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mr peabody

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Psilocybin increases the expression of neuroplasticity-related genes in rats

by Eric Dolan | PsyPost | 15 Nov 2020

Psilocybin rapidly increases the expression of several genes related to neuroplasticity in the rat brain, according to new research published in the Journal of Psychopharmacology. The new findings might help explain the underlying neurobiological mechanisms responsible for long-lasting changes associated with psychedelic drug use.

“Psilocybin induces remarkable subjective effects, but has been largely ignored, scientifically, for many years. Recent studies suggest that it might, in combination with psychotherapy, be effective for treating certain mental disorders. As an aspiring scientific researcher it is very exciting to be part of the re-opening of a scientific field that has been hibernating for decades,” said study author Oskar Hougaard Jefsen, a visiting researcher at the Translational Neuropsychiatry Unit at Aarhus University.

Psilocybin produces profound changes in perception and consciousness through stimulation of serotonin receptors in the brain. But the researchers were interested in learning why the substance has also been shown to produce long-term positive effects on several clinical symptoms.

In their study, 80 rats were injected with one of seven different doses of psilocybin or an inert saline solution. Ninety minutes later, the animals were euthanized so the researchers could extract RNA samples from key brain regions.

The researchers found that psilocybin increased the expression of several plasticity-related genes in the rodent’s prefrontal cortex and hippocampus, areas of the brain associated with executive functioning and memory.

“Psilocybin induces immediate changes in rat brains that resemble the changes we see when nerve cells are stimulated to form new connections. These changes may be part of the explanation why a psilocybin-trip sometimes induces lasting changes in the brain,” Jefsen told PsyPost.

The findings are in line with some previous research. For instance, a study published in Cell Reports found psychedelic drugs increased the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses) in rats and flies.

But Jefsen cautions that the research is still in its early stages.

“We still really don’t know 1) if human and rodent brains react similarly to psychedelic drugs and 2) which of the neurobiological effects that should be considered as important and which should be considered as irrelevant/by-products of the drug effects. It is very difficult to compare effects on rats with effects on humans because rats do not speak (or we don’t speak Rat),” he explained.

“Always be careful of hype and confirmation bias,” Jefsen added. “The evidence that psilocybin is effective for treating psychiatric disorders such as major depressive disorder is still rather weak because of small studies and methodological limitations.”

The study, “Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin,“ was published November 4, 2020.

 
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The Nuances of Ketamine’s Neurochemistry

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

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

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

Ketamine’s novel mechanisms of action

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


Figure 1: Ketamine’s proposed novel mechanisms of action as compiled by Zanos and Gould.3 Note that ketamine binds to NMDA receptors on GABAergic interneurons to disinhibit glutamate release (section ‘a’ in the upper left of the image). Evoked release of glutamate binds to AMPA receptors, in turn releasing BDNF. This figure also illustrates the proposed release of ketamine metabolites.

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

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

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

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

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

While the R and S stereoisomers of ketamine look nearly identical, they are chiral molecules–meaning that they are non-superimposable mirror images (Figure 2). The preceding letters R and S are used to refer to the ‘handedness’ of the isomer. R indicates right-handed, or clockwise geometry, whereas S indicates left-handed, or counterclockwise geometry. Take for example human hands; when facing each-other they are mirror images. However, when rotated they cannot be indistinguishably placed over each other. Chiral molecules are also known in the field of chemistry as enantiomers. Though this difference between the enantiomers is seemingly small, each isomer of ketamine has unique neurochemical effects.


Figure 2: The optical isomers of ketamine.

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

Clinical differences between the effects of the R and S Isomers

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

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

Studies show that S-ketamine has a fourfold greater potency when it comes to inhibiting the NMDA receptor when compared to R-ketamine (also called arketamine).3 Its greater affinity at the NMDA receptor likely contributes to its selection by pharmaceutical companies in developing the drug. S-ketamine also has a greater analgesic potency; its analgesic potency is twice that of the racemate. For this reason, there is a preferential use of s-ketamine when it comes to anesthesia.

Surprisingly, the R-isomer shows longer-lasting anti-depressant effects compared to S-ketamine. A study on mice showed that R-ketamine increased prefrontal 5-HT (serotonin) at significantly greater levels than S-ketamine.7 Another study on mice suggests that R-ketamine produces less psychomimetic side-effects related to mobility, resulting in less distorting side-effects typically associated with ketamine.

