Psychedelic pharmacology

[mr peabody]

An explanation of the effect of psychedelics on the nervous system at the level of the neurone

This article is intended to be a detailed explanation of how hallucinogens affect the brain, via the inhibition and excitation of neurotransmitters in the nervous system. This article is not written by me, but an extremely close friend of mine who is significantly more knowledgeable when it comes to science, and specifically chemistry.

A neurone is a cell that carries electrical impulses. Information is processed and transmitted by the nervous system in the form of electrical and chemical signals. The neurone primarily comprises of a cell body, an axon and dendrites. The axon is a nerve fibre that carries electrical signals away from the cell body, to the end of the neurone. The end of the neurone then connects to the dendrites on the cell body of the next neurone, via a synapse. Drugs cause their effects due to their action on the neurones in the nervous system.

A nerve impulse is a self-propagating wave of electrical disturbance that travels along the surface of the axon membrane. This electrical disturbance comprises of a temporary reversal of the electrical potential difference; not an electrical current. The axon is usually negatively charged compared to the outside of the axon, and this is known as the resting potential, the value of which is usually around -65mV. When a stimulus is received, a reversal in electrical potential difference is caused, and this is known as the action potential (normally around +40mV).

To begin, the inside of the axon is negatively charged, compared with the outside of the axon. The change in potential difference, that is needed to fire off an action potential, is controlled by the movement of sodium and potassium ions in and out of the axon. An ion is a positively or negatively charged molecule. This movement occurs via the action of ion pumps and channels. The ions cannot just diffuse in and out of the axon uncontrollably; this diffusion is prevented by a membrane around the axon. Periodically placed along the membrane are proteins that act as channels for ions to pass through. Sodium gated channels and potassium gated channels open and close to allow the ions to pass through only at specific times. Sodium-potassium pumps transport Na⁺ and K⁺ in and out of the axon.

The inside of the axon starts at around -65mV compared to the outside of the axon. An action potential is reached when the axon is at +40mV compared to the outside of the axon. This value of +40mV is reached by the movement of sodium and potassium ions in and out of the axon. Sodium-potassium pumps transport 2K⁺ into the axon for every 3Na⁺ transported out of the axon. Both sodium and potassium are in the forms of positive ions here. However, more sodium is removed from the axon compared to the potassium brought. This means the overall electro negativity is decreasing in the axon, and the axon is getting closer to reaching the potential difference of +40mV. Sodium ions then begin to diffuse back into the axon naturally, and potassium ions diffuse back out. At this stage however, potassium gated channels are open, whereas sodium gated channels are closed. This means the K⁺ can diffuse out faster than the Na⁺ can diffuse back into the axon. This increases the potential difference further between the inside and the outside of the axon.

Read the full article:

http://disregardeverythingisay.com/p...ucinogens-upon

 

[mr peabody]

CBD and the psychedelic receptor

Lex Pelger - March 29, 2018

In a shorthand that drives scientists mad, serotonin is often called ‘the neurotransmitter of happiness.’ This tag is especially troublesome as more and more flaws become apparent in the ‘serotonin hypothesis’ of depression' – the idea that depression is caused by a serotonin deficit, which a pill (a serotonin reuptake inhibitor) could correct.[1] Serotonin is a complex molecule in the brain and the periphery with a vast and intricate receptor system classified into seven main subtypes that regulate a wide array of physiological functions. Calling serotonin the happiness molecule is short shrift.

The importance of serotonin transcends happy mind states. Conserved as an evolutionary through-line in all bilateral animals, including worms and insects, the serotonin molecule modulates the release of a swathe of other neurotransmitters.[2] Serotonin (which is often abbreviated as 5-HT because of its proper chemical name 5-hydroxytryptamine) is involved in behaviors as diverse as aggression, learning, appetite, sleep, cognition, and reward activity. The receptors for serotonin have become pharmaceutical targets for a range of neuropsychiatric disorders and gut-related conditions. Ninety percent of 5-HT is located in the GI tract, where it regulates intestinal motility.

