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mr peabody

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DMT and Stroke Research

by Tanya Ielyseieva | Truffle Report | 11 Mar 2021

As psychedelics become increasingly viable as treatments for mental and physical health issues, drug developers have begun researching treatments to boost the recovery of neurotransmitter systems throughout the brain and spinal cord. Truffle Report decided to look into the research surrounding DMT and how it can promote structural and functional neural plasticity, and potentially aid in stroke treatment and recovery.

In 2018, one in every six deaths from cardiovascular disease was due to stroke. The World Health Organization (WHO) reports that 15 million people suffer from stroke worldwide each year. Of these, five million die, and another five million are permanently disabled. According to the Centers for Disease Control and Prevention (CDC), stroke is one of the leading causes of death in the United States, with about 795,000 U.S. people suffering a stroke each year.​

What is a stroke?

A stroke occurs when the blood flow that delivers oxygen and nutrients to the brain is blocked by a clot or bursts. When part of the brain can receive neither the blood nor oxygen that it needs to function, brain cells die. The death of the brain cells can lead to a serious physical or mental disability, or in the worst-case scenario, death.

There are three main types of stroke:​
  • Ischemic stroke is the most common, responsible for about 87 percent of total case numbers. During an ischemic stroke the arteries delivering blood to the brain become narrow or blocked, which prevents blood and oxygen from reaching the brain. Ischemic strokes can be thrombotic (the clot forms in one of the arteries supplying blood to the brain) and embolic (the clot forms in the part of the body such as the heart, arteries in the neck, or upper chest).​
  • Hemorrhagic stroke is caused by breakage or leaking in the blood vessel, which leads to bleeding in the brain. This break stops oxygen and other nutrients from reaching brain cells. Hemorrhagic stroke can be intracerebral (tissues surrounding the brain are filled with blood) and subarachnoid (an area between the brain and tissues that is filled with blood).​
  • Transient ischemic attack, often referred to as TIA or mini-stroke, happens when blood flow to the brain is blocked by a temporary clot.​
The symptoms of stroke vary. The only thing that they have in common is sudden and unexpected emergence. The list of symptoms can include:​
  • Confusion, disorientation, memory loss​
  • Trouble speaking and understanding speech​
  • Numbness or weakness in an arm, leg, or the face​
  • Severe headaches​
  • Difficulty seeing or vision loss​

DMT and brain studies

N,N-dimethyltryptamine or DMT is a psychoactive compound that can occur naturally within the human body and induces an intense psychedelic experience when ingested. So why are researchers interested in the DMT as a possible salvation for stroke victims?

Previous studies have shown that DMT has great potential to boost neuroplasticity in the brain and to protect it from hypoxia.

A study by researchers at the University of Wisconsin School of Medicine and Public Health in collaboration with the Isfahan University of Technology in Iran discovered that DMT binds to sigma-1 receptors (Sig-1R), which are located throughout the human body. Sig-1R has a major role in protecting brain cells from losing oxygen, resulting in cell death.

A 2016 study by researchers at the Oslo University Hospital in collaboration with the University of Debrecen in Hungary and Sant Pau Institute of Biomedical Research in Spain investigated the effects of DMT on neurons and immune cells during hypoxic stress. Hypoxic stress occurs when organisms encounter insufficient levels of oxygen. Results showed that DMT increases the survival times of these cell types, suggesting that this psychedelic drug can protect cells from hypoxia-induced cellular stress, meaning DMT helps to keep brain cells alive.

A 2018 study by David Olson showed that psychedelics can change brain cells in rats and flies. DMT was found to promote neuroplasticity.

A 2020 study by researchers at the Complutense University Of Madrid in Spain found that not only does DMT encourage the formation of new neurons and activating neural stem cells, it also helps rodents to better perform memory tasks.

In a 2020 study by researchers at the Semmelweis University in Hungary in collaboration with the University of Oslo, DMT-treated rats had reduced brain injuries and increased motor function. The effects were demonstrated in rats who had ischemia-reperfusion injuries in their brains.

With these studies in mind, researchers are now asking whether or not the effects of DMT can help stroke patients. If so, how do they eliminate the hallucinogenic part of the experience while maintaining the neurogenic benefits?​

Current DMT clinical research

The first company to make the news was Algernon Pharmaceuticals. This Vancouver-based clinical-stage drug developmer is aiming to use DMT to aid acute ischemic stroke recovery with a microdosing protocol, with clinical trials to start as soon as possible in 2021. The study is being led by Dr. Rick Strassman, who famously labelled DMT “The Spirit Molecule” and has Professor David Nutt of Imperial College London attached as a consultant.

However, PharmaDrug has now filed an FDA Orphan Drug Designation for DMT in stroke. This Toronto-based specialty pharmaceutical company aims to use DMT for emergency medical assistance within three hours of stroke symptom onset.

“We are building an industry-leading foundation to explore the clinical potential of DMT in rare neuropsychiatric and neurological disorders. With the submission of our orphan drug application to the FDA now complete, we will move swiftly to accelerate the research and development of DMT for acute ischemic stroke,” said Daniel Cohen, CEO of PharmaDrug, in a press release. “Additionally, we will continue to broaden our DMT clinical programs by taking advantage of valuable FDA regulatory incentives such as orphan drug, fast track and breakthrough therapy designations.”

If DMT is found to be safe for stroke patients, it can potentially prevent damage in the brain and help speed up post-stroke rehabilitation.

