Alchemica

Nose-to-brain delivery of asarones for CNS conditions? Ayurvedic medicine and traditional Chinese medicine (TCM) use Acorus preferably to treat central nervous system (CNS) related diseases such as epilepsy, insanity, mental weakness, or insomnia, Calamus has been widely used internally in both Chinese and Ayurvedic medicine for degenerative central nervous system disorders associated with communication, focus, memory and learning but there are concerns regarding the safety of such orally. The ability of asarones to induce such a broad range of neurotrophic factors (NGF, BDNF, GDNF, CNTF in a dose-dependent manner), alongside other neuroprotective and neurorestorative pharmacological actions, intrigues me. Pharmacologically, α- and β-asarone at lower doses (<50 mg/kg) exhibits a wide range of therapeutic activities such as antidepressant, antianxiety, anti-Alzheimer, and anti-Parkinson effects [1]. Asarones as a therapeutic are limited by poor absolute bioavailability when administered orally, less than 10%, because it is highly lipophilic and has poor solubility in water, coupled with extensive gastrointestinal and/or hepatic first-pass metabolism. There are concerns potentially harmful effects, such as genotoxicity particularly through accumulation in the liver where "both α- and β-asarone can cause hepatomas and might possess mutagenic, genotoxic, carcinogenic, and teratogenic effects". Because the amounts of asarone accumulated in liver may reflect its hepatotoxicity, there is special significance to reducing the amount of asarone in liver. Efforts have been centred on exploring nose-to-brain delivery of asarones, particularly as nanoemulsions [1,2] In humans, 20mg asarone has been added to memantine for AD [3] "...intranasal administration of asarone showed significant nose-to-brain transport, especially in the olfactory bulb, and such treatment yields equivalent or higher concentrations in other brain tissues compared to intravenous or oral administration" I'm personally curious as to whether a simple spray of asarones emulsified in water with a polysorbate emulsifier, delivered via a nasal spray bottle may be simple enough to make a readily available nose-to-brain delivery system "polysorbates [are] a promising excipient to increase drug concentration in both plasma and brain via intranasal route". The main beneficial actions of asarones, as described by [1], are summarised as: " (1) antioxidant properties; (2) the regulation of various neuroprotective signaling pathways; (3) the reduction of aggregate formation and promotion of the clearance of pathogenic protein aggregates; (4) anti-inflammatory properties; (5) the inhibition of microglial activation; (6) the activation of NTFs-mediated neuroprotection; and (7) the modulation of neurotransmitter levels associated with behavioural functions and neuronal cell survival." Actions of asarones on the CNS, taken from [1] Normal vs diseased brain aspects Asarone functions as a neuroprotective effect in both in vivo and in vitro models of neurodegeneration - Enhance BDNF via TrkB and activate the ERK pathway, triggering antidepressant-like effects - Significantly promoted the expression and secretion of neurotrophins, such as nerve growth factor (NGF), BDNF, and GDNF, in a dose-dependent manner. Also effects on CNTF - Maintain equilibrium between glutamate and GABA in the hippocampus, enhancing learning and memory abilities. β-asarone induced the high potentiation of GABAARs -Anxiolytic effects of asarone were partially due to maintaining the balance between excitatory/inhibitory transmissions and attenuating neuronal hyper-excitability of excitatory neurons in the basolateral amygdala. - modulates microglial morphological dynamics, may functionally relate to its influence on neurogenesis - Other monoaminergic effects, particularly antidepressant effects mediated by noradrenergic (α1 and α2 adrenoceptors) and serotonergic (particularly, 5-HT1A receptors) systems. - Enhances tyrosine hydroxylase activity with relevance to Parkinson's My current line of thinking is to make an emulsion of a polysorbate emulsifier with calamus oil 1:1 in water and explore that. Any input appreciated. 1:1:2 Calamus EO:polysorbate solubiliser:saline administered by nasal spray has got quite a strong bit of burn to it but not totally intolerable. Nasal sprays are normally less than 140uL/spray meaing at 25% EO concentration {assume 80% asarones), about 28mg asarone per spray may be possible. Even at that dose, each spray is quite painful but it may be feasible to - via multiple doses scattered through the day - reach a therapeutic dose of asarones intranasally with such. References: Balakrishnan, R.; Cho, D.-Y.; Kim, I.-S.; Seol, S.-H.; Choi, D.-K. Molecular Mechanisms and Therapeutic Potential of α- and β-Asarone in the Treatment of Neurological Disorders. Antioxidants 2022, 11, 281. https://doi.org/10.3390/antiox11020281 Lu, J., Fu, T., Qian, Y., Zhang, Q., Zhu, H., Pan, L., Zhang, M. (2014). Distribution of α-asarone in brain following three different routes of administration in rats. European Journal of Pharmaceutical Sciences, 63, 63–70. . https://doi.org/10.3390/10.1016/j.ejps.2014.06.006 Pan L, Zhou J, Ju F, Zhu H. Intranasal delivery of α-asarone to the brain with lactoferrin-modified mPEG-PLA nanoparticles prepared by premix membrane emulsification. Drug Deliv Transl Res. 2018 Feb;8(1):83-96. doi: https://doi.org/10.1007/s13346-017-0438-8. Dong, Haiying; Wu, Shuqin; Hu, Nan; Xing, Guihua (2018) Efficacy of tenuigenin and β-asarone as augmentations for memantine in the treatment of Alzheimer’s disease https://doi.org/10.1097/WNR.0000000000000952