Biochemist Maurice Rapport isolated serotonin and elucidated its molecular structure in the late 1940s. Two distinct serotonin receptor binding sites – 5-HT1 and 5-HT2 (later renamed 5-HT1A and 5-HT2A) – were identified in the rat brain in 1979. It turns out that cannabidiol (CBD), a promiscuous, non-intoxicating cannabis compound, binds directly to both of these receptors.

Whereas CBD has little binding affinity for the classical cannabinoid receptors, CB1 and CB2, several serotonin receptor subtypes are key docking sites for CBD. The 5HT2A receptor also mediates the actions of LSD, mescaline and other hallucinogenic drugs. But CBD and LSD act at 5-HT2A, the psychedelic receptor, in different ways, resulting in markedly different effects.

Receptor complexes

Reported initially in 2005, the discovery that CBDinteracts directly with these (and other) 5-HTreceptors hints at a broader relationship between the endocannabinoid and serotonergic systems that scientists are still uncovering.

Read the full article here:

http://realitysandwich.com/322794/cb...elic-receptor/

 

[mr peabody]

This figure shows the effects of three psychedelics and one control (VEH) on cortical neurons.


Sprucing up your brain with potent psychedelics

A new study, published June 12 in the journal Cell Reports, found psychedelics, specifically DOI, DMT, and LSD, can change brain cells in rats and flies, making neurons more likely to branch out and connect with one another. The work supports the theory that psychedelics could help to fight depression, anxiety, addiction, and post-traumatic stress disorder.

One of the hallmarks of depression is that the neurites in the prefrontal cortex - a key brain region that regulates emotion, mood, and anxiety - those neurites tend to shrivel up, says Olson. These brain changes also appear in cases of anxiety, addiction, and post-traumatic stress disorder.

Psychedelics are not the most popular drugs for treating depression, but as we better understand how they promote the growth of new dendrites and synapses, we should be better able to develop safer and more effective antidepressants to accomplish the same effect.

More from the Cell report of 12 June 2018:

Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society. Approximately one-third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2-4 weeks of treatment before they experience any beneficial effects. Depression, post-traumatic stress disorder (PTSD), and addiction share common neural circuitry, and have high comorbidity.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.

Read the full article:

https://alfinnextlevel.wordpress.com...-psychedelics/

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[mr peabody]

Neuropharmacology of DMT

Theresa M. Carbonaro, Michael B. Gatch

N,N-Dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals. It is best known for producing brief and intense psychedelic effects when ingested. Increasing evidence suggests that endogenous DMT plays important roles for a number of processes in the periphery and central nervous system, and may act as a neurotransmitter. This paper reviews the current literature of both the recreational use of DMT and its potential roles as an endogenous neurotransmitter. Pharmacokinetics, mechanisms of action in the periphery and central nervous system, clinical uses and adverse effects are also reviewed. DMT appears to have limited neurotoxicity and other adverse effects except for intense cardiovascular effects when administered intravenously in large doses. Because of its role in nervous system signaling, DMT may be a useful experimental tool in exploring how brain works, and may also be a useful clinical tool for treatment of anxiety and psychosis.

Introduction

N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in nature. It is an endogenous compound in animals and in a wide variety of plants found around the globe. Major plant genera containing DMT include Phalaris, Delosperma, Acacia, Desmodium, Mimosa, Virola, and Psychotria, but DMT has been found even in apparently innocuous sources, such as leaves of citrus plants, and in the leaves, seeds, and inner bark of mimosa tenuiflora, which has become a source of livestock poisoning.

DMT has become of interest because when ingested, it causes brief, episodic visual hallucinations at high concentrations. DMT is one of the major psychoactive compounds found in various shamanistic compounds (e.g., ayahuasca, hoasca, yage) used in South America for centuries and has, more recently found its way into Europe and North America as a recreational drug.