 
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Deep neural networks could help illustrate how psychedelics alter consciousness*

by Eric Dolan | PsyPost | 5 Jan 2021

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

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

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

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

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

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

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

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

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

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

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

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

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

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

by Eric Dolan | PsyPost | 18 Mar 2021

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

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

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

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

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

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

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


 

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Predicting the addictive potential of phenethylamines*

by Benjamin Malcolm | Spirit Pharmacist | 16 Jan 2021

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

Types of phenethylamines

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

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

Image Source: Foundation to Psychedelic Pharmacology

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

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

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

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

*From the article here :
 
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mr peabody

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Albert Hofmann

Study reveals how LSD leads to greater brain flexibility

by Kristi Pahr | LUCID NEWS | 12 Mar 2021

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

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

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

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

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

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

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

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

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

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

 

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For example, when comparing the actions of mephedrone (4-methylmethcathinone or 4-MMC) with MDMA it is noted that MDMA has considerably less dopamine release than mephedrone and that mephedrone has dopamine release similar to amphetamine. In addition, mephedrone also has a much shorter half-life than MDMA meaning that pleasurable effects wear off sooner. Frequent re-dosing creates a stacking of physical effects, the risks of behavioral reinforcement and addiction as well as adverse reactions such as cardiovascular events, seizures, or psychosis increases.
Hi there good Sir. STILL not fully crazy yet, just about lol! Nice kava and cannabis effects today.

So that’s interesting. I always distinguished MDMA from LSD in one simplistic way- I felt MDMA was so heavily associated with serotonin , it’s high impact in dopamine release flew under the radar.

With LSD not really being a dopamine producer, as far as I thought back then. More solely serotonin raising, but not in a depleting way like MDMA.

Maybe that’s one reason adding cannabis, kava too possibly, to LSD, hence a flood of Dopamine, which enhances the acid so greatly.

While cocaine, crack is mega dopamine too. But more than any other drug I’ve witnessed, crack cocaine in particular, really cancels out LSD.

So we have different drugs boosting serotonin in different ways, MDMA + LSD, one damaging, one not as we know, in the true sense.

And dopamine from cannabis plus dopamine (and norepinephrine plus lots serotonin too) from kava, fuelling the LSD, the high Dopamine rush from Coke/Crack the opposite.

The MDMA Dopamine/Serotonin does nothing to nullify the LSD but was always my favourite combo for synergy and longevity, though I did also enjoy adding psilocybin to each or both.

There are no doubt many other mechanisms, but I’ve mused over this before.

But I was going to say how MDMA is mostly not an addictive seeking behaviour drug, nothing like Methamphetamine which I’ve never personally tried, due to the higher dopamine release, plus shorter half life.

That makes perfect sense. I’m curious how meth would affect the LSD? My bet would be to nullify it like the cokes.

Anyway, keep taking care Mr Peabody.
 
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Albert Hofmann

Study reveals how LSD leads to greater brain flexibility

by Kristi Pahr | LUCID NEWS | 12 Mar 2021

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

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

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

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


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

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

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

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

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

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

Haha, then you go and throw THIS one on me, right when I’m in the aftermath of 14.5 mg’s in under 2 months, having been astounded to observe myself that despite the massive rocking turbulence at points, my imagination sharpness, mental acuity, particularly social conversational ability and sheer ease of literally- Flexible, easy use of language and word selection, scentence and phrase construction to convey meaning, seems not to have suffered at all but quite the opposite until now anyway.
 
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Whoops, typo above. The kava provides dopamine and norepinephrine and serotonin. Missed out the word kava.
 

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3D reconstruction of dendrites

Vitamins for your neurons

eLife | Neuroscience News | 30 Mar 2021

A vitamin A derivative, induces synaptic plasticity in human cortical neurons.

The brain has an enormous capacity to adapt to its environment. This ability to continuously learn and form new memories thanks to its malleability, is known as brain plasticity.

One of the most important mechanisms behind brain plasticity is the change in both the structure and function of synapses, the points of contact between neurons where communication happens. These sites of synaptic contact occur through microscopic protrusions on the branches of neurons, called dendritic spines. Dendritic spines are very dynamic, changing their shape and size in response to stimuli.

Previous studies have shown that alterations in synaptic plasticity occur in various animal models of brain diseases. However, it remains unclear whether human cortical neurons express synaptic plasticity similarly to those in the rodent brain.

Recently, the vitamin A derivative, All-Trans Retinoic Acid, has been linked to synaptic plasticity. In addition, several studies have evaluated the effects of this derivative in patients with cognitive dysfunctions, including Alzheimer’s disease, Fragile X syndrome, and depression.

However, there is no direct experimental evidence for synaptic plasticity in the adult human cerebral cortex related to vitamin A signaling and metabolism.

To investigate this, Lenz et al. used human cortical slices prepared from neurosurgical resections and treated them with a solution of the vitamin A derivative, All-Trans Retinoic Acid, for 6-10 hours. Lenz et al. employed a variety of techniques, including patch-clamp recordings to measure neuron function as well as different types of microscopy to evaluate structural changes in dendritic spines.

These experiments demonstrated that the derivative promoted the synaptic plasticity in the adult human cortex. Specifically, it increased the size of the dendritic spines and strengthened their ability to transmit signals. In addition, Lenz et al. found that the spine apparatus organelle – a structure found in some dendritic spines – was a target of the vitamin A derivative and promoted synaptic plasticity.

These findings advance the understanding of the pathways through which vitamin A derivatives affect synaptic plasticity, which may aide the development of new therapeutic strategies for brain diseases. More generally, the results contribute to the identification of key mechanisms of synaptic plasticity in the adult human brain.

 
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Ketamine normalizes hyperactivity in a key brain region of depressed patients

by Christian Rigg | PsyPost | 4 Apr 2021

There is no shortage of psychological and pharmacological therapies to combat the world’s most widespread mental health issue, major depressive disorder (MDD). However, a significant portion of the affected population fail to respond to many of these traditional therapies. For this reason, new drugs must be tested and validated. One promising candidate is ketamine –famously but somewhat improperly known as a horse tranquilizer.

