PHARMACOLOGY | +80 articles

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Producing synthetic psilocybin from bacteria and yeast, study*​

by Tanya Ielyseieva | Truffle Report | 15 Feb 2022

In recent years, advancements in the field of psychedelic medicine have been gaining attention, and bringing with them their own concerns about sourcing and production. While psychedelic drugs remain largely illegal for recreational use, a growing body of research is exploring their potential application for the treatment of both mental and physical health conditions, including major depressive disorder, anxiety, alcohol use disorder, and PTSD. Psilocybin mushrooms are most prominent among the psychedelic drugs being researched for their therapeutic potential.

For the new psychedelic industry, the process of extracting psilocybin from these psychedelic mushrooms should ideally produce results that are both timely and cost-effective in order to administer repeatable mental health treatments. However, the current extraction techniques have their challenges, which can include inconsistent yields and chemical instability for natural mushrooms, and a higher price tag for synthetic psilocybin.

At present, scientists are exploring new ways to produce psilocybin without needing to grow magic mushrooms or rely on conventional methods of extracting and producing synthetic psilocybin. COMPASS Pathways has developed and patented a new method of isolating psilocybin through chemical synthesis without the need for any magic mushrooms. While this method can create pure psilocybin, COMPASS Pathways uses 4-hydroxyindole as a starting substrate which results in high production costs with 4-hydroxyindole being around $350 CAD/$275 USD per gram.

As such, scientists are also investigating alternative, biologically-derived methods to produce psilocybin.

Extracting psilocybin from E. coli?

In a 2019 study published in the journal Metabolic Engineering, Miami University researchers led by Andrew Jones discovered a way to sustainably produce psilocybin. The team of researchers took genes responsible for producing psilocybin, added them to the bacteria E. coli, and created a new strain called pPsilo16.

“We are taking the DNA from the mushroom that encodes its ability to make this product and putting it in E. coli,” said Jones. “It’s similar to the way you make beer, through a fermentation process. We are effectively taking the technology that allows for scale and speed of production and applying it to our psilocybin producing E. coli.”

The new strain serves as a “modular biosynthetic production platform” for the psychedelic compound.

“Once we transferred the DNA, we saw [a tiny] peak emerge in our data. We knew we had done something huge,” said Alexandra Adams, lead author.

"The fermentation process for the bacteria resulted in 1.16 g/L of psilocybin – the highest psilocybin titer achieved to date from a recombinant organism and a significant step towards demonstrating the feasibility of industrial production of biologically-derived psilocybin.”

“What’s exciting is the speed at which we were able to achieve our high production. Over the course of this study we improved production from only a few milligrams per liter to over a gram per liter, a near 500-fold increase,” said Jones.

Jones is focused on making the E. coli bacteria a better host in the follow-up clinical studies – the next step toward enabling sustainable production of psychedelic mushrooms at levels required by the pharmaceutical industry.

“This work shows the first reported case of in-vivo psilocybin production using a prokaryotic host,” the study states. “Furthermore, this work highlights the power of tandem genetic and fermentation optimization to quickly identify key process parameters required to enable successful scale-up studies culminating in gram scale production of a high-value chemical product.”

A Danish study and Octarine Bio’s yeast-based production method

A team of Danish researchers at the Technical University of Denmark has presented a novel method for producing high amounts of psilocybin using baker’s yeast, Saccharomyces cerevisiae.

“It’s infeasible 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,” said Nick Milne, former Postdoc at DTU Biosustain and CSO and co-founder of Octarine Bio.

The yeast expresses a key enzyme involved in the psilocybin production pathway and doesn’t need to involve expensive chemicals, reducing the cost of the final product.

“To modify yeast to produce psilocybin, we took the genes that Psilocybe cubensis uses to produce psilocybin, optimized them for expression in yeast, then, through genetic engineering, introduced these genes into the genome of our yeast. The production of psilocybin starts with the amino acid tryptophan, which yeast also naturally produces from simple sugars. To further boost psilocybin production, we increased the yeast’s ability to produce tryptophan by modifying a few of its genes to help channel the yeast’s metabolism towards this amino acid. This is actually a really important aspect of metabolic engineering; these days it’s usually relatively straightforward to engineer an organism to produce a foreign molecule, but getting the organism to produce enough of the molecule to be commercially relevant is a key challenge in the field,” Milne explained in an interview with Technology Networks.

Chemical materials needed to synthesize psilocybin can be expensive, whereas glucose is relatively cheap. The psilocybin compound can be produced in yeast requiring only the addition of sugar and other nutrients.

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

The experiment resulted in 627 mg/L of psilocybin and 580 mg/L of psilocin. Although this number is less than the E. coli study, it was also cheaper to extract.

“The main challenge is to increase the amount of sugar that gets converted into psilocybin. Beyond that, to reach commercial-scale production satisfactory enough to be used for human clinical trials, we need to scale the process from one liter to thousands of liters. The fermentation development is critical, and of course, the other issue that we need to look into is how to efficiently purify psilocybin from the fermentation broth,” said Milne in an interview with Mind Foundation.

