a short adaptation period, they completed about an hour of fMRI scans to capture brain activity under the influence of the substance.
The fourth study involved a completely different species and measurement technique. The 14 mice were given LSD, a sedative called diazepam, or another sedative called dexmedetomidine. Instead of using fMRI, the scientists used wide-field calcium imaging to measure the mice’s brain activity. This technique uses fluorescent markers to directly observe the electrical activity of neurons across the brain surface, providing a different perspective on brain function.
Across all four datasets, the authors investigated two main features of brain signals traveling within the default mode network. First, we calculated the magnitude, which is the total amount and strength of the brain waves traveling. We then measured directionality, specifically examining the proportion of signals that travel from sensory areas to the default mode network in a bottom-up direction.
The researchers found that all of the psychedelics tested significantly reduced the overall magnitude of propagation of cortical activity in the default mode network. In the first study, MDMA reduced the strength of these moving signals compared to both placebo and baseline scans. The exact same pattern emerged in a second study on psilocybin and a third study on LSD.
When looking at mice in a fourth study, the authors noticed a similar decrease in signal magnitude after administration of LSD. When mice were given an active sedative, they had the opposite effect, increasing the magnitude of brain signal movements. This suggests that the reduction in traveling waves is a unique feature of psychedelic drugs, rather than a general effect of taking psychotropic drugs.
In addition to reducing the magnitude of these signals, psychedelics changed the direction in which they traveled. In human studies, MDMA, psilocybin, and LSD have all been shown to reduce the proportion of signals that travel in a bottom-up direction. Instead of information flowing freely from sensory areas to the default mode network, the overall balance of activity shifted away from bottom-up processing.
Studies in mice replicated this change in direction, as LSD significantly reduced bottom-up propagation in the mouse brain. Interestingly, studies with psilocybin showed that this bottom-up directional attenuation persisted for several days after the first dose. Scans acquired within 2 days after the psilocybin session still showed a proportional decrease in bottom-up propagation.
The scientists also investigated whether these movement changes were associated with the drug’s subjective psychological effects. In human studies, participants completed comprehensive questionnaires about their experiences. Scientists have found that a significant reduction in bottom-up signaling correlates with stronger negative emotions, such as fear of losing one’s sense of self and a sense of loss of control.
The results were contrary to the research team’s initial expectations. “Science has yet to understand how psychedelics affect large-scale brain function,” Pines told SciPost. “Our study challenges one of the field’s core assumptions: Many researchers, including myself, expected psychedelics to increase ‘bottom-up’ activity.”
Pines pointed out that the actual data tells a different story. “Instead, we found the opposite,” Pines said. “However, as with any research, this new evidence has caveats and limitations.”
One anticipated problem is how researchers interpret data at a broad level. “In our human data, we accounted for group-level effects, rather than what happens 100% in each individual every time they take a psychedelic,” Pines said. “Although this is standard practice in human neuroimaging studies, it is worth bearing in mind that the effects of psychedelics on individuals can vary widely.”
The concept of bottom-up processing also comes with its own complexities. “Scientists still don’t fully understand so-called bottom-up activity and the different ways it occurs,” Pines says. “Analytically, we only measured bottom-up activity in one direction, rather than comprehensively resolving all possible bottom-up activity in the brain.”
The researchers admit that they needed to narrow their focus to perform the optical flow analysis. “While we have had to be reductionist in assessing the issues of interest, there is no doubt that there are more subtle aspects of bottom-up and top-down activity that have yet to be discovered in psychedelic research and neuroscience in general,” Pines said.
These brain wave changes may explain why psychedelics have certain therapeutic effects. For example, ruminant depression involves excessive automatic negative thinking, which researchers associate with excessive bottom-up cortical transmission. By reducing these bottom-up signals, psychedelics may disrupt the automatic negative thought loops associated with depression.
Reduced bottom-up processing may also pose risks to certain vulnerable populations. People at risk for psychosis already experience impaired bottom-up processing and are often overly dependent on top-down expectations, which can lead to hallucinations. Ingestion of hallucinogens can exacerbate this existing imbalance, providing a biological explanation for why these drugs cause psychotic episodes in susceptible individuals.
The researchers plan to extend this analytical approach to other compounds beyond psychedelics. “This lack of understanding of large-scale brain function is not unique to psychedelic drugs,” Pines says. “Decades of intensive research have revealed much about how alcohol, nicotine, and neurologically active drugs act on individual neurons, but our knowledge of how they affect large-scale brain function is very limited.”
Application of this knowledge could ultimately allow doctors to provide more personalized care. “If we can characterize the effects of neuroactive substances on a broader scale, we can better predict the effectiveness of specific treatments for individual psychiatric patients and adjust prescribing accordingly,” Pines said. “This gives us more confidence in our findings, but it doesn’t settle the question. Further research is still needed.”
The study, “Psychedelics disrupt hierarchical cortical propagation in the default mode network of humans and mice,” was authored by Adam R. Pines, Xue Zhang, John Kochalka, Sam S. Vesuna, Isaac V. Kauvar, Divya Rajasekharan, T. Rick Reneau, Teddy J. Akiki, Laura M. Hack, Joshua S. Siegel, and Leanne. M. Williams.
