• Psychedelic Medicine

PHARMACOLOGY | +80 articles

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Psychedelics*

by David Nichols (2016)

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magneto-encephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network.

Outlook

Dr. Albert Hofmann, the natural products chemist who accidently discovered the effects of LSD in 1943 while working at the Sandoz Laboratories in Basel, Switzerland, wrote an autobiographical account of his discovery titled LSD: My Problem Child. In his book, Hofmann talks about the potential of LSD, which he had hoped would be a promising new tool for psychiatry, but also expresses dismay at the social turbulence that ensued when “LSD was swept up in the huge wave of an inebriant mania that began to spread over the Western world, above all the United States…” Hofmann died in 2008 at the age of 102 years; but in his later years, he was delighted to see that real science had begun to take a thorough approach to unraveling the psychopharmacological mysteries of LSD, which he had always believed would eventually prove to be a miracle drug for psychiatry.

With that in mind, if the positive therapeutic effects of psychedelics continue to be validated by additional well designed clinical studies, it opens up a whole new dimension of medical research. If psilocybin or LSD can acutely abolish depression or anxiety after one or only a few treatments, the question must be asked, “How does that occur?” There are many who believe that such improvement must be related to neurochemical effects, or neuroadaptation, and refuse to believe that the mystical experience may be relevant. Yet both modern and older studies consistently find that those who experience the most profound mystical experiences invariably receive the greatest symptom improvement. Of course, as reductionists, it is understood that the mystical experience must have neurochemical correlates. Even so, understanding what they are, how and why they occur, and how they lead to therapeutic improvement should shed light on the underlying deficits in brain function that lead to these disorders in the first place. Before-and-after brain imaging studies of patients with depression, anxiety, or addictive disorders will show how brain connectivity has changed as a result of psychedelic treatment.

To understand these disorders at the present time with standard state-of-the-art approaches involves a sort of “fishing expedition,” searching for biomarkers that might be clues to the basis of the underlying disorder. Genome-wide association studies plow through many thousands or hundreds of thousands of genes, searching for candidates that might be the underlying causes of affective disorders. One generally cannot do prospective studies, to compare the brain function of the normal patient prior to the onset of his or her disease, and then examine it again after therapeutic improvement. Rather, one begins with a patient who is already sick, and then if therapeutic improvement occurs, usually over a long period of time, one tries to understand how it happened. By contrast, some of the recent treatments of anxiety and depression with psilocybin or LSD are so dramatic, and happen so quickly, that there must be some overt measureable changes in brain function or connectivity that correlate with therapeutic improvement. Learning what these are is the next big challenge, a process that promises to completely revolutionize the way we approach discovering better treatments for a host of human psychiatric disorders.

Considering the most recent scientific and clinical developments in understanding the actions of psychedelics, a statement made in 1980 by Dr. Stanislav Grof seems particularly relevant today: “It does not seem to be an exaggeration to say that psychedelics, used responsibly and with proper caution, would be for psychiatry what the microscope is for biology and medicine or the telescope is for astronomy. These tools make it possible to study important processes that under normal circumstances are not available for direct observation.”

*From the article here :
 
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Psychedelic pharmacology for the 21st century: Breaking convention

by Erika Dyck | Wiley | 11 December 2018

Psychedelics are making a comeback. What was for decades a slow trickle of scientific research has exploded in the last decade into what some are calling a ‘psychedelic renaissance’. Breaking Convention contains a series of essays from one of the growing number of gatherings of researchers, enthusiasts, regulators, artists, and curious bystanders who are interested in watching the reincarnation of psychedelic science. The essays in this volume represent the third instalment of papers, based on presentations held at the Breaking Convention meetings. This particular assembly of papers came from a meeting in Greenwich, London, that was held in 2015.

As lead editor, Ben Sessa explains that the contributions in this volume were selected to help to showcase the wide variety of ideas on the subject, particularly as they span the disciplines. The book contains 26 chapters with a wide range of topics. For example, Dave Nichols provides readers with a rather technical report on the state of chemistry and psychedelics; an essay that does not obviously reveal his own connections with the late Dr. Shulgin (referred to by some as ‘psychedelic genius’) and the more countercultural side of the mushroom debate. Mike Crowley, though, takes mushrooms back to ancient Indian roots and considers both theological and gendered interpretations of their value as sacred chemicals. And, Dale Pendal invites readers to explore psychedelic sensations through poetry, toying with a more creative interpretation of the deep schism that has divided psychedelics into poisons or elixirs.

The mixture of presentations includes social scientists, humanists, and scientists. But, it also spans different generations and approaches to both psychedelics and the war on drugs. Contributions from today's psychedelic stalwarts – Rick Doblin and Amanda Fielding – offer staid appraisals of how the re‐emerging psychedelic science has been a product of multiple disciplinary achievements, namely in neuroscience and drug regulation, but it has also been forced to rely on the philanthropy and faith of non‐scientific and non‐governmental organizations to fund and sustain this research. Doblin, founder of the Multidisciplinary Association for Psychedelics Society, reflects back on his role in this organization and how it has grown into a healthy non‐profit that can now support innovative research. Likewise, Beckley Foundation's founder Amanda Fielding speaks with Michael Pollan, whose interview is captured in the book, to describe how the state of a psychedelic research economy has evolved over the past few years and how she has maintained her own enthusiasm for this campaign to alter cultural attitudes about psychedelics.

Editor Ben Sessa likewise weighs into the discussion with his own provocative introduction. In it, he frames the discussion as both long overdue and poorly understood. Sessa, whose own clinical investigations have bolstered his own claims about the validity of psychedelics for treating addictions, PTSD, and other psychiatric disorders, questions why the clinical evidence has not yet helped to overwhelm the cultural disposition that continues to support prohibition. Sessa suggests that the presented essays help to show us that the discussions are still quite incoherent in many ways, but that despite the lack of consensus on how psychedelics work, there is a growing appetite for exploring that possibility. Sessa reminds us that most of his patients are not in fact facsimiles of the 1960s hippies or radical types bent on altering modern society in fundamental ways, but are indeed people who are suffering with psychiatric and behavioural disorders for whom there are limited options for therapy. Clinical trials repeatedly show promise for exploring psychedelics, yet a lingering war on drugs or fear of risks specific to psychedelics continues to introduce obstacles to funding, research, and treatment.

I did not attend the Breaking Convention conference, though I have attended similar meetings that bring together people across disciplines, many of whom step outside of mainstream academia. The essays in Breaking Convention seem to represent a good selection of the many different voices at these meetings, while still fitting into a familiar trap that has plagued similar conferences. The voices of marginalized people, be those women who are not the first authors on the scientific papers, or Indigenous healers who have developed a different historical relationship with these substances, or even critics of psychedelic science, are not fully integrated into the conversation. The historical appraisals tend to rely on a straw man argument, or an assumption that the work conducted in the 1960s (let alone before that time) was unethical, misguided, unsophisticated, and moreover, needed to be improved upon. Perhaps these are necessary assumptions made to stimulate the current conversation and bolster the enthusiasm of the contemporary psychedelic scene. But, as Sessa suggests, we still do not really know what ‘psychedelic’ means, or how to handle the experience in a cultural sense. These essays provide further evidence that there is a growing curiosity about past knowledge as well as future applications, yet we are still searching for a clear sense as to how best to apply psychedelics to modern life, whether these substances should be decriminalized completely, used in specified clinical settings, handled only by professionals, or distributed more widely. Scientists in the 1950s asked similar questions as they contemplated how psychedelics might affect human evolution. It seems that in many ways, the essays in Breaking Convention are part of reigniting that conversation rather than solving it.​
 
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The pharmacology of psilocybin and psilocin

by Barb Bauer | Psychedelic Science Review | March 13, 2019

Psilocybin and psilocin are two psychedelic compounds found in magic mushrooms. Calling these and other magic mushrooms compounds hallucinogens is an incorrect generalization. A hallucinogenic effect is not always present in users. Therefore, the terms psychedelics or psychotomimetics are the preferred designations put forth by experts in the field.

Several genera of magic mushrooms contain psilocybin and psilocin including Inocybe, Conocybe, Panaeolus, Gymnopilus, and Pluteus. However, psilocin is not the only psilocybin derivative in magic mushrooms. Others include norpsilocin, baeocystin, norbaeocystin, and aeruginascin. The derivatives and amounts present vary in different parts of the mushroom. They also vary in between species and even within batches of the same species.

This article examines the chemical structure of these psychedelics, discusses how the body transforms them, and how they interact with receptors in the brain.

Chemical structures of psilocybin and psilocin

Psilocybin and psilocin (Figure 1) are tryptamine alkaloids and structural analogs of the neurotransmitter serotonin (Figure 2). Psilocybin and psilocin differ from each other at position 4, having a phosphate and hydroxyl group, respectively. As structural analogs of serotonin, both compounds differ from serotonin by having two methyl groups on the amine group on carbon 3. Also, the substituent groups on the benzyl ring of psilocybin and psilocin are in position 4, while the hydroxyl group on serotonin is in position 5.

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Figure 1: The chemical structure of psilocybin and psilocin, two compounds found in magic mushrooms.

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Figure 2: The chemical structure of the neurotransmitter serotonin.

The similarities and differences between the chemical structures of these compounds is key to understanding the effects of psilocybin and psilocin.

Absorption, metabolism, and excretion in mammals

Psilocybin is a prodrug of psilocin. This means the prodrug psilocybin undergoes changes in the body which convert it into the active form, psilocin. Specifically, a chemical process called dephosphorylation removes the phosphate group on psilocybin, creating psilocin.

The dephosphorylation of psilocybin occurs in two ways in different areas of the body.

- The acidic environment in the stomach is a favorable environment for the rapid dephosphorylation of psilocybin.

- Enzymes such as alkaline phosphatase and other non-specific esterases dephosphorylate psilocybin in the intestines, kidneys, and the blood.

The phosphate group on psilocybin in Figure 1 is highly polar. This polarity along with the positively charged amine group makes the molecule zwitterionic and more soluble in water than psilocin. Without the phosphate group, psilocin becomes more lipid soluble than psilocybin, making it metabolically available in the body and more easily absorbed in the intestines.

At this point, psilocin is distributed all over the body via the bloodstream. Being lipid soluble allows psilocin to cross the blood-brain barrier and elicit its effects (see the Biological Interactions section below). Researchers can detect psilocybin and psilocin in human blood plasma 20-40 minutes after oral administration of psilocybin. They find maximum levels in the blood 80-105 minutes after administration.

About 80% of metabolized psilocybin gets excreted in the urine as a compound called psilocin-O-glucuronide (Figure 3). Some psilocin and psilocybin (only 3-10 percent are excreted in the urine, mostly in a conjugated form with glucoronic acid.

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The chemical structure of psilocin-O-glucuronide, a urinary metabolite of psilocybin.

Biological receptor interactions

At last count, there are seven main classes of serotonin receptors containing 14 subtypes. Of these, the 5-HT2A is the serotonin receptor (5-HT is an abbreviation for serotonin, 5-hydroxytryptamine) is studied the most in relation to psychedelic effects. It is important to keep in mind that scientists are not currently studying how the interactions of psilocybin and psilocin with other receptors impacts the psychedelic effect of these compounds.

Psilocybin has a low binding affinity as an agonist for the 5-HT2A receptor compared to the active form of the molecule, psilocin. The difference in the binding affinities of psilocybin and psilocin on the human 5-HT2A receptor is striking. The Ki (disassociation constant) for psilocybin is >10,000 nM, while for psilocin, Ki = 102.7 nM. The lower the Ki value, the less likely the molecule is to dissociate from the receptor. Therefore, these data clearly show that psilocin has a greater agonistic affinity for the 5-HT2A than psilocybin. This clarifies that psilocin is primarily responsible for the psychedelic effect of magic mushrooms, not psilocybin.

Other studies confirm the role of the 5-HT2A receptor in the psychedelic experience. For example, in 1998, Vollenweider, et al., found the 5-HT2A receptor antagonist ketanserin blocks the effects of psilocybin and psilocin. More recently, a study used PET (positron emission tomography) scans and monitored the levels of psilocin in the blood plasma of volunteers after they took psilocybin. The researchers found the subjective experiences of the volunteers were directly related to the levels of psilocin in their blood plasma and the number of occupied (with psilocin) 5-HT2A receptors in their brains.

Signal transduction pathways

Signal transduction is a scientific term for the biochemical reactions that occur when a molecule binds to a receptor on a cell. Different molecules have different signal pathways inside cells that use different types of receptors. Scientists who study psychedelics such as psilocybin and psilocin are interested in serotonin receptors. Understanding these receptors is crucial because psilocybin and especially psilocin, use these same serotonin receptors to bring about their effects in users.

When it comes to the exact cell signal transduction pathway(s) used by psilocin to elicit its psychedelic effects, researchers have an understanding of several aspects of 5-HT2A. Several serotonin receptors including 5-HT2A belong to a family called G-protein coupled receptors (GPCRs). GPCRs are one of the largest and most diverse families of proteins in mammals. These receptors have a unique structure consisting of seven protein helices that span the cell membrane. When a compound binds to the 5-HT2A receptor on a cell, it stimulates an enzyme called phospholipase C. This, in turn, activates another enzyme called protein kinase and also stimulates the release of calcium ions from storage areas in the cell. This enzymatic and biochemical activity culminates in cellular changes that result in the overall perceived effect.

This pathway is only a small piece of the big picture showing how psychedelic drugs work. At a higher level, Baumeister et al. reviewed the pharmacodynamics of classical hallucinogens and summarized three mechanisms by which they are known to work, or may work, in the brain:

- Hallucinogens may disrupt normal serotonin pathways in the brain in several ways. One way may be by binding to presynaptic 5-HT1A receptors in the Raphe nuclei that project into the prefrontal cortex and subcortical structures. This disruption would alter the serotonergic output to the rest of the brain.

