Substances and mechanisms with Dr Charles Nichols

My unofficial Vital Study Zine #16 with observations from Vital Psychedelic Training and recent happenings in the space

Pamela Simard, ‘BDL’

Dr Charles Nichols – son of canonical chemist Dr David Nichols – puts forward a single very good reason for extracting the profound components from psychedelics.

“These drugs are taking so long to develop because the FDA wants much more rigorous testing,” he informs us from the front line of medical authorisation.

One particular medicine on his to-do list Charles found by isolating the properties of mescaline, synthesised from the peyote cactus.

Turns out psychedelics interact with cells in the soft muscle tissue around the heart, as well as the brain. He’s already registered a patent.

While LSD for example “isn’t a very strong anti-inflammatory” Charles says, mescaline has an “extremely potent” effect on inflammatory-based issues like, for example, breathing condition asthma.

The discovery could have major implications for psychedelic healing of previously unconsidered issues. Not just physical struggles like asthma but also schizophrenia, Parkinson’s and Alzheimer’s which are all connected with inflammation.

“So much has to do with inflammation and the over-active immune system right now,” says Charles, pharmacology professor at LSU Health Sciences in New Orleans with a background at Purdue and Vanderbilt universities.

Charles on the job. Embroidered lab coats FTW

‘Inflammation’ is shorthand here for ‘chronic inflammation’. Oxidants produced in the aftermath of a stress hormone spike for example, linger around and screw stuff up over time.

“I never intended to follow my father into psychedelics actually”

It’s a cause of cancer, psoriasis, arthritis, asthma, allergies, Chron’s Disease, hepatitis, neurodegenerative diseases like Parkinson’s, and more. In younger folks chronic inflammation is mostly caused by stress, bad diets and poor sleep.

The chemical aspect in question has nothing to do with the ‘psychedelic’ properties of mescaline. It has the same anti-asthmatic effect on its own sans tripping when tested on Charles’ elite lab rats bred for psychometric testing.

The intrepid rodents tested it out against 25 other designer psychedelics from the drug cupboard Charles inherited from his father David: the pharmacologist who synthesised DMT for Rick Strassman, MDMA for MAPS and psilocybin for PsiloDep 2.

“I never intended to follow my father into psychedelics actually,” says Charles coyly when I ask in the Q&A if he’d ever noticed the hand of fate guiding his work – like it did when Albert Hoffman felt compelled to re-examine the LSD that’d sat on his shelf un-investigated for seven years.

Charles tried to evade his cosmic destiny in vain. Two separate freaky coincidences nudged him towards a career in consciousness expansion.

The eventual pharmacologist initially studied genetics. Even now Charles’ ‘animal models’, creatures bred for testing purposes, are much envied in scientific circles.

Exhausted by the minutiae of fruit fly genetics after finishing a Phd, the younger Charles was restless for change. Twirling absent-mindedly on his lab stool wondering how to enter the world of employment, Charles spied a promo ad for a new book from Vanderbilt University scientist Elaine Sanders-Bush, who he’d heard his father mention.

He called up and asked about assistant roles.

“It turned out the job involved studying the effects of LSD on mouse and rat brains,” says Charles, “it was one of only a handful of labs doing so at the time. They’d run out of budget for now and couldn’t hire anyone. But a few months later Elaine called and asked if I was interested.”

Charles met Sanders and showed her his resumé featuring his education at Perdue University. “Elaine said she knew a Dr David Nichols there, at which point I had to tell her,” confesses Charles.

“Eventually we might isolate the qualities of peak experience, ego dissolution and breaking stuck thinking”

The next turning point came as Charles was working at New Orleans University in the chaotic aftermath of Hurricane Katrina. Struggling to find researchers he took a chance on a visiting Chinese scientist who needed facilities. By 2013 Charles and collaborator Bangning Yu had isolated the effects of mescaline-derived DOI on inhibiting tumour necrosis factor (TNF)-a mediated inflammation, which is associated with asthma, Parkinson’s Disease and many more conditions not previously part of psychedelic research.

‘Our data suggests,’ reads the modest blurb, ‘that sub-behavioural levels of certain psychedelics represents a new, steroid-sparing, small molecule strategy for the treatment of peripheral inflammatory related diseases.’

Targeting diseases on the fringe of psychedelic potential is not where Charles’ quietly vast ambition ends, though.

The basic neuro-scientific explanation of how psychedelics do their thing is the chemicals interact with receptors in the body’s cells. In particular ones given the code ‘5-HT2a’ usually given over to the neurotransmitter serotonin.

LSD contains serotonin in its chemical make-up. It latches on to receptors; hence the lengthy trip. Serotonin certainly isn’t simply ‘the happiness chemical’. It’s related to memory, learning, imagination, sexual arousal, appetite, anxiety and ‘diseases with complex etiologies.’