Following up with a TLC comparison to Tabernaemontana pandacaqui (Banana Bush) seeds T. pandacaqui | PDF Host

I'll start to add some items slowly here that are available. PM me if interested. First up, plain 50g ceremonial cacao hearts (single strong serves) as single or double packs {Edit: only one single heart available]] Possible small donation to a charity of your choice. Single or double packs Heart-centred Cacao with Rose, Saffron and Kanna (low dose) ~50g. Please do not combine with pharmaceuticals or MAOI plants etc [Limited quantity available, EDIT: only 2 single hearts available] Possible small donation to a charity of your choice. Single packs. Tulsi and Rose tea [EDIT: out of stock] Possible small donation to a charity of your choice Functional foods [cognitive and polyphenol blends] still on the way.

You'd want the products that are intermediates to ethanol formation (pyruvate/acetaldehyde) to condense with the phenethylamine and under acidic conditions, undergo a Pictet-Spengler reaction to form THIQs (below). It wouldn't be a high conversion rate as conditions wouldn't be optimal but you'd likely get some conversion, which given the potency of the compounds, may be enough 1-Me-THIQ has actually found some putative therapeutic actions, "1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous antidepressant and parkinsonism-preventing substance that demonstrates neuroprotective activity." I've tried to cover some fermentations of plants here The Science of Fermented Fruits, Veggies and Plant Medicines - Pharmacology, Chemistry & Medicine - The Corroboree (shaman-australis.com) Yeasts are known for reducing some alkene (C=C) and carbonyl (C=O) compounds, which is more applicable to things like mesembrine-type alkaloids in Sceletium

This is an interesting concept. In theory, you could get a tetrahydroisoquinoline form from pyruvate/followed by decarboxylation = equiv. acetaldehyde and mescaline like such. This would bring it's pharmacology potentially more in line with the Lophs. The pharmacology of these THIQ's isn't well studied but they seem to be relatively potent serotonin agonists (nM) for a diverse range of serotonin receptors aside from more classical 5-HT2ARs eg pellotine In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid | ACS Pharmacology & Translational Science https://pubchem.ncbi.nlm.nih.gov/compound/613648

Thanks for the wise input @Ishmael Fleishman. I tend to think people seeking ceremonial cacao are of a different mindset than tastes alone so may tolerate some differences but have to see I want to keep it away from business models and involving payment for goods for several reasons, being more a project I self-fund but agree, making it sustainable is essentially an impossible challenge if one does that but we'll see. A project to do, that I value, more than a sustainable business venture, is the aim Thanks again for the other points