- When hallucinogens bind with postsynaptic 5-HT2A receptors in cortical neurons, this changes cellular signaling and functioning via the excitatory amino acid glutamine. The effect is what the authors describe as “complex manifestations in consciousness.”

- Normally, neurons in the reticular nucleus of the prefrontal cortex regulate sensory input into the brain. Hallucinogens disrupt this process by binding with reticular postsynaptic 5-HT2A receptors. The binding causes another cascade of events, altering the sensory information received by the cortex. The result is the disruption of the normal activity of the sensory cortices.

The need for more research

It is interesting to note from this receptor binding data that psilocin binds well to several other serotonin receptors besides 5-HT2A. For example, notice the Ki values for psilocin compared to psilocybin for 5-HT1A and 5-HT1B. How is this impacting the subjective effects the user is experiencing? Also, what is the effect of the low Ki values both compounds have for 5-HT2B? It is clear that more research is needed in this area to understand these psychedelics and their receptor interactions. Compounding this whole mystery is psilocybin and psilocin being just two of many potentially active compounds in magic mushrooms.

Conclusion

The pharmacology of psilocybin and psilocin is fascinating and complicated. The chemistry of these compounds dictates how the body metabolizes them and how they interact with receptors. Research has made great strides in understanding how psychedelics work with the 5-HT2A receptor, but endless avenues of exploration still exist for the curious researcher.

 
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Disruptive psychopharmacology

Malenka Heifets | Jun 25 2019

The paucity of medications with novel mechanisms for the treatment of mental illnesses combined with the delayed response to currently available medications has led to great excitement about the potential therapeutic utility of previously demonized drugs, which offer the hope of generating rapid symptom reductions in some of the sickest patients. Within the past 2 years, the US Food and Drug Administration approved esketamine for treatment-resistant depression and 2 compounds that are still on the US Drug Enforcement Administration’s most restrictive schedule, MDMA and psilocybin, have received breakthrough therapy designation. If these latter drugs are approved, they will require a new mental health care infrastructure that is capable of administering powerful psychoactive substances while simultaneously incorporating appropriate psychotherapeutic support. The sheer prevalence of the conditions these drugs are meant to treat (depression and PTSD) will mean that clinicians will have to deal with safety issues, including appropriate patient selection, substance abuse potential, and emergent psychiatric and medical crises. These considerations justify investment in elucidating the detailed neural mechanisms by which these drugs work so that we might better control their safety and efficacy while simultaneously developing better treatments with fewer adverse effects.

Investigating mechanism

Although ketamine, MDMA, and psilocybin are pharmacologically distinct, they share the ability to induce an acutely altered state of consciousness, which in the appropriate therapeutic context can lead to a rapid therapeutic onset and, to varying degrees, a durable treatment effect that persists well after the drug has been cleared from the body. Their effects are reminiscent of those of indigenous medicines such as ayahuasca, peyote, and ibogaine, which have been used for centuries across many cultures. It is tempting to hypothesize that a common underlying physiological process is at play, given the similarity in these drugs’ time courses and the common theme of acute psychological transformation. Conversely, it will be important to determine whether these drugs’ benefits are specific to a given constellation of symptoms. A survey of currently registered clinical trials suggests otherwise, as ketamine, MDMA and psilocybin are each being tested for both affective and appetitive disorders.

How best to pursue the mechanisms of action for this next generation of therapeutics? We have argued for a circuits-first approach, which involves using the armamentarium of modern neuroscience tools to define the circuit adaptations that contribute to a drug’s behavioral and therapeutic effects. Once critical circuit nodes are identified, single-cell gene profiling can be performed in their key cell types based on their connectivity, yielding novel molecular targets for the development of next generation drugs with greater efficacy and fewer side effects. Modeling complex human behaviors in animals is particularly valuable when the structure and function of the involved neuroanatomy is highly conserved. This is likely the case for several neuromodulatory systems that contribute to a host of behaviors of direct relevance to psychiatry such as Pavlovian and instrumental conditioning, prosocial approach, aggression, cognitive flexibility, and responses to motivationally significant stimuli.

Of course, it is also critical to define the molecular targets of these new therapeutic agents. For ketamine, this has been more challenging than originally expected, with findings suggesting a need to conceptualize its molecular mechanisms with more nuance than action at a single, broadly distributed glutamate receptor. The complexity of ketamine’s actions emphasizes the critical importance of determining where in the brain it is exerting its therapeutic circuit effects. In contrast to the confusion surrounding ketamine’s molecular targets, a prediction of preclinical studies of LSD, a drug with significant similarity to psilocybin, has been confirmed with the demonstration that LSD’s subjective effects in humans could be blocked by a 5HT2a receptor antagonist. Moreover, hallucinogen-induced changes in functional connectivity in human imaging studies suggest that reverse translation may be possible. For example, it will be advantageous to define the actions of 5HT2a receptors in the putative drug-modulated circuits in human brains in more experimentally tractable animal brains in which molecular and circuit targets can be manipulated with precision and detailed cellular level observations can be made. Identifying parallel circuitry that is influenced by classic hallucinogens in both humans and animals will be challenging. Nevertheless, the more we can define the relevance of evolutionarily conserved behavioral parameters to the efficacy of the therapeutic intervention, the higher the probability of defining the causal neural mechanisms underlying the drug’s therapeutic effects. In turn, more efficacious therapeutic interventions will follow.

Defining clinical variables

Great attention has been paid to the therapeutic setting itself in designing trials of MDMA and psilocybin because efficacy may well depend on both the drug and the therapeutic environment in which it is administered. In patients with posttraumatic stress disorder, MDMA, which enhances positive social interactions, may catalyze the extinction of aversive memories primarily by strengthening the therapeutic alliance. Similarly, the vivid experiences during a psilocybin session that are revisited in subsequent therapy sessions may be central to its potential therapeutic action in addressing existential issues and sources of depression and anxiety. It follows that we should characterize and test the psychotherapeutic component as well as the necessity for the specific drug being tested. This rigor begins with developing appropriate placebo controls because expectancy bias in trials of this nature are likely to have strong effects. Indeed, despite laudable attempts using active placebos, both patients and therapists have been able to identify the treatment given. Using dissociative drugs, such as dextromethorphan, as comparators for psilocybin or psychostimulants, such as methamphetamine, for MDMA warrants serious consideration. These psychoactive controls will help test whether the specific drug being evaluated is necessary for the consequent therapeutic effect.

We also need to understand the optimal dose and timing of therapy. What is the importance of preparatory and integrative therapeutic sessions relative to the drug session? Analyses of psilocybin trial data suggest that the mystical aspect of the acute drug experience scales with therapeutic benefit. But are all patients capable of generating this kind of subjective state? We assume that the events during an acute drug experience are required for a treatment effect to occur. But perhaps, the conscious experience of a drug trip is an epiphenomenon relative to the therapeutic state the drug produces, an effect that would still occur, for example, if the drug of interest was administered during general anesthesia. These hypotheses are testable. Furthermore, using standardized measures of therapeutic alliance and operant tasks to assess cognitive flexibility and reward sensitivity could help establish what parameters are necessary and sufficient to achieve a treatment effect, thereby imbuing preclinical mechanistic studies with predictive utility.

Decades ago, the serendipitous discovery of iproniazid’s antidepressant effect and chlorpromazine’s antipsychotic efficacy led to the development of drugs that helped millions of patients. Preclinical behavioral screening models have had some success in predicting efficacy of drugs with pharmacology similar to already approved therapies, but have generally failed to yield new therapeutic principles or pathways. It is telling that the current wave of therapeutic innovation is based not on insights gained from studying established drugs, but rather on a disruptive new therapeutic approach involving compounds that have been known for quite some time in other contexts. By applying all the tools in our modern armamentarium to understand the mechanisms by which they work, it will be possible to develop better therapies, which will make up the next generation of disruptive psychopharmacology.

 
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Rethinking serotonin could lead to a shift in psychiatric care

Imperial College London | Sep 4, 2017

A better understanding of how a key chemical messenger acts in the brain could lead to a radical shift in psychiatric care, according to a new research paper.

Serotonin is a neurotransmitter which helps brain cells communicate with one another, playing important roles in stabilising mood and regulating stress.

Despite its importance, current models to explain serotonin's function in the brain remain incomplete.

Now, in a review paper published this month in the Journal of Psychopharmacology, researchers from Imperial College London suggest that serotonin pathways are more nuanced than previously thought.

They argue that the existing view should be updated to incorporate a 'two-pronged' model of how serotonin acts.

The researchers believe their updated model could have implications for treating recalcitrant mental health conditions, including depression, obsessive compulsive disorder and addiction, and could exploit the therapeutic potential of psychedelic drugs.

In the brain, serotonin acts via a number of sites called 'receptors' and serotonin has at least 14 of these. Brain drugs such antidepressants, antipsychotics and psychedelics are known to interact with serotonin receptors and two of these are thought to be particularly important -- the so-called serotonin 1A and 2A receptors.

For patients with depression, commonly prescribed drugs called SSRIs (Selective Serotonin Reuptake Inhibitors) can help to relieve symptoms by boosting levels of serotonin in the brain. Evidence suggests an important part of how they work is to increase activity at the serotonin 1A receptor, which reduces brain activity in important stress circuitry, thereby helping a person cope better.

In contrast, psychedelic compounds such as LSD and psilocybin (the psychoactive component of magic mushrooms), are thought to act primarily on the serotonin 2A receptor. Accumulating evidence suggests that psychedelics with psychotherapy can be an effective treatment for certain mental illnesses and, with a focus on the 2A receptor, the authors' paper attempts to explain why.

Writing in the review paper, the researchers say that while the traditional view of developing psychiatric treatments has been focused on promoting 1A activity and often blocking the 2A, the therapeutic importance of activating the 2A pathway -- the mechanism by which psychedelics have their effect -- has been largely overlooked.

"We may have got it wrong in the past," said Dr Robin Carhart-Harris, Head of Psychedelic Research at Imperial and lead author on the paper. "Activating serotonin 2A receptors may be a good thing, as it makes individuals very sensitive to context and to their environment. Crucially, if that is made therapeutic, then the combination can be very effective. This is how psychedelics work -- they make people sensitive to context and 'open' to change via activating the 2A receptor."

According to the researchers, the 1A and 2A pathways form part of a two-pronged approach which may have evolved to help us adapt to adversity. By triggering the 1A pathway, serotonin can make situations less stressful, helping us to become more resilient. However, they argue that this approach may not always be enough, and that in extreme crises, the 2A pathway may kick in to rapidly open a window of plasticity in which fundamental changes in outlook and behaviour can occur.

Growing evidence shows that in conditions such as treatment-resistant depression, obsessive compulsive disorder and addiction, certain brain circuitry may become 'stamped in' and resistant to change. The researchers suggest that in such cases, activating the 2A pathway -- such as through psychedelics -- could potentially offer a way to break the cycle, helping patients to change negative behaviours and thought patterns which have become entrenched.

By enabling the brain to enter into a more adaptive or 'plastic' state and providing patients with a suitably enriched clinical environment when they receive a drug treatment, clinicians could create a window for therapy, effectively making patients more receptive to psychotherapy.

According to the authors, their updated model of how serotonin acts in the brain could lead to a shift in psychiatric care, with the potential to move patients from enduring a condition using current pharmacological treatments, to actively addressing their condition by fundamentally modifying behaviours and thinking.

Professor David Nutt, Director of Neuropsychopharmacology in Imperial's Division of Brain Sciences, explained: "This is an exciting and novel insight into the role of serotonin and its receptors in recovery from depression that I hope may inspire more research into develop 5-HT2A receptor drugs as new treatments."

Dr Carhart-Harris added: "I think our model suggests that you cannot just administer a drug in isolation, at least certainly not psychedelics, and the same may also true for SSRIs. We need to pay more attention to the context in which medications are given. We have to acknowledge the evidence which shows that environment is a critical component of how our biology is expressed."

He added: "In psychiatry, as in science, things are rarely black and white, and part of the approach we're promoting is to have a more sophisticated model of mental healthcare that isn't just a drug or psychotherapy, it's both. I believe this is the future."

'Serotonin and brain function: a tale of two receptors'
by Robin Carhart-Harris and David Nutt is published in the Journal of Psychopharmacology.

https://www.sciencedaily.com/releases/2017/09/170904093724.htm
 
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Roland Griffiths and Matthew Johnson

Tapping into psilocybin’s potential

From the 1940s to the early 1970s, psychedelic drug research had a heyday, where tens of thousands of people participated in trials exploring multiple basic research questions and therapeutic indications. Then, because of the drugs’ association with counterculture and street use, the work fell out of favor.

“It’s really unprecedented in pharmacology, and probably throughout science, that you would have an entire research agenda that looked this promising be put on hold for decades,” says psychiatry researcher Matthew Johnson. Slowly, over time, such studies began again. Johnson and colleague Roland Griffiths have been evaluating drugs, including psilocybin—a psychedelic substance obtained from certain mushrooms—for more than 13 years.

“There are an incredible number of questions that need to be explored,” says Johnson. “These substances tinker with the serotonin system and interact with it in a unique way. What we’re understanding now is that regardless of receptor-level pharmacology, the really interesting changes that occur with these compounds are in brain network dynamics—the way different areas of the brain communicate with each other.”

