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How psychedelics work



How psychedelics work
Photo by Dima Pechurin on Unsplash

Psychedelics, also known as hallucinogens, are a class of psychoactive substances that alter perception, mood and cognitive processes. They work by interacting with specific receptors in the brain and altering the way that the brain processes information.

Classic psychedelics work by activating the serotonin receptors in the brain. Serotonin has a wide variety of functions in the human body including cognition, perception, emotions, appetite and digestion. 

People sometimes call it the “happy” chemical because it contributes to well-being, mood and happiness. 

The scientific name for serotonin is 5-hydroxytryptamine (5-HT). It is a neurotransmitter, meaning that the body uses serotonin to send messages between brain cells. 

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One of the primary ways that psychedelics work is by activating serotonin receptors in the brain, particularly the serotonin 2A receptor (5-HT2A). Activation of the 5-HT2A receptor by psychedelics can result in changes in activity of serotonin and other neurotransmitters, such as dopamine and norepinephrine, which can contribute to the drug’s effects.

The 5-HT2A receptor and the binding of classic psychedelics to it are well studied, which allows chemists to model the relationships between the activity caused by a psychedelic and its structure. Recent efforts have been made to use computational modeling to engineer psychedelic-based therapeutics to increase the diversity of psychedelic compounds and also to engineer compounds that lack hallucinogenic effects, but maintain the therapeutic benefit.

The specific effects of psychedelics can vary widely depending on the chemical structure of the psychedelic, in addition to the dose and the individual’s unique brain chemistry. 

Level up your chemistry knowledge

All classic psychedelics have a similar chemical structure, we call this a chemical scaffold or a pharmacophore. A pharmacophore is like a key. Just as a key is specifically shaped to fit into a particular lock, a pharmacophore is specifically shaped to fit into a biological target, like the 5-HT2A receptor. 

In the figure below, you can see that the basic pharmacophore is a 6-pointed ring with a small chemical “arm” on the right. The pharmacophore is basically a skeleton key that can bind and activate the 5-HT2A receptor, and then the additional chemical groups that make each psychedelic unique can dictate the potency of the drug, duration of the psychedelic experience and types of hallucinogenic effects. 

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Differences in this basic pharmacophore divide psychedelics into two broad families, tryptamines on the left side of the figure and phenethylamines on the right side. The conversed pharmacophore is highlighted in each psychedelic structure in the figure.

The chemical structures of psychedelics – note how the chemical structures are conserved within the two families.

Potency and other drug effects are modulated by how each psychedelic binds to the 5-HT2A receptor. Each of these different psychedelics is a different key, and they all fit into the same lock. 

However, some keys fit perfectly into locks (like serotonin into its receptor). Other keys almost fit a lock, or a key might force its way into a lock and get stuck for a while. The length of time the key is in the lock and/or how tight the key/lock fit is can lead to different psychedelic experiences.

Chemical isomers

Keys can look almost identical and fit different locks. Similarly, chemical molecules called isomers can have almost the exact same chemical structure but they differ only in the position of a chemical group, which can result in different psychedelic effects.

For example, psilocin and bufotenin are both psychedelics with nearly identical chemical structures. The only thing that is different is where the alcohol (-OH) chemical group is located on the aromatic ring. The result is very different hallucinogenic effects.

How psychedelics work

The chemical structures of Bufo and Psilocin are exactly the same, except the -OH group is in different places on the 6-pointed ring.

Psilocybin is a naturally occurring psychedelic substance found in certain types of mushrooms. When consumed, it is converted to psilocin in the body, which is thought to be responsible for its effects including altered states of consciousness, changes in perception and emotional changes. It can also cause visual and auditory hallucinations and alter the sense of time. 

Bufotenin, also called Bufo or “the toad”, is a naturally occurring psychedelic substance found in the skin of some toads and in certain plants. Bufotenin is known to produce effects similar to those of other psychedelics, including altered states of consciousness, changes in perception and emotional changes. However, its effects are generally less intense and shorter-lasting than those of other psychedelics, such as psilocybin or LSD. A typical Bufo trip is about 20 minutes long.

Even these short hallucinogenic trips can be very impactful. On a Joe Rogan episode, former heavyweight boxing champion Mike Tyson described his experience with Bufo and said it profoundly changed his life.