I've been having a bit of an existential crisis - absolutely bored with existence - as disability robs me of significant ability to do things that I find meaningful and valuable on a wider scale, trying to find things that are worthwhile and fulfilling, yet still achievable. I'm curious as to if there is interest in these sorts of things below? Which ones would be of interest? Please note: All items are not intended to diagnose or treat any medical condition. This is just a concept at the moment but I've been exploring some prototypes of plant-based options that may meet unmet needs that may have use to the community. I'm writing here to see firstly what sort of interest there may be in the following options, if there is any and where I should potentially put my efforts into development of options? Even if you have other ideas on things that are legit, I'd like to hear. I'd be looking to base it on a 'Donation to a greater good' based scheme where for example, one could - at their choice - contribute a donation to a relevant charity as exchange for goods - that would be your part to do and I'd simply trust your end of the deal. If you wanted to, covering postage costs after receiving items would be helpful and maybe help me continue to do more in the way of this sort of thing down the track. Not sure how it's going to work longer term and I'm currently finding the research and development pricey but hopefully once that settles, I can minimise costs They'd be fairly small samples, just to get an idea if these options potentially worked for you, and if they did, you could then feel free to source ingredients to make it yourself, and optimise if you like, which I'd encourage. Some of the prototypes I've been exploring: Mind Mend Cognitive Blend Ingredients: Ashwagandha, Brahmi, Shankhpushpi, Lion's Mane, Saffron, Mucuna, Ginkgo, White Peony, Rhodiola. Each level teaspoon (2.7g) provides Ashwagandha (Withania somnifera) root 675mg Brahmi (Bacopa monnieri) 675mg Shankhpushpi (Convolvulus pluricaulis) 675mg 'Neuro Shroom Blend' 675mg Saffron (Crocus sativus) 20mg Suggested serving size: up to 2 level tsp (2.7g ea tsp) three times daily Caution: Not intended to treat any medical condition or replace professional medical advice. Food supplement ONLY. There have been case studies of potential interactions (namely Rhodiola with serotonergics) with some ingredients with pharmaceuticals, please consult your pharmacist for advice. "...current pharmacotherapeutics for [cognitive impairment] neither cure nor halt cognitive decline; they just delay the worsening cognitive impairment" A narrative review found "nutrients and phytonutrients may be promising for treating some aspects of cognitive impairment" with highlighted findings of reviewed clinical trials displaying a wide range of results on cognitive function, with some showing promising effects eg Bacopa monnieri, curcumin, Rhodiola rosea, Saffron, Withania somnifera, and xanthines [1]. While conventional Western medicine hasn't made much progress in treating cognitive issues, schools of medicine like Ayruvedic ones might have some clues for good strategies to intervene with for early interventions, or more prophylactically. As a broader shot-gun approach by utilising a polyherbal formula, the diverse etiology of cognitive issues could potentially be addressed better than the more specific molecular approach adopted commonly in Western medicine. This includes reliance on phytochemical synergies to potentially offer a different, broader and diverse response. That said, as a later intervention in serious cognitive decline, many nutraceuticals offer poor evidence of efficacy. This is a blend of traditional Ayruvedic herbs: Ashwagandha [2], Brahmi [3], Shankhpushpi [4] - all showing promise in addressing cognitive issues - blended with other options with mounting potential benefits for cognitive issues such as Lion's Mane [5], Saffron [6] and Ginkgo [7], Rhodiola and some other herbs [1] http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8445631/ [2] https://doi.org/10.1080/19390211.2017.1284970 [3] https://doi.org/10.1089/acm.2008.0018 [4] https://doi.org/10.3389/fphar.2020.00171 [5] https://doi.org/10.1002/ptr.2634 [6] http://dx.doi.org/10.2174/1570159X19666210113144703 [7] https://doi.org/10.3233/jad-215423 Mind mend.pdf Terpene Dance Spray This one is currently hindered by postage issues as it likely falls under flammable goods and can't be posted. That said, if there is demand, I could maybe look into an option not using ethanol, rather an essential oil solubiliser in water to make it post friendly. That said, I don't want to put effort into things that don't meet a need. It's designed to be a transdermal essential oil spray that I've found quite effective at loosening up to get into a therapeutic dance. I find with significant transdermal administration, I can personally get loose enough to get into the groove. It does however make you reek like a walking diffuser. Essential oil-based dance spray Loosen up naturally and feel the good vibes with a symphony of plant-based actives Terpene Dance Spray.pdf Other items I've been exploring: Ceremonial Cacao bars Polyphenol Blend Trying to utilise rich sources of polyphenols (purple corn anthocyanins, citrus flavonoids etc) to create a broad-spectrum polyphenol blend A 'Golden Paste' option Tea Blends If there's interest in these sorts of things, let me know what sort of things would be useful through the poll above. Much gratitude for any input you can offer. Have a lovely day. Mind mend.pdf Terpene Dance Spray.pdf

