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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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Psychedelic-assisted therapy for treating PTSD in Ukraine brings hope



Photo by Karollyne Videira Hubert on Unsplash

The war in Ukraine brings suffering and trauma, which naturally leads to cases of post-traumatic stress disorder (PTSD) among soldiers and civilians. The Ministry of Health of Ukraine predicts that about 4 million Ukrainian civilians are suffering from PTSD.

According to the WHO, about a quarter of the Ukrainian population may be affected by disorders of mental health. In order to deal with this challenge, Ukraine must ensure access to safe, effective and adequately regulated therapy.

That is also why Ukraine is trying to support the idea that mental health will become an integral part of Ukraine’s “reconstruction.” Czech Republic can in this regard offer a helping hand in the sphere of innovative therapy. That is also one of the reasons why a Ukrainian delegation took part in the international conference Novel Mental Health Treatments and Sustainability of Healthcare Systems: Czechia as a Leader of the EU? which took place in Prague.

Psychedelic-assisted therapy is being increasingly discussed in Ukraine as a way of treating PTSD. Although the use of ketamine as part of mental illness treatment has been legal since 2017, substances such as MDMA and psilocybin are still banned. With a view to global development, which has been inching towards supporting the medical use of psychedelics, Ukrainian institutions are supporting clinical studies for psychedelic-assisted therapy as an innovative way of treating PTSD.

Medical use of psychedelics in PTSD treatment in Ukraine

The potential of psychedelic-assisted therapy in the context of the war in Ukraine was also the focus of one of the conference panels. The panel was attended by Ukrainian MPs Mykhailo Radutskyi, Dmytro Gurin, Rostyslav Tistyk and State Secretary of the Ministry of Internal Affairs Inna Yashchuk.

Over the course of the day, Mykhailo Radutskyi, Member of the Verkhovna Rada of the Parliament of Ukraine and Chairman of the Committee on National Health, Health Care and Health Insurance praised the Czech Republic and said that the country is at the forefront of psychedelic research in Europe.

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“We have a large population suffering from mental health problems, but we will most likely never have enough experts. In Ukraine, we have an information campaign on how to treat soldiers who have returned from the front, and we are proposing a law which would ensure mental health,” Radutskyi stated.

“About 3.5 million people in Ukraine, and not only soldiers and veterans, currently have mental health problems because of the war, over a million war veterans will need psychotherapeutic help, and currently about half of the veterans suffer from PTSD,” said Dmytro Gurin, Ukrainian MP and member of the Committee on National Health, Health Care and Health Insurance.

“Mental health must become an issue and must play a part in the reconstruction of Ukraine. Winning the war is one thing, but we must also win the war on mental health. One way to win this war is through psychedelic-assisted therapy, and our Parliament and the Ministry of Health will support clinical trials.

“I hope that we will soon approve a study researching the potential for treating PTSD through psychedelic-assisted therapy. Our task is to create fitting conditions for future clinical trials.”

State Secretary of the Ministry of Internal Affairs Inna Yashchuk said: “The Ministry of Internal Affairs is setting up mental health centers all over Ukraine, and I estimate that when we win, 80 % of the people will come to their doctors in need of psychological and psychiatric help. So mental health is not a problem today, but it will be a problem for the future.”

Czech Republic wants to help Ukraine with mental health issues

The event also featured a speech by the Governmental Envoy for the Reconstruction of Ukraine, Tomáš Kopečný, who said: “Ukraine’s reconstruction is not only about physical reconstruction, but also about the mental health of Ukrainian civilians and war veterans, it is about increasing capacities on site, so that the support reach is as effective as possible.”

Other experts also believe that one of the outcomes of the panel discussion should consist in the establishment of a structural relationship between the Czech Republic and Ukraine in the field of mental health, which would include scientific cooperation, exchange of know-how and joint research projects.

Scientific supervision of the ongoing exchange between Czechia and Ukraine in the field of mental health is primarily provided by Professor Jiří Horáček of the Faculty of Medicine at Charles University and director of the Centre for Advanced Studies of Brain and Consciousness at the National Institute of Mental Health, who has prepared an innovative clinical study of using ketamine for the treatment of PTSD in Ukrainian veterans.

In Czech Republic, the topic is also addressed by the Psychedelic Research Foundation (PSYRES). Its director, Jana Bednářová, has said that: “Research about psychedelics is crucial for the future of Ukraine and the Czech Republic. While such research will put Czech Republic on the cutting edge of the field in Europe, without breakthrough solutions for Ukraine, it can take an entire generation to regenerate mental health – in comparison, the physical recovery of the country can be a matter of mere years. Our mission is to enlist visionaries, philanthropists, organizations and the general public to support our research projects and activities and help us make treatment available to everyone who may need it.”

