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mr peabody

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RESEARCH INTO PSYCHEDELIC-ASSISTED THERAPY AND NEUROSCIENCE

Neuro Assessment & Development Center

Since 2006, the Third Wave of clinical research and therapeutic applications of psychedelics has been underway. Far from the recreational stigma, Psychedelics have evolved into an accepted treatment of significant issues. Microdosing has become an established method for dealing with ADHD, Depression, and Unlocking creativity. Anyone trapped by the old paradigms will be very surprised.

LSD versus placebo. Research investigating classic psychedelics as treatments for addiction was initiated in the first wave of classic psychedelic research in the mid twentieth-century, but was ultimately terminated as a result of misinformation, stigma, lack of funding, and legal proscription. For the most part, plant medicine and use of psychedelics is misrepresented. There is a taboo in society still. The outspoken work of Michael Pollan, Paul Stamets and many researchers has ushered us to the Third Wave, a tipping point where modern research and communication is informing the public. People are talking about the benefits, though often in corners and in whispers. Ancient and Sacred ceremonies by shamans have been part of every culture, though often demonized. This led to the First Wave of investigation and the discovery of LSD in 1938 by Albert Hoffman, a chemist working for a pharmaceutical company. The benefits evolved quickly and by the 1950's and 60's, the Scientific Method was applied to create the Second Wave. The clinical benefits of psychedelics were well established by research and clinical application was wide spread for those that suffered with Depression, Anxiety, PTSD, Addiction, and other debilitating conditions within major institutions and rehabilitaton centers. The research and clinical applications came to a crashing halt when recreational use and mind expansion efforts overtook clinical application. Psychologists such as Timothy Leary and Ram Dass at Harvard opened the floodgates with uncontrolled experimentation. Then the conservative Nixon-era shut down funding for research and created a negative stigma around these substances with false images and many exaggerations about deaths related to use. This scared the public and created the taboo. It is noted by many researchers that LSD and Psilocybin has no known lethal dosage level and is non-addictive.

It is noted that in the 60's, these drugs were classified as Schedule I, indicating they have a high potential for abuse, not currently accepted as a medical treatment, and lack safety even under the supervision of a doctor. We believe this is not correct and will be re-evaluated very soon. LSD and Psilocybin are about to enter Stage 3 Clinical Trials for Depression and Addicion, meaning that their status will have to change from Schedule I to Schedule III, with widespread clinical application around the corner. There needs to be an End to the Ban and a change in social thought. For further history and why these medicines have been demonized by government and pharmaceutical lobbies, the interested reader is referred to Michael Pollan's 2018 book How to Change your Mind. It likely will.

After remaining hidden for three decades, researchers began bringing Psychedelic Medicine out of the shadows in 2006. Griffiths 2006 study, funded by NIH, opened the doors to legitimate study once again. Many researchers are now investigating the benefits in double-blind trials with major funding. As of 2018, 50 U.S. based researchers hold Class I drug licenses from the DEA to investigate the benefits of LSD, Psilocybin, MDMA, Ketamine, Ayahuasca, and many other substances. Although there is still a taboo amongst the majority when the word "Psychedelic" is said, we believe that like Cannabis, the majority will see the benefits of Psychedlics very soon and that it will be legalized and used in therapeutic, under the guidance and supervision of doctors. The data from research is very hard to argue with. The effectiveness of LSD and Psilocybin to treat Depression and Addiction in research trials has reached rates as high as 80%, without a return of symptoms for six months. There are no treatments (medications or therapies) that come close to the effective benefit. Government will resist and society will remember the stigma. Pharmaceuticals will fight against, because their expensive medications are not as effective. But the conversation has become universal and the benefits are undeniable. This is why large scale studies are beginning and reseachers are opening their vision to the world.

 
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mr peabody

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Hippocampal neurogenesis: The effects of psychedelic drugs

Briony J. Catlow, Ahmad Jalloh, Juan Sanchez-Ramos

Neurogenesis, or the birth of new neurons, occurs throughout the human life span in the hippocampus, a structural node in the neural circuitry responsible for memory and learning. The process of neurogenesis involves proliferation of neural stem/progenitor cells and their differentiation into mature neurons, followed by integration into hippocampal circuitry. The function of new neurons in the hippocampus is not completely understood. The formation of new synaptic connections (and pruning of synapses) between neurons in the hippocampal dentate gyrus and fibers to and from the cerebral cortex is important in the acquisition of new associations (learning), recall of those associations (memory), and extinction of associations (forgetting). Very likely, the new neurons play a role in encoding temporal aspects of episodic memory. Neurogenesis is influenced by many factors, including physical activity, stress, depression, seizures, irradiation, aging, and a variety of psychoactive drugs. Psychedelic drugs are shown to have an impact on hippocampal neurogenesis in a dose-dependent manner and to alter some aspects of memory and learning.

https://www.sciencedirect.com/science/article/pii/B9780128002124000777

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Alkaloids of B. caapi found to stimulate adult neurogenesis in vitro*

Jose Morales-Garcia, Mario de la Fuente Revenga, Sandra Alonso-Gil, Maria Isabel Rodriguez-Franco, Amanda Feilding, Ana Perez-Castillo, Jordi Riba

Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.

Due to their ubiquitous presence in ayahuasca, it can be hypothesized that the β-carbolines contribute to the CNS effects of the tea. Studies in animals have shown that harmine has antidepressant effects in behavioral animal models of depression. Responses after harmine in the forced swim and open field tests are analogous to those obtained with ayahuasca infusions prepared from B. caapi and P. viridis and containing DMT. These findings suggest that DMT is not essential for the behavioral responses observed in animals. Additionally, in contrast with more traditional antidepressants such as imipramine, harmine increases BDNF levels in the hippocampus after both acute and chronic administration. These data suggest that harmine and potentially the other β-carbolines present in B. caapi contribute to the therapeutic effects of ayahuasca observed in clinical studies involving patients with depression.

At the cellular level, antidepressant drug action has been linked to the ability of drugs to stimulate adult neurogenesis. Neurogenesis is the process of generating functional neurons from progenitor cells. In the adult brain of mammals, neurogenesis occurs in two main niches: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus of the hippocampus. Neural stem cells in these areas can be induced to asymmetrically divide, generating new stem cells, and astrocytes, oligodendrocytes or neurons. These newly generated neurons have the capacity to migrate and integrate into existing neural circuits. The activity and phenotypic fate of neural stem cells is determined by both endogenous and exogenous factors. Beyond understanding the mechanisms of adult neurogenesis, we are ultimately interested in its therapeutic capacity. Specifically, despite their various mechanism of action, clinically-effective antidepressants share the common feature of inducing neural stem cell proliferation and differentiation into new neurons.

In conclusion, here we showed that the β-carboline alkaloids present in B. caapi, the plant source of the ayahuasca tea, promote neurogenesis in vitro by stimulating neural progenitor pool expansion, and by inducing cellular migration and differentiation into a neuronal phenotype. The stimulation of neurogenic niches in the adult brain may substantially contribute to the antidepressant effects reported for ayahuasca in recent clinical studies. The versatility and full neurogenic capacity of the B. caapi β-carbolines warrant further investigation of these compounds. Their ability to modulate brain plasticity indicates their therapeutic potential for a broad range of psychiatric and neurologic disorders.