Recreational use of DMT

Most hallucinogens such as lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-methylamphetamine (DOM) cause sensory distortion, depersonalization at high doses, and at least one (N,N-Diisopropyltryptamine, DiPT) causes auditory distortions, whereas some compounds such as DMT (found in ayahuasca), psilocybin (mushrooms) or mescaline (peyote) cause episodic visual effects. In the late 1990s, Rick Strassman conducted the first human research with hallucinogens in 20 years, examining the physiological effects and self-reports from people receiving DMT in carefully controlled settings. A book describing these results was published in the popular press. Strassman concluded that DMT is a powerful tool for self-discovery and understanding consciousness, which may have helped to drive interest in recreational use of DMT and related tryptamine hallucinogens. In recent years, recreational use of DMT has been increasing; for example, Cakic et al., reported that 31% of recreational DMT users endorse psychotherapeutic benefits as the main reason for consumption. Similar to ayahuasca, recreational users have made similar concoctions referred to as pharmahuasca. These are of capsules containing free-base DMT and some monoamine oxidase inhibitors (MAOI) such as synthetic harmaline or Syrian Rue.

It is unclear what proportion of users of hallucinogenic tryptamines have adverse events serious enough for hospitalization, but it seems that the synthetic hallucinogenic compounds, such as 25I-NBOMe may be more dangerous than the plant-derived compounds. Databases derived from Poison Control and Emergency Department visits only sparing differentiate between hallucinogenic compounds taken and lack adequate records of DMT-specific cases. Street drugs mostly contain powdered DMT, whereas ayahuasca also contains harmine-related compounds, which limit toxic effects. However, aside from the acute cardiovascular effects there have been no consistent reports of toxic effects of long-term use of DMT in the literature. In fact, there has been a report that DMT is neuroprotective. Without more data on the recreational use of this class of compounds, it is not possible to conclude whether the synthetic hallucinogens are indeed more toxic or whether the social context may contribute to the effects.

Read the full article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048497/

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[mr peabody]

Unifying Theories of Psychedelic Drug Effects

by Link Swanson

How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories, model psychoses theory, filtration theory, and psychoanalytic theory, and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks, entropic brain theory, integrated information theory, and predictive processing, and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function.

Introduction

Lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), psilocybin, and mescaline, the classic psychedelic drugs, can produce a broad range of effects in perception, emotion, cognition, and sense of self. How do they do this? Western science began its first wave of systematic investigations into the unique effects of mescaline 125 years ago. By the 1950s, rising interest in mescaline research was expanded to include drugs like DMT, LSD, and psilocybin in a second wave of psychedelic science. Because of their dramatic effect on the character and contents of subjective awareness, psychedelic drugs magnified the gaps in our scientific understanding of how brain chemistry relates to subjective experience. Huxley commented that our understanding circa 1954 was "absurdly inadequate" and amounted to a mere clue that he hoped would soon develop into a more robust understanding. "Meanwhile the clue is being systematically followed; the sleuths, biochemists, psychiatrists, psychologists, are on the trail." A third wave of psychedelic science has recently emerged with its own set of sleuths on the trail, sleuths who now wield an arsenal of 21st-century scientific methodologies and are uncovering new sets of clues.

Existing theoretical hurdles span five major gaps in understanding. The first gap is that we do not have an account of how psychedelic drugs can produce such a broad diversity of subjective effects. LSD, for example, can produce subtle intensifications in perception, or it can completely dissolve all sense of space, time, and self. What accounts for this atypical diversity?

The second gap is that we do not understand how pharmacological interactions at neuronal receptors and resulting physiological changes in the neuron lead to large-scale changes in the activity of neural populations, or changes in brain network connectivity, or at the systems-level of global brain dynamics. What are the causal links in the multi-level pharmaco-neurophysiological chain?

