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While many tetrahydroisoquinolines display neurotoxic (salsolinol - 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline)/Parkinson's-inducing effects (1-Benzyl-TIQ), there are some that offer neuroprotection and are of potential merit therapeutically. 

These include 1MeTIQ (1-Methyl-1,2,3,4-tetrahydroisoquinoline) which has a plethora of beneficial effects on the CNS which has placed it in the category of being an 'endogenous neuroprotective agent'. That said, it's clinical utility may be limited by MAO-A and -B inhibition which opens up potential for pharmacodynamic interactions with other medications.

Nonetheless, the array of beneficial CNS actions of 1MeTIQ have led to research interest for both Parkinson's and as an anti-addictive agent.
 

1MeTIQ

Often these are synthesised in vivo by the Pictet-Spengler reaction with aldehydes or pyruvate with the corresponding amine, eg. dopamine and acetaldehyde for salsolinol. While formation of tetrahydro-β-carbolines is much more rapid, the non-indolic isoquinolines generally require more vigorous reaction conditions but still can form in vivo normally through enzymatic catalysis.

That said, reactions of unsubstituted arylethylamines can be difficult with variable results, reaction has long been limited to active substrates which bear strongly electron-donating groups such as a methoxy or a hydroxy group on the benzene ring.

Pictet-Spengler reaction 

Oxidation of the tetrahydro-β-carboline derivatives affords the β-carbolines 

A variety of Pictet-Spengler reaction products are formed in food during roasting, for example it is the reaction that leads to the majority of β-carbolines in coffee, for example norharman/harman. Sugars can also condense with the biogenic amines. These food derived β-carbolines become the predominate dietary source of MAO inhibiting substances

Other common condensation products include those from the aromatic amino acids eg. Trp and aldehydes, which in turn forms the 3-carboxylate. These tend to have GABAA BZD antagonistic/inverse agonistic properties in the β-carbolines ie. being convulsant

Other properties have been ascribed to the THBCs, namely inhibition of serotonin reuptake, and agonist affinity to 5-HT1A/2ARs. For the THIQ's, affinity to the serotonin receptors, including 5-HT7 has been noted.

Decarboxylation of TIQ-1-COOH's is more difficult but THBC-1-COOHs seem to be decarboxylated in MeOH/HCl with heating.

1MeTIQ:
- endogenous amine synthesised in human and animal brain
- exogenous 1MeTIQ has high affinity for brain tissue
- profoundly stimulates dopamine release
- 1MeTIQ expresses neuroprotective properties
 - 1MeTIQ demonstrates antiaddictive potency - considerable potential as a drug for combating substance abuse disease through the attenuation of craving.
- free radical scavenging properties 
- 1MeTIQ reversibly inhibits MAOA and MAOB: in vitro and in vivo studies
- 1MeTIQ is a partial dopamine agonist
- distinct antidepressant-like activity
- possesses mild activity at NMDA receptors.
- may be considered a potential agent useful in the treatment of the cognitive symptoms of schizophrenia. It has no neuroleptic like affinity for DA receptors, however, they interfere with the agonist binding to DA receptors, which suggests that the compounds may suppress excessive dopaminergic transmission at a site different from neuroleptic binding sites 
- Absence of 1MeTIQ toxicity, mutagenicity or carcinogenicity'

"This ability of 1MeTIQ may be of clinical importance and raises hope for its application in neurodegenerative diseases (e.g., Parkinson’s disease) and addiction evoked by drugs of abuse."

Two synthetic routes were proposed, the first being hindered by rapid formation of resinous condensation products and low yields of the copper (II) chelate.

Traditionally, the thermal decarboxylation of Cu (II) amino acid chelates is conducted in DMSO or high boiling point glycols but methylsulfonylmethane was selected as a polar solvent mp ~100 degrees.
 

Synthetic route 1.
 

Synthetic route 2.

Formation of the Cu (II)-Phe chelate was much more quantitative.

To validate the Pictet-Spengler reaction and subsequent decarboxylation with a biogenic amine, equimolar quantities of amine, calcium pyruvate and excess H3PO4 were heated in EtOH. After reacting, the insoluble calcium phosphate removed and ethanolic solution reduced.

This reaction was followed by TLC, A - the starting amine showed complete disappearance in B, being replaced by a new fluorescent high Rf compound. Absence of solubility in alkaline solutions confirmed the loss of the carboxylate.

References
Herraiz T, Chaparro C. Human monoamine oxidase enzyme inhibition by coffee and beta-carbolines norharman and harman isolated from coffee. Life Sci. 2006 Jan 18;78(8):795-802. doi: 10.1016/j.lfs.2005.05.074. Epub 2005 Aug 31. PMID: 16139309.
Antkiewicz-Michaluk L, Wąsik A, Michaluk J. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine with unexpected mechanism of action: new vistas of therapeutic application. Neurotox Res. 2014 Jan;25(1):1-12. doi: 10.1007/s12640-013-9402-7. Epub 2013 May 30. PMID: 23719903; PMCID: PMC3889699.
Antkiewicz-Michaluk L, Filip M, Michaluk J, Romańska I, Przegaliński E, Vetulani J. An endogenous neuroprotectant substance, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), prevents the behavioral and neurochemical effects of cocaine reinstatement in drug-dependent rats. J Neural Transm (Vienna). 2007 Mar;114(3):307-17. doi: 10.1007/s00702-006-0546-y
Antkiewicz-Michaluk L, Romańska I, Wąsik A, Michaluk J. Antidepressant-Like Effect of the Endogenous Neuroprotective Amine, 1MeTIQ in Clonidine-Induced Depression: Behavioral and Neurochemical Studies in Rats. Neurotox Res. 2017 Jul;32(1):94-106. doi: 10.1007/s12640-017-9715-z.
Wąsik A, Możdżeń E, Michaluk J, Romańska I, Antkiewicz-Michaluk L. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous Neuroprotectant and MAO inhibitor with antidepressant-like properties in the rat. Neurotox Res. 2014 May;25(4):323-34. doi: 10.1007/s12640-013-9425-0.
Mozdzen, E., Babinska, I., Wójcikowski, J., & Antkiewicz Michaluk, L. (2019). 1-Methyl-1,2,3,4-tetrahydroisoquinoline - the toxicological research on an exo/endogenous amine with antidepressant-like activity - in vivo, in vitro and in silico studies. Pharmacological Reports. doi:10.1016/j.pharep.2019.06.016
Ishiwata, K., Koyanagi, Y., Saitoh, T. et al. Effects of single and repeated administration of 1,2,3,4-tetrahydroisoquinoline analogs on the binding of [11C]raclopride to dopamine D2 receptors in the mouse brain. J Neural Transm 108, 1111–1125 (2001). doi:10.1007/s007020170001

He believes Heimia is a potent medicinal plant and can sometimes have an effect where it causes a 'detached life-review' where one can allow processing of negative life experiences and memories in a more compassionate, less self-critical and non-judgmental way and thus, has potential for PTSD etc. I'm yet to encounter such effects but would be interested in hearing if anyone has had that sort of effect, or otherwise therapeutic experience with it? He also states significant potentiation of more classical serotonergics. I'm trying to get him to do a recorded talk or something at a later stage but curious on other's experiences with it so I can give him feedback.

Compared to other entheogenic plants, H. salicifolia has been said to have softer, less potent effects [1]. Though H. salicifolia has a long history of traditional use, little is properly known about its possible therapeutic effects, particularly psychopharmacologically.  While some people seem to hold Heimia in high regard, it seems to sometimes gain a reputation of being "not worth it" due to unpleasant experiences, including muscle aches, fatigue etc
 

• There are 24 known alkaloids from the plant, the three most abundant (in order) being cryogenine/vertine, lyfoline, and lythrine (Rother, 1990) with others including nesodine, heimidine, sinicuichine, dehydrodecodine, lythridine (Kitajima et al., 2018; Kitajima et al., 2019). They all belong to a class of alkaloids known as biphenyl quinolizidine lactones, which are the primary biologically active compounds.  Within the genus, there are marked differences in the concentration of the individual alkaloids (Rother, 1990).  
   