*From the study here :
https://www.nature.com/articles/s41598-017-05407-9
 
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mr peabody

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Waves of fluid bathe the sleeping brain*

Neuroscience News | Boston University | Nov 1 2019

New research from Boston University suggests that tonight while you sleep, something amazing will happen within your brain. Your neurons will go quiet. A few seconds later, blood will flow out of your head. Then, a watery liquid called cerebrospinal fluid (CSF) will flow in, washing through your brain in rhythmic, pulsing waves.

The study, published on October 31 in Science, is the first to illustrate that the brain’s CSF pulses during sleep, and that these motions are closely tied with brain wave activity and blood flow.

“We’ve known for a while that there are these electrical waves of activity in the neurons,” says study coauthor Laura Lewis, a BU College of Engineering assistant professor of biomedical engineering and a Center for Systems Neuroscience faculty member. “But before now, we didn’t realize that there are actually waves in the CSF, too.”

This research may also be the first-ever study to take images of CSF during sleep. And Lewis hopes that it will one day lead to insights about a variety of neurological and psychological disorders that are frequently associated with disrupted sleep patterns, including autism and Alzheimer’s disease.

The coupling of brain waves with the flow of blood and CSF could provide insights about normal age-related impairments as well. Earlier studies have suggested that CSF flow and slow-wave activity both help flush toxic, memory-impairing proteins from the brain. As people age, their brains often generate fewer slow waves. In turn, this could affect the blood flow in the brain and reduce the pulsing of CSF during sleep, leading to a buildup of toxic proteins and a decline in memory abilities. Although researchers have tended to evaluate these processes separately, it now appears that they are very closely linked.

To further explore how aging might affect sleep’s flow of blood and CSF in the brain, Lewis and her team plan to recruit older adults for their next study, as the 13 subjects in the current study were all between the ages of 23 and 33. Lewis says they also hope to come up with a more sleep-conducive method of imaging CSF. Wearing EEG caps to measure their brain waves, these initial 13 subjects were tasked with dozing off inside an extremely noisy MRI machine, which, as anyone who has had an MRI can imagine, is no easy feat.

“We have so many people who are really excited to participate because they want to get paid to sleep,” Lewis says with a laugh. “But it turns out that their job is actually–secretly–almost the hardest part of our study. We have all this fancy equipment and complicated technologies, and often a big problem is that people can’t fall asleep because they’re in a really loud metal tube, and it’s just a weird environment.”

But for now, she is glad to have the opportunity to take images of CSF at all. "One of the most fascinating yields of this research," Lewis says, "is that they can tell if a person is sleeping simply by examining a little bit of CSF on a brain scan."

“It’s such a dramatic effect,”
she says.

As their research continues to move forward, Lewis’ team has another puzzle they want to solve: How exactly are our brain waves, blood flow, and CSF coordinating so perfectly with one another? “We do see that the neural change always seems to happen first, and then it’s followed by a flow of blood out of the head, and then a wave of CSF into the head,” says Lewis.


This shows the CSF in the brain during sleep. During sleep, the brain exhibits large-scale waves:
waves of blood oxygenation (red) are followed by waves of cerebrospinal fluid (blue).

"One explanation may be that when the neurons shut off, they don’t require as much oxygen, so blood leaves the area. As the blood leaves, pressure in the brain drops, and CSF quickly flows in to maintain pressure at a safe level."

“But that’s just one possibility,”
Lewis says. “What are the causal links? Is one of these processes causing the others? Or is there some hidden force that is driving all of them?”

*From the article here :
 
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mr peabody

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Analysis of Voacanga africana reveals possible treatment for the aging brain*

Salk News | 1 Aug 2014

Salk scientists find that a plant used for centuries by healers of Sao Tome e Principe holds lessons for modern medicine.

For hundreds of years, healers in Sao Tome e Principe—an island off the western coast of Africa—have prescribed cata-manginga leaves and bark to their patients. These pickings from the Voacanga africana tree are said to decrease inflammation and ease the symptoms of mental disorders.

Now, scientists at the Salk Institute for Biological Studies have discovered that the power of the plant isn’t just folklore: a compound isolated from Voacanga africana protects cells from altered molecular pathways linked to Alzheimer’s disease, Parkinson’s disease and the neurodegeneration that often follows a stroke.

“What this provides us with is a source of potential new drug targets,” says senior author Pamela Maher, a senior staff scientist in Salk’s Cellular Neurobiology Laboratory. The results were published this week in the Journal of Ethnopharmacology.

Antonio Currais, a research associate, was visiting family in his native Portugal when he crossed paths with Maria do Ceu Madureira, an ethnopharmacology researcher at the University of Coimbra. For the past twenty years, Madureira has been surveying the use of herbal medicine on the island. Currais and Maher had developed a series of tests to screen compounds for their potential use in treating neurodegenerative disorders and Currais saw the perfect chance to put the assay to the test. He began a collaboration with Madureira’s team.

“There was already a lot of descriptive information of particular plants that have potential effects on the nervous system,” Currais says. “We took that further to quantitatively document the real neuroprotective action of the compounds in these plants.”

Currais and Maher began studying seven different extracts collected from five species of plants in Sao Tome e Principe. Three of the five had been reported by local healers to have effects on the nervous system and two were used as controls. The Salk research team put each sample through different assays—all conducted in living human and mouse cells—designed to test their potential impact against neurodegeneration.

One assay tested the ability of the plant extracts to protect cells against oxidative stress, a byproduct of metabolism that can cause DNA damage and has been linked to age-related neurodegeneration. Another tested anti-inflammatory properties of the compounds. A third test measured whether the samples could block the build-up of beta-amyloid peptides in neurons, which has been linked to Alzheimer’s disease.

“I was surprised at how potent they were,” says Maher. “I thought maybe we’d see a little bit of activity in some of the assays and then have to separate out individual components to see a more profound effect. But one sample in particular—Voacanga africana—performed exceptionally on all assays, even in its most dilute form."

When Currais and Maher isolated different components of the plant, they found that the anti-inflammatory and neuroprotective effects of the plant were mostly due to one molecule, called voacamine. The compound hasn’t yet been tested in animal models but its performance in the assays suggests that it may have pharmaceutical potential for treating Alzheimer’s, Parkinson’s or stroke.

“There are still a lot of potential sources of drugs in plants that are native to countries around the world and most of them haven’t been tested to any extent,” says Maher. “You can’t test everything, so the best way to approach plant research for drugs is to use the knowledge that’s been around for thousands of years to help you pick and choose what to study with modern techniques. That way you’re not just shooting in the dark.”

Maher, Currais and Madureira are planning more follow up studies on voacamaine and also hope to apply their assays to more plants of interest.

Other researchers on the study were Chandramouli Chiruta and Marie Goujon-Svrzic of the Salk Institute for Biological Studies; Gustavo Costa, Tania Santos, Maria Teresa Batista, Jorge Paiva, and Maria do Ceu Madureira of the University of Coimbra.

Both the Portuguese and American researchers worked in full partnership with local institutions, traditional healers and communities in order to respectfully conduct research in the area of indigenous knowledge, assuring the intellectual property rights and the sharing of benefits that may arise as a result of the study of these local medicinal plants.