The third gap is that we do not know how psychedelic drug-induced changes in brain activity, at any level of description. map onto the acute subjective phenomenological changes in perception, emotion, cognition, and sense of self. This kind of question is not unique to psychedelic drugs but our current understanding of psychedelic drug effects clearly magnifies the disconnect between brain science and subjective experience.

Read the full article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853825/

 

[mr peabody]

N, N-Dimethyltryptamine (DMT), an endogenous psychedelic: Past, present, and future research to determine its role and function

Steven A. Barker

Abstract

This report provides a historical overview of research concerning the endogenous psychedelic N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the “natural” role of an endogenous psychedelic from the effects observed from peripheral administration are also emphasized.

Introduction

Despite their presence in the human pharmacopeia for millennia, we have yet to resolve the biochemical mechanisms by which psychedelics so dramatically alter perception and consciousness. It is the only class of compounds that efficiently and specifically does so. For that matter, we do not fully understand the biochemistry of perception itself or how we live such a vivid and complex internal life in the absence of external stimulation. We do not understand the basic biochemical mechanisms of some of our most common experiences, such as the many human aspects of creativity, imagination or dream states. This is also true for extraordinary states of consciousness such as “visions” or spontaneous hallucinations or phenomena such as near-death experiences (NDE). And it is troubling that we have not sufficiently turned the scientific method on these latter subjects despite the profound role they have played in the evolution of our science, philosophy, psychology and culture.

The experiences derived from the administration of psychedelics are often compared to dream states. However, the experience of administered psychedelic substances is far more intense, robust and overwhelming than the subtlety of mere dreams. By comparison, the natural biochemical processes for our related psychedelic experiences are obviously far more highly regulated, occurring as an orchestrated and inherent function of the “normal” brain. Nonetheless, it is conceivable that attaining an explanation for these related natural human phenomena may lie in resolving the biochemical mechanisms involved in the more dramatic pharmacology of psychedelics, recognizing that the complexities and intensity of the “administered” experience are, essentially, an overdose relative to corresponding natural regulatory controls. Given their status, increased study of psychedelics, particularly with advanced brain imaging and molecular biology approaches, may provide a better understanding of the “common” biochemistry that creates mind.

Perhaps the science behind the discovery of endogenous opioids offers us a corollary. We came to better understand the common human experience of pain through examining the pharmacology of administered opiates and the subsequent discovery of endogenous opioid ligands, receptors and pathways that are predominantly responsible for and regulate the experience and perception of pain. Such may also be the case for understanding perception and consciousness. With the discovery of the endogenous DMT, perhaps, as with the endogenous opioids, we have a similar opportunity to understand perception and consciousness. Recent research has stimulated a renewed interest in further study of this compound as a neuro-regulatory substance and, thus, a potential neuro-pharmacological target. Taking results from these and more classical studies of DMT biochemistry and pharmacology together, this report examines some of the past and current data in the field and proposes several new directions and experiments to ascertain the role of endogenous DMT.

A brief history of DMT

In terms of Western culture, DMT was first synthesized by a Canadian chemist, Richard Manske, in 1931 but was, at the time, not assessed for human pharmacological effects. In 1946 the microbiologist Oswaldo Gonsalves de Lima discovered DMT's natural occurrence in plants. DMT's psychedelic properties were not discovered until 1956 when Stephen Szara, a pioneering Hungarian chemist and psychiatrist, extracted DMT from the Mimosa hostilis plant and administered the extract to himself intramuscularly. This sequence of events formed the link between modern science and the historical use of many DMT-containing plants as a cultural and religious ritual sacrament, their effect on the psyche and the chemical structure of DMT.