Work published last December in the Journal of Psychopharmacology demonstrated that a high dose of psilocybin could produce large, sustained decreases in depression and anxiety among cancer patients with life-threatening diagnoses and clinically significant depression and/or anxiety. Another small study published in the January issue of The American Journal of Drug and Alcohol Abuse found that psilocybin, when administered with cognitive behavioral therapy (CBT) for smoking cessation, resulted in substantially higher six-month smoking abstinence rates than are typically achieved through other medications or CBT alone. About 87 percent of participants rated their psilocybin experiences among the five most personally meaningful and spiritually significant experiences of their lives.

"When administered in carefully controlled settings," says Johnson, "psilocybin’s effects are often akin to “mystical experiences” that people who are deeply religious or practice meditation report—timelessness, a sense of self dissolved to a larger whole and an overall feeling of positivity. What’s more," he adds, “there may be changes in brain network patterns that persist beyond the acute effect, almost like the acute effects may be inducing plasticity and flexibility.”

Additional studies being planned at Johns Hopkins will explore psilocybin’s effects on depression unrelated to cancer and how meditative states compare with psychedelic ones. Meanwhile, researchers at fellow institutions have found that psilocybin may effect change in areas as varied as inflammatory disease, addiction and obsessive-compulsive disorder.

These studies could offer insight into underlying likenesses among these maladies, Johnson says. While depression and addiction currently are considered different disorders, “there might be more in common than we normally realize,” he says. “I think psychedelics are going to be a powerful tool to address those questions.”

 
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Researchers synthesize 6-methylated congeners of psilocybin

by Barb Bauer | PSR | Jul 02 2019

These new compounds will give scientists a better understanding of how serotonin-based psychedelics work.

In a May 2019 study, a team comprised of researchers from the United States, Germany, and Austria published their in vitro biosynthesis of 6-methylated psilocybin congeners in the journal ChemBioChem.1 Specifically, they used naturally-occurring enzymes to synthesize the compounds shown below, 6-methylpsilocbyin, 6-methylbaeocystin, and 6-methylnorbaeocystin. This study is important because these compounds provide a new way to make psilocybin and they can be used in other studies for a better understanding of how serotonergic psychedelics work.

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The route of biosynthesis of the 6-methylated congeners uses some of the same enzymes that Psilocybe mushrooms use to convert tryptophan to psilocybin such as PsiD, PsiK, and PsiM. The synthesis route starts from a compound called 4-hydroxy-6-methyl-L-tryptophan which, as the name says, is already methylated at the 6th carbon. This compound is decarboxylated and phosphorylated using the enzymes PsiD and PsiK from Psilocybe cubensis. Then, the PsiM enzyme is used for methylating the amine group.

The authors cite several studies showing that the methylation of indole compounds at carbon atom 6 “…does not cause consistent pharmacological effects.” This lack of activity is important because these compounds should not interfere with other biochemical pathways if they are going to be part of an effective and useful synthesis route.

Next, the authors of this study plan to work on scaling up the in vitro synthesis of these 6-methylated congeners of psilocybin so they can conduct in vitro assays. One of their main goals is “to discover agonistic or antagonistic effects on 5-HT receptors and, ultimately, for more profound insight into the pharmacology of serotonergic psychedelics.”

 
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The state of the art of Psilacetin (4-AcO-DMT)

by Barb Bauer | PSR | Sep 18 2019

German chemists Albert Hofmann and Franz Troxler performed the first synthesis of psilacetin while working at Sandoz Laboratories in Switzerland. They patented their discovery in 1963 along with other indole esters they had synthesized. Just as Hofmann put LSD aside for five years after synthesizing it in 1938, unaware of its psychedelic properties, psilacetin was patented but shelved. According to the United Nations Office on Drugs and Crime, synthetic tryptamines like psilacetin began appearing in illicit drug markets throughout the 1990s.

The chemistry of Psilacetin

Psilacetin is a structural analog of the magic mushroom compound psilocybin. It is known by other names including 4-AcO-DMT, O-Acetylpsilocin, 4-Acetoxy-DMT, and 4-Acetoxy-N,N-dimethyltryptamine. Psilocybin is a prodrug of psilocin, and psilocin is an analog of the neurotransmitter of serotonin. Chemically, psilacetin is O-acetylated psilocin, whereas psilocybin is O-phosphorylated.

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The pharmacology of Psilacetin

The way psilacetin is metabolized in the human body is unknown. However, based on the chemistry and metabolism of similar tryptamine compounds,3 it is reasonable to assume that psilacetin undergoes deacetylation to form psilocin. From that point, psilocin would follow the accepted theory of binding to the serotonin 5-HT2A receptor, causing a psychedelic effect.

There are no published scientific studies specifically addressing whether psilacetin is metabolically active on its own. The possibility exists that when ingested, psilacetin may bind to serotonin receptors, including 5-HT2A, and elicit a psychedelic effect, perhaps one that is unique from psilocin. According to anecdotal reports, the psychoactivity of psilacetin is immediate when in injected, bypassing the first-pass metabolism in the stomach and liver.

A 2017 substance abuse study using rodents suggests a single administration of 4-AcO-DMT prevents and reverses heroin and nicotine addictions. The authors of the study theorize the mechanism involves preventing the up-regulation of brain-derived neurotrophic factor via serotonin 5-HT2A receptor signaling.

The renowned psychedelic researcher Dr. David Nichols has suggested that psilacetin, like psilocybin, is a prodrug of psilocin. In their 1999 work, Dr. Nichols and Dr. Stewart Frescas synthesized the fumarate salt of psilacetin. In the paper, they also explain the economic advantages of psilacetin:

"The O-acetyl prodrug of psilocin is much more easily prepared than psilocybin, and may offer an economical alternative for clinicians wishing to study the psychopharmacology of psilocin."

"Psilacetin is readily crystallized as the fumarate salt, and is considerably more stable than psilocin itself. It would seem to be an ideal prodrug to replace psilocybin in future clinical studies, since psilocin is the principal metabolite of psilocybin."


Because no scientific studies have been conducted, the only information on the effects of psilacetin are the anecdotal reports captured in online discussion boards and experience reports. Some psilacetin users find its effects similar to psilocybin mushrooms whereas others have distinctly different experiences. Therefore, framing discussions about the effects of psilacetin are frequently in comparison to magic mushrooms. Comparing reports for those who noticed a difference between psilacetin and magic mushrooms could provide insight into the unique clinical attributes of psilacetin. Based on these comparisons, psilacetin appears to give a more colorful experience and imparts more feelings of warmth, relaxation, and euphoria than psilocybin mushrooms. Also, anecdotal reports suggest that the psilacetin experience has a faster onset and shorter duration than magic mushrooms.

The clinical differences between magic mushrooms and psilacetin can be ascribed to (1) the chemical differences between psilacetin and psilocybin and (2) the fact that magic mushrooms include multiple active ingredients, which synergistically produce the user’s experience. In the world of cannabis research, this phenomenon is called the entourage effect. Because of the lack of scientific data about psilacetin, its mechanism of action remains a mystery. Conceivably, psilacetin’s clinical properties arise from binding to serotonin receptor active sites, binding elsewhere on receptors and causing allosteric modulation, or both.

Recent scientific studies on psilacetin

Following 20 years of inactivity, the chemical community recently published new data about psilacetin. Building on the work Nichols and Frescas did in 1999 scientists solved the crystal structure of 4-AcO-DMT fumarate in March 2019. Chadeayne, et al. demonstrated that the solid-state structure is an asymmetric unit containing one 4-acetoxy-N,N-dimethyltryptammonium cation, and one 3-carboxyacrylate anion. Despite its use as a research chemical in the illicit drug market, this work was the first conclusive structural characterization of the molecule.

In a follow-up to this study, the same research team defined the crystal structure of a new solvate form of 4-AcO-DMT fumarate, bis fumarate. The crystal structure consists of two protonated psilacetin molecules that are charge-balanced by one fumarate dianion. This new solvate form of psilacetin is an important discovery because it opens the door to more options for drug development.

Psilacetin as a prodrug of psilocin

Psilocybin is a prodrug of psilocin which means the body metabolizes psilocybin into the active form, psilocin. According to the distinguished psychedelic scientist Dr. David Nichols, psilacetin is also a prodrug of psilocin.

The world-famous chemists Albert Hofmann and Alexander and Ann Shulgin have said that psilocin on its own is an unstable compound compared to psilocybin.4,5 This is because psilocin is more susceptible to oxidation due to the lack of the phosphate group that is present in psilocybin. The degradation of psilocin by oxidation is thought to produce the blue color often seen on psilocybin mushrooms that have been handled or damaged in some way.6

Another reason psilocybin lends itself more easily to manufacturing is that it is readily soluble in water whereas psilocin is not.4 Because of this and the instability of psilocin, manufacturing drugs containing the pure psilocin is not practical and likely not even feasible. Administering a prodrug of psilocin is the logical route to follow for creating effective drug therapies. However, as mentioned earlier, of the two choices, psilacetin is less expensive and easier to synthesize.
Understanding the Entourage Effect

Amid these exciting scientific discoveries is a phenomenon that is integrally tied to the overall effects of psychedelic drugs. Understanding it is critical for producing psychedelic drugs that are as efficient as possible and provide the best possible results for patients. This phenomenon is known as the entourage effect, and it first gained attention in the world of medical cannabis.

Using the compounds in magic mushrooms as an example, ingesting pure psilocybin by itself is very different from the cocktail of chemicals a person receives after eating magic mushrooms. All the psychoactive compounds in magic mushrooms (like baeocystin, norbaeocystin, norpsilocin, and aeruginascin) work together to produce the overall psychedelic experience for the user. On top of that, the types and amount of psychoactive chemicals in magic mushrooms vary from species to species, batch to batch, and even in different parts of the mushroom.

The entourage effect is also seen in the difference between the effects of ingesting psilacetin alone versus magic mushrooms. In general, psilacetin appears to give a more colorful experience and imparts more feelings of warmth, relaxation, and euphoria than psilocybin mushrooms. On the other hand, magic mushrooms elicit more emotions and more visuals than psilacetin. The Urban Dictionary sums up the different effects this way:

The effects are VERY similar to a mushroom trip, except it lasts a little longer than mushrooms (around 7 hours). Its effects, however, differ somewhat from mushrooms. It seems to have a much more relaxing quality to it, which makes it harder to have a bad trip. Several available reports of 4-ACO-DMT compare it favorably to psilocybin, describing it as more euphoric, gentle, warm, and colorful. It has also been described as less jarring/scary, and less likely to produce nausea.

The importance of crystal structures

It is important to remember that small changes at the molecular level can translate into significant changes in effect when it comes to drugs. Therefore, working with compounds at the molecular level is essential for unraveling the mysteries of how drugs work and how other compounds affect them. The new crystalline forms of psilacetin elucidated by these researchers could be used to modulate the effects of each compound in a drug formulation (the entourage effect just discussed). In addition, determining the crystal structures of compounds is essential to understanding their physical properties and for probing their activity at receptors (e.g., via modeling studies).

The future of psilacetin in psychedelic drug research

After 20 years without any studies, the scientific community appears to have renewed its interest in psilacetin. As an easier to synthesize and less expensive alternative prodrug to psilocin, psilacetin could change the landscape of psychedelic drug therapy. This work is also important because of the increasing numbers of recreational drug users who are consuming the chemical despite virtually no information about its chemical or biological properties.

Any therapeutic uses of psilacetin are only speculative at this time, based solely on experience reports. There are many uncontrolled variables woven into these reports, including set, setting, dosage, and purity of the compounds. Further study of the pharmacology of pure psilacetin will lead to a better understanding of how formulating specific combinations of molecules can lead to more effective targeted therapies.

 
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The Mechanisms of Psychedelic Visionary Experiences*

Michael Winkelman | Frontiers in Neuroscience, 2017

Neuropharmacological effects of psychedelics have profound cognitive, emotional, and social effects that inspired the development of cultures and religions worldwide. Findings that psychedelics objectively and reliably produce mystical experiences press the question of the neuropharmacological mechanisms by which these highly significant experiences are produced by exogenous neurotransmitter analogs. Humans have a long evolutionary relationship with psychedelics, a consequence of psychedelics' selective effects for human cognitive abilities, exemplified in the information rich visionary experiences. Objective evidence that psychedelics produce classic mystical experiences, coupled with the finding that hallucinatory experiences can be induced by many non-drug mechanisms, illustrates the need for a common model of visionary effects. Several models implicate disturbances of normal regulatory processes in the brain as the underlying mechanisms responsible for the similarities of visionary experiences produced by psychedelic and other methods for altering consciousness. Similarities in psychedelic-induced visionary experiences and those produced by practices such as meditation and hypnosis and pathological conditions such as epilepsy indicate the need for a general model explaining visionary experiences. Common mechanisms underlying diverse alterations of consciousness involve the disruption of normal functions of the prefrontal cortex and default mode network (DMN). This interruption of ordinary control mechanisms allows for the release of thalamic and other lower brain discharges that stimulate a visual information representation system and release the effects of innate cognitive functions and operators. Converging forms of evidence support the hypothesis that the source of psychedelic experiences involves the emergence of these innate cognitive processes of lower brain systems, with visionary experiences resulting from the activation of innate processes based in the mirror neuron system (MNS).