However, the manner by which ketamine acts is not well known, meaning that clinicians are still circumspect regarding its use in treating MDD. Recently, researchers in New York look at how ketamine affects the subgenual anterior cingulate cortex (sgACC), a region of the brain whose hyperactivity has proven ties to MDD. The recent study, which appeared in Neuropsychopharmacology, helps bridge this gap in the literature.

In the study, 28 patients with MDD and 20 healthy controls underwent function MRI (fMRI) scans both at rest and while completing a monetary incentive-based task. The goal of the incentive task was to activate the sgACC, known to be implicated in reward anticipation.

The results of the study demonstrate a more complex relation between the sgACC and MDD than has been previously suspected. The authors describe a “double dissociation, whereby sgACC hyper-activation to positive feedback is associated with anhedonia [inability to feel happiness], whereas hyper-activation to negative feedback is associated with anxiety.”

This also enabled them to uncover what may be an important physiological distinction in the region, where the posterior region was more closely related to symptoms of anhedonia and the anterior region to anxiety.

In terms of a pharmacological treatment, ketamine was shown to operate by reducing sgACC hyperactivation to positive feedback. If this seems counterintuitive, it is important to remember that many brain centers are inhibitory by nature, meaning that the more active they are, the more strongly they inhibit other areas—thus producing, for example, a reduced response to positive feedback. Interestingly, the ketamine treatment blunted sgACC hyperactivation in response to positive feedback, but not negative feedback.

The neurological underpinnings of MDD are still not well understood. The same can be said for many of the drugs used in treating it. Rigorous clinical testing and exploratory studies like the present are thus essential in improving our understanding of both this disease and treatment options.

The study, “Ketamine normalizes subgenual cingulate cortex hyper-activity in depression“, was authored by Laurel S. Morris, Sara Costi, Aaron Tan, Emily R. Stern, Dennis S. Charney, and James W. Murrough.

 
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Special Report on Neuroscience: Demystifying Psychedelics

by Randall Willis | Exploring Drug Discovery and Development | 26 Mar 2021

Late last year, University of Basel’s Felix Müller and colleagues offered a case report of a 39-year-old wife and mother admitted to their care with severe treatment-resistant depression and complex personality disorder.

She first reported symptoms as a teenager, including feelings of worthlessness and suicidal ideations, that evolved to pseudo-hallucinations (e.g., seeing snakes), panic attacks, and compulsive thoughts. She didn’t seek treatment until she was 22, when her partner committed suicide, and was first hospitalized at age 30 after attempting suicide herself by drug intoxication.

“Over the last years, the patient had been treated with several psychiatric drugs, including antidepressants of different types (escitalopram, sertraline, fluoxetine, duloxetine, moclobemide, reboxetine, trazodone, mirtazapine, vortioxetine, nortriptyline), mood stabilizers (lithium, lamotrigine, valproate), antipsychotics (aripiprazole, quetiapine, olanzapine), and stimulants (modafinil, methylphenidate, atomoxetine),” the authors wrote. “She also had been using benzodiazepines on a regular basis, mostly to cope with fears of contamination.”

She had been prescribed and did not experience long-term relief from 20 or more different drugs in just a few years.

Given her medical history, the woman was started on the psychedelic drug MDMA, which offered only temporary improvement that relapsed quickly. She was then started on weekly, low-dose LSD.

Almost immediately, her mood elevated and over time, she felt calmer and more stable and her suicidal thoughts diminished. Eventually, treatment was continued in an outpatient setting.

Hopefully, the benefits for this woman continue, but beyond this single case, there is growing evidence of a need not only for new treatments for mental health disorders, but for better treatments.

Psychedelics like LSD, MDMA, psilocybin, and others may fill this need, but there is much yet to understand beyond case studies, anecdotes, and old clinical studies.



Failing status quo

“I think it really begins with the unmet needs,” says Roger McIntyre, head of University Health Network’s Mood Disorders Psychopharmacology Unit and the Brain and Cognition Discovery Foundation. “There is a tremendous demand for better treatments for mental illness.”

To hammer home his point, he suggests that up to one in four people in society will be affected by a mental illness at some time in their life.

The condition that has received the most attention, in terms of psychedelics research, is depression, he adds, but he also highlights conditions like PTSD and drug and alcohol use disorders.

“Those three alone account for sizeable distress, not just to people who are affected, but also to society at large with respect to the impairment in their function,” he explains.

Diamond Therapeutics founder and CEO Judy Blumstock echoes these sentiments with numbers from a BIO Industry analysis of venture capital spending in the United States from 2007 to 2016.

“You can see that, by far, cancer gets the most funding,” she says. “But if you look at the psychiatric illnesses, the prevalence is far greater. We're looking at something like 15 million versus 45 million, respectively—three times greater prevalence—and yet, literally, [psychiatric illnesses receive] one-twelfth the amount of funding.”

And this relatively anemic funding occurs despite the direct costs to the US healthcare system, she continues, with psychiatric illness at roughly $170 billion versus cancer at about $80 billion.

For McIntyre, a second reason for the renewed interest in psychedelics is simply the age of the current innovations in psychiatric pharmacology—the fact that most of the current drugs reflect treatments developed in the 1950s.

“The mid-1950s was the introduction, for example, of some of the antipsychotics, the antidepressants, some of the pills for anxiety, and the list grows on from there,” he says.

"And even with these drugs," McIntyre presses, "it is a glass half-full, glass half-empty scenario."

“For about 20 percent or so of people who have a mental illness like depression, just as an example, they do very well with the conventional treatments,”
he says. “The symptoms are under control, if not fully eliminated. They get back to work. They get their livelihood back with their family, their kids.”

But that leaves a huge gap of people for whom the current crop of medicines largely don’t work.

“The symptoms continue to be incredibly distressing,”
he continues. “They are not able to function in their personal lives, their family lives, their work lives.”