Summary and conclusion

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

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

 
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Ayahuasca stimulates the formation of new neurons

Complutense University of Madrid | Neuroscience News | 6 Nov 2020

DMT, a natural component of ayahuasca tea, promotes neurogenesis, a new study reports. Researchers found DMT was capable of activating neural stem cells and promoted the formation of new neurons.

One of the main natural components of ayahuasca tea, dimethyltryptamine (DMT), promotes neurogenesis (the formation of new neurons) according to research led by the Complutense University of Madrid (UCM).

In addition to neurons, the infusion used for shamanic purposes also induces the formation of other neural cells such as astrocytes and oligodendrocytes.

“This capacity to modulate brain plasticity suggests that it has great therapeutic potential for a wide range of psychiatric and neurological disorders, including neurodegenerative diseases”, explained José Ángel Morales, a researcher in the UCM and CIBERNED Department of Cellular Biology.

The study, published in Translational Psychiatry, reports the results of four years of in vitro and in vivo experimentation on mice, demonstrating they exhibit “a greater cognitive capacity when treated with this substance”, according to José Antonio López, a researcher in the Faculty of Psychology at the UCM and co-author of the study.

Changing the receptor eliminates the psychedelic effect

Ayahuasca is produced by mixing two plants from the Amazon: the ayahuasca vine (Banisteriopsis caapi) and the chacruna shrub (Psychotria viridis).

The DMT in ayahuasca tea binds to a type-2A serotonergic brain receptor, which enhances its psychedelic effect. In this study, the receptor was changed to a sigma type receptor that does not have this effect, thus “greatly facilitating its future administration to patients.”

In neurodegenerative diseases, it is the death of certain types of neuron that causes the symptoms of pathologies such as Alzheimer’s and Parkinson’s. Although humans have the capacity to generate new neuronal cells, this depends on several factors and is not always possible.

“The challenge is to activate our dormant capacity to form neurons and thus replace the neurons that die as a result of the disease. This study shows that DMT is capable of activating neural stem cells and forming new neurons,” concluded Morales.

 
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Insights into the neurophysiology of tryptamine-derived psychedelics*

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

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

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

Effects of psilocybin on the Default Mode Network

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

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

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

LSD demonstrates similar effects on the brain

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

How do tryptamine psychedelics affect the whole brain?

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

Summary

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

*From the article here :
 
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DMT research affords new hope for stroke victims

by Nathan White, PhD | Psychedelic Science Review | 16 Dec 2020

A recent study shows DMT reduces the cellular stress caused by a stroke and speeds up recovery time in rats. These findings highlight the expanding therapeutic potential of DMT regarding neurological disorders.

Known for inducing intense hallucinations when administered in high enough doses from an external source1, N,N-Dimethyltryptamine (DMT) is also found in minuscule concentrations naturally within the brain. Whether it plays a physiological role, however, is still very much up for debate, though recent work has found that DMT is elevated in the brain of rats following cardiac arrest.

The psychoactive effects of DMT are thought to occur through stimulating members of the serotonin receptor family, the 5-HT2A receptor in particular.4 Recently though, DMT has also been found to bind to the sigma-1 receptor (Sig-1R) which regulates the response of neural cells to stressors. Cells can become stressed due to a prolonged absence of nutrients and/or oxygen which can lead to damage and eventually the activation of self-termination procedures (apoptosis) to protect the surrounding tissue. As Sig-1R is found in neural cells, it, therefore, can be seen as an attractive therapeutic target to ensure healthy regulation of cell stress in the brain following pathological events such as a stroke.

When cortical neurons (cells found within a layer of the brain) are grown in the lab simulating conditions of a stroke, i.e., lacking oxygen, they become stressed and apoptotic. This effect is averted when these cells are stimulated with DMT; the process of which is mediated via the binding of DMT to Sig-1R. To build upon this finding, researchers undertook a series of experiments examining whether the neuroprotective effects of DMT are present in stroke models using rats.