*From the article here :
https://www.salk.edu/news-release/a...t-reveals-possible-treatment-for-aging-brain/
 
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mr peabody

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Psychedelic drugs could treat depression, and other mental illnesses

by David E. Olson | The Conversation | 20 June 2018https://theconversation.com/profiles/david-e-olson-495815

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

Psychedelics vs. Psychoplastogens

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

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

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

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

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

Panacea or poison?

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

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

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

 
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Scientists discover key neural circuit regulating alcohol consumption

University of North Carolina | Neuroscience News | Dec 13 2019

Specific neurons in the central nucleus of the amygdala regulate alcohol consumption.

Scientists have known that a region of the brain called the central nucleus of the amygdala (CeA) plays a role in behaviors related to alcohol use and consumption in general. It’s been less known which precise populations of brain cells and their projections to other brain regions mediate these behaviors. Now, UNC School of Medicine scientists discovered that specific neurons in the CeA contribute to reward-like behaviors, alcohol consumption in particular.

Published in the Journal of Neuroscience, this research pinpoints a specific neural circuit that when altered caused animal models to drink less alcohol.

“The fact that these neurons promote reward-like behavior, that extremely low levels of alcohol consumption activate these cells, and that activation of these neurons drive alcohol drinking in animals without extensive prior drinking experience suggests that they may be important for early alcohol use and reward,” said senior author Zoe McElligott, PhD, assistant professor of psychiatry and pharmacology.

“It’s our hope that by understanding the function of this circuit, we can better predict what happens in the brains of people who transition from casual alcohol use to subsequent abuse of alcohol, and the development of alcohol use disorders.”

McElligott, who is also a member of the UNC Bowles Center for Alcohol Studies, set out to investigate if a population of neurons that express a specific neuropeptide (neurotensin or NTS) contributes to reward-like behaviors and alcohol drinking. She was especially interested in these neurons in the context of inexperienced alcohol use, such as when a person first begins to drink alcohol. Also, NTS neurons are a subpopulation of other neurons in this CeA brain region that have been implicated in anxiety and fear – known as the somatostatin and corticotropin releasing factor neurons.

Using modern genetic and viral technologies in male mice, McElligott and colleagues found that selectively lesioning or ablating the NTS neurons in the CeA, while maintaining other types of CeA neurons, would cause the animals to drink less alcohol. This manipulation did not alter anxiety-like behavior. It also did not affect the consumption of other palatable liquids such as sucrose, saccharin, and bitter quinine solutions.

“We found that these NTS neurons in the CeA send a strong projection to the hindbrain, where they inhibit the parabrachial nucleus, near the brainstem,” McElligott said.

Using optogenetics – a technique where light activates these neurons – the researchers stimulated the terminal projections of the CeA-NTS neurons in the parabrachial and found that this stimulation inhibited the neurons in the parabrachial. When the scientists stimulated this projection with a laser in one half of the animal’s box, animals would spend more time where the stimulation would occur.

Animals also learned to perform a task to get the laser stimulation to turn on, and they would do this repeatedly, suggesting that they found this stimulation to be rewarding.

“Furthermore, when we stimulated this projection, animals would drink more alcohol as compared to when they had an opportunity to drink alcohol without laser stimulation,” McElligott said. “In contrast to our study where we ablated the NTS neurons, laser stimulation of this parabrachial pathway also caused the animals to consume caloric and non-caloric sweetened beverages. When the animals were presented with regular food and a sweet food, however, laser stimulation did not enhance the consumption regardless of the mouse’s hunger state. This suggests that different circuits may regulate the consumption of rewarding fluids and solids.”

McElligott and her graduate student María Luisa Torruella Suarez, the first author of this study, hope to explore how alcohol experience may change these neurons over time.

“Would these cells respond differently after animals have been drinking high quantities of alcohol over time?” McElligott said. “We also want to discover which populations of neurons in the parabrachial are receiving inputs from these neurons. Fully understanding this circuit could be the key to developing therapeutics to help people with alcohol use disorders.”

 
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Ayahuasca found to stimulate neurogenesis

by Olivia Lerche | The Express | 16 Jun 2016

Scientists have discovered that a psychedelic substance from the Amazon stimulates the birth of new brains cells and could lead to treatment for neurodegenerative diseases such as Alzheimer’s disease. The tea called Ayahuasca, is used as a traditional spiritual medicine in ceremonies in Peru, South America.

The Sant Pau Hospital Barcelona, working in collaboration with the Beckley Foundation and the Spanish National Research Council in Madrid, has released the findings from a study investigating the potential of ayahuasca to promote neurogenesis. The investigators believe these findings will open up a new avenue of research that may help develop drugs to treat diseases such as Alzheimer’s and Parkinson’s.

Dr Jordi Riba, lead investigator, presented preliminary data at the Interdisciplinary Conference on Psychedelic Research in Amsterdam, showing that two compounds - harmine and tetrahydro harmine - which are found in the psychedelic tea, potently stimulated the transformation of stem cells into new neurons.

Amanda Feilding, director of the Beckley Foundation said: “The images from the Beckley/Sant Pau collaboration showing the birth of new neurons are very interesting and suggest that ayahuasca could lead to a new approach in the treatment of neurodegenerative conditions such as Alzheimer’s and Parkinson’s, among others.”

Experts have believed for years that the brain doesn’t make neurons during adulthood. In the 1990s, research changed this finding, showing that new neurons are generated throughout adult life in two regions of the human brain - the area around the ventricles and in the hippocampus. The hippocampus, thought to be the center of emotion and the autonomic nervous system, plays a key role in memory. Its function declines with age and in neurological disorders.

Under normal conditions, the rate of the birth of new neurons is very low, and cannot keep up with the rate of neural death that occurs in diseases such as Alzheimer’s. In the study, neural stem cells were isolated from the hippocampus of adult mice. The stem cells were grown in the lab and substances that are present in ayahuasca were added to the cultures and compared with saline, a placebo control.

Scientists have described the results as ‘impressive’, with ayahuasca substances stimulating the transformation of stem cells into new neurons.

Dr Riba has been studying ayahuasca for twenty years.

*From the article here :
 
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LSD and psilocybin could heal damaged brain cells in people suffering from depression, study shows

by Alex Matthews-King | 12 June 2018

Psychedelics could be 'next generation' of safer treatments for mental health.

Psychedelic drugs like LSD and ecstasy ingredient MDMA have been shown to stimulate the growth of new branches and connections between brain cells which could help address conditions like depression and addiction.

Researchers in California have demonstrated these substances, banned as illicit drugs in many countries, are capable of rewiring parts of the brain in a way that lasts well beyond the drugs' effects.

This means psychedelics could be the "next generation" of treatments for mental health disorders which could be more effective and safer than existing options, the study's authors from the University of California.

In previous studies by the same team, a single dose of DMT, the key ingredient in ayahuasca medicinal brews of Amazonian tribes, has been shown to help rats overcome a fear of electric shock meant to emulate post-traumatic stress disorder (PTSD).

Now they have shown this dose increases the number of branch-like dendrites sprouting from nerve cells in the rat's brain.

These dendrites end at synapses where their electrical impulses are passed on to other nerve cells and underpin all brain activity. But they can atrophy and draw back in people with mental health conditions.

“One of the hallmarks of depression is that the neurites in the prefrontal cortex – a key brain region that regulates emotion, mood, and anxiety – those neurites tend to shrivel up,” says Dr David Olson, who lead the research team.