INTRODUCTION

Institutionalized use of psychedelics in religions of pre-modern societies worldwide reveal the central roles of these substances in the evolution of spiritual experiences, cultures, and religions. The role of psychedelics in human evolution is indicated by evidence that psychedelics bind to human serotonergic receptors with a higher affinity than they do to those receptor systemsin other primates. The reasons for the roles of psychedelics in cultural evolution are revealed by neuropharmacological research on psychedelic effects on brain processes. The interaction of psychedelics with the innate structures of the human brain produces novel forms of information and integrative cognitive processes. This suggests that psychedelic substances operated as environmentalfactors selecting for an enhanced capacity for specific forms of information processing.The neuropharmacological dynamics of psychedelics are central to understanding the nature of spiritual experiences. Psychedelics are associated with pre-modern religious forms and the early history of the current major world religions. Furthermore, there is evidence established by double blind clinical studies that spiritual experiences are directly caused by neuropharmacological effects of psychedelic substances. Why do the pharmacological effects of psychedelics so consistently produce such powerful visionary experiences? While neuropharmacology is conceptualized as the study of the effects of drugs on behavior, the ultimate goal must also offer some explanation of how drugs have effects on people’s experiences.

Why do psychedelics produce the kinds of experiences that lead to the foundation of cultures and religions? How do the pharmacological effects so reliably and quickly produce the kinds of experiences that mystical devotees spend a lifetime pursuing for just a glimpse of these alleged eternal truths? Some might consider the answers to these questions to be beyond the purview of neuropharmacology, perhaps best left to philosophers. But a mature neuropharmacology ought to be able to offer a cogent explanation of how it is that the neurochemistry of an exogenous compound produces activity and functional modifications in the brain that lead people across time and place to report experiences of a profoundly spiritual nature, often with great significance to the individual and even society. A neuropharmacological explanation of psychedelic effectson human experience can be found in the approach of neurophenomenology, “a research programme aimed at bridgingthe explanatory gap between first-person subjective experience and neurophysiological third-person data, through an embodied and enactive approach to the biology of consciousness...Neurophenomenology is then viewed as a novel scientific method building on a corpus of intersubjectively-invariant first-person reports that may broaden the horizon of objective science.” We need to know what is being experienced in order to identify what it is we are ultimately trying to explain. Neurophenomenology is an approach to the understanding of the structure and content of phenomenal experience in terms of principles operating at the neurological level.

Or in other terms, the first person perspectives of personal experience are explained by reference to some homologous causal features identified by third person perspectives on brain operation. If what people experience ought to be explained in terms of pharmacological actions, then psychedelics are an excellent example of this challenge presented to neuropharmacology. The experiences to be explained are not just some debatable philosophical construct but an objective domain of experience revealed by empirical evidence. A variety of research projects provide converging findings that confirm the empirical natureof the domains of altered states of consciousness. These domains of human experience are assessed through psychometric instruments such as: the Altered State of Consciousness Questionnaire, later modified as the APZ-OAV; the Phenomenology of Consciousness Inventory; the Hallucinogen Rating Scale; the Mysticism scale; the Mystical Experiences Questionnaire; and the Five Dimensions of Altered States of Consciousness. These studies provide empirical evidence of common core dimensions to experiences of pharmacologically and non-pharmacologically induced alterations of consciousness.

If the ultimate goal neuropharmacology includes an explanation of the nature of first-person psychedelic experiences in terms of pharmacological, neurological and functionalbrain mechanisms, what is this experience to be explained? What is the nature of psychedelic experiences? There are number forms of psychedelic experience, exemplified in differences in mystical and shamanic psychedelic experiences described below. The empirical data regarding these experiences are startling and perhaps even confusing for the following reasons: 1) Psychedelics reliably elicit experiences that are virtually indistinguishable from mystical experiences induced through prolonged austerities and disciplined contemplative practice, and 2) In contrast to the mystical features of psychedelic-induced experiences, psychedelic use in pre-modern shamanic cultures produced a distinctive worldview characterized by animism, an experience of transforming into an animal, and the perspective of entheogens, viewing these substances as generating experiences of spiritual entities within the person and environment. The differences in psychedelic-induced mystical and shamanic experiences illustrate that while these substances reliably produce certain kinds of experience, the forms of experience may vary considerably—one agent, variable experiences. Secondly, the similarity of psychedelic and non-psychedelic mystical experiences suggests that the explanation of psychedelic experiences is not through mechanisms unique to psychedelics, but rather through shared mechanisms affected by non-drug procedures.

CONCLUSIONS

Similarities in visionary experiences across diverse modes of altering consciousness attest to a common mechanism released by the interruption of the PFC and DMN. The disruption of the top-down control of the brain normally mediated by the functions of the PFC, together with the compromised self-referencing processes of the DMN, leads to the emergence of processes that are normally repressed/regulated lower level brain systems These ancient brain systems are manifested as innate intelligences, modules and operators. Various findings support the hypothesis that one of these innate capacities, the mirror neurons and their operation in the mimetic capacity, is at the basis of psychedelic and other visionary experiences. This novel hypothesis regarding the MSN as a mechanisms of psychedelic visionary experiences is supported by evidence that psychedelics elicit innate brain functions (entoptics), and the roles of the MNS in the integration of visual experience and behavior and in providing a common basis for self and other perceptions.This ancient visual modality of information presentation and knowing elicited by psychedelics has seldom been studied scientifically because of its inaccessibility to intersubjective examination. Unfortunately, no mechanism allows us to share visual experiences to the same extent that words allow us to share our thoughts. The neuropharmacological dynamics of psychedelics powerfully and reliably elicit this mode of symbolic operation, making this modality of consciousness directly and intensely accessible. The repeatable effects of psychedelics in producing such visions and mystical experiences make the man unparalleled tool for the examination of the operation of this cognitive-affective system that is an innate aspect of the human brain-mind. Psychedelics consequently can serve as tools to provoke and expose this system, facilitating the examination of an area of human knowledge that has remained marginalized because of its notoriously subjective qualities. Through the use of psychedelics we can come to better understand the nature of some of the ancient symbolic and conceptual capacities of the human brain and the kind of experiences that generate the human quest for transcendent knowledge and spirituality.

*From the study here :
 
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Scientists discover new compounds in magic mushrooms

by Barb Bauer | PSR | Nov 26 2019

Researchers isolate ß-carbolines from several species of Psilocybe.

There are many mysteries surrounding psychedelic mushrooms (aka psilocybin mushrooms or magic mushrooms). One of the most critical questions is very basic; what compounds do these mushrooms contain? Historically, psilocybin (the most abundant compound) has received much of the attention. Psilocybin is a prodrug that the body metabolizes to psilocin, the compound that acts at the serotonin 5-HT2A receptor to produce the psychedelic effect.

Over the years, researchers have identified other compounds in magic mushrooms such as psilocin, baeocystin, norbaeocystin, and aeruginascin. Now, with the renewed interest in the possible therapeutic uses of psychedelics, scientists are revisiting magic mushrooms at a fundamental level—figuring out what compounds are in them.

Study finds ß-Carboline compounds in magic mushrooms

German scientists have identified new compounds in four species of magic mushrooms and studied their roles in biosynthetic pathways the mushrooms use. The researchers isolated the known magic mushroom compounds psilocybin, psilocin, baeocystin, norbaeocystin, and norpsilocin. The new compounds they isolated belong to a family of chemicals known as ß-carbolines.

ß-carbolines are naturally occurring alkaloid compounds. They are most commonly known as components of the psychotropic beverage ayahuasca. Examples of ß-carbolines include harmine, harmane, and harmaline (ß-carboline is also another name for the compound norharmane).

Much of the effect of ayahuasca is due to the ability of ß-carbolines to inhibit MAO (monoamine oxidase) enzymes. This inhibition makes it possible for the psychedelic compound DMT (dimethyltryptamine, another compound in ayahuasca) to pass out of the digestive system and enter the circulation.

ß-carbolines has some psychotropic effects on their own. Still, without their ability to inhibit MAO enzymes, the full effects of ayahuasca are not realized. ß-carbolines also inhibit the uptake of serotonin, dopamine, epinephrine, and norepinephrine via competitive inhibition of the receptors (Keep in mind that the interactions between an enzyme and a molecule are different from how an allosteric modulator interacts with a molecule).

From a disease standpoint, ß-carbolines are known to play a role in the development of essential tremor (uncontrolled shaking) and have been implicated in Parkinson’s disease.

Magic mushroom synthesize several ß-Carbolines

Using 1D and 2D NMR (nuclear magnetic resonance) spectroscopy, Blei et al. analyzed extracts from Psilocybe cubensis, P. mexicana, P. cyanescens, and P. semilanceata. They identified these ß-carbolines in the extracts: Cordysinin C, Cordysinin D, Harmane, Harmol, Norharmane, and Perlolyrine. These compounds have previously been isolated from fungi and plants in genera such as Cordyceps, Peganum, and Banisteriopsis.

As part of this study, the researchers used stable-isotope labeling with 13C11-L-tryptophan to show the ß-carbolines were biosynthetic products of the Psilocybe species. This means that ß-carbolines in magic mushrooms may contribute to the entourage effect along with the known compounds. As the researchers put it...

"We conclude that Psilocybe mushrooms produce an ayahuasca-like and potentially similarly synergistic set of metabolites that may impact upon onset and duration of their effects."

Also, using MALDI-MS (matrix-assisted laser desorption/ionization mass spectroscopy), the researchers showed that the ß-carbolines accumulated at the hyphal apices (the outer edges of the mycelium).

The effects of magic mushrooms vs. individual molecules

The Blei et al. paper is a pioneering step in studying the chemistry and variability of the compounds in magic mushrooms. This work highlights the chemical complexity of naturally occurring compounds. It helps with the understanding that ingesting magic mushrooms is very different from taking pure psilocybin (or any other single compound isolated from magic mushrooms). The pharmacology of mushrooms is different than individual compounds and understanding this is critical for optimizing the effects of formulations of magic mushroom compounds.

As is often the case with scientific discovery, these study results answer some questions but also pose more. The presence and known effects of ß-carboline compounds in the Psilocybe species they studied, displays the entourage effect in magic mushrooms in a new light. The study authors sum this up well by saying,

Future pharmacological research is therefore warranted to determine to what extent Psilocybe β-carbolines contribute to the actual psychotropic effects of magic mushrooms.

 
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Study finds ALD-52, 1P-LSD, and 1B-LSD are prodrugs of LSD

by Barb Bauer | PSR | Jan 10 2020

Identifying and understanding prodrugs is an essential component of psychedelic drug research.

In a November 2019 study published in Neuropharmacology, researchers tested whether the LSD (lysergic acid diethylamide) derivatives ALD-52 (1-acetyl-LSD), 1P-LSD (1-propanoyl-LSD), and 1B-LSD (1-butanoyl-LSD) are active compounds or prodrugs of LSD.1 The scope of the study included learning about the pharmacological effects and mechanism of action of these 1-acyl-substituted LSD derivatives.

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The study used a three-pronged approach for testing the LSD derivatives: competitive binding studies and calcium mobilization to examine the interaction with serotonin receptors, head twitch response (HTR) studies in mice to assess in vivo activation of serotonin 5-HT2A receptor, and LC/MS (liquid chromatography/ion trap mass spectrometry) to quantify the amount of LSD in the blood of rats treated with two of the three derivatives.

Serotonin receptor interaction and activation

The binding affinity data indicated that the 1-acyl substitution on the LSD derivatives reduced their affinity for 5-HT1A compared to LSD (9.5 nM). The magnitude of the effect depended on the length of the acyl group (note that the higher the Ki, the less affinity the compound has for the receptor):

- 1B-LSD: Ki = 345 nM = 36-fold lower affinity than LSD
- 1P-LSD: Ki = 637 nM = 67-fold lower affinity than LSD
- ALD-52: Ki = 1,054 nM = 111-fold lower affinity than LSD

For 5-HT2A, an acetyl or propanoyl group on LSD’s indole nitrogen reduced receptor affinity by more than 10-fold compared to LSD (14.7 nM). Substitution with a butanoyl group reduced affinity around 5-fold:

- ALD-52: Ki = 174 nM
- 1P-LSD: Ki = 196 nM
- 1B-LSD: Ki = 87.7 nM

Interestingly, the 1-acetyl substitutions increased the affinity of the derivatives at 5-HT2C by about 2-4-fold compared to LSD (45.3 nM):

- ALD-52: Ki = 10.2 nM
- 1P-LSD: Ki = 13.0 nM
- 1B-LSD: Ki = 20.8 nM

After determining the receptor binding affinity for the three LSD derivatives, tests using Gq-mediated Ca2+ flux in HEK cells (calcium mobilization) examined whether the derivatives activated the serotonin receptors.

The data showed that ALD-52, 1P-LSD, and 1B-LSD were very weak partial agonists at the human 5-HT2A compared to LSD. Interestingly, despite showing comparatively high affinity for 5-HT2B and 5-HT2C, the compounds showed no agonist activity at those receptors. This behavior is in contrast to LSD, which is an agonist at recombinant human 5-HT2B and 5-HT2C receptors.

The study also assessed the binding affinity of 1B-LSD for 24 other monoamine receptors. Overall, the data indicated that 1-butanoyl substitution had a detrimental effect on binding to most of the receptors, compared to previously reported data for LSD. The binding affinity at these receptors was 10-100-fold lower than for LSD. The two main exceptions were 1B-LSD binding at the 5-HT2C receptor, as discussed earlier and 5-HT2B.

HTR testing

Although the data indicated the 1-acyl substitution on the derivatives reduced their affinity and efficacy at 5-HT2A, ALD-52, 1P-LSD, and 1B-LSD still induced head twitches in mice and showed a relatively high potency compared to other hallucinogens. The authors noted that “…the rank order of potency of the four lysergamides is inversely proportional to the length of the substituent present on the indole nitrogen.” ALD-52 had about half the potency of LSD and 1P-LSD about one-third. The potency of 1B-LSD was only 14% of LSD.

