Nature's Perspective: Psychedelic Medicine

The speculative answers that this generation of researchers offered were limited by the tools they possessed. The evidence that psychedelics interfered with the function of the neurotransmitter serotonin was rudimentary, and the techniques used to probe brain function were crude. When that first enthusiastic wave of research began to fade amid a political backlash against psychedelics in the 1970s, many psychological ideas remained disconnected from neurobiological mechanisms.

Researchers working on today's 'psychedelic renaissance' are grappling with the same central questions, but have far more precise tools at their disposal. In particular, they have access to neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). And, thanks to volunteers willing to experience the effects of psychedelics in the confines of brain scanners, the way these drugs reconfigure human brain activity has been observed in real time.

These studies revealed that psychedelics cause brain regions whose activity is normally strongly coupled to become less coordinated. And many regions that are generally only loosely connected are beginning to communicate more with each other.

Most researchers agree with this broad summary, but reaching a consensus on the details is proving difficult. Robin Carhart-Harris, who studies psychedelics at the University of California, San Francisco, believes that the actions of these drugs are now "very well" understood. But Felix Müller, a psychiatrist at the University of Basel in Switzerland, is less convinced: "Everything is unclear," he says.

Until now, neuroimaging studies have been small and their results inconsistent. Researchers hope that a new data-sharing initiative will help establish which findings are robust, but different types of experiments will be needed to resolve unanswered questions.

Different perspectives

Classic psychedelic drugs, such as LSD and psilocybin, disrupt neural activity by diffusing through the brain and activating a serotonin receptor known as the 5-HT receptor. _2A . Once stimulated, these receptors make neurons more excitable, and their general activation by psychedelics causes widespread changes in neural networks.

There are 5-HT receptors. _2A They are found throughout the brain, but are most abundant in the cerebral cortex, particularly in areas responsible for cognition and self-awareness. In addition, 5-HT receptors _2A They are highly expressed in the visual cortex and at the ends of the axons that cortical neurons send to other parts of the brain, such as the thalamus, where sensory information is processed. This is consistent with psychedelics causing perceptual distortions.

In 2019, neuroscientist Patrick Fisher of Copenhagen University Hospital used PET scans to show that after a person ingested a relatively high dose of psilocybin, its psychoactive metabolite psilocin occupied 72% of the 5-HT2A receptors. of _brain ² . He also discovered that the subjective intensity of a trip was strongly correlated with the number of receptors occupied.

Researchers now want to use imaging to help establish how psychedelics change the way the brain processes information. In the 1990s, PET scans showed that psilocybin increased brain metabolism in the frontal cortex, but also in the visual cortex. Scientists are now addressing this question primarily using a form of imaging known as resting-state fMRI. “If you want to get a comprehensive view of what’s happening in the brain,” says Katrin Preller, a neuroscientist at the University of Zurich in Switzerland, “resting-state fMRI is the best way to do it.”

Most fMRI scans involve researchers observing which areas of the brain are active when people are actively doing something, such as viewing emotionally charged images or performing a memory task. With resting-state fMRI, the fluctuating blood flow of the brain is recorded when a person is silently absorbed in their thoughts for tens of minutes at a time.

The researchers then divide the brain scan into regions and use statistical methods to look for correlations in blood flow between two or more regions. When correlations are found, the assumption is that these brain regions are communicating and involved in the same cognitive processes – they are said to be functionally connected.

Studies of functional connectivity have shown that the brain contains several discrete networks. Most scientists believe there are about seven or eight discrete networks, including an attention or salience network, with others related to vision, hearing, sensorimotor processing, and executive control. When a person is at ease, the activity is viewed in a collection of areas called the default mode network (DMN).

These networks and their connections can be called, in the words of Leary and colleagues... ¹ , of “common patterns and structures” of the brain. The question is whether psychedelics liberate a person from them.