Read the full story here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088236/

 

[mr peabody]

A new category of medications: Psychoplastogens

In an article published recently in the journal Cell Reports, David Olson, Calvin Ly, and colleagues investigate the biologic actions of a class of drugs that they have named psychoplastogens. The authors provide the following description of drugs that fall into this new class: “To classify the growing number of compounds capable of rapidly promoting induced plasticity, we introduce the term ‘psychoplastogen’ from the Greek roots psych- (mind), -plast (molded), and -gen (producing).” These drugs cause nerve cells in the brain to form new neurites, i.e., projections that extend out from the cell body and have the potential to become axons and dendrites. In addition, these agents enhance the ability of nerve cells to interact with other nerve cells by increasing the number of synapses — the regions where nerve cells connect with one another.

Ketamine appears to be an example of one such drug. Ketamine has been shown to have rapid antidepressant and anti-suicidal properties. Ketamine-like drugs are likely to be approved by the Food and Drug Administration (FDA) for the treatment of depression in the future. Ketamine works by influencing brain receptor systems that respond to the neurotransmitter glutamate. The glutamatergic system then stimulates a variety of chemical pathways in nerve cells that control cell growth and cell connections.

Ly, Olson, and colleagues elegantly demonstrate that another group of drugs are as powerful, or even more powerful, than ketamine in causing cellular changes in brain cells. Whereas ketamine exerts its effect through glutamate-related systems, these other drugs work through serotonergic systems. Although they involve different neurotransmitters, the effects of both groups of drugs lead to similar influences on the chemical systems inside neurons that are involved in growth and development.

Read the full article:

https://www.psychologytoday.com/us/b...ychoplastogens

 

[mr peabody]

An Introduction to Psychedelic Tryptamine Chemistry

by Faan Rossouw

This paper is intended for the general reader that has an appreciation for the beauty of chemistry, and/or desire to learn more about it. I am going to be pedantic throughout the paper, deconstructing technical terms and “dirty pictures” with the assumption that you do not know what they mean. That way we can learn them as we go along. If you are already fluent in Chemistrian, it goes without saying that you are free to skip over these and peruse selectively. This first section is an introductory exploration of the tryptamine class, and will be followed by further forays into other interesting aspects related specifically to this class before I move on.

The Three Main Classes of Psychedelics

There are three classes to which most psychedelic compounds belong – tryptamines, phenethylamines, and ergolines. The tryptamines include most of the well-known naturally-occurring psychedelics, including compounds derived from entheogenic fungi (psilocybin and psilocin), DMT, 5-MeO-DMT, bufotenin, and ibogaine. Mescaline is the only common naturally-occurring phenylethylamine, yet the class includes numerous well-known synthetic compounds such as MDMA and the 2-C’s. Ergolines most notable representatives include the naturally-occurring LSA and the semi-synthetic compound that turned on a generation, LSD.

Tryptamines

Psychedelics of this class are all derived from tryptamine (Figure 2), a ubiquitous endogenous ligand and agonist of the human trace amine-associated receptor 1 (TAAR1). The name tryptamine is derived from its structural similarity to l-tryptophan, an essential amino acid and the precursor to both serotonin and melatonin.

Figure 2. Tryptamine consists of an indole ring connected to an amine through an ethyl attached to position 3.


Substituted Tryptamines

Although the “template” for psychedelics tryptamines is the molecule with all the various positions presented in Figure 2, in actuality there are limitations to how this manifests in psychedelic compounds. This is either because certain modifications are either difficult to impossible, or they lead to inactive compounds. An example of this is if something is attached to position 2 (Figure 2) the compound becomes a serotonin-2A receptor antagonist therefor losing its psychoactivity. Based on these restrictions we can simplify the template presented in Figure 2 to Figure 4, which is called the ‘substituted tryptamine’. The three main changes that synthetic chemists can make to derive psychedelic analogs is derived from this figure.

Figure 4


First, one can add side chains to either position 4 or 5, and those side chains have to contain an oxygen molecule. We can confirm this by looking at all the well known psychedelic compounds that have side chains attached to the ring – bufotenine has a hydroxyl (OH) group at position 5, 5-MeO-DMT has a methoxy (O-CH3) at position 5, psilocin has a hydroxyl (OH) group at position 4, and psilocybin has a phosphoryloxy (OPO3H2) at position 4. All at position 4 or 5, all with an oxygen included.

