• Psychedelic Medicine

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Psychedelic drugs reshape cells to "repair" neurons in our brains

by Peter Hess | June 13, 2018

Psychedelics could show the way to a new generation of medicine.

LSD, DMT, and psilocybin have shaken off a lot of their stigma and reputation as party drugs in the past few years, as scientists begin to investigate their significant healing potential for people with mental illness. Similarly, the drug ketamine, best known as a rave drug, has also shown promise in rapidly treating medication-resistant depression, and like psychedelics, its effects persist after treatment has ended.

New research shows that the way psychedelics repair the brain is very similar to ketamine’s action, which could pave the way for a future class of fast-acting drugs to treat conditions like depression, post-traumatic stress disorder, and substance use disorders. In a paper published Tuesday in the journal Cell Reports, a team of researchers showed evidence that psychedelic drugs can induce structural changes in nerve cells — a trait called neuroplasticity — that could, in turn, help repair brain dysfunction in people with mood and anxiety disorders.

“Psychedelics are some of the most powerful compounds known to impact brain function so I was very interested to know what their mechanisms of action are,” David Olson, Ph.D., an assistant professor of biochemistry and molecular medicine at UC Davis and the corresponding author on the study, tells Inverse. This paper adds to the on growing body of psychedelic neuroscience research by showing some of the changes induced by psychedelics.

Through experiments conducted on cultured rat neurons, as well as the actual brains of fruit flies and rats, Olson and his colleagues found that LSD, DMT, and DOI (2,5-dimethoxy-4-iodoamphetamine, a potent psychedelic amphetamine) increased the number of dendrites (branches) in nerve cells, increased the density of dendritic spines (protrusions on dendrites that help the neurons receive input from other cells), and increased number of synapses (functional connections between neurons). Altogether, these findings suggest that psychedelics induce structural changes to the brain, which Olson says can help treat mental illness.

“The structure of neurons affects their function, and in the case of a lot of neuropsychiatric diseases, particularly mood and anxiety disorders, these are characterized by an atrophy of neurons in the prefrontal cortex, a key brain region that regulates emotion, fear, and reward,” says Olson. “So if we can find compounds that promote growth of those neurons we might be able to repair the circuits are damaged in those diseases.”

Since prefrontal cortex helps control other areas of the brain involved in fear, anxiety, and reward, says Olson, it’s a critical region for the treatment of depression, PTSD, and substance use disorders.

But Olson and his co-authors aren’t just interested in using psychedelics to treat patients. They hope to use psychedelic compounds as tools to dig down into the biochemical signaling pathways that lead to the neuroplasticity observed in this study. By identifying the specific ways in which psychedelics act on the nervous system, Olson and his colleagues hope that they can develop a new generation of drugs that will replicate — or improve upon — the rapid, long-lasting healing effects of ketamine and psychedelics, but without the potential for abuse or challenging experiences.

“That’s the ultimate goal: to use psychedelics as inspiration for better medicine,” Olson says.

Of course, this is just one snapshot of the neuronal changes induced by psychedelics, so further research will be necessary to find out long-term effects on brain function.

“Plasticity is not universally a good thing. We were hoping to induce plasticity in prefrontal cortex, which can be potentially useful for treating mood and anxiety disorders, but promoting plasticity in other parts of the brain, like the amygdala can induce anxiety,” says Olson. “It’s very unclear what the risks are right now.”

https://www.inverse.com/article/53416-exercise-effects-on-circadian-rhythms
 
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How psychedelics help neurons grow

by Alli Feduccia | psychedelic.support | Jun 13 2018

A common question about the recent wave of psychedelic research is, “how do these substances work in the brain to produce a rapid reduction of symptoms and long-lasting improvements for a variety of mental health disorders?” Is it possible there is a common mechanism in the brain underlying the therapeutic effects of all psychedelics?

New findings published by Ly et al. in the prominent scientific journal Cell Reports are the first to show that classic psychedelics (DMT, LSD, psilocin), amphetamine analogs (MDMA, DOI), and ibogaine all converge at one target (mTor) in the brain to promote neuroplasticity. This is a notable finding because depression and stress-related disorders, e.g. PTSD, can cause a loss of synaptic connectivity – the major way that neurons and supporting cells communicate. The researchers showed that when rodent cortical neurons were put into a dish with each of the before mentioned substances, the number and complexity of dendritic branches and arbors greatly increased, meaning the neurons were changing their structure to make new connections. You can think of a tree being sprinkled with natural fertilizer that causes bolting of new branches and leaves to support optimal functioning of the entire system. Reversal of synaptic loss is also observed with ketamine and antidepressant drugs, and thought to the primary way that they reduce depression symptoms.

The research group at the University of California went on to show that the neuronal growth-enhancing properties of these substances occurred within a rodent brain, and not just in cell cultures. DMT infused into the prefrontal cortex of rats, a brain region that exhibits a lose in neurons in patients with neuropsychiatric illnesses, induced growth of dendritic spines comparable to ketamine. The elegant set of well-controlled experiments demonstrate that these drugs in fact do converge on a specific signaling pathway (BDNF – TrkB – mTOR) known to be involved in structural plasticity, and the effects are conserved across rodents and fruit flies. As previously documented, the substances increase brain derived neurotropic factor (BDNF) either through the serotonin system or by enhancing glutamate levels, and now this new evidence points to how the brain is structurally and functionally modified to produce fast-acting antidepressant effects.

Neuroplasticity, and the sprouting of new dendritic spines, is the basis for new learning.

Substances that can promote acquisition of new behaviors and ways of thinking are beneficial for treating mental health disorders, and may alleviate repetitive negative loops of thoughts, excessive rumination, and enable positive behavioral change. These experiments demonstrate neuroadaptations stimulated by many different psychedelics that follow a timeframe similar to the rapid onset of therapeutic effects with lasting gains even after the drug has left the body. The authors coined a new term to describe these related compounds, which could become in vogue if these underlying mechanisms prove correct in humans. “To classify the growing number of compounds capable of rapidly promoting induced plasticity, we introduce the term “psychoplastogen,” from the Greek roots psych- (mind), -plast (molded), and -gen (producing)”.

As exciting as these findings are, we must be cautious when extrapolating results from rodents and flies to humans. Little research has been done in humans with psychedelics and neuroimaging techniques. More is known about ketamine, which has been shown to reverse functional connectivity impairments in patients with major depressive disorder.

Could the same be true for the other psychedelics? The study published in Cell Reports also doesn’t address the added component of therapy that is used in human trials of psychedelic-assisted therapy. However, if neural networks are primed for change or new learning, then self-directed or therapist-directed processing of emotional memories could possibly guide the neuronal adaptations into a direction that supports positive behavioral change. The durable outcomes after MDMA-assisted psychotherapy, for example, suggests that brain circuits have been modified in some way.

This rigorous, well-designed study is particularly notable in present because many scientists and physicians are still skeptical about the large effects of psychedelics shown in recent clinical trials. By understanding neurobiological mechanisms, belief of the therapeutic potential of these substances will likely rapidly propagate amongst scientific communities, as seen with ketamine and cannabis. The expanding body of knowledge on mechanisms for therapeutic response will help fine-tune treatments and possibly aid in the discovery of new drugs for use in psychiatric medicine.

 
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Thomas Varley, Neuroscientist

Do psychedelics trigger neurogenesis? Here's what we know.

by Thomas Varley | Psymposia | 31 Jan 2017

Neurogenesis (the process by which the brain grows new neurons) has become something of a scientific buzzword recently, both in and out of psychedelic circles. It’s not hard to find supplements claiming that, through some pharmaceutical wizardry, you can harness the “power of neurogenesis.” Many psychedelic blogs have gotten very excited by the prospect that drugs like psilocybin might cause neurogenesis, hoping to generate momentum for the psychedelics-as-real-medicines cause.

After all, who could be against neurogenesis? Growing new brain cells does sound like the first step on the path to super powers, or at the very least, seriously enhancing abilities that we already have. But what is neurogenesis? Do psychedelics really cause it? If they do, what doors might that open up?

The vast, vast majority of neurogenesis happens before we are born: you come into this world with most of the neurons you’ll ever have, and over the course of your life they slowly die off. It has long been thought that the number of neurons you’d ever have is fixed at birth, but now we know that’s not quite true: adult neurogensis has been found to happen in a few select brain regions.

Even though adult neurogenesis is happening in the brain, it’s not happening a whole lot, and only in some pretty particular areas. The cerebral cortex (where most of the highest-level stuff happens) isn’t even on the map here. Sadly, neurogenesis isn’t going to turn you into some kind of mega-brain: most of your nervous system will remain unaffected by drugs that trigger neurogenesis. As far as we know, if you have damage to part of your cerebral cortex, taking psychedelics is unlikely to regrow the affected areas.

So should we all pack up and go home?

Not quite―just because neurogenesis isn’t as wide-spread or powerful as popular coverage might make it seem, there’s still reason to get excited. Of the few locations for neurogenesis, what’s happening in the dentate gyrus of the hippocampus is probably the most interesting, at least to those of us interested in psychedelic neuroscience. If those words sound like some kind of Harry Potter spell to you, you’re not alone and you may find some comfort knowing that generations of students have wept their way through neuroanatomy classes working on these same terms. The hippocampus is involved with many different aspects of cognition, but, at the risk of oversimplifying things, its primary role seems to be regulating both learning and memory.

Damage to the hippocampus can result in a variety of interesting and unpleasant effects, including permanent anterograde amnesia (the inability to form new memories), and it’s one of the first places damage from Alzheimer’s Disease manifests in the brain. For reasons that remain unclear, severe cases of major depression are associated with atrophy of the hippocampus, sometimes by as much as 20 percent, which may explain why, as anyone who has suffered from severe depression knows, being depressed is more than just being down all the time. It comes with its own unique constellation of cognitive effects, including memory problems and issues with focusing and concentration. This last finding is particularly interesting when we add in the fact that the balance of evidence suggests that exposure to psychedelics can, in fact, enhance neurogenesis in this region. This has some pretty profound implications for neuroscience and medicine.

It’s actually a little-known fact that there’s been some research that suggests psychedelics can enhance the natural ability to learn new behaviors and form associations. So far, all the work has been done with animals (rabbits and rats, mostly), but the promise is there.

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A CORNAL CUTTING OF A MACAQUE BRAIN, USING A NISSL STAIN. THE HIPPOCAMPUS IS CIRCLED
AND THE DENTATE GYRUS IS LABELED

Two studies using LSD found that the psychedelic enhanced the rate at which rabbits learned a new conditioned behavior, and that higher doses resulted in faster learning. The same researchers found that MDMA, MDA, and DOM all did as well. A more recent study using psilocybin found similar results, albeit only at low doses. It’s hard to draw any strong conclusions from a handful of studies like this―it’s a long way from simple associative learning in a rabbit or rat, to a complex human behavior (like playing the piano), but it’s a start. For researchers interested in treating debilitating psychological conditions like depression using psychedelic medicines, these are enormously promising results.

Why this doesn’t get talked about more in psychedelic circles is beyond me.

So what does this have to do with the idea of neurogenesis? Neurogensis is thought to be one of the mechanisms by which this kind of learning might occur. There have been studies that suggest that, for at least some kind of learning, neurogenesis in the hippocampus may be a key part of the acquisition of new behaviors and pattern recognition. In the interest of fairness, it is worth noting that not every study has validated this theory―there’s still quite a bit of science to be done, but the groundwork has been laid. The same team that was researching the effects of psilocybin on learning in rats found signs of new neural growths in the hippocampus in the rats that had been given the low dose psychedelic treatment and learned the new behavior faster. Unfortunately, as of now, this is the only study that has found a psychedelic triggered neurogenesis AND enhanced learning behavior.

Don’t despair though, there is some circumstantial evidence that should be of interest to those banking on this theory of psychedelic neurogenesis. It has been known for quite a while that the receptor that psychedelic drugs target (the Serotonin 2A receptor) helps regulate the production of a molecule called Brain-Derived Neurotrophic Factor (BDNF, for short). Activate the receptor, and the brain secretes more BDNF. My own (unpublished) research found that that the psychedelic drug DPT (a close analogue of the more famous DMT) increased signs of BDNF in the brains of adult zebrafish, and studies using neurons in a dish and the drug DOI found similar results.

BDNF helps regulate neurogenesis and neuroplasticity: mice that have been artificially rendered unable to produce BDNF show severely distorted nervous systems, with behaviors thought to be related to psychiatric illnesses like eating disorders and OCD. Using genetic techniques to increase BDNF expression can enhance neurogenesis in certain brain regions as well. So far, no one has shown that BDNF causes increased learning capability directly, although participating in learning tasks causes a rapid increase in hippocampal BDNF expression in rats.

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My (tentative) hypothesis is that psychedelic drugs can enhance learning and memory capabilities by, at least partially, increasing the amount of BDNF (and related growth-factors) in the brain through activation of the Serotonin 2A receptor. The evidence for this idea is circumstantial right now―so far there hasn’t been a study that combines all of these different moving parts. At the very least, you would need to show that exposure to something like LSD increased how quickly an animal learned a new task, that levels of BDNF in the brain went up, and there was evidence of increased neurogenesis in the hippocampus. This is a fairly tall order, although not one that’s impossible, not by a long shot. All of the individual parts are well within the capabilities of modern science; it’s getting someone to throw time and money behind the question that’s the trick.

Interestingly, in 2016, the Beckley Foundation, working with scientists at the Sant Pau Institute for Biomedical Research in Spain announced findings that two of the key components in Ayahuasca, harmine and tetrahydroharmine stimulate the differentiation of stem cells into healthy neurons when they’re cultured in a dish. There’s still a lot of work to be done on this topic: researchers are moving ahead studying whether the same effect will be seen in living animals, and, if the findings are replicated, these findings would have big implications for the science of neurogenesis.

How these two molecules might stimulate neurogenesis is an open question: unlike drugs like psilocybin and LSD, which act directly at the 5-HT2A receptor, harmine and tetrahydroharmine act as inhibitors of the enzyme monoamine oxidase (MAO), which degrades natural neurotransmitters like serotonin and dopamine. It may be that, when MAO is inhibited, the increase in free-floating serotonin in the brain can trigger BDNF by binding to the 5-HT2A receptor, much like psilocybin would. It may also be an entirely new pathway that still needs to be discovered. For psychedelic scientists, this is the start of an exciting new world of possibilities.