*From the article here :

No Need for Magic Mushrooms? Producing Synthetic Psilocybin from Bacteria and Yeast

Scientists are using bio-based methods to produce psilocybin from yeast as an alternative to conventional mushrooms growing.

www.truffle.report

 

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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."

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.

New Biosynthesis of Psilocybin and Related Tryptamines

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.

psychedelicreview.com

 

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Scientists create potential cell-based 5-MeO "bio-factory"*

by David E. Carpenter | LUCID | 8 Feb 2022

Medical doctor and researcher Leonard Lerer, along with scientists at the biotechnology company he founded, Back of the Yards Algae Sciences (BYAS), are on their way to making what they claim is the first important scientific contribution toward helping to conserve toad populations. The company says they have successfully reproduced toad parotoid glands and the world’s first known cell-based 5-MeO-DMT, essentially recreating the basic parts of the cell’s structure to carry out the physiological processes of the organism.

“This is breakthrough work,” says Lerer, “as not only is it now possible for researchers to get naturally derived 5-MeO-DMT without milking toads, but it also makes a contribution to the conservation of Incilius alvarius.”

According to Lerer, his company is forging a new trail in creating sustainable, cruelty-free 5-MeO-DMT with a near-term plan of providing researchers — completely free of cost — the cell-based toad material to study. His company plans to operate in the spirit of open science, similar to a statement recently signed by hundreds of scientists working with psilocybin, MDMA, and similar substances, to share in the common good rather than for private gain. “We will give the extract free of charge to researchers on the basis of a commitment to open science. That is, that they make their results publicly available,” says Lerer.

Providing cell-based toad venom to an admittedly limited number of researchers studying 5-MeO-DMT may seem a small contribution relative to the amount of people using toad venom in non-clinical settings. But BYAS’s longterm plan could make a significant difference, says Lerer. He says his company looks to deploy a combination of “cellular agriculture, computational biology, and pre-clinical technologies for the discovery and development of safe, effective, active psychedelic molecules.”

The drug development and clinical testing work for this effort will be done through BYAS’ partner company, Parow Entheobiosciences, which was established to advance their cell-based psychedelics into clinical development for major psychiatric and neurological conditions. According to Lerer, the BYAS-PEB partnership is intended to take the “FDA route” and anticipates an initial meeting with the FDA before the end of 2022 for its first indication of OCD.

Cell-based psychedelics

BYAS was established in 2018 to develop and sell natural food colorant (a booming market that’s projected to be worth $3.2 billion by 2027). It is now focused on sustainable, zero-waste innovations in algae and mushroom extracts for food and agriculture. While investigating the transformative potential of algae and mycelia in food, agriculture, and health, the company expanded their portfolio of sustainable solutions and began producing a line of plant-based products. This includes what the company says is a breakthrough algal heme analog to make plant-based meats taste better (a direct competitor to the Impossible burgers’s GMO soy-based heme).

Then COVID-19 hit, says Lerer, creating a pause and an opening for his current work with cell-based psychedelics. He says their cell-perpetuating mindset was a natural fit for the company’s mission of waste reduction, sustainability, zero-cruelty and re-use of limited resources.

“The pandemic forced us to slow down our production,” says Lerer. “But it has been a huge driver of innovative ideas and some incredible internal initiatives. We had time to grow our R&D program on cellular agriculture of psychoactive tryptamine derivatives for conditions such as PTSD, depression, OCD and addiction.”

Part of that shift towards tryptamines has included obtaining a coveted Drug Enforcement Administration analytical laboratory license to produce those robust cells from toad parotoid glands, which have proven to produce good yields of 5-MeO-DMT that keep on giving. “Our measurements of yield and concentration make us confident that we can upscale,” says Lerer. “We also have proof of concept that we can produce immortalized cell lines that are essentially a bio-factory.”

Lerer and his collaborators, including his brother Professor Bernard Lerer — a neuropsychiatrist and neuropharmacologist — were so confident of their innovation and its promise that in December, 2021, they announced the milestone at an annual meeting of the American College of Neuropsychopharmacology, the world’s leading forum for cutting-edge science on brain function and psychotropic drugs.

During this conference, the BYAS researchers announced the successful production of 5-MeO-DMT from parotoid gland cells taken from an unharmed Sonoran Desert toad. They used these cells to create immortalized cell lines, a technique used extensively in the cultured or lab grown meat industry.

According to Lerer, a paper is currently in preparation for submission to a peer-reviewed journal that will contain detailed methods to ensure that these experiments can be replicated and validated by other researchers. Lerer says that the procedure of harvesting these cells is as invasive as a human topical dermatological biopsy and the donor toad remains alive and thriving.

Is toad-derived 5-MeO equal to synthetic?

Candida Pino, who leads psychedelic ceremonies and is a proponent of using only synthetic 5-MeO-DMT, is a Sonoran Desert toad conservationist. She describes the intrusive practice of collecting toad-derived 5-MeO-DMT. “Incilius alvarius are captured when most active from late May to September when they come out of hibernation,” says Pino. “Held firmly in hand, toads are forced to expel self-protective toxins by squeezing the parotoid glands located behind their eyes. Collecting them to forcefully eject these toxins adds to the list of already significant environmental stressors they endure, including climate change, introduction of fungal pathogens, and habitat loss.”