Read the full article:

http://altdotmind.com/an-introductio...ine-chemistry/

 

[mr peabody]

Towards an integration of psychotherapy and pharmacology: Using psychedelic drug-assisted psychotherapy

The fields of psychology and psychopharmacology have developed along surprisingly divergent historical trajectories, given their shared clinical endpoint. The subsequent schism between drug and psychotherapeutic treatments is artificial, and exaggerated by continued ignorance on both sides of the debate. In fact, such distinctions are relatively contemporary. There exists a rich history of shared psychotherapeutic-drug assisted clinical practices in pre-history and non-Western cultures using the psychedelic (hallucinogenic) drugs. These practices were re-invented in the 1950s and 1960s in Western medicine and are now enjoying a renaissance in contemporary research. It is postulated in this article that further development of psychedelic drug-assisted psychotherapy offers a bright future for the fields of psychology and psychiatry alike.

There exists in psychiatry a fundamental rift between our understanding of mental states (psychological processes) and brain states (organic or neurobiological processes). The Cartesian model drives both professionals and the general public to erect an immovable barrier between the mental and the physical. Despite decades of research into the neurophysiology of the brain, modern psychiatry’s continued pursuit of the pharmacological quick fix maintains this dualistic schism.

This essay will postulate a resolution of these contrasting models through the use of discrete, targeted, drug-assisted psychotherapy using specific pharmaceutical agents (the psychedelic drugs) that directly enhance the psychotherapeutic experience. A brief history of these drugs, their usefulness, their limitations and the state of modern research with psychedelics will be discussed in this paper.

The trouble with pharmacology

Despite their limitations, many of the drugs available to today’s psychiatrist are effective at relieving some of the symptoms of mental disorder. This is well-documented by scientific studies and supported by regulatory bodies such as the National Institute for Clinical Evidence (NICE) that make evidence-based recommendations for doctors to use as part of their clinical practice.

Nevertheless, the multiple factors (from genetics and the environment) that cause mental illnesses shape the vast range of treatment options available. Although drugs may have a role, they alone are insufficient to resolve problems. Combination therapies (psychotherapy alongside medication) are often the most effective. And there are always risks when prescribing medication. The incidence of iatrogenic illness increases year on year and is illustrated particularly in psychiatry. Despite the efforts of the NICE, there are sceptical voices about the ethics of drug trials that are financed and run by the pharmaceutical industry - who clearly have a product to sell.

Read the full article:

https://psychedelicpress.co.uk/blogs...-therapy-sessa

 

[mr peabody]

This is LSD attached to a brain cell serotonin receptor

For the first time, UNC School of Medicine researchers crystalized the structure of LSD attached to a human serotonin receptor of a brain cell, and they may have discovered why an “acid trip” lasts so long.

CHAPEL HILL, NC – A tiny tab of acid on the tongue. A daylong trip through hallucinations and assorted other psychedelic experiences. For the first time, researchers at the UNC School
of Medicine have discovered precisely what the drug lysergic acid diethylamide (LSD) looks like in its active state when attached to a human serotonin receptor of a brain cell, and their first-ever crystal structure revealed a major clue for why the psychoactive effects of LSD last so long.

Dr. Brian Roth

Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in the UNC School of Medicine, led the research, which was published today in Cell.

“There are different levels of understanding for how drugs like LSD work,” Roth said. “The most fundamental level is to find out how the drug binds to a receptor on a cell. The only way to do that is to solve the structure. And to do that, you need x-ray crystallography, the gold standard.”

That is what Roth’s lab accomplished – essentially “freezing” LSD attached to a receptor so his team could capture crystallography images. As it turns out, when LSD latches onto a brain cell’s serotonin receptor, the LSD molecule is locked into place because part of the receptor folds over the drug molecule, like a lid. And then it stays put.