Anyone by chance explored? Agapanthus campanulatus Modified from [1] - rhizome of A. campanulatus used in the initiation of traditional healers due to the presence of active principles as yuccagenin and agapanthagenin but both of them cause gastrointestinal tract and kidney problems (Ndhlala et al., 2013; Bonokwane et al., 2022). Triterpenoid saponins are thought to be the main actives of ubulawu such as Agapanthus companulatus. No alkaloids were detected in Agapanthus campanulatus In vitro assays (ethanol extracts from the leaves) showed good binding affinity to serotonin, dopamine and noradrenaline transporters [2] It is possible that the triterpenoid saponins found in Agapanthus campanulatus and other ubulawu species and their interactions may be responsible for these antidepressant actions, as well as the other reported psychoactive effects [3,4] References Ahmed Mohamed Younis, Alshymaa AbdelRahman Gomaa, Alyaa Hatem Ibrahim, Mohamed S.A. Abdelkader, Samar Yehia Desoukey, The genus Agapanthus: A review of traditional uses, pharmacological and phytochemical attributes, South African Journal of Botany, Volume 150, 2022, Pages 1168-1183, ISSN 0254-6299, https://doi.org/10.1016/j.sajb.2022.09.029 Mikael E. Pedersen, Bernadeta Szewczyk, Katarzyna Stachowicz, Joanna Wieronska, Jacob Andersen, Gary I. Stafford, Johannes van Staden, Andrzej Pilc, Anna K. Jäger, Effects of South African traditional medicine in animal models for depression, Journal of Ethnopharmacology, Volume 119, Issue 3, 2008, Pages 542-548, ISSN 0378-8741, https://doi.org/10.1016/j.jep.2008.08.030 Jean-Francois Sobiecki, Psychoactive Ubulawu Spiritual Medicines and Healing Dynamics in the Initiation Process of Southern Bantu Diviners Journal of Psychoactive Drugs, 44 (3), 216–223, 2012 https://doi.org/10.1080/02791072.2012.703101 Bonokwane Melia Bokaeng, Lekhooa Makhotso, Struwig Madeleen, Aremu Adeyemi Oladapo Antidepressant Effects of South African Plants: An Appraisal of Ethnobotanical Surveys, Ethnopharmacological and Phytochemical Studies Frontiers in Pharmacology, 13, 2022 https://doi.org/10.3389/fphar.2022.895286

These I find tend to get quite battered before they look slightly better as cuttings but they seem quite hardy. I think the lot of emarcidum I sent maybe wasn't in the best of health for cutting as it was flowering etc. I can maybe send more if you need it, or try to root some up for you

I've used two, one that was sold as 'ceremonial grade cacao' was nothing particularly noteworthy. The other, more expensive, was a bit richer and nicer and available at the local market in whatever quantity one wants https://houseofhealthcollective.com.au/lines/ceremonial-cacao-chunks but it comes with the price-tag I agree, particularly initially I had some quite profound experiences using high dose cacao powder/paste Haven't tried it but would guess it could be rather potent More on the β-carbolines in Cacao [1]

If I get the chance, I'll grab you some. I think it's easy enough to get decent effects with the cheap powder but it's not as 'in' as having Peruvian ceremonial grade cacao I did a lot of experimenting with Cacao. It seems quite a useful medicine particularly for cognitive stuff, and in the shorter term as a mood lift. I was playing around with lots of fermenting and other things trying to boost effects but in the long run, simple seems best. Some popular blends were Sceletium, Saffron and Cacao and a few others The β-carbolines are so common in foods as they form in condensation reactions between tryptophan and carbonyl compounds/breakdown products of sugars, which condense in a Pictet-Spengler reaction (often undergoing decarboxylation on roasting). Practically fermenting and roasting many foods will form some (and this seems to be their origin in Cacao), the main ones that seem to be often seen are (nor)harman, which results in measurable MAO-A inhibition from repeated coffee drinking, and tobacco use, which likewise results in significant MAO-A inhibition over long-term use "coffee is the most important exogenous source of these alkaloids in addition to cigarette smoking." [1].

