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INSIGHT: exploring clinical developments in psychedelics 

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Mapping the effects of ketamine on the brain

MIND Foundation’s INSIGHT Conference took place from August 31 to September 3 in Berlin, exploring the latest frontiers in psychedelic medicines – from clinical developments to neuroplasticity, VR, breathwork and beyond.

Bringing together a host of psychedelic researchers, clinicians, entrepreneurs and patients, INSIGHT 2023 put the spotlight on psychedelic neuroscience.

Exploring topics such as non-clinical forms of psychedelic drug use, mindfulness, the philosophy of psychedelic experience, psychedelics in art, as well as patient and therapist spiritualities and more, the conference also facilitated learning from indigenous communities.

See also  Neuroimaging study measures brain activity under psychedelics

Bridging the gap between psychedelics and neuroscience

David Olson, Director of the Institute for Psychedelics and Neurotherapeutics at UC Davis, as well as Co-Founder and Chief Innovation Officer at Delix Therapeutics, presented the talk ‘Bridging the Gap Between Basic Science and Clinical Research in Psychedelic Neuroscience’.

Olson discussed his group’s work in his academic laboratory which is interested in finding new treatments for stress-related neuropsychiatric diseases, such as depression and PTSD.

“A hallmark of all of these illnesses is the atrophy of key brain regions, in particular, the prefrontal cortex,” said Olson. 

“The prefrontal cortex is really critical because it controls motivation, fear and reward. A hypothesis in the field has been that if you could identify chemical stimuli that can induce the growth of cortical neurons, such as the growth of new dendrites, or if you zoom in on one of these dendrites to see the growth of these dendritic spines, if you can promote that type of growth, you might be able to achieve a few different really interesting results.”

See also  Fresh insights into psychedelics’ mechanisms of action

Such results would either be a rapid-acting response, a response that might be sustained over a long period of time, or the treatment might work across indications “because the PFC is such a critical hub”.

Olson highlighted one such molecule as ketamine, which is capable of promoting both neurogenesis and synaptogenesis.

“I think ketamine is super exciting for the field because it’s pushing us in a completely new direction, a direction that is more in line with a healing-based approach trying to repair these damaged neural circuits,” commented Olson.

“One of the issues [with ketamine] is really its lack of circuit level of selectivity. The primary target of ketamine is the NMDA receptor, which is found broadly across the entire brain. When we got into this area, we were thinking very deeply about what receptors might be selectively expressed in the specific neurons and brain regions that we really care about for treating these stress-related neuropsychiatric diseases – that really led us to study the serotonin or 5-HT2A receptor.”

One of the first experiments carried out by Olson and his team was to treat cultured cortical neurons with psychedelics and look at neuronal morphology. The team found that neurons treated with DMT and LSD had substantially more complex dendritic arbors. 

Olson noted that super-resolution microscopy also revealed an increase in the number of dendritic spines and that the team also found that even in short stimulation periods of one hour or 15 minutes, there were profound increases in cortical neuron growth. 

“The trick is you have to give the neurons time to grow,” said Olson. “If you just stimulate for an hour, fix and stain, you see absolutely no change in morphology, but if you stimulate for an hour, give the neurons a couple of days to grow then you can see pretty large differences.

“We find that even after the drug has been cleared from the body, we get this long-lasting increase in dendritic spine density, and that’s accompanied by functional effects including increases in both the amplitude and the frequency of these spontaneous excitatory postsynaptic currents.”

This work was carried out in 2018, and since, a group of researchers at Yale University carried out a study to see how long the effects lasted. The team gave a single dose of psilocybin to male and female mice and found that psilocybin induced an increased density of cortical spines in the prefrontal cortex for over a month.

Olson and his team then wanted to further understand the mechanism behind this process. To do this, the team blocked the 5-HT2A receptor – which is known for mediating the hallucinogenic effects of psychedelics – with an antagonist. 

“If you give a 5-HT2A antagonist to people, you completely block the subjective effects of those drugs. And what we find is that the two antagonists can completely block the effects of psychedelics from the three different structural classes,” Olson said.

The team then looked at two downstream kinases – TrkB and mTOR – finding that when both of these were blocked, psychedelics were no longer able to promote cortical neuron growth. 

Further tests revealed that serotonin could not promote cortical neuron growth despite the 5-HT2A receptor being responsible for psychedelic-induced structural neuroplasticity.

Olson commented: “It didn’t really make sense until we got a particular structure-activity relationship study finished. We started making some small modifications to serotonin-like molecules and we noticed that, as you started to add methyl groups, going from one methyl group to two methyl groups, you saw a much bigger effect on cortical neuron growth. 