LC/MS analysis

The authors reported that the LC/MS analysis indicated, “High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo.” The authors noted that ALD-52 and 1P-LSD appeared to undergo deacetylation at roughly the same rate. This theory was evidenced by the rats have almost identical plasma levels of LSD after being treated with either compound.

In addition to LSD, the analysis also detected ALD-52 and 1P-LSD in the plasma along with several of their metabolites. The data correlated with previously published results for rats and humans.

Identifying and understanding prodrugs

Prodrugs expand drug formulation options by having different solubilities and other physical properties. A prodrug can take the place of a drug that doesn’t have adequate pharmacokinetic or biopharmaceutical activity in the body. They can also provide solutions for compounds that are toxic or have undesirable side effects. Prodrugs may also present an array of options when it comes to harnessing the entourage effect for developing targeted formulations.

The principal finding of this study is that ALD-52, 1P-LSD, and 1B-LSD are prodrugs of LSD. Additional aspects of this work indicate that 1-acyl substituted LSD derivatives are potent hallucinogens despite having less efficacy at the 5-HT2A receptor. Scientists will apply these findings and design new experiments that will answer (and, as is the nature of science, create) additional questions about how psychedelic drugs work.

 
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Structure and function of the Serotonin 5-HT2A Receptor

by Barb Bauer | PSR | 6 Feb 2020

The 5-HT2A receptor is central to the effects of many psychedelics, but it may not be the only receptor involved.

The serotonin 5-HT2A receptor is the one most often associated with the psychedelic experience. The first definitive study indicating its vital role in the effects of psychedelics, specifically psilocybin, was published by Vollenweider et al. in 1988. The 5-HT2A receptor was first cloned in 1990.

The structure of the 5-HT2A receptor

The 5-HT2A receptor has a characteristic form consisting of seven membrane-spanning alpha-helices. The helices are separated by alternating sections of the receptor that form intracellular and extracellular loops.

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A representation of the 5-HT2A receptor with its seven helices -
a characteristic of G protein-coupled receptors (GPCRs).


How do 5-HT2A receptors work?

The 5-HT2A receptor belongs to a family known as GPCRs or G protein-coupled receptors. GPCRs are membrane proteins that are responsible for mediating most of the cellular responses to hormones and neurotransmitters. They are also involved in vision, smell, and taste.

A classification system created by Nichols and Nichols groups serotonin receptors based on their primary signaling mechanism. According to the system, 5-HT2A falls into the group known as Gq coupled receptors. Gq proteins are signaling proteins that couple to the 5-HT2A receptor.

When the 5-HT2A receptor is activated (for example, when serotonin binds to it), the Gq protein activates the cell’s signaling pathways. The activation of Gq causes the hydrolysis of molecules called phosphoinositides, located in the cell membrane. This results in the formation of diacylglycerol, which among other functions, activates the enzyme protein kinase C. This enzyme has a variety of functions in neurons, smooth muscle, and other cell types.

The hydrolysis of phosphoinositides also leads to the formation of inositol phosphates, which increases the amount of calcium within cells. This release of calcium causes a cascade of changes in the cell as part of the signaling pathway. What happens next depends on many factors involved in the physiological function.

The distribution of 5-HT2A receptors

mRNA (messenger ribonucleic acid) coding for the 5-HT2A receptor is expressed throughout the body and the CNS (central nervous system). Not surprisingly, not only do the number of 5-HT2A receptors vary in different tissues, but they also vary between species. For example, regarding the variability between species, testing using [125I]DOI labeling clearly shows 5-HT2A receptors in the corpus striatum in humans, mice, and guinea pigs. However, not in rats, cows, pigs, or monkeys. Like humans, the 5-HT2A receptor in the mouse brain is found primarily the cerebral cortex and the olfactory tubercle.

At a cellular level, 5-HT2A is present in abundance on the apical dendrites of pyramidal cells in the cortex of rodents and primates. This area of the brain is believed to modulate cognitive processes, attention, and working memory.

The effects of 5-HT2A receptor activation

Activation of the 5-HT2A receptor (and its associated signaling protein) results in a variety of responses depending on the tissue and physiological function. Examples include neuronal excitation, vasoconstriction/vasodilation, platelet aggregation, smooth muscle contraction in the bronchi and gastrointestinal tract, memory, and learning.

Also, the UniProt (Universal Protein Resource) database captures the dozens of biological processes that are attributable to the 5-HT2A receptor.

A phenomenon known as tachyphylaxis refers to the development of tolerance to a drug when it is administered repeatedly. The mechanism of tachyphylaxis is not fully understood. For psychedelics, the best theory at this time is that it results from downregulation (reducing or suppressing) of the 5-HT2A receptor. Interestingly, the downregulation of the 5-HT2A receptor can come from repeated exposure to an agonist or antagonist. This behavior is unique in comparison to most of the other GPCRs.

In addition, acquiring tolerance to a drug can cause tolerance to a different drug. This phenomenon is called cross-tolerance. For example, in humans, cross-tolerance at the 5-HT2A receptor occurs between mescaline and LSD16 and between psilocybin and LSD.

The 5-HT2A receptor and the psychedelic effect

Although the 5-HT2A receptor has many functions, it is of particular interest to psychedelic researchers at this time because of its role in the psychedelic response, therapy, and drug research.

The exact mechanism by which 5-HT2A causes psychedelic effects from compounds such as psilocin is not fully understood. Much of the data from studies looking at the neuronal effects of psychedelic drugs are obtained using single cells harvested from brain slices. This is hardly representative of a whole and functioning cortex. However, the current understanding that scientists have is intriguing and offers many opportunities for further investigation.

The psychedelic response results from the binding of an agonist or antagonist molecule to the 5-HT2A receptor. Abundant research over the last several decades has shown that psychedelics enhance signal transmission in the cortex via glutamate, the anionic (and excitatory) form of the amino acid glutamic acid. This enhanced glutamatergic transmission occurs at the level of cortical neurons and also modulates behavioral responses seen with the administration of psychedelics.

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The chemical structure of glutamate which is crucial for eliciting the psychedelic effect
at the 5-HT2A receptor. Glutamate is the anion form of the amino acid glutamic acid.


Adding to the complexity of understanding the psychedelic response is research showing that GPCRs can couple to more than one signaling pathway inside cells. The term for this phenomenon is functional selectivity (aka ligand bias). Unfortunately, not enough is presently known about which other signaling pathways may be involved in the action of psychedelics.

Researchers have also found that the effects of psychedelic drugs may involve receptors other than 5-HT2A. For example, several tryptamine psychedelics such as psilocin and 5-MeO-DMT have a high affinity for the 5-HT1A receptor. Also, the 5-HT2C receptor may play a role, particularly at higher doses. Studies on locomotor activity in mice indicate that higher doses of some psychedelics activate the 5-HT2C receptor. Further, this activation exerts an opposing effect on 5-HT2A. Psychedelic researcher Dr. David Nichols notes in a 2016 review paper that all known psychedelic drugs are agonists at both 5-HT2C and 5-HT2A.

LSD is a unique psychedelic in terms of the receptors that elicit its effects. It has high affinity and agonist activity at dopamine, not serotonin receptors. The dopamine receptors and the effects of LSD will be covered in a separate PSR article.

 
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How DMT switches the brain’s reality channel

by Dr. Andrew Gallimore | KAHPI | 12 Feb 2020

Dr Gallimore explains how the sober brain perceives a 'default reality' and how on DMT it seemingly attunes to a completely different frequency.

When I was a child, my parents kept a tiny 1970s black-and-white TV set in the kitchen, presumably relegated from the living room after we went full technicolor. In contrast to the shiny buttons of our swish 1980s color set, this vintage one employed a circular dial to move between channels. Playing with this dial as a curious child revealed the distinct phases of the channel switch: the crisp black-and-white moving image would first distort as the dial was rotated and interference patterns would encroach. This was followed by a complete breakdown of the image into pure noise with no discernible structure. However, continued rotation of the dial would eventually reveal an entirely new channel which would crackle into view: order gave way to disorder which then gave way to a new order. A couple of decades before our little TV set was built, Hungarian physician Dr. Stephen Szara also discovered a channel switch that seemed to operate in a similar way. Self-experimenting with the newly-identified natural psychedelic molecule, DMT, Szara discovered a channel switch for reality itself.

Referring to DMT — N,N-dimethyltryptamine — as a “100 percent reality channel switch,” Terence McKenna perfectly captured what it’s like to be catapulted into the bizarre realms to which this most mysterious of psychedelic substances grants access: after two or three lungfuls of its curious tasting vapor, the old familiar world begins to distort and break down, as complex geometric forms at first veneer the world and then replace it entirely. The tripper is then propelled through a procession of wild and chaotic imagery before finally, assuming the dosage is sufficient, bursting through a veil into an entirely new, astonishingly strange, world: the DMT space.

Although the superficial parallels with flicking to a new TV channel are obvious, a reality channel switch is actually a rather appropriate descriptor for the effects of DMT on brain activity during a breakthrough trip. To understand how this switch works, we first need to consider how the brain, in the absence of DMT, constructs and maintains the channel of your normal waking world.

Your brain on Channel Consensus Reality

To be born is to be born into a world. To be conscious is to be conscious of a world. Whether you are awake, dreaming, or at the peak of a psychedelic experience, you are always immersed in a world. Of course, the extremely bizarre world of high-dose DMT bears little resemblance to the normal waking world — often referred to as the consensus world — whereas the dream world is usually much more familiar. And, of course, there are other types of worlds that can be distinguished: the fragmented worlds of a schizophrenic patient or the utterly ridiculous and often horrifying worlds that are experienced after taking concentrated Salvia divinorum extracts. But what unites these disparate worlds is their subjectivity: whenever you are conscious, your world is your own unique subjective world experienced from behind your eyes, the world you live in, and the only world you will ever know. While the structure of that world might change dramatically depending on your state, your subjective, phenomenal world is always yours and yours alone.

The world you live in during most of your waking life is clearly your default world, and we can turn to the author Hermann Hesse for a beautiful articulation of what this subjective world actually is: “If the outside world fell in ruins, one of us would be capable of building it up again, for mountain and stream, tree and leaf, root and blossom, all that is shaped by nature lies modelled in us.”

Intuited by Hesse over 100 years ago, your normal waking world is, in more modern scientific parlance, a model of the environment built by your brain. The purpose of this model is to provide you with what philosopher Thomas Metzinger calls a “simulational space” that you can use to navigate and interact with your environment. Obviously there’s a relationship or a mapping between the model and the environment itself, but the world you experience is always this model. When you smoke a sufficient dose of DMT, what changes, in a shockingly dramatic manner, is this model constructed by your brain.

The human brain is obviously an exquisitely complex machine that appears almost magical in its ability to accomplish a bewildering array of complex tasks required for life. But, in truth, the brain really has only a single, albeit extremely complicated, job: to receive, process, and generate information. This information is generated by specialised cells called neurons which fire electrochemical signals that can be passed to other neurons via specialised chemical connections called synapses. The strength of these chemical connections can be increased or decreased to control the flow of information between neurons. The outer layer of your brain is known as the cerebral cortex. It is responsible for building your world model and is essentially a folded sheet containing billions of these interconnected neurons. Closely connected groups of neurons form cortical areas specialised and tuned to receive, process, and generate particular types of information that correspond to particular features of the world, such as lines, colours, textures, spatial relationships, and specific types of objects.

The cortical areas are connected, using synapses, to form networks that control the structure and flow of information through the brain, allowing it to “sculpt” its model of the world. By modifying these patterns of connections, throughout the course of evolution, development, and experience, the brain improves and refines this model. The phenomenal world you experience from moment to moment is the highly complex pattern of information sculpted by these networks of brain areas. Or, equivalently, your phenomenal world is what this pattern of information feels like from your subjective perspective. Your world is built from information.

Of course, this model would be perfectly useless if it didn’t allow you to navigate your environment, to avoid dangers and locate food, to catch the eye of a potential mate and, more generally, to make judicious decisions (“Is that a snake or a coil of rope?”) and predictions (“Is this car going to hit me?”). In other words, the model must be stably tuned in some way to the environment. The brain achieves this tuning by constantly testing its model against incoming sensory information (from the eyes, ears, etc). Essentially, the brain uses the model to predict the patterns of sensory information entering the brain from moment to moment (“If the model I’m using is good, what should I expect to happen next?”). If the prediction is successful, then that sensory information is suppressed, meaning it isn’t passed into the networks of the brain for further processing.

Since neurons use energy, information processing is expensive, so it doesn’t make sense for the brain to process sensory information that’s already part of the model because, in a way, that information is already known. However, if unexpected and surprising patterns of sensory information are received — if the model prediction is incorrect — then error signals are generated, which are then passed into the cortical networks and used to update the model to reduce those error signals.

So, the brain doesn’t need to build its model from scratch from moment to moment, but merely to update it by focusing on unpredictable, surprising information, and filtering out predictable sensory information that fits the model. This constant, real-time, testing and updating against sensory information allows your brain to tune into the environment, locking you into what we might call Channel Consensus Reality.

The robustness of this consensus reality model reveals itself as you descend into REM sleep at night and begin dreaming. It’s no coincidence that most dreams resemble the normal waking world in pretty much all aspects. In fact, dreaming is largely continuous with waking and studies have shown that the proportion of time you spend performing mundane daily activities, such as watching TV or talking on the telephone, is similar in the dream world as it is in the waking world. The crucial difference is that, during dream sleep, your brain is disconnected from sensory information. This renders the dream world familiar and yet distinctly erratic and unstable. The brain is able to rearrange the pieces of its model into unusual, often impossible, ways during a dream, since it isn’t constrained by having to constantly test the model against sensory information. The dream world is thus much more fluid and unpredictable than the normal waking world, despite being an unmistakable variation of it. The similarity of the dreamscape to Channel Consensus Reality isn’t that surprising, since the brain is using the same model to construct the dream world as it does to construct the waking world. What’s more surprising is what happens to the waking world when certain psychoactive molecules enter the brain.

