Sceletium used to create a new antidepressant molecule - are we loosing the complex actions of the plant?

[Alchemica]

On one side, we have expensive pharmaceutical directions of 'optimising' the principle active alkaloid mesembrine through the efforts of Sensorium Therapeutics to come up with new potentially 'better' molecules, while others think Sceletium is more useful as an individually personalised 'precision medicine' phytopharmacological option, where different alkaloid profiles can be used for different therapeutic outcomes [The Conversation]:

 

• Rather than the more typical assumption that mesembrine/mesembrenone fundamentally drive the differing effects, more recent alkaloid profiling suggests that differing chemotypes of Sceletium and in particular the presence of mesembrine alcohols and sceletium A4 may be important contributors in the neurochemical effects [1]. 
   

This opens the potential for a future of precision phytotherapy (use of plants for medicinal purposes), where natural remedies are tailored not just to individuals but to selecting certain plant chemotypes that produce certain combinations of alkaloids. Manipulating the growing conditions and genetic make-up of plants to optimise for alkaloid content is an age-old art.

 

Your thoughts?

From sensorium.bio:

 

Sensorium Therapeutics, Inc. (Sensorium), a neuroscience therapeutics company inspired by nature and guided by human biology to transform mental health treatment, announced today that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application for SNTX-2643, its lead anxiety program. With IND clearance secured, Sensorium enters a new stage of operational maturity, enabling first-in-human dosing and expanding the potential for strategic partnerships and downstream value creation. First in-human dosing will begin in Q3 2025.

 

“A fast-acting, well‑tolerated anxiolytic would be an important innovation for the hundreds of millions worldwide living with anxiety disorders,” said Maurizio Fava, MD, Scientific Advisor to Sensorium and Chair of the Mass General Brigham Academic Medical Centers Psychiatry Department. “FDA clearance of SNTX‑2643 moves us one step closer to that goal.”

 

SNTX-2643 is a first-in-class precision serotonin modulator designed to treat neuropsychiatric conditions including social anxiety disorder (SAD), a leading anxiety disorder underserved by current pharmacologic treatments. Re-engineered from a natural product with a long history of human use, SNTX-2643 could overcome many critical limitations commonly associated with benzodiazepine-like drugs by enabling rapid onset of action, reducing off-target side effects, and avoiding sedation. It acts through unique pharmacology distinct from SSRIs, which are limited by delayed onset and can paradoxically increase acute anxiety in the early stages of treatment.  

 

Taken from Endpoints:
 

Quote

 

“The biology of this drug is truly state-of-the-art in that it builds on recent biological discoveries in terms of how psychedelics work,” Velasquez-Mao said. “It is not a psychedelic compound, but it has psychedelic-like activity on the receptor.” A novel mechanism for an old target Sensorium’s initial funding was used to search nature for promising molecules that would “unlock new aspects of neurobiology,” Hooker said. “If it’s a mechanism that the world has already tested in the clinic, it’s not interesting to us,” he added.

 

The company zeroed in on a molecule derived from a South African succulent known to scientists as Sceletium tortuosum and commonly referred to as kanna. Hooker is listed as an inventor on a patent for compounds derived from mesembrine, a molecule in kanna. He told Endpoints the company’s drug “was inspired by a unique natural product found among the diverse molecules,” but did not confirm if it came from mesembrine. Chewing kanna is linked to rapid calming action within 30 to 60 minutes, Hooker said. And plant extracts are sold in a variety of forms, including supplements. Other researchers have previously shown that kanna inhibits the serotonin transporter, an important protein that moves serotonin in and out of the junctions between brain cells. Antidepressants called selective serotonin reuptake inhibitors (SSRIs) also block the serotonin transporter, but typically take four to six weeks for their effects to kick in, creating a puzzle about why the succulent compound worked so quickly. “We were convinced, quite frankly, that it must be hitting some target that we don’t know about,” Hooker said. “And we went deep. We looked at many hundreds, if not a thousand or more targets.”

 

It turned out that the molecule was binding to the serotonin transporter — a bit of a disappointment at first, given the startup’s novel mechanism mandate. However, while SSRIs directly block the ability of serotonin to bind to the transporter, Hooker said he was surprised to find that Sensorium’s compound binds to a different site on the protein that doesn’t compete with serotonin binding. Hooker is writing a paper to describe the mechanism in more detail. The company is also still trying to figure out exactly why touching the transporter differently has such a seemingly rapid action. Early work suggests it is rooted in downstream signaling proteins called kinases that “fundamentally tune the circuit differently,” he said.