Stroke induction

To starve the brain tissue of oxygen and nutrients and induce brain tissue damage mimicking that seen in stroke victims, cerebral blood was temporarily obstructed by threading nylon through the internal carotid artery. The sudden reintroduction of blood flow by removing the nylon can be equally damaging due to an increase of harmful reactive oxygen species leading to increased oxidative stress and local inflammation. Thus, this stroke model which induces regional brain tissue damage can also be used effectively to study the succeeding inflammatory response.

Post-injury DMT administration and analysis

Immediately after blood flow was restored, rats received an initial dose of DMT followed by a continuous infusion for 24 hours. Behavioural assessments, i.e., observing food consumption habits, were carried out for 30 days to assess motor function. Brains were imaged using magnetic resonance imaging (MRI) to assess the level of damage of the stroke injury. Finally, Apoptotic Protease Activating Factor, Brain-Derived Neurotrophic Factor, and Tumour Necrosis Factor were measured in both the brain and blood of the animals.

What did the data show?

As determined by MRI, the size of the brain lesions in rats that were administered DMT following injury were significantly reduced compared to rats that did not receive DMT. This neuroprotective effect was negated when DMT was co-administered alongside BD1063 (an antagonistic drug that also binds to Sig-1R but doesn’t activate it). This highlights that the neuroprotective effect of DMT is at least partially mediated via Sig-1R signalling.

DMT-receiving rats also appeared to recover motor function much quicker than control rats as determined by increased use of their forearms during feeding. These rats also had a significant reduction of markers indicative of apoptosis and inflammatory signalling molecules in both the brain and in the circulating blood, whereas indicators of neural growth increased.

Study critiques

Regarding experiments measuring motor function, only a single behavioural task was carried out, and other tests could have also been conducted to strengthen this data.9 The particular task used here has also been deemed to best assess motor function over a longer period of time, i.e., two months, something that was not explored in this particular study.

The neural marker measured is relatively broad in its function, i.e., it is involved in neuron survival, differentiation, growth and inducing the formation of new links with other neurons. It is therefore unclear as to its actual role in this study as no experiments were conducted to directly show the presence of new neural cells. More information could have been obtained by using techniques such as ‘EdU labelling’ which tags newly divided cells in live animal models. This would have shown whether DMT treatment induces the formation of new neural cells with the bonus of highlighting their physical location.

Lastly, introducing a delay between injury and DMT administration simulating the typical time from identification of stroke symptoms to seeking medical assistance would better illustrate the potential of DMT as a therapeutic intervention.

Conclusion

This research builds upon previous work highlighting the neuroprotective effects of DMT and strengthens the evidence regarding the mechanism of its effects. The overall focus diverges from exploring the potential effects of naturally occurring DMT and emphasises its therapeutic value when administered from external sources. Although observing the effects of DMT administration so promptly following injury is somewhat impractical, this study provides an interesting proof of concept and opens the door to exploring its properties in other models of neurodegeneration.

 
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Can psychedelics boost brain growth factor levels?*

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

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

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

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

Neuroplasticity and BDNF in health and disease

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

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

Psychedelics can also boost BDNF in animal studies

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

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


A molecular model of the protein known as brain-derived neurotrophic factor (BDNF).

LSD microdose increases blood BDNF in healthy participants

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

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

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

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

Rewiring the brain by taking the path less travelled

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

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


*From the article here:
 
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Medical cannabis found to reduce essential tremor

University of Copenhagen | EurekAlert | 18 Mar 2021

Medical cannabis is a subject of much debate. There is still a lot we do not know about cannabis, but researchers from the Department of Neuroscience at the Faculty of Health and Medical Sciences have made a new discovery that may prove vital to future research into and treatment with medical cannabis.

Cannabinoids are compounds found in cannabis and in the central nervous system. Using a mouse model, the researchers have demonstrated that a specific synthetic cannabinoid (cannabinoid WIN55,212-2) reduces essential tremor by activating the support cells of the spinal cord and brain, known as astrocytes. Previous research into medical cannabis has focussed on the nerve cells, the so-called neurons.

"We have focussed on the disease essential tremor. It causes involuntary shaking, which can be extremely inhibitory and seriously reduce the patient's quality of life. However, the cannabinoid might also have a beneficial effect on sclerosis and spinal cord injuries, for example, which also cause involuntary shaking." says Associate Professor Jean-François Perrier from the Department of Neuroscience, who has headed the research project.