“We tried to correlate the activity of the 5-HT2A receptor when it was heterologously expressed in a non-neuronal cell like a HEC cell with cortical neuron growth, and we saw absolutely no correlation at all. If anything, we saw a slight negative correlation.”

This led the team to the hypothesis that the reason that serotonin cannot do the same thing as something like DMT is because it can’t access the target. 

“We thought maybe the 5-HT2A receptor was on the inside of the cell,” said Olson.

The team began looking for where the neuron was located and found that for the 5-HT2A receptor, everything is localised intracellularly.

Olson concluded: “….psychedelics can promote structural neural plasticity to the activation of a particular intracellular population of the 5-HT2A receptor, really highlighting the role of location bias in their signaling.”

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Ketamine: understanding the K-Hole

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Ketamine: understanding the K-Hole
Photo by Gary Meulemans on Unsplash

Ketamine is an FDA-approved medical anesthetic and recently a prescription nasal spray version of ketamine called esketamine (Spravato) was approved for treatment-resistant depression.

Ketamine is an interesting drug because it can exist in three different forms, R-ketamine (the aesthetic version), S-ketamine (the psychedelic version), and a mixture of the two (racemic ketamine).

Ketamine is typically used to put you under before surgery, however, lighter doses that don’t put you to sleep are being used to treat depression, pain, and other mental health and substance use disorders.

These “off-label” uses have led to the popularization of the therapeutic use of ketamine. This has given rise to ketamine clinics where one can pay out-of-pocket for a dose administered by a doctor in a luxuriously curated “set-and-setting” (more on ketamine therapy in Nina’s Notes #18).

The patented, FDA-approved formulation of S-ketamine, Spravato, is estimated to generate $1 billion in revenue in 2023.

In addition to the rise in ketamine use for mental health, and despite its legality, the recreational use of ketamine is rising in popularity and has quite a history of illegal recreational use.

A term frequently used with the recreational use of ketamine is “k-hole”. People use it by saying things like, they are “stuck in a k-hole” or they could have “fallen into a k-hole.”

What is a k-hole?

A k-hole is the term referring to the dissociated, trance-like state that sometimes follows acute, excessive use of ketamine.

K-holes most often occur in recreational settings, like a nightclub or house party.

The dissociative effects of ketamine are dose-dependent, meaning the more you administer the greater the felt effects.

Receiving a ketamine treatment at a ketamine clinic will likely not result in a k-hole. The dose for the therapeutic experience is finely measured for the client, is administered in a safe clinical setting, and a physician can closely monitor the medicine’s effect.

When in a k-hole, one may be unable to interact with surroundings, control motor functions or maintain awareness of their external reality. An individual may temporarily be unable to speak, walk properly or maintain their balance. They may even find themselves feeling temporarily “paralyzed” or physically inhibited.

These motor-control symptoms are often paired with a strong internal experience, visions or visuals and an altered state of consciousness.

Experientially, it can feel like “falling into a hole” which is where the term k-hole comes from. K-holes can last as long as 5 minutes or up to roughly 30 minutes.

For some, experiencing a k-hole can be highly transformative and powerful, for others it may be a frightening experience.

Why does it happen?

Ketamine is a dose-dependent drug, the larger the dose, the bigger the effects.

While entering a k-hole is rarely the aim of a ketamine user, it can easily happen in a party setting where people may be taking multiple doses within a short period of time.

Ketamine is a white powder, similar to cocaine, which many users ingest through snorting. If a ketamine user has a history of cocaine use, they may use the drug at the same frequency due to previous habits, which can sometimes lead to k-holing.

Why is that? It’s because the half-lives of cocaine and ketamine are both short, but very different.

The half-life of ketamine

Half-life is the time it takes for the total amount of a drug in the body to be reduced by 50%. The half-life of ketamine is about 2.5 hours.

This means that it takes 150 minutes for a dose of ketamine to become a half dose in your body. Meanwhile, the ketamine high lasts about 30-45 minutes. In comparison, the half-life of cocaine is 40-90 minutes, and the high is about 15-25 minutes. Cocaine is metabolized very quickly and the high lasts about a third of the half-life of the drug.

So half of the drug is cleared from the body at close to the same rate as the user feels the effects. Drug gone = effects end.

Because the half-life of Ketamine is about 150 minutes and the high is about 1/5th of that, a user could be going for a second, third or even fourth dose before half of the first dose is metabolized by the body.

So, with repeating doses, the total amount of ketamine in your body builds over time. A user may not feel the strong effects of ketamine anymore, but they still have more than half of a dose still in their body. When they take another dose, they risk falling into a k-hole.