Heimia alkaloids 

The Lythraceae alkaloids have four centers of chirality-three chiral carbon atoms at the quinolizidine ring C-1, C-3, and C-5, and the biphenyl or biphenyl ether link. 
 

The quinolizidine ring of Lythraceae alkaloids can exist in both trans and cis configurations.  Structurally, vertine has a cis-fused quinolizidine ring while lythrine, lyfoline and nesodine possess trans-fused quinolizidine rings. The nitrogen lone pair in those alkaloids with a cis ring juncture is less hindered, as below:

Cryogenine/vertine

Lythrine

Various alkaloids present and their configuration

Rother in 1994 reported absence of any 'psychodysleptic' effects in a “double blind” screening of both vertine and lythrine. 

Cryogenine/vertine:

- cholinergic affinity/mAChR/anti-cholinergic?

- anti-inflammatory/ prostaglandin synthetase inhibitor 

- induces sedation/tranquilising

- spasmolytic activities

- decreases spontaneous motor activity

- dose-related hypothermia

- skeletal and passivity without muscle involvement 

- hyperglycemic

- hypotensive

- vasodilator
 

Cryogenine/vertine has been reported to have tranquilising properties - the central nervous system depression caused by it is selective in nature and pharmacologically distinct from that caused by conventional major tranquilisers.
 

Lythrine may have psychological benefits, particularly in terms of reducing anxiety, in addition to its diuretic, anti-inflammatory, sedative, anti-hypertensive, and vasorelaxant properties. Given lythrine’s vasodilation and resulting blood pressure and heart rate reduction, it was reasonable to assume that it may have anxiolytic effects similar to clonidine. So far, previous research noted, at the doses tested, lythrine did not produce significant anxiolytic effects. Lythrine is the most effective vasorelaxant alkaloid in the plant and potentially has an effect mediated in part, by muscarinic receptors

Four major alkaloids were isolated with their abundance varying considerably: cryogenine/vertine (2.0-8.6 mg/g of dry-weight aerial parts), lyfoline (1.8-6.6 mg/g), lythrine (0.55-0.66 mg/g) and nesodine (0.09-0.55 mg/g) (Blomster et al., 1964; Appel et al., 1965; Dobberstein et al., 1975; Rother, 1989). 
 

•  Sinicuichine and lyfoline were shown to undergo catabolism, while cryogenine was degraded very slowly, if at all. Evidence is presented for the conversion of lyfoline to lythrine
   

The sequential appearance and metabolism of alkaloids in Heimia salicifolia

Whereas vertine and lyfoline are the major compounds, the biphenyl quinolizidines sinicuichine, heimidine, lythrine, nesodine, dehydrodecodine and lythridine accumulate in the field-grown plants, and in much larger amounts than the biogenetically simpler phenylquinolizidinyl esters abresoline, demethoxyabresoline and its H-l0 epimer. The phenylquinolizidinols demethyllasubine-I and -II are only metabolites of young (5- to 10-day-old) plantlets. 

- roots and seeds have been shown to be alkaloid-free
 

In explaining it's diverse herbal action and multitude of potential applications, such treating inflammation, fever, bladder control, constipation, and syphilis, some phytotherapists suggest it may be important to consider how it acts synergistically with other plants/phytoconstituents:
 

It "may contain a variety of active constituents, which must be selected either through the process of preparation, or by the addition of other plant extracts which "turn on" or "turn off' particular chemical compounds. "

None of the reported psychoactive effects brought on by the consumption of the entire plant have yet been matched by any of the single alkaloids discovered so far, but serotonin and dopamine systems in the brain have been hypothesised [1] to potentially interact with Heimia alkaloids, which may help explain the plant's mental effects. 

 Effects normally reported:

• Pleasant drowsiness
• Relaxation of skeletal muscle
• Slowing of the heartbeat
• Dilation of coronary vessels
• Inhibition of acetylcholine
• Enhancement of epinephrine 
• Mild reduction in blood pressure
• Cooling of the body
• Mild intoxication and lightheadedness
• Blurred vision
• Auditory changes (sounds seem distant); and
• Altered memory function. 

Some have mentioned that it may be important to study the correctly prepared material, which may have novel constituents; "It is necessary to study both the fermented product and the dry leaf infusion in order to isolate the compound responsible for the reported mental effects"
 

What is the (sun) fermentation doing to potentially change Heimia's chemistry and psychoactivity?

It has long been believed that fermenting tea before drinking it lessens associated negative effects 

 Is such a process accomplishing:

• enzymatic bioconversions in plant material post-harvest?
• chemical oxidation reactions or degradations, similar to tea fermentation?
• something like a a light/UV mediated photoisomerisation/conversion of alkaloids?

Light-induced (can also be enzyme-catalyzed) cis-trans (geometric) isomerisations (photoisomerisations) of double bonds can impact the biological activity eg The pungent amides in black pepper undergo light-induced photoisomerisations to differing compounds with altered levels of biological pungency

• a bioconversion of alkaloids by yeasts/lactic acid bacteria? [seems unlikely with short duration fermentation normally mentioned]

Fermentation can substantially alter the secondary metabolite composition of plant-based products due to a series of microbial actions such as hydrolysis, methylation, and carboxylation etc. Microbial fermentation is considered to provide a multi-enzyme complex consisting of esterases, dihydrogenases, decarboxylases, and de-aminating and CC-cleaving enzymes etc 

• Something else?
  
   

In a case-study, analysis has been undertaken of a sample from a person who created a brew of Heimia fermented over 24 h by adding yeast and sugar. No mention of light exposure during fermentation was made. Undesirable effects were noted, it resulted in muscle pain of the extremities and the tongue as well as slightly raised temperature, night nausea, headache 

This (yeast-enhanced) fermentation created an alkaloid profile of  demethyllasubine I, demethyllasubine II, heimidine, lythridine, abresoline, 10-epi-desmethoxyabresoline, desmethoxyabresoline, lyfoline, anelisine, dehydrocodine, vertine, nesodine, sinicuichine and lythrine

Other constituents:

Presence of chlorophyll, mucilage, fatty oils, tannins, quinones,  polyphenols, pigments, gum, glucose, starch, and alkaloids within the members of the family. 

Flavonoids like quercetin and kaempferol have been detected, ellagic acid, a sterol known as stigmasterol, as well as triterpenes like ursolic acid

It is a good source of phenolic compounds: Apigenin-7-O-rutinoside, protocatechuic acid; vanillic acid; apigenin-4'-O-methyl ether 7-O-glucoside (acacetin-7-O-β-glucoside); methyl gallate; gallic acid; apigenin-7-O-β-D-4C1-glucoside; 5,7,4'-trihydroxy-3-methoxyflavanone (dihydrokaempferol-3-O-methyl ether); dehydrotrigallic acid; 3,4,3'-trimethoxyellagic acid; 3,3'-dimethoxyellagic acid; 3-methoxyellagic acid; ellagic acid; apigenin; and kaempferol. 1,6-di-O-dehydrotrigalloyl-β-D-4C1-glucopyranose, 5,7,4'-trihydroxy-3-methoxyflavanone (dihydrokaempferol-3-O-methyl ether)

Properties of the individual alkaloids including colour, crystal morphology and mp etc can be found here

[1] Chapter 30 Sinicuichi (Heimia salicifolia (Kunth) Link Lythraceae) Rahmatullah Qureshi, Bushra Jabeen, and Noureddine Chaachouay

The effect of light on the production of Heimia alkaloids
 

Heimia salicifolia: A phytochemical and phytopharmacologic review
 

Biosynthesis of Lythraceae Alkaloids
 

Triandrus Narcissus - N. triandrus cultivars eg cv. 'Hawera'

Many of the Triandrus Narcissus are not yet phytochemically characterised.

Many of these Narcissus have some potential to biosynthesise pharmacologically relevant concentrations of Amaryllidaceae alkaloids of the non-Sceletium-type class, which can be of significant potential toxicity eg lycorine, or potent additional pharmacological action eg galantamine, it seems it may be potentially possible to potentially utilise them as exclusive sources of mesembrine-type alkaloids and interestingly, utilise even renewable aerial parts of the plant, instead of bulb material.