These brain changes also appear in cases of anxiety, addiction, and post-traumatic stress disorder and stimulating them to reconnect could help to address this.

The research, published in the journal Cell Reports today, looked at drugs in several classes including tryptamines, DMT and magic mushrooms; amphetamines, including MDMA; and ergolines, like LSD.

In tests on human brain cells in the lab, flies and rats, it found these substances consistently boosted brain connections.

Dr Olson compared the effects to ketamine, another illicit drug which represents one of the most important new treatments for depression in a generation, and found many psychedelics have equal or greater effects.

A ketamine nasal spray is being fast-tracked through clinical trials after it was shown to rapidly relieve major depression and suicidal thoughts in people who cannot be helped by other treatments.

However its use has to be weighed against its potential for abuse, and its ability to cause a form of drug-induced psychosis.

“The rapid effects of ketamine on mood and plasticity are truly astounding,” said Dr Olson. “The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does.”

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis."


The fact that many of these drugs seem to mimic the groundbreaking benefits of ketamine opens up an array of new treatment options, which may be less open to abuse, if these drugs can make it to clinical trials.

Dr Olson said: “Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives.”

The news that yet more banned substances could help tackle serious and debilitating disease comes as the UK Home Office is embroiled in a row over medicinal cannabis in treating epilepsy.

After months seizure-free, 12-year-old Billy Caldwell had a seizure last night after airport customs officials confiscated his prescription from Canada.

Billy had previously had the UK’s only NHS medical cannabis prescription, for an oil which banished seizures that used to strike 100 times a day, but the Home Office intervened to block his GP from prescribing it.

https://www.independent.co.uk/news/h...-a8395511.html
 
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Psychedelics may help the brain repair itself, study finds

Calvin Ly, Alexandra Greb, Lindsay Cameron, Kassandra Ori-McKenney, John Gray, David Olson

A new study in Cell Reports has found that psychedelics promote structural and functional neural plasticity.

In recent years, psychedelic party drugs such as LSD and MDMA have been studied by scientists for their potential ability to treat mental health problems like depression and anxiety—often in microdoses much smaller than the what a person would take to trip. But while the research into these drugs is promising, there’s still a lot we don’t understand about how they affect the brain. A new study, published Tuesday in Cell Reports, seems to offer the strongest evidence yet that they can actually help repair the brain’s circuitry and function.

The researchers, primarily from the University of California, Davis, exposed lab-cultured neurons from humans, rats, and other animals to various psychedelics. Drugs from different classes were used, including the amphetamine MDMA, the tryptamine psilocin, and the ergoline LSD. The neurons were taken from the prefrontal cortex, an area of the brain thought to be crucial in the development of certain mental illnesses.

Most of the psychedelics tested, the researchers found, promoted the growth of new dendrites from a neuron cell, which help transmit information from other neurons to the cell, as well as increased the density of small protrusions on these dendrites, known as dendritic spines. They also jumpstarted the growth of new connections, or synapses, between individual neurons. Similar effects were also seen in the brains of living test animals.

The net result of these changes, the authors say, is that they improve the brain’s plasticity, which includes its ability to repair itself from damage caused by things like stress or trauma. These changes, the researchers noted, are the reverse of what seems to happen in the brains of people living with chronic depression, post-traumatic stress disorder, or addiction. And they resemble the changes seen in people who take ketamine, an anesthetic and recreational drug that has been retooled in recent years as a fast-acting, if still experimental, antidepressant that some research has found can quickly tamp down suicidal thoughts.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis,” said lead author David Olson, an assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, in a statement. “What is really exciting is that psychedelics seem to mirror the effects produced by ketamine.”

It’s exciting, the authors say, because it means there’s more than one way for drugs to quickly improve a person’s brain plasticity. And the more options available, the better the chances someone can benefit from treatment, especially if other current drugs haven’t worked. Ultimately, it also provides researchers like Olson that many more avenues to pursue in developing more palatable versions of the psychedelic drugs we have available (i.e., versions that don’t cause long, mind-bending trips). The team even wants to rebrand these drugs as “psychoplastogens.”

“Ketamine is no longer our only option,”
Olson said. “Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives.”

Olson’s team is already studying whether non-hallucinogenic analogs of these psychedelics can still improve brain plasticity, and they note that researchers elsewhere are in the middle of developing safer analogs of ketamine, which has some potential for addiction and abuse.

https://www.cell.com/cell-reports/fulltext/
 
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Conor Liston

Ketamine found to reverse the neurodegenerative effects of chronic stress

Ruth Williams | Apr 11, 2019

Imaging of neurons in the brains of living mice reveals how synapses between cells are eliminated in response to stress and reinstated by an antidepressant dose of ketamine. The findings show that while ketamine-induced changes in behavior precede this synaptogenesis, the increased connectivity is required to maintain the drug-modified behavior.

“It’s beautiful work. It’s very elegant and technically sophisticated,” says neuroscientist Jason Radley of the University of Iowa who was not involved with the research. “I think this paper is poised to make a significant contribution.”

“They trace the whole [process] from before stress, after stress, and then after ketamine,”
says psychiatrist and neuroscientist Alex Kwan of Yale School of Medicine who also did not participate in the research, “and they have some very interesting findings in terms of how ketamine affects prefrontal cortical circuits.”

The paper is also “quite timely,” continues Kwan, explaining that although last month the United States Food and Drug Administration approved esketamine—a relative of ketamine—for use as an antidepressant, “we still know very little about how [it] works on the brain.”

Depression and stress tend to afflict sufferers episodically with periods of anxiety, sadness, and feelings of hopelessness interspersed with periods of apparent happiness and health. What happens in the brain during the course of depression and remission, however, is poorly understood.

In clinical trials ketamine has been shown to have dramatic, fast-acting antidepressant effects, altering the mood and behavior of patients within hours. And the drug has similarly fast effects on stressed rodents, providing an experimental model in which to examine the neurological basis of mood transitions. Studies of chronic stress and ketamine treatment in rodents have indicated, for example, that stress leads to the loss of dendritic spines—cellular protrusions that form synapses—in brain cells, while ketamine promotes spine formation. With most data having been obtained from sacrificed animals, however, the dynamics of spine formation and whether it drives the behavioral changes is largely unknown.

Conor Liston of Weill Cornell Medicine and colleagues have now followed the course of chronic stress and treatment within live animals. The team used a previously developed imaging technique involving the permanent insertion of a tiny prism into the animal’s brain to enable visualization under a microscope of cells deep within the cortex.

Using this approach the team could view neurons engineered to produce fluorescent proteins and markers of activity in mice that had been chronically stressed. The animals were either repeatedly dosed with corticosterone—the main stress hormone in rodents—via their drinking water, or were repeatedly restrained, which also raises stress hormone levels. Behaviorally, such mice behave differently than unstressed animals, struggling less when suspended by their tails, showing a reduced preference for sucrose, and becoming less exploratory. When given ketamine, however, the animals revert to activities of a nonstressed animal within a few hours.

Imaging revealed that, during stress, prefrontal cortical neurons, as previously shown, lost numerous dendritic spines. In line with these losses, the cells also exhibited less functional connectivity. That is, the numbers of cortical cells firing in unison decreased, as did the frequency of such ensemble activities.