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Your brain on psychedelics

Although psychedelic plants and fungi have been used by indigenous cultures across the globe for thousands of years, it’s only in the last century that they’ve become firmly rooted in Western culture. The so-called classic psychedelics include LSD, psilocybin (from “magic mushrooms”), mescaline (from the peyote cactus), and DMT, in addition to a range of chemically related molecules, and are unified by their characteristic mechanism of action in the brain. The classic psychedelics exert their effects by binding to a specific type of serotonin receptor — the 5HT2A receptor — that is heavily expressed in layers of the cortex with a crucial role in constructing your world model. Upon binding to the 5HT2A receptor, these psychedelics stimulate the neurons in these layers, making them much more responsive to incoming signals from other neurons and much more likely to fire signals that are then passed to other neurons via their synaptic connections. The overall result is a highly excitable layer of neurons over large areas of the cortex, with information flowing much more freely between cortical areas. Since the brain’s ability to construct a coherent model of the environment relies on a delicately constructed pattern of weighted connections between brain areas, this information free-for-all disrupts or “shakes up” the world model.

When research volunteers are given a psychedelic and placed in an MRI machine, functional imaging scans reveal the distinct patterns of brain activity induced by these substances. In the case of both LSD and psilocybin, normally well-ordered patterns of brain activity are seen to break down as information begins to flow out of formerly well-demarcated networks, and networks that were once disconnected begin speaking to each other.

This is what leading psychedelic researcher Dr. Robin Carhart-Harris calls an “entropic” (i.e. disordered) or “hot” state. From the perspective of the psychedelic user, the world undergoes a distinct shift from being stable and predictable to being unstable, fluid, and unpredictable. The brain’s model of the world begins to fall apart. Naturally, this fragmented model becomes less successful at predicting sensory information, which leads to an increase in error signals flowing through the networks of the cortex. Recall that the brain filters out the sensory information it correctly predicts, with only the unpredicted and surprising information being processed in the form of error signals. By disrupting the brain’s ability to predict sensory information, psychedelics effectively remove this filter and information that would normally be filtered out suddenly fills the world and everything becomes surprising, salient, and novel. Anyone who’s ever taken either LSD or Psilocybe “magic” mushrooms will know the subjective effect of this neurological shift: colours become brighter and more pronounced, objects pop out of the surroundings and become imbued with profound significance and meaning. Everything becomes deeply fascinating, as the entire world is seen anew, as a child.

In short, under the influence of a psychedelic substance, the brain loses its grip on the flow of information both into and through itself. And, naturally, it attempts to correct the situation by updating its model — as it would under normal circumstances when error signals are generated — but it’s unable to form a stable and coherent model which reduces the error signals. As such, it continues searching, updating, and the subjective world becomes unstable, shifting rapidly in response to the unfiltered barrage of information from the environment.

This is clearly observed in the MRI scanner, as the brain seems to move in a disorderly fashion through an expanded number of different patterns of neural activity, many of which are only observed under the influence of a psychedelic. It’s as if the brain has been nudged out of tune and is fumbling with the dial attempting to retune itself. From the tripper’s perspective, the world becomes fluid and unstable: everything moves and flows, objects merge or change their identity from moment to moment, the garden hose on the lawn becomes a coiled snake, the pebbled driveway a bed of gleaming jewels.

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DMT: The reality channel switch

Although DMT also acts mainly via the 5HT2A receptor, its effects upon flooding the brain are dramatically different to regular doses of the other classic psychedelics: rather than simply being nudged out of tune, it’s as if the brain has been switched to an entirely different channel. The brain reaches for the dial and, with effortless precision, shifts to the new frequency. From a more neurological perspective, the brain ceases to construct the normal waking world model and begins to construct an entirely new model, which is experienced as an entirely new world.

Assuming the dosage is sufficient, the breakthrough DMT state doesn’t present itself as a maelstrom of confusion and chaos — although this does typify the early stages of the experience — but rather fully realised worlds of crystalline clarity and replete with a diverse ecology of intelligent beings eager to communicate with the tripper. The switch from Channel Consensus Reality to Channel DMT is swift, efficient, and complete.

While there are still relatively few neuroimaging studies of the DMT state in humans, this data gap is now being filled by the pioneering Centre for Psychedelic Research at Imperial College London (among others), which recently published a detailed study of the effects of DMT on neural oscillations measured using EEG. Neurons are electrochemically active cells and, when very large numbers of these cells are connected and active — as in a human brain — electrical oscillations of various frequencies emerge, synchronise, and propagate across the cortex, and can be detected through the skull. Different frequency bands have particular roles in brain function, and synchronisation of oscillations can help in organising the structure and timing of neural activity. In particular, so-called alpha-oscillations are associated with the brain’s ability to model the world and predict patterns of sensory information. Studies with LSD and psilocybin reliably show a decrease in the strength of these alpha oscillations, as well as desynchronisation of several types of oscillations, indicating the disruption of the brain’s world model and the increase in disorderly patterns of neural activity. However, whilst these effects were also observed in the DMT study — since DMT also acts mainly at the 5HT2A receptor — the researchers also recorded a surprising increase in the strength and synchrony of lower frequency oscillations known as delta and theta oscillations. They described this novel effect as the emergence of “apparent order amidst a background of disorder.” These delta/theta oscillations are normally associated with the dream state, when the sleeper is immersed in a world disconnected from the environment. However, while the dream world is built from the same model as the waking world (but without sensory testing), the DMT world is utterly incomparable and must be constructed using an entirely different model. As such, it’s likely that this new order that emerges during the DMT state indicates that the brain has successfully found a stable new channel — Channel DMT.

Of course, switching to Channel DMT doesn’t necessarily mean that the brain has actually tuned to a freestanding alternate reality populated by conscious intelligent entities. Like all phenomenal worlds, including the waking world and the dream world, the DMT world is constructed by the brain — it is a model built from neural information. This would be the case whether Channel DMT is receiving information from, and tuned to, a normally hidden and inaccessible external environment (as with Channel Consensus Reality) or whether it is constructed while disconnected from sensory information (as with the dream world). Obviously, most scientists would favor the latter explanation, since few would entertain the idea that DMT is somehow gating access to a normally hidden parallel world bursting with wildly giggling elves. However, this orthodox explanation isn’t without its problems.

When the brain switches to Channel DMT, it begins constructing a model of an environment that is entirely unrelated to Channel Consensus Reality. This world model possesses structures, content, and qualities that are characteristically “DMT-esque” and appear common to large numbers of independent users around the globe: a number of entities — including the ubiquitous “machine elves” — as well as the bizarre hypergeometric and curiously technological rooms, temples, and landscapes they occupy have come to typify the DMT state.

Spend some time trawling through the online DMT trip report literature and one can’t help feeling that many DMT users often end up being fired into the same place and meeting the same entities. From an orthodox neuroscientific perspective, this is confounding. As far as we are aware, the brain ought to know how to build only a single type of world model: the old familiar consensus world. This is the world — the interface with the environment — the brain evolved to build and the world it continues to construct even during dreaming. As such, the brain’s ability to suddenly begin constructing a bizarre alien world model bearing no relationship whatsoever to the normal waking world is as confounding as a 5-year-old British child suddenly switching to speaking fluent Central Siberian Yupik. Or, one might compare it to finding an entirely new channel on your TV set and then discovering that the aerial has been disconnected. Where did this bizarre world come from? How did the brain learn to construct a model of it? Of course, it would be much easier to explain this if, as countless DMT users are convinced, Channel DMT is tuned to — receiving and processing information from — an alternate reality existing independently of our brains and, most likely, outside of our Universe. But, of course, as professional and sofa scientists alike are always keen to sneer: that’s impossible.

Confronting DMT means confronting the truly impossible. Nothing about this substance seems to make sense. From inside the trip, as you’re hurled screaming through those luminal corridors of ineffable complexity and beauty, or sat at the feet of beings of unreckonable intelligence and power, it all seems perfectly impossible. And from the outside, from the perspective of scientists and philosophers trying to make sense of this substance, an explanation seems no easier to come by. When Terence McKenna first stumbled across Channel DMT in his tiny Berkeley apartment in the Fall of 1965, he admitted to having never gotten over it. And, to be honest, I’m not convinced I ever will either. It just doesn’t seem possible.

 
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Psilocybin superior to ketamine for prolonged antidepressant effects

by Shane O'Connor | Psychedelic Science Review | 4 April 2020

Results support the idea that serotonin 5-HT2A receptor-directed therapeutic strategies may be superior to ketamine-based treatments for depression.

Those paying attention to developments in psychedelic medicine in past years will have noticed the prominence of two compounds, in particular, psilocybin and ketamine. Though both compounds have demonstrated clinical efficacy in alleviating the symptoms of Treatment-Resistant Depression (TRD), they exert their therapeutic effects through different mechanisms of action.*

Psilocybin is one of the many compounds found in psilocybin mushrooms. It is a prodrug of psilocin, the central compound responsible for the psychedelic effect. Psilocin binds to several serotonin receptors, including but not limited to 5-HT7, 5-HT2B, 5-HT2C and 5-HT2A. Due to its established role in the psychedelic experience, current research primarily focuses on the 5-HT2A receptor.

Ketamine – used as a sedative and anesthetic in human and veterinary medicine – is an antagonist (i.e., blocker) of the NMDA receptor in neurons. Glutamate – the brain’s primary excitatory neurotransmitter- typically binds to the NMDA receptor. However, when ketamine blocks the receptor, glutamate can’t attach to it, thereby decreasing action potential conduction velocity. An action potential is a physiological process that facilitates the transmission of signals in neurons.

*Note that the basis of the therapeutic effect of both compounds is still debated within the scientific community. The hypotheses mentioned in this article represent the most prominent theories.

Setting the stage for the experiment

Despite their pharmacological differences, both psilocybin and ketamine demonstrate robust increases in neuroplasticity – the brain’s ability to reorganize itself by forming new neuronal connections. Many in the scientific community hypothesize changes in neuroplasticity underlie the fast-acting antidepressant (AD) properties of psychedelics. Similar changes in neuroplasticity are associated with conventional antidepressant treatment.

One negative aspect of ketamine’s use in the clinic is abuse liability, and there are safety concerns linked with long-term use. Consequently, it is crucial to define the comparative efficacy of psilocybin and ketamine toward developing safe therapeutic approaches in the clinic for the treatment of depression. A recent study from Louisianna
State University set out to investigate these concerns, testing the safety and efficacy of the two compounds in alleviating depressive-like symptoms in a rat model.

Study design

The study used the Forced Swim Test (FST) to evaluate the antidepressant-like effects of the compounds. In the FST, mice are placed in an inescapable transparent tank filled with water, and escape related mobility behavior is measured.

Immobility is interpreted as a passive coping strategy and labeled depressive-like behavior. Compounds that induce decreased immobility imply an antidepressant-like effect.

Many argue that the FST acts as a poor proxy for the depressive state, as the pathogenesis of the disease in humans stems from a multitude of factors (bereavement, genetics, abuse, socio-economic class, etc.). However, numerous AD treatments have been demonstrated to frequently alleviate the depression-like symptoms exhibited by animals in the test, highlighting the FST predictive validity as a primary screening test for AD.

For the dosing prior to conducting the FST, researchers injected rats with either psilocybin (1 mg/kg), ketamine (5 mg/kg), or saline.

To test the anxiolytic (anxiety-reducing) effect of the two compounds, the study used another staple in behavioral pharmacology, the elevated plus-maze (EPM). This is an apparatus consisting of four equally sized arms, two of which are open runways and two of which are enclosed by walls.

The behavioral model is based on the aversion of rodents to open spaces. This aversion drives the animals to find refuge in enclosed spaces or close to the edges of a confined space. In the EPM, this behavior manifests when animals limit their movements to the enclosed arms. An increased proportion of time spent in the open arms indicates anxiety
reduction.

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Psilocybin demonstrates superior antidepressant-like effects

Animals injected with psilocybin displayed decreased immobility in the FST when compared with the control group 5 weeks after administration (the conclusion of the experiment), symbolizing an antidepressive-like effect. Furthermore, there was no sign of the effects diminishing over time, indicating that the therapeutic effects of a single dose of psilocybin likely last far beyond the five weeks.

Rats administered ketamine displayed significantly decreased immobility compared to the control group when tested at weeks one and two. However, the drug’s durability waned, with immobility increasing at week 3 to the point where it was indistinguishable from the saline-treated animals.

The authors state that these results agree with clinical studies in humans described in the literature. The human studies demonstrate a long-lasting therapeutic effect of psilocybin following a single-administration, compared to the relatively transient antidepressant effect of ketamine.

Measuring the impact of setting

The researchers added an intriguing aspect to this experiment. Reports from clinical research on psilocybin in humans outline a correlation between an individual’s subjective experience and the clinical efficacy of the treatment.

Moreover, how well patients respond to treatment is dependant on ‘set and setting.’ Set refers to the mental state a person brings to the experience. Setting refers to the physical and social environment in which the psychedelic experience takes place.

While the researchers could not directly examine the subjective experience of the animals, they developed a proxy for the setting aspect. A proportion of the psilocybin-dosed rats were exposed to an open field arena 5 minutes per week for the first three weeks. The open field is an arena surround by walls to prevent escape. It represents an anxiety-
inducing environment for the animals as they have an aversion to open, brightly lit areas.