Some of the N. triandrus hybrids have been directly used for their mesembrine-alkaloid pharmacological alkaloid profile in animal studies [1]

Quote

"The aerial parts of Narcissus triandrus were extracted with methanol in a Soxhlet apparatus. The basic extracts were purified by column chromatography with silica gel as adsorbent. Three mesembrine-type of alkaloids were identified: mesembrine (1), mesembrenol (2) and mesembrenone (3), this last one in a very small amount. All were characterized on the basis of their spectroscopic properties. However, none of the previously described alkaloids [such as haemanthamine, lycorenin, lycorin, homolycorin, galanthamin and tazetin] were found." [2]

Narcissus pallidulus, pictured above, contrary to N. triandrus cv. 'Hawera' [which seems like it has the ability to biosynthesise lots of other toxic stuff in it] has an alkaloid profile of 139.9 μg/100 mg⁻¹ DW mesembrine-type alkaloids, mesembrenone 71.0 μg/100 mg⁻¹.  Never seen bulbs around myself in Australia. In vitro alkaloid production has been found to be viable:

In vitro propagation and biosynthesis of Sceletium-type alkaloids in Narcissus pallidulus and Narcissus cv. Hawera

The alkaloid profiles of different Narcissus are discussed in Alkaloid Profile of Fifteen Different Species of Narcissus L. (Amaryllidoideae) Collected in Spain

Alkaloid profile of N. pallidulus showing near exclusivity of mesembrine-type Sceletium alkaloid biosynthesis [doi:10.3390/plants14172793].

Kanna has become more of a 'functional food', finding it's way into everything from Australian Pre-Workout powders, to overseas having broad use in things like functional beverages, chocolates, quick dissolve breath mints, adaptogenic functional food blends etc

I posed the following question to a Psychiatrist:

 

Quote

 

Do you know how real-world relevant the risk of serotonin syndrome is when SSRIs are combined with other substances impacting the serotonin transporter, likely allosterically but also as a potential serotonin releasing agent? The example I'm wondering about is with Kanna/Sceletium and combined SSRI use. I've vaguely (?) heard of adventurous psychs in South Africa trying to augment SSRIs with Sceletium but it has generally become common-place in some communities to put a blanket warning that the combination is contraindicated.

 

Aside from pharmacokinetic interactions, in the real world, pharmacodynamically, is combining something that potentially allosterically modulates SERT to inhibit reuptake, or also potentially releases serotonin (VMAT-2 mediated?) with SSRIs an actual significant risk for precipitating serotonin toxicity? Do you ever hear of say escitalopram with it's allosteric SERT binding, combined with other SSRIs causing cases of serotonin syndrome? I would have thought that SERT was already inhibited to a near maximal occupancy by therapeutic doses of SSRIs and as such, adding another substrate for the transporter is unlikely to pose much added risk, instead they'd probably more just competitively displace each other from SERT unproblematically eg in the same way MDMA+SSRI seems to simply inhibit the pharmacological effect of MDMA via competition of the SSRI for SERT binding?

 

I'm just curious as with Kanna becoming such a common ingredient to the point of functional food status in a way, if there is a legitimate risk of SSRIs having a dangerous interaction with Kanna, or if it's more just a text-book over-reaction, just in case, mentality?

It might also be that half-life for mesembrine seems quite short, not that I've seen a human t1/2 reported yet, subjective effects maybe lasting around 5hrs (?), so even if there is potential serotonin toxicity building, mesembrine may clear relatively quickly from the body and the symptoms come to their own resolution. Still, it's incredibly potent SERT binding for mesembrine, 1.4nM or something, so it's worth having an idea about how real the risks are.

If it means anything, I've briefly explored the combo (with cyproheptadine on hand) and maximal dose sertraline + potent doses of high-mesembrine Kanna (said to be more the serotonin releasing aspect) were not overly remarkable, in that the acute mood elevation/empathogenic/more euphoric aspects, the generally sought after aspects, were greatly attenuated by combination but there was potential signs of maybe slight overheating, sweating etc. No drastic signs of anything too toxic but then my brain is a freak of nature that seems to handle combos that no brain technically should

Their response was: In general I think "potential" adverse interactions can be over-called due to pharmaceutical medicolegal risk (eg. SSRIs and opiates contributing to Serotonin Syndrome- see that combo often but not SS). I suspect Individual pharmacogenomics are more pertinent than interaction profiles (provided it's not a major one like MAOIs) but precision psychiatry is still rudimentary. I agree that the agents would probably compete, with the higher Ki agent more likely to "win out". The danger would be if max dose of 1 agent doesn't cause max occupancy and the additional agent causes increased binding to a dangerous level. Generally don't see serotonin syndrome with SSRI/SSRI combos, but it's generally not effective or good medicine.

Any input you can offer is greatly appreciated.

 

As anyone taken a more 'chillied" approach tp self-mastery?

Interesting I quick search turned up a few planned or theoretical research on possible benefits of psychedelics and tinnitus.

I have tinnitus, which for those who do not know is a clicking, ringing or zapping sound. You might develop tinnitus symptoms from being exposed to loud noise or medication.

The basic explanation for tinnitus is hearing loss. The fine hair in the cochlear are damaged and no longer convert vibration from sound into neural signal. In a response to this drop in input coming into the brain, some brains respond by produce these phantom tinnitus sounds. The issue is that tinnitus can become debilitating, destroying sleep and it is linked to cognitive decline, and dementia.

In essence tinnitus is a problem not with the hearing per say but with the brain, mall-adaptive response, that some people  with hearing loss experience but not all. Therefor treatment should focus on the brain rather the ear, which is where most tinnitus treatments focus their efforts.

Knowing this it made me notice that during a psychedelic experience, that my tinnitus, faded in intensity, also the perception of the sound within my brain seems to change location. Also post dosing there has been a significant improvement in my tinnitus symptoms.

I would like to propose a spit balling theory, that the increase in neural connections between different regions of the brain during psychedelics, compensates for the lack of signal from the cochlear thereby reducing the perception of tinnitus.

Thoughts opinions?

Has anyone else noticed improvements in their tinnitus due to psychedelics?

• 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

AI generated this viewpoint for me:

Bridgesii:

May contain higher levels of anhalonidine and hordenine, contributing to its sharper onset and intensity.

Pachanoi:

Often richer in simple phenolic PEAs, which may influence mood and cardiovascular response.

On a more extensive level, some broader phytochemistry:

Some alkaloids in Cactaceae:

Particularly considering findings by Ogunbodede et. al. who hypothesised 'the cacti with the highest mescaline tissue concentrations would be more likely to be used in shamanic practice' but noted some analytical findings which dispute mesc. % as being the sole determinant of relative potency, such as a comparatively low level in TBM - E. lageniformis (monstrose) [0.48% of dry weight of cactus tissue], despite wide-spread consensus it's potently active, vs E. scopulicola [0.85% % of dry weight of cactus tissue], with some saying ones probably belonging into the range of the species Trichocereus scopulicola,  like cordobensis, generally not even being worth exploration.

I did some extra research and found a new book which explores this topic in some chapters and I found to be a very interesting read - Comprehensive Guide to Hallucinogenic Plants (2025) It took a long time to track down online but eventually found it - I won't upload pdf to forums but if you can't find it, message me and I'll send it through. 

Trichocereus/Echinopsis

May contain things like mescaline, tyramine, 3-methoxytyramine, 3,4-dimethoxyphenylethylamine, 3,5-dimethoxy-4-hydroxy-phenylethylamine and anhalonidine etc.

The book mentions:
 

Pachanoid acid – enhances serotonin signaling
Flavonoids – antioxidant and anti- inflammatory effects

• Kaempferol 
• Quercetin

Betalains (generally in coloured parts) – antioxidant nitrogenous pigments
Sterols like ergosterol – antimicrobial effects

Others:

• Triterpenes bridgesigenins A and B, along with aglycones

The combination of alkaloids, lignans, and other compounds contributes to the psychotropic potency and medicinal properties. The phytochemistry varies between different samples and growth conditions (Moreno- Pedraza et al., 2019).

