Connect with us

Insight

How psychedelics work

Published

on

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. 

See also  What is ketamine therapy?

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. 

See also  What we know about the effect of psychedelics on women’s health

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.”

Stereochemistry

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.

Continue Reading
Click to comment

Leave a Reply

Your email address will not be published. Required fields are marked *

Insight

Designing Safety: Why Trauma-informed Models Must Lead the Psychedelic Renaissance

Published

on

This article was submitted by Lucy da Silva, Psychedelic Support Therapist and CEO Silva Wellness, as part of Psychedelic Health’s op-ed program. To submit article ideas, please email news@psychedelichealth.co.uk

 

I once was addicted to alcohol and drugs, which I was lucky enough to overcome through the 12-step programme. This journey was steeped in peer support and a real sense of community. Over the past five or so years, I have also had my fair share of psychedelic healing experiences, most of them in group settings.

Entering this sphere, I was fortunate to come from a place of internal containment and grounding, since my healing journey had begun long before my first psychedelic experience in a ceremonial setting. As a qualified and experienced psychotherapist, I was well versed in self-care, the analytical lens of Jungian interpretation and, most importantly, trauma knowledge and containment.

What these seeds of experience began to sow for me was an awareness of how clinical excitement can sometimes overshadow the slower work of building adequate systems that protect, hold and integrate – striking the delicate balance between respect for indigenous traditions and the demands of medicine-inspired healing. As a therapist, my work often focuses on the healing that takes place after harm has occurred. But my own experiences in medicine ceremonies (some profound and safe, others not so much) led me to wonder: what would it mean to design safety from the ground up?

The psychedelic field has made extraordinary progress in just a few years. Regulatory frameworks are evolving, clinical trials are expanding, and public interest is growing faster than any of us could have predicted. There’s a palpable sense of momentum—of medicine, culture and consciousness beginning to reconnect. The renaissance is not on its way—it is here! 

Come meet the leaders shaping the future of psychedelic medicine. Join PSYCH Symposium: London 2025, December 4 at Conway Hall.

Yet much of this progress still takes place within the same paradigms that shaped twentieth-century psychiatry: models focused on efficacy and access, rather than on the deeper architecture of care. We talk about scaling treatments, but rarely about scaling safety—about designing systems that protect psychological integrity as much as they deliver clinical outcomes.

The conversation about psychedelic medicine often stops at the clinic door. But the next frontier of innovation isn’t pharmacological; it’s relational, community-driven and systemic. It’s about how we build environments that recognise trauma not as an exception, but as the context from which most people seek healing. This is especially relevant when utilising psychedelics for the treatment of substance use disorders.

Co-Design Workshops: Trauma-Informed Care and Community Integration in Psychedelic Therapy

When we had the opportunity to apply for a government-backed R&D grant, it offered the chance to formalise what I had personally seen and encountered in group settings—as well as what I had heard through anecdotal conversations with individuals I met along the way, including clients who needed help processing uncontained trauma after group experiences.

With the grant focusing on individuals suffering from substance use disorders, I was motivated to propose a trauma-informed model in a group setting supported by community integration initiatives. I also wanted to address the elephant in the room: expanding access. With ketamine treatment via IV costing around £10,000 in the UK, affordability remains a serious issue. My goal was to explore how we can scale treatment options safely. We need to ensure that the very systems we design to help people heal do not inadvertently replicate harm.

Rather than studying participants, we’ll be studying systems, and asking what those systems need to look like to prevent harm before it happens.

Our study (scheduled to kick off in November 2025), Co-Design Workshops: Trauma-Informed Care and Community Integration in Psychedelic Therapy, aims to explore how safety can be intentionally designed into emerging psychedelic care models before they become mainstream. It will run as follows:

  1. Three stakeholder groups (clinicians, peer facilitators and mental health service designers) will participate in a series of co-design workshops.
  2. Using journey mapping and system mapping, the sessions will explore how trauma-informed principles can guide safe, accessible models for group-based ketamine lozenge therapy (KLT).
  3. The aim is to co-create conceptual frameworks that integrate ethical design, accessibility and community wisdom from the outset.

What we hope to learn is that safety is relational, shaped by culture and trust just as much as by clinical control. Trauma-informed practice, emotional readiness, education, and attention to set and setting before any medicine is ingested should form vital components of integration.

Promoting integration as preparation—as the precursor to treatment, as a modality in itself—mirrors what the 12-step programme does so well. Peer-led community, robust support and follow-up systems could become the scaffolding that extends care beyond the session, supporting longevity in healing.

This also ties into the concept of reducing hierarchy by amplifying lived expertise and modelling the inclusivity that psychedelic care must embody. It can help individuals lean towards treatment rather than resist it—a common challenge in both community-led and private addiction treatment programmes.

As the long-term aim of this project is to align proposed frameworks with voluntary sector and NHS infrastructure, we envisage that it could inform future service delivery and policy development. Most importantly, we hope to begin a wider discussion about how future frameworks can be wrapped in nurturing ethics and, above all, safety.

If we can integrate trauma-informed principles from the outset, the future of psychedelic therapy could look very different. We might see small, community-based groups supported by skilled facilitators who understand containment as much as chemistry. Integration models could become embedded within peer networks, where shared experience is part of the medicine itself.

Services could evolve through co-design rather than correction, shaped by lived wisdom as much as professional expertise. In this vision, innovation means not just expanding access, but building safety, inclusion and care by design.

Because the psychedelic renaissance will only ever be as safe as the systems that hold it and designing those systems is the real frontier.