Anxiolytic effects and context

Both psilocybin and ketamine treated animals completed the EPM at the conclusion of the experiment in week 5.

Interestingly, the data revealed the following:

- Rats receiving psilocybin and weekly arena exposure exhibited significantly less anxiety-like behavior in the EPM compared to controls.

- Rats receiving ketamine and weekly arena exposure did not display a significant decrease in anxiety in the EPM.

- Rats receiving psilocybin or ketamine and no arena exposure did not display a significant decrease in anxiety in the EPM.

These results shed light on how environmental factors also play a critical role in the drug’s anxiolytic effects. The authors write:

"Our results suggest that psilocybin facilitates a period of behavioral flexibility in which exploration of a non-home-cage environment reduces their anxiety during future exploration of a novel environment…In this context, psilocybin may open a window during which time certain experiences are salient to the development of new coping
strategies."


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Why are these findings important?

Many criticize the translatability of animal studies and the validity of behavioral tests as representative of neuropsychiatric disease states. How can a handful of tests conducted in specific conditions represent the etiology of such complex, multi-factorial disease states such as depression and anxiety? The honest answer is, they can’t.

However, these behavioral paradigms have strong predictive validity. In other words, they accurately predict how well the outcomes of drug studies in the model predict the action of drugs.

Taking this into account, the study demonstrates the more persistent therapeutic effects of a single administration of psilocybin compared to ketamine and supports the idea that serotonin 5-HT2A receptor directed therapeutic strategies may be superior to ketamine-based treatments in the clinic for depression.

Furthermore, the authors question whether the therapeutic effects of psilocybin are dependent on the individuals’ subjective “peak” experience or are physiological in nature with the peak experience merely serving as a biomarker for antidepressant efficacy.

As far as is known, the animals tested in this experiment do not possess the capacity to contextualize their psychedelic experience and appropriate that information to improve their affective state. Therefore, the authors of the paper claim that the basis for the antidepressant effects is at its core biological in nature, with ego dissolution representing a correlative rather than a causal marker of therapeutic outcome.

 
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New biosynthesis of psilocybin and related tryptamines

by Barb Bauer | Psychedelic Science Review | 9 April 2020

Researchers took the psilocybin-making genes from P. cubensis and put them into S. cerevisiae, allowing them to produce psilocybin, several of its analogs, and a “new to nature” compound.

Psychedelic research is experiencing many scientific advances for producing psychedelic compounds. This is because trying to get meaningful and usable amounts of psilocybin and psilocin from magic mushroom flesh, for example, is not practical. The levels of these compounds in dried mushrooms are only 0.2% – 1.0% of their dry weight. Having ways to make meaningful amounts of these compounds at a reasonable cost is essential for conducting scientific studies from receptor assays to clinical trials in humans.

The Novo Nordisk Foundation Center for Biosustainability in Denmark recently published a study in the journal Metabolic Engineering describing how they bioengineered Saccharomyces cerevisiae to produce psilocybin and other related tryptamine derivatives.

PSR previously reported on several papers describing both synthetic and bioengineering methods for producing psychedelic compounds and derivatives. Both the new techniques (like the one described herein) and improvements on existing methods are critical for the advancement of psychedelic science. Two of these articles are Scientists Engineer E. Coli to Produce Psilocybin and Scientists Synthesize and Test the Magic Mushroom Compounds Baeocystin, Norbaeocystin, Norpsilocin, and Aeruginascin.

What is S. cerevisiae and why use it?

S. cerevisiae is a type of yeast. Milne et al. chose to work with it “due to its long use in industrial production as well as the fact that it naturally produces very few secondary metabolites or other tryptophan derivates, thereby facilitating simple downstream processing and purification.”

They also chose this yeast species because it naturally expresses cytochrome P450 enzymes that convert tryptamine to 4-hydroxytryptamine (read more about this in the section below, Optimizing the Synthesis of Psilocybin). The presence of the enzyme is a significant cost-savings, according to the authors. It eliminates an extra synthesis step used by other yeasts, which require an expensive substrate during production.

Modifying yeast to produce psilocybin analogs

The research team inserted genetic material from magic mushrooms into S. cerevisiae. Specifically, they cut out certain psilocybin-making genes from the magic mushroom Psilocybe cubensis and put them into S. cerevisiae. They did this by using plasmids as vectors for transporting the genes into the target yeast cells. Once inside, the plasmid incorporates the new genes into the yeast’s DNA (the plasmids are “programmed” to know where to insert them). The modified yeast then starts making psilocybin according to the instructions encoded in the magic mushroom’s DNA.

The yeast also makes psilocybin derivatives

Notably, the researchers also detected several psilocybin derivatives being produced by their bioengineered yeast. The observed psilocybin analogs included psilocin, norpsilocin, baeocystin, norbaeocystin, 4-hydroxytrimethyltryptammonium (i.e., dephosphorylated aeruginascin), and the “new to nature” N-acetyl-4-hydroxytryptamine.

Why was only the dephosphorylated version found and not aeruginascin itself? The researchers noticed that the amount of psilocybin that S. cerevisiae made “was accompanied by a concomitant production of psilocin.” They theorized that the same phosphatase enzymes (of which there are several in S. cerevisiae) acting on psilocybin to produce psilocin were doing the same thing to aeruginascin. The action of these enzymes may also explain the presence of norpsilocin, which is dephosphorylated baeocystin.

Another result of this study was the creation of a biosynthetic method for producing a “new-to-nature” tryptamine derivative, N-acetyl-4-hydroxytryptamine.

The researchers made the new compound by adding the gene for the enzyme serotonin N-acetyltransferase into the DNA of a different strain of S. cerevisiae that produces 4-hydroxytryptamine. The compound is structurally similar to the neurotransmitter N-acetylserotonin (normelatonin), differing only in the position of the hydroxyl group in the 4-position instead of the 5-position.

According to the authors, this was,

"…the successful production of a novel molecule structurally similar to both psilocin and normelatonin with potentially novel pharmacological activity."

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Optimizing the synthesis of psilocybin

Initially, the amount of psilocybin produced by the genetically engineered S. cerevisiae was low. The researchers noticed that as the yeast was making psilocybin, there was an increase in extracellular tryptamine. The accumulation of tryptamine suggested to them that its conversion to 4-hydroxytryptamine inside the yeast was not very efficient.

The researchers improved the conversion of tryptamine to 4-hydroxytryptamine by giving the yeast a more efficient gene from P. cubensis. The gene, known as cytochrome P450 reductase, catalyzes the conversion of tryptamine to 4-hydroxytryptamine. After this gene was added to the DNA of S. cerevisiae, the data showed a 29-fold increase in the production of psilocybin and psilocin and significantly reduced levels of extracellular tryptamine.

Continuing research on magic mushroom compounds is needed

This research provides another method for producing meaningful amounts of psilocybin analogs for scientific study and downstream applications. Also, synthesis of the novel compounds N-acetyl-4-hydroxytryptamine and unphosphorylated aeruginascin by strains of S. cerevisiae provides more opportunities for research into their chemistry and pharmacology.

Taking genes from one organism and splicing them into another are well-known techniques. Nevertheless, the application of this technology to create psychedelic compounds represents an exciting new area of research. Other scientists have recently noted that supply problems have limited research into the “minor” tryptamines in magic mushrooms. They also hypothesize that these compounds could have substantial therapeutic value alone or when combined with psilocybin. This recent work discussed above could offer new possibilities for supplying minor tryptamines for further research and development.

 
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DTU Biosustain

Psychedelic compound from magic mushrooms produced in yeast

by Technical University of Denmark | Phys.org | 16 April 2020

Scientists from DTU Biosustain have proven that psilocybin, a potential drug for treating depression and other psychological conditions, can be produced in yeast.

Psilocybin mushrooms have been found to have minimal harmful effects and could potentially benefit those with depression. But they remain illegal even though they offer a groundbreaking alternative to several under-treated psychological conditions.

Nevertheless, psychedelics are currently riding a wave of positive momentum brought on by cannabis, and if psilocybin gets approved as a pharmaceutical drug, production in yeast appears to be the most commercially viable option.

"It's unfeasible and way too expensive to extract psilocybin from magic mushrooms and the best chemical synthesis methods require expensive and difficult to source starting substrates. Thus, there is a need to bring down the cost of production and to provide a more consistent supply chain," says Nick Milne, former Postdoc at DTU Biosustain and CSO and Co-founder of Octarine Bio.

Bio-based production of psilocybin has garnered major interest and researchers have already proved small-scale production in E. coli. However, production in bacteria comes with a wide range of concerns which can be addressed by using yeast instead.

In yeast, the scientists prove that psilocybin can be produced de novo, which means that you can produce the molecule by simply growing the yeast with sugar and other nutrients, without the need to add any other starting substrates.

Producing psilocybin de novo in E. coli is difficult since a key enzyme in the biosynthetic pathway doesn't work in bacteria, and so to get around this problem you need to add an expensive starting substrate, making the whole production process too costly.

"Since yeast and Psilocybe mushrooms are quite closely related species, this enzyme works very well in yeast, providing a much more cost-efficient alternative," says group leader at DTU Biosustain Irina Borodina.

Additionally, yeast also performs better in large-scale fermentation due to its long history in the beer brewing process, and also in the purification process since E. coli produces additional potentially harmful compounds that you would not like to have in your final product.

Challenges still to be solved

In the study published in Metabolic Engineering Journal, the researchers reached fairly high titers, but if production should be scaled up, one major obstacle needs to be overcome.

On psilocybin's core skeleton sits a phosphate group which is cleaved off when the molecule is converted to its active form.

"What we find in the study is that we get a lot of this non-phosphorylated compound psilocin. Essentially, we are losing half of our product because the phosphate group falls off. Dealing with this high amount of psilocin is something that absolutely needs to be solved before realistically moving to a production process," explains Nick Milne.

To fix the issue, a lot more metabolic engineering needs to be done. The good thing for the scientists is that the starting point is a well-studied pathway called the shikimate pathway. There is already a lot of experience working with it, so from that point of view, it should be pretty straight forward.

The valuable derivatives

While de novo production of psilocybin in yeast in these titers should be considered impressive as a proof of concept, the researchers behind the study also underline the importance of producing other natural and novel derivatives.

Psilocybe mushrooms also produce a range of molecules that are structurally similar to psilocybin but are too difficult to purify, making research into their therapeutic effect difficult. In this study, the researchers demonstrated the production of a range of psilocybin pathway derivatives, and further, by combining genes from the melatonin biosynthetic pathway, could demonstrate the production of a completely novel molecule.

This technology has been transferred to Octarine Bio, a spin-out company from The Novo Nordisk Foundation Center for Biosustainability (DTU Biosustain) and the University of Copenhagen, who are interested not only in the large-scale production of psilocybin but also the potential of producing new derivatives.

"Our interest is not only to make kilogram scale production of psilocybin but to use the biological machinery to make new derivatives that aren't available today. Thus, it is very useful that we could not only demonstrate the production of psilocybin but also find many derivatives that could turn out to have important therapeutic relevance," says Nick Milne.

 
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Structure and function of the Serotonin 5-HT2C Receptor

5-HT2C has a role in the psychedelic effect. Understanding it is essential for harnessing the full benefits of nature’s chemical cocktails.

by Barb Bauer | Psychedelic Science Review | 20 April 2020

The Serotonin 5-HT2C Receptor was first cloned by Julius et al. in 1988. At the time, they designated the new receptor 5-HT1C. A new nomenclature for serotonin receptors was proposed by Humphrey et al. in 1993. It placed the receptors into families based on the G proteins they used for signaling and similarities in their DNA amino acid sequences. For example, about 50% of the DNA sequences of 5-HT2A, 5-HT2B, and 5-HT2C are identical.

The structure of the 5-HT2C Receptor

When the Humphrey et al. receptor naming proposal was adopted, 5-HT1C was renamed 5-HT2C because of its similarities to 5-HT2A and 5-HT2B. In a 2012 paper, Seitz et al. describes the similarities between 5-HT2A (considered the primary receptor for psychedelic effects) and 5-HT2C by saying, “These receptors share a high degree of homology, have overlapping pharmacological profiles, and utilize many of the same and richly diverse second messenger signaling systems.” This homology between receptors can make it challenging to design agonist drugs that specifically target 5-HT2C.

The 5-HT2C receptor (5-HT2CR) is a member of the G protein-coupled receptor (GPCR) family. Receptors in this family share a characteristic structure consisting of seven protein helices that span the cell membrane (Figure 1). The helices are separated by alternating sections of the receptor that form intracellular and extracellular loops.

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Figure 1: 5-HT2CR in complex with the serotonin receptor antagonist ritanserin.

What does 5-HT2CR do?

One of the many roles of 5-HT2CR is modulating the effects of the neurotransmitter dopamine. Activation of 5-HT2CR is thought to have an inhibitory influence on dopamine. Since dopamine acts as a reward chemical in the brain, 5-HT2CR is a drug target for therapies for treating drug addiction. Also, 5-HT2CR may play a part in the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants.

A 2007 study found that activation of 5-HT2CR in the amygdala was correlated with anxiety in rats. These findings revealed an opportunity for targeting drugs to 5-HT2CR for treating anxiety. Another 2007 study confirmed the involvement of 5-HT2CR in expressing anxiety. The authors of this study suggested a possible mechanism involving the modulation of corticotropic-releasing hormone in the brain in response to stress.

5-HT2CR also has a role in the regulation of body weight and obesity. Knockout mice who are lacking the gene for 5-HT2CR become severely obese (they also can experience fatal seizures). Lorcaserin (aka Belviq™) is a 5-HT2CR agonist drug designed for weight loss. In 2013, the US Drug Enforcement Administration placed it on Schedule IV because of its hallucinogenic properties. Then, in 2020, Lorcaserin was withdrawn from the market because a clinical trial showed an increase in several types of cancers, including pancreatic, colorectal, and lung.