"We discovered that an injection with the cannabinoid WIN55,212-2 into the spinal cord turns on the astrocytes in the spinal cord and prompts them to release the substance adenosine, which subsequently reduces nerve activity and thus the undesired shaking."

Targeted treatment with no problematic side effects

That astrocytes are part of the explanation for the effect of cannabis is a completely new approach to understanding the medical effect of cannabis, and it may help improve the treatment of patients suffering from involuntary shaking.

The spinal cord is responsible for most our movements. Both voluntary and spontaneous movements are triggered when the spinal cord's motor neurons are activated. The motor neurons connect the spinal cord with the muscles, and each time a motor neuron sends impulses to the muscles, it leads to contraction and thus movement. Involuntary shaking occurs when the motor neurons send out conflicting signals at the same time. And that is why the researchers have focussed on the spinal cord.

"One might imagine a new approach to medical cannabis for shaking, where you - during the development of cannabis-based medicinal products - target the treatment either at the spinal cord or the astrocytes - or, at best, the astrocytes of the spinal cord." says Postdoc Eva Carlsen, who did most of the tests during her PhD and postdoc projects.

"Using this approach will avoid affecting the neurons in the brain responsible for our memory and cognitive abilities, and we would be able to offer patients suffering from involuntary shaking effective treatment without exposing them to any of the most problematic side effects of medical cannabis."

The next step is to do clinical tests on patients suffering from essential tremor to determine whether the new approach has the same effect on humans.

 
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Neuroscientists believe deep neural networks could help illustrate how psychedelics alter consciousness

by Eric Dolan | PsyPost | 5 Jan 2021

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

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

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

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

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

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

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

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

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

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

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

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

 
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Albert Hofmann

MRI scans reveal differences in people with anxiety and depression

by Sarah Sloat | INVERSE | 20 Nov 2017

These debilitating conditions have a physical basis.

In the U.S., 16 million adults are diagnosed with major depression disorder, and 15 million with social anxiety disorder. People with depression often feel persistent sadness and lose interest in things they once cared about, and those with anxiety have an intense fear of being watched and judged. Some of the most debilitating clinical symptoms overlap.

New research, which will be presented next week at the annual meeting of the Radiological Society of North America, is the first evidence that this overlap may be caused by similar structural abnormalities people with depression and social anxiety have in their brains. While the paper is not published yet, the abstract is available online.

Doctors from Sichuan University in Chendgu, China have discovered that patients with depression and anxiety have abnormalities in the grey matter of their brains salience and dorsal attention networks. The salience network determines what stimuli catch the attention of the brain, and the dorsal attention network drives focus and attention.

"These consistent structural differences in the two patient groups may contribute to the broad spectrum of emotional, cognitive, and behavioral disturbances observed in MD [major depression] and SAD [social anxiety disorder] patients," the doctors write. "These findings provide new evidence of shared and specific neuropathological mechanisms underlying MDD [major depressive disorder] and SAD."

In the study, which uncovered the first preliminary evidence of the gray matter changes in the brains of MDD and SAD patients, the researchers used magnetic resonance imaging (MRI) to evaluate the brains of 37 MDD patients, 24 SAD patients, and 41 healthy control individuals.

Compared to the control participants, MDD and SAD patients showed a cortical thickening in the brains insular cortex, which influences perceptions of empathy, self-awareness, and interpersonal experiences. "This thickening," study co-author Youjin Zhao, M.D., Ph.D., explains in a statement, "may be a result of inflammation, and could be the result of both the continuous coping efforts and emotion regulation attempts of MDD and SAD patients."

The researchers found differences between the brains of people with MDD and SAD, too. Brains of patients with depression showed alterations in the regions of the brain that control emotional facial processing, while brains of patients with anxiety had disorder-specific involvement in the regions associated with processing fear.

"What the exact relationship between these disorders and the cortical thickening of the brain, particularly in the anterior cingulate cortex, remains to be understood. More studies with larger sample sizes that use machine learning analysis, are needed, says Zhao, but there may be a future where MRIs can help aid the diagnosis of these widespread, debilitating conditions."

https://www.inverse.com/article/3859...sorder-anxiety
 
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The emerging revival of psychedelics in neuroscience

by Cami Rosso | Psychology Today | 13 Jan 2021

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

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

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

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

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

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

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

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

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

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

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

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

 
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Substance present in ayahuasca brew stimulates generation of human neural cells


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

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

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

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

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

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

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

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

 
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This shows neurons


Neural roots and origins of alcoholism identified

University of Warwick | Neuroscience News | 4 Feb 2021

Researchers have identified a pathway in the brain responsible for the development of alcohol addiction.