The issue has been resonating in Brussels, Czechia among EU leaders in mental health

The Czech Republic was the first country to put mental health back on the EU’s agenda. The Czech trial in Brussels also leads to the topic of psychedelic-assisted therapy in the treatment of PTSD in Ukraine. The topic was first addressed last year by PsychedelicsEUROPE, a platform focussing on the European regulation of psychedelics. The platform has long been working towards the approval of a new regulatory framework for the medical use of psychedelics on the European single market.

“Mental health is becoming a central issue for the EU. We are a little behind the US, the UK and Australia, but the necessary debate about the regulation of psychedelic substances is coming to Europe. In the same way that psychedelic-assisted therapy can help Ukraine, Ukraine can help the EU in this field by providing data from new research which may help with drafting good legislation. This is one of the reasons why mental health ought to be an implicit part of Ukraine’s reconstruction,” said Viktor Chvátal, founder of PsychedelicsEUROPE.

The event was organised by:

The mission of PSYRES, the Psychedelic Research Endowment Fund, is to provide funding to scientific projects and facilities that focus on innovative treatment procedures in the field of mental illnesses. Our task is to support research and study of the potential of psychedelics and their therapeutic use in psychiatry, neurology and addictology. Our activities help with the preparation and implementation of clinical studies and analyses and with the education of the public. We collaborate with doctors, therapists and researchers who deal in depth with altered states of human consciousness.

Institute for Rational Addiction Policies is a multidisciplinary association of independent and prominent experts who address the issue of addiction from all angles – public and individual health, legislation and other legal implications, including security challenges, and economics including market modeling, tax, economic impacts on public budgets, the field of education and prevention, and finally also the fields of social and sociological and political science.

PsychedelicsEUROPE (PE) is an innovative public affairs mental health platform based in Brussels that brings together leading research centres, NGOs, investors, philanthropists and private companies. Based on the latest scientific evidence, PE advocate in the EU for a regulatory environment that promotes modern therapies, cutting-edge research, and innovative industry.

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Psychedelic therapist training programmes are not fit for purpose

We must learn from our mistakes when conducting Psychedelic Assisted Therapy.



Groundbreaking trial to assess real-world efficacy of MDMA therapy for PTSD

Psychologists, therapists and counsellors play a fundamental role in treating common mental health disorders such as anxiety and depression. With little advancement in treatments for common mental health issues for over half a century, reliance on therapy to support people with such conditions is extremely high in the UK.

However, most training programmes for these professionals do not focus enough on skills acquisition and we are simply not training enough therapists to meet the growing demand. This will not fix the nation’s mental health crisis.

Don’t believe me? Look at the variance in outcomes between therapists. Look at the sheer number of people in England who are prescribed antidepressants by their GP. The figure now stands at more than 8 million people, with over 2 million having been taking them for five years. Look at the number of people on waiting lists to start therapy. It all points to a fundamental problem where many people, with a common mental health problem, are unable to access therapy that works.

One of the reasons lies in the way we train therapists. On most training programmes, students are assessed as competent to practice through their academic writing and the submission of one or two, self-selected, recordings of therapy sessions. They typically have a placement to apply their new skills. However, unlike other healthcare professionals, these sessions occur behind closed doors, without direct observation. Imagine training a nurse, a surgeon or a dentist like this.

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This lack of direction observation makes it difficult to know what the trainee is doing with their patients, whether they can consistently deliver therapy with fidelity to the therapy model, and how they interact with patients/clients. It makes it difficult to give the trainee meaningful feedback that will enable them to become better at what they do.

The system encourages higher and higher academic qualifications. However, in my own experience of teaching and supervising mental health professionals, there is no association between competence and the level of academic qualification. Dare I say it, but it is not necessary to have a degree in order to be a highly effective therapist.

This is why Clerkenwell Health has recently launched their Foundations Programme – a practitioner programme for healthcare professionals interested in Psychedelic Assisted Therapy (PAT). Programme participants will be provided with the knowledge required to prepare to safely, ethically and effectively deliver psychedelic treatments.

As we move towards a future where Psychedelic Assisted Therapy (PAT) becomes more mainstream in treating metal health disorders, we must ensure all training programmes robustly assess whether a trainee can consistently deliver high quality therapy that makes measurable difference to patients’ lives. This is what really matters.

Clerkenwell Health’s Foundations Programme leaves no stone unturned. The course explores both the ethical and practical aspects surrounding psychedelic treatments within a regulated healthcare setting, with the teaching delivered by practitioners at the forefront of psychedelic research in the UK, including Dr Sara Tai, Professor of Clinical Psychology at the University of Manchester; Dr David Luke, Associate Professor of Psychology; and Dr Jules Evans, the writer, philosopher and award-winning author of Philosophy for Life.

I asked one organisation, that provides training in PAT, how they selected their trainees, and I was told that it was done “with the gut”. The current approach runs the risk of training a new workforce who are not fit for purpose.