It's pretty hard to get efficacy matching benzodiazepines IMO, even if the plant-based options retain some efficacy in treating symptoms. Also, if there's GABAergic tolerance through use of pharmaceutical GABAergics or drinking etc in prior history, most of these can seem comparatively mild/insufficient. Also, I wouldn't even consider relying on them for serious medical conditions eg seizure control I've in the past tried to rank subjective potency (which considering all my brain has been through shouldn't be taken as representative of normal) of some here as anxiolytics (note: not all GABAergic MoA): Lemon balm < Lower dose Passiflora < Lower dose skullcap < Zizyphus seed < Hops = Valerian < Oral lavender oil 80-160mg = lower dose kava = low dose CBD < Erythrina mulungu < Higher dose 25g+ Passiflora < CBD 600mg + < Higher dose skullcap < High dose kava. In general the flavonoid GABAergic plants can seemingly have some decent GABAA mediated therapeutic effects but often without the abuse potential seen with BZDs eg baicalin That said, sometimes maintaining efficacy can be challenging with such and I can't say that the flavonoid GABAergics tend to have the "enjoyable" nature of BZDs There seems to be distinction between seeking actual symptom reduction eg. anxiolysis vs. desiring inebriation that can make people who enjoy GABAergics dismiss some plant options IMO Then there's things like tetrahydropalmatine which through non-GABAergic mechanisms seems to have potent muscle relaxing activity

No rest for fiends like me I've tried to compile lots of my research into a website for anyone who's bored out of their brains/curious. Alchemica's Research Lair - Phytopharmacology (site123.me)

This area has been of interest to me in the past, even though I'm not into bioassaying these days. Here's a literature review and some research mammillaria | PDF Host

Tried to briefly explore Tabernaemontana undulata to see if it has potential merit for anti-addictive properties. tabernaemontana | PDF Host

It's said by some including herbalistics to be "valued as highly as S. tortuosum in Southern Africa by different tribes and makes a very good Kougoed product". and I vaguely remember Torsten (but don't quote me) making mention of it not really mattering if you grow emarcidum vs tortuosum. Personally, there's something nicer about tortuosum but my brain isn't a good test subject. Phytochemically, it seems the emarcidum is 4'-O-demethylated mesembrine-type alkaloids (phenolic alkaloids) over the parent mesembrine-type alkaloids. It seems to root up a lot easier from cuttings, grows quickly and grows a lot easier in many climates. That said, some people have fermented up emarcidum and not noted much effect but even tortuosum can be hit and miss with some people. Yeah I have varied success with different cuttings at the best of times but good to hear what's worked for you.

My botanical nomenclature probably sucks but that's just to distinguish it from the common hybrids that often get sold as Aptenia cordifolia (eg red flowered varieties). This is the one (sets seed too)

I've devoted quite a bit of time to researching succulents so would like to share the love. Can spare a couple (2) packs [Edit: one left] of free mixed succulents to the first couple of people interested (reply here and I'll get back to you) 1. Sceletium tortuosum cuttings 2. Sceletium emarcidum cuttings 3. Delosperma bosseranum mature plants 4. Delosperma echinatum cuttings 5. Trichodiadema stellatum cuttings 6. Lampranthus spectabilis (red) cuttings 7. Mesembryanthemum (Aptenia) cordifolium (purple) true form seedlings/cuttings. Can also include others including Aptenia haeckeliana if interested 8. maybe some Lampranthus aureus cutting No WA/TAS Something like this: Some of them can be a challenge to root up but see how you go. Only express interest if you're dedicated and keen please. I'll include postage.