The physical origin of alcohol addiction has been located in a network of the human brain that regulates our response to danger, according to a team of British and Chinese researchers, co-led by the University of Warwick, the University of Cambridge, and Fudan University in Shanghai.

The medial orbitofrontal cortex (mOFC) at the front of the brain senses an unpleasant or emergency situation, and then sends this information to the dorsal periaqueductal gray (dPAG) at the brain’s core, the latter area processing whether we need to escape the situation.

A person is at greater risk of developing alcohol use disorders when this information pathway is imbalanced in the following two ways:

Alcohol inhibits the dPAG (the area of the brain that processes adverse situations), so that the brain cannot respond to negative signals, or the need to escape from danger — leading a person to only feel the benefits of drinking alcohol, and not its harmful side effects. This is a possible cause of compulsive drinking.

A person with alcohol addiction will also generally have an over-excited dPAG, making them feel that they are in an adverse or unpleasant situation they wish to escape, and they will urgently turn to alcohol to do so. This is the cause of impulsive drinking.

Professor Jianfeng Feng, from the Department of Computer Science at the University of Warwick and who also teaches at Fudan University, comments: “I was invited to comment on a previous study on mice for the similar purpose: to locate the possible origins of alcohol abuse. It is exciting that we can replicate these murine models in humans, and, of course, go a step further to identify a dual-pathway model that links alcohol abuse to a tendency to exhibit impulsive behaviour.”

Professor Trevor Robbins from the Dept of Psychology at the University of Cambridge comments: “It is remarkable that these neural systems in the mouse concerned with responding to threat and punishment have been shown to be relevant to our understanding of the factors leading to alcohol abuse in adolescents.”

Dr Tianye Jia from the Institute of Science and Technology for Brain-inspired Intelligence at Fudan University, also affiliated with King’s College London, comments:​
“We have found that the same neural top-down regulation could malfunction in two completely different ways, yet leading to similar alcohol abuse behaviour.”

Published in the journal Science Advances, the research is led by an international collaboration, co-led by Dr Tianye Jia from Fudan University, Professor Jianfeng Feng from the University of Warwick and Fudan University, and Professor Trevor Robbins from the University of Cambridge and Fudan University.

A pathway in the brain where alcohol addiction first develops has been identified by researchers in a new study.

The research team had noticed that previous rodent models showed that the mPFC and dPAG brain areas could underlie precursors of alcohol dependence.

They then analysed MRI brain scans from the IMAGEN dataset — a group of 2000 individuals from the UK, Germany, France and Ireland who take part in scientific research to advance knowledge of how biological, psychological and environmental factors during adolescence may influence brain development and mental health.

The participants undertook task-based functional MRI scans, and when they did not receive rewards in the tasks (which produced negative feelings of punishment), regulation between the mOFC and dPAG was inhibited more highly in participants who had exhibited alcohol abuse.

Equally, in a resting state, participants who demonstrated a more overexcited regulation pathway between the mOFC and dPAG, (leading to feelings of needing urgently to escape a situation), also had increased levels of alcohol abuse.

Alcohol use disorder (AUD) is one of the most common and severe mental illnesses. According to a WHO report in 2018, more than 3 million deaths every year are related to alcohol use worldwide, and harmful alcohol use contributes to 5.1% of the global burden of disease. Understanding how alcohol addiction forms in the human brain could lead to more effective interventions to tackle the global problem of alcohol abuse.

 
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always interesting to see how specific substances might manifest their abuse potential

another data point against the common AA trope of all substance use being "equal"
 

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University of Glasgow

Neuroscience students launch Psychedelic Society

by Carmen Blaque | Glasgow Guardian } 2 Feb 2021

The society hopes to promote positive research into psychedelic drugs.