Integration and disintegration

So far, according to a review ³ Published this year, approximately 300 volunteers took a dose of various psychedelics – most commonly psilocybin or LSD – in 17 investigations using resting-state fMRI. All studies have found that the drug changed brain connectivity patterns. In many cases, researchers attempted to identify specific connection changes that correlated well with the self-reported intensity of the trip, or with some particular aspect of it, such as a feeling of ego dissolution.

Together, these studies indicate that psychedelics lead to "more connections between networks and less connectivity within networks," says Manesh Girn, a doctoral student studying psychedelics at McGill University in Montreal, Canada. In other words, the areas of the brain that normally have strong functional connections – and that operate in a network with a fairly limited function – become less connected, suggesting that the drugs disrupt the normal outputs of these networks. And the areas of the brain whose activity is normally only weakly correlated become more connected. Most of the findings are consistent with the sensory areas of the brain having the most influence on overall brain activity after ingestion of psychedelics.

Researchers are now using this neuroimaging data to develop descriptive theories of how psychedelics alter the way the brain processes information. In 2014, Carhart-Harris introduced the idea that psychedelics make the brain more entropic. ⁴ . Adapting this fundamental metric from physics – which quantifies how unpredictable or complex a system is – he proposed that psychedelics make the brain less orderly.

Since then, Carhart-Harris has published several articles analyzing brain signals acquired by fMRI, electroencephalography (EEG), and other methods, and has used mathematical analysis to study their complexity. “The complexity of the signal is reliably increased with psychedelics,” he says, “and it tracks the intensity of the subjective experience very closely.”

^{Another idea that article} 4 of Carhart-Harris Regarding the entropic brain, some have considered that psychedelics dissolve a person's sense of identity by weakening the connections within the DMN – an idea that has gained traction far beyond the research community.

Both hypotheses were influential, but they have their critics. Preller, for example, is skeptical about the role of the DMN. "We don't know how large the contribution of the default mode network is, because there are ten other brain networks that are also altered," she says.

Similarly, several researchers consider entropy to be very nonspecific. Fisher is concerned about how many different methods were used to evaluate it. “You have eight different articles talking about entropy,” he says, “and nobody has any idea if they are communicating the same message.”

Preller's concerns lie in how entropy measurements can be related to specific neural mechanisms. "We really don't understand what they're telling us about biology."

In 2019, Carhart-Harris expanded the idea of ​​the entropic brain into a broader theory of psychedelic effects, termed the REBUS model and the anarchic brain. ⁵ (where REBUS stands for 'relaxed beliefs under psychedelics'). The model is based on an earlier theory of total brain function that conceptualizes the brain as a prediction machine that constantly forms models of what it expects to perceive in the world and then tests whether the sensory data received confirms those models. The REBUS model proposes that psychedelics weaken the constraints that a person's pre-existing beliefs place on their perception of the world and of themselves. This means that, under the influence of psychedelics, sensory inputs and recalled memories are freer to influence the brain and conscious experience.

This year, Girn published an analysis of existing fMRI data that support the model. He discovered that LSD and psilocybin compress the usual hierarchy of connectivity between sensory and associational networks. ⁶ . “These sensory areas – and their concrete, bare processing of the external world – become less separate from the processes conceivably related to our abstract thinking and beliefs,” says Girn. "It doesn't fully validate the REBUS model, but it is consistent."

For Preller, these inconclusive results are a problem. "It's difficult to really test the REBUS model because the predictions are somewhat vague," she says. Instead, her work focuses on a model developed by Franz Vollenweider, a neuroscientist at the University of Zurich who introduced her to psychedelic research. "It's another model rooted in brain anatomy and function," says Preller. Based on research that Vollenweider began in the 1990s on humans and animal models, he proposed the thalamic gating model.

The thalamus is an area of ​​the brain that processes and filters sensory information on its way to the cortex. This filtering, or gating, is regulated by the cortex through axons that express the 5-HT receptor. _2A . Psychedelics appear to interfere with the filtering operation of the thalamus, resulting in more sensory signals reaching the cortex. This is proposed to be central to the psychological effects of psychedelics. “Using fMRI, we analyzed functional and effective connectivity to test what happens in the brain,” says Preller, and the thalamic gating model “aligned very well with what we saw.”