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So if all of this is true, what does it mean?

One of the front-line treatments for mental illnesses like anxiety, PTSD, and OCD is cognitive behavioral therapy (CBT), which is based on the same principles that the researchers are investigating with the classical conditioning studies. Anyone who’s participated in a session of CBT knows that the premise is actually very simple, and very reminiscent of the kind of mechanisms scientists use to train rats. Imagine you have PTSD with a specific trigger that sends you into panic attacks. A CBT approach to treatment might be exposure therapy: in a safe setting, guided by a therapist, you are gently exposed to your triggers, again and again. As time goes on and nothing terrible happens, your brain learns something new; the trigger isn’t dangerous, and slowly, your original response is made extinct. Similar techniques are used for patients with OCD (who might be unable to stop doing a particular ritual because they’re afraid something terrible will happen) and anxiety disorders. CBT is also used to treat depression, and while the mechanisms are a little different, the same basic principles apply.

It’s easy to see why, if it’s true, psychedelic neurogenesis might be useful. If we could use psychedelics to bolster and enhance our own innate capacity for learning, the applications for treatments and therapies would be tremendous. Humans are fundamentally pattern-making machines. Our most impressive technologies stem from our ability to recognize and make patterns, while some of our deepest illnesses, such as drug addiction, OCD, and depression are the result of getting caught in patterns we cannot control. If the theory laid out here is correct (and it may be entirely wrong), this could be another foundational piece on which to build psychedelic therapy. Beyond knowing just that it works, this might give us a robust, scientific understanding of why and how. It also may help us design new paradigms of psychedelic treatment: currently, almost all of the big studies being done are investigating the effects of single, medium-to-high doses of something like psilocybin, but, if psychedelic neurogenesis is real, there may be just as much therapeutic power in a series of repeated lower doses, in the right context. A medical microdose. The possibilities are endless.

Of course, such simplistic solutions should always be taken with a grain of salt: if someone tells you they have an easy-to-digest answer to a problem involving the brain, they’re probably trying to sell you something (keep that quote in mind next time someone tells you that depression is just a lack of serotonin!). Simple theories can ultimately be built into far more complete, and complex pictures, and even if this isn’t the whole picture (which it almost certainly isn’t), it seems like a pretty good place to start.

https://www.psymposia.com/magazine/do-psychedelics-trigger-neurogenesis-heres-what-we-know/
 
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New study shows how psychedelic drugs repair neurons in the brain

by Alanna Ketler | Collective Evolution

In recent years, many psychedelic drugs, such as LSD, DMT, and psilocybin (magic mushrooms) have been able to shake off some of their stigma and bad reputation as scientists have discovered their promising results for the treatment of a variety of mental health disorders. Even ketamine, a common tranquilizer, often used as a party drug has been found to be able to treat cases of treatment-resistant depression, with the effects lasting long after the treatment has ended.

New research has been able to show that the way that psychedelics repair the brain is similar to how ketamine can repair the brain. This could signify the beginning of a class of fast-acting drugs to treat a wide array of mental health disorders from depression, post-traumatic stress disorder, and addiction. A paper which was recently published in the journal Cell Reports noted how a team of researchers showed evidence that psychedelic drugs can induce structural changes in nerve cells, this is also known as neuroplasticity, this could help repair brain dysfunction and aid those suffering from mood and anxiety disorders.

“Psychedelics are some of the most powerful compounds known to impact brain function so I was very interested to know what their mechanisms of action are,” David Olson, Ph.D., an assistant professor of biochemistry and molecular medicine at UC Davis and the corresponding author on the study, tells Inverse.

This paper merely adds to a large growing body of psychedelic neuroscience research by showing some of the direct changes in the brain while under the influence of psychedelic substances.

The Study

Experiments were conducted on cultured rat neurons as well as on the brains of fruit flies and rats. Olson and his colleagues were able to find that LSD, DMT, and DOI actually increased the number of dendrites (branches) in nerve cells, increased the density of dendritic spines and increased the number of synapses, which are the functional connection between neurons. These findings certainly suggest that psychedelics absolutely do induce structural changes to the brain, which is why Olson believes they are so effective at treating mental illness.

“The structure of neurons affects their function, and in the case of a lot of neuropsychiatric diseases, particularly mood and anxiety disorders, these are characterized by an atrophy of neurons in the prefrontal cortex, a key brain region that regulates emotion, fear, and reward,” says Olson. “So if we can find compounds that promote the growth of those neurons we might be able to repair the circuits are damaged in those diseases.”

The prefrontal cortex helps control the other areas of the brain that are involved in fear, anxiety, and reward. This is a critical region for the treatment of depression, PTSD and substance abuse disorders.

Olson and the co-authors of this study aren’t only interested in using psychedelics to treat patients. They want to be able to use psychedelic compounds as tools to dig deeper into the biochemical signalling pathways that lead to the neuroplasticity observed in this study. Being able to identify the specific ways in which psychedelic substances act on the nervous system, Olson and his colleagues hope to be able to develop a new generation of drugs that can emulate the same, long-lasting effects of ketamine and other psychedelic substances, but without the potential for abuse or other challenging experiences.

“That’s the ultimate goal: to use psychedelics as inspiration for better medicine,” Olson says.

https://www.collective-evolution.com...-in-the-brian/
 
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Psychedelics forge new connections between neurons

by Cici Zhang | Chemical & Engineering News

About one-third of people with depression do not find relief from their symptoms with current drugs for the disease. In recent years, psychiatrists have become interested in using low doses of the anesthetic ketamine as an antidepressant because it often works in patients who don’t respond to conventional drugs and it is fast acting—having an effect within hours instead of weeks or even months. But the drug has undesirable side effects. It can produce out-of-body feelings, hallucinations, and it has the potential for abuse. Scientists need to understand how ketamine works as an antidepressant so they can design new molecules that lack the negative aspects of the anesthetic.

Now, a study reports that other psychedelic compounds have similar effects on neurons as ketamine does: "They promote the growth of connections between neurons. The work suggests new chemical scaffolds that could mimic ketamine’s antidepressant properties," says lead author David Olson of the University of California, Davis.

Previous research had shown that ketamine can rapidly grow synapses—the connections between neurons—in brain areas that regulate emotion and mood, possibly accounting for the drug’s fast-acting therapeutic effects. In the current study, the UC Davis team found that DMT, DOI, and LSD increased the number of synaptic connections in the brains of rats and fruit flies, as well as in cultured neurons from the animals. As with ketamine, the effects were long lasting. When the researchers injected rats with DMT, they still observed synaptic changes 24 hours later, well after the animals had cleared the drug from their bodies, Olson says. The team previously had demonstrated that DMT produced antidepressant-like effects and stopped behaviors that resemble post traumatic stress disorder in rats.

In the new study, the scientists also determined that these other psychedelics promote synaptic growth through a similar signaling pathway involving the protein mTOR that ketamine does. Ronald Duman, a researcher at Yale University who studies ketamine, says "the findings are interesting and important because they could explain how these agents might treat mood disorders." While ketamine activates the mTOR pathway by blocking N-methyl-D-aspartate receptors on neurons, the psychedelic compounds do so via activating a different target, the 5-HT2A receptor, which according to Duman suggests a novel approach for treating depression.

Roland Griffiths, a neuroscientist at Johns Hopkins University School of Medicine agrees that the new study is important. “Almost nothing is known about the neural mechanisms underlying the ability of psychedelics to produce enduring change in moods, attitudes, and behavior,” he says.

But David Feifel, a professor emeritus of psychiatry at University of California, San Diego, who has used ketamine to treat patients with depression, says more work is needed before the reported mechanisms can be identified as those responsible for these drugs’ antidepressant properties. "The next step," he says, "would be to block the pathway outlined in this study and then see if that prevents the drugs from producing an antidepressant effect in animals."

https://webcache.googleusercontent.c...&ct=clnk&gl=ca
 
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Cambridge

The control interrupt model of psychedelic action

by James L. Kent | Psychedelic Information Theory

The brain is an information processing organ that uses top-down signal modulation to control the flow of bottom-up sensory input. Feedback modulation of incoming signal is an example of self-stabilizing control in a signal processing system. Using the tenets of cognition and control theory it is possible to describe a model in which hallucinogens periodically interrupt the top-down modulatory control of perception to create sensory interference patterns, multisensory frame destabilization, and altered states of consciousness.

Bottom-up perception, top-down control

What we perceive as waking consciousness is a synthesis of bottom-up sensation modified by top-down expectation and analysis. Incoming sensation is gated by the top-down focus of the subject. Inhibitory feedback subtracts background noise while excitatory feedback resolves and amplifies salient data. This configuration describes a signal filter/amplifier with an inhibitory/excitatory feedback loop to control signal focus and content discrimination. The top-down filtering and focusing of incoming sensory signal is an autonomic reflex and is perceptually seamless; the brain blocks background noise, transitions focus, and recognizes objects smoothly and without disrupting subjective frame continuity.

Constraint, control, and feedback inhibition

Feedback excitation is applied in sensory circuits to amplify salient input, but the majority of the brain’s feedback circuits are inhibitory, meaning that human consciousness is more constrained than unconstrained. In dynamical information processing systems, signal constraint and error correction is applied through negative feedback to subtract or cancel perturbation and noise entering the signal channel; this is known as control theory. In sensory networks, such as the layers of the cortex or the retina, fast inhibition is applied laterally to boost contrast discrimination in sensory detail; this is called lateral inhibition. Fast inhibition in the cortex can also be applied from the bottom-up as well as laterally, this is called the synaptic triad of fast inhibition. Inhibition can also be applied from the top-down, allowing the cortex to gate sensory input from the thalamus; this is called feedback inhibition, and it is typically tonic, meaning top-down feedback produces an inhibitory effect over many consecutive spike trains for extended periods of channeled focus. When the brain is alert and focused, this also means it is highly constrained by inhibitory feedback.

In human consciousness control is applied through negative feedback to constrain perception. When people express their fears about psychedelics, the most commonly voiced concern is the fear is losing control; this is because psychedelics subvert the constraints of sensory feedback control to allow perception and behavior to become unconstrained by tonic inhibition. Tonic inhibition is expressed from learned concepts about the self and ego, and suppresses what is considered abnormal or outside the acceptable range of consciousness. Linear consciousness is constrained and focused on real-time ego behavior; nonlinear consciousness is unconstrained and goes wherever it is driven by input state variables, or set and setting.

In order for a perceptual system to transition from a linear to a nonlinear state, negative feedback control must be subverted. If control is entirely removed then perception becomes totally unconstrained, leaving a system that is quickly overloaded with too much information. If control is placed in a state where it is partially removed or in a toggled superposition where it is alternately in control and not in control over the period of a rapid oscillation, then the constraints of linear sensory throughput will bifurcate into a nonlinear spectrum of multi-stable output with signal complexity correlating to the functional interruption of control. Common entheogenic wisdom states that you must relinquish control and submit to the experience to get the most out of psychedelics. Holding onto control causes negative experiences and amplifies anxiety; letting go of control and embracing unconstrained perception is a central psychedelic tenet. This demonstrates that psychedelics directly subvert feedback control over linear perception to promote states of unconstrained consciousness.

Control interrupt model of psychedelic action

Before the mind can start hallucinating the top-down modulatory control of consciousness must first be interrupted. Interrupting top-down control of consciousness allows the mind to destabilize into novel information processing configurations. When top-down control of waking consciousness is destabilized, neural oscillators in the brain will spontaneously organize into coherence with the most energetic local drivers. This process can be described in terms of oscillator entrainment and resonance; when the modulatory driver maintaining global oscillator coherence is interrupted, uncoupled oscillators will naturally fall into synchrony with most energetic periodic drivers in the environment. In this state the normally inflexible configurations of consciousness and perception become extensible and open to the influence of environmental feedback. This explains why psychedelics create synesthesia or cross-sensory representations of energetic sensory drivers, and why set and setting have a profound influence on the tone and content of a psychedelic experience.

When top-down modulatory control of consciousness is interrupted, the seamless nature of multisensory perception degrades and the subject begins to experience hallucinations. Early indicators of modulatory interruption would include periodic high-frequency distortion or noise in sensory networks. In tactile networks this periodic interruption may be felt as parasthesia, or phantom tingling and throbbing; in visual networks it may be perceived as phosphenes, or strobing or pulsating of light intensity, possibly fast enough to produce geometric hallucinations; in audio networks it may be perceived as tinnitus, ringing, humming, buzzing, or tones that cycle up and down in pitch. These are all descriptions of field-based hallucinations generated in response to periodic interruptions along multisensory signal pathways. The speed and intensity of the control interrupt, and thus the speed and intensity of the hallucinations, are a direct result of the hallucinogen’s pharmacodynamics and method of ingestion.

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Using an ADSR envelope we can model the intensity with which any
hallucinogen interrupts multisensory frame perception.


Control interrupt envelopes

Using control interrupts as the source of hallucinogenesis, we can model hallucinogenic frame distortion of multisensory perception the same way we model sound waves produced by synthesizers; by plotting the attack, decay, sustain, and release (ADSR envelope) of the hallucinogenic interrupt as it effects consciousness. For example, nitrous oxide (N20) inhalation alters consciousness in such a way that all perceptual frames arise and fall with a predictable “wah-wah-wah” time signature. The throbbing “wah-wha-wah” of the N20 experience is a stable standing wave formation that begins when the molecule hits the neural network and ends when it is metabolized, but for the duration of N20 action the “wah-wah-wah” completely penetrates all modes of sensory awareness with a strobe-like intensity. The periodic interrupt of N20 can be modeled as a perceptual wave ambiguity that toggles back and forth between consciousness and unconsciousness at roughly 8 to 11 frames-per-second, or @8-11hz.5 Consciousness rises at the peak of each “wah” and diminishes in the valleys in between. On sub-anesthetic doses, N20 creates a looping effect where frame content overlaps into the following frame, causing a perceptual cascade similar to fractal regression. We can thus model the interrupt envelope of N20 as having a rounded attack, fast decay, low sustain, medium release, with an interrupt frequency of @8-11hz. Any psychoactive substance with a similar interrupt envelope will produce results that feel similar to the N20 experience. (Fig. 3) For instance, Smoked Salvia divinorum (vaporized Salvinorin A&B, or Salvia) has an interrupt envelope similar to N20, except Salvia has a harder attack, a slightly longer decay, a more intense sustain, a slightly longer release, and a slightly faster interrupt frequency (@12-15hz). These slight changes in the frequency and shape of interrupt envelope cause Salvia to feel more physically intense, more hallucinatory, and more disorienting than N20, even though they share a similar throbbing or tingling sensation along the same frequency range.

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Modeling the interrupt envelope for N2O and Salvia we can see N2O
has a hard but rounded attack and decay. In contrast Salvia has a
slightly faster and more intense ADSR profile, describing a more
biting and disorienting effect on multisensory perception.


Using interrupt envelopes we can contrast smoked Salvia or inhaled N20 with vaporized DMT (N,N-dimethyltryptamine), which when smoked has similar onset and duration to both substances but very different hallucinogenic effects. Unlike the throbbing periodicity of N20, vaporized DMT produces an interrupt frequency associated with high-pitched carrier waves and high-speed frame flicker (24-30+ hz). The frequency of DMT’s interrupt is so rapid the entire body ramps up in panicked response to the new driver. The rate of DMT’s visual frame flicker is fast enough to instantly produce and sustain geometric hallucinations and fully realized animations.7 Taking these subjective effects into account we can model DMT’s interrupt envelope as having a moderate attack, long decay, medium sustain, long release, and high frequency (24-30+hz). The moderate attack means DMT’s perceptual frame interference is less of a physical throbbing than N20, but because of a higher frequency and longer frame release the rendering of DMT hallucination is more fluid, detailed, seamlessly aliased, and fades longer over a higher number of frames.

The interrupt envelopes modeled here are approximate and based on reported subjective effects, but may also give some insight into the pharmacodynamics of each substance.8 Following the logic of the Control Interrupt Model, it can be assumed that each hallucinogen has a unique interrupt envelope based on receptor affinity, receptor density, rate of metabolism, and so on, and each unique interrupt envelope creates a distinct type of interference pattern in multisensory perception. The interrupt envelope for any substance will also change if the substance is ingested orally as opposed to vaporized or injected; the speed of absorption into the bloodstream will naturally affect the intensity of ADSR values. This is why each psychedelic can produce unique sensations and hallucinations, and why each psychedelic can produce subtle variations in the speed and intensity of hallucination depending on method of ingestion.

By modeling the interrupt envelope of a psychoactive substance it is possible to accurately predict its subjective results on multisensory perception. Non-drug sources of hallucination, such as those caused by psychosis, deprivation, fever, or schizophrenia, may also have unique and quantifiable control interrupt envelopes related to erratic multisensory frame modulation.

Control interrupt and shamanism

If consciousness must have a top-down control frequency to remain stable, and psychedelics produce a periodic interruption of this control frequency, then the interaction between the perceptual control frequency and the periodic hallucinogenic interrupt can be described as a wave interference pattern in global oscillator coherence. Subjects on moderate doses of psychedelics can override the hallucinogenic interrupt and retain global coherence via energetic physical movement or repetitive behaviors like chanting or dancing. Conversely, if the subject lies motionless then the interrupt fully destabilizes consciousness into a depersonalized dreamlike trance. These reports indicate that even though psychedelics destabilize top-down modulatory control of consciousness, feedback control and system stability can be entrained back into coherence via external periodic drivers, including rhythmic motor activity, drumming, singing, chanting, rocking back and forth, dancing, and so on. It is no accident that these are also the basic formal elements of shamanic ritual.

In physical terms, the shaman is the primary energetic driver, or resonator, in the production of a standing hallucinogenic interference pattern in the consciousness of the subject. By prescribing a psychedelic substance the shaman introduces the control frequency interrupt, and through ritual craft and showmanship the shaman applies new periodic drivers to influence the tone and texture of the resulting interference pattern. By mixing the hallucinogenic control interrupt with a custom periodic driver the shaman can fully entrain consciousness and manipulate all facets of the subject’s mind with high precision. This description of the precision wave-based manipulation of neural oscillators within the psychedelic state can be called applied psychedelic science, physical shamanism, or Shamanism in the Age of Reason.

 
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Study uncovers psilocybin-induced changes in brain connectivity*

by Eric Dolan | PsyPost | Jan 20 2020

New research published in Biological Psychology sheds light on the neurophysiological underpinnings of the psychedelic experience. The study provides new details about how psilocybin — the active component in “magic” mushrooms — changes the communication patterns between regions of the brain.

Psychedelics are currently being investigated for the treatment of psychiatric disorders. However, it is still unclear how they change brain activity and connectivity to induce their unique effects,” explained study author Katrin Preller of the University of Zurich and Yale University.

We therefore conducted a study to investigate the time-dependent effects of psilocybin on brain connectivity and the association between changes in brain connectivity and receptor pharmacology.”

In the study, 23 healthy human participants underwent MRI brain scanning 20 minutes, 40 minutes, and 70 minutes after receiving either psilocybin or a placebo. The researchers observed reduced connectivity between brain areas involved in planning and decision-making but increased connectivity between areas involved in sensation and movement while the participants were under the influence of the psychedelic drug.

Preller and her colleagues conducted a similar study on LSD, and obtained “virtually identical” results.

Psilocybin – similar to LSD – induced a pattern of brain connectivity that is characterized by increased synchronization of sensory brain regions and decreased connectivity of associative networks,” she told PsyPost.

Increased sensory processing but altered integration of this sensory information may therefore underlie the psychedelic state and explain the symptoms induced by psilocybin. Furthermore, this pattern of changes in connectivity was closely associated with spatial expression of the serotonin 2A and 1A receptors – pinpointing these receptors as critical for the effects of psilocybin.”

Another drug called ketanserin, a serotonin 2A antagonist, prevented the effects of both psilocybin and LSD, suggesting that changes in brain connectivity caused by these psychedelic drugs are linked to stimulation of the serotonin 2A receptor.

In this study we investigated different time points from administration to subjective peak effects. Future studies need to investigate how psilocybin impacts brain connectivity during a later phase and post-acutely,” Preller noted.

*From the article here :
 
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Ketamine found to reverse neural changes that underlie depression-related behaviors*

Neuroscience News | April 11, 2019

The formation of prefrontal cortex dendritic spine formation sustains the remission of depressive related symptoms and behaviors following ketamine treatment by restoring lost spines.

Researchers have identified ketamine-induced brain-related changes that are responsible for maintaining the remission of behaviors related to depression in mice — findings that may help researchers develop interventions that promote lasting remission of depression in humans.

Major depression is one of the most common mental disorders in the United States, with approximately 17.3 million adults experienced a major depressive episode in 2017. However, many of the neural changes underlying the transitions between active depression, remission, and depression re-occurrence remain unknown. Ketamine, a fast-acting antidepressant which relieves depressive symptoms in hours instead of weeks or longer, provides an opportunity for researchers to investigate the short- and long-term biological changes underlying these transitions.

“Ketamine is a potentially transformative treatment for depression, but one of the major challenges associated with this drug is sustaining recovery after the initial treatment,” said study author Conor Liston, M.D., Ph.D., of Weill Cornell Medicine, New York City.

To understand mechanisms underlying the transition from active depression to remission in humans, the researchers examined behaviors related to depression in mice. Researchers took high-resolution images of dendritic spines in the prefrontal cortex of mice before and after they experienced a stressor. Dendritic spines are protrusions in the part of neurons that receive communication input from other neurons. The researchers found that mice displaying behaviors related to depression had increased elimination of, and decreased the formation of, dendritic spines in their prefrontal cortex compared with mice not exposed to a stressor. This finding replicates prior studies linking the emergence of behaviors related to depression in mice with dendritic spine loss.

In addition to the effects on dendritic spines, stress reduced the functional connectivity and simultaneous activity of neurons in the prefrontal cortex of mice. This reduction in connectivity and activity was associated with behaviors related to depression in response to stressors. Liston’s group then found that ketamine treatment rapidly restored functional connectivity and ensemble activity of neurons and eliminated behaviors related to depression. Twenty-four hours after receiving a single dose of ketamine, mice exposed to stress showed a reversal of behaviors related to depression and an increase in dendritic spine formation when compared to stressed mice that had not received ketamine. These new dendritic spines were functional, creating working connections with other neurons.

The researchers found that while behavioral changes and changes in neural activity in mice happened quickly (three hours after ketamine treatment), dendritic spine formation happened more slowly (12-24 after hours after ketamine treatment). While further research is needed, the authors suggest these findings might indicate that dendritic spine regrowth may be a consequence of ketamine-induced rescue of prefrontal cortex circuit activity.

Although dendritic spines were not found to underly the fast-acting effects of ketamine on behaviors related to depression in mice, they were found to play an important role in maintaining the remission of those behaviors. Using a new technology developed by Haruo Kasai, Ph.D., and Haruhiko Bito, Ph.D., collaborators at the University of Tokyo, the researchers found that selectively deleting these newly formed dendritic spines led to the re-emergence of behaviors related to depression.

“Ketamine is the first new anti-depressant medication with a novel mechanism of action since the 1980s. Its ability to rapidly decrease suicidal thoughts is already a fundamental breakthrough,” said Janine Simmons, M.D., Ph.D., chief of the NIMH Social and Affective Neuroscience Program. “Additional insights into ketamine’s longer-term effects on brain circuits could guide future advances in the management of mood disorders.”

*From the article here :
 
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The Neuroscience of Psychedelics*

by Louis Wain and Anil Ananthaswamy | INVERSE

“Everything became imbued with a sense of vitality and life and vividness. If I picked up a pebble from the beach, it would move. It would glisten and gleam and sparkle and be absolutely captivating,” says neuroscientist Anil Seth.

“Somebody looking at me would see me staring at a stone for hours.”

Or what seemed like hours to Seth. A researcher at the UK’s University of Sussex, he studies how the brain helps us perceive the world within and without, and is intrigued by what psychedelics such as LSD can tell us about how the brain creates these perceptions.

So a few years ago, he decided to try some, in controlled doses and with trusted people by his side. He had a notebook to keep track of his experiences. “I didn’t write very much in the notebook,” he says, laughing.

Instead, while on LSD, he reveled in a sense of well-being and marveled at the “fluidity of time and space.” He found himself staring at clouds and seeing them change into faces of people he was thinking of. If his attention drifted, the clouds morphed into animals.

Seth went on to try ayahuasca, a hallucinogenic brew made from a shrub and a vine native to South America and often used in shamanistic rituals there. This time, he had a more emotional trip that dredged up powerful memories.

Both experiences strengthened Seth’s conviction that psychedelics have great potential for teaching us about the inner workings of the brain that give rise to our perceptions.

He’s not alone. Armed with fMRI scans, EEG recordings, computational models of the brain, and reports from volunteers tripping on psychedelics, a small but growing number of neuroscientists are trying to take advantage of these drugs and the hallucinations they induce to better understand how the brain produces perceptions.

The connections are still blurry, but the studies are beginning to provide new support for a provocative, more-than-a-century-old hypothesis: that one of the fundamental functions of the brain — and the root of everything we perceive — is to make best guesses about the causes of information impinging on our senses at any given moment.

Proponents of this idea have argued that these powers of prediction enable the brain to find meaning amid noisy and ambiguous sensory information, a crucial function that helps us make sense of and navigate the world around us.

When these predictions go haywire, as they seem to under psychedelics, the perceptual aberrations provide neuroscientists with a way to probe the workings of the brain — and potentially understand what goes wrong in neuropsychological conditions, such as psychosis, that cause altered perceptions of reality.

The predictive brain

The idea that the brain is, in essence, a prediction machine traces its modern roots to the 19th century German physicist and physician Hermann von Helmholtz. He noted that our brains have to make inferences about the possible causes of the signals we receive via our senses.

He pointed in particular to our ability to perceive different things given the same sensory information (a good example of this would be the famous optical illusion that can appear either as the silhouette of two people facing each other or as the contours of a vase).

Given that the sensory input isn’t changing, Helmholtz argued that what we perceive must be based on the brain’s prediction of what’s there, based on prior knowledge.

Over the past century, these ideas have continued to intrigue philosophers, neuroscientists, computer scientists, and others. The modern version of the theory is called predictive processing.

In this view of perception, the brain is not a passive organ that simply collates information from the senses. Rather, it’s an active coconspirator. It’s constantly predicting the causes of incoming information, whether from the world outside or from within the body.

In this view of perception, “the brain is actively … creating hypotheses that are the best explanation for the sensory samples that it’s receiving,” says computational neuroscientist Karl Friston of University College London. These predictions lead to perceptions, which can remain unconscious or enter conscious awareness.

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The brain is constantly trying to predict the causes of sensory inputs, and these predictions lead to perceptions. When the sensory inputs are ambiguous, the predictions can keep changing. In this case, your brain may predict that you’re seeing a vase — or two people facing each other. -JOHN SMITHSON

In a landmark 1999 paper that established predictive processing as a leading hypothesis of brain function, two computer scientists, Rajesh Rao and Dana Ballard (now at the University of Washington in Seattle and the University of Texas at Austin, respectively) developed a detailed model of predictive processing — specifically, addressing regions of the brain involved in recognizing objects and faces.

Those regions comprise levels of a pathway that begins in the retina, moves on to the lateral geniculate nucleus of the thalamus, and then to higher and higher levels of the cerebral cortex, named V1, V2, V4, IT, and onward.

In Rao and Ballard’s model, each brain area that constitutes a level in such a hierarchy makes predictions about the activity of the level below:​
  • V2, for example, predicts the neural activity it expects of V1 and sends a signal down to V1 indicating this prediction​
  • Any discrepancy between the prediction and the actual activity in V1 generates an error signal that moves up from V1 to V2, so that V2 can update its expectations of V1​
  • So predictions flow down, from higher to lower layers, and errors move up, from lower to higher layers​
In this way of thinking, the lowest layer — the one closest to the retina — makes predictions about the incoming sensory information, and the highest layers — IT and above — hypothesize about more complex features like objects and faces. Such predictions, continually updated as we move around, are what we perceive.

In the years since Rao and Ballard’s paper, neuroscientists have begun to find experimental evidence that supports such computational models.

For example, the theory predicts that sensory stimuli that are expected or unsurprising should generate less neural activity in lower levels of the hierarchy (because they generate fewer error signals). And fMRI scans of neural activity in the lower layers of the visual cortex in people looking at computer-generated images bear this out.

But predictive processing can go wrong, posit behavioral and clinical neuroscientist Paul Fletcher and his student Juliet Griffin of the University of Cambridge in the UK — and when that happens, we may perceive things that aren’t real, be they aberrations of sight, sound, or other senses.

It’s an idea that piques the interest of those who study conditions such as schizophrenia, which is often accompanied by psychosis.

“If predictive processing helps us to understand how the mind connects to external reality, I think it follows that it is a useful way of understanding situations in which the mind seems disconnected from reality,” says Fletcher.

Indeed, Fletcher notes, such disconnection is essentially the definition of psychosis. (Griffin and Fletcher explored the potential connection between predictive processing and psychosis in the 2017 Annual Review of Clinical Psychology.)

Prior expectations

An important aspect of predictive processing is that each hypothesis generated by a level in the hierarchy is associated with a notion of confidence in the hypothesis, which in turn is based on prior expectations.

The higher the confidence, the more a given level ignores error signals from the level below. The lower the confidence, the more a given level listens to upward-moving error signals.

Could psychedelics be altering our perception of reality by messing with this process? Friston and Robin Carhart-Harris, a psychologist and neuroscientist at Imperial College London, think so.

In 2019, they put forward a model called REBUS, for “relaxed beliefs under psychedelics.” According to their model, psychedelics reduce the brain’s reliance on prior beliefs about the world. “We feel them with less confidence,” says Carhart-Harris. “They are less reliable under psychedelics.”

If that’s what psychedelics do, one result could be an increase in cognitive flexibility. Conversely, blocking the receptors in the brain that are activated by psychedelics might do the opposite — make beliefs more rigid.

Neuroscientists often think of the brain as organized into hierarchical levels. The concept of predictive processing holds that each level makes predictions about the activity of the level below. These predictions flow down the hierarchy, and lower levels generate an error signal that indicates the difference between the predicted and actual sensory inputs. These error signals flow upward, and higher levels use them to refine their predictions. Predictions at the highest level help to create perceptions.

Some evidence for this comes from experiments with rats in which researchers gave the animals a drug that blocks the main type of receptor on the surface of neurons that responds to LSD and other classic psychedelic drugs.

These receptors, called 5-HT2A serotonin receptors, are densely distributed in the regions of the cortex responsible for learning and cognition. Blocking 5-HT2A receptors, it turns out, makes rats cognitively inflexible: They are no longer able to spontaneously change from one behavior to another in order to get a reward. In the context of predictive processing, the finding suggests that the 5-HT2A-blocker made the rats’ brains more tightly constrained by prior beliefs about the world.

Conversely, when psychedelics bind to 5-HT2A receptors, they seem to make the brain less reliant on prior expectations and more reliant on actual sensory information. This could account for the vivid perceptual experiences they cause.

According to the predictive processing model, a brain on psychedelics gives more weight to information entering the lower layers, which deal with concrete visual features — say, the shape and color of a flower.

Constraints imposed by abstract beliefs and expectations about the flower are relaxed. “All of these higher-level constructs have been dissolved,” says Friston. “It can be a very pleasurable experience.”

If psychedelics mess with prior beliefs, that might also explain why they cause one to hallucinate a reality that’s untethered from real-world expectations.

Take, for example, Seth’s experience of seeing clouds morphing into familiar faces. According to Friston, the brain’s visual system has strong prior beliefs — for instance, that clouds are up in the sky. Another prior belief would be that there are no faces up there.

Normally, this would make it nearly impossible to perceive, say, Lucy in the sky (with or without diamonds). But as psychedelics take hold, higher levels of the predictive processing hierarchy begin to make otherwise untenable predictions about the world outside. These predictions become perceptions. We start hallucinating.

Of course, psychedelic hallucinations are not only visual. They can involve all types of altered perceptions. In 2017, for example, neuropsychologist Katrin Preller of the University Hospital for Psychiatry Zurich in Switzerland and colleagues found that people listening to music that they normally considered meaningless or neutral felt heightened emotions and attributed an increased sense of meaningfulness to the music while on LSD.

Friston argues that these altered perceptions extend even to our sense of self, which in the predictive processing framework is based on the brain’s internal models of all aspects of our own being.

Psychedelics would, again, loosen the hold of these internal models. “You now lose a precise sense of self,” says Friston. Indeed, a survey by Carhart-Harris and colleagues suggests that a breakdown of the boundaries of the self could be one explanation for why some people on psychedelics report mystical feelings of a sense of unity with their surroundings.

Disrupted connections

If psychedelics do act on the brain to change predictive processing, it’s not clear how they do it. But in recent studies, researchers have found ways to approach these questions.

One way to gauge changes occurring in brains on psychedelics is to measure something called Lempel-Ziv complexity, a tally of the number of distinct patterns that are present in, say, recordings of brain activity over the course of milliseconds using a method called magnetoencephalography (MEG). “The higher the Lempel-Ziv complexity, the more disordered over time your signal is,” says Seth.

To determine the degree of disorder of human brains on psychedelics, Seth’s team, in collaboration with Carhart-Harris, looked at MEG data collected by researchers at the Cardiff University Brain Research Imaging Centre in Wales.

The volunteers were given either LSD or psilocybin, the hallucinogenic ingredient in “magic mushrooms.” On psychedelics, their brain activity was more disordered than it was during normal waking consciousness, according to an analysis of the MEG signals that was published in 2017.

Seth says that while the increase in disordered brain signals does not definitively explain people’s psychedelic experiences, it’s suggestive. “There’s a lot of mind-wandering and vagueness going on,” says Seth. “The experience is getting more disordered and the brain dynamics are getting more disordered.”

But he says there’s more work to do to establish a clear connection between the two.

More recently, Seth, Carhart-Harris, and colleagues took another look at the brain on psychedelics, using a statistical metric called Granger causality. This is an indication of information flow between different regions of the brain, or what neuroscientists call functional connectivity.

For example, if activity in brain region A predicts activity in brain region B better than the past activity of B itself does, the Granger causality metric suggests that region A has a strong functional connection to region B and drives its activity. Again, using MEG recordings from volunteers on psychedelics, the team found that psychedelics decreased the brain’s overall functional connectivity.

One possible interpretation of these Granger and Lempel-Ziv findings is that the loss of functional organization and increase in disorder is disrupting predictive processing, says Seth. Verifying that would involve building computational models that show exactly how measures of Granger causality or Lempel-Ziv complexity change when predictive processing breaks down, and then testing to see if that’s what happens in the brains of people on psychedelics.

In the meantime, evidence that psychedelics mess with functional connectivity is mounting. In a randomized, double-blind study published in 2018, Preller and colleagues gave 24 healthy people either a placebo, LSD, or LSD along with a 5-HT2A blocker that impeded the drug’s effects. The subjects were then scanned inside an MRI machine, allowing researchers to measure activity in different brain regions and assess their connectedness.

Those people on LSD alone showed widespread changes: Their brains showed an increased connectivity between lower-order brain regions responsible for processing sensory input, but decreased connectivity between brain regions that are involved in the conceptual interpretation of sensory inputs.

Preller thinks this might explain the heightened sensory experiences caused by LSD. Indeed, the team also found corroborating evidence, using data from the Allen Human Brain Atlas, a detailed map of gene activity: Areas of the brain that produce the 5-HT2A receptor overlapped with the regions of altered connectivity, suggesting that LSD affects these brain regions the most.

Then Preller and colleagues did a more targeted study, using fMRI data to look for changes in functional connectivity between the thalamus and the cortex. The thalamus sits in the center of the brain and processes information from the senses before sending relevant signals up to the cortex.

But information also flows in the other direction. In the predictive processing model, signals going down from the cortex to the thalamus would represent predictions, and signals flowing up to the cortex would represent errors. Researchers have long hypothesized that psychedelics may cause the thalamus to function less effectively, says Preller.

This may be happening on LSD: Her study, published in 2019, showed that the flow of information from the thalamus up to certain cortical areas increased in people on LSD and the flow going in the opposite direction decreased.

Altered brain waves

Additional hints of how psychedelics could interfere with predictive processing have come from an entirely different way of looking at brain function. In 2019, Carhart-Harris got intrigued by a paper he read about potential brain signatures of predictive coding (which is how researchers refer to the way predictive processing may be realized in the brain). He saw a way to test the hypothesis that psychedelics are messing with the brain’s prior beliefs.

The paper by computational neuroscientist Andrea Alamia of Centre de Recherche Cerveau et Cognition, CNRS, in Toulouse, France, and a colleague, involved a simplified model of predictive coding.

Each level represents a population of neurons — in, say, the LGN and V1 layers of the visual system. The input to the model is a random sequence of numbers, where each number represents the intensity of a light signal.

The model has two key parameters:​
  • One is the time it takes for a prediction or error to travel from level to level​
  • The other is the time it takes for a population of neurons to return to their baseline activity after the input has waned​
The team found that as the model tries to predict the intensity of the input and each level tries to update itself based on the error signal it gets when its predictions are wrong, the model produces waves of signals with a frequency of about 10 hertz, which researchers call alpha waves. These waves ripple up and down through the levels of the model.

In the presence of inputs, the alpha waves travel up from the lower to the higher levels in the hierarchy. In the absence of inputs, the waves travel down. “These are all computational results,” says Alamia.

So, to check their model against actual data, the team looked at EEG recordings of electrical brain activity previously collected in volunteers who had been asked to either gauge the intensity of light signals (presence of input) or close their eyes (absence of input).

The team found traveling alpha waves that move up in the presence of inputs and down when the eyes were closed — exactly as in their model of predictive coding.

Carhart-Harris found the results exciting. “I wrote the French team, and I said, ‘Look, we’ve got psychedelic data, and I have a very clear hypothesis for you,’” he says.

The hypothesis was simple. Start with EEG recordings of people with their eyes closed, without psychedelics. The alpha waves should be traveling down. Then, inject them with a psychedelic. They’ll start having visual hallucinations and the alpha waves should switch direction.

That’s because the psychedelic, according to the REBUS model, should cause information to flow from lower to higher levels, even with eyes closed and in the absence of real sensory input. “There’s just a drug on board that makes you see all these crazy visions,” says Carhart-Harris.

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.
*From the article here :
 
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Neuroscientists uncover how magic mushrooms 'rebalance' the brain

by Emma Betwel | INVERSE | 17 April 2020

New models of the brain are bringing us one step closer to psilocybin-based medicine.

There's no reset button on your brain. But the more scientists learn about magic mushrooms, the more we know that they're about as close to a reset button as we can get.

Psilocybin — the hallucinogenic chemical in certain mushrooms — can reshape cells in the brain, and increasingly, shows potential for treating addiction or depression. Now, using new brain models, scientists are getting a better idea of how it all happens.

Scientists constructed a model of the human brain on psilocybin, illuminating how magic mushrooms allow our brain to access untapped potential. This model shows that, under the influence of psilocybin, the brain creates a feedback loop of neuron activity and neurotransmitter release (the chemical messengers that neurons use to communicate).

This finding was published Monday in Proceedings of the National Academy of Sciences.

That dynamic creates a one-two punch that could allow the brain to tap into otherwise inaccessible states, including the "destabilization" of individual brain networks and the creation of a more "global" network across the brain.

"That destabilization is one hypothesis that scientists have used to explain why magic mushrooms can create psychedelic experiences. But it could also underscore why it has potential as treatment for disorders like depression," explains Morten Kringlebach, the study's first author and a senior research fellow at the University of Oxford.

"Using this model will be crucial for truly understanding how psilocybin can rebalance neuropsychiatric disorders such as treatment-resistant depression and addiction," Kringlebach tells Inverse.

How do magic mushrooms affect the brain?

This study is based on brain images taken from nine participants who were either injected with psilocybin or a placebo. The scientists used those images to create a "whole-brain connectome" which provides a picture of all the physical neurons in the brain, as well as the activity of the neurotransmitters that are being shuttled back and forth.

"During your average day in the human brain, neurons are constantly firing and neurotransmitters are traveling well-trodden paths through the brain, somewhat like cars on a freeway. On magic mushrooms, those networks are 'destabilized,'" Kringlebach explains.

Previous research has shown that new networks appear in tandem. It's as if those cars on the freeway were given free rein to stray from the highway and take back roads towards new destinations.

Scientists are beginning to understand how this works. For instance, psilocybin (as well as psychedelics like DMT) mimic serotonin, a neurotransmitter related to feelings of happiness or love. Kringelbach suggests that these mushrooms do more than simply affect serotonin flow in the brain.

"We wanted to investigate the role of neurotransmission in dynamically changing the activity in whole-brain networks — and how this changes neurotransmitter release in return," he explains.

The models showed that the brain is able to tap into new networks by coupling the effects of neuron activity and the release of neurotransmitters, like serotonin. The release of neurotransmitters and the firing of neurons work together – and when you have one without the other, the whole system falls apart.

When the scientists adjusted their model to have these processes work independently, they found that they weren't able to recreate the same "destabilization" of networks that you would usually see when someone is on magic mushrooms. The same breakdown in their pattern happened when they replaced the typical serotonin receptors utilized by magic mushrooms (5-HT2A receptors) with other types of serotonin receptors.

Taken together, this suggests that both the receptors themselves, and the patterns of neuron activity are necessary for psilocybin to really work.

The future of magic mushrooms

"Knowing that both receptors and neuron activity are needed, could help better understand how to use the drug as a therapy. In turn, these models can help us visualize an enduring mystery within the human brain," says Kringlebach.

"It has long been a puzzle how the brain's fixed anatomical connectome can give rise to so many radically different brain states; from normal wakefulness to deep sleep and altered psychedelic states," he says.

We only have a fixed amount of hardware in the brain, yet we're running highly complicated software that produces dreams, consciousness, and — if someone is on a drug like DMT — "breakthrough experiences."

If the magic mushrooms demonstrate anything, it's that the brain can learn to use its fixed hardware in very different ways, if the right ingredients are involved. The trick is figuring out what tools the brain needs to run different types of software on that hardware.

In the future, the team hopes that their model could help us learn how we can run different types of software in our brains, and in doing so, help treat conditions like depression.

"This new model will give us the much needed, causal tools for potentially designing new interventions to alleviate human suffering in neuropsychiatric disorders," Kringlebach says.

 
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Neuronal and neurotransmitter systems dynamic coupling explains the effects of psilocybin

UPF Barcelona | Neuroscience News | 16 April 2020

Computational simulations reveal the integration of both neuronal and neurotransmitter systems at a whole-brain level is vital to fully understand the effects of psilocybin on brain activity.

Interest in research into the effects of psilocybin has increased significantly in recent years due to its promising therapeutic effects in neuropsychiatric disorders such as depression, anxiety and addiction.

It is widely accepted that the brain’s powerful ability to adapt its behaviour flexibly is largely due to the neurotransmitter system. Psilocybin is the substance responsible for the psychoactive effect caused by nearly 200 species of fungi. This substance has a particular affinity for serotonin receptors found primarily in the brain, but also in other parts of the body such as the stomach. Upon consumption, psilocybin selectively changes the function of serotonin receptors, thus generating an altered state of consciousness characterized by the dissolution of the ego, changes in the quality and attribution of thoughts, impaired visual and sensory perception, and greater awareness of repressed memories.

An international team of researchers has developed a computational biophysical model of the entire brain that integrates real data about its anatomical structural connectivity, the functional dynamics of neurons and a map which shows the concentration of serotonin receptors in various brain regions.

This international research, published on 13 April in the journal Proceedings of the National Academy of Sciences, was led by Gustavo Deco, ICREA research professor and director of the Center for Brain and Cognition at the Department of Information and Communication Technologies (DTIC) at UPF, with the participation of Josephine Cruzat, a member of his team, Morten Kringelbach, a neuroscientist at the University of Oxford (UK), and other scientists from research centres in Germany, Denmark, the US, Portugal and the UK.

This work has shown that the new dynamic model of the whole brain is capable of addressing one of the major challenges in neuroscience: to explain the paradoxical flexibility of brain function despite having a fixed anatomical structure

Study of psilocybin’s mechanisms of action in humans

This theoretical and experimental study modelled the interaction between neuronal and neurotransmitter systems throughout the brain to explain how psilocybin affects brain activity. To study the drug’s mechanisms of action, Morten Kringelbach, Josephine Cruzat and Gustavo Deco analysed data from functional magnetic resonance imaging (fMRI) in 16 healthy subjects. In the experiment, participants were given small doses of psilocybin intravenously or saline solution (placebo effect) while in the scanner, to measure their brain function. The experimental part of the study was carried out at Imperial College London under the direction of Robin Carthart-Harris, co-author of the study.

The functional data acquired under the conditions of placebo and psilocybin were then combined with data from diffusion magnetic resonance imaging (dMRI) capturing brain structure by describing the anatomical connections between the different brain regions; and with data on the density of serotonin receptors estimated by positron emission tomography (PET).

The integration of neuronal and neurotransmitter systems at whole-brain level is important to fully explain the effects of psilocybin on brain activity.

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Interest in research into the effects of psilocybin has increased significantly in recent years due to its
promising therapeutic effects in neuropsychiatric disorders such as depression, anxiety and addiction.


As explained by by Deco and Cruzat, co-authors of the work, “the computational simulations performed in this study revealed that the integration of neuronal and neurotransmitter systems at the whole-brain level is important to fully explain the effects of psilocybin on brain activity, specifically through the stimulation of serotonin receptors 5 -HT2A, involved in psychoactive modulation.”

Overall, the remarkable flexibility of human brain function depends crucially on the bidirectional dynamic participation of neuronal and neurotransmission systems. According to the authors, this new approach provides a better and deeper understanding of the effects of psilocybin on the brain and may lead to the development of new treatments for neuropsychiatric diseases such as depression, anxiety and addiction.

 
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Brain morphology may help explain differing psilocybin experiences

by Barb Bauer | Psychedelic Science Review | 17 April 2020

Understanding brain morphology differences may prove essential for creating effective psychedelic drug formulations.

Scientists have some understanding of the receptor mechanisms involved in the psychedelic experience. The current theory is that the binding of an agonist or partial agonist to the serotonin 5-HT2A receptor elicits a psychedelic effect via signaling pathways. Some experts hypothesize that the 5-HT2C receptor may also be involved.

The general effects of psilocybin (actually, its active metabolite psilocin) are documented, and they cover a range of emotional, cognitive, and perceptual changes. Set and setting (aka context) is known to play a critical role in the subjective effects of psychedelics. Despite this understanding, there is still considerable unexplained variability in the individual experience from ingesting psilocybin.

Now, research is showing that the morphology of certain parts of the brain may be a predictor of the magnitude of the psychedelic experience from psilocybin.

In February 2020, a research team, including Franz Vollenweider, published a randomized, double-blind, placebo-controlled study in Biomedicines. In this study, the authors built on previous research supporting the hypothesis that “Individual brain morphology measures can be used to predict various pharmacological challenges and behavior.” Specifically, the team measured the thickness of areas in the cingulate cortex of people’s brains and compared it to their subjective ratings from ingesting psilocybin.

Study design

The study recruited 55 people from local universities (33 men and 22 women) with a mean age of 25 years. They were randomly divided into three groups. The low and high dose groups received 0.16 mg/kg and 0.215 mg/kg psilocybin, respectively, in two sessions at least ten days apart. The control group received maltose as a placebo.

One hour after each psilocybin dose, the participants underwent a magnetic resonance imaging (MRI) of their brain. The areas of the brain the researchers measured the thickness of were in the right hemisphere. They were the rostral anterior cingulate, caudal anterior cingulate, and the posterior cingulate (Figure 1). The authors stated that they chose these areas because they have a high expression of 5-HT2A receptors compared to other regions of the limbic system. For the control area, they chose a part of the right hemisphere called the post central, where there is low expression of 5-HT2A receptors.

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Figure 1: Schematic showing the brain regions used in the analyses. (A) Right hemisphere cingulate cortex region used in primary analyses. Dark purple = rostral anterior cingulate; medium purple = caudal anterior cingulate; light purple = posterior cingulate. (B) Red = right hemisphere post central region used as the control region analysis.

The Five-Dimensional Altered State of Consciousness (5D-ASC) questionnaire was administered to each participant six hours after each dose. Of the 11 sub-scales measured in the 5D-ASC, the researchers focused on the data from four of them: experience of unity, spiritual experience, blissful state, and insightfulness.

Results

The data revealed that there were no significant differences in the four 5D-ASC sub-scale ratings based on dose. The authors theorized this might be because the doses reflected the high and low ends of the medium dose range for psilocybin based on the literature. They recognized two doses being a strength of the study, but also a limitation because they were not sufficiently different to detect any dose effects. Therefore, the authors then looked at all the data together, regardless of the dose.

Analyzing the data in this way, the researchers observed that the thickness of the right hemisphere rostral anterior cingulate predicted ratings for the four 5D-ASC sub-scales (i.e., the thicker the region, the higher the person’s subjective experience ratings). Conversely, the thickness of the caudal and posterior cingulate areas was not predictive of the sub-scale ratings. The authors noted that these results correlate with previous studies in the literature.

The authors stated, “This is the first study to evaluate brain morphology as a predictor of the emotional subjective experience of psilocybin in healthy controls.” They hypothesized from the data that,

"...morphology metrics such as cortical thickness may reflect differences in brain substrates that mediate drug effects. Investigating the relationship between psilocybin modulation and cingulate structure could provide insight into mechanisms underlying psilocybin’s profound emotional effects and provides a theoretical framework for brain-based predictors of 5HT2A psychedelic modulation."

 
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Psychedelics help patients restore cognitive abilities

by Tim Hinchliffe | The Sociable | 19 May 2020

With over 25 years in the “brain preservation business,” Dr. Roger McIntyre is one of the world’s most recognized experts in mood disorders.

He is also the CEO of Champignon Brands — the only clinic in Canada to perform psilocybin dosing, with Health Canada approval.

“We now think depression is a disconnection syndrome no different than your PC and your motherboard. There’s something disconnected.”

Dr. McIntyre tells The Sociable that mood disorders are the great enemy of the state because they debase human capital by reducing cognitive function.

“The reduction in human GDP is coming from cognition, and that’s what took me towards very novel treatments like ketamine and psychedelics because we really need to find treatments that can try to improve people’s cognitive abilities and reduce their cognitive disabilities,” said Dr. McIntyre.

When we think of lowered cognitive capabilities, we may assume that there’s a lowering of IQ, but Dr. McIntyre assures that IQ does not go down with mood disorders like depression, but rather, circuit connectivity is disrupted in the brain, and that psychedelics can provide that proverbial Crtl, Alt, Delete.

“We now think depression is a disconnection syndrome no different than your PC and your motherboard. There’s something disconnected,” he says.

But it’s not just depression that Dr. McIntyre describes as a “disconnection syndrome.” He says that most mood disorders stem from the same source problem — a disconnect in the brain circuitry — something wrong with the motherboard, what he calls “CNN, or Circuits, Nodes, and Networks.”

“We now think that if you have autism, schizophrenia, anorexia nervosa, depression, bipolar, dementia, Alzheimer’s — the convergent view now is that although those are not the same disease states, they share something in common — there’s something wrong with the motherboard,” he said.

“Just imagine your motherboard on your PC. You go to turn it on one morning and it’s not turning on, or it’s really slow. That, metaphorically, is what depression does to your brain. There’s something wrong with the circuit connectivity.”

This is where metaphor and reality blend. Thanks to technology in the lab, specialists like Dr. McIntyre can actually see which parts of the brain are lighting up and which ones are disconnected in real-time, just like peeking inside a computer.

“And it’s not just a metaphor,” he says. “When we do experiments in the lab using MRI and looking at the brain, we are able to tease out the networks in the brain. It’s really incredible, you can actually see the networks live in a real living, breathing brain.”

“It’s really incredible, you can actually see the networks live in a real living, breathing brain.”


If the brain is like a slow or poorly-operating computer, then psychedelics work like fast-acting defrag tools and antivirus software that help reset and rewire the motherboard brain, so it can think clearly again.

And thinking clearly can have a profoundly positive impact on mood.

In successful treatment cases, the differences can be like night and day.

As one of Dr. McIntyre’s patient’s described it, “My brain was like a Commodore 64 while I was depressed; now it’s like a Pentium, zapped-up, turbo-charged brain again.”

When someone has a mood disorder, it doesn’t mean that they are any less smart, it just means that their circuit connectivity is off and needs to be reset.

“The cool thing about ketamine and psychedelics,” according to Dr. McIntyre, "is the brain resets very quickly, like after one or two doses."

And it’s not just a reset of a certain area of the brain; it’s a reset of the entire brain — the full effects of which have yet to be entirely understood.

A person can take an antidepressant, which can reset their mood, but it won’t reset their cognitive functionality.

“While antidepressants of the conventional variety take longer to work, they are more localized. They don’t help certain circuits like cognition, for example,” said Dr. McIntyre.

Psychedelic treatments, on the other hand, can reset the mood, the cognitive functionality, and a whole lot more.

If mood disorders can be classified as disconnection syndromes, then psychedelics look to be the software that can reconnect the circuitry.

 
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Psychedelics Promote Structural and Functional Neural Plasticity

Calvin Ly, Alexandra C. Greb, Lindsay P. Cameron, Jonathan M. Wong, Eden V. Barragan, Paige C. Wilson, Kyle F. Burbach, Sina Soltanzadeh Zarandi, Alexander Sood, Michael R. Paddy, Whitney C. Duim, Megan Y. Dennis, A. Kimberley McAllister, Kassandra M. Ori-McKenney, John A. Gray, David E. Olson

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.

Discussion

Classical serotonergic psychedelics are known to cause changes in mood and brain function that persist long after the acute effects of the drugs have subsided. Moreover, several psychedelics elevate glutamate levels in the cortex and increase gene expression in vivo of the neurotrophin BDNF as well as immediate-early genes associated with plasticity. This indirect evidence has led to the reasonable hypothesis that psychedelics promote structural and functional neural plasticity, although this assumption had never been rigorously tested. The data presented here provide direct evidence for this hypothesis, demonstrating that psychedelics cause both structural and functional changes in cortical neurons.

Prior to this study, two reports suggested that psychedelics might be able to produce changes in neuronal structure. Jones et al. (2009) demonstrated that DOI was capable of transiently increasing the size of dendritic spines on cortical neurons, but no change in spine density was observed. The second study showed that DOI promoted neurite extension in a cell line of neuronal lineage. Both of these reports utilized DOI, a psychedelic of the amphetamine class. Here we demonstrate that the ability to change neuronal structure is not a unique property of amphetamines like DOI because psychedelics from the ergoline, tryptamine, and iboga classes of compounds also promote structural plasticity. Additionally, D-amphetamine does not increase the complexity of cortical dendritic arbors in culture, and therefore, these morphological changes cannot be simply attributed to an increase in monoamine neurotransmission.

The identification of psychoplastogens belonging to distinct chemical families is an important aspect of this work because it suggests that ketamine is not unique in its ability to promote structural and functional plasticity. In addition to ketamine, the prototypical psychoplastogen, only a relatively small number of plasticity-promoting small molecules have been identified previously. We observe that hallucinogens from four distinct structural classes (i.e., tryptamine, amphetamine, ergoline, and iboga) are also potent psychoplastogens, providing additional lead scaffolds for medicinal chemistry efforts aimed at identifying neurotherapeutics. Furthermore, our cellular assays revealed that several of these compounds were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine. In fact, the plasticity-promoting properties of psychedelics and entactogens rivaled that of BDNF. The extreme potency of LSD in particular might be due to slow off kinetics, as recently proposed following the disclosure of the LSD-bound 5-HT2B crystal structure.

Importantly, the psychoplastogenic effects of psychedelics in cortical cultures were also observed in vivo using both vertebrate and invertebrate models, demonstrating that they act through an evolutionarily conserved mechanism. Furthermore, the concentrations of psychedelics utilized in our in vitro cell culture assays were consistent with those reached in the brain following systemic administration of therapeutic doses in rodents. This suggests that neuritogenesis, spinogenesis, and/or synaptogenesis assays performed using cortical cultures might have value for identifying psychoplastogens and fast-acting antidepressants. It should be noted that our structural plasticity studies performed in vitro utilized neurons exposed to psychedelics for extended periods of time. Because brain exposure to these compounds is often of short duration due to rapid metabolism, it will be interesting to assess the kinetics of psychedelic-induced plasticity.

A key question in the field of psychedelic medicine has been whether or not psychedelics promote changes in the density of dendritic spines. Using super-resolution SIM, we clearly demonstrate that psychedelics do, in fact, increase the density of dendritic spines on cortical neurons, an effect that is not restricted to a particular structural class of compounds. Using DMT, we verified that cortical neuron spine density increases in vivo and that these changes in structural plasticity are accompanied by functional effects such as increased amplitude and frequency of spontaneous EPSCs. We specifically designed these experiments to mimic previous studies of ketamine so that we might directly compare these two compounds, and, to a first approximation, they appear to be remarkably similar. Not only do they both increase spine density and neuronal excitability in the cortex, they seem to have similar behavioral effects. We have shown previously that, like ketamine, DMT promotes fear extinction learning and has antidepressant effects in the forced swim test. These results, coupled with the fact that ayahuasca, a DMT-containing concoction, has potent antidepressant effects in humans, suggest that classical psychedelics and ketamine might share a related therapeutic mechanism.

Although the molecular targets of ketamine and psychedelics are different (NMDA and 5-HT2A receptors, respectively), they appear to cause similar downstream effects on structural plasticity by activating mTOR. This finding is significant because ketamine is known to be addictive whereas many classical psychedelics are not. The exact mechanisms by which these compounds stimulate mTOR is still not entirely understood, but our data suggest that, at least for classical psychedelics, TrkB and 5-HT2A receptors are involved. Although most classical psychedelics are not considered to be addictive, there are still significant safety concerns with their use in medicine because they cause profound perceptual disturbances and still have the potential to be abused. Therefore, the identification of non-psychedelic analogs capable of promoting plasticity in the PFC could facilitate a paradigm shift in our approach to treating neuropsychiatric diseases. Moreover, such compounds could be critical to resolving the long-standing debate in the field concerning whether the subjective effects of psychedelics are necessary for their therapeutic effects. Although our group is actively investigating the psychoplastogenic properties of non-psychedelic analogs, others have reported the therapeutic potential of safer structural and functional analogs of ketamine.

Our data demonstrate that classical psychedelics from several distinct chemical classes are capable of robustly promoting the growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, our studies highlight the similarities between the effects of ketamine and those of classical serotonergic psychedelics, supporting the hypothesis that the clinical antidepressant and anxiolytic effects of these molecules might result from their ability to promote structural and functional plasticity in prefrontal cortical neurons. We have demonstrated that the plasticity-promoting properties of psychedelics require TrkB, mTOR, and 5-HT2A signaling, suggesting that these key signaling hubs may serve as potential targets for the development of psychoplastogens, fast-acting antidepressants, and anxiolytics. Taken together, our results suggest that psychedelics may be used as lead structures to identify next-generation neurotherapeutics with improved efficacy and safety profiles.

*See the entire study here :
 
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The effects of psychedelics on the brain's 'consciousness conductor'

by Rich Haridy | Vew Atlas | 14 Jun 2020

New research reveals psilocybin seems to reduce neural activity in a brain region called the claustrum.

A new Johns Hopkins study, looking at how psilocybin influences a mysterious brain region called the claustrum, is just one of several compelling recent articles shining a light on how our brains generate our experience of consciousness.

In 2004, Francis Crick, one of the 20th century’s greatest scientific minds, died of colon cancer. Crick was best known for describing the structure of DNA in the 1950s with collaborator James Watson, but over the last couple of decades of his life his research focused on perhaps the biggest scientific question of them all: how does our brain generate what we consider to be consciousness?

The last paper Crick ever penned homed in on a small and still relatively mysterious brain region called the claustrum. Co-authored with Christof Koch, Crick was reportedly still editing the manuscript in hospital the day he died. Subsequently published in 2005, the paper presented a novel hypothesis - the claustrum may be key to our experience of consciousness, unifying and co-ordinating disparate brain areas to help generate our singular experience.

“The claustrum is a thin, irregular, sheet-like neuronal structure hidden beneath the inner surface of the neocortex in the general region of the insula,” wrote Crick and Koch in the landmark paper. “Its function is enigmatic. Its anatomy is quite remarkable in that it receives input from almost all regions of cortex and projects back to almost all regions of cortex.”

The extraordinarily unique way the claustrum connects different brain regions fascinated Crick. While some researchers had previously suggested the claustrum could potentially be the brain’s epicenter of consciousness, Crick and Koch presented a different analogy to describe the role of this mysterious brain region.

“We think that a more appropriate analogy for the claustrum is that of a conductor coordinating a group of players in the orchestra, the various cortical regions,” the pair wrote. “Without the conductor, the players can still play but they fall increasingly out of synchrony with each other. The result is a cacophony of sounds.”

It's like a highway

A new study, published in the journal Current Biology, is describing in unprecedented detail how the claustrum communicates with other brain regions. The project, an international collaboration between researchers in Sweden and Singapore, somewhat backs up Crick’s "consciousness conductor" hypothesis, revealing the claustrum is less like a singular hub for cortical inputs and more like a collection of specialized synaptic pathways connecting specific cortical regions.

“We found that the synaptic connectivity between the cortex and claustrum is in fact organized into functional connectivity modules, much like the European route E4 highway or the underground system,” says Gilad Silberberg, lead author on the study, from the Karolinska Institutet.

Another recent and even more focused study zoomed in on the claustrum’s role in coordinating slow-wave brain activity. A team from Japan’s RIKEN Center for Brain Science generated a transgenic mouse model in which they could artificially activate neurons in the claustrum through optogenetic light stimulation.

... it is so exciting that we are getting closer to linking specific brain connections and actions with the ultimate puzzle of consciousness. - Yoshihiro Yoshihara

The research discovered slow-wave activity across a number of brain regions increased in tandem with neural firing in the claustrum. Slow-wave brain activity is most often linked to a key period of sleep associated with memory consolidation and synaptic homeostasis.

“We think the claustrum plays a pivotal role in triggering the down states during slow-wave activity, through its widespread inputs to many cortical areas,” says Yoshihiro Yoshihara, team leader on the new RIKEN research. “The claustrum is a coordinator of global slow-wave activity, and it is so exciting that we are getting closer to linking specific brain connections and actions with the ultimate puzzle of consciousness.”

So, if increased claustrum activity seems to orchestrate a kind of synchronized slowing down of brain activity across a number of different cortical regions, what happens when claustrum activity is suppressed?

The claustrum under the influence of psychedelics

One hypothesis has suggested dysfunctional claustrum activity could play a role in the subjective effects of psychedelic drugs. One of the fundamental neurophysiological characteristics of a psychedelic experience is widespread dysregulation of cortical activity. Brain networks that don’t normally communicate will suddenly spark up connections under the influence of psilocybin or LSD. So a team from Johns Hopkins University set out to investigate exactly how psilocybin influences claustrum activity.

Due to the claustrum’s location in the brain its activity has traditionally been quite difficult to study in humans. However, a recently developed functional magnetic resonance imaging (fMRI) technique has afforded researchers a new and detailed way to measure claustrum activity. The Johns Hopkins study recruited 15 subjects to measure claustrum activity after either a placebo or a dose of psilocybin.

The study found psilocybin reduced claustrum neural activity between 15 and 30 percent. The overall reductions in claustrum activity also directly correlated with the subjective psychedelic effects of the drug.

More specifically, psilocybin seemed to significantly alter how the claustrum communicated with a number of brain regions fundamentally involved in attentional tasks and sensory processing. For example, under the influence of psilocybin, functional connectivity between the right claustrum and the auditory and default mode networks significantly decreased, while right claustrum connectivity with the fronto-parietal task control network increased.

“Our findings move us one step closer to understanding mechanisms underlying how psilocybin works in the brain,” says Frederick Barrett, one of the authors on the new study. “This will hopefully enable us to better understand why it’s an effective therapy for certain psychiatric disorders, which might help us tailor therapies to help people more.”

As Barrett suggests, this new insight into the effect psilocybin has on claustrum activity may shine a light on how this psychedelic drug generates its beneficial therapeutic effects. Psilocybin in particular has been found to be significantly useful in treating major depression and substance abuse disorders. The Johns Hopkins scientists hypothesize psilocybin’s action on the claustrum may play a key role in both the subjective effects of this psychedelic drug, and its beneficial therapeutic outcomes.

Further research is certainly necessary to verify this hypothesis, and the next step for the Johns Hopkins team will be to use this new claustrum imaging technique to investigate the brain region in subjects with a variety of psychiatric disorders. Fifteen years on from Francis Crick’s passing his final work is still inspiring new research. The new wave of psychedelic science, in tandem with novel neuroimaging techniques, brings us closer and closer to understanding how our brains create consciousness.

The new study was published in the journal Neuroimage.

Source: Johns Hopkins Medicine

 
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How to change your ability to change

by Abigail Calder, MSc | Psychedelic Science Review | 7 Dec 2020

The monoamine hypothesis of depression leaves many patients without effective help. It’s time for a paradigm shift, and psychedelics may be leading the way.

Until recently, the story of depression went something like this: Due to a complex interplay of factors, including stress and genetics and other imperfectly understood things, the brain lacks enough monoamine neurotransmitters – particularly serotonin. Treatment, therefore, means replacing the missing neurotransmitters with specialized drugs that increase the brain’s serotonin levels.

That works persistently well – for about 12% of patients. And for some doubly unlucky people, antidepressants may be even worse than a placebo. Sometimes, scientific stories are missing a few chapters.​

Disorders of rigidity

Rather than a simple serotonin deficiency, depression can also be seen as a disorder of rigidity.

It traps people in negative thinking. Depressed patients tend to interpret ambiguous information negatively, and because life is often ambiguous, this has disastrous results. Patients develop a decidedly negative self-image, pessimistic expectations for the future, and a sense of hopelessness that is difficult to shake.

Although it is difficult to directly relate mental states with biological events, scientists see a potential connection between cognitive rigidity and a kind of biological rigidity, specifically reductions in neuroplasticity. Neuroplasticity, roughly speaking, is the brain’s ability to form new connections and adapt to the constant changes in the world around it. Depressed brains suffer from a pronounced lack of neuroplasticity, particularly in regions relevant for mood regulation and self image. Neurons atrophy and send out fewer dendritic spines to connect with their neighbors, and the brain produces fewer growth factors that stimulate neuroplasticity. This sometimes begins with chronic stress, although other triggers certainly exist. The resulting lack of biological flexibility may be one reason depressive disorders are so hard to break free from.​

How to change your ability to change

If impaired neuroplasticity is an important part of depression’s pathophysiology, it stands to reason that stimulating plasticity could reduce symptoms. Antidepressants seem to stimulate neuroplasticity to some extent, but they must be taken chronically, cause objectionable side effects, and take two weeks to work at all. Thus, some scientists are looking to other plasticity-stimulating molecules: those that work well, work quickly, and work after being taken only once. Since 2018, they have a name: the psychoplastogens.

Many psychoplastogens are psychedelics, and indeed, most psychedelics stimulate neuroplasticity. Ketamine, which also rapidly reduces depressive symptoms, is also in this class, as are several molecules with no psychoactive effects at all.8 Psychoplastogens are all characterized by their ability to cross into the brain and rapidly stimulate neuroplasticity, and those that are the most useful do this only in particular circuits and brain regions. Most importantly, changes in neuroplasticity seem to stick around: Ketamine’s antidepressant effects last for 1-2 weeks, while in clinical trials with psilocybin, patients seem to need treatment anywhere between once a month and just once, period.

This theory also has an essential second chapter: psychoplastogens are best combined with psychotherapy. There is still no magic pill that can cure depression. Instead, these drugs may open up a “window of plasticity” during which the brain – the patient, really – is more responsive to therapy. Enhanced neuroplasticity alone is not automatically good; it has to happen in the right neural circuits and, ideally, be paired with therapeutically helpful experiences. Therapy and other supportive activities give the newly plastic brain a positive direction in which to change.​

Theory means “a work in progress”

The neuroplasticity theory may explain a lot, but all theories are works in progress. So far, scientists have found evidence that psychedelics stimulate several important elements of neuroplasticity in rodents, and they have reason to conclude that this could also happen in humans. But just as depression isn’t reducible to “too little serotonin,” it is also not simply caused by “too little plasticity.” Psychiatry is moving away from such reductionist views.

It also isn’t clear yet whether impaired neuroplasticity in certain neural circuits directly causes depression, or whether stimulating plasticity is truly a reason that psychedelic therapy works in humans, as opposed to other aspects of the subjective psychedelic experience and its underlying biology. And human research still suffers from “technical difficulties”: measuring neuroplasticity in the lab involves slicing brains up or putting them through what is essentially a professional blender. Although scientists can measure proxies of neuroplasticity without turning anyone’s brain into a smoothie, the resulting data can be hard to interpret. This means that we have little direct evidence of psychedelics stimulating neuroplasticity in humans.

But although the unknown can disappoint, it is also promising. Psychedelics also seem to treat anxiety, addictions, and PTSD in addition to depression, and researchers are also interested in obsessive-compulsive disorder, eating disorders, and even personality disorders. Could these also be “disorders of rigidity?” Psychologists have long wondered if a general pathology underlies seemingly distinct mental health problems, especially because many of these disorders tend to occur together. While one could rightly criticize this idea as too simple, pursuing it in research may nevertheless bring science closer to the more complex truth. Perhaps impaired neuroplasticity isn’t the cause of all of these disorders, but it may be standing in the way when people try to get better.​

The take-home message

A new story of depression goes like this: at some point in a patient’s life, the brain’s natural ability to adapt begins to atrophy. This loss of neuroplasticity may happen in circuits that regulate mood, and once they are impaired, the brain ends up “stuck” in a depressive disorder. Restoring neuroplasticity could reopen the highway to health.

As with many theories, this one is attractive because it explains an initially mysterious observation. Ketamine, psychedelics, and other psychoplastogens seem to be astonishingly effective at treating depression, and likely other disorders as well. The neuroplasticity theory of drugs and depression elegantly explains why. If it stands the test of time and science, this theory could lead to more breakthroughs in research on mental health and beyond.

 
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The Neuroanatomy of a Psychedelic Trip: The Basics

by Zeus Tipado | Healing Maps | 20 Oct 2021

There’s a good chance that anyone reading this article has genuine interest in psychedelics. And there’s an even greater chances you’ve already done psychedelics. And now you want to know what was happening in your brain that made you feel connected with some ethereal entity. Or at the very least stared at the leaves of a tree for an enormous amount of time. So let’s talk about the neuroanatomy of a psychedelic trip. Specifically what happens in your brain when you take a psychedelic. You’ll learn a lot, I promise.

The subjective experience of psychedelics (the trip) is something we can all connect with. With modern psychedelic neuroscience we’re learning that they play an integral part in the treatment of anxiety, stress-related behavior, depression. Along with a mix of other cognitive states that have alluded modern pharmaceuticals and contemporary therapy. The effects of psychedelics have been a catalyst for a surge of much-needed research within the field of neuroscience.

The role of neuroreceptors

If you’re familiar with the term ‘serotonin receptors’ then you’re already on your way. The majority of psychedelics you see today are serotonergic agonists. Which means they bind to serotonin receptors, or 5-HT2A receptors in your brain. This applies to the usual cast of characters: psilocybin, LSD, DMT, also known as tryptamines. MDMA (and the 2C family) falls under the category of phenethylamines, but has relatively the same neurological effects of tryptamines.

These two types of psychedelics mostly bind to 5-HT2A receptors. And to a lesser extent, other 5-HT receptors like 5-HT2B and 5-HT2C. These 5-HT2 receptors are generally responsible for a person’s well-being, stress, and anxiety levels. And they can also be implicated in degenerative diseases like Alzheimer’s, and neurodivergence like aspergers.

So how do they work with psychedelics?

We also know when a person takes psychedelics, these receptors (which are mostly located in pyramidal neurons in the brain) tend to strengthen and rebuild almost instantly when these serotonergic agonists, or psychedelics, are introduced. This is called spinogenesis (the strengthening of spine dendrites in axons of these neurons) along with neurogenesis (the repair and restoration of these neurons).

This is important because things like daily stress, worrying, and rumination make these neurons atrophy. And when they atrophy, they lose their structural integrity. This is a direct link to larger problems like depression and PTSD. We’ll cover exactly how this happens later in the article.

There are instances in which a serotonergic agonist like LSD can be taken in such large amounts that it also becomes a dopaminergic agonist or that it binds to dopamine receptors. Usually, this behavior does not occur much with psychedelics.

However, it’s a common neurological process that happens when a person takes drugs with addiction capabilities — like cocaine, meth, nicotine, and alcohol. In fact, the brain activates dopamine when a person generally does anything addictive, like compulsive eating. Or even when listening to music.

Not all psychedelics are serotonergic agonists

The psychedelic ketamine operates on an entirely different neurochemical process. While most psychedelics embrace receptors, ketamine does the opposite and works as an antagonist, or a receptor blocker. Ketamine isn’t concerned with serotonin, but, instead focuses on the NMDA receptor — working as an NMDA antagonist compared with most other psychedelics, which are serotonergic agonists.

This is an important distinction, considering that ketamine is the only federally legal psychedelic

You can actually get a shot of Spravato, a ketamine inhaler, most likely at a ketamine clinic near you.

All of these receptors (5-HT2, DA, and NMDA) are part of the monoamine system, a group in which nearly all psychedelics fall under. Receptors are only a small part of a much larger neuroanatomical process that goes down when you take psychedelics. Now, let’s get familiar with these areas of the brain that are modulated by psychedelics — or die trying. Actually, it’s not that severe. Just learn these parts of the brain.

Diving into the brain

The brain has an enormous amount of parts like gyruses, ducts, sulcuses, fissures, fibres, lobes, decussations. All of which you don’t need to know for this article. While I think neuroanatomy is a blast, there’s absolutely no way you share the same enthusiasm. So we’re going to focus on very specific areas of the brain that are known to be activated (or deactivated) during psychedelics.

When it comes to monoamine receptors in the brain, your thalamus, amygdala, medial prefrontal cortex (mPFC) and the cingulate cortex is where a lot of the action happens. There are other parts of the brain that have these receptors like the hippocampus, but for an introduction to the neuroanatomy of a trip we won’t be discussing these areas. The length of this article would be bonkers if we explored every brain area affected by psychedelics. Eventually, we’ll address them all. But, for now, we’ll start with the basics.

The thalamus

Located deep within your brain is the thalamus. Which is undisputedly one of the most active parts of your brain when on psychedelics.

Your thalamus is an interesting area located next to your lateral ventricle. And it’s responsible for processing all stimuli that’s internal (signals within your body) and external (signals received outside your body, like from your environment). Since every stimulus goes through your thalamus, it serves as a ‘reality filter.’ It processes everything you see and feel. It then feeds it back to your brain to create a ‘perception.’

How do psychedelics affect your thalamus?

Psychedelics have been shown to disrupt mechanisms of the thalamus. This can lead to what’s known as ‘sensory gating’ in the brain. Imagine you’re watching Netflix. And in the middle of a movie, the audio becomes delayed by a half-second while the video remains the same. This is fractionally insignificant when comparing it to the length of the movie. But this small sensory gating, or desynchronization will have a major effect on the movie itself. Now imagine reality as a movie and you can easily see how sensory gating will have a peculiar effect on perception.

Another interesting attribute of psychedelics is that it decreases your cerebral blood flow (CBF) in your thalamus. You shouldn’t be that alarmed, the blood flow in your brain is always shifting depending on what cognitive tasks you’re undertaking. However while under psychedelics, the blood flowing in your thalamus decreases. The more it decreases, the stronger the subjective experience of the psychedelic becomes.

When there’s a decrease in cerebral blood flow, it’s usually an indicator of a decline in ‘functional connectivity’

Functional connectivity is a common term in psychedelic neuroscience. It is the relationship that two (or more) brain areas have with one other. Areas of our brain have ‘factory setting’ functional connectivity with other parts of the brain. An example of this would be the thalamus and the primary visual cortex. We use our eyes and visual cortex to see something. The thalamus filters everything including color, light, even orientation of objects, and feeds it to the rest of our brain.

When the psychedelics hit, it decreases existing relationships (or functional connectivity) your thalamus has with familiar parts of the brain. While simultaneously increasing functional connectivity with new, more unfamiliar parts of the brain. Your thalamus (along with other areas) begins to slide in the DMs of other random parts of the brain and weird, temporary relationships begin to form over psychedelics. That’s also the story of your life.

Amygdala

Th
e amygdala is a small part of your brain located around your temporal lobe next to your thalamus. It’s often referred to as one, but we actually have two of them lodged in our brain. It’s pretty tiny, but it’s like an all-star for psychedelic brain activity. With most parts of the brain, the amygdala’s purpose is multi-faceted. But our understanding of its function is primarily to process fear and emotional-behavior relating to fear. It’s an area one wouldn’t normally expect to be associated with psychedelics, but when a person is tripping, interesting things tend to happen.

Like the thalamus, a decrease of cerebral blood flow in the amygdala correlates with the intensity of a psychedelic trip. Robin Carhart-Harris saw this connection in his 2015 study at Imperial College London in which he used MDMA to shift cerebral blood flow of the amygdala. Just two years later, Carhart-Harris discovered that as cerebral blood flowed within the amygdala decreased, it also lowered symptoms of depression within an individual.

What do psychedelics do to fear-processing within the amygdala?

Well, glad you asked. It’s actually been a focus of psychedelic neuroscience for over half a decade. And the research has been some of the wildest psychedelic studies I’ve ever seen.

In 2015, Rainer Kraehenmann from the University of Zurich wanted to see what psilocybin would do to the amygdala when participants were presented with the Positive and Negative Affect Schedule (PANAS). It’s basically a test to evaluate reactions to positive and negative stimuli. Researchers found that reactions to negative stimuli were lower compared to placebo. This also correlated with an overall increase of positive mood within a person. They were vibing to the point where bad things just didn’t affect them as much.

Patients with anxiety (and anxiety-induced depression) generally show a higher amygdala response to fearful faces. Selective serotonin reuptake inhibitors (SSRI) drugs (like Prozac and Zoloft) combat that effect in the amygdala by suppressing amygdala activity, which lowers emotional responses to fearful faces (along with other fear-based stimuli).

In 2018, Imperial College London’s Leor Roseman administered psilocybin to people with treatment-resistant depression and surprisingly found that amygdala activity in response to fearful faces is heightened, which also correlated with a decrease in depression. This indicates that unlike SSRIs, psychedelics (combined with psychological support after the trip) helps a person confront negative stimuli and work through the experience for a positive therapeutic result. The same effects on the amygdala also tend to appear with LSD.

The cingulate cortex

The cingulate cortex lays in the posterior (back) and the anterior (front). And it covers another part of your brain called the corpus callosum. Which lies basically in the center of your head. Along with the amygdala, it’s part of the ‘limbic system.’

And the cingulate cortex is mostly responsible for regulating behavior, emotional response, and decision making. When it comes to psychedelics, the cingulate cortex is responsible for what neuroscientists call ‘oceanic boundlessness.’

First off, there’s an incredibly high amount of 5-HT2A receptors located in the cingulate cortex. Which makes it a hotspot for psychedelic activity. The cingulate cortex also shows a very high sensitivity to LSD. Primarily when assessed with a scale called the ‘Perturbational Integration Latency Index’ (PILI). It’s a pretty extravagant name. But it’s designed to determine the difference between an ordered brain state (or equilibrium), and brain states of absolute chaos. If you’re wondering, the cingulate cortex on psychedelics tends to go towards a state of unconstrained chaos.

Most of this ‘chaos’ lies in how the cingulate cortex talks to the other parts of the brain, specifically the medial prefrontal cortex.

Normally these two parts of the brain have a pretty tight relationship and are always communicating with each other.

When a person takes a serotonergic agonist like psilocybin, the cingulate cortex and the medial prefrontal cortex do a thing called ‘decoupling.’

This means they’ve stopped talking to each other, left each other on read, and are talking to other parts of the brain, chaotically.

Normally this decoupling wouldn’t cause any alarm, in fact it’s a pretty common thing within the brain. However, when the cingulate cortex decouples from the medial prefrontal cortex during a psychedelic trip, it leads to an ego-dissolution. Ego dissolution (or oceanic boundlessness) is the sense of ‘self’ dissolving into your environment — or, in some cases, the entire universe.

The ayahuasca study

Before we leave the cingulate cortex for our next brain area, I need to tell you about one of the wildest psychedelic studies I’ve ever read, and it just so happens to involve the cingulate cortex. In 2015, José Carlos Bouso wanted to evaluate what effects ayahuasca had on the brain. When seeking participants for studies like this, the usual criteria is to find a person that has a little familiarity with psychedelics. However, having ‘little familiarity’ just wasn’t enough for Bouso. His study came with one requirement: Participants did ayahuasca fifty times in a two-year span.

I’ll repeat that. The requirement was at least fifty ayahuasca trips in the span of only two years. Everyone reading this just lost their psychonaut card.

That’s like having an ayahuasca experience every other week for two years straight. He looked at the size of each participants’ cingulate cortex compared to people that never tried ayahuasca. What he found with people that dosed on ayahuasca was that their cingulate cortex was thicker on the anterior part but thinner on the posterior. What’s even more shocking is despite these clear structural differences, researchers did not find any decreased neuropsychological performance in the participants. They were all cognitively-healthy people. In fact it appeared ayahuasca helped them overcome maladaptive behavior, like addiction.

The medial prefrontal cortex

The
Medial Prefrontal Cortex (mPFC), sometimes just referred to as the medial frontal cortex. And it has been a neuroscientific goldmine for scientists studying psychedelics over the past few years. Like its name implies, the mPFC is located right in the front of your brain, just above your eyes — your forehead essentially.

Unlike the other parts of the brain, the mPFC shows its highest activity when a person is at rest. We don’t fully know its purpose. However, one theory is that it involves things like contemplation, long-term memory retrieval, and decision making.

If you’ve made it this far, then you know the mPFC loves talking to the cingulate cortex. And when you take psychedelics this relationship goes haywire. There’s actually lots going on with the mPFC under psychedelics — and you’ll have no choice but to learn about them below.

When did we first learn about the mPFC?

We first discovered that the medial prefrontal cortex had anything to do with psychedelics in 2008. Back then scientists used DOI (2,5-dimethoxy-4-iodoamphetamine), a Shulgin synthesized psychedelic to administer the effects of serotonergic agonists on lab rats. If you’re human, the only reason to take DOI is if you want to trip sleeplessly for twenty-four hours. Because that’s exactly what it does. The study was groundbreaking in that it showed psychedelics will disrupt the mPFC, along with the pyramidal cells within the area, the same neurons that are usually serotonin (5-HT2A) receptors in the brain.

What about since then?

Since that study, there have been other experiments to determine the function of mPFC under psychedelics. Notably, by Robin Carhart-Harris in 2012, showing a decrease in functional connectivity of the prefrontal cortex when the intensity of a psilocybin trip hit. This effect gains support from a 2018 study by Maurizio S. Riga, showing a decrease in ‘neural oscillations’ within the mPFC while having a psychedelic experience under 5-MeO-DMT. Neural oscillations are basically the result of neuronal activity in the brain. Similar to how a person’s voice is the end result of that person communicating with you.

Now that we know the medial prefrontal cortex is largely responsible for the subjective experience of a psychedelic trip, which therapeutic effects (if any) lie within this mPFC neural chaos? Is it just about seeing fancy colors and fractal shapes? Well, it just so happens the most significant neuroscience study on psychedelics’ interaction within the mPFC happened in 2021. And it has undoubtedly changed how we view psychedelics forever.

If there’s one person you need to remember from this article on the neuroanatomy of a psychedelic trip, it’s Yale University’s Ling-Xiao Shao.

Before her paradigm-shifting study published this April, it was theorized that psychedelics may have a role in a process called neurogenesis. Basically neurogenesis is the growth and repair of neurons in the brain. This is an idea that has been associated with psychedelics’ role in certain parts of the brain, but never fully understood or realized. Shao’s historic study showed that psilocybin, through the interaction of 5-HT2A receptors, causes neurogenesis in the brain, specifically spinogenesis, as it repairs, strengthens, and grows dendritic spines within pyramidal cells.

This sounds amazing, but what does it actually mean?

Mental states like depression, anxiety, PTSD have been shown to atrophy neurons in the medial prefrontal cortex. This weakening of dendrites within these neurons (along with other neuroanatomical structures) happen when stressors occur in a person’s life. Whether it’s the dread of a Monday office workload or ongoing trauma from a relationship, stressors tend to hammer mPFC neurons which may lead to larger cognitive problems. However stress wrecking a person’s mental well being isn’t a new idea. It’s an overarching theme in most mental-wellness therapy.

Shao’s work showed that by physically repairing the biological evidence of stress (like weakened dendrite spines within neurons), it directly correlates to an improvement of certain maladaptive cognitive states (like depression and chronic stress).

Just like repairing tires worn down from daily wear-and-tear makes a car run smoother.

Likewise, almost immediately after neurons get an introduction to psilocybin, a variety of beneficial effects on the brain occur.

The growth of these neurons continues to happen at least a day after taking psilocybin. And this growth could remain days, weeks, even months after the initial trip. This neuronal growth also correlates with the subjective experience after the trip. Or the ‘afterglow’, as it is colloquially referred to in psychedelics. Afterglow is a timeline after a psychedelic experience long theorized to have therapeutic benefits for an individual. During this period people reportedly have a decline in anxiety. And, in some instances, experiences so transformative that it forces a complete redefinition of ethics and morals.

Conclusion

That’s a lot to take in, so be proud of making it this far. There is a secret though that I’ve been hiding from you this entire time. There are many areas of the brain I could have selected. But all the ones in this article actually work in tandem in brain networks like the Default Mode Network (DMN). Psychedelics also affect these wide-scale neural networks. And they have revealed further new neurological mechanisms of what happens to our brain under psychedelics.

We can’t venture into brain networks like the DMN, Salience Network, or the Frontoparietal Network (aka the Central Executive Network). We’ve shared entirely too much time together with this article. You have things to do — so do I. However, you now have just a little more knowledge on how the brain interacts with psychedelics. Don’t worry, ‘The Neuroanatomy of a Psychedelic Trip: Brain Networks’ will be coming soon.

 
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Image (a) is an untreated brain, while image (b) is a brain on psilocybin.

New insights into psilocybin’s effect on the brain

by Georgia Perry | Lucid News | 27 April 2020

Scientists get closer to understanding why psychedelics show promise for treating mental illness.

In an effort to explore the effect of psilocybin on the healthy brain, an international team of scientists created a biophysically realistic whole-brain model, described by the researchers as a “technical tour de force.” The researchers reported on this model in a paper published in the Proceedings of the National Academy of Sciences.

The groundbreaking model enabled them to observe how psilocybin impacts the activity of neurons and neurotransmitters. “Longer term, this could provide a better understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction,” they wrote in the paper.

Psilocybin and other psychedelics are known to affect the neurotransmitter balance of serotonin receptors in the brain, but up to this point “little has been known of this process,” write two of the paper’s authors, Morten Kringelbach and Gustavo Deco, in an email to Lucid News. The model they created sheds new light on these dynamics. “Using this model will be crucial for truly understanding how psilocybin can rebalance neuropsychiatric disorders such as treatment-resistant depression and addiction,” the researchers added.

To create the whole-brain model they analyzed functional resonance imaging (fMRI) data from 16 healthy subjects. Then, nine subjects each underwent two fMRI scans over separate sessions, in which they were given either a 2mg dose of psilocybin or a placebo saline solution. "The findings reveal that when psilocybin was introduced, neural networks were disrupted and neurotransmitters forged new pathways between neurons,” writes Mental Daily.

“It has long been a puzzle how the brain’s fixed anatomical connectome can give rise to so many radically different brain states; from normal wakefulness to deep sleep and altered psychedelics states,” write Kringlebach and Deco. The whole brain model they created is capable of addressing this puzzle, in addition to advancing scientific understanding of psilocybin.

"The new model," they write, “will give us the much needed, causal tools for potentially designing new interventions to alleviate human suffering in neuropsychiatric disorders.”

They are currently using the model for a new psilocybin study for depression, conducted by Dr. Robin Carhart-Harris, who was also involved in this study.

 
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Psychedelic drugs affect how the brain is wired

by David Olson | The Conversation | The Daily Beast

Researchers know that mind-altering drugs including LSD, DMT, and MDMA affect brain function, but new findings show they can alter the structure of the brain as well.

It seems that psychedelics do more than simply alter perception. According to the latest research from my colleagues and me, they change the structures of neurons themselves.

My research group has been studying the effects of psychedelics on neuronal structure and function, and we found that these compounds cause neurons to grow. A lot. Many of these compounds are well-known and include lysergic acid diethylamide (LSD), psilocin (from magic mushrooms), N,N-dimethyltryptamine (DMT, from ayahuasca) and 3,4-methylenedioxymethamphetamine (MDMA, aka ecstasy).

These are among the most powerful drugs known to affect brain function, and our research shows that they can alter the structure of the brain as well. Changes in neuronal structure are important because they can impact how the brain is wired, and consequently, how we feel, think and behave.

Prior to our study, few compounds were known to have such drastic and rapid effects on neuronal structure. One of those was ketamine—a dissociative anesthetic and quite possibly the best fast-acting antidepressant that we have available to us at the moment.

If you think of a neuron like a tree, then its dendrites would be the large branches, and its dendritic spines—which receive signals from other neurons—would be the small branches. Some of these small branches might have leaves, or synapses in the case of a neuron. In fact, neuroscientists often use terms like “arbor” and “pruning” much like a horticulturist would.

“When we grew neurons in a dish—which is not unlike growing a plant in a pot—and fed them psychedelic compounds, the neurons sprouted more dendritic branches, grew more dendritic spines, and formed more connections with neighboring neurons.”

Thanks to studies on ketamine, slow-acting antidepressants and chronic stress models of depression, scientists now know that depression is not simply the result of a “chemical imbalance,” as pharmaceutical companies like to suggest. It is far more complicated and involves structural changes in key neural circuits that regulate emotion, anxiety, memory and reward.

Rethinking depression

One of the hallmarks of depression is the atrophy of neurons in the prefrontal cortex—a region of the brain that controls anxiety and regulates mood among other things. Basically, these branches and spines shrivel up, disconnecting from other neurons in the brain. One hypothesis for why ketamine is so effective is because it can rapidly regrow the arbors and spines of these critical neurons.

Like ketamine, psychedelics have shown promise in the clinic for treating neuropsychiatric diseases. The DMT-containing herbal tea known as ayahuasca produces fast-acting antidepressant effects within a day, psilocybin eases the anxiety of terminally ill cancer patients and MDMA can reduce fear in those suffering from post-traumatic stress disorder(PTSD). Our recent papers suggest the intriguing possibility that psychedelic compounds and ketamine might share a common therapeutic mechanism.

Strictly speaking, a psychedelic is a “mind-manifesting” drug—a definition that’s open to interpretation. They tend to produce perceptual distortions or hallucinations by activating 5-HT2A receptors. Our research group has found that compounds typically regarded as psychedelics, like LSD and DMT, as well as those that are sometimes called psychedelics, like MDMA, and those that are not usually called psychedelics, like ketamine, are all capable of profoundly impacting neuronal structure.

Psychedelics vs. Psychoplastogens

Our group has coined the term “psychoplastogen” to refer to such compounds, and we believe that these molecules may hold the key to treating a wide variety of brain diseases.

Our studies on neurons grown in dishes, as well as experiments performed using fruit flies and rodents, have demonstrated that several psychoplastogens, including psychedelics and ketamine, encourage neurons to grow more branches and spines. It seems that all of these compounds work by activating mTOR—a key protein involved in cell growth.

The biochemical machinery that regulates mTOR activity is intricate. As we tease apart how psychedelics and other psychoplastogens turn on mTOR signaling, we might be able to engineer compounds that only produce the therapeutic effects on neuronal growth while bypassing pathways that lead to undesired hallucinations.

The field has known for some time now that psychedelics can produce lasting positive effects on brain function, and it’s possible that these long-lasting changes result from the psychoplastogenic effects of these drugs. If true, this would suggest that psychoplastogens might be used to repair circuits that are damaged in mood and anxiety disorders.

Many diseases, such as depression and anxiety disorders, are characterized by atrophy of dendritic branches and spines. Therefore, compounds capable of rapidly promoting dendritic growth, like psychedelics, have broad therapeutic potential. The number of papers demonstrating that psychedelics can produce therapeutic effects continues to grow every year.

Panacea or poison?

However, we should temper our enthusiasm because we do not yet know all of the risks associated with using these drugs. For example, it’s possible that promoting neuronal growth during development could have negative consequences by interfering with the normal processes by which neural circuits are refined. We just don’t know, yet.

Similarly, it is unclear what effects psychoplastogens will have on the aging brain. It’s important to keep in mind that excessive mTOR activation is also associated with a number of diseases including autism spectrum disorder (ASD) and Alzheimer’s disease.

To me, it’s obvious that we need to understand how these powerful compounds affect the brain, in both positive and negative ways, if we hope to fully comprehend the fundamental laws governing how the nervous system works and how to fix it when it doesn’t.

By David E. Olson, assistant Professor, Department of Chemistry; Department of Biochemistry & Molecular Medicine; Center for Neuroscience, University of California, Davis

 
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Examining the cognitive neuroscience of psychedelics

by Joel Ng, MA | Psychedelic Science Review | 4 Aug 2020

Much research has been conducted into the use of psychedelics in concurrence with therapy as novel treatments for a host of mental disorders, from OCD (obsessive-compulsive disorder) to depression to substance abuse. Such research has only just started to regain popularity after the widespread ban on psychedelic substances in the 1970s. However, less is known about how psychedelics work on a granular level. A deeper understanding of psychedelics, and being able to closely tie neurochemical changes caused by psychedelics with subjective experiences, could expand our understanding of the brain and advance mental health care greatly.

A recent paper published by Drs. Robin Carhart-Harris and Karl Friston in the Journal Pharmacological Reviews suggests a new way of explaining how psychedelics affect the brain’s way of understanding one’s environment, and by extension, provides a potential explanation for how psychedelics work in treating mental disorders. Their model is known by the acronym REBUS, which stands for “relaxed beliefs under psychedelics.”

The REBUS model and prior beliefs

The authors view the brain as an engine that generates mental models of the world with the purpose of predicting future sensory data. These predictions are called ‘priors’, meaning ‘prior beliefs’. Much of human behaviour and cognition are based on these priors. For example, there is the mental model of how a washroom sink functions – turn this knob, water comes out. This can be extended beyond beliefs about the physical nature of the world, also including more abstract beliefs. For example, drug addiction could be viewed through the lens of a prior: “taking this drug leads to large amounts of reward.”

Usually, priors that are inaccurate reflections of the world are updated by incoming sensory data. New information from the senses updates the model to better reflect reality. Sometimes, however, new sensory information is ignored by the brain, due to priors being too rigid to be updated. An example of this is drug addicts who keep abusing their drug of choice even after the negative aspects of drug addiction cause significant damage to their lives or depressed individuals with otherwise comfortable lives. Carhart-Harris and Friston suggest that psychedelics decrease the rigidity of priors – making priors more malleable to incoming sensory data. Likening this process to heating a metal to increase its plasticity, psychedelics allow new information to better mould the prior into something more reflective of reality. This model explains how psychedelic trips can often result in long-term changes in individuals even after the trip ends by promoting a reorganization of the brain’s way of perceiving the world.

What does the dissolution of priors feel like on the individual level? One of the most accepted models of personality, the five-factor model of personality, describes five domains of personality – Openness, neuroticism, extraversion, agreeableness, and conscientiousness. Openness, the factor of interest in this case, broadly describes an individual’s level of affinity for new experiences, people, and viewpoints. Personality analyses of subjects who ingested psilocybin showed significant increases in their openness domains over a year after the psilocybin dose. Viewing these results, broadly, this dissolution of priors feels like an imposed sort of openness of mind, where the psychedelic compound forces one to be more open-minded regarding incoming information. As information about the world enters the consciousness – information that might otherwise have been previously ignored to retain prior cognitive structures – psychedelic mind-states are less able to discount this information, which subjectively feels like being more open-minded.

Learning from the brains of children

Psychedelics’ effect on the serotonin 5-HT2 receptors in the brain has been theorized as the main neurochemical process by which psychedelics exert an effect on subjective experience. Interestingly, psychedelics induce certain biological events that are similar to childhood. First, serotonin receptors, which are the primary receptors that psychedelics act on, are more numerous in children than in adults. Second, neurogenesis and brain plasticity, both traits that are more pronounced in childhood brains, are induced by psychedelics. All in all, the evidence indicates that psychedelic states of mind and childhood states of mind bear great similarities. Learning about the world and the individual’s relationship with it takes place at a critical period in one’s childhood, one that psychedelics might be able to reactivate in adults.

With this implication in mind, one can examine further the interesting mental abilities of children, abilities that fade away as they grow up. For example, enhanced learning potential and enhanced memory are just two of the things that children are capable of that adults are not. Children with an eidetic memory often lose this ability as they grow. This is an ability that has, anecdotally, been retriggered in psychedelic mind-states. However, more rigorous research is required to corroborate these accounts.

Other advantages of the REBUS model

One additional benefit of the REBUS model of viewing psychedelic effects on cognition is that it can explain a host of other subjective effects that psychedelics produce, from ego dissolution, altered time perception, geometric hallucinations, and magical thinking. All of the previously stated subjective effects can be seen as the result of new information altering previously rigid cognitive structures like the ego, subjective experiences of time units, visual recognition and classification of objects, and large-scale worldviews on the nature of reality.

Lastly, and perhaps most importantly, this model allows the psychiatric community to better explain exactly why and how psychedelics seem to be extremely effective at treating certain types of mental illnesses. Conditions including anxiety, depression, PTSD (post-traumatic stress disorder), viewed as maladaptive priors that are immune to sensory information updates in sober mind-states, are able to be integrated with new information in the psychedelic mind-state due to the reduced rigidity of the priors. Depressed individuals remaining depressed after positive events in their lives can be viewed as the prior “I am not worth anything” resisting integration with the new information. This resistance is reduced in the psychedelic mind-state, allowing for psychedelic-enhanced psychotherapy to be more effective than regular psychotherapy.

The impact on psychedelic therapy

In conclusion, authors Carhart-Harris and Friston posit a new model of viewing the brain, one that also explains the subjective and neurochemical effects of psychedelics on the brain. This model sheds more light on many facets of psychedelics, from the recreational, subjective effects of psychedelics to more serious medical effects that might one day pave the way to greater, more effective mental health treatments for a variety of individuals.

 
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