"And even if the drugs do work,"
he adds, "they often take a considerable time to kick in. It might take four to eight weeks for the maximum therapeutic effect to kick in."

McIntyre then adds another complication. "The rates of suicide, which he says have not decreased in Canada and have actually increased in the United States over the last three decades," he says.

“Suicide is not a mental illness,” he stresses, “but suicide is most often associated with mental illness, like depression. So, it stands to reason that if you treat the mental illness that should help suicide.”

He is quick to acknowledge other modalities of treatment, such as counseling and talk therapy, but suggests that they are not filling the unmet need gap either.

But with six decades of experience, why are the success rates so low?



Working in the dark

One of the inherent challenges of psychiatric illness is that they have largely been diagnosed based on symptoms rather than quantifiable molecular markers, as is the evolving case with other neurological conditions like Alzheimer’s disease or Parkinson’s disease.

“One of the ways that psychiatric diagnosis is made is through what's called DSM-5, the fifth in a series of diagnostic and statistics manuals,” says Lyle Oberg, cofounder and CEO of Mynd Life Sciences.

In depression’s case, he continues, if the patient has five of the eight symptoms and they're debilitated for more than two weeks, they are diagnosed with depression.

“There's no test,” Oberg continues. “If you exhibit these symptoms, you have depression.”

This complicates prescribing, he presses, offering the example of the SSRIs, which first entered the market in the 1980s with Eli Lilly’s blockbuster Prozac.

“You've got various SSRIs—just sons of Prozac—and when you combine that with the DSM-5 diagnosis, what you get is basically a trial-and-error type of approach to medicine,” he says. “Someone goes in, they have the classic 5/8 symptoms, they’re diagnosed as depressed, and the doctor says here try this.”

The patient tries the treatment and they come back after three or four months because it didn’t work. Or it did work, but it took that long to know.

“Either way, it's been three or four months that they have been in depression,” Oberg presses. “They've had horrible symptoms, and in many cases, it just doesn't work. And there's no telling exactly why it doesn't work. You're just going by symptoms.”

Not to trivialize the challenge, but Diamond’s head of pipeline development Jeffrey Sprouse recounts with some humor his time working on SSRIs.

“I remember using fluoxetine in the laboratory before the age of Prozac,” he explains. “I was at Pfizer when its SSRI hit the market, and at Lundbeck when their SSRI hit the market. So, I've been trailing this for quite a while.”

“The joke that we always told each other was that all of these drugs would ride their wave of sales and use, fall into generic forms and then fall out of favor,”
he recalls, “and we still wouldn't know how they worked.”

There's always been some working hypotheses, he is quick to add. But the science was challenging, and it was never clear why it took SSRIs so long to work.

“They raise levels of serotonin quickly on the first dose, within minutes,” Sprouse offers. “So, why does it take so long for the therapeutic effects to kick in?”

Part of the challenge to understand the mechanisms of these drugs was the technology available at the time, suggests Joseph Araujo, chief scientific officer and director of Mindset Pharma, as well as president and CEO of InterVivo Solutions.

“Before molecular pharmacology, the assays that were available were phenotypic if we're talking about animal models, where you're looking for patterns in behavior,” he offers. “And a lot of the most promising psychiatric drugs were developed prior to molecular pharmacology.”

Without knowing or by making assumptions on the molecular causes of diseases, he continues, one really limits their bandwidth in developing new drugs.

Given the historical prevalence of clinical data and the relative paucity of molecular understanding with psychedelics, Araujo describes the current interest and approaches as something of a “back to the future” scenario.

“We have the advantage that we now know about the serotonin 5-HT2A target,” he enthuses. “When psilocybin was studied previously, nobody knew about serotonin receptors or which serotonin receptor was important So, it's really a nice circular pattern happening in drug discovery, and I think good timing for it as well, with all of the increased neuropsychiatric needs.”

“The nice thing about 2021 is that there are so many ways to accelerate research,”
says Oberg. “Even from the point of view of knockout mice—that in itself is massive.”

“Before CRISPR, you couldn't do that,”
he stresses. “So that saved five or 10 years of a drug’s identification.”

In recent years, animal models of psychiatric illness and mood disorders have been called into question with suggestions that, at best, behavioral changes seen in rodents and other organisms are poor proxies for human mental processing.

Gabriella Gobbi, head of the Neurobiological Psychiatry Unit at McGill University, has heard these complaints and sees things quite differently. Given her 30 years of experience in animal research and treating patients, she suggests that the drugs that work in patients also work in behavioral animal models and in electrophysiology.

“The main problem of drug discovery in mental health is the lack of scientists and clinicians who have a background to translate basic research into clinical trials,” she explains. “While translational medicine is less challenging in other areas of medicine, in mental health we have to deal with the brain, which is a complex system, and not an organ.”

“Consequently,”
she presses, “the interpretation of data from behavioral animal models, neurobiology, electrophysiology, and molecular biology requires a lot of knowledge and expertise and capacity of integration.”

Likewise, reflecting on his experience, Araujo suggests that there are clear consistencies between changing animal behavior and 5-HT2A agonists, offering head twitch in mice and wet dog shakes in rats as examples when trying to understand if an animal is having a psychedelic experience.

“Ultimately, one of the bigger challenges is to try and understand whether that behavioral effect is due to what you think it's due to, in this case, potentially a hallucinogenic type of experience that maybe the animal is perceiving or maybe not perceiving,” he offers. “As we move along, we can look at some more sophisticated animal models and begin to better understand what those drugs are doing, and maybe benchmark what has been done in the literature in the past.”

He points to drug discrimination experiments, where you train animals to a dose level that you would anticipate has a hallucinogenic-like effect, and then test other compounds to see if the animal responds similarly to those compounds.

“You can also begin to get into models that assess things like cognitive improvements,” he adds, “maybe in a micro-dose situation where you might see some cognitive benefit.”