She notes that a belief that toad-derived 5-MeO-DMT provides a purer experience than synthetic is not the same as scientific evidence. “Anecdotal evidence suggests that the effects of 5-MeO-DMT are the same whether it is delivered via toad toxins or synthetic,” says Pino. “A preference for ‘natural’ is based on a perception that is not scientifically based but is likely more of a placebo effect.”

Lerer’s team looks to get to the bottom of that. BYAS is examining the potential entourage effect of natural toad venom and checking if those anecdotal reports of its superiority are indeed factual. In collaboration with Hadassah BrainLabs in Israel — which studies non-human models of psychiatric and neurological diseases — BYAS and PEB are exploring whether natural, full-spectrum entheogens including psilocybin outperform synthetic psychedelics in conditions such as depression, OCD, and PTSD, including on measures of neuroplasticity. Lerer believes the data from those tests will inform their cell-based toad venom work moving forward. He says the first results will be available later this year and all results will be presented at conferences and published in peer-reviewed journals.

“In three to four months we’ll have the psilocybin comparison data,” says Lerer. “This platform will then be used for toad secretion to answer the similar question: is natural really better than synthetic or is this anecdotal?”

The bigger picture, says Lerer, includes BYAS and PEB collaborating to identify other natural entheogenic molecules or combinations of molecules that can treat specific conditions, including OCD (their lead indication), depression, PTSD, autism, schizophrenia, and TBI. With this goal in mind, he says BYAS is building up its library of entheogenic biomass including hundreds of different types of mushrooms, cacti, and plants.

To protect their Incilius alvarius research, BYAS has stated its intention to make its patented cell reproduction process available to other researchers in the future. The company is concerned that they and other researchers will have similar obstacles that psilocybin companies are currently experiencing. This includes trying to secure patents on natural molecules that are part of the planet’s entheogenic heritage. Lerer says he wants to prevent that, adding, “Our aim is to make our cell-based Incilius alvarius extract available to other researchers and focus on identifying novel molecules with therapeutic applications.”

*From the article here :

Scientists Create Cell-Based Psychedelic Toad Venom, a Potential 5-MeO-DMT “Bio-Factory” - Lucid News

The innovation may be the ethical alternative to the controversial practice of collecting Bufo toad venom.

www.lucid.news

 

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Morning glories may be a source of new psychedelics and medicines

New research shows that the compounds are contained in multiple species.

by B. David Zarley | FREETHINK | 17 Jan 2022

With their beautiful blue trumpet bells unfurling to greet the sun, the morning glory adds a splash of color to the start of your day.

Its seeds, however, may do a bit more than that — new research has found that, thanks to a symbiotic relationship with a fungus, this common flower may be a source for new psychedelic drugs.

The flower-fungus relationship can lead to the creation of compounds called ergot alkaloids. Ergot alkaloids have been used to treat Parkinson’s disease and brutally painful migraine and cluster headaches for decades. But they’re also closely related to LSD.

Examining the seeds of morning glories taken from collections around the globe, researchers from Tulane, Indiana University, and West Virginia University found that a quarter of the 210 morning glory species they examined had some form of ergot alkaloid in their seeds.

“We have known a lot about the fungal alkaloid chemistry and its effects on the mind and body for a long time,” Tulane plant and fungal biologist Keith Clay said.

This new study is the first to show just how intermingled morning glory and egot evolution is — a relationship that is “manifested by different mixtures and concentrations of ergot alkaloids across the morning glory evolutionary tree.”
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New research has found that, thanks to a symbiotic relationship with a fungus, the common flower may be a source of new psychedelic compounds called ergot alkaloids.​

In some cases, that symbiotic relationship can be encoded in evolution, the authors explain in their study, published in Communications Biology. Organisms that help another one out may get a leg up in the reproduction game, like wasps who harbor bacteria that produce compounds which help fight off infection in their larvae — larvae that have inherited the microbial symbiote from their mother.

Some plants have a similar relationship with fungi. In certain grasses, the ergot fungus — cause of Saint Anthony’s Fire — creates ergot alkaloids that don’t stay contained in the fungus’s thready, root-like structures, but can actually be passed down in the seeds.

These ergot alkaloids make the plants less fun to eat, and everybody wins.

Some species of morning glory have forged a similar relationship. The ergot alkaloids contained in their seeds “have been of longstanding interest given their toxic effects on humans and animals, medical applications and psychoactive properties,” the researchers wrote.

One ergot alkaloid, lysergic acid, is particularly famous: it’s the inspiration behind LSD, a synthetic derivative.
​

Ergot alkaloids inspired LSD, and treat migraines and Parkinson’s.​

New potential: Naturally occurring ergot alkaloid compounds have long been used among Indigenous American communities for their mental and physical effects.

Finding a trove of new ergot alkaloid compounds means potential for new psychedelics, which in turn may end up being useful as mental health therapies or perhaps anti-inflammatories.

The new compounds may have uses beyond the psychedelic. Currently, ergot alkaloids’ potential to constrict the blood vessels around the head also make them cluster and migraine headache medications, while their ability to goose nerve cells in a way similar to dopamine means they can be used as a treatment for Parkinson’s.