Illegal hallucinogenic drugs such as LSD, magic mushrooms and DMT have become increasingly researched amongst the scientific community in the past decade. Government grants have been issued in the UK to study such compounds, in hope to ease the mental health burden in the UK. Traditional pharmaceutical antidepressants, such as SSRI’s, fail to work for up to half of individuals. For the individuals who do respond, various side effects are common. With antidepressant medications seeing a 48% increase in the past decade in Scotland, the need for innovative treatments is paramount.

Dr Adrian James from The Royal College of Psychiatrists has recently stated that coronavirus will worsen the UK's mental health problems: “It is probably the biggest hit to mental health since the second world war.” Neuroscience students at the University of Glasgow have launched a Psychedelic Society to raise awareness about the potential for psychedelics to treat various mental health conditions such as depression, PTSD, anorexia, and addiction.

The Psychedelic Society are inspired by previous acts of social change that have occurred at the University of Glasgow. The University’s Climate Action Society contributed to the University’s plan of divestment from fossil fuels in 2013, with full divestment estimated to occur by 2024. Students at the University of Glasgow Psychedelic Society are hopeful that the University will also see the urgency to study psychedelic medicine and hope that they can make social change through providing students and staff with general education surrounding the therapeutic potential of psychedelics, in addition to the scheduling status of these substances.

Psychedelics are Schedule 1 controlled substances, which not only makes them illegal but makes scientific research extremely difficult. The University of Glasgow's Psychedelic Society is hopeful that they can make changes to the current scheduling which would make research easier and help those who are in desperate need. With ecological scientists such as Dr Sam Gandy showing that psychedelics can also increase nature-relatedness - which could, in turn, increase positive environmental behaviour - psychedelics offer hope for the current climate crisis.

The society is inspired by political scientist Erica Chenoweth from Harvard University, who found that past historical acts of change occur when around 3.5% of the population are in active participation. The society is hopeful that others will engage to help lower the scheduling of psychedelics, which could help research and ultimately save the lives of those who have not benefited from other mental health treatments.

Professor Davit Nutt, a former advisory committee of the misuse of drugs was famously sacked for stating that ecstasy and LSD are less harmful than drugs such as alcohol, has been invited to talk as part of the society's psychedelic science event. Professor David Nutt, who is now chair of Drug Science and deputy head of the Imperial College London's Centre for Psychedelic Research, is also hopeful that psychedelics could help those suffering from mental health illness, which has been proven from clinical trials. Professor Nutt stated: “The results were quite remarkable, possibly the most powerful single-intervention impact in depression there’s ever been, half participants were depression-free at one week and about a third were depression-free at three months.”

Psychedelic Research Centers are launching around the world, and UK leading institutions such as Imperial College London, have a dedicated Centre for Psychedelic Research and have made a significant contribution to psychedelic science and mental health in recent years. Students at the University of Glasgow's Psychedelic Society are hopeful that Scotland's universities will follow, to pave the way for the healing potential of psychedelics.

 

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Psilocybin and Neurogenesis*

by Patrick Smith | Entheonation

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

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

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

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

What are neurogenesis and neuroplasticity?

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

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

What are the benefits of neurogenesis and neuroplasticity?

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

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

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

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

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

Psilocybin, neurogenesis and neuroplasticity

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

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

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

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

How to use psilocybin to boost neuroplasticity

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

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

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

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

How to microdose with magic mushrooms for neuroplasticity

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

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

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

*From the article here :
 
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Adult neurogenesis may hold clues for more effective treatment of alcoholism

IOS Press | Neuroscience News | 10 Feb 2021

A new series of studies review the roles neuroplasticity and neurogenesis play in alcohol addiction and recovery.

Neuroplasticity, the remarkable ability of the brain to modify and reorganize itself, is affected by or in response to excessive alcohol, whether through individual consumption or exposure in the womb. It is now well accepted that the birth and integration of new neurons continue beyond development and into adulthood.

New discoveries and insights on how alcohol impacts this and other plastic processes are discussed in “Alcohol and Neural Plasticity,” a special issue of Brain Plasticity.

“The discovery and evolution of our acceptance of the role of adult neurogenesis in brain structure and function have revolutionized our understanding of the brain’s response to insult, but has also introduced a potential mechanism of recovery in some regions,” explains Guest Editor Kimberly Nixon, PhD, The University of Texas at Austin, College of Pharmacy, Austin, TX, USA.

