In a 1964 book, The Psychedelic Experience, psychologists Timothy Leary, Ralph Metzner and Richard Alpert wrote1 that a psychedelic drug is like “a chemical key” that “opens the mind, frees the nervous system of its ordinary patterns and structures”.
In the 1950s and 1960s, many scientists and psychiatrists were fascinated by psychedelics — both natural ones, such as psilocybin (from ‘magic mushrooms’) and mescaline (from certain cacti), and artificial ones, such as LSD, which was first synthesized in 1938. They asked how psychedelics reshape consciousness, perception and cognition; how these drugs shake people’s sense of self; and whether psychedelics could be used to treat psychiatric disorders.
Part of Nature Outlook: Psychedelic medicine
The speculative answers that this generation of investigators offered were constrained by the tools they possessed. Evidence that psychedelics interfered with the function of the neurotransmitter serotonin was rudimentary, and the techniques used for probing brain function were coarse. When that first enthusiastic wave of investigation started to fade amid a political backlash against psychedelics in the 1970s, many psychological ideas remained unlinked to neurobiological mechanisms.
Researchers working in today’s ‘psychedelics renaissance’ are wrestling with same core questions but have at their disposal much sharper tools. 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 have revealed that psychedelics cause brain regions whose activity is normally robustly coupled to become less coordinated. And many regions that are usually only loosely connected start to communicate with each other more.
Most researchers agree with this broad summary, buy dmt online but reaching a consensus on the details is proving difficult. Robin Carhart-Harris, who studies psychedelics at the University of California, San Francisco, thinks the actions of these drugs are now “pretty well” understood. But Felix Müller, a psychiatrist at the University of Basel in Switzerland, is less convinced: “Everything is quite unclear,” he says.
So far, 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 views
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-HT2A receptor. Once stimulated, these receptors make neurons more excitable, and their blanket activation by psychedelics causes widespread changes to neural networks.
There are 5-HT2A receptors throughout the brain, buy dmt powder online but they are most abundant in the cerebral cortex, particularly in areas responsible for cognition and self-awareness. Furthermore, 5-HT2A receptors are highly expressed in the visual cortex, and on the ends of axons that cortical neurons send elsewhere in the brain, such as the thalamus, where sensory information is processed. This is consistent with psychedelics causing perceptual distortions.
In 2019, neuroscientist Patrick Fisher at Copenhagen University Hospital used PET imaging to show that, after a person took a relatively high dose of psilocybin, its psychoactive metabolite psilocin occupied 72% of the brain’s 5-HT2A receptors2. He also found that a trip’s subjective intensity correlated strongly with how many of these receptors were occupied.
Researchers now want to use imaging to help establish how psychedelics change the way the brain processes information. In the 1990s, dmt carts for sale PET imaging showed that psilocybin increased brain metabolism in the frontal cortex, but also in the visual cortex. Scientists are now mainly addressing this question using a form of imaging known as resting-state fMRI. “If you want to have a general overview of what happens in the brain,” says Katrin Preller, a neuroscientist at the University of Zurich in Switzerland, “resting-state fMRI is the best way to do that.”
Most fMRI involves researchers observing which brain areas are active when people are actively doing something, such as viewing emotionally loaded images or performing a memory task. With resting-state fMRI, the brain’s fluctuating blood flow is recorded when a person lies quietly absorbed in their thoughts for tens of minutes at a time.
Researchers then divide the brain scan into regions and use statistical methods to look for correlations in blood flow between two or more regions. buy 4 aco dmt online When correlations are found, the assumption is that these brain regions are communicating and are engaged in the same cognitive processes — they are said to be functionally connected.
Studies of functional connectivity have shown that the brain contains various discrete networks. Most scientists think 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, activity is seen across a collection of areas called the default mode network (DMN).
These networks and their connections might be called, in Leary and colleagues’ words1, the brain’s “ordinary patterns and structures”. The question is whether psychedelics free a person from them.
Integration and disintegration
So far, according to a review3 published this year, roughly 300 volunteers have taken a dose of various psychedelics — most commonly psilocybin or LSD — across 17 investigations using resting-state fMRI. Every study found that the drug changed the brain’s connectivity patterns. In many, buy dmt crystals online the researchers tried to identify specific connectional changes that correlated well with the self-reported intensity of the trip, or with some particular aspect of it, such as a sense of ego dissolution.