The researchers reported 36 new ergot alkaloid compounds, suggesting to them that even more examples of the symbiosis will be uncovered with continuing research.

Morning glories may be a source of new psychedelics and medicines

Researchers have found that the symbiotic relationship between a fungus and a morning glory holds the potential for new psychedelic compounds and medicines.

www.freethink.com

 

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

Sprucing up your brain with Potent Psychedelics

al fin next level | 15 June, 2018

A new study in the journal Cell Reports found that 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.

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.

The neuroplasticity described in the 12 June 2018 paper in Cell consists of “neuritogenesis,” or the growth of dendrites and synaptic buttons — providing a denser connectivity between neurons. Another form of neuroplasticity which may take place under some conditions is “neurogenesis,” or the growth of stem cells which develop into neurons. In adults, this may occur in the hippocampus and along the ventricular lining of the brain. The hippocampus is the region of the medial temporal lobes thought to play a prominent role in the retention of long term memories. More on hippocampal neurogenesis:

Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis.

It is possible that some psychedelic mixtures may stimulate the transition of neural stem cells into functioning neurons:

When grown with ayahuasca compounds, the stem cells in the neurospheres also began to differentiate (change their properties) to resemble neurons more effectively than under control conditions. This means that the stem cells started to lose their stem-cell-like properties, and started making proteins that are found in adult neurons. Overall, it seems that exposing neural stem cells to harmine, THH, and harmaline encourages them to grow and change into new neurons more effectively than under control conditions.

This is all very controversial

Many neuroscientists still doubt that adult human brains can generate new neurons past adolescence. Proving that psychedelics can promote the growth of new neurons in the brain (eg hippocampus) will take some time, and perhaps a somewhat different perspective on neuropharmaceutical ethics than is dominant at this time.

It is less controversial to pursue the use of ketamine derivatives to promote new “branching” of existing neurons. But ketamine does not seem to be as effective at neuritogenesis as LSD, DMT, or psilocybin. In other words, some old prejudices may need to fall in order to achieve a better solution to an age-old scourge of the human spirit.

Here at the Al Fin Institutes of Neuroscience, we prefer the use of occasional treatments for chronic ailments over the everyday medication of persons. As people age, their ailments may tend to accumulate — as do the number of treatments required. Many persons may take as many as 10 to 20 medication doses per day. The use of psychedelics or psychedelic analogs for treating depression would likely be of an intermittent nature, rather than daily, and would help to cut down on the total daily dosage regimen.

We actually prefer to avoid medication altogether

If possible, the avoidance of pharmaceuticals is best. Electromagnetic or photic approaches to treating depression are preferred, as are other alternatives such as advanced neurofeedback, mindfulness, and cognitive behavioural therapies.

Still, some people have experienced relief from depression lasting 6 months or longer from a single psychedelic experience, if well designed and overseen.

We have barely begun to understand all the productive approaches to functional neuroplasticity in the treatment of neurologic and neuropsychiatric disorders.

Renewed scientific interest in the use of psychedelics to treat disorders of the spirit can be seen as a positive sign.

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

 

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An introduction to Psychedelic Phenethylamines​

by Ben Malcolm | Spirit Pharmacist | 7 May 2021

Phenethylamine (PEA) is a neurotransmitter that is naturally produced by our bodies. The chemical structure of phenethylamine also acts as a backbone for a variety of sympathomimetics with activity at sympathetic and central nervous systems.

How do phenethylamines act?

Phenethylamines can exert a variety of effects that varies from agent to agent based on the way it interacts with its neuronal target. Phenethylamine can cause neurotransmitter release through interactions with neurotransmitter packaging and reuptake pumps. It can also block those neurotransmitter reuptake pumps to increase the amount of neurotransmitter in the synapse. Phenethylamine can also directly stimulate the postsynaptic receptors to exert its effects.

Classes of phenethylamines

Phenethylamines could be broadly categorized into four classes: neurotransmitters, non-psychoactive sympathomimetics, psychostimulants, and ‘psychedelics’

The neurotransmitter class includes phenethylamine itself as well as norepinephrine, dopamine, and epinephrine which are endogenous catecholamines that act as chemical messengers at adrenergic and dopaminergic synapses.

Some phenethylamines have been selectively engineered for specificity at certain adrenergic receptors. For example, albuterol and phenylephrine are selective for postsynaptic adrenergic receptors. Phenylephrine specifically binds alpha-1 receptors which causes vascular smooth muscle contraction leading to vasoconstriction. Albuterol specifically binds the beta-2 receptors on smooth muscle to cause relaxation which leads to bronchodilation and airway opening. These agents are considered non-addictive and non-psychoactive.

Psychostimulants include amphetamine, methamphetamine, methcathinone and cathinone which are non-selective for adrenergic receptors in the sympathetic and central nervous system. Activation of receptors by these agents induces a release of norepinephrine and dopamine neurotransmitters from the synapse. The release of dopamine by the presynaptic cell is thought to give rise to the addictive potential of these agents.