Read the full article:

https://www.med.unc.edu/pharm/news/...d-attached-to-a-brain-cell-serotonin-receptor

 

[mr peabody]

Neuroendocrine associations underlying the persistent therapeutic effects of classic serotonergic psychedelics

Emmanuelle A. D. Schindler, Ryan M. Wallace, Jordan A. Sloshower & Deepak C. D’Souza

Recent reports on the effects of psychedelic-assisted therapies for mood disorders and addiction, as well as the effects of psychedelics in the treatment of cluster headache, have demonstrated promising therapeutic results. In addition, the beneficial effects appear to persist well after limited exposure to the drugs, making them particularly appealing as treatments for chronic neuropsychiatric and headache disorders. Understanding the basis of the long-lasting effects, however, will be critical for the continued use and development of this drug class. Several mechanisms, including biological and psychological ones, have been suggested to explain the long-lasting effects of psychedelics. Actions on the neuroendocrine system are some such mechanisms that warrant further investigation in the study of persisting psychedelic effects. In this report, we review certain structural and functional neuroendocrinological pathologies associated with neuropsychiatric disorders and cluster headache. We then review the effects that psychedelic drugs have on those systems and provide preliminary support for potential long-term effects. The circadian biology of cluster headache is of particular relevance in this area. We also discuss methodologic considerations for future investigations of neuroendocrine system involvement in the therapeutic benefits of psychedelic drugs.

Introduction

There has been a resurgence of interest in the therapeutic potential of classic serotonergic psychedelic drugs, such as psilocybin, LSD, and DMT, all compounds that bind and activate serotonin 2A receptors. Psilocybin has been reported to treat depression and anxiety in cancer patients, obsessive-compulsive symptoms, and alcohol and tobacco addictions, as well as enhance attitude, mood, and behavior. In early studies, LSD has been shown to be effective in the treatment of alcoholism, and it improved affect and sleep while reducing pain in cancer patients. More recently, LSD has been shown to improve quality of life in patients with life-threatening disease. Surveys have also described relief from cluster headache with LSD and psilocybin. Ayahuasca, the botanical brew containing DMT and a monoamine oxidase A inhibitor, produces an antidepressant effect and reduces symptoms of panic and hopelessness. There are ongoing studies investigating the effects of psychedelics in depression, drug and alcohol addiction, and headache disorders. One of the most intriguing features of psychedelics’ therapeutic profile is the apparent persistence of therapeutic effects after limited exposure, such measures as antidepressant effects, cigarette smoking reduction/cessation, and termination of cluster headache attacks. While the mechanisms of this ability to produce long-term effects are not fully understood, neuroplastic, genetic, and psychological, processes are some of those postulated to be involved. The neuroendocrine system is another potential player in the lasting effects of psychedelics after limited exposure, particularly as the conditions shown to benefit from psychedelic therapy have demonstrable neuroendocrine aberrations. In this review, we describe certain structural and functional aspects of the neuroendocrine pathologies in neuropsychiatric disorders and cluster headache, as well as the effects that classic serotonergic psychedelics have on these systems. Where applicable, those associations with the most supportive evidence for a persisting therapeutic effect will be discussed. This review will also serve to unify existing theories for the persisting effects of classic serotonergic psychedelics and highlight methodological strategies for future research in this area.

Theories for the persisting effects of classic sertogeneric psychedelics

Classic serotonergic psychedelics are those compounds that bind and activate the 5-HT2A receptor and cause significant alterations in sensorium and consciousness. While other drugs, such as MDMA, THC, and ketamine, are often included in the category of psychedelic drugs and may have indirect effects on 5-HT2A receptors, their pharmacology is nevertheless distinct. For the purposes of this discussion, the pharmacologic definition of a 5-HT2A receptor agonist with psychotropic effects will be used when discussing psychedelics. The terms psychedelic and hallucinogen will also be used interchangeably.