Upon ketamine treatment, these stress-associated cellular changes were largely reversed. However, while the unified firing activity was restored quickly—following a similar time path to that of the behavioral changes, spine regrowth was delayed by 12 to 24 hours. This was “unexpected,” says Liston. Based on previous studies, “the assumption was that spines played some critical role,” he adds.

Further experiments indicated that spine regrowth serves to maintain rather than promote the behavioral changes. When ketamine-induced spines were quickly eliminated (using a combination of clever genetics and light stimulation), the behavior of mice in the tail suspension test returned to that of apparently stressed mice when tested after two days. In treated mice whose synapses were not eliminated, by comparison, the nonstressed behavior lasted up to a week after the ketamine dose.

“This is a very important study that provides evidence that ketamine-induced changes in neuronal structure underlie its sustained antidepressant effects,” chemist and neuroscientist David Olson of the University of California, Davis. "Going forward," he adds, “Strategies aimed at stabilizing these structural changes could prolong the therapeutic effects of ketamine.”

 
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Can 5-MeO-DMT unlock the mystery of neurogenesis?

by Troy Farah | Nov 14, 2018

2018 has been an incredible year for advances in psychedelic research, including psilocybin mushrooms, ketamine and more, not to mention a landmark year for MDMA and cannabis. Meanwhile, some research on a much lesser known psychedelic, 5-MeO-DMT, has slipped past national attention.

Known as 5-methoxy-N,N-dimethyltryptamine, this potent little molecule is most famous for occurring in the venom of a desert toad species, but it’s also present in many plant species or can be made synthetically. It’s in a class of chemicals called tryptamines, which includes DMT, psilocybin and even serotonin and melatonin.

Like many psychedelics, 5-MeO-DMT is highly active at serotonin receptors, but also at acetylcholine, glutamate and dopamine receptors as well, although at much lower potency. This has led some scientists to theorize that many DMT-related drugs could help with mood disorders. Some case studies have shown tryptamines to help with depression, anxiety, PTSD and more—but scientists still aren’t sure how exactly it all works.

The answer may lie in neurogenesis. In a newly published study in Frontiers in Molecular Neuroscience, Brazilian researchers looked at whether 5-MeO-DMT can stimulate neurogenesis in mice. After a single injection of 100 micrograms, the rodents showed significant cell proliferation compared to placebo.

Neurogenesis is exactly what it sounds like—the creation of new brain cells. When you’re young, the brain is constantly making new neurons. This activity slows down in adulthood, except in a few key places in the brain, such as a part of the hippocampus called the dentate gyrus. By stimulating this process, we can potentially fight diseases like Alzheimer’s.

The DG may be small, but it is thought to help form new memories, modulate mood disorders, and may even play a role in addiction. The debate is still raging over this, of course, with some studies saying the DG makes hundreds of new neurons per day, and others showing little change. But one theory suggests neurogenesis may improve a range of cognitive processes, especially in older people.

Perhaps 5-MeO-DMT can help us answer those questions. In the Brazilian study, the mice were injected with a drug called BrdU that helps scientists look at dividing cells in living tissue. Then, the mice were sacrificed by making them overdose on ketamine and xylazin. Unfortunately, it’s only possible to really look at these cell changes by cutting open the brains of mice—part of the reason this experiment hasn’t been done in humans—but at least they were euthanized peacefully.

The mice brains were washed and preserved, and the researchers found that 5-MeO-DMT not only produced more new neurons compared to controls, but they matured faster and survived better.

“Cells from animals submitted to a single 5-MeO-DMT injection showed dendrites with more branches and intersections,” the researchers wrote. Dendrites are the long branches of nerve cells that play an important role in brain chemistry. Like a tree, healthy branches means healthy brain cells. “Interestingly, chronic antidepressant therapy also accelerates the maturation of dendrites… To our knowledge, this work was the first to demonstrate a direct effect of a naturally occurring psychoactive compound in adult neurogenesis.”

There are some limitations to this research. For one, mice aren’t humans, so the conclusions that can be drawn are limited. Second, the researchers aren’t entirely sure how 5-MeO-DMT could be fostering neurogenesis, so what this means for the future of mental health remains to be seen.

With a few exceptions, there isn’t much new research on 5-MeO-DMT or related drugs. Last year, a different Brazilian team gave lab-grown mini-brains 5-MeO-DMT and found it had anti-inflammatory properties, and also promoted the growth of dendrites. Another rodent study shed some light on how 5-MeO-DMT works at serotonin receptors, but most studies are few and far between. There was also a first-of-its-kind epidemiological study that looked at spiritual and recreational use of 5-MeO-DMT, and concluded it has, “low potential for addiction, and might have psychotherapeutic effects.” Otherwise, that’s about it.

There may be a reason why 5-MeO-DMT research is largely ignored in the press. The chemical name is complex and difficult to remember, and most of this science is in very early stages.

There is still far too little research on 5-MeO-DMT to draw any strict conclusions on how it may benefit—or harm—humans; however, the positives seem stronger than the negatives. But this is exactly the point. While so much attention is centered on drugs like LSD and magic mushrooms, this compound is overlooked, and clearly could use more academic interest.

It would be wrong not to mention that federal scheduling has played a role in dampening this research. While 5-MeO-DMT has been used for centuries in some cultures, the United States only placed it in the highly illegal Schedule I category in 2011. Studying Schedule I drugs like marijuana, LSD and mescaline is notoriously difficult, so many institutions don’t even bother. If we really want to unlock the mysteries of this chemical—and what it can teach us about consciousness and the human mind—we must loosen restrictions on psychedelic research. The potential benefits are too important to ignore.

 
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Psychoplastogens: a promising class of plasticity-promoting neurotherapeutics

by David Olson | Journal of Experimental Neuroscience | Sep 19, 2018

Neural plasticity—the ability to change and adapt in response to stimuli—is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens—a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants. Their use in psychiatry represents a paradigm shift in our approach to treating brain disorders as we focus less on rectifying “chemical imbalances” and place more emphasis on achieving selective modulation of neural circuits.

By definition, psychoplastogens are small molecules and thus plasticity-promoting proteins like BDNF do not fall into this category. To be classified as a psychoplastogen, a compound should produce a measurable change in plasticity (eg, changes in neurite growth, dendritic spine density, synapse number, intrinsic excitability, etc.) within a short period of time (typically 24-72 hours) following a single administration. Because their impact on neural plasticity enables subsequent stimuli to reshape neural circuits, they should produce relatively long-lasting changes in behavior that extend beyond the acute effects of the drug. In addition to ketamine, several other psychoplastogens have been identified, all of which produce fast-acting antidepressant effects in humans.

Recently, our group has demonstrated that psychedelic compounds such as lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and 2,5-dimethoxy-4-iodoamphetamine promote dendritic branching and/or increase spine/synapse number both in cultured cortical neurons and in vivo.3 These results provide a potential explanation for the known ability of these compounds to produce long-lasting changes in personality and positively impact circuits relevant to the treatment of mood, anxiety, and substance use disorders. Although our cellular studies have shown that a wide variety of psychedelic compounds produce psychoplastogenic effects similar to ketamine, our in vivo work thus far has primarily focused on the effects of DMT—the archetype for all tryptamine-containing psychedelics.