Phenethylamine psychedelics

There is only one phenethylamine that is a classic psychedelic, which is mescaline. MDMA and other novel designer psychostimulants often include serotonergic pharmacology and many act to increase serotonin or bind ‘psychedelic’ 5HT2A receptors. These substances often have considerable pharmacology at other neurotransmitter systems such as dopamine and norepinephrine. These drugs typically release serotonin more readily than norepinephrine or dopamine and are thought to provide a hybrid of psychostimulant and psychedelic properties. MDMA and many others may be arguably better classified as enactogens ‘to touch within’ or empathogens ‘generating a state of empathy’ than psychedelics ‘mind-manifesting’. They are colloquially considered “heart openers” due to effects increasing emotional openness and expansiveness. Novel psychedelic phenethylamines and their ranges in effects are described in Alexander and Ann Shulgin’s work PIHKAL.

More recent trends in designer psychedelic stimulants have utilized cathinone rather than amphetamine as the chemical backbone to create a new genesis of analogous compounds to various amphetamine-based psychedelic stimulants. For example, methylone is the cathinone-version of MDMA. These analogues may share much overlapping pharmacology, although there are also significant differences in their effects.

Psychedelic phenethylamines | Targets and effects

Psychedelics phenethylamines have a wide variety of target receptors, although commonly have serotonergic action and it could be considered a pharmacologic definition of their class that they have activity or bind with 5HT2A receptors. Activity at other post-synaptic receptors (e.g. 5HT1A, 5HT2C) may also influence effects. Their activity at norepinephrine and dopamine neurotransmitter systems is shared with traditional psychostimulants.

Psychedelic phenethylamines commonly act to increase neurotransmitter levels, oftentimes by interrupting storage of neurotransmitters in vesicles and reversing the flow the neurotransmitter reuptake pumps. Some may appreciably block neurotransmitter reuptake themselves or have inhibitory activity at monoamine oxidase.

The actions on the monoamine systems (serotonin, norepinephrine, dopamine) differ between substances, ultimately causing variations in subjective experience, safety, and addictive potential. Psychedelic phenethylamines often comes in a 'series' of compounds (e.g. DOx, 2Cx, 25x-NBOMe). Let’s take a quick look at MDMA as a ‘reference’ compound.

MDMA

MDMA could be considered a reference compound for psychedelic phenethylamine activity. It has a complex mechanism of action which is primarily serotonergic. MDMA causes a release of primarily serotonin from presynaptic vesicles through VMAT2 inhibition. The SERT receptor reverses the normal reuptake flow of serotonin and releases 5HT back into the synapse causing an intrasynaptic increase in 5HT. The process of MDMA’s release of serotonin has been termed ‘carrier-mediated’ release. This increase in serotonin neurotransmission increases activation to the 5HT2A receptors, which MDMA also weakly binds. Due to its ability to increase serotonin there is a potential for serotonin toxicity to occur with MDMA overdose or when mixed with monoamine oxidase inhibitors (MAOIs). Contraindication with MAOIs is common to psychedelic phenethylamines due to so many having significant effects in increasing neurotransmitters. There are additional neurohormonal effects of MDMA to consider due to the release of oxytocin and antidiuretic hormone. Neurohormonal effects could play a role in therapeutic effects (oxytocin - enhanced bonding and trust) or adverse effects (antidiuretic hormone - SIADH).

Addiction potential of psychedelic phenethylamines

The addiction potential of phenethylamines is likely driven by pleasurable and euphoric effects in addition to dopamine-mediated reinforcement. The variability in the ability of psychedelics to reinforcement properties creates a spectrum of addictive potential among agents:​

• Mescaline is not considered to be reinforcing and has low addictive potential​
• MDMA has some reinforcing properties and addictive potential, although release less dopamine than amphetamine​
• Novel designer phenethylamines with short durations of action and heavier release of dopamine carry significant addictive potential​

Phenethylamine toxicology

In addition to the addiction potential of these agents there are also toxicities associated with these agents when high doses are used chronically. Neurotoxicity can result in damage to serotonergic and/or dopaminergic neurotransmitter systems resulting in depression, anxiety, fatigue, insomnia, irritability, and difficulty with emotional regulation. As with any agent, overdose is a possibility with psychedelic phenethylamines. Overdose toxidromes may have features of stimulant overdose or serotonin syndrome present including hyperthermia, seizures or myoclonus, muscle rigidity, and complications such as rhabdomyolysis.

High notes

Psychedelic phenethylamines are part central nervous system stimulant and part psychedelic. Some may be more appropriately termed entactogens or serotonergic amphetamines than psychedelics. They are pharmacologically diverse in actions, yet all bind 5HT2A receptors. MDMA is being advanced in clinical trials although there are hundreds of other designer psychedelic phenethylamines that could have therapeutic potential. With widespread use of novel designer substances, processes of discovery could be accelerated, however uncertainty in risk profiles creates potential for significant risks to public health.

Introduction to Psychedelic Phenethylamines

This article introduces psychedelic phenethylamines, discusses mechanisms in which psychedelic phenethylamine exert effects, and summarize the genesis of novel designer phenethylamines

spiritpharmacist.mykajabi.com

 

[mr peabody]

Mescaline

Psychedelic Science Review

Mescaline is well known for being a compound found primarily in the tops (aka buttons) of the peyote cactus Lophophora williamsii.