Together, these studies indicate that psychedelics lead to “more connections between networks, and less connectivity within networks,” says Manesh Girn, a PhD student who studies psychedelics at McGill University in Montreal, Canada. In other words, brain areas that usually have strong functional connections — and that operate in a network that has a fairly circumscribed function — become less connected, suggesting that the drugs disrupt those networks’ normal outputs. And brain areas whose activity is normally only weakly correlated become more connected. buy bufotenine online Most findings are consistent with the brain’s sensory areas having more influence on overall brain activity after psychedelics were taken.
Robin Carhart-Harris discusses how psilocybin can be used to treat depression.Credit: Thomas Angus, Imperial College London
Researchers are now using these neuroimaging data to develop descriptive theories of how psychedelics alter the way brains process information. In 2014, Carhart-Harris introduced the idea that psychedelics make the brain more entropic4. Adapting from physics this fundamental metric — which quantifies how unpredictable or complex a system is — he proposed that psychedelics make the brain less ordered.
Carhart-Harris has since published multiple papers looking at brain signals, acquired through fMRI, electroencephalography (EEG) and other methods, and used mathematical analyses to study their complexity. “Signal complexity is reliably increased with psychedelics,” he says, “and it tracks the intensity of the subjective experience very closely.”
Another idea that Carhart-Harris’s paper on the entropic brain considered was that psychedelics dissolve a person’s sense of self by weakening connections within the DMN — an idea that gained traction far beyond the research community.
Both buy 5 bromo dmt online hypotheses have been influential, but they have their critics. Preller, for example, is sceptical 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 too nonspecific. Fisher is troubled by how many different methods have been used to assess it. “You’ve got eight different papers talking about entropy,” he says, “and nobody has any idea whether they’re communicating the same message.”
Preller’s concerns lie with how entropy measurements can be related to specific neural mechanisms. “We really do not understand what they tell us about the biology.”
In 2019, Carhart-Harris folded the idea of the entropic brain into a grander theory of psychedelics’ actions, termed the REBUS model and the anarchic brain5 (where REBUS stands for ‘relaxed beliefs under psychedelics’). The model builds on a previous 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, then tests whether incoming sensory data confirm these 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 supports the model. He found that LSD and psilocybin compress the usual hierarchy of connectivity between sensory and association networks6. “These sensory areas — and their bare, concrete processing of the external world — become less separate from the processes conceivably related to our abstract thinking and beliefs,” Girn says. “It doesn’t fully validate the REBUS model, but it’s consistent.”
For Preller, such inconclusive results are a problem. “It’s difficult to really test the REBUS model because the predictions are somewhat unspecific,” she says. Her work instead centres on a model developed by Franz Vollenweider, a neuroscientist at the University of Zurich who introduced her to psychedelics research. “It is more a model rooted in brain anatomy and brain function,” Preller says. From research Vollenweider began in the 1990s in humans and animal models, he proposed the thalamic gating model buy ayahuasca tea online.
The thalamus is a brain area that processes and filters sensory information en route to the cortex. This filtering, or gating, is regulated by the cortex through axons that express the 5-HT2A receptor. Psychedelics seem to interfere with the thalamus’s filtering operation, resulting in more sensory signals reaching the cortex. This is proposed to be central to the psychological effects of psychedelics. “Using fMRI, we looked at functional and effective connectivity to test what happens in the brain,” Preller says, and the thalamic gating model “aligned very well with what we saw.”
Preller acknowledges that the gating model and REBUS both focus on sensory data gaining greater influence over global brain function — and accepts 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 fMRI findings suggest a central role for the claustrum7, a small subcortical region rich in 5-HT2A receptors. Like the thalamus, the claustrum exists in a loop with the cortex.
What next?
Resting-state fMRI studies have often come to contradictory conclusions, making it difficult to know which theory best explains the effects of psychedelics. This uncertainty led Fisher to coordinate a systematic review3 that was concerned about the small sample sizes of these studies. It also highlighted many methodological differences, including the drug dose used, how scanning data were processed, and what methods of data analysis were used. “For many of those decision points,” Fisher says, “there’s not a clear-cut right or wrong answer.” But he thinks a more standardized approach would increase the reliability of the data buy dmt carts online
His 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 could be difficult. “If you’re keeping people’s eyes closed, they’re going to fall asleep in the placebo condition,” says Doss. “Then you’re comparing that to a condition in which people are wide awake, because you can’t fall asleep on psychedelics.”