Our initial efforts investigating the plasticity-promoting properties of psychedelics focused on DMT for a variety of reasons. First, the simple structure of DMT represents the minimal pharmacophore for all tryptamine-containing psychedelics as others such as LSD, ibogaine, psilocybin, and 5-MeO-DMT can be considered either conformationally restricted or substituted analogues of DMT. Like ketamine, a single intraperitoneal injection of DMT increases dendritic spine density as well as the frequency and amplitude of spontaneous excitatory postsynaptic currents in the PFC of rats 24 hours after administration. As the half-life of DMT in rats is on the order of 15 minutes, the compound is cleared from the body within 24 hours and thus these changes in neuronal structure and function must reflect plasticity and not simply the acute effects of the drug. Moreover, DMT produces behavioral effects in rodents that mirror those of ketamine such as promoting fear extinction learning and reducing immobility in the forced swim test. In humans, a DMT-containing tisane known as ayahuasca has been shown to produce rapid and sustained antidepressant effects.

The advent of psychoplastogenic compounds has enabled us to move beyond simplistic therapeutic strategies aimed at controlling monoamine levels toward the selective modulation of neural circuits—a fundamental shift in our approach to treating CNS disorders. Significant progress has been made in recent years and provides hope that modern research on ketamine, psychedelics, and other psychoplastogens will lead to safe and effective strategies for harnessing neural plasticity to treat mood and anxiety disorders such as depression and PTSD. As the number of psychoplastogenic compounds continues to grow, so do our chances of identifying the next generation of medicines for treating neuropsychiatric and neurodegenerative diseases. Regardless, it is clear that psychoplastogens can serve as powerful tools for understanding the basic biology of neural plasticity.

Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics
 
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Albert Hofmann

5-HT2A agonism and multisensory binding

by James L. Kent | Psychedelic Information Theory

Most visual hallucinogens are active as full or partial agonists at the 5-HT2A receptor subtype, and all produce similar visual hallucinations that are immediately recognizable as psychedelic.1 Although the 5-HT2A receptor subtype is not the only receptor implicated in hallucinogenesis, it is one of the most studied hallucinogenic targets and offers some insights into the quality of classical psychedelic interaction. 5-HT2A receptors are ubiquitous throughout the nervous system, found in the sensory cortex, the frontal cortex, the olfactory cortex, the basal ganglia, the cerebellum, the hippocampus, thalamic nuclei, brainstem nuclei, sensory neurons, platelets, fibroblasts, intestines, smooth muscles, and cardiovascular systems. By following the pathways of 5-HT2A modulated signal transduction through the human organism it is possible to extrapolate that psychedelic experience is not limited to mere hallucination, but is instead a complex multi-layered experience integrated throughout all biological signaling systems. The layering of cellular signaling systems mediated by 5-HT provides a framework for viewing the 5-HT2A pathway as a primary modulator for homeostatic feedback regulation of multisensory awareness, behavior, and learning. 5-HT2A receptor agonists (hallucinogens) promote disinhibition and excitability in 5-HT mediated pathways, indicating that psychedelic action is the product of spontaneous nonlinear feedback excitation in the recurrent circuits responsible for real-time binding of sensation to multisensory perception, affective behavior, and the process of consciousness.

5-HT2A receptor mechanics

The 5-HT2A receptor is a G protein-coupled receptor (GPCR), which means it does not activate ion channels or directly alter cell polarity, but instead sets off a chain reaction of intracellular signaling systems involving phosphatidylinositol (PI) hydrolysis, the production of inositol trisphosphate (IP3), the release of calcium (Ca2+), and the activation of protein kinase C (PKC) and various mitogen-activated protein kinases (MAPK). PKC regulates a variety of cellular functions at the membrane, including signal transduction, receptor desensitization, and synaptic formation and strengthening responsible for learning and memory.10 MAPK regulates fundamental intracellular functions such as gene expression, proliferation, cell growth, and survival. It is interesting to note that Salvinorin A, another potent hallucinogen not active at the 5-HT receptor, also stimulates PKC and MAPK signaling pathways via Kappa Opioid receptors. These receptor-mediated secondary pathways undoubtedly play a role in psychedelic neuroplasticity and cellular regeneration, but these secondary messengers are not necessarily directly responsible for hallucination and psychedelic effect. Hallucinogenesis is more likely related to tonic disinhibition of neural assemblies normally stabilized by tonic feedback inhibition. In other words, 5-HT2A agonism does not cause neurons to fire, it activates cellular signaling pathways for learning and growth in the wake of stimulus, which, over time, promotes hypersensitivity and uninhibited network cross-excitability.

Layer V pyramidal cells and perceptual binding

In the human brain the highest density of 5-HT2A receptors are expressed on the dendrites of cortical layer V pyramidal cells, and the highest density of layer V dendrites project upward into the arbors of cortical layer I, the very outward surface of the brain. 5-HT2A receptors in the dendritic arbors of pyramid cells are primarily responsible for modulating asynchronous (late) glutamate release in the wake of incoming sensory spike trains, presumably for enhanced top-down aliasing (reconstruction and rendering) of salient sensory data. Sensory signal rising to the dendrites of the cortical surface encodes a highly detailed reconstruction of external perception for latent real-time analysis and progressive perceptual filling. Multiple layers of the neocortex have descending columnar dendrites or ascending recurrent axon collaterals to provide real-time sensory feedback to apical rendering layers, allowing a seamless representation of perception to be shared across the cortex. Cortical layer V neurons receiving input through apical dendrites are one of the primary conduits for binding coherent sensory perception across the entire cortical surface of the brain.

Layer V pyramidal cells are unique in that they mediate multiple pathways of perceptual feedback analysis. For example, in the visual cortex layer V pyramidal cells are responsible for synchronizing corticothalamic activity with the thalamic nuclei via descending axons; they mediate feedback discrimination in columnar circuits via recurrent collaterals ascending through Layers I-IV; they mediate reciprocal interareal connections via laterally branching arboreal and basilar dendrites; and they mediate afferent cortico-cortical signal flow to the pre-frontal cortex (PFC) along both dorsal and ventral processing streams. Through lateral, vertical, elliptical, and recurrent feedback connections, layer V pyramidal cells bind multisensory frame data across the cortex with a functional refresh rate of roughly 15 to 30 frames-per-second (FPS), which means these neurons must process and neutralize incoming sensory spike trains at roughly every 30-60 milliseconds. Loss of precise synchrony and coupling in these circuits would necessarily lead to loss of temporal fidelity in multisensory frame binding. Agonism, disinhibition, excitation, and destabilization in layer V recurrent circuits would necessarily lead to global multisensory frame aliasing errors, feedback synesthesia, and eventual perceptual overload.