Archaeologists have found evidence of the use of peyote by Native Americans as far back as 5,700 years ago, making it the oldest known plant drug containing a bioactive compound.

In their book PiHKAL: A Chemical Love Story, Alexander and Ann Shulgin dubbed mescaline one of the “Magical Half Dozen” compounds that they considered the most important out of all those they synthesized and studied.

The Chemistry of Mescaline

Mescaline is a phenethylamine alkaloid that is substituted at positions 3, 4, and 5 by methoxy groups.4 It was first isolated by Heffter in 1898. Ernst Spath was the first to synthesize mescaline in 1918. Slotta and Heller determined its correct molecular structure in 1930. The Shulgins described the appearance of pure mescaline synthesized in the lab as “magnificent”, adding, “Long, glistening needles that are, in a sense, its signature and its mark of purity.”

Over the years, a variety of synthesis methods for mescaline have been developed. The biosynthesis pathway of mescaline in L. williamsii and other species was determined in the 1960s. The synthesis begins with the amino acid tyrosine, which is hydroxylated to L-DOPA. Then, L-DOPA is decarboxylated to dopamine, which undergoes hydroxylation to 3,4,5-trihydroxy- ß-phenethylamine (5-hydroxydopamine). In the last step, 3,4,5-trihydroxy- ß-phenylethylamine is methylated to form mescaline. A recent study found genes in L. williamsii that code for enzymes such as tyrosine/DOPA decarboxylase, hydroxylases, and O-methyltransferases which may catalyze some steps of the synethesis.

The Pharmacology of Mescaline

Pure mescaline, either synthetic or isolated from a natural source, requires relatively high doses to achieve its full psychedelic effects. Peyote buttons contain a variety of compounds besides mescaline such as hordenine, N-methylmescaline, pellotine, anhalonine, and lophophorine. By themselves, some of these compounds have no psychopharmacological activity. But when administered in certain combinations, they potentiate and alter the effects of mescaline.

Mescaline is an agonist of the serotonin 5-HT2A and 5-HT2C receptors. It has a Ki (dissociation constant) of about 550 nM at 5-HT2A and 300 nM at 5-HT2C using cloned human receptors.

Although they are chemically unrelated, the hallucinogenic effects of mescaline are similar to LSD. Furthermore, cross-tolerance between mescaline and LSD is known to occur in humans.

Mescaline has a half-life in the human body of about 6 hours after oral administration. The compound is almost completely eliminated (92 percent) within the first 48 hours, most of it unchanged (55-60 percent). Urinary excretion peaks at about the second hour after ingestion. Urinary metabolites include 3,4,5-trimethoxyphenylacetic acid (27-30 percent), N-acetyl-ß-(3,4-dimethoxy-5-hydroxyphenyl) ethylamine (5 percent), and N-acetyl-mescaline (less than 0.1 percent).

The Applications and Potential of Mescaline

Despite the current interest in psychedelic research, there is virtually no work being done with pure mescaline. Historically, research studies have focused on the effects of peyote, which contains a cocktail of chemicals besides mescaline.

However, in 1966, a research team including James Fadiman and Myron Stolaroff studied the effects of mescaline on 27 healthy men, testing for changes in their problem-solving abilities. The results indicated that mescaline (and LSD, which they also tested) facilitated created problem-solving in the volunteers. They found the psychedelics particularly effective in the illumination (aka eureka) phase of problem-solving. The data also suggested that the improvement in problem-solving may last for several weeks.

*From the article (including references) here :

Mescaline

Mescaline is a compound found primarily in the tops (buttons) of the peyote cactus. Archaeologists have found evidence of the use of peyote by Native Americans as far back as 5,700 years ago, making it the oldest known plant drug containing a bioactive compound.

psychedelicreview.com

 

[mr peabody]

3,4,5-Trimethoxyphenethylamine

MEDIUM | 24 May 2022

“The mescaline experience is my favorite of the traditional psychedelics (LSD, psilocybin, mescaline). I find it has the advantages of acid: a lucid, penetrating, focused ability of the mind, rather than the more dreamy, drifting state I get from mushrooms. However, I feel totally relaxed with mescaline, even calmer than I feel on mushrooms, and there’s no trace of the metallic edge usually felt on acid.

Eating whole cactus produces a more body-oriented high than pure mescaline. San Pedro usually produces a very smooth, flowing experience. However, the effects of Peyote are quite different due to its unique mixture of alkaloids. With Peyote, the first couple hours of the experience are very dream-like, drifting, almost a delirium type state. During this time I feel groggy and sleepy and can do little more than lay back and sink into the feeling, which is not unpleasant. Some element of Peyote also acts as an emetic, making most people nauseous about two hours into the trip.