“Pressing different 5-HT2a receptors, and others, creates the various effects,” says Charles. Identifying medical properties could be just the beginning, he insists: “Eventually we might isolate the qualities of peak experience, ego dissolution and breaking stuck thinking.”

That’s not all. A new testing system Charles has designed examines the long terms effects of a single dose, identifying ‘persistent normalisation of stress-induced hippocampal dysfunction relevant to depression and other psychiatric conditions’

Find out more about Charles’ astonishing findings and their implications in this issue’s contents just below. You can also see Charles present his findings here, talk about inflammation and more with Mind and Matter here, and his thoughts on psychedelics and genetics plus more over on the New Psychonaut YouTube lecture channel. Follow Charles on Twitter at @lab_nichols.

If you want to go deep on neuroscience may I recommend Tokyo-based, Cambridge-educated neuroscientist Dr Andrew Gallimore’s extensive guide.

Here’s what’s in this week’s issue of your multi-syllabic Vital Student Zine, themed along Vital Psychedelic Training’s core pillars of study:

These five items I pulled from the week’s research are themed along Vital’s natural element-themed structure. Air provides an overview of psychedelic use, Fire concerns therapeutic applications, Water covers ‘space holding’ – the art of keeping it together, Earth is where you’ll find medical matters, and Ether discusses integration, the process of bringing psychedelic power into regular life. Click straight through to your pet subject.

Appliance of Science

Approach

Purists sneer at scientific tinkering. But lab studies showed Dr Nichols how psychedelics heal the body. Could he uncover the secret of profundity too?

By Ryoichi Kurokawa

Neuroscience is different to other aspects of psychedelic study, ‘since it is so spectacularly and usefully right over so many things.’

Raymond Tallis wrote those semi-satirical words in Aping Mankind: Neuromania, Darwinitis and the Misrepresentation of Humanity. Neuroscience ‘is often given authority where it has none’ warns Tallis.

Grudgingly I admit all those long words and graphs might come across well in a formal context. During a presentation to drug legislators, for example. Certainly compared to showing a clip of Tales from the Trip on the the meeting room’s wall-mounted LCD screen. 

So it’s sweetly satisfying for heads to beat bureaucrats at their own game with the slew of pro-psychedelic neuroscience stats flooding out of respected institutions.

Granted, the arcane apparatus of the psychedelic experience itself remains beyond even the grasp of they who have mastered the most multisyllabic words from this incomprehensible, in-style, inculcation. 

“That’s still a wide open mystery,” confesses Dr Charles Nichols, eminent psychedelic pharmacologist and Vital neuroscience lecturer.

“Specific pathways may be involved in the psychedelic process”

Charles is the son of Dr David Nichols, chemist to the stars. David made the DMT for Rick Strassman, MDMA for MAPS and psilocybin for Johns Hopkins.

“Back in the 2000s my father’s lab looked at the cross talk downstream from when G-alpha-i protein interacts with a specific beta and gamma that activates a hormone called Src, which then activates a series of enzymes. That’s the very top effector.”

Right. No wonder nobody’s got to the bottom of it as yet. 

“Specific pathways may be involved,” Charles whispers conspiratorially to the cheap seats.

No talk of neuroscience in these pages is complete without a mention of Greatest Living Englishman Dr Robin Carhart-Harris.

Dr Carhart-Harris’ sympathetic yet rigorous research at scientific bastion Imperial College London brought the psychedelic experience its medical legitimacy. His REBUS, ‘relaxed beliefs under psychedelics’ model is widely considered the neatest summation of psychedelic neuroscience. (without wishing to damn it with faint praise). 

“My lab studies what psychedelics do that serotonin doesn’t”

For anyone too embarrassed to ask the scientific way to say ‘tripping’ is ‘Relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system.’ Obviously.

Dr Charles Nichols is a pharmacologist developing new drugs. Unlike his celebrated psychedelic chemist dad Dr David, Charles has the benefit of Carhart-Harris’ research, or its slipstream at least.

Charles uses his prodigious skill with the pestle, mortar and petri dish to identify, isolate and augment certain properties within his arsenal of exotic designer psychedelics.

Specifically, “The study is my lab now is around what psychedelics do that serotonin itself doesn’t,” says Charles. 

Which is a lot.

He’s already found that mescaline-derived DOI has a tremendously positive effect on inflammatory conditions including asthma. And, he’s worked out that it’s not even one of the bits that makes you trip. Which has implications aplenty for widespread use. And the sensitive conversation around non-psychedelic psychedelics.

(Ethnobotanist Richard Evans Schultes wrote in 1938, “Some of the ills listed as responding to peyote were tuberculosis, pneumonia, scarlet fever, intestinal ills, diabetes, rheumatic pains, colds, grippe, fevers and venereal diseases.” Cheers Mark Gunther of Lucid News).

