Switching the Reality Channel

How might we use psychedelics to discover and explore entirely new worlds? 🧵

(art by Paul Robertson) Being immersed in a world is a fundamental part of what it means to be human: whether you’re awake, dreaming, or at the peak of a DMT trip, there is always a world in every direction...

The Imperial College Psychedelic Research Group finally published the results of the world’s first pilot study, led by Lisa Luan @lisaxiaolu, of extended-state DMT, which has come to be known as DMTx...

Here is my breakdown of this landmark study...🧵 @lisaxiaolu This study comes almost seven years after Rick Strassman and myself proposed a retooling of target-controlled intravenous infusion for extending the DMT state from a few minutes to potentially much much longer...

The story of Bromo-DragonFLY

The world’s most potent psychedelic…???

Bromo-DragonFLY is an extremely potent and long-lasting synthetic psychedelic with a unique molecular structure…

But where did it come from? A long thread... Bromo-DragonFLY is a beautiful example of drug design performed by one of the best in the business — Dave Nichols at Purdue — and shows how a deep understanding of drug-receptor interactions can be used to generate molecules of truly exceptional potency...

The Fascinating Pharmacology of “Mad Honey” (aka “Heart Stopping Honey”)

And its connection to Poison Dart Frogs…

Mad Honey has become popular of late and is sold promising effects ranging from relaxation to full-blown visionary states.

Let's look at the pharmacology... 🧵 At lower doses, this is a typical report:

"A light, gently pleasant buzz flowed over my whole body. I felt slightly dizzy and relaxed, and had a mild sense of lightness and euphoria."

Higher doses can cause confusion, delirium, fainting, and heart problems...

Pharmacological evidence for a Psilocybe mushroom entourage effect?

Do different mushroom species/strains exhibit consistently different effects elicited by distinct alkaloid profiles?

Well, we might now have some actual pharmacological evidence (albeit in animals) for this… In my series of Substack posts on a possible “entourage effect” in Psilocybe mushrooms, I discuss whether or not different relative concentrations of three major alkaloids, psilocybin, baeocystin, and norbaeocystin, might be responsible for such an effect.
alieninsect.substack.com/p/do-different…

Shulgin’s “essential amphetamines” comprise eleven psychoactive amphetamines, all derived in a single step from the naturally-occurring essential oil components of many plants, from nutmeg to anise to parsley... All of these “essential precursors” are derived from the amino acid phenylalanine, with differing patterns of oxygen-bearing groups around the phenyl ring.

The Curious Pharmacology of Nutmeg Intoxication.

(Part 1 of Shulgin's Essential Amphetamines)

It’s long been known that nutmeg (Myristica fragrans), when ingested in large doses, can induce something of a mind-altering effect...

And the pharmacology is rather interesting...🧵 The medical literature includes many examples of people consuming large quantities of ground nutmeg and being presented to the emergency room with symptoms ranging from nausea and blurred vision to multi-sensory hallucinations and “bizarre behaviour”...

Why is the Fly Agaric Psychedelic?

Muscimol is the major psychedelic component of the Fly Agaric Mushroom and can also be derived by decarboxylation of the other major component, ibotenic acid.

And it's also psychedelic. But why? Let's look at the pharmacology...🧵 Muscimol works by activating the inhibitory GABA-A receptor, which is also the site of activity of some of the most popular sedatives used to treat anxiety and insomnia, as well as alcohol (ethanol)...

Are Magic Mushrooms Pre-packaged Ayahuasca?

Beta-carbolines (primarily harmine & harmaline) are most commonly associated with the ayahuasca vine, Banisteriopsis caapi.

But they've also been detected in Psilocybe mushrooms... could they contribute to their effects? 🧵 The beta-carbolines form the crucial MAO inhibitory component of the ayahuasca brew that allows DMT to be orally active.

A chemical analysis published in 2020 revealed their presence, somewhat surprisingly, in no less than five species of Psilocybe mushrooms.

@RCarhartHarris has, in my opinion, done more to advance our understanding of the neuroscience of psychedelics and their potential as revolutionary treatments for debilitating and life-destroying psychological illness than almost anyone else on the planet. 1/6 Having met and spoken with Robin on a number of occasions, he is also one of the most humble, generous, and kind scientists I have ever met. His work has been essential in helping me formulate many of my own ideas about psychedelics and their role in our world and human life. 2/6

Why are Magic Mushrooms Orally Active But DMT Isn’t?