 Mescaline: The forgotten psychedelic

Mescaline binds with a low μmolar affinity to the serotonin 5HT1A/2A/2B/2C, adrenergic, dopamine D1/2/3 and TAAR1 (trace amine-associated receptor 1 that regulates dopamine, noradrenaline, and serotonin neurotransmission) receptors. Mescaline also binds to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters but with lower affinity

At high doses, it potentially leads to an increase in the release and/or reuptake of serotonin (dos Santos et al., 2016; Freedman et al., 1970), although this is not proven.

The nature of the psychoactive effects may be modulated by, among other things:

Adrenergic α1A and α2A receptors may modulate the pharmacodynamics, together with broad serotonergic receptor activation. 

5-HT2A vs 5-HT1A selectivity
5-HT2A vs 5-HT2C selectivity, etc

5-HT2A/2C interactions are not the only factors that influence potency in humans and pharmacokinetics may potentially have a significant impact on in vivo effects. Namely, interactions with other monoamine receptors, lipophilicity, receptor activation, functional selectivity, and metabolism via cytochrome P450 enzymes or amine oxidases could also play a role.

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Mescaline: 4.00 Alpha2C, 3.97 5ht2b, 3.61 5ht1a, 3.44 Imidazoline1, 3.16 5ht1e, 2.92 Alpha2A; 0.00: 5ht2a, 5ht2c, 5ht6, 5ht1d, D1, D2, D3, D4, D5, Alpha1A, Alpha1B, 5ht5a, Alpha2B, 5ht7, Beta1, Beta2, SERT, DAT, NET, 5ht1b, Sigma1, Sigma2, DOR, KOR, MOR, M1, M2, M3, M4, M5, H1, H2, CB2, CB1, Ca+ Channel, NMDA

 

The affinities of mescaline have been reported to be in the following order: 5-HT1A > 5-HT2A > 5-HT2C > 5-HT2B, with a 5-HT2A: 5-HT1A ratio of 0.73 and a 5-HT2A: 5-HT2C ratio of 2.7. (Moya et al., 2007; Rickli et al., 2015).

The characteristic effects of mescaline in animal studies are not only mediated via serotonergic and noradrenergic receptors but also via dopamine receptors, as pre-treatment with low doses of either serotonin or dopamine antagonists almost completely blocked the effects of mescaline 

From the book earlier: In addition to mescaline, Trichocereus contains other phenethylamine and tetrahydroisoquinoline alkaloids such as tyramine, hordenine, 3-methoxytyramine, anhalamine, anhalinine, anhalonidine, and anhalidine (Ogunbodede et al., 2010). Some of these compounds act as MAO inhibitors and enhance or prolong the effects of mescaline (Kapadia & Fayez, 1970). Anhalonidine also shows activity at 5-HT2A receptors (Pardanani et al., 1977) [? is this correct]. More recently, it has been described as to act as a potent inverse agonist of the serotonin 5-HT7 receptor

Small phenolic alkaloids may impact the resultant mood effects, or add peripheral side-effects:

• Tyramine was unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects
   

• Hordenine has significant pharmacological activity and is used by some as a psychostimulant at low doses, including in the nootropic community. The sympathomimetic effect of hordenine is based on its structural similarity to various neurotransmitters (dopamine and adrenaline) and potentially has activity as a competitive MAOI substrate, more selective to MAO-B. It results in high blood pressure, and it also increases respiratory and cardiac functions (Frank et al. 1990).   Inhibited noradrenaline uptake and stimulated noradrenaline release. Hordenine is a low-potency D2 dopamine receptor agonist and "might contribute to the mood elevating properties". Resembles both adrenaline and nicotine in activity 
   

• 3-methoxytyramine is a neuromodulator that can exert physiological actions, partially via activating TAAR1. While likely rapidly degraded normally, concentrations increased notably by inhibiting MAO
   
• N-methylmescaline, although less potent than the parent alkaloid, may modulate the effect. 

• 3,4-dimethoxyphenethylamine occurs naturally along with mescaline in various species of cacti. Said to potentially modulate the effect of other alkaloids. DMPEA has activity as a MAOI along with its naturally occurring N-methylated homologs see: https://doi.org/10.1002/jps.2600660741, it seems to produce no notable effects when tested even with very high doses, such as 1,000 mg orally 

• Trichocereine (N,N-dimethylmescaline) in one study at 9 mg/kg orally (630 mg for a 70-kg person) was found to produce no notable mental disturbances in humans but others have noted potential psychoactivity eg @ 400 mg sublingually and reported that it produced moderate psychedelic effects with a one-hour onset (compared to two hours for mescaline) and a "proportionally shorter" duration and  at doses of up to 800 mg (presumably orally), being less active than mescaline .  
  
  In animals, produced marked excitation similar to that induced by amphetamine. [note: pharmacologically, for psychedelic activity: phenethylamines generally cannot tolerate even a single N-substitution, with the exception of derivatives like N-2-methoxybenzyl etc, which increases activity. Small groups such as N-methyl or ethyl abolish 5-HT2A activity.]. 
  
  Trichocereine may have actions through monoamine transporters rather than receptors.
  
  Reported as the major component of the mescaline-containing cactus Trichocereus terscheckii

• The beta-hydroxylated macromerine, found in some cacti, is classified as psychoactive but not significantly MAOI inhibitory

• MMDPEA, with empathogenic-like action, is a minor alkaloid potentially found in cacti. It resulted in a peaceful elevation of mood, euphoria, enhancement of visual perception, and the generation of closed-eye mental imagery. At dosages above 300 mg, visual distortions that resemble those of standard doses of mescaline are said to begin to appear. 
   

• Removal of the 5-methoxy group from mescaline caused about a 50% loss of previous activity, while demethylation of the 4- methoxy group resulted in a complete loss of all conventional activity. It is not clear how it's binding profile/pharmacological activity is altered by such
  
  A polar moiety such as a OH on the 4-position gives compounds with very low 5-HT2A affinity, probably in part through decreases in the overall hydrophobicity of the molecule, preventing it partitioning into the central nervous system
   

• The fairly potent MAO-A inhibitory action of carnegine suggests that this and similar alkaloids, if present in a cactus or one of its extracts, might potentiate the effects of mescaline. 
   
• Candicine also penetrates a blood-brain barrier model and seems to have nicotine-like effects
   
• Coryneine stimulates acts like a weak D1 (or D1 + D5) dopamine receptor partial agonist but may not reach the CNS effectively

THIQs - mildly psychoactive - calming /sedative
 

• Phenolic tetrahydroisoquinolines peyotline  and anhalonidine were found to produce no sensory distortions, characteristic of the effects of mescaline, at doses of up to 250 mg. These compounds appear to induce a calming or sedative effect. Two methylenedioxy tetrahydroisoquinolines, lophophorine and anhalonine, were also found to lack any mescaline-like effects.
   
• Pellotine has sedative/hypnotic like effects. Trials note delayed onset (30–45 minutes post-administration) due to slow BBB penetration. 

Lophophora

It can be concluded that the more than 60 alkaloids of Lophophora williamsii, in combination, exert the total psychopharmacological effect

Peyote constituents: chemistry, biogenesis, and biological effects
https://doi.org/10.1002/jps.2600591202

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The most important alkaloid in peyote is mescaline, which was isolated by Arthur Heffner in 1897. The fresh plant contains approximately 0.4% of the active ingredient, in the dried plant this value can reach 3–6% (Spinella 2001; Ogunbodede et al. 2010). In addition to mescaline, several other alkaloids have also been identified, including N- methylmescaline, N- acetylmescaline, hordenine, pellotine, anhalonine, lobivine, tyramine, N- methyltyramine, anhalidine, anhalonidine, lophophorine, homopiperonylamine (Spiith 1919). It is probable that, in addition to mescaline, other alkaloids also play a role in the develop ment of the hallucinogenic effect or strengthen the effect of mescaline. The distribution of alkaloids in the plant is uneven, they accumulate in different plant parts. Mescaline is present in the green and above- ground parts of the cactus, being the most concentrated in the buds. Hordenine can be found in the root, while lophorine can be detected both in the above- ground parts and in the root. Pelotine is the second most abundant alkaloid in L. williamsii. Anhalinine is also an alkaloid present in larger quantities (Lundstrom and Agurell 1968; Kapadia and Fayez 1970; Dinis- Oliveira et al. 2019).