Nonlinear destabilization in thalamocortical feedback loops

The most potent psychedelics are 5-HT2A receptor agonists; the highest density of 5-HT2A receptors are in the dendrites of layer V pyramidal cells; layer V pyramidal cells bind information in feedback projections throughout the brain. Taking these factors into account it is reasonable to assume that psychedelic hallucinogenic activity is due to nonlinear signal destabilization and amplification via recurrent layer V feedback projections. Psychedelic hallucination is achieved by partial or full agonism along recurrent layer V binding pathways; the introduction of a competing agonist in the 5-HT2A modulatory system leads directly to loss of localized inhibition and self-sustaining excitation of autonomic sensory binding complexes. Destabilization of layer V projections is most acute where signal travels in recurrent loops or feedback circuits that resolve incoming multisensory data in real time. The primary circuits for binding real-time frame data include the cortico-striato-thalamo-cortical (CSTC) loops, and the more distributed cortico-thalamo-cortical feedback loops (or thalmocortical loops) which pass information from the cortex through the basal ganglia and back into the thalamus for discrimination and gating of incoming signal flow to the cortex. These loops can be described as attention-controlled feedback filters which drive and stabilize external perception and behavior. CSTC loops provide real-time sensory feedback for fine-tuning eye movements, motor reflexes, emotional responses, and cognitive value placed on stimulus. Destabilization in signal coupling along thalamocortical feedback pathways will necessarily lead to problems with sensory gating, multisensory frame resolution, and fast temporal aliasing.

There are specific perceptual effects one would expect to see as a result of instability in thalamocortical feedback loops between the thalamus to the visual cortex, such as a subtle flickering or pulsing of light intensity; geometric grids and matrices; the perception of halos or auras around light sources; increased luminosity of reflective objects; the softening of line and texture resolution; and the inability to hold sharp focal contrast between foreground and background in depth perception. Sensory filling in the visual periphery relies on fast temporal aliasing of visual signal for real-time results, and this temporal aliasing can be subverted by optical illusions which create a sense of movement in the periphery. A competing 5-HT2A agonist would necessarily disrupt the precise inhibitory timing in the cortical columns needed for peripheral edge detection and sensory filling, leading to shifting line and depth ambiguities. If the rate of multisensory frame saturation or neutralization was slowed or interrupted by even a few milliseconds, incoming sensation would begin to layer over itself with increasing levels of smoothing, liquidity, and phantom frame echo decaying in the wake of sensation.

5-HT2A receptor agonists can destabilize multisensory perception in a number of ways. The most general explanation is that 5-HT2A agonists introduce a competing excitatory impulse that disrupts the precise timing of sensory binding in the apical dendrites and recurrent circuits of the thalamus and cortex. Evidence indicates that 5-HT2A agonists promote a late release of glutamate from layer V pyramidal cells following strong incoming spike trains, resulting in the generation of asynchronous excitatory postsynaptic currents (EPSCs). Asynchronous EPSCs in recurrent sensory circuits are normally helpful for resolving important perceptual data, but if the subject is unable to inhibit evoked ESPCs caused by exogenous modulators (hallucinogens), this late signaling action can lead to glutamate flooding and tonic sensory saturation in perceptual neural assemblies, which is consistent with manic states of hallucinogenesis. There is evidence that 5-HT2A agonists lead to lateral disinhibition in the cortex by blocking presynaptic uptake of 5-HT at the lateral inhibitory synapse, or by overriding tonic GABAB inhibitory postsynaptic potentials (IPSPs) with asynchronous ESPCs at the lateral-inhibitory synapse. Loss of inhibition at the lateral synapses in columns of the visual cortex would lead directly to shifting and wiggling in peripheral line, texture, and contrast resolution. As thalamocortical feedback circuits become increasingly disinhibited they may fall into coherent self-sustaining states of underconstrained perception, promoting phantom sensory activity such as hallucination and spontaneous dream imagery. In the disinhibited state mild stimulus may not provoke hallucinogenic response, but intense stimulation would drive sudden localized feedback coherence, nonlinear signal amplification, and frame latency errors. The sudden shift from stabilized brain focus to states of elicited thalamocortical feedback excitation can be described in terms of a nonlinear, non-equilibrium phase transition in response to energetic sensory drivers.

5-HT2A cross-agonism and holistic organism re-modulation

Looking beyond the cortex, it is worth mentioning that 5-HT2A receptors are also found in the midbrain, olfactory systems, the brainstem, intestines, and all over the body in smooth muscles and cardiovascular systems. There is some evidence that 5-HT2 agonists have a secondary effect at the locus ceruleans in the brainstem (LC), promoting adrenal activity in the presence of strong sensory drivers. Sensory driving of adrenal release may promote a synesthetic burst of emotional intensity accompanying any strong multisensory experience. There is evidence that 5-HT agonist hallucinogens inhibit sensory gating in the thalamus, allowing more raw sensation to flood the cortex; this is consistent with decreased gating and nonlinear feedback amplification in thalamocortical loops. A common early side-effect of hallucinogen use is stomach tightening and intestinal cramping; this is undoubtedly due to 5-HT2A agonism interfering with serotonergic modulation of smooth muscle contraction in the gut. 5-HT2A cross-agonism in the intestines can lead to nausea and purgation, and reports of intense hallucinations and peak psychedelic experiences typically increase immediately following release of intestinal discomfort. This indicates that radical interruption and re-modulation of all 5-HT2A pathways, from the intestines to the cortex, may be a common precursor to peak psychedelic experiences and states of bodily transcendence.

Because of the multiple systems affected by 5-HT2A receptor agonism, it would be overly reductive to point to a single pathway as being responsible for full psychedelic activation. The synergistic effect of multi-layered 5-HT2A agonism is felt subjectively as a throbbing or pulsation of energy which suffuses the entire body, builds in strength and complexity, and culminates in a cathartic multisensory release of highly charged transformative content. At the sensory level glutamate flooding saturates perception. At the emotional level adrenal response drives sensual intensity. At the frame level aminergic destabilization leads to disorientation and loss of temporal ego cohesion. At the cognitive level aminergic destabilization drives irrationality, depersonalization, and hallucinogenic dream states. At the circulatory level 5-HT2A agonism promotes vasoconstriction and increases blood pressure. At the somatic level an interruption of digestive functioning drives metabolic destabilization and energetic intracellular signaling. At the organism level the holistic effects of prolonged 5-HT2A agonism become nonlinear, meaning they begin to generate complex energetic output in response to sensory input over time. This multi-layered organism activation can be formally described as a runaway biological feedback process, or a nonlinear cellular signaling loop which drives increasing cellular coupling complexity over the duration of synergistic agonism.

 
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Single dose of 5-MeO-DMT found to stimulate cell proliferation and neuronal survivability

Rafael Vitor Lima da Cruz, Thiago Moulin, Lyvia Lintzmaier Petiz, Richardson Leao

Psychoactive tryptamines are a class of molecules that act as neurotransmitter in the vertebrate brain. 5-MeO-DMT is found in a great variety of plants in South America, with an even greater diversity of chemical analogs. It is a serotonin agonist that acts in a non-selective manner in 5-HT2A >5-HT2C >5-HT1A receptors. However, 5-MeO-DMT also acts in many glutamate, dopamine and acetylcholine receptors. 5-MeO-DMT is one of the main active ingredient of Ayahuasca, a millenarian decoction used as sacrament by south American indigenous tribes, known to induce powerful hallucinogen states when administered together with monoamine oxidase inhibitors. At present, Ayahuasca is used by many syncretic churches ritualistically, as way to heal many physical and mental illness with or without scientific knowledge about the effects. Recent studies also suggest that Ayahuasca can potentially treat recurrent depression even in a placebo controlled frame.