In models of Fetal Alcohol Spectrum Disorder, earlier research found that gestational exposure to moderate levels of alcohol in mice throughout a period equivalent to the first and second human trimesters profoundly impacted neurogenesis. In a follow up study published in this special issue, lead investigator Lee Anna Cunningham, PhD, Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA, and colleagues examined the functional and structural consequences of prenatal alcohol exposure on adult-generated neurons.

They found no direct effects of prenatal alcohol exposure on adult hippocampal neurogenesis in mice housed under standard conditions, but prenatal alcohol exposure impaired the neurogenic response to enriched environment. These mice also performed poorly in a neurogenesis-dependent pattern discrimination task and displayed impaired enrichment-mediated increases in dendrite complexity.

“This study further underscores the impact of moderate gestational alcohol exposure on adult hippocampal plasticity and supports adult hippocampal neurogenesis as a potential therapeutic target to remediate certain neurological outcomes in fetal alcohol syndrome,” notes Dr. Cunningham.

The mechanisms of recovery from adult alcohol use disorder are not clear, although reactive neurogenesis has been observed following alcohol dependence. Dr. Nixon and colleagues studied the role of adult-born neurons in the recovery of hippocampal learning and memoryduring withdrawal and abstinence from alcohol dependence. They hypothesized that reducing reactive neurogenesis would impair functional recovery. Adult male rats were subjected to a four-day binge alcohol exposure, and then reactive neurogenesis was chemically inhibited. Despite reducing this potential mechanism of hippocampal repair, learning and memory behavior still recovered and were identical to controls.

“Further work is needed to better characterize and differentiate how adult-born neurons contribute to both hippocampal impairments in alcohol misuse but also recovery in abstinence,” Dr. Nixon says.

The special issue also reviews several key issues: the effect of combined alcohol and cocaine exposure on neural stem cells and adult neurogenesis; the neurotoxic effects of binge alcohol consumption, highlighting the scarcity of work on females and the aged; the role of immune activation as a mechanism of alcohol’s effects on synaptic and structural plasticity; and one of the first in-depth discussions of alcohol’s neurophysiological effects on hippocampal excitatory activity during alcohol withdrawal. This activity may underlie the hyperexcitability that is seen in alcohol withdrawal and can be a fatal complication of non-medically supervised “detox” from alcohol.

Also included are a review and data paper on alcohol effects on synaptic mechanisms that underlie the various behavioral deficits that occur with the development of alcohol abuse disorder and a developmental study that offers insight into our understanding of alcohol’s effects at synapses during juvenile development.

“The overarching goal of most of our research programs is to find a potential therapeutic target that could be utilized to develop a drug to treat addiction,” Dr. Nixon observes. “The progress I hope for is that if we can find a novel approach or target within these various plasticity systems, it will be more efficacious in the treatment of alcohol use disorders and more people will seek treatment. That said, much of this work is very novel and translational, but not yet near the drug development stage.”

 
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Microdoses of DMT produce positive effects on mood and anxiety in rodents*

Lindsay Cameron, Charlie Benson, Brian DeFelice, Oliver Fiehn, and David Olson

Drugs capable of ameliorating symptoms of depression and anxiety while also improving cognitive function and sociability are highly desirable. Anecdotal reports have suggested that serotonergic psychedelics administered in low doses on a chronic, intermittent schedule, so-called “microdosing”, might produce beneficial effects on mood, anxiety, cognition, and social interaction. Here, we test this hypothesis by subjecting male and female Sprague Dawley rats to behavioral testing following the chronic, intermittent administration of low doses of the psychedelic N,N-dimethyltryptamine (DMT). The behavioral and cellular effects of this dosing regimen were distinct from those induced following a single high dose of the drug. We found that chronic, intermittent, low doses of DMT produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction. Additionally, male rats treated with DMT on this schedule gained a significant amount of body weight during the course of the study. Taken together, our results suggest that psychedelic microdosing may alleviate symptoms of mood and anxiety disorders, though the potential hazards of this practice warrant further investigation.