Things like L. diffusa contain higher amounts of tetrahydroisoquinolines like pellotine

• pellotine is the main abundant alkaloid (86.2%) in L. diffusa followed by anhalonidine (3.8%) and mescaline (1.2%) while contains zero to trace amounts of hordenine, anhalinine, and lophophine by using available limited literature studies.
• Pellotine is the inverse agonist for 5-HT7 receptor with an EC50 of 291 nM. Pellotine exhibits good affinity to 5-HT1DR and 5-HT6R with K of 117 nM and 170 nM. Pellotine reduces intracellular cAMP levels, thereby reducing neuronal excitability and neurotransmitter release.

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The pharmacological actions of pellotine were primarily studied in the early 20th century, with initial experiments conducted by Heffter. Heffter’s reports on the sleep- inducing properties of pellotine in humans sparked a further investigation of the compound in clinical settings (Cassels and Sáez- Briones, 2018). Boehringer and Sohn briefly promoted pellotine as a sleep aid before the advent of less expensive synthetic barbiturates eclipsed it. The fact that pellotine hadto be obtained from a natural source restricted its usage as a general sedative and was one of its key disadvantages at the time. Heffter, who discovered pellotine initially, also wrote about its effects on people. He was initially interested in figuring out what made peyote psychedelic but discovered that pellotine had a distinct sleep- inducing effect rather than any hallucinogenic effects (Ríos- Carrasco, 2017). In his self- experiment, dosages between 50 and 240 mg caused dizziness without any visual changes and slowed heart rate. Heffter was unable to stay awake and saw no aftereffects the next day. These findings prompted more research into the possible benefits of pellotine as a sleep aid. Jolly studied the use of pellotine as a possible painkiller and sleep aid in 1896, focusing mostly on patients with neuritis, multiple sclerosis, and tabes dorsalis (neurosyphilis). A modest analgesic effect, however distinct from morphine, was achieved by the oral or subcutaneous injection of 40–60 mg of pellotine. The effects of greater dosages were comparable to those of methylsulfonal (Trional) or chloral hydrate in the evening, when doses of 20–60 mg caused sleep. As adverse effects, vertigo, tinnitus, and a drop- in heart rate were noted. Jolly concluded that pellotine could be a beneficial sleeping aid, although some patients did not experience any effects. The same year, Pilcz administered pellotine beginning at a dosage of 20 mg to 58 patients from the Vienna Psychiatric Clinic. Pellotine showed no impact in 21% of patients; as a result, these instances were eliminated from the research. 49% of patients slept off within 90 minutes after treatment and slept well all night. 20 mg was adequate to provide equivalent results in 33% of subjects. When other hypnotics had failed, pellotine was discovered to work well with no obvious negative effects (Anderson, 1996). Hutchings administered doses of 15–30 mg of pellotine for up to 3 weeks to 11 mental patients to study their reactions to repeated dosages. No long- term side effects were observed, and no withdrawal symptoms were reported upon discontinuation of treatment. Patients experienced natural and calm sleep, waking up feeling refreshed. Additional daytime sleep of up to four hours was obtained when pellotine was administered during the day. Within the first hour after administra tion, minor side symptoms such as nausea, vomiting, vertigo, and dizziness appeared. When nausea and dizziness were reported, Hutchings observed a change in pulse rate (Chaachouay & Zidane, 2021). Even in the absence of sleep induction, pellotine seemed to have a soothing effect.

Why doesn't massive doses of serotonin let me talk to DMT Machine Elves, commune with serpents and jaguars, or re-experience my childhood sexual abuse in a safe, positive context, allowing me to feel compassion for my abuser? Instead, SSRIs just make you numb and dead inside.

Can someone explain this in a way that a non-technical person can understand?

Firstly, a brief simple introduction to this sort of simple analysis – thin layer chromatography or TLC – for someone who might not be experienced. 
 
One method of rapid, DIY @ home [presumptive] analysis is centered on using colour reagents which react with the tested material to give an idea of it’s constituents, based on colour changes. These are commonly used in the ‘pill testing’ community etc. These generally require a concentrated, relatively pure, mostly uncoloured material to test and in this case, the other coloured constituents of a plant material may interfere with accurate detection of any colour change. 

While I'm a polyphenol fiend, I also cherish the healing phytochemical rainbow. Today for my carotenoids, I'm having a tiny bit of saffron, some T. erecta flowers and kale. Have a glass of tomato juice, too. Still got some chlorella left, so I'll have a dose.

While saffron crocins are really healing, so are β-Carotene, lutein, zeaxanthin and things like lycopene, which keep the brain working well

β-Carotene

β-Carotene improves memory, recognition and verbal skills

Really became a fan of spirulina for awhile but cost made it a bit of an issue. Keen to know if anyone here with mental illness or autism has tried it themselves? Started to start add chlorella - chlorella tended to reduce oxidative stress and significantly prevented the decline of cognitive ability, it also buffered stress responses, diminishing the impact of stressors by reducing the HPA response.

Noticed the spirulina not only helps with mood and cognition but when I was using that, helped the ASD stuff (my premorbid issue). It's also good for the body on the whole, nicely restorative. One component, β-carotene is a strong antioxidant but interestingly may do more for autistic traits.

While phycocyanin and related constituents are one interesting component, potently neurorestorative, improving oxidative status, improving neuroinflammation, protecting from demyelination and axonal loss, modulating the expression of genes related to remyelination, gliogenesis and axon-glia processes etc, spirulina is rich in β-Carotene

β-Carotene oral supplementation to animal model of ASD significantly reduced restricted and stereotyped behaviours and interests, increased social interactions and communication, CD38, and oxytocin, probably by enhancing brain neuroplasticity without toxicity [ref].

All-trans retinoic acid is a potent inducer of CD38 and can be used as a novel therapeutic strategy in autism. It's been put forward the prospect that retinoids are potential therapeutic agents in autism and possibly other disorders that are characterized by dysfunctional social cognition/relationships especially where oxytocin has been suggested to play a role.

"There is a longstanding notion that vitamin A plays a role in psychiatric illness likely based on the profound effects of retinoids on brain development and processes such as long-term potentiation (LTP) and mood regulation

Intriguingly, the cortex of retinoic acid deprived rats is characterized by beta-amyloid accumulation and other changes that parallel those in Alzheimer’ disease. Additionally, normal memory loss in aging rats can be alleviated by vitamin A therapy. In the adult hippocampus, retinoids are essential for the maintenance of synaptic plasticity including LTP and neurogenesis. The hippocampus is a brain region dependent upon neural plasticity for its function in learning and memory. CD38 transcription is correlated with cognitive function in ASD and secondly, that retinoids are potential therapeutic agents in autism."

Crocins

The crocins are hydrophilic carotenoids that can act as antioxidants, improve learning and memory, be used for treatment of brain injury, mood disorders, OCD, joint pain and muscle dysfunction in osteoarthritis, metabolic syndrome and related mood disorders and neurodegenerative damage, and have a protective effect against brain damage

Aside from the NMDA affinity and sigma-1 binding, there is evidence that crocins act as reuptake inhibitors of dopamine and norepinephrine.

"The antioxidant properties of saffron derivatives may also be relevant. Mood disorders are associated with elevated oxidative stress and a deficit of exogenous antioxidants, affecting immune and inflammatory responses in a way, which may promote neurodegeneration (Leonard and Maes, 2012). There is good evidence that the antioxidants in saffron extracts protect against oxidative stress in the central nervous system (Mehri et al. 2015; Oruc et al. 2016), constituting a second potential mechanism of therapeutic action.

The most important indicator of the quality and commercial value of the saffron is its contents of crocin I and II, which are specified in trade standards. The Chinese Pharmacopoeia stipulates that the total content of crocin I and II should not be less than 10.0 %."

In an analysis of 63 saffrons, the crocin I content range was 6.6–23.7 %.

Considering a therapeutic dose is sometimes considered to be 30mg crocins that works out to be about 127-455mg saffron going on crocin I. I stuck with 300mg/day for my saffron dose for bad days - cost is ~ $4/gram from my Indian shop for decent stuff.