I find the mescaline experience to be more visual than mushrooms or acid. However, I’ve only experienced really spectacular visuals when using synthetic mescaline. My high tolerance to most psychedelics, along with the capacity of my stomach, has prevented me from ever being as high as I would have liked when eating whole cactus. Like psilocybin, mescaline tends to link me with collective evolutionary consciousness more than synthetics like LSD. The experiences produced by these natural psychedelics seem more “significant” than an acid high, which is more analytical. An acid high often seems to be a by-product of magnifying the mind, whereas with mushrooms and cactus one feels they are in touch with something ancient, spiritual, and personal. Mescaline has a unique signature in this context which I find most magical, a feeling that the Gods or protective allies are smiling down on me. The duration can be 6 to 14 hours depending on the amount consumed. The “coming back” portion of a mescaline trip is smoother than with the other traditional psychedelics. And I’ve never felt the “drained of energy” or “neural overload” feeling that can come after an intense acid trip. This allows for a more conscious and therapeutic return to regular consciousness, after which I can easily sink into sleep and wake up feeling refreshed.

Some aspects of the mescaline high are quite distinct from LSD or mushrooms. The visions produced by mescaline have a different character and structure. When being overtaken by a full strength mescaline trip, I’ve felt more than with any traditional psychedelic that I was an extraterrestrial being, immersing myself in new sensory phenomena for the first time. Where LSD or psilocybin heighten and clarify the sense of hearing, mescaline produces auditory hallucinations, heightening the hearing sense but also causing sounds to be quite different than normal. Mescaline also sharpens the olfactory sense to a much finer degree than LSD or psilocybin. I’ve particularly noted this in my ability to perceive the smells of numerous different plants when using synthetic mescaline outdoors. As for aphrodisiacal use of mescaline, wow!, it brought energies out of me that I never knew I had.”

3,4,5-Trimethoxyphenethylamine

“The mescaline experience is my favorite of the traditional psychedelics (LSD, psilocybin, mescaline). I find it has the advantages of…

medium.com

 

[mr peabody]

James Keim, Guy Bowles and Jon Cassel, Mimosa’s COO

​

These natural psilocybin droplets come in exact dosages and don’t upset your stomach

by Colin Newton | LUCID | 8 Jun 2022

Developing psilocybin for use in therapy is a balancing act. In their natural state, the potency of psilocybin mushrooms can be inconsistent, which makes administering precise doses difficult in clinical and research settings. Synthetic psilocybin is notably more consistent, but focusing on just one active substance contained in these mushrooms excludes the potential spectrum of experiences offered by other compounds in these fungi.

Jim Keim, CEO of Mimosa Therapeutics, thinks he’s found a balance. Mimosa cultivates the mycelium root structures of psilocybin mushrooms in bioreactors creating a product that Keim says has an exact and consistent potency containing all the natural compounds found in the fungi. It is sold by the company in elegant droplets Keim calls Pearls.

Raised in a liquid culture, the Pearls are tiny, ethereal globes made from mycelium that resemble caviar. “We have this beautiful way to offer the best of both worlds,” says Keim. “It’s both the consistency of synthetics, but the full spectrum of mushroom fruiting bodies.”
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Keim is a psychotherapist with a background in trauma therapy. He encountered the therapeutic potential of psychedelics when he came to the San Francisco Bay Area and saw firsthand both the dramatic difference psychedelics could make in his clients’ lives, and how cautious therapists had to be with a controlled substance that could be of varying quality and consistency.

“People were rightfully very, very careful,” says Keim. “It constrained the quality of training and the ability to pass knowledge on.”

As the move toward decriminalization of psychedelics continued to gather momentum, Keim wanted to produce dependable psilocybin for other therapists coming into the field. Mimosa is the result of that desire, a Public Benefit Corporation focusing on delivering non-synthetic psilocybin in a way that is both manageable for providers and responsive to the evolving market of therapeutic psychedelics.

“Many psychedelic therapists such as myself prefer different mushrooms for different contexts, goals, and types of emotional distress,” says Keim. He notes that there are also benefits from naturally occurring synergistic substances in mushrooms that could have an entourage effect to help potentiate psilocybin. “The discovery of MAOI’s in mushrooms by our VP, Felix Blei is an example of one well-understood potential contributor to this effect,” said Keim, referring to monoamine oxidase inhibitors (MAOIs) that are also present in ayahuasca.
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Customizing ratios of compounds

According to Keim, the goal of Mimosa is to customize the ratios of various compounds found in fungi and the experience they provide, without using extraction or other post-harvest technologies. “Another goal is to quickly evolve our offerings to continually improve them with facilitator and therapist feedback, expanding the range of experiences that our offerings can provide,” says Keim.

Keim believes that the evolution of therapeutic substances in response to consumer/clinician feedback is nearly impossible for drugs seeking FDA approval. “That process requires one to make a staggering investment in one, stagnant drug and then stick with it for a decade of approval process antics,” says Keim.

Keim founded Mimosa in 2020 with Amanda Feilding, founder and director of the Beckley Foundation, and Bob Stanley, co-founder, senior garden steward and pastor of the Sacred Garden Community and founding chair of Decriminalize Nature Oakland.

Amanda Feilding and Antoni Gandia

The team also currently includes mushroom scientist Felix Blei, formulation chemist Tyra Callaway, and Alan Rockefeller, who Keim suspects is one of the only mycologists to get a fan page on Facebook.

Less than two years after its founding, the company has launched a production lab in Amsterdam and a mushroom genetics lab in Oakland, California. “We can study DNA in Oakland, and we can actually produce our offerings in Europe,” says Keim.

