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Exploring the placebo effect in psychedelic studies



Exploring the placebo effect in psychedelic studies
Photo by Diana Polekhina on Unsplash

The placebo effect is the mysterious power our minds have to make us feel better, even when we are taking just a sugar pill instead of real medicine. 

Several studies have shown that this effect is a legitimate biopsychosocial phenomenon that is an integral part of the overall treatment response.

Research has found that the placebo effects can be as strong as the effect of the actual medicine in randomized controlled trials (RCTs).

When scientists want to test a new drug, they use what’s called a double-blind RCT.

In this trial design, two groups of people are tested, one gets the real medicine and the other gets a fake one (the placebo).

The twist? Neither the people taking the medicine nor the ones giving it know which is which. This helps to make sure that the results are trustworthy and not biased.

Even with this careful setup, it’s tough to uphold the true integrity of the double blind information and sometimes the secret of who got the drug and who didn’t gets out.

This is especially true in psychedelic studies.

The RCT design assumes that the effects of a drug being studied can be isolated, added, and/or subtracted from the “nonspecific effect” of context and person, studied by the placebo.

However, despite the goal of blinding, it is rare for trials to uphold blinding integrity and incorporate this information into the results.

While these trials are great for assessing the added benefit of novel drugs, they don’t always show us the full power of the placebo effect.

It’s a hidden superpower we are still trying to understand.

The History of placebo in the clinic

In 1772, a Scottish doctor named William Cullen reported prescribing a remedy to a patient despite believing it to be inefficacious. He explains that sometimes “it is necessary to give a medicine and [this is] what I call a placebo.”

The role of the placebo was to give patients hope and to make doctors’ work easier in difficult or desperate cases.

Placebos were considered as inert substances with “fake” psychological but benign effects. They were believed that they cannot cause harm, but may relieve symptoms.

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It was only in the 1950s, with the rise of informed consent and autonomy as pillars of medical ethics, that the practice of deceiving patients “for their own good” was put into question. Today, the deceptive use of placebos is seen as a relic of an older era.

However, despite this change in mindset, 46-95% of doctors prescribed placebos in 2018.

Placebos in research

In the 20th century, placebos began to be used in research to assess the added benefit of drugs and to discard harmful or ineffective treatments. By 1946 the comparative experimental framework was advocated for in clinical trials.

The placebo effect

In 1955  Dr. Henry Beecher wrote an article called The Powerful Placebo, which catapulted the ideas on the placebo into popularity and changed the way researchers thought about the placebo effect.

He found that about one-third of participants in clinical trials were experiencing relief from their symptoms.

Before, placebos were often just given to patients to make them feel better, and many brushed them off as just “all in the mind.”

However, in research, the placebo effect led to discerning between useful and non-useful treatments. This insight from Dr. Beecher helped scientists figure out which treatments really worked and which didn’t.

In 1962, the RCT design comparing the effects of treatment and placebo groups became the gold standard for pharmaceutical manufacturers to demonstrate efficacy and safety to regulators.

Placebo in Psychedelic Studies

Using a placebo in psychedelic studies is a challenge. It is very obvious to the recipient who receives a placebo versus a psychedelic.

And placebo effects have been shown to be enhanced by the setting of the psychedelic study.

A recent study looked at placebo psychedelics alone in the context of a psychedelic party. Researchers threw a party for 33 students. They gave them placebo, telling them it was similar to psilocybin, the hallucinogenic molecule found in psychedelic mushrooms.

The party had music, colorful lights, mesmerizing paintings and visual projections.

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Some of the people at the party were in on the secret. They were there to act like they were feeling the effects of “the drug” and to make the study participants believe that there was no placebo control group.

The results indicated that context and expectations can promote psychedelic-like effects.

The party vibes and expectations made the participants feel like they had a psychedelic trip, even without taking any real drugs.

The individual variability within the placebo effects was considerable.

Some felt nothing, while others felt like they’d taken a strong dose of psilocybin.

In psychedelic studies, it is much more difficult to use the traditional framework for assessing the effectiveness of a drug against a placebo. The environment and mindset, often referred to as “set and setting” can play a huge role in the effects of the drug.

The effects can be synergetic. The drug influences the “set and setting” and the “set and setting” influences the drug effect. Since the party setting can itself be a game changer on the effects of the drug, these elements should be seen as factors central to psychedelic science, and cannot be disregarded as noise.

How to control for the placebo effect in psychedelic studies?

A group of drug experts including Prof. David Nutt, Robin Carhartt-Harris, Balázs Szigeti and David Erritzoe, recently wrote a preprint (an article shared prior to peer-review) on the fallibility of placebo control.

When people think they are getting the true drug but aren’t, their expectations can mess with the results of the trial.

They call this combination of weak blinding and positive treatment expectancy, activated expectancy bias (AEB).

The effect of AEB is an uneven distribution of expectancy effects between placebo and drug due to patients recognizing what they received in psychedelic randomized controlled trials.

To counteract the bias, the researchers proposed the Correct Guess Rate Curve (CGRC), a computational model and novel analytical tool that can estimate what the results of the trial would look like if everyone was completely in the dark about whether they got the real drug or a placebo.

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Results from the CGRC suggest that placebo-controlled studies are more fallible than conventionally assumed leading to researchers thinking a drug works when in fact it does not.

The CGRC can help fix this bias, and it is cost effective and less resource intensive.

Most solutions to improve blinding are difficult to implement and resource intensive. Thanks to these experts, we now have a useful tool to make drug research more reliable.

With the resurgence of psychedelic research in randomized controlled trials, it has highlighted the antiquated system we have used for the last century to evaluate drug effectiveness.

The idea of “set and setting” should not stand alone for use in psychedelic research. Perhaps more treatments could benefit from improved set and setting.

Furthermore, in psychedelic studies the psychedelics are given in a treatment regime that involves psychotherapy, resulting in the name psychedelic-assisted therapy.

The idea is not to give the treatment to the patient and send them on their way. The psychotherapist will prepare the patient for treatment, be with them during treatment, and help them integrate in follow-up sessions.

It would be interesting if more treatments used the structure as described above. Most treatments are given after a very brief talk with a doctor, and then usually results in a “give me a call if you don’t improve.”

What if the doctor said: “call me if you improve or if you don’t.” Perhaps it could strengthen the doctor-patient relationship. Even “the placebo effect” could be integrated into a person’s recovery.

The holistic approach of psychedelic-assisted therapy, where the journey is as important as the treatment itself, offers a promising blueprint for future medical practices.

By fostering deeper doctor-patient relationships and harnessing the power of the placebo effect, we could revolutionize the way we heal and care.

This article was first published on Nina’s Notes 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.

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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.

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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.

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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.

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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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