“I look at life differently, I look at people differently. It’s almost like dying and being reborn… It’s inconceivable. I tried to explain it to some people, to my wife, I don’t have the words to explain it. It’s almost like you’re dying, you’re submissive, you’re humble, you’re vulnerable — but you’re invincible still in all.”


Furthermore, psychedelic chemicals are very complex. Just like a key, chemical molecules are 3-dimensional, and chemists call this stereochemistry. They can exist as mirror images of each other, like your right and left hands. Chemists call this chirality, and the mirror images are referred to as R- and S-enantiomers.

A mixture of the R and S enantiomers is called a racemic mixture, and the individual R or S enantiomer can be isolated to a pure substance of just one enantiomer. All three substances, the racemic, the R- and the S-enantiomer, can have different potency, psychedelic effects, or lack psychedelic effects. 

You may have heard about racemic mixtures in reference to the anesthetic drug ketamine. 

The R and S enantiomers of Ketamine. Figure from Jelen, L.A et al. “Ketamine: A tale of two enantiomers” DOI:10.1177/0269881120959644

The racemic mixture of ketamine is a mixture of the two mirror images of the molecule, and it is typically used as an anesthetic and is known to produce a range of effects, including dissociation (a feeling of disconnection from one’s body and surroundings), hallucinations, and altered states of consciousness.

“Esketamine” is the isolated S-enantiomer of ketamine, meaning scientists isolated one of the mirror-image chemicals of ketamine. Additionally, Esketamine is the pharmaceutical trade name of a nasal spray that has been approved by the US Food and Drug Administration (FDA) for the treatment of treatment-resistant depression in adults in combination with an oral antidepressant. It is thought to produce its antidepressant effects by inhibiting the action of a neurotransmitter called glutamate in a specific region of the brain called the prefrontal cortex. 

Ketamine is not a classic psychedelic and acts primarily on the NMDA (N-methyl-D-Aspartate) receptor, rather than the 5-HT2A receptor.

Psychedelic effects

Now that you’re a chemistry expert, you know that tryptamines and phenethylamines have similar chemical structures to serotonin (5-HT), which explains why they bind the serotonin receptor. However, these chemicals produce different pharmacological effects than our naturally occurring serotonin.

Serotonin can influence learning, memory, happiness as well as regulating body temperature, sleep, sexual behavior and hunger. While psychedelics can produce a range of psychological effects, including altered states of consciousness, altered perception, and changes in mood and thought.

Most psychedelics bind the 5-HT2A receptor, however, that is not the only serotonin receptor. There are 14 distinct 5-HT receptors in humans, and some psychedelics, like LSD, bind most of the 14 receptors. In addition, some psychedelics will bind other neurotransmitter receptors, like the dopamine receptors. It is currently not known which of the receptors mediate the potential therapeutic actions of psychedelics, and recent studies suggest 5-HT2A is not acting alone.

Remember how the receptors act as a lock, and the psychedelics act as a key. When the psychedelic binds the receptor, it can hold the lock in an activated (unlocked) or deactivated (locked) state. The serotonin receptor acts like a dam that controls the flow of ions from outside of a brain cell (a neuron) to the inside. When the receptor is activated by a psychedelic and unlocks the dam, this leads to a flow of ions into the neuron which excites the cell and changes its usual activity.

This flow of ions in neurons in the frontal cortex of the brain, are thought to increase dendritic excitability. Dendrites are the branches of neuron cells, and psychedelics have been shown to promote the formation of new dendritic spines – called promoting neuroplasticity. Neuroplasticity is a way for the brain to rewire itself. Neuroplasticity can promote learning, development and forming new memories. 

It has been demonstrated in lab-grown neuron cells that the dendritic spine size, density, and number of dendrites on each cell increased after psychedelic treatment. In another study with psilocybin, the dendritic spine density remained elevated up to 1 month after the initial administration of psilocybin.

Visual hallucinations are believed to occur in the primary visual cortex of the brain. It has been found that neuronal firing decreases in response to LSD. However little else is known. 

Not only are visual hallucinations a mystery to scientists. It is also not understood how behavioral changes are linked to the biological action of psychedelics. Understanding this link would be beneficial to identifying which individuals are more likely to respond positively to psychedelic therapies.

This article was first published in Nina’s Notes on 28 December and is republished on Psychedelic Health with permission.

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Ketamine: understanding the K-Hole



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



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



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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