Drugs capable of ameliorating symptoms of depression and anxiety while also improving cognitive function and sociability are highly desirable. Anecdotal reports have suggested that serotonergic psychedelics administered in low doses on a chronic, intermittent schedule, so-called “microdosing”, might produce beneficial effects on mood, anxiety, cognition, and social interaction. Here, we test this hypothesis by subjecting male and female Sprague Dawley rats to behavioral testing following the chronic, intermittent administration of low doses of the psychedelic N,N-dimethyltryptamine (DMT). The behavioral and cellular effects of this dosing regimen were distinct from those induced following a single high dose of the drug. We found that chronic, intermittent, low doses of DMT produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction. Additionally, male rats treated with DMT on this schedule gained a significant amount of body weight during the course of the study. Taken together, our results suggest that psychedelic microdosing may alleviate symptoms of mood and anxiety disorders, though the potential hazards of this practice warrant further investigation.

*See the entire article here :
 

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Engineering psychoplastogens: Toward a safer alternative for treating depression*

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

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

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

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

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

Neural plasticity and the neurotrophic hypothesis

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

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

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

What are psychoplastogens?

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

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

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

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

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


Figure A: The chemical structure of compounds possessing the DMT pharmacophore.5 The DMT portion (highlighted in black) is the
core scaffold of several known psychoplastogenic compounds.

Working on DMT: Engineering isoDMT analogues

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

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

Chemically, isoDMT is identical to DMT except that the indole nitrogen atom of isoDMT is located in the 3-position instead of the 1-position. These arrangements are shown in Figure B.


Figure B: The only difference between the chemical structures of DMT (1) and isoDMT (2) is that the C1 and C3 substituents
of the indole are transposed.

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

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


Figure C: The chemical optimization of indole N-alkylation.

The Dendritogenesis Assay

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

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


Figure D: Images of cortical neurons treated with the compounds indicated. VEH = vehicle control. The indole N-H of tryptamine
derivatives is not necessary to promote dendritogenesis.

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


Psychedelic potential

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

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

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

*From the article here :
 
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Psychedelic Neuroimaging

by Ruth Williams | The Scientist

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

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

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

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

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

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

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

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

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

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

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

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

 

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The nuances of ketamine’s neurochemistry

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

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

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

Ketamine’s novel mechanisms of action

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


Figure 1: Ketamine’s proposed novel mechanisms of action, as compiled by Zanos and Gould. Note that ketamine binds to NMDA receptors
on GABAergic interneurons to disinhibit glutamate release (section ‘a’ above). Evoked release of glutamate binds to AMPA receptors, in turn
releasing BDNF. This figure also illustrates the proposed release of ketamine metabolites.

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

BDNF is also a factor in synaptic plasticity and its production can lead to resilience to chronic stress.3 The metabolites of ketamine also have antidepressant effects which are NMDA-independent. Ketamine’s metabolites (2R,6R)-HNK and (2S,6S)-HNK are released by the breakdown of ketamine and promote AMPAR-mediated synaptic potentiation.

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

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

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

While the R and S stereoisomers of ketamine look nearly identical, they are chiral molecules–meaning that they are non-superimposable mirror images (Figure 2). The preceding letters R and S are used to refer to the ‘handedness’ of the isomer. R indicates right-handed, or clockwise geometry, whereas S indicates left-handed, or counterclockwise geometry. Take for example human hands; when facing each-other they are mirror images. However, when rotated they cannot be indistinguishably placed over each other. Chiral molecules are also known in the field of chemistry as enantiomers. Though this difference between the enantiomers is seemingly small, each isomer of ketamine has unique neurochemical effects.


Figure 2: The optical isomers of ketamine.

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

Clinical differences between the effects of the R and S isomers

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

The S-isomer (also known as esketamine) is currently isolated and distributed for a higher cost than the racemic mixture.3 The isomer withstood a non-inferiority trial when compared to the racemic mixture, indicating equivalence between s-ketamine and racemic in treating depression.5 S-ketamine was FDA approved in 2019 for the treatment of TRD and is administered nasally as the drug Spravato.

Studies show that S-ketamine has a fourfold greater potency when it comes to inhibiting the NMDA receptor when compared to R-ketamine (also called arketamine).3 Its greater affinity at the NMDA receptor likely contributes to its selection by pharmaceutical companies in developing the drug. S-ketamine also has a greater analgesic potency; its analgesic potency is twice that of the racemate.5 For this reason, there is a preferential use of s-ketamine when it comes to anesthesia.

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

Summary and conclusion

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

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


 
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