Preller acknowledges that both the gating model and REBUS focus on sensory data gaining greater influence over overall brain function – and accepts that they are not mutually exclusive.

In addition to these theories, Manoj Doss, a cognitive neuroscientist at Johns Hopkins Medical School in Baltimore, Maryland, says that the fMRI findings suggest a central role for claustrum 7, a small subcortical region rich in ^receptors 5-HT 2A _. Like the thalamus, the claustrum exists in a loop with the cortex.

What's next?

Resting-state fMRI studies often reach contradictory conclusions, making it difficult to know which theory best explains the effects of psychedelics. This uncertainty led Fisher to coordinate a systematic review. ³ concerned about the small sample size of these studies. He also highlighted many methodological differences, including the drug dosage used, how the scan data was processed, and which data analysis methods were employed. "For many of these decision points," says Fisher, "there isn't a clear right or wrong answer." But he believes a more standardized approach would increase the reliability of the data.

Their review offered several recommendations, such as always having research participants close their eyes to minimize variability in sensory inputs. But getting researchers to do this can be difficult. "If you keep people's eyes closed, they will fall asleep in the placebo condition," says Doss. "So you're comparing this to a condition where people are wide awake, because you can't sleep with psychedelics."

Fisher's review is indicative of increasing efforts to unite the field. Notably, Girn is the co-leader of a new data-sharing project that will allow researchers to analyze each other's results. “Everyone’s out there with their little datasets,” says Girn. "What if you put it all together?"

One of the goals, says Girn, is to examine models of psychedelic action and have researchers collectively decide which specific changes in functional connectivity would support each one. The next step is to check if these changes are detected across multiple datasets.

But many researchers doubt that reanalyzing existing data will provide all the insights needed to understand psychedelics. Müller and Doss say that the effects of psychedelics should be compared with those of other psychoactive substances. Even caffeine increases measures of brain entropy, says Doss, casting doubt on the idea that increased entropy is a direct indicator of psychedelic states.

This year, Müller published a study on LSD along with two powerful psychoactive drugs that are not classic psychedelics: MDMA (often known as ecstasy) and amphetamine. LSD increased functional connectivity between the thalamus and sensory cortices, which is consistent with the thalamic gating model. But the same thing happened with MDMA and amphetamine, showing that this effect is not specific to psychedelics. ⁸ . What made LSD stand out was something else: it increased connectivity between the attention-salience network and the rest of the brain.

Doss also wonders if resting-state fMRI has become too dominant. Instead of letting people's minds run freely in the scanner, he wants researchers to run specific tests of cognition, memory, and perception to observe the changes in brain activity that accompany alterations in these processes. He points to a study led by Vollenweider that used fMRI to assess the reaction of the amygdala – a region of the brain that processes emotions – when people saw faces with expressions of fear. ⁹ . LSD dampened that response. “We should restrict cognition,” says Doss, “and try to get to these smaller mechanisms.”

Researchers also need to confront the diversity of psychedelic experiences. These experiences vary, both between and within journeys, from the sublime to the terrifying, from the profound to the frivolous, and from introspection to awe at the infinitude of the universe. "On a trip, you can go to heaven and to hell," says Carhart-Harris.

Soon, he will use neuroimaging to examine psychedelic substates to observe connectivity changes related to fight and bliss states. "The assumption is that they will have quite different dynamic signatures," he says.

There is also a growing push to use neuroimaging to understand not only the acute effects of psychedelics, but also the long-term effects that may underlie the medicinal effects proposed by psychedelics. Such studies have already begun, suggesting changes in functional connectivity. potentially associated with antidepressant actions , for example.

For now, however, these small studies and their inconclusive, often controversial results, are once again generating much debate. Preller welcomes requests for larger, more rigorous studies and the involvement of more researchers. "This is a sign of a field maturing," she says. "Eventually, we'll get there."