Don't think I have any M. crystallinum seed left from when I grew it and I found it hard to propagate from cuttings as it's so fleshy but it's pretty easy to grow from seed so I'd personally just grab some cheap seeds eg Ice plant seeds | The Seed Collection

Nice summary, well done. As another area that's been researched (and patented): We also see immunological benefits, ultra-potent blockade of proinflammatory markers like TNF-α at pM levels (sub-psychoactive doses) with some 5-HT2AR agonists like ®-DOI which is promising on many levels, it plays a key role in inflammation, its production and signaling contribute to many inflammation related diseases. TNF-α and TNF-α receptor-mediated inflammatory pathways have been strongly implicated in a number of diseases including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, irritable bowel syndrome, Crohn's disease, and septicemia (e.g., Reimold, 2002; Popa et al., 2007; Williams et al., 2007). Significantly, TNF-α and other cytokine induced inflammatory pathways also have been linked to psychiatric conditions such as depression and bipolar disorder (Dunn et al., 2005; Kim et al., 2007), as well as schizophrenia (Saetre et al., 2007), and neurodegenerative diseases like Alzheimer's and Parkinson's disease and stroke (Tweedie et al., 2007). US9642819B2 - Low dosage serotonin 5-HT2A receptor agonist to suppress inflammation - Google Patents

Either overexpression of 5-HT2Rs with increased binding density or an altered regional expression of 5-HT2s seems to be common. There are polymorphisms of the 5-HT2A gene that can lead to changes in the density of those receptors but it more likely seems to be a complex interplay of genetics, environment and life-experiences that shape such an outcome [1]. There's likely epigenetic effects where adverse trauma could be transmitted transgenerationally, leading to an impact on, in part, the serotonin system. Not easily, it would likely only be if you're part of a special research study such would be possible Depending how potent an antagonist it is of the 5-HT2A receptor. Often as a "washout" a period of greater than 5 half-lives is used to estimate the practically total elimination of a drug and the cessation of it's pharmacological effects "Starting from a steady state, 5 half-lives will remove 97% or a drug; whereas 10 half-lives will remove 99.9% of a drug"

Things like ketanserin have been used as 5-HT2AR antagonists to block/attenuate the 'psychotomimetic' effects of psychedelics but interestingly, the combined effects of a 5-HT2AR antagonist and classical hallucinogens seems to retain some of the therapeutically beneficial effects ie antidepressant and some neural effects [1] so it's likely there would be attenuation of the hallucinogenic effects by sandomigran, particularly with a less potent agonist like mescaline (cyproheptadine which is related is OTC and probably would do the same). Similarly, olanzapine with decent affinity to 5-HT2ARs (along with D2Rs) seems to be used by some as an antipsychotic 'trip kill' [2] and is often conventional medicine's go to, to attenuate a bad trip/psychotic reactions. That said other schools of thought suggest the trip should not be aborted with such and instead benzodiazepines used as an anxiolytic to support a less anxiety-provoking reaction and social support be used more. Mescaline is quite a 'shotgun' pharmacologically, with diverse binding profiles aside from 5-HT2 agonism ie adrenergic affinity etc. The stimulant effects from adrenergic etc activity might be somewhat attenuated by the antihistaminergic activity of sandomigran. ie Mescaline has strong affinity [3] to 4.00 Alpha2C, 3.97 5ht2b, 3.61 5ht1a, 3.44 Imidazoline1, 3.16 5ht1e, 2.92 Alpha2A receptors much more so than 5-HT2ARs.' Serotonin antagonists particularly 5-HT2 antagonists seem to be used in depression (think things like mirtazapine, which has that as a partial mechanism of action) as antagonism of the 5-HT2 receptor can have some pro-dopaminergic effects. Similarly, there are some PET studies linking depression and suicidality to overly high densities of 5-HT2 receptors, and it is thought one of the therapeutic effects of 5-HT2A agonists on depression (so too SSRIs) is to downregulate the excessively dense level of 5-HT2Rs, a similar outcome can be achieved through 5-HT2 antagonism. The density (Bmax) of 5-HT2A receptors was significantly higher (by 39%) in depressed patients than in controls. Suicidal patients had significantly higher Bmax values than controls or non-suicidal patients. [4] Not personal experience but I've heard of people using feverfew which has some evidence base for use. You might want to consider such.

Been trying to find answers to whether Bobinsana bark should be treated as a potential MAOI due to possible β-carbolines or if the modern guides are correct in stating: Here's some very preliminary TLC results and a write-up Bobinsana.pdf Note: The initial UV fluorescent band was only visible with one wavelength light and a more typical UV light failed to show it, contrary to more common β-carbolines which were strongly visible If anyone has input that would be appreciated. Bobinsana.pdf

Thanks for the interest. All done for now.

Can now offer quite a few free larger plants if anyone's interested: