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Psychedelics and the Default Mode Network

by Jasmine Virdi | Psychedelics Today | 4 Feb 2020

Modern neuroscience has demonstrated that psychedelics such as LSD, psilocybin, the active ingredient in magic mushrooms, as well as ayahuasca operate to significantly reduce activity in the brain’s default mode network (DMN). This reduction in DMN activity functions as a kind of ‘rebooting’ of the brain, and is thought to be linked to one of the most enduring therapeutic effects of psychedelic substances.

What is the Default Mode Network?

The default mode network refers to an interconnected group of brain regions that are associated with introspective functions, internally directed thought, such as self-reflection, and self-criticism. Increased activity of the DMN is correlated with the experience of mind-wandering and our capacity to imagine mental states in others (i.e. theory of mind) as well as our ability to mentally “time travel,” projecting ourselves into the past or future.

The functioning of the DMN is considered essential to normal, everyday consciousness and is at its most active when a person is in a resting state and their attention is not externally directed on a worldly task or stimulus. For example, if you put somebody in an MRI scanner and don’t give them anything to do, their mind will start wandering and you will see the regions that make up the DMN light up.

The functional connections that make up the DMN increase from birth to adulthood, with the DMN not being fully active until later in a child’s development, emerging around the age of five as the child develops a stable sense of narrative self or “ego.”

As we mature, we learn to respond to life’s stimuli in a patterned way, developing habitual pathways of communication between brain regions, particularly those of the DMN. Over time, communication becomes confined to specific pathways, meaning that our brain becomes more ‘constrained’ as we develop. It is these constrained paths of communication between brain regions that quite literally come to constitute our ‘default mode’ of operating in the world, coloring the way we perceive reality.

Evolutionarily speaking, it has been hypothesized that the DMN plays a major role in our survival, helping us form a continuous sense of self, differentiating ourselves from the world around us. The DMN has been described by psychiatrist Matthew Brown as the part of the brain which serves to “remind you that you are you."

Overactivity of the DMN and mental health conditions

The DMN has been found to be particularly overactive in certain mental health conditions, such as depression, anxiety, and OCD. Matthew Brown likens DMN overactivity to experiences of “hypercriticality,” “rigid thought patterns," and “automatic negative thought loops” about oneself.

Imagine that you are at a party, telling a joke that gets met with an awkward silence. Initially, people might think “Oh no, that wasn’t so funny,” but they tend to quickly move on to the next leg of the conversation, forgetting about it entirely. However, you go home that evening, finding yourself completely unable to sleep because you are wrought with worry about the bad joke you told, what a fool you appeared to be, and how others might be judging you harshly for it. This is a classic example of DMN overactivity and the negative thought patterns which tend to be visible in people who suffer from depression, anxiety, and OCD.

How do psychedelics affect the Default Mode Network?

Psychiatric doctor and ayahuasca researcher Simon Ruffell likens the effects of psychedelics on the DMN to “defragmenting a computer.” When you ingest a psychedelic, activity of the DMN is significantly decreased whilst connectivity in the rest of the brain increases.​
“Brain imaging studies suggest that when psychedelics are absorbed they decrease activity in the default mode network. As a result the sense of self appears to temporarily shut down, and thus ruminations may decrease. The brain states observed show similarities to deep meditative states, in which increased activity occurs in pathways that do not normally communicate. This process has been compared to defragmenting a computer. Following this, it appears that the default mode network becomes more cohesive. We think this could be one of the reasons levels of anxiety and depression appear to reduce.”
Dr. Simon Ruffell, Psychiatrist and Senior Research Associate at King’s College London​

Due to psychedelics’ ability to disrupt the activity of the DMN, they have a particularly strong therapeutic potential when it comes to changing negative thought patterns. For example, a study by Imperial College London assessed the impact of psilocybin-assisted therapy on twelve patients with severe depression. Results demonstrated that psilocybin-assisted therapy was able to dramatically reduce their depression scores for a period of up to three months.

A follow-up study suggested that the therapeutic impact of psilocybin was linked to its ability to ‘reset’ the DMN, turning it off and reconsolidating it in a way that is a little less rigid than before.

In general, it has been shown that psychedelics produce increases in psychological flexibility, positing another explanation for why we see decreases in depression and anxiety following a psychedelic experience. Based on what we know about the DMN, we could hypothesize that it plays an influential role in one’s ability to be psychologically flexible.

Matthew Brown gave an analogy for how psychedelics are able to reset the DMN, enabling an increased sense of psychological flexibility:​
“If you do the same thing repeatedly, it is like you are walking down the same path all the time. Naturally, that path becomes very well worn and easy to walk down. However, you realize that maybe there is another path that might be more advantageous for you and you want to try walking down that path. Psychedelics ‘mow the lawn’ so that it doesn’t seem that the weeds are quite so high and you can walk down that new path a little bit more easily.”

Entropic brain theory and the 'reducing valve

Psychedelics tend to disrupt the activity of the DMN, temporarily disintegrating the highly organized system of networks that it is made up of, allowing for “less ordered neurodynamics”, and a greater degree of entropy within the brain. That is to say that open, freer conversations begin to take place between brain regions that are normally kept separate.

According to the ‘entropic brain’ theory, the state of consciousness associated with psychedelics is comparable to that which exists in early childhood – we experience awe and wonder, looking at everything in the world around us as wholly novel.

These findings are in line with writer and philosopher Aldous Huxley’s early reflections on the psychedelic experience, in which he described psychedelic consciousness as “Mind at Large” in that it grants us access to a larger set of brain functions, allowing us to tap into an unbounded state of consciousness which extends beyond the individual and into the collective. He theorized that in order “to make biological survival possible, Mind at Large has to be funneled through the reducing valve of the brain and nervous system.”

In this case, we can think of the “reducing valve” as a metaphor for the DMN which in some sense serves “to protect us from being overwhelmed and confused by this mass of largely useless and irrelevant knowledge, […] and leaving only that very small and special selection which is likely to be practically useful.”

The Default Mode Network and ego death

In 2016, a breakthrough study by Imperial College London used a combination of neuroimaging techniques to measure electrical activity and experiential reports from participants to investigate the link between brain activity and reported psychological responses to LSD in twenty volunteers.

Results demonstrated that LSD dampens the function of the DMN, and that this decrease in activity strongly correlated with the subjective experience of “ego dissolution” or “ego death”, indicating that the DMN performs a vital part in sustaining the “ego” or “self.”

Similarly, researchers at Johns Hopkins University published a pioneering study, demonstrating that psilocybin is able to produce mystical-type experiences in participants, such as the experience of ego death. These experiences were considered to be deeply meaningful by participants and were seen to elicit sustained positive changes in attitude and behaviour.

Generally, it’s our ego – our sense of “I” – that tends to create and harbor negative thought patterns. In conditions such as depression and anxiety, we become self-absorbed, narrowly focused on thoughts about ourselves, unable to take a step back and see the bigger picture. The ego erects boundaries that can lead to us feeling isolated from the people around us, disconnected from nature and even ourselves.

In a state of ego dissolution, these boundaries are let down and a great “zooming out” takes place where you begin to see things on a macroscopic level. You are no longer an individual isolated from life as it takes place around you, but rather you are interconnected with everything through the web of life. It is not a logical, but rather a felt experience of incredible love and reconnection.

When asked about the therapeutic implications of having an experience like ego dissolution, Matthew Brown explained that it can be tremendously healing as our consciousness is able to extend itself beyond the confines of our individual experience, and become one with nature’s larger whole.

“You realize that you are extremely insignificant, and perhaps that sounds defeating. However, it can be very freeing to realize that you are just one human who is existing for a very small blip of time in the grand scheme of the universe.” — Dr. Matthew Brown, DO, MBA, ABPN, Child, Adolescent, Adult Psychiatry

It is important to note that although experiences of ego death can lead to deep personal insight, and thus have therapeutic benefits, they can also be terrifying. Author of Changing our Minds, Don Lattin reminds us that ego death can be a “fearful and/or enlightening experience” that “depends in large part on whether mind travelers are ready for the journey, what baggage they bring along, and who’s accompanying them.”

Perhaps what is most interesting about the ego death experience, and the temporary rewiring of the brain enabled by psychedelics, is the long-lasting, enduring therapeutic effects that remain beyond the temporality of the drug. The resetting of the DMN combined with the powerful experience of ego death induced by psychedelics are often described as amongst the most meaningful of experiences in a person’s life. Such experiences help us to break free from negative thought patterns, become more psychologically flexible as well as dissolve the barriers between ourselves and the world around us, realizing our place in the interconnected web of life.

Jasmine Virdi is a freelance writer, editor, and proofreader. She currently works for the fiercely independent publishing company Synergetic Press, where her passions for ecology, ethnobotany and psychoactive substances converge. Jasmine’s goal as an advocate for psychoactive substances is to raise awareness of the socio-historical context in which these substances emerged in order to help integrate them into our modern-day lives in a safe, grounded and meaningful way.

 
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The role of the claustrum in the psychedelic experience

by Shane O'Connor, MS | Psychedelic Science Review | 19 Aug 2020

Brain scans show that psilocybin modulates claustrum connectivity in brain networks.

The claustrum is one of the most enigmatic structures in the brain. This thin sheet of subcortical neurons is noteworthy in that it is connected with almost all cortical areas, including motor, somatosensory, visual, auditory, limbic, associative, and prefrontal cortices. Additionally, it receives neuromodulatory input from subcortical structures

Fifteen years ago, Sir Francis Crick (co-discoverer of the double helix structure of DNA) and Christof Koch, Chief Scientist at the Allen Institute for Brain Science, published an influential review making an argument for the claustrum as the ‘seat of consciousness’, driving a renewal of interest in the brain structure. In this paper, the pair suggested a function for the claustrum in binding information to generate the conscious experience.

Brain networks and the claustrum

Due to the nature of its connectivity and neuromodulatory input, the claustrum aids in the differentiation between task-relevant and task-irrelevant information, allowing the organism to ignore irrelevant information and proceed with goal-oriented behaviour. In particular, the claustrum has been linked to brain networks implicated in attention; the default mode network (DMN) and task-positive networks such as the Central Executive Network (CEN).

Similarly, recent findings suggest that psilocybin alters the integrity of and coupling between large-scale brain networks, including the DMN as well as sensory and executive control networks. This observation has led to the hypothesis that psilocybin may modulate claustrum function in humans.

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Coronal plane section of the human brain showing the location of the claustrum on one side.

Researchers believe that psilocybin may acutely decrease activity within the DMN, an arrangement of functional connections in the brain that is responsible for introspection and planning. The downregulation of the DMN by psilocybin may temporarily lead to increased connectivity between brain regions that ordinarily don’t communicate with one another, corresponding to the subjective experience of “ego-dissolution” and the consequent generation of new perspectives and insights.

Task-positive networks also play an essential role in the attention and executive. Shifts in attention and executive function also characterise the subjective effects of psychedelic drugs. Psilocybin dose-dependent changes in executive function include impaired associative learning, working memory, and episodic recall.

The observations that psilocybin perturbs the same brain networks that are functionally connected the claustrum implicates the claustrum as a target of psilocybin. Furthermore, the effects of psilocybin are primarily achieved through its action as a partial agonist of the serotonin 2a (5-HT2A) receptor. 5-HT2A receptor protein is highly expressed in the claustrum.

In a recent study, Barrett et al. tested the hypothesis that psilocybin disrupts claustrum activity and functional brain connectivity in humans.

Study design

In the Barrett et al. study, 15 participants completed two brain scanning procedures (fMRI), each beginning 90 min after administration of placebo or a moderate dose of psilocybin (10mg/70kg). The timing of scanning procedures corresponded with peak subjective effects of this dose of psilocybin.

Immediately after each resting-state scan, participants rated the degree to which they experienced a series of subjective effects during their resting-state scan, which included:

The overall strength of psilocybin-like effects.
Now-ness: the feeling of being in the present moment.
Letting go: the degree to which a person was able to let go of control of the experience.
Equanimity: equipoise, felt a sense of being in balance, emotional balance.

Psilocybin modulates claustrum connectivity in brain networks

Brain scanning procedures demonstrated that psilocybin modulated the activity of both left and right claustrum during the acute effects of psilocybin, and led to alterations in both left and right claustrum connectivity with brain networks that support sensory and cognitive processes. In particular, psilocybin decreased functional connectivity of the right claustrum with DMN and increased right claustrum connectivity with task-positive networks.

These results corroborate with pioneering psychedelic studies which demonstrated reductions in DMN connectivity and increases in the connectivity of task-positive networks following psilocybin administration. However, how this network disruption occurs is unclear. The results of the study by Barrett et al. support the idea that the claustrum may be involved at a circuit-level to exert psilocybin-induced disturbances in both the DMN and task-positive networks.

Subjective effects and claustrum function

Furthermore, the Barrett et al. study found that the subjective effects of psilocybin were found to be associated with measures of claustrum activity. The subjective effects of psychedelic drugs are characterised by alterations in attention and executive function. These shifts in attention and executive function may manifest in user-reported subjective effects of psychedelic drugs, including the difficulty of putting the experience into words (ineffability), and the potentially challenging subjective effects of depersonalisation, confusion, and paranoid delusions.

Given the association of the claustrum with executive and task-based networks and top-down control of action, the authors of the study posit that the claustrum may play a role in subjectively sensed alterations in executive function through modulation of frontal cortical regions with which the claustrum connects.

Conclusions and context

In conclusion, the study by Barrett et al. supports a possible role of the claustrum in the subjective effects of psilocybin. Moreover, the results suggest a potential mechanism for brain network alterations observed in the psychedelic state by way of aberrant claustrum activity.

Given the network disturbances that underlie neuropsychiatric disorders, including mood and substance use disorders, the broad connectivity of the claustrum indicates this nucleus may play a role in those disease states—disease states in which psilocybin has proven to exert therapeutic relief. The current study underlines the need for further efforts to examine the potential role of the claustrum in therapeutic effects of psilocybin.

 
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The neuroscience of psychedelic visuals

by Dr. James Cooke | Reality Sandwich | 30 Aug 2020

‘Psychedelic’ can be applied not only to a class of chemical, but to a whole style of visual art, inspired by the visions that these chemicals produce. Why do these substances produce similar visual experiences across different individuals and where do these experiences come from? From breathing walls to melting hands, from symbolic imagery to entity encounters, psychedelic visions can tell us something about who and what we are.

During everyday waking consciousness we typically perceive a stable world of objects. This feels like a completely passive process–just open your eyes and there’s the world, no effort required. In reality, the felt simplicity of this experience masks the highly complex processing going on in your brain that allows you to see. Your retina is not a clear window through which your soul looks out onto the world. Instead it is a fleshly surface similar to the rest of your body, a piece of meat that blocks the light from the outside world, rather than letting it in.

When we see, what actually happens is that the patterns of light are transformed into electrochemical signals that are sent down the optic nerve to the brain. The brain, sitting in your pitch-black skull, learns to actively build models of the objects out there in the world that these electrochemical clues relate to. Your normal perception can be understood as a controlled hallucination, kept in check by the data coming in through your senses and by your expectations of the world around you. However, this balance between the internal creativity of the models in your brain and the extent to which they are kept in check can be altered.

Psychedelics interact with brain cells to alter their activity in ways that disrupt the normal process of perception. At low doses of a psychedelic, the visual world becomes distorted in reliable ways. Perhaps you experience trails of light following your hands as you move them, or you perceive the walls to be breathing. This can be understood as the result of a temporary impairment in the Default Mode Network (DMN).

The DMN is a group of brain areas that builds up expectations about the world and uses them to keep our perception in check. When its ability to do this is reduced, our internal models of the visual world are free to make guesses about what we’re seeing. We may overestimate the distance of the wall then correct for our error based on the sensory data. Give the newfound flexibility offered to the brain areas involved in this process, they may underestimate, then overestimate. This process can continue on and on, resulting in a pendulating interpretation of the wall’s distance and the perception of the walls breathing. The same goes for the precise position of one’s hand in space over time.

We’ve all seen shapes in the clouds or perhaps faces in the bark of a tree. Here we are using ambiguous sensory input and are finding internal models in our brains that roughly match the pattern. When on a psychedelic this process goes into overdrive and can result in us mistaking a flower for a lizard or a bowl of spaghetti for a bowl of worms. Why do we tend to see natural shapes like animals and not artificial ones? Why lizards and worms and not buildings and airplanes?

Our visual system evolved to recognize the patterns of the natural world that are relevant to survival and so, when given to opportunity to play, our visual systems show us these natural forms that we were built to detect. We have templates for snakes and spiders deeply programmed into us for example, something that simply isn’t the case for modern dangerous objects like cars and guns.

Our hallucinations can be thought of as what our brains expect to see, something that may also account for why we perceive colors to be highly saturated in the psychedelic state, as we’re experiencing the more pure template of the color than we typically experience in daily life. Understanding the basis of hallucination in our evolutionarily programmed expectation of the visual world also offers a way of understanding why eyes, serpents, and insects are so common in higher-dose psychedelic experiences, as these are highly biologically relevant patterns for us as a species.

The models in our brain that underlie perception are constructed by networks of brain cells. The vast computational power of such networks has resulted in their being imitated in modern Artificial Intelligence systems. Artificial Neural Networks such as Google’s Deep Dream can be trained to recognize different images, resulting in the construction of models in the neworks in a way that approximates learning in the brain. When we dream or hallucinate, the contents of these models become active with no sensory input to keep them in check. The same can be done with the artificial Neural Networks. When it is tasked with generating rather than recognizing images, they produce distinctly psychedelic visuals. The fact that this is the case provides striking evidence that certain psychedelic visuals are generated by the models in your brain being pushed into “create” mode.

At higher doses geometric patterns can be observed, especially when one closes one’s eyes, thereby excluding the sensory data that would otherwise keep one’s models in check. The patterns of the natural word are geometric in essence, all patterns are. Geometric hallucinations can reveal certain common patterns that are fundamental to our experience of the world. Psychedelics are not the only way to shift the visual brain into a mode where it displays their core patterns. When one “sees stars” after being hit on the head, the visuals being perceived are called phosphenes. Phosphenes can also be seen when pressure is placed on the eyeball. These geometric patterns are routinely experienced in the psychedelic state and have been observed in ancient cave art, leading to the suggestion that early cave art represents the earliest attempts of our species to carry back the experiences of the psychedelic state.

At high doses of classical psychedelics, people routinely experience ancient imagery exemplified in the art of cultures as found in ancient Egypt and Mesoamerica. Mesoamerican cultures are known to have ingested psychedelic mushrooms and it has been suggested that religion in ancient Egypt for a time revolved around the consumption of such mushroom, based on the similarity of depictions of Egyptian crowns to different stages of the development of this type of mushroom. The psychoactive blue lotus is also believed to have been consumed ritually in ancient Egypt. From our contemporary perspective, the styles depicted in the artworks feel as if they originated in these cultures. In reality the imagery of the psychedelic experience may have come first and the art later.

Another experience that can be had at high doses, especially with DMT, is the experience of visiting another “dimension”. In such an experience the person typically feels as if they have left their body behind and have been transported to another world. Understanding that our perception of the world around us is not the passive experience of a true picture of the world but instead is a controlled hallucination generated by our minds allows us to explain such experiences. As in a dream, the brain is pushed into a creative mode where it is especially decoupled from the sensory data coming from the world around. Certain contents, such as snakes and eyes, can be readily explained by the idea that they reflect deeply programmed visual patterns that are relevant to survival.

Not all of the contents fit neatly into this interpretation however, with visions of technology being particularly difficult to account for. One speculative explanation for such visions is that they reflect geometric hallucinations varying in three dimensions of space and in time.

When having the experience of moving to another dimension it is common to experience passage down a tunnel. It has been suggested by “the Godfather of LSD”, Stan Grof, that the tunnel experience is a memory of the experience of birth, although the fact that those born by cesarean section can still experience tunnels seems to rule this explanation out. Neurobiologist Jack Cowan has argued that spontaneous activity moving across the visual cortex might translate into the experience of concentric rings, as a result of the way that the retina maps onto the surface of the cortex.

Dramatic psychedelic experiences can feel like they reflect actual experiences of pre-existing phenomena that exist outside oneself, rather than being generated from within. This shouldn’t be a surprise as our perception always presents us with the feeling of an objective reality outside of ourselves, even though it is a controlled hallucination created inside us.

The nature of these experiences has led some scientists and philosophers to suggest that the material world is secondary to another reality that we interact with in these states, this ultimate reality varying from a spiritual realm, other dimensions, baseline reality in which our current world is merely a simulation, or a universal consciousness that underpins reality itself. The challenge of these perspectives, other than overturning the current prevailing paradigm, is to explain why low doses produce effects that are so readily explained by our understanding of how normal perception functions in the brain, and at high doses why these other worlds are show patterns that are biologically relevant to us, such as human eyes and natural imagery.

Psychedelic experiences can allow us to delve into our deepest personal programming and beyond into our deepest evolutionary programming, bequeathed to us by countless ancestors. Understanding the origin of psychedelic visions as coming from within does not reduce their meaning. We get the opportunity to explore ancient patterns on which our sense of meaning itself is scaffolded, we may confront aspects of Jung’s collective unconscious or realize how our visions connect us in time to our unimaginably long past as an evolved creature. Understanding how such experiences are generated, while interesting, is not necessary to derive pleasure and benefit from them. The value really is in the experience itself, whatever is going on behind the scenes.

 
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To capture simultaneous and continuous measurements of the neuromodulators dopamine and serotonin,
the study authors designed a microelectrode capable of taking 10 measurements per second.


Serotonin and dopamine linked to decision-making: Study

by Amanda Heidt | The Scientist | 16 Oct 2020

In a first-of-its-kind study, researchers monitored subsecond changes in levels of the neurotransmitters in the human brain, unlocking new insight into their function.

Long associated with reward and pleasure, dopamine and serotonin may also be involved in general cognition, shaping how people perceive the world and act on those perceptions, a new study finds.

For the first time, researchers have continuously and simultaneously monitored the two neuromodulators in the human brain. The results, published October 12 in Neuron, offer new opportunities to test hypotheses previously studied mostly in animal models.

“This study isn’t just measuring dopamine and serotonin; it’s building upon the deep foundation looking at neural mechanisms for perceptual decisions in animals and humans” and linking the findings of these studies together, Tim Hanks, a neuroscientist at the University of California, Davis, who was not involved in the study, tells The Scientist.

“There’s a growing recognition that [dopamine and serotonin] have more refined and nuanced roles than what may have once been believed, and this study really makes that case clear in human decision-making,
" said Hanks.”

Both neuromodulators have been heavily studied in animals, but animals require training to carry out decision-making tasks—training that often comes with a reward. As a result, it can be difficult to tease apart the decision-making from the reinforcement they receive in return. “Animals are a limited model of the rich thoughts and behaviors that we see in humans,” says Dan Bang, a neuroscientist at University College London and the lead author of the new study.

To study dopamine and serotonin signaling in humans, the team recruited five volunteers who were set to undergo brain surgery to treat either Parkinson’s or essential tremors and agreed to have their neurochemicals monitored during the procedure. Surgeons keep patients awake during the operation and use probes to measure brain activity for safety. The research team, led by Read Montague, a neuroscientist at Virginia Tech, was able to insert its own microelectrode into the caudate nucleus of four of the volunteers and the putamen of the fifth. Both structures are regions of the striatum and are involved in movement, learning, and reward.

As they underwent surgery, each participant completed a modified version of a common visual task called the random dot motion paradigm. In each round of the task, a person was shown a cloud of flickering dots moving across a screen. Some dots moved together in the same direction, while the rest moved randomly; the proportions undergoing each type of movement determined the difficulty of the task. In the standard test, the dots disappear, and the subject must indicate whether they had, on average, been moving toward the left or the right. In the amended protocol, participants were instead shown a random angle after the dots had disappeared and had to decide whether the dots had been moving to the left or right of that angle.

"This is definitely putting the importance of dopamine and serotonin into a new light." - Ken Kishida

In this way, the scientists were able to vary the difficulty and uncertainty of a person’s perception by changing both the number of dots moving in synchrony and how close their path of motion came to the randomly selected reference angle. After making their choice, participants rated how sure they were of their decision.

A microelectrode continuously measured both dopamine and serotonin levels in the caudate nucleus or putamen, taking 10 measurements each second. Scientists have never before been able to monitor these neurotransmitters at such biologically relevant speeds in humans. Less-invasive methods such as PET scanning or fMRI typically take only one measurement per minute.

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The probe used in the study is made of carbon fiber and uses low voltages to detect dopamine and serotonin activity in real time.

Within the caudate nucleus, serotonin levels were linked to uncertainty around perceptions in three of the four participants. When the task was more difficult and the outcome more uncertain, as estimated by the task variables and the participants’ self-reported uncertainty about their decisions, serotonin levels spiked shortly after the dots appeared on the screen. When the task was easier, serotonin dropped. In some previous human and animal studies, dopamine has had the opposite relationship with serotonin, and therefore with uncertainty, but in the new study, variations in the caudate nucleus’s dopamine levels did not track consistently with perceptual uncertainty.

In the putamen, however, the team did find strong evidence in support of opposing roles for dopamine and serotonin in relation to action, as evidenced by the time it took participants to make their choice about the direction of the dots. Both an increase in dopamine and a corresponding decrease in serotonin were associated with the subject’s choice to act, and both the change in neuromodulator levels and the decision itself happened more quickly when the task was easier and less uncertain.

"Taken together, these findings suggest that beyond their role as reward chemicals, dopamine and serotonin may contribute to cognition more generally, linking how we perceive the world and how we then go on to make decisions,” says Ken Kishida, a neuroscientist at the Wake Forest School of Medicine and a coauthor on the study. “This is definitely putting the importance of dopamine and serotonin into a new light.”

Even though this is a new finding in humans, it dovetails with what some researchers have begun to find in animals, says Armin Lak, a neuroscientist at the University of Oxford who was not involved in the study. In his own work, Lak has found links between dopamine and perception in rodents. “It’s really nice, for those of us working in neuroscience, to see this spectrum of studies all the way from animals to human volunteers.”

The biggest limitation of the new study, Lak adds, is the small sample size. Some of the team’s results, such as their data on the putamen, stem from only a single person. Kishida also points out that while dopamine levels varied more between people than did serotonin levels, that may be because some of the patients had Parkinson’s, a disease caused by dysregulated dopamine signaling.

Moving forward, the team plans to refine its microelectrode to recognize additional neurochemicals, such as norepinephrine. Having shown that the responses of neuromodulators can differ by brain region, they would also like to expand to include the cortex, amygdala, and hippocampus.

Better understanding of how dopamine and serotonin interact and their roles in different parts of the brain will also have important implications for treating neuropsychiatric disorders such as Parkinson’s and depression, says Hanks. Many treatments target these two modulators, but they do so across the entire brain and over longer time scales, so more knowledge could lead to more targeted and effective therapies.

“Because these neuromodulators have complex roles that depend on brain region, some will see it as a challenge, because it means that we can’t just use a medication that’s affecting [the brain] diffusely,” Hanks tells The Scientist. “But at the same time, I would argue that this represents a tremendous opportunity to make [therapies] even more effective.”

 
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Scientists unlock the neurological code of dissociation

by Sarah Ratliff | LUCID News | 15 Oct 2020

A team of bioengineers from Stanford University have recreated neural activity correlated with dissociative states, such as those induced by ketamine, in the brains of mice.

Scientists are unlocking the neurological code of dissociation, a form of altered consciousness that is frequently associated with psychedelic drug use. The findings, published in Nature, point toward a possible future when psychedelic states can be created through technology rather than substances

Using data obtained from sophisticated brain imaging technology as their guide, a team of bioengineers from Stanford University were able to manipulate the activity of neurons in the brains of mice, getting them to fire in synchronized rhythms that recreate patterns correlated with dissociative states. Even more significantly, the researchers were able to recreate the same rhythmic patterns in the brain of one human test subject, who suffered from a form of epilepsy that causes dissociative episodes.

Initially, some of the mice used in the experiment were fed doses of ketamine, an anesthetic with psychedelic qualities that will cause dissociation if taken in large enough quantities. During follow-up monitoring, the researchers discovered rhythmic and coordinated firing of neurons in the retrosplenial cortex, an area of a mouse’s brain that acts as an interface for a range of cognitive functions.

“It was like pointing a telescope at a new part of the sky, and something really unexpected jumped out at us” Dr. Karl Deisseroth, a Stanford neuroscientist who participated in the project, told NPR.

Excited by the implications of this discovery, the researchers turned to a cutting-edge technology known as optogenetics, which relies on finely-tuned, precisely-aimed light beams to provoke neural responses in individual cells. Applying optogenetic techniques, they were able to replicate the neural patterns of dissociation in the brains of mice that had not been given ketamine.

Neural activity in the brain of the human subject was monitored through electrodes that had been implanted by doctors, to aid in the treatment of their epilepsy. When the patient reported dissociative symptoms, the scientists detected rhythmic oscillations in an area of the brain known as the posteromedial cortex (PMC), which is connected to self-awareness and self-reflection and is structurally analogous to the retrosplenial cortex in the brains of mice.

Once again, the scientists were able to replicate these patterns of activity artificially, this time using high-frequency electrical signals. During this procedure, the patient reported symptoms of dissociation that were identical to those produced as a side effect of the epilepsy, proving that the link between rhythmic brain patterns and dissociation were more than coincidental.

Exploring the therapeutic potential of dissociation

Rhythmic oscillations in the brain are associated with integrated consciousness, learning, and memory. They strengthen neural connections and induce more vibrant functioning at the cellular level.

Conversely, scattered or chaotic firing of neurons is a sign of dysfunction. This type of activity is associated with debilitating neurological conditions like Parkinson’s disease, schizophrenia, and epilepsy.

When someone experiences dissociation, their conscious awareness seems disconnected from their mind, body, and the surrounding environment. Dissociation represents a profound dislocation of consciousness, somewhat akin to an out-of-body experience.

But as these latest experimental findings make clear, dissociation is not synonymous with neural chaos, unlike the epilepsy that sometimes precipitates it. It is instead an alternative form of consciousness that can emerge under certain unusual circumstances, sparked by a diverse range of potential causal factors.

If experienced frequently and organically, dissociation can be a sign of mental illness. But when carefully controlled, the invocation of dissociative states can have actual therapeutic value.

Psychedelic-assisted (ketamine) therapy, which leverages the drug’s capacity to cause dissociation, has proven especially useful for the treatment of depression. The changes in consciousness caused by dissociative episodes appear to relieve the symptoms of depression within a few hours, producing strong anti-depressant effects that may last for a week or more.

A 2019 study published in the journal Science found that the therapeutic consumption of ketamine can rapidly improve the functioning of mood-related brain circuitry. The drug helps regenerate broken or frayed connections between individual neurons within these circuits, by initiating the creation of new synapses (connectors) to replace those that have been lost. Synaptic destruction is a known side effect of stress, and exposure to chronic, long-term stress is believed to play a vital causative role in the onset and continuation of depression.

Notably, when doses of ketamine are too low to cause dissociation, they don’t appear to offer the same benefits.

“There seems to be this link between dissociation and the anti-depressive effect of ketamine,” explains Dr. Ken Solt, an anesthesiologist from Harvard Medical School who helped summarize the results of Stanford University study for an accompanying article.

Ketamine use can facilitate the mind-altering rhythms that correlate with dissociation. But theoretically, any process that can spark the firing of neurons in a controlled manner, in sequence and in predictable patterns, could produce these same rhythms. Presumably, dissociative states could therefore be created on demand, eliminating the need for any chemical supplement.

The promise of Psychedelic-Assisted Therapy—and its alternative

Psychedelic-assisted therapy relies on the mind-altering effects of ketamine to cause positive changes in neural functioning. But now that scientists have discovered a way to recreate that drug’s distinctive neural signature of dissociation, it may be only a matter of time before simulated forms of psychedelic-assisted therapy will be developed, possibly using optogenetic techniques like those adopted in the Stanford study.

As of now, ketamine is used primarily to treat depression. But preliminary research into the drug’s effect on PTSD and bipolar disorder has yielded positive outcomes for these conditions as well.

Psychedelic-assisted therapy may ultimately prove beneficial for men and women suffering from a broad variety of mental health conditions. If technologically-based methodologies for creating dissociative states can duplicate those results, they could function as an attractive alternative treatment for professionals and patients who aren’t comfortable prescribing or using psychedelics.

 
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What is the Default Mode Network?

by Sabrina Eisenberg, MS | Psychedelic Science Review | 18 Nov 2020

A default level of brain activity sheds light on the source of consciousness and mechanisms of ego death.

What happens when a person lays down and draws their attention away from the outside world? They might think of this as a ‘resting state’ in which neural activity decreases. Researchers considered an alternate proposal upon noticing mental activity in consistent, task-independent areas during the ‘resting state’, activity which was absent during goal-directed behavior. Raichle and colleagues referred to these areas as part of the Default Mode Network (DMN), reflecting the presence of a baseline, or ‘default’ level, of neural activity. The following article will discuss the DMN, its relationship to psychedelics, and its role in current and future research.


Oxygen Extraction Factor and DMN

Researchers used the oxygen extraction factor (OEF) to assert the DMN’s existence in the brain. The OEF is the ratio of oxygen consumed from the blood to local oxygen availability (by means of blood flow). Whereas blood flow changes significantly depending on activity, oxygen consumption remains at a nearly constant level. A decrease in OEF represents an increase in blood flow and vice versa. Rather than relying solely on blood flow levels to determine neural activity, the OEF allows for a more comprehensive view of the brain’s energy dynamics.

The OEF in the default mode, or the mean OEF, is typically uniform and constant across brain areas regardless of spatial variances. A decrease in OEF from the mean represents an activation relative to the baseline of neuronal activity, whereas an increase represents a deactivation.


Location and purpose of the DMN

Key areas associated with the DMN are the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC) and precuneus, inferior parietal lobule, lateral temporal cortex (LTC), and hippocampal formation. These areas confirm the DMN’s association with emotion and memory centers, rather than the sensorimotor cortex. These associations are unsurprising, given the correlation of the DMN with introspection, autobiographical memory, daydreaming, and future envisionment. The high levels of neural connectivity in these regions signify their importance as hubs of information transfer.

Reframing the initial distinction between the DMN and other areas as intrinsic versus evoked activity, rather than rest versus task, distinguishes the DMN as a communication hub. The large proportion of the brain’s energy budget devoted to functional activity, nearing 90%, underscores the importance of intrinsic activity at baseline. Theories propounded to explain the afforded budget include the DMN as an adaptation serving to gather pertinent external information, a necessary tool for future planning, and a foundation for our sense of self.

Understanding how the DMN reacts to self-referential thought processes, rumination, and awareness demonstrates its role as an essential tool in comprehending biological mechanisms for the subjective experience of various psychological states and mental illnesses. Increased activity has been shown in the DMN of patients with schizophrenia, depression, and social phobia, but reduced in autism, Alzheimer’s disease, during hypnosis, meditative states.


DMN and Psychedelics
It appears that when activity in the default mode network falls off precipitously, the ego temporarily vanishes, and the usual boundaries we experience between self and world, subject and object, all melt away.” – Michael Pollan

The DMN cannot be discussed without considering its influence in the field of psychedelic research. When Carhart-Harris and colleagues originally studied the brain on psilocybin, they expected a flourish of activity where they instead found a significant drop-off, represented by decreased blood flow. Recalling from the earlier discussion of OEF, decreased blood flow indicates an increase in OEF, and, consequently, a deactivation from baseline. Concurrently, a decrease in positive coupling between the PCC and mPFC demonstrated possible evidence for a restructuring of the standard hierarchical model of neuronal activity.

Carhart-Harris returned to the idea of a restructured neural model in his theory of entropy and the return to the “primary state.” He theorized that psychedelics instigate highly disordered states, or states of high-entropy, by facilitating the collapse of the normally organized DMN and a decoupling between the DMN and medial temporal lobe. This returns the brain to a regressive, unconstrained state of cognition, or “primary state,” allowing exploration into latent thought and an insight into the unconscious mind.

Unconstrained thought can result in unexpected connections between brain networks. Considering the DMN’s association with metacognition and self-relevant thought, it is not difficult to see the link between a drop-off in the DMN’s activity and a phenomenon such as ego death, which is frequently experienced under the influence of psilocybin.

Not only psilocybin but LSD and ayahuasca decrease the integrity of and activity in areas of the DMN, correlating with ego-dissolution and altered consciousness. Decreased oscillatory power and desynchronization in DMN areas, and a more recently proposed association between the DMN and the claustrum, represent additional mechanisms linking psychedelics and ego dissolution.

Aside from consciousness, the DMN offers a basis to postulate the biological mechanism for psilocybin’s antidepressant effects. Two possible explanations are the serotonin 5-HT2A receptor and resting-state functional connectivity (RSFC). Following suit from the theme of positive effects of disintegration, decreased activity in the mPFC via 5-HT2A receptor stimulation may counteract the brooding, pessimism, and depression associated with an overactive mPFC.

Counter to this logic, increased DMN RSFC one-day post psilocybin treatment was predictive of later treatment response. Carhart-Harris likened this response to a ‘reset’ or normalization of acutely lowered RSFC similar to that seen after treatment with electro-convulsion therapy (ECT). This theory, and the research upon which it is speculated, is not entirely consistent within the literature and would benefit from future research along its lines.


Summary

The DMN’s suggested role in self-referential thought can further the study of psychedelics, the understanding of mental illness and psychological states, and the interplay between the two. Examples of this interaction are the study of the DMN as an explanation for the effect of psychedelics on increased exercise performance, and the study of psilocybin-assisted mindfulness training modulating self-consciousness and DMN connectivity with lasting effects.

This serendipitous discovery led to and continues to shed light on, insights about consciousness and the mechanisms through which psychedelics influence brain chemistry and the relevant conceptualization of the ego. Whether explaining psychedelics as a therapeutic agent or garnering basic knowledge about psychological states and conditions, the DMN has proven useful to researchers across many domains.

 
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The Nuances of Ketamine’s Neurochemistry

Melody Pezeshkian, BS | Psychedelic Science Review | 15 Feb 2021

What's similar and different about the R and S isomers of ketamine?

Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, can produce antidepressant effects more rapidly than current first-line treatments for depression. Ketamine is a racemic (50-50 mixture of the R and S isomers) drug known for its dissociative, anesthetic, and antidepressant effects. Ketamine’s novel mechanism of action, contrasting to that of typical SSRI’s, has driven its popularity in the field of psychiatry and clinical psychology. The drug has been clinically approved for treatment-resistant depression (TRD) and is being studied for the treatment of other mental illnesses.

Ketamine’s novel mechanisms of action

Ketamine acts as an antagonist at the NMDA receptor, a glutamatergic, ligand-gated ion channel. As a quick refresher, gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that works to stabilize the levels of glutamate released in the brain. Glutamate is an excitatory neurotransmitter. Ketamine binds to the NMDA receptors found on GABA-eric interneurons and inhibits GABA release. By Inhibiting the release of GABA, more excitatory glutamate molecules become available in the cortex, via disinhibition, which may contribute to ketamine’s antidepressant effects.

Researchers are discovering that ketamine’s antidepressant mechanism of action is not solely dependent on its activity at the NMDA site.3 Ketamine activates α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) which are another major ionotropic, glutamate receptor (Figure 1). AMPARs are activated via glutamate release and subsequently induce the production of brain-derived neurotrophic factor (BDNF), a growth factor that possesses anti-depressant effects.

BDNF is also a factor in synaptic plasticity and its production can lead to resilience to chronic stress. The metabolites of ketamine also have antidepressant effects which are NMDA-independent. Ketamine’s metabolites (2R,6R)-HNK and (2S,6S)-HNK are released by the breakdown of ketamine and promote AMPAR-mediated synaptic potentiation.

Ketamine can be isolated into ‘R’ and ‘S’ Isomers

The racemic (50-50) mixture of ketamine can be consumed via different routes of administration—orally, nasally, intravenously. However, racemic mixtures can also be filtered to isolate one isomer.

Isomers are molecular structures with the same chemical formula but with a different molecular geometry. Some isomers, known as structural isomers, have atoms that are connected in different ways (consider butane and isobutane). However, in the case of ketamine’s R and S isomers, the atoms are connected in the same structural way but differ in their spatial orientation. Isomers differing in spatial orientation but maintaining structural similarity are known as stereoisomers.

While the R and S stereoisomers of ketamine look nearly identical, they are chiral molecules–meaning that they are non-superimposable mirror images. The preceding letters R and S are used to refer to the ‘handedness’ of the isomer. R indicates right-handed, or clockwise geometry, whereas S indicates left-handed, or counterclockwise geometry. Take for example human hands; when facing each-other they are mirror images. However, when rotated they cannot be indistinguishably placed over each other. Chiral molecules are also known in the field of chemistry as enantiomers. Though this difference between the enantiomers is seemingly small, each isomer of ketamine has unique neurochemical effects.

R and S Ketamine have different therapeutic ratios, meaning that isomers vary in the ratio needed to induce different therapeutic effects. Isomers may differ in their affinity for certain biological targets, which enables them to produce significantly different therapeutic effects from one another. Similarly, one isomer may have certain adverse effects compared to another. Studying isomer differences can shed light on the benefits of one isomer over a racemic mixture, or over the other.

Clinical differences between the effects of the R and S Isomers

Neither isomer has been studied extensively in human trials however, some research elucidates differences between them.

The S-isomer (also known as esketamine) is currently isolated and distributed for a higher cost than the racemic mixture. The isomer withstood a non-inferiority trial when compared to the racemic mixture, indicating equivalence between s-ketamine and racemic in treating depression. S-ketamine was FDA approved in 2019 for the treatment of TRD and is administered nasally as the drug Spravato.

Studies show that S-ketamine has a fourfold greater potency when it comes to inhibiting the NMDA receptor when compared to R-ketamine (also called arketamine). Its greater affinity at the NMDA receptor likely contributes to its selection by pharmaceutical companies in developing the drug. S-ketamine also has a greater analgesic potency; its analgesic potency is twice that of the racemate. For this reason, there is a preferential use of s-ketamine when it comes to anesthesia.

Surprisingly, the R-isomer shows longer-lasting anti-depressant effects compared to S-ketamine. A study on mice showed that R-ketamine increased prefrontal 5-HT (serotonin) at significantly greater levels than S-ketamine. Another study on mice suggests that R-ketamine produces less psychomimetic side-effects related to mobility, resulting in less distorting side-effects typically associated with ketamine.

Summary and conclusion

Ketamine acts as an NMDA receptor antagonist to produce novel antidepressant effects with both R and S isomers as well as the racemic displaying comparable anti-depressant effects. While esketamine is currently being touted as the major clinical resource for TRD, it is important to call attention to the varying effects of isomers.

Most studies that suggest evidence of differences between the isomers have been conducted using mice. However, some results suggest similar findings in humans. Scientists continue to study the mechanisms and effects of the ketamine R and S isomers. Understanding the complete pharmacology and effects of the racemic and other mixtures is a wide-open area in the field of psychedelic research. Much remains unknown about the effects of ketamine and the mechanisms of action of its metabolites, necessitating further research on the drug and its potential benefits.

 
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Insights into the neurophysiology of tryptamine-derived psychedelics*

by Justin R. Kulchycki, MS | Psychedelic Science Review | 14 Dec 2020

Brain imaging research reveals where psychedelic compounds such as psilocybin and LSD manifest their effects.

Given the recent clinical interest in psychedelic compounds, many researchers have sought to elucidate their mechanism of action from a neurophysiological perspective. These research teams are seeking to understand changes in brain activity between the psychedelic state and normal waking consciousness. More specifically, the goal of these studies is to characterize the networks and regions of the brain affected by psychedelic ingestion. This can be accomplished with functional magnetic resonance imaging (fMRI), which accurately produces real-time depictions of brain activity.

Effects of psilocybin on the Default Mode Network

A seminal 2012 study at Imperial College London was the first to use fMRI to characterize brain activity between psychedelic and non-psychedelic states. In this work, Carhart-Harris et al. used fMRI to record alterations in brain activity before and after injections of placebo and psilocybin. The paramount discovery was that psilocybin appeared to reduce overall cerebral blood flow. The brain regions which demonstrated the most consistent deactivation were the posterior cingulate cortex and the medial prefrontal cortex. These two regions reside in the default mode network (DMN), which refers to specific areas of the brain involved in various domains of cognitive and social processing, as well as autobiographical memory recollection.

In normal waking consciousness, activity in the posterior cingulate cortex and medial prefrontal cortex is relatively high compared with other regions of the brain. Interestingly, the degree to which activity in these regions was decreased was proportional to the intensity of the subjective effects reported by the volunteers. There is speculation that the posterior cingulate cortex is involved in consciousness, formulation of the self, and ego. The “ego-dissolution” phenomenon is a commonly reported experience following the administration of high doses of psychedelics. While this could be related to decreased posterior cingulate cortex activity, no direct quantitative relationship has been observed between the disintegration of the DMN and ego-dissolution.

A study published earlier this year from the University of Zurich also examined psilocybin-induced neurophysiological changes in volunteers. Like the previously mentioned study, this group used fMRI to capture changes in brain activity as the psilocybin-induced psychedelic state began to manifest in their volunteers. Their results supported the findings of the group at Imperial College London, in that associative regions become disintegrated with the rest of the brain upon psilocybin ingestion. Additionally, this study found that sensory areas of the brain, which are related to motor function, sensation, and visual perception become more integrated with the rest of the brain in the psychedelic state.

LSD demonstrates similar effects on the brain

The team at the University of Zurich also conducted a similar study with LSD, another tryptamine-derived hallucinogen. Observations regarding the neurophysiological effects of LSD are consistent with the two previously mentioned studies using psilocybin. LSD ingestion results in a decreased connectivity of associative regions of the brain, and increased integration of sensory and somatomotor regions. Moreover, participants who showed relatively higher connectivity in the somatomotor network also reported a higher intensity of subjective effects.

How do tryptamine psychedelics affect the whole brain?

A study from the Institute for Scientific Interchange in Turin, Italy indicates that psilocybin induces more persistent connections throughout the brain as a whole compared with normal waking consciousness. This work was conducted using the original fMRI data collected at Imperial College London. The researchers say psilocybin induces a more intercommunicative mode of brain function. This may mean there is more sharing of information between brain regions that don’t associate with each other in normal waking consciousness. Furthermore, the researchers speculate that this intercommunicative mode of brain function may be the root of the synesthesia phenomenon associated with the psychedelic experience.

Summary

Collectively, these studies help describe the neurobiological mechanisms of tryptamine-derived hallucinogens. The general observation is higher-level functional networks involved in various cognitives processes become less integrated, and sensory and somatomotor networks become more integrated. What’s more, there seem to be more persistent connections formed throughout the whole brain during the psychedelic state relative to normal waking consciousness. These studies add to the psychedelic knowledge base which other researchers can tap into for further investigation.

*From the article here :
 
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Can psychedelics boost brain growth factor levels?*

by Lily Aleksandrova, MSc, PhD | Psychedelic Science Review | 11 Oct 2020

Research suggests that BDNF can help rewire and overwrite stubborn neural pathways by creating new connections that facilitate more flexible and adaptive thoughts and behaviours. Psychedelics appear to tap into this mechanism.

Our ability to adapt to and survive in an ever-changing environment largely depends on our brain’s ability to change and adapt through growth and reorganization. Neuroplasticity is the process of growing new or reshaping existing connections between neurons. It is now recognized as the core mechanism behind how we are able to learn and remember – often simply put as “cells that fire together wire together.”

Neurotrophins (from Greek: “brain food or nourishment”) are growth factors released by activated brain cells, which act as fertilizer to trigger growth and rewiring in response to an event. Particularly, brain-derived neurotrophic factor (BDNF) regulates neuronal development and survival and triggers adaptive neuroplasticity.

Neuroplasticity and BDNF in health and disease

Importantly, threats to our well-being such as stress, ageing and depression are associated with decreases in BDNF levels, hindering the brain’s ability to effectively change and adapt.1–3 In chronically depressed patients, for example, impaired neuroplasticity can eventually lead to key brain areas actually shrinking, most prominently seen in the hippocampus, and to pronounced cognitive impairments such as rigid, negative thinking and memory loss.

On the other hand, boosting BDNF and neuroplasticity can be therapeutic, aiding recovery after physical brain injury (e.g. in stroke or Parkinson’s disease) or psychological stress/trauma (e.g. in depression or PTSD). Not coincidentally, things that are good for us – proper nutrition, exercise, deep sleep, meditation, environmental and social enrichment – all boost BDNF and the brain’s capacity to grow, rewire and heal, ultimately reshaping our neuroanatomy and, in turn, our outlook and behaviour.

Psychedelics can also boost BDNF in animal studies

Animal studies have reported that acute and chronic administration of various psychedelic compounds, including LSD, psilocybin, DMT, and other ayahuasca-derived alkaloids, can increase BDNF production and neurogenesis (the formation of new neurons). Findings vary widely depending on the species, compound, dose and frequency of administration used in a particular animal study. Curiously, sustained psychedelic treatment of mammalian neurons in a dish appears to consistently facilitate their growth, with LSD as the most potent drug reported.

Preclinical work with DMT shows that neuroplastic changes can take place even after low, sub-hallucinogenic doses. This represents an important finding, given the cultural and scientific interest in “microdosing.” Microdosing is defined as the repeated administration of psychedelics at low doses, usually several-fold lower than a recreational dose that causes a psychedelic experience (or ~10-20μg in the case of LSD).


LSD microdose increases blood BDNF in healthy participants

Despite the accumulating preclinical evidence, human data supporting the link between psychedelics, BDNF, and neuroplasticity are still very limited. Recently, a Dutch double-blind, placebo-controlled clinical trial was conducted to address this research question in the context of LSD microdosing in healthy volunteers.

A within-subject design was used, where individual subjects received both placebo and a single LSD microdose (5μg, 10μg or 20μg) during separate experimental sessions. Serial blood samples were collected before and after administration. Plasma levels of BDNF, known to reflect concentrations in the brain, were then measured using a validated antibody-based assay.

The study, which included a total of 27 participants, demonstrated that the relationship between LSD dose and resulting BDNF concentration is far from simple and linear. The data indicated that compared to placebo, LSD increased circulating BDNF levels at the 5μg dose with the effect peaking at 4h, as well as at the 20μg dose, producing a larger boost in BDNF that appears to peak after 6h.

Oddly, in the 10μg LSD group, the observed effect on BDNF failed to reach statistical significance. This is likely due to study limitations such as missing data points, variability in test groups, and the low number of subjects tested. Despite this, these encouraging preliminary findings show that low doses of LSD can acutely increase BDNF levels in healthy subjects, warranting future studies in patient populations. Similar to what has been previously observed with other compounds such as ketamine. LSD induces complex dose- and time-dependent changes in BDNF.

Rewiring the brain by taking the path less traveled

An important hallmark of disorders involving deficits in neuroplasticity is the presence of rigid, maladaptive and often destructive thought and behavioural patterns, which become ingrained over time. Exciting new research supports the therapeutic potential of neuroplasticity-based interventions, including psychedelic-assisted psychotherapy. Psychedelics can unlock a state of heightened neuroplasticity, which when combined with therapy, creates a window of opportunity for rewiring.

Thus, the stubborn neural pathways that cause emotional (or even physical) pain and distress, as in the case of depression, PTSD and even chronic pain, can be rapidly overwritten by new connections that facilitate more flexible and adaptive emotions, thoughts and behaviours. Ultimately, boosting the levels of BDNF can prime our brain to learn faster, remember better, grow stronger, age slower and stay resilient in the face of challenge.


*From the article here:
 
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Neuroscientists believe deep neural networks could help illustrate how psychedelics alter consciousness

by Eric Dolan | PsyPost | 5 Jan 2021

Cutting-edge methods from machine learning could help scientists better understand the visual experiences induced by psychedelic drugs such as dimethyltryptamine (DMT), according to a new article published in the scientific journal Neuroscience of Consciousness.

Researchers have demonstrated that “classic” psychedelic drugs such as DMT, LSD, and psilocybin selectively change the function of serotonin receptors in the nervous system. But there is still much to learn about how those changes generate the altered states of consciousness associated with the psychedelic experience.

Michael Schartner, a member of the International Brain Laboratory at Champalimaud Centre for the Unknown in Lisbon, and his colleague Christopher Timmermann believe that artificial intelligence could provide some clues about that process.

“For me, the most interesting property of brains is that they bring about experiences. Brains contain an internal model of the world which is constantly updated via sensory information, and some parts of this model are consciously perceived, i.e. experienced,” Schartner explained.

“If this process of model-updating is perturbed — e.g. via psychedelics — the internal model can go off the rails and may have very little to do with the actual world. Such a perturbation is thus an important case in the study of how the internal model is updated, as it can be directly experienced by the perturbed brain – and verbally reported.”

“The process of generating natural images with deep neural networks can be perturbed in visually similar ways and may offer mechanistic insights into its biological counterpart — in addition to offering a tool to illustrate verbal reports of psychedelic experiences,” Schartner said.

A deep neural network is what artificial intelligence researchers call an artificial neural network with multiple interconnected layers of computation. Such networks can be used to generate highly realistic images of human faces — including so-called “deep fake” images — and are also being used in facial recognition technology.

In a study published in Nature Communications, researchers found a striking similarity between how the human brain and deep neural networks recognize faces.
“Deep neural networks — the work horse of many impressive engineering feats of machine learning — are the state-of-the-art model for parts of the visual system in humans,” Schartner told PsyPost. “They can help illustrate how psychedelics perturb perception and can be used to guide hypotheses on how sensory information is prevented from updating the brain’s model of the world.”

Schartner was previously involved in research that found psychedelic drugs produced a sustained increase in neural signal diversity. His colleague Timmermann has authored research indicating that LSD decreases the neural response to unexpected stimuli while increasing it for familiar stimuli.
Both findings provided some insights into the brain dynamics that underlie specific aspects of conscious experience.

"But the neural correlates of consciousness are still far from clear,” Schartner said. “The ventral visual stream in human brains seems key for visual experiences but is certainly not sufficient. Also, the exact role of serotonin in the gating of sensory information is still to be explained. Another big open question is how exactly the feedback and feed-forward flows of neural activity need to be arranged to bring about any experience.”

He added: “Psychedelics are not only an important tool for fundamental research about the mind-body problem but they also showed promising results in the treatment of depression and anxiety.”

The study, “Neural network models for DMT-induced visual hallucinations“, was published December 12, 2020.

 
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The emerging revival of psychedelics in neuroscience

by Cami Rosso | Psychology Today | 13 Jan 2021

There’s a common saying that goes, “Everything old is new again.” Does this pithy maxim apply to psychedelics? Psychedelic drugs, also known as hallucinogens or psychotomimetic drugs, may be in the early stages of a neuroscience renaissance in the form of legal medication since its research heyday in the 1950s and early 1960s. On Monday, Culver-City-based Kernel, a brain-computer interface (BCI) pioneer, announced a partnership with Toronto-based biotech Cybin to apply Kernel’s Flow for real-time quantification of brain activity to conduct research on psychedelics for treatment of mental health disorders.

“The ability to collect quantitative data from our sponsored drug development programs with Kernel’s Flow is potentially game-changing in terms of our ability to measure where psychedelics work in the brain in real-time, and how we ultimately design our future therapeutics,” stated Doug Drysdale, CEO of Cybin, in a statement released on Monday.

In 2016, visionary entrepreneur, venture capitalist (OS Fund), and author Bryan Johnson founded Kernel with his own investment and is the current CEO. Johnson also founded Braintree, which acquired Venmo in 2012, and was later sold for USD 800 million in 2013 to PayPal Holdings, Inc., which was then a wholly owned subsidiary of eBay.

Recently Kernel made a brain-computer interface breakthrough with its non-invasive Neuroscience as a Service (NaaS) brain recording technologies called Flux and Flow. Flux catches the magnetic fields produced by brain activity, and Flow tracks cortical hemodynamics, or the brain’s blood flow. In July 2020, Kernel announced USD 53 million funding from General Catalyst, Khosla Ventures, Eldridge, Manta Ray, and Tiny Blue Dot.

Psychedelics are an emerging area of treatment for a wide range of disorders such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD), narcolepsy, treatment-resistant depression, and more mental health issues. The Cybin partnership with Kernel is just one example.

Last week, the Icahn School of Medicine at Mount Sinai in New York announced the launch of its Center for Psychedelic Psychotherapy and Trauma Research. The Center plans to research psychedelic compounds such as psilocybin and MDMA in efforts to discover novel therapeutics to help veterans and civilians who are struggling with depression, anxiety, PTSD, and similar stress conditions and mental health disorders.

Last month, psychedelic medicine startup Beckley Psytech raised GBP 14 million in equity funding from Jim Mellon, the British billionaire entrepreneur and founder of the longevity biopharma Juvenescence, Richard Reed, the co-founder of Innocent Drinks, and other investors. Beckley Psytech is researching a psychedelic agent called 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) that is structurally similar to other indoleamine hallucinogens like LSD. 5-MeO-DMT is found in nature from a variety of plants such as the calcium tree that is native to the Caribbean and South America, as well as certain species of toads, such as the Sonoran Desert toad, which is also known as the Colorado River Toad (Bufo alvarius).

In November 2020, billionaire Peter Thiel invested EUR 10 million (~USD 12 million) via Thiel Capital in Atai Life Sciences, a biotech accelerator with headquarters in Berlin that is focused on providing a platform for companies developing novel treatments for depression, mild traumatic brain injury, generalized anxiety disorder, PTSD, anxiety, and addiction using lead compounds that include psilocybin, MDMA derivatives, N, N-dimethyltryptamine, noribogaine, deu-mitragynine, N-acetlycysteine, deu-Etifoxine, arketamine, and ibogaine. Thiel was an early investor in Facebook, and the entrepreneur who co-founded PayPal, and Palantir Technologies, among other companies.

Johns Hopkins University’s psychedelics research center received USD 17 million in funding in 2019 from investors that include Tim Ferriss, the famed podcaster and author of The 4-Hour Workweek, WordPress co-founder Matt Mullenweg, TOMS founder and former Navy SEAL Blake Mycoskie, angel investor Craig Nerenberg, and the Steven & Alexandra Cohen Foundation. The Center for Psychedelic and Consciousness Research at Johns Hopkins Medicine aims to identify new treatments using psychedelics for various diseases such as addiction, PTSD, post-treatment Lyme disease syndrome, anorexia nervosa, alcohol use with patients with major depression, and Alzheimer’s disease.

In the spring of 2019, the U.S. Food and Drug Administration (FDA) approved Spravato (esketamine), a nasal spray by Johnson & Johnson that is a chemical similar to anesthetic ketamine, and used for treatment-resistant major depressive disorder. The fast-acting antidepressant is a glutamate NMDA (N-methyl-D-aspartate) receptor modulator, which are associated with synaptic plasticity.

There is a global need for mental health therapeutics. Over 264 million people globally suffer from depression according to a 2017 Global Health Metrics study that was funded by the Bill & Melinda Gates Foundation and later published in The Lancet. An estimated eight million adult Americans have PTSD during a given year according to the U.S. Department of Veterans Affairs. In 2017, roughly 792 million people worldwide suffer from a mental health disorder according to Our World in Data.

With new investments and neuroscience breakthroughs, visionary entrepreneurs, cutting-edge biotech startups, research scientists, and pharmaceutical companies are trailblazing with novel therapeutics and rapidly thawing the psychedelic winter.

 
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Harmine found to stimulate generation of human neural cells*

D'Or Institute for Research and Education | Science Daily | 7 Dec 2016

Harmine increases the number of neural progenitors, cells that give rise to neurons, study suggests

Ayahuasca is a beverage that has been used for centuries by Native South-Americans. Studies suggest that it exhibits anxiolytic and antidepressant effects in humans. One of the main substances present in the beverage is harmine, a beta-carboline which potential therapeutic effects for depression has been recently described in mice.

Human neural progenitors exposed to harmine, an alkaloid presented at the psychotropic plant decoction ayahuasca, led to a 70 percent increase in proliferation of these cells. The effect of generating new human neural cells involves the inhibition of DYRK1A, a gene that is over activated in patients with Down syndrome and Alzheimer's Disease. Thus harmine could have a potential neurogenesis role and possibly a therapeutic one over cognitive deficits.

"It has been shown in rodents that antidepressant medication acts by inducing neurogenesis. So we decided to test if harmine, an alkaloid with the highest concentration in the psychotropic plant decoction ayahuasca, would trigger neurogenesis in human neural cells," said Vanja Dakic, PhD student and one of the authors in the study.

In order to elucidate these effects, researchers from the D'Or Institute for Research and Education (IDOR) and the Institute of Biomedical Sciences at the Federal University of Rio de Janeiro (ICB-UFRJ) exposed human neural progenitors to this beta-carboline. After four days, harmine led to a 70% increase in proliferation of human neural progenitor cells.

Researchers were also able to identify how the human neural cells respond to harmine. The described effect involves the inhibition of DYRK1A, which is located on chromosome 21 and is over activated in patients with Down syndrome and Alzheimer's Disease.

"Our results demonstrate that harmine is able to generate new human neural cells, similarly to the effects of classical antidepressant drugs, which frequently are followed by diverse side effects. Moreover, the observation that harmine inhibits DYRK1A in neural cells allows us to speculate about future studies to test its potential therapeutic role over cognitive deficits observed in Down syndrome and neurodegenerative diseases," suggests Stevens Rehen, researcher from IDOR and ICB-UFRJ.

*From the article here :
 
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Psilocybin and Neurogenesis*

by Patrick Smith | Entheonation

Neurogenesis and neuroplasticity are two terms you might have heard before – especially if you’ve been learning about psychedelics.

Our brains have the potential to change and grow over the course of our lives, and if they are more “plastic” in later life we are less likely to suffer from depression, and we may find it easier to learn new things. Psychedelics have been shown to have the potential to boost this neuroplasticity in our brains.

Psilocybin, the main psychedelic ingredient of magic mushrooms, has an important link to neurogenesis and neuroplasticity. An important study shows that psilocybin can influence neuroplasticity in rodent brains – but the direction of the effect depends on dosage.

Since microdosing with magic mushrooms is one of the easiest ways to bring psilocybin into your daily life, could the neuroplastic effects of magic mushrooms be most effective and accessible in small doses? We investigate here…​

What are neurogenesis and neuroplasticity?

Neurogenesis is the specific term for the growth of new brain cells – but it falls under the umbrella of neuroplasticity. Neuroplasticity is the term used to describe pretty much any change in the way brain cells (neurons) connect to each other, grow, and communicate.

There are six main forms of neuroplasticity (including neurogenesis), which we’ve illustrated here:​
  1. Changes in the number of connections between neurons​
  2. Changes in where neurons connect to each other​
  3. The growth of brand new neurons (neurogenesis)​
  4. Changes in the strength of the connections between neurons (also known as synaptic plasticity)​
  5. Changes in the response of neurons to signals​
Although all brains are capable, to some extent, of neuroplasticity – most of the changes in the brain happen in childhood. Our adult brains stay pretty stable. This is why boosts in neuroplasticity in adulthood are special, and usually have pretty healing effects!​

What are the benefits of neurogenesis and neuroplasticity?

Although research into neuroplasticity is still in its infancy, we know some of the benefits of increases in neuroplasticity in adult mammals.

Loads of evidence suggests that neuroplasticity in one particular area of the brain, the hippocampus, is crucial for learning and memory. When both humans and rodents are learning tasks, or remembering patterns, the hippocampus is very active – and synaptic plasticity (changes in the strength of the connections between neurons) seems to be a crucial part of this.

There’s also a strong connection between neuroplasticity and the fight against depression. People with depression are more likely to have signs of reduced numbers of neurons and connections between neurons across different areas of the brain. This is thought to be how some of the most common antidepressants work; by boosting neuroplasticity.

In general, the research into neuroplasticity suggests that having a brain capable of changing its structure and activity may help you adapt more quickly to new information, and be more flexible – skills that are crucial in psychological wellbeing.

Pursuits such as exercise and meditation have been proven to boost neuroplasticity, and changing to a diet that includes less sugar and fat, and superfoods like walnuts and blueberries, has been shown to increase neuroplasticity in rodents.​

Psilocybin, neurogenesis and neuroplasticity

As well as changes to your lifestyle, taking psychedelics can also influence neuroplasticity. Studies using both psilocybin and other common psychedelics have shown how they can change the connectivity and growth of neurons.

LSD and DMT have been shown to help rat neurons create more complex connections between each other, and the psychoactive components of the ayahuasca vine have been shown to boost the growth of mouse neurons.8,9 But the results with psilocybin aren’t as clear cut…

One study in mice found that small doses (0.1mg/kg) of psilocybin increased the growth of new brain cells in the hippocampus, while high doses (1mg/kg) reduced this growth. Although we don’t know for sure that something similar is happening in humans, it suggests that dosage could be really important if you’re using psychedelics to boost neuroplasticity!

However, while small doses of psilocybin may be better at boosting the growth of brain cells, we know that larger doses are effective at changing the way neurons communicate. Studies show that typical tripping doses of psilocybin allows neurons to connect with each other along unusual pathways, and then reset themselves into a more stable and healthy configuration after the trip. This kind of neuroplasticity is much more about the patterns of connection throughout the brain, rather than the growth of new cells in particular areas – but it can be particularly important for the fight against depression.​

How to use psilocybin to boost neuroplasticity

From the research we have so far, it seems that small doses of psilocybin are more likely to boost neurogenesis (the growth of new brain cells), while larger doses have a greater effect on the connectivity between brain cells. While both of these types of neurogenesis and neuroplasticity could likely impart benefits such as increased creativity, reduced depressive symptoms, and boosted psychological flexibility, it’s hard to know which is better.

There is plenty of evidence that shows a single moderate or high dose of psilocybin can have therapeutic effects, especially in the treatment of depression and anxiety. So if you’re looking for an immediate and powerful boost to neuroplasticity, a magic mushroom retreat or ceremony where larger doses are used might be your best option.

Conversely, there is barely any research into the effects of microdosing with magic mushrooms, so we don’t know for sure the role of neurogenesis or neuroplasticity with small doses. Taking what we can from the study on mice, we know that doses closer to a microdose (around 1-2mg of psilocybin) seem to boost neurogenesis more than larger doses – it’s just hard to know what this means for humans, and whether a microdosing regimen will be overall more beneficial for neuroplasticity than a single large dose.

Despite the lack of evidence, what we do know is how to amplify any benefits to neuroplasticity if you’re microdosing with magic mushrooms…

How to microdose with magic mushrooms for neuroplasticity

If you’re new to microdosing with magic mushrooms, check out our Seeker’s Guide for an introduction. But if you want to microdose with magic mushrooms specifically for neuroplasticity, you should also try to combine your microdosing with some additional practices.

There’s a lot of evidence connecting wellbeing practices with neuroplasticity, so to maximize any neuroplasticity benefits you should incorporate these things as much as you can:​
  • Yoga and exercise. Increases in neuroplasticity could help you learn new exercise routines faster than normal, and help them remain a permanent fixture on your calendar.​
  • Meditation or regular affirmation (prayer). You may find meditation easier to learn if magic mushrooms are giving you a boost in neuroplasticity, and meditation has also been proven to increase neuroplasticity in itself.​
  • Healthy dieting. Microdosing may be the best time to try out a new, healthier diet, as you may find it easier to stick to – and switching away from high-fat high-sugar diets has been shown to increase neuroplasticity.​
  • Therapy or counseling. If a boost in neuroplasticity is helping improve your psychological flexibility, now may be the perfect time to get professional guidance in how to best apply any increased capacity for self-reflection.​
Making these pursuits part of your microdosing routine could not only help to maximize any boost in neuroplasticity that psilocybin gives you, but the effects of microdosing could also help you adapt to these lifestyle changes much faster than normal! Many people report that microdosing helps them enjoy exercise more, or actually get joy from changing to a healthier diet.

As always, when microdosing with magic mushrooms for neuroplasticity you should be keeping a journal to help monitor any effects and find your perfect dose. You should stop if you feel any negative effects, and even if you are feeling great during your regimen you should never microdose for more than three months at a time.

*From the article here :
 
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Engineering psychoplastogens: Toward a safer alternative for treating depression*

by Veronica Migliozzi, MSc | Psychedelic Science Review | 14 Jan 2021

Identification of psychoplastogenic isoDMT analogs is a concrete step forward in using psychedelics for treating patients who suffer from depression.

Depression is the most common and debilitating mental disease, causing various symptoms that affect both the way a person feels and their daily activities. It induces excessive rumination in patients who also start to manifest a decrease in self-confidence and increases in guilt and helplessness.

A recent report from the World Health Organization stated that at a global level, over 300 million people are estimated to suffer from depression. This is equivalent to about 4.4% of the world’s population.

Although traditional antidepressants such as selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NERIs), and tricyclics have been enjoying some success in treating people with this disorder, two main issues need to be addressed:
  1. Approximately one-third of patients do not show response to any class of antidepressant, while others respond only partially.
  2. Their effects on plasticity in the brain are quite slow and require chronic administration.

Neural plasticity and the neurotrophic hypothesis

Neural plasticity is the ability of the brain to change and adapt in response to stimuli2. Its dysregulation has been identified as a contributing factor to depression.

In fact, the neurotrophic hypothesis posits that a loss of trophic support in the prefrontal cortex (PFC) and the hippocampus leads to atrophy of these brain regions, which ultimately disrupts critical mood-regulating circuits.2 Traditional antidepressants can counteract these structural changes, such as the retraction of neurites, loss of dendritic spines, and elimination of synapses. And, by increasing the expression of brain-derived neurotrophic factor (BDNF), they promote the growth of neurons in both PFC and hippocampus.

Nevertheless, in a 2018 paper, Calvin Ly et al. suggested another class of compounds called psychoplastogens that might have value as fast-acting antidepressants with efficacy in patients who do not respond to traditional ones.

What are psychoplastogens?

The term psychoplastogen was first introduced in 2018 by a research team led by Calvin Ly. It describes a growing number of compounds capable of rapidly promoting structural and functional neural plasticity. Coming from Greek words psych-= mind, –plast= molded, and –gen=producing, this class includes psychedelics such as N,N-Dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin as well as the dissociative anesthetic ketamine.

Working through a similar molecular mechanism, both serotonergic psychedelics and ketamine produce a measurable change in plasticity (e.g. neurite growth, dendritic spine density, synapse number, intrinsic excitability, etc.) within a short period of time (typically 24-72 hours) following a single administration.

Molecularly speaking, psychoplastogens appear to induce changes in neuronal structure by activating mTOR, the mammalian target of rapamycin. mTOR belongs to the protein kinase family of enzymes and is involved in cell growth, autophagy, and the production of proteins necessary for synapse formation.

However, in a 2018 paper, Dr. David Olson pointed out that although extremely promising, ketamine, for example, is still far from an ideal therapeutics as it has the potential for abuse. For this reason, he and his colleagues focused their attention on psychedelics as psychoplastogenic compounds that could be used to treat depression. Moreover, Dr. Olson explained that...
Although our cellular studies have shown that a wide variety of psychedelic compounds produce psychoplastogenic effects, our in vivo work thus far has primarily focused on the effects of DMT— the archetype for all tryptamine-containing psychedelics.

However, another issue needed to be addressed by Dr. Olson. Many DMT derivatives such as noribogaine, LSD, and psilocin (shown in Figure A) are well known as potent psychedelics. This is the main adverse effect in treating patients suffering from depression with psychedelics.

Working on DMT: Engineering isoDMT analogues

Two years later in a 2020 paper, Lee E. Dunlap collaborated with Dr. Olson to investigate how to decrease the hallucinogenic potential of psychedelics.

Extending on the extraordinary work of Glennon and colleagues in 1984, Dunlap and his team began by analyzing the efficacy of small series of compounds called isoDMT (N, N-Dimethylaminoisotryptamine) analogs. These molecules are well-validated to be less psychedelic than DMT. Nevertheless, their power in maintaining the ability to promote plasticity in depression still works as well as their fast-acting antidepressant properties.

Chemically, isoDMT is identical to DMT except that the indole nitrogen atom of isoDMT is located in the 3-position instead of the 1-position.

Usually, the synthesis of isoDMT and related analogs requires multiple steps and harsh conditions. On the contrary, Dunlap’s lab developed an operationally simple and robust method for synthesizing a variety of isoDMTs.

In principle, related analogs could be accessed in a single step through N-alkylation of the corresponding indoles or related heterocycles.

The Dendritogenesis Assay

In the same paper, Dunlap and colleagues used a phenotypic assay to test the ability of isoDMTs analogs to increase dendritic arbor complexity in cultures of cortical neurons. The results of the assay compared the ability of DMT, isoDMT, and some isoDMT analogs to increase dendritic arbor complexity.

The data indicated that although isoDMT and its analogs have the indole N-H at a different ring location than DMT, they still increased dendritic arbor complexity.

Moreover, Dunlap et al. confirm the hypothesis that a basic nitrogen atom is necessary to promote plasticity. In fact, compounds such as the N,N-dimethylamide analog of isoDMT did not promote neuronal growth.


Psychedelic potential

In the same work, Dunlap and his colleagues analyzed the affinity of isoDMTs for the serotonergic receptor 5-HT2A and their ability to elicit a mouse head-twitch response (HTR), a well-validated behavioral proxy for hallucinations. Two extraordinary results were observed:
  1. Despite their chemical modification, the isoDMTs still retained the affinity for 5-HT2A receptors as compared to their DMT counterparts.
  2. Mice treated with isoDMTs did not produce any HTR, demonstrating that psychedelic potential and psychoplastogenity can be decoupled.
Conclusion

In present-day society, depression is at the heart of peoples’ everyday lives shaping their feelings, thoughts, and behaviors. Nowadays, traditional antidepressants are usually prescribed to treat this condition. However, these treatments still lack efficacy sometimes, have a slow mechanism of action, and also require chronic administration.

Working with psychoplastogens, Drs. Olson and Dunlap and their colleagues have developed molecules with a much safer profile highlighting their efficacy in maintaining a strong therapeutic potential without being psychedelic. Taken together, these findings not only offer a glimmer of hope in treating patients suffering from depression, but they may also represent a step forward in the decriminalization and the demystification of psychedelic research.

*From the article here :
 
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Psychedelic Neuroimaging

by Ruth Williams | The Scientist

“Ego dissolution,” and other things that happen to the human brain on LSD.

Two papers—one published in PNAS and another in Current Biology—report how brain activity is altered in people given doses of lysergic acid diethylamide (LSD). Using two different brain imaging approaches, the authors of both studies detailed the particular changes in activity that associate with arguably the best-known effects of LSD: visual hallucinations and an increased sense of unity with one’s surroundings—referred to in the Current Biology paper as “ego dissolution.”

“This work is very important with regards to the insights it gives us on how hallucinogens, specifically LSD, affect the brain,” said psychiatrist and behavioral scientist Charles Grob of the University of California, Los Angeles, who was not involved in either study. “Now we have a better understanding of the neurobiological substrate for the psychedelic experience.”

Research into psychedelic drugs, such as LSD and psilocybin—the hallucinogenic component in magic mushrooms—took a nosedive in the 1960s and 70s, following the banning of these substances. “Research with humans was not occurring in the United States and Europe from [then on],” said Grob. By the 90s and 2000s, research on these drugs started to slowly pick up, Grob said, reflecting a “greater receptivity on the part of the regulatory agencies to allow this sort of research.”

Previous studies have suggested that compounds like LSD, in combination with psychotherapy, could be effective treatments for alcoholism, anxiety, and tobacco addiction, among other things.

Aside from their potential clinical use, the drugs also offer insight into the nature of consciousness itself, said cognitive and computational neuroscientist Anil Seth of the University of Sussex, U.K., who also did not participate in the work. “One of the main ways to try to understand the neural basis of consciousness is to try to induce different kinds of experience and see what happens in the brain,” he said, and “LSD is a very potent way of manipulating somebody’s experience of the world and of themselves.”

To examine LSD’s effects, Imperial College London’s David Nutt and Robin Carhart-Harris together with their colleagues recruited 20 healthy volunteers, all of whom had reported taking a psychedelic drug at least once before. The subjects were given injections of 75 micrograms of LSD—“equivalent to about one blotter of LSD taken orally and recreationally,” said Carhart-Harris—and then their brains were analyzed by functional magnetic resonance imaging (fMRI) and magnetoencephalographies (MEG). In addition, the volunteers were asked to rate various aspects of their experiences and to answer an Altered States of Consciousness questionnaire. As a control, the subjects’ brains were analyzed a couple of weeks before or after the LSD analyses, at which point they were given a saline placebo injection.

Connecting the participants’ ratings and questionnaire answers to the imaging data, the team found that LSD-induced visual hallucinations correlated with an increase in cerebral blood flow to the visual cortex, a pronounced increase in connectivity between the visual cortex and other brain regions, and a decrease in the power of visual cortex alpha waves, which are thought to generally inhibit neural activity. The authors suggested that this reduced alpha power may allow uninhibited visual cortex activity, which—together with the increased connectivity between normally unrelated brain regions—could help explain the subjects’ ability to visualize unusual images even with their eyes closed.

Aside from the increased connections with the visual cortex, LSD induced a global increase in connectivity across the brain, which was correlated with the participants’ sense of ego dissolution. In contrast, connections within specific systems, such as the default mode network, appeared to reduce.

“If you look at connectivity within [known] systems, what you see with both psilocybin and LSD is a weakening of connections,” said Carhart-Harris. “But when you look at the relationships between the different systems . . . they relate to each other much more.” Overall, the result appears to be a “unified, more integrated brain,” he said.

Understanding the neurobiological basis of ego dissolution is particularly interesting, because “this break down of self-referential processing may be the driver of clinical change,” said cognitive neuroscientist Fred Barrett of the Johns Hopkins School of Medicine in Baltimore who was not involved in the work. Put another way, it is this ego-dissolving, mind-expanding aspect of the psychedelic experience that seems to be associated with the drugs’ treatment successes.

It’s possible that psychedelic drugs offer a “re-equilibration of connectivity,” said Grob. “Patterns of a [psychiatric] disorder are often entrenched,” he added, “and there maybe some value in loosening things up.”

 
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The Nuances of Ketamine’s Neurochemistry

by Melody Pezeshkian, BS | Psychedelic Science Review | 15 Feb 2021

What's similar and different about the R and S isomers of ketamine?

Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, can produce antidepressant effects more rapidly than current first-line treatments for depression. Ketamine is a racemic (50-50 mixture of the R and S isomers) drug known for its dissociative, anesthetic, and antidepressant effects. Ketamine’s novel mechanism of action, contrasting to that of typical SSRI’s, has driven its popularity in the field of psychiatry and clinical psychology. The drug has been clinically approved for treatment-resistant depression (TRD) and is being studied for the treatment of other mental illnesses.​

Ketamine’s novel mechanisms of action

Ketamine acts as an antagonist at the NMDA receptor, a glutamatergic, ligand-gated ion channel.3 As a quick refresher, gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that works to stabilize the levels of glutamate released in the brain. Glutamate is an excitatory neurotransmitter. Ketamine binds to the NMDA receptors found on GABA-eric interneurons and inhibits GABA release. By Inhibiting the release of GABA, more excitatory glutamate molecules become available in the cortex, via disinhibition, which may contribute to ketamine’s antidepressant effects.

Researchers are discovering that ketamine’s antidepressant mechanism of action is not solely dependent on its activity at the NMDA site. Ketamine activates α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) which are another major ionotropic, glutamate receptor. AMPARs are activated via glutamate release and subsequently induce the production of brain-derived neurotrophic factor (BDNF), a growth factor that possesses anti-depressant effects.

BDNF is also a factor in synaptic plasticity and its production can lead to resilience to chronic stress. The metabolites of ketamine also have antidepressant effects which are NMDA-independent. Ketamine’s metabolites (2R,6R)-HNK and (2S,6S)-HNK are released by the breakdown of ketamine and promote AMPAR-mediated synaptic potentiation.

Ketamine can be isolated into ‘R’ and ‘S’ isomers

The racemic (50-50) mixture of ketamine can be consumed via different routes of administration—orally, nasally, intravenously. However, racemic mixtures can also be filtered to isolate one isomer.

Isomers are molecular structures with the same chemical formula but with a different molecular geometry. Some isomers, known as structural isomers, have atoms that are connected in different ways (consider butane and isobutane). However, in the case of ketamine’s R and S isomers, the atoms are connected in the same structural way but differ in their spatial orientation. Isomers differing in spatial orientation but maintaining structural similarity are known as stereoisomers.

While the R and S stereoisomers of ketamine look nearly identical, they are chiral molecules–meaning that they are non-superimposable mirror images. The preceding letters R and S are used to refer to the ‘handedness’ of the isomer. R indicates right-handed, or clockwise geometry, whereas S indicates left-handed, or counterclockwise geometry. Take for example human hands; when facing each-other they are mirror images. However, when rotated they cannot be indistinguishably placed over each other. Chiral molecules are also known in the field of chemistry as enantiomers. Though this difference between the enantiomers is seemingly small, each isomer of ketamine has unique neurochemical effects.

R and S Ketamine have different therapeutic ratios, meaning that isomers vary in the ratio needed to induce different therapeutic effects. Isomers may differ in their affinity for certain biological targets, which enables them to produce significantly different therapeutic effects from one another. Similarly, one isomer may have certain adverse effects compared to another. Studying isomer differences can shed light on the benefits of one isomer over a racemic mixture, or over the other.​

Clinical differences between the effects of the R and S isomers

Neither isomer has been studied extensively in human trials however, some research elucidates differences between them.

The S-isomer (also known as esketamine) is currently isolated and distributed for a higher cost than the racemic mixture. The isomer withstood a non-inferiority trial when compared to the racemic mixture, indicating equivalence between s-ketamine and racemic in treating depression. S-ketamine was FDA approved in 2019 for the treatment of TRD and is administered nasally as the drug Spravato.

Studies show that S-ketamine has a fourfold greater potency when it comes to inhibiting the NMDA receptor when compared to R-ketamine (also called arketamine). Its greater affinity at the NMDA receptor likely contributes to its selection by pharmaceutical companies in developing the drug. S-ketamine also has a greater analgesic potency; its analgesic potency is twice that of the racemate.5 For this reason, there is a preferential use of s-ketamine when it comes to anesthesia.

Surprisingly, the R-isomer shows longer-lasting anti-depressant effects compared to S-ketamine.3,6 A study on mice showed that R-ketamine increased prefrontal 5-HT (serotonin) at significantly greater levels than S-ketamine. Another study on mice suggests that R-ketamine produces less psychomimetic side-effects related to mobility, resulting in less distorting side-effects typically associated with ketamine.​

Summary and conclusion

Ketamine acts as an NMDA receptor antagonist to produce novel antidepressant effects with both R and S isomers as well as the racemic displaying comparable anti-depressant effects. While esketamine is currently being touted as the major clinical resource for TRD, it is important to call attention to the varying effects of isomers.