 

But why go through the hassle of making a bona fide drug if people can just take the plant? It’s an obvious question, and one that Hooker gets a lot, and he says the bioavailability, half-life and metabolic stability of the natural molecule are simply not good enough.

 

“You could never, with the plant alone, have a reliably efficacious and safe treatment,” Hooker said. Sensorium has created hundreds of derivatives of the natural molecule to make a version dubbed SNTX-2643, which can be taken orally once a day. Hooker hopes it will provide an alternative to anxiety medications, including SSRIs and benzodiazepines. Hooker declined to say when the Phase 1 study would wrap up.

 

 

https://en.wikipedia.org/wiki/SNTX-2643

[wachumacallit]

It wouldn't matter which path performed best in clinical trials. The profitable, proprietary option wins out -- no contest. 

It's potentially risky though, since everyone knows that isolating, concentrating, and commodifying plant alkaloids typically ends in social disaster. I'm not saying the novel drug is anything like crack cocaine (versus coca leaf). But it might prove just as harmful as, say, Prozac. 

Most westerners -- health bureaucrats, prescribing doctors, as well as consumers themselves -- prefer the (illusory) "magic bullet." 

Personalised plant therapeutics sounds like a time-consuming affair. At least in cultures with no established history of traditional use. But isn't that a basic principle of shamanic healing? 

I can see the market opening up to accommodate both pathways. Big wins for Big Pharma (via the government-subsidised masses) and bespoke plant remedies (for economic and cultural elites).

What I don't see, necessarily, is just compensation being paid to the custodians of traditional plant knowledge. Colonialism in Africa, under the aegis of western biomedicine, is abysmal. It's essentially organised biopiracy, sanctified in the name of global health. And wouldn't it be a prudent strategy to ameliorate (if not remedy) the causes of social anxiety in the first place?

LOL, bitterly. Such questions only should play a more prominent role in determining how we should proceed.

 

[Starward]

On 11/2/2025 at 1:16 PM, Alchemica said:

SNTX-2643 is a first-in-class precision serotonin modulator

 

Nothing will come this. They have not even finished stage 1 trials. Not to mention stage 2 nor stage 3, nor FDA approval nor marketing. They will raise a few billions, then pocket the cash. As people and society continues to fall apart.

  

On 11/2/2025 at 8:54 PM, wachumacallit said:

wouldn't it be a prudent strategy to ameliorate (if not remedy) the causes of social anxiety in the first place?

 

The system and those in power, have a singular and terminal intent to ensure their own supremacy. Increasing social anxiety is but one more lever they have to stratify society to their advantage. This is the way of the world, always has been always will be.

 

 

 

[wachumacallit]

From the piece linked above (The Conversation): 

a future of precision phytotherapy (use of plants for medicinal purposes), where natural remedies are tailored not just to individuals but to selecting certain plant chemotypes that produce certain combinations of alkaloids. Manipulating the growing conditions and genetic make-up of plants to optimise for alkaloid content is an age-old art.

 

The researchers tested "two chemotypes" -- I remember these being discussed years ago, in an old conference/seminar video presentation, hosted online by one of the ethnobotanical organisations (speaker was the leading advocate and start-up entrepreneur, who'd already brought a kanna therapeutic to market -- but I forget his name). The existence of these two chemotypes was pointed out by Indigenous healers: "not this plant, but that one from over there" was the gist of their instruction to a westerner pharmaceutical researcher, who otherwise would have been oblivious. 

 

Honouring Indigenous knowledge means ... paying for it. That's the fundamental issue for me: how the benefits will be shared equitably with traditional custodians. Western science is hardly known for its social conscience or sense of moral obligation. Its track record on biopiracy should give us all pause for concern. Not that that's a legal or regulatory requirement, by any means. 

[withdrawl clinic]

i haven't read the technical pharma stuff, but can say that isolated sceletium alks are very powerfull, and once prduced a very instant euphoric experience for me after pyrolysing the alks. and i don't even like any kind of ssri's, has as well potential to produce synergies with other drugs.

[-RC-]

"... and from the ashes

of the frankenpsych meds

rose the premise whereby

all

natural

psychedelics

were finally able to be 

palatably 

forbidden

by law,

as the dependence-inducing

pharmaceuticalised equivalent

could now be purchased

for a moderate price,

thus satiating

the corporate deities

of the economic firmament as well..."  - Me