For Sprouse, it is perhaps less about leveraging new technologies so much as being able to access technologies that existed but were perhaps previously outside of the neuropsychopharmacologist’s price point.

“I was brought up in drug discovery when everything was high-throughput and large-scale,” he recounts. “I think what's changed more recently is the ability to probe fewer molecules and fewer endpoints to actually get to an answer.”

Thus, while acknowledging the shortcomings of early research into SSRIs, he is hopeful looking forward.

“I think, if we were to do this all over again starting today, we'd have the tools to understand them better,” says Sprouse. “But because of their history, we're not spending all that much time in trying to figure it out anymore. I think we'll do a better job with the psychedelics.”



Diamond in the rough

Timing has been a vital factor not just in terms of technological and molecular advances, however, as Blumstock discovered in trying to launch Diamond Therapeutics back in 2006.

Her interest in the field of psychedelics was first piqued by an article in The Economist called “The God Pill,” and from there she found the work of University of Arizona’s Francisco Moreno, who demonstrated some efficacy of psilocybin in a small group of patients with obsessive-compulsive disorder.

Given her experience in the capital markets and her then current position at MaRS Innovation (now Toronto Innovation Acceleration Partners), 2006/2007 seemed like a good time to explore this market with the launch of Diamond. She was wrong.

“It was just not the right time,” Blumstock acknowledges in retrospect. “But something was nevertheless burning away at me. Why can't we do this?”

“This is something that should be done,”
she recalls. “And then finally, in late 2017, it seemed like now was the right time to launch Diamond properly.”

Following that initial enthusiasm, the company focused its efforts on psilocybin.

“With psilocybin, there's a great deal of research out there already, and it seems like an ideal starting point for drug discovery and drug development, with at least one obvious liability, which is the hallucinogenic side of it,” she explains.

“When we started the company, we had active debate about psilocybin as a known molecule versus an NCE [new chemical entity] program, which is more of a typical pharma program,” she continues. “And we just decided we wanted to have our cake and eat it, too.”

“We just determined that psilocybin was such an amazing gift to be given, that we understand so much about it already,”
she presses. “So, we are trying to explore both and understand as much as we can about psilocybin in the hope that it guides us to novel drugs.”

“Psilocybin obviously is of tremendous importance to Diamond,”
adds Sprouse. “Even though it's a small molecule—a simple molecule—it's going to have multiple actions, and we know from this huge body of usage that there's some therapeutic value there.”

“But we also want to think about other molecules, because I think we're going to learn a lot along the way,”
he offers. “We're going to learn a lot about patient response and the ideal patient. The ability to essentially map drug to patient is something that we're going to give very serious thought to.”

Sprouse also acknowledges the commercial and intellectual property reasons to press for NCEs, but for him at least, this consideration is secondary.

“The thing that is most motivating is the thinking that small differences that you might observe in a molecule you're patterning using psilocybin as a parent may end up being huge in terms of patient benefit,” he suggests.

Similarly recognizing the potential of chemical diversity is Mindset Pharma.



Changing mindset

Like Diamond, Mindset is focused on psilocybin as a starting point.

“Using a whole range of different strategies, we've created a number of different families of new drugs with interesting characteristics that could make them really well suited to a number of different use cases and indications,” explains company CEO James Lanthier.

"And a key part of developing those compound families," he continues, "is the company’s focus on developing synthetic processes to generate not only psilocybin and myriad derivatives, but also completely novel compounds." As he explains, "there is a major need in the market for a more efficient, lower-cost method to produce GMP-grade psilocybin."

“We're really focused on preclinical development, and from a business strategy standpoint with all the capital rushing into the space and the regulatory momentum, we felt like there was going to be a real demand for next-generation drugs that were really more optimized and that could enjoy full patent protection,”
Lanthier explains. “In comparison, a lot of the development efforts by groups in the space had focused on classic drugs and a lot of those on formulations of the classic drugs.”

“We knew when we initially started that in order to differentiate Mindset’s psychedelics program from competitors in the field, we had to be creative and let the science drive the company’s innovations to create novel, patentable NCEs and thereby a solid IP [intellectual property] portfolio,”
echoes Mindset chief scientific adviser Malik Slassi. “From the beginning, this was the first thing we did. We had to come up with novel patentable small-molecule psychedelic drug candidates.”

Araujo elaborates on the company’s three families of compounds, which reflect Mindset’s decision to let the science drive the clinical indication rather than focus initially on a psychiatric target.

“The first [family] can be divided into deuterated compounds and prodrugs, which we feel could rapidly be developed to clinical candidates and really present as quick next-generation psilocybin-like compounds,” he explains. “They're going to be very similar to psilocybin with respect to drug characteristics while potentially reducing some of the metabolic liability.”

The second family works from a different chemical scaffold with a restricted side chain, he continues, adding that in-vitro and in-vivo tests suggest many of the compounds have a greater effect size than psilocybin.

“We're trying to optimize those for shorter durations of action, which we think would be really well suited for a psychedelic-assisted psychotherapy,” he offers.

Mindset’s least mature category, he presses, includes compounds with lower effect size at the 5-HT2A receptor, but with extended half-lives, suggesting potential for a much longer duration of action.

“Those compounds, we think, fit an ideal profile for potential micro-dosing applications, particularly in patient populations that might be compromised, or where you don't want them to potentially experience hallucinogenic-type effects—juvenile ADHD and geriatric Alzheimer's disease patients come to mind,” he says.

Slassi reinforces that having such a diversity of candidates really allows the company to stay open to indications beyond depression and anxiety disorders. And the growing volumes of in-vitro and in-vivo data as well as the IP are attracting interest from Big Pharma and biotechs.

Not everyone in this field, however, sees 5-HT2A as their primary target.