Psychedelics possess less ‘inhibitory’ effects on brain receptors that might suppress ‘excitatory’ ones, compared to serotonin. They hit the accelerator while cutting the brakes: boosting neurotransmission while hindering the body’s autonomous attempts to bring body chemistry back to ‘normal’.

“The profound and mystical effect itself is still a mystery”

This initiates a ‘synaptic cascade’ of excitatory messages. Once that gets to the Raphe nuclei in the brain stem connected to the whole brain, it’s blast off.

The resulting “downstream cross talk” takes an unusual route through the nervous system. Precisely what is a little vague. Zen meditation buff Dr Bryan Roth is on it with a system he calls ‘TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome’. He’s also the guy making the non-psychedelic psychedelics for DARPA.

“All psychedelics have a surprisingly different set of reactions with the 5-hydroxytryptamine receptors associated with serotonin,” says Charles, “but they all work on 5-hydroxytryptamine receptor 2a.” 

Neuroscientists gave it with the catchy nickname ‘5-HT2a’. Relax, they’ve got loads more.

Mescaline for example only activates two other receptors besides 5-HT2a. LSD’s “complex pharmacology” on the other hand means it interacts with 17 different receptors in total.

‘The phrase 5-HT2a agonist has supplanted psychedelic, which still carries faint whiffs of hippie-era hedonism,’ tech bible Wired tipped us off in its recent feature The High-Stakes Race to Engineer New Psychedelic Drugs.

Wicked Wheeze

Medical

A chemical component of mescaline can treat asthma, perhaps many more physical problems. And it’s not even the bit that makes you trip

Keith Coventry, ‘Inhaler’ in the permanent collection at the Southbank

Dr Charles Nichols’ major research breakthrough is the isolation of anti-inflammatory properties from the active agent in peyote.

Mescaline, in 1917 the first psychedelic ever synthesised, could treat conditions ranging from asthma to psoriasis and complex neurodegenerative disorders.

Dr Nichols’ lab has isolated anti-inflammatory properties within a designer drug variant of mescaline called DOI.

Mescaline enjoyed significantly better results than steroidal treatments when tested on Charles’ premium lab rats. And mice.

It’s almost certainly down to 5-HT2a receptors in the soft muscle around the heart becoming activated by psychedelics too.

Charles’ experiments showed mescaline/DOI prompted ‘extremely potent inhibition of tumour necrosis factor (TNF)-α-mediated inflammation.’

I hope you’re sitting down to take in what happens after that, ‘cos it might be a bit much to get your head around straight away:

‘5-HT2A receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-α-mediated proinflammatory markers,’ says the report barely managing to contain its enthusiasm. That’s not all.

‘Including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor κB, with IC50 values of only 10 to 20 pM.’

Unbelievable.

Importantly, these anti-inflammatory aspects of mescaline/DOI are chemically separate to its psychedelic properties. Any medicines derived from them wouldn’t prompt a psychedelic experience.

This isn’t just good news for any asthma sufferers who don’t fancy turning themselves on each time they need a blast of their inhaler. 

“We analysed 25 different psychedelics and revealed no correlation between behavioural potency and their ability to cure asthma”

It’s also a boon for folks who could do with help for their conditions as soon as possible. 

“One reason for isolating non-psychoactive components is the Federal Drug Association,” says Charles, “Even a minute psychoactive component requires much more rigorous testing.” New medicines derived from psychedelics that don’t blow the patient’s mind, make it to market much faster.

“Pretty much every everything nowadays seems to involve some aspect of of inflammation,” comments Charles, “the neuro-immune network hypothesis has become a really hot field. It underlies a lot of psychiatric disorders,” he says, citing depression, schizophrenia plus Parkinson’s and Alzheimer’s diseases. 

This doesn’t mean that someone on the wrong end of Alzheimer’s should be obliged to trip balls. Or kids with asthma.

“Inflammatory cells exist in the lungs, that affect asthma, and all over the body,” says Charles, “the brain has a primitive immune system too. Biopsies have revealed inflammation in the brains of a subset of depressed patients: cytokines and microglia are increased. Unmedicated schizophrenics have a significant amount of neuro-inflammation, plus it’s associated with drug abuse.”

“LSD is actually a poor anti-inflammatory and DMT has none of the properties at all,” says Charles when I ask him about his asthma breakthrough.

It only came about when he was left without a researcher after Hurricane Katrina, and took a chance on visiting professor Bangning Yu who needed a lab and complimented his own research.

“We analysed 25 different psychedelics and revealed no correlation between behavioural potency and their ability to cure asthma,” says Charles, “We will be able to engineer drugs that have less psychedelic activity, potentially even no psychedelic activity, but full anti-inflammatory properties.” 

He’s already honed a version of lab psychedelic DOI that has two-thirds less of the mind-expanding effects, but offers the same relief from asthmatic wheezing.