What happens in a k-hole?

A k-hole can lead to intense feelings of dissociation causing feelings of being disconnected from or unable to control one’s own body.

It may also affect the ability to speak and move easily. One way to think about a k-hole is a state between intoxication and a coma. Some refer to a k-hole as an out-of-body or near-death experience. A k-hole can be frightening and induce strong feelings of powerlessness. This can be especially intense if the ability to speak is affected.

Others might not notice someone in a k-hole. They might just look immobile and intoxicated, but their mind is far from quiet. They may be experiencing vivid, dream-like hallucinations and distortions of time and space. Other k-hole symptoms include confusion, unexplainable experiences and floating sensations.

While some people find the psychedelic experience enjoyable, others find it terrifying. Some describe falling into a k-hole like a bad LSD trip. Keep in mind the whole experience may last from 10 minutes to an hour.

Signs of a ketamine overdose

Know the signs of a ketamine overdose so that if someone at a party is exhibiting symptoms, you can get them immediate medical attention.

Although the risk of an overdose from ketamine is low, it can increase outside of a clinical setting. The overdose risks are higher when ketamine is mixed with other substances such as alcohol, opioids or other recreational drugs.

Overdose symptoms can include anxiety, chest pain, elevated blood pressure, hallucinations, loss of consciousness, nausea or vomiting, rapid or irregular heart rate, and seizures.

A k-hole, however, is a common experience due to excessive use of ketamine over a short period of time. It is not a ketamine overdose.

Though a k-hole is a temporary experience, there are several long-term side effects with extended recreational ketamine use, such as bladder problems, cognitive effects, heart problems, and seizures.

While there is no way to guarantee a perfectly safe experience with ketamine, using it outside of doctor supervision, its effects can be extremely unpredictable compared to other drugs.

With the rising popularity of ketamine in both medical and recreational spheres, this calls for a balanced perspective, appreciating the therapeutic potential of ketamine while being acutely aware of its potent effects and the dangers of excessive use.

This article was first published on Nina’s Notes and is republished on Psychedelic Health with permission.

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Beyond Psilocybin: the fascinating world of functional mushrooms

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Beyond Psilocybin: the fascinating world of functional mushrooms

I typically write about psilocybin, the hallucinogenic compound in mushrooms. But mushrooms have many more interesting properties than just psilocybin.

There are well over 14,000 species of mushroom-producing fungi that have been identified so far. It is believed that many more exist and have yet to be discovered. In 2017, an article in Microbiology Spectrum estimates that there are between 2.2 and 3.8 million different species of fungi.

Functional mushrooms are a category of mushrooms that have been traditionally used for their health benefits.

See also  Lion’s mane boosts memory through nerve growth, say researchers 

They have been incorporated into Eastern medicine for thousands of years, especially in Asian cultures. These mushrooms are not your typical culinary mushrooms. They are often found in supplements, teas or other preparations to be used for health-enhancing benefits.

Popular Functional Mushrooms

Reishi (Ganoderma lucidum)

Known as the “mushroom of immortality,” reishi mushrooms are often used for immune support and to promote relaxation.

Reishi mushrooms may positively affect white blood cells, a critical part of your immune system. A 2006 study found that ingesting reishi could increase the number of white blood cells in those with colorectal cancer.

They were also shown to improve the function of lymphocytes in athletes when they are exposed to stressful conditions.

Reishi mushrooms may also reduce fatigue and depression.

Lion’s Mane (Hericium erinaceus)

This pom-pom shaped mushroom is native to North America, Asia and Europe.

It is recognized for its potential neuroprotective effects, protecting nerves from disease or decline.

Lion’s mane has also been studied for its effect on neurons, and has gained the title “the smart mushroom” due to its potential to boost cognitive function and minimize brain fog.

It may also have potential benefits in addressing the cognitive decline associated with conditions like Alzheimer’s and Parkinson’s diseases. The bioactive compounds in Lion’s mane, hericenones and erinacines, may promote the production of growth factors and protect against brain damage.

Chaga (Inonotus obliquus)

Chaga is a black, parasitic mushroom, which looks like a lump of burnt coal.

It’s high in fiber, low in calories, but rich in minerals and vitamins.

Chaga has been used to treat diabetes, parasites, tuberculosis, and inflammation.

The oldest reference to the use of chaga mushrooms as a medicine comes from Hippocrates in his Corpus Hippocraticum, in which chaga is used to wash wounds.

For medical treatment, chaga is usually ground to a fine powder and made into a tea for its antioxidant properties and immune support.