Deficits in adult neurogenesis are associated with the physiopathology of depression and modulation of neurogenesis is behind the action of several antidepressants. Serotonin reuptake inhibitors, for example, rescue normal neurogenesis levels in animal models of depression. Adult neurogenesis is known to occur in two sites in the brain, the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle. There is some debate whether or not SVZ neurogenesis responds to mood disorders and psychoactive drugs, but the effect of mood disorders in SGZ Radial glial Like cell proliferation and neuronal survivor is prolifically described. Interestingly, alkaloids from one of the plants used in the Ayahuasca brew stimulate neurogenesis in vitro; however, it is not known whether in vivo adult neurogenesis is affected by psychoactive tryptamines.

In this study we tested if a single dose of 5-MeO-DMT affects neurogenesis in mice. We found that after a single intracerebroventricular injection of 5-MeO-DMT, cell proliferation in the DG was significantly larger in comparison to saline. Moreover, the number of DCX cells are also higher for experimental group, these same DG granule cells show more complex dendritic trees when compared to control animals. Finally, we found that after hyperpolarization, potential duration was shorter, and action potential threshold was higher in newborn neurons in mice treated with 5-MeO-DMT.

In this work we show that a single dose of 5-MeO-DMT increases proliferation of neural progenitors and accelerates the maturation of newborn GC. We first used BrdU staining to show that 5-MeO-DMT treatment increases proliferation in the DG Next, we used an inducible Cre recombinase line under the control of a marker of neurogenesis crossed with a fluorescent reporter to identify newborn neurons. We also show that the total number of DCX cells in the ventral hippocampus of adult mice are increased, and that those cells are indeed neurons. Dendritic trees of newborn neurons from 5-MeO-DMT-treated mice were significantly more complex as compared with saline-treated mice. AP threshold was lower and AHP potential was longer in newborn cells from 5-MeO-DMT-treated mice compared to controls.

The higher number of BrDU+ cells indicate that a larger number of cells are entering in the S-phase of cell-cycle, but cannot elucidate the type of progenitor cell that is being affected. Studies using antibodies against GFAP, nestin and Sox2, might confirm if those BrdU+ cells are indeed RGL cells, the neural stem progenitors cells from adult DG. Also, future experiments may confirm whether the increase in BrdU+ cells following 5-MeO-DMT injection is due to the lengthening of S-phase or a higher recruitment of RGL.

The choice of a single dose treatment, was made to address the gap between the molecular mechanisms, subjective and hormonal effects underlying Ayahuasca acute administration to depression diagnosed patients. The bulk of Ayahuasca tea, are composed of several psychoactive substances including DMT analogs and MAOi. The scope of present study is to unveil the effect of the main psychoactive compound in the Ayahuasca without adding any bias due to other psychoactive compounds also present in the concoction. To study the specific contribution of the 5-MeO-DMT to the adult neurogenic process, we needed to isolate the effect of the 5-MeO-DMT from another psychoactive components of the Ayahuasca. For example, the harmine and B-carbolines acting as MAOi, in such way, using oral or intraperitoneal administration may reduce the availability of 5-MeO-DMT to the central nervous system, since the monoamine oxidase will readily destroy any tryptamine, in the blood stream, gut and brain. Hence 5-MeO-DMT can be easily degraded, we choose to deliver the 5-MeO-DMT ICV to reduce the chemical inactivation prior to the arrival of the molecule to the brain. Additionally has been reported elsewhere that the harmine per se can increase neurogenesis at least in vitro cultured hippocampal cells.

Increased proliferation after 5-MeO-DMT injection does not indicate neuronal commitment. Thus, we performed histological analysis in mice injected with 5-MeO-DMT. Our results indicate a greater number of DCX cells in the ventral hippocampus of 5-MeO-DMT treated animals, showing that the total numbers of neuron that reach neuronal maturity are also increased, in addition to the initial increase in proliferation right after 5-MeO-DMT injection as evinced by our proliferation assay. Serotonin has been shown to increase granule cell proliferation in the adult DG. However, serotonin does not seem to affect specialization of newborn cells in the SGZ. Our results, on the other hand, suggest that 5-MeO-DMT not only has a positive effect on proliferation and survivability, but also on the maturation of GC. Hence, our results imply that the positive effect of 5-MeO-DMT in adult neurogenesis differs from that of serotonin alone.

Our current-clamp recordings indicate that young neurons from 5-MeO-DMT-treated mice show faster maturation than cells from control animals. Mature GC show a higher AP threshold and are able to fire in higher frequencies. These differences in maturation were also found in the morphology of dendritic trees. Dendritic complexity is a major indicative of cell maturation. Cells from animals submitted to a single 5-MeO-DMT injection showed dendrites with more branches and intersections. Interestingly, chronic antidepressant therapy also accelerates the maturation of dendrites. Future studies should address how tryptamine analogs affect the temporal expression of voltage-dependent currents. Our preliminary results indicate that the hyperpolarizing-activated current, Ih, is larger in novel GC in animals injected with 5-MeO-DMT when compared with saline Also, it will be interesting to examine changes in Cl− reversal potential as GC show a depolarized potential until adolescence.

Dorsal Raphe Nucleus profusely targets the SGZ but a previous work have shown that lowering serotonin levels in the brain can increase neurogenesis. Yet, serotonin agonists and serotonin uptake inhibitors seem to increase neurogenesis. Hence, specific 5HT receptors might be involved in neurogenesis modulation. 5-HT1A, 5-HT2A and 5-HT2C, 5-MeO-DMT targets, are all expressed in the DG. While 5-MeO-DMT is a strong 5-HT2A and 5-HT2C agonist, this compound acts in other receptors. Hence, we cannot affirm that the effect of 5-MeO-DMT in neurogenesis occurs through 5-HT2A and 5-HT2C receptors. Future studies using agonists and antagonists are necessary for dissecting the molecular mechanism of 5-MeO-DMT action in neurogenesis.

In conclusion, we show here that a single dose of 5-MeO-DMT can increase proliferation, survivability and accelerate maturation of newborn neurons in the DG. To our knowledge, this work was the first to demonstrate a direct effect of a naturally occurring psychoactive compound in adult neurogenesis. New lines of investigation have suggested that serotoninergic hallucinogens can significantly improve severe depression and anxiety. Thus, the effect of 5-MeO-DMT in modulating neurogenesis could throw light on the mechanism behind the beneficial effects of hallucinogenic compounds in mood disorders.

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00312/full
 
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Psychedelic drugs change the structure of neurons

by Andy Fell | UC Davis | Jun 12 2018

A team of scientists at the University of California, Davis, is exploring how psychedelic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes could suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics that show effects similar to ketamine

Olson’s group has demonstrated that other psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Behavioral studies also hint at the similarities between other psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder, or PTSD, and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

Psychedelics vs. Psychoplastogens

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

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

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

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

https://www.ucdavis.edu/news/psychedelic-drugs-change-structure-neurons/
 
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Psychedelic drugs reshape cells to "repair" neurons in our brains

by Peter Hess | June 13, 2018

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

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

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

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

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

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

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

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

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

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

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

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

by Alli Feduccia | psychedelic.support | Jun 13 2018

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

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

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

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

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

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

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

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

 
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Thomas Varley, Neuroscientist

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

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

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

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

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

So should we all pack up and go home?

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

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

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


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

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

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

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

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

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



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

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

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



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

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

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

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

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

by Alanna Ketler | Collective Evolution

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

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

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

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

The Study

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

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

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

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

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

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

by Cici Zhang | Chemical & Engineering News

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

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

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

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

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

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

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