Most studies that suggest evidence of differences between the isomers have been conducted using mice. However, some results suggest similar findings in humans. Scientists continue to study the mechanisms and effects of the ketamine R and S isomers. Understanding the complete pharmacology and effects of the racemic and other mixtures is a wide-open area in the field of psychedelic research. Much remains unknown about the effects of ketamine and the mechanisms of action of its metabolites, necessitating further research on the drug and its potential benefits.

 
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Intl Brain Laboratory at Champalimaud Centre for the Unknown

Deep neural networks could help illustrate how psychedelics alter consciousness*

by Eric Dolan | PsyPost | 5 Jan 2021

Cutting-edge methods from machine learning could help scientists better understand the visual experiences induced by psychedelic drugs such as dimethyltryptamine (DMT), according to a new article published in the scientific journal Neuroscience of Consciousness.

Researchers have demonstrated that “classic” psychedelic drugs such as DMT, LSD, and psilocybin selectively change the function of serotonin receptors in the nervous system. But there is still much to learn about how those changes generate the altered states of consciousness associated with the psychedelic experience.

Michael Schartner, a member of the International Brain Laboratory at Champalimaud Centre for the Unknown in Lisbon, and his colleague Christopher Timmermann believe that artificial intelligence could provide some clues about that process.

“For me, the most interesting property of brains is that they bring about experiences. Brains contain an internal model of the world which is constantly updated via sensory information, and some parts of this model are consciously perceived, i.e. experienced,” Schartner explained.

“If this process of model-updating is perturbed — e.g. via psychedelics — the internal model can go off the rails and may have very little to do with the actual world. Such a perturbation is thus an important case in the study of how the internal model is updated, as it can be directly experienced by the perturbed brain – and verbally reported.”

“The process of generating natural images with deep neural networks can be perturbed in visually similar ways and may offer mechanistic insights into its biological counterpart — in addition to offering a tool to illustrate verbal reports of psychedelic experiences,”
Schartner said.

A deep neural network is what artificial intelligence researchers call an artificial neural network with multiple interconnected layers of computation. Such networks can be used to generate highly realistic images of human faces — including so-called “deep fake” images — and are also being used in facial recognition technology.

In a study published in Nature Communications, researchers found a striking similarity between how the human brain and deep neural networks recognize faces.

“Deep neural networks — the work horse of many impressive engineering feats of machine learning — are the state-of-the-art model for parts of the visual system in humans,” Schartner told PsyPost. “They can help illustrate how psychedelics perturb perception and can be used to guide hypotheses on how sensory information is prevented from updating the brain’s model of the world.”

Schartner was previously involved in research that found psychedelic drugs produced a sustained increase in neural signal diversity. His colleague Timmermann has authored research indicating that LSD decreases the neural response to unexpected stimuli while increasing it for familiar stimuli.

Both findings provided some insights into the brain dynamics that underlie specific aspects of conscious experience.

"But the neural correlates of consciousness are still far from clear,” Schartner said. “The ventral visual stream in human brains seems key for visual experiences but is certainly not sufficient. Also, the exact role of serotonin in the gating of sensory information is still to be explained. Another big open question is how exactly the feedback and feed-forward flows of neural activity need to be arranged to bring about any experience.”

He added: “Psychedelics are not only an important tool for fundamental research about the mind-body problem but they also showed promising results in the treatment of depression and anxiety.”

*From the article here :
 
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New evidence that a single dose of psilocybin can boost brain connections*

by Eric Dolan | PsyPost | 18 Mar 2021

Scientists in Denmark believe the psychedelic substance psilocybin might produce rapid and lasting antidepressant effects in part because it enhances neuroplasticity in the brain. Their new research, published in the International Journal of Molecular Sciences, has found evidence that psilocybin increases the number of neuronal connections in the prefrontal cortex and hippocampus of pig brains.

Psilocybin — the active component in so-called “magic” mushrooms — has been shown to have profound and long-lasting effects on personality and mood. But the mechanisms behind these effects remain unclear. Researchers at Copenhagen University were interested in whether changes in neuroplasticity in brain regions associated with emotional processing could help explain psilocybin’s antidepressant effects.

“Both post-mortem human brain and in vivo studies in depressed individuals have shown a loss of synapses through the down-regulation of synaptic proteins and genes,” the authors of the study wrote. “Hence, upregulation of presynaptic proteins and an increase in synaptic density may be associated with the potential antidepressive effects of psychedelics.”

The researchers had previously conducted tests to establish the proper dose of psilocybin needed to produce psychoactive effects in pigs, who were examined because their brains are anatomically similar to the brains of humans.

A group of 12 pigs received a psychoactive dose of psilocybin, while a separate group of 12 pigs received inert saline injections. Half of the pigs were euthanized one day after the administration of psilocybin, while the rest were euthanized one week later.

An examination of brain tissue from the hippocampus and prefrontal cortex revealed increases in the protein SV2A in pigs who had received psilocybin. SV2A, or synaptic vesicle glycoprotein 2A, is commonly used as a marker of the density of synaptic nerve endings in the brain. SV2A is typically reduced in patients with major depressive disorder.

“We find that a single dose of psilocybin increases the presynaptic marker SV2A already after one day and that it remains higher seven days after,” the researchers said, adding that the “increased levels of SV2A after intervention with a psychedelic drug adds to the scientific evidence that psychedelics enhance neuroplasticity, which may explain the mechanism of action of its antidepressant properties.”


 
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Predicting the addictive potential of phenethylamines*

by Benjamin Malcolm | Spirit Pharmacist | 16 Jan 2021

Phenethylamine (PEA) is both a naturally occurring neurotransmitter and chemical backbone for several other types of medications and neurotransmitters. Legendary psychedelic chemist Alexander Shulgin synthesized dozens of novel psychedelic phenethylamines that he documents in his and his wife’s book PIHKAL (Phenethylamines I have Known and Loved). He is credited with re-synthesizing MDMA as well as inventing designer phenethylamines such as 2CB.

Types of phenethylamines

Phenethylamines are much broader than a class of psychedelics and are primarily known as ‘sympathomimetics’ because of their actions on the sympathetic (fight or flight) nervous system. Catecholamine neurotransmitters like norepinephrine and dopamine as well as the hormone epinephrine are the chemical mediators of sympathetic neurotransmission and drugs derived from phenethylamine traditionally used of therapeutic purposes mimic their actions.

Non-psychoactive phenethylamines include bronchodilator medications used for asthma such as albuterol while psychoactive phenethylamines include psychostimulants such as amphetamine, methamphetamine, and cathinones (‘bath salts’). Psychostimulants such as amphetamine act as ‘releasers’ of norepinephrine and dopamine, which stimulate the sympathetic nervous system. It is release of dopamine in the central nervous system that is thought to drive the habituating and addictive potentials of amphetamine. Thus, paying attention to dopamine releasing effect of phenethylamines is an important clue in understanding risk for habituation, re-enforcement, or addiction.

Image Source: Foundation to Psychedelic Pharmacology

The psychedelic phenethylamines tend to act as ‘releasers’ of serotonin and be able to bind 5HT2A receptors, although preserve some of the effects of traditional stimulants by acting on norepinephrine or dopamine. They are hybrids between traditional stimulants and psychedelics. The prototype psychedelic phenethylamine is 3,4-methylendioxymethamphetamine (MDMA). MDMA tends to be euphoric and preserve the ego structure. It carries some risks of habituation, dependence, or addiction linked to release of dopamine. MDMA tends to distort sensory perceptions or cause hallucinations much less than classical tryptamine psychedelics (e.g. psilocybin, LSD, DMT). For these reasons one may consider MDMA more of a serotonergic amphetamine than a true psychedelic.

Comparative pharmacology of amphetamine, MDMA and 4-MMC: Dopamine & duration of action

The degree of effect on dopamine neurotransmission and duration of action appear to help guide understanding of habituation. When comparing phenethylamine psychedelics like MDMA with novel designer phenethylamines, substances with higher release of dopamine and shorter duration of action can tempt the user to frequently re-dose. For example, when comparing the actions of mephedrone (4-methylmethcathinone or 4-MMC) with MDMA it is noted that MDMA has considerably less dopamine release than mephedrone and that mephedrone has dopamine release similar to amphetamine. In addition, mephedrone also has a much shorter half-life than MDMA meaning that pleasurable effects wear off sooner. Frequent re-dosing creates a stacking of physical effects, the risks of behavioral reinforcement and addiction as well as adverse reactions such as cardiovascular events, seizures, or psychosis increases.

None of this is to raise alarm bells about the addictive potential of MDMA or demonize amphetamine and cathinones. On the contrary, if we know traditional stimulants can be therapeutic and know that serotonergic psychedelics can also be therapeutic, drugs that hybridize their effects deserve thorough exploration for therapeutic potentials. The point is that the mechanisms of phenethylamine psychedelics are rather broad and tends to differentially effect serotonin, norepinephrine, and dopamine neurotransmitter systems. Psychedelic actions and effects occur due to release of serotonin and modulation of ‘psychedelic’ 5HT2A receptors while propensity for re-dosing and habituation is linked to duration of action and effects on dopamine. Chemical fingerprinting of psychedelic phenethylamines across neurotransmitter systems and measurement of basic pharmacokinetic parameters may guide harm reduction efforts as drugs with high potential for habituation and re-dosing are identified among the sea of alphabet-amines (phenethylamine psychedelics) available in today’s clandestine marketplaces.

*From the article here :
 
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Albert Hofmann

Study reveals how LSD leads to greater brain flexibility

by Kristi Pahr | LUCID NEWS | 12 Mar 2021

Research into consciousness has been gaining ground lately, but the majority of the studies have revolved around the loss of consciousness: sleep, anesthesia, and coma. A recent paper delves into LSD’s impact on consciousness in the waking brain – and the results are unexpected.

Research recently published in the journal NeuroImage shows that LSD allows the normally strict neuronal pathways in the brain to become more flexible, allowing the brain to explore and make connections separate from those that are typically allowed by brain structure.

“In general, integration and segregation of information are fundamental properties of brain function: we found that LSD has specific effects on each,” says Andrea Luppi, Ph.D. candidate at the University of Cambridge and lead author of the study. “We also know that brain structure has a large influence on brain function under normal conditions. Our research shows that under the effects of LSD, this relationship becomes weaker: function is less constrained by structure."

"This is largely the opposite of what happens during anesthesia.”


Luppi’s team examined data collected by Dr. Robin Carhart-Harris and Dr. Leor Roseman from the Centre for Psychedelic Research at Imperial College London for a separate study. The data included functional magnetic resonance imaging (fMRI) that examined brain activity in 20 volunteers. Volunteers underwent two MRI sessions, one after taking a placebo and one after taking 75 micrograms of LSD.

MRI results showed marked changes in the typical segregation and integration of stimuli in areas of the brain that normally do not interact. “Reduced similarity between structural and functional connectivity indicates that under the effects of LSD, brain regions interact functionally in a way that is less constrained than usual by the presence or absence of an underlying anatomical connection,” researchers wrote in the study.

These new interactions explain the dramatic altered consciousness one experiences after consuming LSD. “Being less constrained by pre-existing priors due to the effects of LSD, the brain is free to explore a variety of functional connectivity patterns that go beyond those dictated by anatomy – presumably resulting in the unusual beliefs and experiences reported during the psychedelic state, and reflected by increased functional complexity,” reads the study.

“Studying psychoactive substances offers a unique opportunity for neuroscience: we can study their effects in terms of brain chemistry, but also at the level of brain function and subjective experience,” said Dr. Luppi.

“In particular, the mind is never static, and neither is the brain: we are increasingly discovering that when it comes to brain function and its evolution over time, the journey matters just as much as the destination. A more thorough characterization of how psychedelics influence the brain may also shed light on potential clinical applications – such as the ongoing research at the new Centre for Psychedelic Research in London.”

This research was a collaborative effort between Dr. Luppi and Dr. Robin Carhart-Harris and Dr. Leor Roseman from the Centre for Psychedelic Research at Imperial College London, who collected and shared the data and was supervised by Dr. Emmanuel Stamatakis from the Cognition and Consciousness Imaging Group at the University of Cambridge.

 
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