There is a TGA listed coated tablet containing either 11 mg or 14 mg of standardised saffron extract (affron), derived from the stigmas of Crocus sativus L. and standardised to contain >3.5% Lepticrosalides® (a measure of bioactive compounds present in saffron, including safranal and crocin. Two tablets daily constitutes a dose.

As I mentioned before:

Saffron (Crocus sativus L.) has demonstrated antidepressant effects in clinical studies and extensive anxiolytic effects in experimental animal models. It reputedly has acute effects.

Quite quickly, it increases mood, reduces anxiety and manages stress without side effects in studies. It has been traditionally used for the treatment of insomnia and other diseases of the nervous systems, it has sleep quality improving effects. Crocins attenuated schizophrenia-like behavioural deficits. It has a satiating effect and decreases the frequency of snacking events. It's been used in emotional disorders and it was found that using saffron (30 mg/day) was effective in relieving symptoms in some cases.

Crocin can regulate HPA axis activity and has therapeutic effects in stress disorders, potentially PTSD where it is effectve in an animal model. It may serve an appropriate treatment for subjects who experience a extremely stressful or traumatic event.

Saffron and its metabolites have proven to be effective in different models of psychiatric disorders, including depression and anxiety. It is as least effective as first-line medications for MDD in quality studies with less side effects.

It's got a good safety margin, while 30mg may prove effective “to a daily maximum dose of 1.5 grams there has not been any risk documented. Lethal dose is 20 g and the abortive dose, 10 g, because as such it was employed in the past due to its stimulating action on the smooth muscle of the uterus. 5 g daily dose can already cause intoxication accompanied by vomiting, bloody diarrhea, hematuria, skin hemorrhages in nose, lips and eyelids, vertigo and dulling. The skin and mucous membranes take a yellowish colour similar to jaundice”.

Crocin is an isolated chemical compound that belongs to a group of commercial carotenoid derived from the stigma branches of dried saffron. The spice’s high antioxidant capacity explains most of its preventive or healing properties in relation to chronic and degenerative diseases

Crocin and crocetin may have a neuroprotective effect because of their anti-inflammatory action in microglial cells, as tested in rat brains, accompanied by a reduction in neurotoxic molecules (TNF-α, interleukin-1β and intracellular ROS. The restoration of a redox balance in brain tissues can be a good therapeutic strategy to limit neuro-inflammation and consequently tissue oxidative damage). Many of the anti-inflammatory effects of crocin demonstrated in animal models of neuronal degeneration could be mediated by its direct effects on microglia homeostasis.

It also has anti-adiposity effects

Crocin can be considered as healthcare product to prevent age-related brain diseases, it is able to enhance memory function in an aging model through anti-glycative and anti-oxidative properties which finally can suppress brain inflammatory mediators and increase protective pathways

Crocin can improve learning and memory and may prevent neurodegenerative disorders including Alzheimer's disease. Saffron is a source of novel acetylcholinesterase inhibitors. It is not mutagenic and prevents alcohol-induced disorders of memory and learning. Its mechanism is thought to be prevention of the inhibitory effect of ethanol on N-methyl-D-aspartate (NMDA) glutamate receptors in the hippocampus. It has clear binding capacity at the PCP binding side of the NMDA receptor and at the sigma(1) receptor
 

There is an anti-fatigue effect of crocetin - its intake improved performance when taken 4 h before a physical fatigue-inducing task

Treatment with saffron extract for seven consecutive days in a study conducted in rats in an experimental model of MS improved learning and memory impairment and alterations in the parameters of oxidative stress in the hippocampus. Clinically saffron was able to reduce MS symptoms - crocetin might prevent demyelination and neurodegeneration. Such findings show that saffron may potentially prove useful in the treatment of MS through the inhibition of oxidative stress and the infiltration of leukocytes to the CNS.

Saffron protects many cells of the dopaminergic system with relevance to Parkinson's disease.

Studies on the bioactive substances of saffron in depression indicate that the crocin acts by inhibiting the reuptake of dopamine and norepinephrine neurotransmitters, while safranal inhibits the reuptake of serotonin. There are in vivo studies suggesting inhibitory effects on the monoamine oxidases, MAO-A and MAO-B, enzymes responsible for the degradation of the neurotransmitters, as mentioned above, leading to an increase in their levels in the synaptic space and reducing depressive symptoms.

Saffron extracts and crocetin had a clear binding capacity at the PCP binding side of the NMDA receptor and at the sigma-1 receptor while crocins attenuated schizophrenia-like behavioural deficits. Crocin has been shown to be an antioxidant and neural protective agent

Saffron is a potential efficacious and tolerable treatment for major depressive disorder with anxious distress. [1] It increased mood, reduced anxiety and managed stress without side effects, offering a natural alternative to standard treatments [2] Saffron is as effective as fluvoxamine in the treatment of patients with mild to moderate OCD [3]

A recent review found:
 

"Saffron, derived from the stigma of Crocus sativus flower, is commonly used as a spice and as medicine in the Middle East and in South Asia. In patients with mild to moderate anxiety, extracts of saffron were reported to be effective in relieving symptoms in several RCTs (Akhondzadeh et al., 2005; Mazidi et al., 2016; Talaei, Hassanpour Moghadam, Sajadi Tabassi, & Mohajeri, 2015). Studies also show that the effects are comparable to standard antidepressant drugs such as fluoxetine (Moosavi, Ahmadi, Amini, & Vazirzadeh, 2014; Noorbala, Akhondzadeh, Tahmacebi‐Pour, & Jamshidi, 2005; Shahmansouri et al., 2014) and imipramine (Akhondzadeh, Fallah‐Pour, Afkham, Jamshidi, & Khalighi‐Cigaroudi, 2004).Saffron reduced anxiety and depression scores in women with premenstrual syndrome as well (Agha‐Hosseini et al., 2008)."

[1] https://www.ncbi.nlm.nih.gov/pubmed/27701683
[2] https://www.ncbi.nlm.nih.gov/pubmed/28735826
[3] https://www.ncbi.nlm.nih.gov/pubmed/29062366

Lutein & Zeaxanthin

Good sources of lutein and zeaxanthin include kale, spinach, turnip greens, summer squash, pumpkin, paprika, yellow-fleshed fruits and avocado

Supplementation with the these carotenoids significantly reduces stress, cortisol, and symptoms of sub-optimal emotional and physical health. Low blood serum or plasma concentrations of the xanthophyll carotenoids lutein and zeaxanthin have been implicated in poorer cognitive health in older adults. They may assist with cognitive control. They have anti‑inflammatory and antioxidative effects and putative neurotrophic effects. The dietary intake of carotenoids should be promoted as this may have a substantial positive effect on cognition, memory and things like stroke prevention and stroke mortality reduction. Supplementation appears to benefit neurocognitive function by enhancing cerebral perfusion, even if consumed for a discrete period of time in late life. Higher intakes may result in the ability to respond to cognitive tasks more efficiently, maintaining high performance while displaying neural indices indicative of lower cognitive load.

Lycopene

Lycopene is the major carotenoid in tomatoes. Tomatoes contain a matrix of many bioactive components, including vitamin C, vitamin E, other carotenoids (a-, beta-, gamma- carotene, lutein), and flavonoids.

The processing that heated tomato products is said to increase the bioavailability of key phytonutrients and antioxidants, such as lycopene, lutein and other carotenoids

The consumption of foods rich in carotenoids that possess significant antioxidant and inflammatory modulating properties has been linked to reduced risk of neuropathology. Lycopene helps to protect against induced cognitive dysfunction.

Lycopene inhibits glutamate release in cortical synaptosomes

Lycopene food sources may be useful in neurodegenerative conditions, including AD ad PD.

Lycopene significantly improved cognitive deficits and were accompanied by the attenuation of inflammatory injury via blocking the activation of NF-κB p65 and TLR4 expressions and production of cytokines. It could ameliorate oxidative stress induced neuroinflammation and cognitive impairment possibly via mediating Nrf2/NF-κB transcriptional pathway. In degenerative conditions, it causes modifications in the activity of cholinesterase and antioxidant pathways.