A new model in mind

Mynd Life Sciences is taking a different approach to psychedelics development in mental health. Rather than focus on the impact of compounds like psilocybin on serotonin receptors, the company is instead pursuing links between depression and inflammation.

The inflammatory model has gained traction over the past few years. Indeed, earlier studies of anti-TNF-based therapies commonly given modulate autoimmune disorders such as rheumatoid arthritis and psoriasis have shown therapeutic benefits when aimed at depression.

“There was a correlation between rheumatoid arthritis and depression,” says Oberg, “and people used to think well, ‘I'm depressed because I have rheumatoid arthritis.’

“In actual fact, what they're now seeing is that it's the same process that causes the depression as causes the rheumatoid arthritis. And that process is looking more and more like a chronic inflammatory process.”


A large-scale study of patients in the United States, he further explains, identified the presence of a common gene: the human mycogene.

“This gene is the switch that turns the body from a pro-inflammatory state into an anti-inflammatory state,” Oberg says. “It turns macrophages from M1 to M2, and it's a trigger gene.”

In a study published in 2013, Timothy Powell and colleagues at King’s College London performed a transcriptomic analysis of the inflammatory cytokine pathway in patients receiving the SSRI escitalopram for major depressive disorder. They found that the pathway regulator ABCF1 (human mycogene) was upregulated following SSRI administration and that the effect was larger in patients classified as responders than in non-responders.

Following data such as this, Mynd is using psilocybin as a starting point and to date, has generated 38 analogues, which it hopes to winnow down to three or four candidates for preclinical screening and optimal anti-inflammatory activity.

Further facilitating their understanding of the disease pathology, the identification of a gene target allows them to engineer knockout rodents to determine what effect, if any, the presence or absence of the gene has on animal behavior and response to treatment.



'Easy dose it'

Much as with any drug development program, the goal is to improve efficacy while minimizing side effects. Thus, as is seen in much of the clinical development of cannabinoids, one could easily imagine a desire to remove the psychoactive or hallucinatory components of psychedelics while retaining psychiatric efficacy.

There is a debate, however, as to whether—at least in some cases—the psychedelic experience is part of the healing.

“I keep hearing that mysticism experiences are critical to the therapeutic effect, that you have to have a trip to have the therapeutic effect, there has to be some type of out of body experience or whatever,” recalls McIntyre. “I don't know that's true.”

That said, he understands how a patient might confound a psychedelic experience with improvement in depressive symptoms. And it could be that the two are linked, but in biological terms rather than psychological terms; that is, the “trip” may be symptomatic of the neural rewiring that leads to psychiatric benefit.

“The theoretical and prevailing view of psychedelics is that what we're effectively doing is disconnecting and reconnecting the circuits,” McIntyre explains. “And when you disconnect/reconnect the circuits in the brain, that process critical to the benefit may also be what's subserving the psychedelic experience.”

He offers a comparison with a faulty computer. Remove and replace some wires to reset the computer, but he questions what the computer “experiences” as its screen flashes and components power off and on.

From a pharmacological perspective, Sprouse wonders if the question isn’t moot, suggesting that he sees no merit in fixating solely on the psychedelic dose. Instead, he wants to understand the dose response curve.

In practical terms, different compounds almost assuredly require different doses for different individuals in different indications.

“Maybe there's the need for a psychedelic effect in one patient group, but not another,” he says. “I think there's some richness here that warrants examination.”

Efforts to avoid the psychedelic effect have led many to explore the concept of micro-dosing, a term of which Sprouse is not fond. Typically, it is considered one-tenth the minimum dose that induces the psychedelic experience.

“The real challenge is there are very few studies that have been well designed that have really examined micro-dosing,” says Araujo. “There's a lot of anecdotal information that's really difficult to draw conclusions from.”

That said, he notes that some groups have initiated placebo-controlled clinical trials evaluating micro-dosing.

Diamond, for one, will shortly publish results from their efforts to evaluate low-dose ketamine and low-dose psilocybin in animal models. And the company recently initiated a collaboration with McGill’s Gobbi, who has been studying low-dose LSD.

In late January, Gobbi and colleagues published their effort to understand the molecular basis of low-dose LSD’s influence on social behavior, which mimics the increased empathy seen in human subjects.

“The key finding of this paper was that low doses of LSD enhance social behavior in mice,” explains Gobbi. “By binding the 5-HT2A receptor, LSD indirectly enhances the AMPA neurotransmission by also promoting mTOR complex phosphorylation and plasticity in the glutamatergic neurons of the prefrontal cortex.”

The findings are critical to the use of LSD to treat psychiatric illnesses because at higher doses, the compound becomes a dopaminergic agonist and likely increases the risk of psychotic-like symptoms.

“Moreover, it suggests that drug discovery research should focus on designing highly selective 5-HT2A agonists with a wider therapeutic window and higher safety profile,” she adds.

For the most part, Araujo echoes Sprouse’s openness to the possibilities.

“What about a molecule that doesn't necessarily activate the receptor to the same extent?” he asks. “Is that a micro-dose effect at a higher dose?”

“Again, I think we'll have to follow the science, understand what the effect is, and what the right dose is for the right compound,”
he explains. “Ultimately, I think, there are going to be patients for whom, for whatever reason, a macro-dose or a large dose or a hallucinogenic experience might not be the right approach, and so there needs to be more than one option for different patients.”

Any hope of answering these questions, however, will come from a deeper understanding of the science behind these compounds and their effects.

“In my career, I've seen a number of very promising medicines—not in the psychedelic area but in the more conventional pharmacotherapeutic area—that have come along, and these drugs unfortunately did not demonstrate superiority over the placebo in the clinical trial,” he recounts. “And there's two interpretations of that.”

One is simply that the drug did not work as expected, which is unfortunate but just a part of doing business. The other possibility, he suggests, is that the drug did work, but that the trials weren’t designed properly.