Is 5-HT2CR involved in the psychedelic effect?

Receptor studies using cloned rat 5-HT2CR indicate that psilocin, for example, has a high affinity for 5-HT2CR. Its Ki value at the receptor is 97.3 nM19 (to learn more about receptor affinity data and what it means, see the Psychedelic Science Review article Binding of Psilocin and Psilocybin to Serotonin Receptors). Here are the Ki values at 5-HT2CR for some other psychedelic compounds:

- Serotonin = 5.8 nM (human)
- LSD = 1.1 nM (human)
- 5-MeO-DMT = 100 nM (pig)
- MDMA = >10,000 nM (rat)
- Psilocybin >10,000 nM (rat)


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In his 2016 paper Psychedelics, Dr. David Nichols states,

"All known psychedelics are agonists at both 5-HT2A and 5-HT2C receptors."

Interestingly, he goes on to say,

"…higher doses of particular psychedelics may lead to activation of the 5-HT2C receptor, which often functionally opposes the effects of 5-HT2A receptor activation."

An example of this comes from a 2009 study conducted by Halberstadt et al. They observed that low doses of the hallucinogenic amphetamine DOI (2,5-dimethoxy-4 iodoamphetamine) increase locomotor activity in mice while higher doses reduce it. They made the same observation with the head twitch response (HTR), a behavior model that indicates the activation of 5-HT2A.

Allosteric modulation may influence the contribution each serotonin receptor makes to the overall effects of psychedelics. The behavior of GPCRs is modulated by many things, including neurotransmitters, hormones, and ions. In addition to the impact of these physiological influences, psychedelics may also be modulators of GPCR function resulting in an entourage effect similar to the compounds in cannabis. Multiple active compounds from naturally occurring sources set the stage for the entourage effect playing a critical role in making formulations.

 
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Scientists solve crystal structure of the freebase of 5-MeO-DALT

by Barb Bauer | Psychedelic science Review | 29 April 2020

Understanding the structure of this synthetic analog of 5-MeO-DMT may help explain the effects of naturally occurring chemical cocktails.

A team of scientists from CaaMTech and the University of Massachusetts Dartmouth has reported the synthesis of the freebase form of 5-MeO-DALT (5-methoxy-N,N-diallyltryptamine). In recent months, the same research team has published several articles describing other structurally related tryptamine compounds in new crystalline forms.

In the April 2020 study published in the journal IUCrData, the authors describe the crystal structure of 5-MeO-DALT as follows:

'The indole unit is nearly planar with a deviation from planarity of 0.015 A°. The methoxy group is in the same plane, with the indole and methoxy group showing an r.m.s. deviation of only 0.025 A°. The ethylamine group is turned significantly from the indole plane…'

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The molecular structure of the freebase of 5-MeO-DALT showing labeling of the atoms.

What is 5-MeO-DALT?

5-MeO-DALT is a synthetic tryptamine analog of 5-MeO-DMT (O-methylbufotenine), a compound found naturally in toad secretions. The consensus among experts is that 5-MeO-DALT was first synthesized by Alexander and Ann Shulgin.10 Studies have shown that 5-MeO-DALT induces the head twitch response in mice. As such, these results indicate it has psychedelic effects that are mediated via the serotonin 5-HT2A receptor.

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The chemical structures of 5-MeO-DALT and 5-MeO-DMT. 5-MeO-DALT is a synthetic analog of the naturally occurring 5-MeO-DMT.

Why crystal structures are important in psychedelic research

Crystal structures are essential for helping researchers “see” properties and effects at a molecular level, giving them a better understanding of how receptors, other proteins, and compounds look and act in nature. While molecular modeling software can provide helpful insight into the three-dimensional configuration of molecules, X-ray crystallography provides empirical data about a compound’s physical properties.

The crystal structure of the freebase form of 5-MeO-DALT is essential to understanding its physical properties and for studying its activity at receptors by using modeling studies. Although it is a synthetic compound, further investigation of 5-MeO-DALT could help shed light on the pharmacology involved in the effects of ingesting toad secretions.

Crystal structures do not fully explain the interaction of drugs with receptors. However, the information scientists obtained from these studies help to clarify some aspects of a given drug’s structure, interaction, and function. Understanding the pharmacology of psychedelic compounds could lead to formulations that provide predictable and positive effects while minimizing unwanted or harmful side effects.

 
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Antidepressant-like effect with a single dose of ibogaine and noribogaine*

This is the first preclinical study to examine the anti-depressive effects of ibogaine and noribogaine.

by Barb Bauer | Psychedelic Science Review | 7 May 2020

There is significant experimental evidence showing the effectiveness of ibogaine and its primary metabolite noribogaine in treating various substance abuse disorders in animals. There are also case studies and reports describing ibogaine’s effectiveness in giving fast and long-lasting relief from drug cravings and withdrawal symptoms in humans. Researchers are at work teasing apart the mechanisms that are causing the anti-addictive effects of these compounds.

As is typical in scientific research, new knowledge gives rise to further questions and applications of the findings. In the case of ibogaine and noribogaine, researchers are now investigating their effects on depression. If ibogaine and noribogaine have antidepressant-like effects, this may be contributing to their anti-addictive properties.

An April 2020 study published in ACS Chemical Neuroscience investigated the effects of ibogaine and noribogaine on an animal model of depression.

Study design

The study has two main parts. The first utilized a behavioral assay for rodents called the forced swim test (FST), which measures their depressive behavior. Briefly, the theory is that the experiment causes stress on the rodents (stress is often a component in major depression in humans). Rats that are not depressed will try to escape by swimming and trying to climb out. Depressed rodents will not attempt to escape, indicating “behavioral despair.”

The second aspect of the study was gathering pharmacological data. The researchers measured the concentration of ibogaine and noribogaine in the blood plasma and brains of rats over time. By aligning these data with the FST results, they could associate behaviors with the presence and concentration of each compound.

Separate groups of rats received ibogaine and noribogaine in doses 20 or 40 mg/kg, i.p. before the FST and pharmacokinetic measurements. The control groups received i.p. injections of 5% ethanol and saline, the vehicle (carrier) of the test compounds

The FST was run at 3 and 24 hours after administration. The researchers chose these times because of studies in the literature. This previous work showed that ibogaine and noribogaine are expected to have pharmacologically and behaviorally relevant concentrations in the brain by 3 hours. Conversely, by 24 hours, the concentration of the compounds should be too low to cause any effects.

The pharmacokinetic measurements were done at several time intervals after the administration of ibogaine and noribogaine. All the rats used in the study were of the same type, age, sex, and had similar body weights.

The effects are time- and dose-dependent

Three hours after i.p. administration of ibogaine, both test groups of rats displayed a significant reduction in their immobility in the FST compared to controls. The more significant effects were observed in for the rats given the 40 mg/kg dose. Both ibogaine and noribogaine were found in the brain tissue and plasma of the rats at this time. The figure below shows brain concentrations of ibogaine and noribogaine of 9.9 µM/L and 21.0 µM/L, respectively, at three hours.

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Graph showing concentrations of ibogaine and noribogaine in rat brains over time after
intraperitoneal injection of 40 mg/kg ibogaine.


As expected, by 24 hours, no significant effect was observed in the FST for either dose. Concurrently, ibogaine was not detectable in the brain tissue or plasma of the rats. There was only a small residual amount (averaging 0.5 µM/L) of noribogaine detected.

Noribogaine i.p. administration of 40 mg/kg had a “significant and robust” dose-dependent antidepressant-like effect on the rats in the FST and was correlated with high concentrations in the brain. The 20 mg/kg dose did not produce these effects. Interestingly, noribogaine’s effects had a shorter duration than ibogaine in the FST. The effects were present 30 minutes after administration but were gone at three hours.

Ibogaine alone does not drive the antidepressant-like effects

In the next step, the data were analyzed to see if ibogaine by itself was causing the antidepressant-like effect or if the metabolite noribogaine was also at work. To test this, the researchers had to use a different route of administration for the compounds.

Compounds are subject to first-pass metabolism in the liver when they are given via an i.p. injection. However, intravenous (i.v.) administration of ibogaine bypasses this metabolism, resulting in less ibogaine being converted to noribogaine.

Using an i.v. administration of ibogaine also required a change in doses. This is because at a test dose of 10 mg/kg i.v., they observed behavioral impairments in the rats such as tremors, forepaw tapping, and staggering locomotion that lasted for 30 minutes. These effects could impact the results of the FST. Therefore, the i.v. doses of ibogaine were lowered for the test groups to 1 and 5 mg/kg, respectively. The FST was done one after i.v. administration.

Statistical analysis of the data showed no significant effect on immobility at either ibogaine dose. However, the researchers observed “…a trend for reduction in the immobility time…” from the 5 mg/kg dose. Yet, there was no robust antidepressant-like effect in the FST, as was seen after i.p. administration of ibogaine. Pharmacokinetic analysis showed there was only a minimal amount of noribogaine in the brain at the time.

Taking the trend for reduction in immobility along with results along with the data from i.p. administration of ibogaine, the authors theorized that “Ibogaine itself does not drive the antidepressant-like effect found in the FST after ibogaine i.p. administration.”

They commented further: “While it is likely that ibogaine would show a reduction in the immobility time at higher concentrations, it is not feasible to examine higher doses due to the above-mentioned behavioral side effects that are not compatible with animal performance in the FST.”

What is causing the antidepressant-like effect?

Knowing that ibogaine was not acting alone to produce the antidepressant-like effects, the next step was to figure out if and how noribogaine (or another compound) was involved.

In analyzing all the FST and pharmacokinetic data, the authors made these general observations:

- When either ibogaine or noribogaine alone was present in the rat’s brains at three hours after dosing, there was no statistically significant antidepressant-like effect in the FST.

- When both compounds were present at lower individual concentrations in rat brains at three hours after dosing, there was a significant reduction in the immobility time in the FST.

In summary, the authors stated,

"…both ibogaine and noribogaine were present in rat brain at concentrations that cannot produce the same behavioral outcome on their own."

Therefore, these results suggest that both ibogaine and noribogaine are required to elicit the antidepressant-like effects seen in the FST. The authors suggest there may be a synergistic or additive effect produced when both compounds are present. It is also possible that an unknown metabolite of ibogaine that causes an antidepressant-like effect is formed after i.p. but not i.v. administration.

Summary

This study suggests that ibogaine or noribogaine alone in the blood and brain of rats does not have an antidepressant-like effect When both compounds are present there is a significant antidepressant-like effect. However, it is unclear if the entourage effect or an unknown metabolite is involved. Further research is needed to answer these questions.

In conclusion, the authors said,

"…our findings provide preclinical confirmation of the recently reported antidepressant effects of ibogaine in opioid-dependent subjects. It is therefore conceivable that the antidepressant efficacy may contribute to the anti-addictive property of ibogaine and noribogaine"

*From the article here :
 
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Stopping bad LSD trips with “Off-Switch” Technology

Technology developed by MindMed and Liechti Lab may help ease some of the concerns surrounding psychedelic therapy.

by Barb Bauer | Psychedelic Science Review | 5 May 2020

Part of the stigma that still haunts efforts to develop LSD-assisted psychotherapy is the possibility of patients experiencing bad trips, particularly at high doses. The startup psychedelic pharmaceutical company MindMed and the Liechti Lab at the University Hospital in Basel, Switzerland, have been collaborating on the development of a new technology that may stop the effects of LSD in its tracks. This new invention may transform LSD from a long-lasting drug into a shorter-acting therapeutic compound.

In an April 21, 2020 press release, MindMed announced the patent filing of what they call a “neutralizer technology” that can shorten and stop a patient’s LSD trip while they are undergoing therapy.

Few details of the invention are available

The press release contains no details on the technology, such as the compounds involved, the receptors they are targeting, or other mechanisms of action. MindMed does say that the technology is “based on surprising experimental results from work and collaboration conducted in the lab.” Also, the press release indicates that although MindMed has filed a patent, the technology requires further development before using it can be marketed for use in therapy sessions.

Dr. Matthias Liechti, head of Liechti Lab, told New Atlas, “I can say that we have a planned program exploring the use of a range of compounds to be used to treat negative acute experiences with hallucinogens to increase their clinical safe use. Classically, such treatments included benzodiazepines or haloperidol. Ketanserin has so far been used to investigate the mechanism of action of psychedelic substances.”

Dr. Liechti continued,

"The novel concept is to reduce the duration of action and the effect intensity of a psychedelic in high doses, for example, in cases where panic develops or in overdoses and after the hallucinogen has been ingested. The rapidity of the effect will depend on the specifics of the formulation that is being tested and developed."

Technology part of a more extensive partnership

The collaborative work between Liechti Lab and MindMed goes beyond the LSD neutralizer technology. An April 1, 2020 MindMed press release announces a longer-term partnership between the companies which is centered on Liechti Lab’s years of research on psychedelic compounds. Under the terms of the agreement, “MindMed gains exclusive worldwide rights to data, compounds, and patent rights associated with the Liechti laboratory’s research with LSD and other psychedelic compounds, including data from preclinical studies and eight completed or ongoing LSD clinical trials.”

JR Rahn, co-founder, director, and co-CEO of MindMed told New Atlas, “The innovative and original work of the Liechti Laboratory is a treasure trove of novel data on LSD. We are just at the beginning of several significant discoveries that have the potential to further the application of psychedelics as therapeutic medicines. If developed, these discoveries will benefit both patients and therapists working in the psychedelic medicine space.”

 
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