Lycopene reverses neurochemical deficts, oxidative stress, apoptosis and physiological abnormalities in PD mice

Oral lycopene administration attenuates insulin signaling deficits, oxidative stress, neuroinflammation, and cognitive impairment

In models of epilepsy, when used alongside conventional anti-convulsants, lycopene significantly restored the seizure score, latency, thiobarbituric acid reactive substance, reduced glutathione, catalase, superoxide dismutase, and gamma-aminobutyric acid levels near to normal

Carotenoids may modulate inflammation and enhance antioxidant defenses within both the central nervous system (CNS) and systemic circulation. Increased levels of lycopene also appear to moderate decline in the essential pyridine nucleotide [NAD(H)] in both the plasma and the CSF.

Kind regards

JF

Got a referral to a urologist but they will only offer me drugs, one is a tamsulosin an Alpha blockers and Vasodilater got a script from the GP for it and all I have gotten so far is an ever growing headache due to Vasodilation I suspect. The other drug is a combination drug that prevents testosterone conversion, and is used for gender transition. As much as I love breasts I do not want any of my own. It also thins body hair, and makes your head hair grow back thick and long.

I jokingly said "I always wanted to be a woman".

Interesting the GP just pushed the drugs and had no comment on lifestyle and diet. Which seems to be a contributor, salt, red meat, processed foods, poor hidration, obesity, are possible contributors. It seems that Benign Prostate Hyperplasia is another symptom of the modern Western diet and lifestyle. As it is unknown in pre industrial societies.

It seems that surgery is really the only effective options however if done by an incompetent surgeon you can have even worse side effects, who can damage you bladder or pelvic floor nerves. However it seems they hold out on the surgery until you are really dying in pain and agony. 

A quick search for non pharmacultical only brought up Stinging Nettle Root (Urtica dioica) as anything with data support its use. Saw Palmetto is no better than placebo. I have started taking large daily amounts of Pumpkin Seeds, half as effective as tamsulosin but no side effects. Lycopene looks promising but short of drinking tomato paste and tumeric in water there is no regular way to dose Lycopene.

Anyone have suggestions?

Fentanyl has never been as big of a problem in Australia as it has been in the US. However, nitazenes have been seized in increasing amounts in the UK and Australia. Recently, 4 people died of opioid overdoses in Melbourne taking cocaine adulterated with nitazenes. I fear this issue will escalate in Australia and we may see a similar situation with nitazenes here as we have seen with fentanyl in the US.

At some point, someone is deliberately mixing cocaine or other drugs with nitazenes or fentanyl. Resultingly, people who may be opioid-naïve and were expecting to take cocaine or meth end up dying of an overdose.

I'm curious why this is happening and what these people stand to gain from doing this. Are they trying to get customers addicted to opioids? 

If people die in this way surely it prompts an investigation, I don't know how the scumbags doing this are benefitting from it.

Converting spearmint to the active ingredient in oregano - carvacrol

I found obtaining carvacrol quite challenging in Australia. Most of the wild oregano oils are 200mg/mL EO in olive oil. Importing was an option but it's cheap and simple to make your own.

Carvacrol is an interesting molecule as besides anti-microbial properties, it has a plethora of beneficial effects:

It's a classical isomerisation, this one is acid catalysed.

The classical procedure involves refluxing in sulfuric acid which isn't the nicest [1]. I prefer to use cation exchange resins which are cheap and easily available and bypass the nastiness of boiling acids. The idea is they're a polystyrene resin (macroporous, so lots of surface area) that has sulfonic acid R-SO3^- groups on it, in the acidic H⁺ form. They're solid and not too nasty and can be reused.

Purifying spearmint essential oil [2] - optional.

Whilst there is some dispute on the formation of a carvacrol-bisulfite adduct, formation has been noted but as a water-soluble solution. I had challenges with it but see how you go. A suitably high concentration of carvone in the spearmint allows direct isomerisation without purification.

A classical (old) approach to purifying carbonyl compounds is to form their bisulfite adduct, which is crystalline and can then be converted back to the carbonyl compound with dilute acid.

The general procedure is as follows:

Formation of bisulphite adduct: A fresh saturated NaHSO3 solution (7.5 g NaHSO3 dissolved in 15 mL of distilled water) was added to 12 mL of ethanol. A minimum of water is use to dissolve the formed crystals. The essential oil (5 mL) was added to the solution of sodium bisulphite. After a vigorous shaking of the solution and storage in ice bath for 30 min, vacuum filtration afforded white solid which were washed with ethanol and dried at room temperature

This can then be converted to the pure carbonyl fraction with base.

Isomerisation of carvone to carvacrol [3]

Dry the cation exchange resin at 120 deg C in an oven overnight.

Solid catalyst (15 g macroporous cationic exchange resin, H+ form) was added to carvone (25 mL, 160 mmol) under mechanical stirring. The mixture was heated using an oil bath at 75 deg. C until transformation was complete (greater than 1 min)

The reaction can also be done at room temperature with catalytic NaI in acetone but that's more complex [3].

You can follow the reaction with your nose, the spearmint odour being replaced with a pungent spicy oregano smell.

Being phenolic, it can be purified by adding NaOH solution to form the phenolate salt which is water soluble, then liberating the phenol with acid.

[1] Lab 4 Carvone to Carvacrol Lab 4 Carvone to Carvacrol - Converting Carvone into Carvacrol Introduction: This week’s lab focuses - Studocu

[2] Ouédraogo, I. W., S. Sassiémiké, and Y. L. Bonzi-Coulibaly. "Chemical extraction via bisulphite adduct of carbonyl compounds from essential oils." Phys. Chem. News 50 (2009): 104-110.

[3] Gozzi, C., Convard, A., & Husset, M. (2009). Heterogeneous acid-catalysed isomerization of carvone to carvacrol. Reaction Kinetics and Catalysis Letters, 97(2), 301–306. doi:10.1007/s11144-009-0030-4 

Vanilla to 'ginger'

Vanillin is a common phenolic aldehyde. It readily undergoes conversion to dehydrozingerone via a simple base-catalysed aldol reaction with acetone [1].

First you need to make up a 2.5M solution of NaOH. This means 2.5 mole NaOH in a litre of water. The molecular mass of NaOH is 40 g/mol so 2.5M = 40g x 2.5 = 100g/L . 100mL is plenty, so 10g NaOH (CAUTION) in 100mL water. 

In a 50 mL round-bottom flask, add 0.5 g (3.3 mmol) of vanillin then 5 mL (67.5 mmol) of acetone with vigorous stirring. After vanillin has dissolved completely (usually very fast) add 2.63 mL NaOH 2.5 M (the concentration of NaOH is important as using more concentrated NaOH will produce a thick paste mixture which extends reaction time and further complicates the precipitation process).

Allow to stand overnight and then dropwise add dilute acid (2.5 mL 6M HCl etc). Cool in a freezer and collect the yellow shards of dehydrogzingerone.

You could get fancy and form other ginger constituents but that's beyond the scope of this simple introduction.

 [1] “Crossed Aldol Reactions in Water Using Inexpensive and Easily Available Materials as a Tool for Reaction Optimization Teaching in an Undergraduate Organic Chemistry Laboratory” Kevin A. Ruiz, Marta López, Gottfried Suppan, and Kamil Makowski

Journal of Chemical Education 2023 100 (10), 4160-4160 DOI: 10.1021/acs.jchemed.3c00902

Inside the brain, MAOs are present in two isoforms: MAO-A and MAO-B which differ in preferred substrates and regional location. MAO-A preferentially deaminates 5-HT and NE and MAO-B, small amines like benzylamine and phenethylamine. DA and p-tyramine are common substrates of both isoforms. MAO-A is often the target of antidepressant therapies. The activity of MAO-B is generally higher in patients affected by neurodegenerative diseases like Alzheimer's and Parkinson's, as such being used therapeutically, particularly in PD.

Renewed interest in the field has come also from the recent findings that MAO-B inhibitors have neuroprotective and antioxidant effects and play a role in delaying apoptotic neuronal death and in protecting crucial mitochondrial functions.