This is where McIntyre sees an opportunity to move forward from the studies of the past.

“If you really want to understand the efficacy and the safety, you have to have adequate studies,” he says. “And what I've noticed about the psychedelic space in general, there is heterogeneity in the way these studies are being done.”

“I'm all for heterogeneity and creativity, but sometimes you just want to keep it simple,”
he suggests. “My concern is that if these drugs are really going to help people, we could spoil the broth so to speak, because we're not adhering to good clinical practice research parameters.”

In the absence of such a considered approach, there is a risk that we will end up with even more interesting data, but no better understanding of the potential for psychedelics in mental health.





Gateway drugs

Ultimately, the success of the renaissance of psychedelics research will hinge on the clinical outcomes and improvements in patients’ lives. Many, however, point to other factors that helped launch this renewed interest, with cannabis leading the way.

“When you take a look at the people involved in the psychedelic research, a lot of them came from cannabis,” explains Lyle Oberg, founder and CEO of Mynd Life Sciences. “You have a lot of people that made money in the cannabis industry in Canada who have now migrated into the psychedelic area, which in itself makes a large amount of research money available.”

“People saw that cannabis worked,”
he adds. “They saw the analogies between psychedelics and cannabis in that both of them were working. It became a very easy stretch to take a look at cannabis and psychedelics.”

“The success of cannabis in Canada maybe allowed people to look at these compounds with a more liberal view,”
echoes Judy Blumstock, founder and CEO of Diamond Therapeutics, addressing the rapid growth of drug discovery companies exploring the psychedelic space north of the US border. “But I think there's very strong interest in the US, as well, and worldwide.”

Joseph Araujo, chief scientific officer and director at Mindset Pharma as well as president and CEO of InterVivo Solutions, recognizes a Canadian effect in terms of both social and regulatory acceptance of cannabis.

“What's happened with cannabis, I think, has really paved the path forward for looking at controlled drugs in unique ways and with the goal of medicinal applications,” he says.

“Interestingly, the hallucinogens are Schedule Three in Canada, whereas in most of the world, they’re Schedule One,” he adds. “So that might be another influence factor that has made maybe research easier in Canada.”

For his part, Blumstock’s colleague and head of pipeline development Jeffrey Sprouse also sees inspiration beyond the cannabis experience.

“I think there's a story that you can tell with the cannabinoids, with cannabis, but I actually prefer the story that you could construct with ketamine,” he says.

“I've been interested in psychiatry targets for years—antidepressants, anxiolytics, etc.—and once you get beyond the SSRIs, it gets very quiet,” he explains. “It is this desert and without really much hope of improvement.”

And then ketamine came along.

“Research done right around 2000 by a group at Yale led by Rob Berman uncovered this amazing response in depressed patients,” Sprouse recounts. “Not only was it durable and a significant effect, but it was one that occurred rather quickly, which was always the Holy Grail of antidepressive research.”

Unlike SSRIs, he says, which are useful but can take upwards of 12 weeks to see any effect, ketamine offered its effects rapidly and once patients moved through the K-hole, they began to feel much better.

“That reset the table for everybody,” he enthuses. “Suddenly, there was a direction to move, a different mechanism, one that you could link to downstream pathways from serotonin.”

McGill University’s Gabriella Gobbi, who recently signed a collaborative research agreement with Diamond Therapeutics, agrees with the importance of this discovery.

“The approval of the derivate of ketamine, which belongs to the non-classical hallucinogens category, for the treatment-resistant depression encouraged the exploration of other hallucinogenic drugs in mental health,” she says.

"Suddenly," Sprouse continues, "the treasure trove of anecdotal information about psychedelics takes on a whole new significance, so why not broaden the thinking beyond ketamine to other psychedelics?"

“Some of the research that Diamond has sponsored is more or less focused on commonalities between ketamine-like molecules, the dissociative anaesthetics, with the psychedelics like psilocybin and LSD,”
he explains.

So, the old concerns that cannabis was a gateway to other drugs may have been true; just not in the way everyone thought.

 
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mr peabody

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18-MC has unique brain functions and mechanisms

by Alexandria H. Jaeger, MSc | Psychedelic Science Review | 20 Apr 2021

18-MC is challenging standard anti-addiction treatments and brain research.

The non-psychedelic compound known as 18-Methoxycoronaridine (18-MC) has become a recurring character in iboga like alkaloid research, as its unique effects trail the resurgence of psychedelic research. 18-MC mirrors the anti-addiction properties of ibogaine, interrupting a person’s dependence on stimulants, opiates, alcohol, and nicotine. As a promising compound, it has caught the eye of many researchers interested in treating addiction.

18-MC has often been researched alongside ibogaine. However, researchers are finding that 18-MC has some unique effects compared to ibogaine, alluding to the possibility of unique brain pathways. For example, unlike ibogaine, 18-MC reduces addictive behavior without affecting appetite. Secondly, its capabilities and mechanisms are not identical for all substances of abuse. Much of 18-MC’s potency and functionality is unknown, which continues to challenge the scientific understanding of addiction in the human brain.

What does 18-MC reveal about receptors in the brain?

Brain receptors can be activated (by an agonist) or inhibited (by an antagonist), by different molecules. These interactions contribute to the larger neural circuity that makes up peoples’ experiences and behaviors. Because cells have an electrical current, the receptor activation response can be measured through isolating a specific receptor channel on a cell and watching the change in current with the exposure to different drugs (Figure 1).


Figure 1: Panel A – Whole-cell patch-clamp recording of alpha-2-beta-3 nicotinic acetylcholine receptors (α3β4 nAChRs) with both ibogaine (IBO) and 18-MC (18MC) show inhibition of the receptor as compared to its activation with the neurotransmitter acetylcholine (ACh). Panel B – A dose-dependent response of both ibogaine and 18-MC shows reduced ACh-evoked currents.