What’s more, all of the existing programmes use ‘psychedelic-psychobabble’. Trainees are taught to ‘trust the medicine’, ‘trust your instinct’ or ‘trust that the participant has the power to heal themselves’. These terms are not widely understood within mainstream healthcare and have, in some cases, led to acts of gross misconduct.

We need a more sober, science-led and evidence-based approach to training. Clerkenwell Health’s Foundations Programme tries to achieve this by providing learners with a thorough background in the history, current state of evidence, treatment modalities, putative mechanisms of actions, and future of psychedelics.

Patient safety, robust standards and clinical effectiveness are of utmost importance in our work at Clerkenwell Health. It’s for these reasons that we’ve launched the Foundations Programme, a course which carefully selects its trainees, assesses their competence and efficacy and is scientifically and theoretically robust. This is not the place where you can try out some psychedelics and suddenly feel qualified to be a psychedelic assisted therapist. This is the place where healthcare professionals come to train in evidence-based practices that are proven and safe. PAT must grasp the golden opportunity to set the standard for a new paradigm in mental healthcare.

If you’re interested in learning more about Clerkenwell Health’s Foundations Programme, you can find out more here:

This article was written by Dr Sarah Bateup, Scientific Advisor at Clerkenwell Health. Sarah has delivered over 30,000 hours of therapy and taught at Kings College London and Exeter University before joining ieso digital health where she helped scale the company from 10 therapists to 1000.

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Psilocybin therapy for end-of-life care supported by 79% of Canadians



The Entourage Effect in Mushrooms: Natural psilocybin may outperform synthetic

A new survey has revealed that over 79% of Canadians support psychedelic-assisted therapy for existential distress at the end of life.

People facing a terminal diagnosis often experience significant distress. Depression, anxiety, existential distress and loss of meaning or purpose can make this type of diagnosis difficult to deal with.

Current treatments consist of counselling of cognitive behaviour therapy (CBT), but these are not always effective for everyone, creating a need for innovative new approaches to end-of-life care.

Increasing research is now showing that psychedelic therapy may be beneficial for treating existential distress in patients diagnosed with incurable diseases.

For example, a review published in 2018 in Neuropsychopharmacol Biol Psychiatry found that patients with life-threatening diseases associated with symptoms of depression and anxiety benefitted from the anti-anxiety and anti-depressant properties of psychedelics.

The studies reviewed anecdotally reported that patients experienced quality of life improvements along with a reduced fear of death.

A randomized double-blind trial carried out by John Hopkins University also revealed that high-dose psilocybin produced significant decreases in depression, anxiety and death anxiety, and improvements in quality of life, life meaning, and optimism.

A further clinical trial from New York University found that 60% to 80% of participants experienced anti-anxiety and anti-depressive effects from the treatment, along with benefits for existential distress, quality of life, and attitudes towards death, noting that “the psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.”

Supporting psychedelics for end-of-life care

In light of psychedelic therapy’s inclusion in Canada’s Special Access Programme in 2022, which enables authorised patients to receive access to these therapies if other treatments have been unsuccessful, a team of researchers set out to understand the public’s opinion on the potential easing of rules surrounding the medical use of psilocybin.

The survey, published in Palliative Medicine and carried out by Michel Dorval and Louis Plourde at Université Laval’s Faculty of Pharmacy and researchers from McGill University, Université de Montréal and UQAR, revealed that nearly four out of five Canadians support the use of psilocybin as a treatment for end of life existential distress.

In a statement, Dorval commented: “Studies have already shown that psilocybin, combined with psychotherapy, produces rapid, robust and lasting anxiolytic and antidepressant effects in patients suffering from advanced cancer.

“This substance can bring about a profound awareness that leads the patient to view existence from a different perspective. Treatment with psilocybin, combined with psychotherapy, can produce relief for up to six months.

“Our results seem to indicate that the social acceptability of this intervention is high in the Canadian population. If we consider only Québec respondents, the acceptability rate is similar to the national average.”

The findings also revealed that public support for psilocybin is higher among respondents who have already been exposed to palliative care, as well as higher in respondents who have already used psilocybin.

“Having been close to loved ones at the end of life, or having witnessed their distress, could explain this openness to new approaches designed to help people at this stage of their life,” added Dorval.

“There are still many prejudices against psychedelic substances. Familiarity with these substances probably helps to better understand their true effects as well as their therapeutic potential.”

The authors write: “The social acceptability of psilocybin-assisted therapy for existential distress at the end of life is rather high in Canada. These findings may contribute to efforts to mobilise resources and improve access to this emerging therapy in palliative and end-of-life care settings.”

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Psychedelic Health is a journalist-led news site. Any views expressed by interviewees or commentators do not reflect our own. We do not provide medical advice or promote the personal use of psychedelic compounds. Please seek professional medical advice if you are concerned about any of the issues raised.

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