Figure 1. Structures of some synthetic MAO-B inhibitors

Kava pyrones can inhibit MAO-B reversibly: The order of potency was desmethoxyyangonin > (±)-methysticin > yangonin > (±)-dihydromethysticin > (+)- dihydrokavain > (±)-kavain.

A long time ago, I was interested in simple molecules that could effectively and selectively inhibit MAO-B. About the simplest one I could find was Ro 16 6491, a metabolite of moclobemide.

Some of the pharmaceutical options such as selegiline have additional non-MAOI benefits such as acting as catecholamine activity enhancers, or for safinamide, inhibition of glutamate release, SERT and DAT, affinity to sigma receptors and blockade of calcium and sodium channels

An endogenous MAO-B inhibitor is isatin:

Isatin (indole-2,3-dione) is an endogenous indole found in the mammalian brain, peripheral tissues and body fluids. It is proposed isatin can be formed from indole in the body, typically produced by tryptophan catabolism in the gut. It accumulates in the brain, modulating brain function and produces multiple CNS effects, which include changes in gene expression. It exerts neuroprotective effects.

• can be present in humans in the  <0.1 to > 10 µM range and levels increase in response to stress
• able to cross the blood-brain barrier
• endogenous inhibitor of monoamine oxidase (MAO), more selective for MAO-B than for MAO-A (Ki for MAO-A = 60-70 μM; Ki for MAO-B = 3 μM).  Physiological concentrations of isatin in vitro inhibit monoamine oxidase B but administered at high doses, it can act on both MAO isoforms
• Induces dopamine release - intrastriatal administration of 1, 5 or 10 μM isatin, for 1 h, significantly increased dopamine levels to 355 ± 104%, 700 ± 72%, and 1241 ± 146%, when compared with basal values, respectively. These dopamine enhancements were synergistically enhanced by co-administration of L-dopa, caffeine etc 
• anxiogenic/proconvulsant effect with lower dose-levels (around 20 mg/kg in animal models), an effect lost at higher doses (above 50 mg/kg) instead becoming sedative, potentially though inhibitory effect on central atrial natriuretic peptide receptors and stimulation of 5-HT3
• increases glutamate levels, possibly activates NMDA receptors and nitric oxide production, which can promote a further increase in the dopamine release.
• significantly increased 5-HT concentrations in the hypothalamus and cortex
• weak inhibition of D-amino acid oxidase (DAAO) by isatin (about 20% at 20 μM), leading to modulation of NMDAR
• regulation of the brain levels of ACh

There has been extensive research around natural products which can inhibit MAO-B but ones that are sufficiently potent, selective and available in pure form for convenient dosing are more limited. Unfortunately, most natural products are generally comparatively poor MAO-B inhibitors relative to synthetic options, in the micromolar-millimolar affinity range.

Some classes of natural MAO-B inhibitors include β-carbolines, flavonoids, xanthines, xanthones, and alkaloids, a review can be found in [1].

Natural

•             Geiparvarin

•             Desmethoxyyangonin, a constituent of kava extract; modest affinity

•             Catechin and epicatechin, poor affinity

•             Garlic

•             Rosiridin

Figure 2. Some natural MAO-B inhibitors from [1]

An Australian plant, Geijera parviflora, contains geiparvarin, a coumarin derivative in the leaves which inhibits MAO-B

Some simple small molecule MAO-B inhibitors include methyl piperate, a derivative of piperine from black pepper. Whilst there is some dispute on the MAO-A/B selectivity, one source claims it is more selective for, and relatively potent towards MAO-B [2].

Figure 3. Structure of methyl piperate

Recent research [3] identified ethyl ferulate as a novel neuroprotective MAO-B inhibitor, displaying greater affinity than rasagiline

Figure 4. Structure of ethyl ferulate

Ferulic acid is conveniently available pure in small and bulk quantities fairly cheaply and serves as a convenient material for the simple synthesis of ethyl ferulate via a Fisher esterification with ethanol [4].

Figure 5. Binding of ethyl ferulate to hMAO-B from [3]

“Ethyl ferulate could bind to the active site (substrate-binding site) of human MAO-B (hMAO-B) by hydrogen bound in a relative low binding energy (Binding energy = -6.47 kcal/mol

…analysis showed that ethyl  ferulate exhibited a higher affinity with hMAO-B than rasagiline mesylate, suggesting hMAO-B was a molecular target of ethyl ferulate.”

One benefit to ethyl ferulate is it is a lipophilic ester derivative of a well-studied molecule, also with it’s own beneficial properties. That said, being an ester, it is likely subject to extensive hydrolysis in the GI tract and on first pass metabolism, which could hinder it's use.

Ferulic acid is a phenolic compound that exhibits neuroprotective effects in the central nervous system [5, 6]. It has antidepressant properties by increasing the 5‐HT, NE, and DA levels in the synaptic cleft of frontal cortex and hippocampus via regulating the monoamine system. It also has antioxidant, anti-inflammatory and neurotrophic effects.

Ethyl ferulate

-novel natural compound that could be used for therapeutic purposes as a potent inducer of HO-1 for the protection of brain cells against oxidative and neurodegenerative conditions.

- Potently suppress microglia-mediated neuroinflammation by binding to MAO-B

Improving the properties of ferulates

Both the phenethyl ester and phenethylamide [7,8] of ferulic acid seem to have potent MAO-B inhibitory properties, the amide having the properties of resistance to hydrolysis in vivo by esterases

[1] Carradori, S., D’Ascenzio, M., Chimenti, P., Secci, D., & Bolasco, A. Selective MAO-B inhibitors: a lesson from natural products. Molecular Diversity, 18(1), 219–243. (2013) doi:10.1007/s11030-013-9490-6 

[2] Lee SA, Hwang JS, Han XH, Lee C, Lee MH, Choe SG, Hong SS, Lee D, Lee MK, Hwang BY. Methylpiperate derivatives from Piper longum and their inhibition of monoamine oxidase. Arch Pharm Res. (2008) Jun;31(6):679-83. doi: 10.1007/s12272-001-1212-7.

[3] Zou X, Gao S, Li J, Li C, Wu C, Cao X, Xia S, Shao P, Bao X, Yang H, Liu P, Xu Y. A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury. Front Pharmacol. (2022) Oct 13;13:1004215. doi: 10.3389/fphar.2022.1004215.

[4] Esterification, Purification and Identification of Cinnamic Acid Esters

[5] Dong X, Zhao D. Ferulic acid as a therapeutic agent in depression: Evidence from preclinical studies. CNS Neurosci Ther. (2023) Sep;29(9):2397-2412. doi: 10.1111/cns.14265.

[6] Sgarbossa A, Giacomazza D, di Carlo M. Ferulic Acid: A Hope for Alzheimer's Disease Therapy from Plants. Nutrients. (2015) Jul 15;7(7):5764-82. doi: 10.3390/nu7075246.

[7] Badavath, V. N., Baysal, İ., Uçar, G., Mondal, S. K., Sinha, B. N., & Jayaprakash, V. (2015). Monoamine Oxidase Inhibitory Activity of Ferulic Acid Amides: Curcumin-Based Design and Synthesis. Archiv Der Pharmazie, 349(1), 9–19. doi:10.1002/ardp.201500317

[8] Koichi Takao, Kazuhiro Toda, Takayuki Saito, Yoshiaki Sugita, Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities, Chemical and Pharmaceutical Bulletin, 2017, Volume 65, Issue 11, Pages 1020-1027, Released on J-STAGE November 01, 2017, Online ISSN 1347-5223, Print ISSN 0009-2363, https://doi.org/10.1248/cpb.c17-00416 

Early visualisation of mesembrine-type alkaloids via TLC was plagued by the use of crude iodine vapor visualisation which was non-specific, making accurate detection of alkaloids problematic.

As noted previously, there are several distinct Sceletium chemotypes which makes having a specific reference material a challenge, coupled with extremely variable alkaloid levels in the raw plant material.
 

To improve the visualisation technique, Dragendorff's reagent was selected as an alkaloid-selective method. This uses a potassium bismuth iodide complex which forms with (mainly tertiary nitrogenous) alkaloids to form a yellow-red-orange-brown colouration 

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