The pharmacology of psychedelics has long been considered in their unique effects. The primary focus has involved the 5-HT2A receptor, as the binding affinity of psychedelics at this receptor is strongly correlated to the typical human dose for hallucinogenesis. The roles of specific intracellular 5-HT2A receptor components and scaffolding proteins, such as B-arrestin, have been considered in identifying a marker for hallucinogenesis. The relative potencies and efficacies at activating 5-HT2A-mediated phosphatidylinositol hydrolysis and arachidonic acid release have also been investigated, but were not found to predict psychedelic potency or discriminate psychedelic from non-psychedelic drugs.

The density of 5-HT2A receptors can be manipulated to measure changes in the response to psychedelics. For instance, repeated daily administration of the psychedelic DOI in rats and rabbits leads to a reduction in cortical 5-HT2A receptor density by about 50%. Serotonin2A receptor reduction is accompanied by significant attenuations in 5-HT-elicited PI hydrolysis signaling, as well as psychedelic-elicited behaviors, such as head movements in rodents and rabbits. In rats, chronic administration of either LSD or DOI attenuated the locomotor inhibition induced by either drug. Similarly in rabbits, chronic administration of DOI significantly decreased the head bob response to either DOI or LSD. Such cross-tolerance was also shown in cats when a single dose of the psychedelics DOM, LSD, or mescaline attenuated DOM-elicited behaviors 24 h later. In humans, tolerance, or tachyphylaxis, to a psychedelic’s effects occurs within about 3 days of daily exposure; sensitivity returns in about as many days. Unlike other psychedelics, however, DMT does not readily induce tolerance, which may be due to its short half-life or other yet unidentified factors. For instance, human subjects who received closely spaced repeated administrations of intravenous DMT failed to demonstrate tolerance to the psychedelic effects of the drug. The ability of psychedelics to induce tolerance is relevant in the consideration of their use as therapeutic agents.

Read the full article:

https://gizmodo.com/new-lsd-research...y-o-1823901901

 

[Skorpio]

The Ly paper is a really good one, as is the Swanson paper, which imo is one of the better descriptions of the psychadelic experience.

The Ly paper brings up a very interesting question: "can the neurogenic effects of psychadelics be divorced from the psychological trip?"

 

[clubcard]

The only things I can add is that 7,N,N TMT is VERY DMT-like to some people, kind of unpleasent to others while α,7-dimethyltryptamine (being chiral) when resolves is like AMT (S) AND like MDA (R). Now Upjohn went to α-ethyltryptamine & 7-methyl & 7-methyl- α-ethyltryptamine BUT they both have significant MAOI activity and are hazardous. The 7-Me DOES result in a lower duration (the 7-Me offers the body a site to oxidise) so if you can resolve, α,7-dimethyltryptamine offers an MDA & 4-6 hour AMT-like compound but the mixture is viewed from 'amazing' right through to 'awful' so I do wonder if the metabolism makes the racemate less reliable.

 

[novaveritas]

The only things I can add is that 7,N,N TMT is VERY DMT-like to some people, kind of unpleasent to others while α,7-dimethyltryptamine (being chiral) when resolves is like AMT (S) AND like MDA (R). Now Upjohn went to α-ethyltryptamine & 7-methyl & 7-methyl- α-ethyltryptamine BUT they both have significant MAOI activity and are hazardous. The 7-Me DOES result in a lower duration (the 7-Me offers the body a site to oxidise) so if you can resolve, α,7-dimethyltryptamine offers an MDA & 4-6 hour AMT-like compound but the mixture is viewed from 'amazing' right through to 'awful' so I do wonder if the metabolism makes the racemate less reliable.

So youre claiming α,7-dimethyltryptamine, (7 methyl AMT) doesn't have the great and potentially very dangerous properties (lethal) of being simultaneously an MAOI and a serotonin releaser? Sounds like highly implausable and dangerous speculation