As this project begins, we have a rare opportunity to slow down—to listen, collaborate and build the ethical foundations before psychedelic care becomes fully mainstream. Trauma-informed design reminds us that safety is not simply the absence of harm, but the presence of trust, transparency and relationship.

If we can weave those qualities into the structures that support psychedelic work, from the clinic to the community, we stand a chance of creating a field that heals without replicating old wounds.

This study is just the first step, but it marks an invitation to the wider field: to design consciously, collectively and with care at the centre.

Because the question is no longer whether psychedelics can heal, it’s whether we can design the systems that allow that healing to endure.

Image by andreas160578 from Pixabay

 

Continue Reading

Insight

Is Ketamine Therapy Only Reaching The Wealthy? Dr. Celia Morgan On Expanding Equitable Access

Published

on

Dr. Celia Morgan is one of the UK’s leading figures in ketamine and psychedelic research, especially in the domain of addiction and mental health.

Based at the University of Exeter, she holds the Chair of Psychopharmacology and leads trials exploring how ketamine, paired with psychotherapy, can break cycles of relapse in substance misuse.

Morgan has led some of the largest clinical trials on ketamine-assisted therapy for alcohol use disorder and will be speaking at the upcoming PSYCH Symposium: London 2025, to be held at Conway Hall on December 4.

“I think that the most promising findings from our work with ketamine are of the sense of agency and autonomy in their recovery that the people we are working with experience,” she told Psychedelic Health in a written interview.

Still, she thinks several key challenges need to be tackled for these treatments to be able to reach more people. One of the biggest of such challenges is ensuring equitable access to these treatments.

“We see a relatively homogenous and privileged group in most studies, our work has tried to address this,” she said.

Building the infrastructure to safely deliver these treatments in public healthcare systems is another big challenge for the industry, she said.

Yet the healthcare sector can also take advantage of Ketamine’s regulated status to allow for a faster roll-out, when compared to other psychedelics like MDMA or psilocybin.

“Some of the recent recommendations by the Royal College fo Psychiatrists are steps on the way towards more widespread use,” she said.

What distinguishes Morgan in the psychedelics field is her dual commitment. She studies the risks and harms of recreational ketamine use while simultaneously designing controlled, clinical applications for it.

One of her flagship projects is Exeter’s KARE trial (Ketamine for Reduction of Alcohol Relapse), which blends ketamine infusions with psychotherapy for patients with alcohol use disorder. Early published data show dramatic improvements in abstinence rates during six-month follow-ups, far exceeding baseline relapse rates. Morgan has also worked on trials for gambling disorder and other behavioral addictions, expanding the frontier of what ketamine-assisted therapy might treat.

Morgan also plays a role in academia’s response to the psychedelic renaissance, she’s a co-lead on Exeter’s postgraduate certificate in psychedelic studies, a program designed to train clinicians, researchers, and therapists in the science and ethics of psychedelic medicine.

“I think its important to keep on with our efforts to study, regulate and roll out these treatments principally for the patients who might benefit from psychedelics as I have seen first hand in my work,” she said.

Picture is extracted from an interview with Dr. Morgan at PSYCH Symposium’s 2022 edition.

Continue Reading

Evegreen

Did Psychedelics Influence Early Christianity? A New Review Examines the Evidence

Published

on

A newly published academic review has revisited one of the most sensational — and disputed — theories in psychedelic history: that early Christianity emerged from fertility cults using psychoactive mushrooms.

Released 9 August in the journal Religions, Richard S. Ascough’s paper, John Allegro and the Psychedelic Mysteries Hypothesis, takes a fresh look at the 1970 book The Sacred Mushroom and the Cross by Semitic philologist John M. Allegro.

Allegro claimed that Christian theology, symbols and even the figure of Jesus could be traced back to ancient rituals involving the psychoactive mushroom Amanita muscaria. His argument rested on bold linguistic links between Sumerian and Semitic languages — links that experts swiftly dismissed as unsubstantiated.

Discredited but enduring

Ascough’s review details how Allegro’s thesis was rejected almost immediately in academic circles. Mainstream scholars pointed out that Sumerian is a language isolate, making the connections Allegro proposed linguistically impossible. The fallout was severe — the book damaged Allegro’s reputation and ended his academic career.

Yet, as Ascough points out, the theory refused to disappear. In the decades since, it has surfaced repeatedly in psychedelic counterculture, cited by authors such as Carl Ruck and Terence McKenna. While scholars abandoned the thesis, parts of the public embraced it as part of a broader fascination with the potential spiritual role of entheogens.

Three key takeaways

Ascough distils his reassessment into three main findings:

  • Reception – Universally dismissed by academics, the theory nonetheless gained a cult following in popular psychedelic discourse.

  • Methodology – Allegro’s linguistic analysis is fundamentally flawed; modern scholarship offers no evidence for the deep language connections he claimed.

  • Legacy – The thesis’ real impact lies in how it helped spark public interest in the idea that psychoactive substances may have shaped religious traditions.

In short, Ascough frames Allegro’s work as “a historical curiosity” — important for its cultural footprint but not as a credible piece of entheogenic research.

Why it matters now

The review lands at a time when psychedelics are being investigated for regulated medical use in treating depression, PTSD, and end-of-life anxiety. By separating historical speculation from scientific evidence, Ascough’s work helps keep the conversation grounded.

It also highlights a longer lineage of public fascination with psychedelics — one that stretches from ancient myth to 20th-century counterculture, and now into 21st-century clinics and labs.

For those following the evolution of psychedelic medicine, the review is both a look back at one of the field’s most colourful controversies and a reminder of how far the evidence base has advanced.

Article picture is an illustration made using generative AI tools.

Continue Reading

Trending

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.

Copyright © 2025 PP Intelligence Ltd.