The Magical Chemistry of Psilocin…

We take it for granted that tripping on Psilocybe mushrooms is as simple as plucking them and munching them down. However, their oral activity relies on a curious quirk of their chemistry… For a psychoactive tryptamine to be orally active, it has at least two hurdles to jump:

Firstly, it must be absorbed into the bloodstream from the gut, pass through the liver, and survive metabolic degradation long enough to reach the brain.

Psychoactive Alkaloid Profiles of Psilocybe Mushrooms

A new study published last month (pubmed.ncbi.nlm.nih.gov/36430546/) revealed how the proportions of different psychoactive alkaloids can vary dramatically between species, giving each its own "alkaloid fingerprint"... Psilocybe cubensis: mainly psilocybin and, to a lesser extent, psilocin.

P. semilanceata: psilocybin & baeocystin.

P. cyanescens: high concentrations of psilocybin, psilocin, & baeocystin

Inocybe aeruginascens: primarily aeruginascin, with lower levels of psilocybin.

Trip Killers: For when it all gets too much… from vitamin B3 to ketanserin…

Let’s look at some of the pharmacological interventions that have been used to kill (or at least diminish) a psychedelic trip that takes a turn for the worst… With the proper set and setting, the likelihood of a so-called “bad trip” can be minimised. Further, with the aid of an experienced sitter, trips that take a negative turn can often be shifted in a more positive direction.

Psilomethoxin: The tale of a curious molecular hybrid of psilocin and 5-MeO-DMT

Psilocin (4-OH-DMT) and 5-MeO-DMT are both DMT derivatives that differ only in the position and identity of the group on the indole ring... (1/15) In 2005, a reader of Sasha and Ann Shulgin's TIHKAL wondered why Sasha hadn’t included the DMT derivative with both groups — a kind of structural blend of psilocin and 5-MeO-DMT... (2/15)

A Single Dose of Psilocybin for Treatment-Resistant Depression...

A brand new study published in the New England Journal of Medicine suggests a single dose of 25mg psilocybin can significantly improve the symptoms of depression for at least 12 weeks... Participants received either 10mg, 25mg, or a control of 1mg synthetic psilocybin, accompanied by psychological support over 6 hours (75-79 in each group). They were then followed up for 12 weeks and their depression rating scores monitored...

The Electrochemical Language of the Mushroom...

Do mushroom mycelial networks use an electrochemical language similar to that of the human brain???

Perhaps... let's look at some of the evidence... The human brain generates inordinately complex patterns of information using sequences of electrochemical signals known as action potentials fired by the vast network of neurons from which it is constructed...

Is ketamine a psychedelic? A dissociative anaesthetic? A dissociative psychedelic?

Ketamine is unusual in being somewhat psychedelic at low doses, but has unique dissociative anaesthetic effects at high doses.

How does this work? Let's find out... In line with these subjective effects, ketamine has been shown to increase neural activity at low concentrations, but shift to an overall suppressive effect on the brain as the concentration is increased...

Adrenochrome: Fantastical Psychedelic or Pure Fantasy?

Adrenochrome boasts perhaps the coolest name of any drug, and is name-dropped in some major works of 20th century literature.

But is this curious purple molecule all it's cracked up to be?

Let's find out... In Fear and Loathing in Las Vegas, Hunter S. Thompson claimed that adrenochrome “makes pure mescaline seem like ginger beer. You’ll go completely crazy if you take too much.”

How Does DMT Switch Your Brain's Reality Channel? A thread...

A wonderful new paper published in Nature Communications reveals how psychedelics, such as LSD, “flatten the brain’s control attractor landscape”. What does this mean and how can this study inform what’s happening in the brain when you smoke DMT and are transported to an entirely different reality?

Why are 5% of people unaffected by DMT?

Terence McKenna claimed that around 5% of people to whom he gave DMT experienced no effect whatsoever. This was supported by Rick Strassman’s study in the 1990s: 3 of 53 subjects were unaffected by the drug, even at the highest dose. Why? DMT (and other classic psychedelics, such as LSD, psilocin, and mescaline) act primarily via the 5HT2A serotonin receptor — a type of metabotropic receptor.

Why is psilocybin (or LSD or mescaline) psychedelic? A (long) thread.

Whether you’re awake, dreaming, or in a peak psychedelic state, your experienced world is always a model constructed by your brain as a pattern of cortical activity. When you ingest a psychedelic, it is this world model that changes. But how and why? Let's see...

Your cortex is constructed as a mosaic of closely packed cylindrical structures built from neurons — these are your cortical columns.