“The mushroom is like the apple on an apple tree. The fungi pops up a fruiting body. That’s not the organism; that’s the reproductive organ,” adds Keim. “All the alkaloids of interest start underground.”

The resulting Pearl is very consistent in potency, which is measured with high tech lab equipment, says Keim. An unexpected side effect of the mycelium pearls is their gentleness on the stomach and the taste—or lack thereof.

“They’re very neutral in taste, and mushrooms are kind of objectionable tasting to some people,” adds Keim. “They cause significantly less nausea.”

The Pearls are currently being beta tested in the Netherlands, where psilocybin mycelium, sometimes known as truffles, is legal to grow and sell, says Keim. The owner of two smart shops there are giving away free samples of the Pearls.

Also for sale in the Netherlands is Nycer, Mimosa’s mycelium Pearls in microdosing form designed to increase focus and enhance creativity, awareness and mood. “It’s kind of like the way you wish coffee worked,” says Keim.

Keim’s vision for Mimosa is to continue to evolve its products. “We want to offer a palate of experience,” he says. “Too many companies are taking a big pharma approach—one pill fits all. Once you start working on that process, it’s eight to ten years before it’s approved. You can’t be responsive. You can’t be nimble.”
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Delivering precise dosing

According to Keim, a responsive and nimble approach to psilocybin is also beneficial for individuals. Psychedelic experiences can range from a warm hug to cosmic encounters, and Keim says Mimosa wants to help therapists facilitate those custom experiences for their clients. Whether they are experiencing PTSD, addiction, anxiety or depression, says Keim, Mimosa has a novel method of delivering precise levels of psilocybin for therapeutic use.

John Turner, psychedelic advocate and founder of the website Trippingly, is an early investor in Mimosa and an advisor to the company. Turner says he believes that the market for products like the Pearls is a welcome addition to the market for its flexibility and scalability “Improving nature while keeping entirely natural is this crazy innovation they’ve done,” he says.

Turner says clinicians and therapists need the ability to do precise dosing. “The FDA model where people need really precisely dosed psilocybin, these guys are opening up an all natural path to do a clinical track offering,” he says.

While he believes that the Mimosa product is ideal for therapeutic purposes, Turner says offering a consistent quality of psilocybin also supports personal growth for individual experiences. Turner notes that his own experience of Pearls was positive in ways he wasn’t expecting.

Turner says he typically has nausea with psilocybin mushrooms, and even with LSD, but not with Pearls. He says his experience with Pearls transformed how he saw mushrooms. “Consuming them is really pleasant,” says Turner. “The onset is relatively quick. And I had zero nausea.”

"The quality of the experience becomes especially important as the market for psychedelics opens up," says Turner. “The biggest risk we all face is people having bad experiences as psychedelics become more prevalent.”
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Licensing For broad therapeutic use

Mimosa has one of the world’s largest magic mushroom genetics libraries, and its bioreactors allow the company to cultivate mushrooms quickly and precisely, says Keim. “It takes six to eight weeks to grow mushrooms. It takes us a week to ten days,” Keim adds. “We can control the dosage. We can even change the ratio of alkaloids.”

In an effort to make Mimosa’s products as available as possible, Keim and co-founder Bob Stanley wrote a patent pledge, granting a royalty-free license to individuals commercially producing psilocybin mycelium until they start earning over $500,000 or $1 million in certain cases. “Patents can be used in very abusive ways,” says Keim. “We want to show how patents can be used in a protective way.”

Like brewers of craft beer, Keim would like to see facilitators engaged in the process. “Everyone who creates beer makes excitement about beer,” he says. “There’s a general raising of standards that comes back in a golden circle. We want to be part of that golden circle. We want to create a cloud of people who are interested in this.”

Keim says Mimosa expects to roll out their products for broader availability in both the U.S. and Europe in April. They are also hoping that their licensing structure encourages other producers around the world. “We want to encourage people to actually jump into this market,” he adds.

Turner says Mimosa’s offering means that more people can have high quality psilocybin in responsible settings. He says this is due in part to Mimosa’s licensing strategy of encouraging others to produce Pearls.

“What we all need to do in the psychedelic world is be nimble.You need flexibility on who owns the manufacturing,” says Turner. “What Mimosa brings is this really nimble business model. I don’t think many companies can do that economically. They can license their tech and still make money doing that, and they can scale up and down.”

Turner believes that the pattern of decriminalization for psychedelics will likely follow cannabis: non-uniform and state-by-state. Accordingly, adjusting to the scale on which one can grow and sell psychedelics in any given area – be it Oakland, Portland or Seattle – will be valuable, says Turner.

According to Turner, Mimosa has the means to adjust production in a way that will produce affordable psilocybin while still maintaining quality. “That’s the nimbleness we’re going to have to deal with psychedelics until this gets legalized,” says Turner. “It’s going to be interesting. Nobody knows how it’s going to play out, but it ain’t going away.”

These Natural Psilocybin Droplets Come in Exact Dosages and Don't Upset Your Stomach - Lucid News

Mimosa Therapeutics has created a cultured psilocybin mycelium product called Pearls that can be precisely dosed like synthetic psilocybin, but contains all the mushroom’s compounds.

www.lucid.news