18-MC has a high promiscuity binding pattern. This means that the molecule connects to a range of receptors that contribute to a variety of brain pathways. Although 18-MC may shake hands with many receptors, it does not have a strong connection with any type in particular. This is a confusing neuropharmacology pattern to have for something with such strong anti-addictive properties. It makes studying the neural circuitry difficult to pin down. However, through the research of ibogalogs, one aspect has become more well understood. The binding of 18-MC to the alpha3beta4 nicotinic acetylcholine receptor (Figure 1) results in inhibition. It is this receptor inhibition that is responsible for 18-MC’s sustained anti-addictive properties.

What does 18-MC reveal about brain functioning?

A closer look at the neurobiology brings into focus that ibogaine and 18-MC have different anti-addictive mechanisms. This challenges the known brain pathways thought of as the main addiction ‘highways.’ Therefore, these lesser-known paths may be contributing to its effects.

Chronic drug use increases the dopamine response in the mesotelencephalic system of the brain. This dopamine highway originates out of the ventral tegmental area (VTA) and transmits to the nucleus accumbens (NAc), creating sensitization (Figure 2).


Figure 2: Schematic of various brain areas hypothesized to be involved in anti-addictive pathways.

However looking closer at this dopamine highway in the context of 18-MC, scientists have made some interesting observations. For example, 18-MC does not trigger the expected glial cell-line derived neurotrophic factor (GDNF) expression or dopamine changes in the NAc. Even if 18-MC is injected directly into specific brain regions within the dopamine anti-addictive highway, these expected responses don’t occur. Also, direct infusion of 18-MC into the VTA, an area specifically lacking α3β4 nAChRs, does not promote reduced drug-seeking behavior.

North of the mesotelencephalic highway is the habenula, a brain region rich in α3β4 nAChRs (Figure 2). It is a critical part of the neural circuitry of anti-addiction in the brain. Studies have found that direct infusion of 18-MC into this brain region reduces drug-seeking behavior, without affecting the main southbound dopamine highway (specifically NAc). This furthers the hypothesis that the α3β4 nAChRs are key to understanding the various anti-addiction pathways in the brain.

While 18-MC does not appear to work solely on dopamine receptors, it tunes the dopamine circuitry through a variety of pathways in new ways. In the end, 18-MC may look similar to ibogaine behaviorally, however it is likely working through different brain pathways.

Is 18-MC the missing key for treating addiction?

18-MC continues to gain traction in the story of anti-addiction medication, driven primarily by the opioid epidemic. With unique brain pathways, it presents as an interesting compound that is likely to shadow ibogaine research through clinical trials. Contributing to this growing narrative of beneficial compounds with the ability to reduce addiction to a variety of substances, 18-MC is currently a soft-spoken molecule in a highly polarizing group of psychedelics.

 

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Dissociated hippocampal neurons transiently expressing psychLight1 and psychLight2.

A psychedelic-like drug without hallucinogenic side effects

Cell | Neuroscience News | 28 Apr 2021

SUMMARY: PsychLight, a newly developed genetically encoded fluorescent sensor, helped researchers identify a psychedelic compound that acts on beneficial neural pathways to treat psychiatric disorders without the hallucinogenic effect.

Psychedelic drugs have shown promise for treating neuropsychiatric disorders such as depression and posttraumatic stress disorder. However, due to their hallucinatory side effects, some researchers are trying to identify drugs that could offer the benefits of psychedelics without causing hallucinations.

In the journal Cell on April 28, researchers report they have identified one such drug through the development of a genetically encoded fluorescent sensor–called psychLight–that can screen for hallucinogenic potential by indicating when a compound activates the serotonin 2A receptor.

“Serotonin reuptake inhibitors have long been used for treating depression, but we don’t know much about their mechanism. It’s like a black box,” says senior author Lin Tian, an associate professor in the Department of Biochemistry and Molecular Medicine in the School of Medicine at the University of California, Davis.

“This sensor allows us to image serotonin dynamics in real time when animals learn or are stressed and visualize the interaction between the compound of interest and the receptor in real time.”

Tian’s lab joined forces with the lab of David E. Olson, an assistant professor in the Department of Chemistry at UC Davis, whose lab is focused on drug discovery.

“This paper was an exceptionally collaborative effort,” says Olson, a co-author on the study.

“My lab is really interested in the serotonin 2A receptor, which is the target of both psychedelic drugs and classic antipsychotics. Lin’s lab is a leader in developing sensors for neuromodulators like serotonin. It just made perfect sense for us to tackle this problem together.”

Experts believe that one of the benefits of using psychedelic drugs over existing drugs is that they appear to promote neural plasticity–essentially allowing the brain to rewire itself.

If proven effective, this approach could lead to a drug that works in a single dose or a small number of doses, rather than having to be taken indefinitely. But one thing that researchers don’t know is whether patients would be able to gain the full benefit of neural plasticity without undergoing the “psychedelic trip” part of the treatment.

In the paper, the investigators report that they used psychLight to identify a compound called AAZ-A-154, a previously unstudied molecule that has the potential to act on beneficial pathways in the brain without hallucinogenic effects.

“One of the problems with psychedelic therapies is that they require close guidance and supervision from a medical team,” Olson says.

“A drug that doesn’t cause hallucinations could be taken at home.”

The serotonin 2A receptor, also known as 5-HT2AR, belongs to a class of receptors called G protein-coupled receptors (GPCRs). “More than one-third of all FDA-approved drugs target GPCRs, so this sensor technology has broad implications for drug development,” Tian says.

“The special funding mechanisms of BRAIN Initiative from the National Institutes of Health allowed us to take a risky and radical approach to developing this technology, which could open the door to discovering better drugs without side effects and studying neurochemical signaling in the brain.”

*From the article here :
 
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