Cordyceps (Cordyceps sinensis)

Fortunately, not the Cordyceps that infect the brains of mankind in the popular The Last of Us series.

Though creepy to look at, Cordyceps is a fungus that lives on certain caterpillars in the high mountain regions of China.

It is traditionally used to boost energy and improve athletic performance.

Cordyceps is believed to increase the flow of oxygenated blood throughout the body, boost metabolic rates, increase stamina and help muscle recovery.

Turkey Tail (Trametes versicolor)

Turkey tail is valued for its immune-boosting properties, specifically its medicinal properties as an antitumor, antimicrobial, immunostimulant and antioxidant.

It is also believed to improve bone strength and regulate blood glucose.

And some report that turkey tail can prevent urinary tract infections (UTIs) and protect against age-related cognitive decline.

Shiitake (Lentinula edodes)

Apart from being a popular culinary mushroom, shiitake is also known for its immune-modulating effects.

Traditional Chinese medicine considered shiitake a food that enhances vital energy. It is a great source of nutrients, high in protein, low in fat, and contains iron, calcium, zinc, along with vitamins B, E and D.

Easily accessible at any grocery store or market, shiitake mushrooms can be prepared to eat, or taken as a supplement for its functional properties.

What are some popular functional mushroom products?

You may have seen Ultimate Shrooms in your local health store. It’s a product that contains Cordyceps, Reishi, Chaga, Lion’s mane, Turkey Tail, Maitake, Shiitake and Oyster mushrooms.

Live Ultimate, the brand behind Ultimate Schrooms recommend adding two tablespoons with a full glass of water, juice or smoothie in the morning on an empty stomach.

Mushroom Coffee is also gaining popularity, like the product Four Sigmatic which contains Chaga and Lion’s Mane.

Some functional mushrooms, like Reishi, are less appetizing when eaten in their natural form. Thus people have begun consuming them in a power form, adding them to smoothies, teas and coffee, to improve the taste.

Functional mushrooms can offer a wide range of health benefits, though it’s essential to purchase mushrooms from a reputable source, and understand their proper preparation. Not all claims for health benefits have been substantiated by clinical trials.

It is also important to consult a healthcare professional before incorporating functional mushrooms into your diet and routine, especially for those with pre-existing medical conditions.

This article was first published on Nina’s Notes and is republished on Psychedelic Health with permission.

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Report reveals prevalence of ayahuasca use

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Report reveals prevalence of ayahuasca use

A report has revealed that the consumption of ayahuasca is increasing in several countries.

Published by Carlos Suárez Álvarez and the International Center for Ethnobotanical Education, Research and Service (ICEERS), the report documents ayahuasca use across the Netherlands, Spain, the USA and Colombia.

Ricard Faura, the Bridge Weaver for ICEERS and collaborator on this research, commented: “It is clear that the global landscape of ayahuasca practices is evolving dynamically and steadily and this global expansion presents great challenges. 

“It is therefore crucial to have a clear understanding of what is happening. This is why our research sheds light on the details of this expansion in various countries around the world and contributes to formulating a more inclusive and informed future.”

Use across continents 

The report reveals that Colombia, which has deep-rooted cultural ties with ayahuasca, has the highest percentage of ayahuasca drinkers among the studied nations. 

The prevalence was attributed to the ayahuasca practices within Indigenous communities and the support they have received at the institutional level. 

The country with the second highest prevalence of ayahuasca drinkers is Spain, followed by the Netherlands, where, the report highlights, a long-standing ayahuasca community faces tightened regulations on the importation of the medicine, reflecting the delicate balance between traditional practices and legal frameworks. 

However, the USA is the country with the highest number of ayahuasca drinkers globally.

Reported deaths

According to the report, there is an estimated four million ayahuasca drinkers worldwide. 

Following analysis of deaths reported by the media, the report found 58 documented cases of ayahuasca-related deaths. 

ICEERS has stated that so far “no forensic examination has determined that ayahuasca caused these deaths”. 

ICEERS stated: “This ICEERS research underscores the importance of accurate reporting, responsible practices, and informed dialogue about ayahuasca. 

“The organisation encourages further research and open discussions to support the well-being of individuals seeking the benefits of ayahuasca in a diverse range of cultural and legal contexts.

“This analysis not only broadens the understanding of ayahuasca’s global footprint but also navigates the complex terrains of legal, cultural, and social factors that shape ayahuasca consumption in diverse contexts. 

“These findings underscore the need for a well-informed, respectful approach to ayahuasca to support its reverent integration across diverse landscapes.”

The Netherlands, Spain, the USA and Colombia countries have are part of an in-depth research project published by ICEERS earlier this year.

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